BGCS Covid Forum 7th April 2020 Introduction and Welcome• Sudha Sundar, BGCS President• BGCS Covid Forum Chairs John Butler and Sonali Kaushik • Case 1 – Radicality of interval debulking surgery in stage IV ovarian cancer

when extensive cytoreduction can not be performed due to C-19• Presenter - Rasiah Bharathan, Leicester , Lead Discussant – Christina

FotopolouCase 2 - What to do if surgery can not be performed after 6 cycles of NACT?

• Presenter –Rachel Jones, Swansea, Lead Discussant - Agnieszka MichaelCase 3 – Recurrent Vulva cancer post-RT – how to balance the risks of radical surgery, chemotherapy, watch and wait, reirradiation?

• Presenter – Sadaf Ghaem Maghami, Imperial , Lead Discussant – Jason Yap

Summary and Close

Case 1: Approach to IDS during COVIDPresenter - Rasiah Bharathan, Leicester Discussant – Christina Fotopolou, Imperial• PS1• Stage 4 HGSC ( pericardiac nodes )• Ca125 1433 at presentation• IDS cancelled after cycle 4 – Covid• Cycle 5 given• CT• There is improvement in the peritoneal disease ascites as well as in the retroperitoneal

lymphadenopathy. There is improvement in the previously noted splenic lesion. Similarly there is reduction in the right paracardiac node. No evidence of any inguinal, pelvic lymphadenopathy. Previously noted pelvic mass has been removed. No focal parenchymal lung nodule identified. Mediastinal nodes have become smaller with similar improvement in the retroperitoneal nodes. No focal destructive bony lesion seen.

Discussion points – Case 1- Christina Fotopolou

• Continue to 6th cycle of chemo in view of Covid 19?• Proceed with radical debulking procedure at Local Cancer Centre but

no removal of pericardiac nodes (Risks of Covid explained to patient)?• Proceed with limited surgery no bowel resection to reduce covid

risks?

ü Value of IDS after increasing number of NAC cyclesü Value of removal of tumor affected LN in ovarian debulkingsü Omission of bowel surgery to reduce complications?

Impact of number of NAC cycles on survival

Meta-Analysis publications 1989-2005: 22 cohorts / 835 pts with FIGO III-IV ovarian cancer

• all pts had pre-OP platinum-based chemotherapy followed by interval-OP

• Prognostic factors: year, % FIGO IV, % „optimal debulking“, chemotherapy +/- taxanand number of pre-OP chemotherapy courses > 3 –> neg. impact

-4.1 mos. median OS per pre-OP chemo-course > 3 courses

Outcome becomes inferior with longer duration of pre-OP chemotherapy (= longer time with significant tumor volume -> higher risk for resistance ?)

Bristow RE, Chi DS (2006A meta-analysis. Gynecol Oncol 103: 1070-1076

Impact of removal of tumor involved LN on survival

- bulky- non bulky

R

Systematic LNDl pelvic ³ 25 LN

l para-aortic ³ 15 LN

Æ systematic LND

l only: removal of“bulkynodes”

FIGO IIIB - IV (pleura)

£ 75 years

Intra-abdominalresidual disease£ 1 cm

n= 21

6

n= 211

Value of systematic LND vs removal of only bulky LN (P. Benedetti Panici et

al., JNCI 97, 2005)

n= 216

n= 211

PFS OS

% 5 years: 31.2 vs. 21.6 % 49.5 vs. 48 %

HRall: 0.75 (p = 0.01) 0.97 (n.s.)

