J.B. Vermorken - Ovarian cancer - State of the art


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  • ICON7 - primary endpoint was again PFS, but in this case by RECIST criteria only, and demonstrated a statistically significant, though more modest benefit for PFS favoring the experimental arm. Similar to GOG 0218, the maximal effect appears at ~ 12 months, max duration therapy with BEV
  • Retrospective subset analysis of 465 with advanced disease demonstrated a more robust impact on PFS similar to GOG 218 - HR 0.68
  • J.B. Vermorken - Ovarian cancer - State of the art

    1. 1. State of the Art in Ovarian cancer Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium 3rd EASO Masterclass in Clinical Oncology Amman, 2011
    2. 2. Epithelial Ovarian Cancer Epidemiology <ul><li>The crude incidence of ovarian cancer in the European Union is 18/100.000 women per year, the mortality is 12/100.000 women per year </li></ul><ul><li>The median age at diagnosis is 63 years. The incidence increases with age and peaks in the 8th decade. Between the age of 70-74 years the age-specific incidence is 57/100.000 women per year </li></ul><ul><li>* ESMO minimum Clinical Recommendations </li></ul><ul><li>Ann Oncol 19 (suppl 2): ii14-ii16, 2008 </li></ul>
    3. 3. Five-year Survival in Ovarian Cancer 30 years of experience Vol. Year Cases Ia IV Overall (n) % 16 1963-68 4588 66.7 5.0 27.3 19 1976-78 6724 72.3 4.5 29.8 21 1982-86 10912 82.3 8.0 35.0 23 1990-92 7059 83.5 11.1 41.6 25 1996-98 4116 89.3 13.4 46.4 26* 1999-01 4911 89.3 18.6 49.7 Int. J Gynecol Obstet 2006 (Suppl 1)
    4. 4. Epithelial Ovarian Cancer Milestones <ul><li>Surgery according to FIGO guidelines </li></ul><ul><ul><li>At least LNS and peritoneal staging in early ovarian cancer </li></ul></ul><ul><ul><li>Upfront maximal surgical debulking in advanced ovarian cancer </li></ul></ul><ul><li>Chemotherapy evolution </li></ul><ul><ul><li>Introduction of platinum compounds </li></ul></ul><ul><ul><li>Introduction of taxanes </li></ul></ul><ul><li>The set-up of the GCIG in 1997 </li></ul>
    5. 5. Epithelial Ovarian Cancer Milestones http://ctep.cancer.gov/resources/gcig/index.html
    6. 6. Are There Any New Developments in Early Ovarian Cancer? FIGO I-IIa <ul><li>Grade and completeness of staging are the most strongest prognostic factors </li></ul><ul><li>Low risk patients do not need chemotherapy as an adjuvant treatment (5-yr survival ≥ 95%) </li></ul><ul><li>High-risk patients do need adjuvant platinum-based chemotherapy: combined analysis of ICON-1 and ACTION trial* showed 5-yr OS 82%vs 74%, p=.008 </li></ul><ul><li>Three vs six cycles: no significant difference in outcome, but recurrence rate with 6 cycles was 24% lower than with 3 cycles, and significantly more toxicity </li></ul><ul><li>*Trimbos et al, JNCI 2003 Bell et al, Gynecol Oncol 2006 </li></ul>
    7. 7. Prognostic Factors in Advanced-Stage Ovarian Cancer Stages IIb-IV <ul><li>Postsurgery During Relapse </li></ul><ul><li>Pre-chemotherapy Chemo </li></ul><ul><li>Residual disease Type of chemo Time since last CT </li></ul><ul><li>Performance status CA 125 fall Disease bulk </li></ul><ul><li>Stage Interval debulking Histology </li></ul><ul><li>Grade No. disease sites </li></ul><ul><li>Age Perf. Status </li></ul><ul><li>Ascites Time since DX </li></ul><ul><li>Histology </li></ul><ul><li>Proliferation markers </li></ul><ul><li>Quantitative pathol. features </li></ul><ul><li>Ploidy </li></ul><ul><li>Molecular markers (unclear) </li></ul>Eisenhauer et al, 1999 (modified)
