Ovarian cancer: Surgery, when and how preferably? P. Mathevet CHUV, UNIL

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1 Ovarian cancer: Surgery, when and how preferably? P. Mathevet CHUV, UNIL

2 Ovarian tumor context More than 70% of cases are diagnosed at an advance stage (stage IIIC-IV). The extension occurs through the peritoneum leading to implants on the serosa of different organs, but frequently invades also deeply. The performance of a complete surgery (R0) is the essential prognostic factor.

3 Ovarian tumors (OT) context Important interest in a screening tool in the general population : Large ongoing studies with CA 125 dosage and then pelvic sonography: PLSO ( cases) and UKCTOCS ( cases). Preliminary results = > 30% of OT are missed and the number of stage I or II screened are reduced. Current development of genomic and proteomic markers. Main limit for screening = natural history of OT. 2 different biological models of OT: 1 very aggressive tumor with major peritoneal extension since the initial steps of the disease. And 1 less aggressive tumor remaining at stage I even in case of large ovarian masses..

4 Dissemination IIIC 70% des cas

5 Early ovarian cancer (stage I-II) Surgery is the primary treatment: Hysterectomy + bilateral adnexectomy + peritoneal washing + pelvic and para-aortic lymph-node dissection + resection of the omentum and all abnormal peritoneal lesions. Rare cases of fertility preservation (stage IA grade 1 ovarian cancer). Chemotherapy is usually performed as adjuvant treatment.

6 Advanced ovarian cancer (stage III-IV) Which type of surgery.. Surgery with complete tumoral resection Notion of residual tumor Multi-organ surgery Therapeutic sequence: surgery/ chemotherapy Primary surgery Interval surgery Which surgeon... (after 3 or 4 courses, followed by 3 other courses) Coherence between objectives and competences

7 Which type of surgery?

8 Which type of surgery: History Meigs 1934: -Introduction of the concept of cytoreductive surgery Griffith 1975: -Inverse relation between the tumoral residue and the survival. -Improved prognostic if tumoral residue is 1,5 cm. -Introduction of the concept of optimal tumoral resection.

9 Surgery of advanced OT. The most important prognostic factor is complete resection of all tumoral implants (Cochrane Data Base 2011). Does an ultraradical surgery (multiple visceral resections) is required to obtained this complete resection? Which benefit from lymph-node dissections?

10 Complete resection in advanced OT Méta-analysis 81 studies, from 1989 to 1998, patients Results Tumoral residue - only independent prognostic factor Each +10% R0 is associated with a 5.5% increase in median OS - Studies with <25% of optimal surgery, median OS = 24 mois - Studies with >75% of optimal surgery, median OS = 34 mois Bristow R et al, JCO 2002

11 Survival impact of complete cytoreduction to no gross residual disease for advanced-stage ovarian cancer: A meta-analysis 18 relevant studies analyzed each 10% increase in the proportion of patients undergoing complete cytoreduction to no gross residual disease was associated with a significant and independent 2.3 month increase in cohort median survival compared to a 1.8 month increase in cohort median survival for optimal cytoreduction (residual disease 1cm). Chang SJ Gynecol Oncol. 2013

12 Advanced OT: complete resection Modification of the surgical approach: Group 1: , (n = 168 patients) Pelvic optimal surgery (45% optimal R <1cm) Group 2: , (n = 210 patients) Results Pelvic and sus mesocolic optimal surgery (80% R optimal) Both groups well balanced 5 years survival Group 2 > Group 1 OS: Group 2 = 47% Vs Group 1 = 35% RFS: Group 2 = 31% Vs Group 1= 14% (p<0,01) Chi DS, et al, Gynecol Oncol 2009

13 Ultra-radical surgery in advanced ovarian cancer Morbidity quite high (A prospective French study on 180 patients comparing standard and ultraradical surgery, PloS 2012): 1 post-operative death. 25 % major complications requiring a new surgery in the ultra-radical group vs 4% with standard surgery. The benefits of an ultra-radical surgery has not been demonstrated (Cochrane Data Base 2011)

14 Interest of lymph-node dissections in stage IIIC OT A randomized study from Italy (Benedetti- Panici P, et al., J Natl Cancer Inst. 2005): No benefit in OS, small benefit in RFS. Induce an increase in morbidity. Large multicentric studies ongoing, in France=CARACO, in Deutschland=LION

15 Which therapeutic sequence? Surgery or chemotherapy first?

16 Rational for primary surgery Reducing the risk of apparition of chemoresistant cellular clones The large tumoral masses have a reduced vascularization and are less sensitive to chemotherapy. The proliferating index, is more important in the small tumoral masses so they are more sensitive to chemotherapy. The small tumor volumes require less chemotherapy cycles. Reducing the tumoral masses and eliminating the ascites improve the health of the patient. Tropé, EJSO 2006

17 Rational for primary chemotherapy The benefit of primary surgery has not been demonstrated through a randomized study. The possibilities of optimal resection are probably correlated to the biological characteristics of the tumors. The ultra-radical surgery is associated with an important morbidity. This may induce delay in the initiation of the chemotherapy. Limited survival benefit of primary surgery if the resection is incomplete.

