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Randomised Trial of Hyperfractionation Versus
Conventional fractionation in T2 Squamous cell carcinoma of
The Vocal CordRTOG 9512
(EORTC 22992)
Pages : 958-963
REFERENCE :
ADDITIONAL REFERENCES :
Objectives
Primary : To test whether Hyperfractionation improves the local
control rate for early stage (T2N0) squamous cell carcinoma of the true vocal cord (compared to conventional fractionation)
Secondary : To determine the acute and late radiotherapy toxicity
associated with each of the fractionation schedules To examine overall and disease-free survival patterns
associated with each of the fractionation schemes
Sample Size
The protocol specified a target sample size of 240 patients
Based on detecting a 55% reduction in local failure
Corresponding to an improvement in 5-year local control from 70% to 85% or a hazard rate (HR) of 0.456
The sample size was increased by 10% to guard against patients retrospectively being reclassified as ineligible
Patient Selection
Inclusion criteria : Patients with histologically proven invasive squamous cell carcinoma
arising from the true vocal cord
Disease limited to stage T2N0
The bulk of the tumor must be present on the vocal cord with extension to adjacent areas
For lesions causing impaired mobility (T2b) at least two physicians must be in agreement that the vocal cord is impaired
The minimum age for entry is 18 years
Karnofsky performance status > 60
The patient must sign a study-specific informed consent form
Patient Selection
Exclusion Criteria : Patients with verrucus carcinoma or adenocarcinoma were excluded
Patients with tumors extending to pre-epiglottic space, pyriform sinus, a fixed cord or cartilage invasion were not eligible (T3-T4)
Clinical or radiographic evidence of lymphadenopathy in the neck
Evidence or suspicion of distant metastases
Patients with a prior or concurrent malignancy (other than non-melanoma skin cancer) were ineligible, unless previous cancer was treated 5 years or more prior to the current tumor and the patient had remained continually disease free
Patient Selection
Exclusion criteria (continued) : Karnofsky status < 60
Patients with complete stripping or laser excision of all gross disease
Prior radiotherapy to the mid-neck or larynx
Patients with recurrence or persistent tumor following any treatment
Patients for whom follow-up by the registering physician was not feasible
PROTOCOL SCHEMA
AJCC ‘T’ STAGING FOR GLOTTIC CANCER : 7th EditionT2 - Tumour extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility
MODIFIED AJCC ‘T’ STAGING FOR GLOTTIC CANCER T2a - Tumour extends to supraglottis and/or subglottis, without impaired vocal cord mobility
T2b – Tumour causes impaired vocal cord mobility with or without extension into supraglottic or subglottic structures
Radiation Therapy Technique
Beam : Cobalt 60
Linear Accelerators with 4-6 MV Photon beams With 6 MV Photons : Bolus (2-5mm) over the anterior half of the larynx
in patients with lesions involving the anterior larynx or patients with minimal soft tissue anterior to the thyroid cartilage
Radiation Therapy Technique
Radiation Dose-Fractionation
Standard Fractionation Arm : Treatment to the primary site :
70 Gy in 35 fractions (2 Gy per fraction, once a day, five days a week in seven weeks )
Boost fields :
Will begin at 50 Gy so that the target volume (primary site plus at least 1.0 cm dosimetric margin) should receive at least 90% of maximum dose
Hyperfractionation Arm : Treatment to the primary site :
79.2 Gy in 66 Fractions (1.2 Gy per fraction, twice a day with a minimum of a 6 hour interval, five days a week in 6-1/2 weeks)
Boost fields :
Will begin at 60 Gy so that the target volume (primary site plus at least 1.0 cm dosimetric margin) should receive at least 90% of maximum protocol dose
Radiation Therapy Technique
