Ovarian Cancer Dr Helen Mackay

Ovarian Cancer: A huge subject! The basics First line treatment GOG 172 (IP chemotherapy) and its aftermath!!! Second line and beyond!!!! Where do we go from here???

Cancer Incidence Cancer Deaths* Women 668,470 Women 272,810 32% Breast 12% Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4% Ovary 4% Non-Hodgkin lymphoma 4% Melanoma of skin 3% Thyroid 2% Pancreas 2% Urinary bladder 20% All Other Sites 25% Lung & bronchus 15% Breast 10% Colon & rectum 6% Ovary 6% Pancreas 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Multiple myeloma 2% Brain/ONS 24% All other sites ONS=Other nervous system. Source: American Cancer Society, 2004.

Ovarian TNM FIGO Description Tx T0 T1 T1a T1b T1c T2 T2a T2b T2c T3 IB IC II IIA IIB IIC III IIIA IIIB IIIC IV Not assessed No tumor Ovaries alone One ovary Both Rupture/+washings Pelvic ext Uterus+/-tubes Other tissues ascites-ve Above +ascites positive Peritoneal mets outside pelvis Microscopic 2 cm or less 2 cm +/- regional node Metastasis excluding peritoneum

Ovarian Cancer Is often asymptomatic in its early stages Most patients have widespread disease at the time of diagnosis Yearly mortality in ovarian cancer is approximately 65% of the incidence rate Suboptimally debulked stage III-IV patients reveals a 5-yr survival rate of <10% Early stages of the disease are curable in a high percentage of patients

Ovarian Cancer

Ovarian Cancer - Prognosis Stage 1 a + b >90% Stage 1 c 80% Stage 2 50% Stage 3 30% Stage 4 10% But really depends on response to chemotherapy and PS!

Treatment Surgery Upfront,delayed or interval? Chemotherapy Radiation

Surgery Accurate staging Debulking disease Midline incision; full exploratory laparotomy TAH & BSO Omentectomy Lymph node assessment/sampling Washings

Interval debulking surgery Improve PFS Response may decrease the extent of surgery Increase rate of optimal cytoreduction Information on chemosensitivity

IDS EORTC improved survival GOG same Cochrane review 2009 no conclusive evidence for or against BUT benefit in pts undergoing inadequate initial surgery. All patients should be optimally debulked if possible!

Neoadjuvant chemotherapy Who? Traditionally poor PS, Extensive disease, significant co morbitidities. Resource availability? But EORTC 55971 Survival is the same neoadjuvant chemo vs upfront debulking surgery NEJM paper eagerly awaited!!!!

Who do you treat? Stage II,III,IV Stage Ib/c, stage 1a? ICON 2/ACTION trials Stage 1A ovarian cancer Adjuvant Carbo vs no treatment post surgery Overall improvement in survival by 7% with Carbo Impact most apparent in patients who did not have optimal staging surgery Meta analysis Trope and Kaern JCO 25 (2007)

Advanced Ovarian Cancer Advanced disease, sub-optimally debulked disease GOG 111: Cisplatin and paclitaxel significantly better than cisplatin/cyclophosphamide N=386 RR 73% vs 60% PFS: 18 vs 13 months (p<0.001) OS: 38 vs 24 months (p<0.001)

Confirmatory Studies EORTC/NCIC Trial. N= 680 (OV10) Additional trials Cisplatin/Taxol (3hr) better than cisplat/cyclo RR 59% vs 45% PFS 15.5 vs 11.5 months OS 35.6 vs 25.8 months Additional trials Carboplatin+ taxol instead of cisplatin+ taxol (reduced neurotoxicity) GOG 158 Carboplatin + taxotere similar activity to carbo + taxol GOG 132: High dose cisplatin = cisplatin/taxol

But ICON 3. N= 2074 patients Carboplatin or CAP vs Carbo/Taxol Median OS 35.4 vs 36.1 months Med. PFS16.1 vs 17.3 months No difference in any of the subgroups Would suggest standard dose carboplatin is sufficient.

But GOG 111 high risk stage ¾ suboptimally debulked ICON 3 stage ¾ >2cm trend to benefit for carbo tax 2:1 randomisation 331 patients high risk. Carbo taxol remains the standard of care!

Chemotherapy Current Standard of Care: Carboplatin AUC 5 or 6 and taxol 175mg/m2 over 3 hours Well tolerated, low neurotoxicity Single agent carboplatin AUC 5 (measured) or AUC 6 (Calculated)

Improve outcome How? Treat earlier higher dose more drugs: doublets /triplets Better drugs: targeted agents longer time: more is better? administer it differently - intra-peritoneally intra-operatively All of the above! mechanisms of failure drug resistance

More is better? 11 randomised trials increasing platinum dosage 2 positive Phase II high dose chemotherapy: no benefit BUT…………..

Doublets triplets and different designs: or lets make things complicated!!! NCIC OV16 Randomized clinical trial: Taxol and Carboplatin (8 cycles) vs Sequential couplets of Cisplatin/topotecan (4) and carboplatin/taxol (4) Endpoints: Progression Free survival Overall survival, response rate, toxicity ICON5 4 arms Carbo/Taxol vs doublets triplets including gemcitabine/topotecan/liposomal doxorubicin

What next??

