ABSTRACT
OBJECTIVE: Serial circulating tumor cell (CTC) counts have demonstrated predictive and prognostic value in patients with metastatic breast, colorectal, and prostate cancer. In a phase III study of pegylated liposomal doxorubicin (PLD) with trabectedin vs. PLD for relapsed ovarian cancer, we evaluated the correlation, if any, between numbers of CTCs and progression free survival, (PFS) and overall survival (OS). METHODS: CTCs were isolated from peripheral blood (10 mL) using the CellSearch system and reagents (Veridex). A CTC is defined as EpCAM+, cytokeratin+, CD45-, and is positive for the nuclear stain DAPI. The normal reference range for CellSearch is <2 CTC/7.5 mL of blood. Hazard ratios adjusted for known prognostic factors were estimated by Cox regression. RESULTS: Two-hundred sixteen patients had baseline CTC measurements of which 111 (51.4%) were randomized to the trabectedin+PLD arm; 143/216 patients (66.2%) were platinum-sensitive. Thirty-one of 216 patients (14.4%) had 2 or more CTCs detected prior to the start of therapy (range 2-566). Univariate Cox regression analyses indicated that patients with ≥2 CTCs prior to therapy had 1.89- (p=0.003) and 2.06-fold (p=0.003) higher risk for progression and death respectively. Multivariate analyses that include baseline CA-125, platinum sensitivity status, largest diameter lesion, number of tumor lesions, ECOG PS, and tumor grade show that patients with elevated baseline CTC had 1.58- (p=0.058) and 1.54-fold (p=0.096) higher risk for progression and death respectively. CONCLUSIONS: Results from this study indicate that elevated numbers of CTCs impart an unfavorable prognosis for ovarian cancer patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/drug therapy , Neoplastic Cells, Circulating/pathology , Ovarian Neoplasms/blood , Ovarian Neoplasms/drug therapy , Dioxoles/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Female , Humans , Middle Aged , Multivariate Analysis , Neoplasm Recurrence, Local/pathology , Ovarian Neoplasms/pathology , Polyethylene Glycols/administration & dosage , Survival Rate , Tetrahydroisoquinolines/administration & dosage , TrabectedinABSTRACT
PURPOSE: The objective of this study was to compare the efficacy and safety of trabectedin plus pegylated liposomal doxorubicin (PLD) with that of PLD alone in women with recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy. PATIENTS AND METHODS: Women > or = 18 years, stratified by performance status (0 to 1 v 2) and platinum sensitivity, were randomly assigned to receive an intravenous infusion of PLD 30 mg/m(2) followed by a 3-hour infusion of trabectedin 1.1 mg/m(2) every 3 weeks or PLD 50 mg/m(2) every 4 weeks. The primary end point was progression-free survival (PFS) by independent radiology assessment. RESULTS: Patients (N = 672) were randomly assigned to trabectedin/PLD (n = 337) or PLD (n = 335). Median PFS was 7.3 months with trabectedin/PLD v 5.8 months with PLD (hazard ratio, 0.79; 95% CI, 0.65 to 0.96; P = .0190). For platinum-sensitive patients, median PFS was 9.2 months v 7.5 months, respectively (hazard ratio, 0.73; 95% CI, 0.56 to 0.95; P = .0170). Overall response rate (ORR) was 27.6% for trabectedin/PLD v 18.8% for PLD (P = .0080); for platinum-sensitive patients, it was 35.3% v 22.6% (P = .0042), respectively. ORR, PFS, and overall survival among platinum-resistant patients were not statistically different. Neutropenia was more common with trabectedin/PLD. Grade 3 to 4 transaminase elevations were also more common with the combination but were transient and noncumulative. Hand-foot syndrome and mucositis were less frequent with trabectedin/PLD than with PLD alone. CONCLUSION: When combined with PLD, trabectedin improves PFS and ORR over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer.
