INTRODUCTION. General principles

PRACTICE GUIDELINES AHNS Series: Do you know your guidelines? Principles of radiation therapy for head and neck cancer: A review of the National Comprehensive Cancer Network guidelines Zhen Gooi, MBBS, 1 Carole Fakhry, MD, MPH, 1 David Goldenberg, MD, 2 Jeremy Richmon, MD, 1 Ana P. Kiess, MD, PhD, 3 * The Education Committee of the American Head and Neck Society (AHNS) 1 Department of Otolaryngology Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland, 2 Department of Surgery, Division of Otolaryngology Head and Neck Surgery, The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania, 3 Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland. Accepted 2 February 2016 Published online 25 March 2016 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24448 ABSTRACT: This article is a continuation of the Do You Know Your Guidelines series, an initiative of the American Head and Neck Society s Education Committee to increase awareness of current best practices pertaining to head and neck cancer. The National Comprehensive Cancer Network guidelines for radiotherapy in the treatment for head and neck cancers are reviewed here in a systematic fashion according to site and stage. These guidelines outline indications for primary and adjuvant treatment, as well as general principles of radiotherapy. VC 2016 Wiley Periodicals, Inc. Head Neck 38: 987 992, 2016 KEY WORDS: head and neck cancer, National Comprehensive Cancer Network (NCCN), radiation, guidelines, principles INTRODUCTION Radiotherapy (RT), either as primary or adjuvant therapy, is a major tool in the treatment of all head and neck cancers. The National Comprehensive Cancer Network (NCCN) Guidelines for head and neck cancer is a comprehensive manual that specifies algorithmic, decisionmaking pathways for management of this disease based on analysis of existing evidence in the literature by a multidisciplinary, subspecialist panel from NCCN member institutions. 1 This review aims to summarize the NCCN guidelines pertaining to the use of RT for definitive and adjuvant treatment of head and neck cancer, and it is organized by anatomic site and stage. The NCCN guidelines reviewed here are version 1.2015. Treatment recommendations are classified according to levels of evidence and consensus among NCCN panel members. Category 1 recommendations are based on high level evidence with uniform NCCN consensus that the intervention is appropriate. Category 2A and 2B recommendations are based upon lower level evidence with a significant NCCN panel member consensus (Category 2A, 85% to <100%, Category 2B, >50, <85% consensus) that the intervention is appropriate. Category 3 treatment recommendations are based upon any level of evidence with major disagreement among NCCN panel members on the suitability of the given treatment. Throughout this review, treatment *Corresponding author: A. P. Kiess, Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Weinberg 1440 Oncology, 401 N. Broadway, Baltimore, MD 21231. E-mail: akiess1@jhmi.edu recommendations are category 2A unless specifically stated. As treatment recommendations are based on staging, accurate workup incorporating history, physical examination, and radiologic imaging when indicated is necessary. General principles Conventional fractionation for definitive RT in head and neck cancer involves the delivery of 66 Gy (2.2 Gy/ fraction) to 70 Gy (2.0 Gy/fraction) daily Monday to Friday in 6 to 7 weeks to high-risk sites, defined as the primary tumor and involved lymph nodes. When concurrent chemoradiation is used, the typical dose to high-risk sites is 70 Gy (2.0 Gy/fraction) and the typical chemotherapy is single-agent cisplatin given every 3 weeks at 100 mg/ m 2. Radiation doses to low-risk and intermediate-risk sites depend on specific risk factors and whether 3D conformal RT or intensity-modulated RT (IMRT) is utilized. For IMRT, it is suggested that these sites receive 54 to 63 Gy in 1.6 to 1.8 Gy fractions, and for 3D conformal RT or sequentially planned IMRT, these sites receive 44 to 50 Gy in 2.0 Gy fractions. These techniques will be discussed further below. Altered fractionation regimens have been demonstrated in large randomized clinical trials to improve locoregional control over conventional fractionation, with the disadvantage of increased acute toxicities for accelerated regimens. 2 4 However, evidence for an absolute survival benefit with altered fractionation is mixed. 4 6 Currently, hyperfractionation (81.6 Gy over 7 weeks, 1.2 Gy per fraction twice daily) and accelerated fractionation regimens (66 70 Gy, 2.0 Gy/fraction, 6 HEAD & NECK DOI 10.1002/HED JULY 2016 987

