PROGNOSTIC FACTORS AND FIRST LINE CHEMOTHERAPY IN AOC

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1 PROGNOSTIC FACTORS AND FIRST LINE CHEMOTHERAPY IN AOC Giorgia Mangili RUF ginecologia oncologica medica IRCCS San Raffaele Milano

2 STANDARD CHEMOTHERAPY The standard chemotherapy in advanced ovarian cancer (FIGO IIB-IV) is carboplatin-paclitaxel The recommended regimen is carboplatin AUC and paclitaxel 175 mg/m²/ 3h, every three weeks x 6

3 ADVANCED OVARIAN CANCER: GOG PHASE III CAP vs CP P (IP) vs Obs (Path CR) 097 Cisplatin Dose Intensity (DI) 104 IP-Cisplatin vs IV-Cisplatin 111 Cisplatin-Paclitaxel vs Cisplatin-Cyclophosphamide 114 Carboplatin (AUC 9) IP-Cisplatin - Paclitaxel 132 Sequential Single-Agent vs Combination 152 Interval Cytoreduction 158 Carboplatin-Paclitaxel (3 h) vs Cisplatin-Paclitaxel (24 h) h vs 96 h Paclitaxel with Cisplatin 164 ABMT Consolidation 172 IP-Cisplatin & IP-Paclitaxel vs IV 178 Paclitaxel Consolidation 182 Carbo-Paclitaxel & Gemcitabine, Topotecan, PEG-Lipo-Dox 212 Paclitaxel and PG-Paclitaxel Consolidation 218 Carbo-Paclitaxel +/- Bevacizumab

4 FIRST LINE CHEMOTHERAPY IN AOC Other platinum-based chemotherapy Two versus three drugs Weekly treatment Role of intraperitoneal chemotherapy Antiangiogenetic agents Neoadjuvant chemotherapy Prognosis factors

5 R A N D O M I Z E GOG ICON 5 I Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m 2 (d1) x8 II Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m 2 (d1) Gemcitabine 800 mg/m 2 (d1,8) x8 III Carboplatin AUC 5 (d1) Paclitaxel 175 mg/m 2 (d1) Doxil 30 mg/m 2 (d1, every other cycle) x8 IV V Carboplatin AUC 5 (d3) Topotecan 1.25 mg/m 2 (d1-3) Carboplatin AUC 6 (d8) Gemcitabine 1 g/m 2 (d1,8) x4 x4 Carboplatin AUC 6 (d1) Paclitaxel 175 mg/m 2 (d1) x4 Bookman MA, et al. J Clin Oncol (2009)

6 GOG 182 ICON 5: OS Bookman MA, et al. J Clin Oncol (2009)

7 MITO 2 ASCO 2009 MITO: STUDY DESIGN CONTROL ARM Carboplatin AUC 5, day 1 Paclitaxel 175 mg/m 2, day 1 Treatment repeated every 21 days, 6 cycles EXPERIMENTAL ARM Carboplatin AUC 5, day 1 PLD 30 mg/m 2, day 1 Treatment repeated every 21 days, 6 cycles Toxicity profile of carboplatin plus PLD as first-line treatment of advanced ovarian cancer is different from carboplatin plus paclitaxel There was no statistically significant difference in response rate between carboplatin plus PLD and carboplatin plus paclitaxel Final analysis for the primary endpoint (PFS) will be performed as soon as the required number of events will be reached

8 Isonishi S. et al.,j Clin Oncol 2008 JGOG: DOSE-DENSE WEEKLY PACLITAXEL Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratified: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS I Paclitaxel 180 mg/m 2 Carbolatin AUC = 6 Accrual: 637 pts (intent-to-treat) x6-9 II Carboplatin AUC = 6 x6-9 Paclitaxel 80 mg/m 2 /w x3 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel

9 Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer. Women assigned to dose-dense paclitaxel and carboplatin had a 29% lower risk of disease progression and a 25% lower risk of death than did patients assigned to the conventional regimen

