Surgery in Stage IIb-IV Ovarian Carcinoma Ignace Vergote University Hospitals Leuven, European Union VVOG Eerste Jaarvergadering 2009 AIOM 2000

1-A 1: Is there a need to strictly define the extent and type of surgery for patients in first-line trials? Tissue should be obtained for histopathologic diagnosis to confirm the presence of primary ovarian or peritoneal carcinoma. Staging should be performed according to FIGO guidelines. For example, this includes at least lymph node sampling and peritoneal staging in early stage invasive disease (FIGO I – IIA). Up-front maximal surgical effort at cytoreduction with the goal of no residual disease should be undertaken. When cytoreductive surgery is not possible initially, it should be considered in patients who do not have progressive disease after 3 to 5 cycles of chemotherapy. Patients with ovarian cancer should have their surgery performed by an appropriately trained surgeon with experience in the management of ovarian cancer. Level of Acceptance: 13 / 13

TOTAL RESIDUAL TUMOR LOAD Stage III – Vergote Gyn Oncol 1998 < 1g: no visible residual tumor 1 - 10g: less than 10 residual lesions of < 1 cm

Systematic Pelvic and Paraaortic Lymphadenectomy in Ovarian Cancer Stage Number + ve Pelvic + ve PA - ve PA - ve Pelvic II 7 3 (43%) 1 (14%) III 67 34 (51%) 9 (13%) IV 11 8 (73%) 1 (9%) Burghardt E et al. Gynecol Oncol 1990; 40: 103 – 106.

Randomized Prospective Study of the Role of Lymphadenectomy Stage III – IVA Epithelial Ovarian Cancer Intraperitoneal residual tumor < 1 cm Pelvic and paraaortic lymphadenectomy Resection of bulky nodes 6 cycles of PC or PT Second-look optional Benedetti-Panici J Nat Cancer Inst 2005; 97: 1-6

LYMPHADENECTOMY FOR ADVANCED OVARIAN CANCER Overall Survival 1 2 3 4 5 0.0 0.2 0.4 0.6 0.8 1.0 Overall Survival Years from Randomization Lymphadenectomy No Lymphadenectomy P = 0.768 Events Totals 99 211 103 216

CHARACTERISTICS Benedetti-Panici JNCI 2005 Characteristic Control % Lymphadenectomy % (N=211) (N=216) Median Age 56 yr 53 yrs FIGO stage IIIB 17.5 19.0 IIIC 76.8 76.9 IVA 5.7 4.2 Residual disease None 37.4 37.0 < 1 cm 55.9 60.2 1-2 cm 5.7 1.9 Missing data 0.9 0.9

AGO – OVAR OP.3 (LION) Lymphadenectomy In Ovarian Neoplasms R n = 640 epithelial invasive ovarian cancer FIGO IIB - IV ECOG 0/1 and no CI against LNE no visible extra- and intra-abdominal tumor residuals no bulky lymph nodes System. Lymphadenectomy pelvic para-aortic R n = 640 no Lymphadenectomy Endpoints: OS, PFS, QoL Strata: centre, PS ,age

Neoadjuvant or primary debulking Neoadjuvant or primary debulking? Ovarian carcinoma Stage II-IV Leuven Series 1993- 2003 (n = 288) Median survival 56 months < 1 cm No residual tumor Primary debulking (n = 192) 86% 78% Interval debulking (n = 96) 79% TOTAL Vergote et al, IGCS 2004

Indications for neoadjuvant chemotherapy Leuven Policy 1993 - 2008: 15% IIIc-IV 1. Tumors larger than 2 cm around the superior mesenteric artery or behind the porta hepatis, or 2. Intrahepatic (multiple) metastases or several extraabdominal metastases (excluding resectable inguinal or supraclavicular lymph nodes) larger than 2 cm , or 3. Poor general condition (e.g. > 80 years) making a “maximal surgical effort” to no residual tumor impossible, or 4. Extensive serosal invasion (e.g. plaques) of the intestines necesitating bowel resections of > 1.5 m

