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MON 2011 - Slide 10 - J.B. Vermorken - Ovarian cancer

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  • 1. Optimal Treatment of Ovarian Cancer Jan B Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium Masterclass, Ermatingen, Switzerland, April 4, 2011
  • 2. Epithelial Ovarian Cancer-Stage III: Initial Therapy Case #1
    • A 59 year old female school teacher presents with abdominal pain and ascites. Physical exam reveals a 15cm pelvic mass. CA-125 is elevated to 325, and a CT scan confirms pelvic and peritoneal disease. She undergoes a total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and optimal tumor debulking for stage IIIC ovarian cancer. BUN and creatinine levels are normal. She is an insulin-dependent diabetic under good control. Her ECOG performance status is 0.
  • 3. Epithelial Ovarian Cancer-Stage III: Initial Therapy Case #1
    • Your choice for treatment is:
    • Paclitaxel + carboplatin
    • Docetaxel + carboplatin
    • Intravenous + intraperitoneal chemotherapy
    • Other
  • 4. Epithelial Ovarian Cancer: Recurrent Disease Case #2 A 62 year old post-menopausal woman presents with bulky pelvic and abdominal recurrence of her epithelial ovarian cancer. 10 months previously she achieved a complete response after treatment with carboplatin- paclitaxel x 6 cycles. She still suffers some peripheral neuropathy (grade 1). Her ECOG performance status is 1. The patient would like to receive aggressive treatment for her recurrent disease.
  • 5. Epithelial Ovarian Cancer: Recurrent Disease Case #2 Should this patient have debulking surgery? Yes/No What chemotherapy would you give this patient? Carboplatin-paclitaxel (Taxol) Carboplatin-gemcitabine (Gemsar) Carboplatin-PLD (Caelyx) PLD-trabectedin (Yondelis) Carboplatin monotherapy PLD (Caelyx) Topotecan (Hycamtin) Gemcitabine Other
  • 6. Outline
    • Milestones in the treatment of ovarian cancer
    • Standard management of advanced ovarian cancer
    • Various ways to improve results beyond PAC-CARBO
    • Potential roles of targeted therapies
    • Types of relapsed ovarian cancer
    • Strategies towards treatment of relapsed disease
    • Take-home messages
  • 7. Epithelial Ovarian Cancer (EOC) Introduction
    • Most deadly gynecologic cancer in western world
    • There is no proven screening test
    • Many women present with vague symptoms; abdominal bloating, change in bowel or bladder habits, early satiety, or abdominal pain  many present with advanced disease
    • Initial evaluation: history and PE, imaging studies, assessment of CA-125, biopsies a/o colonoscopy
  • 8. Epithelial Ovarian Cancer Epidemiology
    • 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
    • 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
    • * ESMO minimum Clinical Recommendations
    • Ann Oncol 19 (suppl 2): ii14-ii16, 2008
  • 9. 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)
  • 10. Epithelial Ovarian Cancer Milestones
    • Surgery according to FIGO guidelines
      • At least LNS and peritoneal staging in early ovarian cancer
      • Upfront maximal surgical debulking in advanced ovarian cancer
    • Chemotherapy evolution
      • Introduction of platinum compounds
      • Introduction of taxanes
    • The set-up of the GCIG in 1997
  • 11. Epithelial Ovarian Cancer Milestones http://ctep.cancer.gov/resources/gcig/index.html
  • 12. Advanced Ovarian Cancer 1998-2011 Treatment
    • Paclitaxel + Carboplatin (TC)
      • Generally agreed standard
      • “ Control Arm” of all recent randomized trials
      • No other regimen shown to outperform it
    • However, results far from perfect:
      • Median TTP: 15-18 mo
      • Median OS: <3 yrs
  • 13. How to Improve Outcome in Advanced OC Beyond PAC-CARBO
    • Increase rate of optimal cytoreduction (definition ODS)
      • concept of NACT
      • role for interval debulking?