HRper protocol: 0.69 0.93

medianHR: + 7 months + 2.4 months(22.4 vs. 29.4) (56.3 vs. 58.7)

median roh: + 5 months + 5,6 months

Removal of bulky nodes only: inferior PFS, same OS

Panici et al. J Natl Cancer Inst 2005

Value of removal of microscopically involved LN: lessons of the LION trial

Presented by: Philipp HarterAGO & KEM

Essen, Germany

• We have learned that patients with complete resection during upfront surgery and treated in quality assured centres can have an excellent prognosis (median OS ~ 67.2 months; median PFS ~ 25.5 months)

• Systematic pelvic and para-aortic LNE in patients with advanced ovarian cancer with both intra-abdominal complete resection and clinically negative LN neither improve overall nor progression-free survival

….despite detecting (and removing) sub-clinical retroperitoneal lymph node metastases in 56% of patients

• Systematic LNE of clinical negative LN in patients with advanced ovarian cancer and complete resection should be omitted.

Impact of surgical radicality on morbidity & survival

CHORUS Study: Post-op Complications• Any grade 3/4 complication PS = 24% vs. NACT = 14%

• Discharge within 14 days post-op PS = 74% vs. NACT = 92%

3

5 56

21 1

0.004

7

0.5 0.5

3

0 01 1

012345678

Haemor

rhage

Nausea

Vomitin

g

Infec

tion

Veno

us…

Bowel

obstr

uctio

n

Fistul

a: int

estina

l/rec

tal

Fistul

a:…

Perc

enta

ge o

f pat

ient

s

PS NCT

Complications affecting >5% & other important post-op complications

Kehoe et.al. Lancet 2015

28-days surgical mortality upfront vs interval debulking surgery

PS NACT

Surgery 14 (5.6%) 1 (0.5%)

• Review of deaths within 28 days of surgery• PS

• Disease progression = 4• Pulmonary embolism = 2; infection = 3;

problems with fluid balance or renal failure = 2; hemorrhage = 1; intra-operative problems = 1

• Still under review = 1

• NACT • Pulmonary embolism = 1

Kehoe et.al. Lancet 2015

• (Systematic) Paraaortic LND: <1% - 5%• Stoma: 10%• Bowel resection: 10%

23 

 

2.6 Overall survival rates according to largest residual tumor and

treatment arm.

Overall survival Treatment arm and largest residual tumor

Patients (N)

Observed Events (O)

Hazard Ratio (90% CI)

P-Value (Wald Test)

Median (90% CI) (Months)

% at 5 Year(s) (90% CI)

PDS - No residual 62 42 1.00 0.0002 (df=5) 44.98 (34.30, 53.59) 31.31 (20.77, 42.40)

PDS- 1 – 10 mm 74 52 1.37 (0.97, 1.93) 0.1309 (df=1) 32.26 (26.91, 37.39) 23.47 (14.63, 33.54)

PDS - > 10 mm 169 136 1.87 (1.39, 2.50) 0.0004 (df=1) 25.66 (21.62, 28.55) 14.82 (10.06, 20.45)

NACT- No residual 152 100 1.11 (0.82, 1.51) 0.5616 (df=1) 38.18 (32.69, 43.96) 27.50 (20.51, 34.92)

NACT- 1 – 10 mm 87 67 1.73 (1.25, 2.40) 0.0054 (df=1) 27.01 (24.28, 31.74) 17.52 (10.33, 26.27)

NACT- > 10 mm 53 41 1.71 (1.19, 2.46) 0.0144 (df=1) 25.49 (22.80, 32.16) 19.91 (10.24, 31.88)

PDS: Primary debulking surgery; NACT: Neoadjuvant chemotherapy: CI: Confidence intervals.

