REPORTS OF PRACTICAL ONCOLOGY AND RADIOTHERAPY

REPORTS OF PRACTICALONCOLOGY ANDRADIOTHERAPY

ISSN: 1507–1367 Vol. 26 No. 2 March–April

ClinicalMarcela De la Torre Tatiana Hadjieva Marco Krengli Jin-yi Lang José Luis López Guerra Hugo Raúl Marsiglia Carmen Llacer Moscardo Jirí Petera Adela Poitevin-ChaconPrimož Strojan

The journal of Polish Society of Radiation Oncology; Czech Society for Radiation Oncology, Biology and Physics; Hungarian Society for Radiation Oncology; Slovenian Society for Radiotherapy and Oncology; Polish Study Group of Head and Neck Cancer; Guild of Bulgarian Radiotherapists; Catalan Occitan Oncology Group (GOCO) affiliated with Spanish Society of Radiotherapy and Oncology; Romanian Society of Radiotherapy and Medical Oncology; Portuguese Society of Radiotherapy—Oncology; Latin American association of Therapeutic Radiation Oncology; Mexican Society of Radiation Oncologists (SOMERA); and the Greater Poland Cancer Centre.

RepoRts of pRactical OncOlOgy and RadiOtheRapy

BiologyMichał Masternak

BrachytherapyOvidiu Florin Coza Ferran Guedea Csaba Polgár

PhysicsTomasz Piotrowski

Surgical OncologyWojciech Golusiński

Editor-in-ChiefJulian Malicki


ISSN: 1507–1367

Co-editors

Beatriz Amendola Christian H. Flores BalcázarDimos BaltasVictor Bourel Ioana BrieBoŽidar Casar Antoni Castel MillánMaja Čemažar Laura Cerezo PadellanoFelipe CouñagoJoanna Cygler Maria del Carmen Rubio RodriguezAndreas Dietz Elitsa EnchevaLuis E. Fong de los Santos Roumen Gabrovski Jacek Jassem Barbara Jereczek-Fossa Tomas KazdaJoanna Kaźmierska Tomasz Kolenda Adam Konefał György Kovács Sunil Krishnan Paweł Kukołowicz Pedro C. Lara René Leemans Miquel Macia Andrzej Mackiewicz

Editorial Advisory Board

Tibor Major Janina Markowska Andrzej Marszałek Michał Michalak Piotr Milecki Arturo Navarro MartinJosef NovotnyMiha OražemLuis A. Perez Romasanta Primož PeterlinRafael Piñeiro RetifGaber PlavcPhilip Poortmans Diana-Cristina PopAndrzej Roszak Angeles Rovirosa Beata Sas-Korczyńska Pierre Scalliet Igor SirákJan Skołyszewski Krzysztof Składowski Vratislav StrnadGiovanni SuccoZoltán Takácsi-Nagy Rafał Tarnawski Uulke Van der HeideMilan Vošmik Jacek Wachowiak Michał Waligórski

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Managing EditorJustyna Łapińska



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Reports of Practical Oncology and Radiotherapy — the journal serves researchers and practi-tioners in the fields of clinical oncology, ra-diation oncology, medical physics and radio-biology as well as cancer biology, providing an international platform to exchange practi-cal, multidisciplinary clinical and scientific knowledge and achievements in oncology and related disciplines. The journal recognises the

increasing need for effective interdisciplinary collaboration in the fight against cancer. Ar-ticles published in the journal in recent years cover diverse issues in oncology, cancer biol-ogy and medical physics, particularly on clini-cal studies and trials, radiotherapy treatment planning, clinical dosimetry, treatments based on non-ionizing radiation, tumor genetics and its microenvironment and cancer diagnostics.

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2021, Volume 26, Number 2


cOntents

ReseaRch papeRs

Influence of hyperbaric oxygen therapy on bone metabolism in patients with neoplasmZaida Salmón-González, Javier Anchuelo, Juan C. Borregán, Alvaro Del Real, José A. Riancho, Carmen Valero ........................................................................................................................................... 163

Dosimetric and clinical outcomes of CT based HR-CTV delineation for HDR intracavitary brachytherapy in carcinoma cervix — a retrospective studyAnis Bandyopadhyay, Arnab Kumar Ghosh, Bappaditya Chhatui, Dhiman Das .................................. 170

The impact of HER2-directed targeted therapy on HER2-positive DCIS of the breastGary. D. Lewis, Waqar Haque, Andrew Farach, Sandra S. Hatch, E. Brian Butler, Polly A. Niravath, Mary R. Schwartz, Elizabeth Bonefas, Bin S. Teh ...................................................... 179

Phase I dose escalation trial of stereotactic radiotherapy prior to robotic prostatectomy in high risk prostate cancerCasey Liveringhouse, Austin Sim, Kosj Yamoah, Michael Poch, Richard B. Wilder, Julio Pow-Sang, Peter A.S. Johnstone ........................................................................................................ 188

Comparative dosimetrical analysis of intensity-modulated arc therapy, CyberKnife therapy and image-guided interstitial HDR and LDR brachytherapy of low risk prostate cancerGeorgina Fröhlich, Péter Ágoston, Kliton Jorgo, Gábor Stelczer, Csaba Polgár, Tibor Major ................. 196

Proton re-irradiation of unresectable recurrent head and neck cancersKonstantin Gordon, Igor Gulidov, Alexey Semenov, Olga Golovanova, Sergey Koryakin, Tatyana Makeenkova, Sergey Ivanov, Andrey Kaprin ............................................................................. 203

A three-dimensional printed customized bolus: adapting to the shape of the outer earGorka Gomez, Montserrat Baeza, Juan Carlos Mateos, Jose Antonio Rivas, Florencio Javier Luis Simon, Diego Mesta Ortega, María de los Ángeles Flores Carrión, Eleonor Rivin del Campo, Tomas Gómez-Cía, Jose Luis Lopez Guerra .............................................................................................. 211

Prophylactic corticosteroid to prevent pain flare in bone metastases treated by radiotherapyGustavo Arruda Viani, Juliana Fernandes Pavoni, Ligia Issa De Fendi ................................................. 218

Feasibility of SBRT for hepatocellular carcinoma in Brazil — a prospective pilot study Andre Tsin Chih Chen, Fabio Payão, Aline Lopes Chagas, Regiane Saraiva De Souza Melo Alencar, Claudia Megumi Tani, Karina Gondim Moutinho da Conceição Vasconcelos, Manoel de Souza Rocha, Heloisa de Andrade Carvalho, Paulo Marcelo Gehm Hoff, Flair José Carrilho ...................................... 226

Impact of COVID-19 pandemic on patients and health professionals of a radiation oncology department at a Spanish tertiary hospitalJesús Romero, Raquel Benlloch, Jorge Obeso, Olga Engel, Beatriz Gil, Sofía Córdoba, Irma Zapata, Marta López, Francisca Portero ................................................................................................................ 237

Dose measurements in a thorax phantom at 3DCRT breast radiation therapyElsa Bifano Pimenta, Luciana Batista Nogueira, Tarcísio Passos Ribeiro de Campos ............................ 242


ISSN: 1507–1367

Evaluation of patient organ doses from kilovoltage cone-beam CT imaging in radiation therapyAlper Özseven, Bahar Dirican ................................................................................................................... 251

Dosimetric predictors of acute bone marrow toxicity in carcinoma cervix — experience from a tertiary cancer centre in IndiaRohith Singareddy, Harjot Kaur Bajwa, Mahendra M. Reddy, Alluri Krishnam Raju .......................... 259

Chemoradiotherapy or chemotherapy as adjuvant treatment for resected gastric cancer: should we use selection criteria?Houyem Mansouri, Ines Zemni, Leila Achouri, Najet Mahjoub, Mohamed Ali Ayedi, Ines Ben Safta, Tarek Ben Dhiab, Riadh Chargui, Khaled Rahal ............................................................ 266

Evaluation of two-dimensional electronic portal imaging device using integrated images during volumetric modulated arc therapy for prostate cancer Shoki Inui, Yoshihiro Ueda, Shunsuke Ono, Shingo Ohira, Masaru Isono, Yuya Nitta, Hikari Ueda, Masayoshi Miyazaki, Masahiko Koizumi, Teruki Teshima ..................................................................... 281

Review aRticles

Radiotherapy for cervical cancer: Chilean consensus of the Society of Radiation OncologyFelipe Carvajal, Claudia Carvajal, Tomás Merino, Verónica López, Javier Retamales, Evelyn San Martín, Freddy Alarcón, Mónica Cuevas, Francisca Barahona, Ignacio Véliz, Juvenal A. Ríos, Sergio Becerra .................................................................................................................. 291

Novel coronavirus mitigation measures implemented by radiotherapy centres in low and middle-income countries: a systematic reviewAndrew Donkor, Vivian Della Atuwo-Ampoh, Craig Opie, Frederick Yakanu, Dorothy Lombe, Jamal Khader

letteRs tO editOR

Second line of treatment for HER2-positive gastric cancer: an evolving issueGiandomenico Roviello, Martina Catalano, Alberto D’Angelo, Valeria Emma Palmieri ....................... 316

Pleural radiation-induced sarcoma: a SEER population-based description of a rare entityPierre Loap, Youlia Kirova ......................................................................................................................... 318

case RepORt

A rare case of melanotic hyperpigmentation of the tongue secondary to radiotherapyOrla A. Houlihan, Guhan Rangaswamy, Orla McArdle .......................................................................... 320

cOntents

163https://journals.viamedica.pl/rpor

research paper

reports of practical Oncology and radiotherapy 2021, Volume 26, Number 2, pages: 163–169

DOI: 10.5603/rpOr.a2021.0022submitted: 05.01.2020

accepted: 30.01.2021

Address for correspondence: Zaida Salmón González, Department of Internal Medicine, University Hospital Marqués de Valdecilla, Avenida de Valdecilla s/n, 39008 Santander, Spain; e-mail: [email protected], [email protected]

Influence of hyperbaric oxygen therapy on bone metabolism in patients with neoplasm

Zaida Salmón-González1, Javier Anchuelo2, Juan C. Borregán3, Alvaro Del Real1, José A. Riancho1, Carmen Valero1

1Department of Internal Medicine, Hospital Marqués de Valdecilla-IDIVAL, University of Cantabria, Santander, Spain2Service of Radiation Oncology, Hospital Marqués de Valdecilla, Santander, Spain

3Service of Intensive Care, Hospital Marqués de Valdecilla Santander, Spain

AbstrAct

background: hyperbaric oxygen therapy (hBOT) is useful in the treatment of complications due to radiotherapy in

patients with neoplasm. Its effects on bone metabolism are unclear. In our study, we analyzed the effects of hBOT on bone

remodeling in oncological patients with radiotherapy.

Materials and methods: prospective clinical study in 23 patients with neoplasms undergoing treatment with hBOT due

to complications of radiotherapy (hemorrhagic cystitis, proctitis or radionecrosis) and 25 patients with chronic anal fissure.

The average number of hBOT sessions was 20 ± 5 (100% oxygen, 2.3 atmospheres and 90 min per day). serum levels of ami-

noterminal propeptide of type I collagen (p1Np), c terminal telopeptide of type I collagen (cTX), alkaline phosphatase (ap),

25hydroxyvitamin D (25-OhD), parathyroid hormone (pTh), were measured at 3 time points: T0 (before beginning hBOT), T1

(at the end of hBOT) and T2 (6 months after hBOT).

results: at baseline, the patients with neoplasm have higher bone turnover than those with anal fissure. These differences

were 41% in cTX (0.238 ± 0.202 ng/mL in neoplasm and 0.141 ± 0.116 ng/mL in fissure; p = 0.04), 30% for pTh (46 ± 36 pg/mL

in neoplasm and 32 ± 17 pg/mL in fissure; p = 0.04) and 15% for alkaline phosphatase (80 ± 24 U/L in neoplasm and 68 ± 16

U/L in fissure; p = 0.04). In the group with neoplasm, the values of p1Np decreased 6% after hBOT (T0: 49 ± 31 ng/mL, T2: 46

± 12 ng/mL; p = 0.03). also, there were non-significant decreases in pTh (–34%) and cTX (–30%).

conclusions: patients with neoplasm and complications with radiotherapy have an increase in bone remodeling that may

be diminished after hBOT.

Key words: hyperbaric oxygen therapy; neoplasm; radiotherapy; bone turnover markers

Rep Pract Oncol Radiother 2021;26(2):163–169

Introduction

Oxygen is critical for maintaining bone cellular functions and changes in partial pressure of oxygen directly impact bone cell function [1]. Hypoxia is associated with excessive bone resorption, decreas-ing formation and mineralization [2, 3]. However,

hyperoxia could have opposite effects, regulating the expression of the hypoxia-inducible factor 1α (HIF-1a) [4], increasing formation and decreasing bone resorption [5–8]. The change of bone turn-over rate could affect the bone quality. Hyperbaric oxygen therapy (HBOT) has shown to be useful for the treatment of patients with neoplasms and

This article is available in open access under creative common attribution-Non-commercial-No Derivatives 4.0 International (cc BY-Nc-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially

© 2021 Greater poland cancer centre. published by Via Medica. all rights reserved.e-IssN 2083–4640IssN 1507–1367


ISSN: 1507–1367

Reports of Practical Oncology and Radiotherapy 2021, vol. 26, no. 2

https://journals.viamedica.pl/rpor164

secondary complications from radiotherapy [9–11] due to its anti-inflammatory and antioxidant effects [12–16]. However, the actions of HBOT on bone metabolism in these patients are unknown.

In our study we aimed to analyze the effects of HBOT on bone remodeling in oncological patients that had been treated with radiotherapy.

Materials and methods

Prospective study (October 2018–October 2019) in 23 patients with neoplasms undergoing treat-ment with HBOT and 25 patients with chronic anal fissure (control group) who will also receive HBOT. The mean age of all patients was 60 ± 14 yrs. (range 30–87 yrs.; 60% males). In all cases, the indication to receive treatment with HBOT was made by their specialist doctor (radiation oncologist, oncologist, general surgeon and gastroenterologist). 23 patients had neoplasm history but, without bone metasta-ses (9 adenocarcinomas of the rectum or colon, 5 carcinomas of the head and neck, 3 carcinomas of the prostate, 3 gynecological adenocarcinomas, 2 cutaneous carcinomas and 1 ductal carcinoma of the breast), all with complications due to radio-therapy (cystitis 30%, proctitis 30% and radione-crosis 40%). The patients with chronic anal fissure received HBOT after not improving with conven-tional treatment.

The average total radiotherapy dose was 50.7 Gy in all patients with tumors. In pelvic tumors it was 44–50.4 Gy (1.8–2 Gy/fraction) to the pelvis (tu-

mor/tumor bed and lymphatic areas), one patient received also 15 Gy/fraction with high dose rate brachytherapy as boost. In head and neck cancer it was 70 Gy (2 Gy/fraction) to the tumor and patho-logical nodes and 63–45 Gy (1.8–2 Gy/fraction) to the latero-cervical chains and supraclavicular fossa. In others tumors, the dose was 35 Gy (7 Gy/frac-tion).

We excluded pregnant women and patients with previous HBOT. The patients were exposed to HBOT inside a hyperbaric chamber (Galeazzi, Italy; 100% oxygen; 2.4 atmospheres absolute for 90 min. Fig. 1) while breathing through an oral-nasal mask 5 times a week. All subjects were evaluated prospectively. At baseline, clinical data were collect-ed on standardized data forms. The determinations in both groups were obtained at three time points: T0 (before beginning HBOT), T1 (at the end of HBOT) and T2 (6 months after HBOT). The aver-age number of HBOT sessions in all patients was 20 ± 5 (range 8–31), similar in both groups (21 ± 4 in neoplasm and 19 ± 4 in anal fissure).

The study protocol was approved by the Insti-tutional Review Board and all patients gave their written informed consent.

Blood samples were obtained in a fasting state between 08:30 and 12:00 am. Routine chemistries were analyzed the same day. Other parameters were analyzed in serum aliquots stored at −80°C. Se-rum total calcium, creatinine, alkaline phosphatase (AP), phosphorus and albumin were determined by standard automated methods in an ADVIA 2400

Figure 1. hyperbaric oxygen therapy

Zaida Salmón-González et al. Influence of hBOT on bone metabolism in patients with neoplasm


Chemistry System (Siemens Medical Solutions Di-agnostics, Los Angeles, CA USA). Serum concen-trations of 25hydroxyvitamin D (25-OHD), para-thyroid hormone (PTH), aminoterminal propep-tide of type I collagen (P1NP), and C terminal telo-peptide of type I collagen (CTX) were determined by a chemiluminescent immunoassay in an iSYS (IDS-iSYS Multi-Discipline Automated Analyzer, Pouilly-en Auxois, France). The detection limit of serum 25OHD was 5 ng/mL, its intra-assay coef-ficient of variation (CV) was < 10, and its inter-as-say CV was < 15. The detection limit of PTH was 6 pg/mL, intra-assay and inter-assay CV were 2.6 and 5.8%, respectively. The P1NP limit of detection was 0.14 ng/mL with an intra-assay and inter-assay CV of 2.9 and 4.7%, respectively. The intra-assay and inter-assay CV of β-CTX were 3.2 and 6.2%. The glomerular filtration rate was estimated using the new CKD-EPI equation from serum creatinine concentration..

statistical analysisThe results were expressed as mean ± SD for

quantitative variables and percentage for qualita-tive variables. We used the Kolmogorov-Smirnov test to check for normal distribution. Quantitative variables were analyzed by Student t- test if the vari-ables had a normal distribution, or the nonpara-metric Mann-Whitney U test were used to compare between-group differences. The Paired-Samples T Test or Wilcoxon tests were used to compare within-subject changes. The value of p < 0.05 was considered statistically significant.

results

Patients with neoplasm have at baseline (T0) higher bone turnover than those with anal fissure. These differences in T0 were 15% for alkaline phos-phatase (80 ± 24 U/L in neoplasm and 68 ± 16 U/L in fissure; p = 0.04), 41% in CTX (0.238 ± 0.202 ng/mL in neoplasm and 0.141 ± 0.116 ng/mL in fissure; p = 0.04), and 30% for PTH (46 ± 36 pg/mL in neoplasm and 32 ± 17 pg/mL in fissure; p = 0.04) (Fig. 2). The levels of P1NP (49 ± 31 ng/mL in neoplasm and 43 ± 24 ng/mL in fissure; p = 0.44) and 25-OHD (20 ± 12 ng/mL in neoplasm and 19 ± 11 ng/mL in fissure; p = 0.72) were similar. After HBOT (T1 and T2) the differences in CTX and PTH between both groups largely disappeared

and were only maintained in alkaline phosphatase (Fig. 2).

In the neoplasm group there were no early chang-es (T1) after HBOT in values of bone turnover with respect to baseline, but there was a significant de-crease in the bone formation marker (P1NP) after 6 months (T0:49 ± 31 ng/mL and T2:46 ± 12 ng/mL; p = 0.03). Also, we observed a non-significant de-crease in PTH (34%; T0: 46 ± 36 pg/mL, T2: 30 ± 14 pg/mL; p = 0.62) and CTX (30%; T0: 0.238 ± 0.202 ng/mL, T2:0.165 ± 0.134 ng/mL; p = 0.95) after 6 months of HBOT in these patients (Tab. 1).

In the group of chronic anal fissure, the values were similar through the whole study period and we saw no influence of HBOT (Tab. 2).

All patients included in the study presented a clinical improvement (85% in cancer patients and 90% in patients with chronic anal fissures) with a decrease in pain and bleeding mainly.

Discussion

Bone turnover markers have an important role in bone metabolism. Measurement of P1NP ap-pears to be a more sensitive marker of the bone formation rate and CTX of the bone resorption rate. The change of the bone turnover rate could affect the bone quality. Patients with neoplasms, with or without metastases, have an increase in bone remodeling; in bone resorption as well as in bone formation [18, 19]. In our study baseline we found an increase in bone remodeling in patients with tumors who have not developed metastases. Radiotherapy may contribute to deregulating bone remodeling via different mechanisms [20, 21]. Ra-diation-induced bone loss is a potential health con-cern for cancer patients undergoing radiotherapy [22]. In our study, the oncology patients are treated with radiotherapy despite the absence of metastases and all of them received treatment with HBOT due to complications of radiotherapy (cystitis, proctitis or radionecrosis).

On the other hand, HBOT has shown to be use-ful in the treatment of radiotherapy complications like hemorrhagic cystitis, secondary proctitis [9] or radiation-induced skin necrosis [23, 24] due to its anti-inflammatory, antioxidant and immuno-modulatory effects [25]. In our study, we observed a significant decrease of P1NP, as a bone formation marker, as well as a tendency to decrease the bone



table 1. Bone metabolism in patients with neoplasm

T0 T1 T2

Glomerular filtrate 74 (20)77 (19)

p = 0.04

81 (14)

p = 0.14

albumin [g/dL] 4.2 (0.3)4.2 (0.3)

p = 0.90

4.3 (0.5)

p = 0.55

Total calcium [mg/dL] 9.1 (0.4)9.1 (0.2)

p = 0.38

9.1 (0.4)

p = 0.90

phosphorus [mg/dL] 3.3 (0.4)3.2 (0.4)

p = 0.39

3.0 (0.3)

p = 0.77

25OhD [ng/mL] 20 (12)20 (12)

p = 0.64

18 (9)

p = 0.62

alkaline phosphatase [U/L] 80 (24)85 (36)

p = 0.58

96 (59)

p = 0.08

20%

Fissure Neoplasm

0

10

20

30

40

50

PTH

0,141 0,1380,123

0,238

0,211

0,165

0

0,05

0,1

0,15

0,2

0,25

CTX

43 4137

4953

46

0

10

20

30

40

50

60

P1NP

0

20

40

60

80

100

120

AP

p = 0.04 p = 0.05 p = 0.33

p = 0.44 p = 0.19 p = 0.07

T0 T1 T2

32 34 35

4641

30

p = 0.04 p = 0.32 p = 0.52 T0 T1 T2

T0 T1 T2

68 66 61

80 8596

p = 0.04 p = 0.025 p = 0.026 T0 T1 T2

Figure 2. Bone metabolism in neoplasm and fissure; T0: before beginning hBOT, T1: at the end of hBOT, T2: 6 months after hBOT



resorption marker, in oncological patients after HBOT. The reduction of the inflammation in these complications (proctitis, cystitis and radionecrosis) after HBOT could be accompanied by a decrease in the remodeling in our patients, in this way estab-lishing a relationship between inflammation and bone [26]. The fact that we found no changes in

bone turnover after HBOT in patients with anal fis-sure, caused by internal anal sphincter hypertonia [27], may support this hypothesis.

Our study has several limitations because of the small sample size and we do not know if these results were generalized to other conditions and HBOT schedules. Nevertheless, to the best of our

table 2. Bone metabolism in patients with anal fissure

T0 T1 T2

Glomerular filtrate 87 (7)87 (8)

p = 0.37

86 (11)

p = 0.11

albumin [g/dL] 4.3 (0.3)4.3 (0.3)

p = 0.60

4.3 (0.2)

p = 0.49

Total calcium [mg/dL] 9.1 (0.2)9.0 (0.2)

p = 0.22

9.0 (0.2)

p = 0.42

phosphorus [mg/dL] 3.3 (0.5)3.3 (0.5)

p = 0.85

3.2 (0.4)

p = 0.73

25OhD [ng/mL] 19 (11)18 (10)

p = 0.33

26 (13)

p = 0.13

alkaline phosphatase [U/L] 68 (16)66 (16)

p = 0.35

61 (17)

*p = 0.06

–10%

p1Np [ng/mL] 43 (24)41 (23)

p = 0.41

37 (13)

p = 0.19

–14%

pTh [pg/mL] 32 (17)34 (16)

p = 0.75

35 (21)

p = 0.85

9%

cTX [ng/mL] 0.141 (0.116)0.138 (0.092)

p = 0.64

0.123 (0.084)

p = 0.46

–12%

Mean (sD). T0: before beginning hBOT, T1: at the end of hBOT, T2: 6 months after hBOT; p value: corresponds to a statistically significant difference between T0 and T1; p* value: corresponds to a statistically significant difference between T0 and T2; % — percentage of change

table 1. Bone metabolism in patients with neoplasm

T0 T1 T2

p1Np [ng/mL] 49 (31)53 (34)

p = 0.19

46 (12)

*p = 0.03

–6%

pTh [pg/mL] 46 (36)41 (33)

p = 0.06

30 (14)

p = 0.62

–34%

cTX [ng/mL] 0.238 (0.202)0.211 (0.144)

p = 0.34

0.165 (0.134)

p = 0.95

–30%

Mean (sD). T0: before beginning hBOT, T1: at the end of hBOT, T2: 6 months after hBOT; p value: corresponds to a statistically significant difference between T0 and T1; *p value: corresponds to a statistically significant difference between T0 and T2; % — percentage of change



knowledge, this represents the first study that ana-lyzes the effects of HBOT on bone turnover mark-ers in patients.

In conclusion, patients with neoplasms and com-plications of RT have an increased bone remodel-ing. HBOT, in these patients, could have certain effects on bone homeostasis, but more studies are needed to elucidate the true effect of treatment with HBOT on bone metabolism and its long-term con-sequences.

conflict of interestAuthors declare that they have no conflict of inter-est.

FundingNone declared.

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170 https://journals.viamedica.pl/rpor

research paper




Address for correspondence: Dr Anis Bandyopadhyay, Associate Professor, Flat no. 102, P-756/1, Parnasree, Kolkata 700060; e-mail: [email protected]

Dosimetric and clinical outcomes of CT based HR-CTV delineation for HDR intracavitary brachytherapy in

carcinoma cervix — a retrospective study

Anis Bandyopadhyay, Arnab Kumar Ghosh, Bappaditya Chhatui, Dhiman DasDepartment of Radiotherapy, Medical College Kolkata, Kolkata, India

AbstrAct

background: Brachytherapy for carcinoma cervix has moved from point a based planning to optimization of dose based on

hr-cTV. Guidelines have been published by Gec esTrO on hr-cTV delineation based on clinical gynecological examination

and Mr sequences. These have given significant clinical results in terms of local control. however, many centers around the

country and worldwide still use cT based planning, which restricts hr-cTV delineation, as disease and cervix can rarely be

differentiated on a planning cT. Various studies have been done to develop cT based contouring guidelines from the available

data, but enough evidence is not available on the clinical outcome when treatment is optimized to hr-cTV contoured on cT

images. The purpose of this study is to find out the relation between local control and dosimetry of hr-cTV as delineated on

cT images.

Materials and methods: patients of locally advanced carcinoma cervix treated radically with eBrT of 50 Gy in 25# and at least

4 cycles of concurrent weekly cisplatin having a complete or partial response to eBrT were taken for study. all patients had

completed cT based Intracavitary brachytherapy to 21 Gy in 3# of 7 Gy per # with dose prescription at point a and optimiz-

ing dose to reduce bladder and rectal toxicity. Follow up data on locoregional recurrence was obtained. hr-cTV delineation

was done retrospectively on the treatment plan following guidelines by Viswanathan et al. eQD2 doses for eBrT+BT were

calculated for point a and hr-cTV D90. The dosimetric data to hr-cTV and to point a were then compared with patients with

locoregional control and with local recurrence.

results: 48 patients were taken, all had squamous cell carcinoma. The median age was 48 years. 33.33% were stage IIa, the

rest were stage IIB. Median follow-up was 30 months with 25% developing recurrence of the disease. hr-cTV D90 eQD2 dose

was significantly higher in patients with locoregionally controlled disease than in patients with local recurrence (83.97 Gy10

vs. 77.96 Gy10, p = 0.002). patients with hr-cTV D90 eQD2 dose greater than or equal to 79.75 Gy 10 had better locoregional

control than patients receiving dose less than 79.75 Gy10 (p = 0.015). Kaplan Meier plot for pFs showed significantly improved

pFs for patients receiving hr-cTV D90 dose of at least 79.75 Gy10 (log-rank p-value = 0.007). Three year progression free sur-

vival was 87.1% in patients receiving hr-cTV D90 dose of at least 79.75 Gy10.

conclusion: cT based hr -cTV volume delineation with the help of pre brachytherapy clinical diagrams and MrI imaging may

be feasible in a select subgroup of patients with complete or near-complete response to external beam radiation.

Key words: carcinoma cervix; brachytherapy; hr-cTV; cT scan





ISSN: 1507–1367

Anis Bandyopadhyay et al. cT based hr-cTV delineation for hDr intracavitary brachytherapy


Introduction

Carcinoma cervix is one of the major contribu-tors to the cancer burden in developing countries like India. The widespread risk factors favor the high incidence of the disease in the rural parts of the nation. The government had taken utmost measures to implement screening programs like Lugol’s iodine screening, Pap smear examination, and health education programs with a prime idea to aid early diagnosis and prompt treatment [1]. Although screening programs are available, they remain highly unutilized leading to a large number of patients presenting at a locally advanced stage at the first point of contact with healthcare. With the majority presenting at a locally advanced stage of the disease, radiation therapy becomes the primary treatment modality in our country.

The basic treatment of locally advanced carcino-ma of the cervix is external beam radiotherapy with concurrent chemotherapy followed by brachyther-apy, radical surgery being preserved for selected cases only [2, 3]. Brachytherapy forms the most in-tegral part of carcinoma cervix radiotherapy aiding to deliver a very high local dose to the region. For many years, the dose was prescribed to Point A as described by Todd and Meredith and dose report-ing was done based on the International Commis-sion of Radiation Units and Measurements (ICRU) 38 protocol [4], with orthogonal radiographs as im-aging. However, high dose rate (HDR) brachythera-py requiring multiple applications, slight variations in the application geometry led to a change in posi-tions of point A and dose reporting points resulting in reporting variations [5, 6]. Another drawback was that the original definition being based solely on anatomical landmarks was not identified on a radiograph. Point-based prescription also did not correlate well with local control [7].

With the introduction of modern imaging devic-es like Computed Tomography (CT) scan and Mag-netic Resonance Imaging (MRI), dose prescription to the actual Clinical Target Volume (CTV) and dose reporting to target and Organ at Risk (OAR) made more sense than arbitrary points [8]. Most recent guidelines recommend MRI based Image Guided Adaptive Brachytherapy for Carcinoma [9–14]. Evidence from RetroEMBRACE and EM-BRACE I studies have shown improvement in sur-vival which also paved the way for dose prescription

to High Risk Clinical Target Volume (HR-CTV) from conventional point A [15, 16]. However, recommendations for HR-CTV and intermediate risk clinical target volume (IR-CTV) delineation are provided by guidelines I–IV by Gynaecology Groupe Européen de Curiethérapie and the Euro-pean SocieTy for Radiotherapy & Oncology ( Gyn GEC ESTRO) which is applicable only for MRI based applications [10, 11, 13, 14]. Although con-sidered the gold standard, limitations to the use of MRI based brachytherapy is the availability of ad-vanced MRI simulator, MRI compatible applicators, and some degree of institutional experience.

Such standards cannot be maintained in re-source-constrained high volume institutions in our country which only have CT simulators. Certain drawbacks of CT based target delineation are the inability to identify the Gross Tumour Volume (GTV) from normal cervical tissue, and difficulty to identify the upper border of the cervix [17]. Various attempts at HR-CTV delineation based on CT scan have been made, with the study by Viswanathan et al. [17–19] being the most standardized of them. This study has provided contouring guidelines and atlas for standardized CT based HR-CTV delinea-tion based on Gyn GEC ESTRO MRI recommen-dations, although, data on clinical outcome of such recommendations are inadequate. A part of the sample of the RetroEMBRACE study had patients who had been treated following Viswanathan et al. guidelines, however, the clinical outcome from that subgroup was not separately reported in the [15].

Our objective is to determine whether dose to HR-CTV delineated on a CT scan based on avail-able guidelines correlate with adequate local control in locally advanced carcinoma cervix treated with intracavitary brachytherapy.


Computer tomography based intracavitary brachytherapy was started in Medical College Hos-pital, Kolkata, around 2006; however, for over a de-cade target delineation was not routinely done. Only around and after 2013, CT based HR-CTV contour-ing was started in selected cases, however, dose pre-scription and planning was still point-based. We have retrospectively selected a cohort of patients receiving intracavitary HDR brachytherapy during the period from January 2015 till December 2015 for this study.



patient selectionThe inclusion criteria were biopsy proven cas-

es of locally advanced carcinoma cervix who had completed external beam radiotherapy with a total dose of 50 Gy in 25 fractions in 5 weeks with at least 4 cycles of concurrent Cisplatin chemotherapy, had a complete or partial response to external beam ra-diotherapy (EBRT) as validated by post-EBRT clini-cal examination and/or by MRI, and received CT based intracavitary brachytherapy with 3 fractions of 7 Gy per fraction with dose prescription to point A as per our institutional protocol. Other inclusion criteria were Performance Status of 0 or 1 before starting brachytherapy, normal blood and bio-chemistry profile, and treatment completion within 9 weeks. Presence of any degree of uterine prolapse, past pelvic surgery apart from biopsy, intracavitary applications other than standard tandem ovoid or tandem ring, and EBRT dose other than 50 Gy, altered fractionation were excluded from the study. The presence of a retroverted uterus or an imperfect application also led to the exclusion from the study.

During the study period selected, a total of 245 patients of cervical cancers were treated at our de-partment, among whom 72 cases received postop-erative radiotherapy and the remaining 173 were treated radically with radiotherapy. Among these, 51 needed interstitial application or combination of intracavitary and interstitial application due to residual parametrial disease or less than near com-plete response to EBRT, which could not be cov-ered with a standard intracavitary technique. The remaining 122 patients were screened and only 48 deemed suitable for the study as per the inclusion and exclusion criteria.

external beam radiotherapyAll patients in the study had completed EBRT to

the whole pelvis to a total dose of 50 Gy in 25 frac-tions over 5 weeks with concurrent weekly Cispla-tin 40 mg/m2 body surface area (BSA). The EBRT machine was a Theratron 780C (Best Theratronics, Canada) Cobalt 60 unit. The treatment was done using a conventional 4 field box technique. The stringent EBRT inclusion criteria were to ensure that the limitations of the EBRT technique and re-porting had less control on the outcome in terms of local control and the local control thus assessed can be attributed more to the dosimetry of brachy-therapy.

BrachytherapyBrachytherapy was delivered using an Iridium

192 remote after loader (GammaMed plus, Varian Medical Systems, Palo Alto, California) based on our Institutional Protocol of 3 fractions of 7 Gy per fraction weekly. Two types of CT compatible appli-cators, namely Fletcher and Ring applicators, were used for Intracavitary brachytherapy (ICBT) appli-cation. The applicators consisted of uterine tandem with various angles (15°, 30°, 45°). Before each ap-plication, a urinary catheter was inserted and the catheter balloon was inflated with contrast media (7 mL) to localize the bladder neck. Patients followed specific instructions for rectal preparation before the ICBT procedure which included the taking of bisacodyl tablets (20 mg) the previous night and use of sodium phosphates enema early in the morning on the day of the procedure. Appropriate anterior and posterior vaginal packing was used to fix the applicator position and to displace the bladder and rectum away from the vaginal applicators. After the intracavitary application, the applicator was fixed with the help of roller gauze bandages.

All patients underwent a CT scan followed by treatment planning during the first and third frac-tion of brachytherapy application, the treatment for the second fraction was done based on the ap-proved plan of the first fraction. Before the scan, 10 mL of diluted Contrast in NS (Normal Saline) is instilled in the bladder as a routine protocol. No intravenous contrast is given as a routine proce-dure. To minimize patient movement during CT scans, every attempt was made to keep the applica-tor in position and to complete the entire proce-dure within the shortest possible time. The scan was taken with 3 mm slice thickness through the pelvis, from the highest point of the iliac crest to the up-per thigh using a 16 slice CT simulator (Brilliance Big Bore, Philips, Amsterdam, Netherlands); all CT slices were transferred to the treatment planning computer. Contouring of the organs at risk, OARS (bladder, rectum, and sigmoid colon) was done on axial sections as solid organs. The treatment planning was done using Varian Treatment Plan-ning System (Eclipse version 13.5, Varian Medical Systems, Palo Alto, California). The planning was done using a uniform loading pattern with dose prescriptions to point A only. The plan was further optimized by dose point optimization to keep the bladder, rectum and sigmoid D2cc doses limited



to 85 Gy3 equivalent dose in 2 Gy fraction (EQD2) 70 Gy3 EQD2 and 70 Gy3 EQD2, respectively. Dose prescription to HR-CTV was not done.

study technique and data collectionBrachytherapy plans were accessed in the Treat-

ment Planning Computer; HR-CTV contouring was done following Viswanathan et al. guidelines with the help of available pre-brachytherapy MR images [17]. The presence of any post-EBRT vi-able disease in the parametrium led to exclusion of cases. Contouring was rechecked by another senior radiation oncologist, and with any discordance by more than 10%, the volume was redrawn. The vol-ume of HR-CTV, bladder, and rectum was collected from dose statistics. HR-CTV D90, D98, rectal dose (2cc, 1cc, 0.1cc), bladder dose (2cc, 1cc, 0.1cc), sig-moid dose (2cc) was collected from DVH (Dose Volume Histogram). Dimensions of HR-CTV were recorded from appropriate sagittal, coronal, and axial sections. Follow up information was evalu-ated from records, data on disease recurrence was noted. The recurrence was detected clinically and confirmed either by MRI/PET — positron emis-sion tomography computed tomography (PET-CT) or wherever possible, by biopsy. Local recurrence was defined as any clinical and/or radiological evi-dence of disease in the pelvis in patients achieving complete response clinically after completion of brachytherapy.

Definitions HR-CTV — high-risk clinical target volume. It is the volume bearing the highest risk for recurrence and is selected by clinical examination and imaging at the time of brachytherapy (ICRU 89);HR-CTV D90 — it is the minimum dose received by 90% of the volume of the HR-CTV;HR-CTV D98 — it is the minimum dose received by 98% of the volume of the HR-CTV (near mini-mum target dose);D2cc — minimum dose received by maximally ir-radiated 2cc volume (OAR).

analysis of dataThe statistical analysis was done using IBM SPSS

(Statistical Package for the Social Sciences) 20 soft-ware. Descriptive statistics were used to report pa-tient characteristics and dose-volume characteris-tics of HR-CTV and OARs. Comparison of mean

Point A and HR-CTV D90 and D98 dose in patients with disease recurrence and locoregionally con-trolled disease was done using Independent Sam-ples T-test with a significance level of 0.05. Fisher’s exact test was used to compare local recurrence in terms of HR-CTV D90 dose. Kaplan Meier time to event analysis was used to assess progression-free survival (PFS). The time to progression was taken from completion of brachytherapy to any evidence of local progression/recurrence.

results

48 patients were taken for the study; all had his-tologically proven Squamous Cell Carcinoma. The median age was 48 years. 13 patients (27.1%) were in the pre-menopausal age group, the rest were post-menopausal. 32 patients (66.67%) were Inter-national Federation of Gynecology and Obstetrics (FIGO) Stage IIB, the rest were at FIGO Stage IIA [19]. 45.83% of patients had received at least 4 cy-cles of concurrent cisplatin 40 mg/m2 BSA (Tab. 1).

The dose-volume parameters are reported in Table 2. Mean point A EQD2 dose was 77.62 ± 2.10 Gy10. Mean HR-CTV volume was 28 ± 5.03 cc and mean HR-CTV D90 and D98 EQD2 dose was 82.46 ± 6.58 Gy10 and 69.29 ± 3.96, respectively. The rectal volume, bladder volume, and their respective D2cc, D1cc, and D0.1cc EQD2 doses are mentioned in Table 2. Age, bladder volume, rectal volume, and HR-CTV volume were not significantly different between patients with recurrent and locoregionally

table 1. patient characteristics

Patient characteristics

Median age48 years

(minimum — 35 years, maximum — 62 years)

Menopausal status

premenopausal

postmenopausal

13 (27.1%)

35 (72.9%)

Histopathology

squamous cell carcinoma 48 (100%)

FIGO stage

IIa

IIB

16 (33.33%)

32 (66.67%)

concurrent ct cycles received

4

5

26(54.17%)

22 (45.83%)

FIGO — International Federation of Gynecology and Obstetrics; cT — cisplatin



controlled disease (p-value = 0.272, 0.767, 0.556 and 0.575, respectively, all non-significant, from independent samples T-test).

A median follow up was 30 months with 36 (75%) patients having locoregionally controlled dis-ease and 12 (25%) developing local recurrence. The comparison of mean doses to Point A and HR-CTV in patients with local recurrence and locoregion-ally controlled disease are reported in Table 3. The mean point A EQD2 dose in patients with local re-currence of disease and loco-regionally controlled disease was 77.94 ± 2.49 Gy10 and 77.52 ± 1.99 Gy10 respectively (non-significant, p-value 0.59 from unpaired T-test). The mean HR-CTV D90 EQD2 dose in patients with local recurrence and patients with loco-regionally controlled disease was

77.96 ± 4.81 Gy10 and 83.97 ± 6.46 Gy10, respectively. Mean HR-CTV D90 EQD2 dose was significantly greater in patients with locoregionally controlled disease (p-value = 0.002, significant). Similarly, HR-CTV D98 EQD2 dose was significantly higher in patients with locoregionally controlled disease (p-value = 0.013).

The total prescription dose to point A was 79.75 Gy10 (from 50 Gy EBRT and 3# of 7 Gy to point A ICBT). Thus, for comparison of clinical outcome, we divided the patients into two groups based on whether the HR-CTV receives the prescription dose (79.75 Gy10 EQD2) or not (Tab. 4). During the follow up period, the patients who received an HR-CTV D90 EQD2 dose of more than or equal to 79.75 Gy10 EQD2 had significantly higher lo-coregional control than patients receiving less than 79.75 Gy10 EQD2 ( 87.1% vs. 52.9%,p = 0.015, Fish-er’s exact test).

Figure 2 represents Kaplan Meier plot for pro-gression free survival based on HR-CTV D90 EQD2 dose.

Progression free survival was significantly better for patients receiving HR-CTV D90 EQD2 dose of 79.75 GY10 or more (p-value = 0.007, log-rank test). The median PFS was not reached. Three-year pro-gression free survival was 87.1% in patients receiv-ing HR-CTV D90 EQD2 dose of 79.75Gy10 or more, while it was 52.9% in patients receiving HR-CTV D90 dose of less than 79.75 Gy10.

table 2. Dose volume characteristics

Mean ± SD

Hr-ctV volume 28 ± 5.03 cc

Hr-ctV dimensions

height

Width

Thickness

3.27 ± 0.27 cm

3.15 ± 0.52 cm

2.9 ± 1.8 cm

rectal volume 48.12 ± 19.73 cc

bladder volume 70.31 ± 16.83 cc

Point A EQD2 77.62 ± 2.10 Gy10

Hr-ctV D90 EQD2

D90 eQD2

D98 eQD2

82.46 ± 6.58 Gy10

69.29 ± 3.96 Gy10

rectum dose

D2cc eQD2

D1cc eQD2

D0.1cc eQD2

68.31 ± 5.75 Gy3

72.78 ± 7.01 Gy3

82.53 ± 10.79 Gy3

bladder dose

D2cc eQD2

D1cc eQD2

D0.1cc eQD2

81.30 ± 10.34 Gy3

87.15 ± 10.32 Gy3

100.22 ± 12.39 Gy3

sigmoid D2cc EQD2 64.28 ± 2.68 Gy3

table 3. comparison of mean point a and hr-cTV doses in patients with disease recurrence and locoregionally controlled disease

Mean ± standard deviation [Gy10] p-value (independent samples t-test)Local Recurrence Loco regionally controlled

point a eQD2 77.94 ± 2.49 77. 52 ± 1.99 0.59

hr-cTV D90 eQD2 77.96 ± 4.81 83.97 ± 6.46 0.002

hr-cTV D98 eQD2 67.36 ± 3.82 69.94 ± 3.76 0.013

table 4. Locoregional control in patients based on hr-cTV D90 eQD2 dose (less than 79.75 Gy10 or more than equals to 79.75 Gy10)

Local recurrence

Loco regionally controlled

disease

Hr-ctV D90 EQD2 dose

Less than 79.75 Gy10

More than equal to 79.75 Gy10

47.1%, (8)

12.9%, (4)

52.9%, (9)

87.1%, (27)



Discussion

MRI based adaptive brachytherapy is the gold standard for intracavitary brachytherapy of carci-noma cervix and recent recommendations are pro-

vided by Gyn GEC ESTRO [10, 11] working group and ICRU 89(9). The standard was set based on the results of various studies [21–23]. With the publica-tion of results of RetroEMBRACE & other studies, improvement in target coverage and overall sur-vival was shown with [15, 24, 25].

However, implementation of such recommen-dations is not just limited to knowledge, training, and experience, it requires state of the art equip-ment and applicators, much of which is not avail-able at state-funded high volume centers. A prac-tice pattern survey by the same author among young radiation oncologists in India found that only about 9% of centers use routine MRI based planning versus 50% using CT based planning [25]. This is perhaps because most centers have a CT simulator which is essential for EBRT plan-ning, and hence the availability of CT based rec-ommendation is very essential for brachytherapy planning in such centers. However, the use of CT as cervical brachytherapy imaging is limit-ed by the poor anatomical delineation [17]. The GTV cannot be delineated on a CT scan, there is a limited visualization of parametrial disease, the upper end of the cervix cannot be differenti-ated from the uterus, and the disease extension on the uterine cavity cannot be visualized. In this study we have selectively included the subgroups of patients without any residual parametrial dis-

Figure 1. Brachytherapy planning cT in various sections showing hr-cTV (red), bladder (blue), and rectum (yellow) contouring and isodose curves covering hr-cTV in various sections. A–c. hr-cTV contoured on cT scan in sagittal, coronal, and axial sections, respectively. c, D. 90% (green) and 100% (white) isodose curves covering the hr-cTV in coronal and sagittal sections. E. Dose color wash showing covering of hr-cTV with 90% isodose in the axial section

a B c

D e F

Figure 2. Kaplan-Meier plot for progression-free survival based on hr-cTV D90 eQD2 dose. Green curve represents patients receiving hr-cTV D90 dose ≥ 79.75 Gy10, blue curve represents patients receiving hr-cTV D90 dose of < 79.75 Gy10

1.0

0.8

0.6

0.4

0.2

0.0

0 10 20 30 40Months to progression

Cum

surv

ival



ease post EBRT or concurrent chemoradiotherapy, thus eliminating the contouring uncertainties of the parametrial disease.

A study by Rahul Krishnatry et al. suggested that no significant dosimetric difference in terms of V100, D90, and D100 exists between CT and MR contouring, standardized guidelines were not dictated [21]. The requirement of CT guidelines has been addressed in various trials that have tried to establish a CT based guidelines for CTV contour-ing in the cervix [17–19, 27]. The recommendations provided by JRSOG [26] used MRI scans at diagno-sis and at brachytherapy to delineate cervical CTV. Those recommendations could not be taken in our study as the contouring was done retrospectively and MRI plates were not always available for refer-ence. The CT standardized guidelines provided by Viswanathan et al. [18] did not require the use of MRI scans or contrast enhancement. The updated guidelines from the same author were adopted for our study [17].

The CT based HR-CTV contouring recommen-dations lacked adequate clinical data on local con-trol and survival. However, in the RetroEMBRACE, 139/731 (19.1%) of patients were treated with CT based HR-CTV contouring, separate data on the clinical outcome of that particular subgroup was not available [15].

Although our study showed good locoregional control in the group where HR-CTV D90 received at least 79.75 Gy10 EQD2 (from table 4), there was more local failure in our study population, which is more than historical image-guided brachytherapy cohorts [15, 27–30]. A study by Mahanshetty et al. reported local control in 22/24 patients after a median follow up of 10 months [31]. A study by D Simpson et al. reported a 1-year locoregional failure of 2.2% [30]. Kusada et al. reported a 2-year local control of 83% [32]. Rijkmans et al. reported a 3-year overall survival and local control of 93% and 86% with the use of image-guided brachyther-apy [29].

Our inferior local control could be due to several limitations in our study. Firstly, the study protocol was designed after completion of patients’ treat-ment, so there was no protocol for quality control of EBRT and brachytherapy technique and our study relied on treatment decisions, dose prescription and optimization partially from institutional proto-cols and partially from treating physician’s experi-

ence. Secondly, the HR-CTV contouring was done post-treatment, so dose prescription and optimiza-tion was not based on HR-CTV so the recommend-ed D90 dose of ≥ 85 GY10 could not be achieved in several patients. However, our aim was not to achieve good local control in the population which was not under the control of the study protocol, we wanted to show whether dose to the HR-CTV contoured on CT scan had any impact on local con-trol. We managed to show a significantly good local control in patients who received the prescription dose to HR-CTV compared to those who did not. A comparative study from TMH, Mumbai, inferred that HR-CTV volumes can be contoured on CT as compared with MRI, provided there is documenta-tion of disease at diagnosis by clinical drawings and MRI, and real-time acquisition of TRUS images at various levels in relation to the cervical canal dur-ing the procedure [19]. However, since there is an overestimation of HR-CTV volumes on CT based contouring as compared to MRI based contouring, this could result in a lower HR-CTV D90 that cor-relates to local control.

Though more validation is required with a pro-spective protocol with quality control of EBRT and ICBT, dose prescription and optimization to HR-CTV and a longer follow up, this study merits in providing an indirect validation of using CT based HR-CTV contouring backed by providing clinical results of recurrence correlation with the mean D90 of the HR-CTV thus contoured. Incor-poration of real-time ultrasonography may add to the validity and reliability of such CT based delin-eation. However, since original dose prescription and optimization were not done to HR-CTV, there was no control on the toxicity profile of OAR based on HR-CTV dosimetry, hence no comment could be made on the same.

conclusion

CT based HR-CTV volume delineation with the help of pre-brachytherapy clinical diagrams and MRI imaging may be feasible in a select subgroup of patients with complete or near-complete response to External Beam radiation. Prospective studies need to be undertaken to rationalize dose prescrip-tion CT based HR-CTV as this would popularise image-based adaptive brachytherapy, especially in the resource constraint settings.



conflict of interestNone declared.


acknowledgementsThe authors would like to thank all staff and faculty the Department of Radiotherapy Medical College Kolkata, with special thanks to the physics team of Mr Jayanta Kumar Pal and his colleagues and the brachytherapy nurses team for rendering their support and cooperation in undertaking this study.

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research paper




Address for correspondence: Dr. Bin S. Teh, Department of Radiation Oncology, Houston Methodist Hospital, Cancer Center, and Research Institute, Weil Cornell Medical College, 6565 Fannin, Ste#DB1-077, Houston, Texas 77030, United States, tel: 713-441-4800, fax: 713-441-4493; e-mail: [email protected]

The impact of HER2-directed targeted therapy on HER2-positive DCIS of the breast

Gary. D. Lewis1, Waqar Haque2, Andrew Farach2, Sandra S. Hatch3, E. Brian Butler2, Polly A. Niravath4, Mary R. Schwartz5, Elizabeth Bonefas6, Bin S. Teh2

1Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States2Department of Radiation Oncology, Houston Methodist Hospital, Houston, Texas, United States

3Department of Radiation Oncology, University of Texas Medical Branch, Galveston, Texas, United States4Department of Clinical Medicine in Oncology, Houston Methodist Hospital, Houston, Texas, United States

5Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, United States6Breast Health Houston, Houston, Texas, United States

AbstrAct

background: In invasive breast cancer, her2 is a well-established negative prognostic factor. however, its significance on

the prognosis of ductal carcinoma in situ (DcIs) of the breast is unclear. as a result, the impact of her2-directed therapy on

her2-positive DcIs is unknown and is currently the subject of ongoing clinical trials.

In this study, we aim to determine the possible impact of her2-directed targeted therapy on survival outcomes for

her2-positive DcIs patients.

Materials and methods: The National cancer Data Base (NcDB) was used to retrieve patients with biopsy-proven DcIs diag-

nosed from 2004–2015. patients were divided into two groups based on the adjuvant therapy they received: systemic her2-

directed targeted therapy or no systemic therapy. statistics included multivariable logistic regression to determine factors

predictive of receiving systemic therapy, Kaplan-Meier analysis to evaluate overall survival (Os), and cox proportional hazards

modeling to determine variables associated with Os.

results: altogether, 1927 patients met inclusion criteria; 430 (22.3%) received her2-directed targeted therapy; 1497 (77.7%)

did not. patients who received her2-directed targeted therapy had a higher 5-year Os compared to patients that did not

(97.7% vs. 95.8%, p = 0.043). This survival benefit remained on multivariable analysis. Factors associated with worse Os on

multivariable analysis included charlson-Deyo comorbidity score ≥ 2 and no receipt of hormonal therapy.

conclusion: In this large study evaluating her2-positive DcIs patients, the receipt of her2-directed targeted therapy was

associated with an improvement in Os. The results of currently ongoing clinical trials are needed to confirm this finding.

Key words: DcIs; her2; molecular status; targeted therapy; breast cancer





ISSN: 1507–1367



Introduction

Ductal carcinoma in situ (DCIS) of the breast is a pre-invasive form of breast cancer that is defined by neoplastic proliferation of epithelial cells that is confined to the mammary ductal system [1]. It is estimated that DCIS makes up approximately 20% of all new diagnoses of breast cancer and up to 40% of all cases detected via mammogram [2–4]. While DCIS is a pre-cancerous lesion, finding DCIS war-rants treatment as it is believed to be a precursor to invasive breast cancers (IBC) [5]. As a result, considerable research efforts have been aimed at understanding the mechanisms of this progression.

