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Current state of upfront treatment for newly diagnosed advanced ovarian cancer Ursula Matulonis, M.D. Associate Professor of Medicine, HMS Program Leader, Medical Gyn Oncology Dana-Farber Cancer Institute Boston, MA Email: [email protected] Phone: 617 632-2625 Agenda Review trials for upfront management of newly diagnosed advanced ovarian cancer Review ongoing studies Review new therapies being tested Ovarian cancer 2010 22,500 cases diagnosed per year in the United States and 16,500 deaths per year1. Most patients are diagnosed in late stages; no screening test exists. Pathology: 4 different types (serous, endometrioid, clear cell and mucinous) 1Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA: Cancer J Clin 59(4):225-49, 2009 Unique aspects of newly diagnosed advanced ovarian cancer Upfront surgical management is standard of care: allows access to tissue OC is very chemotherapy sensitive at diagnosis; >80% of cancers will respond to platinum- and taxane-based chemotherapy upfront at dx. Cancer becomes more treatment-refractory following recurrence. Few but some CTC’s. Outcomes for newly diagnosed ovarian cancer have reached a plateau with platinum/taxane combinations. Ovarian cancer staging Stage I: confined to ovary(ies) Stage II: local spread to pelvis Stage III: Stage IIIA: microscopic upper abdominal spread Stage IIIB: upper abd implants <2 cm Stage IIIC: ≥ 2cm implants and/or +nodal involvement Stage IV: spread outside the abdominal cavity. Definition of “extent of debulking” is what is residual post surgical debulking: optimal cytoreduction/debulking: ≤ 1cm residual suboptimal debulking: > 1cm residual cancer Advanced ovarian cancer PFS and OS for newly diagnosed advanced ovarian cancer Study Median PFS Median OS Comments GOG 111 18 mos 38 mos Suboptimally and stage IV GOG 158 21 mos 57.4 mos Optimally cytoreduced only GOG 172 24 mos 65 mos Optimally cytoreduced only. Longest survival observed in advanced ovarian cancer GOG 182 16 mos 44 mos Both optimal and suboptimal. Study compared 5 arms of treatment Weekly pac vs q21 d 28 mos (vs. Lancet 09 17 mos) Not reached Both optimal and suboptimal EORTC neoadjuvant IGCS 2008 29/30 mos Neoadjuvant vs. upfront debulking NEJM 1996 JCO 2003 NEJM 2006 JCO 2009 GOG 218: ASCO 2010 Both 12 mos GOG111: Survival By Treatment Pac + cis (38 mos) Cy + cis (24 mos) Alive (N) Died (N) Cisplatin/ cyclophosphamide 28 174 13.0 Cisplatin/paclitaxel 45 138 18 Treatment McGuire WP, et al. N Engl J Med. 1996;334:1-6. Median PFS Relative Survival (mo) Risk – 0.69 RANDOMIZE GOG0182-ICON5: Schema I Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m2 (d1) x8 II Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m2 (d1) Gemcitabine 800 mg/m2 (d1,8) x8 III Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m2 (d1) Doxil 30 mg/m2 (d1, every other cycle) x8 IV Carboplatin AUC 5 (d3) x4 Topotecan 1.25 mg/m2 (d1-3) V Carboplatin AUC 6 (d8) Gemcitabine 1 g/m2 (d1,8) Carboplatin AUC 6 (d1) x4 Paclitaxel 175 mg/m2 (d1) x4 JCO 2008 GOG0182-ICON5: Progression-Free Survival GOG0182-ICON5: Overall Survival Primary Therapy—IP Median PFS, months IV GOG 1041 GOG 1142 GOG 1723 — 22 18.3 Hazard ratio IP — 28 23.8 Median OS, months IV — 0.78 (P = .01) 0.80 (P = .05) 41 52 50 Hazard ratio IP 49 63 66 PFS = Progression-free survival; OS = Overall survival; IV = Intravenous; IP = Intraperitoneal. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK, et al. N Engl J Med. 2006;354:34-43. 0.76 (P = .02) 0.81 (P = .05) 0.75 (P = .03) GOG #172 Armstrong et.al. N Engl J Med 2006;354:34-43 BRCA Analysis DNA Banking Ovarian cancer Optimal (<1cm) Stage III Stratify: Gross residual Planned 2nd look R A N D O M I Z E Second look Laparotomy (if chosen) Paclitaxel 135 mg/m2/24h Cisplatin 75 mg/m2 q 21 days x 6 Paclitaxel 135 mg/m2/24h Cisplatin 100 mg/m2 IP D2 Paclitaxel 60 mg/m2 IP D8 q 21 days x 6 GOG #172: outcomes Regimen 1 Intravenous Regimen 2 Intraperitoneal Progression-free 18.3 mos 23.8 mos Overall Survival 49.5 mos 66.9 mos (GOG 172) Figure 1 By Treatment Group 1.0 Rx Group IV IP Proportion Progression-Free 0.9 0.8 PF Failed Total 50 160 210 63 142 205 0.7 23.8 months for IP group 0.6 0.5 (Δ = 6 months) 0.4 0.3 18.3 months for IV 0.2 0.1 0.0 0 12 24 36 Months on Study 48 60 GOG Protocol 172 By Treatment Group 1.0 IP median overall survival = 66 months 0.9 (Δ = 16 months) Proportion Surviving 0.8 0.7 0.6 0.5 IV median overall survival = 49.5 months 0.4 0.3 0.2 Rx Group 0.1 Rx IV Group IV IP IP 0.0 0 12 Lost to Follow-up Alive 5 93 11 117 24 Alive Dead Total Dead Total 78 117 210 93 88 205 127 101 210 205 36 48 Months on Study Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 N Engl J Med. 2006;354:34-43. 60 GOG Protocol 172 Toxicity G3/4 G3/4 G3/4 G3/4 G3/4 G3/4 G3/4 G3/4 G3/4 *P ≤ 0.05 Leukopenia* Platelet GI* Renal* Neurologic Event* Fatigue* Infection* Metabolic* Pain* IV, % (N = 210) 64 4 24 2 9 4 6 7 1 IP, % (N = 201) 76 12 46 7 19 18 16 27 11 Modulating Toxicity of IP Therapy New approaches to improve toxicity profile – Timing of catheter placement – Timing of chemotherapy relative to surgery relative to catheter placement – Agents used – Supportive care (anti-emetics, IV fluids, myeloid growth factor) Successful use of IP therapy requires: – – – – Training Skill Experience Dedication GOG 252: Newest upfront IP study IGCS Bangkok October 25th 2008 Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) Randomisation Primary Debulking Surgery 3 x Platinum based CT Interval debulking (not obligatory) > 3 x Platinum based CT Neoadjuvant chemotherapy 3 x Platinum based CT Interval debulking if no PD > 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Statistical considerations 704 patients were required in order to show noninferiority with respect to survival between PDS and NACT, with a one-sided type I error of 0.05 and a power of 80%. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Baseline Characteristics (ITT) FIGO Stage IIIc IV Serous Age CA125 > 30 KU/L Largest metastasis (mm) PDS NACT -> IDS 77% 23% 64% 62 (25-86) 98% 80 (0-400) 77% 23% 58% 62 (33-81) 99% 80 (0-389) Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical findings and results (PP1) Metastases before > 2 cm Metastases before > 10 cm No residual after surgery ≤ 1 cm after surgery PDS (n = 329) 95% 62% NACT -> IDS (n = 339)* 68% 27% 21% 46% 53% 82% * % calculated on the 306 patients who underwent IDS. Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Surgical characteristics (PP1) PDS (n = 329) NACT -> IDS (n = 339)* 2.7% 0.6% 8% 2% 1.2% / 0.3% 0,3% / 0.6% Operative time (minutes) 180 180 Red blood cell transfusion 51% 53% Hemorhage Grade 3/4 7% 1% 2.4% 0.3% Postoperative mortality (< 28 days) Postoperative fever Gr 3-4 Fistula (bowel/GU) Venous Gr 3/4 NACT + IDS versus PDS: ITT Median PFS Progression-free survival PDS: 12 months 100 IDS: 12 months 90 HR for IDS:0.99 (0.87, 1.13) 80 70 60 50 40 30 20 10 0 (years) 0 O N 320 360 320 357 1 2 3 4 Number of patients at risk : 168 60 39 26 177 60 36 20 5 17 13 6 7 3 7 8 2 1 Treatment Upfront debu Neoadjuvant NACT + IDS versus PDS: ITT Overall survival 100 90 Median survial 80 70 PDS: 29 months 60 IDS: 30 months HR for IDS:0.98 (0.85, 1.14) 50 40 30 20 10 0 (years) 0 2 4 6 8 10 O N 259 361 Number of patients at risk : 183 68 16 2 Treatment Upfront debulking s 251 357 191 11 1 Neoadjuvant chemo 56 NACT + IDS versus PDS: ITT Survival time: Figo stage Events / Patients Statistics EORTC 55971 Upfront debulking Neo-adj. Chemo (O-E) Var. III 190 / 276 191 / 273 IV 68 / 81 59 / 83 258/ 357 (72.3 %) 250/ 356 (70.2 %) Total Test for heterogeneity Chi-square=0.5, df=1: p>0.1 *90% CI everywhere -1.8 94.7 4 31.4 HR & CI* (Upfront debulking : Neo-adj. Chemo) 2.2 126.1 |1-HR| % ± SD 2% ±9 increase 0.25 0.5 1.0 2.0 4.0 Upfront debulking Neo-adj. Chemo better better Treatment effect: p>0.1 NACT + IDS versus PDS: ITT Survival time: Age Events / Patients Statistics EORTC 55971 Upfront debulkingNeo-adj. Chemo (O-E) Var. <50 50-70 >70 Total 34 / 46 31 / 56 172 / 244 161 / 221 53 / 71 259/ 361 (71.7 %) Test for heterogeneity Chi-square=2.59, df=2: p>0.1 *90% CI everywhere 6.1 15.5 0 82.7 59 / 80 -2.6 26.9 251/ 357 (70.3 %) 3.5 125.1 HR & CI* (Upfront debulking : Neo-adj. Chemo) |1-HR| % ± SD 3% ±9 increase 0.25 0.5 0.8 1.0 2.0 4.0 Upfront debulking Neo-adj. Chemo better better Treatment effect: p>0.1 Multivariate analysis for OS(PP1) P values Optimal debulking Histological type (9 categories) Largest tumor size at randomisation Figo Stage (IIIc vs IV) Country (14 categories) 0.0001 0.0003 0.0008 Age WHO PS Differentiation Grade Treatment arm 0.0020 NS NS NS 0.0008 0.0014 Conclusions In Stage IIIc-IV OVCA, NACT followed IDS produces similar OS and PFS outcomes compared to standard primary debulking followed by chemotherapy in FIGO Stage IIIc-IV ovarian carcinoma. 2. There does not seem to be a subgroup based on 1. Stage IIIc or IV 2. Age 3. WHO performance 4. Histological type ovarian cancer 5. Countries with high or low optimal debulking rate for which PDS or NACT -> IDS result in better survival. 1. Because of the overall poorer PFS and OS compared to other studies, the use of neoadjuvant chemotherapy is not considered the standard of care in the United States, but is reserved for patients who are too ill to undergo initial surgery or those patients who have clearly non-debulkable cancer. PFS and OS for newly diagnosed advanced ovarian cancer Study Median PFS Median OS Comments GOG 111 18 mos 38 mos Suboptimally and stage IV GOG 158 21 mos 57.4 mos Optimally cytoreduced only GOG 172 24 mos 65 mos Optimally cytoreduced only. Longest survival observed in advanced ovarian cancer GOG 182 16 mos 44 mos Both optimal and suboptimal. Study compared 5 arms of treatment Weekly pac vs q21 d 28 mos (vs. Lancet 09 17 mos) Not reached Both optimal and suboptimal EORTC neoadjuvant IGCS 2008 29/30 mos Neoadjuvant vs. upfront debulking NEJM 1996 JCO 2003 NEJM 2006 JCO 2009 GOG 218: ASCO 2010 Both 12 mos Dose dense paclitaxel versus q 3 week paclitaxel for newly diagnosed ovarian cancer 1 631 eligible patients were enrolled Eligibility: stage II to IV epithelial ovarian cancer Pts could have upfront or interval debulking surgery Primary endpoint was PFS Treatment1: Paclitaxel 180 mg/m2 + carboplatin AUC 6 day both day 1 or