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 363;10 nejm.org september 2, 2010 943

original article

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer

Ignace Vergote, M.D., Ph.D., Claes G. Tropé, M.D., Ph.D., Frédéric Amant, M.D., Ph.D., Gunnar B. Kristensen, M.D., Ph.D.,

Tom Ehlen, M.D., Nick Johnson, M.D., René H.M. Verheijen, M.D., Ph.D., Maria E.L. van der Burg, M.D., Ph.D., Angel J. Lacave, M.D.,

Pierluigi Benedetti Panici, M.D., Ph.D., Gemma G. Kenter, M.D., Ph.D., Antonio Casado, M.D., Cesar Mendiola, M.D., Ph.D., Corneel Coens, M.Sc., Leen Verleye, M.D., Gavin C.E. Stuart, M.D., Sergio Pecorelli, M.D., Ph.D., and Nick S. Reed, M.D., for the European Organization for Research and

Treatment of Cancer–Gynaecological Cancer Group and the NCIC Clinical Trials Group* — a Gynecologic Cancer Intergroup Collaboration

From the University Hospitals Leuven, Leuven (I.V., F.A.), and the European Or-ganization for Research and Treatment of Cancer Headquarters, Brussels (C.C., L.V.) — both in Belgium; Norwegian Radium Hospital and the Institute of Medical In-formatics, Oslo (C.G.T., G.B.K.); Univer-sity of British Columbia, Vancouver, Can-ada (T.E., G.C.E.S.); Royal United Hospital, Bath (N.J.), and Gartnavel General Hos-pital and Beatson Oncology Center, Glas-gow (N.S.R.) — both in the United King-dom; Vrije Universiteit Medical Center, Amsterdam (R.H.M.V.), Erasmus MC Uni-versity Medical Center Rotterdam, Rot-terdam (M.E.L.B.), and Leiden University Medical Center, Leiden (G.G.K.) — all in the Netherlands; Hospital Universitario Central de Asturias, Oviedo, Spain (A.J.L.); University of Rome La Sapienza, Rome (P.B.P.), and the University of Brescia, Brescia (S.P.) — both in Italy; and Hospital Universitario San Carlos (A.C.) and Hos-pital Universitario 12 de Octubre (C.M.) — both in Madrid. Address reprint requests to Dr. Vergote at University Hospitals, K.U. Leuven Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Herestraat 49, B-3000 Leuven, Belgium, or at ignace.vergote@uzleuven.be.

*Other collaborators are listed in the Ap-pendix.

N Engl J Med 2010;363:943-53.Copyright © 2010 Massachusetts Medical Society.

A bs tr ac t

BackgroundPrimary debulking surgery before initiation of chemotherapy has been the standard of care for patients with advanced ovarian cancer.

MethodsWe randomly assigned patients with stage IIIC or IV epithelial ovarian carcinoma, fallopian-tube carcinoma, or primary peritoneal carcinoma to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery (so-called interval debulking surgery).

ResultsOf the 670 patients randomly assigned to a study treatment, 632 (94.3%) were eligible and started the treatment. The majority of these patients had extensive stage IIIC or IV disease at primary debulking surgery (metastatic lesions that were larger than 5 cm in diameter in 74.5% of patients and larger than 10 cm in 61.6%). The largest residual tumor was 1 cm or less in diameter in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. Postoperative rates of adverse effects and mortality tended to be higher after primary debulking than after interval debulking. The hazard ratio for death (intention-to-treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemo-therapy, was 0.98 (90% confidence interval [CI], 0.84 to 1.13; P = 0.01 for non-inferiority), and the hazard ratio for progressive disease was 1.01 (90% CI, 0.89 to 1.15). Complete resection of all macroscopic disease (at primary or interval surgery) was the strongest independent variable in predicting overall survival.

ConclusionsNeoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy as a treatment option for patients with bulky stage IIIC or IV ovarian carcinoma in this study. Complete resec-tion of all macroscopic disease, whether performed as primary treatment or after neoadjuvant chemotherapy, remains the objective whenever cytoreductive surgery is performed. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003636.)

The New England Journal of Medicine Downloaded from nejm.org on June 30, 2011. For personal use only. No other uses without permission.

Copyright © 2010 Massachusetts Medical Society. All rights reserved.