Although DCIS has been thought to be single disease entity, there is evidence that DCIS, much like invasive breast cancer, encompasses a broad and heterogenous group of diseases that can be dif-ferentiated by varying degrees of biological aggres-siveness [6]. For example, classifying DCIS similarly to IBC may be a way to determine prognoses based on disease biology [7, 8]. However, individualizing treatment options and management based on this information is still controversial. While patients with IBC receive personalized systemic treatment based on their specific molecular subtype, patients with DCIS are treated fairly uniformly. Indeed, after initial local therapy (surgery with or without radio-therapy), the hormone receptor status is the only factor that may affect systemic treatment [9–11].

However, there is growing interest in using HER2-targeted therapy for HER2-amplified DCIS patients. While there is conflicting evidence on the effect of HER2 positivity on disease characteristics and patient outcomes [7, 8, 12–17], there remains strong interest in the role of HER2-targeted thera-py. The National Surgical Adjuvant Breast and Bow-el Project (NSABP) is currently running a clinical trial (B-43) examining the effect of trastuzumab on the risk of in-breast tumor recurrence for pa-tients with HER2 positive DCIS [4]. Given the lack of evidence and defined management guidelines, we aimed to use the National Cancer Data Base (NCDB) to determine the effects of HER2-targeted therapy on survival outcomes.


This study used the NCDB, which is a hospi-tal-based cancer registry sponsored by the Ameri-

can College of Surgeons (ACoS) and the Ameri-can Cancer Society. It collects data from over 1500 hospitals with ACoS-accredited cancer programs, accounting for 70% of all newly-diagnosed cases in the United States [18–22]. The most recent data from the NCDB included data from 2004–2015. A case list of patients with biopsy-proven DCIS was retrieved from the NCDB. Diagnosis was based on the International Classification of Disease for Oncology, third edition (ICD-O-3) codes of 8201, 8230, 8500, 8501, 8503, 8507, and 8522. Patients with invasive breast cancer were specifically exclud-ed. In order to be included in the study, patients were required to have a positive HER2 status. No specific cutoffs for HER2 positivity are mandated by the NCDB but each institution is accredited by the American College of Surgeons and pathology reports are required to follow the format, criteria, and guidelines of the College of American Patholo-gists [23].

Patient characteristics retrieved and recorded in-cluded age, race, Charlson-Deyo comorbidity score, type of insurance, income, facility type, margin sta-tus, receipt of hormonal therapy, estrogen recep-tor (ER) status, progesterone receptor (PR) status, and DCIS grade. Patients who received systemic therapy were coded as having received HER2-tar-geted therapy. Because patients with DCIS are not candidates for non-endocrine, cytotoxic systemic therapy, this assumption was felt to be reasonable. Patients were divided into two cohorts: those who received HER2-targeted therapy and those who did not.

All statistical tests were two-sided, with a thresh-old of p < 0.05 for statistical significance, and were performed using STATA (version 14, StataCorp, College Station, TX). The c2 test analyzed categori-cal proportions between groups. Univariable and multivariable logistic regression modeling was uti-lized to determine characteristics that were predic-tive of the receipt of HER2-targeted therapy. The Kaplan-Meier method was used for survival analy-sis, and comparisons between the two treatment paradigms were performed with the log-rank test for all patients. Overall survival (OS) was defined as the interval between the date of diagnosis and the date of death or last contact. Multivariable Cox proportional hazards modeling was additionally used to identify variables associated with OS in the entire cohort.

Gary. D. Lewis et al. The impact of her2-directed targeted therapy on her2-positive DcIs of the breast


results

Altogether, 1927 patients met the inclusion criteria. The majority of patients in the cohort were over the age of 50, Caucasian, had a Charl-son-Deyo Comorbidity Score of 0 and were treated

at a non-academic facility. Overall, 430 (22.3%) re-ceived HER2-directed targeted therapy, while 1497 (77.7%) did not. Patient characteristics for the two groups are listed in Table 1. Patients with ER(–) disease were more likely to receive HER2-directed targeted therapy. There was no relation between

table 1. Baseline characteristics of patients in each of the cohorts

CharacteristicHER2-targeted therapy

(n = 430) (%)

No HER2-targeted therapy

(n = 1497) (%)p-value

Age (years) 0.601

≤ 50 92 (21.4%) 303 (20.2%)

> 50 338 (78.6%) 1194 (79.8%)

race 0.778

caucasian 371 (86.3%) 1271 (84.9%)

african american 41 (9.5%) 157 (10.5%)

Other/ not recorded 18 (4.2%) 69 (4.6%)

charlson-Deyo score 0.813

0 374 (87.0%) 1319 (88.1%)

1 50 (11.6%) 18 (10.6%)

≥ 2 6 (1.4%) 20 (1.3%)

Insurance 0.670

Medicaid 25 (5.8%) 86 (5.7%)

private 274 (63.7%) 902 (60.3%)

Medicare 116 (27.0%) 455 (30.4%)

Uninsured 8 (1.9%) 24 (1.6%)

Government/other 7 (1.6%) 30 (2.0%

Income 0.457

≤ 62999 UsD 281 (65.4%) 938 (62.7%)

≥ 63000 UsD 147 (34.2%) 555 (37.1%)

Not recorded 2 (0.5%) 4 (0.3%)

Facility type 0.432

academic 108 (25.1%) 417 (27.9%)

Non-academic 317 (73.7%) 1068 (71.3%)

Not recorded 5 (1.2%) 12 (0.8%)

Margin status 0.306

Negative 416 (96.7%) 1440 (96.2%)

positive 10 (2.3%) 50 (3.3%)

Not recorded 4 (0.9%) 7 (0.5%)

Hormonal therapy 0.898

Yes 220 (51.2%) 777 (51.9%)

No 167 (38.8%) 581 (38.8%)

Not recorded 43 (10.0%) 139 (9.3%)



the receipt of HER2-directed targeted therapy and insurance type, income, facility type, margin status, grade, or receipt of hormonal therapy.

The Kaplan-Meier curves comparing survival for patients either receiving treatment with or without HER2- directed therapy are illustrated in Figure 1. Patients who received HER2–directed targeted therapy had a higher 5-year OS compared to pa-

tients that did not (97.7% vs. 95.8%, p = 0.043, Fig. 1). This survival benefit for HER2-directed tar-geted therapy remained statistically significant on multivariable analysis. On multivariable analysis, factors associated with worse OS included Charl-son-Deyo Comorbidity Score ≥ 2 and no receipt of hormonal therapy. The results of the univariable and multivariable analysis are displayed in Table 2.

table 1. Baseline characteristics of patients in each of the cohorts


(n = 430) (%)


(n = 1497) (%)p-value

Estrogen receptor status 0.034

positive 261 (60.7%) 992 (66.3%)

Negative 169 (39.3%) 499 (33.3%)

Not recorded 0 (0.0%) 6 (0.4%)

Progesterone receptor status 0.665

positive 199 (46.3%) 726 (48.5%)

Negative 221 (51.4%) 742 (49.6%)

Not recorded 10 (2.3%) 29 (1.9%)

Grade 0.295

1 13 (3.0%) 57 (3.8%)

2 65 (15.1%) 278 (18.6%)

3 275 (64.0%) 897 (59.9%)

Not recorded 77 (17.9%) 265 (17.7%)

1.00

0.75

0.50

0.25

0.00

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Discussion

To the best of our knowledge, this study repre-sents the largest study of HER2 positive DCIS pa-tients. In addition, this analysis is the first to exam-ine the potential impact of HER2-directed targeted therapy on survival outcomes for DCIS patients. Several observations can be made from this analysis. First, as expected, the overall survival of all patients with HER2 positive DCIS was very high, with OS rates at five years > 95% with or without the use of HER2-targeted therapy. Second, the presumed use of HER2-targeted therapy was associated with improved OS amongst patients with HER2 positive DCIS. These results are interesting and highlight the importance of the NSABP B-43 clinical trial results, as the patient characteristics of our study popula-tion are similar to patients that were enrolled in the B-43 trial. A comparison of the patient character-istics collected from that trial with a comparison of our data is displayed in Table 3. The distribution of age and hormone receptor status between the two cohorts was similar. Our study population had slightly lower rates of high-grade DCIS compared to the B-43 cohort, which may have been due to high-er rates of unrecorded tumor grade in the NCDB. Overall, HER2 positivity in our cohort was associ-ated with high nuclear grade, which is concordant with the existing literature [4, 24–26].

This is the first study to suggest that the use of HER2-directed therapy is associated with an im-

provement in overall survival amongst patients with HER2 positive DCIS. Our study is also the first to indicate a potential clinical benefit on survival out-comes for this patient population. Previous work has demonstrated that trastuzumab can effectively cross the basement membrane of the ductal system and may have clinical efficacy for HER2 positive DCIS [27–29]. If the NSABP trial has similar find-ings, HER2-directed targeted therapy may allow more treatment options for patients with DCIS, especially those with HR receptor negative disease. In addition, due to the significant heterogeneity of DCIS, another available targeted treatment option opens the door for more personalized cancer treat-ment. Finally, HER2-directed targeted therapy may serve as a mechanism to reduce the risk of progres-sion of DCIS to invasive cancer, opening up the possibility of HER2-directed targeted therapy as a form of monotherapy.

Overall, HER2-directed therapy (in the form of trastuzumab) has demonstrated a strong safety record. In a preliminary report of HER2 positive DCIS patients in NSABP B-43, 5% of patients in the trastuzumab arm reported grade 3 toxicities with no cases of grade 4 or 5 toxicities [4]. In invasive breast cancer, trastuzumab has been studied exten-sively and found to have an acceptable safety pat-tern, even with regards to cardiotoxicity [30–32]. However, when compared to invasive cancer, the therapeutic ratio of trastuzumab for HER2 posi-tive DCIS may not be as strong. DCIS patients as

table 3. comparison of her2 positive DcIs patient characteristics between our study and the NsaBp B-43 trial [4]

Current Study NSABP B-43 trial [4]


(n = 430) (%)


(n = 1497) (%)

HER2-targeted therapy (n = 713) (%)


(n = 715) (%)

Age (years)

≤ 50 92 (21.4%) 303 (20.2%) 161 (22.6%) 164 (22.9%)

> 50 338 (78.6%) 1194 (79.8%) 552 (77.4%) 551 (77.1%)

Estrogen receptor status

positive 261 (60.7%) 992 (66.3%) 423 (59.3%) 409 (57.2%)

Negative 169 (39.3%) 499 (33.3%) 290 (40.7%) 304 (42.5%)

Not recorded 0 (0.0%) 6 (0.4%) 0 (0.0%) 2 (0.3%)

Grade

Well differentiated 13 (3.0%) 57 (3.8%) 10 (1.4%) 5 (0.7%)

Moderately differentiated 65 (15.1%) 278 (18.6%) 108 (15.1%) 122 (17.1%)

poorly differentiated 275 (64.0%) 897 (59.9%) 595 (83.5%) 588 (82.2)

Not recorded 77 (17.9%) 265 (17.7%) – –



a whole do very well in terms of survival outcomes. Indeed, our study found an OS of 95.8% at five years. Even with a survival benefit at 5 years for HER2-directed therapy, it is possible that with long term follow-up the toxicity of therapy may erase any benefits. As a result, it is likely that not all HER2 positive DCIS patients will benefit from treatment, only patients at the highest risk. The results of the NSABP B-43 trial are likely to be very helpful in delineating which patients receive benefit.

The cost of therapy must also be taken into ac-count. As a monoclonal antibody, the costs of man-ufacturing trastuzumab are already significant, even without including costs associated with administra-tion, monitoring, and staffing [33]. For a patient population that already does well, cost-effectiveness studies will need to be performed to determine the societal value of more aggressive treatment, espe-cially in the current health care climate of continu-ously rising (and often prohibitive) costs.

Our study has several limitations due to its reli-ance on the NCDB. First, our study had a relatively short follow-up due to the lack of widespread HER2 reporting in the NCDB until more recently. How-ever, there was still a significant difference in sur-vival based on receipt of HER2-directed therapy, although it is possible that the survival curves may plateau or cross with additional follow-up. Next, we must acknowledge the retrospective nature of the study with all its associated biases. HER2 status is not normally assessed and reported in DCIS; there may be potential bias in the patients who underwent HER2 testing. This may explain why the percentage of patients receiving systemic targeted therapy in our study (22.3%) was higher than expected; cur-rently, there is no standard clinical indication for non-endocrine systemic therapy. In addition, the NCDB does not record the use of specific targeted agents. We had to assume that patients recorded as receiving systemic therapy received HER2-directed targeted therapy. Although this assumption cannot be assured, it is highly unlikely that DCIS patients received non-endocrine cytotoxic chemotherapy; it is much more likely that these patients received HER2-directed therapy, especially given that these patients all had HER2 positive disease.

The lack of central review of pathology speci-mens is another limitation. However, our patient characteristics were similar to those found in the NSABP B-43 trial (which did have central pathol-

ogy review), giving credence to our findings. We must also point out that the definitions for HER2 positivity have changed over time. In 2007, the defi-nition of HER2 positivity was > 30% of tumor cells positive by immunohistochemistry (IHC) or a ratio of HER2 to CEP17 of > 2.2 by in-situ hybridization (ISH) [34]. In 2013, this definition was adjusted to > 10% of tumor cells positive by IHC, which was consistent with the entry criteria for trials examin-ing the role of trastuzumab [34]. Alternatively, for ISH, a HER2/CEP17 ratio of > 2 (depending on the number of signals per cell) was used as a cut-off for HER2 positivity [34]. Additional changes to the guidelines were made in 2018 [35]. Given, the generally lower thresholds for HER2 positivity in these refinements, the number of DCIS patients defined as HER2 positive would be expected to in-crease. The impact this would have on the benefit of HER2-directed targeted therapy is unclear.

conclusions

In the treatment of HER2-positive DCIS pa-tients, the presumed receipt of HER2-directed tar-geted therapy was associated with an improvement in OS. This survival benefit remained statistically significant on multivariable analysis. This study is the largest study of HER2 positive DCIS patients to date, and our findings highlight the need for addi-tional prospective data; we eagerly await the results of the currently ongoing clinical trials on this topic.

conflict of interestThe authors declare that no conflicts of interest exist.

FundingThere are no financial disclosures for the authors.

DisclaimersPresented in part as an abstract at the 2018 San Antonio Breast Cancer Symposium.

acknowledgementsNone.

DeclarationsThere was no funding for this study. The authors report no conflicts of interest. This study follows the principles of the Declaration of Helsinki. As



all patient information in the NCDB database is de-identified, this study was exempt from institu-tional review board evaluation.

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research paper




Address for correspondence: Casey Liveringhouse, Radiation Oncology Department, Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612, tel: (813) 745-5134; e-mail: [email protected]

Phase I dose escalation trial of stereotactic radiotherapy prior to robotic prostatectomy in high risk prostate cancer

Casey Liveringhouse1, Austin Sim1, Kosj Yamoah1, 3, Michael Poch2, Richard B. Wilder5, Julio Pow-Sang2, Peter A.S. Johnstone1, 4

1Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, United States2Department of Genitourinary Oncology, Moffitt Cancer Center and Research Institute, Tampa, United States

3Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, United States4Department of Health Outcomes and Behavior, Moffitt Cancer Center and Research Institute, Tampa, United States

5Oncology Analytics, Plantation, United States

AbstrAct

background: The aim of the study was to investigate the safety of combining preoperative stereotactic body radiotherapy

(sBrT) with robotic radical prostatectomy (rp) for high risk prostate cancer (hrcap). Many patients with hrcap will require

adjuvant or salvage radiotherapy after rp. The addition of preoperative sBrT before rp may spare patients from subsequent

prolonged courses of rT.

Materials and methods: eligible patients had NccN hrcap and received a total of 25 Gy or 30 Gy in five daily fractions of

sBrT to the prostate and seminal vesicles followed by robotic rp with pelvic lymphadenectomy 31-45 days later. The primary

endpoint was prevalence of acute genitourinary (GU) and gastrointestinal (GI) toxicity. secondary endpoints were patient-

reported quality of life (QOL) and biochemical recurrence (Bcr).

results: Three patients received preoperative sBrT to 25 Gy and four received 30 Gy. Median follow-up was 18 months. high-

est toxicity was grade 2 and 3 in six (85.7%) and one (14.3%) patients, respectively. all patients developed grade 2 erectile

dysfunction and 4 of 7 (57%) developed grade 2 urinary incontinence (UI) within a month after surgery. One patient devel-

oped acute grade 3 UI, but there was no grade ≥ 4 toxicity. One patient experienced acute grade 2 hemorrhoidal bleeding.

On QOL, acute GU complaints were common and peaked within 3 months. Bowel symptoms were mild. Two patients with

pN+ experienced Bcr.

conclusions: preoperative sBrT before robotic rp in hrcap is feasible and safe. The severity of acute GU toxicity with preop-

erative sBrT may be worse than rp alone, while bowel toxicity was mild.

Key words: high risk prostate cancer; prostatectomy; stereotactic radiotherapy





ISSN: 1507–1367

Introduction

Much attention has been given to the emergence of stereotactic body radiotherapy (SBRT) as a stan-dard therapy of lung [1, 2] and liver lesions [3, 4]. Considerable literature has emerged regarding de-

finitive therapy of prostate cancer with SBRT [5–8], typically consisting of five fractions of 7.25–8.00 Gy/fraction delivered either daily or every other day. Prior to 2020, this technique involving ul-tra-hypofractionation was recommended in the National Comprehensive Cancer Network (NCCN)

Casey Liveringhouse et al. preoperative sBrT for high risk prostate cancer


Guidelines on prostate cancer for patients with very low risk to favorable intermediate risk disease be-cause of the preponderance of data supporting the addition of hormonal therapy to conventionally fractionated radiotherapy for unfavorable inter-mediate to high-risk disease [9, 10]. Beginning in 2020, the NCCN Guidelines recommend defini-tive SBRT consisting of 7.25–8.00 Gy × 5 fractions as a treatment option for high risk and very high risk prostate cancer. However, preoperative SBRT remains investigational.

Recently, the use of SBRT preoperatively has been described in small trials in the breast [11] and pancreatic [12] cancer literature. This technique is attractive for several reasons: (a) it allows for tis-sue collection both before and after a significant local intervention; (b) it could potentially serve to remove the need for far longer courses of adjuvant [13–15] or salvage [16] RT which may be subse-quently required in up to 54% of patients with ad-verse pathologic features. However, the surgical safety of such a technique is unknown.

The aim of the study was to evaluate the safety and feasibility of preoperative SBRT followed by robotic radical prostatectomy (RP) for patients with high risk adenocarcinoma of the prostate (HRCaP).


This was a single institution phase I, dose-escala-tion trial using a traditional 3 + 3 design. The study was approved by the H. Lee Moffitt Cancer Center and Research Institute’s institutional review board and registered (clinicaltrials.gov NCT02572284); all participants gave their informed consent. Patients were staged and assessed for eligibility based on their pre-treatment clinical characteristics rather than their pathological characteristics. They were eligible if they had: 1) Gleason score 4 + 4 or 4 + 5 adenocarcinoma on prostate biopsy; 2) ≤ 4 cores with grade group (GG) 4–5 adenocarcinoma; and 3) ≤ cT3aN0M0 stage IIIC disease. Patients under-went pre-study bone scans and pelvic imaging to rule out obvious metastases. Magnetic resonance imaging of the prostate/pelvis was not required. All procedures and pathology review were performed at the Moffitt Cancer Center.

Prevalence of acute toxicity according to Com-mon Terminology Criteria for Adverse Events (CT-CAE v4 form) was the primary endpoint. Second-

ary endpoints included patient reported quality of life (QOL) measures on the American Urology Association Symptom Index (AUA) and Expanded Prostate Cancer Index Composite (EPIC) patient questionnaires, as well as biochemical recurrence (BcR). QOL surveys and toxicity assessments were recorded at baseline, one month after SBRT, monthly after RP for three months, then every three months thereafter.

SBRT was delivered in five fractions over one week and prescribed to the planning target volume (PTV) with RP performed 31–45 days post-RT, depending on operating room availability. All pa-tients had 3–4 gold fiducial seeds placed in the prostate under transrectal ultrasound guidance prior to treatment planning by commuted tomog-raphy (CT). SBRT dosimetry constraints are out-lined in the Appendix. The lowest daily dose used was 5.00 Gy per fraction delivered to the PTV based on published data: 5.00 Gy × 5 followed by surgery has been shown to be safe in rectal cancer [17, 18]. Three patients were treated at this dose level. If one (i.e., ≥ 33%) of the three planned pa-tients experienced a dose-limiting toxicity (DLT), defined as CTCAEv4 grade ≥ 3 toxicity attributable to preoperative SBRT alone or preoperative SBRT and surgery, then three additional patients would have been treated at this level with dose escalation only if there were no additional DLT. No DLT was noted at a daily dose of 5.00 Gy, so the dose was escalated to 6.00 Gy for the next three patients. While no DLT was observed at the 6.00 Gy dose, there were reports of such toxicities at the 7.00 Gy dose in patients being treated on a similar trial at another institution (Daniel Spratt, University of Michigan, unpublished data), so one additional patient was treated at 6.00 Gy and the trial was closed.

Patients with positive surgical margin (PSM), seminal vesicle invasion (SVI), or extraprostatic extension (EPE) on the prostatectomy specimen were followed without additional radiotherapy to the prostate bed since they had already received the maximal radiotherapy dose. For the purpose of the protocol, we considered this would be analogous to a situation where a patient receives postoperative radiotherapy to the prostatectomy bed for disease progression after PSM, SVI, or EPE. Postopera-tive diagnostic prostate specific antigen (PSA) was monitored every 3–6 months.



If a patient developed recurrent prostate can-cer, defined as an increase in PSA ≥ 0.2 ng/mL post-prostatectomy [19] , he was not eligible for further local RT, although patients were eligible for radiotherapy to sites other than the prostatectomy bed, e.g., distant metastases. Patients who devel-oped recurrent prostate cancer after preoperative SBRT and RP were evaluated by a medical oncolo-gist for active surveillance versus androgen depriva-tion therapy (ADT).

results

patient characteristicsBaseline characteristics are detailed in Table 1.

The median time to RP after completion of SBRT was 35 days (range 31–45). Post-operative GS ranged from 7–9, and five patients (71.4%) had GS downgraded from 8 on prostate biopsy to 7 on RP. The median pre-treatment PSA was 8.40 ng/mL (range 5.93–51.70). Two patients had 2–3 high-risk features: one had GG 5 and a preoperative PSA >20 ng/mL; another had GG 5, a preoperative PSA > 20 ng/mL and cT3a disease. No patient had features of NCCN very high-risk disease. Two patients had pathologically confirmed positive pelvic lymph nodes. Surgical margins were positive in three of seven cases (43%).

physician-reported adverse eventsHighest grade toxicity was grade 2 and 3 in

six (85.7%) and one (14.3%) patients, respective-ly. Prevalence of urinary incontinence (1A) and overall GU toxicity (1B) are summarized in Fig-ure 1. Adverse events occurring in the post-SBRT

period (0-1 month) were mild, most commonly grade 1 cystitis. There was no urinary inconti-nence in the post-SBRT period. All seven patients experienced at least one grade 2 GU event in the acute post-RP period (0–1 month), most com-monly erectile dysfunction (100%). Six patients experienced urinary incontinence within the 2–5-month period following RP, including four patients with grade 2 and one with grade 3, which was the only grade ≥ 3 GU adverse event. Two patients experienced acute GI adverse events, including one grade 1 and one grade 2 hemor-rhoidal bleed, both within 0-1 month following RP. Two patients (28.5%) experienced late ad-verse events within the study period, including one grade 1 erectile dysfunction and one grade 1 urinary incontinence at 5 months, and grade 2 erectile dysfunction at 8 months. All GI and GU toxicities for each individual patient can be seen in the Supplementary Table S1.

patient-reported quality of lifePatient-reported QOL scores were determined

by EPIC and AUA questionnaires at follow-up visits. Patient reported QOL scores closely mir-rored physician assessments of toxicity. Overall AUA score rose from baseline starting within one month of completing SBRT and peaking within 2–5 months following RP (Fig. 2). Complaints of urinary leakage rose from baseline 0–1 months post-RP and were persistent through 6–9 months (Fig. 3A). Total AUA scores correlated closely with the EPIC overall urinary score, which rose from baseline 0–1 months post-RP and peaked between 2–5 months (Fig. 3B). Bowel complaints were mild


PatientAge [yrs]

SBRT dose [Gy]

Days to RP

Gleason Score PSA [ng/mL] StageSurgical margins

F/U [m]

Most recent

PSABiopsy RP Pre-op Post-op Clinical Pathologic

1** 62 25 31 4 + 5 5 + 4 25,33 0,59 cT3a ypT3bN1 (+) 34 1,25

2 54 25 36 4 + 4 3 + 4 7,91 < 0.02 cT1c ypT3aN0 (+) 26 < 0.02

3 58 25 32 4 + 4 4 + 3 t5 8,4 < 0.02 cT1c ypT2cN0 (–) 10 < 0.02

4 64 30 31 4 + 4 4 + 3 t5 8,66 < 0.02 cT1c ypT3aN0 (+) 24 < 0.02

5 64 30 35 4 + 4 3 + 4 5,93 < 0.02 cT2b ypT2aN0 (–) 17 < 0.02

6 58 30 36 4 + 4 3 + 4 5,94 < 0.02 cT2a ypT3aN0 (–) 18 < 0.02

7** 66 30 45 4 + 5 4 + 5 51,7 3,69 cT1c ypT3aN1 (–) 12 < 0.02

F/U — follow-up; m — months; sBrT — stereotactic body radiotherapy; rp — radical prostatectomy; psa — prostate specific antigen; **patient experienced biochemical recurrence

https://journals.viamedica.pl/rpor/article/view/RPOR.a2021.0027#supplementaryFiles



and peaked within one month following RP, and then recovered to baseline (data not shown).

Oncologic outcomesTwo patients developed BcR (Tab. 1, patient 1 and

patient 7). Each patient who experienced BcR had GG 5 on prostate biopsy, pre-treatment PSA > 25 ng/mL with detectable post-operative PSA, and pathologically positive pelvic lymph nodes. Patient 1 was treated to the 25 Gy dose level, had ypT3b disease with PSM, and post-operative PSA of 0.59

which rose to 0.78. Patient 7 was treated to the 30 Gy dose level, had ypT3a disease with negative surgical margins, and post-operative PSA of 3.69 which rose to 7.15. Neither had evidence of distant metastasis on CT scans of the chest, abdomen and pelvis, or on radionuclide bone scans. Both were given ADT with leuprolide and bicalutamide after multi-disciplinary evaluation and achieved an un-detectable PSA.

Discussion

The present study reports short-term results of a phase I dose-escalation protocol investigating the safety of preoperative SBRT to 25 or 30 Gy in 5 daily fractions consisting of 5–6 Gy perfraction, followed by robotic RP with pelvic lymph node dissection for HRCaP. With a median follow-up of 18 months, all seven patients experienced some degree of mild to moderate acute post-operative GU or GI tox-icity, while two patients (28.5%) experienced late grade 1 or grade 2 events. Two patients, both with pre-treatment PSA > 20 ng/mL, GG 5 and pN+ disease, experienced BcR. The moderate toxicity profile suggests that this combined modality treat-ment paradigm is feasible and safe for patients with HRCaP.

There is increasing interest in combining pre-operative RT followed by RP for high-risk disease. Several clinical trials evaluating the safety of such

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Figure 1. A. prevalence of ≥ G1 or ≥ G2 urinary incontinence; b. prevalence of any ≥ G1 or ≥ G2 genitourinary adverse event

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Figure 2. Mean (± standard error), minimum, and maximum total aUa scores



an approach are currently active or completed. Re-cently published short-term results of a similar trial of 11 patients treated with preoperative SBRT to 24 Gy in three fractions over five days to the prostate and seminal vesicles followed by RP showed the highest GU toxicity of grade 2 and grade 3 in four (36.4%) and two (18.2%) patients, respectively [20]. The authors reported that one patient had grade 2 and two patients had grade 3 urinary incontinence, and at 12 months, the only grade ≥ 2 toxicity was incontinence. Another similarly designed trial of preoperative RT to the prostate alone to 25 Gy in five daily fractions in 15 patients with favorable intermediate to high-risk disease reported that 40% developed late grade 3 vesicourethral anastomotic stricture, urinary incontinence, or both [21, 22]. While that trial has considerably longer follow-up of 12.2 years, 11 of the 12 late GU events occurred within two years. Differences in treatment tech-nique may account for the increased rate of late grade 3 adverse events compared to the present study, as 14 of 15 patients in the Glicksman trial were treated with three-dimensional-conformal RT techniques, which has been associated with in-creased toxicity compared to modern techniques such as SBRT [23]. Further, the median time to RP following RT was just six days, compared to 14 days in the study by Parikh et al. and 35 days in the present study. It is possible that the interval between neoadjuvant RT and surgery may affect the risk for complications, as has been shown for

rectal cancer [24]. Another published trial in the preoperative setting included twelve men treated with preoperative RT to a max dose of 54 Gy to the prostate and seminal vesicles and 45 Gy to the pel-vic lymph nodes in 1.8 Gy per fraction. The authors reported moderate GU toxicity, with late grade ≥ 2 events in 42%, including 17% with symptomatic urinary stricture requiring dilation, similar to our results, allowing for differences in sample size [25]. While small, the present results add to the grow-ing literature that combined modality treatment with preoperative SBRT followed by RP with pelvic lymph node dissection is feasible and safe but may result in increased severity of urinary incontinence compared to RP alone.

The risk of GI or GU adverse events for prostate cancer patients treated with preoperative RT ap-pears to be similar to patients treated with post-op-erative RT in phase III clinical trials. EORTC 22911 reported that the rate of late ≥ 2 GU toxicity was 21.3% in patients treated with post-operative RT, and 70.8% had late toxicity of any kind or grade [13]. Hackman et al. reported that nearly all pa-tients treated with post-operative RT experienced late toxicity, including 91% with grade 2 and 56% with grade 3, primarily urinary disorders and erec-tile dysfunction [14]. The ARO 96-02 trial is an outlier compared to similar trials, as only one out of 148 patients treated with adjuvant RT had grade 3 toxicity [26]. In the SWOG 8794 study, QOL scores were initially worse for patients treated in

Figure 3. A. Mean (± standard error), minimum, and maximum epIc frequency of urine leakage scores; b. Mean (± standard error), minimum, and maximum epIc overall urinary function scores

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the RP plus adjuvant RT arm compared to the RP alone arm. However, after two years the patients treated with adjuvant RT had superior QOL [15, 27]. In these phase III trials of adjuvant RT, the rate of urinary toxicity was higher for RP plus RT than for RP alone, though adjuvant RT was not al-ways associated with worse GI toxicity. Given that cause-specific survival after EBRT plus ADT or RP alone remains high, and many patients with HR-CaP treated with RP will not require adjuvant or salvage therapy [28–30], a high safety threshold is needed for a combined modality approach.

Two patients in this trial were found to have pathologically positive lymph nodes, raising the question of optimal management for pN+ disease in this setting. Retrospective data suggest the ad-dition of adjuvant pelvic RT to ADT may improve outcomes in selected patients with pN+ disease af-ter RP [31–34]. In the current protocol, the role of ADT was left to provider discretion, while RT was delivered preoperatively to the prostate and seminal vesicles only without treatment of regional lymphatics. In the study reported by Glicksman et al., two patients were found to have regional nodal disease after RP, and they were treated with ADT without additional radiotherapy [21, 22]. The two patients in the study by Parikh et al. who had patho-logically positive pelvic lymph nodes were treated more aggressively with ADT and additional RT to the pelvic lymph nodes based upon multi-disciplin-ary recommendation [20]. The addition of adjuvant RT targeted at lymph nodes should be carefully considered and determined in multi-disciplinary fashion, as the population most likely to benefit has not been defined and carries the risk for signifi-cant increase in toxicity. In the absence of positive lymph nodes or biochemical recurrence, combin-ing preoperative SBRT with RP may allow patients to avoid ADT altogether.

A theoretical advantage of preoperative SBRT is that it might ablate extra-prostatic microscopic disease, which could improve the ability to achieve negative surgical margins with current nerve-spar-ing surgical techniques. The reported rates of posi-tive margins following RP vary substantially from 11–48%, but laparoscopic robot-assisted RP has been shown to decrease the rate compared to con-ventional laparoscopic RP [35]. Glicksman et al. re-ported that seven of 14 (50%) patients had positive margins after preoperative RT, which the authors

felt was related to the short timeframe between RT and surgery [21, 22]. However, the rate of positive surgical margin was 43% in the present study, de-spite significantly longer interval between RT and surgery. Thus, preoperative SBRT may not signifi-cantly alter the rates of positive surgical margin.

A further theoretical advantage for the preop-erative delivery of SBRT is that it allows for tis-sue examination afterwards, which could improve prognostication and therapeutic decision making, as has been extensively demonstrated in the breast cancer literature for neoadjuvant chemotherapy [36]. Multiple studies of neoadjuvant hormonal or systemic therapy have demonstrated the rarity of pathologic complete response in high risk pros-tate cancer (reviewed in [37]). While we did not evaluate specifically for pathologic response, 71% of patients in our trial had a downgraded GS from 8 on prostate biopsy to 7 on RP. This phenomenon has been previously described [38, 39] and has been associated with improved outcomes [40]. Tissue evaluation after RT can also provide insight into tumor biology and the effects of RT delivery. The prostate cancer tissue obtained from RP of patients who received preoperative RT showed evidence of long-term growth arrest via induction of p53 path-ways [22]. Similarly, evaluation of prostate tumor samples for the presence of infiltrating immune cells after preoperative SBRT showed infiltration of myeloid, rather than lymphoid immune pop-ulations [41]. In the burgeoning era of precision medicine, continued study of tumor response to neoadjuvant therapy should remain a priority, as such information may be useful to further optimize individual therapy in prostate cancer.

conclusion

The present study demonstrates preoperative SBRT followed by robotic RP with pelvic lymph node dissection for HRCaP is feasible and safe. Interpretation of results from this trial is limited by the small sample size and short median follow-up of 18 months. Longer follow-up is required to eval-uate the incidence of late toxicity, while subsequent studies are required to determine the efficacy in comparison to established therapeutic options and to define the patient population, if any, who would most benefit from this combined modality treat-ment regimen.



conflicts of interestNone declared.


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research paper




Address for correspondence: Georgina Fröhlich, National Institute of Oncology, Centre of Radiotherapy, Ráth György Street 7–9, H-1122 Budapest, tel: (+36) 1-224-8600, fax: (+36) 1-224-8620; e -mail: [email protected]

Comparative dosimetrical analysis of intensity-modulated arc therapy, CyberKnife therapy and image-guided interstitial

HDR and LDR brachytherapy of low risk prostate cancer

Georgina Fröhlich1, 2, Péter Ágoston1, 3, Kliton Jorgo1, 3, Gábor Stelczer1, Csaba Polgár1, 3, Tibor Major1, 3

1Centre of Radiotherapy, National Institute of Oncology, Budapest, Hungary2Faculty of Science, Eötvös Loránd University, Budapest, Hungary

3Department of Oncology, Faculty of Medicine, Budapest, Hungary

AbstrAct

background: The objective of the study was to dosimetrically compare the intensity-modulated-arc-therapy (IMaT), cyber-

Knife therapy (cK), single fraction interstitial high-dose-rate (hDr) and low-dose-rate (LDr) brachytherapy (BT) in low-risk

prostate cancer.

Materials and methods: Treatment plans of ten patients treated with cK were selected and additional plans using IMaT, hDr

and LDr BT were created on the same cT images. The prescribed dose was 2.5/70 Gy in IMaT, 8/40 Gy in cK, 21 Gy in hDr and

145 Gy in LDr BT to the prostate gland. eQD2 dose-volume parameters were calculated for each technique and compared.

results: eQD2 total dose of the prostate was significantly lower with IMaT and cK than with hDr and LDr BT, D90 was 79.5

Gy, 116.4 Gy, 169.2 Gy and 157.9 Gy (p < 0.001). however, teletherapy plans were more conformal than BT, cOIN was 0.84, 0.82,

0.76 and 0.76 (p < 0.001), respectively. The D2 to the rectum and bladder were lower with hDr BT than with IMaT, cK and LDr

BT, it was 66.7 Gy, 68.1 Gy, 36.0 Gy and 68.0 Gy (p = 0.0427), and 68.4 Gy, 78.9 Gy, 51.4 Gy and 70.3 Gy (p = 0.0091) in IMaT, cK,

hDr and LDr BT plans, while D0.1 to the urethra was lower with both IMaT and cK than with BTs: 79.9 Gy, 88.0 Gy, 132.7 Gy and

170.6 Gy (p < 0.001). D2 to the hips was higher with IMaT and cK, than with BTs: 13.4 Gy, 20.7 Gy, 0.4 Gy and 1.5 Gy (p < 0.001),

while D2 to the sigmoid, bowel bag, testicles and penile bulb was higher with cK than with the other techniques.

conclusions: hDr monotherapy yields the most advantageous dosimetrical plans, except for the dose to the urethra, where

IMaT seems to be the optimal modality in the radiotherapy of low-risk prostate cancer.

Key words: prostate cancer; intensity-modulated arc therapy; cyberknife therapy; interstitial high-dose-rate brachytherapy;

interstitial low-dose-rate brachytherapy





ISSN: 1507–1367

Introduction

Prostate cancer is the second most common can-cer in men worldwide and the fourth most com-monly occurring cancer overall. There were 1.3 mil-lion new cases in 2019. It is estimated that 33,000 deaths from this disease will occur this year [1]. The standard of care in the curative treatment of low-

and selected intermediate-risk prostate cancer is external beam radiotherapy with intensity-modu-lated arc therapy (IMAT) or with CyberKnife (CK) technique or interstitial high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy (BT) [2].

Since the α/β value of prostate tumour is low, dose escalation has an essential role in the devel-opment of all radiotherapy modalities [3–5]. The

mailto:[email protected]

Georgina Fröhlich et al. Dosimetric comparison of prostate IMaT, cyberKnife, hDr and LDr BT


more complex the techniques, the more capable they are of escalating the dose to the tumour, while sparing the organs at risk (OARs). The IMAT tech-nique results improved OAR sparing with accept-able planning target volume (PTV) coverage [6]. Stereotactic radiotherapy with CyberKnife dem-onstrated favourable tumour control, better patient reported quality of life and lower levels of toxicity [7]. The use of BT, as a boost, has been linked with improved biochemical progression free and overall survival [8, 9]. What is more, modern LDR mono-therapy approach results in improved quality of life, as a consequence of lower acute urinary and rectal toxicity [11], with the dose coverage of the target volume (D90, the minimum dose delivered to 90% of the prostate) correlating with local tumour con-trol [11], and the dose of the most exposed part of the OARs with normal tissue toxicity [12].

Despite the wide-spread application of these state-of-the-art techniques, no detailed analysis of all of these treatment techniques exists. Leszczyński et al. compared the dose distributions of intensity modulated prostate radiotherapy versus the IMAT technique [13]. Yang et al. investigated the dosimet-ric differences among IMAT, HDR and LDT BT for 10 patients, but HDR BT was not a single fraction monotherapy in their study [14]. Andrzejewski et al. studied the feasibility of dominant intraprostatic lesion (DIL) boosting using IMAT, proton therapy or HDR BT for 12 patients [15]. Georg et al. exam-ined the optimal radiotherapy technique among IMAT, proton-, carbon-ion therapy and HDR or LDR BT, but HDR BT was not a single fraction monotherapy for the 10 studied patients [2]. Mor-ton et al. studied HDR and LDR BT techniques against IMAT external beam therapy [16]. Fuller et al. dosimetrically compared CK and HDR BT plans for their first 10 patients treated with CK, but not all of the OARs relevant to CK treatment were evalu-ated [17]. King examined HDR versus LDR BT as monotherapy and boost in a radiobiological model [18]. Skowronek made a practical comparison be-tween HDR and LDR prostate BT [19].

At our institute, all of the four widely used treat-ment techniques are available. To take the advan-tage of this situation, the aim of the present study is a detailed dosimetric comparison of intensity-mod-ulated arc therapy, CyberKnife therapy, interstitial high-dose-rate and low-dose-rate brachytherapy, as monotherapy in low-risk prostate cancer.


Ten CK plans of patients with organ confined prostate cancer treated at our institute were includ-ed in this study. Selection criteria for treatment were the following: PSA < 15 ng/mL and/or GS ≤ 7 and/or Stage T ≤ 2c [20].

CK treatments were performed with non-co-planar fields using CyberKnife M6 linear accelera-tor (Accuray, Sunnyvale, CA, USA). Gold fiducial markers were implanted into the prostate gland to guide the placement of radiation beams during treatment. The CTV was extended by an isotropic 3 mm margin, 8 Gy was delivered to this prostate PTV in each fraction according to an ongoing phase II prospective trial in our institute. A total of 5 fractions (total dose 40 Gy) were given every second working day. For treatment planning Ac-curay Precision 1.1 treatment planning system (TPS) (Accuray, Sunnyvale, CA, USA) was used. The dose was prescribed to the 80−85% isodoses (Fig 1B). The relative volume of the PTV receiv-ing at least the prescribed dose (V100) had to be at least 95%. The detailed description of our treatment method can be found in our previous publication [21].

On the CT series made for CK treatment plan-ning, additional plans using IMAT, HDR and LDR BT were created using the same contour set. Where urethra was not identifiable on CT im-ages, it was contoured between the bladder and the penile channel using a 15 mm pearl. IMAT plans were made in Eclipse v13.7 TPS (Varian Medical Systems, Palo Alto, USA) with a beam energy of 10 MV using 2 full arcs (Fig. 1A). CTV was extended using an isotropic 5 mm margin. The prescribed dose was 70 Gy, the dose of the daily fractions was 2.5 Gy for the PTV [22]. The protocol of our PROMOBRA study was applied for treatment planning in both HDR and LDR BT plans [23]. The prescribed dose in HDR BT was 21 Gy (V100 ≥ 95%) to the CTV of the CK plan, as the BT PTV, in a single treatment fraction using Ir-192 radioactive source. HIPO method was used to optimize the plans in the Oncentra Prostate v3.1 TPS (Elekta Brachytherapy, Veen-dendaal, The Netherlands) (Fig. 1C). In LDR BT the prescribed dose was 145 Gy (V100 ≥ 95%) to the same CTV. IPSA optimisation method in the Oncentra Prostate v3.1 TPS (Elekta Brachy-



therapy, Veendendaal, The Netherlands) was used to calculate the virtual positions of the I-125 iso-topes (Fig. 1D). The detailed description of our treatment method can be found in our previous publications [24–27].

The equivalent dose given in 2 Gy fractions (EQD2) was calculated for each technique using the linear-quadratic radiobiological model [28, 29]. The α/β of prostate was assumed 1.5 Gy, while for OARs 3 Gy was used [30, 31]. 1 year was estimated in LDR BT as overall treatment time, as during this time 89% of the prescribed dose is delivered. The

following dose-volume parameters were used for quantitative evaluation of plans:• D90: the minimum dose delivered to 90% of

PTV (Gy);• COIN: conformal index [32];• D0.1(x), D2(x): the minimal dose of the most ex-

posed 0.1 and 2 cm3 of the critical organ x (Gy),where x: rectum (r), urethra (u), bladder (b), hips

(h), sigmoid (s), bowel bag (bb), testicles (t) and pe-nile bulb (p).

Friedman ANOVA and Fisher-LSD (Least Sig-nificant Difference) post-hoc tests were used (Sta-

Figure 1. axial cT slide (left) and 3D reconstruction (right) of a prostate intensity-modulated arc therapy (A), cyberKnife (b), an interstitial high-dose-rate prostate brachytherapy (c) and an interstitial low-dose-rate prostate brachytherapy plan (D). red: prostate, yellow: prostatic urethra, light green: bladder, brown: rectum, dark brown: sigmoid, khaki: bowel bag, slate blue: femoral heads, lavender: penis, purple: penile bulb, orange: testicles

a

B

c

D



tistica 12.5, StatSoft, Tulsa, OK, USA) to compare EQD2 dose-volume parameters of IMAT, CK, HDR and LDR BT techniques.

results

The mean volume of the PTV was 105.7 cm3 (42.2–189.3 cm3) in IMAT, 85.5 cm3 (31.5–159.2 cm3) in the CK and 61.8 cm3 (19.8–126.2 cm3) in both BT plans (which is equal to the original CTV) on average. We found that EQD2 total dose of the prostate was significantly lower with IMAT and CK than with HDR and LDR BT, D90 was 79.5 Gy, 116.4 Gy, 169.2 Gy and 157.9 Gy (p < 0.001). How-ever, IMAT and CK plans were more conformal than BT plans, COIN were 0.84, 0.82, 0.76 and 0.76 (p < 0.001).

In our comparison, the D2 to the rectum and bladder were lower with HDR BT than with IMAT, CK and LDR BT, it was 66.7 Gy, 68.1 Gy, 36.0 Gy and 68.0 Gy (p = 0.0427), and 68.4 Gy, 78.9 Gy, 51.4 Gy and 70.3 Gy (p = 0.0091) in IMAT, CK, HDR and LDR BT plans, while D0.1 to the urethra was lower with both IMAT and CK than with both BT modalities: 79.9 Gy, 88.0 Gy, 132.7 Gy and 170.6 Gy (p < 0.001), respectively. D2 to the hips was higher with IMAT and CK, than with BTs: 13.4

Gy, 20.7 Gy, 0.4 Gy and 1.5 Gy (p < 0.001), while D2 was higher to other organs with CK, than with the other techniques: 1.1 Gy, 17.9 Gy, 0.8 Gy and 2.8 Gy (p < 0.001) for the sigmoid; 0.9 Gy, 11.2 Gy, 0.7 Gy and 0.8 Gy (p < 0.001) for the bowel bag; 0.4 Gy, 20.7 Gy, 0.6 Gy and 4.2 Gy (p = 0.0017) for the testicles; and 4.9 Gy, 10.3 Gy, 1.7 Gy and 3.2 Gy (p = 0.0057) for the penile bulb in IMAT, CK, HDR and LDR BT plans. The detailed results can be found in Table 1.

Discussion

Dose escalation has a fundamental role in the radiotherapy of low- and selected intermediate-risk prostate cancer [3–5]. Several high-tech telether-apy and BT techniques are widely used, such as image-guided and intensity-modulated teletherapy, arc therapy, stereotactic radiotherapy with linear accelerators or CyberKnife and interstitial HDR or LDR BT [2, 3, 6–9, 11, 12]. In the present study, all of the four widely used radiotherapy techniques (IMAT, CK, HDR and LDR BT) were compared dosimetrically using the linear-quadratic radiobio-logical model.

Although these techniques rapidly developed parallelly, the dosimetrical differences were con-

table 1. Mean eQD2 total doses of intensity-modulated arc therapy (IMaT), cyberKnife (cK), high-dose-rate (hDr) and low--dose-rate (LDr) brachytherapy of prostate cancer. D90: the minimum dose delivered to 90% of prostate, cOIN: conformal index, D0.1(x), D2(x): the minimal dose of the most exposed 0.1 and 2 cm3 of ‘x’ organ at risk, where x are rectum (r), urethra (u), bladder (b), hips (h), sigmoid (s), bowel bag (bb), testicles (t) and penile bulb (p). *Friedman aNOVa **Fisher-LsD post-hoc test

EQD2 IMAT CK HDR LDR p* **post hoc

D90 [Gy] 79.5 116.4 169.2 157.9 < 0.001 IMaT, cK

cOIN 0.84 0.82 0.76 0.76 < 0.001 IMaT-LDr, hDr

D0.1(r) [Gy] 86.4 80.0 55.3 93.5 0.0280 hDr, LDr

D2(r) [Gy] 66.7 68.1 36.0 68.0 0.0427 hDr

D0.1(u) [Gy] 79.9 88.0 132.7 170.6 < 0.001 all

D2(b) [Gy] 68.4 78.9 51.4 70.3 0.0091 hDr

D0.1(h) [Gy] 17.3 26.5 0.6 2.1 < 0.001 IMaT, cK

D2(h) [Gy] 13.4 20.7 0.4 1.5 < 0.001 IMaT, cK

D0.1(s) [Gy] 1.3 20.7 0.9 3.8 < 0.001 cK

D2(s) [Gy] 1.1 17.9 0.8 2.8 < 0.001 cK

D0.1(bb) [Gy] 1.1 12.1 1.1 1.3 < 0.001 cK

D2(bb) [Gy] 0.9 11.2 0.7 0.8 < 0.001 cK

D0.1(t) [Gy] 0.4 23.0 0.7 4.7 0.0006 cK, LDr

D2(t) [Gy] 0.4 20.7 0.6 4.2 0.0017 cK, LDr

D0.1(p) [Gy] 15.2 23.7 3.2 5.0 0.0014 IMaT, cK

D2(p) [Gy] 4.9 10.3 1.7 3.2 0.0057 IMaT, cK



spicuous from the beginning. Leszczyński et al. have pointed out that the treatment delivery time is significantly reduced using the IMAT technique compared to intensity-modulated radiotherapy [13]. Yang et al. [14] concluded that HDR and LDR BT significantly reduce the dose to the rectum, bladder and femoral heads compared with IMAT. The mean EQD2 dose to the urethra was 80.3 Gy in IMAT, 70.2 Gy in HDR and 104.9 Gy in their LDR BT plans. They stated that for localised prostate cancer, HDR BT provides the advantage in sparing the urethra compared with IMAT and LDR; how-ever, HDR BT was not a single-fraction treatment in this study. Our results are not in agreement with this, the EQD2 dose to the urethra was the lowest in the IMAT plans, D0.1 was 79.9 Gy. It was higher, 88.0 Gy, with the CK technique, while still higher using HDR or LDR BT: 132.7 Gy and 170.6 Gy (all of the differences are significant). However, it has to be mentioned, that the relative D0.1 dose to the urethra — in proportion to the EQD2 D90 dose — was 100.5% in IMAT, 75.6% in CK, 78.4% in HDR and 108.0% in the LDR plans. In terms of the other OARs sparing, HDR resulted in the lowest dose. This difference between the studies can be explained by the different fractionation and prescribed dose. Yang et al. used 78 Gy physical dose in 39 fractions in IMAT, 34 Gy in 4 fractions in HDR and 145 Gy in 1 fraction in LDR BT plans and calculated only mean dose of the OARs instead of volumetric doses.

Andrzejewski et al. studied the feasibility of DIL boosting and concluded that higher boost doses were achieved using proton therapy compared to IMAT, keeping doses of major OARs at similar lev-els, but HDR BT was superior to IMAT and proton therapy, both in terms of OAR sparing and boosting of the DIL [15]. EQD2 D50 to DIL were 110.7 Gy, 114.2 Gy and 150.1 Gy in IMAT, proton therapy and HDR BT plans, while the mean dose of the rectal wall was 30.5 Gy, 16.7 Gy and 9.5 Gy, and the mean dose to the bladder wall were 21.0 Gy, 15.6 Gy and 6.3 Gy, respectively. Georg et al. examined the optimal radiotherapy technique in the radio-therapy of localised prostate cancer and stated that HDR and LDR BT techniques were clearly superior in terms of the bladder and rectal wall sparing, in contrast with IMAT, proton- and carbon-ion ther-apy, with the lowest values for HDR BT [2]. How-ever, they did not examine the dose to the urethra.

Based on our comparison, also single fraction HDR monotherapy yields the most advantageous plans, except in terms of the dose to the urethra where IMAT proves to be the optimal modality.

Morton et al. investigated HDR BT against LDR BT and IMAT external beam therapy in a clinical point of view [16]. They concluded that HDR BT enables more consistent implant quality than LDR BT, with evidence of lower acute and late toxicity. Higher disease control rates are also reported with HDR monotherapy than with the IMAT technique. These clinical results are in good agreement with our dosimetrical results. HDR BT resulted in the most optimal treatment plans in terms of both dose coverage of the prostate and the dose to OARs, ex-cept for the urethra.

Fuller et al. pointed out that urethra dose is lower for virtual CK than for virtual HDR BT plans, sug-gesting that the CK technique may more effectively limit urethra dose [17]. Bladder maximum point doses were higher with HDR BT, but bladder dose fall-off beyond the maximum dose region was more rapid with this technique than using CK therapy. Our study added a new result to this conclusion, specifically using IMAT the dose to the urethra is lower than CK and both BT modalities.

Based on the radiobiological examination of King, HDR and LDR BT achieve superior tumour control when compared with IMAT using conven-tional doses, and HDR BT might achieve superior tumour control compared with LDR [18]. This re-sult supports the clinical evidence for equivalent outcomes in localised prostate cancer with either HDR or LDR BT. However, HDR BT dose escalation regimens might be able to achieve higher biologi-cal effectiveness and hence improved outcomes in contrast to IMAT. In the same manner, in our plans, higher EQD2 total doses can be reached to the pros-tate with BT techniques than with external radiation techniques, and this dose is the lowest using IMAT.

Skowronek [19] demonstrated that all available clinical data regarding HDR and LDR BT suggests that they are equally effective, stage for stage, in providing high tumour control rates. The important difference in dosimetric control is that HDR doses can be escalated safely providing such a flexibility that does not exist for LDR BT. Our examination also gave one vote for HDR BT, as the most ap-propriate technique of dose escalation in prostate radiotherapy.