    • Increase efficacy of cytotoxic chemotherapy
      • adding a third drug
      • maintenance/consolidation therapy
      • dose-dense therapy
    • Modulate resistance
      • modulating agents
      • increase dose / exposure (systemic / regional)
    • The use of targeted therapies
  • 14. Biologic Characteristics of Tumor vs Aggressiveness of Surgery in ADOVCA A basis for NACT? Chemosensitive Successful Debulking Survival
  • 15. Neoadjuvant Chemotherapy followed by IDS versus Surgery followed by Chemotherapy A prospective randomized study
    • Phase III trial – India (New Delhi)
    • 128 stage III/IV (pleural effusion only)
    • Arm A: primary surgery  6 x TC
    • Arm B: 3 x TC  IDS  3 x TC
    • Results :
      • Higher optimal debulking rate in B (p<.0001)
      • Decrease blood loss in B (p<.003)
      • Reduced postoperative infections (p<.04)
      • Quality of life score better in B (p<.001)
      • Disease-free and overall survival not different to date
    • Kumar et al, ASCO abstract #5531 (2007)
  • 16.  
  • 17. Vergote et al, N Engl J Med 2010; 363: 943-953
  • 18. Vergote et al, N Engl J Med 2010; 363: 943-953
  • 19. How to Improve Outcome in Advanced OC Beyond PAC-CARBO
    • Increase rate of optimal cytoreduction (definition ODS)
      • role for interval debulking?
      • concept of NACT
    • Increase efficacy of cytotoxic chemotherapy
      • adding a third drug
      • maintenance/consolidation therapy
      • dose-dense therapy
    • Modulate resistance
      • modulating agents
      • increase dose / exposure (systemic / regional)
    • The use of targeted therapies
  • 20. Front-line Trials in Advanced Ovarian Cancer Adding a third drug* Lead Group Arm I Arm II Accrual Outcome AGO TC TC + epirubicin 1282 no benefit NSGO TC TC + epirubicin 887 no benefit AGO TC TC -> TPT 1308 no benefit GOG TC TC + GEM 4312 no benefit TC + LPD GEM + C -> TC TPT + C -> TC NCIC-CTG TC TPT + P -> TC 819 no benefit AGO TC TC + GEM 1742 no benefit * GCIG trials
  • 21. Consolidation/Maintenance Therapies Cytotoxic therapy Study Patients Randomization Results Scarfone ’02 n=162 III-IV, SSL, pCR Pt-Tax based Epirubicin x 4 vs observation OS NS Pfisterer (2003) n=1308 IIb-IV Tax-Carbo Topotecan x 4 vs observation PFS NS OS NS De Placido (2004) n=273 III-IV, SSL, pCR < 2 cm, Pt-based Topotecan x 4 vs observation PFS NS OS NS Markman ’03 N=277 III-IV Tax-Carbo, cCR Paclitaxel 3 or 12 cycles PFS 21 mo vs 28 mo P < 0.005
  • 22. Markman et al, JCO 2003; 21: 2460-2465
  • 23. Schema New Ovarian Elaborate Trial: NOVEL Trial Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancer FIGO Stage II-IV Conventional TC (c-TC)   Paclitaxel 180mg/m 2 , day 1   Carboplatin AUC 6.0, day 1   every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC)   Paclitaxel 80mg/m 2 , days 1,8,15   Carboplatin AUC 6.0, day 1   every 21 days for 6-9 cycles   Randomization Stratification; Residual disease: < 1cm, > 1cm FIGO Stage : II vs. III vs. IV Histology : clear cell/mucinous vs.serous/others Isohishi et al, ASCO 2008 (abstract #5506) Katsumata et al, Lancet 2009: 374: 1331-1338
  • 24. Dose-dense TC (weekly T, 3-weekly C) ASCO 2008 * /Lancet 2009 PFS dd-TC vs c-TC: HR 0.714 p=0.0015 OS dd-TC vs C-TC: HR 0.735 p=0.0496 *Isohishi et al for JGOG, Katsumata et al. Lancet 2009; 374:1331-8
  • 25. How to Improve Outcome in Advanced OC Beyond PAC-CARBO
    • Increase rate of optimal cytoreduction (definition ODS)
      • role for interval debulking?