Carboplatin/paclitaxel Carboplatin/paclitaxel + bevacizumab ICON-7 Stratification factors: stage, residual disease status, country Carboplatin/paclitaxel observation 1520 stage IIB-IV patients Carboplatin/paclitaxel + bevacizumab bevacizumab 6 cycles (4.5 months) 12 cycles (7.5 months) Treatment: Carboplatin AUC = 6 Paclitaxel 175 mg/m2 Bevacizumab 7.5 mg/kg (All treatments q 3 weeks)

Bevacizumab yes or no? coming to a journal near you Fall 2010!!!!

IP chemotherapy: Rationale Peritoneal cavity is the major route of spread of ovarian cancer Debulking surgery can reduce cancer volume Lengthy exposure to high concentration of drugs Diffusion of drug across 2-3 layers of cells

Limitations Poor penetration of bulky disease Less exposure of drug to extraperitoneal disease Complications Catheter problems Infection Abdominal pain Inadequate drug distribution

Results GOG 172 N =415 IV IP Neg second look N=202 41% 57% PFS 18.3 mos 23.8 mos Overall Survival 49.7 mos 65.6 mos Rel. Risk PFS .77

Median survival time for randomized trials comparing IV versus IV/IP Study Identifer/ Authors/ Year Published Number of patients Median duration of survival for control regimen (months) Median duration of survival for experimental regimen (months) SWOG 8502/ GOG 104, Alberts et al, 1996 546 41 49* Polyzos et al, 1999 90 52 63 Gadduci et al, 2000 113 25 26 GOG 114/ SWOG 9227, Markman et al, 2001 462 51 67* Yen et al, 2001 118 48 43 Armstrong et al, 2006 415 49.7 65.6*

Study / Year Control Regimen Experimental Regimen Eligible patients No of patients 1994 Cisplat 100 mg.m2 IV; cyclo 600 mg/m2 Q 3 weeks x 6 Cisplat 200 mg/m2 IP; etoposide 350 mg/m2 IP Q 4 weeks x 6 Stage IIC-IV 62 GOG 104 1996 Cisplat 100 mg/m2 IV Cyclo 600 mg/m2 IV Cisplat100 mg/m2 IP Stage III, < 2 cm residual 546 Greek 1999 Carbo 350 mg/m2 IV; Cyclo 600 mg/m2 IV Carbo 350 mg/m2 IP; Cyclo 600 mg/ m2 IV Stage III 90 GONO 2000 Cisplat 50 mg/m2 IV; Cyclo 600 mg/m2 IV; Epi 60 mg/m2 IV Q 4 weeks x 6 Cisplat 50 mg/m2 IP; Cyclo 600 mg/ m2 IV; Epi 60 mg/m2 IV Stage II-IV, < 2 cm residual 113 GOG 114 2001 Cisplat 75 mg/m2 IV taxol 135 mg/m2 (24 hr) IV Carbo(AUC9) IV q 28 days x 2; Cisplatin 100 mg/ m2 IP; Paclitaxel 135 mg/m2 (24 hr) IV q 3 weeks x 6 Stage III, < 1 cm residual 462 Taiwan Cisplat 50 mg/m2 IV; Cyclo 50 mg/m2 IV; Epi/ Dox 50 mg/m2 IV Cisplat 100 mg/m2 IP Cyclo 500 mg/m2 IV; Epi/ Dox 50 mg/m2 IV 118 GOG 172 2005 Cisplat 75 mg/m2 IV; Taxol 135 mg/m2 (24 hr) IV Taxol 135 mg/m2 (24 hr) IV; Cisplat 100 mg/m2 IP; Taxol 60 mg/m2 IP on day 8 415

NCI clinical statement 2006 “ Based on the evidence of these 3 randomised phase III trials a combination of IV and IP chemotherapy conveys a significant survival benefit to women with optimally debulked epithelial ovarian carcinoma”

BUT……toxicity GOG 172: GI toxicity 46% vs 24% Infection 16% vs 1% leuopenia 76% vs 64% GOG 114 GI toxicity 20% vs 8% leucopenia 96% vs 62% GOG 104 GI toxicity 18% vs 2% leucopenia 40% vs 50%

Completion rate for prescribed courses of chemotherapy (%) Study identifier/ Author/ Year of publication IV regimen (%) IP/IV regimen for IP administration (%) SWOG 8501/ GOG 104, Alberts et al, 1996 58 GOG 114/ SWOG 9227, Markman et al, 2001 86 71 Gadducci et al, 2000 96 65 EORTC 55875, Piccart et al, 2003 NA 56 GOG 172, Armstrong et al, 2005 90 42

Ozols et al. NEJM 2006

Summary 21.6% decrease in risk of death! Unproven benefit ,toxic,quality of life issues (North American detractors/ Europe) Limited population stage III optimally debulked UPFRONT! Cost/resources

Consolidation of Remission More chemotherapy - doesn’t work 6 vs 12 cycles – no difference Monthly taxol – 3 months vs 12 months paclitaxel improvement in TTP – improvement in DFS by 3 months for 12 months additional therapy DSM closed trial on basis of difference in TTP so no information on survival or QL Not been adopted as recommendation until survival difference and QL evaluated.