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 363;10 nejm.org september 2, 2010 943

original article

Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer

Ignace Vergote, M.D., Ph.D., Claes G. Tropé, M.D., Ph.D., Frédéric Amant, M.D., Ph.D., Gunnar B. Kristensen, M.D., Ph.D.,

Tom Ehlen, M.D., Nick Johnson, M.D., René H.M. Verheijen, M.D., Ph.D., Maria E.L. van der Burg, M.D., Ph.D., Angel J. Lacave, M.D.,

Pierluigi Benedetti Panici, M.D., Ph.D., Gemma G. Kenter, M.D., Ph.D., Antonio Casado, M.D., Cesar Mendiola, M.D., Ph.D., Corneel Coens, M.Sc., Leen Verleye, M.D., Gavin C.E. Stuart, M.D., Sergio Pecorelli, M.D., Ph.D., and Nick S. Reed, M.D., for the European Organization for Research and

Treatment of Cancer–Gynaecological Cancer Group and the NCIC Clinical Trials Group* — a Gynecologic Cancer Intergroup Collaboration

From the University Hospitals Leuven, Leuven (I.V., F.A.), and the European Or-ganization for Research and Treatment of Cancer Headquarters, Brussels (C.C., L.V.) — both in Belgium; Norwegian Radium Hospital and the Institute of Medical In-formatics, Oslo (C.G.T., G.B.K.); Univer-sity of British Columbia, Vancouver, Can-ada (T.E., G.C.E.S.); Royal United Hospital, Bath (N.J.), and Gartnavel General Hos-pital and Beatson Oncology Center, Glas-gow (N.S.R.) — both in the United King-dom; Vrije Universiteit Medical Center, Amsterdam (R.H.M.V.), Erasmus MC Uni-versity Medical Center Rotterdam, Rot-terdam (M.E.L.B.), and Leiden University Medical Center, Leiden (G.G.K.) — all in the Netherlands; Hospital Universitario Central de Asturias, Oviedo, Spain (A.J.L.); University of Rome La Sapienza, Rome (P.B.P.), and the University of Brescia, Brescia (S.P.) — both in Italy; and Hospital Universitario San Carlos (A.C.) and Hos-pital Universitario 12 de Octubre (C.M.) — both in Madrid. Address reprint requests to Dr. Vergote at University Hospitals, K.U. Leuven Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Herestraat 49, B-3000 Leuven, Belgium, or at ignace.vergote@uzleuven.be.

*Other collaborators are listed in the Ap-pendix.

N Engl J Med 2010;363:943-53.Copyright © 2010 Massachusetts Medical Society.

A bs tr ac t

BackgroundPrimary debulking surgery before initiation of chemotherapy has been the standard of care for patients with advanced ovarian cancer.

MethodsWe randomly assigned patients with stage IIIC or IV epithelial ovarian carcinoma, fallopian-tube carcinoma, or primary peritoneal carcinoma to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery (so-called interval debulking surgery).

ResultsOf the 670 patients randomly assigned to a study treatment, 632 (94.3%) were eligible and started the treatment. The majority of these patients had extensive stage IIIC or IV disease at primary debulking surgery (metastatic lesions that were larger than 5 cm in diameter in 74.5% of patients and larger than 10 cm in 61.6%). The largest residual tumor was 1 cm or less in diameter in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. Postoperative rates of adverse effects and mortality tended to be higher after primary debulking than after interval debulking. The hazard ratio for death (intention-to-treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemo-therapy, was 0.98 (90% confidence interval [CI], 0.84 to 1.13; P = 0.01 for non-inferiority), and the hazard ratio for progressive disease was 1.01 (90% CI, 0.89 to 1.15). Complete resection of all macroscopic disease (at primary or interval surgery) was the strongest independent variable in predicting overall survival.

ConclusionsNeoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy as a treatment option for patients with bulky stage IIIC or IV ovarian carcinoma in this study. Complete resec-tion of all macroscopic disease, whether performed as primary treatment or after neoadjuvant chemotherapy, remains the objective whenever cytoreductive surgery is performed. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003636.)