      • concept of NACT
    • Increase efficacy of cytotoxic chemotherapy
      • adding a third drug
      • maintenance/consolidation therapy
      • dose-dense therapy
    • Modulate resistance
      • modulating agents
      • increase dose / exposure (systemic / regional)
    • The use of targeted therapies
  • 26. IP Chemotherapy in ADOVCA “Recognition at last” Vermorken JB. Ann Oncol 2006; 17 (suppl. 10): x241-x246
  • 27. IPCT vs IVCT in Advanced Ovarian Cancer Overall survival Investigators No. of Overall survival (mo) year published pts Control arm Exp. Arm Alberts et al, 1996 546 41 49 1 Polyzos et al, 1999 90 25 26 Gadducci et al, 2000 113 51 67 Markman et al, 2001 462 52 63 2 Yen et al, 2001 118 48 43 Armstrong et al, 2006 415 50 66 3 1 p = 0.02; 2 p = 0.05; 3 p = 0.03
  • 28. Pooled Data (all cisplatin studies) HR 0.79 (95% CI : 0.70, 0.89)
  • 29. Conclusions on IPCT
    • Combined use of IV and IP chemotherapy leads to a significant survival benefit in women with optimally debulked EOC (median + 12 mo).
    • Based on the most recent trials, strong consideration should be given to a regimen with IP cisplatin (100 mg/m²) and a taxane (whether IV or IP).
    • Toxicities, inconvenience and costs of IP therapy are justified by the improved survival.
  • 30. How to Improve Outcome in Advanced OC Beyond PAC-CARBO
    • Increase rate of optimal cytoreduction (definition ODS)
      • role for interval debulking?
      • concept of NACT
    • Increase efficacy of cytotoxic chemotherapy
      • adding a third drug
      • maintenance/consolidation therapy
      • dose-dense therapy
    • Modulate resistance
      • modulating agents
      • increase dose / exposure (systemic / regional)
    • The use of targeted therapies
  • 31. 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
  • 32. Summary of Completed OC Trials with Bevacizumab (B) Trial Rec/Prim Regimen Outcome Toxicity Burger et al 2007 Rec B 15 mg/kg RR 21%, PFS 4.7 mo G 3/4 GI G3 RR  , G4 Prot Cannistra et al 2008 Rec B 15 mg/kg RR 15.9%, PFS 4.4 mo OS 10.7 GIP 11% ATE 6.8% G3 RR  9.1% Micha et al 2007 Prim B 15 mg/kg + TC RR 80% G 3/4 ANC 48.3% G3 RR  11% DVT 11%
  • 33. First-Line Trial of Bevacizumab in Ovarian Cancer (GOG#218)
    • Stage III°
    • Optimal and
    • Suboptimal or
    • Stage IV
    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
  • 34. Key Results There is clear clinical effect of bevacizumab on PFS
    • Per protocol analysis:
      • Significant improvement of PFS in Arm III only
      • Per protocol analysis: 3.8 mo increase PFS (med) HR 0.717, p <0.0001
      • ~ half of all progression events occurred on therapy
    • CA 125 censored PFS (sensitivity analysis):
      • Similar outcomes (HR 0.645), but 25% fewer events
    • Overall survival and QoL: to be discussed
    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)
  • 35. First-Line Trial of Bevacizumab in Ovarian Cancer (ICON - 7)
    • Stage Ic - IV°
    • Excluding those scheduled for further surgery
    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
  • 36. Recurrent Ovarian Cancer Vermorken JB. Second line randomized trials in epithelial ovarian cancer; Int J Gynecol Cancer 2008; vol. 18 (suppl. 1): 59-66
  • 37. Surveillance Options for Monitoring Disease Activity
    • Second-look laparotomy
    • Physical examination (pelvic exam)
    • Serum tumor marker (CA-125) levels
    • Radiographic imaging
    • Magnetic resonance
    • Computed tomography
    • Positron emission tomography (+CT)
