Organ-Sparing in Radiotherapy for Head-and-Neck Cancer: Improving Quality of Life,

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This is an overview of select studies characterizing the effect of radiation on normal tissues in the treatment of head-and-neck cancer. Recommendations for organ-at-risk dose constraints aiming to reduce risks of xerostomia and dysphagia, the factors which have the highest effect on patient quality of life, are discussed, along with their supporting evidence. Recent advances in technology and biology, and their implications for reducing toxicity are explored. Considerations related to organ-sparing in the setting of treatment deintensification for good-prognosis head-and-neck cancer are also discussed.

Introduction

Over the past 2 decades, intensification of therapy for poor prognosis, smoking- and alcohol-related head-and-neck cancer (HNC), by adding concurrent chemotherapy or altering fractionation, has improved tumor control.1, 2 In parallel, a distinct population of patients with human papilloma virus (HPV)-associated, nonsmoking-related HNC with a relatively good prognosis has emerged.3 The improved outcomes in both groups of patients has increased the relative importance of toxicity and decline in quality of life (QOL) associated with more aggressive therapy.

The use of intensity-modulated radiation therapy (IMRT) in HNC has led to reduced toxicity and improved QOL compared to conventional techniques by allowing for enhanced sparing of organs at risk (OARs).4, 5, 6 However, despite these advances, adverse effects continue to be a significant source of morbidity in patients treated with radiotherapy for HNC, particularly xerostomia and dysphagia.7 Recent technological advances have sought to further reduce these toxicities. In this article, we define the most relevant OARs related to xerostomia and dysphagia, review the current understanding of appropriate dose-function thresholds, explore promising techniques for limiting irradiation of these organs while maintaining adequate tumor control, and discuss implications in organ-sparing of treatment deintensification for good-prognosis, HPV-related HNC.

Section snippets

Xerostomia

Xerostomia is a multifactorial process consisting of multiple components, including reduced salivary output, decreased salivary pH, and increased viscosity.8, 9 These changes not only result in the uncomfortable sensation of a dry mouth, but affect other functions as well. These include dysfunction of mastication,10 altered taste,11 swallowing dysfunction,12, 13 and difficulties with speech.14 Radiation-induced saliva changes also affect the normal flora of the mouth, which can increase the

Parotid Glands

Initial efforts to improve xerostomia focused on parotid-sparing techniques. Multiple studies have shown parotid-sparing IMRT to be associated with reduced rates of xerostomia, primarily in terms of observer-rated and objective measure.4, 5, 6, 19 Multiple dose-function studies have identified useful OAR parameters to guide treatment planning. Chera et al20 suggested that as a parallel organ, the preservation of parotid function may depend on a critical percentage of gland volume receiving a

Submandibular Glands

A likely contributor to the persistence of significant xerostomia following parotid-sparing IMRT is radiation-induced damage of other salivary glands, including the SMGs and minor salivary glands within the OC. Several studies have demonstrated a correlation between SMG dose and xerostomia.27, 28, 29, 30 In a prospective study, Little et al31 showed that increasing mean doses to the SMGs, in addition to bilateral parotid glands and OC, were associated with worse patient- and observer-reported

Minor Salivary Glands

As described earlier, the minor salivary glands are present throughout the most of the OC and pharynx. Owing to this distribution and lack of a discrete organ, studying the effects of radiation on the minor salivary glands have proven difficult. Various reports have used mean dose to the OC as a surrogate for minor salivary gland dose. In this capacity, mean OC dose has been found to be an independent predictor of xerostomia, although the relative importance has not been consistent in all

Salivary Stem Cells

Although the studies earlier primarily focused on mean doses to salivary structures, emerging evidence suggests that doses to regions enriched with salivary stem cells may be more influential.37 Work by van Luijk et al38 suggest that stem and progenitor cells of the parotid gland are located in regions containing the major ducts. Irradiation of these sites in rat parotid glands resulted in different salivary output, which was based on the site irradiated, rather than on the mean dose to the

Summary of Salivary Gland Planning Recommendations

Taking the aforementioned data into account, we recommend limiting mean parotid-gland dose to 26 Gy, mean cSMG dose to <39 Gy, and mean OC dose to <30 Gy, although we recommend assigning the OC dose constraint a low priority for optimization. Further study of salivary stem cells may lead to improved OAR definitions and planning goals.