Radiation Therapy Irradiation Portals
Lateral opposing fields At least a 2.0 cm margin in all directions around the tumor volume will be used
for the first 50 Gy (Standard fractionation arm) and 60 Gy (Hyperfractionation arm)
6x6 cm field - Centred over the mid thyroid cartilage Upper border : 0.5-1.0 cm above the thyroid notch
Posterior border : 1 cm behind the thyroid cartilage
Inferior border : At the bottom of the cricoid cartilage
At least 1 cm fall off anteriorly
Tissue compensators (wedges) : Encouraged to enhance homogeneity
Typical field arrangement for Lateral opposing Fields
Radiation Therapy Technique
Boost Fields :
Weighted lateral fields, oblique fields or an AP field may be used to boost the primary tumor
Boost field borders must encompass the initial tumor volume with at least a 1.0 cm margin
Target volume for Initial large field Minimal target volume for Boost fields
Evaluation and Follow up
Acute Toxicity :
During Radiation Therapy
4 weeks after the completion of Radiation Therapy
Tumour control and Late Toxicity
Clinically by mirror examination or clinic endoscopy
Every 3 months in 1st year
Every 4 months in 2nd year
Twice an year in 3rd year
Annually thereafter
Statistical Analysis
Enrolment : Prospective Randomised controlled trial
April 1996 – July 2003
87 Institutions
250 patients diagnosed to have biopsy proven Squamous cell carcinoma, T2N0 Glottic cancer were enrolled and randomised
11 patients were excluded from the final analysis and data analysis was done for a total of 239 patients
250 patients of Biopsy proven Squamous Cell Carcinoma,
T2N0 Glottic cancer enrolled and Randomised in 1:1 ratio
Data of 239 patients used for final evaluation purposes
11 Patents excluded from the final data analysis
4 – Standard Fractionation arm:
2 – Nodal disease2 – Restaged as T3-T4
7 – Hyperfractionated arm :3 – Nodal disease
3 – Restages as T3-T41 – Withdrawn consent
COMPARABLE
Statistical Analysis
Local control rates
Cumulative incidence method to account for the competing risk of death without local failure.
Patients were censored for loco regional control after 5 years.
Disease-free and overall survival rates
Kaplan-Meier method.
Cox proportional hazards model with T-subcategory as a covariate :
Used to estimate and test the Hazard Ratio (HR) between the Hyperfractionated (HFX)and the Standard Fractionation (SFX) arms.
HR<1 indicated a reduction in failure rate after HFX.
Statistical Analysis
Patients without clinical complete response (CR) in the primary site :
Classified as having a local failure (LF)
The time of failure was backdated to study day 1
Patients with CR who subsequently experienced local recurrence :
Considered as failures on the date of reported relapse
Otherwise patients were censored at their last follow-up visit
Patients were considered to be at risk for failure until they died
Statistical Analysis
Disease-free survival (DFS) included :
Local recurrence or persistent local disease
Nodal failure
Distant metastasis
Second primary tumor of all sites, or
Death from any cause
The date of DFS failure was the first occurrence of any of these events, otherwise patients were censored at their last follow up visit
Patient-reported voice quality was not measured
Results
Acute Toxicity : Similar Grade 1 and 2 toxicities in both arms
Higher incidence of Acute grade 3 toxicity was seen with Hyperfractionation than with Standard fractionation
33.3% vs 22.7%; p=0.084
Seen mainly in forms of :
Laryngeal oedema
Mucosal reactions
Skin reactions
Results
Late Toxicity : No difference in 5-year cumulative incidence of late grade 3 toxicity
8.5% after Standard fractionation
8.5% after Hyperfractionation
Occurrence of Grade 1 and 2 toxicities were also found to be similar in both arms
3 patients required tracheostomy after standard fractionation while 2 required following Hyperfractionation