  • 38. Patient VBH (°1944): CA-125 Levels Vermorken JB. Int J Gynecol Cancer 2008; vol. 18 (suppl. 1): 59-66 04/1997: ADOVCA IIIc CAPx3  IDS  CAPx4 05/1999: 1st relapse TCx6  CR 02/2002: 2nd relapse GVPx6  CR 10/2003: 3rd relapse DIPx5  SD 01/2006: PD Caelyxx7  PR 01/2005: PD TPTx4  PR 08/2006: PD GPd1+8 (low dose) Normal range
  • 39. Recurrent Epithelial Ovarian Cancer Type of relapse (1)
    • Asymptomatic CA-125 increase 55-70%
    • Median time to 3 months
    • symptomatic relapse (1-14)
    • Symptomatic relapse: 30-45%
    • Abdomen 31%
    • Pelvis 36%
    • Abdomen + pelvis 14%
    • Nodes 7%
    • Distant (liver) 23%
  • 40. Recurrent Epithelial Ovarian Cancer Type of relapse (2)
    • Disease category
    • Refractory disease
    • Persistent disease
    • TC-resistant
    • TC-sensitive
    • Characteristic
    • PD during 1st-line, NC best response
    • PR to 1st-line (clinic or marker)
    • CCR (or NED) to 1st-line,
    • relapse < 6 months
    • CCR (or NED) to 1st line,
    • relapse > 6 months
    Sabbatini and Spriggs, 1998 (modified)
  • 41. Proportion of Patients Relapsing at Various Time Points Modified from Piccart et al, J Natl Cancer Inst. 2000; 92: 699-708 OV-10: Randomized Intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in advanced ovarian cancer 8% 20% 50%
  • 42. Realistic Goals of Second-line Therapy in Ovarian Cancer
    • Improve cancer-related symptoms
    • Optimize overall quality of life
    • Delay time to symptomatic disease progression
    • Prolong overall survival
    • Achieve an “objective response”
    • Markman M, 2002
  • 43. When to Treat? Harries and Gore, 2002
  • 44. Early Treatment of Relapsed Ovarian Cancer Based on CA125 Level Alone versus Delayed Treatment Based on Conventional Clinical Indicators Results of the Randomized MRC OV05 and EORTC 55955 Trials Gordon Rustin (Mount Vernon Cancer Centre) and Maria van der Burg On behalf of all OV05 and 55955 Collaborators 31 st May 2009
  • 45. 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
  • 46. 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
  • 47. 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
  • 48. Conclusions
    • In early treatment arm based on rise in CA125
      • Second-line chemotherapy started a median of 4.8 months earlier
      • Third-line chemotherapy started a median of 4.6 months earlier
    • This early treatment did not improve overall survival
        • HR=0.98, 95% CI 0.80-1.2, p=0.85
        • Absolute difference at 2 years 0.7% (95%CI -5.8, 7.6%)
    • Early chemotherapy does not improve Qol
    Rustin GJ et al, Lancet 2010; vol 376: 1155-1163
  • 49. Recurrent Epithelial Ovarian Cancer Treatment options
    • Hormonal therapy
    • Single agent chemotherapy
    • Combination chemotherapy
    • Non cytotoxic chemotherapy
    • Surgery
    • Radiotherapy
    • Palliative care
  • 50. Single Agent Chemotherapy in ROC Relationship with platinum sensitivity Agent Response rates (%; range) Refractory Resistant Sensitive Platinum < 10 27-34 59-77 Paclitaxel 3-22 11-37 22-55 Topotecan 6-11 15-18 19-33 Gemcitabine 15-20 19-27 34 Epirubicin 11 a 14 36 Liposomal dox 11 9-15 18-37 Vinorelbine 15-30 21-33 29 Etoposide 27 27 34 Altretamine 10-14 40 Trabectedin 7 37 Conte PF, 2000; Vermorken JB 2000 ( a PFI < 3 mo) Johnston & Gore 2001, Stebbing & Gaya 2002 Monk et al, 2008
  • 51. Chemotherapy Options in Platinum-Sensitive Recurrent Ovarian Cancer (ROC)
    • Traditionally, ROC patients with TFI > 6 mo have been retreated with platinum-based chemotherapy ICON-4 trial: Platinum/paclitaxel > Pt-alone (PFS, OS  )
    • Cumulative toxicity from primary therapy (neuro) can preclude retreatment with paclitaxel/carboplatin