The New England Journal of Medicine Downloaded from nejm.org on June 30, 2011. For personal use only. No other uses without permission.

Copyright © 2010 Massachusetts Medical Society. All rights reserved.

Can CT predict operability?Pre-operative CT imaging shows a high specificity

and NPV by rather variably low sensitivity and PPV in accurately predicting the various tumordissemination patterns of OC disease.

Nasser et al. IJGC 2017

Diaphragm Spleen Large bowel Small

bowel

Rectum Porta hepatis Mesentery LN

Sensitivity (%) 32 26 46 44 39 57 31 63

Specificity (%) 99 99 98 99 99 99 99 78

PPV (%) 95 71 89 88 94 80 92 61

NPV(%) 70 91 85 94 83 98 81 78

Survival data depending of surgical effort

Surgery in CHORUS • median OS: 23 months• median PFS: 10.8 months

Maximal effort upfront surgery (LION)• Median OS: 67.2 mo• Median PFS: 25.5 mo

With Number of Subjects at RiskProduct-Limit Survival Estimates

323 289 271 248 227 210 194 184 167 135 93 55 28 11324 308 297 282 252 228 208 187 170 144 105 66 30 10

LNENo LNE

0 6 12 18 24 30 36 42 48 54 60 66 72 78

OS_month

0.0

0.2

0.4

0.6

0.8

1.0

Sur

vival

Pro

babi

lity

No LNELNEArm

+ Censored

0 6 12 18 24 30 36 42 48 54 60 66 72 78

OS_month

0.0

0.2

0.4

0.6

0.8

1.0

Sur

vival

Pro

babi

lity

No LNELNEArm

+ Censored

Arm N E Median OS HR (95%CI)LNE 323 134 65.5 months 1.057 (0.833-1.341)No LNE 324 140 69.2 months 1Total 647 274

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n al

ive

274 233 200 158 132 73 44 20 12 5 0NACT276 222 185 151 126 63 32 17 9 2 1PS

N

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96Time from randomisation (months)

PS NACT

intention-to-treat populationOverall survival

Kehoe et.al. Lancet 2015

Harter et.al. ASCO 2017

Case 2: Patient at 6 cycles of NACT ? Surgery ? Continue

Presenter –Rachel Jones, SwanseaDiscussant - Agnieszka Michael, Royal Surrey

• Lack of HDU beds- patients previously being considered for PDS/IDS are starting SACT

• Continue chemo beyond 6 cycles? – BRCA positive add PARP

• If IDS after 6 cycles should they be offered another couple of cycles?

Discussant - Agnieszka Michael, Royal Surrey

Cytoreductive surgery in ovarian cancer

• meta-analysis- *JCO 2002 March 1; Bristow et al• 6885 pts– FIGO stage III/IV– 53 studies involving platinum-based treatment–Maximum or optimal cytoreductive procedure correlated with

median survival– >75% tumour cytoreduction-median survival 37 m vs 23 moths– Each 10% increase in cytoreduction –increase in median survival of

5.5 %

Maintenance chemotherapy in first line ovarian cancer

• No benefit of continuing platinum chemotherapy – studies that explored the delivery of 8 to 12 cycles of a platinum drug

failed to reveal superior survival outcomes• No benefit of continuing paclitaxel chemotherapy – SWOG /GOG study-conduct a phase 3 randomized trial comparing 3

cycles to 12 cycles of single agent paclitaxel-some PFS survival but no OS;

Increased toxicity

Maintenance PARP inhibitors +/-Bevacizumab

• New data from PRIMA trial –benefit from Niraparib treatment in all women (not CDF approved) –median PFS 21.9m vs 10.4m

• New data PAOLA trial –benefit from maintenance Olaparib and Bevacizumab PFS ITT -22.1 vs 16.6m (bev alone)

• SOLO2 –maintenance Olaparib in BRCA mutated ovarian cancer PFS 19·1 m vs 5·5m

COVID-19

• Assessment of each patient individually • Essential to test all patients for BRCA –germline and somatic (?

