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Role of Surgical Trials in Gynaecological Oncology Research Henry Kitchener, University of Manchester ANZGOG, March 2013 Role of Surgery in Gynaecological Oncology Curative Pallative Debulking and relief of obstruction. Salvage The most sucessful primary treatment for early stage disease. Isolated metastasis; localised recurrence. Cost effective Cheaper and less complex than many treatments. 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 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 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 Surgical volume as current standard of care Setting Trend 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 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 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) 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 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 Influences on surgical outcomes Lancet 2009;374 1097-1104 Stage 0-1 Stage 2a Stage 2b Stage 3 Stage 4 (Innovation) (Development) (Exploration) (Assessment) (Long term) Number and types of patients Single digit, highly selected (or pre-human) Few, selected Many, mixed but not all Many, variable Almost all Number of surgeons Very few Few, innovators Many Many, early majority Most, late majority Ethics Sometimes Yes Yes Yes No Learning curve in human beings No Yes Yes Maybe No Table 2: Stages of surgical innovation (IDEAL paradigm) Lancet 2009; 374: 1089-96 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 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 RCT of primary surgery in ovarian cancer Neoadjuvant chemotherapy If responding, randomise after 3 cycles Surgery No surgery Continue chemo Continue chemo Relapse Relapse Primary outcome: progression free survival, quality of life (1,6,12 months), overall survival 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. RCT of surgery in primary peritoneal cancer Eligible Women Registered Laporoscopy & Biopsies Chemo 3 Cycles Response Continue Chemo Surgery Follow Up Chemo Surgery trials in endometrial cancer (1) To demonstrate whether lymphadenectomy directed therapy is more beneficial than non selected adjuvant therapy in high grade disease Challenges •Eligibility •Quality control •Extent of lymphadenectomy •Choice of adjuvant therapy 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 No Lymphadenectomy Lymphadenectomy (pelvic/PA) Lymph node negative Vaginal Brachytherapy Lymph node positive Lymph nodes unknown 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. 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” 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 Cervical Tumour < 2 cms across > 1 cm margin SHAPE Trial Randomise Rad Hyst & PLND + SLN Positive Nodes Simple Hyst & PLND + SLN Negative Nodes Adjuvant treatment policy Negative Nodes HR Chemoradiation HR IR Radiation IR LR Follow up only LR 1° Outcome Pelvic relapse free survival (700 patients) 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