NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

Transcription

1 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of ultra-radical (extensive) surgery for advanced ovarian cancer Treating advanced ovarian cancer with extensive surgery Cancer of the ovary has usually reached an advanced stage when it is detected so it cannot all be removed by standard surgical technique. Extensive or ultra-radical surgery aims to improve the outcome by removing all or almost all visible traces of the tumour. Introduction The National Institute for Health and Care Excellence (NICE) has prepared this overview to help members of the Interventional Procedures Advisory Committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This overview was prepared in March Procedure name Ultra-radical (extensive) surgery for advanced ovarian cancer. Specialist societies BASO ~ The Association for Cancer Surgery British Gynaecological Cancer Society Royal College of Obstetricians and Gynaecologists. Page 1 of 27

2 Description Indications and current treatment Ovarian cancer is the leading cause of death from gynaecological cancer in the UK, and its incidence is rising. It is the fifth most common cancer in women, with a lifetime risk of about 2% for women in England and Wales. Early symptoms of ovarian cancer are similar to those of other conditions and include persistent bloating, pain in the pelvis and lower abdomen, and urinary frequency and/or urgency. Most women who have ovarian cancer present with advanced disease and the outcome is generally poor, with an overall 5-year survival rate of less than 35%. The stage of the disease at diagnosis is the most important factor affecting outcome and is defined by the International Federation of Gynecology and Obstetrics (FIGO) system. The main treatments for ovarian cancer are surgery and chemotherapy. Surgery usually involves bilateral salpingo-oophorectomy, total abdominal hysterectomy and omentectomy. Potentially curative surgery requires resection of all macroscopic disease. More commonly, the goal is to reduce the diameters of the remaining pieces of tumour tissue to less than 1 cm (optimal debulking). Advanced ovarian cancer is also sometimes treated by radiotherapy to shrink the tumour and reduce pain. What the procedure involves The aim of ultra-radical surgery for advanced ovarian cancer is to remove all visible disease and thereby improve survival compared with standard, less radical surgery. Extensive or ultra-radical surgery for advanced ovarian cancer is a development and extension of standard surgery. In addition to techniques used in standard and radical surgery (including hysterectomy, bilateral excision of ovary and fallopian tubes), ultra-radical surgery incorporates at least 1 of the following: extensive peritonectomy, including partial resection of the diaphragm resection of subcapsular liver metastases, cholecystectomy splenectomy, resection of the tail of the pancreas other bowel resections, partial gastrectomy. Clinical assessment International Federation of Gynecology and Obstetrics (FIGO) classification system Stage 1 - the tumour is confined to the ovary Page 2 of 27

3 Stage 2 - the tumour involves one or both ovaries and has extended into the pelvis Stage 3 - the tumour involves one or both ovaries with microscopically confirmed peritoneal metastasis outside the pelvis and/or regional lymph node metastasis (if cancer cells are found only in fluid taken from inside the abdomen the cancer is stage 2) Stage 4 - there is distant metastasis beyond the peritoneal cavity (if ovarian cancer is only found on the surface of the liver and not within the liver itself, then the cancer is stage 3). Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to ultra-radical (extensive) surgery for advanced ovarian cancer. Searches were conducted of the following databases, covering the period from their commencement to 1 February 2013: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type Patient Intervention/test Outcome Language Criteria Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patients with advanced ovarian cancer. Ultra-radical (extensive) surgery. Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. Page 3 of 27

4 List of studies included in the overview This overview is based on approximately 1422 patients from 5 nonrandomised comparative studies and 1 case series 1 6. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A. Page 4 of 27

5 Table 2 Summary of key efficacy and safety findings on ultra-radical (extensive) surgery for advanced ovarian cancer Abbreviations used: ASA, American Society of Anesthesiologists; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OR, odds ratio Study details Key efficacy findings Key safety findings Comments Kommoss S (2010) 1 Number of patients analysed: 267 Reoperation Study design issues: Extended surgery=12.5% (11/88) Retrospective study. Non-randomised comparative study Overall survival was significantly worse in Standard surgery=13.2% (5/38) Postoperative chemotherapy Germany patients who underwent incomplete tumour Incomplete debulking (any kind of was administered in 90% of Recruitment period: resection compared with patients with procedures)=14.2% (20/141) all patients. Study population: patients with ovarian cancer and complete debulking and standard surgery: macroscopic spread beyond the pelvis (FIGO stage IIIB to IV) HR=3.61, 95% CI 1.97 to 6.61, p<0.001 Study population issues: n=267 (38 patients completely debulked by standard techniques only, 88 patients completely debulked by extended surgery, 141 patients incompletely debulked) Age: median 64 years (range 29 89) Patient selection criteria: patients with FIGO stage IIB or IV ovarian cancer undergoing primary surgery. Patients with FIGO stage IIIC based on nodal status only were excluded. Technique: cytoreduction by standard surgical techniques included total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal tumour resection in the pelvis and paracolic gutters, systematic para-aortic lymphadenectomy up to the renal vessels, bilateral pelvic lymphadenectomy, resection of sigmoid colon and appendectomy. Extended surgery was assigned to patients needing resection of the diaphragm, resection of liver metastases, distal pancreatectomy, cholecystectomy, resection of the lesser omentum, bowel resection, splenectomy, gastric resection, nephrectomy, resection of bladder or ureter, and resection of lymph nodes beyond the pelvic or para-aortic lymph nodes up the renal vessels. Follow-up: median 38 months Conflict of interest/source of funding: not reported. There was no statistically significant difference in overall survival between patients with complete debulking by either extended surgery or standard surgery: HR=1.37, 95% CI 0.70 to 2.69, p=0.36 The observations were similar for progressionfree survival but time to progression was shorter in patients if extended surgery was needed for complete resection: HR=1.73, 95% CI: 1.06 to 2.84, p=0.028 Median operative time (minutes) Extended surgery=465 Standard surgery=340 Postoperative temperature >38 C for >3 days Extended surgery=17.0% (15/88) Standard surgery=5.3% (2/38) Incomplete debulking (any kind of procedures)=12.1% (17/141) Postoperative pulmonary embolism or thrombosis Extended surgery=6.8% (6/88) Standard surgery=5.3% (2/38) Incomplete debulking (any kind of procedures)=3.5% (5/141) Other severe postoperative complications Extended surgery=10.2% (9/88) Standard surgery=2.6% (1/38) Incomplete debulking (any kind of procedures)=5.7% (8/141) 60-day mortality Extended surgery=3.4% (3/88) Standard surgery=0% (0/38) Incomplete debulking (any kind of procedures)=5.7% (8/141) Patients treated by extended surgery were younger than the other 2 groups (median 61 versus 66 years, p<0.001). Page 5 of 27