    8. 8. Management of Advanced-Stage Ovarian Cancer Stages IIb-III (IV) <ul><li>Upfront radical cytoreductive surgery </li></ul><ul><li>In case this is not possible, a second attempt should be made </li></ul><ul><li>Platinum-based chemotherapy </li></ul><ul><li>Six cycles </li></ul><ul><li>No second-look </li></ul>Consensus meeting, 1998 Bergen (the Netherlands)
    9. 9. Optimal First-line Chemotherapy in ADOVCA: Historical Perspective Alkylating Cisplatin Carboplatin Paclitaxel Agents     Doxorubicin topotecan?, LPD? gemcitabine? Epirubicin
    10. 10. Advanced Ovarian Cancer 1998-2011 Treatment <ul><li>Paclitaxel + Carboplatin (TC) </li></ul><ul><ul><li>Generally agreed standard </li></ul></ul><ul><ul><li>“ Control Arm” of all recent randomized trials </li></ul></ul><ul><ul><li>No other regimen shown to outperform it </li></ul></ul><ul><li>However, results far from perfect: </li></ul><ul><ul><li>Median TTP: 15-18 mo </li></ul></ul><ul><ul><li>Median OS: <3 yrs </li></ul></ul>
    11. 11. Standard of Care <ul><li>Optimal Surgery </li></ul><ul><li>( = «  No residual Disease » ) </li></ul><ul><li>+ </li></ul><ul><li>TC Chemotherapy </li></ul>
    12. 12. Lessons from Studies of Histotype <ul><li>Histotype matters </li></ul><ul><li>Mucinous, endometrioid and clear cell cancers are distinct entities with different genetic changes, gene expression profiles and sensitivities to chemotherapy </li></ul><ul><li>Separate trials will be required </li></ul><ul><li>Recent discoveries in clear cell cancer suggest changes in chromatine remodeling may provide a target </li></ul><ul><li>Bast, presented at Valencia meeting 2011 </li></ul>
    13. 13. How to Improve Outcome in Advanced OC Beyond PAC-CARBO <ul><li>Increase rate of optimal cytoreduction (definition ODS) </li></ul><ul><ul><li>concept of NACT </li></ul></ul><ul><ul><li>role for interval debulking? </li></ul></ul><ul><li>Increase efficacy of cytotoxic chemotherapy </li></ul><ul><ul><li>adding a third drug </li></ul></ul><ul><ul><li>maintenance/consolidation therapy </li></ul></ul><ul><ul><li>dose-dense therapy </li></ul></ul><ul><li>Modulate resistance </li></ul><ul><ul><li>modulating agents </li></ul></ul><ul><ul><li>increase dose / exposure (systemic / regional) </li></ul></ul><ul><li>The use of targeted therapies </li></ul>
    14. 14. New Data for Advanced Ovarian Cancer <ul><li>NACT an alternative for not optimal resectable FIGO IIIc (Vergote et al, NEJM 2010) </li></ul><ul><li>No benefit from adding a third drug to TC </li></ul><ul><li>No role for consolidation/maintenance cytotoxic CT? 1 study positive for PFS (12 vs 3 cycles paclitaxel PFS 28 vs 21 months, p<.005): Markman et al, JCO 2003) </li></ul><ul><li>Dose dense TC superior (JGOG study) Confirmatory studies ongoing </li></ul><ul><li>IP therapy finally recognized </li></ul>
