Phase III Randomized Trial of Weekly Cisplatin and Irradiation Versus Cisplatin and Tirapazamine and Irradiation in Stages IB2, IIA, IIB, IIIB, and IVA Cervical Carcinoma Limited to the Pelvis: A Gynecologic Oncology Group Study

Abstract

A B S T R A C T PurposeThis prospective, randomized phase III intergroup trial of the Gynecologic Oncology Group and National Cancer Institute of Canada Clinical Trials Group was designed to test the effectiveness and safety of adding the hypoxic cell sensitizer tirapazamine (TPZ) to standard cisplatin (CIS) chemoradiotherapy in locally advanced cervix cancer. Patients and MethodsPatients with locally advanced cervix cancer were randomly assigned to CIS chemoradiotherapy versus CIS/TPZ chemoradiotherapy. Primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and tolerability. ResultsPFS was evaluable in 387 of 402 patients randomly assigned over 36 months, with enrollment ending in September 2009. Because of the lack of TPZ supply, the study did not reach its original target accrual goal. At median follow-up of 28.3 months, PFS and OS were similar in both arms. Three-year PFS for the TPZ/CIS/RT and CIS/RT arms were 63.0% and 64.4%, respectively (log-rank P ϭ .7869). Three-year OS for the TPZ/CIS/RT and CIS/RT arms were 70.5% and 70.6%, respectively (log-rank P ϭ .8333). A scheduled interim safety analysis led to a reduction in the starting dose for the TPZ/CIS arm, with resulting tolerance in both treatment arms. ConclusionTPZ/CIS chemoradiotherapy was not superior to CIS chemoradiotherapy in either PFS or OS, although definitive commentary was limited by an inadequate number of events (progression or death). TPZ/CIS chemoradiotherapy was tolerable at a modified starting dose.

Integrative Analysis of DCE-MRI and Gene Expression Profiles in Construction of a Gene Classifier for Assessment of Hypoxia-Related Risk of Chemoradiotherapy Failure in Cervical Cancer

“…Two head and neck cancer signatures have shown promise as predictive hypoxia biomarkers (12,42,43), illustrating the potential of gene signatures for hypoxia stratification. For cervical cancer, the optimal hypoxia-targeting drug has yet to be defined (7,8), and careful considerations in the study design have to be done due to toxicity problems. Future work should involve multicenter studies for verifying the classifier's prognostic value and testing the predictive impact in a clinical trial.…”

“…Thus, hypoxia is both a potential marker for predicting risk of recurrence and a target in new treatment strategies combined with radiotherapy. Adjuvant hypoxia-modifying treatment has been shown to improve the efficacy of radiotherapy in cervical cancer (6), and combination trials to find the optimal drug have been performed (7,8) and are underway (ClinicalTrials.gov identifier NCT02394652). In many trials, difficulties in detecting drug effects and toxicity are major problems, as patients are randomized to the adjuvant treatment without knowledge of the hypoxia status of the tumor (9).…”

Oxygen-Enhanced MRI Is a Major Advance in Tumor Hypoxia Imaging

“…A meta-analysis of over 10,000 patients enrolled in nearly 90 randomized trials over the past 40 years revealed an OR of 0.77 in favor of hypoxia modification strategies (9). Phase III trials have been conducted utilizing radiotherapy with or without (i) increasing oxygen delivery with hyperbaric oxygen (10,11) or carbogen breathing with nicotinamide (12); (ii) the hypoxic cytotoxin, tirapazamine (13,14). Evofosfamide, another hypoxic cytotoxin, was found to yield improved survival in a randomized phase II trial when combined with gemcitabine in patients with pancreatic cancer (15).…”

The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery

“…A satisfactory TPZ/CisPt chemoradiotherapy starting dose was identified. 17 [DiSilvestro 2014] Despite promising results from a phase II trial of combined chemoradiotherapy of head and neck cancers using TPZ combined with CisPt, the phase III trial found no difference in patients (with advanced head and neck cancer not selected for the presence of hypoxia) in overall survival compared to CisPt chemoradiation alone. 18 [Rischin 2010] It is unknown why the phase III trials of DiSilvestro and Rischin failed to reproduce the promising in vitro results or phase II trials of TPZ/CisPt treatments.…”