Biopsy) • Patients with stage IV disease –maintenance treatment • Patients with primary peritoneal cancer

No easy solution –patients who would benefit from surgery and can not have it will suffer as a result

Case 3: Recurrent Vulvo-vaginal cancer post RTPresenter - Sadaf Ghaem Maghami, Imperial

Discussant – Jason Yap, Birmingham

• 75yrs, PS1• Diagnosis:2006 PMB, G3 SCC vagina rt side• EBRT + Cisplatin, RT implant completed Nov 2006• PMx: high BMI, DM, HTN, Pacemaker, COPD• Rx : Metformin, Ramipril, Statin, inhaler

Now

• Jan 2020• Vulval lesion ( slow growth)• EUA• 3-4 cm left vaginal mass. Likely resectable close to bone and

sphincter, may need flap• Biopsies G3 SCC• CT PET: local disease in previous RT field

Options

• Chemotherapy to hold disease• Repeat RT• Brachytherapy• Wait and see• Consider posterior exenteration in ? 6/52 when Covid situation

improves

Case discussion: Recurrence VSCC in a background of post-

radiotherapy field

Jason YapPan Birmingham Gynaecological Cancer Center

75 yoRecurrent Vulva/Vagina2006 PMB G3 stage 3 scc vagina r sideEBRT cisplatin, RT implant completed Nov 2006PMHx. High BMI, DM, Pacemaker (no MRI) COPD (ex-smoker)Rx Metformin rampiril, statin, inhalerPS 1

1/2020 vulva lesion (slow growth)EUA 3-4 cm left vaginal mass and labia feels mobile likely resectable close to bone and sphincter may need local flapBiopsies G3 SCCCT PET only local disease in previous RT field

Case Summary

OPTIONS:1. Chemotherapy to hold disease unwise given RT (Previous RT)2. Repeat RT3. Brachytherapy4. Wait and see5. Consider Posterior exenteration in 6/52 ?when C-19 improved

Challenges1. Recurrence VSCC on a background of radiotherapy field

- potentially limited to chemotherapy +/- surgery- plastic reconstruction challenges- altered anatomy

2. Background medical comorbidities – Cardiovascular, DM, COPD- anaesthetic risks & exposure to COVID19 if surgery now- plastic reconstruction challenges

3. Location of tumour- proximity to vital organs – bladder and anus

4. Rare disease – lack of evidence5. COVID19 outbreak

- highly likely require ITU/HDU bed support post-op- hospital acquired COVID19

Chemo-Radiotherapy & recurrence

• Radiotherapy +/-Cisplatin (61/87)• 3 yrs local recurrence 39% (34/87)• Median recurrence time/death 7.4months• PFS 40% & OS 57% (3 yrs)• Adverse prognostic factors

- Age >68- No previous chemo- primary radiotherapy

• Treatment for recurrence- Surgical resection- If surgery not feasible > palliative

chemo +/- DXT- Palliation only

Systemic treatment in VSCC

• Systematic review of literature on chemotherapy treatment in VSCC

• 5 studies evaluates chemotherapy in recurrence disease after DXT

• 12 studies evaluates resectability after NACT

Read et al.: Summary

• Chemotherapy alone has poor outcomes• Combination chemotherapy may be effective• Improves resectability after chemotherapy

Back to current case – point to note

• Survival is usually good in isolated local VSCC (5-yr survival ~60%), Nooij et al 2016 (PMID: 27637349)

• NACT may be of benefit in current COVID19 outbreak• Consider using combination chemotherapy if tolerable• Potentially reduce size of tumour and reduce surgical morbidities

or need for exenteration or extensive plastic reconstruction• Palliative chemo+/-DXT or symptom control is an alternative• Did patient have BGLND already? If not, GLND should be

considered if surgical treatment