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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 Considerationsin 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 strategiesCompounds 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