Evidence-based systemic treatment of ovarian cancer

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Evidence-based systemic treatment of ovarian cancer

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1. Evidence-based systemic treatment of ovarian cancer Charlie Gourley University of Edinburgh Cancer Research Centre

2. Role of primary surgery in ovarian cancer Important for staging Important for disease management Maximal debulking surgery has prognostic importance

3. AGO-OVAR 3

4. Role of interval debulking surgery in ovarian cancer EORTC 55971 (and CHORUS) 718 pts 1° debulk ? CT x 6 vs CT x 3 ? interval debulk? CT x 3 No residual after surgery: 21% in PDS vs 53% in NACT <1cm after surgery: 46% in PDS vs 82% in NACT Post-op mortality: 2.7% in PDS vs 0.6% in NACT G3/4 post-op fever, haemorrahge and venous complications also ? in NACT and interval debulking group Median PFS and OS virtually identical between the arms http://www.sgo.org/content.aspx?id=2788

5. Role of chemotherapy in early ovarian cancer Risk of relapse is highly dependent upon: Stage Adequate surgery Grade

6. Potential for Relapse: Disease Stage and Diagnosis

7. ICON1 and ACTION trials To date the only large randomised contolled trials in early ovarian cancer Patients randomised to observation or chemotherapy

8. ICON1 vs ACTION

9. ICON1 vs ACTION

10. ICON 1 and ACTION combined - OS

11. ICON 1 and ACTION combined - PFS

12. ICON1 and ACTION trials Pooled data shows overall survival benefit of 8% at 5 years (82% vs 74%; CI 2-12%, p=0.008) Pooled data shows PFS benefit of 11% at 5 years (76% vs 65%; CI=5-16%, p= 0.001) Of the 925 patients in the combined analysis, only 1/6 were optimally staged

13. ICON1 and ACTION separate When ICON1 analysed independently a similar OS result was obtained (HR=0.66; 95% CI=0.45-0.97, p=0.03) When ACTION analysed separately there was no significant difference in OS, although there was a significant difference in PFS

14. ACTION study Only 1/3 of patients underwent optimal staging (despite efforts to maximise) Amongst patients in the observation arm, optimal staging was assoc with a statistically signif improvement in OS (HR=2.31, 1.08-49.6, p=0.03) and PFS (HR=1.78, 1.02-3.24, p=0.04) No such assoc in the chemo arm

15. ACTION study In the non-optimally staged patients, adjuvant chemotherapy was assoc with signif improvement in OS and PFS In the optimally staged patients, there was no benefit from adjuvant chemo ? Suboptimally staged group may benefit from chemo because it contains occult stage III patients

16. Early stage disease : what do we do? Ensure patients optimally staged if at all possible Adjuvant chemo for all stage 1C or above, all clear cell and all grade 3

17. Role of chemotherapy in advanced ovarian cancer GOG 111: McGuire et al, NEJM, 1996 OV-10: Piccart et al, JNCI, 2000 GOG 132: Muggia et al, JCO, 2000 ICON3: Lancet, 2002

18. 410 patients with stage III or IV ovarian ca, none debulked to <1cm comparison of IV cisplatin and cyclophosphamide to IV cisplatin and paclitaxel

20. 680 patients with stage IIB-IV ovarian ca either optimally or suboptimally debulked randomised to cisplatin paclitaxel vs cisplatin cyclophosphamide

22. 648 patients with suboptimally debulked stage III/IV ovarian cancer patients randomised post-operatively to cisplatin or paclitaxel or cisplatin and paclitaxel

24. 2074 patients looser entry criteria: ”clinician certain that patient required chemo“ As a result 10% are stage 1 carboplatin and paclitaxel versus ‘control’ (single agent carboplatin or CAP)

26. Carboplatin/Taxol as the ‘gold standard’ 1st line in advanced disease 4 large randomised trials adding paclitaxel to platinum based chemotherapy Differing results 2 positive (GOG-111 and OV10) 2 negative (GOG-132 and ICON3) Why the difference?