10 PROGRESSION FREE SURVIVAL PATIENTS WITH MEASURABLE LESIONS Dose.dense Conventinal P CR 29 (20%) 21 (16%) 0.44 PR 53 (36%) 51 (38%) 0.81 ST 43 (29%) 42 (31%) 0.80 PD 4 (3%) 9 (7%) 0.16 N E 18 (12%) 12 (9%) 0.44 There was greater haematological toxicity in the dose-dense treatment group than in the conventional treatment group Fewer than half the patients assigned to the dose-dense regimen completed treatment according to the study protocol Clear-cell and mucinous adenocarcinoma of the ovary is associated with low sensitivity to chemotherapy and poor survival

11 As compared with intravenous paclitaxel plus cisplatin, intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel improves survival in patients with optimally debulked stage III ovarian cancer. Only 42% of the patients in the intraperitoneal therapy group completed six cycles of the assigned therapy Women who received intraperitoneal treatment had a 25% reduction in the risk of death NCI Clinical Announcement

12 RANDOMIZED TRIAL COMPARING IV versus IP/IV STUDY IDENTIFIER/YEAR PUBLISHED Kirmani et al., 1994 Polyzos et al., 1999 Gadducci et al., 2000 GOG 114/ SWOG 9227, Markman et al., 2001 Yen et al., 2001 GOG 172 Armstrong et al., 2006 CONTROL REGIMEN EXPERIMENTAL REGIMEN ELIGIBLE PATIENT Cisplatin IV Cyclophosphamide IV Carboplatin IV Carboplatin IP Cyclophosphamide IV Cyclophosphamide IV Cisplatin IV; Cisplatin IP Cyclophosphamide IV; Cyclophosphamide IV; Epidoxorubicin IV Epidoxirubicin IV Cisplatin IV Carboplatin IV x 2; Cisplatin Paclitaxel 135 mg/m2 IV IP; Paclitaxel IV Cisplatin IV Cisplatin IP Cyclophosphamide IV; Cyclophosphamide Epidoroxorubin/ Epidoxirubicin/ Doxorubicin IV Doxorubicin 50 IV Cisplatin IV; paclitaxel IV Paclitaxel IV; Cisplatin mg/m2 IP; Paclitaxel2 IP on day 8 DDP/VP16 IP Stage IIC-IV 62 Stage III 90 Stage II-IV, < 2 cm residual Stage III, < 1 cm residual Stage III, < 1 cm residual Stage III, < 1 cm residual N PATIENT

13 Results show that there were no statistically significant differences between the two treatment regimens in survival rate. The comparison between both groups in terms of time to progression and response rate did not show any statistically significant difference. The risk of drug-related serious adverse events was higher in the group of patients receiving additional topotecan.

14 The addition of gemcitabine to carboplatin plus paclitaxel: increased treatment burden reduced PFS time did not improve OS

15 ICON 7: BEVACIZUMAB IN OVARIAN CARCINOMA Stage & extent of debulking: I III debulked 1cm vs I III debulked >1 cm vs IV and inoperable stage III I II Paclitaxel 175 mg/m 2 Carboplatin AUC = 6 Carboplatin AUC = 6 Paclitaxel 175 mg/m 2 x6 x6 Bevacizumab 7.5 mg/kg q3w X18 The addition of concurrent and maintenance bevacizumab significantly improved PFS

16 BEVACIZUMAB IN OVARIAN CARCINOMA Two randomized trials of primary chemotherapy with bevacizumab (GOG 0218 and ICON7) were presented and discussed at the 2010 Annual Meetings of ASCO, the European Society for Medical Oncology (ESMO), and the International Gynecologic Cancer Society (ICGS) These trials demonstrate ion-free survival in patients treated with bevacizumab concurrently with standard carboplatin and paclitaxel chemotherapy and then as maintenance therapy Overall survival data are not yet available a progression-free survival advantage Do these results justify approval of the agent for this purpose? Does the cost vs. benefit of the drug warrant approval? Targeting vascular endothelial growth factor (VGEF) is a valid strategy Development of other drugs that involve this pathways is important The goal will be to discover similar agents that have a better cost/benefit and can be given by mouth Berek 2011