    15. 15. Targeted Therapies in Ovarian Cancer Target Drug(s) ErbB kinases Gefitinib, erlotinib, lapatinib, canertinib, cetuximab, pertuzumab, matuzumab, trastuzumab MUC1 / PEM Pemtumomab MUC16 (CA 125) Oregovomab mTOR / AKT Temsirolimus, everolimus, deforolimus Apoptosis pathway AEG35156, OGX-011 Angiogenesis Bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, vatalanib Endothelial cells Combretastatin, Oxi4503 Matrix metalloproteinases BAY 12-9566, marimastat
    16. 16. First-Line Trial of Bevacizumab in Ovarian Cancer (GOG#218) <ul><li>Stage III° </li></ul><ul><li>Optimal and </li></ul><ul><li>Suboptimal or </li></ul><ul><li>Stage IV </li></ul>R A N D OM I Z E Paclitaxel/Carbo (PC) + placebo x6  placebo x16 PC+bev* x6  placebo x16 PC+bev x6  bev x16 *Dose of bevacizumab 15 mg/kg q 3 weeks °Total number of patients 2000
    17. 17. Key Results There is clear clinical effect of bevacizumab on PFS <ul><li>Per protocol analysis: </li></ul><ul><ul><li>Significant improvement of PFS in Arm III only </li></ul></ul><ul><ul><li>Per protocol analysis: 3.8 mo increase PFS (med) HR 0.717, p <0.0001 </li></ul></ul><ul><ul><li>~ half of all progression events occurred on therapy </li></ul></ul><ul><li>CA 125 censored PFS (sensitivity analysis): </li></ul><ul><ul><li>Similar outcomes (HR 0.645), but 25% fewer events </li></ul></ul><ul><li>Overall survival and QoL: to be discussed </li></ul>Proportion surviving progression free Months from randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 + BEV (Arm II) Chemo (Arm I) + BEV -> BEV maintenance (Arm III)
    18. 18. First-Line Trial of Bevacizumab in Ovarian Cancer (ICON - 7) <ul><li>Stage Ic - IV° </li></ul><ul><li>Excluding those scheduled for further surgery </li></ul>R A N D OM I Z E Paclitaxel/Carbo (PC) PC+bev* x6  bev x12 *Dose of bevacizumab 7.5 mg/kg q 3 weeks °Total number of patients 1500
    19. 19. ICON-7: PFS http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf Accessed 15 October 2010 Academic analysis
    20. 20. PFS: FIGO stage III suboptimal and FIGO stage IV with debulking Number at risk Control 234 205 98 36 14 2 Research 231 213 159 56 10 1 1.00 0.75 0.50 0.25 0 Proportion alive without progression Time (months) 0 3 6 9 12 15 18 21 24 27 30 10.5 15.9 Control Research http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf Accessed 15 October 2010 Control (n=234) Research (n=231) <ul><ul><li>Events, n (%) </li></ul></ul>173 (74) 158 (68) <ul><ul><li>Median, months </li></ul></ul>10.5 15.9 <ul><ul><li>Log-rank test </li></ul></ul>p<0.001 <ul><ul><li>Hazard ratio (95% CI) </li></ul></ul>0.68 (0.55–0.85) <ul><ul><li>Restricted mean </li></ul></ul>13.3 16.5
    21. 21. Kristensen G. et al, ASCO 2011, abstract #LBA5006
    22. 22. Kristensen G. et al, ASCO 2011, abstract #LBA5006
    23. 23. GOG #218: Patient Inconvenience and Toxicity <ul><li>23% risk of developing grade 2 hypertension </li></ul><ul><li>10% risk for grade 3 to 4 hypertension </li></ul><ul><li>2.3% risk for ≥ grade 3 GI perforation hemorrhage fistula formation </li></ul>