6 Abbreviations used: ASA, American Society of Anesthesiologists; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OR, odds ratio Study details Key efficacy findings Key safety findings Comments Aletti GD (2006) 2 Number of patients analysed: 194 Perioperative mortality (within 30 Study design issues: days)=1.5% (3/194) (patients were 75, Retrospective cohort study of Retrospective cohort study Optimal cytoreduction (defined as residual 76 and 83 years old; none had consecutive patients. disease <1 cm) was achieved in 67.5% undergone any aggressive procedure) The overall proportion of USA Recruitment period: (131/194) of patients. patients treated by radical or standard surgery was not Study population: patients with stage IIIC ovarian cancer n=194 Age: mean 64 years (range 24 87) Patient selection criteria: patients with FIGO stage IIIC ovarian cancer. Exclusion criteria included patients who received neoadjuvant chemotherapy before surgery. Technique: standard surgery included hysterectomy, omentectomy, stripping of pelvic peritoneum, or limited resection of peritoneal-based nodules; radical surgery included any diaphragmatic surgery, bowel resection, splenectomy, or extensive abdominal peritoneal stripping or resection. All patients were scheduled for treatment with first-line postoperative chemotherapy. Follow-up: mean 3.5 years (range ) Conflict of interest/source of funding: not reported 5-year disease-specific overall survival rate=35% (68/194; 95% CI 28.7 to 42.0) 5-year disease-specific overall survival rates for patients with optimal cytoreduction (n=131): Radical surgery (n=69) =46% Non-radical surgery (n=62) =47%, p= year disease-specific overall survival rates for all patients with carcinomatosis n=144): Radical surgery =38% Non-radical surgery =9%, p< year disease-specific overall survival rates for patients with carcinomatosis who underwent successful optimal cytoreduction (n=82): Radical surgery =44% Non-radical surgery =17%, p<0.001 In multivariate analysis, residual disease and radical surgery were independent factors predicting patient survival. Patients with better ASA scores (1 or 2 versus 3 or 4) were more likely to have aggressive procedures (59% versus 36% respectively, p=0.005). reported. Procedures classified as radical surgery in this study fit the definition of ultraradical surgery used for this overview. Page 6 of 27

7 Abbreviations used: ASA, American Society of Anesthesiologists; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OR, odds ratio Study details Key efficacy findings Key safety findings Comments Eisenhauer EL (2006) 3 Number of patients analysed: 262 (57 versus 122 versus 83) Non-randomised comparative study USA Recruitment period: Study population: patients with stage IIIC IV epithelial ovarian cancer n=262 (57 extensive upper abdominal surgery to achieve optimal cytoreduction, 122 optimal cytoreduction by standard techniques, 83 suboptimal cytoreduction) Age range: years Patient selection criteria: exclusion criteria included prior surgical exploration at another institution, histology consistent with non-epithelial, mucinous or borderline carcinoma, pathology consistent with primary peritoneal or fallopian tube carcinoma, neoadjuvant chemotherapy, stages IA IIIB and stage IIIC based on nodal metastases only. Technique: standard surgery included hysterectomy, oophorectomy, omentectomy and/or bowel resection. Extensive surgery included diaphragm peritonectomy or full-thickness resection, splenectomy with or without distal pancreatectomy, cholecystectomy for gallbladder surface tumour, or resection of parenchymal liver or porta hepatis disease. Follow-up: median 36 months (range 1 94) Conflict of interest/source of funding: not reported 68% (179/262) of patients were optimally cytoreduced. Complete response to chemotherapy: Extensive surgery=82% (47/57) Standard surgery=78% (95/122) Suboptimal cytoreduction=57% (47/83), p<0.001 Median progression-free survival (months): Extensive surgery=24 (95% CI 17 to 31) Standard surgery=23 (95% CI 18 to 28) Suboptimal cytoreduction=11 (95% CI 10 to 13, p<0.001) Median overall survival (months): Extensive surgery=not reached by 68 months Standard surgery=84 Suboptimal cytoreduction=38 (95% CI 30 to 46, p<0.001) Statistically significant prognostic factors on multivariate analysis included stage, optimal status and ascites. 69% (57/83) of patients with suboptimal cytoreduction had surgery prior to May 2000 when upper abdominal procedures began to be used. When stratified by time period, progression-free survival and overall survival were equivalent (p=0.63 and p=0.59) before and after extensive surgery was introduced. Major surgical complications for all patients undergoing surgery after December 2000 (denominators not stated): p=0.54 Extensive surgery=12% (n=7) Standard surgery=7% (n=5) Suboptimal cytoreduction=8% (n=4) There is likely to be some patient overlap with Chi DS, 2009 and Chi DS, Study design issues: Retrospective study. The records of all eligible patients were reviewed and divided into 3 groups based on extent of surgery and postoperative residual disease. Optimal cytoreduction was defined as 1 cm. Extensive upper abdominal surgery was introduced in Complete response was defined as complete disappearance of all target or non-target lesions and/or normalisation of serum CA- 125 level Study population issues: The postoperative treatment course was similar in the 3 groups, with patients receiving equivalent primary chemotherapy regimens, numbers of cycles, consolidation therapy, and type of consolidation. Page 7 of 27