27. Trials of platinum and taxanes in 1st line treatment of advanced ovarian cancer

28. Why the differences? Extent of cross over to a taxane, especially at relapse Differences in patient entry criteria Differences in the control group e.g. cyclophosphamide, dose of cisplatin Probably a taxane at some stage in ovary cancer important

29. Advanced disease : what do we do? Carboplatin-containing chemotherapy is the minimum treatment required Fit patients should be offered carboplatin and paclitaxel

30. Intraperitoneal chemotherapy Subject of NCI Clinical Announcement 7 randomised trials meta-analysis IP chemotherapy associated with a 21.6% decrease in the risk of death (HR = 0.79, 0-70-0.89) Survival advantage of approximately 12 months

31. NCI Alert 05.01.06

32. IP chemotherapy

33. GOG 172 Stage III optimally debulked (<1cm residum) Randomised to paclitaxel 135 mg/m2, 24h + cisplatin 75mg/m2 or IV paclitaxel 135mg/m2, 24 h, day 1 + IP cisplatin 100mg/m2 day 2 + IP paclitaxel 60mg/m2 day 8 N=429

34. Toxicity of IP chemotherapy Increased abdominal pain (11-20% gd 3) Increased risk of infection and fever (16 vs 6%) Catheter complication rate around 33% Dose intensity of IP route (only 42% completed all 6 IP cycles in GOG 172) However QOL equal at 12 months post chemotherapy in GOG 172

35. Arguments against IP Increased toxicity No comparison to carboplatin/taxol IV No cost benefit anaylsis Slow recruitment to studies (select group) Patient choice Comorbidities Not suitable with adhesions

37. Treatment of relapsed ovarian cancer; considerations Platinum sensitivity Symptoms Disease imminently life-threatening? Residual toxicity from previous treatments Overall fitness

38. Treatment Considerations in Recurrent Ovarian Cancer Refractory disease: no response or incomplete response to platinum-based therapy Relapsed disease: progression after clinical complete response Platinum sensitive: ? 6 month platinum-free interval Platinum resistant: ? 6 month platinum-free interval

39. Effect of PFI on Response Rate

40. Management of Rising CA-125 in an Asymptomatic Patient Highly predictive of clinical recurrence within median of 4-6 months1,2 No benefit for immediate chemotherapy (based on CA125) compared to delayed chemotherapy at time of clinical progression OV05 study (Rustin, ASCO 2009) Asymptomatically rising CA125 is good setting to test non-toxic biological agents

41. Platinum-sensitive relapse Re-expose to platinum, either in the form of single-agent carboplatin or carboplatin and paclitaxel (ICON-4)

42. ICON 4/AGO-OVAR 2.2 2 parallel randomized multicenter trials

43. Paclitaxel/Platinum vs Conventional Platinum-Based Chemotherapy: PFS

44. Paclitaxel/Platinum vs Conventional Platinum-Based Chemotherapy: OS

45. Platinum-resistant relapse Dose-dense platinum Liposomal doxorubicin Topotecan Gemcitabine Which is better? Few randomized trials have been performed Topotecan vs paclitaxel Liposomal doxorubicin vs topotecan Gemcitabine vs liposomal doxorubicin

46. PLD vs Topotecan in Recurrent/Refractory Ovarian Cancer

47. PLD vs Topotecan: Patients With Platinum-Refractory Disease

48. PLD vs Topotecan: Patients With Platinum-Sensitive Disease

49. Pick of the novel treatment strategies Compounds in recently completed or ongoing trials Bevacizumab mAb directed against VEGF-A Being tested in 1st line setting GOG218 and ICON7 Olaparib Poly(ADP)-Ribose Polymerase (PARP) inhibitor Phase Ib study shows evidence of efficacy in germline BRCA1/2 mutation carriers

53. Escalation Phase (n=46, Jul05 – Mar07) 10 dose level cohorts from 10mg daily given for 2 of 3 days to 600mg bd continuous oral dosing Various tumour types; BRCA carrier status not mandatory

54. Expansion Phase (n=56; Jan07-Feb08) at 200mg bd continuous All BRCA mutation carriers 50 ovarian (46 evaluable), 4 breast, 2 prostate

55. Expansion Phase (n=56; Jan07-Feb08) at 200mg bd continuous All BRCA mutation carriers 50 ovarian (46 evaluable), 4 breast, 2 prostate

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