COMPARABLE
Results
117 Deaths
25% attributed to the study cancer
20% to second primary cancers
40% unrelated to cancer or treatment (comorbid conditions)
15% unknown
Results Local Control :
67 patients experienced local failure by 5 years
35 in Standard fractionation versus 26 in Hyperfractionation
Local control rates :
70% versus 78% for Standard fractionation and Hyperfractionation
HR=0.70, p=0.14
Locoregional Control : 10 patients had isolated nodal relapse as site of first failure
4 in Standard fractionation versus 6 in Hyperfractionation
Loco regional control rates :
67% versus 73% for Standard fractionation and Hyperfractionation
HR=0.77, p=0.26
Trend towards improved Local Control in Hyperfractionated arm
Results – Sub stage analysis
Sub stage analysis
T2a T2b
5 year Local Control
76.8% 70.0% HR=1.51 95% CI = 0.93-
2.44 p=0.10
5 year Locoregional
control
74.1% 63.3% HR=1.65 95% CI = 1.05-
2.59 p=0.03
5 year Disease Free Survival
52.4% 31.4% HR=1.62 95% CI = 1.19-2.22 p=0.002
5 year Overall Survival
77.5% 50.0% HR=2.06 95% CI = 1.43- .97 p=0.0001
Results – Sub stage analysis based on Fractionation
T2a T2b
P value for interaction
5 year Local Control
HR=0.58 95% CI 0.30-1.12
p=0.11
HR=0.87 95% CI 0.42-1.78
p=0.70
0.42
5 year Locoregional control
HR=0.61 95% CI 0.33-1.14
p=0.12
HR=1.00 95% CI 0.52-1.93
p=0.99
0.28
5 year Disease Free Survival
HR=0.74 95% CI 0.49-1.11
p=0.15
HR=0.86 95% CI 0.54- 1.38
p=0.54
0.63
5 year Overall Survival
HR=0.6595% CI 0.39-1.08
p=0.10
HR=1.06 95% CI 0.62-1.79
p=0.84
0.19
NOT
SIGNIFICANT
Discussion
The only prospective trial of Hyperfractionation conducted specifically in T2N0 glottic cancer
Results showed an 8-point difference in local control (78% vs 70%) at 5 years favouring hyperfractionation (p=0.14)
This corresponded to a 30% reduction in the hazard rate (HR=0.70) as well as a trend for improved disease-free survival
There were no significant differences in outcomes between Standard fractionation and Hyperfractionation by sub stage (T2a vs T2b)
Discussion
The rationale for hyperfractionation in this trial was drawn from 2 large fractionation studies enrolling mostly non larynx cases
EORTC 22791 – Oropharyngeal tumors Better local control and overall survival with Hyperfractionation
RTOG 9003 – Locally advanced head and neck cancers Better local control, disease free survival and overall survival i]with
Hyperfractionation and concomitant boost
Discussion
Accelerated fractionation 225 cGy per fraction per day (Slight Hypofractionation)
Found to be effective at increasing local control with acceptable toxicity
Yamazaki et al 1 :
Significant benefit from accelerated fractionation in a randomized trial of T1 glottic carcinomas using 2.25 Gy per fraction up to 63 to 66 Gy (LC, 92%vs 77%; p=0.004)
Moon et al 2 :
Compared 225 cGy fractions to 63 to 67.5 Gy for T1-T2 glottic cancers in a randomized trial
Local progression free survival was 11 points higher (89% vs 78%) in the hypofractionated arm
Underpowered to show significance (p=0.213)1. Hideya Yamazaki, Kinji Nishiyama, Eiichi Tanaka, Masahiko Koizumi, Masashi Chatani, Radiotherapy for early glottic carcinoma (T1N0M0): Results of prospective randomized study of radiation fraction size and overall treatment time, International Journal of Radiation Oncology*Biology*Physics, Volume 64, Issue 1, 1 January 2006, Pages 77-81
2. Sung Ho Moon, Kwan Ho Cho, Eun Ji Chung, Chang Geol Lee, Kyu Chan Lee, Gyu-Young Chai, Ki Mun Kang, Jong Young Lee, Woong-Ki Chung, Woo Yoon Park, Jin Hee Kim, A prospective randomized trial comparing hypofractionation with conventional fractionation radiotherapy for T1–2 glottic squamous cell carcinomas: Results of a Korean Radiation Oncology Group (KROG-0201) study, Radiotherapy and Oncology, Volume 110, Issue 1, January 2014, Pages 98-103
Discussion
Hliniak et al 3 :