8 Abbreviations used: ASA, American Society of Anesthesiologists; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OR, odds ratio Study details Key efficacy findings Key safety findings Comments Rafil A (2012) 4 Number of patients analysed: 180 Complications Study design issues: Major=12% (21/180) (16 in radical Retrospective study. Non-randomised comparative study surgery group versus 5 in standard All patients were managed by Mean hospital stay=13.7±9.7 days surgery group, p=0.013). 19 (90%) a gynaecologist-oncologist. France needed further surgery. The last 30 patients from Recruitment period: Minor=22% (40/180) each centre were selected for 1 patient died within 30 days after inclusion. surgery from multi-organ failure The primary aim of the study Study population: patients with advanced ovarian (presenting with necrotising pancreatitis was to assess postoperative cancer on day 2). morbidity and mortality. n=180 (85 radical surgery versus 95 standard surgery) Age: mean 62 years (range 20 83) Patient selection criteria: primary epithelial ovarian cancer stage IIIC and IV (stage IIIC included patients with bulky peritoneal disease, but not those with lymph node involvement only). All procedures had to achieve complete (residual tumour <2 mm) cytoreduction. Technique: standard surgery included hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, peritonectomies involving the pelvis, and pelvic and para-aortic lymphadenectomies; radical surgery included standard surgery with any of the following procedures: bowel resection, splenectomy, caudal pancreatectomy, large stripping of the peritoneum, liver resection. Follow-up: 30 days Conflict of interest/source of funding: none Patients who had radical surgery had an increased risk of complications (OR 2.05, 95% CI: 1.09 to 3.85).Bowel resection was associated with an increased risk of complications (OR 3.4, 95% CI: 1.81 to 6.81) (Diaphragmatic and small bowel resections were not associated with increased complications). All complications: Peritonitis=2.8% (5/180) Pelvic abscess=3.9% (7/180) Sus-mesocolic abscess=3.3% (6/180) Parietal abscess=2.8% (5/180) Sepsis=2.8% (5/180) Urinary tract infection=1.1% (2/180) Fistula=2.2% (4/180) Haemoperitoneum=1.7% (3/180) Intra-abdominal haematoma=1.1% (2/180) Seroma formation=7.8% (14/180) Bowel obstruction=1.1% (2/180) Functional ileus=2.8% (5/180) Pleurisy=3.3% (6/180) Pancreatitis=0.6% (1/180) Two external reviewers independently reviewed the patient records. Procedures classified as radical surgery in this study fit the definition of ultraradical surgery used for this overview. Page 8 of 27

9 Abbreviations used: ASA, American Society of Anesthesiologists; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OR, odds ratio Study details Key efficacy findings Key safety findings Comments Chi DS (2009) 5 Number of patients analysed: 378 (210 Major complications versus 168) Infectious Non-randomised comparative study USA Recruitment period: Study population: patients with stage IIIC IV ovarian, tubal and peritoneal cancer n=378 (210 underwent primary surgery between 2001 and 2004 when a more comprehensive debulking of upper abdominal disease was used; 168 patients treated between 1996 and 1999 were controls) Age: median 60 years (range 25 95) Patient selection criteria: exclusion criteria included mucinous and carcinosarcoma histologies, nonepithelial cancers, low malignant potential tumours and patients who received neoadjuvant chemotherapy. Technique: pelvic and/or para-aortic lymphadenectomies were done at the discretion of the surgeon. Extensive upper abdominal surgery included diaphragm peritonectomy and/or resection, splenectomy, distal pancreatectomy, partial liver resection, cholecystectomy, and resection of tumour from the porta hepatis (performed only as necessary to achieve optimal cytoreduction). Follow-up: median 60 months Conflict of interest/source of funding: 2 authors were speakers for Genzyme and 1 also received research support from Plasma Surgical. Optimal cytoreduction Study group=80% (167/210) Control group=46% (78/168), p<0.01 No grossly visible residual disease Study group=27% (57/210) Control group=11% (19/168), p< year progression-free survival rates Study group=31% Control group=14% HR 0.76; 95% CI 0.60 to 0.95, p= year overall survival rates Study group=47% Control group=35% HR 0.76; 95% CI 0.59 to 0.99, p=0.03 Median overall survival Study group=54 months Control group=43 months, p=0.03 Study group=10% (21/210) Control group=4% (7/168), p=0.015 Gastrointestinal Study group=4% (8/210) Control group=2% (3/168) Haematological Study group=2% (5/210) Control group=0% (0/168) Cardiopulmonary Study group=2% (4/210) Control group=0.6% (1/168) Thromboembolic Study group=1% (3/210) Control group=2% (3/168) Perioperative mortality Study group=1% (2/210) Control group=0.6% (1/168) There is likely to be some patient overlap with Chi DS, 2010 and Eisenhauer EL, Study design issues: Retrospective study. Patients in the control group underwent primary cytoreduction between 1996 and Optimal cytoreduction was defined as residual tumour 1 cm. 38% (79/210) of patients in the study group had extensive upper abdominal procedures versus none in the control group. Study population issues: Baseline characteristics in the 2 groups were similar with regard to age, primary site of disease, stage of disease, tumour grade, median CA-125, median platelet count, and ASA class. There was a significantly higher proportion of serous tumours in the study group but this was not a significant prognostic factor on univariate analysis. A similar proportion of patients in the 2 groups completed chemotherapy regimen. Page 9 of 27