It has to be mentioned, that in our study, the virtual BT plans were made on the planning CT of the CK, and this anatomy is not optimal for BT planning. Furthermore, the EQD2 prescribed dose was higher in both BT techniques than in the IMAT and CK plans, as the recommended, clinically used fractionation was applied in our plans. Despite that, HDR BT proved to be the optimal choice in the aspects of sparing most of the OARs beside dose coverage of the prostate. LDR BT resulted in higher dose to the OARs with approximately equivalent prescribed dose to the prostate.

conclusions

Using single fraction HDR and LDR BT, total dose of the prostate is higher than with IMAT or CK techniques and, accordingly, dose to the ure-thra is also higher with both BT modalities us-ing the recommended fractionation scheme. Dose to the rectum and bladder is lower with HDR BT than with IMAT, CK and LDR BT, while dose to the sigmoid, bowel bag, testicles and penile bulb are higher with CK than using the other examined techniques. Overall, HDR monotherapy yields the most advantageous plans in the radiotherapy of low- and intermediate risk prostate cancer, except in terms of the dose to the urethra where IMAT proves to be the optimal modality.

conflict of interest This paper ws supported by the János Bolyai Re-search Scholarship of the Hungarian Academy of Sciences and the ÚNKP-18-4 New National Excel-lence Program of the Ministry of Human Capaci-ties.

FundingThis study was supported by the János Bolyai Re-search Scholarship of the Hungarian Academy of Sciences and the ÚNKP-18-4 New National Excel-lence Program of the Ministry of Human Capaci-ties.

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http://dx.doi.org/10.1016/S1538-4721(02)00101-0

http://dx.doi.org/10.1016/S1538-4721(02)00101-0






http://dx.doi.org/10.1007/s12253-019-00623-2


http://dx.doi.org/10.1016/s0167-8140(18)30660-1

http://dx.doi.org/10.1016/s0167-8140(18)30660-1

http://dx.doi.org/10.1007/s00066-010-2081-x


http://dx.doi.org/10.1016/j.brachy.2011.01.003


http://dx.doi.org/MagyOnkol.2011.55.3.170

http://dx.doi.org/MagyOnkol.2011.55.3.170


http://dx.doi.org/10.1016/j.ejmp.2014.08.002


http://dx.doi.org/10.1259/0007-1285-62-740-679


http://dx.doi.org/10.1118/1.598063


http://dx.doi.org/10.1016/s0360-3016(99)00330-2

http://dx.doi.org/10.1016/s0360-3016(99)00330-2


http://dx.doi.org/10.3109/0284186X.2012.719635

http://dx.doi.org/10.3109/0284186X.2012.719635


http://dx.doi.org/10.1016/s0360-3016(97)00732-3



research paper




Address for correspondence: Konstantin Gordon, Ph.D. Senior Researcher, Radiation Oncologist , Department of Proton Therapy, A. Tsyb Medical Radiological Research Centre, 249036, Korolev str. 4, Obninsk, Russia, tel: 0079105184148; e-mail: [email protected]; [email protected]

Proton re-irradiation of unresectable recurrent head and neck cancers

Konstantin Gordon 1, Igor Gulidov2, Alexey Semenov1, Olga Golovanova3, Sergey Koryakin3, Tatyana Makeenkova1, Sergey Ivanov4, Andrey Kaprin5

1Department of Proton and Photon Therapy, A. Tsyb Medical Radiological Research Center, Obninsk, Russia 2Radiation Therapy Department, A. Tsyb Medical Radiological Research Center, Obninsk, Russia

3Radiophysics Department, A. Tsyb Medical Radiological Research Center, Obninsk, Russia4A. Tsyb Medical Radiological Research Center, Obninsk, Russia

5National Medical Research Center of Radiology, Obninsk, Russia

AbstrAct

background: This study presents a retrospective analysis (efficacy and toxicity) of outcomes in patients with unresectable

recurrence of previously irradiated head and neck (h&N) cancers treated with proton therapy. Locoregional recurrence is the

main pattern of failure in the treatment of h&N cancers. proton re-irradiation in patients with relapse after prior radiotherapy

might be valid as promising as a challenging treatment option.

Materials and methods: From November 2015 to January 2020, 30 patients with in-field recurrence of head and neck cancer,

who were not suitable for surgery due to medical contraindications, tumor localization, or extent, received re-irradiation with

intensity-modulated proton therapy (IMpT). sites of retreatment included the aerodigestive tract (60%) and the base of skull

(40%). The median total dose of prior radiotherapy was 55.0 Gy. The median time to the second course was 38 months. The me-

dian re-irradiated tumor volume was 158.1 cm3. patients were treated with 2.0, 2.4, and 3.0 GyrBe per fraction, with a median

equivalent dose (eQD2) of 57.6 Gy (a/b = 10). radiation-induced toxicity was recorded according to the rTOG/eOrTc criteria.

results: The 1- and 2-year local control (Lc), progression-free survival (pFs), and overall survival (Os) were 52.6/21.0, 21.9/10.9,

and 73.4/8.4%, respectively, with a median follow-up time of 21 months. The median overall survival was 16 months. acute

grade 3 toxicity was observed in one patient (3.3%). There were five late severe side effects (16.6%), with one death associated

with re-irradiation.

conclusion: re-irradiation with a proton beam can be considered a safe and efficient treatment even for a group of patients

with unresectable recurrent h&N cancers.

Key words: re-irradiation; proton therapy; head and neck cancer; disease control; toxicity; unresectable





ISSN: 1507–1367

Introduction

Head and neck (H&N) cancers are among the most common cancers, accounting for more than 500,000 new cases, with around 300.000 deaths

each year [1]. Despite treatment intensification in the last decades, the 5-year overall survival still varies between 40% to 50% [2]. Most patients have a high risk of locoregional recurrence or sec-ond metachronous tumors occurring marginal or



https://orcid.org/0000-0002-3146-5615



close to previously irradiated volume [3, 4]. Sur-gery as a salvage option for relapse is considered to be highly efficient, with 5-year overall survival approaching 40% [5]. Surgery can provide addi-tional benefit by removing radio- and chemore-sistant tumor cells that create a higher possibility of a combined cure. However, many patients are not candidates for surgical approaches because of the recurrent tumor extent or medical contrain-dications [6, 7]. With chemotherapy alone, which has been the most common option for inoperable patients, the response rate is relatively low, limited to a median survival time of 7–8 months [8]. Re-ir-radiation with conventional or hypofractionation (SBRT) showed promising results as a potentially curative treatment, although increasing severe tox-icities rates up to 40% [9, 10].

While locoregional failure after the second ra-diotherapy (RT) course is still common, some pa-tients might be irradiated again. It has become criti-cally important to spare normal tissue as much as possible, owing to its impact on the quality of life (QoL) and further treatment.

Since recurrence treatment goals are not only to cure the patient but also to provide acceptable QoL, proton therapy (PT) becomes more frequently used as a re-irradiation approach over the last decades [11]. Dosimetric and radiobiological advantages of protons offer better organs at risk sparing and may benefit previously irradiated patients.

In this study, we present a proton therapy with pencil beam results for the second irradiation of in-field recurrence of head and neck cancer in pa-tients who were not eligible to undergo surgery nei-ther before nor after PT, due to comorbidity and/or tumor extent. Disease control, treatment-related toxicity, and influencing factors were analyzed.


A group of 30 patients treated for a local recur-rence of H&N cancer with a proton beam to a pre-viously irradiated site, between November 2015 and January 2020, was approved for retrospective analy-sis by a local institutional review board, including waivers of informed consent due to the retrospec-tive nature of the study. All patients were more than 18 years old, with biopsy-confirmed diagnosis, both at initial treatment and recurrence, with a period from a prior RT of at least six months, and without

signs of severe (grade 3–4) persistent toxicity. All patients included in the study had a minimum of 3 months of follow-up time. Before the treatment, the patient’s medical history and current possible options were discussed at the multidisciplinary tu-mor board.

The second RT course was delivered via a fixed horizontal, spot-scanning proton beam, in a seated position [12]. A daily image-guidance was per-formed with built-in cone-beam computer tomog-raphy (CB-CT). Simulation CT was obtained with-out intravenous contrast, with a 1-mm slice thick-ness. The patient was immobilized using a standard thermoplastic mask. Both MRI with contrast and 18FDG-PET/CT scans in a non-treatment position were obligatorily fused.

If it was possible, previous RT-plans were reg-istered in the treatment planning system (TPS) to the new CT. The problem of radiation therapy in Post-Soviet states is that there are still hospi-tals providing treatment with the 2D technique, via non-multileaf collimator linear accelerators or 60Co-units. So, some of our patients received con-ventional RT. In such a situation, field setup and treatment parameters were reconstructed in TPS, according to the patient’s RT medical records.

The gross tumor volume (GTV) was delineated by a combination of a tumor recognized on MR-im-ages and 18FDG-PET/CT scans, co-registered to the simulation CT. Additionally, we reduced a clinical volume (CTV) to a 5-mm margin adapted to the patient’s CT anatomy by using molecular imaging. For the planning target volume (PTV) generation, the corresponding CTV was expanded by a 3-mm margin to the skull base site, and by 5 mm in the case of the aerodigestive tumor localization, for covering setup uncertainties.

As almost half of our patients had previously received conventional radiotherapy, it was risky to relay reconstructed doses to OARs completely. So, the strategy for critical structures sparring was to reduce the dose as much as achievable [13].

The total doses in the case of prior conformal RT to the OARs were based on QUANTEC group articles and calculated to its biologically effective dose (BED) (a/b = 3) to estimate the risk of toxici-ties in the normal tissues. Serial OARs (i.e., spinal cord, optic nerves, chiasma, and brain stem) were allowed to receive a cumulative dose < 120–125% from its QUANTEC-proposed tolerance, as nerve

Konstantin Gordon et al. proton re-irradiation of unresectable recurrent h&N cancers


tissue was shown to recover 20–25% tolerance after one year from RT [14].

Proton therapy (PT) was delivered once a day, five times per week, by the intensity modulation technique, always supported with CB-CT imaging before each field. PT dose was prescribed to the PTV with a goal of at least 95%. According to the re-irradiation nature and additional CTV margin presence, OAR dose constraints took priority over PTV coverage, in instances where both were not achievable. Relative biological effectiveness (RBE) of 1.1 for protons was assumed. Patients were treat-ed with 2 (n = 3), 2.4 (n = 9) and 3 GyRBE (n = 18) per fraction, with the median EQD2 (a/b = 10) of 57.6 Gy [range, 42.1 to 68.0]. Fractionation sched-ules were based on a tumor volume and a patient’s performance status.

Adjuvant systemic therapy was delivered by the prescriptions of the treating medical oncologist.

All patients were screened first in 4–6 weeks after finishing PT, and then every three months, unless the patient has required another frequency due to progression or severe toxicity. Both MR imaging with intravenous contrast and 18FDG PET/CT, if necessary, were used to estimate the local efficacy, according to RECIST 1.1 criteria. Acute and late side effects were assessed by a radiation oncologist and recorded based on the RTOG/EORTC schema. Late toxicity was defined as an occurred event > 12 weeks after PT end.

statistical methodsClinical endpoints were to evaluate local control

(LC), progression-free survival (PFS), and over-all survival (OS), measured from the time of PT completion (LC, OS) or the date of remission (PFS). Each value was calculated using the Kaplan-Meier method (and reverse K-M for median follow-up time) with analysis performed in GraphPad Prism 8 (p-value < 0.05, assumed as statistically signifi-cant). A log-rank test was applied to a comparison between analyzed factors.

results

patient characteristics and treatment parameters

The median follow-up time from the finishing of proton re-irradiation was 21 months [range, 3 to 25]. Patient, tumor, and treatment characteristics

are described in Table 1. The median time from pre-vious RT was 38 months [range, 8 to 285]. Confor-mal prior radiotherapy received 21 patients (70%). None of the patients were operable, both before and after the PT, due to medical contraindications or re-currence extent, or both factors. Adjuvant systemic treatment (i.e., chemotherapy, target, or immune therapy) was given to 20% (n = 6) of the patients.

Twenty-three (76.7%) of recurrent tumors were squamous cell carcinomas, with 13.3% (n = 4) of adenocarcinomas and 10% (n = 3) having neuro-endocrine histology, all of them localized in the field of the first RT course. Re-irradiated sites in-cluded: nasopharynx (n = 10, 33.4%), oral cavity (n = 9, 30%), parotid glands (n = 6, 20%) and maxillary sinuses (n = 5, 16.6%). Two patients (6.6%), with the longest period from the first RT course (126 and 285 months) and morphology differences from the previous diagnosis had a sec-ondary primary tumor. According to the largest

table 1. patient and treatment characteristics

Patient characteristics Number

Total patients 30

Median follow-up time in months 21

Gender

Female 18 (60%)

Male 12 (40%)

Median age in years 62,5

Median Karnofsky score 70

Median prior rT dose in Gray 55

Median interval from initial rT in months 38

conformal prior rT 21 (70%)

Non-conformal prior rT 9 (30%)

histology

squamous cell carcinoma 23 (76.7%)

adenocarcinoma 4 (13.3%)

Neuroendocrine cancer 3 (10%)

retreatment site

aerodigestive tract 18 (60%)

skull base 12 (40%)

pT dosimetry

Median irradiated volume in cm3 158.1

Median D95 90.4

Median BeD (a/b = 10) 69.1

Median eQD2 (a/b = 10) 57.6

rT — radiotherapy; pT — proton therapy; BeD — biologically effective dose; eQD2 — equivalent dose



recurrence tumor extension, all patients were also categorized based on anatomical site: aerodiges-tive tract (n = 18, 60%) and skull base (n = 12, 40%), with a view to obtain more specific report-ing of treatment outcomes.

The median treated tumor volume was 158.1 cm3 [range, 13.2 to 280.1]. Despite prioritizing OAR-sparing over PTV coverage, the median D95 was 90.4% [range, 85.3 to 100]. The example of the proton dose distribution is illustrated in Figure 1.

Treatment outcomes of tumor control were assessed by regular MR imaging and clinical ex-amination, with medical oncologists and surgeons enrolled. For suspicious findings, PET/CT with 18FDG or ultrasound-guided biopsy were used. Ra-

diographic findings were described following the RECIST v1.1 criteria.

Tumor control and outcomesThe 1- and 2-year local control rates were 52.6%

and 21%, respectively (Fig. 2). The median local con-trol was 15 months. Eighteen patients (60%) have a locoregional recurrence. The majority of the recur-rence (n = 15) occurred in-field/marginal, with re-gional node metastasis observed in 3 patients (10%), out of the irradiated field. Only one patient (3.3%) had distant metastasis (in the brain stem). The 1- and 2-year PFS rates were 21.9% and 10.9%, respectively (Fig. 3). The 1-year OS was 73.4%, with a rapid fall in the following year, with a 2-year OS rate of 8.4% (Fig. 4). Meanwhile, one patient had a non-cancer death (myocardial infarction), and one patient died from treatment-related late toxicity (carotid blow-out syndrome). The median overall survival was 16 months. The comparison between retreatment sites showed significant differences in the groups, with skull base localization associated with lower overall survival (hazard ratio 0.40, 95% CI: 0.1590 to 1.020; p = 0.03) (Fig. 5). This occurrence might be linked to PTV coverage decreasing to spare OARs in this com-plicated anatomical area (SB median D95 — 91.3% vs. AD median D95 — 97.7%), though no significant correlation has been confirmed.

Following correlation analyses of recurrent tu-mor histology, systemic therapy, proton irradiation parameters (i.e., total dose, tumor volume, fraction-ation, or time to prior RT), as much as performance status, gender, or age were not significantly associ-ated with outcomes.

Figure 1. representative proton reirradiation plan (IMpT)

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Figure 2. Local control rate after proton re-irradiation (Kaplan-Meir plot)

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Figure 3. progression-free survival after proton re-irradiation (Kaplan-Meier plot)



Treatment-related toxicity All of our patients tolerated proton irradiation

well, without any treatment gaps. Radiation der-matitis was observed in 11 patients, with 2 cases of grade 2 toxicity, and grade 1 in the rest. Mucositis grade 1–3 was recorded in 29 patients: 18 patients had grade 1, and in 10 cases, grade 2 toxicity oc-curred. One patient (3.3%) experienced grade 3 mucositis. Persisting xerostomia after initial radi-ation therapy was observed in 100% of patients. Twenty patients (66.7%) additionally had chew-ing trismus and swallowing difficulties before PT. Nonetheless, none of these patients described an increase in the symptoms after the retreatment. Se-vere late toxicity occurred in 5 cases (16.6%): 3 radiation-induced necrosis (including one tempo-ral lobe damage) and one new incidence of chewing trismus, with one death caused (carotid bleeding), after three months of re-irradiation. The second review of treatment plans showed a possibility of those incidences being due to prior non-conformal treatment with a range of dosimetry uncertainties, and recurrent tumors’ growth close to OARs. No correlations between late toxicity and retreatment side were observed.

Discussion

Thirty inoperable patients with recurrent H&N cancer, treated with IMPT for the second course, were selected for retrospective analysis. For this study group, we evaluated treatment efficacy and related toxicity using IMPT for re-irradiation.

Locoregional recurrence after H&N therapy con-tinues to be the most frequent pattern of failure,

especially in locally advanced tumors, so it causes death in most of the cases. The highest period at risk is the first two years after the treatment, with more than 2/3 incidences [15]. Almost 15% of H&N patients are at risk of developing secondary primary cancer, with an increased incidence rate within long-term survival [7].

Maximal surgical resection remains the treat-ment of choice, with 5-year OS reaching 40% [5, 16]. Janot et al. showed in GORETEC phase III trial adjuvant chemoradiation improved both locore-gional control (p < 0.0001) and disease-free survival (p = 0.01), without significant influence on overall survival (p = 0.50). However, significantly higher toxicity rates were observed (grade 3 in 28% cases, and 39% with late grade 4 complications) [17]. Nev-ertheless, salvage surgery can only be provided for around 30% of all such patients. However, surgical success is always linked with tumor location (better outcomes for laryngeal cancer and neck nodes) and extension, alongside comorbidity [18]. For those patients, who are not operable, chemotherapy alone has only a median survival of 7.4 months, with relatively low impact of cetuximab addition (to 10.1 months) [19]. It is evident that in the final results of most studies dedicated to the H&N re-irradiation, surgery plays a remarkable role. Meanwhile, our cohort’s poor outcomes during the second year cor-respond to the lack of up-front surgery, as all of our patients were inoperable.

Two randomized trials, RTOG 9610 [10] and RTOG 9911 [20], had positive outcomes combining RT and chemotherapy. These studies showed that 1/3 of patients were locoregionally controlled, with 10 to 30% 2-year OS rate, yet with severe toxicities

100

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Figure 4. Overall survival after proton re-irradiation (Kaplan-Meier plot)

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Follow-up in months

Figure 5. Overall survival from retreatment site. aB — aero-digestive tract; sB — skull base; hr = 0.40, 95% cI: 0.1590–1.020; p = 0.0399

Ove

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grade 3–4 observed in around 40% of re-irradiated patients. At the same time, 10% of patients suffered from toxicity-related death.

The most complicated re-irradiation points are persistence radioresistant tumor cells (even after high-dose RT) and reduced tissue tolerance [14, 21, 22]. So, the main challenges in re-irradiation are to determine the actual tumor extent, deliver high doses (> 60 Gy), and spare normal tissue. In the last decade, IMRT-technique shows promising outcomes, with 32% 5-year OS, but with a severe toxicity risk of up to 48% [23]. However, even with IMRT, the high doses cannot be delivered, being met with OAR constraints from the previous ra-diotherapy course. Proton therapy advantages (i.e., precise dose distribution, rapid dose fall, biological and immune features) may benefit H&N patients with recurrence [24].

In 2016, Phan et al. published the retrospective data about proton re-irradiation with 60 patients included, demonstrating 1-year OS 83.8% and 16.7% of grade 3 late toxicity [11]. After complet-ing PT, 58% of the patients received upfront sur-gery, and 73% received concurrent and adjuvant systemic therapy, though without significant con-sequences for the outcomes. The multi-institution-al study by McDonald et al. included 61 patients, re-treated with PT for H&N recurrence or second primary tumor. Authors reported 2-year estimated OS of 32.7%, with a remarkable impact of surgery on outcomes: median OS with salvage surgery was 25.1 months vs. 10.3 months without operation, p = 0.008. Acute grade ≥3 toxicities were seen in 14.7% and 24.6% in the late setting, including three related deaths [25]. A multi-institutional report, published in 2016 by Romesser et al. with 91 pa-tients involved, described a 25.1% risk of failure in 12 months and a favorable toxicity profile.

In our study group, we observed 73.4% of 1-year OS, while all of our patients could not undergo surgery, so the initial prognosis was relatively poor. The relapse patterns are in agreement with other studies: with mostly in-field/marginal recurrences and relatively low risk of distant progression [26]. Bulky tumors (prevailed in our cohort) or CTV > 50 cm3 are shown to be associated with higher toxic-ity and poor outcomes [11, 23]. Though the lower toxicity rate of protons is usually accounted for in its dose distribution, recent experimental studies reported lower expression of factors involved in

lymph- and angiogenesis, inflammation, and im-mune tolerance [27].

Adverse events from re-irradiation play a sig-nificant role in decreasing the QoL in H&N pa-tients. Besides, conventional radiotherapy is asso-ciated with severe complications. Even with novel photon RT approaches, second irradiation still causes a significantly higher toxicity rate. The low toxicity outcomes observed in proton studies are promising, although longer follow-up of long-term survivors is necessary to estimate tissue damage risks related to re-irradiation. A balance between RT-treatment intensification and adverse events is quite challenging in H&N re-irradiation. The rec-ommended re-RT dose for tumor growth control might be ≥ 60–66 Gy, whereas most critical OARs located at the H&N area could already exceed their limits after prior radiotherapy. Furthermore, there is still no consensus about dose constraints for re-irradiation. Chan et al. published data about re-irradiation of recurrent T3/T4 nasopharyngeal cancer, dividing OAR’s limits into absolute (i.e., spinal cord D1cc < 65 Gy or brain stem D1% < 78 Gy) and desirable cumulative doses (e.g., optic nerve 78 Gy, temporal lobe D1cc < 84.5 Gy) [28]. In contrast, some authors maintain more conservative doses (e.g., myelon BED < 100–120 Gy) [9].

Generally, many patients with recurrent H&N cancer may not survive long enough to meet po-tential adverse effects because of low survival chances. We observed only one death related to carotid bleeding, one of the most morbid toxici-ties associated with re-irradiation in the head and neck area [29]. Nevertheless, the carotid artery dose constraints are used mostly for SBRT (with a value from 32.5 to 34.0 Gy for hypofractionation) and rarely assessed in a fractionated RT [30].

As the retreatment of H&N cancers is extreme-ly controversial and complicated, it is essential to define significant prognostic factors to divide patients into several groups, which could guide for therapy choice. Thus, Mattew C. et al., based on the results of IMRT of 412 patients, identified three prognostic groups: 1) >2 years from RT and resected tumor (2-year OS, 61.9%); 2) >2 years from RT and unresected tumor, in good perfor-mance status (2-year OS, 40.0%) and 3) the rest of patients, who do not meet these criteria, with a poor prognosis (2-year, 16.8%) [31]. This classi-fication can potentially help better understand pa-



tient selection for re-RT and adjuvant treatment, following given indicators.

conclusion

Although this study has a limitation in its retro-spective nature, we demonstrate that proton beam therapy can be a safe and effective treatment for patients with recurrent H&N cancers, even with unresectable tumors. Proton’s physical and radio-biological advantages provide a good compromise between delivering higher radiation doses and spar-ing previously irradiated zones. We achieved an ad-equate one-year tumor control with reasonably low rates of toxicity. Meanwhile, further investigations are required in the field of proton re-irradiation (e.g., flash-protons) in combination with novel sys-temic therapy agents for intensification of adjuvant treatment.

conflict of interestsAll authors know of no conflicts of interest associ-ated with this publication.

FundingThere has been no significant financial support for this work that could have influenced its outcome

ethical approvalThe study was approved for a retrospective analysis by a local institution ethics committee, including waivers of patient’s informed consent due to the retrospective nature of the study.

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research paper




Address for correspondence: Jose Luis Lopez Guerra, M.D., Ph.D. Department of Radiation Oncology, Virgen del Rocío University Hospital. Manuel Siurot avenue, s/n. 41013, Seville (Spain), tel: (+34) 95 501 2105, fax: (+34) 95 501 2111; e-mail: [email protected]

A three-dimensional printed customized bolus: adapting to the shape of the outer ear

Gorka Gomez1, Montserrat Baeza2, Juan Carlos Mateos2, Jose Antonio Rivas2, Florencio Javier Luis Simon2, Diego Mesta Ortega3, María de los Ángeles Flores Carrión4, Eleonor Rivin del Campo5, Tomas Gómez-Cía6, 7,

Jose Luis Lopez Guerra3, 6

1Biomedical Informatics, Biomedical Engineering and Health Economy, Institute of Biomedicine of Seville (IBIS)//Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain

2Radiation Physics, University Hospital Virgen del Rocio, Seville, Spain3Department of Radiation Oncology, University Hospital Virgen del Rocio, Seville, Spain

4Department of Radiation Oncology, Juan Ramón Jiménez Hospital, Huelva, Spain 5Department of Radiation Oncology, Tenon University Hospital, Hôpitaux Universitaires Est Parisien,

Sorbonne University Medical Faculty, Paris, France 6Instituto de Biomedicina de Sevilla (IBIS/HUVR/CSIC/Universidad de Sevilla), Seville, Spain

7Department of Plastic Surgery, University Hospital Virgen del Rocio, Seville, Spain

AbstrAct

background: The skin-sparing effect of megavoltage-photon beams in radiotherapy (rT) reduces the target coverage of

superficial tumours. consequently, a bolus is widely used to enhance the target coverage for superficial targets. This study

evaluates a three-dimensional (3D)-printed customized bolus for a very irregular surface, the outer ear.

Materials and methods: We fabricated a bolus using a computed tomography (cT) scanner and evaluated its efficacy. The

head of an alderson rando phantom was scanned with a cT scanner. Two 3D boluses of 5- and 10-mm thickness were de-

signed to fit on the surface of the ear. They were printed by the stratasys Objet260 connex3 using the malleable “rubber-like”

photopolymer agilus. cT simulations of the rando phantom with and without the 3D and commercial high density boluses

were performed to evaluate the dosimetric properties of the 3D bolus. The prescription dose to the outer ear was 50 Gy at 2

Gy/fraction.

results: We observed that the target coverage was slightly better with the 3D bolus of 10mm compared with the commercial

one (D98% 98.2% vs. 97.6%).The maximum dose was reduced by 6.6% with the 3D bolus and the minimum dose increased by

5.2% when comparing with the commercial bolus. In addition, the homogeneity index was better for the 3D bolus (0.041 vs.

0.073).

conclusion: We successfully fabricated a customized 3D bolus for a very irregular surface. The target coverage and dosimetric

parameters were at least comparable with a commercial bolus. Thus, the use of malleable materials can be considered for the

fabrication of customized boluses in cases with complex anatomy.

Key words: three-dimensional printing; bolus; radiation therapy; auricular skin





ISSN: 1507–1367



Introduction

Radiation therapy (RT) is one of the most common treatments for cancer. RT effectively treats cancer by using high-energy beams to pin-point and destroy cancer cells. The interaction between incident high energy photons and elec-trons from the body tissue produce secondary electrons. Chemical reactions induced by these secondary electrons are known as major molec-ular mechanism of RT. Due to kinetic energy transmitted from the photon, deposition of the secondary electron occurs after a few millime-ters of travel in the forward direction from the interaction point. Because there are no interac-tion points upstream from the surface to produce secondary electrons, RT dose of the surface dose is low [1]. Electron conformal therapy has been used for treating superficial cancers, owing to the fact that it results in a specific dose distribu-tion. In addition, the electron beam have a sharp distal fall off, reducing unnecessary irradiation to the underlying healthy normal tissue. How-ever, inhomogeneous dose delivery can occur in the target volume owing to irregularities in the skin surface and varying target depths [2]. Con-sequently, a bolus is widely used to enhance the target coverage for superficial targets.

Several studies have demonstrated the clinical efficacy of the bolus in different settings [3, 4]. The University of Texas M.D. Anderson Cancer Cen-ter [3] reported the outcome of 70 patients with non-metastatic angiosarcoma. Fifty out of 70 pa-tients underwent RT. Tissue equivalent bolus mate-rial was applied to the skin surface to ensure ad-equate dose to the entire thickness of the dermal tissues and to minimize the dose to underlying brain tissue. They conclude that custom wax bolus or another similar device may be necessary to pro-vide adequate dose build up to the skin surface. An Australian study [4] explored the effect of the chest wall bolus technique on chest wall recurrence. This was a retrospective cohort study of 254 patients treated with adjuvant postmastectomy RT between 1993 and 2003. In all, 143 (56%) patients received RT with whole chest wall bolus, 88 (35%) patients with a parascar bolus, and 23 (9%) with no bolus. On multivariate analysis, whole chest wall bolus was found to be a significant predictor for early cessation of RT resulting from acute skin toxicity.

In addition, a failure to complete RT because of acute skin toxicity was associated with chest wall recurrence.

A commercial bolus cannot easily be applied on irregular surfaces, where unwanted air gaps exist between the bolus and body surface, thereby resulting in decreased surface doses. In order to solve this issue, three-dimensional boluses (3D boluses) have been successfully fabricated and ap-plied to Rando phantoms with the use of 3D print-ing technologies [5]. This technique has been used for a variety of medical applications, including educational training tools [6]. In this regard, the application of 3D printing technology to radia-tion oncology has formed a strong research focus [7, 8]. Burleson et al. [7] designed a custom 3D bolus to treat the Rando phantom nose. The agree-ment between measured and calculated values was good, with 86.5% of data points passing gamma requirements of 2 mm distance to agreement and 5% dose difference. In this context, we explore the RT application possibility of a 3D printed bolus made of malleable material for the very irregular shape of the outer ear.


scanning and printing procedure The head of an Alderson Rando phantom (The

Phantom Laboratory, Salem, NY, USA) was uti-lized for the fabrication process. Next, the image data of the phantom were acquired with the use of Toshiba Aquileon LB (Toshiba Medical Systems Corporation) and exported to the workstation. The image data were reconstructed, and a customized 3D bolus was designed and fabricated by a Stratasys Objet260 Connex3 using PolyJet technology (Stra-tasys Ltd., Eden Prairie, MN, USA) with the mal-leable ̀ rubber-like’ photopolymer Agilus (Stratasys, Eden Prairie, MN, USA). 3D boluses of 2 to 10 mm thickness were designed to fit onto the ear. The case was immobilized using a standard S-frame with a thermoplastic mask and clear headrests. Com-puted tomography (CT) simulations of the Rando phantom with and without the 3D and commercial high density boluses were performed to evaluate the dosimetric properties of the 3D boluses. The CT images were acquired with a slice thickness of 2.5 mm contiguously and the outer ear was delineated as the target (15 cc).

Gorka Gomez et al. 3D printed bolus for the ear


Treatment planningIntensity-modulated RT plans were generated

in the Eclipse treatment planning system version 10.0 (Varian Medical System, Palo Alto, CA, USA) with the use of the Dose Volume Optimizer (DVO) optimization algorithm v.10.0 and the calculation Anisotropic Analytical algorithm (AAA) v.10.0. The prescription dose to the target (outer ear) was 50 Gy at 2 Gy/fraction. The treatment machine was a Clinac DHX, 120 MLC millennium with 6 MV beam energy. Dosimetric parameters of 6 plans [2 without bolus, 1 with commercial bolus, and 3 (5-mm, 10-mm, and 10-mm thickness + gel) with 3D printed bolus] were assessed (Tab. 1). The RT plans consisted of 5 sliding window Intensity-Mod-ulated Photon-Beam Therapy (IMRT) fields at gan-try 0º, 35º, 70º, 105º and 140º. The collimator was set to 358º and the dose rate was 300 um/min. The objective functions used were adapted to each case to get the optimal results according to the clinical practice.

To ensure adequate dose coverage, two ap-proaches were “applied”, depending on whether or not there was a bolus. The plans with a bolus were prescribed to the mean dose (Dmean) according ICRU 83 [9]. A virtual target volume without a bo-lus was created excluding the 3 mm closest to the skin surface. For the plan without a bolus, the goal was to cover 95% of the virtual target covered by 95% of the prescription dose. The following do-simetric parameters were estimated for all cases: maximal dose (Dmax), Dmean, minimum dose (Dmin), V95% (volume receiving at least 95% of the prescription dose), dose received by 2% of tar-

get volume (D2), D95, D98, and homogeneity index (HI) proposed in ICRU-83 [9].

Dosimetric characterizationFor this purpose, we designed and printed flat

boluses with different thicknesses. The attenuation and scatter properties of the 3D printed (malleable “rubber-like” photopolymer, Agilus©) and commer-cial (poliorganosiloxano, eXaSkin©) boluses were physically evaluated for a 6-MV clinical photon beam on a water-equivalent RW3 slab phantom in three configurations: without a bolus, with a com-mercial bolus (5 and 10 mm thickness), and with six 3D printed boluses (2 to 10 mm thickness), thus obtaining nine measures. We then selected the 5- and 10-mm 3D boluses for comparison with the commercial bolus. The irradiations were per-formed delivering 300 monitor units (MU), with a dose rate of 400 MU/min, using a 10 × 10 cm2 open field with 0-degree gantry angle at 1000 mm skin-to-source distance (SSD). A Gafchromic EBT3 film (International Specialty Products, Wayne, NJ) were cut (2 × 3 cm) and placed below the boluses providing depth dose measurements. Measurement films were scanned 24 hours after irradiation using a desktop flat-bed transmission Epson Expression Scanner 10000 XL (Epson, Long Beach, CA). The film scanner was operated with a resolution of 72 dpi in the 48-bit red-green-blue (RGB) mode.

physical measurements To evaluate the calculation algorithm AAA for

the 3D bolus, we irradiated a field of 10 cm × 10 cm with 300 MU and the gantry at 90º to get the per-

table 1. Dosimetric parameters of 6 plans (prescribed dose: 50 Gy): 2 without bolus, 1 with commercial bolus, and 3 with three-dimensional (3D) printed bolus

Parameter No bolus No bolus*Commercial

bolus3D bolus (0.5 cm)

3D bolus (1 cm)

3D bolus (1 cm) + gel

Dmax [Gy (%)] 60.5 (121) 59.4 (118.8) 54.2 (108.4) 55 (110) 51.7 (103.4) 51.7 (103.4)

Dmean [Gy (%)] 45.3 (90.6) 52.3 (104.6) 50 (100) 50 (100) 50 (100) 50 (100)

Dmin [Gy (%)] 7.8 (15.6) 40.2 (80.4) 45.2 (90.4) 44.1 (88.2) 47.8 (95.6) 47.9 (95.8)

V95% (%) 55.5 95.3 100 99.6 100 100

D2% [Gy (%)] 56.4 (111) 57 (114) 52.4 (104.8) 52.5 (105) 51.1 (102.4) 51.1 (102.4)

D95% [Gy (%)] 25.2 (112.8) 47.5 (95) 49.2 (98.4) 48.7 (97.4) 49.3 (98.6) 49.3 (98.6)

D98% [Gy (%)] 20.7 (41.4) 46.2 (92.4) 48.8 (97.6) 48.4 (96.8) 49.1 (98.2) 49.1 (98.2)

homogeneity index**

0.787 0.208 0.073 0.083 0.041 0.040

*Virtual target volume without bolus excluding the 3 mm closest to the skin surface; ** homogeneity index (hI) proposed in the International commission on radiation Units and Measurements report 83 [(D2% – D98%)/D50%]. an hI of zero indicates that the absorbed-dose distribution is almost homogeneous



cent depth dose (PDD) profile under the three fol-lowing conditions in the Rando phantom: without a bolus, with a commercial bolus, and with the 3D boluses. Gafchromic EBT3 films (ISP Corporation, Wayne, NJ, USA) were cut and inserted along the horizontal direction in the phantom. After irradia-tion, the films were scanned in the RGB mode with an Epson 10000XL flatbed scanner according to the manufacturer recommendations for the film. The scanned images were analyzed with the use of the Omnipro I’mRT Version 1.7 (IBA Dosimetry, Schwarzenbruck, Germany) package. The calibra-tion curves of the EBT3 film were determined in the red channel. A more detailed description of the film dosimetry with the use of the Gafchromic EBT films was provided in a previous study [10]. For the analysis, film dose measurements were smoothed applying a Gaussian filter 3 × 3 and the percent-age of points that meet the gamma value (5%, 3 mm) < 1 was obtained. The PDD profiles corre-sponding to the measured dose in the EBT film and

the calculated dose in treatment planning system were compared.

results

We fabricated the customized 3D bolus (Fig. 1). CT simulation indicated it fit the ear acceptably (Fig. 2). Due to the irregular shape of the outer ear anatomy, there was some air gap between the bolus and the phantom surface with the commercial bo-lus (Fig. 2). We observed that the target coverage was slightly better with the 3D bolus of 10 mm compared with the commercial one (D98% 98.2% vs. 97.6%; Tab. 1). The maximum dose was reduced by 6.6% with the 3D bolus and the minimum dose increased by 5.2% when comparing with the com-mercial bolus. In addition, the homogeneity index was better for the 3D bolus (0.041 vs. 0.073; Tab. 1).

Table 2 shows the measured doses with the 2–10 mm thickness 3D-bolus as well as those with the 5–10 mm thickness commercial bolus. There was

Figure 1. Three-dimensional (3D) printed customized bolus of the outer ear. A. View of the designed 3D bolus; b. printed result obtained with malleable material; c. smulation scan setup of the bolus on the rando phantom

a B c

a B

Figure 2. computed tomography scan showing (A) commercial bolus, and (b) three-dimensional printed customized bolus for the irregular shape of the outer ear. arrows indicate air gaps



a 4% and 2% difference between the 3D-bolus and the commercial bolus when evaluating the 5 and 10mm thickness, respectively.

Figure 3 shows the isodose lines corresponding to the plans with and without the bolus. We observe

that the target coverage is better with the 3D bolus and it is similar compared with the commercial bolus. Figure 4A shows the dose-volume histogram of the ear with and without the 3D bolus, and Table 1 summarizes the relevant dosimetric parameters

table 2. calculated doses with 2–10 mm thickness 3D-bolus and the measured doses with 5–10 mm thickness commercial bolus.

Bolus type Thickness [mm] Mean dose [cGy] Standard deviation [cGy]

Three-dimensional printed

0 69.1 2.2

2 212.3 3.0

4 271.7 2.7

5 305.3 6.5

6 303.6 4.2

8 310.6 4.5

10 320.9 4.1

commercial5 318.1 6.3

10 313.0 6.4

Figure 3. Isodose lines corresponding to the plans without (A) and with the commercial (b) and the three-dimensional printed customized (c) bolus

a B c

Figure 4. Dose volume histogram of the target corresponding to the plans with and without the bolus (A) and the percent depth dose analysis with the use of Gafchromic eBT3 film (b)

Dose [Gy]

Volu

me

(%)

Perc

ent D

epth

Dos

e (%

)

Depth [cm]

a B



for all plans. Further, the PDD curves correspond-ing to the measured dose in the EBT film and the calculated dose in treatment planning system were comparable (Fig. 4B).

Discussion

Megavoltage photon RT penetrates through the skin to irradiate deep-seated tumors, with skin-sparing property. The build-up effect is con-sidered a major benefit because of the reduction in skin toxicity. Hence, to treat superficial lesions, a commercial bolus is commonly used in such situ-ations to increase the surface dose in radiation on-cology units [11]. In case of an irregular surface region of a patient, unwanted air gaps under the bolus might occur between the bolus and patient skin due to the malleability of bolus material. It has been reported that an air gap of 4 mm causes a re-duction of dose to the basal layer of approximately 0–4% depending on field size, angle of incidence and other patient specific parameters and a reduc-tion of up to 10% could be seen at the basal cell layer for a 10 mm air gap [12]. Our pertinent find-ings can be summarized as follows. First, the target coverage was similar and even slightly better with the 3D bolus compared with the commercial one. Second, the maximum dose was reduced with the 3D bolus and the minimum dose increased when comparing with the commercial bolus. Finally, the homogeneity index was better for the 3D bolus.

Fujimoto et al. [13] customized a patient-specific 3D bolus using a 3D printing technique and evalu-ated its clinical feasibility for photon RT. The virtual target volume was delineated below the surface of the phantom in the vicinity of the nose. In the physical evaluation, the 3D-bolus provided effective dose coverage in the build-up region, which was equivalent to the commercial-bolus. With regard to the clinical feasibility and in agreement with us, the air gaps were lesser with the 3D-bolus when com-pared to the commercial-bolus and the prescription dose could be delivered appropriately to the target volume. The 3D-bolus had potential use for air-gap reduction compared to the commercial-bolus and facilitated target-volume dose coverage and homo-geneity improvement. In addition, there was not any dosimetric improvement when adding gel be-tween the 3D-bolus and the ear surface. It seems that the air gaps between the body surface and the

3D bolus were not large enough to cause a lack of electronic balance. Hence, it is not necessary to use this gel to fill the virtual space after the 3D bolus application.

In algorithms that do not take heterogeneities into account, the calculation accuracy for commer-cial boluses tends to be lower. For instance, the Eclipse planning system uses a dose volume opti-mizer optimization algorithm for IMRT that does not optimize adequately in areas of low or high density. That could be the reason why dosimetric parameters with the 3D bolus are slightly better than those of the commercial high density bolus. The 3D bolus had a radiological density similar to water. Both the optimization algorithms and the calculation algorithms are precise in this set-ting. The planning system appropriately assigns the Hounsfield number to its density and the calcula-tion algorithm is valid.

The design of a 3D bolus with the use of CT scans leads to unwanted radiation exposure of the patient [14]. To be able to make the bolus with little patient involvement and in minimal time, it has been proposed that the patient does not need to have a second CT done with the printed bolus for treatment planning [7]. The printed bolus den-sity is overridden in Eclipse with a Hounsfield unit number of 260. Then, the treatment plan can be cal-culated on the new CT using the same delivery pa-rameters. Others [5] have proposed the use of a 3D surface scanner for the 3D bolus fabrication to re-duce unnecessary radiation exposure. Park et al. [5] successfully fabricated a customized 3D bolus for a nose using a 3D surface scanner instead of a CT scanner. In comparison with the process based on the CT scan, the fabrication process based on a 3D surface scanner is simple and less time-consuming because this approach can skip several steps in the normal process from the contouring of the body surface to the generation of the STL file. The target presented in this report is challenging due to the very irregular surface of the ear. Although a 3D sur-face scanner could be used, the complex anatomy of the ear hinders the acquisition of images. The CT scanner improves overall image quality in this case. In addition, clinical information is crucial for the 3D bolus design in order to have a more customized therapy.

Our dosimetric analysis in this study showed that satisfactory target coverage could be achieved



with the proposed 3D bolus. Moreover, our PDD analysis with EBT film confirmed that the bolus fabricated could increase the surface dose effec-tively, and this dose was comparable with that of a commercial bolus. This is in agreement with prior studies focused mainly on the nose [5, 15]. Another benefit could be when the bolus should be replaced during the treatment for some reason [16]. The 3D bolus can be replaced fast and accurately reproduc-ing the previous one, thus assuring equivalent treat-ment reproducibility.

conclusion

We successfully fabricated a 3D bolus to cover a very irregular surface. The fabrication process was simple and fast. The bolus, made of malleable material, suitably fitted the surface, and the surface dose was sufficiently enhanced. The designed bolus is potentially useful for high-accuracy dose delivery through the reduction of unexpected air gaps in the case of irregularly shaped patient-skin surfaces. In addition, the 3D bolus can be replaced easily if necessary with the exact shape of the previous one. Thus, we believe that the use of a 3D bolus and mal-leable materials can be seriously considered for the fabrication of customized boluses for very irregular surfaces.

conflict of interest and FundingAuthors declare that we do not have any financial support or relationships that may suppose conflict of interest.

ethical standardsResearch not involving human participants and/or animals. Informed consent is not required for this study.

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5. park JW, Oh sean, Yea JiW, et al. Fabrication of malle-able three-dimensional-printed customized bolus us-ing three-dimensional scanner. pLos One. 2017; 12(5): e0177562, doi: 10.1371/journal.pone.0177562, indexed in pubmed: 28494012.

6. Valverde I, Gomez-ciriza G, hussain T, et al. Three-dimen-sional printed models for surgical planning of complex congenital heart defects: an international multicentre study. eur J cardiothorac surg. 2017; 52(6): 1139–1148, doi: 10.1093/ejcts/ezx208, indexed in pubmed: 28977423.

7. Burleson s, Baker J, hsia anT, et al. Use of 3D printers to cre-ate a patient-specific 3D bolus for external beam therapy. J appl clin Med phys. 2015; 16(3): 5247, doi: 10.1120/jacmp.v16i3.5247, indexed in pubmed: 26103485.

8. park K, park s, Jeon MJ, et al. clinical application of 3D-printed-step-bolus in post-total-mastectomy electron conformal therapy. Oncotarget. 2017; 8(15): 25660–25668, doi: 10.18632/oncotarget.12829, indexed in pubmed: 27784001.

9. Bethesda MIcorUaM: IcrU report 83.. prescribing, recording, and reporting photon-Beam Intensity-Modulated radiation Therapy (IMrT). J IcrU. 2010; 10(1), doi: 10.1093/jicru/ndq002.

10. carrasco Ma, perucha M, Luis FJ, et al. a compari-son between radiochromic eBT2 film model and its predecessor eBT film model. phys Med. 2013; 29(4): 412–422, doi: 10.1016/j.ejmp.2012.05.008, indexed in pubmed: 22738767.

11. Vyas V, palmer L, Mudge r, et al. On bolus for megavolt-age photon and electron radiation therapy. Med Dosim. 2013; 38(3): 268–273, doi: 10.1016/j.meddos.2013.02.007, indexed in pubmed: 23582702.

12. Butson M, cheung T, Yu p, et al. effects on skin dose from unwanted air gaps under bolus in photon beam radiother-apy. radiat Measure. 2000; 32(3): 201–204, doi: 10.1016/s1350-4487(99)00276-0.

13. Fujimoto K, shiinoki T, Yuasa Y, et al. efficacy of patient-specific bolus created using three-dimensional printing technique in photon radiotherapy. phys Med. 2017; 38: 1–9, doi: 10.1016/j.ejmp.2017.04.023, indexed in pubmed: 28610688.

14. park JW, Yea JW, park JW, et al. Three-dimensional cus-tomized bolus for intensity-modulated radiotherapy in a patient with Kimura’s disease involving the auricle. cancer radiother. 2016; 20(3): 205–209, doi: 10.1016/j.canrad.2015.11.003, indexed in pubmed: 27020714.

15. Kim sW, shin hJ, Kay cs, et al. a customized bolus pro-duced using a 3-dimensional printer for radiotherapy. pLos One. 2014; 9(10): e110746, doi: 10.1371/journal.pone.0110746, indexed in pubmed: 25337700.

16. robar JL, Moran K, allan J, et al. Intrapatient study com-paring 3D printed bolus versus standard vinyl gel sheet bolus for postmastectomy chest wall radiation therapy. pract radiat Oncol. 2018; 8(4): 221–229, doi: 10.1016/j.prro.2017.12.008, indexed in pubmed: 29452866.

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http://dx.doi.org/10.1159/000429576






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http://dx.doi.org/10.1093/ejcts/ezx208


http://dx.doi.org/10.1120/jacmp.v16i3.5247



http://dx.doi.org/10.18632/oncotarget.12829


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http://dx.doi.org/10.1016/s1350-4487(99)00276-0

http://dx.doi.org/10.1016/s1350-4487(99)00276-0



http://dx.doi.org/10.1016/j.canrad.2015.11.003






http://dx.doi.org/10.1016/j.prro.2017.12.008




research paper




Address for correspondence: Gustavo Arruda Viani, Dr. Rubem Aloysio Moreira St. 155, 4021686, São Paulo, fax: 55-16-34021744, tel: 55-16-34026584; e-mail: [email protected]

Prophylactic corticosteroid to prevent pain flare in bone metastases treated by radiotherapy

Gustavo Arruda Viani, Juliana Fernandes Pavoni, Ligia Issa De FendiFaculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), Ribeirão Preto, Brazil

AbstrAct

background: The aim of this study was to evaluate the effectiveness of prophylactic corticosteroids to prevent pain flare (pF)

in bone metastases treated with radiotherapy performing a meta-analysis of randomized clinical trials (rcT).

Materials and methods: rcTs were identified on Medline, embase, the cochrane Library, and the proceedings of annual

meetings through June 2020. We followed the prIsMa and MOOse guidelines. a meta-analysis was performed to assess if

corticosteroids reduce the pF, pain progression, and the mean of days with pF compared with the placebo. a p-value < 0.05

was considered significant.

results: Three rcTs with a total of 713 patients treated were included. The corticosteroids reduced the occurrence of early

pF 20.5% (51/248) versus 32% (80/250) placebo, Or = 0.55 (95% cI: 0.36–0.82, p = 0.002). The mean days of pF were reduced

to 1.6 days (95% cI: 1.3–1.9, p = 0.0001). prophylactic corticosteroids had more patients with no pF and no pain progression,

Or = 1.63 (95% cI: 1.14–2.32, p = 0.007). No significant corticosteroids effect was observed for pain progression (p = ns) and

late pF occurrence (p = ns).

conclusion: prophylactic corticosteroids reduced the incidence of early pF, the days with pF, resulting in a superior rate of pa-

tients with no pF and no pain progression, but with no significant benefit for reducing pain progression or late pF occurrence.

Key words: bone metastases; radiotherapy; pain flare; corticosteroids; meta-analysis





ISSN: 1507–1367

Introduction

Bone pain due to metastases is the most com-mon symptom demanding treatment in oncological patients [1]. Beside the pain, bone metastases (BM) can cause spinal cord compression, pathological fractures, and hypercalcemia [2]. All these compli-cations secondary to BM have a massive impact on the quality of life (QoL).

Radiotherapy (RT) has a long history in the treat-ment of bone pain due to BM [2]. Several random-ized clinical trials and meta-analyses show a sig-nificant reduction in pain and metastasis-related

bone events with RT administration [3]. However, after the onset of an RT course, some patients may develop a transitory worsening of bone pain [4]. This effect is denominated as PF. The estimated incidence rate of PF is around 40% [5]. In general, the effect occurs within the first 5 days after day one of RT administration (88%) and, frequently, it has a mean duration of 3 days [6, 7]. The radiobiologic mechanism that explains the occurrence of PF after RT is associated with the cytotoxic effect in the tissue irradiated [8, 9]. RT produces and triggers an inflammatory response in the bone target ir-radiated. The inflammatory response induced by

Gustavo Arruda Viani et al. prophylactic corticosteroid to prevent pain flare in bone metastases


RT increases pro-inflammatory cytokines and che-mokines in the local tissue, which worsens bone pain transitionally [9]. The relationship between RT and inflammatory response in the bone tissue has actively supported the design of randomized clinical trials evaluating glucocorticoids to prevent PF after RT [5, 10, 11]. Recently, some randomized clinical trials have been published, demonstrating contradictory results about corticosteroids’ efficacy in reducing the incidence of PF [12–14]. The dif-ferences in the sample size, corticosteroids dose, and treatment duration are considered some of the problems of the studies analyzed individually.

Meta-analysis is a valuable tool to solve medical literature problems, mainly related to sample size and insufficient power of studies to find statistical differences between the arms of randomized clini-cal trials [15].

Based on this scenario, we designed a meta-anal-ysis of randomized clinical trials to provide a gener-al overview of the outcomes of the prophylactic use of corticosteroids to prevent PF in bone metastases irradiated.


We conducted a systematic review and me-ta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement [16]. Two reviewers per-formed the research, selecting articles initially by title and abstract, and then read the full article.

A systematic search was conducted by two of the investigators in PubMed, the Cochrane Cen-tral Register of Controlled Trials, and Embase for studies assessing the treatment outcomes of pro-phylactic corticosteroids to prevent PF in painful bone metastases treated with radiotherapy: (“bone and bones” [MeSH Terms] OR (“bone” [All Fields] AND “bones” [All Fields])) OR “bone and bones” [All Fields]) OR “bone” [All Fields]) AND (“metas-tase” [All Fields]) OR “metastasis” [All Fields]) OR “neoplasm metastasis” [MeSH Terms]) OR (“neo-plasm” [All Fields] AND “metastasis” [All Fields])) OR “neoplasm metastasis” [All Fields]) OR “metas-tases” [All Fields]) OR “metastasize” [All Fields]) OR “metastasized” [All Fields]) AND (“radiothera-py” [MeSH Terms] OR “radiotherapy” [All Fields]) OR “radiotherapies” [All Fields]) OR “radiothera-py” [MeSH Subheading]) OR “radiotherapy s” [All

Fields]) AND (“pain” [MeSH Terms] OR “pain” [All Fields]) AND (“flare” [All Fields] OR “flares” [All Fields]). The lists containing the articles and reviews were checked, and possible related articles were tracked to complement the electronic query. Searches were performed from January 2000 up to June 2020 and were limited to publications in any language.

study selectionWe included only randomized clinical trials that

evaluated the treatment outcomes of prophylactic corticosteroids to prevent PF compared with pla-cebo in painful bone metastases treated by radio-therapy. Retrospective, non-randomized prospec-tive studies and case reports were excluded.

patientsWe included studies of patients with painful

bone metastases from any histological subtype, submitted or not to previous treatment with the metastatic lesion located in any bone treated by RT, and who received corticosteroids as a preventive treatment of the PF.

