A phase III study comparing concurrent gemcitabine (Gem) plus cisplatin (Cis) and radiation followed by adjuvant Gem plus Cis versus concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix

Abstract

CRA5507 Background: Cervical cancer is the second-most common cancer among women worldwide, in both incidence and mortality. Current standard therapy for locally advanced disease consists of concurrent Cis and external-beam radiation (XRT). This multicenter, open-label, randomized, phase III trial aimed to improve outcomes, capitalizing on the synergistic activity of Gem, Cis, XRT, and the potential value of adjuvant therapy. Methods: Eligible patients (pts) with bulky stage IIB to IVA, 18–70 years of age, chemotherapy- and radiotherapy-naive, with a Karnofsky Performance Status score ≥70, were randomized to Arm A: Cis 40 mg/m2 followed by Gem 125 mg/m2 weekly × 6 doses with concurrent XRT (50.4 Gy: in 28 fractions: 1.8 Gy/day, 5 days/week), followed by brachytherapy (brachy) (30–35 Gy) and then 2 adjuvant 21-day cycles of Gem (1,000 mg/m2 on Days 1 and 8) plus Cis (50 mg/m2 on Day 1); or Arm B: Cis 40 mg/m2 weekly × 6 doses with concurrent XRT followed by brachy, given as in Arm A. Primary endpoint was progression-free survival (PFS) at 3 years, compared between arms using Kaplan-Meier methods and a Z-statistic. Results: 515 pts were enrolled between 5/02 and 3/04 (259 pts Arm A, 256 pts Arm B). Median age was 46 years; stage IIB/IIIB/IVA in 61/37/2% of pts. Compliance in the concurrent and brachy phase was >90% for both arms; adjuvant cycles were completed by >75% of pts in Arm A. PFS at 3 years was 74% in Arm A compared to 65% in Arm B, resulting in a statistically significant improvement (p = 0.029). Overall survival (log-rank p = 0.0224) and time to progressive disease (log-rank p = 0.0008) were also significantly improved. Significantly more pts in Arm A experienced grade 3/4 toxicities (86.5%), compared to pts in Arm B (46.3%; Fisher's p < 0.001). In Arm A, 2 pts died due to causes probably related to treatment compared to 0 pts in Arm B. Conclusions: This novel regimen of concurrent Gem plus Cis and XRT followed by brachy and adjuvant Gem plus Cis significantly improved outcomes in pts with locally advanced carcinoma of the cervix, at the expense of increased but acceptable toxicity, compared to the current standard of care. [Table: see text]