10 Abbreviations used: ASA, American Society of Anesthesiologists; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OR, odds ratio Study details Key efficacy findings Key safety findings Comments Chi DS (2010) 6 Number of patients analysed: % (31/141) of patients had grade3 5 complications within 30 days of surgery (significant complications leading to invasive radiological intervention, USA Recruitment period: reoperation, unplanned ICU admission, chronic disability, or death) Study population: patients undergoing extensive upper abdominal procedures during primary cytoreduction of advanced ovarian cancer n=141 Age: median 60 years (range 38 82) Patient selection criteria: all patients with stage IIIC and IV ovarian, fallopian tube, and peritoneal carcinoma who underwent extensive upper abdominal procedures during primary cytoreduction. Patients with nonepithelial cancer, low malignant potential tumours, and those who received neoadjuvant chemotherapy were excluded. Technique: extensive upper abdominal procedures included diaphragm peritonectomy and/or resection, splenectomy, distal pancreatectomy, partial liver resection, cholecystectomy, and resection of tumour from the porta hepatis. In addition to hysterectomy, oophorectomy, omentectomy and lymphadenectomy, the most common other surgical procedure was large bowel resection (56% of patients). Follow-up: median 38 months (range 3 68) Conflict of interest/source of funding: none Cytoreductive outcome: No gross residual disease=30% (42/141) Residual disease cm=60% (85/141) Residual disease >1 cm=10% (14/141) Median overall survival=57 months 5-year overall survival=49% Symptomatic pleural effusion needing drainage=8.5% (12/141) Pancreatic leak needing drainage=2.8% (4/141) Intra-abdominal collection needing drainage=2.1% (3/141) Bleeding needing return to operating room=2.1% (3/141) Aspiration pneumonia needing intubation=0.7% (1/141) Acute respiratory failure needing intubation=0.7% (1/141) Pneumothorax needing placement of chest tube=0.7% (1/141) Anastomotic leak needing drainage=0.7% (1/141) Gastrointestinal bleeding needing endoscopic evaluation=0.7% (1/141) Small bowel obstruction needing return to operating room=0.7% (1/141) Colostomy ischaemia=0.7% (1/141) Perforated duodenal ulcer*=0.7% (1/141) Acute cardiopulmonary failure*=0.7% (1/141) *Postoperative mortality=1.4% (2/141) There is likely to be some patient overlap with Chi DS, 2009 and Eisenhauer, Study design issues: Retrospective study. Other issues: 6% (9/141) of patients did not complete the prescribed course of postoperative chemotherapy because of the following reasons: death,4; lost to follow-up, 4; and intolerance, 1. Page 10 of 27

11 Efficacy Overall survival A non-randomised comparative study of 267 patients treated by ultra-radical or standard surgery reported no statistically significant difference in overall survival between the 2 groups in patients with optimal debulking (hazard ratio 1.37, 95% confidence interval 0.70 to 2.69, p=0.36) 1. A retrospective cohort study of 194 patients treated by ultra-radical surgery or standard surgery reported 5-year disease-specific overall survival rates for patients with optimal cytoreduction (n=131) of 46% and 47% respectively (p=0.80) 2. In the same study, 5-year disease-specific overall survival rates for patients with carcinomatosis who underwent optimal cytoreduction (n=82) were 44% and 17% respectively (p<0.001). A non-randomised comparative study of 262 patients treated by ultraradical or standard surgery reported median overall survival of 84 months for patients with optimal cytoreduction by standard surgery and 38 months for patients with suboptimal cytoreduction (p<0.001); median overall survival for patients with optimal cytoreduction by ultra-radical surgery had not been reached by 68 months 3. A non-randomised comparative study of 378 patients treated either before or after extensive upper abdominal surgery was introduced reported 5-year overall survival rates of 35% and 47% respectively (p=0.03) 5. Median overall survival was 43 months in patients treated before extensive upper abdominal surgery was introduced and 54 months in patients treated after (p=0.03). A case series of 141 patients treated by extensive upper abdominal procedures during primary cytoreduction reported 5-year overall survival of 49% 6. Progression-free survival The non-randomised comparative study of 262 patients treated by ultra-radical or standard surgery reported median progression-free survival of 24 months for patients with optimal cytoreduction with ultra-radical surgery, 23 months for patients with optimal cytoreduction by standard surgery and 11 months for patients with suboptimal cytoreduction (p<0.001) 3. The non-randomised comparative study of 378 patients treated either before or after extensive upper abdominal surgery was introduced reported 5-year progression-free survival rates of 14% and 31% respectively (p=0.01) 5. Safety Overall Major complications were reported in 19% (16/85) of patients treated by ultraradical surgery and 5% (5/95) of patients treated by standard surgery in a nonrandomised comparative study of 180 patients (p=0.013) 4. Major complications were reported in 12% of patients with optimal cytoreduction by ultra-radical surgery, 7% of patients with optimal cytoreduction by standard surgery and 8% of Page 11 of 27