Extraperitoneal hysterectomy with resection of pelvic peritoneum

Liver AIOM 2000

Pleura AIOM 2000

Lung AIOM 2000

Optimal Cytoreduction Rates for Advanced Ovarian Cancer at MSKCC

Advanced Ovarian Cancer Median Survival: 1975 - 2008 Memorial Sloan Kettering Cancer Centre 80 60 months 40 20 1975 1983 1986 1996 1998 2003 2006 Alkeran multi-drug cisplatin paclitaxel IP therapy

IGCS Meeting October 25th Bangkok Randomised trial comparing primary debulking surgery (PDS) with neoadjuvant chemotherapy (NACT) followed by interval debulking (IDS) in stage IIIC-IV ovarian,fallopian tube and peritoneal cancer.

Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tuba or peritonal cancer FIGO stage IIIc-IV (n = 718) Randomisation Primary Debulking Surgery Neoadjuvant chemotherapy 3 x Platinum based CT 3 x Platinum based CT Interval debulking (not obligatory) Interval debulking if no PD > 3 x Platinum based CT > 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications

Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical findings and results (PP1) Metastases before > 2 cm 95% 68% Metastases before > 10 cm 62% 27% No residual after surgery 21% 53% ≤ 1 cm after surgery 46% 82% Unknown substracted. * % calculated on the 306 patients who underwent IDS.

Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS ≤ 1cm residual per country (PP1) Total PDS (n = 329) NACT -> IDS (n = 339)* Difference PDS-IDS Belgium (n=133) 83% 72% 94% 22% Argentina (n=48) 71% 68% 74% 6% The Netherlands (n=104) 59% 40% 77% 37% Sweden (n=23) 75% 35% Norway (n=82) 55% 73% 38% Italy (n=38) 52% 64% 34% Spain (n=62) 49% 44% 58% 14% UK (n=101) 47% 63% Canada (n=84) 29% Unknown substracted in PDS - IDS arm nog te corrigeren in PP1 voor IDS in primaire arm. Totaal voor unknown nog te corrigeren.

Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical characteristics (PP1) Postoperative mortality (< 28 days) 2,7% 0,6% Postoperative fever G3-4 8% 2% Fistula (bowel/GU) 1,2% / 0,3% 0,3% / 0,6% Operative time (minutes) 0/1-10mm/> 10 mm 180 300/190/120 199/180/140 Red blood cell transfusion 51% 53% Hemorhage Grade 3/4 7% 1% Venous Gr 3/4 2,4% 0,3% Range operation time to te voegen. Hospitalisatieduur? Tijd van randomisatie tot PDS of NACT. Omit red blood cell transfusion in slide?

NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14)

NACT + IDS versus PDS: PP1 Please check in multivariate analysis whether high optimal debulking (per country) rate predicts for OS.

NACT + IDS versus PDS: PP1 Please check in multivariate analysis whether high optimal debulking (per country) rate predicts for OS. < 5 cm : hazard ratio: 0.74; 95% confidence intervals 0.52-1.05

Multivariate analysis for OS(PP1) P values Optimal (no residual) debulking 0.0001 Histological type (9 categories) 0.0003 Largest tumor size at randomisation 0.0008 Figo Stage (IIIc vs IV) Country (14 categories) 0.0014 Age 0.0020 WHO PS NS Differentiation Grade Treatment arm Largest tumour size, age, FIGO stage and country are strong independent prognostic factors. The prognosis deteriorates with larger tumour size, older age and FIGO stage IV Differentiation grade and histologic type are competing prognostic factors. ordered from best to worst: mixed, endometrioid, serous, undifferentiated, mucinous and clear cell WHO PS is significant as a univariate factor. Its effect is absorbed mainly but not exclusively through Age). Treatment arm is not at all a prognostic factor.

Criticisms/Questions on 55971 in Bangkok Why still stressing the importance of optimal debulking ( = no residual tumor)? Multivariate analysis And … Does no residual at IDS have the same impact as at PDS?

Optimal Debulking and treatment arm: PP1 Optimal = no residual tumor Suboptimal = 1-10 mm residual Other > 10 mm PDS = primary debulking surgery NACT = neoadjuvant chemotherapy Please check in multivariate analysis whether high optimal debulking (per country) rate predicts for OS.