    24. 24. GOG #218: Cost-Effectiveness <ul><li>Based on PFS and bowel perforation rates </li></ul><ul><li>Incremental cost-effectiveness ratios (ICERs) per PF live-year saved (PF-LYS) were estimated </li></ul><ul><li>For the 600 patients entered onto each arm of GOG #218: </li></ul><ul><li>Cohn DE et al, J Clin Oncol 2011; 29: 1247-1251 </li></ul>Treatment Total Cost ICER ($) ICER per PF-LYS ($) TC 2.5 M 247.616 Referent TCB 21.4 M 1.9 M 479.712 TCB + B 78.3 M 5.6 M 401.088
    25. 25. Recurrent Ovarian Cancer: Important Issues <ul><li>Presentation (asymptomatic 55-70%; TFI*) </li></ul><ul><li>Realistic goals </li></ul><ul><li>When to treat </li></ul><ul><li>How to treat </li></ul><ul><li>New combinations and compounds </li></ul><ul><li>*<6 months; 6-12 months; <12 months </li></ul>
    26. 26. Realistic Goals of Second-line Therapy in Ovarian Cancer <ul><li>Improve cancer-related symptoms </li></ul><ul><li>Optimize overall quality of life </li></ul><ul><li>Delay time to symptomatic disease progression </li></ul><ul><li>Prolong overall survival </li></ul><ul><li>Achieve an “objective response” </li></ul><ul><li>Markman M, 2002 </li></ul>
    27. 27. When to Treat? Harries and Gore, 2002
    28. 28. Trial Design Ovarian cancer in complete remission after first-line platinum based chemotherapy and a normal CA125 CA125>2 x upper limit of normal RANDOMIZED Early treatment Clinician and patient informed Delayed treatment Clinician not informed , treatment delayed until clinically indicated REGISTER Blinded CA125 measured every 3 months Rustin GJ et al, Lancet 2010; vol 376: 1155-1163
    29. 29. Overall Survival HR=1.00 (95%CI 0.82-1.22) p=0.98 Early Delayed Abs diff at 2 years= 0.1% (95% CI diff= -6.8, 6.3%) Rustin GJ et al, Lancet 2010; vol 376: 1155-1163
    30. 30. Time from Randomisation to First Deterioration in Global Health Score (or death) Proportion alive without deterioration in GHS Number at risk Rustin GJ et al, Lancet 2010; vol 376: 1155-1163
    31. 31. Chemotherapy Options in Platinum-Sensitive Recurrent Ovarian Cancer (ROC) <ul><li>Traditionally, ROC patients with TFI > 6 mo have been retreated with platinum-based chemotherapy ICON-4 trial: Platinum/paclitaxel > Pt-alone (PFS, OS  ) </li></ul><ul><li>Cumulative toxicity from primary therapy (neuro) can preclude retreatment with paclitaxel/carboplatin </li></ul><ul><ul><li>AGO OVAR 2.5: carbo/gemcitabine vs carbo (PFS  ) </li></ul></ul><ul><ul><li>OCEANS: carbo/gemcitabine ± bevacizumab (study) </li></ul></ul><ul><ul><li>CALYPSO: PLD/carbo vs paclitaxel/carbo (PFS  ) </li></ul></ul>
    32. 32. OCEANS Trial : a Randomized, Double-Blind Placebo-Contr. Ph III Trial of CT +/- Bev In Platinum (Pt) –Sensitive Recurrent EOC <ul><li>Stratification variables: </li></ul><ul><li>Platinum-free interval (6–12 vs >12 months) </li></ul><ul><li>Cytoreductive surgery for recurrent disease (yes vs no) </li></ul>Gemcitabine 1,000mg/m 2 , days 1, 8 q3w Carboplatin AUC4 q3w Gemcitabine 1,000mg/m 2 , days 1, 8 q3w Carboplatin AUC4 q3w <ul><li>Platinum-sensitive recurrent ovarian cancer </li></ul><ul><li>Measurable disease </li></ul><ul><li>ECOG PS 0/1 </li></ul><ul><li>No prior chemotherapy for recurrent disease </li></ul><ul><li>No prior Avastin </li></ul><ul><li>(n=484) </li></ul>Placebo q3w Avastin 15mg/kg q3w Carboplatin/gemcitabine for 6 (up to 10) cycles PD PD Aghajanin C et al –MSKCC (LBA # 5007) PFS ?
