1. Neoadjuvant Chemotherapy or Primary Debulking Surgery in Advanced Ovarian Cancer Ignace Vergote, MD PhD University Hospitals Leuven, Belgium IGCS Santa Monica 2006

2. Surgery in advanced ovarian carcinma Optimal surgery = no residual tumor. Should some patients be selected for neoadjuvant chemotherapy, and if so how?

3. Primary Cytoreductive Surgery Bristow et al JCO 2002 25% 25mo 75% 34mo

4. TOTAL RESIDUAL TUMOR LOAD Stage III – Vergote Gyn Oncol 1998

5. Ovarian carcinoma Stage II-IV Leuven Series 1993- 2003 (n = 288) < 1 cmNo residual tumor Primary debulking (n = 192) 86%78% Interval debulking (n = 96) 86%79% TOTAL86%78% Vergote et al, IGCS 2004

6. Indications for neoadjuvant chemotherapy Leuven Policy 2006 1. Tumors larger than 2 cm around the superior mesenteric artery or around 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

7. Is there a place for neoadjuvant chemotherapy in advanced ovarian cancer? What do the randomizezd studies on interval debulking surgery in patients that are/can not be optimally debulked primarily show us? EORTC Trial, M. van der Burg et al., NEJM 1995 GOG 152, P. Rose et al. NEJM 2004

8. CR PR SD No surgery Surgery EORTC IDS Study design Eligibility: Epithelial ca WHO PS 0-2 FIGO IIb-IV > 1cm residual Stratification at WHO PS CP: Cisplatin 75 mg/m 2 Cyclophosphamide 750 mg/m 2 q. day 21 Institute Response 3CP randomization for: Endpoints: - PFS - Survival 3 x CP Randomisation Registration 3 x CP PD Off study Clinical evaluation

9. Interval Debulking Surgery EORTC GCG study 55865 The reduction of the risk of deaths is 40%, p=0.0114 median follow-up 9.3 years years 02468101214 0 10 20 30 40 50 60 70 80 90 100 10-Years Overall Survival median 10-years Surgery 26 m14% No Surgery19 m 7% Overall Wald test: p<0.0001 Overall Wald test: p<0.0001

10. Interval Debulking Surgery GOG Protocol #152 Eligibility Stage III or (IV) suboptimal ovarian carcinoma (> 1 cm in diameter) residual intraperitoneal disease Appropriate ovarian cancer surgery: defined as a laparotomy with an adequate excision to explore the entire abdominal cavity, with a maximal effort to resect the uterus, tubes, ovaries, omentum, and all gross residual ovarian cancer.

11. GOG 152

12. Patient Characteristics GOG 152EORTC IDS Chemotherapy TPCP Stage IV6% 21% Performance St 27%17% Residual after primary surgery 1 – 2 cm 12% 6% 2 – 5 cm56% 30% 5 – 10 cm23%38% > 10 cm 9% 26%

13. EORTC IDS and GOG 152 trials Conclusions Based on GOG 152 IDS (Interval Debulking Surgery) does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecologic oncologist.Based on GOG 152 IDS (Interval Debulking Surgery) does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecologic oncologist. However, based on the EORTC IDS trial, interval debulking by an experienced surgeon improves survival in some patients who have not been optimally operated primarily (poor medical condition, or too extensive spread in relation to general condition), or inexperienced surgeon, …However, based on the EORTC IDS trial, interval debulking by an experienced surgeon improves survival in some patients who have not been optimally operated primarily (poor medical condition, or too extensive spread in relation to general condition), or inexperienced surgeon, …

14. Should some patients be selected for neoadjuvant chemotherapy followed by interval debulking, and if so how?

15. Predictive Models for Cytoreduction CA125 > 500 Imaging (CT) –Peritoneal burden –Mesenteric involvement –Pelvic sidewall infiltration –Upper abdominal lymphadenopathy –Omental/gastric infiltration THESE MODELS ARE SIMPLY NOT GOOD ENOUGH

16. Imaging to predict operability in advanced ovarian cancer? Nelson –Yale (JCO, 1993): Attachment of tumor on CT to spleen or tumors larger than 2 cm on diaphragm, liver surface, mesentery, gall bladder fossa were regarded as inoperable! 6/18 judged to be inoperable were optimally debulked!!!

