1. Role of Surgical Trials in Gynaecological Oncology Research Henry Kitchener, University of Manchester ANZGOG, March 2013

2. Role of Surgery in Gynaecological Oncology  Curative  The most sucessful primary treatment for early stage disease.  Pallative  Debulking and relief of obstruction.  Salvage  Isolated metastasis; localised recurrence.  Cost effective  Cheaper and less complex than many treatments.

3. Horizon scanning reveals a changing role for surgery  Ovarian cancer  To follow chemotherapy (Grade I)  To treat recurrence (unproven)  More aggressive primary debulking (unproven)  Lymphadenectomy (unproven)  Endometrial cancer  to rationalise staging by  Full lymphadenectomy (unproven)  Sentinel node dissection (feasible)  Implications of obesity epidemic

4. Horizon scanning reveals a changing role for surgery  Cervical cancer  Becoming ever rarer in GCIG (not in developing world)  Reduced role of radical hysterectomy  Sentinel node detection (feasible)  Vulval cancer  Will become rarer following HPV vaccination  Sentinel node detection (feasible)  Completion surgery following chemo/radiation or antiviral therapy

5. Influences on surgical trends  Epidemiology  Disease incidence  Population characteristics (obesity, aging etc)  Prevention strategies  New non surgical treatments  New techniques (eg laporoscopic, robotic)  Extent of surgery

6. Surgical volume as current standard of care SettingTrend Upfront treatment of ovarian cancer  Second line treatment for recurrence  Primary treatment of endometrial cancer  Primary treatment of cervical cancer  Primary treatment of vulval cancer 

7. Extent of cancer surgery Bipolar trend in surgery More radical surgical attempt  To debulk  To salvage Less radical surgery  To conserve function  To reduce morbidity

8. Drivers for clinical trials in surgery  Surgical practice needs an evidence base  Effectiveness  Cost effectiveness  Funders want to encourage surgical trials  Need to address standard of care  Need to evaluate new procedures  (need to get into NEJM/Lancet)

9. Challenges facing surgical trials  Surgical culture which does not demand evidence  “Conviction based” resistance to trial design  Reluctance to get involved in trials  Lack of commercial sponsorship  Except when new equipment is being evaluated  Definition of a control arm  Point in time of equipoise  Randomisation  The complexity of a surgical intervention

10. Types of clinical trials and other high quality studies  Randomised controlled trials  Phase II (feasibility)  Phase III (superiority, non inferiority, cost effectiveness)  Prospective non randomised studies  Paired with standard of care e.g. sentinel node  Stand alone with success self evident e.g. a new vaccine against cervical cancer

11. Lancet 2009;374 1097-1104 Influences on surgical outcomes

12. Stage 0-1 (Innovation) Stage 2a (Development) Stage 2b (Exploration) Stage 3 (Assessment) Stage 4 (Long term) Number and types of patients Single digit, highly selected (or pre-human) Few, selectedMany, mixed but not all Many, variableAlmost all Number of surgeons Very fewFew, innovatorsManyMany, early majority Most, late majority EthicsSometimesYes No Learning curve in human beings NoYes MaybeNo Table 2: Stages of surgical innovation (IDEAL paradigm) Lancet 2009; 374: 1089-96

13. Ovarian cancer surgery trials (1)  Hypothesis: super aggressive surgery does not improve survival Challenges Control arm Patient acceptance Feasible? Interface between “normal” and “aggressive” surgical effort Randomise Normal debulking effort Aggressive debulking effort Chemotherapy Primary outcome: overall survival

14. Ovarian cancer surgery trials (2) Hypothesis: Surgery does not improve survival in ovarian cancer  Platinum sensitive disease may not need debulking  Platinum resistant disease may not benefit from debulking  Surgery can be palliative Challenges Timing of surgery Patient acceptance Doctor acceptance Feasible Need for palliation

15. RCT of primary surgery in ovarian cancer Neoadjuvant chemotherapy If responding, randomise after 3 cycles SurgeryNo surgery Continue chemo Relapse Primary outcome: progression free survival, quality of life (1,6,12 months), overall survival

16. Primary Peritoneal cancer R Clayton & S Kehoe for NCRI Hypothesis-Surgery may be non contributory in platinum sensitive women. Population-Women with small ovarian mass and obvious upper abdominal disease. Intervention-Debulking surgery after 3 cycles of CP if there has been a relapse. Primary Outcome- Progression free survival.

17. Eligible Women Registered Laporoscopy & Biopsies Chemo 3 Cycles Response Surgery Chemo Continue Chemo Follow Up RCT of surgery in primary peritoneal cancer

18. Surgery trials in endometrial cancer (1) Challenges Eligibility Quality control Extent of lymphadenectomy Choice of adjuvant therapy To demonstrate whether lymphadenectomy directed therapy is more beneficial than non selected adjuvant therapy in high grade disease

19. Surgical trials in endometrial cancer (2) High-risk Endometrial Cancer Clinical stage 1, grade 3 endometrioid ? Clinical stage 1, Serous cancer ? Clinical stage 1, grade 2 with deep invasion Sentinel node substudy Lymphadenectomy (pelvic/PA) No Lymphadenectomy Lymph node negative Lymph node positive Lymph nodes unknown Vaginal Brachytherapy Chemotherapy and Radiation Therapy* or Chemotherapy alone** Follow-up, toxicity and quality of life * EBRT + 2cylces of concurrent cisplatin, followed by 4 cycles of carboplatin/paclitaxel ** 6 cycles of carboplatin/paclitaxel; vaginal brachytherapy at group preference Schedule by group preference, stated before and used consistently thoughout trial.

20. Surgical trials in endometrial cancer (3)  To determine the clinical effectiveness of sentinel node detection Design: incorporate initial sentinel node detection into a lymphadenectomy protocol  Allows direct comparison of accuracy, reliability  Enables controlled learning of technique  Allows comparison of “SND outcomes” with trial outcomes  A positive SN/-ve lymphadenectomy counts as “lymph node positive”

21. Role of surgical trials in cervical cancer  To determine the need for radical hysterectomy in small volume (< 2cms) stage 1a2/1b  SHAPE Trial  To determine the clinical effectiveness of sentinel node detection

22. Cervical Tumour < 2 cms across > 1 cm margin Rad Hyst & PLND + SLN Simple Hyst & PLND + SLN Positive Nodes Adjuvant treatment policy Negative Nodes Chemoradiation Radiation Follow up only 1° Outcome Pelvic relapse free survival (700 patients) Randomise HR IR LR SHAPE Trial

23. Conclusion  Surgical trials in cancer are challenging but necessary  Developments in cancer care require re-evaluation of surgery  Surgical trials may benefit from GCIG collaboration  Several important trials can be considered which challenge standard of care