Radiation Radiation - Alon Dembo et al. BUT early stage disease optimally debulked disease Whole abdomen and pelvis field BUT no RCT comparing with chemotherapy no treatment

Treatment of Advanced Ovarian Cancer

Treatment of Advanced Ovarian Cancer 10-15% 15% 40% 50-70%

Standard of Care – Second Line Platinum Sensitive Platinum free interval > 6m Platinum combination ICON 4 – TC > C OS 29 vs 24m OV15 – GemC > C 47% vs 31% PFS 8.6 vs 4.8 m Calypso Carbo caelyx> CT PFS 11.3 vs 9.4 (p=0.0005) High completion rates Platinum Resistant What agent? Any differentiation? QL and Toxicity Caelyx Topotecan Gemcitabine Etoposide Capecitabine

Caelyx™ vs Topotecan (Survival Platinum Sensitive) 100 90 80 70 60 50 40 30 20 10 Pegylated Liposomal Doxorubicine Topotecan Hazard Ratio = 0.63 [0.47 – 0.85] Stratified Log-rank p = 0.002 Patient Alive (%) Median 112 weeks Median 77 weeks 26 52 78 104 130 156 182 208 234 Time (Weeks) Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322; European Cancer Conference 2003.

Caelyx™ vs Topotecan (Survival Platinum Sensitive) 100 90 80 70 60 50 40 30 20 10 Pegylated Liposomal Doxorubicine Topotecan Hazard Ratio = 0.63 [0.47 – 0.85] Stratified Log-rank p = 0.002 Patient Alive (%) Median 112 weeks Median 77 weeks 26 52 78 104 130 156 182 208 234 Time (Weeks) Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322; European Cancer Conference 2003.

Caelyx™ vs Topotecan Grade 4 toxicity 17.2% vs 71% Caelyx grade 3 PPE 22% Neuropenia grade 3/4 12%vs 77% PCC transfusion 57.8% vs 14.9% G CSF 4.6% vs 29% Quality of life the same

Carboplatin Combinations In Ovarian Cancer (Efficacy Results) % % (n = 392) (n = 178) %

Ovarian Cancer and Bevacizumab (phase II) GOG CCC Bevacizumab 15mg/kg q 3/52 Bevacizumab 10mg/kg q 2/52 Cyclophosphamide 50mg od N=62 N=29 1 or 2 previous chemotherapy courses At least 1 previous course of chemotherapy RR 17.7% (CR 4.8%) RR 21% SD 54.8% SD 59% 6month PFS 38.7% 6month PFS 57% Median PFS 4.7months Median PFS 5.8months Median OS 17months Median OS not reached

Combination Bevacizumab Regimens in Ovarian Cancer Carboplatin Paclitaxel (n=43, Penson, ASCO 2006) Cyclophosphamide (N=70) (Schultheis ASCO 2006) Erlotinib (n= 13) Friberg ASCO 2006 Bevacizumab 15 mg/kg q3w (+maintenance) 10 mg/kg q2w 15 mg/kg q3w Other drugs Carboplatin AUC5 Paclitaxel 175 mg/m2 q3/52 50 mg/d Erlotinib 150 mg/d Prev. regimens ≤3 Pt sensitivity Pt Refractory 4 refractory, 2 resistant, 7 sensitive Toxicity Neuro, HT, PE, Wound healing (No GI perf, ATE) III/IV (>5%): HT, fatigue, Na↓, pain Diarrhoea, GI perforation (2/13), HT Response CT: CR 56%, PR 22% Ca-125: CR 89%, PR 7% CR 0%, PR 25%, SD 15% CR 1 (8%), PR 1 (8%) SD 7 (54%) Median PFS (m) 6.6 4.1

GI Perforation Historically, incidence of GIP in ovarian cancer is low Clinical trials to date (3-15%) Associations with: GI involvement of tumor Bowel obstruction / thickening Heavily-pretreated patients ? response

PARP inhibitors PAR chains are degraded via PARG DNA damage Repaired DNA PARP DNA damage Binds directly to SSBs Repair enzymes PAR Nicotinamide +pADPr NAD+ Once bound to damaged DNA, PARP modifies itself producing large branched chains of PAR

Responders by RECIST (%) Responders by RECIST or GCIG (%)   # evaluable Responders by RECIST (%) Responders by RECIST or GCIG (%) Phase I (23) Phase II (24) Total 46 33 13 (28%) 11 (33%) 21 (46%) 20 (61%) Platinum Sensitive (>6 months) 10 7 5 (50%) 1 (14%) 8 (80%) -- Platinum Resistant (≤6 months) 25 26 8 (32%) 10 (38%) 11 (44%) Platinum Refractory 11 0 (0%) 2 (18%)

The Future Personalised oncology? rare tumors: clear cell etc BRCA 1 and 2 Molecular signatures MTOR Hedgehog Trials trials and more trials of which more from Dr Oza!