17. Cytoreduction and Microarrays Berchuck Am J Obstet Gynecol 190:910, 2004 RNA 44 patients (19 optimal, 25 suboptimal) Affymetrix chip (22,283) –Top 120 genes used in model –MAP2K4 & MAP3K7 (metastases suppressing genes) Predictive accuracy: 72.7%

18. Imaging to predict operability in advanced ovarian cancer? Leuven (Eur J Gyn Oncol, 1998 and Gyn Obstet Invest, 2003): - CT with peritoneography is superior to standard CT. - Petscan can give addtional information to CT, but still both techniques are less sensitive than laparoscopy to detect predict operability.

19. Open laparoscopy was performed in patients with a suspect pelvic mass and on CT an omental cake and/or large volume ascites. In all patients the fascia and skin were carefully closed. Chemotherapy or surgery was started as soon as possible (median 9 days, range 2 - 14 days). In 71 patients the port sites were completely excised at the time of debulking. Vergote et al Int J Gynecol Cancer 2005 15:776-9. Open Laparoscopy in stage III and IV ovarian carcinoma (n=173, 1995 - 2002)

20. 32% of the patients has no ovarian carcinoma stage III or IV (metastases from other primaries, stage I-II, benign,..) 90% of the patients with advanced ovarian carcinoma judged to be operable were optimally debulked. Open Laparoscopy in stage III and IV ovarian carcinoma (n=173, 1995 - 2002)

21. Open Laparoscopy in advanced ovarian carcinoma (n=173) – Port site met’s 30/173 (17%): 22 only on microscopy (i.e. 31% of those with complete port site resection). 8 (5%) also clinical 21 primary debulking (6 clinical) 9 interval debulking (2 clinical).

22. Open Laparoscopy in advanced ovarian carcinoma (n=173) – Port site met’s After a follow-up ranging from 3 – 70 months (median 34 months) none of the patients relapsed in the port sites during the whole course of their disease, following primary chemotherapy and surgery.

23. Open Laparoscopy in stage III and IV ovarian carcinoma (n=173) Port site metaNo port site meta (n = 30) (n = 143) Med time to R/ 12d 8d Ascites 83% 72% Serous 87% 82% Stage IV 13% 31% Median OS Not reached 29 months 3 years OS 68% 37% None of the variables are significantly different

24. Other studies on laparoscopy to judge operability Fagotti et al (Gyn Oncol 2005): Optimal reduction in 90% of the patients jugded to be operable. Deffieux et al (Int J Gyn Cancer 2006). 10/11 patients thought to be resectable were resected to no residual tumor.

25. Other studies on laparoscopy to judge operability Angioli et al (Gyn Oncol 2006): Optimal reduction (R0) in 96% of the patients jugded to be operable (i.e. n = 53/87 or 61%). Definitions for inoperability: Extended visceral peritoneal disease Extended small bowel involvement Large involvement of upper abdomen (diaphragm, liver, porta) Heavily bleeding tumors

26. Open laparoscopy in advanced ovarian cancer Open laparoscopy in 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). Port site metastases are frequent (17%) especially on pathological examination, but do not influence survival.

27. What are the Retrospective data on Neoadjuvant Chemotherapy, (with or without Interval Debulking Surgery) ?

28. Neoadjuvant Chemotherapy in Advanced Ovarian Carcinomas (Retrospective) In 17 retrospective studies patients treated with neoadjuvant chemotherapy followed by interval debulking have a similar survival as patients treated with primary debulking, and a higher rate of optimal debulking. N = 856

29. Randomisation Neo-adjuvant Chemotherapy in advanced ovarian cancer (EORTC/NCIC-CTG) Ovarian, tuba or peritonal cancer FIGO stage IIIc-IV (n = 704) Upfront Debulking Surgery Neoadjuvant chemotherapy 3 x Platinum based CT Interval debulking (not obligatory) Interval debulking if no PD 3 x Platinum based CT > 3 x Platinum based CT Endpoints: Survival, Progression Free Survival, Quality of Life, Complications

30. Randomisation Neo-adjuvant Chemotherapy in advanced ovarian cancer (EORTC/NCIC-CTG) Ovarian, tuba or peritonal cancer FIGO stage IIIc-IV (n = 704) Upfront Debulking Surgery Neoadjuvant chemotherapy 3 x Platinum based CT Interval debulking (not obligatory) Interval debulking if no PD 3 x Platinum based CT > 3 x Platinum based CT Endpoints: Survival, Progression Free Survival, Quality of Life, Complications

31. CONCLUSION Primary or debulking or neoadjuvant chemotherapy Primary optimal debulking surgery (i.e. no residual tumor) by a gynecologic oncologist remains the standard of care. The role of neaoadjuvant chemotherapy followed by interval debulking surgery will be better defined next year by the randomized EORTC-NCIC study.