InterventionWe evaluated the efficacy of corticosteroids as an

intervention to prevent PF. Studies administrating oral or intravenous corticosteroids before and dur-ing the radiotherapy course were included. Stud-ies using multiple or single radiotherapy schedules with any total dose were included. Studies using conformational radiotherapy, tomotherapy, intensi-ty-modulated radiotherapy, or VMAT, or stereotac-tic body radiotherapy (SBRT) were allowed.

OutcomesThe primary endpoint of the meta-analysis was

the incidence of PF. PF was considered a minimum of a two-point increase in the worst pain score for the treated site without reducing analgesic intake, or > 25% increase in analgesic intake based on daily oral morphine equivalence without reducing the worst pain score. We considered PF to be early when the event occurred between days 0–5, or late when it started on 6–14 days. Pain progression was defined as either an increase in the worst pain score of two or more without analgesic decrease or an analgesic increase of 25% or more from baseline without reducing the worst pain score.



clinical dataTwo reviewers independently selected data using

a standardized method. The following information was collected: author, year, study design, number of patients, gender, bone location, histological sub-type, RT dose and RT technique, dexamethasone dosage, PF rate, pain progression rate, and days of PF. Two reviewers were in charge of gathering all data for all studies using a standardized data extraction form. A third reviewer was used to solve different issues by consensus.

Data synthesis and analysisThe rates of events of each outcome were calcu-

lated using the Odds ratio with the 95% confidence interval. The comparison for continuous variables was performed by mean difference estimation.

The I2 statistic illustrates the percentage of di-vergence across studies that is due to heterogeneity rather than chance. An I2 value lower than 25% was interpreted as a low level of heterogeneity. We used the random-effect model due to a relevant variation in studies’ characteristics. Two distinct methods were used to examine and explain the diversity among different studies results: subgroup analyses and meta-regression. A p-value lower than 0.05 was considered significant in all analyses. The meta-analysis was performed using the Open Me-ta-Analyst free open software.

results

We identified in our searches 1,980 studies re-porting the occurrence of PF after RT in painful bone metastases. After applying the inclusion cri-teria, 1,964 studies were excluded. The published studies were excluded due to many reasons, as described in the flowchart in Figure 1. Therefore, we selected 3 studies, including 713 patients using prophylactic dexamethasone to prevent PF after RT in painful BM compared with placebo. All studies were RCTs, and all of them were published from 2014 to 2020. In general, the treatment groups were similar for age, sex, and histological type. The main difference between the RCTs was due to the tumor location included in the Youssef et al. In this study, the authors only included patients with spine me-tastases randomized to receive methylprednisolone or placebo (saline infusion). Table 1 summarizes the characteristics of the studies included in the

present meta-analysis. The placebo was the control arm in the other two trials, with dexamethasone 8 mg/4–5 days as a similar intervention arm. In Youssef et al., the intervention arm was intravenous methylprednisolone (5 mg/kg) the day before RT.

early pF rateTwo studies with 498 patients reported early PF

as an outcome. Pooling the early PF rates of stud-ies, comparing dexamethasone versus placebo, the rate of early PF was 20.5% (51/248) versus 32% (80/250) placebo, resulting in an OR = 0.55 (95% CI: 0.36–0.82, p = 0.002), with no heterogeneity, I2 = 0% (Fig. 2A).

Late pFThree RCTs with 611 patients reported late

PF rate as an outcome. Pooling the late PF rate of RCTs, comparing dexamethasone versus place-bo, the rate of late PF was 18.6% (56/301) versus 21.6% (67/310), providing an OR = 0.74 (95% CI: 0.41–1.33), with no heterogeneity, I2 = 0% (Fig. 2B).

Mean days with pFThree studies, including 611 patients, reported

the mean days with PF. Combining the studies and calculating the mean difference between cor-ticosteroids and placebo arms, a significant differ-ence was found of 1.94 days (95% CI: –1.3 to –2.5, p < 0.0001), with heterogeneity I2 = 78%, p = 0.001) (Fig. 3A). In the sensitivity analysis, we removed the Youssef study by exploring the heterogeneity due to the inclusion of only spinal metastases. After that, the two studies combined gave a mean difference in PF days of –1.6 (95% CI –1.3 to –1.9, p = 0.0001), with no heterogeneity, I2 = 16%, p = 0.27, validating the outcome (Fig. 3B).

No pF/no pain progressionTwo studies with 498 patients reported no PF/PP

as an outcome. Pooling the no PF/PP of studies, comparing dexamethasone versus placebo, the rate of no PF/PP was 52% (129/248) versus 40% (100/250) placebo, resulting in an OR = 1.63 (95% CI: 1.14–2.32, p = 0.007), (Fig. 2), with no hetero-geneity, I2 = 0% (Fig. 4A).

pain progressionTwo studies reported PP as an outcome. Two

studies with 498 patients reported PP as an out-



Records identified throughdatabase searching

(n = 1977)

Additional records identifiedthrough other sources

(n = 3)

Records after duplicates removed(n = 1980)

Records screened(n = 16)

Full-text articles assessedfor eligibility

(n = 3)

Studies included inqualitative synthesis

(n = 3)

Studies included in quantitative synthesis (meta-analysis)

(n = 3)

Includ

edEligibility

Screen

ing

Iden

tification

Records excluded(n = 1964)

Full-text articles excluded, with reasons

(n = 13)

ź Prospective nonrandomized studies

ź Phase IIź Prospective studies

Figure 1. Flowchart of studies included in the meta-analysis

table 1. characteristics of the studies included in the meta-analysis

Study Chow et al. [14] Liden et al. [12] Youssef et al. [13]

Variables Corticosteroid Placebo Corticosteroid Placebo Corticosteroid Placebo

patients 148 150 100 100 60 60

age (mean) 67 68 65 63

Male (%) 59 55 62 62 58 55

Histology (%)

Lung

Breast

prostate

28

22

24

29

22

25

17

27

30

25

23

30

36

26

7

30

23

10

Location

spine

Other

30

70

40

60

100 100

rt fractionation (%)

single

Multiple

100

0

100

0

77

23

81

19 100 100

corticosteroid Dexamethasone Dexamethasone Methylprednisolone

corticosteroid dosage8 mg/day for 5 days

8 mg/day for 4 days

5 mg/kg 1 days before rT



Figure 4. A. No pain flare and no pain progression; b. pain progression

Figure 2. A. early pain flare; b. Late pain flare

Figure 3. A. Mean of days with pain flare without sensitivity analysis; b. Mean of days with pain flare with sensitivity analysis



come. Pooling the PP of studies, comparing dexa-methasone versus placebo, the rate of PP was 11.2% (28/248) versus 13.6% (34/250) placebo, resulting in an OR = 0.81 (95% CI: 0.4–1.3, p = NS) (Fig. 4B), with no heterogeneity, I2 = 0%.

Discussion

The present study is the first meta-analysis, in-cluding only randomized clinical trials, assessing the benefit of prophylactic corticosteroids admin-istration to prevent PF in painful BM. We gathered a total of 3 RCTs to estimate the incidence of PF, PP, and days of PF, comparing corticosteroids with placebo. In general, the heterogeneity for most of the outcomes evaluated was not significant, which validated our findings. We divided the analysis of PF into early and late, mainly to investigate if the corticosteroids effect is durable or transitory. The meta-analysis shows a significant effect of cortico-steroid for PF occurrence in the first week of the ini-tiation of radiotherapy. On the other hand, prophy-lactic treatment had no significant difference com-pared with the placebo for the late occurrence of PF. This finding raises the question if corticosteroids dosage or the short intake time (4–5 days) is inef-fective in producing a long-lasting protective effect for the occurrence of PF. In both RCTs using oral dexamethasone, a dose of 8 mg/day for 4–5 days was used. The RCT conducted by Liden et al. had three arms with one of them using 8mg for 1 day followed by 3 days of placebo. The early PF rate in this arm was 73%, with no significant difference for 8 mg per 4–5 days (52%) in the early evaluation. Although our study was not designed to evaluate the length of corticosteroids administration, these data make this question inevitable. The literature reports that the majority of PF occurs during the first week of RT [4, 7]. However, our data shows that late PF was significant in the placebo arms in all RCTs (21.6%), and a more extended treatment schedule with cor-ticosteroids may be necessary to find a significant difference for this endpoint. The RCT conducted by Yousef et al. randomized 120 patients to receive a 24-h infusion of methylprednisone (5 mg/kg) or placebo (normal saline infusion) the day before the initiation of radiotherapy. Four (7%) patients in the intervention group and 12 (20%) patients in the pla-cebo group had PF (p < 0.05). The dose of corticoste-roids in their study was much higher than the doses

used in the other two studies. If we convert the dose used by Youssef et al. 5 mg/kg would be equivalent to 65 mg/day for a 70 kg patient. This brutal differ-ence in corticosteroids dosage between Youssef et al. and other trials had a direct impact on the rate and duration of PF. The mean duration of PF in Youssef et al. was 125 days in the intervention group and 375 days in the placebo group. Combining the three trials, the mean of PF days was significant but with heterogeneity. When Youssef trial was excluded, the result remained significant and with no heterogene-ity, which validates the outcomes. Another question arising from our data regards the sample size of the studies. The studies may be considered under-powered to detect the estimated difference from the statistical assumptions. For instance, Chow et al. [14] postulated a difference in the incidence of 17% between the arms. However, the group difference was 8.9% in the intention-to-treat, and the inci-dence of late PF was practically the same between placebo and dexamethasone (9.4% and 10%) [14]. Thus, even increasing the sample size, it is improb-able to imagine a significant difference between the arms. Our meta-analysis clarifies this point, with data from 611 patients randomized with a difference of 3% between the treatment arms and no statistical significance was detected. The absence of the benefit in the corticosteroids arm of reducing late PF reveals the necessity of changing the treatment strategy. For us, the way to do that would be to increase the corti-coid dose or increase administration time to reduce the occurrence of late PF significantly. One example of this strategy is the corticosteroids administration to avoid cranial hypertension during brain metasta-ses radiotherapy course. Brain metastases typically are treated with the administration of 16 mg/day of dexamethasone during 10 fractions of whole-brain radiotherapy without clinical severe adverse effects. Based on this experience, the changing of cortico-steroids dose or intake time should not pose a sig-nificant challenge.

Pain progression was another endpoint evaluated in our meta-analysis, and no significant difference between intervention and placebo was observed. RT effectively reduces the pain of BM independent-ly of the histological subtype and the radiotherapy schedule employed [3]. Although corticosteroids have co-analgesic properties, the effectiveness of RT in reducing pain is so significant that the addiction of corticosteroids provides no benefit for this out-



come. On the other hand, the combination effective-ly maintained a high proportion of patients without PF and no pain progression than the placebo.

Although our study is a meta-analysis of RCTs, it has some limitations. The evaluation of some aspects with a possible relationship with PF oc-currence in a meta-regression analysis was not ex-plored, such as tumor histology, RT fractionation, bone location, and pain score baseline. We also did not evaluate the adverse effects of corticosteroids administration. However, in all the published RCTs the adverse effects had no significant differences between the study arms, which demotivated us to analyze this endpoint, and also none of the RCTs performed a subgroup analysis of these possible prognostic factors to provide information for per-forming a metaregression.

conclusion

Prophylactic corticosteroids reduce significant-ly the occurrence of early PF in bone metastases treated with radiotherapy. It also reduces the mean of days with PF and maintains a significant patient rate with no PF and no pain progression. However, the corticosteroids did not affect the incidence of late PF. Although it has co-analgesic properties, its use combined with RT did not produce any differ-ence in the pain progression rate compared with the placebo. Consequently, its use should be strictly recommended to reduce early PF and shorten the days with PF in bone metastases treated with RT. Our findings call attention for a change in the strat-egy to prevent PF in future randomized clinical trials, which should consider increasing the corti-costeroids dose or the time of intake, establishing the late PF rate as the primary endpoint.

conflict of interest The authors declare that they have no competing interests.

FundingThe authors declare none funding to produce the research.

ethical statement The present study is a meta-analysis of published randomized clinical trials and the ethical commit-tee approval was not necessary.

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research paper




Address for correspondence: Andre Tsin Chih Chen, MD, PhD, Av. Dr. Arnaldo, 251 Sao Paulo, SP, Brazil 01246-000; e-mail: [email protected]

Feasibility of SBRT for hepatocellular carcinoma in Brazil — a prospective pilot study

Andre Tsin Chih Chen1, Fabio Payão2, Aline Lopes Chagas3, Regiane Saraiva De Souza Melo Alencar3, Claudia Megumi Tani3, Karina Gondim Moutinho da Conceição Vasconcelos1, Manoel de Souza Rocha4,

Heloisa de Andrade Carvalho5, Paulo Marcelo Gehm Hoff6, Flair José Carrilho3 1Department of Radiation Oncology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas,

Faculdade de Medicina da USP, Sao Paulo, SP, Brazil 2Department of Radiology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas,

Faculdade de Medicina da USP, Sao Paulo, SP, Brazil 3Department of Gastroenterology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas,

Faculdade de Medicina da USP, Sao Paulo, SP, Brazil 4Department of Radiology, Instituto de Radiologia, Hospital das Clinicas, Faculdade de Medicina da USP, Sao Paulo, SP, Brazil

5Department of Radiation Oncology, Instituto de Radiologia, Hospital das Clinicas, Faculdade de Medicina da USP, Sao Paulo, SP, Brazil 6Department of Clinical Oncology, Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas,

Faculdade de Medicina da USP, Sao Paulo, SP, Brazil

AbstrAct

background: The aim of the study was to evaluate the feasibility and safety of stereotactic body radiotherapy (sBrT) for the

treatment of hepatocellular carcinoma in Brazil. sBrT is an evolving treatment in hcc patients not candidates to other local

therapies. Its adoption in clinical practice has been heterogeneous, with lack of data on its generalizability in the Brazilian

population.

Materials and methods: We conducted a prospective pilot study involving hcc patients after failure or ineligibility for tran-

sarterial chemoembolization. patients received sBrT 30 to 50 Gy in 5 fractions using an isotoxic prescription approach. This

study is registered at clinicaltrials.gov NcT02221778.

results: From Nov 2014 through aug 2019, 26 patients received sBrT with 40 Gy median dose. Underlying liver disease was

hepatitis c, hepatitis B and alcohol-related in, respectively, 50%, 23% and 19% of patients. Median lesion size was 3.8 cm

(range, 1.5–10 cm), and 46% had multiple lesions. Thirty-two percent had tumor vascular thrombosis; median pretreatment

alpha-fetoprotein (aFp) was 171.7 ng/mL (range, 4.2–5,494 ng/mL). 1y-local progression-free survival (pFs) was 86% (95% cI:

61% to 95%), with higher local control in doses ≥ 45Gy (p = 0.037; hr = 0.12). 1y-liver pFs, distant pFs and Os were, respec-

tively, 52%, 77% and 79%. Objective response was seen in 89% of patients, with 3 months post-sBrT median aFp of 12 ng/mL

(2.4–637 ng/mL). There were no grade 3 or 4 clinical toxicities. Grade 3 or 4 laboratory toxicities occurred in 27% of patients.

conclusion: sBrT is feasible and safe in patients unresponsive or ineligible for Tace in Brazil. Our study suggests doses

≥ 45 Gy yields better local control.

Key words: radiosurgery; stereotactic body radiotherapy; therapeutic chemoembolization; hepatocellular carcinoma;

clinical trial





ISSN: 1507–1367

Andre Tsin Chih Chen et al. sBrT for hcc in Brazil


Introduction

Hepatocellular carcinoma (HCC) is the 6th most commonly diagnosed cancer and the 4th leading cause of cancer death worldwide [1]. Incidence is close to mortality, highlighting tumor aggressive-ness. The majority of cases are diagnosed in devel-oping countries [1, 2].

In South America, the majority of patients is diagnosed at late stages, as reflected in Transarte-rial Chemoembolization (TACE) being the most common treatment for HCC [3]. TACE improves survival mainly in patients without major vascular thrombosis [4, 5]. However, treatment efficacy is re-duced after multiple sessions. TACE should not be repeated when substantial necrosis is not achieved after two rounds of treatment or when follow-up treatment fails to induce noticeable necrosis at sites that have progressed after an initial tumor response [6]. There is paucity of effective local therapies after failure or ineligibility for TACE [7, 8].

Stereotactic Body Radiotherapy (SBRT) is an emerging treatment option that uses highly focused radiation in few sessions to treat HCC. Phase I and II studies have shown encouraging results [9–16], but incorporation of SBRT by guidelines has been heterogeneous [6, 17–19]. Additionally, developing countries are underrepresented in the published literature of liver SBRT, with most studies coming from Asia, North America and Europe. In 2014, we initiated a prospective pilot study to evaluate the feasibility and safety of SBRT in patients un-responsive or ineligible for TACE in the Brazilian population.


This was a single-arm prospective pilot study. Patients were recruited at Instituto do Cancer do Estado de Sao Paulo, an academic tertiary cancer center in Brazil. HCC diagnosis was according to the American Association for the Study of Liver Diseases (AASLD) 2010 guidelines [20]. Before en-rolling, patients 1) had received at least two previous sessions of TACE and had remained with a viable tumor or 2) were ineligible for TACE (e.g., tumor vascular thrombosis (TVT), severe post-emboliza-tion syndrome, medical comorbidities).

Eligible patients had 1 to 5 HCC lesions with maximum diameter of 10 cm and no extra-hepatic

disease. Uninvolved liver had to be ≥ 700 cc [21], accounting for at least 40% of total liver volume. All patients had Child-Pugh score A, Eastern Co-operative Oncology Group (ECOG) performance 0 to 1, hemoglobin ≥ 8 mg/dL, platelets ≥ 45 × 109/L, neutrophil count > 1.2 × 109/L, total bilirubin ≤ 2 mg/dL, International Normalized Ratio (INR) < 1.7, alanine aminotransferase (ALT) and aspartate ami-notransferase (AST) < 6 × the upper limit of normal (ULN), albumin > 2.8 mg/dL and serum creati-nine < 1.5 × ULN.

Exclusion criteria were previous radiation ther-apy (RT) to the upper abdomen, clinically detect-able ascites, encephalopathy, main or common bile duct involvement, esophageal bleeding in the previous 3 months, large esophageal varices with red color signs or patients with severe gastrointes-tinal symptoms. Concomitant systemic treatment was not allowed; a minimum interval of 4 weeks from the last systemic treatment was required be-fore enrollment. Patients with other malignant neoplasms were allowed if HCC carried a worse prognosis.

Patients that fulfilled the inclusion criteria and agreed to participate in the study signed written informed consents. The study was conducted in accordance with the ethical guidelines of the Dec-laration of Helsinki and posterior revisions [22], as reflected in a priori approval by the institutional review committee.

radiation planning and treatment delivery

Patients were immobilized using a customized vacuum cushion (body fix®) and had abdominal compression or Active Breathing Control® to re-duce liver motion throughout respiration. Multi-phasic Computed Tomography (CT) for radiation planning was acquired in the exhale breath-hold. Additionally, fluoroscopy and four-dimensional CT (4D-CT) were performed to evaluate liver motion.

Gross Tumor Volume (GTV) was defined as 1) arterial-enhancing lesions with washout on venous or delayed phase or 2) washout in venous or delayed phase for infiltrative HCC. To improve target de-lineation accuracy, diagnostic magnetic resonance imaging (MRI) co-registration was performed as needed. There was no clinical target volume (CTV) expansion (CTV = GTV). Fluoroscopy and 4D-CT information were used to account for tumor mo-



tion through the respiratory cycle to generate the internal target volume (ITV). A 5 mm margin was added to the ITV to generate the planning target volume (PTV).

Doses of 30 to 50 Gy in 5 daily fractions were prescribed using an isotoxic approach as proposed by RTOG 1112 [23]. We prescribed the highest dose that could meet the mean liver dose, according to Table S1 (supplementary material online). Plan-ning was performed using Volumetric Modulated Arc Therapy (VMAT). Treatment was delivered in consecutive working days with 6 MV linear ac-celerator Elekta Axesse®. At each treatment frac-tion, fluoroscopy and CBCT were performed, with 6-degree couch correction and reimaging before treatment. No fiducials were used.

Systemic therapy after SBRT was not standard-ized in the trial protocol. Patients typically received sorafenib after progression to the trial treatment.

endpoints Our primary endpoint was local progression-free

survival (LPFS), measured per modified Response Evaluation Criteria in Solid Tumors (mRECIST) [24] and defined as the absence of increase of 20% in the sum of all diameters of treated lesions. Pre-existing TVT progression was considered local progression. Imaging modality was preferentially CT. MRI was ordered as needed for additional le-sion conspicuity. Baseline imaging modality (CT or MRI) was maintained throughout follow-up for consistency.

Secondary endpoints were liver progres-sion-free survival (PFS), defined as absence of new liver lesions or new TVT; distant PFS, defined as the absence of extra-hepatic disease; overall survival (OS) and toxicity measured by the Com-mon Terminology Criteria for Adverse Events (CTCAE) v.4.0. All time-to-event endpoints were measured from the start of SBRT. Patients that received liver transplant were censored for LPFS at the day of transplantation, but remained at-risk for other endpoints.

Patients were followed monthly in the first 3 months and every 3 months thereafter. Liver imag-ing was performed every 3 months.

statistical analysisThis pilot study was planned with a convenience

sample size of 25 patients.

Survival was estimated by the method of Ka-plan-Meier and compared using the log-rank test. Continuous variables were compared using Wilcoxon rank-sum test. HR were calculated us-ing Cox regression. Statistical significance was set to p ≤ 0.05. There were no corrections for multiple comparisons. We used Stata Release 14, College Station, TX for statistical analyses. The study is registered at ClinicalTrials.gov number NCT02221778.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

results

From November 2014 through August 2019, twenty-six patients received SBRT and were ana-lyzed. Fig. S1 shows the flow diagram of patients (supplementary material online). Median follow-up for patients alive was 28.5 months (range 6.2–65.7 months). No patient was lost to follow-up.

Table 1 describes patients’ characteristics. Me-dian age was 69 years, with eleven (42%) patients older than 70 years of age. Underlying liver disease was hepatitis C, hepatitis B and alcohol-related, in respectively, 50%, 23% and 19% of patients. All patients were Child-Pugh score A. Three (12%) patients received previous hepatectomy, one re-ceived RFA and 21 (81%) patients received previ-ous TACE. Of these, the status after the last TACE was progressive disease in 62% and stable disease (no response) in 38% of patients. TVT was present in 7 (27%) patients, and was the main reason of ineligibility for TACE. Median alpha-fetoprotein (AFP) was 171.7 ng/mL (range 4.2–5,494 ng/mL) and 13 (50%) patients had AFP > 200 ng/mL. Medi-an SBRT prescription dose was 40 Gy (range 30–50 Gy) in 5 fractions.

Local progression-free survivalLPFS at 1 and 2 years were, respectively, 86%

(95% CI: 61–95%) and 64% (95% CI: 29–85%). Me-dian LPFS was 34.7 months (Fig. 1A). Patients that received SBRT dose ≥ 45 Gy had a higher chance of local control. Median LPFS for patients that re-ceived ≥ 45 Gy was not reached vs. 12.1 months in patients that received < 45 Gy (p = 0.037; HR = 0.12, 95% CI: 0.01–1.19) (Fig. 1B). Table 2 shows univariate analysis of prognostic factors associated with LPFS,




liver PFS and OS. Previous TACE had no impact on LPFS (p = 0.811; HR = 0.76, 95% CI: 0.08–6.92).

Liver PFS at 1 and 2 years were, respectively, 52% (95% CI: 28–71%) and 26% (95% CI: 8–48%) Me-dian Liver PFS was 12.1 months (Fig. 2). Hepatitis C negatively impacted liver PFS, with HR 3.58 (95% CI: 1.15–11.18; p = 0.02) (Tab. 2).

Distant PFS at 1 and 2 years were similar at 77% (95% CI: 53–90%). Median distant PFS was not reached.

Median survival was 21 months. OS at 1 and 2 years were, respectively, 79% (95% CI: 57–91%) and 42% (95% CI: 22–61%) (Fig. 3). Higher SBRT dose, presence of TVT, AFP > 200 ng/mL were not statistically associated with OS, whereas patients with Hepatitis C had worse survival (p = 0.046; HR = 2.56; 95% CI: 0.98–6.67) (Tab. 2). We recom-mend caution in interpreting these results due to our small sample size.

table 1. patients characteristics

Characteristics n (%) Median (range)

Age 69 (42–80)

Gender

Male 21 (81%)

Female 5 (19%)

EcOG

0 18 (69%)

1 8 (31%)

child A 26 (100%)

bcLc stage

a 9 (35%)

B 5 (19%)

c 12 (46%)

Underlying liver disease

hepatitis B 6 (23%)

hepatitis c 13 (50%)

alcohol 5 (19%)

Nash 2(8%)

schistosomiasis mansoni 1 (4%)

Number of Previous tAcE 2 (0–5)

0 5 (19%)

1 3 (12%)

2 7 (27%)

3 6 (23%)

4 1 (4%)

5 4 (15%)

Number of lesions 47 (100%) 1 (1–4)

size of largest lesion [cm] 3.8 (1.5–10)

tumor vascular thrombosis 7 (27%)

Dose [Gy] 40 (30–50)

AFP

> 200 ng/mL 13 (50%)

≤ 200 ng/mL 13 (50%)

baseline laboratory values

aFp [ng/mL] 171.7 (4.2–5494)

aLT [U/L] 39 (7–119)

asT [U/L] 44 (10–162)

aLp [U/L] 103 (59–246)

GGT [U/L] 109 (19–612)

Bilirubin [mg/dL] 0.9 (0.2–1.9)

albumin [g/dL] 4.0 (3.3–4.8)

INr 1.14 (1.00–1.49)

creatinin [mg/dL] 0.87 (0.56–1.32)

platelets [× 109/L] 117 (52–300)

ecOG — eastern cooperative Oncology Group; BcLc — Barcelona clinic Liver cancer classification; Nash — nonalcoholic steatohepatitis; Tace — transarterial chemoembolization; Gy — Gray; aFp — alpha-fetoprotein; aLT — alanine aminotransferase; asT — aspartate amino-transferase; aLp — alkaline phosphatase; GGT — gamma-glutamyl transferase; INr — international normalized ratio

1.00

0.75

0.50

0.25

0.00

1.00

0.75

0.50

0.25

0.00

Number at risk 26 10 3 2 1

0 12 24 36 48Time (months)

Number at riskDose < 45 14 3 0 0 0Dose ≥ 45 12 7 3 2 1

0 12 24 36 48Time [months]

a

B

p = 0.037

Figure 1. Local progression-free survival. Kaplan-Meier estimates of local progression-free survival (A) all patients. Dashed lines depict 1- and 2-year local progression-free survival of 86% and 64% (b) By prescription dose of 45 Gy. patients receiving dose ≥ 45 Gy had better local control (p = 0.037; log-rank test)



table 2. Univariate analysis of prognostic factors for survival endpoints

Prognostic factor Median (months) HR (95% CI) p

Local progression-free survival

Total dose [Gy]

≥ 45 Not reached 0.12 (0.01–1.19) 0.037

< 45 12.1

hepatitis c

Yes Not reached 0.26 (0.03–2.25) 0.189

No 16.8

Tumor vascular thombosis

Yes Not reached 2.1 (0.39–14.4) 0.326

No 34.7

alpha-fetoprotein [ng/mL]

> 200 34.7 2.74 ( 0.49–15.20) 0.230

≤ 200 Not reached

Number of lesions

3 or more Not reached 0.71 (0.08–6.27) 0.758

1 or 2 34.7

Diameter of largest lesion

> 3cm 16.8 1.06 (0.18–5.91) 0.946

≤ 3cm 34.7

previous Tace

Yes 34.7 0.76 (0.08–6.92) 0.811

No Not reached

Liver progession-free survival

Total dose [Gy]

≥ 45 15.9 0.64 (0.21–1.92) 0.428

< 45 9.8

hepatitis c

Yes 8.9 3.58 (1.15–11.18) 0.019

No 15.9


Yes 8.9 1.49 (0.46–4.81) 0.492

No 15.4


> 200 9.1 1.62 (0.55–4.73) 0.364

≤ 200 15.4

Number of lesions

3 or more 7.1 1.11 (0.34–3.58) 0.850

1 or 2 15.4


> 3cm 12.1 0.69 (0.20–2.33) 0.550

≤ 3cm 9.1

previous Tace

Yes 12.1 1.19 (0.26–5.34) 0.817

No 9.8



ToxicityTreatment was well tolerated, without treat-

ment-related grade 3 or 4 clinical toxicities. Grade 3 or 4 laboratory toxicities occurred in 7 (27%)

patients (Tab. 3). Most of these were transient, oc-curring 1 to 3 months following treatment and sub-siding thereafter. One patient died of progressive liver failure 6 months following treatment. After multidisciplinary team discussion, we considered

1.00

0.75

0.50

0.25

0.00


0 12 24 36 48Time [months]

Figure 2. Liver progression-free survival. Kaplan-Meier estimate of liver progression-free survival. Dashed lines depict 1- and 2-year overall survival of, respectively, 52% and 26%

1.00

0.75

0.50

0.25

0.00


0 12 24 36 48Time [months]

Figure 3. Overall survival. Kaplan-Meier estimate of overall survival. Dashed lines depict 1- and 2-year overall survival of, respectively, 79% and 42%

table 2. Univariate analysis of prognostic factors for survival endpoints

Prognostic factor Median (months) HR (95% CI) p

Overall survival

Total dose [Gy]

≥ 45 26.5 0.82 (0.32–2.11) 0.686

< 45 18.2

hepatitis c

Yes 14.3 2.56 (0.98–6.67) 0.046

No 26.5


Yes 17.6 1.51 (0.56–4.08) 0.408

No 22.0


> 200 17.6 1.80 (0.70–4.64) 0.212

≤ 200 22.0

Number of lesions

3 or more 36.7 0.61 (0.20–1.88) 0.739

1 or 2 21.0


> 3 cm 18.2 0.85 (0.32–2.21) 0.394

≤ 3 cm 24.9

previous Tace

Yes 24.9 0.36 (0.11–1.22) 0.088

No 17.6

Tace — transarterial chemoembolization



the death not directly related to SBRT, but possibly related. A detailed discussion of the case can be found online in the supplementary appendix.

radiologic responseEighty-nine percent of patients had objective re-

sponse per mRECIST, with complete and partial response in, respectively, 54% and 35% of patients (Table S2, online). In patients who responded, me-dian time for the best response was 3.7 months (IQR: 3.1–6.8 months; range 2–12.6 months). Fig-ure 4 shows the case of an 80-year-old woman with hepatitis B and a single 4 cm HCC lesion that was treated to 45 Gy. The lesion responded continuously until reaching complete response per mRECIST at 12.6 months. Following complete response, the non-enhancing lesion continued to reduce until 31 months.

alpha-fetoproteinMedian pretreatment AFP was 171 ng/mL (IQR:

12–868 ng/mL); 3 months after SBRT, median AFP reduced to 12 ng/mL (IQR: 6.3–85.6 ng/mL) (p = 0.003; Wilcoxon signed-rank test for paired

samples) (Fig. S2, Supplementary File). Before treatment, 21 (81%) patients had AFP above ULN (> 10 ng/mL). For these, AFP was a good marker of response.

Discussion

To the best of our knowledge, no prospective data has been reported using SBRT to treat HCC in Latin America. Our findings indicate the technique is feasible in a Brazilian referral cancer center.

Our study suggests that SBRT has substantial activity against HCC in our patient population. We achieved 1-year LPFS of 86% in a sample of pre-viously treated patients, with median lesion size of 3.8 cm, AFP > 200 ng/mL in 50% and TVT in 27% of patients. Objective response was seen in 88% of patients, with 54% achieving complete response during follow-up. Patients that received SBRT dose ≥ 45 Gy had a significant longer LPFS.

Other prospective SBRT trials treating HCC-on-ly have reported similar results, with Bujold et al. reporting local control at 1 year of 87% [11] and Andolino et al. with local control at 2 years of 90%

table 3. Treatment related toxicity

Toxicity Grade 1 Grade 2 Grade 3 Grade 4

clinical 10 (38%) 5 (19%) 0 (0%) 0 (0%)

Nausea 5 (19%) 2 (8%) 0 (0%) 0 (0%)

anorexia 7 (27%) 0 (0%) 0 (0%) 0 (0%)

Diarrhea 3 (12%) 0 (0%) 0 (0%) 0 (0%)

Fatigue 2 (8%) 1 (4%) 0 (0%) 0 (0%)

Gastritis 3 (12%) 1 (4%) 0 (0%) 0 (0%)

Dyspepsia 3 (12%) 1 (4%) 0 (0%) 0 (0%)

chest wall pain 2 (8%) 1 (4%) 0 (0%) 0 (0%)

rib fracture 0 (0%) 1 (4%) 0 (0%) 0 (0%)

pneumonitis 0 (0%) 1 (4%) 0 (0%) 0 (0%)

radiation dermatitis 1 (4%) 0 (0%) 0 (0%) 0 (0%)

Laboratory 7 (27%) 12 (46%) 6 (23%) 1 (4%)

platelet 12 (46%) 8 (31)%) 4 (15%) 0 (0%)

Bilirubin 9 (35%) 9 (35%) 1 (4%) 1 (4%)

aLT 17 (65%) 3 (12%) 0 (0%) 0 (0%)

asT 14 (54%) 5 (19%) 2 (8%) 0 (0%)

aLp 15 (58%) 2 (8%) 0 (0%) 0 (0%)

INr 13 (50%) 1 (4%) 0 (0%) 0 (0%)

albumin 6 (23%) 3 (12%) 0 (0%) 0 (0%)

Toxicity graded according to the common Terminology criteria for adverse events v4.0. Data presented as n (%). aLT — alanine aminotransferase; asT — aspartate aminotransferase; aLp — alkaline phosphatase; INr — international normalized ratio




[10]. A recent meta-analysis from thirty-two pro-spective and retrospective studies involving 1950 HCC patients reported pooled 1- and 2-year lo-cal control rates of 85.7% (95% CI: 80.1–90.0) and 83.6% (77.4–88.3) [25]. Taken together, these re-sults suggest SBRT is an adequate strategy for HCC not candidate to other therapies. This strategy could be further explored in elderly and frail patients that carry a greater risk to invasive procedures [26].

It is of note that LPFS was similar between pa-tients that received TACE and patients that did

not receive it due to ineligibility. Although upfront SBRT is feasible in localized HCC prior to TACE, the clinical benefit of such approach is currently under investigation [27].

In our study, radiologic and laboratory response were not immediate, requiring at least 3 months for initial evaluation. Our median time for the best radiological response was 3.7 months, with patients achieving complete response up to one year after treatment. After RT, cancer cells undergo reproduc-tive death, that is, loss of capacity to reproduce in-

Figure 4. complete response after stereotactic body radiotherapy (sBrT). Images of an 80-year-old patient who underwent sBrT with 45 Gy to a single 4 cm lesion (white arrow). A. pre-treatment magnetic resonance imaging (MrI); b. sBrT isodose curves. c–F. Follow-up MrIs showing continuous reduction of the treated lesion. In images (c) and (D), transient alterations due to lower isodoses are seen in surrounding liver parenchyma. In images (E) and (F), the gallbladder, with its characteristic homogeneous contrast enhancement, is seen to the right of the arrow. Images are not at the same level due to changes in liver size and shape

a B

c D

e F



definitely [28]. A cell may still be physically intact, may be able to make proteins or synthesize DNA, but it has lost its reproductive integrity. Most cells will die while attempting to divide (mitotic death), while some will die by apoptosis [28]. Therefore, after SBRT, from a radiobiological standpoint, the presence of early arterial enhancement with early “washout” should not be considered a sign of vi-ability. Until there is no volume progression, le-sions should be considered controlled [10, 11, 29, 30]. Such an approach differs from TACE or ra-diofrequency ablation and highlights the need to understand RT mechanisms of action to interpret follow-up images.

The possibility of treating TVT with SBRT ex-pands treatment strategies to this group of patients that is usually not candidate to local therapy. In our study, median survival for patients with TVT was 17.6 months. Yoon et al. conducted a random-ized study comparing TACE plus conformal RT vs sorafenib in patients with TVT and absence of dis-tant metastases [31]. Among 90 patients enrolled, 79% had multiple lesions, with median size of the largest lesion of 9.7 cm. TACE + RT had longer time to progression (4.2 months vs. 2.8 months; p < 0.001) and median survival (13.1 months vs. 10.2 months; p = 0.04). In our opinion, current evidence suggests that RT is an adequate local treat-ment even in the context of TVT.

Despite our good local control, failure in the remaining liver continues to be a problem. As re-ported by Takeda et al. [14], this was our main pat-tern of failure. In our exploratory analysis, baseline hepatitis C was associated with progression in the untreated liver.

Our median survival of 21 months is within the range of previously prospective studies using SBRT [9–14]. Survival is highly influenced by patient’s baseline characteristics. For instance, Bujold et al., in a sample with a median tumor size of 7.2 cm, 55% TVT and 12% extra-hepatic disease, reported median survival of 17 months [11]. Andolino et al. studied SBRT in a more favorable population, with single lesion in 85% of patients, no TVT, median lesion size of 3 cm and 10% prior therapy. The au-thors reported a median survival of 44 months [10].

In comparison with systemic therapy, the SHARP study [32] reported median survival of 10.7 months in a sample with 36% of TVT and 53% of extra-he-patic disease. The Asia Pacific study [33] reported

median survival of 6.5 months in a sample with 36% of TVT and 69% of extra-hepatic disease. Rec-ognizing the tremendous limitations of compari-sons across studies, survival of SBRT trials compare favorably to sorafenib.

Toxicity was acceptable in our study, with no grade 3 or 4 clinical toxicities. One death was possi-bly related to treatment and is within the previously reported range of up to 6.9% [11].

Our study has several limitations. First, it’s a pro-spective pilot study with a small sample size. Our accrual period was long and reflect the nature of salvage treatment in a complex disease. After failure or ineligibility for TACE, a significant proportion of patients had a worsening liver function or had tumors beyond the inclusion criteria of our trial. Our study generates hypothesis and highlights the importance of conducting worldwide representa-tive phase III trials to definitely establish the role of SBRT in the treatment of HCC.

There are two ongoing phase III randomized tri-als of SBRT in HCC. IAEA E33036 [27] is compar-ing TACE vs SBRT in the setting of unresectable HCC unsuitable for conventional ablative therapies. RTOG 1112 [23] is currently testing the suggested benefit of adding SBRT to sorafenib for locally ad-vanced HCC.

conclusion

In conclusion, SBRT is feasible in our Brazilian population. Our study suggests that higher SBRT dose improves local progression-free survival with acceptable toxicity. It should be considered as a treatment option in HCC patients unresponsive or ineligible for TACE, before referral to systemic therapy.


Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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http://dx.doi.org/10.1053/jhep.2003.50047




http://dx.doi.org/10.1016/S0140-6736(18)30010-2

http://dx.doi.org/10.1016/S0140-6736(18)30010-2




http://dx.doi.org/10.1016/S1470-2045(17)30683-6


http://dx.doi.org/10.1007/s12094-010-0492-x








http://dx.doi.org/10.1007/s00432-015-1929-y










http://dx.doi.org/10.1002/hep.29086


http://dx.doi.org/10.1093/annonc/mdy308

http://dx.doi.org/10.1093/annonc/mdy308


http://dx.doi.org/10.1002/hep.24199




http://dx.doi.org/10.1001/jama.2013.281053


https://www.rtog.org/ClinicalTrials/ProtocolTable.aspx.

https://www.rtog.org/ClinicalTrials/ProtocolTable.aspx.

http://dx.doi.org/10.1055/s-0030-1247132






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https://www.iaea.org/projects/crp/e33036

https://www.iaea.org/projects/crp/e33036











http://dx.doi.org/10.1016/S1470-2045(08)70285-7



research paper




Address for correspondence: Jesús Romero, Servicio de Oncología Radioterápica; Hospital Universitario Puerta de Hierro, Calle Joaquín Rodrigo, 1; Majadahonda, 28222 Madrid, Spain; e-mail: [email protected]

Impact of COVID-19 pandemic on patients and health professionals of a radiation oncology department

at a Spanish tertiary hospital

Jesús Romero 1, Raquel Benlloch1, Jorge Obeso1, Olga Engel1, Beatriz Gil1, Sofía Córdoba1, Irma Zapata1, Marta López1, Francisca Portero2

1Servicio de Oncología Radioterápica; Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain2Servicio de Microbiología, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain

AbstrAct

background: The sanitary emergency created by the cOVID-19 pandemic forced us to take exceptional measures that affect

decision-making and administration of treatments with radiotherapy. The aim of the study was to analyze the impact of the

cOVID-19 pandemic on patients and professionals in a radiation oncology department.

Materials and methods: We implement a plan with the objectives of maintaining radiotherapy treatment in those patients

who need it and, at the same time, reducing the risk of spreading the virus to staff and patients. This plan included measures

aimed at limiting the patient’s stay in hospital, selecting those patients in whom radiotherapy cannot be delayed and protect-

ing against infection through the use of physical protective measures.

results: Between March 16 and May 31, 2020, 360 patients received radiotherapy in our department. In 14 patients (4.7%)

the start of treatment was delayed by an average of 28 days. Four patients had a positive cOVID-19 polymerase chain reaction

(pcr) (6.6% and 1.1% of tested and all patients, respectively). among the professionals, two pcrs were positive (16.6% and 4%

of tested and all individuals, respectively). In the serology analysis 4 out of 50 department members were IgG positive (8%).

conclusions: Despite the fact that our department is located in a region with a high incidence of cOVID-19 infection, the

impact of the pandemic on our patients and staff has been moderate. The implementation of measures against infection and

an adequate selection of patients for treatment allows radiation oncology departments to maintain clinical activity.

Key words: coronavirus; cOVID-19; radiotherapy; cancer





ISSN: 1507–1367

Introduction

A novel coronavirus called severe acute respira-tory syndrome coronavirus 2 (SARS-CoV-2) was identified in December 2019 in Wuhan, China, as the cause of a respiratory infection called corona-virus disease (COVID-19). The infection spread throughout the rest of the world and was declared

a pandemic by the World Health Organization on March 11, 2020. By August 1, more than 17 million people had been infected and more than 680,000 people had died from COVID-19 according to the World Health Organization.

The disease is characterized by fever and respi-ratory symptoms. In most cases, patients present with mild illness, but up to 15% of patients require

https://orcid.org/0000-0001-8778-1388



hospitalization and oxygen supplementation, and 5% progress to severe illness with respiratory failure and multi-organ dysfunction [1].

The management of cancer patients is a chal-lenge because they have a higher risk of contract-ing COVID-19 as well as developing a more seri-ous disease because their immunosuppressed state caused by both the tumor and cancer treatments [2, 3]. Cancer patients undergoing chemothera-py or surgery have a higher risk of clinically se-vere events (odds ratio: 5.34, 95% CI: 1.80–16.18; p = 0.0026) after adjusting for other risk factors [2]. Oncologists face the dilemma of treating pa-tients to prevent cancer progression or, conversely, delaying cancer treatment to prevent the spread of COVID-19.

In this report we share our experience in the management of patients undergoing radiotherapy during the pandemic in a region with a high preva-lence of COVID-19 infection. We analyze the im-pact of the COVID-19 pandemic on the delivery of treatments in a radiation oncology department and determine the effectiveness of a contingency plan in reducing the risk of contagion for patients and healthcare personnel.


The university hospital Puerta de Hierro is a public tertiary hospital that covers an area with population of 462,000. Around 1,600 new patients per year are treated in the department of Radiation Oncology, which has four linear accelerators and a high-rate brachytherapy unit. The department is comprised of 50 members: 20 doctors (12 staff radiation oncologists and 8 residents), 22 radio-therapy technicians, 5 oncology nurses, 2 nursing assistants and 1 administrative secretary. Before the pandemic, approximately 30 new patients and 300 follow-up visits per week were seen, and a mean of 130 patients received radiotherapy in our depart-ment daily.

Laboratory testsThe tests were performed in the Microbiology

laboratory of the hospital. The viral RNA in the nasopharyngeal swab was detected by PCR (PCR, cobas® SARS-CoV-2, Roche). COVID-19 ELISA IgM+IgA and IgG (Vircell) was used for detection of specific antibodies in a blood sample.

contingency planThe sanitary emergency created by the pandemic

forced us to take exceptional measures that affect decision-making and administration of treatments with radiotherapy or chemoradiotherapy. The two objectives of the plan were to guarantee treatment with radiotherapy in those patients who need it and to reduce the risk of spreading the virus to health-care personnel and patients.

To meet these objectives, measures were imple-mented aimed at limiting the patient’s stay in hos-pital, selecting those patients in whom radiotherapy cannot be delayed and protecting against infection through the use of physical protective measures.

Some of the measures adopted were the follow-ing:• follow-up visits were conducted distantly by

phone when appropriate;• the first visits for new patients were maintained

except in tumors in which the delay in treatment was acceptable, such as benign tumors, breast and prostate cancer;

• various hypofractionation schemes were adopted whenever possible. Some of the schedules used in the most frequent tumors were the following:

• breast — patients > 50 years old, without boost and no chemotherapy: 5 weekly fractions of 2.66 Gy/f over 5 weeks. For the rest of patients: 15 fractions of 2.66 Gy/f with integrated boost, if appropriate, at 3 Gy/f,

• prostate — 20 fractions of 3 Gy/f over 4 weeks,• lung — 20 fractions of 2.66 Gy/f over 4 weeks for

non-small cell. For small cell limited stage, 15 fractions of 2.66 Gy/f and prophylactic cranial irradiation (PCI) with 10 fractions of 2.5 Gy/fx. For extended stage in selected patients, 5 fx of 4 Gy/f without PCI.In patients with head and neck, cervical and lung

cancers, enlargements of the overall treatment time were compensated by adding 0.6 Gy to the total dose for each day lost up to a maximum of 6 Gy;• to assist in decision making, patients were clas-

sified according to their survival expectations and the potential relief of disabling symptoms (Tab. 1);

• patients were frequently asked about the pres-ence of fever, cough, or dyspnea, and also about potential contacts with COVID-19 patients. In suspected cases, a PCR test, chest X-ray, and laboratory tests were performed to rule out CO-

Jesús Romero et al. Impact of cOVID-19 pandemic on patients and health professionals


VID-19 infection. In patients with a diagnosis of COVID-19 pneumonia and/or positive PCR, treatment was interrupted until the patient had a clinical situation that allowed the restart of radiotherapy;

• protective measures were established for all health personnel consisting of the use of surgical masks, gloves, and protective face shields. The accelerator table and all devices in the treatment room were carefully cleaned with hydroalcohol-ic solution before each treatment. The patients were given a surgical mask and we tried to avoid crowding in the waiting room.

results

Between March 16 and May 31, 2020, 360 pa-tients received radiotherapy in our department. Among them 280 patients started treatment during the period analyzed, which represents an average of 5.86 treatment initiations per day. An average of 86.65 daily radiotherapy sessions were admin-istered in the four radiotherapy units and a to-tal of 37 high-rate brachytherapy procedures were performed. During this period there was a 27% decrease in the number of patients treated with re-spect to the same period of the previous year. This decrease is attributable to a lower referral of pa-tients for postoperative radiotherapy due to a dras-tic decrease in surgical interventions, as well as the delay in the start of radiotherapy in some patients.

The start of radiotherapy was delayed in 14 pa-tients (4.7%) according to the contingency plan or by patient decision. The mean delay time until the start of radiotherapy was 28 days (7–58).

One or more PCR tests were performed on 60 patients (Tab. 3). The test was positive only in 4

patients (6.6% of the patients tested and 1.1% of the total of 360 patients receiving radiotherapy). The mean time for PCR negativization was 6 days. In 2 additional patients, the diagnosis of COVID-19 was established by a compatible clinical picture without performing PCR. Three patients presenting with viral pneumonia required admission and there were no deaths for COVID-19 in our series. In patients with a diagnosis of COVID-19, the mean time of interruption of radiotherapy was 20 days (6–45) and this enlargement could only be partially com-pensated in some patients.

One or more PCRs were performed in 12 staff members with symptoms compatible with COV-ID-19 infection, of which 2 were positive (16.6% of tested individuals and 4% of all department mem-bers). In the seroprevalence study carried out in May 2020 to all members of the department, 4 out of 50 individuals (8%) had IgG antibodies against COVID-19 (Tab. 2).

As the health crisis progressed, it was necessary to reorganize the department’s units due to a 30% decrease in the workforce motivated by the recruit-ment of doctors by the hospital administration to treat patients with COVID-19 and by sick leaves due to COVID-19 infection or quarantine.

Discussion

With 1063 confirmed cases and 130 deaths per 100,000 populations by May 19, 2020, the autono-mous region of Madrid is one of the European areas with the highest incidence of COVID-19 infection. The pandemic has nearly collapsed the regional health system due to a low availability of diagnostic tests and protection equipment, insufficient ICU beds and mechanical ventilators, and a high num-

table 1. classification of patients according to their survival expectations, risk of relapse and potential relief of disabling symptoms

High prioritycurative treatments with survival > 50% in rapidly growing tumors in which delayed treatment can compromise survival

patients with spinal cord compression in whom radiation therapy can produce neurological recovery

Medium prioritycurative treatments with survival between 10–50%

postoperative radiotherapy in patients with macroscopic residue of fast growing tumors or with 5-year recurrence risk > 20%

Low priority

palliative radiotherapy that produces symptomatic relief

postoperative radiation therapy with complete resection and 5-year recurrence risk < 20%.

radical radiotherapy in patients in whom the delay does not impact control or those in whom hormonal therapy or other treatment allows delay of treatment



ber of healthcare professionals infected by COV-ID-19. To deal with the situation created by the CO-VID-19 pandemic we launched a contingency plan with the aim of maintaining radiotherapy treatment but reducing the spread of the virus through pro-tective measures.

Since the beginning of the pandemic, various recommendations have been published regarding the management of radiation oncology depart-ments [4–6]. As in our contingency plan, these recommendations are based on the limitation of the patient’s stay in the hospital; use of hypofrac-tionation schemes; selection of high-risk patients in whom treatment should be performed; and in the adoption of protection measures against CO-VID-19 of patients and staff. However, the real impact of the COVID-19 pandemic in radiation oncology departments in terms of the number of patients and delays in radiation treatments, as well as the number of professionals and patients with COVID-19 infection has been rarely reported. Ma-

licki et al. [7] analyzed the impact of precautionary measures in response to COVID-19 in a large Ra-diation Oncology center in Poland and found a re-duction of 37% in the number of patients treated daily, which is similar to the 27% observed in our series. These authors [7] found an incidence of 2 out of 159 tested staff members with positive PCR (1.2%) compared to 16.6% in our department. This difference is probably due to the fact that in our center PCR was only performed in individuals with symptoms or risky contact, as well as the higher incidence of COVID-19 infection in our region.

conclusions

Despite the fact that our department is located in a region with a high incidence of COVID-19 infection, the impact of the pandemic on our pa-tients and staff has been moderate. The imple-mentation of measures against infection and an adequate selection of patients for treatment allow

table 2. cOVID-19 pcr and cOVID-19 eLIsa IgM and IgG results in patients and healthcare professionals

Tested

individuals (%)Positive test (% of tested)

Positive test

(% of total)

COVID-19 PCR

Patients 60/360 (16.6%) 4/60 (6.6%) 4/360 (1.1%)

Professionals

radiation oncologist

radiotherapy Technicians

Others members

total

6/20 (30%)

6/22 (27.7%)

0/8 (0%)

12/50 (24%)

2/6 (33.3%)

0/22 (0%)

0/8 (0%)

2/12 (16.6%)

2/20 (10%)

0/22 (0%)

0/8 (0%)

2/50 (4%)

COVID-19 ELISA IgM and IgG

Professionals

radiation oncologists

radiotherapy Technicians

Others members

total

20/20 (100%)

22/22 (100%)

8/8 (100%)

50/50 (100%)

IgM–, IgG+: 2/20 (10%)

IgM+, IgG+: 1/20 (5%)

IgM+, IgG–: 1/20 (5%)

IgM–, IgG–: 16/20 (80%)

IgM–, IgG+: 1/22 (4.5%)

IgM+, IgG+: 0/22 (0%)

IgM+, IgG-: 1/22 (4.5%)

IgM–, IgG–: 20/22 (90.9%)

0%

IgM–, IgG+: 2/50 (4%)

IgM+, IgG+: 2/50 (4%)

IgM+, IgG–: 2/50 (4%)

IgM–, IgG–: 46/50 (76%)

Jesús Romero et al. Impact of cOVID-19 pandemic on patients and health professionals


radiation oncology departments to maintain clini-cal activity

conflicts of interestAll authors declare that they have no conflicts of interest for this work.


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4. Filippi ar, russi e, Magrini sM, et al. Letter from Italy: First practical indications for radiation therapy departments during cOVID-19 outbreak. Int J radiat Oncol Biol phys. 2020; 107(3): 597–599, doi: 10.1016/j.ijrobp.2020.03.007, indexed in pubmed: 32199941.

5. Zhang Li, Zheng Z, hu G, et al. prevention and control measure to avoid cross infection during radiotherapy in coronavirus disease 2019 (cOVID-19) epidemic in Wuhan, china. radiother Oncol. 2020; 149: 104–106, doi: 10.1016/j.radonc.2020.04.011, indexed in pubmed: 32342880.

