Introduction

Article Outline

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This issue of Seminars in Radiation Oncology focuses on the management of squamous cell carcinoma of the head and neck, the third time in 10 years that various aspects of this subject have been addressed. This frequency reflects both the complexity of the issues and the magnitude of progress that has been made. Altered fractionation and concurrent chemoradiation, which were once both investigational strategies, are now well-established tools for the management of locally advanced disease. The article by Bernier provides an overview of the state-of-the-art of the delivery of concurrent chemoradiation both in definitive and adjuvant postoperative settings. Two themes emerge: first, the improvement in survival results predominantly from improved local-regional control with a small but suboptimal systemic adjuvant effect from the chemotherapy and, second, the improvement in survival is obtained at the expense of an increase in toxicity that is generally underreported.

The use of induction chemotherapy followed by local-regional treatment has been controversial ever since its inception in the 1970s. The current iteration of this treatment philosophy consists of the use of multiagent systemic induction followed by concurrent chemoradiation and is designed primarily to address the increased risk of distant failure that has evolved in the context of improved local-regional control from concurrent chemoradiation. The article by Brizel and Vokes explores the data in favor of and against this strategy of sequential induction followed by concurrent chemoradiation.

Chemoradiation is used as the definitive treatment for patients with unresectable disease and in lieu of surgery for the purpose of organ preservation for patients having technically resectable disease. Functional organ preservation would be more informative terminology because nonsurgical “organ preservation” may be either not possible or not meaningful when the tumor itself has destroyed the organ as often occurs in cases of advanced laryngeal carcinoma. The disease may still be resectable, and surgery with reconstruction may offer the best opportunity for disease eradication and function restoration. The article by Scher and Esclamado examines the settings in which surgery constitutes the optimal primary treatment modality. The surgical salvage of local-regional failures after concurrent chemoradiation can be especially challenging. Their article also describes the principles of evaluation and management of these situations and reviews the therapeutic outcomes.

The adjuvant surgical management of the node-positive neck after chemoradiation is both a controversial and evolving topic. Although neck dissection used to be performed almost irrespective of clinical and radiographic response to radiotherapy, many patients who are complete responders are now followed clinically. The use of positron-emission tomography–computed tomography scanning in this decision-making process has increased rapidly. Lango et al examine the different facets of the decision-making process including the increasing use of function-sparing surgical techniques that reduce the morbidity of neck dissection.

Increased acute morbidity is the flipside of the coin of increased local-regional control and overall survival that has resulted from the therapeutic intensification achieved with the delivery of radiotherapy and chemotherapy. Mucositis is the most acutely debilitating of these toxicities and can adversely affect the timely delivery of radiotherapy. Rosenthal and Trotti discuss different clinical strategies that have been designed to ameliorate mucositis and provide practical suggestions for its management. Dysphagia is a long-term sequela of head and neck radiotherapy. Both its significance to patients and awareness of it among providers has increased in tandem with increasing numbers of long-term survivors and the emerging prominence of the organ function–preservation philosophy. Murphy and Gilbert describe approaches to swallowing assessment and rehabilitation after therapy.

The competition between therapeutic efficacy and toxicity represents the balancing of risk and reward in treatment decision making. The use of highly conformal radiotherapy such as intensity-modulated radiation therapy adds an additional dimension to this challenge. Improper target delineation may increase the risk of a recurrence even as treatment-induced toxicity itself is diminished. Conversely, failure to properly delineate volumes and dose-limiting constraints of critical normal tissues may lead to unintended toxicities including worsened mucositis and dysphagia. Eisbruch and Gregoire provide a comprehensive site-based discussion of the issues that must be addressed in the delineation both of target volumes and normal tissue volumes for patients undergoing intensity-modulated radiation therapy.

Recently, the combination of radiotherapy and epidermal growth factor receptor inhibition was proven to improved survival. This watershed showed proof of principle of the benefit of combining physically and biologically targeted modalities and reinforced the concept that improvements in local-regional control alone can in fact lead to significant improvements in overall survival. The last 2 articles by Le and Raben and by Harari et al shift the focus to the incorporation of molecularly targeted therapy to the treatment paradigm. The first article provides an overview of the current state-of-the-art of the use of cetuximab with radiotherapy and describes other ongoing trials that are incorporating different agents that are directed at other targets. The final article provides an in-depth discussion of various signal transduction pathways responsible for growth, proliferation, and apoptosis that should provide the foundation for the testing of other agents in conjunction with (chemo)radiation.

Surveillance Epidemiology and End Results (SEER) data from 1975 to 2002 show an approximate 5% to 8% improvement in 5-year overall survival for squamous head and neck cancer. Most of this improvement occurred in oropharyngeal carcinomas and was of a similar magnitude to that attained with the addition of concurrent chemotherapy to radiotherapy. Moreover, this same time period has witnessed an increase in the overall proportion of head and neck cancers that are of oropharyngeal origin. Many of these cancers are probably caused by human papilloma virus (HPV), have arisen in patients with no prior history of tobacco use, and may have a better prognosis than non–HPV-associated cancers.

Thus, we close on a potentially sobering note. Has the prognosis for head and neck cancer improved because of synergy obtained from improved integration of function-sparing radiotherapy, surgery, and chemotherapy or is it because of a favorable evolution in the biology of the disease itself? Perhaps HPV-positive disease can be treated with less intensive, less morbid therapy. Conversely, HPV-negative disease may require even more intensive treatment. Attempts to answer these questions will no doubt play a very significant role in future clinical trial design and be an important part of the subject matter of a future issue of this journal.