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Surgery in Stage IIb-IV Ovarian Carcinoma

Surgery in Stage IIb-IV Ovarian Carcinoma. Ignace Vergote University Hospitals Leuven, European Union VVOG Eerste Jaarvergadering 2009. 1-A 1: Is there a need to strictly define the extent and type of surgery for patients in first-line trials?

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Surgery in Stage IIb-IV Ovarian Carcinoma

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  1. Surgery in Stage IIb-IV Ovarian Carcinoma Ignace Vergote UniversityHospitals Leuven, European Union VVOG EersteJaarvergadering 2009 AIOM 2000

  2. 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

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

  4. Systematic Pelvic and Paraaortic Lymphadenectomy in Ovarian Cancer Burghardt E et al. Gynecol Oncol 1990; 40: 103 – 106.

  5. 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

  6. 1.0 0.8 0.6 Overall Survival Events Totals 99 211 103 216 0.4 0.2 No Lymphadenectomy Lymphadenectomy P = 0.768 0.0 0 1 2 3 4 5 Years from Randomization LYMPHADENECTOMY FOR ADVANCED OVARIAN CANCER Overall Survival

  7. CHARACTERISTICS Benedetti-Panici JNCI 2005 Characteristic Control % Lymphadenectomy % (N=211) (N=216) Median Age56 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

  8. AGO – OVAR OP.3 (LION) Lymphadenectomy In Ovarian Neoplasms • 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

  9. Neoadjuvant or primary debulking? Ovarian carcinoma Stage II-IV Leuven Series 1993- 2003 (n = 288)Median survival 56 months Vergote et al, IGCS 2004

  10. Indications for neoadjuvant chemotherapyLeuven 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

  11. Extraperitoneal hysterectomy with resection of pelvic peritoneum

  12. Liver AIOM 2000

  13. Pleura AIOM 2000

  14. Lung AIOM 2000

  15. Optimal Cytoreduction Rates for Advanced Ovarian Cancer at MSKCC

  16. Advanced Ovarian Cancer Median Survival: 1975 - 2008 Memorial Sloan Kettering Cancer Centre 80 60 months 40 20 0 1975 1983 1986 1996 1998 2003 2006 Alkeran multi-drug cisplatin paclitaxel IP therapy

  17. 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.

  18. Ovarian, tuba or peritonal cancer FIGO stage IIIc-IV (n = 718) Randomisation Primary DebulkingSurgery Neoadjuvant chemotherapy 3 x Platinum based CT 3 x Platinum based CT Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS 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

  19. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDSSurgical findings and results (PP1) * % calculated on the 306 patients who underwent IDS.

  20. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS≤ 1cm residual per country (PP1)

  21. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDSSurgical characteristics (PP1)

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

  23. NACT + IDS versus PDS: PP1

  24. NACT + IDS versus PDS: PP1 < 5 cm : hazard ratio: 0.74; 95% confidence intervals 0.52-1.05

  25. Multivariate analysis for OS(PP1)

  26. 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?

  27. 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

  28. PDS vs PDS+IDS vs IDS: ITT

  29. PDS vs PDS+IDS vs IDS: ITT

  30. 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..

  31. 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.

  32. AGO analysis (n=3126) – IGCS Bangkok 64% ≤ 1 cm 33% No residual tumor

  33. AGO analysis (n=3126) – IGCS Bangkok 64% ≤ 1 cm 33% No residual tumor Stage IIIc – IV 57% ≤ 1 cm

  34. AGO analysis (n=3126) – IGCS Bangkok

  35. 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, …).

  36. 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?

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

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

  39. 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, …

  40. 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).

  41. Surgery in stage IIb-IV ovarian carcinoma (1) • In stage IIb – IIIb ovariancarcinoma is primary debulking the standard of care. • Thissurgeryshouldincludehysterectomy, bilateral oophorectomy, omentectomy and resection of all intra- and retroperitonealsuspiciouslesions. • Pelvic and para-aorticsystematiclymphadenectomy is recommended in stage IIb-IIIb (due to the high number of patientswith metastatic lymphnodes - altoughnorandomized data are available).

  42. Surgery in stage IIb-IV ovarian carcinoma (2) 4. No residualtumor is the only correct definition of optimal debulking in Stage IIb-IVdisease. 5. Prior to surgerypatientsshouldundergo a complete imagingwith at least a CT abdomen and gynaecological ultrasound. Pet-CT, MRI and CT thorax mightbeused, ifavailable, in selected cases. 6. In cases with proven unresectable (e.g. extraabdominal) diseaseit is preferred to prove the diagnosis withBIOPSY (laparoscopyortrucut). If FNAC is used, the otherstrict criteria as used in the EORTC-NCIC-CTG trial, shouldbeused to excludeotherprimary tumors.

  43. 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.

  44. 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

  45. Indications for neoadjuvant chemotherapyLeuven 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.

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