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http://dx.doi.org/10.1016/S1470-2045(20)30096-6

http://dx.doi.org/10.1016/S1470-2045(20)30096-6









http://dx.doi.org/10.1016/j.adro.2020.03.006






research paper




Address for correspondence: Elsa Bifano Pimenta, Department of Nuclear Engineering,Federal University of Minas Gerais, Belo Horizonte, MG 31270-901, Brazil; e-mail: [email protected]

Dose measurements in a thorax phantom at 3DCRT breast radiation therapy

Elsa Bifano Pimenta1, Luciana Batista Nogueira2, Tarcísio Passos Ribeiro de Campos1

1Department of Nuclear Engineering, Federal University of Minas Gerais, Belo Horizonte, Brazil2Department of Anatomy and Image, Federal University of Minas Gerais, Belo Horizonte, Brazil

AbstrAct

background: The anthropomorphic and anthropometric phantom developed by the research group NrI (Núcleo de radiações

Ionizantes) can reproduce the effects of the interactions of radiation occurring in the human body. The whole internal radia-

tion transport phenomena can be depicted by film dosimeters in breast rT. Our goal was to provide a dosimetric comparison

of a radiation therapy (rT) plan in a 4MV 3D-conformal rT (4MV-3DcrT) and experimental data measured in a breast phantom.

Materials and methods: The rT modality was two parallel opposing fields for the left breast with a prescribed dose of 2.0 Gy

in 25 fractions. The therapy planning system (Tps) was performed on caT3D software. The dose readings at points of interest

(pOI) pre-established in Tps were recorded. an anthropometric thorax-phantom with removal breast was used. eBT2 radio-

chromic films were inserted into the ipisilateral breast, contralateral breast, lungs, heart and skin. The irradiation was carried

out on 4/80 Varian linear accelerator at 4MV.

results: The mean dose at the Oar’s presented statistically significant differences (p < 0.001) of 34.24%, 37.96% and 63.47%

for ipsilateral lung, contralateral lung, and heart, respectively. The films placed at the skin-surface interface in the ipsilateral

breast also showed statistically significant differences (p < 0.001) of 16.43%, –10.16%, –14.79% and 15.67% in the four quad-

rants, respectively. In contrast, the pTV dosimeters, representative of the left breast volume, encompassed by the electronic

equilibrium, presented a non-significant difference with Tps, p = 0.20 and p = 0.90.

conclusion: There was a non-significant difference of doses in pTV with electronic equilibrium; although no match is achieved

outside electronic equilibrium.

Key words: radiochromic film; breast cancer; thorax phantom





ISSN: 1507–1367

Introduction

Treatment planning systems (TPS) are software tools used for external radiotherapy. TPS predicts dose distributions and generates beam shapes al-lowing the optimization of the tumor control prob-ability (TCP) and the reduction of the likelihood of normal tissue complications (NTCP) [1].

Meanwhile, most TPSs present some limitations in predicting superficial doses in the skin, in in-terfaces of heterogeneous materials, in the voids, and low density regions such as the lungs [1, 2]. Radiotherapy of breast cancer involves a complex anatomy and various tissues of highly different den-sities, including soft tissue, lung, bone, and air [3]. Unlike acrylic phantoms, the anthropomorphic and

Elsa Bifano Pimenta et al. Dose measurements in a thorax phantom at 3DcrT breast radiation therapy


anthropometric phantom developed by the NRI (Núcleo de Radiações Ionizantes) research group from UFMG can reproduce the effects of the inter-actions of radiation with the human body. Briefly, this thorax phantom contains the synthetic heart, lungs, and spinal cord similar in density to their human counterparts, mimicking heterogeneous thoracic anatomy [4].

Electronic equilibrium occurs when scattering secondary electrons from primary photon radiation achieves paths with the angular isotropic distribu-tion. Such conditions have been studied in homo-geneous water medium exposed by energetic pho-tons in which Compton scattering is a predominant process [5]. Besides, an inhomogeneous medium causes electronic disequilibrium and reduction of absorbed energy in regions close to the inhomo-geneity materials. Such longitudinal electron dis-equilibrium results in a build-up region. The effect of the build-up occurs when the beam passes from a lower density to a higher density medium, and the re-build-up occurs in the reverse direction, from the highest to the lowest density [6, 7]. On the TPS, dose calibration occurs only in a homogeneous me-dium in which electronic equilibrium condition is held. Herein, dose is defined as absorbed energy per specific mass. The TPS dose calculation in the build-up region is estimated from the data’s ex-trapolation measured on the basis of the maximum dose depth using adjusted functions [8].

In the case of high energy photons in low density material or in small beam’s portals, the lateral elec-tron path can be larger than the field size and, thus, lateral electron disequilibrium (LED) can occur. In the low density lung tissue, the dose from scattered electrons is deposited further away from the inter-action points, far from than the correction algo-rithm predicts. Therefore, the dose is overestimated in the high dose region (infield) and underestimat-ed in the low dose region of the lung, outside the ra-diation field [3].The effects of LED on the lung dose are generally poorly accounted for by commercial dose calculation algorithms which oversimplify the secondary electron trajectory [9–15].

In addition, the surface dose can be influenced by the contamination of electrons from the collima-tor system, by the secondary scattering photons of the gantry and also by backscattering photons from the underlying tissue layers, mainly unpredictable by TPS [16]. Most of the commercially available

TPS calculate the exit dose under the full scatter conditions and cannot accurately provide the en-trance skin doses [8].

Therefore, the reproduction of the internal do-simetry through detectors in phantoms may in-crease the knowledge of the effects of the interac-tion of radiation on the human being in radio-therapy, especially in heterogeneous interfaces, skin surface and low density material, as present in breast radiation therapy where electronic disequi-librium persists.

The goal was to provide a 4MV-3DCRT dosim-etry in a realistic breast thorax phantom, investigat-ing especially the inhomogeneous organs interfaces and skin, regions with non-electronic equilibrium, matching values with TPS for the propose of adopt-ing anthropomorphic and anthropometric phan-toms in a clinical routine.


The 3D-crT therapy planThe plan was performed in the CAT3D TPS,

from Mevis Medical Company, supported by the Pencil Beam Convolution algorithm. The chosen modality was the three-dimensional conformal RT (3D-CRT) based on two parallel opposite fields ap-plied in the ipsilateral breast exposure of an anthro-pometric and anthropomorphic thorax phantom with a prescribed dose of 2.0 Gy in 25 fractions. The planning target volume (PTV) and the following organs at risk (OAR) were selected: lungs, heart, and contralateral breast.

The planning was optimized matching the com-bination of two weighted modulated irradiation fields in which monitor units (MU) associated with each field, collimator, gantry and angular positions were set. A suitable planning conformation was proposed, covering the whole PTV, and minimizing the exposure of the OAR’s. The secondary collima-tors known as jaws determine the size of the field. The wedges were set in order to modify the dose distributions. A 15° wedge filter was used for each field to avoid beam divergence, as shown in Table 1.

Preparation of anthropomorphic and anthropo-morphic breast phantom

A thorax phantom was previously prepared, as described by Schettini et al. 2007 [17]. Some adjust-ments were adopted, including the skin, heart and muscle manufactured. Breasts were fabricated and



adapted to the thorax phantom. The proportion of glandular tissue and adipose tissue of the breasts was 50:50 to represent a fibroadipose breast. The glandular tissue was made of a natural elastomer in the weight percentage of 77%, including 10% graphite powder, 0.3% NH4Cl (0.1%), NH4 (4.1 g) present in the elastomer, (NH4)2SO4 (0.9%), NH4H2PO4 (0.18%), C28H30Na8O27 (0.3%), NaH2PO4 (0.3%), KC (0.2%), H2O (7.7%) pres-ent in the elastomer, NaCl (0.08%). After drying, the tissue lost 15% in weight, already considered in its elementary chemical composition. The chemi-cal elements constitution of glandular TE achieved were: carbon (78.0%), hydrogen (10.9%), oxygen (7.6%), nitrogen (3.4%), sodium (0.1%), phospho-rus (0.1%), sulfur (0.2%), chlorine (0.2%) and po-tassium (0.1%), based on stoichiometric calcula-tions using the constituent compounds.

The adipose tissue surrounding the breast was manufactured with 30% paraffin, 25% carnauba wax and 45% polyol mineral oil. The thorax muscle tissue and the heart were fabricated with the same material as the glandular tissue; however, with small differ-ences in proportion to match the elementary chemi-cal composition of the heart tissues in mass weight.

For the manufacture of skin tissue, 50% animal col-lagen gelatin and 50% hydraulic silicone were mixed [18]. The ribs and spine were made of animal bone powder, washed, dried, sieved, sterilized, glued with orthophytalic resin. The similarity of the elementary chemical composition, number of Hounsfield, and coefficients of conversion of fluency-Kerma to pho-tons and neutrons were verified for each organ of the phantom, already documented in literature [17].

phantom and dosimeter positioningEBT2 radiochromic films of 3 × 2 cm2 were

placed in each quadrant of the skin of the ipsilat-eral breast, where the films, coded as BS1, BS2, BS3 and BS4, were placed in the upper medial, upper lateral, lower lateral and lower medial quadrant, respectively, as shown in Figure 1A. The measure-ments in OARs were performed by inserting into the ipsilateral breast, contralateral breast, lungs, and heart in the coronal axis as in the scheme shown in Figure 1B. The absorbed dose in PTV was mea-sured with four M1, M2, M3 and M4 films of differ-ent sizes due to the anatomical shape of the breast. They were inserted into the ipsilateral breast of the thorax phantom (Fig. 1C), along the axial axis, as shown in Figure 1D.

table 1. radiotheraphy protocol of the 3D-conformal radiotherapy (3DcrT)

Parameters ML Fielda LM Fielda

Isocenter Iso Iso

Field X 160 160

Field Y 100 100

Table ang 0 0

Gantry ang 233 48

Gantry rot 0 0

collim ang 11 350

Weight 1.1 1

Wedge Filt W15 W15

Wedge pos ccW cW

Tray Factor 1 1

head–jaw 0 0

Feet–jaw 0 0

right–jaw 0 0

Left–jaw 0 0

ssD 727.6 725.6

Device 0 0

MU 145.0 134.8

ssD — source to surface distance; MU — monitor unit

Figure. 1. The films Bs1, Bs2, Bs3 and Bs4 placed in each quadrant on ipsilateral breast skin (A). The organ at risk (Oar) films were inserted in the two lungs and in the heart myocardium (b). The planning target volume (pTV) films (M1, M2, M3 and M4) were inserted into the ipsilateral breast of thorax phantom (c) along the axial axis (D)

a B

c D



Irradiation on LINacThe irradiation was performed on the Varian mod-

el 4/80 Varian linear accelerator at 4MV spectrum, made available from the Institute of General Radio-therapy and Megavoltage of Minas Gerais, Brazil.

Dose versus optical density correlationCalibration was performed in a water-tank phan-

tom at 100 cm SSD, holding a set of films in depth ranging from 1.5 cm to 19.5 cm with increments of 2.0 cm. The film’s response was correlated with absorbed dose measured in a secondary standard ionizing chamber dosimeter, placed in the same depth in the same water tank phantom. The dose interval was 0 to 4.0 Gy. The calibration films were digitized in the transmission mode scanner.

The optical densities (OD) of the red (R) com-ponent of the set of digitized films were gener-ated. A correlation between doses as a function of OD was achieved adjusting the data. The follow-ing polynomial function was obtained empirically based on Beer-Lambert’s law [19]:

y = A.OD + B.ODn (1)

in which the coefficients A and B are estimated from the experimental data correlating the ab-sorbed dose (y) as a function of the OD, where n is the degree of the polynomial function.

Dose analysis and intercomparisonAll M1 to M4 and BS1 to BS4 dosimeters were

digitized and an HP Scanjet G4050 scanner. The RGB components were split and R-component im-age treated. Optical density was evaluated in the R-component image on a pixel basis. Based on Eq. 1, dose distribution was generated on the images, sup-

ported by the ImageJ software. The absolute mean doses and standard deviation of the data from films present on the PTV and OAR were evaluated. For the dosimetric intercomparison, a CAT3D tool, namely POI, was used. It allowed the reading of the absolute dose at points of interest (POI) pre-estab-lished in the TPS. This tool is usually used to define the isocenter of the PTV.

The calibration radiochromic conditions were at the same as those for the LINAC dose calibration, with a similar temperature and pressure environ-ment. The calibration curve was fed with similar dose data as the TPS.

statistical analysisStudent t-test with the significance level of 5%

was used to compare the means of the doses from the radiochromic films with the mean values in the POIs from TPS.

results

The therapy planFigure 2 depicts the CT images of the phantom

and the plan adopted for this dosimetric study, pro-vided by the CAT3D MEVIS Medical Company.

Dose versus optical density responseThe parameters found in the calibration curve

of the films were a = 5.57 ± 3.39; b = 91.47 ± 94.16; n = 2.57 ± 0.93 with a coefficient of determination of 0.998.

Internal phantom dosimetry compared to Tps

Figure 3 depicts the spatial dose maps gener-ated in M1, M2, M3 and M4 films of the internal

Figure 2. The 3D-conformal radiotherapy (3D-crT) plan performed in caT3D based on axial images registered by the cT. Images were superposed to the axial cT image sections, and a sagittal reconstruction was performer



left-breast exposed with 3D-CRT. Table 2 shows the doses in the dosimeters in the breast.

Discussion

The ideal equation for the calibration curve is still questionable, but a second or higher order polyno-mial is often used in adjusting the calibration equa-tion based on Taylor’s theorem [20–23]. In our case, the coefficient of determination of 0.998 provided

a suitable value which guarantees a well-adjusted mathematical representation of the data. This was consistent with Silva et al. (2018) which has found n equal to 2.5 for both water and solid water in the range of 50–450 cGy with 4 MV Varian’s Clinac 6XSN11 [26].

The film calibration was performed in water since this material is the recommended reference standard for the determination of absorbed dose in the IAEA document TRS 398 [24]. According to

table 2. comparison of eBT2 film and caT3D

Films Dose Film [Gy] Dose TPS [Gy] Difference (%)

M1 1.31. ± 0.11 2.04 ± 0.05 –55.35 (p < 0.001)

M2 1.95 ± 0.17 2.05 ± 0.21 –5. 17 (p = 0.20)

M3 1.93 ± 0.17 2.02 ± 0.84 –4.38 (p = 0.90)

M4 1.16 ± 0.10 1.99 ± 0.07 –71.35 (p < 0.001)

Ipsilateral lung 0.30 ± 0.03 0.20 ± 0.22 34.24 (p < 0.001)

contralateral lung 0.03 ± 0.00 0.02 ± 0.00 37.95 (p < 0.001)

heart (myocardium) 0.26 ± 0.02 0.09 ± 0.02 63.47 (p < 0.001)

Bs1 1.12 ± 0.10 0.94 ± 0.66 16.43 (p < 0.001)

Bs2 1.13 ± 0.10 1.24 ± 0.5 –10.16 (p = 0.10)

Bs3 1.18 ± 0.10 1.35 ± 068 –14.79 (p < 0.001)

Bs4 0.95 ± 0.08 0.8 ± 0.15 15.67 (p < 0.001)

Figure 3. spatial dose maps generated within M1 (A), M2 (b), M3 (c) and M4 (D) dosimeters placed in the left-breast exposed with the 3D-conformal radiotherapy (3D-crT), in which XY-scales were in mm and dose scale in Gy

400

300

200

100

100 200 300 400 500 600 700 800 mm

mm

400

300

200

100

200 400 600 800 1000mm

mm

400

300

200

100

200 400 600 800 1000 mm

mm

350

300

250

200

150

100

50

100 200 300 400 500 600 700 mm

mm

Dose [Gy]

> 2.0

< 1.0

a B

c D



TRS 398, this material is the most similar to the hu-man tissue composition for photons. Thus, it is ex-pected that the absorption and scattering properties of radiation are equivalent [25, 26]. The calculation tables often used in dose calibration in radiotherapy centers, which are the same for clinical cases, are prepared in water.

The calibration curve was built based upon the relationship between the dose and the optical densi-ty of the film in an equilibrium electronic condition. Indeed, it captured the relationship between the amount of organic chemical reactions that produce color on the film to the concentration of secondary electrons and free radicals induced by radiation ex-posure in the film. Hence, regardless of the distinct phenomenon of secondary electron and photon in-teractions in a medium or interfaces, the correla-tion between chemical reactions and free radicals is preserved. Nevertheless, the chemical reaction rate is energy-dependent, which explains a slight variation of the radiochromic color density with the incident particle energy. Although the radiation in-tensities are distinct in the phantom and in the cali-bration tank of water, their internal energy spectra were provided by the same LINAC radiation source; therefore, the energy-dependence may be negligible.

After TPS was installed, commissioning and modeling were carried out. Commissioning was done for various dose measurements in wa-ter-tank phantom at various depths, LINAC’s en-ergies, and field sizes. These measurements were converted into tables, and those values were re-corded in TPS, called modeling tables. In addi-tion, a secondary water-dosimetry is performed monthly using the data in the table to check the dose and TPR20/10. In this way, our radiochro-mic-film-based dosimeter was validated with the doses in the TPS, since both used the same sec-ondary water dosimetry and water-tank phantom. Those experiments were performed at the time of the LINAC calibration data, under similar tem-perature and pressure conditions.

The breast phantom anatomy, especially the chest wall thickness, and the uncertain positioning in the detector relative to the breast surface and thorax, among other factors, influenced the dose measure-ments and its comparison to TPS. Whereas the maximum dose depth for a 4MV photon beam is 1.0 cm, the M1 and M4 films positioned near the breast surface in the equivalent adipose tissue were

encompassed by the build-up region; therefore, TPS could not predict dose well in a non-electronic equilibrium environment.

Table 2 summarizes the comparison of radio-chromic film and TPS based pencil beam algo-rithm. The dose in the build-up region close to the skin was not accurately considered by the TPS, justifying the low average doses provided by the PTV in the positions of the M1 and M4 films, since those films were placed around the breast surface, enclosed in the build-up region. In addition, the same can be said for the high percentage differ-ences in ipsilateral breast skin whose values were within ± 20%.

The mean doses of M2 and M3 films in PTV were within the recommendations of the ICRU report No. 50, where the absorbed dose delivered cannot vary more than ± 5% with respect to the prescribed dose [27]; while the values of the M1 and M4 films near the surface were not in agreement. The dif-ferences between mean dose measurements in the phantom and found in the TPS were 4.91% and 4.20%. The t-test for dosimetric intercomparison of sections M2 and M3 showed a non-significant difference.

Nogueira et al. (2015) have measured the ab-sorbed dose in 3D CRT left-breast radiation therapy in a sagittal film placed at the center of a synthetic breast [28]. Their RT-protocol followed the dose prescribed of 1.8 Gy in 28 fractions. The average dose per fraction at the sagittal dosimeter placed at the center of the breast was 1.9 ± 0.2 Gy, and the TPS was 1.84 ± 0.2 Gy at the same position [28]. Indeed, the dose distribution at the whole PTV varied from 100% up to 112% of the prescribed dose; while TPS provided 100% up to 105% [28]. Our experiment provided 96% of the prescribed dose at M2 and M3 dosimeters placed on the trans-verse plane inside the breast. In both experiments, the film positioning, the Linac-type and the TPS protocols were distinct; however, in the left-breast, inside the electronic equilibrium region, the doses were compatible with the prescribed dose. In the same experiment, the skin dose of the ipsilateral breast varies from 1.0 to 1.4 Gy, having an average dose of 1.20 ± 0.10 Gy [28]. In the ipsilateral breast skin, the dose achieved 1.10 ± 0.10 Gy, evaluated on three films placed on the breast-skin [29]. In our experiment, BS1 up to BS4 provided an average dose of 1.09 ± 0.09 Gy.



The percentage dose discrepancy on the heart can be explained by the heterogeneity of the lung. The radiochromic film might have detected a build-up region, possibly present in the lung-heart interface due to its 0.3/1.05 density ratio, while the TPS’s are known to be inaccurate in regions outside the electronic unbalance such as build-up regions. The non-reproducibility of the heart positioning in the phantom may also have contributed to the percent-age difference, since the distance between the heart and the radiation field may have been altered after the insertion of the films. The percentage differ-ences in lung dose can be explained by the difficulty of TPS (in this case, Pencil Beam) to accurately predict the variations of the local electron den-sity of the lung and, therefore, adequately respond to the effects of electronic lateral scattering and re-build-up.

It has been observed that the main limitations in the experimental dose measurements in the phan-tom are due to anatomic discrepancies with hu-man beings. Indeed, the tomographic representa-tion used in TPS was the same as in the physical phantom. Thus, the same anatomic discrepancies were reproduced on the TPS. The build-up region in the skin-interface can be addressed in the physi-cal phantom and in its modelling feed in the TPS. Despite the dosimetric correlation, a comparison to a human being dosimetry cannot be called, es-pecially near the regions that have an anatomical discrepancy with human anatomy.

Despite the anatomic discrepancies and posi-tioning errors of the phantom, the limitations of the dose calculations of the TPS software persist in the heterogeneous interfaces, skin surface and low-density material, often present in breast radia-tion therapy. Such limitations showed up also in the tomographic-phantom modelling used in the TPS. Lack of electronic disequilibrium persists, and it was responsible for the overall differences between dose predicted by a TPS and measured values in the phantom.The overall responses of several well-known therapy planning systems (TPS) have been investigated in literature [30], with distinct complexity and modeling hetero-geneity, doses in blocked regions, or tangential effects. According to the IAEA pilot study, CAT3D TPS is among the most accurate systems available on the market. EBT2 films present limitations, es-pecially in calibration procedures; however, there

are recommendations in its use in quality assur-ance in radiation therapy where dose uncertainty of up to 2.8% is acceptable [31]. We found that EBT2 dosimeter is a suitable tool for reproduc-ing normalized spatial dose distribution into an-thropometric and anthropomorphic phantoms, to study heterogeneity among other conditions. In the present paper, the dosimeter was able to capture internal build-up phenomena in 3DCRT breast radiation therapy.

In summary, our findings were experimen-tal mean doses in M2 and M3 films to the PTV in agreement with TPS, while discrepancy values of the M1 and M4 films at the PTV but near the skin-surface. Experimental overdose of 34.24%, 37.96% and 63.47% for the ipsilateral lung, con-tralateral lung, and heart, respectively, 15% to the skin at the internal right side of the breast, and 10% sub dose outside. Such values demonstrated poor dose predictions of the pencil beam convolu-tion algorithm calculation in sites of non-electronic equilibrium environment.

The measurement of doses in phantoms can pro-vide much information about the interactions of the radiation with tissues. Film detectors may con-tribute to recording such data. The intercomparison with TPS is a challenge since there are large uncer-tainties in film positioning, calibration processes, and absence of precise reference points.

conclusions

Dosimetry, including a realistic breast phantom, was a useful tool to record phenomena such as build-up, re-build-up, electronic side balance and electronic contamination, complementing the in-formation of the TPS by depicting doses in regions where those calculated values are imprecise, as in the skin dose and organ interfaces with high het-erogeneity. Indeed, our findings show statistically non-significant difference between the electron-ic-equilibrium PTV regions and the experimental and TPS values. However, for near heart-lung inter-faces, discrepancies were up to 40%. Skin measured doses matched with values found in literature, with ± 20% of TPS data. Therefore, there are no robust protocols that can establish quality control of the internal dose in overall regions of the patients. Our findings support the adoption of an anthropo-morphic and anthropometric phantom as a tool to



help physicists carry out a more comprehensive QA program routine.

conflict of interestsThe authors declare that there is no conflict of inter-ests regarding the publication of this paper.


acknowledgmentsThe authors express their gratitude to the medi-cal physicist Sávio F. Rosa for his support and as-sistance in experimental support. In addition, we express our gratitude to the Institute of General Radiotherapy and Megavoltage of Minas Gerais for providing the facility, and CNEN for financial sup-port with a master’s degree scholarship. We thank MEVIS Medical Company for all the technical support and availability of the planning software, which has been useful in learning and research in the field of radiotherapy. We are thankful to CNPq, REBRAT-SUS project.

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http://dx.doi.org/10.1118/1.2828196


http://dx.doi.org/10.1118/1.2938522


http://dx.doi.org/10.1107/S1600577517005641


http://dx.doi.org/10.1016/j.apradiso.2014.12.022




http://dx.doi.org/10.1007/s13246-011-0072-6



research paper




Address for correspondence: Alper Özseven, Department of Radiation Oncology, Suleyman Demirel University Hospital, Isparta, Turkey, tel: (+90) 246 211 9538; e-mail: [email protected]

Evaluation of patient organ doses from kilovoltage cone-beam CT imaging in radiation therapy

Alper Özseven 1, Bahar Dirican 2

1Suleyman Demirel University, Medical Faculty, Isparta, Turkey2University of Health Sciences, Gulhane Medical Faculty, Ankara, Turkey

AbstrAct

background: currently, cBcT system is an indispensable component of radiation therapy units. Because of that, it is impor-

tant in treatment planning and diagnosis. cBcT is also an crucial tool for patient positioning and verification in image-guided

radiation therapy (IGrT). Therefore, it is critical to investigate the patient organ doses arising from cBcT imaging. The purpose

of this study is to evaluate patient organ doses and effective dose to patients from three different protocols of elekta synergy

XVI system for kV cBcT imaging examinations in image guided radiation therapy.

Materials and methods: Organ dose measurements were done with thermoluminescent dosimeters in alderson raNDO

male phantom for head & neck (h&N), chest and pelvis protocols of the elekta synergy XVI kV cBcT system. From the measured

organ dose, effective dose to patients were calculated according to the International commission on radiological protection

103 report recommendations.

results: For h&N, chest and pelvis scans, the organ doses were in the range of 0.03–3.43 mGy, 6.04–22.94 mGy and 2.5–25.28

mGy, respectively. The calculated effective doses were 0.25 msv, 5.56 msv and 4.72 msv, respectively.

conclusion: The obtained results were consistent with the most published studies in the literature. although the doses to

patient organs from the kV cBcT system were relatively low when compared with the prescribed treatment dose, the amount

of delivered dose should be monitored and recorded carefully in order to avoid secondary cancer risk, especially in pediatric

examinations.

Key words: kV cBcT; equivalent organ dose; effective dose; image guided radiation therapy; alderson rando phantom





ISSN: 1507–1367

Introduction

Cancer is still accepted as the deadliest among all diseases [1]. In order to cure cancer, several treatment modalities have been used in recent years. Radiation therapy is one of the main treat-ment methods used in cancer treatment along with surgery and chemotherapy. Especially, when the surgery and chemotherapy are not feasible, radia-tion therapy is the only treatment choice for some

cancer forms. Additionally, due to the vital status of radiation therapy in many cancer types, treatment delivery accuracy of radiation therapy becomes critical for cancer patients [2]. One of the most important factors that make cancer treatment ef-ficacious is irradiation of the targeted tumor tissue under appropriate conditions, as well as protecting normal tissues surrounding the tumor as much as possible. It is essential that the patient is positioned correctly before and during the treatment in order

https://orcid.org/0000-0001-6128-6426

https://orcid.org/0000-0002-1749-5375



to get favorable results [3]. The first step of treat-ment delivery is correct positioning of the patient on a treatment couch. Although the technician can align the patient on the treatment couch correctly from the external perspective; the position of nor-mal tissues or tumor may not be as they should be from the internal point of view. For this reason, imaging the corresponding part of the treatment region before treatment is prerequisite for perfect treatment delivery.

Nowadays, image guided radiation therapy (IGRT) is accepted to be the standard treatment modality especially for challenging treatment cases and, especially, for arc therapy. Generally, Cone Beam Computed Tomography (CBCT) is believed to be one of the most useful imaging methods in radiation therapy. Moreover, CBCT is not only used in cancer treatment for imaging head& neck (H&N), thorax and pelvis regions, but also used in the examination of the man-dible and nasal region in dentistry. Commonly, CBCT imaging systems are named in terms of the energies produced by the X-ray generator dur-ing imaging processes. The platforms which use million-voltage (MV) X-ray energies for imaging are called MV-CBCT. On the other hand, some of the systems use kilo-voltage (kV) X-ray energies for this process and these platforms are named kilo-voltage CBCT (kV-CBCT). They consist of a kV generator that produces X-rays in kilo-volt energies and a flat-panel detector, most often called electronic portal imaging device (EPID), that detects these attenuated X-rays. During the imaging process the kV-generator and flat-panel detector complete their rotation around the cor-responding region of the body by obtaining high quality projection data [3–5].

Verifying position accuracy before and during the treatment of the patient is done by analyzing simultaneous images taken of the patient with the help of electronic portal imaging devices. EPID is a part of digital radiography that provides ease of use in imaging technology and equipped with the latest technological developments. In addition to AP and LAT images that are used conventionally at 90 degrees angle to each other, it is important to obtain a 3-dimensional image in order to estab-lish patient position accuracy in all axes by using EPID [6]. On the other hand, beside having many advantages, the main disadvantage of this imaging

system is delivering undesired radiation dose to the patient. The repeated use of a CBCT system in all fractions of treatment could increase the probabil-ity of developing secondary cancer risk, especially in pediatric patients [7, 8]. Because of that, these imaging systems should be used carefully and the additional undesired imaging dose to patient or-gans should be monitored and measured.

The purpose of this study is to evaluate patient organ doses from three different protocols of the Elekta Synergy XVI system for kV CBCT imaging examinations in image guided radiation therapy using Alderson Rando male phantom. In addition to that, from the measured organ doses, effective dose to patients were calculated by using ICRP 103 recommendations.


The measurements of patient organ doses from kV-CBCT scans were collected by using Elekta Synergy Platform that was equipped with X-ray Volume Imaging (XVI) system release 4.5 (Elek-ta Oncology Systems Ltd, Crawley, UK) (Fig. 1). The X-ray source is attached to a retractable arm with a fixed source to isocenter distance of 100 cm (Fig. 1).

Imaging process and measurementsFor H&N, thoracic and pelvic scans; Head &

Neck S20, Chest M20 and Pelvis M20 presets were performed, respectively. The field of view in axial and longitudinal axis were described in detail in the study of Hyer et al. [9]. Moreover, the detailed

Figure 1. elekta synergy platform equipped with XVI system

Gantry

kV detector

MV detector

kV X-ray detector

Alper Özseven, Bahar Dirican Organ doses from kV cBcT imaging


parameters for each imaging protocol are listed in Table 1.

In this study a total of 20 patient organ dose measurements were carried out in an Alderson Rando anthropomorphic male phantom (Phantom Laboratory, Salem, NY, USA). In addition to that, effective doses to the patient were calculated from the measured organ doses. The detailed list of or-gans measured in the study is displayed in Table 2. In the Alderson Rando phantom, soft tissue, bone and lungs are equivalent to their true density. The bones in the Rando phantom are real human bones, and there are cavities equivalent to those in human body. The male RANDO phantom is made of 36

slices, each with a thickness of 2.5 cm, except for slice 35 which is 9 cm thick. Each slice from slice number 1 to 34 contains a grid of holes, 5 mm in diameter, separated at 3 cm distance (Fig. 2).The positions of TLDs in the RANDO phantom were positioned in consistence with the recommenda-tions of Golikov&Nikitin and Scalzetti [10, 11].

The measurements were repeated three times for each scanning protocol. The arithmetic mean of these measurements was recorded as the average dose for the corresponding organ. The mean dose and standard deviation for each measurement were calculated by using the SPSS software version 22 (Armonk, NY, IBM Corp., USA).

table 1. exposure parameters for kV cBcT scanning protocols

Head & Neck S20 Chest M20 Pelvis M20

X-ray voltage [kVp] 100 120 120

X-ray [mas] 36.6 1056 1056

Gantry rotation [degree] 360 360 360

Nominal projection number 366 660 660

table 2. The measured organ doses (mGy) and calculated effective dose to patient (msv) from single kV cBcT scan

Organ Head & neck scan Chest scan Pelvic scan

Brain 2.80 ± 0.01

Oral mucosa 3.25 ± 0.01

salivary gland 3.18 ± 0.02

Thyroid 3.23 ± 0.01

Lens 3.43 ± 0.03

esophagus 0.73 ± 0.02 15.04± 0.08

Lungs 0.03 ± 0.00** 17.83 ± 0.08

Thymus 17.93 ± 0.09

spleen 15.26 ± 0.08

heart 22.94 ± 0.10

adrenals 11.93 ± 0.06

skin 0.29 ± 0.00 ** 8.22 ± 0.04 2.89 ± 0.02

Liver 15.77 ± 0.07 2.50 ± 0.02

stomach 11.70± 0.06 5.18 ± 0.03

Kidneys 6.04 ± 0.03 13.10 ± 0.05

pancreas 7.88 ± 0.04 7.43 ± 0.04

Gall bladder 23.52 ± 0.09

small intestine 25.28 ± 0.09

colon 24.25 ± 0.09

Bladder 11.53 ± 0.07

effective dose 0.25* 5.56* 4.72*

*Denotes underestimated effective doses for each scan (some of the organs with tissue factor couldn’t be measured); **Denotes the standard deviation is less than 0.01



Scalzetti et al. offered a new proposal about the hole position of organs in the Alderson Rando phantom based on three-dimensional Cartesian coordinate system. According to that conjecture, the center hole of each slice was accepted as the (0,0) central point in a rectangular frame (Fig. 3).

Lens and skin doses were measured by placing TLD on the surface of corresponding part of the phantom. Eight TLDs were used to compute the skin doses in each preset by locating the TLDs in the anterior, posterior, left and right surface of the phantom.

TLD calibrationBefore starting the calibration process, Ele-

ment Correction Coefficient (ECC) factors were calculated for each thermoluminescent dosimeter (TLD), and the TLDs which are within ± 5% ac-ceptance limit were selected for use. In total, 116 lithium fluoride TLDs (TLD-100 LiF) were used for each measurement. The TLDs used are in the form of a square prism with dimensions 3.2 mm × 3.2 mm × 0.9 mm. In order to make the measure-ments more accurate, each TLD has been calibrated individually before measurements for the photon energy of 100 kVp and 120 kVp. Same beam pa-rameters were used for the calibration as during the measurements (Fig. 4). TLDs were irradiated in a poly-methyl methacrylate holder. After that, irradiated TLDs were read with Harshaw 3500 TLD reader (Harshaw Thermo Electron, Solon, USA). From the beam and dose parameters used in the calibration process (mAs, mGy), Reader Calibra-tion Factor (RCF) was computed for each scanning protocol which was used in the calculation proce-dure of patient organ doses.

calculation of organ doses and effective dose

Patient organ dose measurements were carried out in an Alderson Rando anthropomorphic male phantom by TLD placed in hole positions of organs. The definition of equivalent dose is based on the mean absorbed dose, DT , in the volume of a speci-fied organ or tissue T, due to radiation of type R [12]. The unit of absorbed dose is Gray (Gy). The mean absorbed dose, DT to a specific organ or tissue T, is calculated by using equation 1 [12].

Figure 2. alderson rando male phantom

Figure 3. center hole in cartesian coordinate system assigned by scalzetti et al. and hole numbers logic in alderson rando phantom (e.g. slice 31)

Figure 4. calibration process of LiF TLDs



DT = ∑i Di fi (1)

where DT denotes the mean absorbed dose of the specified organ in miligray (mGy), Di is the arith-metic mean dose of the TLDs for the correspond-ing organ within the slice i of phantom, fi denotes the fraction of total organ mass in the slice i of the Alderson RANDO phantom. Equivalent dose in an organ or tissue, HT, is then defined by equation 2 [12]:

HT =∑R wR DT (2)

where wR is the radiation weighting factor for radiation R. Radiation weighting factor is equal to one for photons [12].

After calculating patient equivalent organ dos-es (HT), effective dose (Deff) were computed in milisievert (mSv) by using Equation 3 which is de-fined by the International Commission on Radio-logical Protection (ICRP). The effective dose, Deff, is defined by a weighted sum of organ or tissue equivalent doses [12].

Deff = ∑T wT HT (3)

where wT is the tissue weighting factor prescribed by ICRP [12].

In this study, the tissue weighting factors, which were suggested in the ICRP 103 publication, were used [12]. In addition to that, 0.0086 value was assigned for remainder organs as suggested by the ICRP 103 publication. Besides, while in the ICRP 60 report, the upper large intestine (ULI) was in-cluded in remainder organs, in the ICRP 103 re-port, the upper large intestine and lower large in-testine (LLI) were combined and named as colon. Moreover, in this study, while calculating the colon dose, the formula suggested in the ICRP 67 report was used, which is mass weighted average of the doses of both ULI and LLI as Colon Dose = 0.57 ULI + 0.43 LLI [12–14].

Fraction values of the skin were obtained from the study of Huda & Sandison [15]. All the other or-gans fractions were reported in literature. Because of the lack of information about the hole location for red bone marrow (RBM) and bone surface in the RANDO phantom, the equivalent doses were not able to be measured for these organs. In addi-tion to that, since an Alderson RANDO male phan-

tom was used, the breast dose was not measured. Moreover, because of the gonads were out of the beam line in pelvic irradiation, the equivalent dose of the gonads was not calculated. As a result, the effective dose was underestimated for the patient.

results

The maximum organ dose for H&N, thoracic and pelvic scans were at the lens, heart and small intestine, with equivalent doses value of 3.43 mGy, 22.94 mGy and 25.28 mGy, respectively. The cal-culated effective dose to the patient for H&N S20, Chest M20 and Pelvis M20 were 0.25 mSv, 5.56 mSv and 4.72 mSv, respectively. The measured organ doses and calculated effective dose to the patient are displayed in Table 2.

Discussion

Position accuracy, which is among the most de-termining factors that affect the quality of treat-ment, is performed in a flawless manner with de-vices using advanced technology such as CBCT. Because of that, CBCT is of critical importance in today’s radiotherapy treatment, and researchers have examined the quality assurance parameters of this system from the beginning of implementation [16–21].

On the other hand, beside this unique properties of CBCT, delivering to the patient an additional dose for this procedure is its major drawback. In this study, the absorbed organ doses and the effec-tive dose given to the patient were measured on an Alderson RANDO phantom for the imaging proto-cols applied to different parts of the body using the kV CBCT imaging system on the Elekta Synergy Platform.

The organ doses highly rely on exposure param-eters and the geometry of the scanning procedure, such as field of view size and depth of measure-ment. In literature, a large spectrum of research has been conducted. Although most of the studies were carried out with similar exposure parameters, a considerable number of them applied different scanning parameters.

Most of the recent studies have indicated that secondary cancer risk due to X-ray exposure from diagnostic imaging of the CBCT systems is more than anticipated, especially for pediatric patients [7].



In this study, the calculated doses were just for a single course of an imaging process. Because of that, treatment delivery dose of radiation therapy may differ for different types of cancer and the total imaging dose for the entire course of radiotherapy might be increased. In other words, for a single patient, the obtained values in Table 2 could be multiplied by the total fraction number of the ra-diotherapy. In such case, the dose taken from the imaging process could rise to higher values during the course of treatment.

Hyer et al. measured effective dose with opti-cal-fiber based scintillation detectors for the Elekta Synergy XVI system. It was one of the most com-prehensive study in literature for investigating the organ doses from CBCT imaging. Although similar exposure parameters for H&N and Chest kV CBCT irradiations were used; our results in this study are different. In the chest scanning protocol, the organs doses, such as the heart, lung, liver, stomach and kidney, were calculated to be lower. In addi-tion, while the dose to the esophagus was found to be close to the measured value in this study; the thyroid dose was calculated higher as 19.24 mGy. On the other hand, all measured organ doses for H&N scanning protocol were lower than that of those calculated in this study. Furthermore, the ef-fective dose measurements reported for H&N and Chest irradiation were consistent with the findings of our study which were 0.04 mSv and 7.15 mSv, respectively [9].

Remarkably, although higher exposure param-eters were applied for H&N imaging in the study of Amer et al., the obtained surface dose of the phan-tom was consistent with our study [22].

A feasibility study was carried out for the Elekta Synergy XVI system on the Alderson rando phan-tom by Sykes et al. In that study, the image quality and the delivered dose values were compared in high exposure and low exposure scanning modes. In H&N imaging, it was reported that surface and internal absorbed dose values were measured to be about 1 mGy, which was performed with the same exposure parameters in this study. The resultant values were approximately 1 in 3 of the values ob-tained in the present study [23].

Moon et al. used glass dosimeters to measure patient organ doses in a RANDO female phantom with the same exposure parameters and scanning geometry for the chest and pelvic scan of the cur-

rent study. The reported organ doses were in good agreement with those obtained from this study for the chest scan, particularly for the lungs, stomach, liver and thymus. On the other hand, the doses measured from the pelvic scan were lower for al-most all specified organs. Nevertheless, the effec-tive dose value for the pelvic scan was completely consistent with this study, which was 4.09 mSv. The underlying reason for that consequence can be that the number of tissues included in the calculation was higher than that of our study [24].

Dufek et al. evaluated and compared the organ and effective doses for different version of OBI and XVI systems in an Alderson RANDO male phan-tom by using a great number of TLDs. Although the exposure parameters for H&N scans were similar, the calculated organ doses were lower than this study. The doses for most of the organs in the H&N region were lower than 0.1 mGy in that study. The maximum organ doses reported for the salivary gland and oral mucosa as 0.9 mGy and 1.1 mGy, respectively. These measured doses were lower than the doses obtained in this study, i.e. about 3 mGy [25].

In this study, similar to the studies in the lit-erature, it is shown that decreasing dose parameter values, particularly mAs and the projection num-bers, are critical factors in the reduction of the dose delivered to the patient.

It should be noted that during the imaging pro-cess, trading off image quality in order to give the patient lower dose may cause repeat imaging. In other words, it is important to be able to achieve the “As low as diagnostically acceptable” (ALADA) principle without ignoring the “As low as reason-ably achievable” (ALARA) principle. This under-standing will allow both the reduction of the dose given to the patient and an imaging procedure with sufficient imaging quality.

conclusions

In this study, the equivalent doses of 20 organs and effective dose to patients were measured with TLDs in an Alderson RANDO male phantom for Elekta Synergy XVI system with the most used clin-ical protocols of kV CBCT. The equivalent organ doses and effective doses were estimated according to the ICRP 103 recommendations. The obtained findings were consistent with most of the published



results in literature. Although the doses to patient organs from the kV CBCT system were relatively low when compared with the prescribed treat-ment dose, the amount of delivered dose should be monitored and recorded carefully in order to avoid secondary cancer risk, especially in pediatric examinations.


FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. None of the authors have any financial support or relationships that may pose conflict of interest.

acknowledgementsThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. None of the authors have any financial support or relationships that may pose conflict of interest.

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research paper




Address for correspondence: Dr Rohith Singareddy, DNB Radiation Oncology, Basavatarakam Indo American Cancer Hospital and Research Institute, Road number 10, Banjara hills Hyderabad 500034, Telangana, India, tel: (+91) 9160390945; e-mail: [email protected]

Dosimetric predictors of acute bone marrow toxicity in carcinoma cervix — experience from a tertiary cancer

centre in India

Rohith Singareddy 1, Harjot Kaur Bajwa1, Mahendra M. Reddy2, Alluri Krishnam Raju1

1Department of Radiation Oncology, Basavatarakam Indo American Cancer Hospital and Research Institute, Hyderabad, Telangana, India2Department of Community Medicine, Sri Devaraj Urs Medical College, Kolar, Karnataka, India

AbstrAct

background: The objective of this study was To determine the dose volume parameters predicting acute haematological

toxicity in carcinoma cervix patients undergoing concurrent chemoradiotherapy.

Materials and methods: all patients that presented to the hospital between Jan 2019 and Dec 2019 were prospectively

analyzed. patients diagnosed to have carcinoma cervix and planned for concurrent chemoradiation by volumetric modulated

arc therapy (VMaT) were included for analysis. patients were assessed at baseline and every week during treatment for acute

haematological toxicities. Dose volume parameters from treatment plans were correlated with rTOG grade of haematological

toxicities.

results: a total of 34 patients diagnosed to have squamous cell carcinoma of cervix were treated by radical radiotherapy by

VMaT technique and concurrent chemotherapy. The most common stage of presentation was stage IIB (61.7%). 29 patients

(85.2%) completed five cycles of weekly cisplatin. statistical analysis for sensitivity and specificity of dosimetric parameters

was performed using receiver operating characteristic (rOc) curve. The probability of developing bone marrow toxicity was

analyzed using T test. Mean dose to bone marrow exceeding 28.5 Gy was significantly associated with bone marrow toxicity

(sensitivity — 82.4%, specificity — 70.6%). On analyzing dose volume parameters, volume of bone marrow receiving 20 Gy,

30 Gy and 40 Gy (V20, V30 and V40) more than 71.75%, and 49.75% and 22.85%, respectively, was significantly associated with

bone marrow toxicity.

conclusions: Our study concludes that mean dose to bone marrow exceeding 28.5 Gy has high sensitivity and specificity for

predicting bone marrow toxicity in patients receiving IMrT. Volume of bone marrow receiving 20 Gy, 30 Gy and 40 Gy signifi-

cantly correlated with acute haematological toxicity.

Key words: carcinoma cervix; hematologic toxicity; bone marrow sparing





ISSN: 1507–1367

Introduction

Concurrent chemoradiation therapy (CCRT) combined with brachytherapy is the current stan-dard of care for the management of locally ad-vanced carcinoma cervix [1, 2]. More than 40% of

active bone marrow is located in the pelvic region which receives varying degree of exposure during pelvic radiotherapy for cervical cancer resulting in acute hematological toxicity [3]. This acute toxicity is more severe with combined therapy compared with radiation therapy alone [4].

https://orcid.org/0000-0003-0398-9347



Over the past few years, there has been rising interest in using Intensity Modulated Radiotherapy (IMRT) for the treatment of gynecologic cancers to reduce side effects, mainly related to the bowel and bladder [5, 6]. Non bone marrow sparing IMRT can result in significant volume of marrow receiv-ing low dose of radiation [7]. There is limited data regarding predictors of acute hematological toxicity in carcinoma cervix patients receiving concurrent chemoradiotherapy with IMRT. We report the dose volume parameters associated with increased bone marrow toxicity in that scenario.


This study was a prospective observational study that included patients treated between January 2019 and December 2019. The study was approved by the institutional scientific and ethics committee. Patients diagnosed to have Carcinoma Cervix and planned for concurrent chemoradiation by IMRT were included for analysis. Patients that required postoperative adjuvant radiation, extended field ir-radiation and those who had not received chemo-therapy were excluded from analysis. Patients were assessed at baseline and every week during treat-ment for acute hematological toxicities. Bone mar-row dose volume parameters from treatment plans (mean dose, V20, V30 and V40) were correlated with RTOG grade of acute hematological toxicities.

simulation A CT scan of each patient in the treatment posi-

tion was obtained using our departmental scanner (Philips Brilliance, Netherlands). The scan param-eters consisted of a large field-of-view pelvic proto-col with a 3-mm-slice thickness. The CT scans were obtained from the L1 vertebral body to 5 cm below the ischial tuberosities. Intravenous contrast was administered to all patients before CT. In addition, all patients were immobilized with a thermoplastic mask.

radiotherapy treatmentAll patients were treated by the Rapid Arc IMRT

technique (Elekta Synergy LINAC). The clinical target volume (CTV) and critical organs were con-toured on individual axial CT slices in all patients. The clinical target volume was defined as the gross tumor plus areas containing potential microscopic

disease, including the cervix and uterus (if present), the superior third of the vagina (or superior half of the vagina, if clinically involved), the parame-tria, and the regional lymph nodes. The planning margins consisted of 15 mm around the cervix and uterus, 10 mm around the vagina and parametria, and a 5- to 7-mm margin around the nodal re-gions. The prescribed dose to the planning target volume (PTV) was 50 Gy in 2Gy daily fractions. The organs at risk included the bladder, bowel, rec-tum and femur heads. For each patient, freehand contours of the low-density regions inside the bone were contoured as the surrogate for bone marrow (Fig. 1). The window was adjusted to bone range while contouring to bring uniformity. To eliminate inter observer variations, all contouring was done by a single physician and verified by another physi-cian for all patients. The contouring began at 2 cm above the uppermost border of PTV and ended at 2 cm below the lower border of the PTV. No con-straint was prescribed to the pelvic bone marrow as the bone marrow was not defined as an OAR. Dose–volume histograms (DVHs) corresponding to the delivered IMRT plan were generated and the volume of bone marrow receiving 20, 30 and 40 Gy (V20, V30, and V40, respectively) was quantified.

Brachytherapy As per the institutional protocol, all patients re-

ceived the first fraction of HDR brachytherapy after three weeks from the start of treatment (after 30 Gy EBRT). The total dose prescribed was 21 Gy in 3 fractions, 7 Gy per fraction to point A, one fraction per week. The technique used for brachytherapy was 3 dimensional image guided brachytherapy.

Figure 1. Free hand contouring of the inner cortex of the pelvic bone for bone marrow delineation

Rohith Singareddy et al. Dosimetric predictors of acute bone marrow toxicity in carcinoma cervix


chemotherapy All patients were planned to receive weekly cispl-

atin at a dose of 40 mg/m2 along with external beam radiotherapy. Cisplatin was typically held under the following conditions: white blood count (WBC) 2.0 × 109/L, absolute neutrophil count (ANC) 1.0 × 109/L, platelet count 50 × 109/L, or creatinine clearance less than 50 mL/min.

Toxicity Patients were assessed at baseline and every week

during treatment for acute hematological toxici-ties. Dose volume parameters from treatment plans (mean dose, V20, V30 and V40) were correlated with RTOG grade of acute hematological toxicities. Overall toxicity was defined as haematological tox-icity manifesting in the form of anemia, leukopenia or thrombocytopenia.

statistical analysis Statistical analysis for sensitivity and specificity

of dosimetric parameters was performed using an ROC curve. The probability of developing bone marrow toxicity was analyzed using a T test.

results

A total of 34 patients diagnosed to have squa-mous cell Carcinoma of Cervix were treated by radical radiotherapy by IMRT and concurrent chemotherapy (weekly cisplatin 40 mg/m2). The median age was 54 years (39–73 years). The most

common stage of presentation was stage IIB (61.7%).

No patient experienced delays or breaks in pelvic RT because of acute toxicity. The median cispla-tin dose per cycle was 60 mg. 29 patients (85.2%) completed five cycles of weekly cisplatin whereas four patients received four cycles and one patient received three cycles of chemotherapy. The mean PTV volume was 1248.2 cc and the mean bone marrow volume was 382.3 cc. The mean dose to the bone marrow was 29.5 Gy and the V20, V30 and V40 were 72.85%, 49.76% and 25.24%, respectively.

hematologic toxicityThe incidence of Grade 1 acute hematologic

toxicity was 41% whereas 50% patients developed Grade 2 toxicity during the course of treatment. None of the patients developed Grade 3 or 4 he-matologic toxicities. There was a significant differ-ence in the mean dose to the pelvic bone marrow between those who had developed overall haema-tological toxicity of Grade 2 compared to those who had Grade 0 and Grade 1 toxicity (p = 0.001). The ROC curve showed that a cut-off level of 28.85 Gy mean dose had a sensitivity of 82.4% and a specific-ity of 70.6% in classifying the overall toxicity level. Similar findings where noted with respect to mean dose to the pelvic bone marrow and anemia and leukopenia (Tab. 1 and 2).

The mean volumes of the bone marrow receiv-ing 20, 30, 40 Gy i.e., V20, V30, V40, respectively, across different toxicity groups, i.e. anemia, leuko-

table 1. Mean dose to pelvic bone marrow administered across different toxicity profiles (n = 34)

Type of toxicityToxicity status

(n)

Mean dose administered [Gy]

(Mean ± SD)p-value*

Overall toxicity

present

(n = 17)31.1 ± 2.8

0.001absent

(n = 17)27.9 ± 2.4

anemia

present

(n = 13)31.4 ± 2.9

0.002absent

(n = 21)28.4 ± 2.5

Leukopenia

present

(n = 07)31.8 ± 3.5

0.023absent

(n = 27)28.9 ± 2.7

sD — standard deviation



penia and overall toxicity is as shown in Table 3. There was a significant difference between the two groups (with toxicity and without toxicity) among all types of toxicity (anemia, leukopenia and overall toxicity) across all the three pelvic bone marrow receiving radiation levels i.e., V20, V30 and V40 except for V20 with anemia.

The obtained cut-off levels with respective sen-sitivity and specificity in classifying the different toxicity groups with respect to the volume of bone marrow receiving V20, V30 and V40 are as re-ported in Table 4 (except for V20 with anemia as there was no significant difference between toxicity groups).

With the cut-offs obtained from the ROC curve, relative risk was significant for overall toxicity across V20 and V30 and across V30 for anemia;

whereas no significant risk was found for leukope-nia (Tab. 5).