Paclitaxel 80 mg/m2 days 1, 8, 15 + carboplatin AUC 6 day 1 (dose dense group) Creatinine clearance calculated by Jelliffe and treatment given for 6 cycles Katsumata et al, Lancet 2009 Progression-free survival PFS for: DD Pac: 28 months q3 week: 17.2 mos HR 0.75 (95% CI: 0.58-0.88) p=0.015 Katsumata et al, Lancet 2009 Overall survival 3 year OS for: DD Pac 72% q3 week: 65% HR 0.75 (95% CI: 0.57-0.98) p=0.03 Katsumata et al, Lancet 2009 Progression-free survival according to baseline characteristics Lancet, 2009 Grade 3/4 anemia was higher in the dose dense group From: Katsumata et al, Lancet 2009 GOG—Frontline Trials GOG -218 GOG-218 Optimal or Suboptimal EOC, PPC, FT cancer Paclitaxel Paclitaxel Paclitaxel Carboplatin Carboplatin Carboplatin Placebo Bevacizumab Bevacizumab Placebo Placebo Bevacizumab ×15 months ×15 months ×15 months Survival, PFS primary endpoints Biologic & QOL endpoints EOC = Epithelial ovarian cancer; PPC = Primary peritoneal cancer; FT = Fallopian tube; PFS = Progression-free survival; QOL = Quality of life. GOG 218 results To be presented at ASCO 2010 Preliminary results were released via press release in March 2010 (www.gene.com). Patients receiving carboplatin/taxol/bevacizumab + bevacizumab maintenance did better than carbo/taxol alone. Patients receiving carboplatin/taxol/bevacizumab (no maintenance) did equally well as patients receiving carboplatin/taxol alone. At this point, our group is not using bevacizumab off study. www.gene.com Newer biologics being added to upfront treatment PARP inhibitors Src inhibitors Other anti-angiogenics besides bevacizumab Notch inhibitors Protocol 10-065 Pilot study screening for druggable mutations in both recurrent and newly diagnosed advanced ovarian cancer. Opened March 2010; 28 pts enrolled thus far. CLIA-approved PIK3CA, KRAS, and BRAF testing at LMM (for clinical decision making). OncoMap platform used thereafter to test for 1100 mutations in 100 oncogenes (for research). Standard of Care for pts with advanced epithelial ovarian cancer: 2010 Upfront debulking surgery by a gynecologic oncologist. If optimally cytoreduced (i.e. ≤ 1cm tumor remaining), options are: Placement of an IP port and IP/IV tx1, IV carboplatin/paclitaxel, or clinical trial. If suboptimally cytoreduced, options are: IV carboplatin/paclitaxel (q3 week or weekly paclitaxel)3 or clinical trial Neoadjuvant chemotherapy2 has demonstrated equivalent results to upfront cytoreduction → chemotherapy, but this appears more popular in Europe than the U.S. with lower OS and PFS overall compared to other studies. Armstrong DK, et al, N Engl J Med 354(1):34-43, 2006. 2 Vergote I et al. IGCS 2008 Meeting: Abstract #2008_1767. Available at: http://www.igcs.org/Abstract/meeting_2008_1767.html. 1 3 Following completion of upfront chemotherapy CA125 monitoring every 3 months; although off study, controversy exists whether or not this is of benefit1 Several drugs are being tested in the first maintenance setting. There is no standard of care for use of maintenance therapy2 GJ et al, J Clin Oncol 27(18s):Abstr 1, 2009. 2Foster et al, Gyn Onc 115:290-301, 2009 1Rustin Conclusions Standard of care for newly diagnosed advanced ovarian, tubal or peritoneal cancer remains a platinum and taxane combination New options for patients include dose dense administration of paclitaxel Results of GOG 218 asking question of role of bevacizumab in newly diagnosed patients to be presented at ASCO 2010