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BALKAN MCO 2011 - J. Vermorken - First line treatment of ovarian cancer: surgery and adjuvant therapy
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BALKAN MCO 2011 - J. Vermorken - First line treatment of ovarian cancer: surgery and adjuvant therapy

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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
  • The US National Cancer Institute accepts PFS as BEV is incorporated in all three arms of GOG 252, our IP versus dose dense IV trial
  • And in our dose dense study attempting to confirm the results of the JGOG study presented by Prof Katsumata, where bevacizumab is optional but where cost is not an issue, 80% have opted BEV at entry, prior to randomization.

BALKAN MCO 2011 - J. Vermorken - First line treatment of ovarian cancer: surgery and adjuvant therapy BALKAN MCO 2011 - J. Vermorken - First line treatment of ovarian cancer: surgery and adjuvant therapy Presentation Transcript

  • First-line Treatment of Ovarian Cancer: Surgery and Adjuvant Therapy Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium Balkan Masterclass in Clinical Oncology, Dubrovnik, Croatia 2011, 11-15 May
  • 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)
  • 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
  • Prognostic Factors in Early Ovarian Cancer Stage I Study No. of pts Median Strongest group involved FUP (yr) prognostic factors Vergote et al 1545 3.5 + -10.1 Grade 2001 Zanetta et al 350 9 Grade 1998 Completeness of staging + Norway; + Sweden
  • Prognostic Factors in Advanced-Stage Ovarian Cancer Stages IIb-IV
    • Postsurgery During Relapse
    • Pre-chemotherapy Chemo
    • Residual disease Type of chemo Time since last CT
    • Performance status CA 125 fall Disease bulk
    • Stage Interval debulking Histology
    • Grade No. disease sites
    • Age Perf. Status
    • Ascites Time since DX
    • Histology
    • Proliferation markers
    • Quantitative pathol. features
    • Ploidy
    • Molecular markers (unclear)
    Eisenhauer et al, 1999 (modified)
  • GCIG Consensus Statements (2004) on Surgery
    • Tissue should be obtained for histologic diagnosis
    • Staging should be performed according to FIGO guidelines (e.g. for EOC at least LNS and peritoneal staging)
    • Up-front maximal surgical effort at cytoreduction with the goal of no residual disease should be undertaken
    • If not possible, a second attempt in those without PD after 3-5 cycles of chemotherapy should be made
    • Surgery should be done by a appropriately treated surgeon with experience in the management of ovarian cancer
    • 3 rd OCCC (Thipgen et al, Ann Oncol 2005)
  • Why Strict Guidelines of Surgery in Front-Line Trials
    • To avoid inclusion of tumors other than celomic epithelial carcinoma of the ovary and peritoneal cavity
    • Results of therapy depend to a great degree on the composition of the study population with regard to stage or extent of disease
    • Volume of disease, particulary in patients with FIGO stage III disease, impacts on response to chemotherapy and survival*
    • *Hoskins et al, Gynecol Oncol and Am J Obstet Gynecol 1994
  • Bristow et al, 2002
  • 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
  • Optimal Chemotherapy of Advanced Ovarian Cancer: Historical Perspective Alkylating Cisplatin Carboplatin Paclitaxel Agents     Doxorubicin topotecan?, LPD? gemcitabine?
  • 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
  • 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
  • Potential Role of Interval Debulking in OC Suboptimally debulked Study Stage of Chemotherapy No. of Outcome Group disease pts EORTC* IIb-IV 3 x CP II 3 x CP 319 49%  1995/2001 RD > 1 cm vs 6 x CP risk of death GOG III-IV 3 x TP II 3 x TP 550 no risk 2002 RD > 1 cm vs 6 x TP reduction * van der Burg et al (NEJM 1995 [2001]) ° Rose et al (NEJM, 2004)
  • Survival By Treatment 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 p=0.0032 Years O N Number of patients at risk: 122 159 84 40 16 5 Surgery 138 160 64 21 10 4 No Surgery Treatment
  • Biologic Characteristics of Tumor vs Aggressiveness of Surgery in ADOVCA A basis for NACT? Chemosensitive Successful Debulking Survival
  • 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)
  •  
  • Vergote et al, N Engl J Med 2010; 363: 943-953
  • New Data for Advanced Ovarian Cancer
    • NACT an alternative for not optimal resectable FIGO IIIc (Vergote et al, NEJM 2010)
    • No benefit from adding a third drug to TC
    • 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)
    • Dose dense TC superior (JCOG study) Confirmatory studies ongoing
    • IP therapy finally recognized
  • 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
  • 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
  • IP Chemotherapy in ADOVCA “Recognition at last” Vermorken JB. Ann Oncol 2006; 17 (suppl. 10): x241-x246
  • 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
  • Pooled Data (all cisplatin studies) HR 0.79 (95% CI : 0.70, 0.89)
  • 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.
  • 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
  • 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%
  • 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
  • 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)
  • 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
  • ICON-7: PFS http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf Accessed 15 October 2010 Academic analysis
  • 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)
      • Events, n (%)
    173 (74) 158 (68)
      • Median, months
    10.5 15.9
      • Log-rank test
    p<0.001
      • Hazard ratio (95% CI)
    0.68 (0.55–0.85)
      • Restricted mean
    13.3 16.5
  • GOG #218: Patient Inconvenience and Toxicity
    • 23% risk of developing grade 2 hypertension
    • 10% risk for grade 3 to 4 hypertension
    • 2.3% risk for ≥ grade 3 GI perforation hemorrhage fistula formation
  • GOG #218: Cost-Effectiveness
    • Based on PFS and bowel perforation rates
    • Incremental cost-effectiveness ratios (ICERs) per PF live-year saved (PF-LYS) were estimated
    • For the 600 patients entered onto each arm of GOG #218:
    • Cohn DE et al, J Clin Oncol 2011; 29: 1247-1251
    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
  • GOG Ovarian Strategy: GOG 252 IV Paclitaxel 135 mg/m 2 day 1 IP Cisplatin 75 mg/m 2 day 2 IP Paclitaxel 60 mg/m 2 day 8 IV Bevacizumab 15 mg/kg IV Paclitaxel 80 mg/m 2 weekly IP Carboplatin AUC 6 IV Bevacizumab 15 mg/kg IV Paclitaxel 80 mg/m 2 weekly IV Carboplatin AUC 6 q 3 wk IV Bevacizumab 15 mg/kg q 3 wk Bevacizumab q 3 wk Maintenance x 22 Control R A N D O M I Z E Optimal disease (  1 cm residual)
  • GOG Ovarian Strategy: GOG 262 IV Paclitaxel 175 mg/m2 IV Carboplatin AUC 6 +/- IV Bevacizumab 15 mg/kg Control IV Paclitaxel 80 mg/m2 weekly IV Carboplatin AUC 6 q 3 wk +/- IV Bevacizumab 15 mg/kg q 3 wk Bevacizumab q 3 wk Maintenance x 22 R A N D O M I Z E Suboptimal disease (  1 cm residual)
  • 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