12 patients with suboptimal cytoreduction, in the non-randomised comparative study of 262 patients 3. Perioperative mortality Perioperative mortality rates (period not specified) were 1% (2/210) for patients treated after the introduction of extensive upper abdominal surgery and less than 1% (1/168) for patients treated before the introduction of extensive upper abdominal surgery in the non-randomised comparative study of 378 patients day mortality rates were 3% (3/88) for patients with complete cytoreduction by ultra-radical surgery, 0% (0/38) for patients with complete cytoreduction by standard surgery and 6% (8/141) for patients with incomplete cytoreduction in the non-randomised comparative study of 267 patients day mortality was 1% (2/141) in the case series of 141 patients 6. One patient died within 30 days after surgery from multi-organ failure (presenting with necrotising pancreatitis on day 2) in the non-randomised comparative study of 180 patients; it is not clear whether she was treated by ultra-radical or standard surgery 4. Pleural effusion Symptomatic pleural effusion needing drainage was reported in 9% (12/141) of patients in the case series of 141 patients 6. Pancreatic leak Pancreatic leak needing drainage was reported in 3% (4/141) of patients in the case series of 141 patients 6. Intra-abdominal collection Intra-abdominal collection needing drainage was reported in 2% (3/141) of patients in the case series of 141 patients 6. Haemorrhage Bleeding needing a return to theatre was reported in 2% (3/141) of patients in the case series of 141 patients 6. Haematological complications (not otherwise defined) were reported in 2% (5/210) of patients treated after the introduction of extensive upper abdominal surgery and 0% (0/168) for patients treated before the introduction of extensive upper abdominal surgery in the non-randomised comparative study of 378 patients (p=not stated) 5. Infection Infectious complications (not otherwise defined) were reported in 10% (21/210) of patients treated after the introduction of extensive upper abdominal surgery and 4% (7/168) for patients treated before the introduction of extensive upper Page 12 of 27

13 abdominal surgery in the non-randomised comparative study of 378 patients (p=0.015) 5. Validity and generalisability of the studies It was difficult to select relevant studies for inclusion because few studies use the term ultra-radical surgery. Studies have been selected for inclusion in table 2 where the intervention fits the definition of ultra-radical surgery, as described in the procedure description of this overview. There are no randomised controlled trials comparing ultra-radical surgery against standard surgery with intention-to-treat analysis. All the studies included in table 2 are retrospective and are subject to bias. One study only included patients with stage IIIC ovarian cancer so the results may not be representative of all patients with advanced stage disease 2. In 1 non-randomised comparative study, patients treated during 2 time periods were compared; in the later period, the surgical paradigm was changed to include extensive upper abdominal procedures 5. Not all patients treated during the later period had extensive upper abdominal surgery. One study included resection of sigmoid colon as standard surgery 1. Existing assessments of this procedure There were no published assessments from other organisations identified at the time of the literature search. Related NICE guidance Below is a list of NICE guidance related to this procedure. Appendix B gives details of the recommendations made in each piece of guidance listed. Interventional procedures Cytoreduction surgery followed by hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis. NICE interventional procedure guidance 331 (2010). Complete cytoreduction for pseudomyxoma peritonei (Sugarbaker technique). NICE interventional procedure guidance 56 (2004). Page 13 of 27

14 Clinical guidelines Ovarian cancer: the recognition and initial management of ovarian cancer. NICE clinical guideline 122 (2011). Technology Appraisals Guidance on the use of paclitaxel in the treatment of ovarian cancer. NICE technology appraisal 55 (2003). Ovarian cancer (advanced) - paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan (review). NICE technology appraisal 91 (2005). Trabectedin for the treatment of relapsed ovarian cancer. NICE technology appraisal 222 (2011). Specialist Advisers opinions Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. The advice received is their individual opinion and does not represent the view of the society. Miss A Olaitan (Royal College of Obstetricians and Gynaecologists). The Specialist Adviser performs the procedure regularly. The procedure is established practice and no longer new. Anecdotal adverse events include pneumothorax, injury to large blood vessels, bowel, urinary tract, and nerves. Key efficacy outcomes include better patient survival. There are uncertainties about the efficacy of the procedure because there are insufficient data to support the benefits. The procedure needs extensive surgical training. The potential impact of this procedure on the NHS is minor, in terms of numbers of patients eligible for treatment and use of resources. Patient Commentators opinions NICE s Patient and Public Involvement Programme sent xxx questionnaires to xxx trusts for distribution to patients who had the procedure (or their carers). NICE received xxx completed questionnaires. Page 14 of 27

