Gynecologic Cancers Bradley J. Monk, M.D. Associate Professor Division of Gynecologic Oncology Chao Family Comprehensive Cancer Center University of California Irvine Medical Center Orange CA USA 92868
A randomized trial in ovarian cancer (OC) of early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials) G. J. Rustin, M. E. van der Burg on behalf of MRC and EORTC collaborators; Mount Vernon Cancer Centre, Middlesex, United Kingdom; Erasmus MC University Medical Center, Rotterdam, Netherlands J Clin Oncol 27:15s, 2009 (suppl; abstr 1) 2
Ovarian Carcinoma: CA-125 • Serum glycoprotein (OC- • CA-125 cloned in 2001 [3] 125) – Mapped to • Discovered during a chromosome 19 search to boost an (p13.3) immunotherapy – Gene: MUC16 ( Corynebacterium – Very large molecule parvum ) [1] • Blood test introduced in 1981 – Elevated in 82% of ovarian cancers; 1% in controls [2] 1. Bast RC, et al. J Clin Invest. 1981;68:1331-1337. 2. Bast RC, et al. N Engl J Med. 1983;309:883-887. 3. Yin BW, et al. J Biol Chem. 2001;276:27371-27375.
Trial Profile Registered patients N=1442 Non randomised patients N (%) 421 (29) CA125<2ULN and no relapse at trial closure 61 (4) Simultaneous relapse and CA125>2ULN 213 (15) Relapsed without CA125>2ULN Randomised 56 (4) Died 133 (9) Patient withdrawal N=529 (37%) 29 (2) Other/unknown reasons Early treatment Delayed treatment N=265 N=264 N=254 (96%) started second-line N=233 (88%) started second-line chemotherapy chemotherapy
Baseline characteristics: All randomised patients (N=529) Early Delayed Age Median (range) 60 (35-86) 61 (37-93) FIGO I 9% 8% stage II 11% 10% III 68% 69% IV 12% 13% WHO PS 0 69% 75% 1 29% 25% 2 & 3 2% <1% Histology Serous 66% 59% Endometroid 12% 12% Mucinous 3% 3% Clear cell 4% 4% Undifferentiated 8% 6% Adenocarcinoma not otherwise specified 6% 15% Other 1% 1%
Second-line chemotherapy Regimen administered Early Delayed N (%) N (%) Single agent platinum 78 (29) 67 (25) Combination platinum (no taxane) 40 (15) 33 (13) 91 (34) 101 (38) Platinum + taxane based Taxane without platinum 15 (6) 9 (3) Other 28 (11) 15 (6) Unknown treatment 2 (1) 8 (3) No treatment given 11 (4) 24 (9) Not yet given (no clinical relapse) 0 7 (3) Total 265 264
Time from randomisation to second-line chemotherapy 1.00 Proportion alive not started second-line chemotherapy Median (months) Early 0.8 0.75 Delayed 5.6 HR=0.29 (95% CI 0.24, 0.35) p<0.00001 0.50 0.25 0.00 0 3 6 9 12 15 18 21 24 Months since randomisation Number at risk Early 265 23 16 14 11 11 10 10 9 264 177 116 91 69 56 49 42 33 Delayed
Overall Survival HR=1.00 (95%CI 0.82-1.22) p=0.98 Abs diff at 2 years= -0.1% 1.00 (95% CI diff= -6.8, 6.3%) Proportion surviving 0.75 Early Delayed 0.50 0.25 0.00 0 6 12 18 24 30 36 42 48 54 60 Months since randomisation Number at risk Early 265 247 211 165 131 94 72 51 38 31 22 264 236 203 167 129 103 69 53 38 31 19 Delayed
Time from randomisation to first deterioration in Global Health Score (or death) 1.00 Median (months) Early 3.1 Proportion alive without Delayed 5.8 deterioration in GHS 0.75 HR=0.71 (95% CI 0.57, 0.87) p=0.001 0.50 0.25 0.00 0 6 12 18 24 Months since randomisation Number at risk 190 68 44 23 12 Early Delayed 194 93 55 38 25
Conclusions • In early treatment arm based on rise of 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=1.00, 95% CI 0.82-1.22, p=0.98 • Absolute difference at 2 years -0.1% (95%CI -6.8, 6.3%) • Early chemotherapy does not improve Qol
June, 2009: SGO Statement on Use of CA125 for Monitoring Ovarian Cancer • Role of secondary cytoreduction not addressed • Not stratified for residual disease after cytoreduction • Remission not confirmed by imaging • Treatment at relapse not standardized • “Patients and their physicians should still have the opportunity to choose [CA125 monitoring] as a philosophy of active management that includes participation in trials of novel therapies”
