Phase III study of tirapazamine, cisplatin and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck

D. Rischin, L. Peters, B. O'Sullivan, J. Giralt, K. Yuen, A. Trotti, J. Bernier, J. Bourhis, M. Henke, R. Fisher, Gr Trans-Tasman Radiation Oncology

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Background: Promising results in a randomized phase II trial with the hypoxic cytotoxin, tirapazamine combined with cisplatin and radiation led to this phase III trial known as HeadSTART. Methods: Patients with previously untreated Stage III or IV (excluding T1–2N1 and M1) SCC of the oral cavity, oropharynx, hypopharynx or larynx, were randomized to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either cisplatin (100 mg/m2) on day 1 weeks 1, 4 and 7 (CIS) or cisplatin (75 mg/m2) plus tirapazamine (290 mg/m2/day) on day 1 of weeks 1, 4 and 7 and tirapazamine alone (160 mg/m2/day) on days 1, 3 and 5 of weeks 2 and 3 (CIS/TPZ). The primary endpoint was overall survival (OS). Secondary endpoints included failure-free survival (FFS), time to locoregional failure (LRF), toxicity and quality of life. The planned sample size was 850, which provides 90% power to detect a difference in 2-year survival rates of 60% v 70% (HR = 0.69). A comprehensive prospective review of radiotherapy protocol compliance was conducted, blinded to treatment arm. Results: 861 patients were accrued from 89 sites in 16 countries. In an intention to treat analysis the 2-year OS rates were 65.7% CIS and 66.2% CIS/TPZ (95% CI: -5.9% to 6.9% CIS/TPZ-CIS). There were no significant differences in FFS or time to LRF. More hearing loss was observed with CIS, while more diarrhea and muscle cramps were observed with CIS/TPZ. No significant differences in acute radiation toxicities were observed. 20% patients were found to have major deviations in the radiotherapy plan with the potential for an adverse impact on tumor control. This was associated with an increased risk of death (HR=1.56; p=< 0.0001), any failure (HR=1.65; p< 0.0001), and locoregional failure (HR=1.82; p=0.0002).There was some evidence of a treatment effect in patients without major radiotherapy deviations, HR for risk of LRF (CIS/TPZ:CIS) 0.74, 95% CI: 0.53 to 1.04. Conclusions: We found no evidence that the addition of TPZ to chemoradiation, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves overall survival. Radiotherapy deviations had a major adverse impact on treatment outcome.
Idioma originalUndefined/Unknown
RevistaJournal of Clinical Oncology
Estat de la publicacióPublicada - 20 de maig 2008

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