15 Section to be inserted where Patient Commentary was not gathered NICE s Patient and Public Involvement Programme was unable to gather patient commentary for this procedure. Section to be inserted where Patient Commentators raised no new issues The Patient Commentators views on the procedure were consistent with the published evidence and the opinions of the Specialist Advisers. Section to be inserted where Patient Commentators raised new issues The Patient Commentators raised the following issues about the safety/efficacy of the procedure which did not feature in the published evidence or the opinions of Specialist Advisers, and which the Committee considered to be particularly relevant: [insert additional efficacy and safety issues raised by Patient commentators and highlighted by IPAC, add extra rows as necessary]. [Last item in list]. Issues for consideration by IPAC None other than those described above. Page 15 of 27

16 References 1. Kommoss S, Rochon J, Harter P et al. (2010) Prognostic impact of additional extended surgical procedures in advanced-stage primary ovarian cancer. Annals of Surgical Oncology 17: Aletti GD, Dowdy SC, Gostout BS et al. (2006) Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstetrics & Gynecology 107: Eisenhauer EL, Abu-Rustum NR, Sonoda Y et al. (2006) The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian cancer. Gynecologic oncology 103: Rafil A, Stoeckle E, Jean-Laurent M et al. (2012) Multi-center evaluation of post-operative morbidity and mortality after optimal cytoreductive surgery for advanced ovarian cancer. PLoS ONE 7: e Chi DS, Eisenhauer EL, Zivanovic O et al. (2009) Improved progressionfree and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecologic Oncology 114: Chi DS, Zivanovic O, Levinson KL et al. (2010) The incidence of major complications after the performance of extensive upper abdominal surgical procedures during primary cytoreduction of advanced ovarian, tubal, and peritoneal carcinomas. Gynecologic oncology 119: Page 16 of 27

17 Appendix A: Additional papers on ultra-radical (extensive) surgery for advanced ovarian cancer The following table outlines the studies that are considered potentially relevant to the overview but were not included in the main data extraction table (table 2). It is by no means an exhaustive list of potentially relevant studies. Article Number of patients/ follow-up Direction of conclusions Reasons for non-inclusion in table 2 Aletti GD, Dowdy SC, Podratz K et al. (2007) Relationship among surgical complexity, short-term morbidity, and overall survival in primary surgery for advanced ovarian cancer. American Journal of Obstetrics & Gynecology 197: n=219 Despite the increased risk of complications, more complex surgery carried a survival benefit in all the risk groups No separate results for ultraradical surgery. Ang C, Chan KKL, Bryant A et al. (2011).Ultra-radical (extensive) surgery versus standard surgery for the primary cytoreduction of advanced epithelial ovarian cancer. Cochrane Database of Systematic Reviews, Issue 4. DOI: / CD pub2 Systematic review n=1 study (194 patients) The evidence suggested that ultra-radical surgery may result in better survival. It was unclear whether there were any differences in progression-free survival, QoL and morbidity between the two groups. The one study that was included has been summarised in table 2 (Aletti et al, 2006) Chi DS, Eisenhauer EL, Lang J et al. (2006) What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecologic Oncology 103: n=465 Median followup=38 months Removal of all macroscopic disease is associated with prolonged survival and should be the goal of primary cytoreductive surgery. A more relevant study from the same centre is included (Chi et al, 2010) Chi DS, Franklin CC, Levine DA et al. (2004) Improved optimal cytoreduction rates for stages IIIC and IV epithelial ovarian, fallopian tube, and primary peritoneal cancer: a change in surgical approach. Gynecologic Oncology 94: Nonrandomised comparative study n=140 The use of extensive upper abdominal surgical procedures significantly increased the rate of optimal primary cytoreduction. A more recent study from the same centre is included (Chi et al, 2010). Colombo PE, Mourregot A, Fabbro M et al. (2009) Aggressive surgical strategies in advanced ovarian cancer: a monocentric study of 203 stage IIIC and IV patients. European Journal of Surgical Oncology 35: n=203 The survival of patients with advanced ovarian cancer is mainly influenced by 3 factors: Extent of disease at diagnosis Biology of tumour and its chemosensitivity Size of residual disease after surgery The main aim of the study was to evaluate the place of surgery in the therapeutic sequence. Page 17 of 27

18 Article Number of patients/ follow-up Direction of conclusions Reasons for non-inclusion in table 2 Crawford SC, Vasey PA, Paul J et al. (2005) Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an international comparison within the SCOTROC-1 Trial. Journal of Clinical Oncology 23: n=1077 Increased progression-free survival associated with optimal surgery is limited to patients with less advanced disease, arguing for case selection rather than aggressive debulking in all patients irrespective of disease extent. Lymphadenectomy may have beneficial effects on progression-free survival in optimally debulked patients. Results are not presented separately for ultra-radical surgery. Domingo S, Gurrea M, Pellicer A (2011) How to improve the optimal cytoreductive surgery in advanced ovarian carcinoma. Gynecological Surgery 8: Review To improve the cytoreductive rates in the actual management strategy, a change is necessary, selecting the cases not suitable for primary debulking surgery and adding, if necessary, procedures different than the ovarian tumour resection, like bowel resections, peritonectomies (particularly diaphragmatic ones) and splenectomies. No metaanalysis. Eisenkop SM, Spirtos NM, Lin WCM (2006) Splenectomy in the context of primary cytoreductive operations for advanced epithelial ovarian cancer. Gynecologic Oncology 100: n=49 The need for splenectomy to achieve complete cytoreduction is a reflection of advanced disease but is not a manifestation of tumour biology precluding long-term survival. Small case series Eisenkop SM, Spirtos NM. (2001) Procedures required to accomplish complete cytoreduction of ovarian cancer: Is there a correlation with biological aggressiveness and survival? Gynecologic Oncology 82: n=213 The need to remove a large number of peritoneal implants correlates with biological aggressiveness and diminished survival, but not significantly enough to preclude long-term survival or justify abbreviation of the operative effort. More recent studies are included. Gerestein CG, Nieuwenhuyzen-de Boer GM, Eijkemans MJ et al. (2010) Prediction of 30-day morbidity after primary cytoreductive surgery for advanced stage ovarian cancer. European Journal of Cancer 46: n=293 Followup=30 days 30-day morbidity was seen in 99 (34%) patients 30-day morbidity could be predicted by age, WHO performance status, operative time and extent of surgery. Only a proportion of patients were treated by ultra-radical surgery. Guidozzi F, Ball JH (1994) Extensive primary cytoreductive surgery for advanced epithelial ovarian cancer. Gynecologic oncology 53: n=30 Followup=5 years 43% of patients developed serious postoperative complications. 1-year survival=76% (23/30) 5-year survival=23% (7/30) Small case series. Page 18 of 27

