Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer

Tanguy Y. Seiwert, Daniel J. Haraf, Ezra E W Cohen, Kerstin Stenson, Mary Ellyn Witt, Allison Dekker, Masha Kocherginsky, Ralph R. Weichselbaum, Helen X. Chen, Everett E. Vokes

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123 Scopus citations

Abstract

Purpose: We conducted a phase I dose escalation study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab, when added to the standard FHX (fluorouracil [FU], hydroxyurea [HU], radiation) chemoradiotherapy platform in poor-prognosis head and neck cancer (HNC) patients. Patients and Methods: Patients with recurrent, previously radiated or poor-prognosis, treatment-naive HNC were eligible. Treatment was repeated every 14 days for seven cycles: Bevacizumab was escalated 2.5 to 10 mg/kg, FU 600 to 800 mg/m2 (120 hours continuous infusion), and hydroxyurea from 500 to 1,000 mg (twice daily for 5 days), starting day 1. At the MTD, the cohort was expanded. Results: Forty-three patients were treated. DLT was reached at level 3 (bevacizumab 5 mg/kg, FU 800 mg/m2, HU 1,000 mg) with two grade 3 transaminase elevations and one grade 4 neutropenia, attributed to the combination of chemotherapy with bevacizumab. For level 4, chemotherapy doses were reduced (FU 600 mg/2, HU 500 mg), and bevacizumab escalation continued to 10 mg/kg. Treatment of six assessable patients resulted in one venous thrombosis; this dose level was expanded to 26 patients. Late complications included five patients with fistula formation (11.6%) and four with ulceration/tissue necrosis (9.3%). Serious toxicities (hemorrhage/ thrombosis/death) were comparable to prior reirradiation reports. Median overall survival for reirradiated patients with recurrent, nonmetastatic disease was 10.3 months [95% CI, 5.6 to 13.5]; 2-year cumulative incidence of death resulting from disease was 51.7% (95% CI, 31.7 to 68.5). Conclusion: Bevacizumab can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m2 every 2 weeks with decreased chemotherapy doses because of neutropenia. The regimen shows antitumor activity. Observed fistula formation/tissue necrosis may be bevacizumab related, and further investigation should proceed with careful monitoring.

Original languageEnglish (US)
Pages (from-to)1732-1741
Number of pages10
JournalJournal of Clinical Oncology
Volume26
Issue number10
DOIs
StatePublished - Sep 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Seiwert, T. Y., Haraf, D. J., Cohen, E. E. W., Stenson, K., Witt, M. E., Dekker, A., Kocherginsky, M., Weichselbaum, R. R., Chen, H. X., & Vokes, E. E. (2008). Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. Journal of Clinical Oncology, 26(10), 1732-1741. https://doi.org/10.1200/JCO.2007.13.1706