International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationPhase 1 Trial of Bevacizumab With Concurrent Chemoradiation Therapy for Squamous Cell Carcinoma of the Head and Neck With Exploratory Functional Imaging of Tumor Hypoxia, Proliferation, and Perfusion
Introduction
Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous group of tumors that involve the oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, and paranasal sinuses. Despite stepwise advances in the treatment of HNSCC, the outcomes remain modest for patients with advanced-stage disease, with 5-year absolute survival rates on the order of 30% to 50% (1). Recently, targeted therapies directed against the epidermal growth factor receptor, integrated with radiation therapy (RT) or chemotherapy, have shown effectiveness in improving overall survival in the definitive (1) and metastatic/recurrent setting (2). These results provide evidence that a molecularly targeted therapy can enhance the efficacy of curative RT and cytotoxic chemotherapy in the metastatic/recurrent setting.
Rich vascular supply and overexpression of vascular endothelial growth factor (VEGF) receptors are common in HNSCC and are indicative of a poor prognosis (3). Tumor hypoxia is prevalent in HNSCC (4) and is associated with poor outcome after radiation (5). Antiangiogenic therapy has been postulated to improve hypoxia status and thereby improve patient outcome in this setting (6). Bevacizumab is an anti-VEGF monoclonal antibody that has been approved by the U.S. Food and Drug Administration in several solid tumor settings. Recent preclinical studies have demonstrated a synergistic effect between RT and bevacizumab for reducing proliferation in HNSCC tumor models 7, 8.
To date, limited studies examining bevacizumab in combination with cisplatin-based chemoradiation therapy in HNSCC have been performed. We completed a phase 1 dose escalation trial with the primary objective of examining the safety and feasibility of combining bevacizumab with RT and cisplatin in patients with locoregionally advanced HNSCC. The secondary objectives included time to disease progression and survival and ability of bevacizumab to affect biological imaging surrogates of tumor hypoxia, proliferative capacity, and tumor perfusion. We report the clinical outcomes and the correlative imaging results.
Section snippets
Patients
Patients with confirmed diagnoses of locoregionally advanced SCC of the oropharynx, hypopharynx, or larynx (stage III/IV disease) were prospectively enrolled in a phase 1 trial. The eligibility criteria are described in Supplement E1 (available online at www.redjournal.org). The trial was approved by the University of Wisconsin Scientific Review Committee and Institutional Review Board. All patients provided study-specific informed consent.
Chemotherapy delivery
All patients received a single induction dose of
Patients
Between 2007 and 2010, 10 patients with locoregionally advanced HNSCC were enrolled (Table 1). All patients had stage IV HNSCC. Although testing for human papillomavirus (HPV) was not incorporated into trial eligibility, retrospective tissue analyses demonstrated that tumors from all patients stained positively for p16, a surrogate for HPV positivity. Although patients with tumors of the oropharynx, hypopharynx, or larynx were eligible for enrollment, all 10 patients accrued had cancer of the
Discussion
Antiangiogenic therapies hold promise for many solid tumors. To date, the data are limited regarding the use of bevacizumab in conjunction with chemoradiation therapy for locally advanced HNSCC treated with curative intent. We demonstrate that the incorporation of bevacizumab with comprehensive cisplatin-based chemoradiation therapy for HNSCC appears safe and feasible. Additionally, novel correlative imaging results indicate that bevacizumab can affect HNSCC tumors by reducing tumor
Acknowledgment
The authors thank the patients, their families, and the UWCCC Radiation Oncology research staff, particularly Ms. Diana Trask, for their invaluable contributions to this work.
References (40)
- et al.
Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival
Lancet Oncol
(2010) - et al.
Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy: An international multi-center study
Radiother Oncol
(2005) - et al.
Tumor perfusion rate determined noninvasively by dynamic computed tomography predicts outcome in head-and-neck cancer after radiotherapy
Int J Radiat Oncol Biol Phys
(2003) - et al.
A randomized phase II study of 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy compared with bevacizumab plus 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy for intermediate-stage and T4N0-1 head and neck cancers
Ann Oncol
(2011) - et al.
Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): A phase 2 multi-institutional trial
Lancet Oncol
(2012) - et al.
Concomitant chemoradiation versus radical radiotherapy in advanced squamous cell carcinoma of oropharynx and nasopharynx using weekly cisplatin: A phase II randomized trial
Ann Oncol
(2010) - et al.
Thrombosis associated with angiogenesis inhibitors
Best Pract Res Clin Haematol
(2009) - et al.
Correlation of PET images of metabolism, proliferation and hypoxia to characterize tumor phenotype in patients with cancer of the oropharynx
Radiother Oncol
(2012) - et al.
Platinum-based chemotherapy plus cetuximab in head and neck cancer
N Engl J Med
(2008) - et al.
Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: A meta-analysis
Clin Cancer Res
(2005)
Tissue oxygen distribution in head and neck cancer patients
Head Neck
Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy
Science
Combined effects of bevacizumab with erlotinib and irradiation: A preclinical study on a head and neck cancer orthotopic model
Br J Cancer
Enhancement of radiation response with bevacizumab
J Exp Clin Cancer Res
Imaging proliferation in vivo with [F-18]FLT and positron emission tomography
Nat Med
Kinetic analysis of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) in head and neck cancer patients before and early after initiation of chemoradiation therapy
J Nucl Med
Copper-62-ATSM: A new hypoxia imaging agent with high membrane permeability and low redox potential
J Nucl Med
Assessment of tumor hypoxia by 62Cu-ATSM PET/CT as a predictor of response in head and neck cancer: A pilot study
Ann Nucl Med
Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer
Nat Med
From RECIST to PERCIST: Evolving considerations for PET response criteria in solid tumors
J Nucl Med
Cited by (40)
Copper Isotopes in Theranostics
2022, Nuclear Medicine and Molecular Imaging: Volume 1-4PET Imaging for Head and Neck Cancers
2021, Radiologic Clinics of North AmericaDelivery of radioimmunotherapy for solid tumors
2021, Systemic Drug Delivery Strategies: Volume 2 of Delivery Strategies and Engineering Technologies in Cancer ImmunotherapyRole of Non-FDG-PET/CT in Head and Neck Cancer
2021, Seminars in Nuclear MedicineDual inhibition of VEGF and PARP suppresses KRAS-mutant colorectal cancer
2020, Neoplasia (United States)Functional imaging early during (chemo)radiotherapy for response prediction in head and neck squamous cell carcinoma; a systematic review
2019, Oral OncologyCitation Excerpt :The full texts of 254 studies were reviewed (Figure 1). Finally we included 52 articles in which CT-perfusion (n = 4) [17,36-38], functional MRI (n = 22) [11,39-58], and PET (n = 29) [8,16,31,32,41,53,58-80] were used (Table 1). Functional MRI techniques were studied using DCE (n = 7) and DWI (n = 17), of which 3 studies used IVIM and one study used both DWI and DCE.
Clinical trial supported by Genentech Inc and the University of Wisconsin Carbone Cancer Center.
Conflict of interest: none.