Discussion

The increasing use of IMRT in the treatment of carcinoma cervix has resulted in reduced treat-ment related toxicities and improved quality of life. Various studies have demonstrated the superi-ority of IMRT in providing reduced bone marrow doses as compared to 3DCRT [8, 9]. In resource limited countries like India, the burden of car-cinoma cervix is high and patient affordability is a concern. Most of the patients of carcinoma cervix are treated with conventional four field and few with IMRT. Data is limited regarding the predictors of bone marrow toxicity in patients of

table 2. cut-off points of mean dose to pelvic bone marrow on toxicity with its sensitivity and specificity

Type of toxicity Cut-off points (in Gy) Sensitivity (%) Specificity (%)

Overall toxicity 28.85 82.4 70.6

anemia 29.70 76.9 76.2

Leukopenia 29.70 85.7 66.7

table 3. Distribution of mean irradiated bone marrow volumes across different toxicities (n = 34)

Type of toxicity

(n)Bone marrow

volumeToxicity status

Mean bone marrow volume

(Mean ± SD)p-value

Overall toxicity

(present = 17

absent = 17)

V20present 75.6 ± 5.4

0.004absent 70.1 ± 5.1

V30present 54.7 ± 7.9

0.001absent 44.0 ± 7.9

V40present 31.0 ± 11.6

0.003absent 19.5 ± 9.1

anemia

(present = 13

absent = 21)

V20present 75.1 ± 5.5

0.096absent 71.5 ± 5.8

V30present 55.4 ± 8.2

0.004absent 46.3 ± 8.2

V40present 32.5 ± 11.9

0.003absent 20.7 ± 9.4

Leukopenia

(present = 07

absent = 27)

V20present 78.8 ± 6.4

0.002absent 71.3 ± 4.8

V30present 56.8 ± 9.7

0.020absent 47.9 ± 8.3

V40present 33.1 ± 13.4

0.046absent 23.2 ± 10.7

sD — standard deviation



carcinoma cervix undergoing concurrent chemo-radiation with IMRT.

Our study demonstrated that the cutoff of 28.85 Gy mean dose to bone marrow was significantly associated with Grade 2 or higher hematological toxicity in patients treated with concurrent chemo-radiation with IMRT. The cut off values for V20, V30 and V40 were 71.75 Gy, 49.75 Gy and 22.85 Gy, respectively. The incidence of acute grade 2 hematological toxicity was 50% in our study. The percentage of patients developing Grade 2 leuko-penia and anemia was 20.5% and 38.2%. Mell et al. [7] reported an association between the volume of whole-pelvis BM receiving low-dose radiation (V10 > 90 Gy and V20 > 75 Gy) and acute hemato-logical toxicity. Overall, 25 patients (67.6%) experi-enced leukopenia during treatment. The percentage of patients developing Grade 2 or worse leukope-nia and anemia was 43.2% and 13.5%, respectively. This was in contrast to our patients who reported

a higher incidence of anemia than leukopenia. Only 59.5% patients received all planned chemotherapy, 32.4% had one or more cycles held and 8.1% were noncompliant with the planned chemotherapy course. 85.2% patients received five cycles of weekly cisplatin in our study.

A comparison of two different contouring meth-ods on CT scan by Mahantshetty et al. [10] revealed that free hand contouring of inner cavity of the bone is a better surrogate of active bone marrow com-pared to whole bone contouring. In our study, we used the free hand contouring method on planning CT. Data is emerging on the identification and spar-ing of functional bone marrow to further reduce hematologic toxicities. Liang et al. [11] demonstrat-ed favorable outcomes of a functional bone marrow sparing IMRT technique using 18F-FDG-PET, MRI and CT to identify functional BM. Another phase 2 study published by Mell et al. [12] reported reduced incidence of acute neutropenia using PET CT based

table 5. calculated relative risk (rr) with 95% confidence interval (cI) with cut-offs obtained from receiver operating characteristic (rOc) curve across different toxicities and bone marrow volumes (n = 34)

Type of toxicityBone marrow

volumeCut-off points RR 95% CI p-value

Overall toxicity

V20 ≥ 71.75 4.15 1.45–11.85 0.008

V30 ≥ 49.75 4.67 1.63–13.34 0.004

V40 ≥ 22.85 1.83 0.88–3.82 0.105

anemia

V20 – – – –

V30 ≥ 49.75 5.50 1.43–21.18 0.013

V40 ≥ 23.80 2.53 0.96–6.65 0.059

Leukopenia

V20 ≥ 72.20 3.17 0.71–14.10 0.130

V30 ≥ 51.20 3.57 0.80–15.86 0.094

V40 ≥ 24.65 3.17 0.71–14.10 0.130

table 4. cut-off points of mean irradiated bone marrow volumes on toxicity with its sensitivity and specificity

Type of toxicity Bone marrow volume Cut-off points (in %) Sensitivity (%) Specificity (%)

Overall toxicity

V20 71.75 82.4 76.5

V30 49.75 82.4 82.4

V40 22.85 64.7 64.7

anemia

V20 – – –

V30 49.75 84.6 71.4

V40 23.80 69.2 66.7

Leukopenia

V20 72.20 71.4 63.1

V30 51.20 71.4 66.7

V40 24.65 71.4 63.0



bone marrow sparing IG-IMRT. The feasibility of utilizing the above techniques in resource limited settings and high volume centres is limited and needs further evaluation.

Kumar T et al. evaluated the association between pelvic bone marrow dose volume parameters and the probability of acute hematological toxicity in a cohort of cervical cancer patients, receiving de-finitive chemoradiation plus image-guided adaptive brachytherapy [13]. 114 patients were included of whom 75.4% were treated with 3D radiation thera-py and 24.6% with IMRT. In multivariate analysis, grade 4 hematological toxicity was associated with lower pelvis V5 > 95%, lower pelvis V20 > 45%, to-tal pelvic bone V20 > 65%, and iliac crests Dm > 31 Gy. In patients treated by IMRT, G3+ leukopenia correlated with LS bone V30 > 91%, lower pelvis V15 > 65%, lower pelvis V20 > 48%, lower pelvis Dm > 21.7 Gy. Grade 3+ neutropenia correlated with LS bone V30 > 94%, iliac crest V20 > 84%, lower pelvis V15 > 65%. Grade 4 hematological toxicity was associated with lower pelvis V5 > 95% and lower pelvis V15 > 65%. Our patients did not report any Grade 3 or 4 hematological toxicities and we did not divide the bone marrow into different zones so a direct comparison with their results is difficult. We did not find any significant correla-tion between volume of the bone marrow receiving lower doses of radiation (V5 and V15) and bone marrow toxicity.

Our study is limited by a small sample size and inability to contour functional bone marrow. The strengths of our study are the use of IMRT for all patients and good compliance with chemotherapy. We believe this is the first study to report predictors of hematologic toxicity in carcinoma cervix patients receiving HDR brachytherapy along with chemo-radiotherapy. The contribution of brachytherapy to active bone marrow is limited and needs to be evaluated in a prospective setting. These results can serve as a surrogate for carcinoma cervix patients treated with IMRT. This would help in predicting the course of acute toxicities in these patients and treating them effectively.

conflict of interestThe authors declare no conflict of interest.

FundingNo funding was taken to perform the study.

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http://dx.doi.org/10.1088/0031-9155/5/3/302


http://dx.doi.org/10.1016/s0167-8140(03)00197-x


http://dx.doi.org/10.1016/s0360-3016(00)00771-9


http://dx.doi.org/10.1016/s0360-3016(02)03801-4







http://dx.doi.org/10.1097/IGC.0000000000000292


http://dx.doi.org/10.1097/IGC.0b013e3182664b46

http://dx.doi.org/10.1097/IGC.0b013e3182664b46






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http://dx.doi.org/10.2147/CMAR.S195989



research paper




Address for correspondence: Ines Zemni, MD, Department of surgical oncology, Salah Azaiez Institute , Bab Saadoun , Boulevard 9 Avril 1938 Tunis 1006, Tunisia, 00216 25 560736, e-mail: [email protected], [email protected]

Chemoradiotherapy or chemotherapy as adjuvant treatment for resected gastric cancer: should we use selection criteria?

Houyem Mansouri1, Ines Zemni 1, 2, Leila Achouri3, Najet Mahjoub4, Mohamed Ali Ayedi1, 2, Ines Ben Safta1, 2, Tarek Ben Dhiab1, Riadh Chargui1, Khaled Rahal1

1Department of Surgical Oncology, Salah Azaiez institute of oncology, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunisia2Laboratory of Microorganisms and Active Biomolecules, Faculty of sciences, University of Tunis El Manar, Tunisia

3Department of surgical oncology, Regional Hospital of Jendouba, Tunisia4Department of medical oncology, Regional Hospital of Jendouba, Tunisia

AbstrAct

background: The management of gastric adenocarcinoma is essentially based on surgery followed by adjuvant treatment.

adjuvant chemotherapy (cT) as well as chemoradiotherapy (cTrT) have proven their effectiveness in survival outcomes

compared to surgery alone. however, there is little data comparing the two adjuvant approaches. This study aimed to com-

pare the prognosis and survival outcomes of patients with gastric adenocarcinoma operated and treated by adjuvant radio-

chemotherapy or chemotherapy

Materials and methods: We retrospectively evaluated 80 patients with locally advanced gastric cancer (LGc) who received

adjuvant treatment. We compared survival outcomes and patterns of recurrence of 53 patients treated by cTrT and those of

27 patients treated by cT.

results: after a median follow-up of 38.48 months, cTrT resulted in a significant improvement of the 5-year pFs (60.9% vs.

36%, p = 0.03) and the 5-year Os (55.9% vs. 33%, p = 0.015) compared to adjuvant cT. The 5-year Os was significantly in-

creased by adjuvant cTrT (p = 0.046) in patients with lymph node metastasis, and particularly those with advanced pN stage

(p = 0.0078) and high lymph node ratio (LNr) exceeding 25% (p = 0.012). also, there was a significant improvement of the pFs

of patients classified pN2–N3 (p = 0.022) with a high LNr (p = 0.018). cTrT was also associated with improved Os and pFs in

patients with lymphovascular and perineural invasion (LVI and pNI) compared to chemotherapy.

conclusion: There is a particular survival benefit of adding radiotherapy to chemotherapy in patients with selected criteria

such as lymph node involvement, high LNr LVI, and pNI.

Key words: gastric cancer; chemoradiotherapy; chemotherapy; survival





ISSN: 1507–1367

Introduction

Gastric cancer is the fifth most commonly di-agnosed cancer in the world and the third lead-ing cause of death related to cancer, representing a real health problem worldwide [1]. The overall survival rate of patients who have undergone only

surgery is around 45% at 5 years and has undergone little change over the past decade. Local recurrences on the tumor bed, on the anastomosis, and in the locoregional lymph nodes occur in 40 to 65% of patients after resection for curative purposes. To compensate for this, an extension of the surgical procedure was recommended without reaching the



https://orcid.org/0000-0002-7244-8248

Houyem Mansouri et al. cTrT or chemotherapy as adjuvant treatment for resected gastric cancer


goal of improving survival or reducing the rate of locoregional recurrence [2, 3]. Thus, for patients with stage > IB, who are at high risk of recurrence, it is undoubtedly necessary that an adjuvant treat-ment is offered after surgery [2, 4]. The gastro-intestinal cancer intergroup (INT-0116) was the first phase III trial to demonstrate that adjuvant concomitant radio-chemotherapy improves recur-rence-free survival and overall survival [5]. On the other hand, several meta-analyses have demonstrat-ed the survival benefit of adjuvant chemotherapy in gastric cancer [6–8]. Furthermore, two randomized controlled phase III clinical trials showed that ad-juvant therapy prolonged survival and decreased recurrence [5, 9]. Clinical trials have also directly compared postoperative CT alone with CRT for pa-tients with locally advanced gastric cancer and the meta-analysis of three randomized clinical trials showed that CRT reduced the risk of locoregional relapses, but without significant improvement in distant relapse and overall survival [10]. Results of the ARTIST phase III randomized controlled trial showed that both adjuvant CT and CTRT are tolerated and equally beneficial in preventing re-lapse and suggested that CTRT had significantly improved the DFS in patients with node-positive disease and with intestinal-type [11]. Given these results, the choice of the optimal adjuvant thera-peutic attitude remains a subject of controversy.

This study aimed to compare retrospectively the prognosis and survival outcomes of patients with gastric adenocarcinoma operated and treated by adjuvant radio-chemotherapy or chemotherapy alone and to assess the toxicity and safety of the tow treatment modalities to identify suitable patients for an intensified adjuvant treatment.


patientsWe retrospectively evaluated 80 patients with

LGC who received adjuvant treatment from Janu-ary 2005 to December 2015. Patients were eligible for analysis if they had histological confirmation of gastric cancer, had curative gastrectomy with nodal dissection. Exclusion criteria included the use of neoadjuvant treatment, metastatic disease at diag-nosis, and patients with coexisting malignancies or those who could not tolerate the adjuvant treatment because of other systemic diseases.

We started identifying medical files, clinic (age, gender, reason of counseling, WHO status), endo-scopic data (tumors site, size, aspect), tumor mark-ers (CA 19-9 and CEA level), histological data (his-tological type, tumors size, differentiation grade, number of removed nodes, parietal infiltration depth, lymphovascular invasion (LVI), perineu-ral tumor invasion (PNI), lymph node status and the lymph node ratio (LNR) that corresponded to the ratio between metastatic and dissected lymph nodes. The lymph nodes metastasis (N stage) and the depth of invasion (T stage) were classified according to the TNM staging system 8th edi-tion elaborated by the American Joint Commit-tee on Cancer/International Union Against Cancer (AJCC/UICC) TNM staging system (AJCC/UICC). In this study, Histological classification was based on the WHO classification and Lauren classifica-tion with 3 subgroups: intestinal type, diffuse type, and mixed type [12]. Poorly differentiated tumors included moderately differentiated tubular adeno-carcinoma, independent signet ring cells adenocar-cinoma, and mucinous adenocarcinoma.

surgical procedureThe surgical variables included the type of proce-

dure (total versus partial gastrectomy), the extent of lymph node dissection (D0, D1.5, and D2) based on the different updated versions of the Japanese Gastric Cancer Treatment Guidelines [13–15]. Lymphad-enectomy was classified into three types according to the site of the tumor and the type of gastrecto-my: D1 dissection, D1.5 dissection, and D2 dissec-tion. A D1.5 lymphadenectomy corresponds to a D2 lymphadenectomy with no dissection of the hilar and the splenic artery (relay 10 and 11). Splenectomy was performed in cases of metastatic lymph nodes at the hilum of the spleen or because of iatrogenic injury. The extent of stomach resection was related to the primary tumor site: total gastrectomy was performed in all proximal tumor locations and total gastric tu-mors, and subtotal gastrectomy was performed for distal tumor locations, provided that a 5- to 6-cm safety margin was present. After undergoing gas-trectomy, patients were assigned to either adjuvant chemo radiotherapy or adjuvant chemotherapy.

adjuvant chemotherapyWe used 4 regimens of adjuvant chemothera-

py: The LV5FU2 regimen consisted of Leucovo-



rin 100 mg/m2 in 2 hours infusion days 1–2 and 5-FU 400 mg/m2 as a bolus followed by daily 22 h infusion of 600 mg/m2 every 14 days for nine cycles. The ELF regimen consisted of Folinic acid at a dose of 300 mg/m2 given as a 10-minute IV infusion, followed immediately by Etoposide 120 mg/m2 given as a 50-minute IV infusion, followed by bolus 5-FU 500 mg/m2 for 3 consecutive days. The cycles were repeated every 22 days. Patient treated with the FOLFOX4 regimen received an intravenous infusion of oxaliplatin (85 mg/m2 2 hours) at day 1, a bolus injection of Leucovorin (200 mg/m2) at days 1–2, bolus injection of 5-FU (400 mg/m2) at days 1–2, and continuous intrave-nous infusion of 5-FU (600 mg/m2) for 22 hours at days 1–2.

adjuvant chemo radiotherapyIn the CRT group, a contrast-enhanced com-

puted tomography scan with 3 mm-thick slices was conducted from the top of the diaphragm to the bottom of L4. The target volumes were defined as per INT 0116 protocol [16] and included the residual stomach, tumor bed, anastomosis, and the regional lymph nodes. Most radiotherapy plans were 3-dimensional conformal radiotherapy (3D-CRT). Photon beams from linear accelerators with the energy of 6/10 or 6/23 MV were used for ra-diotherapy planning. The planning target (PTV) volume for each patient was generated from the clinical target volume (CTV) plus 1 cm margins. The prescription dose was 45–50.4 Gy, with 1.8 Gy daily fractions administered over 5–5.6 weeks. As-sociated chemotherapy regimen was based either on the INT 0116 trial using 5 cycles of intravenous bolus 5-fluorouracil and leucovorin (FUFOL regi-men) before, during, and after radiotherapy, or 9 cycles of simplified LV5FU2 regimen (two to four cycles before radiotherapy, then three cycles during radiotherapy and, finally, four cycles after radio-therapy) delivered as follows: 2-hour infusion of leucovorin 200 mg/m2 on day 1 followed by a 400 mg/m2 bolus of 5FU on day 1, then a continuous infusion of 5FU 2400 mg/m2 over 46 hours. Some patients received 6 cycles of modified FOLFOX (three cycles during radiotherapy and three cycles after radiotherapy) administrated as follows: ox-aliplatin 85 mg/m2, leucovorin 200 mg/m2, bolus fluorouracil 400 mg/m2, and infusional fluoroura-cil 1600 mg/m2).

Data regarding treatment toxicity were recorded according to the National Cancer Institute — Com-mon Toxicity Criteria (NCI-CTC, version 4.0) (17).

statistical methodsThe categorical variables were presented as num-

bers and percentages. Continuous variables were expressed as the mean ± standard deviation (SD) with ranges. Moreover, some continuous variables were converted to dichotomous variables for conve-nience, including the age (< 70 years vs. ≥ 70 years), the weight loss (< 10% vs. ≥ 10%), the tumor size (< 50 mm vs. ≥ 50 mm) and the NRLN (≤ 15 LN vs. > 15 LN). To compare the continuous variables with normal distribution we used the T-test. To compare the categorical variables we used the c2 or Fisher test if the assumption for the first has not complied.

OS was defined as the time from surgery to death, or the end of follow-up and PFS was de-fined as the time from surgery to disease recur-rence, as confirmed by using imaging. The rate and types of recurrence were compared between the two groups. Loco-regional recurrences correspond to recurrences occurring in the tumor bed, to anas-tomotic and lymph node recurrences. Metastatic relapses corresponded to hepatic, peritoneal, bone, pulmonary, and ovarian sites. The Progression-free survival (DFS) and overall survival (OS) rates were obtained using the Kaplan Meier methods. In the case of comparing subgroups, the log-rank test was used. We used the Statistical Package for Social Science (SPSS), version 20.0 for Windows, and a p-value less than 0.05 was considered significant.

results

patients’ characteristicsFrom January 2005 to December 2015, a total

of 80 patients were eligible for the study, 53 in the CTRT group and 27 in the CT group. Baseline char-acteristics are summarized in Table 1. Age, gender, performance status, and tumor location as well as surgical procedures were similar between groups. However, the proportion of patients with stage III/IV disease was significantly higher in the CT cohort than in the CTRT group (85.2% vs. 54.7%, p = 0.007). Groups were not balanced regarding the lymph node status: lymph node metastasis was more frequent in the CT group than in the CTRT




VariablesAll patients

n (%)CT ADJ

n (%)CTRT n (%)

p

GenderMen 48 (60%) 13(48.1%) 35 (66%)

0.122Women 32 (40%) 14 (51.9%) 18 (34%)

age (years)

Mean ± sD [mm] 59.21± 12.89 62.66±11.43 57.45±13.33 0.087

≤ 65 55(68.8%) 17 (63%) 38 (71.7%)0.425

> 65 25 (31.2%) 10 (37%) 15 (28.3%)

asa scoreasa1–2 69 (86.2%) 24 (88.9%) 45 (84.9%)

0.625asa3 11 (13.8%) 3 (11.1%) 8 (15.1%)

Weight loss< 10% 31 (43.1%) 11(42.3%) 20 (45.5%)

0.923≥ 10% 41 (56.9%) 15 (57.7%) 26 (56.5%)

Tumor location

proximal 10 (12.5%) 3 (11.1%) 7 (13.2%)

0.833Middle 1/3 29 (36.2%) 11 (40.7%) 18 (34%)

Distal 41 (51.2%) 13 (48.1%) 28 (52.8%)

UIcc stageI–II 28 (35%) 4 (14.8%) 24 (45.3%)

0.007III–IV 52 (65%) 23 (85.2%) 29 (54.7%)

UIcc stage

I 2 (2.5%) 0 (0%) 2 (3.8%)

0.014II 26 (32.5%) 4(14.8%) 22 (41.5%)

III 47 (58.8%) 19(70.4%) 28 (52.8%)

IV 5 (6.2%) 4 (14.8%) 1 (1.9%)

pT stage

pT1 2(2.5%) 0 2(3,8%)

0.162

pT2 18(22.5%) 4(14,8%) 14(26,4%)

pT3 31(38.8%) 9 (33,3%) 22 (41,5%)

pT4 29 (36.2%) 14 (51,9%) 15(28,3%)

pN stage

N0 7 (8.8%) 0 7 (13.2%)

0.120N1 20(25%) 8 (29.6%) 12 (22.6%)

N2 26 (32.5%) 7 (25.9%) 19 (35.8%)

N3 27 (33.8%) 12 (44.4%) 15 (28.3%)

LN statusN– 7 (8.8%) 0 7 (13.2%)

0.048N+ 73 (91.2%) 27 (100%) 46 (86.8%)

LNr≤ 25% 39 (48.8%) 12 (44.4%) 27 (50.9%)

0.582> 25% 41 (51.2%) 15 (55.6%) 26 (49.1%)

NrLN< 15 LN 16 (20%) 7 (25.9%) 9 (17%)

0.344≥ 15 LN 64 (80%) 20 (74.1%) 44 (83%)

resectionTG 41 (51.2%) 13 (48.1%) 28 (52.8%)

0.692pG 39 (48.8%) 14 (51.9%) 25 (47.2%)

LND

D1 7 (8.8%) 4 (14.8%) 3 (5.7%)

0.423D1.5 20 (25%) 6 (22.2%) 14 (26.4%)

D2 53 (66.2%) 17 (63%) 36 (67.9%)

Tumor size

[mm]

< 50 mm 32 (40%) 12 (44.4%) 20 (37.7%)0.592

≥ 50 mm 48 (60%) 15 (55.6%) 33 (62.3%)

Differentiation

Well 40 (50%) 11 (40.7%) 29 (54.7%)

0.358Moderly 23 (28.8%) 8 (29.6%) 15 (28.3%)

poorly 17 (21.2%) 8 (29.6%) 9 (17%)



group (100% vs. 86.8%, p = 0.048) with more ad-vanced N stage, (stage N3 accounted for 44.4% in the CT group vs. 28.3% in the CTRT group) and more patients with a LNR exceeding 25% (55.6% vs. 49.1%). The two groups were comparable regarding the histological subtype, the grade of differentiation, and tumor size. However, lymphovascular space in-vasion lymphovascular (LVI) were more frequent in the CT group than in the CRT group (59.3% vs. 39.6%) and more perineural invasion (PNI) was ob-served in the CT group (59.3 vs. 37.7%). However, these differences were not statistically significant (p = 0.096 and p = 0.067, respectively).

adjuvant treatment Patients assigned to adjuvant chemotherapy re-

ceived variable regimens. From all, twelve patients received the LV5FU2 regimen (44.4%), 7 patients received the FOLFOX regimen (25.9%), 8 patients received the ELF regimen (29.6%), and two patients received ELF regimen (7.4%).

In the CTRT group, the most frequent associ-ated chemotherapy was the LV5FU2 regimen in 41

patients (77.4%), followed by the FUFOL regimen in 8 patients (15.1%) and the FOLFOX regimen in 4 patients (7.5%).

ToxicityThe toxicity of each treatment is summarized in

Table 2. The most frequent toxicity in the CTRT group were gastrointestinal in 37.7% of cases and hematologic toxicity in the CT group 66.66% of cas-es. The most common grade 3 and 4 adverse events in the CT group were asthenia/anorexia (33.3%), hematologic (29.6%), and infectious (14.8%); while, the most common grade 3–4 adverse event in the CTRT was gastrointestinal toxicity (13.2%). No death during treatment was recorded in the two groups. Treatment discontinuity was recorded in 26.4% of patients in the CTRT group (14 patients) and 29.6% in the CT group (8 patients). The most common cause of treatment discontinuity in the CTRT group was toxicity in 50% of cases followed by disease progression in 28.57% and loss of follow up in 21.42% of cases. For the CT group, treatment discontinuity was secondary to toxicity in 50% of


VariablesAll patients

n (%)CT ADJ

n (%)CTRT n (%)

p

Lauren typeIntestinal 59 (73.8%) 19 (70.4%) 40 (75.5%)

0.624Mixed/diffuse 21 (26.2%) 8 (29.6%) 13(24.5%)

LVINo 43 (53.8%) 11 (40.7%) 32 (60.4%)

0.096Yes 37 (46.2%) 16 (59.3%) 31 (39.6%)

pNINo 44 (55%) 11 (40.7%) 33 (62.3%)

0.067Yes 36 (45%) 16 (59.3%) 20 (37.7%)

cT aDJ — adjuvant chemotherapy; cTrT — adjuvant radiochemotherapy; NrLN — number of retrieved lymph nodes; N– — no lymph node metastasis , N+ — lymph node metastasis; LVI — lymphovascular invasion; pNI — perineural invasion

table 2. adverse events

Toxicity

Chemoradiation group (n = 53) Chemotherapy group (n = 27)

Grade 1 n (%)

Grade2 n (%)

Grade 3 n (%)

Grade 4 n (%)

Grade 5 n (%)

Grade1 n (%)

Garde 2 n (%)

Grade3 n (%)

Grade4 n (%)

Grade 5 n (%)

hematologic 4 (7.5%) 1 (1.88%) 3 (5.6%) 2 (3.7%) – 3 (11.1%) 7 (25.9%) 8 (29.6%) – –

Gastrointestinal 8 (15%) 5 (9.4%) 7 (13.2%) – – 2 (7.4%) 8 (29.2%) 2 (7.4%) 3 (11.1%) –

Mucositis 4 (7.5%) 2 (3.7%) 1 (1.88%) – – 5 (18.5%) 7 (25.9%) 4 (14.8%) 4 (14.8%) –

asthenia/ /anorexia

– 2 (3.7%) – – – 5 (18.5%) 6 (22.2%) 9 (33.3%) –

Neuropathy 1 (1.88%) 1 (1.88%) – – – 1 (3.7%) 3 (11.1%) 1 (3.7%) – –

Infectious – 1 (1.88%) – – – 1 (3.7%) 5 (18.5%) 4 (14.8%) – –

renal – – – – – – 4 (14.8%) – – –



cases followed by disease progression in 37.5% and lost of follow up in 12.8% of cases.

relapses and progression free survivalThe median follow-up was 38.48 ± 28.67 months

(range, 4–139 months). Data of the first relapse only were recorded and categorized as loco-re-gional or distant (Tab. 3). After a mean follow-up of 18.85 ± 15.60 (3–75 months), recurrence oc-curred in 42.5% of patients within 22.5 months in the CTRT group and 14 months in the CT group (p = 0.182). The overall rate of recurrence was higher in the CT group (55.6%) compared to the CTRT group (35.8%) without significant difference (p = 0.092). The frequency of locoregional and dis-tant relapses was higher in the CT group (22.2% and 44.4%, respectively) compared to the CTRT group (18.9% and 32.1%, respectively) without significant difference. Additionally, peritoneal recurrence was significantly higher in the CT group compared to the CTRT group (37% vs. 9.4%, p = 0.003).

The 5-year PFS was 60.9% in the CTRT group and 36% in the CT group (p = 0.03) (Fig. 1). Sub-group analyses were performed to identify patient populations who may benefit from CTRT (Tab. 4) showing that significant benefit from the addition of radiotherapy to adjuvant chemotherapy could not be excluded in women (p = 0.008), patients under 70 years old (p = 0.035), intestinal-type GC (p = 0.032), moderately/poorly differentiated tu-mors (p = 0.022) and positive LVI tumor (p = 0.03) (Fig. 3). There also was a trend toward improved PFS with adjuvant CTRT in patients with ad-vanced-stage III and IV (29.5% vs. 53.8%, p = 0.213) with increased outcomes especially in patients with pT3–T4 tumors (64% vs. 35.6%, p = 0.051). In the

73 patients with node-positive disease, 5-year PFS was slightly different (59.9% in CTRT group vs. 36% in CT group, p = 0.057) (Fig. 2). Furthermore, the subgroup analysis demonstrated the superior-ity of adjuvant CTRT compared to CT in terms of PFS in patients classified pN2–N3 (57.8% vs. 16.5%, p = 0.022) with a lymph node ratio greater than 25% (58.6% vs. 11.7%, p = 0.018). Moreover, we found that the benefit of adjuvant CTRT was statistically evident mainly for patients who had a D2 lymphadenectomy (56% vs. 28.4%, p = 0.01). Nevertheless, it seems that in patients who did not have extended lymphadenectomy, the CTRT brings a gain of 19.5% on PFS at 5 years but also an obvi-ous increase in PFS in patients whose number of

table 3. comparative study of pattern of relapse*

SiteAll patients

n (%)CT group (n = 27)

CTRT group (n = 53)

p

Overall recurrence 34 (42.5%) 15 (55.6%) 19 (35.8%) 0.092

Locoregional recurrence 16 (20%) 6 (22.2%) 10 (18.9%) 0.723

Distant recurrence 29 (36.3%) 12 (44.4%) 17 (32.1%) 0.277

peritoneal 15 (18.8%) 10 (37%) 5 (9.4%) 0.003

Liver 13 (16.3%) 6 (22.2%) 7 (13.2%) 0.301

Lung 8 (10%) 1 (3.7%) 7 (13.2%) 0.255

Ovary 2 (2.5%) 1 (3.7%) 1 (1.9%) 1

Bone 1 (1.3%) 0% 1 (1.9%) 1

*patients relapsed at multiple sites. The total number of recurrence sites was greater than the number of relapsed patients; cT — chemotherapy; cTrT — radio chemotherapy

Figure 1. Kaplan-Meier survival curves of progression-free survival in all patients. There was a significant difference between adjuvant chemotherapy (cT) group and adjuvant radiochemotherapy (cTrT) (p = 0.03)



removed lymph nodes was less than 15 (77.8% vs. 21.4%, p = 0.056).

Overall survivalThe 5-year overall survival was significantly

higher in the CTRT group compared to the CT

group (55.9% vs. 33%, p = 0.015) (Fig. 5, Tab. 5). The subgroup analysis revealed that adjuvant CTRT resulted in an improved overall survival compared with adjuvant CT, especially in women (p = 0.014), patients with ASA score under 3 (p = 0.007), stage pT3–pT4 tumors (58.5% vs. 34.4%, p = 0.048), pa-

table 4. Univariate analysis of the 5 years progression-free survival (pFs)

Variables5 years PFS

PCT ADJ CTRT

all patients (n = 80) 36% 60.9% 0.03

GenderMen 51.4% 59.3% 0.671

Women 23.8% 64.8% 0.008

age (years)< 70 32.1% 59.8% 0.035

≥ 70 47.6% 65.5% 0.440

asa scoreasa1–2 36.1% 66.1% 0.014

asa3 33.3% 33.3% 0.918

Weight Loss< 10% 56.1% 72.2% 0.613

≥ 10% 24.4% 51.9% 0.054

UIcc stageI–II 75% 70.7% 0.801

III–IV 29.5% 53.8% 0.213

pT stagepT1–T2 37.5% 57.4% 0.416

pT3–T4 35.6% 64% 0,051

pN stageN0–N1 72.8% 16.5% 0.919

N2–N3 16.5% 57.8% 0.022

LN statusN– – 66.7% Na

N+ 36% 59.9% 0.057

LNr≤ 25% 61.4% 64.1% 0.708

> 25% 11.7% 58.6% 0.018

NrLN< 15 LN 21.4% 77.8% 0.056

≥ 15 LN 41.3% 56.9% 0.182

resectionTG 38.1% 70.2% 0.077

pG 35.4% 50.9% 0.226

LNDD1/D1.5 50.6% 70.1% 0.581

D2 28.4% 56.3% 0.01

Tumor size [mm]< 50 mm 37.4% 84.4% 0.016

≥ 50 mm 33.3% 45.1% 0.324

DifferentiationWell differentiated 78.8% 83% 0.661

Others 0% 30.1% 0.022

Lauren typeIntestinal 37.8% 68.8% 0.032

Mixed/diffuse 30% 33.8% 0.568

LVINo 88.9% 86.7% 0.828

Yes 0% 20.6% 0.03

pNINo 88.9% 90.1% 0.930

Yes 0% 13.5% 0.076

cT aDJ — adjuvant chemotherapy; cTrT — adjuvant radiochemotherapy; NrLN — number of retrieved lymph nodes; N– — no lymph node metastasis; N+ — lymph node metastasis; LVI — lymphovascular invasion; pNI — perineural invasion



tients with lymph node metastasis (51.5% vs. 33%, p = 0.046) (Fig. 6) and particularly those with ad-vanced pN stage (p = 0.0078) and high lymph node ratio exceeding 25% (49% vs. 8.8%, p = 0.012). Moreover, some histological criteria were associ-ated with an improved overall survival with CTRT compared to adjuvant CT notably intestinal sub-type (p = 0.017), LVI positive tumors (p = 0.006) (Fig. 7), PNI positive tumors (p = 0.027) (Fig. 8). In the case of D2 lymphadenectomy, the benefit in terms of overall survival was higher in the adjuvant CTRT group compared to the adjuvant CT group (51.5% vs. 29.4%, p = 0.008) on the other hand,

there was no significant difference between the two groups in the event of D1–D1.5 lymphadenectomy with a gain of 20.9% in terms of OS at 5 years in the CTRT group. Also, the adjuvant CTRT allowed a 47.7% increase in the overall survival of patients whose number of lymph nodes removed was less than 15 compared to the adjuvant CT (p = 0.07).

Discussion

Despite the advancement in adjuvant and neoad-juvant therapy, the 5-year survival rate for patients with positive lymph node gastric cancer is as low

Figure 2. Kaplan-Meier survival curves of progression-free survival in lymph node-positive patients. There was a tendency to significant difference between adjuvant chemotherapy (cT) group and adjuvant radiochemotherapy (cTrT) (p = 0.057)

Figure 3. Kaplan-Meier survival curves of progression-free survival in LVI-positive patients. There was a significant difference between adjuvant chemotherapy (cT) group and adjuvant radiochemotherapy (cTrT) (p = 0.03)

Figure 4. Kaplan-Meier survival curves of progression-free survival in pNI-positive patients. There was a significant difference between adjuvant chemotherapy (cT) group and adjuvant radiochemotherapy (cTrT) (p = 0.076)

Figure 5. Kaplan-Meier survival curves of overall survival in all patients. There was a significant difference between adjuvant chemotherapy (cT) group and adjuvant radiochemotherapy (cTrT) (p = 0.015)



as 15–20%, and even node-negative patients have a 5-year survival rate of 45–55% in the case of ad-vanced T stage (T3–T4N0) [18] with recurrence rates ranging from 20% to 40% within 2 years after complete resections depending on specific factors such as the initial stage of the disease, proximal

location and Lauren’s histological type [19]. These data justify the need for an adapted or even inten-sified adjuvant therapeutic strategy to reduce the relapse rate depending on these prognostic factors. Although the role of adjuvant chemotherapy (CT) has been established and adjuvant CT is routinely

table 5. Univariate analysis of the 5 years overall survival (Os)

Variables5 years OS

pCT ADJ CTRT

all patient (n = 80) 33% 55.9% 0.015

GenderMen 43.1% 54.7% 0.300

Women 23.6% 58.9% 0.014

age (years)< 70 31% 59.2% 0.033

≥ 70 37.5% 40.4% 0.304

asa scoreasa1–2 32.9% 60.7% 0.007

asa3 33.3% 25% 0.976

Weight Loss< 10% 42.4% 64.4% 0.230

≥ 10% 29.6% 43.9% 0.131

UIcc stageI–II 50% 70.9% 0.176

III–IV 29.3% 42.8% 0.260

pT stagepT1–T2 25% 51.4% 0.112

pT3–T4 34.4% 58.5% 0.048

pN stageN0–N1 75% 69.1% 0.948

N2–N3 13% 48.8% 0.007

LN statusN– - 83.3% Na

N+ 33% 51.5% 0.046

LNr≤ 25% 57.1% 62.7% 0.437

> 25% 8.8% 49% 0.012

NrLN< 15 LN 19% 66.7% 0.07

≥ 15 LN 36.6% 53.1% 0.08

resectionTG 28% 64.5% 0.016

pG 39% 47.4% 0.277

LNDD1/D1.5 42.2% 63.1% 0.472

D2 29.4% 51.5% 0.008

Tumor size [mm]< 50 mm 33.3% 84.7% 0.002

≥ 50 mm 33.3% 36.9% 0.471

DifferentiationWell differentiated 79.5% 77.2% 0.858

Others 0% 29% 0.007

Lauren typeIntestinal 33.8% 62.2% 0.017

Mixed/diffuse 30% 32.6% 0.483

LVINo 90 % 76.9% 0.507

Yes 0% 23.7% 0.006

pNINo 90% 8.3% 0.659

Yes 0% 16.3% 0.027

cT aDJ — adjuvant chemotherapy; cTrT — adjuvant radiochemotherapy; NrLN — number of retrieved lymph nodes; N– — no lymph node metastasis; N+ — lymph node metastasis; LVI — lymphovascular invasion; pNI— perineural invasion



used for D2-dissected gastric cancer, the value of combining postoperative RT with CT is still largely debated. Our study suggested the superiority of adjuvant CTRT to adjuvant CT not only in terms of reducing the risk of overall recurrence but also in improving the 5-year OS, especially in patients with lymph node metastasis, high LNR and lym-phovascular and perineural invasion which is the most interesting feature. Moreover, based on the literature data, we aimed to identify selection cri-teria to propose intensive adjuvant treatment for a subgroup of patients presenting conventional pe-jorative prognostic factors of survival. These results

were consistent with data from the literature regard-ing the prognostic impact of CTRT on recurrence. However, it seems that our study is distinguished by encouraging results in favor of CTRT in improving overall survival (55.9% vs. 33%; p = 0.015).

Very few studies have compared adjuvant CT with adjuvant CTRT and most of them did not show a significant improvement of overall sur-vival by associating RT to CT despite the gain in terms of recurrence survival. The ARTIST trial was the first phase III study that compared the adju-vant treatment with chemotherapy (6 cycles of XP — capecitabine and cisplatin) in 172 patients vs. the association of chemotherapy and radiotherapy (2 cycles of XP + XP and radiotherapy + 2 more cycles of XP) in 188 patients after D2-lymphadenectomy [20]. The addition of XRT to XP chemotherapy did not significantly prolong the 3-year disease-free survival (DFS) (78.2% vs. 74.2%; p = 0.862). More-over, in the updating of their results after 7 years of follow-up, DFS remained similar between treat-ment arms (HR = 0.740; 95% CI = 0.520–1.050; p = 0.0922), OS was also similar (HR = 1.130; 95% CI = 0.775–1.647; p = 0.5272) but the addition of radiotherapy provided an improvement in dis-ease-free survival for node-positive patients [11]. In a South Korean phase III study of Kim et al, 90 patients having had R0 surgery with D2 dissection were randomized between two arms: an adjuvant CT arm (44 patients) and an adjuvant CTRT arm (46 patients) [21]. In this study, although five-year

Figure 8. Kaplan-Meier survival curves of overall survival in patient with pNI positive tumors. There was a significant difference between adjuvant chemotherapy (cT) group and adjuvant radiochemotherapy (cTrT) (p = 0.027)

Figure 6. Kaplan-Meier survival curves of overall survival in lymp node-positive patients. There was a significant difference between adjuvant chemotherapy (cT) group and adjuvant radiochemotherapy (cTrT) (p = 0.046)

Figure 7. Kaplan-Meier survival curves of overall survival in patient with LVI positive tumors. There was a significant difference between adjuvant chemotherapy (cT) group and adjuvant radiochemotherapy (cTrT) (p = 0.006)



disease-free survival (DFS), which was the pri-mary endpoint of this trial, was not significantly improved in the combined modality, locoregional recurrence-free survival (LRRFS) (93.2% vs. 66.8%, p = 0.014) and metastatic recurrence-free survival (73.5% vs. 54.6%, p = 0.056) were improved. In contrast to these two trials, a significant benefit in 5-year RFS (45.2% vs. 35.8; p = 0.012), but not in OS, was shown in a Chinese multicenter random-ized trial in which patients with D2-dissection were randomly assigned to chemotherapy alone (165 patients) or intensity-modulated RT plus concur-rent chemotherapy (IMRT-C) (186 patients) [22]. In this study, the IMRT-C was associated with an increase in the median duration of RFS compared to chemotherapy (50 months vs. 32 months) and the hazard ratio for recurrence was 1.35 (95% CI: 1.03–1.78; p = 0.029). These data support our re-sults as we found significant improvement in PFS at 5 years (60.9% vs. 36%, p = 0.03) with adjuvant radiochemotherapy compared to adjuvant CT.

The analysis of the patterns of recurrence of our patients revealed that locoregional and dis-tant relapses were more frequent in the adjuvant CT group than in the CTRT group without a sig-nificant statistical difference, which is in line with the results of the ARTIST trial where locoregional relapse was more frequent in the XP arm (13%) than in the XPRT arm (7%; p = 0.033) and dis-tant metastases were observed in 27% and 24% of patients in the XP and XPRT arms, respectively (p = 0.5568) [11]. Moreover, in the randomized study of Zhu et al. the rate of distant metastasis was slightly higher in the chemotherapy group (26.7% vs. 24.2%, p = 0.595) [22].

The meta analysis of the results of the two ran-domized controlled trials from South Korea [20, 21] and the study of China [22] comparing ad-juvant chemotherapy and CRT, which included a total of 895 patients, showed that postoperative CTRT significantly improved locoregional recur-rence-free survival (HR = 0.53, 95% CI = 0.32–0.87, p = 0.01) and disease-free survival (HR = 0.72, 95% CI = 0.59–0.89, p = 0.002); without a significant improvement of distant metastasis recurrence-free survival (HR = 0.86; 95% CI = 0.66–1.11; p = 0.25) and overall survival (HR = 0.79, 95% CI = 0.61–1.03, p = 0.08) [10].

In our study, the analysis of subgroups according to the extent of lymphadenectomy had demonstrat-

ed the superiority of CTRT to CT as an adjuvant treatment to D2 lymphadenectomy both in terms of OS and PFS. In the group of patients with less extensive lymphadenectomy, CTRT offered a bet-ter OS (19% vs. 66.7%) and PFS (21.4% vs. 77.8%) without significant difference. This last observation agrees with the data from the SWOG/INT-0116 trial where the CTRT improved the oncological results of all patients who had mostly had D0–D1 dissection [23]. Paradoxically, Dikken et al. had retrospectively compared survival and recurrence patterns of 91 patients in phase I and II studies evaluating more intensified postoperative CRT with 694 patients from the Dutch Gastric Cancer Group Trial (DGCT) that randomly assigned patients be-tween D1 and D2 lymphadenectomy and suggested that the addition of CTRT seemed to be beneficial in preventing local recurrence after D1-dissection, but not after D2-dissection [24].

Consequently, the role of adjuvant RT remains unclear after an adequate lymphadenectomy but it seems that the identification of a high-risk sub-group for loco-regional recurrence among D2-dis-sected patients is essential and of higher priority than assessing the efficacy of a regular application of adjuvant CRT in all D2-dissected gastric cancer patients [25].

Regardless of the type of lymphadenectomy, the lymph node status remains largely involved in the therapeutic indications since it represents a prog-nostic factor determining survival and recurrence [26, 27]. In fact, in our study, the adjuvant CTRT allowed a significant improvement in the overall 5-year survival of patients with lymph node in-volvement (p = 0.046), with a tendency to better progression-free survival (p = 0.057). These data appear to be consistent with those of the ARTIST trial where the subgroup analysis of 396 patients with node-positive disease revealed that the 3-year DFS was significantly improved in the XPRT arm compared to the XP arm (76% vs. 72% in XPRT arm; p = 0.04) and found that in patients without lymph node involvement, chemotherapy would be more beneficial than CTRT in terms of DFS (HR = 1.359, 95% CI = 0.477–3.876) with no sig-nificant difference [11]. Moreover, we have found that the benefit provided by the adjuvant CTRT in terms of OS (13% vs. 48.8%, p = 0.0078), but espe-cially in terms of PFS (16.5% vs. 57.8%, p = 0.022), was significantly higher than the adjuvant CT, es-



pecially in patients with more advanced pN stages (pN2–pN3). This is consistent with the Korean re-port of Chang et al. which revealed that N3 patients are at substantial risk of regional recurrence as well as peritoneal and distant spread despite D2 dissec-tion and adjuvant chemotherapy suggesting that an intensified treatment by chemoradiotherapy would improve survival outcomes [28].

As lymph node ratio (LNR) was previously iden-tified as an independent prognostic factor after D1 and D2 lymph node dissections [29, 30], we com-pared the prognostic impact of adjuvant CTRT to that of adjuvant CT according to the lymph node ratio. This subgroup analysis had demonstrated that, unlike patients whose LNR was less than 25%, those whose lymph node ratio was greater than 25% and treated with adjuvant CTRT had a sig-nificant gain of 40.2% in terms of OS at 5 years and 46.9% in terms of PFS at 5 years compared to patients who received adjuvant CT. These find-ings are consistent with the results of the subgroup analysis of the ARTIST trial were the effect of ra-diotherapy in patients with a high lymph node ratio (≥ 0.083) was different from the effect in patients with a low lymph node ratio in both DFS (HR = 2.03; 95% CI = 1.44–2.87; p < 0.01) and overall survival (HR = 1.98; 95% CI = 1.38–2.83; p < 0.01) suggest-ing that the lymph node ratio might represent an absolute, reproducible factor that could help se-lect patients for CTRT [11]. On the other hand, the integration of the notion of the lymph node ratio during the evaluation of the prognostic con-tribution of adjuvant CTRT was mentioned in the retrospective study by Costa et al. [31]. Indeed, this study included 142 patients (90 patients treat-ed with surgery only and 52 patients treated with resection followed by adjuvant CTRT) classified according to the LNR (NR0 = 0%, NR1 = 1–9%, NR2 = 10–25%, NR3 > 25%) and concluded that the individuals with a lower LNR had no benefit with adjuvant CTRT both in OS (78.8% vs. 76.9%) and DFS (81.8% vs. 76.9%), whereas those with a higher LNR treated by CTRT had a significant improvement in OS (71.4% vs. 30.9%; p = 0.038) and superior but not statistically significant gain regarding DFS (48.9% vs. 30.3%; p = 0.145). In view of these data, it seems that lymph node involvement represents a decisive element in favor of the inten-sification of the adjuvant treatment of locally ad-vanced gastric cancers by associating radiotherapy

with chemotherapy, which represents the rationale of the ongoing ARTIST II trial aiming to evaluate the benefit of adjuvant combined therapy only in pN+ patients.

Depth of parietal invasion has long been con-sidered an independent factor for survival and recurrence in gastric cancer [32–34] and authors consider this parameter as a determining factor of the delay of relapses. In fact, in the study by Otsuji [35], the depth of parietal infiltration represents an independent factor determining the time to recur-rence with a median time of 11.7 months in the T4 stages, and 15.5 months in the pT3 stages, 22.2 months in pT2 stages, and 39.5 months in pT1 stages without forgetting that lymph node involve-ment is significantly correlated with the depth of parietal invasion. Based on these data, we suggest a combined strategy for T3–T4 tumors as we found that in this group of patients the benefit provided by CTRT compared to CT both in terms of OS (34.4% vs. 58.5%; p = 0.048) and PFS (35.6% vs. 64%; p = 0.051) is superior. Whereas in the case of earlier tumors the two strategies remain compa-rable.

Moreover, as PNI and LVI have been investigated as prognostic factors of recurrence and overall sur-vival in resected gastric cancer [36, 37], we found that CTRT provided better overall survival rates and lower recurrence in the subgroup of patients with PNI and LVI compared to adjuvant chemo-therapy and this significant difference was not re-ported in cases of PNI and LVI negative tumors. Our findings are similar to those reported by Yu et al. who evaluated the influence of adjuvant RT on recurrence at each locoregional subsite, and inves-tigated which subgroups received the most benefit by comparing failure patterns between CCRT and chemotherapy groups of the ARTIST trial [38]. In this study, the authors used Forest plots to repre-sent locoregional recurrence-free survival (LRRFS) HRs and 95% CIs and demonstrated that patients with lymphovascular invasion (HR = 0.45, 95% CI = 0.22–0.90, p = 0.02) showed greater LRRFS benefit from XPRT than XP. It is therefore wise to consider that these two histological data would be helpful to select patients for an intensified treat-ment with radiotherapy as suggested by the review of Agolli et al. [39].

In addition, the results of our study agree with those of the Mac Donald trial suggesting that post-



operative CTRT would be more effective in the intestinal type [16]. The ARTIST trial also dem-onstrated that the effect of the addition of radio-therapy on DFS and OS differed by Lauren clas-sification (interaction p = 0.04 for PFS; interaction p = 0.03 for OS). The Forest plot of HRs and 95% CIs for disease-free survival revealed that the ef-fect of radiotherapy in patients with intestinal-type GC (HR = 0.442, 95% CI = 0.231–0.845) was dif-ferent from the effect in patients with diffuse GC (HR = 0.826, 95% CI = 0.543–1.255) [11].

And, finally, in 2016, in the CRITICS study, 788 patients were randomized after preoperative che-motherapy with ECX or EOX and surgery between a group of postoperative chemotherapy (393 pa-tients) and a group of postoperative radiochemo-therapy (395 patients) [40]. This international study showed the absence of difference in terms of OS be-tween the two groups (41.3% in the CT adj arm and 40.9% in the CTRT adj arm, p = 0.99) with different profiles of toxicity: higher grade III hematological toxicity in the adj CT arm (44% vs. 34%; p = 0.01) and higher grade III gastrointestinal toxicity in the CTRT arm (37% vs. 42%; p = 0.14), which is in line with our results where the rate of grade 3–4 gastrointestinal toxicity was 22.6% in the CTRT group and 18.5% in the CT group and the rate of grade 3–4 hematological toxicity was higher in the CT group (29.6%) than in the CTRT group (9.3%). Moreover, most comparative studies have shown no increase in grade 3–4 treatment-related toxicity in the CTRT group with modern RT techniques (IMRT or CT-based 3D-CRT) compared with the chemotherapy alone group [10].

However, our study has certain limitations. In-deed, this is a retrospective monocentric study in-cluding a small number of patients with variable CT regimens, which leads to a higher risk of selec-tion bias. Furthermore, there was a different stage distribution between the two groups, with more stage III patients in the CT group than in the CRT group (70.4% vs. 52.8%; p = 0.014), which reflects the attitude adopted in our institution favoring an aggressive systemic treatment strategy for locally advanced tumors likely to present a higher risk of metastatic recurrence rather than locoregional recurrence. This high rate of stage III in the CT group did not translate into a statistically signifi-cant difference in terms of survival and CTRT was still superior to adjuvant CT. In addition, our study

included patients whose lymphadenectomy was not extensive with a rate of D1-lymphadenectomy of 8.8% and a number of LN lower than 15 in 20% of the cases. However, our results remain interpretable since the interest of an extended lymphadenectomy remains a subject of controversy in the area of ad-juvant therapies and new techniques of irradiation taking into account the morbidity associated with lymph node surgery reported in the majority of randomized studies.

conclusion

Even if there are no strict recommendations con-cerning the intensification of the adjuvant treatment of locally advanced gastric cancers by associating radiotherapy with chemotherapy, the indication of this combined approach should take into account the prognostic factors that have a significant im-pact on recurrence and survival outcomes to select patients who can benefit from this approach, es-pecially those with lymph node involvement, high LNR LVI, and PNI.

conflicts of interestThe authors declare no conflicts of interest.

FundingThe author(s) received no financial support for the research, authorship, and/or publication of this ar-ticle.

ethics approvalThe ethics review board approved this study and did not require informed consent from study par-ticipants since this was a strictly registry-based study.

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research paper




Address for correspondence: Yoshihiro Ueda, Department of Radiation Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuou-ku, Osaka, 537-8567, Japan, fax: +81-6-6981-3000; e-mail: [email protected]

Evaluation of two-dimensional electronic portal imaging device using integrated images during volumetric modulated

arc therapy for prostate cancer

Shoki Inui1, 2, Yoshihiro Ueda1, Shunsuke Ono1, Shingo Ohira1, Masaru Isono1, Yuya Nitta1, Hikari Ueda1, Masayoshi Miyazaki1, Masahiko Koizumi2, Teruki Teshima1

1Department of Radiation Oncology, Osaka International Cancer Institute, Osaka, Japan2Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Suita, Japan

AbstrAct

background: The aim of the study was to evaluate analysis criteria for the identification of the presence of rectal gas during

volumetric modulated arc therapy (VMaT) for prostate cancer patients by using electronic portal imaging device (epID)-based

in vivo dosimetry (IVD).

Materials and methods: all measurements were performed by determining the cumulative epID images in an integrated

acquisition mode and analyzed using perFracTION commercial software. systematic setup errors were simulated by moving

the anthropomorphic phantom in each translational and rotational direction. The inhomogeneity regions were also simulated

by the I’mrT phantom attached to the Quasar phantom. The presence of small and large air cavities (12 and 48 cm3) was con-

trolled by moving the Quasar phantom in several timings during VMaT. sixteen prostate cancer patients received epID-based

IVD during VMaT.

results: In the phantom study, no systematic setup error was detected in the range that can happen in clinical (< 5-mm and

< 3 degree). The pass rate of 2% dose difference (DD2%) in small and large air cavities was 98.74% and 79.05%, respectively,

in the appearance of the air cavity after irradiation three quarter times. In the clinical study, some fractions caused a sharp

decline in the DD2% pass rate. The proportion for DD2% < 90% was 13.4% of all fractions. rectal gas was confirmed in 11.0%

of fractions by acquiring kilo-voltage X-ray images after the treatment.

conclusions: Our results suggest that analysis criteria of 2% dose difference in epID-based IVD was a suitable method for

identification of rectal gas during VMaT for prostate cancer patients.