      • AGO OVAR 2.5: carbo/gemcitabine vs carbo (PFS  )
      • OCEANS: carbo/gemcitabine ± bevacizumab (study)
      • CALYPSO: PLD/carbo vs paclitaxel/carbo (PFS  )
  • 52. CALYPSO Study Schema Ovarian cancer in late relapse (> 6 months) after 1 st - or 2 nd -line platinum-based therapy (previous taxane required) International, Intergroup, Open-label, Randomized Phase III Study
    • Stratification:
    • Therapy-free interval (6-12 mo vs > 12 mo)
    • Measurable disease (yes vs no)
    • Center
    R A N D O M I Z E Experimental arm: CD PLD 30 mg/m 2 IV d 1 Carboplatin AUC 5 d 1 Control arm: CP Paclitaxel 175 mg/m 2 IV d 1 Carboplatin AUC 5 d 1 Q 28 days x 6 courses* Q 21 days x 6 courses* *or progression in patients with SD or PR Pujade-Lauraine et al, J Clin Oncol 2010; 28: 3323-3329
  • 53. Progression-Free Survival (ITT) Pujade-Lauraine et al, J Clin Oncol 2010; 28: 3323-3329
  • 54. CALYPSO study: Toxicity Toxicity (G3/4); % CD (n=466) CP (n=501) P Value Neutropenia 35 46 <0.01 Thrombocytopenia 16 6 <0.001 Severe HTOX - Leading to TRT disc 28 6 39 15 <0.01 <0.001 Alopecia (≥ G2; %) 7 84 <0.001 HSR 6 19 <0.001 Sensory neuropathie 5 27 <0.001 HSF (G2-3) 12 2 <0.001 Nausea 35 24 <0.001 Mucositis 14 7 <0.001 Pujade-Lauraine et al, J Clin Oncol 2010; 28: 3323-3329
  • 55. Chemotherapy Options in Platinum-Resistant Recurrent OC or for those with Partially Platinum-Sensitive Disease (TFI 6-12 mo)
    • Numerous agents are available that can be used as a single agent:
      • gemcitabine, PLD, topotecan, paclitaxel, docetaxel, oral etoposide, altretamine, trabectedin, and hormonal agents
    • Take into consideration the patient’s anticipated tolerability and cumulative toxicity from front-line therapy
  • 56. Trabectedin – Structure and Origin Scotto. Anticancer Drugs 2002; 13 (Sup 1): s3-s6 A B C Trabectedin Structure: 3 tetrahydroisoquinolone rings
    • Trabectedin (ET-743; Yondelis®) is a novel, marine-derived anticancer agent originally isolated from marine Caribbean tunicate Ecteinascidia turbinata and is now produced synthetically.
    • Chemically comprised of three fused rings (A, B and C), each of them with one or more different functions.
  • 57. An Open-label Multicenter Randomized Phase 3 Study Comparing DOXIL/CAELYX and Trabectedin with DOXIL/CAELYX Alone in Advanced ROC
    • Advanced Recurrent Epithelial Ovarian Cancer
      • One prior regimen
      • Evaluable and measurable disease
      • Platinum-sensitive and -resistant
    Accrual Goal: 650 patients Primary endpoint: PFS/OS Other endpoints: RR, Safety BJ Monk Principal Investigator A Poveda Chairman SC
    • Translational Research:
    • Pharmacokinetics
    • Pharmacogenomics
    • Pharmacoeconomics
    • Quality of Life
    • Circulating tumor cells
    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
  • 58. OS in the Partially Platinum-Sensitive Population Poveda et al. Annals of Oncology 2010 ; doi:10.1093/annonc/mdq352
  • 59. Safety Profile Selected Grade 3-4 Clinically Relevant AEs PLD n=330 n (%) Trabectedin + PLD n=333 n (%) Hand-foot syndrome 65 (20) 13 (4) Mucosal Inflammation 19 (6) 7 (2) Stomatitis 17 (5) 3 (1) Monk BJ et al. J Clin Oncol 28:3107-3114 (EPAR). Yondelis H-773-II-08 Assessment Report. European Medicines Agency (EMEA), January 2010
  • 60. Mean ALT Among All Patients During Treatment With Trabectedin + PLD 0 1 2 3 4 5 6 Cycle Mean ALT/ULN 1 2 3 4 5 6 7 8 n= 333 309 271 230 205 169 125 105 ALT elevation leading to: Dose Reduction: 18 (5%) Dose Delay: 12 (4%)
  • 61. PARP Inhibitors
    • 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.
