Clinical Investigation
Phase 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

Presented in part at the 52nd Annual Meeting of the American Society for Radiation Oncology, October 31 - November 4, 2010, San Diego, CA, and the 2011 Annual Meeting of the American Society of Clinical Oncology, June 3-7, 2011, Chicago, IL.
https://doi.org/10.1016/j.ijrobp.2014.11.029Get rights and content

Purpose

A phase 1 trial was completed to examine the safety and feasibility of combining bevacizumab with radiation and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) treated with curative intent. Additionally, we assessed the capacity of bevacizumab to induce an early tumor response as measured by a series of biological imaging studies.

Methods and Materials

All patients received a single induction dose of bevacizumab (15 mg/kg) delivered 3 weeks (±3 days) before the initiation of chemoradiation therapy. After the initial dose of bevacizumab, comprehensive head and neck chemoradiation therapy was delivered with curative intent to 70 Gy in 33 fractions with concurrent weekly cisplatin at 30 mg/m2 and bevacizumab every 3 weeks (weeks 1, 4, 7) with dose escalation from 5 to 10 to 15 mg/kg. All patients underwent experimental imaging with [18F]fluorothymidine positron emission tomography (FLT-PET) (proliferation), [61Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) PET (Cu-ATSM-PET) (hypoxia), and dynamic contrast-enhanced computed tomography (DCE-CT) (perfusion) at 3 time points: before bevacizumab monotherapy, after bevacizumab monotherapy, and during the combined therapy course.

Results

Ten patients were enrolled. All had stage IV HNSCC, all achieved a complete response to treatment, and 9 of 10 remain alive, with a mean survival time of 61.3 months. All patients experienced grade 3 toxicity, but no dose-limiting toxicities or significant bleeding episodes were observed. Significant reductions were noted in tumor proliferation (FLT-PET), tumor hypoxia (Cu-ATSM-PET), and DCE-CT contrast enhancement after bevacizumab monotherapy, with further decreases in FLT-PET and Cu-ATSM-PET during the combined therapy course.

Conclusions

The incorporation of bevacizumab into comprehensive chemoradiation therapy regimens for patients with HNSCC appears safe and feasible. Experimental imaging demonstrates measureable changes in tumor proliferation, hypoxia, and perfusion after bevacizumab monotherapy and during chemoradiation therapy. These findings suggest opportunities to preview the clinical outcomes for individual patients and thereby design personalized therapy approaches in future trials.

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.

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      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.

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    Clinical trial supported by Genentech Inc and the University of Wisconsin Carbone Cancer Center.

    Conflict of interest: none.

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