Key words: in vivo dosimetry (IVD); electronic portal imaging device (epID); prostate cancer; rectal gas; patient-specific quality

assurance (Qa)





ISSN: 1507–1367

Introduction

High-precision radiation therapy, such as in-tensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT), can be used to create a steep dose gradient and com-

plement dose distribution [1, 2]. These techniques enable the target dose to be increased and the organ at risk (OAR) dose to be decreased. Treatment of prostate cancer patients has often used IMRT and VMAT, resulting in better tumor control and re-duced toxic effects in the bladder and rectum [3–5].



However, a steeper dose gradient, more complex dose distribution, and a smaller planning target vol-ume (PTV) margin may cause geometrical uncer-tainties, such as interfractional and intrafractional setup variation and organ movement, that displace the target from the treatment field. Image-guided radiation therapy (IGRT) is used to aid precise dose delivery to the target. This method enables the in-terfractional setup variation to be reduced as much as possible.

Intrafractional organ movement in prostate can-cer treatment has been studied over the past 20 years [6, 7]. Some studies have used magnetic reso-nance imaging (MRI) to monitor intrafractional prostate and rectum movement in real time during treatment [6–11]. These studies suggest that rectal gas causes a distended rectum, thereby displacing the prostate. This indicates that rectal gas can be used as an indicator of intrafractional rectum and prostate movement. Moreover, rectal gas causes an increase in the inhomogeneity of the density of ma-terials in the beam path, altering the dose distribu-tion and causing the appearance of hot spot in the rectal wall and prostate. It is therefore important to determine the presence of rectal gas during treat-ment.

Several studies reported that an electronic por-tal imaging device (EPID) had usefulness in the dose verifications for pre-treatment [12, 13]. EP-ID-based in vivo dosimetry (IVD) is one of the patient-specific quality assurance (QA) methods and it is widely used to detect major treatment er-rors during radiation therapy [14–22]. EPID-based IVD is also a real-time verification system that is easy to use and does not require additional setup time for IMRT and VMAT. This system ensures safety and accuracy on a daily basis by measuring and analyzing the beam penetrating the patient’s body during treatment in the integrated acquisition mode. Such a verification system is an additional tool that can help reveal major treatment errors such as intrafractional patient and organ move-ment during IMRT and VMAT. However, little has been done to identify the presence of rectal gas using EPID-based IVD in VMAT for prostate can-cer patients. We hypothesized that inhomogeneity regions such as those with rectal gas can be changed owing to the beam passing through the patient’s body and detected using EPID-based IVD. Hence, the aim of this study was to evaluate analysis cri-

teria for the identification of the presence of rectal gas when EPID-based IVD is used in VMAT for prostate cancer patients. A phantom study identi-fied the magnitude of error in EPID-based IVD when setup error and rectal gas in the range that can happen in a clinical study occurs. In a clinical study, the feasibility of using EPID-based IVD to detect rectal gas was assessed based on the results of the phantom study.

Material and methods

This research consists of three parts: two phan-tom studies and one clinical study. Settings that are common among the three studies are described in the following section, while settings specific to each study are specified in the section after that.

common settingsIn the phantom and clinical studies, all computed

tomography (CT) scans were performed using a GE Dual Energy instrument (64 slices, General Electric Co., Waukesha, WI). The parameters of the CT im-ages were 2.0-mm slice thickness and 500-mm field of view with dimensions of 512 × 512 pixels. All the CT images were transferred to an Eclipse planning system (version 13.7.14, Varian Medical Systems, Palo Alto, CA). In Eclipse, all plans were calculated with the analytical anisotropic algorithm for dose calculation with inhomogeneity corrections, and exported to the PerFRACTION software (version 1.7.3, Sun Nuclear Corporation, Melbourne, FL) as DICOM files.

PerFRACTION, which uses GPU-accelerated convolution/superposition algorithm (Sun Nu-clear Dose Calculator) and is independent of the Eclipse planning system, is a commercial software for pre- and on-treatment patient-specific QA by using the EPID images. This system was used for the on-treatment patient-specific QA (Fraction N) in our study. The feature of PerFRACTION is au-tomatic retrieval of the acquired new EPID im-ages and comparison of these images against the baseline images through various user-defined tests including gamma analysis, percentage dose dif-ference (DD), and distance-to-agreement (DTA) for any criteria and threshold. The beam model of PerFRACTION is created by Sun Nuclear Corpo-ration following the data of percent depth dose,

Shoki Inui et al. evaluation of two-dimensional electronic portal imaging device during VMaT


output factor, and profile in reference condition and VMAT planning often used in our institute.

EPID-based IVD was performed using a linear accelerator, TrueBeam STx (Varian Medical Sys-tems) equipped with a gantry-mounted on-board imager and an EPID, aS1200 PortalVision image detector (Varian Medical Systems). The square pixels of the EPID had a side length of 0.34 mm, yielding a total area of approximately 40 × 40 cm2 (1190 × 1190 pixels). All EPID images were ob-tained in the integrated acquisition mode, and a source-to-imager distance of 160 cm was used for both the stationary and rotational settings. The lin-ear accelerator was equipped with high definition multileaf collimators (MLCs), the widths of which were 2.5 mm for the first 32 leaves from the central point and 5 mm for the rest.

specific settingsFirst phantom study

To assess the detectability of a setup error in EPID-based IVD, an anthropomorphic phantom (Kyoto Kagaku, Japan) was used (Fig. 1A). In CT images of the anthropomorphic phantom, the prostate was contoured as the target volume, while the rectum, bladder, and small and large bow-els were contoured as OARs. A single-arc VMAT plan using 2 Gy fractions with 6-MV photons was created for target contouring. The plans were op-

timized to deliver the mean of the prescribed dose to the PTV.

To acquire baseline measurements, the anthro-pomorphic phantom was correctly set up by using cone-beam computed tomography (CBCT) image guidance and irradiated while the cumulative EPID images were acquired. Systematic setup errors were simulated by shifting the phantom by 1, 3, 5, and 10-mm in the anterior-posterior (AP), superior-in-ferior (SI), and left-right (LR) directions. Angular setup errors were also simulated by shifting the phantom by 1° and 3° in the pitch, roll, and yaw rotations. The EPID images were captured for each condition.

second phantom studyTo assess the detectability of inhomogeneity re-

gions in the rectum in EPID-based IVD, an I’mRT phantom comprised of a body phantom (IBA Dosimetry, Schwarzenbruck, Germany) was used (Fig. 1B). The mock prostate structure set down-loaded from AAPM TG119 was registered on CT images of the I’mRT phantom with MIM Maes-tro (MIM Software Inc., OH, USA). A single-arc VMAT plan using 2 Gy fractions with 6-MV pho-tons was optimized to deliver the mean of the pre-scribed dose to the PTV.

To acquire baseline measurements, the I’mRT phantom was correctly set up by using CBCT im-

Figure 1. A. The anthropomorphic phantom for the verification of systematic setup error. b. The I’mrT phantom for the verification of inhomogeneity region. c. The position of the air cavity in the I’mrT phantom. D. The programmable motion platform stuck on the I’mrT phantom and made up the air cavity after several times during irradiation

a B

Dair cavity

c



age guidance and irradiated while the cumulative EPID images were acquired. Multiple-size air cavi-ties which simulated rectal gas were created in the I’mRT phantom. We prepared the air cavities with diameters of 2 and 4 cm because the mean rectal diameter in clinical study was about 3 cm. Each air cavity, with volume of either 12 (2 × 2 × 3) cm3 or 48 (4 × 4 × 3) cm3 was created 1 cm below the middle of the I’mRT phantom (Fig. 1C).

Rectal gas may occur during irradiation, so we established a system controlling the time when gas is produced in the I’mRT phantom. The I’mRT phantom was attached next to a programmable motion platform (Quasar Respiratory Motion Platform; Modus Medical Devices Inc., London, ONT, Canada) (Fig. 1D). At the time when gas was scheduled to occur, some blocks attached to the programmable motion platform were pulled, and air cavities of volumes 12 (2 × 2 × 3) cm3 and 48 (4 × 4 × 3) cm3 were created 1 cm below the middle of the I’mRT phantom. The timing of when the air cavities occurred was controlled by mov-ing the motion phantom during irradiation. Three timings were prepared and followed: at 25% (T25%), 50% (T50%), and 75% (T75%) of the single-arc irradia-tion time. The I’mRT phantom with small and large air cavities were also measured during single-arc VMAT from beginning to end (T0%). The EPID im-ages were captured for each condition with I’mRT phantom with each air cavity.

clinical studyFrom August 2017 to May 2018, 16 patients

with histologically proven low-, intermediate- or high-risk localized prostate cancer underwent VMAT at the Osaka International Cancer Institute. The patients were aged 65 to 81 years (median: 77 years). All patients were required to empty their bladder and evacuate their bowels 1 h before the CT simulation. For the CT simulation, they were immobilized using the Vac-Lock Cushion (Civco Medical Solutions, Iowa, USA) for the pelvis region and they were given leg support and a pillow. Af-ter the immobilization devices were fixed, a treat-ment-planning CT scan was performed. If the rec-tum was deemed too large, the patients had to retake the scan after the rectum was emptied. After CT simulation, the target volumes and OARs (i.e., the rectum, bladder, and small and large bowels) were contoured by radiation oncologists following

the recommendations in Reports 50 and 62 of the International Commission on Radiation Units [23, 24]. All the patients were treated with 6-MV pho-tons using single-arc VMAT and received doses of 74 Gy in 37 fractions or 78 Gy in 39 fractions. The doses were prescribed at mean dose for the PTV.

All the patients received daily soft tissue regis-tration, which was performed using CBCT, and planning CT in a 6 degree of freedom couch. If the rectum was full of rectal gas near the prostate, the patient was encouraged to evacuate their bowels and registration was performed again. All the pa-tients received VMAT while the cumulative EPID images were acquired in all the sessions. The EPID image in the first treatment session was defined as the baseline image. After treatment, all the pa-tients were subjected to registration using a pair of orthogonal kilo-voltage X-ray images and DRR to determine the presence of rectal gas.

Data analysisTwo-dimensional (2D) analysis in PerFRAC-

TION was performed using gamma and DD meth-ods. Analysis criteria of 3%/3 mm, 2%/2 mm, and 1%/1 mm, and 3%, 2%, and 1%, respectively, were used for the gamma and DD analysis above 10% of maximum signal threshold. The presence of rectal gas after treatment was confirmed via offline re-views (Varian Medical Systems).

results

phantom studySingle-arc VMAT was performed on the an-

thropomorphic phantom to assess the effect of sys-tematic setup error on EPID-based IVD, and the results are shown in Table 1. The gamma analysis revealed > 95% in shifts of the AP and LR direc-tions, and pitch, roll, and yaw rotations (Fig. 2). The pass rates of the DD were the same as those of the gamma analysis in the AP and LR directions of less than 5-mm shift, and pitch, roll, and yaw rotations. In the SI direction, the pass rates for the DD of 1% in more than 3-mm shifts, and for the gamma of 1%/1 mm and for the DD of 2% in more than 5-mm shifts were less than 95%.

Table 2 illustrates the effect of the presence of inhomogeneity regions on EPID-based IVD in I’mRT phantom with an air cavity. A larger air cav-ity resulted in decreased pass rates for the gamma



analysis of 1%/1 mm and the DD of 3%, 2%, and 1%. A longer presence time for inhomogeneity regions during irradiation resulted in decreased pass rates for the gamma analysis of 1%/1 mm and the DD of 3% of a large air cavity, and for the DD of 2% and 1% of large and small air cavities. However, all criteria of the gamma analysis were

more than 90% pass rates for all phases in a small air cavity (Fig. 3).

Based on these results of phantom studies, we evaluated the results of the clinical study by using the DD of 2% (DD2%). At T75%, the air cavity ap-peared after 75% of the irradiation time and stayed for 25% of the irradiation time. Because the mean

Figure 2. The comparison of the gamma and dose difference (DD) analysis in systematic setup error simulated by shifting the anthropomorphic phantom by 5 mm in the ap direction. The epID images of expected dose are baseline. Dose profile X and Y are horizontal and vertical lines in the gamma index and difference

table 1. systematic setup error simulated by shifting anthropomorphic phantom

Direction ShiftGamma (%) DD (%)

3%/3 mm 2%/2 mm 1%/1 mm 3% 2% 1%

No shift 100.00 100.00 100.00 100.00 100.00 100.00

ap + 1 mm 99.99 99,98 99.98 99.98 99.98 99.95

+ 3 mm 99.99 99.98 99.98 99.98 99.98 99.83

+ 5 mm 99.99 99.98 99.96 99.98 99.98 97.05

+ 10 mm 99.99 99.95 99.33 99.87 98.77 79.59

sI + 1 mm 99.99 99.98 99.56 99.93 98.85 96.49

+ 3 mm 99.99 99.01 96.84 97.25 95.77 89.77

+ 5 mm 99.98 97.73 94.80 95.29 93.08 80.31

+ 10 mm 99.85 95.74 89.87 90.59 85.28 69.17

Lr + 1 mm 99.99 99.98 99.98 99.99 99.98 99.97

+ 3 mm 99.99 99.98 99.95 99.99 99.87 97.03

+ 5 mm 99.99 99.98 99.65 99.84 98.63 94.46

+ 10 mm 99.97 99.76 96.98 97.44 94.28 85.88

pitch + 1° 100.00 100.00 100.00 100.00 100.00 99.95

+ 3° 100.00 100.00 100.00 100.00 100.00 99.87

roll + 1° 100.00 100.00 100.00 100.00 100.00 99.86

+ 3° 100.00 100.00 100.00 100.00 100.00 99.77

Yaw + 1° 100.00 100.00 100.00 100.00 100.00 99.21

+ 3° 100.00 100.00 100.00 100.00 100.00 99.17

DD — dose difference; ap — anterior-posterior; sI — superior-inferior; Lr — left-right



value of DD2% at T75% in the large and small air cavities was about 90%, DD2% < 90% was defined as the possibility of the rectum of being full of rectal gas during irradiation.

clinical studyA total of 614 fractions from 16 patients were

subjected to EPID-based IVD during VMAT. Among the total, 25 fractions were irretrievable

table 2. Inhomogeneity regions simulated using the I’mrT phantom with air cavity

Air cavity [cm3] Method Criteria T0% T25% T50% T75% T100%

12 (2 × 2 × 3)

Gamma (%)

3%/3 mm 99.98 99.98 99.99 99.99 100.00

2%/2 mm 98.79 99.97 99.98 99.98 100.00

1%/1 mm 91.55 92.29 97.96 98.61 100.00

DD (%)

3% 92.46 92.78 99.98 99.99 100.00

2% 81.63 84.30 96.14 98.74 100.00

1% 61.32 74.90 79.37 86.09 100.00

48 (4 × 4 × 3)

Gamma (%)

3%/3 mm 99.73 99.82 99.99 99.99 100.00

2%/2 mm 96.27 98.01 99.45 99.98 100.00

1%/1 mm 80.91 87.98 93.80 96.90 100.00

DD (%)

3% 69.76 80.52 83.19 88.89 100.00

2% 59.03 60.97 73.86 79.05 100.00

1% 40.44 46.98 55.11 56.50 100.00

The appearance of air cavity was controlled by moving the motion phantom after quarter (T25%), half (T50%), and three to four times (T75%) during one-arc VMaT. The I’mrT phantom with small and large air cavities during VMaT from beginning to end were also measured (T0%). None of air cavity was also measured (T100%); DD — dose difference

Figure 3. The comparison of the gamma and dose difference (DD) analysis in inhomogeneity regions simulated using the I’mrT phantom which had a small air cavity with or without the programmable motion platform movement. at T0%, the air cavity had stayed in the irradiation time from beginning to end. at T50%, the air cavity appeared after 50% of the irradiation time and had stayed for 50% of the irradiation time. The epID images of expected dose are baseline. Dose profile X and Y are horizontal and vertical lines in the gamma index and difference



because of a defect in data transmission. Figure 4 illustrates the daily variation in the pass rate in the EPID-based IVD for three representative patients. There was almost no change in the pass rate for some patients, but the pass rate changed for oth-ers in about one to three fractions. Figure 5 shows an example of a fraction with full rectal gas after clinical treatment displayed using PerFRACTION software. Some fractions could be used to confirm the location of rectal gas during treatment via the analysis of EPID images the same as Figure 5. Ta-ble 3 summarizes the analysis results of the clini-cal study for EPID-based IVD for prostate cancer. The results of nearly 90% of the fractions were DD2%>90% in all the patients. The average DD2% value of the fractions with an empty rectum and a rectum full of rectal gas after irradiation were 96.12% and 86.13%. Moreover, the proportion of DD2% < 90% indicated that there were more frac-

tions with a rectum full of rectal gas than with an empty rectum (Fig. 6).

Discussion

Several studies have reported that EPID-based IVD can be used to identify major treatment errors such as intrafractional patient and organ movement [15–22]. However, these studies did not clearly

table 3. results of clinical study for epID-based IVD for prostate cancer

All patients (n = 16, 589 fractions) Fraction (%)

DD2% ≥ 90% 510 (86.59)

DD2% < 90% 79 (13.41)

empty rectum after irradiation 524 (88.96)

rectum full of rectal gas after irradiation 65 (11.04)

DD2% — dose difference criteria 2%

Figure 6. Dose difference distribution for the presence or absence of rectal gas after irradiation in a clinical study; DD2% — dose difference criteria 2%

Figure 4. The daily transition of the pass rate in epID-based IVD for three representative patients

a

B

c

Figure 5. example of a fraction appeared rectal gas during treatment in a clinical study (Fraction 9 in patient 10). sagittal view of kV images (A) before, (b) after irradiation, with pTV, bladder, and rectum contoured in red, blue, and brown. c. The result of the epID image analyzed by DD2% in clinical study. The epID image of expected dose is that of Fraction 1 in patient 9. Dose profile X and Y are horizontal and vertical lines in the gamma index and difference



show the cause of treatment errors identified by the EPID images. In the prostate cancer patients, the main cause of these was patient body movement and the occurrence of rectal gas during treatment. Therefore, to the best of our knowledge, this study is the first one to focus on the detectability of setup error and rectal gas during VMAT for prostate can-cer patients by using EPID-based IVD.

In terms of the analysis method, previous reports suggested that the DTA component of the gamma method masked the setup error in the EPID im-ages of individual IMRT fields [22, 25]. Our results confirmed these findings in VMAT. In the phantom study, the pass rates of gamma method in all criteria were more than 90% in a small air cavity (12 cm3), but those of DD of 2% and 1% were less than 90%. The gamma method could not detect small changes unlike the DD method. Therefore, we used the DD method for data analysis.

Some researchers proposed that EPID-based IVD could be used to successfully detect system-atic setup errors in the head region [22, 26]. This is not in agreement with our findings because no sys-tematic setup error was detected when simulating the anthropomorphic phantom in the range that can happen in clinical (< 5 mm and < 3 degree). This is because the bone structure and body surface in the case of head cancer are more complicated than those for prostate cancer. Because the prostate is located in the center of the pelvic region, the VMAT plan is less subject to changes of the beam pass. Moreover, several reports found that system-atic setup errors were detected in 3-dimensional conformal radiotherapy (3DCRT) [15, 26]. This is because the dose distribution of the 3DCRT was sharper than that of VMAT in the edge of each field. Hence, EPID-based IVD is inadequate for systematic setup error detection in the VMAT plan for the pelvic region.

However, our study demonstrated that EP-ID-based IVD is useful for identifying inhomoge-neity regions in the I’mRT phantom. In the pelvic region, an inhomogeneity region is highly sugges-tive of rectal gas. EPID-based IVD could detect small air cavities with a diameter of 2 cm. In addi-tion, our data indicated chronological changes in the air cavity during VMAT. Larger air cavities and a longer stop time resulted in decreased pass rates. It is suggested that EPID-based IVD is better for identifying inhomogeneity regions than detecting

systematic setup errors. Moreover, the mean rectal diameter in our clinical study was 3 cm, which was between the sizes of the large and small air cavities in the phantom studies. We decided to assess the occurrence of rectal gas for DD2% < 90% in the clinical study by calculating the mean values of T75% in the large and small air cavities on the assumption that rectal gas appears during treatment.

We measured and analyzed the EPID images in the clinical study to confirm the correlation be-tween the pass rates and occurrence of rectal gas during VMAT. The proportion of DD2% < 90% was 13.4% for all the patients. Rectal gas was confirmed in 11.0% of fractions. Rosario et al. reported that the prostate position error was detected in 13.0% of fractions by using automatic detection of implant-ed gold seeds and the imaging application Auto Beam Hold (Varian Medical Systems) [27]. This is in agreement with our results which demonstrated the proportion of rectal-gas-positive cases and the decrease in the DD2%. However, the proportion of DD2% < 90% and fractions with a rectum full of rectal gas after irradiation was only 5.8% in our study. There is a possibility that rectal gas goes in and out of the rectum during and after irradiation because there was no rectal gas before irradiation by using X-ray image registration. In addition, the proportion of DD2% < 90% in rectal-gas-positive cases was larger than that in rectal-gas-negative cases, but about 50% of the gas-positive cases had DD2% > 90%. This may be because rectal gas ap-peared from the completion of treatment to the acquisition of kV images. Moreover, we did not quantify changes in bladder volume in each condi-tion because the main cause of the decline in DD2% was the presence of inhomogeneity regions, accord-ing to the results of the phantom study. Some stud-ies reported that EPID-based IVD had effects on the detection of rectal gas in 3DCRT for rectal and prostate cancer [15, 20]. Woodruff et al. found that prostate cancer patients had a lower pass rate than other cancer patients for EPID-based IVD, which was due to the rectum being filled with rectal gas in CBCT scans in the last week of treatment [18]. Col-lectively, it is proposed that EPID-based IVD can indicate the presence of rectal gas during VMAT.

Most of the fraction in DD2% < 90% had not the point dose over 5% dose difference, indicat-ing that patient specific QA was acceptable in our study. This is because a large amount of rectal gas



causes the point dose over 5% dose difference, but we have often stopped the treatment by using CBCT images when a large amount of rectal gas was detected near the target. However, VMAT plan is steeper dose gradient and more compli-cated dose distribution. Therefore, the occurrence of a small amount of rectal gas near the target is imprecated in the lower target cover. Connolly et al. found that local recurrence was the greatest on the rectal side compared to other locations af-ter radiation therapy for prostate cancer patients [28]. One reason for this may be the presence of rectal gas during treatment. It is not possible to determine the accurate dose for a target because the presence of rectal gas can cause changes in the beam pass by repeating complicated build up and down. Many reports suggest that the presence of rectal gas induces intrafractional prostate and rec-tum movement that prevents accurate treatment [6–11]. The presence of rectal gas is the predictor of performing accurate treatment. Therefore, it is important to identify if rectal gas is present dur-ing treatment and obtain evidence for accurate treatment. EPID-based IVD in VMAT can detect the rectal gas and monitor accurate treatment in each fraction. It is hoped that the outcome of this study will contribute to accurate radiation therapy for prostate cancer patients. One of the limitations of this study is that we were not able to compare the EPID image for the planning CT with that in each fraction. This can be used to more accurately determine the presence of rectal gas in the future.

conclusion

This study clearly demonstrates that analysis cri-teria of 2% dose difference in EPID-based IVD can identify the presence of rectal gas during VMAT for prostate cancer patients. It was difficult for EP-ID-based IVD in VMAT for prostate cancer pa-tients to detect systematic setup errors of the range that can happen in a clinical study.

conflicts of interestThe authors declare that there are no conflicts of interest.

Financial discrosure None declared.

acknowledgementsWe thank Editage (https://www.editage.jp/) for pro-viding English language editing for our manuscript. This study was supported by JSPS KAKENHI Grant (17K15817) to Yoshihiro Ueda.

Presentation at the conference: ESTRO2019 in Milan (EP-1747)

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reVIeW arTIcLe




Address for correspondence: Tomás Merino, Diagonal Paraguay 319, Santiago 8330032, Chile, tel: 23546832; e-mail: [email protected]

Radiotherapy for cervical cancer: Chilean consensus of the Society of Radiation Oncology

Felipe Carvajal1, 3, Claudia Carvajal1, Tomás Merino4, 5, Verónica López1, Javier Retamales1, Evelyn San Martín2, Freddy Alarcón1, Mónica Cuevas1, Francisca Barahona1, Ignacio Véliz1,

Juvenal A. Ríos6, Sergio Becerra5

1Departamento de Radio Oncología, Instituto Nacional del Cáncer, Santiago, Chile2Departamento de Radio Oncología, Hospital Clínico de Magallanes, Punta Arenas, Chile

3Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile4Departamento de Hemato-Oncolgía. Pontificia Universidad Católica de Chile, Santiago, Chile

5Departamento del Cáncer, Ministerio de Salud, Santiago, Chile6Programas para el Futuro, Facultad de Estudios Interdisciplinarios, y Escuela de Medicina, Facultad de Ciencias, Universidad Mayor,

Santiago, Chile

AbstrAct

background: cervical cancer is a public health problem in Latin america. radiotherapy plays a fundamental role both as

definitive or adjuvant treatment. There are important intra and inter-country differences regarding access and availability of

radiotherapy facilities in this region.

The aim of a study was to standardize the basic clinical and technical criteria for the radiation treatment of patients with cc in

chile and provide a guide for Latin american radiation Oncologists.

Materials and methods: Forty-one expert radiation oncologists from the chilean radiation Oncology society made a con-

sensus using the Delphi methodology.

results: There was a high degree of agreement for each of the recommendations. Those with the lowest percentage were

related to the definition of the conformal 3D technique as the standard for definitive external radiotherapy (81%) and the

criteria for extended nodal irradiation (85%).

conclusions: These recommendations present an updated guide for radiotherapy treatment of patients with cervical cancer

for Latin america. Those should be implemented according to local resources of each institution.

Key words: uterine cervical neoplasms; radiotherapy; brachytherapy; consensus





ISSN: 1507–1367

Introduction

Cervical cancer (CC) is an important prob-lem for public health in Latin America. Accord-ing to GLOBOCAN, it’s the sixth most frequent malignancy in Chilean’s women, with incidence of 12.2/100,000 women, (age-adjusted rate) and mor-tality of 5.0/100,000 [1]. Early diagnosis screening with the Papanicolaou test is essential but the cov-

erage of the Chilean population is only about 59%, with zones that fluctuate between 72.2% (Los Ríos’s region) and 45.5% (Antofagasta’s Region) [2]. Ra-diation therapy plays a fundamental role in CC for the primary (definitive) and adjuvant (postopera-tive) settings, with treatment schemes that combine external beam radiotherapy (EBRT), high dose rate (HDR) or low dose rate (LDR) brachytherapy, and concomitant chemotherapy (CCT) [2]. The acceler-



ated evolution of the technology in imaging and ra-diation equipment during the last decades has im-plied a paradigm shift in different types of cancer, including the gynecological ones. Latin America is a region with different realities within and between countries regarding access and availability of ra-diotherapy facilities [3–5]; therefore, it is of high importance to have a regional consensus to define treatment strategies. The present consensus aims to standardize the basic clinical and technical criteria for the radiation treatment of patients with CC in Chile and provide a guideline for Latin American Radiation Oncologists.


The board of the Chilean Society of Radiation Oncology (SOCHIRA) convened national experts in radiation oncology with experience in the man-agement of patients with CC. To generate a national consensus. We used a three phase modified Delphi method [6].

The first phase was an online survey developed to ask for the management of different clinical cases and common management practices. We distribut-ed the survey by e-mail to national specialists using a digital platform. Subsequently, national specialists were called to make a review of the literature, in-cluding PUBMED database, recent publications in conferences of the specialty and recommendations of international groups in order to prepare propos-als for recommendations based on the evidence and consider the opinions or comments provided by 44 national experts through the online survey previ-ously indicated.

In the second phase, the proposal for final rec-ommendations based on the answers from the first phase was distributed to 89 specialists in oncologi-cal radiotherapy from the country.

Participants had to specify anonymously their level of agreement to the statements using a 5-point Likert’s scale [7]: 1 = Strongly disagree, 2 = Dis-agree, 3 = Neither agree nor disagree, 4 = Agree, 5 = Strongly agree.

The consensus in a recommendation was estab-lished if more than 66% of the answers were 1 and 2, or 4 and 5 for each question, according the sug-gestions of the literature [6, 8]. Finally, the third phase was carried out in person to review the re-sults of online voting and define consensus on those statements that reached only partial consensus in phase 2. Degrees of recommendation and levels of evidence were assigned to each recommendation [9] (Tab. 1). To maintain agreement with pivotal studies and avoid confusion, the use of the 2009 version of the FIGO classification in CC was main-tained [10].

results and Discussion

41 of 89 radiation oncologists completed the dis-tributed survey with recommendations for its vali-dation, 33 of them routinely treat patients with CC. Within this group, the median number of patients with CC treated by each radiation oncologist was 30 per year. Of a total of 19 radiation oncologists dedicated to gynaecology cancer in Chile, 17 re-sponded to the survey (90%). The median number of CC patients treated by each of these experts was 60 per year.

table 1. Level of evidence and grade of recommendation determined by the technical committee of explicit Guarantees in health (Ges), Ministry of health, chile

Grade Description

aHighly recommended: Based on good quality studies

systematic reviews of randomized clinical trials, randomized clinical trials, other systematic reviews with or without meta-analysis, health technology assessment reports.

Brecommended: Based on moderate quality studies

randomized studies with methodological limitations or other forms of non-randomized controlled studies.

crecommendation based exclusively on expert opinion or descriptive studies, case series, case reports or other uncontrolled studies with a high potential for bias.

IInsufficient information

The available studies do not allow to establish the effectiveness or benefit / harm balance of the intervention, there are no studies on the subject or there is not enough consensus to consider that the intervention is supported by practice.

Bp recommendation based on the experience and practice of a group of experts.

Felipe Carvajal et al. radiotherapy for cc: chilean consensus of the society of radiation oncology


The recommendations are summarized in the Table 2. The detail is available in Appendix.

Questions and brief analysis of evidence

There are several international clinical guide-lines on CC. We published here the first one, to our knowledge, developed in Latin America. There are consensuses that are oriented to the delinea-tion of target volumes [11–13], specific topics in

BT [14–17] and others related to multidisciplinary management of cervical CC [18–20]. Recently, the American Society for Radiation Oncology (ASTRO) has published a consensus focused on RT developed using a Delphi method with rec-ommendations consistent with ours [21]. We fo-cused on defining a desirable technical maximum and a required minimum in order to consider the existing differences and limitations in Chile and Latin America. In addition, we include a guideline regarding the indication of extended field radio-

table 2. recommendations of the sOchIra for radiotherapy treatment in cervical cancer

RecommendationsGrade of

recommendationLevel of

evidencePercentage of

agreement

The use of adjuvant eBrT is recommended in the following situations: WItHOUt platinum based cct: sedlis criteria: 1) ILV+ and deep third, any T 2) ILV+ middle third and tumor larger than 2 cm 3) ILV + superficial third and tumors greater than or equal to 5 cm 4) ILV–, middle third and tumor of 4 cm also 5) ILV+, deep third and 4 cm tumor. WItH platinum based cct: Peters criteria 1) lymphadenopathy (+) 2) parametrium (+) 3) margin (+)

a 1 98%

IMrt technique in adjuvant Ebrt is recommended. conventional 3D technique is a valid option, considerations of a higher acute and late toxicity must be taken

B 1 86%

45 Gy in 25 fractions is recommended as adjuvant schedule dose

Other accepted fractionation schedules are 50.4 Gy in 28 fractions, 50 Gy in 25 fractions of 2 Gy day, 46 Gy in 23 fractions

B 2 95%

routine use of brachytherapy as a boost dose in adjuvant setting is not recommended. Its use can be considered in the case of a close or positive vaginal margin, for a total eQD2 dose of 65–70 Gy

c 4 90%

The use of definitive radiotherapy (eBrT plus brachytherapy) is recommended in patients with an early stage (IB1, IIa1) in the case of surgical contraindication or patient rejection

B 1 100%

The use of definitive radiation therapy (external rT plus brachytherapy) with concomitant chemotherapy is recommended in patients with an advanced stage: IB2 and ≥ IIa2 to IVa

a 1 100%

3D conformal technique is recommended as standard for definitive radiotherapy

IMrT is an option to consider given its theoretical and clinical benefits derived from other pelvic neoplasms, with the use of an appropriate IGrT protocol and consideration of internal movements

B 3 81%

45 Gy in 25 fractions is recommended as definitive radiotherapy schedule dose

Other accepted fractionation schedules are 50.4 Gy in 28 fractions, 50 Gy in 25 fractions, 46 Gy in 23 fractions

B 2 95%

total treatment time ≤ 50–56 days is recommended

early referral to BT is recommendeda 2 100%

Parametrial boost with external radiation therapy is not recommended. For its omission consider: 1) clinical and imaging evaluation of parametrial involvement. 2) To have the ability to perform interstitial brachytherapy if required

In case of not complying with the previous points, it is accepted to perform a sequential parametrial boost up to 54–59.4 Gy or its equivalent with integrated simultaneous boost, considering the increased risk of acute and mainly late complications

a 2 93%

The inclusion of lumbo-aortic (Lao) lymph nodes is recommended in selected high-risk patients, according to the EMbrAcE II protocol: ≥ 1 common iliac lymph node matastases, ≥ 3 pelvic lymph node matastases. In the case of lymph node metastases in Lao, it should be extended to at least 3 cm above the highest

B 3 85%



therapy, parametrial boost, overall treatment time and the need to implement interstitial BT in facul-ties involved in the treatment of patients with CC. A review of literature related with our recommen-dations are presented below.

What are the indications for adjuvant radiation therapy?

Adjuvant radiotherapy (RT) in CC has been evaluated in different phase III clinical studies and meta-analyses, demonstrating that in patients with intermediate and high risk of recurrence there is a clear benefit with its use in terms of progres-sion-free survival (PFS) and overall survival (OS) [22–26]. In relation to patients classified as in-termediate risk based on the inclusion criteria of the GOG 92 study that considers lymph vascular invasion, depth of invasion and tumor size (“Sedlis criteria”), an increase in PFS was observed at 5 years of 53% to 62% when comparing adjuvant RT versus surgery alone, with less local and distant recurrence [22, 23]. Regarding high-risk cases of postoperative recurrence, defined as those where there was compromise of lymph nodes, parame-tria, or surgical margin in the radical hysterec-tomy (“Peters criteria”), the GOG 109 study dem-onstrated benefits of platinum based radiochemo-therapy (RQT) versus RT alone with improvement

in 5-year OS from 66% to 80% and in 5-year PFS from 79% to 83% [24, 25].

Is intensity modulated radiation therapy (IMrT) better than conventional 3D

treatment for adjuvant external beam radiotherapy?

The RTOG 1203 study [27] is the only random-ized clinical trial that has evaluated the compari-son between IMRT technique and conventional 3D conformal. It randomized 289 patients to conven-tional 3D technique or IMRT in adjuvant setting, 75% without concomitant chemotherapy. Initial re-sults showed a significant decrease in acute and late gastrointestinal and genitourinary toxicity reported by patients [27, 28].

What is the appropriate dose and fractionation in adjuvant setting? The dose and fractionation used in the different

clinical studies is variable. The protocols of the piv-otal studies used for exclusive adjuvant EBRT 46 to 50.4Gy in 23 to 28 fractions [22, 23], and in GOG 109 study, planned RT to the pelvis in a scheme of 49.3 Gy in 29 fractions, adding a lumboaortic nodal field of 45 Gy in 25 fractions in case of compro-mised common iliac lymph nodes [24, 25]. Also, there are other studies that consider schemes from

table 2. recommendations of the sOchIra for radiotherapy treatment in cervical cancer

RecommendationsGrade of

recommendationLevel of

evidencePercentage of

agreement

sequential boost to pelvic lymph node macroscopic disease is recommended up to 55–60 Gy or its equivalent with integrated simultaneous boost (sIB) (preferably sIB with IMrT technique)

In LAo lymph nodes macroscopic disease, without evidence of systemic spread on PEt/ct, sequential boost of up to 60 Gy or its equivalent with integrated simultaneous boost is recommended, ideally using the IMrT technique in both cases

B 2 100%

the use of HDr technique is recommended

LDr technique is accepted as an optiona 2 97%

Brachytherapy treatment planning based on 3D images (cT and/or MrI) with volumetric prescription and evaluation is recommended

Use applicator adapted to residual disease or anatomy of the patient. Interstitial brachytherapy is recommended if required

2D dosimetry prescription a point and report rectal and bladder point accepted. In case of using the LDr technique, a prescription should be made for point a and a report of the rectal and bladder point should be made

a 2 98%

It is recommended to have an initial pelvic MrI evaluation (before Ebrt) and one immediately before brachytherapy. It can be a simulation MrI or fused diagnostic MrI. prioritize MrI prior to brachytherapy. If there is no access to MrI, treatment based on simulation cT or ultrasound performed by an expert is accepted

a 2 98%

eBrT — external beam radiotherapy; ccT — concomitant chemotherapy; ILV — ipsilateral lung volume IMrT — intensity modulated radiation therapy; eQD2 — equivalent dose at fractionation of 2 Gy; IGrT — image-guided radiation therapy; hDr — high dose rate; LDr — low dose rate peT — positron emission tomography; cT — computed tomography; MrI — magnetic resonance imaging



45 to 50.4 Gy between 1.8 and 2 Gy daily [29–31]. The IMRT protocol in adjuvant context (RTOG 1203) allows the use of 45 Gy or 50.4 Gy in frac-tions of 1.8 Gy daily depending on the researcher’s preference. Approximately 60% of patients received 45 Gy in 25 fractions [27].

Is the use of brachytherapy (BT) boost recommended in the adjuvant setting?

Depending on the extent of surgical resection, the vaginal dome may be at higher risk of recur-rence, but randomized clinical studies did not con-sider BT boost in addition to EBRT [22–25],with only retrospective reports of its use in the context of patients with positive margins [32]. Considering the lack of evidence, the American Brachytherapy Society (ABS) generated a consensus on its use recommending adjuvant BT in addition to EBRT with an equivalent dose close to 70 Gy in patients with close or compromised vaginal margins, with non-radical hysterectomy, large or deeply invasive tumors, parametrial involvement or extensive lym-phovascular invasion [14].

What are the indications for definitive radio(chemo)therapy?

In early stages (stages FIGO I to IIA1 except IB2) the usual treatment is surgery, but it is important to highlight that definitive RT offers similar results in terms of survival and therefore can be offered as an oncological equivalent alternative. A prospec-tive randomized study [33, 34] with 170 patients in each arm in stages I–II found that there were no differences in 5-year survival between exclusive RT and surgery.

In locally advanced stages (FIGO stages IB2 and IIA2 or higher), the evidence favors the use of definitive RTQT since the publication of the five classic randomized studies of the late 20th century [24, 35–38] that motivated the NCI alert and the meta-analysis published a decade later with up-dated data from individual patients from 15 ran-domized studies [39] again giving robust support to definitive RTQT as standard treatment in advanced stages.

Is IMrT better than conventional 3D treatment for definitive eBrT?

Various retrospective [40–42] and prospective uncontrolled studies [43–45] and a meta-analysis

[46], have shown equivalence in oncological re-sults and a significant decrease in acute and chronic toxicity both genitourinary and gastrointestinal in benefit of the IMRT technique. However, there are no published randomized clinical trials confirming the benefits of using IMRT compared to conven-tional 3D as definitive therapy.

What is the appropriate dose and fractionation of the eBrT

in definitive radiotherapy?The dose and fractionation used in different

clinical studies during the EBRT phase is vari-able, including patients from 40.8 Gy in 24 frac-tions to 51 Gy in 30 fractions according to their FIGO stage [24, 35–38]. The American Brachy-therapy Society guideline recommends 45 Gy in 25 fractions [15]. On the other hand, the current ESGO/ESTRO/ESP guideline recommends a dose of 45–50.4 Gy in 1.8 Gy daily fractions [18, 47]. Retrospective studies have shown that most of the tumor response in the EBRT phase occurs before 45 Gy [48]. Three extra fractions to reach 50.4 Gy provide little tumor control and, on the other hand, decrease the possibility of dose es-calation during adaptive brachytherapy [48, 49. In this context, the GEC/ESTRO network in its EMBRACE studies [50] went from recommend-ing a 45–50.4 Gy dose with EBRT (1.8 Gy daily fractions) to a 45 Gy dose in 25 fractions for all patients in the EMBRACE II protocol [51].

Is there an overall treatment time that determines the best oncological

outcome?The overall treatment time impact was demon-

strated in studies prior to the concomitant che-motherapy era showing a pelvic control loss of 7–8% per extra week [52–55]. Considering the above, the American Brachytherapy Society rec-ommends that the total treatment time should not exceed 8 weeks [15]. This data has been corrobo-rated at the concomitant chemotherapy era by the EMBRACE group who showed that, considering a median of 49 days of treatment, an extra week is equivalent to 1–2.5% local control loss depending on the size of the residual tumor volume. Consid-ering the previous data, the EMBRACE II group recommends maintaining a total treatment time of ≤ 50 days [56].



What is the role of parametrial boost in definitive radiation therapy?

Parametrial boost with EBRT has not been used routinely or standardized in clinical trials [24, 35–38]. It has been observed that its application leads to unpredictable doses at the tumor and the organs at risk [57] which can lead to a decrease in local control and increased toxicity. An Austra-lian retrospective study evaluating the omission of external beam parametrial boost in patients with parametrial involvement defined by physical ex-amination and magnetic resonance showed no dif-ference in terms of local control compared to the group of patients without parametrial involvement [58]. In the last decade the trend has been to im-plement 3D image guided adaptive brachytherapy with parametrial boost application as needed at the brachytherapy planning, being the current recom-mendation of the GEC-ESTRO network. Current ESGO/ESTRO/ESP guidelines advise against the use of parametric treatment with external radio-therapy beyond 45–50.4 Gy [47].

What is the role of extended field radiotherapy (lumboaortic area)

in definitive radiotherapy? In cervical cancer patients it is estimated that

the probability of pelvic and lumboaortic nodal involvement increases progressively as the disease stage progresses affecting overall survival (OS) and disease-free survival (DFS) [59]; therefore, ad-equate staging is essential for treatment planning. Current international guidelines consider FDG PET-CT as the preferred option for staging given its high specificity (approx. 90%) and sensitivity (approx. 70%) in patients with advanced local in-volvement [18, 60, 61]. The benefit of prophylactic extended field towards the lumboaortic region in patients without compromise in that zone has been evaluated in several studies (including EORTC 1988 and RTOG 7920), demonstrating contradic-tious improvement in OS and no benefit in other studies. However, treatment in these studies was not performed with concomitant chemotherapy, so the actual benefit may be overestimated [62–65]. Regarding patients with compromised lumboaortic nodes, the contribution of extended field versus pelvic field is also controversial, since the clinical trial that studied it (RTOG 9001) did not include CT in patients with extended field but it did for

those treated exclusively with a pelvic field [37, 66]. More current retrospective studies report benefit in DFS and local control with acceptable toxicity [67], but it’s not clear what the characteristics of pa-tients who should receive this modality are. Vargo et al. showed that extended field IMRT achieves 95% control in lumboaortic-negative patients and 89% in lumboaortic-positive patients [68]. The EM-BRACE group showed that at the time of diagnosis 47% of the patients had nodal involvement, mainly in the pelvis (internal, external and common iliac region), but nodal recurrences after treatment gen-erally occurred in the lumboaortic region constitut-ing 69% of all nodal failures. Of these failures, 78% had not received RT in that region, so identifying high-risk groups to treat is essential [50]. Due to all of the above, the EMBRACE II group defined a high-risk lumboaortic recurrence or distance fail-ure group: those patients who have 1 or more com-mon iliac lymphadenopathy or those with the pres-ence of 3 or more pelvic lymphadenopathy, with the aim to study the role of lumboaortic RT in those who meet these requirements.

In cases with a lumboaortic involment, a paraor-tic field covering at least 3 cm cephalic to the ad-enopathy will be planned.

It’s clear that the available evidence is not cat-egorical for the use of extended lumboaortic field, so the proposed plan is to follow the rationale of the main research group active in the subject (EM-BRACE II) [50].

Is there an optimal dose to deliver in macroscopic node disease?

There are retrospective studies that have evalu-ated the dose necessary to achieve adequate con-trol of macroscopic lymph node disease [69–71]. These studies, have shown that a dose of ≥ 57.5 Gy achieves a better oncological outcome. It is impor-tant to consider, in this context, that brachytherapy also provides doses to the lymph node areas, mainly to the iliac-obturator region, being able to add up to 5 Gy on average. In the case of lumbo-aortic lymphadenopathy, extended field irradiation has been performed with a dose of 45 Gy in 25 frac-tions of 1.8 Gy [37, 62, 63, 65–67]. Boost dose to the lymphadenopathy have been performed with doses of up to 60 Gy in conventional fractionation, considering studies that show a better nodal control with doses ≥ 57.5 Gy [69]. For pelvic macroscopic



node disease, current ESTRO guidelines recom-mend a dose of 55–60 Gy considering the contribu-tion of brachytherapy [47].

Is hDr brachytherapy technique better than LDr brachytherapy?

Both techniques are similar from the perspective of oncological outcome and toxicity of the treat-ment. However, the HDR technique has some ad-vantages over LDR [72–76] as it:• allows better positioning of the applicator in the

patient during the treatment session;• enables image-guided treatment;• allows an outpatient treatment, unlike LDR

brachytherapy that requires hospitalization (1–3 days);

• decreases the risk of complications due to im-mobilization of the patient;

• decreases the risk of radiation exposure to per-sonnel;

• decreases the risk of radioactive accidents.In this context, the International Atomic Ener-

gy Organization has had among its objectives that radiotherapy faculty have a transition from LDR brachytherapy to HDR [77].

Is 3D treatment planning better than 2D in brachytherapy?

Image-guided (3D) treatment allows evaluating the response to treatment during radiotherapy and adapting the volumes to be treated with brachyther-apy. The STIC Trial, a non-randomized prospective study, shows that a 3D based treatment planning in cervical cancer allows better local control and lower toxicity rate than 2D dosimetry [78]. Currently, the Groupe Européen de Curiethérapie of the European Society for Radiation Oncology (GEC-ESTRO) rec-ommends the Magnetic Resonance-guided Brachy-therapy technique [16]. In 2008, the GEC-ESTRO began the study “International Study on MRI-Based Brachytherapy in Cervical Cancer” (EMBRACE) [50] reaching the recruitment of > 1,300 patients in 27 countries in 2015. Pending its results, in 2010 the GEC-ESTRO started the retrospective study RetroEMBRACE, whose data shows that the local control at 5 years is 89%. The concept of adaptive radiation therapy is focused on the volume of the primary tumor (GTV-T) and how it changes during RQT [79–81]. To achieve adequate doses, the com-bination of intracavitary and interstitial applicators

(IC/IS) is essential in large tumors, seeking to in-crease the dose in tumor tissue without increasing the toxicity of organs at risk (OAR) [82–85].

What is the contribution of 3D images for the brachytherapy treatment

planning?Sectional images (CT or MRI) provide valid and

reliable information on the extent and configura-tion of individual tumors and their topography, making it easier to define the volumes to be treated (compared to clinical examinations without imag-ing support). By providing greater precision regard-ing the extension and spatial arrangement of the target, 3D images allow to increase the treatment dose in high-risk areas, protecting organs at risk near the tumor. The main advantage of MRI is its superior quality in the representation of soft tissues; therefore, when it is available, MRI is the imaging method of choice as it allows better differentiation between tissues, estimating parametrial involve-ment and tumor size [16, 17, 86–90].

conclusion

The recommendations presented are the result of the discussion of the evidence among national gy-naecological radiotherapy specialists. Radiotherapy continues to play a fundamental role in the curative treatment of cervical cancer, whether as definitive therapy or adjunctive to surgery, concomitant or not with chemotherapy. To optimize the manage-ment of this pathology, it is recommended that new diagnostic modalities, such as PET-CT and MRI which allow a better selection of patients who will benefit from radiotherapy treatment with curative intent, should be incorporated as well as planning and adaptation of the treatment corrected. The op-timal treatment should be carried out in a period not exceeding 56 days and, ideally, in less than 50 days, which is a quality standard that requires to ar-ticulate human resources in comprehensive cancer centres and foster homes, among others. Regard-ing the radiotherapy technique, the use of IMRT is recommended as a treatment option when to reduce the dose to organs at risk. The need to mi-grate to an adaptive 3D image based brachytherapy technique with an interstitial support option is em-phasized. These recommendations are available to standardize and improve clinical practice and must



be adapted to each radiotherapy centre according to its local reality.

conflict of interestThe authors (F.C., C.C., T.M., V.L., J.R., E.S.M., F.A., M.C., F.B., I.V., J.A.R., S.B.) declare that have no conflicts of interest to be declared.

FundingThe authors (F.C., C.C., T.M., V.L., J.R., E.S.M., F.A., M.C., F.B., I.V., J.A.R., S.B.) declare that have no sponsorship/funding to be declared.

Financial/other relationshipsThe authors (F.C,. C.C., T.M., V.L., J.R., E.S.M., F.A., M.C., F.B., I.V., J.A.R., S.B.) declare that have no financial or other relationships to be declared.

author contributionsF.C., C.C., T.M. were involved in the conception, design, preparation and final revision of the manu-script and participated in the collection and interpre-tation of data. V.L., J.R., E.S.M., F.A., M.C., F.B., I.V., J.A.R. were involved in the preparation of the first draft and critically revised the final version of the manuscript. S.B. Revised critically the final version of the manuscript. All authors read and approved the final version of the manuscript to be published and are accountable for all aspects of this work.

acknowledgementsAcknowledgements to all members of Chilean So-ciety of Radiation Oncology.

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http://dx.doi.org/10.2217/fon-2016-0295


http://dx.doi.org/10.6004/jnccn.2015.0137


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reVIeW arTIcLe




Address for correspondence: Andrew Donkor, Faculty of Health, University of Technology Sydney, IMPACCT (Improving Palliative, Aged and Chronic Care through Clinical Research and Translation), NSW Australia; Korle-Bu Teaching Hospital, National Centre for Radiotherapy and Nuclear Medicine, Accra, Ghana; e-mail: [email protected]

Novel coronavirus mitigation measures implemented by radiotherapy centres in low and middle-income countries:

a systematic review

Andrew Donkor1, 2, Vivian Della Atuwo-Ampoh3, Craig Opie4, Frederick Yakanu2, Dorothy Lombe5, Jamal Khader6

1Faculty of Health, University of Technology Sydney, IMPACCT (Improving Palliative, Aged and Chronic Care through Clinical Research and Translation), NSW Australia

2Korle-Bu Teaching Hospital, National Centre for Radiotherapy and Nuclear Medicine, Accra, Ghana3Department of Medical Imaging, School of Allied Health Sciences, University of Health and Allied Sciences, Ghana

4Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, Australia5Cancer Diseases Hospital, Zambia

6King Hussein Cancer Center, Amman, Jordan

AbstrAct

background: The aim of the study was to identify strategies adopted by radiotherapy centres in low- and middle-income

countries (LMIcs) to mitigate the effects of cOVID-19. studies summarising cOVID-19 mitigation strategies designed and

implemented by radiotherapy centres in LMIcs to avoid delays, deferrments and interruptions of radiotherapy services are

lacking.

Materials and methods: a systematic review was conducted and reported in accordance with the preferred reporting items

for systematic review and meta-analysis guideline. Ovid embase, Ovid MeDLINe and cINahL were searched for peer-reviewed

articles that reported measures adopted by radiotherapy centres in LMIcs to reduce the risk of cOVID-19. Information on dif-

ferent strategies were extracted from the included studies and textual narrative synthesis was conducted.

results: Of 60 articles retrieved, eleven were included. Majority of the studies were conducted in china. Ten of the included

studies employed a qualitative design. Four themes were identified: preparing and equipping staff; reinforcing infection pre-

vention and control policies; strengthening coordination and communication; and maintaining physical distancing. studies

reported that radiotherapy centres had: formed cOVID-19 response multidisciplinary team; maximised the use of telehealth;

adjusted the layout of waiting areas; divided staff into teams; dedicated a room for isolating suspected cases; and adopted

triage systems.

conclusions: Local adaptation of established global strategies coupled with timely development of guidelines, flexibility and

innovation have allowed radiotherapy leaders to continue to deliver radiotherapy services to cancer patients in LMIcs during

the cOVID-19 crisis. robust data collection must be encouraged in LMIcs to provide an evidence-based knowledge for use in

the event of another pandemic.

Key words: radiotherapy; cancer; cOVID-19; implementation; low and middle-income countries





ISSN: 1507–1367




Introduction

The challenges posed by novel coronavirus (COVID-19) are unprecedented, and policy and decision-makers around the globe are dealing with several complexities and uncertainties. No vaccine is currently available. As predicted by mathemati-cal models, the number of severe acute respira-tory syndrome coronavirus 2 (SARS-CoV-2) in-fections increased in the winter season of low- and middle-income countries (LMICs) in the southern hemisphere, which is a major concern because of the fragile health systems [1, 2]. Governments have demonstrated strong commitments by adopt-ing measures, such as stay-at-home recommenda-tions, business closures and travel restrictions to contain the spread of the virus [3] Some studies have demonstrated that people with cancer are at greater risk from COVID-19 because they often have multiple comorbidities, tend to be older and immunosuppressed due to the disease or its treat-ment [4]. In some countries, patients were ad-vised not to visit hospitals because of COVID-19 infection risk [5]. However, this is not a realistic long-term solution for radiotherapy centres and people living with cancer.