    • 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
      • Continuous oral olaparib (AZD 2281)  57.6% clinical benefit
      • Phase II ongoing in platinum-sensitive serous OC after 2 or more platinum-containing regimen
  • 62. Take-Home Messages for ADOVCA
    • Upfront surgery followed by 6 cycles of Pt-Tax-based CT is still standard
    • Paclitaxel + carboplatin (TC) generally agreed standard
    • 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.
    • A dose-dense therapy approach may be of benefit
    • Intraperitoneal chemotherapy suitable for selected patients
    • Targeted therapy is promising (in particular anti-angiogenic approaches), but not yet standard
  • 63. Take-Home Messages for ROC
    • For the management of recurrent ovarian cancer the factors that need to be taken in consideration are:
      • Platinum sensitivity
      • Toxicity from prior treatment
      • Toxicity of available agents
      • Combinations vs single agents
      • Patients’ preference
      • Cost of treatment
  • 64.  
  • 65. Radiotherapy after Induction Chemotherapy in ADOVCA for Consolidation During 1988-1993: 742 patients with stage III EOC received 4 cycles of AP or EP Those will cCR or cPRor NED  second look At SL 3 groups: pCR, pPR, sPR 172 could be randomized: 98 in pCR group Whole abdominal radiotherapy  Rec.n=16; 50%* 6 cycles of AP or EP  Rec.n=25; 71%* no further therapy  Rec.n=23; 74%* Sorbe B, 2003 (* p=0.027)
  • 66. Sorbe B, 2003 (progression-free survival  , p=0.032)
  • 67. Consolidation/Maintenance Therapies Non-cytotoxic therapy Reference Patients Randomization Results Hall ’04 n=300 Ic-IV, Pt-based cCR-SD INF-  x 3 wk -> PD vs observ. PFS NS OS NS Hirte ’01 n=243 NED or resp (<2cm) Post Pt/Tax BAY-129566 vs placebo PFS NS OS NS Ehlen ’02 n=345 III-IV cCR Ovarex vs placebo OS NS Immune resp. vs no resp. TTR > 2-fold (p < 0.001) Seiden ’04 n=447 pCR at 2nd look post Pt-based CT MUC1+, Ic-IV Y90-R1549X1 vs control PFS NS OS NS
  • 68. Ovarian Carcinoma: FIGO nomenclature (Rio de Janeiro 1988) Stage I Growth limited to the ovaries (A, B or C) II Growth involving one or both ovaries with pelvic extension (A, B or C) III Growth involving on or both ovaries and histologically confirmed implants outside the pelvis a/o positive LN (A, B or C, depending on size of extrapelvic lesions and +/- LN IV Growth involving one or both ovaries with DM. In case of pleural effusion cytology should be positive
  • 69. What Have we Learned from Randomized Trials?