18 Interval surgery Experience from Lyon D. Benayoun Thesis 96 patients stage IIIc-IVa from 1999 to cases of interval surgery as they were deemed initially non operable on a R0 goal (A group) 52 cases of primary surgery (B group) All cases treated with Carbo+Taxol

19 Interval surgery: Lyon s experience D. BenayounThesis

20 Interval surgery: Lyon s experience D. BenayounThesis

21 Interval surgery (Vergote 2010, NEJM 2010) Randomized study between primary maximal surgical effort and interval surgery after 3-4 courses of neo-adjuvant chemotherapy. Stage IIIC-IV (pleural effusion). 670 patients randomized: 336 patients with primary surgery 334 patients with interval surgery From 1998 to 2006 in 59 European or Canadian centers.

22 Interval surgery (Vergote 2010, NEJM 2010) Median surgery time (minutes) Primary surgery = 165 min (10-720) Interval surgery = 180 min (30-560) Median surgery time (minutes) for the R0 patients: Primary surgery = 312 min Interval surgery = 194 min

23 Interval surgery (Vergote 2010, NEJM 2010) Complications Interval surgery Post-op death Primary surgery 2.5 % Hemorrhage gr % 4.1 % Infection gr % 1.7 % Fistula 1.3 % 0.6 % Thrombo-embolism gr % 0% 0.7 %

24 Interval surgery Improved cytoreduction efficiency. According to Vergote: 41.6% of optimal surgery (residue <1cm) in the primary surgery group vs 80.7% in the interval surgery group. 19.4% complete surgery (R0) in the primary surgery group vs 50.2% in the interval surgery group.

25 Interval surgery (Vergote 2010)

26 Interval surgery (Vergote 2010)

27 Interval surgery (Vergote 2010) Vergote I et al, NEJM 2010

28 Interval surgery. Reduced surgical morbidity related to more limited surgery: Less risk of bleeding, Less risk of thrombo-embolism, Less fistula, Less operating time, Reduced mortality, Not delay in the initiation of chemotherapy, Comparable therapeutic efficacy.

29 Interval surgery Assesses tumor chemosensitivity: 80 to 90% of OT stage III-IV are sensitive to Taxol + Carbo. But 10-20% are refractory and a second line chemotherapy is used to test their sensitivity to other drugs. Moreover, the interest of a maximalist surgery in these patients is probably nil.

30 Interval surgery. Importance of initial staging. Contribution of laparoscopy. Abdominal exploration of good quality. Quality assessment of tumor resectability (score Fagotti...). Biopsy for histological precise diagnostic. The histological type may impact on the therapeutic approach.

31 R0: probably possible

32 Advanced OT: peritonectomie Diaphragmatic resection

33 R0: probably not possible

34 R0: probably possible

35 R0: probably not possible

36 Advanced OT: Omentum and transverse colon +/- splenectomy.

37 Laparoscopic Fagotti s score Study of 7 parameters: omental cake" peritoneal carcinomatosis, diaphragmatic carcinomatosis, mesenteric retraction, infiltration of the bowel, infiltration of the stomach, and liver metastases. Each parameter has a value of 0-2. A score 8 is predictive of incomplete surgery.

38 Interval surgery Limitations of this approach: In theory, neoadjuvant chemotherapy (even if it is effective) can select resistant clones and be unfavorable. May delay a complete surgery that was feasible primary.

39 Which therapeutic sequence Start by assessing the quality of the resection. Tools: clinic: condition, operability CT: Bristow s score PET-CT: search for extra abdominal lesions laparoscopy: Fagotti score pretreatment evaluation by an experienced team If fully resectable: first surgery

40 Which therapeutic sequence If the tumor is fully resectable (= R0) without too much visceral organic resections = primary surgery should be done. If there is a risk of incomplete or too much aggressive surgery = chemotherapy should be used first and then interval surgery.

41 Which surgeon?

42 Which surgeon? A competent and trained surgeon whatever is its formation (general surgeon, gynecologic oncologist.). Working in a team with expert oncologist.

43 Surgeon and survival Scottish National Cancer Registry, N=1866 Junor, BJOG 1999

44 Which surgeon?

45 The Ugly Makes the surgery a disaster with long recovery

46 The Bad Lying concerning the quality of the resection he made

47 The one, you are working with or the one you would be

48 Which surgeon? A competent and trained surgeon whatever is formation (general surgeon, gynecologic oncologist.). Working in a team with expert oncologist.

49 Site of treatment and survival Norwegian Cancer Registry, N=198 (year 2002) TH: teaching hospital NTH: non teaching hospital Paulsen, Int J Gynecol Cancer, 2006

50 Bristow RE, Gynecol Oncol 2012 Based on National Cancer Data Base. OS was correlated with hospital case volume: very high (>35 cases a year) = reference; high (21-35 cases) = HR 0.98, 95% CI= ; intermediate (9-20 cases) = HR 1.08, 95% CI= ); and low (< ç cases) = HR 1.14, 95% CI=

51 Conclusion For advanced OT we should consider the evaluation of the best possible treatment sequence. Meigs is obsolete! Traditionally, surgery was the first and important therapeutic tool. The increase effectiveness of new chemotherapy protocols, should lead to integrate them in a preferential place in advanced ovarian cancer.

52 New treatments in OT