Radiotherapy is a critical component of univer-sal health coverage and it is crucial for policy and decision-makers to prioritise this essential service to avoid disruptive effects from COVID-19. Most radiotherapy centres in LMICs already face re-source issues including understaffing and budget constraints. The problems faced in these countries are compounded by misinformation, sociocultural and religious issues, as well as poor sanitary con-ditions. The delivery of safe and effective radio-therapy services in LMICs in a time of COVID-19 pandemic relies on appropriate policy, healthcare organisation, community and patient-level inter-ventions. An analysis of an online Twitter discus-sion by members of the global radiation oncology community highlighted the importance of creat-ing and implementing a programme that prepares, communicates, operates and compensates when radiotherapy is paused during the COVID-19 pan-demic [6].

Radiotherapy leaders in high-income coutries (HICs) have generally pursued cautious policies to help staff, cancer patients and their families stay safe at radiotherapy centres during the COVID-19

pandemic [7]. Some have adopted: physical dis-tancing by reorganising spaces and reducing the number of acompanying family members; triage systems; hand hygiene; use of personal protective equipment (PPE) for all cancer patients regardless of known COVID-19 status; and use of telehealth for training, multidisiciplinary team meetings and follow-ups [7, 8]. Similar strategies are now increas-ingly being implemented in most LMICs often with limited support, weak infrastructure and less robust local evidence. As a result, the prospect for sustain-ing and providing equitable radiotherapy service is questionable [9].

To avoid unsustainable service delivery, it is criti-cal that radiotherapy leaders in LMICs formulate and implement COVID-19 policy responses, which align with local priorities, needs and resources. At present, no studies have been conducted to identify and understand lessons learned based on LMICs radiotherapy centres’ experiences in responding to the COVID-19 pandemic. Therefore, the aim of this study is to identify strategies adopted by radio-therapy centres in LMICs to mitigate the effects of COVID-19.


This systematic review is reported in accordance with the preferred reporting items for systematic review and meta-analysis (PRISMA) guideline [10].

eligibility criteriaIncluded studies satisfied three criteria, which

were: i) studies had to focus on COVID-19 and radiotherapy services in any country classified as LMIC as defined by the World Bank Group; ii) studies have to describe measures adopted to re-duce the risk of COVID-19 in a radiotherapy centre; and iii) primary studies published in peer-reviewed journals of any design and in English language. Editorials, opinion pieces, comments, letters, stud-ies focused on high-income settings and studies in languages other than English were excluded.

Information sourcesThree electronic databases were searched, name-

ly: Ovid Embase, Ovid MEDLINE(R) and In-Pro-cess & Other Non-Indexed Citations and CINAHL. A manual search of the reference lists of included studies was performed.

Andrew Donkor et al. prophylactic corticosteroid to prevent pain flare in bone metastases


search strategyThe search strategy included terms relating to

four concepts: i) cancer; ii) radiotherapy; iii) CO-VID-19; and iv) LMICs. Subject headings, indexed keywords and free text terms relating to the four concepts appearing in titles and/or abstracts were combined using “AND” or “OR” (see Appendix 1 in Supplementary File). The initial search strategy was developed in Ovid MEDLINE and adapted for other databases. Databases were searched on 1 July 2020 and updated on 3 August 2020.

study selectionTwo authors screened titles and abstracts of all

citations retrieved for inclusion. Conflicts were re-solved through discussion. Studies were excluded if they clearly did not meet the inclusion criteria. Full texts of studies not excluded during the title and abstract screening were obtained.

Data extractionAn electronic data extraction form was devel-

oped, and two reviewers independently abstracted the contents of each included study. The data ex-tracted included: study characteristics; character-istics of strategies implemented; reasons for adopt-ing the strategy; and implementation challenges. Abstracted data were then discussed through an online platform. The risk of bias for each study was appraised using Joanna Briggs Institute Critical Ap-praisal Checklist for Qualitative Research indepen-dently by two reviewers and disagreements were resolved via discussion [11].

Data synthesisTextual narrative synthesis was conducted. Includ-

ed studies were independently coded by two reviews without a framework. Through thematic analysis, studies were arranged into homogeneous groups, and similarities and differences were compared across studies [12]. Each study was read and reread to achieve immersion, identify ideas and/or concepts of interest and completed with data reduction and com-parison. Emerging themes were explored, refined and any discrepancies were resolved through discussion.

results

Of the 60 articles retrieved, seven articles were removed due to duplication. The remaining 53 ar-

ticles were screened, and 11 articles were excluded based on their title and abstract. Next, 42 articles underwent full-text review and 31 were excluded because they did not satisfy the inclusion criteria, leaving 11 articles for data extraction (see Fig. 1). The level of evidence for all of the included studies was low.

characteristics of included studiesCharacteristics of the included studies are dis-

played in Table 1. The majority of the studies were conducted in China [13–16]. Other studies were conducted in Iran [17–19], Brazil [20] and Zambia [21]. Ten of the included studies employed a quali-tative design [13–16, 18–22]. A variety of methods were used including case reports [13, 14, 16, 19, 21], experts consensus [17, 18, 20, 22], cross-sec-tional survey [23] and critical review [15]. There is a strong support for hypofractionated radiother-apy. Four studies reported the radiotherapy frac-tionation schedules implemented during the CO-VID-19 pandemic period (Tab. 2) [17, 21, 22, 24].

Thematic analysisFour themes emerged: preparing and equipping

staff; reinforcing infection prevention and control policies; strengthening coordination and commu-nication; and maintaining physical distancing. Dif-ferent mitigation measures have also been sum-marised in a matrix with 21 subthemes (Fig. 2).

preparing and equipping staffWithin this theme, studies acknowledged the

importance of preparing and equipping staff and supporting staff to manage emerging psycho-social risks. Five studies reported providing staff with initial and ongoing education and training on correct use, maintenance and disposal of PPE, hand hygiene, disinfection procedures, isolation policies, symptoms of COVID-19 and latest na-tional guidelines on diagnosing and managing CO-VID-19 [13–15, 18, 21, 22]. Strategies frequently mentioned for delivering training included educa-tional pamphlets and a blend of web-based learning and hands-on experience [14, 18, 21, 22]. In the early phase of the pandemic, lack of effective infec-tion control programmes and weak enforcement mechanisms were major factors associated with in-creased person-to-person transmission resulting in several radiation oncologists, two radiation thera-



pists and an unknown number of patients having been infected with COVID-19 [15].

Eight studies reported that preparing and equip-ping staff with programmes, policies and resourc-es, such as non-contact temperature assessment

devices, telehealth equipment, PPE, sterilisation technologies and disinfectants were crucial to sup-port and protect staff to deliver safe radiotherapy [13–17, 19, 21, 22]. Lack of access to affordable PPE and stock shortages were obstacles to cancer

Figure 1. prIsMa flow diagram

Records identified throughdatabase searching:

CINAHL (3), MEDLINE (16), EMBASE (37)

Additional records identifiedthrough other sources

(n = 4)

Records after duplicates removed(n = 53)

Records screened(n = 53)

Full-text articles assessedfor eligibility

(n = 42)

Studies included inqualitative synthesis

(n = 11)

Includ

edEligibility

Screen

ing

Iden

tification

Records excluded(n = 11)

ź Wrong population (n = 3)

ź Wrong setting (n = 13)ź Lacks detailed strategy

to mitigate COVID-19 (n = 8)

Full-text articles excluded, with reasons

(n = 31

ź Editorials (n = 5)

ź Brief opinion (n = 1)ź Letter (n = 1)

table 1. summary of studies included in the review

Authors Aim Design Country Measures

aghili, Jafari & Vand rajabpoor 2020

To consider some of the best feasible brachytherapy regimes during the pandemic

expert consensus

Iran

adoption of a triage system

cOVID-19 testing

Interruption of the treatment for at least two weeks for confirmed cOVID-19 cases

escalation of dose per fraction and reducing the number of fractions

Baldotto et al. 2020

To outline guidelines that are both consensus-based, representing major cancer treatment medical societies, and localised, taking into account local needs for managing these patients.

expert consensus

Brazil

Discuss stereotactic ablative radiotherapy (saBr) in patients with stage I and II disease, especially if ≥ 70 years of age and at higher surgical risk

prefer hypofractionated radiotherapy when possible

Use of ppe


cOVID-19 testing

Use of telehealth for multidisciplinary team meetings





Gupta et al. 2020

To clarify the common doubts being faced by the high-volume centres regarding the functioning of the department, the treatment of patients and the safety of radiation personnel

expert consensus

India

clean waiting area with adequate distancing between the waiting benches and the patients

Time slots defined for patients and treating no more than 5 patients per hour

stringent use mask and follow standard hand hygiene

education for staff on the correct use of ppe

Thermal screening of all patients/staff at radiation premises

staff divided into two groups

Use of telemedicine to minimise patients’ visits

The potential benefits and risks of altered fractionations discussed with patients

Minimal use of radiation accessories

Withholding post-graduate teaching/online teaching platform

cOVID-19 testing for patients with travel history

home quarantine for staff with direct contact with confirmed cOVID-19 case

Lombe et al 2020

To report the response of a comprehensive cancer centre in a lower-middle income country to prevent cOVID-19 transmission and how the implementation of pragmatic strategies have served as a springboard to improve cancer services beyond the cOVID-19 pandemic.

case report Zambia

establishment of local taskforce

staff training to ensure that all staff were adequately trained in the prevention of cOVID-19 transmission

Facilitation of good hygiene practices


rethinking of patient scheduling

Use of telehealth for meetings

Motlagh et al. 2020

To provide recommendations and possible actions that should be considered by patients, their caregivers and families, physician, nurses, managers and staff of medical centres involved in cancer diagnosis and treatment

expert consensus

Iran

regular disinfection of the surfaces

patients wearing of disposable gown

patients wearing face masks when receiving their treatment

adopt a triage system

Use teleconferencing

patients and their companions to wear while at the facility

Weekly educational sessions to update staff

creating a call centre to answer the questions of patients and their families

Limit the number of patient companions

saab et al. 2020

To investigate the impact of the pandemic and its associated response on the care of children with cancer in the Middle east, North

cross- -sectional

Middle east, North africa, and West asia region

restrictions on visit to the facility

social distancing in waiting rooms

closed the playroom/entertainment area

phone/virtual clinic screening for all patients before appointments

Use of face mask by patient, family member, and staff

Full ppe for all health care professionals

regular surface disinfection

proper hand hygiene

Opportunity for staff to work from home

splitting of staff into two teams

hypofractionation of radiotherapy when possible

Use of telehealth for follow-up, teaching activities and multidisciplinary team meetings



care delivery [23]. The recommended solution in-cluded improving communication lines for better centralised ordering and distribution of PPE [14].

Another study indicated that staff managing their mental health and psychosocial well-being during the COVID-19 crisis was essential due to increased



samiee et al. 2020

To present our policy and recommendations at a private radiology-oncology centre

case report Iran

Developed cOVID-19 policies and guidelines

Use of face mask by patient, family member, and radiotherapy staff

avoid, defer or shorten radiotherapy when possible

Use of telehealth for follow-up visits

cancelled weekly visits for patients under treatment

create a direct hotline and Whatsapp discussion platform


Use of ppe

Opportunity to work from home

practice physical distancing of at least 1.5 m

stopped the use of physical wedges

Dedicated clinic for further cOVID-19 assessment and quarantine

Wang et al. 2020

To present the measures preventing and controlling cOVID-19 taken at our hospital over the past 2 months, as well as their corresponding effects.

case report china


Training for all radiotherapy staff

partitioned the radiotherapy centre into zones

regular disinfection of the environment and equipment

Good air ventilation

Use of telehealth


restriction on the number of escorts

a cloth or disposable sheet for each patient

Use of ppe

cOVID-19 testing

Dedicated hospital for further cOVID-19 assessment and quarantine

proper waste management

Wei et al. 2020

To detail our infection control experience at the radiotherapy centre of the hubei cancer hospital

case report china

Formation of an ad hoc emergency infection control team

partitioned the clinical area of the radiotherapy centre into three zones

Training for radiotherapy staff

staff rotation with no overlap


Wearing of face mask for all patients and accompanying carers

cOVID-19 testing

Dedicated isolation room for suspected cases


hand hygiene

Use of telehealth for appointment, follow-up and consultations

a strict single-patient rule

spacing of two meters or more at the waiting area

Use of ppe

effective disinfection of the environment and equipment

Good air ventilation

strict adherence of medical waste management regulations





Wu et al. 2020

To briefly review the radiation therapy management in Wuhan since January 2020, with the hope that the experience learned, and the lessons learned will help guide practice in other regions that are or might be facing outbreaks of this disease

critical review

china


health education fo patients


staff training

Divided the radiotherapy centre into zones

single-use clear wrap for immobilisation devices

Use of ppe

Xie et al. 2020

To report our experience and preliminary outcomes of 209 rT patients, who were treated at the Zhongnan hospital of Wuhan University (ZhWU) during the period when the city was locked down on Jan 23, 2020

case report china


cOVID-19 testing

Isolation space for suspected cases


Wearing of face mask for all patients and carers

strict distancing of at least 1.5 m apart

Daily disinfection

a buddy system to expedite the notification of unwell team members

Use of ppe

splitting of staff into teams

strict hand hygiene

effective disposal of medical hazard waste

prohibition of team gatherings

table 2. radiotherapy fractionation schedules adopted by LMIcs during the cOVID-19 pandemic

Authors Country Site Fractionation schedules

aghili, Jafari & Vand rajabpoor 2020

Iran head and neckOral tongue pT1–T2, N0: 39 Gy/13 fxa in 7 days, two times daily instead of 60 Gy/30 fx by external radiotherapy

prostate

Monotherapy in low-risk patients: recommend delaying the treatment for 3–5 months

high risk: two fractions of 13.5 Gy a or 15 GY for booster dosages after external radiotherapy in one session

Baldotto et al. 2020 Brazil LungInitial disease: 45–54 Gy/3 fx

Locally advanced disease: 60 Gy/30 fx or 55–60 Gy/20 fractions or 60 Gy/15 fx (recommended)

Gupta et al. 2020 India head and Neck postoperative: 55 Gy/25 fx

cervix45 Gy/20 fx

Two sessions of 9 Gy each delivered one week apart*

Brain high grade: 40 Gy/15 fx

rectumpreoperative, short course: 25 Gy/5 fx (recommended)

postoperative: 45 Gy/ 20 fx

Breast

Whole breast only: 26 Gy/5 fx

chest wall only: 26 Gy/5 fx

Nodal irradiation needed: 40 Gy/15 fx

palliative

painful bone metastasis: 8 Gy/1 fx

spinal cord compression < 48 hr: 8 Gy/1 fx

symptomatic brain metastasis: 8 Gy/1 fx

Tumour bleed: 8 Gy/1 fx

superior ve na cava obstruction (symptomatic patients only): 20 Gy/5 fx



stress [23]. However, the findings also showed that helpful coping strategies are significantly needed for staff, cancer patients and their families.

reinforcing infection prevention and control policies

All studies reported radiotherapy management commitment to reinforcing infection prevention and control policies to reduce the risk of transmis-sion of COVID-19 at radiotherapy centres [13–23]. In most of these studies, staff wearing proper PPE (e.g. gowns, masks, face shields and gloves) [13–16, 18, 21, 22], keeping treatment and other rooms well-ventilated [13, 14, 16], disinfecting surfaces that patients and staff are in constant contact with, such as treatment couch [13–16, 18, 19] adhering to

strict hand hygiene [13, 14, 16, 18, 21, 22] and man-aging waste effectively [13, 14, 16] were approaches frequently reported for creating safe infection con-trol practice. Four studies reported cancer patients and their accompanying carers were required to wear face masks when entering the radiotherapy facility to protect themselves in a preventive man-ner [14, 18, 19, 22]. Shortages of face masks in the community was a critical barrier. As a result, one study recommended providing cancer patients with sanitary packages containing face masks, gloves and hand sanitisers on arrival [18].

All studies highlighted the importance of adopt-ing triage systems to sort, assess and prioritise staff, cancer patients and their carers entering the radio-therapy centre [13–23]. From these studies design-ing a flow chart helped facilitate the COVID-19

table 2. radiotherapy fractionation schedules adopted by LMIcs during the cOVID-19 pandemic

Authors Country Site Fractionation schedules

Lombe et al 2020 Zambia Breastchest wall: 50 Gy/25 fx or 28.5 Gy/5 fx (recommended)

supraclavicular + chest wall: 50 Gy/25 fx or 40 Gy/10 fx (recommended)

cervix50 Gy/25 fx or 41.25 Gy/15 fx (recommended)

7 Gy/4 fx or 8 Gy x 3; 9 Gy x 2 one week apart; 9.4 Gy x 2 one week apart (recommended)*

prostate high risk: 74 Gy/37 fx or 60 Gy/20 fx (recommended)

palliativespinal cord compression: 20 Gy/5 fx or 30 Gy/5 fx or 8 Gy/1 fx (recommended)

*Dose of brachytherapy; Fx — fraction; Gy — Gray

Figure 2. cOVID-19 mitigation measures adopted by radiotherapy centres in LMIcs



screening and testing process [16, 19]. Daily body temperature check at the entrance and asking can-cer patients and their carers series of questions were critical to identifying if they presented symptoms indicative of COVID-19. Moreover, further studies showed that most radiotherapy centres in LMICs had implemented suspect case testing for staff, can-cer patients and carers who have had close contact with a COVID-19 case and/or have symptoms of COVID-19 [13, 14, 16–19, 22, 23]. Overall, a sus-pect case testing included chest computed tomog-raphy (CT) scan and polymerase chain reaction (PCR) test [16] . Often studies highlighted that if results were abnormal, suspected cases were im-mediately transported to a designated infectious disease institution equipped to manage suspected or confirmed cases of COVID-19 in line with na-tional guidelines [13, 16].

Four studies reported that some radiotherapy centres strategy to mitigate the spread of the CO-VID-19 included dividing the facility into three zones: clean zone; semi-contaminated zone; and contaminated zone [13–15, 18]. Administrative of-fices, medical physics and dosimetry offices were reported as clean zones while semi-contaminated zones included changing and restrooms, patient corridors and waiting areas. Contaminated zones comprised treatment vaults, simulation rooms, consulting rooms, console areas and front desk ar-eas [14]. Posting reminder signs for staff to remove contaminated PPE before leaving designated con-taminated zones was essential to avoid cross-con-tamination [14, 19].

strengthening coordination and communication

Studies recognised that strengthening good com-munications among staff, and between staff and cancer patients can enhance coordination and mo-bilise support around policy to provide safe radio-therapy services, including brachytherapy for can-cer patients with the maximum level of protection [17]. A belief commonly reported was the percep-tion that eliminating COVID-19 soon was a false hope. Therefore, most radiotherapy centres have undertaken efforts that included forming COV-ID-19 response multidisciplinary teams intended to improve internal coordination and communication by rapidly developing clinical guidelines (e.g. lung, breast, cervical and prostate cancers), policies and

channel advice on health and safety during the CO-VID-19 pandemic [14, 21]. Some studies revealed that the COVID-19 response multidisciplinary team was responsible for coordinating all aspects of infection control activities, which included staff training, radiotherapy workflow modification and management of PPE [14, 21].

Further initiatives to strengthening coordination and communication included establishing a hotline for cancer patients and their families as well as using social media (e.g. WhatsApp) for cancer patients to notify the designated staff member responsible for handling complaints [19]. Other studies reported discussing radiotherapy with new cancer patients via telehealth (either phone or video) and making decisions on avoiding, deferring or shortening treat-ment [19]. All studies acknowledged that COVID-19 is a challenging situation and information keeps changing as new guidelines are developed. Therefore, providing weekly information sessions for all staff to update and advice staff on the latest changes to cancer and COVID-19 guidelines was essential [18].

Maintaining physical distancingAll studies reported that radiotherapy centres

had implemented multiple strategies to allow for physical distancing to reduce the likelihood of ex-posure to micro-droplets infections [13, 14, 16, 18, 19, 21–23]. Adjusting the layout of waiting areas, rethinking appointments to reduce the capacity of patient flow (e.g. two patients for every 30–40 min-utes timeslot), allowing a single patient in a con-sultation room at a time, designating separate en-trance and exit and restricting the number of carers accompanying patients were among the most fre-quently mentioned strategies to create space while maintaining a distance of at least one meter around individuals [13, 16, 18, 19, 21].

Four studies reported that splitting staff into two or three separate teams helped to reduce the num-ber of staff on-site at any given time [13, 14, 16, 22]. Particularly, a single study indicated that schedules were modified to ensure there was no overlap of staff [14]. Similarly, some radiotherapy centres have developed a flexible arrangement that allows certain staff, such as medical physicists and dosimetrists to work from home. Staff with proper equipment and training were able to perform remote treatment planning [14]. In one study, simulation sessions were reduced to two days per week [19].



Five studies reported that radiotherapy centres had arranged a dedicated space for isolation of any patient, carer and/or staff who develops COVID-19 symptoms at the radiotherapy site [13, 14, 16, 18, 19]. The availability of isolation room helped keep suspected cases separate while awaiting transfer to a dedicated COVID-19 facility. Some studies showed that staff and other patients who may have been in contact with confirmed COVID-19 case were asked to practice self-quarantine [13].

A large number of studies indicated increased use of telehealth instead of face-to-face consulta-tions to mitigate the spread of the COVID-19 [13, 18–23]. Telehealth provided a crucial advantage in the delivery of multidisciplinary team meetings, follow-ups with patients after treatment irrespec-tive of location, triage for patient booking appoint-ment and education [13, 18–23]. Inherently, issues relating to implementing and sustaining telehealth in radiotherapy, as well as infrastructure that facili-tate equitable telehealth access during COVID-19 were not examined in the included studies. Without sustainability planning and actions to address bar-riers to accessing telehealth, radiotherapy leaders risk creating telehealth programmes that exclude specific individuals and populations, such as rural patients.

Discussion

This systematic review was conducted to synthe-sise the current evidence on measures implemented by radiotherapy centres in LMICs to reduce the risk of contracting COVID-19. The literature indicates that radiotherapy centres in LMICs have imple-mented multi-component strategies to: reinforce infection prevention and control policies; prepare and equip staff; strengthen coordination and com-munication; and maintain physical distancing. The most commonly reported strategies included: us-ing telehealth; wearing PPE; hand hygiene, split-ting staff into separate teams; zoning; working from home; training staff; weekly information sessions; developing guidelines, procedures and protocols; adjusting the layout of waiting areas; designating separate entrance and exit; restricting the number of accompanying carers; adopting triage systems; COVID-19 testing; and arranging a dedicated space for isolation. However, it is difficult to determine the effectiveness of these strategies because includ-

ed studies have methodological limitations and provided minimal information about their impact.

Radiotherapy staff are committed to providing safe services to cancer patients and must be pro-tected against COVID-19 at all times [8]. There is evidence showing that more than 3,300 health-care workers in China have been infected as of March 2020 [25]. Recognising that transmission occurs via symptomatic and asymptomatic indi-viduals, preparation and protection are especially important. Effective protection of radiotherapy staff is likely to be dependent on a combination of special training on infection control, availability and proper use of PPE, provision of safe air (good ventilation) and administrative controls, such as triage systems to identify, isolate, investigate and effectively manage individuals who may present COVID-19 symptoms. Developing and implement-ing evidence-based COVID-19 control policies and procedures provide guidance for reducing the risk of transmission of COVID-19 in the radiotherapy setting [6]. To protect staff, cancer patients and their families, radiotherapy leaders have both ad-ministrative and supervisory responsibilities to pe-riodically evaluate and revise COVID-19 infection control policies and procedures. The review shows that a radiotherapy centre COVID-19 infection control policy ideally needs to update cleaning and disinfection procedures and outline arrangements for isolating and transferring suspected cases to a dedicated COVID-19 facility for further inves-tigation and management, so patients with CO-VID-19 do not infect others.

In many LMICs, cancer patients and their ac-companying carers are required to wear facemasks when entering a radiotherapy centre to provide additional protection when needed. However, it presents additional communication challenges for both staff and cancer patients. Radiotherapy lead-ers taking advantage of technology, such as speech applications on smartphones, can help address communication challenges. As COVID-19 spreads globally, demand for PPE has increased creating shortage problems. It is estimated that the need for surgical masks, gloves and face shields could reach 2.2 billion, 1.1 billion and 8.8 million, respective-ly, through the end of 2020 (UNICEF 2020 [26]). Other studies have shown that adequate produc-tion and distribution of PPE are crucial to caring for patients during COVID-19 pandemic [27, 28].



Our review supports those findings. For example, to optimise the supply of PPE, radiotherapy cen-tres in LMICs could implement strategies such as: creating partnerships with not-for-profit organisa-tions and/or national coalition of centres in cancer care; training staff on PPE donning and doffing procedures; storing PPE in secured and monitored locations; providing facemasks to patients at the entrance; ensuring extended use of facemasks; and limiting face-to-face contact by maximising the use of telehealth.

Findings from the review suggest that the emer-gence of COVID-19 has caused a rapid adoption of telehealth in radiotherapy services, with no in-formation on sustainability. This finding is con-sistent with previous studies, which recommend careful planning, implementation and evaluation to ensure equity and sustainability of telehealth after the COVID-19 crisis [29, 30]. Telehealth in radio-therapy services helps maintain physical distancing. New cancer patient consultations, multidisciplinary team meetings and follow-up are made possible through telehealth. If telehealth is to have signif-icant impact in radiotherapy services in LMICs, leaders need to: develop education and training for cancer patients to acquire the requisite digital skills; advocate for free or less expensive internet service charges; secure funding to expand and sus-tain telehealth; and identify cancer patients who are unable to engage in video follow-up due to the lack of device [31].

It is worth noting that COVID-19 practical ra-diotherapy treatment recommendations for can-cers, such as breast, cervix, lung, head and neck, prostate and colorectal, have been published by var-ious international and national organisations and societies [32–34]. For palliative non small cell lung carcinoma, 8-10 Gy/1 fraction is strongly recom-mended [35]. Consensus-based recommendations from American Society for Radiation Oncology and European Society for Radiology and Oncol-ogy strongly suggest 50 Gy/16 fractions for early larynx cancer (T1N0) [34]. However, more robust evidence is required to support some of the frac-tionations for head and neck tumors [35].

strengths and limitationsThis is the first systematic review to synthesise

the evidence on COVID-19 mitigation measures implemented by radiotherapy centres in LMICs.

Multiple electronic databases were searched to mi-nimise the risk of missing studies. However, it is possible that other studies were not identified be-cause of the rapidly changing field and publication rate. Majority of the studies were from China and it may not be possible to generalise the results. None of the studies described an intervention that uses incentive to both encourage self-isolation and pre-pare staff to face a health crisis, such as COVID-19.

conclusion

As radiotherapy centres in LMICs navigate through and beyond COVID-19, it is important to seize the opportunity to recognise and address challenges to strengthen radiotherapy workforce. Engaging and equipping staff, cancer patients and their families with the necessary resources, infor-mation, knowledge and skills are critical success factors to ensure adherence to measures, such as physical distancing and quarantine. A coordinated approach to communicating messages to staff, can-cer patients and their families is equally important to prevent confusion, mistrust and uncertainty. Subsequent studies are needed to explore and ex-plain the effectiveness of the strategies identified in the review. The real strength of radiotherapy leaders to reduce the risk of COVID-19 in radio-therapy centres in LMICs comes from their abil-ity to be flexible and innovative. New models for radiotherapy services may emerge from the CO-VID-19 pandemic. Robust and high quality data collection must be encouraged in LMICs to provide an evidence-based knowledge for use in the event of another pandemic.

conflict of interestsThe authors declare that they have no competing interest.


authors contributionsAll authors contributed to the study design, manu-script development, editing and completion of the manuscript. The article search and management were performed by A.D. Article screening and data extraction were completed by A.D. and V.D.A.-A. Data synthesis was performed by A.D. and V.D.A.-



A. and consensus discussion with the team. All the authors read and approved the final manuscript.

ethics approval and consent to participateThis article is based on a secondary analysis of the existing literature and does not contain any studies with human participants or animals performed by any of the authors. The PRISMA guideline for con-ducting systematic and meta-analysis was followed.

consent for publicationNot applicable.

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http://dx.doi.org/10.1016/s0140-6736(20)30644-9


https://www.unicef.org/supply/stories/covid-19-impact-assessment-and-outlook-personal-protective-equipment



http://dx.doi.org/10.1056/NEJMp2006141


http://dx.doi.org/10.1016/j.scitotenv.2020.138532

http://dx.doi.org/10.1016/j.scitotenv.2020.138532


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http://dx.doi.org/10.1007/s10995-020-02967-7


http://dx.doi.org/10.1186/s12889-020-09301-4


http://dx.doi.org/10.1056/CAT.20.0123











LeTTer TO eDITOr




Address for correspondence: Giandomenico Roviello MD PhD, Department of Health Sciences, University of Florence, viale Pieraccini, 6, 50139, Florence, Italy; e-mail: [email protected]

Second line of treatment for HER2-positive gastric cancer: an evolving issue

Giandomenico Roviello1, Martina Catalano1, Alberto D’Angelo2, Valeria Emma Palmieri1

1Department of Health Sciences, University of Florence, Florence, Italy2Department of Biology and Biochemistry, University of Bath, Bath, England, United Kingdom

Key words: trastuzumab; paclitaxel; ramucirumab; second line; gastric cancer





ISSN: 1507–1367

Dear editor,

We read with great interest the manuscript writ-ten by Makiyama et al [1]. In this paper, the authors reported outcome results of the randomized phase II study WJOG7112G (T-ACT Study). The study compared the efficacy of single agent paclitaxel to paclitaxel plus the continuous administration of trastuzumab beyond progression in HER2-positive advanced gastric cancer patients who progressed following trastuzumab first-line standard chemo-therapy. A total of 91 patients were randomized; of these, 46 received paclitaxel while, in contrast, 45 received paclitaxel plus trastuzumab. The median progression-free survival (PFS) was 3.2 months in the paclitaxel arm and 3.7 months in the paclitaxel with trastuzumab, whereas the overall response rate (RR) was 32% in the paclitaxel arm and 33% in the paclitaxel with trastuzumab arm. Lastly, the median overall survival (OS) was 10 months for both arms. The authors concluded that the strategy of trastuzu-mab beyond progression failed to improve PFS in patients diagnosed with HER2-positive advanced gastric cancer.

To date, there is urgent need to identify the opti-mal second or further line of therapy for the treat-ment of metastatic GC [2, 3] patients. Ramuciru-mab is a monoclonal antibody against VEGFR2 [4]

approved as the second or further line of treatment for the HER2-positive population. However, as dis-cussed by the authors, a limited number of studies have described the efficacy of ramucirumab for this subgroup of patients so far. In 2019, De Vita et al. [5] evaluated the efficacy and safety of ramucirum-ab plus paclitaxel in a small subgroup of 20 patients affected by gastric cancer from the RAINBOW trial who were previously administered with trastuzu-mab. The authors observed a median PFS of 4.2 months, a RR of 45.0% and a median OS of 11.4 months (Tab. 1). Although a comparison between the studies is difficult due to the different clinical characteristics of evaluated patients and the source of the data (retrospective versus prospective), we must report a lower efficacy for the trastuzumab be-yond progression strategy compared to “standard” second-line paclitaxel plus ramucirumab regimen. Moreover, a meta-analysis published in 2018 [6] showed that continuation of trastuzumab beyond first-line therapy added to second-line therapy did not prolong OS.

More recently, the antibody-drug conjugate named trastuzumab deruxtecan, consisting of tras-tuzumab plus a cleavable tetrapeptide-based linker and a cytotoxic topoisomerase I inhibitor, showed significant improvements in terms of clinical re-sponse and OS — compared with standard thera-

Giandomenico Roviello et al. second line of treatment for her2-positive gastric cancer


pies — in patients with HER2-positive advanced GC who progressed while receiving at least two previous therapies, including trastuzumab [7].

Therefore, we strongly agree with the statement of the authors to compare future clinical trial of new anti-HER2 agents with paclitaxel plus ramu-cirumab as the control arm. However, considering a potential crosstalk between HER-2 signalling and angiogenesis [8], we strongly encourage the pos-sibility to perform future combination trials us-ing anti-HER2 therapies plus ramucirumab-based regimens.

conflict of interestThe authors declare that there are no conflicts of interest.

Financial disclosureThe authors declare that there is no financial inter-est.

references

1. Makiyama a, sukawa Y, Kashiwada T, et al. randomized, phase II study of Trastuzumab Beyond progression in patients With her2-positive advanced Gastric or Gastro-esophageal Junction cancer: WJOG7112G (T-acT study). J clin Oncol. 2020; 38(17): 1919–1927, doi: 10.1200/JcO.19.03077, indexed in pubmed: 32208960.

2. roviello G, D’angelo a, roudi r, et al. Novel agents in heavily pretreated Metastatic Gastric cancer: More shadows Than Lights. J Oncol. 2019; 2019: 5692317, doi: 10.1155/2019/5692317, indexed in pubmed: 31354820.

3. roviello G, Fancelli s, Gatta Michelet Mr, et al. Tas-102 in gastric cancer: Development and perspectives of a new biochemically modulated fluroropyrimidine drug combination. crit rev Oncol hematol. 2020; 152: 102987, doi: 10.1016/j.critrevonc.2020.102987, indexed in pubmed: 32485527.

4. afshari F, soleyman-Jahi s, Keshavarz-Fathi M, et al. The promising role of monoclonal antibodies for gas-tric cancer treatment. Immunotherapy. 2019; 11(4): 347–364, doi: 10.2217/imt-2018-0093, indexed in pubmed: 30678552.

5. De Vita F, Borg c, Farina G, et al. ramucirumab and paclit-axel in patients with gastric cancer and prior trastuzumab: subgroup analysis from raINBOW study. Future Oncol. 2019; 15(23): 2723–2731, doi: 10.2217/fon-2019-0243, indexed in pubmed: 31234645.

6. Ter Veer e, van den ende T, creemers a, et al. continua-tion of trastuzumab beyond progression in her2-positive advanced esophagogastric cancer: a meta-analysis. acta Oncol. 2018; 57(12): 1599–1604, doi: 10.1080/0284186X.2018.1503421, indexed in pubmed: 30264641.

7. shitara K, Bang YJ, Iwasa s, et al. DesTINY-Gastric01 Inves-tigators. Trastuzumab Deruxtecan in previously Treated her2-positive Gastric cancer. N engl J Med. 2020; 382(25): 2419–2430, doi: 10.1056/NeJMoa2004413, indexed in pubmed: 32469182.

8. alameddine rs, Otrock ZK, awada a, et al. crosstalk be-tween her2 signaling and angiogenesis in breast cancer: molecular basis, clinical applications and challenges. curr Opin Oncol. 2013; 25(3): 313–324, doi: 10.1097/ccO.0b013e32835ff362, indexed in pubmed: 23518595.

table 1. Main outcomes in patients with her2 positive gastric cancer treated with second line trastuzumab beyond progression or paclitaxel with ramucirumab plus paclitaxel

Study Treatment NumberResponse rate

(%)PFS

(months)OS

(months)

T-acT Trastuzumab beyond progression + paclitaxel 45 33 3.7 10

raINBOW paclitaxel + ramucirumab 20 45 4.2 11.4

Os — overall survival; pFs — progression-free survival

http://dx.doi.org/10.1200/JCO.19.03077

http://dx.doi.org/10.1200/JCO.19.03077


http://dx.doi.org/10.1155/2019/5692317


http://dx.doi.org/10.1016/j.critrevonc.2020.102987


http://dx.doi.org/10.2217/imt-2018-0093


http://dx.doi.org/10.2217/fon-2019-0243


http://dx.doi.org/10.1080/0284186X.2018.1503421

http://dx.doi.org/10.1080/0284186X.2018.1503421




http://dx.doi.org/10.1097/CCO.0b013e32835ff362

http://dx.doi.org/10.1097/CCO.0b013e32835ff362



LeTTer TO eDITOr


DOI: 10.5603/rpOr.a2021.0033submitted 19.08.2020accepted: 03.02.2021

Address for correspondence: Pierre Loap, Institute Curie, Department of Radiation Oncology, Paris, France, tel: +33 631339838; e-mail: [email protected]

Pleural radiation-induced sarcoma: a SEER population-based description of a rare entity

Pierre Loap, Youlia KirovaInstitute Curie, Department of Radiation Oncology, Paris, France

Key words: radiation-induced sarcoma; pleural sarcoma; seer database





ISSN: 1507–1367

Dear editor,

Radiation-induced sarcomas (RIS) represent rare complications of radiation therapy but their prog-nosis is poor. The consensual definition was first proposed by Cahan in 1948 [1] based on prior his-tory of radiation therapy and occurrence of a his-tologically-proven sarcoma within the irradiation fields after a latency period longer than five years. The pleura is made of tissues of diverse histologi-cal origin (mesothelium and connective tissues, such as blood or lymphatic vessels) explaining the diversity of radiation-induced pleural side-effects, such as effusion, thickening or mesothelioma. Yet, pleural RIS have never been evaluated in epidemio-logical studies. We aimed to better understand the characteristics of pleural RIS based on the SEER Program cancer registry.

seer registry analysis

Pleural sarcomas were identified in the SEER 18-registry database (1973–2015), using the SEER*STAT software (version 8.3.6) for data ex-traction. Identification was based on biopsy-prov-en sarcoma histology (classified as “IX Soft tissue and other extraosseous sarcomas”, according to the Classification for International Classification for Childhood Cancer Recode ICD-O-3/World Health

Organization 2008), on pleural primary localiza-tion (classified as “C-38.4-Pleura”, according to the International Classification of Diseases, 10th Revi-sion, Clinical Modification (ICD-10-CM) classifica-tion system) and on malignant behavior (excluding neoplasms of intermediate malignancy, according to the WHO classification, such as solitary fibrous tumors or histiocytomas). Among pleural sarco-mas, we identified pleural RIS based on Cahan RIS definition (1): • there should be a prior history of cancer occur-

ring at least five years before pleural sarcoma occurrence;

• this previous cancer should have been treated with radiation therapy. This information was available in the SEER radiation/chemotherapy database;

• the pleura had to be included in the expected irradiation fields, as is the case for homolateral breast or lung cancers. Out of 8 million cancer patients from the 18-reg-

istry SEER database (1973–2015), 197 malignant pleural sarcoma patients were identified (0.0024%). Median age was 66 (3-91). There were 133 (67.5%) male and 64 (32.5%) female patients. The most fre-quent specified histological types were angiosar-comas (n = 27, 13.7%), synovial sarcomas (n = 24, 12.2%), spindle cell sarcomas (n = 24, 12.2%) and fibrosarcomas (n = 13, 6.6%).

Pierre Loap, Youlia Kirova pleural rIs: a seer population-based description of a rare entity


Of these 197 pleural sarcoma patients, three fulfilled criterions for pleural RIS (Tab. 1). Age at sarcoma diagnosis ranged between 54 and 74. All patients were women, previously irradiated for homolateral breast cancer. The median la-tency period before sarcoma occurrence ranged between 14 and 20 years. Surgery was attempt-ed for one patient. Median overall survival was 4 months.

Discussion

Development of radiation-induced sarcoma oc-curs in 0.03% to 0.2% of post-irradiation follow-up, over a 10-year period [2]. Pleural RIS are exceed-ingly rare; in addition to the three patients identi-fied in the SEER registry, only one other case has been described [3]: angiosarcoma developed four years after lung irradiation. Treatment may rely on surgery when possible and chemotherapy, but over-all survival seems very poor.

All pleural RIS cases from the SEER database occurred after breast radiation therapy; this rare diagnosis should, therefore, be suspected in front of pleural effusion or mass years after homolateral breast radiation-therapy. However, in a cohort of 16,000 breast cancer patients, Kirova et al. found that the most frequent RIS localization were the breast and the chest wall [4]. Interestingly, no pleu-ral RIS were evidenced, despite frequent inclusion of anterior thoracic pleura into tangential radia-tion fields. Tissue radiation sensitivity differences for sarcoma carcinogenesis could be hypothesized. Current state-of-the-art breast radiation therapy techniques, such as intensity modulated radiation therapy, tend to increase lung and pleura exposure compared with traditional irradiation approaches [5]. Long-term studies focusing on recent radiation therapy techniques will thus be needed to evaluate late pleuro-pulmonary toxicity.

conflict of interestThe authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; member-ship, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial in-terest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject mat-ter or materials discussed in this manuscript.

FundingThe authors declare that they have no funding and no financial support.

Data sharingResearch data are stored in an institutional reposi-tory and will be shared upon request to the corre-sponding author.

references1. cahan W, Woodard h, higinbotham N, et al. sarcoma in

irradiated bone. report of eleven cases. cancer. 1948; 1(1): 3–29, doi: 10.1002/1097-0142(194805)1:1<3::aid-cncr2820010103>3.0.co;2-7, indexed in pubmed: 9428476.

2. sheth Gr, cranmer LD, smith BD, et al. radiation-induced sarcoma of the breast: a systematic review. Oncologist. 2012; 17(3): 405–418, doi: 10.1634/theoncolo-gist.2011-0282, indexed in pubmed: 22334455.

3. Miller r, Mudambi L, Vial Mr, et al. radiation-induced angiosarcoma as a cause of pleural effusion. am J respir crit care Med. 2017; 196(4): e10–e11, doi: 10.1164/rccm.201702-0442IM, indexed in pubmed: 28510475.

4. Kirova YM, Vilcoq Jr, asselain B, et al. radiation-induced sarcomas after radiotherapy for breast carcinoma: a large-scale single-institution review. cancer. 2005; 104(4): 856–863, doi: 10.1002/cncr.21223, indexed in pubmed: 15981282.

5. aznar Mc, Duane FK, Darby sc, et al. exposure of the lungs in breast cancer radiotherapy: a systematic review of lung doses published 2010-2015. radiother Oncol. 2018; 126(1): 148–154, doi: 10.1016/j.radonc.2017.11.022, indexed in pubmed: 29246585.

table 1. characteristics of pleural radiation-induced sarcomas from the seer database (1973–2015)

Diagnosis year

Sex Age Irradiated tumor LatencyPleural RIS histology

Surgery Outcome

1995 Female 54right breast invasive

carcinoma16 years Fibrosarcoma No

Died after 18 months

2000 Female 74right breast invasive

carcinoma14 years

spindle cell sarcoma

YesDied after 1 month

2014 Female 84Left breast invasive

carcinoma20 years synovial sarcoma No

Died after 4 months

http://dx.doi.org/10.1002/1097-0142(194805)1:1%3C3::aid-cncr2820010103%3E3.0.co;2-7

http://dx.doi.org/10.1002/1097-0142(194805)1:1%3C3::aid-cncr2820010103%3E3.0.co;2-7





http://dx.doi.org/10.1164/rccm.201702-0442IM

http://dx.doi.org/10.1164/rccm.201702-0442IM







case repOrT




Address for correspondence: Dr. Orla A Houlihan, St Luke’s Radiation Oncology Network, Highfield Road, Rathgar, Dublin 6, Ireland; tel: +353 (0)1 852 8416; e-mail: [email protected]

A rare case of melanotic hyperpigmentation of the tongue secondary to radiotherapy

Orla A. Houlihan, Guhan Rangaswamy, Orla McArdleSt. Luke’s Radiation Oncology Network, Dublin, Ireland

AbstrAct

Melanotic hyperpigmentation of the mucosa secondary to radiotherapy is a rare occurrence. It is a diagnosis of exclusion. Lit-

erature review has identified only two case reports published to date. We present a case of a patient treated at our institution.

an 18-year-old male patient of Nigerian descent underwent radical radiotherapy (36 Gy in 18 daily fractions) to his right neck

for paediatric type follicular lymphoma over a period of four weeks. he developed hyperpigmented tongue lesions during

the third week of radiotherapy. There was no associated tongue discomfort, inflammation, infection, or pigmentation change

elsewhere in the oral mucosa. review of medications and past medical history did not demonstrate any potential contributing

factors. Full blood count and biochemistry, morning cortisol levels and coagulation screen were all normal apart from mild

neutropenia and lymphopenia. his oral cavity received a mean dose of 16.4 Gy, with the right side of his tongue receiving up

to 37.5 Gy as this was within the planning target volume (pTV). he had an excellent response to radiotherapy and remains in

remission. The tongue lesions resolved spontaneously 3 months post treatment.

Key words: hyperpigmentation; tongue; radiotherapy; lymphoma





ISSN: 1507–1367

Introduction

Hyperpigmented lesions on the tongue are not uncommon and are associated with a wide variety of potential causes. These include physiological [1], medication-induced, such as pegylated interferon, ribavirin [2–4] and chemotherapy [5], endocrine causes, including Addison’s disease [6], malignancy such as malignant melanoma [7], and others [8, 9]. Radiotherapy is listed as a potential aetiology for this occurrence in only two publications [10, 11].

We describe a case report of a patient who devel-oped melanotic hyperpigmentation of the tongue during radiotherapy treatment.

case report

An 18-year-old male student of Nigerian descent presented with a lump in his right neck and was subsequently diagnosed with stage II paediatric type follicular lymphoma. He had a diagnosis of epilepsy, although was seizure-free for the previ-ous seven years and cerebral palsy due to pre-term birth. He did not take any regular medications. He was a non-smoker and did not drink alcohol.

At multidisciplinary team discussion, the tu-mour was felt to be inoperable due to close prox-imity to neurovascular structures. Chemotherapy was recommended; however, he declined any sys-

Orla A. Houlihan et al. Melanotic hyperpigmentation of the tongue secondary to radiotherapy


temic treatment due to concerns regarding fertility. After much deliberation he agreed to proceed with a course of radical radiotherapy. Physical examina-tion of the neck prior to commencing radiotherapy was significant for a 4.3 cm × 3.4 cm right neck lump in the submandibular region. Oral cavity ex-amination was unremarkable.

He was treated with fractionated volumetric arc radiotherapy (VMAT), using 6MV photon beams. The gross tumour volume (GTV) was contoured. The clinical target volume (CTV) was delineated according to involved site radiotherapy guidelines with a 15 mm cranio-caudal margin. A 5mm mar-gin was applied to form the planning target vol-ume (PTV), as per our institutional protocol. The prescription dose was 36 Gy in 18 daily fractions, treating five days per week over a period of 4 weeks.

During the third week of radiotherapy he devel-oped hyperpigmented lesions on his oral tongue, as shown in Figure 1. On examination, these dark macules were located on the dorsum and lateral borders of the tongue. The mucosa of the tongue was intact with no signs of infection or inflamma-tion. On palpation, the tongue was non-tender and of normal texture. The rest of the oral cavity was clear, with no signs of mucositis and there were no hyperpigmented lesions elsewhere. The lesions did not cause him any symptoms, specifically, they did not cause him any pain nor did they affect his taste. The radiotherapy plan was reviewed. The do-simetric distribution of radiotherapy delivered to the oral cavity is illustrated in Figure 2. The right posterolateral tongue was included in the PTV, and so the maximum dose received by the tongue was

37.5 Gy. The entire oral cavity received a minimum of 6.8 Gy, while the mean dose delivered was 16.4 Gy. He had no systemic symptoms and otherwise was tolerating radiotherapy very well.

Review of medications and past medical history did not demonstrate any potential aetiology for the hyperpigmented lesions. Full blood count and bio-chemistry, morning cortisol levels and coagulation screen were all normal apart from mild neutropenia and lymphopenia. A dermatology consult was ob-tained and we planned to observe the lesions while he remained asymptomatic but to biopsy should he develop any symptoms.

As he was otherwise well we continued his course of radiotherapy as planned with no interruptions. The hyperpigmented lesions began to resolve spon-taneously following completion of radiotherapy and had resolved completely by three months (Fig-ure 1). He remains well and cancer-free at 2.5 years post treatment, with no recurrence of the tongue lesions.

Discussion

This case describes the rare phenomenon of ra-diotherapy-induced melanotic hyperpigmentation of the tongue. It is a diagnosis of exclusion. Hyper-pigmentation of the tongue has been reported in multiple publications, however, the authors could only find two publications which describe this oc-currence as a direct result of radiotherapy [10, 11].

One paper by Amdur et al. [10] reports on three patients of African American ethnicity undergoing radiotherapy to the brain who developed hyper-

Figure 1. Our patient’s tongue during week three of radiotherapy (left) and three months following completion of radiotherapy (right)



pigmentation of the tongue. All patients received low dose radiotherapy to the oral cavity due to exit beam dose. There was no associated mucositis or other oral cavity side effects. The hyperpigmenta-tion was limited to the oral tongue. It developed near the end of the five to six week course, gradually faded after three months and completely resolved by twelve months.

Barrett et al. [11] reported hyperpigmentation of the buccal mucosa and dorsum of the tongue of a Caucasian male. This occurred six months fol-lowing completion of radical radiotherapy to meta-static carcinoma in the cervical lymph nodes. The oral cavity was included within the target volume for this patient and he experienced side effects of diffuse mucositis, dry mouth and oral discomfort related to the high dose of radiation received. The hyperpigmentation subsequently progressed within a few months to the lateral border of the tongue with hyperkeratosis. Incisional biopsy demon-strated interspersed areas of epithelial atrophy and hyperparakeratosis, candida infection, increased melanin deposition within basal keratinocytes and pigmentary incontinence, in addition to scattered abnormal irradiation fibroblasts but no vascular changes typical of irradiation.

In our patient the dose to the oral cavity and tongue was due to the location of PTV. While the right side of his tongue received a higher radia-tion dose compared to the left side, the distribution of hyperpigmentation was even throughout the tongue.

The pathophysiology of melanotic hyperpigmen-tation of the tongue secondary to radiotherapy is unclear; however, it appears to be a temporary phe-nomenon with spontaneous resolution after a pe-riod of months. Melanin is produced in epidermis, hair follicles, cochleae, eyes (choroid, irises, retinal pigment epithelium), heart, lung and brain (lep-tomeninges, sustantia nigra, locus coerulus) [12]. Its production is not limited to melanocytes and ectopic synthesis in adipose tissue has been report-ed [13]. Our patient did not have a biopsy, which would have definitively proven the pigmentation was secondary to melanin production. It is unusual that the hyperpigmented macules just appeared in the tongue of our patient, and not other areas where melanocytes are located, including the rest of the oral cavity. This was also the case in the paper by Amdur et al. [10].

Our patient’s presentation is similar to that docu-mented by Amdur et al. [10], in terms of ethnicity, timing and anatomical distribution of hyperpig-mentation. It is markedly different from that re-ported by Barrett et al. [11], raising the possibil-ity for differing pathophysiology. Ethnicity may be relevant to our patient’s presentation due to the increased activity of melanocytes in African, Asian and Mediterranean populations, which increases the preponderance of physiologic pigmentation in these populations [1, 14]. Barrett et al. [11] suggest that radiation-induced inflammation may cause stimulation of melanocytes, resulting in hyperpig-mentation.

Figure 2. axial (left) and sagittal (right) dosimetric distribution of radiotherapy delivered to the oral cavity in our patient’s radiotherapy plan. contours: pTV (red), oral cavity (cyan)

Orla A. Houlihan et al. Melanotic hyperpigmentation of the tongue secondary to radiotherapy


conclusion

Melanotic hyperpigmentation of the tongue sec-ondary to radiotherapy is a rare phenomenon; how-ever, it does occur. It is a diagnosis of exclusion and it is essential that affected patients are investigated fully by means of a comprehensive history, clinical examination and laboratory tests, with consider-ation for biopsy and radiological investigations if clinically appropriate. It is a potential side effect of radiotherapy to the head and neck region, and clini-cians should be aware of its existence.



acknowledgementsWe would like to thank our patient who has con-sented to the writing of this case report.

author contributionsO.A.H., G.R. and O.M. were involved in the care of this patient and wrote the paper. All authors have approved the final article.

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2. Gurguta c, Kauer c, Bergholz U, et al. Tongue and skin hyperpigmentation during peG-interferon-alpha/ribavi-rin therapy in dark-skinned non-caucasian patients with chronic hepatitis c. am J Gastroenterol. 2006; 101(1): 197–198, doi: 10.1111/j.1572-0241.2005.00323.x, indexed in pubmed: 16405555.

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http://dx.doi.org/10.4103/0976-237X.73205


http://dx.doi.org/10.1111/j.1572-0241.2005.00323.x


http://dx.doi.org/10.14219/jada.archive.2009.0073

http://dx.doi.org/10.14219/jada.archive.2009.0073


http://dx.doi.org/10.1046/j.1365-2133.2003.05422.x



http://dx.doi.org/10.4103/0976-237X.107450

http://dx.doi.org/10.4103/0976-237X.107450


http://dx.doi.org/10.1016/s0266-4356(03)00025-1

http://dx.doi.org/10.1016/s0266-4356(03)00025-1



http://dx.doi.org/10.1016/j.tripleo.2007.07.047


http://dx.doi.org/10.1016/0030-4220(94)90209-7

http://dx.doi.org/10.1016/0030-4220(94)90209-7


http://dx.doi.org/10.1096/fj.08-116327


http://dx.doi.org/10.1016/s0738-081x(02)00225-0

http://dx.doi.org/10.1016/s0738-081x(02)00225-0


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