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Head and Neck Cancer Section Heading Section sub Combined Chemoradiation Therapy in the Treatment of Squamous Cell Carcinoma of the Head and Neck—An Evolving Paradigm Zachary S Morris, 1 Pranshu Mohindra, MD 1 and Tim J Kruser, MD 2 1. Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, US; 2. Radiation Oncology Consultants, Ltd, and Delnor Hospital, Geneva, Illinois, US Abstract Combined modality chemoradiation therapy is a standard-of-care treatment for locally advanced squamous cell carcinoma of the head and neck (SCCHN) and is recommended as an adjuvant treatment for certain patients with high-risk features on surgical pathology. In this article, we review the data from clinical trials that have established this role for chemoradiation therapy in the treatment of head and neck cancer, and discuss prior and ongoing studies that have investigated concurrent versus induction chemotherapy in the definitive treatment setting. We briefly review historical and ongoing studies that have explored the impact of radiotherapy fractionation on clinical outcome in patients treated with chemoradiation. Finally, we explore the emerging role of molecular-targeted agents in multimodality treatment approaches for SCCHN. In appropriately selected patients the demonstrable survival benefit of chemoradiation outweighs the risks for additional toxicities. Simultaneous advances in surgical techniques and increasing understanding of the role of viral etiologies pose a number of important questions regarding appropriate combination of multimodality therapy. Keywords Head and neck cancer, squamous cell carcinoma, chemotherapy, radiation, molecular-targeted therapy Disclosure: The authors have no conflicts of interest to declare. Received: May 13, 2013 Accepted: July 20, 2013 Citation: Oncology & Hematology Review (US), 2013;9(2):115–121 Correspondence: Zachary S Morris, MD, PhD, K4/B100 CSC, 600 Highland Ave, Madison, WI 53792, US. E: zmorris@uwhealth.org Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most-common neoplasm globally with ~600,000 cases diagnosed annually. The past 20 years have yielded a wealth of clinical trial data and this has transformed the standards of care for treatment of SCCHN. Historically, poor local disease control and overall survival have provided impetus for a multitude of clinical trials evaluating multimodality therapy in patients with SCCHN. The intricate anatomy and the critical functional and social roles of the head and neck region have no doubt also motivated significant efforts to identify alternatives to oncologic resection of malignant tumors in this region. In this review, we summarize the historical development of combined chemoradiation therapy in the treatment of SCCHN, provide an update of recent literature in this field, and discuss contemporary clinical questions that future studies may resolve. Concurrent Chemoradiation—From Experimental to Preferred Treatment Clinical investigation into the role of combined chemoradiation treatment for SCCHN dates to at least the late 1960s, with early studies exploring sequential and concurrent use of single agents including fluorouracil (5FU), bleomycin, cisplatin, methotrexate, and mitomycin. 1 Such trials demonstrated poor response to single agent chemotherapy alone while pointing to cisplatin as the most effective single-agent with a 25–30 % response rate. 2–4 Subsequent studies explored the role © To u ch MEdical MEd ia 2013 of multi-agent chemotherapy and demonstrated marked improvement in disease response to 70  % with combined cisplatin and bleomycin 5 and >90  % response rates with cisplatin and continuous infusion 5FU. 6,7 Importantly, these early studies pointed to a potential survival benefit from the addition of chemotherapy to traditional definitive treatments of radiation and/or surgery for SCCHN and prompted further investigation in larger randomized phase III trials. With refinement of chemotherapeutic regimens, consideration turned to the potential for definitive and organ-sparing chemoradiation approaches in patients with locally advanced SCCHN. This work was initially advanced by a series of single-institution studies demonstrating viability of definitive chemoradiation as an alternative to surgery for glottic and supraglottic laryngeal tumors. 8–10 The historically important Veteran Affairs Laryngeal Cancer Study ultimately demonstrated that induction chemotherapy (ICT) followed by radiation could achieve organ preservation in SCCHN patients without compromise in overall survival. 11 This trial established a rationale for the landmark Radiation Therapy Oncology Group (RTOG) 9111 study, which addressed the appropriate sequencing of chemotherapy and radiation in patients with locally advanced supraglottic or glottic larynx cancer. Patients were randomized to: ICT followed by radiation; concurrent chemoradiation (CCRT); or radiation alone. 12,13 The results of RTOG 9111 demonstrated superiority of CCRT in terms of locoregional disease control and larynx 115