19 Article Number of patients/ follow-up Direction of conclusions Reasons for non-inclusion in table 2 Hockel M. (2006) Ultra-radical compartmentalized surgery in gynaecological oncology. European Journal of Surgical Oncology 32: n=74 At a median follow-up period of 29 months (1-112 months) 5- year overall and recurrence-free survival probabilities are 56% (95% CI: 42-69) and 56% (42-70) Small case series. Ultra-radical compartmentalized pelvic surgery may salvage selected patients with locally advanced and recurrent gynaecologic malignancies including those with pelvic side wall disease traditionally not considered for surgical therapy. Hoffman MS, Zervose E (2008) Colon resection for ovarian cancer: intraoperative decisions. Gynecologic oncology 111: S56 65 Review The preponderance of data suggests that colon resection to achieve optimal cytoreduction has a positive impact on survival. No metaanalysis. Kuhn W, Florack G, Roder J et al. (1998) The influence of upper abdominal surgery on perioperative morbidity and mortality in patients with advanced ovarian cancer FIGO III and FIGO IV. International Journal of Gynecological Cancer 8: Nonrandomised comparative study n=107 Resection of tumourous diaphragmatic peritoneum suggests that survival improves if complete tumour removal is feasible. Other forms of upper abdominal surgery, including splenectomy and partial pancreatic resection, have a high rate of morbidity and mortality and probably no benefit in terms of survival. Therefore the risk-benefit ratio of these latter procedures has to be evaluated separately in each case. Larger studies are included. Lim MC, Kang S, Song YJ et al. (2010) Feasibility and safety of extensive upper abdominal surgery in elderly patients with advanced epithelial ovarian cancer. Journal of Korean Medical Science 25: n=137 Median followup=38 months Optimal cytoreduction was feasible in 87.5% of the elderly while 95.2% of young patients were optimally debulked (p=0.237). Within the cohort, the complication profile was not significantly different between the young and the elderly, except for pleural effusion and pneumothorax (p=0.028) The main focus of the study was to assess the feasibility and safety of extensive upper abdominal surgery in the subset of elderly patients. Magtibay PM, Adams PB, Silverman MB et al. (2006) Splenectomy as part of cytoreductive surgery in ovarian cancer. Gynecologic oncology 102: n=112 Median followup=17 months In patients with clinically significant upper abdominal disease, splenectomy as part of primary or secondary cytoreductive surgery is associated with modest morbidity and mortality. The risk-benefit ratio of aggressive surgical cytoreduction must be considered. A larger case series is included. Page 19 of 27

20 Article Number of patients/ follow-up Direction of conclusions Reasons for non-inclusion in table 2 Manci N, Bellati F, Muzii L et al. (2006) Splenectomy during secondary cytoreduction for ovarian cancer disease recurrence: surgical and survival data. Annals of Surgical Oncology 13: n=24 Median followup=30 months Median progression-free and overall survival from the time of secondary surgery were 34 and 56 months, respectively. Splenectomy as part of secondary cytoreduction is a feasible and safe procedure. Small case series. Michel G, De Iaco P, Castaigne D et al. (1997) Extensive cytoreductive surgery in advanced ovarian carcinoma. European Journal of Gynaecological Oncology 18: 9 15 n=152 2-year survival rate was 80% in the absence of residual tumour versus 22% when the residuum exceeded 2 cm in diameter. Only a proportion of patients were treated by ultra-radical surgery. Peiretti M, Zanagnolo V, Aletti G et al. (2010) Role of maximal primary cytoreductive surgery in patients with advanced epithelial ovarian and tubal cancer: Surgical and oncological outcomes. Single institution experience. Gynecologic oncology 119: n=259 Median followup=30 months A more extensive surgical approach is associated with prolonged disease-free interval and improved survival in patients with stages IIIC-IV epithelial ovarian and fallopian tube cancer. Moreover all patients with no residual tumour seem to have the best prognosis. Only a proportion of patients were treated by ultra-radical surgery. Revaux A, Rouzier R, Ballester M et al. (2012) Comparison of morbidity and survival between primary and interval cytoreductive surgery in patients after modified posterior pelvic exenteration for advanced ovarian cancer. International Journal of Gynecological Cancer 22: n=63 The specific morbidity of this surgical procedure remained low compared with the overall morbidity in cases of extensive surgery. There were no significant differences in survival between primary and interval surgery. Small case series. Sonnendecker EW, Guidozzi F, Margolius KA (1989) Splenectomy during primary maximal cytoreductive surgery for epithelial ovarian cancer. Gynecologic oncology 35: n=6 Three patients (50%) currently have no evidence of disease 14, 25, and 32 months after surgery. The remaining 2 patients died of recurrent disease 19 and 58 months following primary operation. Small case series Tsoloakidid D, Amant F, Van Gorp K et al. (2010) Diaphragmatic surgery during primary debulking in 89 patients with stage IIIB IV epithelial ovarian cancer. Gynecologic Oncology 116: Nonrandomised comparative study n=89 Diaphragmatic surgery increases the rates of optimal primary debulking surgery and improves survival with an acceptable and manageable morbidity rate. Larger studies are included. van Dam PA, Tjalma W, Weyler J et al. (1996) Ultraradical debulking of epithelial ovarian cancer with the ultrasonic surgical aspirator: a prospective randomized trial. American Journal of Obstetrics & Gynecology 174: RCT (ultraradical surgery with or without the use of an ultrasonic surgical aspirator) n=40 Cavitational ultrasonic surgical aspirator-assisted cytoreductive surgery of advanced ovarian carcinoma is more effective in eradicating disease and reduces morbidity. Disease-free and overall survival were similar in the 2 groups. Small RCT comparing ultraradical surgery with or without use of an ultrasonic surgical aspirator. Page 20 of 27