Dysphagia

Although less common than xerostomia, dysphagia is a prevalent side effect following radiotherapy for HNC and can lead to significant detriment in QOL.7, 39, 40 In addition, dysphagia can increase the risk of aspiration, which in the postradiation setting can be undetected by the patient owing to desensitization of the mucosa and can lead to aspiration pneumonia.41 Radiation-induced dysphagia is influenced by multiple factors. Physiological swallowing is a complex process that relies on the

Dose-Function Relationships With Swallowing Structures

Multiple studies have sought to identify IMRT planning parameters with the aim to reduce dysphagia, with most studies identifying the pharyngeal constrictor muscles, upper esophageal sphincter, and larynx as important OARs.44, 49, 50, 51 Typically, mean dose thresholds of 50-60 Gy have been reported, below which dysphagia risk was limited. When analyzing only patients with oropharyngeal cancer, mean doses to the superior constrictors have been most significantly associated with dysphagia,44, 52,

Relationship Between Xerostomia and Dysphagia

Multiple studies have shown that objective evaluation of swallowing function has underestimated patient-reported dysphagia.57, 58 One explanation for this is that subjective dysphagia is likely influenced by xerostomia, which contribution is not captured by objective measures of swallowing function. Among the different patterns of postradiotherapy dysphagia identified in 1 prospective cohort study, improvement in transient dysphagia (defined as grade 2 dysphagia 6 months after treatment) was

Summary of Swallowing-Structure Planning Constraints

Taking the aforementioned into account, we recommend limiting the mean dose to the uninvolved pharyngeal constrictor muscles to <50 Gy and limiting the mean dose to the uninvolved larynx to <20 Gy when using whole-neck IMRT, a dose which is readily achievable in split-field IMRT where a laryngeal block is placed in the anterior supraclavicular field.

Adaptive Radiotherapy

Adaptive radiotherapy (ART) describes regenerating a patient's radiation plan based on midtreatment anatomical and geometric changes. Throughout a given treatment course, it is relatively common for changes in target or normal structure to occur. The most common OAR change is medial movement and reduction in volume of the parotid glands. This is most commonly seen in patients who experience significant weight loss during treatment. Without intervention, such a change could result in significant

Proton Beam Therapy

Considerations regarding the use of proton therapy in treating HNC, specifically intensity-modulated proton therapy (IMPT), is discussed in a separate article in this issue and will only be briefly summarized here. The unique properties of IMPT, namely dose deposition characterized by the Bragg peak and a lack of exit dose beyond the specified range, contribute to an improvement in dose conformality compared to IMRT. This higher conformality may improve both the dosimetry and function in

Implications of Treatment Deintensification

The topic of deintensification in HPV-related HNC is discussed in a separate article in this issue of Seminars in Radiation Oncology. We discuss later OAR-sparing considerations that are relevant to this discussion.

A single-arm, phase II deintensification trial by Chera et al76 used a dose of 60 Gy in 30 fractions with less-intense concurrent chemotherapy consisting of weekly cisplatin at 30 mg/m2.An ongoing randomized NRG-oncology study, HN002, compares this regimen to 60 Gy accelerated

Conclusion

Recent biologic and technologic advances provide powerful tools for improving tumor control and QOL following radiotherapy for patients with HNC. We have reviewed seminal and recent work which forms the foundation for current recommendations related to normal-tissue sparing. As science and technology continue to progress, the therapeutic ratio of radiotherapy for HNC may further increase. However, with each development, thorough study is required to ensure that a favorable balance of patient

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    Supported in part by the Newman Family Foundation and by NIH, United States, Grant RO1 CA-184153.

    Conflicts of interest: none.

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