    • Some dose schedules or routes of administration are better than others for a specific drug
    • Some drugs are better than others in terms of efficacy
    • In specific circumstances some drugs are to be preferred with respect to toxicity
    • In specific circumstances combination chemotherapy is superior to single agent chemotherapy
    Vermorken JB. Int J Gynecol Cancer 2008; vol. 18 (suppl. 1): 59-66
  • 70. Randomized trials in Relapsed Ovarian Cancer Some drugs are better than others Patient Drug schedule No of Outcome Category patients Plat-Tax 1 leuprorelin 3.75 mg 78 DFS  (p<.05) Refr/resist treosulfan 7.0 g/m² with treo; OS ns Plat-Tax 2 treosulfan 7.0 mg/m² 357 PFS  (p<.0001) Pretreated topotecan 1.5 mg/m², d1-d5 with top; OS  * Platinum 3 PLD 50 mg/m², q.4 wks 474 OS  (p=.05) Pretreated topotecan 1.5 mg/m², d1-5, q.3 wks with PLD; 2-yr S 35 % vs 24 % Platinum 4 PLD 40 mg/m², q 4 wks 153 OS  p=.048 Pretreated Gemcitabine 1000 mg/m², d1, 8, 15 q 4 wks with PLD MS 56 vs 51 wks 1 du Bois et al, 2002; 2 Meier et al, 2004 (* p=.0068 in TFI > 6 mo), 3 Gordon et al, 2001/2004, 4 Ferrandina et al, 2008 q.4 weeks q.3 weeks
  • 71. Differences in Safety Profiles of Therapies for Recurrent Ovarian Cancer Drug HTOX Non-hematologic Toxicity ANC PLT Alopecia N/V STOM NEURO PPE HEP Paclitaxel  -   -  - - Topotecan    -  - - - PLD (Caelyx)*      -  - Treosulfan     - - - - Etoposide  -  -  - - - Gemcitabine   - - - - -  Vinorelbine  -   -  - - Oxaliplatin -  -  -  - - Hexamethylmelanine  - -  -  - - Grade 3+4:  < 5%;  6 – 20%;  > 20%; * Dose 50 mg/m² Vermorken JB. Int J Gynecol Cancer 2008; vol. 18 (suppl. 1): 59-66
  • 72. Randomized Trials: Combo versus Mono Meta-analysis
    • Methods:
      • Systematic review (8 RCT; 6 phase III)
      • Data pooled (Mantel Hanzsel Peto model)
      • Total number of patients: 2312
    • Results:
      • Improved response rate (HR 1.32), PFS (HR 0.67) and OS (HR 0.77) with combo but, only in pt-sensitive population.
    • Orlando et al, ASCO abstract #5524 (2007)
  • 73. Overall Survival at 2 Years NOGGO GONO ARNO 96 Cantù ICON IV GEICO AGO OVAR Overall (95% CI) 0.065 1 15.173 Favours Combo Favours Mono Study Odds ratio (95% CI) % Weight Bolis 1.81 (0.51,6.42) 1.30 (0.88,1.92) 0.53 (0.29,0.96) 0.71 (0.40,1.26) 0.69 (0.30,1.60) 0.82 (0.62,1.08) 0.16 (0.07,0.39) 0.77 (0.50,1.21) 0.80 (0.68,0.95) 1.8 19.5 8.4 9.1 4.2 38.3 3.7 14.9 95% CI Odds Ratio P-value 0.676-0.952 0.802 0.012
  • 74. Trabectedin: A Unique Mechanism of Action
    • Unique in covalently binding to the minor groove of DNA and bending the double helix towards the major groove (A).
    • Binding to DNA results in apoptosis after failure to repair DNA by cellular transcription coupled nucleotide excision repair (TC-NER) mechanisms (B).
    • Trabectedin inhibits the transcriptional activation of certain inducible genes (C).
      • Induces cell cycle arrest at G2/M and apoptosis through a p53 independent mechanism.
        • Aune GJ, Furuta T, Pommier Y. Anti-cancer drugs 2002; 13:545-555.
    (A) (B) (C)
  • 75. PFS Final Analysis- Independent Oncology Radiological + Clinical (Intent to Treat population) Monk BJ et al. J Clin Oncol 2010; 28:3107-3114 PFS Events: 432 HR: 0.72 (0.60-0.88) p=0.0008 #censored: 239 Trabectedin+PLD Median=7.4 months PLD Median=5.6 months