GOOI ET AL. fractions per week) are accepted for oral cavity, oropharyngeal, hypopharyngeal, supraglottic, and paranasal sites. The NCCN guidelines draw attention to the increased toxicity burden with altered fractionation when chemoradiation is used and concede that the optimal radiation dose and fractionation regimens in these circumstances have not been agreed upon. In addition, it is stated that chemoradiation should be administered by experienced teams with substantial supportive care. As a general principle, postoperative RT is recommended by the NCCN for pathologic features to include advanced T stage (pt3 or pt4), multiple positive nodes, and/or perineural/lymphatic/vascular invasion. RT should be commenced within 6 weeks after surgical resection. Site-specific exceptions and additions to these indications will be noted in the sections below. Postoperative RT to high-risk sites involves the delivery of 60 to 66 Gy (2.0 Gy/fraction) daily Monday to Friday in 6 to 6.5 weeks, whereas low-risk to intermediate-risk sites should receive either 44 to 50 Gy (2.0 Gy/fraction) or 54 to 63 Gy (1.6 1.8 Gy/fraction). In cases of squamous cell carcinoma with extracapsular nodal disease and/or positive surgical margins, the NCCN guidelines issue a category 1 recommendation for the use of concurrent systemic therapy together with RT based on data from the Radiation Therapy Oncology Group 9501 and European Organisation for Research and Treatment of Cancer 22931 clinical trials. 7 9 As above, when concurrent chemoradiation is used, the typical chemotherapy is single-agent cisplatin given every 3 weeks at 100 mg/m 2. 10 IMRT involves the modulation of radiation beams to reduce doses to normal structures while still delivering effective doses to target sites, utilizing computer-based inverse planning. 11 IMRT has been shown to reduce longterm toxicity in oropharyngeal, paranasal, and nasopharyngeal cancers without any compromise in overall survival. 12 17 NCCN guidelines currently state a preference for the use of either IMRT or 3D conformal RT for treatment of all head and neck subsites, with IMRT preferred for paranasal and nasopharyngeal cancers. Methods of delivering IMRT include the simultaneous integrated boost (SIB) and sequential (SEQ) technique. In the SIB technique, a single IMRT plan is delivered with differing dose levels to different target volumes ( dose painting ) for each fraction of treatment throughout the entire course. This may be integrated with either conventional (5 fractions/week) or accelerated (6 fractions/week) fractionation. 1 In the SEQ technique, radiation is delivered with an initial lower dose plan during the first 5 weeks of therapy, followed by separate boost plan(s) to intermediate/high-risk areas in the last 2 weeks. 1 The choice of SIB versus SEQ is often based on institutional experience, but some prefer SIB to increase dose conformality to the targets, whereas others prefer SEQ in order to keep dose per fraction at 1.8 to 2.0 Gy. The modified SEQ, or concomitant boost accelerated, schedule involves dose delivery to subclinical targets once a day for 6 weeks with the addition of a boost dose as a second daily fraction during the last 12 treatment days. 1 Other treatment aspects of RT that the NCCN guidelines highlight include nutrition, speech, and swallowing assessment, dental care, and follow-up. Specific recommendations are made regarding indications for prophylactic feeding tube placement, including severe weight loss before treatment and anticipated large fields of high-dose radiation. 1 Dental care before RT should include elimination of potential sources of infection, treatment of active dental caries and periodontal disease, and dental extractions to be carried out 2 weeks before RT. 1 Follow-up of patients who have received RT should include assessment of thyroid function every 6 to 12 months. 1 Lip cancer Although NCCN guidelines recommend surgical resection as the preferred treatment modality for clinical stage T1 to T4a, any N lip cancers, definitive RT is also mentioned as an alternative treatment option. 1 A clinical scenario in which RT is recommended is superficial cancer involving most of the lower lip. 1,18 For definitive therapy, RT may consist of external beam RT (EBRT) and/or interstitial brachytherapy in either a high-dose rate (HDR) or low-dose rate (LDR) form, with the provision that brachytherapy is carried out in centers of expertise. 1,19 LDR brachytherapy is delivered at a dose of 0.4 to 0.5 Gy per hour for a total of 20 to 35 Gy as a boost dose if combined with 50 Gy of EBRT, or 60 to 70 Gy over several days if utilized as sole therapy. 1 HDR brachytherapy is delivered as a boost dose for a total of 21 Gy at 3 Gy/ fraction when combined with 40 to 50 Gy of EBRT, or 45 to 60 Gy at 3 to 6 Gy/fraction if used as sole therapy. 1,19 For adjuvant therapy, EBRT may be recommended according to the General principles section above. Oral cavity cancer For clinical stage T1 to T4a, any N oral cavity cancers, surgical resection is recommended as the preferred treatment option. 1 For stage T1 to T2, N0, definitive radiation is presented as an alternative treatment option. 1 Similar to lip cancers, EBRT and/or LDR or HDR brachytherapy are presented as potential modes of RT. 1 For clinical stage T3N0; T1 to T3, N1 to N3; or T4a, any N, definitive RT is not recommended. After surgery, adjuvant EBRT may be considered according to the General principles section above, as well as for nodal disease in levels IV or V. Oropharynx For all stages of oropharyngeal cancer, primary EBRT is presented as a treatment option. For T1 to T2, N0 to N1 cancers, definitive radiation as a single modality may be used. 20,21 For T2, N1 cancers, the addition of concurrent chemotherapy with radiation carries with it a category 2B recommendation. 1 For T3 to T4a, N0 to N1, or any T, N2 to N3 cancers, concurrent chemotherapy with cisplatin is highly recommended when definitive radiation is used (category 1 recommendation). 22 24 Induction chemotherapy before radiation treatment for these stages has a category 3 recommendation. 1 After surgery, adjuvant EBRT may be considered according to the General principles section above, as well as for nodal disease in levels IV or V. 988 HEAD & NECK DOI 10.1002/HED JULY 2016