Influence of residual disease and extreme drug resistance assays on outcome in patients with epithelial ovarian cancer A. Karam, J. Wang Chiang, E. Fung, V. Nossov, B. Y. Karlan The David Geffen School of Medicine at UCLA, Los Angeles, CA; Santa Clara Valley Medical Center, San Jose, CA; Cedars-Sinai Medical Center, Los Angeles, CA J Clin Oncol 27:15s, 2009 (suppl; abstr 5504) 12
Kern and Weisenthal, JNCI 1990
Kern and Weisenthal, JNCI 1990
Aims and Methods • Aims: – Effects of EDR assay-guided therapy in epithelial Ovarian Cancer (EOC) – Outcomes in the primary and recurrent setting • Retrospective review – 377 EOC patients at Cedars Sinai Medical Center, Los Angeles – EDR assays between 1995 and 2005 • End points – Time to first recurrence (TTP) – Overall survival (OS) – Survival after recurrence (RS)
Demographic and Clinical Characteristics Variable Frequency Percent Age, years Median (Range) 59.0 (24.4-89.1) Race White 315 87.7 Non-white 44 12.3 Residual Disease at 1 ° CRS Microscopic 76 29.9 0.1-1 cm 145 57.1 ≥ 1 cm 33 13.0 FIGO Stage I/II 34 10.2 III/IV 300 89.8 Tumor Grade 1 11 3.9 2 14 4.9 3 260 91.2 Histology Papillary Serous 265 77.9 Other 75 22.1
Adjuvant Therapy and Recurrence Variable Frequency Percent Primary Chemotherapy Platinum and taxane 231 88.8 Platinum based 25 10.7 Other 4 1.5 2 ° CRS No 93 36.0 Yes 165 64.0 Recurrence type Platinum resistant 75 29.4 Platinum sensitive 180 70.6 Residual Disease at 2 ° CRS Microscopic 63 42.6 0.1-1 cm 55 37.2 ≥ 1 cm 30 20.3 Status NED 85 22.8 AWD 28 7.5 DOD 251 67.3 DOC 9 2.4
EDR Assay Results EDR assay results Frequency Percent EDR Assay at 1 ° CRS No 125 36.5 Yes 217 63.5 N EDR Assays 1 292 85.4 ≥2 50 14.6 EDR assay results Carboplatin EDR 57 18.2 Cisplatin EDR 52 15.8 Cyclophosphamide EDR 85 26.1 Taxol EDR 51 15.7 Platinum EDR 81 23.1 Taxane EDR 58 17.2 Platinum + taxane EDR 15 4.5
Multivariate Analysis Multivariate Disease progression Death Characteristic HR 95% CI p HR 95% CI p Age decades 1.12 0.98 1.28 0.1 1.33 1.13 1.56 0.001 Stage Stage <III 1.0 1.0 Stage ≥ III 3.61 0.86 6.4 0.09 2.78 0.68 11.3 0.15 Tumor grade Grade 1 1.0 1.0 Grade 2 or 3 1.87 0.68 5.14 0.23 5.41 0.73 40.1 0.10 1 ° CRS residual Microscopic 1.00 1.00 0.1 to 1.0 cm 1.94 1.33 2.84 0.001 1.59 1.03 2.45 0.04 >1.0 cm 3.61 2.07 6.29 <0.001 2.14 1.09 4.20 0.03 Adjuvant chemotherapy Platinum and taxane 1.00 Other 0.94 0.23 3.86 0.93 EDR assay None 1.0 At primary surgery 1.13 0.75 1.72 0.55 CRS=Cytoreductive Surgery
Multivariate Analysis Multivariate Death after recurrence Characteristic HR 95% CI p 2 ° CRS residual disease Microscopic 1.0 0.1 to 1.0 cm 1.14 0.74 1.77 0.55 >1.0 cm 2.84 1.71 4.71 <0.001 No 2 ° CRS 2.13 1.28 3.54 0.004 Initial PFS <6 months 1.00 6 to 12 months 1.15 0.75 1.76 0.52 12 to 24 months 1.32 0.83 2.08 0.24 >24 months 1.25 0.84 1.86 0.28 EDR assay None 1.0 At recurrence 0.83 0.55 1.27 0.40 CRS=Cytoreductive Surgery
Conclusion • EDR did not predict outcomes in EOC patients • Age and disease residual important for outcome • Rationale for assays remains strong – Continued research – Gene-expression/microarray profiles
Limitations and Strengths • Limitations: – Retrospective nature – Selection and ascertainment bias – Incomplete information on salvage chemotherapy • Strengths: – Size of patient population – Treated with platinum and taxane chemotherapy – Long follow-up (median ~5 years)
A randomized, phase III study (AGO-OVAR-9, GINECO-TCG, NSGO-OC- 0102): Gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer (OC): Survival of FIGO stage I-IIA patients J. Herrstedt, J. Huober, F. Priou, H. Müller, M. Baekelandt, C. Kurzeder, J. Pfisterer, A. Stähle, I. Ray-Coquard, A. du Bois Odense University Hospital, Odense, Denmark; University of Tuebingen, Tuebingen, Germany; Centre Hospitalier , La Roche sur Yon, France; Philipps University, Marburg, Germany; The Norwegian Radium Hospital, Oslo, Norway; University Hospital Ulm, Ulm, Germany; Ubbo-Emmius-Klinik gGmbH, Aurich, Germany; St. Vincentius-Krankenhäuser, Karlsruhe, Germany; Centre Léon Bérard, Lyon, France; HSK, Dr. Horst Schmidt Klinik GmbH, Wiesbaden, Germany J Clin Oncol 27:15s, 2009 (suppl; abstr LBA5510)
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