Michael F Milosevic1, Carol A Townsley2, Naz Chaudary3, Blaise Clarke4, Melania Pintilie5, Stacy Fan6, Rachel Glicksman6, Masoom Haider7, Sunmo Kim6, Helen MacKay8, Ivan Yeung9, Richard P Hill10, Anthony Fyles9, Amit M Oza8. 1. Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada. Electronic address: mike.milosevic@rmp.uhn.ca. 2. Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada. 3. Department of Advanced Molecular Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada. 4. Department of Pathology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Canada. 5. Department of Clinical Study Coordination and Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto, Canada. 6. Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, Canada. 7. Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Medical Imaging, University of Toronto, Toronto, Canada. 8. Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada. 9. Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada. 10. Department of Radiation Oncology, University of Toronto, Toronto, Canada; Department of Advanced Molecular Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Abstract
PURPOSE: 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.
PURPOSE: 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.
Authors: Keehoon Jung; Takahiro Heishi; Omar F Khan; Piotr S Kowalski; Joao Incio; Nuh N Rahbari; Euiheon Chung; Jeffrey W Clark; Christopher G Willett; Andrew D Luster; Seok Hyun Yun; Robert Langer; Daniel G Anderson; Timothy P Padera; Rakesh K Jain; Dai Fukumura Journal: J Clin Invest Date: 2017-07-10 Impact factor: 14.808