21 Article Number of patients/ follow-up Direction of conclusions Reasons for non-inclusion in table 2 Wimberger P, Lehmann N, Kimmig R et al. (2007) Prognostic factors for complete debulking in advanced ovarian cancer and its impact on survival. An exploratory analysis of a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecologic Oncology 106: RCT (different chemotherapy regimens) n=761 Surgery in centres with surgeons who performed comprehensive surgical debulking including retroperitoneal lymphadenectomy and peritoneal stripping was associated with higher rates of complete debulking compared to surgery in other centres (32.8% versus 22.9%, p=0.007). This resulted in a markedly improved overall survival (p=0.045). Comparative groups included patients who had both types of surgery. Page 21 of 27

22 Appendix B: Related NICE guidance for ultra-radical (extensive) surgery for advanced ovarian cancer Guidance Interventional procedures Recommendations Cytoreduction surgery followed by hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis. NICE interventional procedure guidance 331 (2010). 1.1 Current evidence on the efficacy of cytoreduction surgery (CRS) followed by hyperthermic intraoperative peritoneal chemotherapy (HIPEC) for peritoneal carcinomatosis shows some improvement in survival for selected patients with colorectal metastases, but evidence is limited for other types of cancer. The evidence on safety shows significant risks of morbidity and mortality which need to be balanced against the perceived benefit for each patient. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. 1.2 Clinicians wishing to undertake CRS followed by HIPEC for peritoneal carcinomatosis should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy in relation to the potential morbidity and mortality and the prolonged recovery period, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having CRS followed by HIPEC for peritoneal carcinomatosis (see section 3.1). 1.3 Patient selection and treatment should be carried out in the context of a multidisciplinary team, including oncologists and surgeons with experience in this operation. 1.4 NICE encourages further research into this procedure which should take the form of randomised controlled trials (RCTs) with clear descriptions of patient selection criteria and the types of cancer being treated. The chemotherapy regimens used should be well defined. Outcome measures should include survival and quality of life. Complete cytoreduction for pseudomyxoma peritonei (Sugarbaker technique). NICE interventional procedure guidance 56 (2004). 1.1 Current evidence on the safety and efficacy of complete Page 22 of 27

23 cytoreduction for pseudomyxoma peritonei does not appear adequate for this procedure to be used in the NHS outside centres funded by the National Specialist Commissioning Advisory Group (NSCAG). 1.2 Clinicians wishing to undertake complete cytoreduction for pseudomyxoma peritonei should take the following action. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. Use of the Institute's information for the public is recommended. Audit and review clinical outcomes of all patients having complete cytoreduction for pseudomyxoma peritonei. 1.3 Publication of safety and efficacy outcomes will be useful in reducing the current uncertainty. The Institute may review the procedure upon publication of further evidence. 1.4 These recommendations apply only to the use of this technique to treat pseudomyxoma peritonei. The Institute will consider complete cytoreduction for peritoneal carcinomatosis separately. Clinical guidelines Ovarian cancer: The recognition and initial management of ovarian cancer. NICE clinical guideline 122 (2011). 1.4 Management of advanced (stage II IV) ovarian cancer Note that recommendations 1.1 and 1.2 in NICE technology appraisal guidance 55 ('Guidance on the use of paclitaxel in the treatment of ovarian cancer') are on first-line chemotherapy in the treatment of ovarian cancer Primary surgery If performing surgery for women with ovarian cancer, whether before chemotherapy or after neoadjuvant chemotherapy, the objective should be complete resection of all macroscopic disease Intraperitoneal chemotherapy Do not offer intraperitoneal chemotherapy to women with ovarian cancer, except as part of a clinical trial. Technology appraisals Guidance on the use of paclitaxel in the treatment of ovarian cancer. NICE technology appraisal 55 (2003) 1.1 It is recommended that paclitaxel in combination with a platinum-based compound or platinum-based therapy alone (cisplatin or carboplatin) are offered as alternatives for firstline chemotherapy (usually following surgery) in the treatment of ovarian cancer. 1.2 The choice of treatment for first-line chemotherapy for ovarian cancer should be made after discussion between the Page 23 of 27