PDS vs PDS+IDS vs IDS: ITT Please check in multivariate analysis whether high optimal debulking (per country) rate predicts for OS.

PDS vs PDS+IDS vs IDS: ITT Please check in multivariate analysis whether high optimal debulking (per country) rate predicts for OS.

Criticisms/Questions on 55971 in Bangkok Why still stressing the importance of optimal debulking ( = no residual tumor)? Does no residual at IDS have the same impact as at PDS? The optimal debulking rate was too low, but No effect of PDS over IDS in countries with high debulking rates, and..

AGO analysis (n=3126) – IGCS Bangkok AGO-OVAR 3 (Cisplatin/Paclitaxel vs. Carboplatin/Paclitaxel) - A du Bois JNCI 2003 AGO-OVAR 5 / GINECO (Carboplatin/Paclitaxel +/- Epirubicine) – A du Bois JCO 2006 AGO-OVAR 7 / GINECO (Carboplatin/Paclitaxel +/- Topotecan) - J Pfisterer JNCI 2006 3,126 of 3,388 randomized pts. (92.3%) included of whom 1,837 (58.8%) had died within a median observation period of 53.9 months. Age [median; range] 58.9 (19.6-83.6) yrs PS ECOG 0 1,190 38.1 ECOG 1 1,592 50.9 ECOG 2 326 10.4 Stage FIGO IIB-IIIA 448 14.4 FIGO IIIB 366 11.7 FIGO IIIC 1,779 56.9 FIGO IV 530 17.0 Grading G1 244 7.8 G2 998 31.9 G3 1,702 54.4 Histology Serous 2,296 73.4 Endometrioid 272 8.7 Mucinous 147 4.7

AGO analysis (n=3126) – IGCS Bangkok 64% ≤ 1 cm 33% No residual tumor Age [median; range] 58.9 (19.6-83.6) yrs PS ECOG 0 1,190 38.1 ECOG 1 1,592 50.9 ECOG 2 326 10.4 Stage FIGO IIB-IIIA 448 14.4 FIGO IIIB 366 11.7 FIGO IIIC 1,779 56.9 FIGO IV 530 17.0 Grading G1 244 7.8 G2 998 31.9 G3 1,702 54.4 Histology Serous 2,296 73.4 Endometrioid 272 8.7 Mucinous 147 4.7

AGO analysis (n=3126) – IGCS Bangkok 64% ≤ 1 cm 33% No residual tumor Stage IIIc – IV 57% ≤ 1 cm Age [median; range] 58.9 (19.6-83.6) yrs PS ECOG 0 1,190 38.1 ECOG 1 1,592 50.9 ECOG 2 326 10.4 Stage FIGO IIB-IIIA 448 14.4 FIGO IIIB 366 11.7 FIGO IIIC 1,779 56.9 FIGO IV 530 17.0 Grading G1 244 7.8 G2 998 31.9 G3 1,702 54.4 Histology Serous 2,296 73.4 Endometrioid 272 8.7 Mucinous 147 4.7

AGO analysis (n=3126) – IGCS Bangkok Stage IIIc - IV ≤ 1 cm No residual 1 – 10 mm AGO 57% 24% 33% EORTC-NCIC 46% 21% 25% Age [median; range] 58.9 (19.6-83.6) yrs PS ECOG 0 1,190 38.1 ECOG 1 1,592 50.9 ECOG 2 326 10.4 Stage FIGO IIB-IIIA 448 14.4 FIGO IIIB 366 11.7 FIGO IIIC 1,779 56.9 FIGO IV 530 17.0 Grading G1 244 7.8 G2 998 31.9 G3 1,702 54.4 Histology Serous 2,296 73.4 Endometrioid 272 8.7 Mucinous 147 4.7

AGO primary debulking analysis compared with EORTC-NCIC 55971 PDS arm My interpretation: The modest differences in debulking rates can be explained by the fact that in 55971 small IIIc‘s are under represented (e.g. diagnosis of IIIc-IV was made on imaging, median size of largest metastases 8cm, …).

