No Benefit of Adding Tirapazamine to Cisplatin Chemoradiation in Locally Advanced Cervical Cancer
In a phase III intergroup trial (Gynecologic Oncology Group Protocol 219) reported in the Journal of Clinical Oncology, DiSilvestro et al in the Gynecologic Oncology Group and National Cancer Institute of Canada Clinical Trials Group evaluated the addition of the hypoxic cell sensitizer tirapazamine to standard cisplatin chemoradiotherapy in patients with locally advanced cervical cancer. Due to a shortage of tirapazamine, the study did not reach its initial target accrual goal. The addition of tirapazamine did not improve progression-free or overall survival.
Study Details
In the study, 387 patients with stage IB2, IIA, IIB, IIIB, or IVA cervical carcinoma limited to the pelvis were randomly assigned to receive either cisplatin at 40 mg/m2 on days 1, 8, 15, 22, 29, and 36 (n = 194) or tirapazamine at 290 mg/m2 and cisplatin at 75 mg/m2 on days 1, 15, and 29 and tirapazamine at 220 mg/m2 on days 8, 10, 12, 22, 24, and 26 of chemoradiotherapy (n = 185) in addition to standard radiation therapy. After a planned interim safety analysis, the tirapazamine dose was reduced from 290 to 220 mg/m2 and cisplatin from 75 to 60 mg/m2 on days 1, 15, and 29 in the tirapazamine group. The primary endpoint was progression-free survival.
Patients in the tirapazamine and control groups were well matched for age (median, 47 and 48 years), race (eg, 72% and 66.6% white), Gynecologic Oncology Group performance status (eg, 0 in 76% in both), tumor grade (eg, 2 in 56% and 54%, 3 in 36% and 40%), stage (eg, IIB in 44% and 48%, IIIB in 28% and 26%), histology (eg, squamous cell in 85% and 84.5%), sampling of para-aortic lymph node (82% vs 87%), brachytherapy (low-dose rate in 28% and 27%, high-dose rate in 70% and 71%), and cooperative group (eg, Gynecologic Oncology Group for 90% and 86%).
No Difference in Outcome
Target accrual was 750 eligible patients with follow-up until 256 events (146 in control group). At the time of analysis, there were 136 events among 379 evaluable patients. Median follow-up was 28.3 months.
The tirapazamine and control groups did not differ in 3-year progression-free survival (63.0% vs 64.4%, P = .7869) or overall survival (70.5% vs 70.6%, P = .8333). In multivariate analysis adjusting for age, stage, and pre- vs post–dose modification enrollment period, the treatment effects for progression-free survival (hazard ratio [HR] = 1.063, P = .8344) and overall survival (HR = 1.174, P = .5929) were not significant, and there was no significant interaction between treatment and enrollment period for either progression-free survival (P = .3609) or overall survival (P = .6158).
Toxicity
At an interim analysis, the tirapazamine group had significantly increased rates of grade 3 or 4 leukopenia, gastrointestinal toxicities, and metabolic abnormalities, necessitating the dosage change. Overall, during the trial, the tirapazamine group had significantly greater rates of higher-grade adverse events (all P < .05 for trend) for dermatologic adverse events (grade 3 or 4 in 16% vs 0%), vomiting (grade 2-4 in 61% vs 33%), diarrhea (grade 3 in 19% vs 11%), motor neuropathy (grade 1 or 2 in 11% vs 1%), and pain (grade 3 in 29% vs 3%). Rates of discontinuation for toxicity (6.5% vs 2.6%) and refusal of study therapy (9.2% vs 5.2%) were higher in the tirapazamine group.
The investigators concluded, “[Tirapazamine/cisplatin] chemoradiotherapy was not superior to [cisplatin] chemoradiotherapy in either [progression-free survival] or [overall survival], although definitive commentary was limited by an inadequate number of events (progression or death). [Tirapazamine/cisplatin] chemoradiotherapy was tolerable at a modified starting dose.”
Paul A. DiSilvestro, MD, of Brown University, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by grants from the National Cancer Institute and a Canadian Cancer Society Research Institute grant. The study authors reported no potential conflicts of interest.
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