17 PROGNOSTIC FACTORS Ethnicity & Race Age Performance status Stage of Disease Histology Grade Residual tumor Loss of heterozygosity (LOH) at micro-satellite markers DXS454 (Xq21-q23 Gene expression of Angiopoietin-1 (Ang-1) & Angiopoietin-2 expression of VEGF-C, VEGF-D and VEGFR-3 2 ETS-1 positive p21 COX-2 over-expression Ki67 antigen prostasin Osteopontin PLK1 cathepsin D expression multidrug resistance-1 protein Fibronectin ERBB2 KLK15

18 PROGNOSTIC FACTORS: HSR DATA UNIVARIATE ANALYSIS predictors of survival P value age CA ascites > carcinomatosis residual disease histology diaphragm disease NS grading NS time to chemotherapy NS radical procedures NS MULTIVARIABLE ANALYSIS survival predictive model P value- RR histology residual disease carcinomatosis ascites

19 PROGNOSTIC FACTORS:SURGERY HSR DATA

20 SURGEON EXPERTISE TUMOR DISSEMINATION OPTIMAL DEBUKING PERFORMANCE STATUS AGE

21 SEER DATA: Age N % distribution Total Age % survival < % % > %

22 PROGNOSTIC FACTORS FOR STAGE III EOC: AGE Increasing age was associated with increased risk of disease progression or death 10 years : 6 % of disease progression 12% of death Winter III WE. JCO 2007

23 ROGNOSTIC FACTORS: PERFORMANCE STATUS PFS PS N patients Median (month) P OS Median (month) (41.4%) < (50.1%) ( 8.5%) P GOG protocoll N :111, 114,132,152,158,172 cisplatin/carboplatin and paclitaxel PS 1-2 decreased PFS and OS (also without PS 374 patients) PS was an indipendent predictor of recurrence and survival Data from NCI have demonstrated that elderly patients with good PS tolerate the same chemotherapy of younger women Winter G JCO 2007

24 HIGH RISK PATIENTS High tumor dissemination (HTD) stage IV Poor performance status (ASA 3) nutritional status (preoperative albumin levels < 3.0 g/dl) Age 75 years 38 patients (6.6 %) median overall survival for this group was17 months Aletti G, Gynecol Oncol 2011

25 The overall accuracy rate of the laparoscopic procedure ranged between 77.3 and 100%. At a PIV 8 the probability of optimally resecting the disease at laparotomy is equal to 0, and the rate of unnecessary exploratory laparotomy is 40.5%. The authors concluded that a laparoscopic score of 8 is the threshold of operability. Discussant It is difficult to generalize this data especially to centers with higher rates of optimal debulking/complete resection rates. Other centers report complete resection and optimal debulking rates up to 85% to 90%, resulting in 10% to 15% of unnecessary surgeries (P Harter, Int J Gynecol Cancer 2009).

26 MULTIVARIABLE ANALYSIS P VALUE Stage (IIIC vs IV) Performance status (0-1 vs 2-3) Number of implants (<75vs>75) p=0.006 p=0.04 p=0.005 Complete cytoreduction is possible for the majority of patients and improves survival, even compared to operations with minimal (<1 cm) residual disease. Unless their medical condition prohibits anesthesia and surgery, patients with advanced epithelial ovarian cancer should undergo primary cytoreductive surgery with the intention of complete tumor removal

27 ECOG PERFORMANCE STATUS ECOG Score Karnofsky Score Activity Level Fully active, unrestricted activities of daily living Ambulatory, but restricted in strenuous activity Ambulatory, and capable of self care. Unable to work. Out of bed for greater than 50% of waking hours Limited self care, or confined to bed or chair 50% of waking hours. Needs special assistance Completely disabled, and no self care 5 0 Dead GOG performance status of 0, 1, or sometimes 2 high risk patients where are these patients? hospitalization for emergency

28 HOSPITALIZATION FOR EMERGENCY > access from Emergency Department per year performance status age tumor dissemination comorbidity

29 PREDICTORS OF SUBOPTIMAL SURGERY Multivariable analysis P optimal cytoreduction 61 % hospitalization for emergency 19% Age>65 NS CA 125>750 NS Ascites> carcinomatosis Diaphragmatic tumor NS High tumor dissemination 0.02 Hospitalization for emergency 0.002

30 GRAZIE PER L ATTENZIONE