Criticisms/Questions on 55971 in Bangkok Why still stressing the importance of optimal debulking ( = no residual tumor)? Does no residual at IDS have the same impact as at PDS? The optimal debulking rate was too low? Was is the optimal timing for IDS?

Optimal timing of interval debulking surgery (Bristow & Chi 2006)

Predictive Models for Optimal Cytoreduction CA125 Imaging (CT/MRI/PET) Microarrays THESE MODELS ARE SIMPLY NOT GOOD ENOUGH

Open Laparoscopy in stage III and IV ovarian carcinoma (n=228, 1995 - 2002) 55 patients (19%) with suspect ovarian mass in combination with omental cake and/or ascites had no ovarian carcinoma stage III or IV (metastases from other primaries, stage I-II, benign, ..) 90% of the patients with advanced ovarian carcinoma (n = 173) judged to be operable were optimally debulked. Vergote et al Int J Gynecol Cancer 2005 15:776-9) This figure of 90% optimal debulking after laparoscopy is confirmed by 2 Italian series (Fagotti et al and Angioli et al) and is much higher than for every published CT scoring system, CA125, and even microarrays, …

Open laparoscopy in advanced ovarian cancer is the best technique to: make a histological diagnosis, exclude other primary tumors (or benign disease) evaluate operability, plan operating time of debulking surgery refer patients to a tertiary center (video/CD).

Surgery in stage IIb-IV ovarian carcinoma (1) In stage IIb – IIIb ovarian carcinoma is primary debulking the standard of care. This surgery should include hysterectomy, bilateral oophorectomy, omentectomy and resection of all intra- and retroperitoneal suspicious lesions. Pelvic and para-aortic systematic lymphadenectomy is recommended in stage IIb-IIIb (due to the high number of patients with metastatic lymph nodes - altough no randomized data are available).

Surgery in stage IIb-IV ovarian carcinoma (2) 4. No residual tumor is the only correct definition of optimal debulking in Stage IIb-IV disease. 5. Prior to surgery patients should undergo a complete imaging with at least a CT abdomen and gynaecological ultrasound. Pet-CT, MRI and CT thorax might be used, if available, in selected cases. 6. In cases with proven unresectable (e.g. extraabdominal) disease it is preferred to prove the diagnosis with BIOPSY (laparoscopy or tru cut). If FNAC is used, the other strict criteria as used in the EORTC-NCIC-CTG trial, should be used to exclude other primary tumors.

Neoadjuvant or primary debulking in Stage IIIc or IV ovarian carcinoma Neoadjuvant or primary debulking in Stage IIIc or IV ovarian carcinoma? Leuven opinion on the EORTC study The EORTC-GCG NCIC-CTG 55971 study was performed in patients with very advanced Stage IIIc-IV disease on CT (62% > 10cm met’s at PDS). In such cases neoadjuvant chemotherapy followed by interval debulking does not worsen the prognosis.

AND during the laparoscopy Neoadjuvant or primary debulking in Stage IIIc or IV ovarian carcinoma? Leuven opinion on the EORTC study 3. Sometimes it is technically more difficult to obtain a no residual tumor status after interval than after primary debulking surgery (e.g. due to fibrosis). 4. Hence, in our institution, patients with suspicion of Stage IIIc or IV disease undergo laparoscopy to evaluate the extent of the disease AND during the laparoscopy

Indications for neoadjuvant chemotherapy Leuven Policy 2009: about 50% (?) IIIc-IV 1. Tumors larger than 2 cm around the superior mesenteric artery or behind the porta hepatis, or 2. Intrahepatic (multiple) metastases or several extraabdominal metastases (excluding resectable inguinal or supraclavicular lymph nodes) larger than 2 cm , or 3. Poor general condition (e.g. > 80 years) making a “maximal surgical effort” to no residual tumor impossible, or 4. Extensive serosal invasion (e.g. plaques) of the intestines necesitating bowel resections of > 1.5 m 5. Patients that can not be (easily) debulked to no residual tumor (e.g. more than 1 bowel resection, expected operative time more than 4 hours, poor general condition, > 5cm met’s ..) are selected for neoadjuvant chemotherapy at laparoscopy.