Sorafenib Increases Tumor Hypoxia in Cervical Cancer Patients Treated With Radiation Therapy: Results of a Phase 1 Clinical Study

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• 作者：Michael F. Milosevic ; MD^&lowast ; ; ^&dagger ; ; ^{mike.milosevic@rmp.uhn.ca" class="auth_mail" title="E-mail the corresponding author} ; Carol A. Townsley ; MD^&Dagger ; ; Naz Chaudary ; PhD^§ ; ; Blaise Clarke ; MD^‖ ; ^¶ ; ; Melania Pintilie ; MSc^# ; Stacy Fan ; BMSc^&lowast ; ; Rachel Glicksman ; BMSc^&lowast ; ; Masoom Haider ; MD^&lowast ; &lowast ; ; ^&dagger ; &dagger ; ; Sunmo Kim ; PhD^&lowast ; ; Helen MacKay ; MD^&Dagger ; ; ^&Dagger ; &Dagger ; ; Ivan Yeung ; PhD^&lowast ; ; ^&dagger ; ; Richard P. Hill ; PhD^&dagger ; ; ^§ ; ; ^§ ; § ; ; Anthony Fyles ; MD^&lowast ; ; ^&dagger ; ; Amit M. Oza ; MD^&Dagger ; ; ^&Dagger ; &Dagger ;
• 刊名：International Journal of Radiation Oncology*Biology*Physics
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：94
• 期：1
• 页码：111-117
• 全文大小：853 K

文摘

Preclinical studies have shown that angiogenesis inhibition can improve response to radiation therapy (RT). The purpose of this phase 1 study was to examine the angiogenesis inhibitor sorafenib in patients with cervical cancer receiving radical RT and concurrent cisplatin (RTCT).

Methods and Materials

Thirteen patients with stage IB to IIIB cervical cancer participated. Sorafenib was administered daily for 7 days before the start of standard RTCT in patients with early-stage, low-risk disease and also during RTCT in patients with high-risk disease. Biomarkers of tumor vascularity, perfusion, and hypoxia were measured at baseline and again after 7 days of sorafenib alone before the start of RTCT. The median follow-up time was 4.5 years.

Results

Initial complete response was seen in 12 patients. One patient died without achieving disease control, and 4 experienced recurrent disease. One patient with an extensive, infiltrative tumor experienced pelvic fistulas during treatment. The 4-year actuarial survival was 85%. Late grade 3 gastrointestinal toxicity developed in 4 patients. Sorafenib alone produced a reduction in tumor perfusion/permeability and an increase in hypoxia, which resulted in early closure of the study.

Conclusions

Sorafenib increased tumor hypoxia, raising concern that it might impair rather than improve disease control when added to RTCT.