    33. 36. Main reason for discontinuation of Bev = PD
    34. 37. CALYPSO (n=973 patients) q 4 wks q 3 wks PLD 30 mg/m², d1 Carbo AUC 5 PACL 175 mg/m², d1 Carbo AUC 5, d1 Efficacy* PFS 11.3 mo PFS 9.4 mo* Toxicity PLT, HFS, nausea** mucositis ANC, alopecia, HSR** sensory neuropathy *HR 0.82 (95% CI 0.72-0.94), p=0.005 **p<0.01 Pujade-Laurain et al, J Clin Oncol 2010; 28: 3323-3329
    35. 38. Chemotherapy Options in Platinum-Resistant Recurrent OC or for those with Partially Platinum-Sensitive Disease (TFI 6-12 mo) <ul><li>Numerous agents are available that can be used as a single agent: </li></ul><ul><ul><li>gemcitabine, PLD, topotecan, paclitaxel, docetaxel, oral etoposide, altretamine, trabectedin, and hormonal agents </li></ul></ul><ul><li>Take into consideration the patient’s anticipated tolerability and cumulative toxicity from front-line therapy </li></ul>
    36. 39. Trabectedin – Structure and Origin Scotto. Anticancer Drugs 2002; 13 (Sup 1): s3-s6 A B C Trabectedin Structure: 3 tetrahydroisoquinolone rings <ul><li>Trabectedin (ET-743; Yondelis®) is a novel, marine-derived anticancer agent originally isolated from marine Caribbean tunicate Ecteinascidia turbinata and is now produced synthetically. </li></ul><ul><li>Chemically comprised of three fused rings (A, B and C), each of them with one or more different functions. </li></ul>
    37. 40. An Open-label Multicenter Randomized Phase 3 Study Comparing DOXIL/CAELYX and Trabectedin with DOXIL/CAELYX Alone in Advanced ROC <ul><li>Advanced Recurrent Epithelial Ovarian Cancer </li></ul><ul><ul><li>One prior regimen </li></ul></ul><ul><ul><li>Evaluable and measurable disease </li></ul></ul><ul><ul><li>Platinum-sensitive and -resistant </li></ul></ul>Accrual Goal: 650 patients Primary endpoint: PFS/OS Other endpoints: RR, Safety <ul><li>Translational Research: </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Pharmacogenomics </li></ul><ul><li>Pharmacoeconomics </li></ul><ul><li>Quality of Life </li></ul><ul><li>Circulating tumor cells </li></ul>R A N D O M I z E doxil 50 mg/m 2 every 4 wks doxil 30 mg/m 2 plus trabectedin 1.1mg/m 2 every 3 wks Monk BJ et al, J Clin Oncol 2010; 28(19):3107-14.
    38. 41. Monk BJ et al, J Clin Oncol 2010; 28(19):3107-14.
    39. 42. An Open-label Multicenter Randomized Phase 3 Study Comparing DOXIL/CAELYX and Trabectedin with DOXIL/CAELYX Alone in Advanced ROC Monk BJ et al, submitted
    40. 43. PARP Inhibitors <ul><li>Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a key enzyme in the repair of DNA . Inhibition of PARP leads to accumulation of breaks in DS-DNA and cell death. </li></ul><ul><li>PARP inhibitors are in particular exciting in cancers with germline mutations in the BRCA gene, but benefit might be wider (> 50% of patients with high-grade sporadic EOC possibly have loss of BRCA function </li></ul><ul><ul><li>Continuous oral olaparib (AZD 2281)  57.6% clinical benefit </li></ul></ul><ul><ul><li>Phase II ongoing in platinum-sensitive serous OC after 2 or more platinum-containing regimen </li></ul></ul>
    41. 44. Phase 2 Randomized Placebo-controlled Study of Olaparib in Pts with Platinum-Sensitive relapsed Serous OC Ledermann J et al (# 5003) n = 265
    42. 47. Phase 2 Random. Placebo-controlled Study of Olaparib in Pts with Platinum-Sensitive Relapsed Serous OC Ledermann J et al (# 5003) <ul><li>Overall survival data : immature </li></ul><ul><li>QoL : no ≠ in improvement / time to worsening </li></ul>
    43. 48. Take-Home Messages for ADOVCA <ul><li>Upfront surgery followed by 6 cycles of Pt-Tax-based CT is still standard </li></ul><ul><li>Paclitaxel + carboplatin (TC) generally agreed standard arm for trials </li></ul><ul><li>NACT followed by surgery in stages IIIc-IV OC showed the same OS and PFS as PDS with less morbidity in one large randomized GCIG trial. </li></ul><ul><li>A dose-dense therapy approach may be of benefit </li></ul><ul><li>Intraperitoneal chemotherapy suitable for selected patients </li></ul><ul><li>Targeted therapy is promising (in particular anti-angiogenic approaches), but not yet standard </li></ul>