Function, muscles, and sparing by IMRT for head-and-neck cancer.

The tight dose distributions achieved by intensity modulated radiation therapy (IMRT) allow investigations of the sparing of many organs and tissues during head-and-neck cancer (HNC) radiation therapy, with potential reduced toxicity and improved function and quality of life. These organs include the major salivary glands, oral cavity (containing minor salivary glands, taste buds, and mucosa), structures related to swallowing (pharyngeal constrictors [PCs], larynx, and upper esophagus), muscles of mastication, mandible, cochleas, brachial plexus, sternocleidomastoid muscles, carotid arteries, the nausea-related area postrema in the dorsal medulla, and more. Because dose trade-offs are the hallmark of IMRT planning, organ-at-risk (OAR) sparing must be carefully balanced against competing issues of target coverage, increased doses to other normal structures, and the time required for including multiple OARs in the contouring and treatment planning processes. Because the most common and prominent late sequelae of radiation therapy for HNC are xerostomia and dysphagia, most sparing efforts by IMRT concentrate on reducing these sequelae. Although the OARs for xerostomia are obvious (the major and minor salivary glands), the case of dysphagia is much more complex. The process of efficient swallowing requires exquisite timing and coordination of more than 30 pairs of muscles and 6 cranial nerves (1). To reduce dysphagia and aspiration by IMRT, one must identify the specific organs whose damage or dysfunction causes dysphagia, establish correlations between their doses and dysphagia severity, and determine whether sparing these organs improves dysphagia compared with similar therapy without a sparing aim. The paper by Pearson et al in this current issue of the Red Journal adds to the relevant literature (2). These investigators used functional MRI before and after swallowing in healthy volunteers to assess which muscles are active in hyolaryngeal elevation, an important step in preventing aspiration. They found that 2 muscle groups, the suprahyoid and longitudinal pharyngeal muscles, demonstrated significant functional activity during hyolaryngeal elevation. While the distal insertions of the longitudinal pharyngeal muscles are included within the circular PC OAR contours, their proximal insertions to the base of skull and the suprahyoid muscles are not currently included as OARs in IMRT trials. Given their important functional role in swallowing, the authors argue that these muscles need to be considered during IMRT planning that aims to reduce dysphagia and aspiration. Because this study was performed in healthy volunteers rather than in patients receiving radiation therapy, the question arises as to what we may expect following full-dose irradiation of these and other muscles and nerves responsible for deglutition. Although the precise mechanisms of radiation injury of muscles are incompletely defined, acute microvascular injury and muscle edema are commonly implicated pathogenic mechanisms, with vessel and myofilament atrophy, collagen deposition, and characteristic late myofilament and vascular lesions appearing after many months (3). The resulting ischemic and inflammatory changes are postulated to promote fibrogenic cytokine signaling and myofibroblast activity, eventually resulting in clinically significant fibrosis (3). Peripheral nerve injury is similarly mediated by microvascular damage that produces early Schwann cell loss and microvascular fibrosis and necrosis, followed by demyelination, axonal degeneration, and nerve fiber loss (3). Secondary demyelination resulting from nerve entrapment by perineural fibrosis has also been proposed. Radiation injury in both skeletal muscles and peripheral nerves is observed more frequently and after shorter latency periods with larger fraction sizes, consistent with the radiobiology of late-responding tissues (3). Clinical reports have similarly shown that although most cases of radiation-related muscle or peripheral nerve injury after single fraction radiation