Overview of Ovarian Cancer. Dr. Sinead Noonan 13/03/2012

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1 Overview of Ovarian Cancer Dr. Sinead Noonan 13/03/2012

2 Ovarian Cancer 4 th most common cause of cancer death in women 15,000 deaths/year in the US Each year 300 new cases in Ireland 80% epithelial cell origin (EOC) Other types: Germ Cell Tumours Sex Cord Stromal Tumours Lipoid cell Tumours Ovarian Sarcomas Lymphoma 50% of cases > age 65

3 Epithelial Ovarian Cancer Histology Incidence Serous 40-50% Most common Endometrioid 15-25% 2 nd most common Mucinous 6-16% Clear Cell 5-11% Poorer prognosis currently managed as one entity may have different natural histories different targeted therapies in the future

4 Proposed model of ovarian carcinogenesis by American Society of Clinical Oncology Landen C N et al. JCO 2008;26:

5 Ovarian Cancer Surgery is required to accurately stage ovarian cancer (if disease below the diaphragm) CA125 is useful in follow-up

6 Ovarian Cancer Stage Description Incidence Survival I Confined to ovaries 20% 90% II Confined to pelvis 5% 65% III Peritoneal or nodal 58% 20-45% IV Distant metastases 17% <5% Absence of effective screening programmes

7 Treatment Complete surgical staging/optimal reductive surgery Chemotherapy Clinical Trials

8 Surgery Stage Ia and Ib TAH/BSO Stage Ic or high grade TAH/BSO/omentectomy + adjuvant treatment Debulking surgery volume of residual disease can relate to survival may follow chemotherapy Stage IV patients role of surgery unclear

9 Chemotherapy Adjuvant chemotherapy Neoadjuvant chemotherapy Relapse Platinum sensitive Vs Platinum resistant Topetecan and Liposomal Doxorubicin Targeted therapies

10 Alkylating agents, Pre 70s 5yr survival <7% 1978 Cisplatin Ca-125 as biomarker Tied to ovarian ca 1980 s Taxanes FDA approves carboplatin BRCA 1 and 2 linked to ovarian ca risk IP chemo in addition to IV prolongs survival Bevacizumab 1996 Topotecan Late 90 s 1999 Liposomal doxurubicin 2006 Late Low malignant potential v poorly differentiated Neoadjuvant chemo in advanced ovarian ca

11 Carbo/taxol GOG 111 cis/cyclo v cis/paclitaxel GOG 158 Paclitaxel/ Cisplatin Paclitaxel/ Carboplatin P value N Completed 6 cycles 85% 87% Grade 3-4 GI Leukopenia Renal Metabolic toxicity 25% 63% 3% 8% 10% 59% 1% 3% <0.05 <0.05 <0.05 <0.05 Grade 2-4 Thrombocytopenia 5% 39% <0.05 Recurrence 76% 73% PFS 19.4 mo 20.7 mo RR 0.88 (95% CI ) Deaths 58% 53% OS 48.7 mo 57.4 mo RR 0.84 (95% CI )

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13 Summary of Key Clinical Trials Cisplatin/Paclitaxel standard of care for ovarian cancer in 1996 (GOG 111) Platinum agents are the single most effective agents (GOG 132) Carboplatin/Paclitaxel not inferior to Cisplatin/Paclitaxel; may be superior (GOG 158) Docetaxel/Carboplatin can be substituted for Paclitaxel/Carboplatin without compromising efficacy (SCOTROC) Non-inferiority for other carboplatin-containing doublets The addition of a third chemotherapy does not improve OS or PFS (GOG 182) Maintenance therapy has not been shown to improve survival

14 Platinum resistance Relapse < 6 months after completion of chemotherapy Poorer survival If disease is platinum sensitive then patient is rechallenged with the same regimen

15 Other Agents Topetecan Phase II studies demonstrated a response rate Liposomal Doxorubicin Doxorubicin contained in liposomes Most effective in platinum sensitive ovarian cancer Single agent Gemcitabine/Paclitaxel/Docetaxel

16 Intra-peritoneal chemotherapy Optimally debulked Stage III disease Cisplatin 100mg/m 2 Disadvantages: GI Side Effects Infection Logistics Cost Only 42% complete 6 cycles in GOG-0172

17 Intra-peritoneal chemotherapy Treatment hazard ratios (HR) for progression-free survival (PFS) for i.p. versus i.v. therapy. χ2 heterogeneity (3 d.f.) = 0.629; p =.89. Trimble E L et al. The Oncologist 2008;13: by AlphaMed Press

18 Dose Dense Chemotherapy ITT analysis Japanese study Eligibility Stage II-IV Residual disease > 1cm included Carboplatin AUC 6 Paclitaxel 180mg/m2 3/52 Carboplatin AUC 6 Paclitaxel 80mg/m2 1,8, 15

19 Dose-dense Chemotherapy Results 632 patients Stage II (19%) III (66%) IV (15%) Serous histology (56%) Grade 3 (24%) Residual disease 1 cm (46%) Primary debulking surgery (89%) Standard Dosedense N Completed 6 cycles 73% 62% P value Grade 3-4 Anemia 44% 69% p< Response rate Complete response Partial response 54% 16% 38% 56% 20% 36% Deaths 124 (39%) 96 (30%) PFS 17.2 mo 28 mo HR 0.71 (95% CI, ), p= OS (3-year) 65.1% 72.1% HR 0.75 (95% CI ), p=0.03

20 PFS with dose dense taxol

21 OS with dose dense taxol

22 New Targets Angiogenesis involved in tumour growth and metastasis formation Approved in Colon, Lung, Breast and Renal tumours Epithelial ovarian cancer expresses VEGF

23 Bevacizumab Bevacizumab is a monoclonal antibody that prevents VEGF from binding to its receptors

24 Front-line Trials: GOG N = 2000 pts Survival, PFS primary endpoints Biologic and QoL endpoints GOG-218 EOC, PP, FT cancer Primary Treatment Phase Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Maintenance Phase Placebo x 15 mos Placebo x 15 mos Bevacizumab x 15 mos PI: Burger

25 ICON 7: Frontline Bevacizumab Epithelial ovarian, fallopian, or primary peritoneal cancer Optimal or suboptimal cytoreduction, stage I-IV Primary endpoint: PFS I Paclitaxel 175 mg/m 2 3 hrs + Carboplatin AUC 6 + Placebo q 21 days* R A N D O M I Open: Z Oct 20, 2006 Closed: (ongoing) Target E II accrual: 1520 pts (2 Y) *Starting with C1 or C2. Paclitaxel 175 mg/m 2 3 hrs + Carboplatin AUC 6 + Bevacizumab 7.5 mg/kg q 21 days* x 6 x 6 Bevacizumab (36 wks total)

26 ICON 7 GOG 0218 High risk FIGO stage I /IIA clear cell or grade III Stage IIb-IV epithelial ovarian ca/io peritoneal ca/fallopian tube ca ECOG 0-2 Adequate Coag/RLB profiles Written informed consent FIGO III/IV (epithelial/1o peritoneal/fallopian) ECOG 0-2 Entered 1-12 weeks post surgery Measureable and non measureable disease (initially stage III and no lesions > 1cm excluded) Adequate fbc/rlb/coag

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30 Future Directions Division of patients according to histological subtype and designing clinical trials and tailoring treatments accordingly Intra-peritoneal therapy? Dose dense chemotherapy? Targeted therapies Newer anti-angiogenesis agents PARP inhibitors mtor inhibitors Histone deacetylase inhibitors vaccines

31 Thank you!