Randomized with T1- T3, N0 glottic and supraglottic cancers
66 Gy in 33 fractions over 45 days or accelerated treatment of 66 Gy in 38 days by delivery twice a day on Thursdays.
There was no benefit in overall locoregional control (p=0.37)
In the subset of glottic cancers, Loco regional control was higher (p=0.04)
3. A. Hliniak, B. Gwiazdowska, Z. Szutkowski, E. Kraszewska, P. Kukolowicz, A. Jarzabski, B. Sochacka, M. Mazurkiewicz, K. Paprota, W. Oliskiewicz, O. Zadrożna, P. Milecki, M. Kubiak, L. Czopkiewicz, M. Jagas, S. Góźdź, A. Wieczorek, A. Woytowicz, B. Cisowska, H. Magdziarz, S. Nowakowski, W. Kośniewski, I. Laskosz, A. Serafin, E. Gradoń, A multicentre randomized/controlled trial of a conventional versus modestly accelerated radiotherapy in the laryngeal cancer: influence of a 1 week shortening overall time, Radiotherapy and Oncology, Volume 62, Issue 1, January 2002, Pages 1-10
Discussion
Retrospective analysis at several centers have found that 225 cGy fractions over 25-28 treatments produce excellent outcomes
Chera et al 1 :
T1-T2 Glottic Cancer patients
Found overall treatment time to be a significant factor
Better outcomes with 225-cGy fractions
Le et al 2 :
Fraction size, total dose, and overall time had impacts on the control of T2 glottic cancers
1. Bhishamjit S. Chera, Robert J. Amdur, Christopher G. Morris, Jessica M. Kirwan, William M. Mendenhall, T1N0 to T2N0 Squamous Cell Carcinoma of the Glottic Larynx Treated With Definitive Radiotherapy, International Journal of Radiation Oncology*Biology*Physics, Volume 78, Issue 2, 1 October 2010, Pages 461-466
2. Quynh-Thu X. Le, Karen K. Fu, Steward Kroll, Janice K. Ryu, Jeanne M. Quivey, Thomas S. Meyler, Richard M. Krieg, Theodore L. Phillips, Influence of fraction size, total dose, and overall time on local control of T1–T2 glottic carcinoma, International Journal of Radiation Oncology*Biology*Physics, Volume 39, Issue 1, 1 August 1997, Pages 115-126
Discussion
Garden et al :
Retrospective evaluation of 228 T2 Glottic Cancer patients
3 different fractionation schedules
Conventional : <=2 Gy/fraction; Once daily treatment
Accelerated : >2Gy/fraction; Once daily treatment
Hyperfractionation : 1.1-1.2 Gy/fraction; Twice daily treatment
80% local control with both Hypofractionation and Hyperfractionation
Discussion
Tumors with impaired cord mobility (T2b) are found to have poorer prognosis as compared to without impairment of vocal cord mobility (T2a)
In this study, there was a trend for better local control in T2a versus T2b disease
Significant differences in loco regional control, disease-free survival, and overall survival
No differential effect by fractionation was seen
These results were in concordance with the meta analysis conducted by McCoul and Har-El 1
Pooled data from 21 reports and found a statistically better outcome in T2a disease
Comparison of 5-year local control of disease for lesions with impaired vocal cord mobility (T2b) vs those with normal vocal cord mobility (T2a) showed a statistically significant difference
Odds Ratio = 1.83; 95% CI 1.52-2.20; P < .001
1. McCoul ED, Har-El G. Meta-analysis of Impaired Vocal Cord Mobility as a Prognostic Factor in T2 Glottic Carcinoma.Arch Otolaryngol Head Neck Surg.2009;135(5):479-486
Conclusions
This trial was the 1st prospective randomised control trial done to see the effectiveness of Hyper fractionated Radiation Therapy in T2N0 Glottic cancers
The trial did not achieve its aim of 55% reduction in local failure at 5 years with improvement in 5 year local control from 70% to 85%
However, this trial did show an improvement in local control with Hyperfractionation as compared to conventional fractionation (78% versus 70%), with acceptable toxicity
Conclusions
This trial did not compare accelerated fractionation (2.25Gy/fraction per day) with Hyperfractionation
The accelerated fractionation regimen still holds good for good local control and survival benefit in T2N0 glottic cancers
Conclusions
Tumors with impaired cord mobility (T2b) have a worse outcome as compared to T2a tumors
The sub staging should be included in the AJCC Classification
Also, as there was no effect of fractionation seen in T2b tumors, other modalities of treatment should be explored
? Addition of concurrent chemotherapy
THANK YOU !!!!!
EORTC 22791
325 patients with T2-3 oropharyngeal cancer
Randomized to :
Conventional fractionation : 70 Gy in 35 fractions (2Gy per fraction)
Hyperfractionation : 80.5 Gy in 70 fractions (1.15Gy per fraction; Twice daily treatment)
Hyperfractionation increased :
5 year Local Control (40→59%)
5 year Overall Survival (31→47%)
Benefit primarily for T3 tumors
RTOG 9003
268 patients with locally advanced Head and neck cancer
Randomized to
Conventional fractionation : 70 Gy in 35 fractions (2Gy per fraction)
Hyperfractionation : 81.6 Gy in 68 fractions (1.2Gy per fraction; Twice daily treatment)
Split-course : 67.2 Gy in 42 fractions (1.6Gy per fraction; Twice daily treatment with a 2 weeks break)
Concomitant boost : 72 Gy [with b.i.d. RT for last 12 fractions (1.8 and 1.5 Gy)]
Concomitant boost and hyperfractionated RT improved 2-year LRC (54%), DFS (39%), and OS (53%) compared to standard or split-course accelerated RT