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Ovarian Cancer

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

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Ovarian Cancer

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  1. Ovarian Cancer Dr Helen Mackay

  2. 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???

  3. Cancer Incidence Cancer Deaths* Women668,470 Women272,810 • 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.

  4. Ovarian

  5. 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

  6. Ovarian Cancer

  7. 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!

  8. Treatment • Surgery • Upfront,delayed or interval? • Chemotherapy • Radiation

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

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

  11. 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!

  12. 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!!!!

  13. 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)

  14. 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)

  15. Confirmatory Studies • EORTC/NCIC Trial. N= 680 (OV10) • 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

  16. 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.

  17. 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!

  18. 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)

  19. 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

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

  21. 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

  22. What next??

  23. 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)

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

  25. 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

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

  27. Results GOG 172 N =415

  28. 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* Median survival time for randomized trials comparing IV versus IV/IP

  29. “ 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” NCI clinical statement 2006

  30. 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%

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

  32. Ozols et al. NEJM 2006

  33. 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

  34. 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.

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

  36. Treatment of Advanced Ovarian Cancer

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

  38. 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

  39. 100 90 80 70 60 50 40 30 20 10 0 0 26 52 78 104 130 156 182 208 234 Caelyx™ vs Topotecan(Survival Platinum Sensitive) PegylatedLiposomalDoxorubicine Topotecan Hazard Ratio = 0.63 [0.47 – 0.85] Stratified Log-rank p = 0.002 Patient Alive (%) Median 112 weeks Median 77weeks Time (Weeks) Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322; European Cancer Conference 2003.

  40. 100 90 80 70 60 50 40 30 20 10 0 0 26 52 78 104 130 156 182 208 234 Caelyx™ vs Topotecan(Survival Platinum Sensitive) PegylatedLiposomalDoxorubicine Topotecan Hazard Ratio = 0.63 [0.47 – 0.85] Stratified Log-rank p = 0.002 Patient Alive (%) Median112weeks Median 77 weeks Time (Weeks) Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322; European Cancer Conference 2003.

  41. 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

  42. Carboplatin Combinations In Ovarian Cancer(Efficacy Results) (n = 105) % % (n = 392) (n = 178) %

  43. Ovarian Cancer and Bevacizumab (phase II)

  44. Combination Bevacizumab Regimens in Ovarian Cancer

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