NCCN GUIDELINES ON RT FOR HEAD AND NECK CANCER Although treatment deintensification strategies in the use of RT are being explored in clinical trials for human papillomavirus (HPV)-related oropharyngeal cancer, the NCCN guidelines currently state that there is still a lack of data in support of such strategies, and that HPV tumor status should not influence treatment strategies. 1 The guidelines do support HPV tumor detection to determine prognosis and advocate for the enrollment of patients with HPV-related cancers in suitable clinical trials. 1 Hypopharynx For T1N0 or selected T2N0 hypopharyngeal cancers, definitive RT as a sole treatment modality is an option. For T2 to T3, any N or T1, N-positive cancers, definitive RT is a treatment option in conjunction with either induction or concurrent chemotherapy. When concurrent chemotherapy is used, the preferred systemic agent is highdose cisplatin (category 1). 1 If induction chemotherapy is used and there is a complete response (CR) in the primary site and stable/improved neck disease, definitive radiation has a category 1 recommendation, whereas concurrent chemoradiation has a category 2B recommendation. 1,25 In cases of partial response (PR) and stable/ improved neck disease, either surgery or concurrent chemoradiation (category 2B) are treatment options. 1 Surgery is recommended if there is less than PR in the primary site after induction chemotherapy. 1 For T4a, any N staging, the preferred treatment modality is surgery, with RT and/or induction chemotherapy having a category 3 treatment recommendation. 1 If induction chemotherapy is used for T4a, any N staging, definitive radiation or chemoradiation is recommended for CR or PR in the primary site but has no role if there is less than PR in the primary site or progression of neck disease. 1 Adjuvant RT after surgery is recommended according to the General principles section above. Nasopharynx For T1N0M0 nasopharyngeal cancers, NCCN guidelines recommend definitive radiation as a single modality. 1 For all other more advanced stage cancers, concurrent chemoradiation followed by adjuvant chemotherapy is the preferred treatment regimen, with alternatives to include concurrent chemoradiation alone (category 2B) or induction chemotherapy followed by chemoradiation (category 3). 26,27 In cases of M1 disease, concurrent chemoradiation is a treatment option in selected patients with limited distant metastasis, small tumor burden, or symptoms in the primary or nodal sites. 1 Glottic larynx For carcinoma in situ, endoscopic resection is recommended as the preferred treatment modality. 1 Primary RT is considered a treatment option for T1 to T2, selected Tis, and selected T3 cancers. 1 Treatment doses for earlystage glottis cancer differ from other sites and are 60.75 to 66 Gy for TisN0, 63 to 66 Gy for T1N0, and 65.25 to 70 Gy for T2N0, in 2.0 to 2.25 Gy/fraction. 1 For more advanced stages, radiation doses are similar to other sites, as discussed in the General principles section above. 1 For T3 to T4a, any N, radiation with either concurrent or induction chemotherapy is a treatment option, 1,22,28 although for T4a staging, surgery is stated as the preferred option. 1 When induction chemotherapy is used, a CR at the primary site should be followed by definitive radiation (category 1). 1 A PR at the primary site can be followed by RT alone (category 1) or concurrent chemoradiation (category 2B). 1 In nonresponders, RT is not a treatment option and patients should undergo surgical resection. 1 After surgery, adjuvant RT may be considered according to the General principles, but it is not required for stage pt3 in the absence of other adverse features and may not be required for highly selected stage pt4a with favorable features. 1 Supraglottic larynx Definitive RT as a single modality is a treatment option for T1 to T2, N0; T1 to T2, N-positive, and selected T3, N0 to N1 supraglottic cancers. 1 Definitive RT with either concurrent or induction chemotherapy is a treatment option for T3, N0 to N3 and T1 to T2, N-positive cancers. 1,22,28 For T4a, N0 to N3 cancers, surgery is the preferred treatment option, whereas RT with either concurrent or induction chemotherapy is an alternative option for patients who decline surgery. 1,22,28 When induction chemotherapy is used as a treatment strategy, definitive RT has a category 1 recommendation for either CR or PR but is not a treatment option when there is less than PR. 1 Adjuvant RT may be considered according to the General principles but is not required for stage pt3 in the absence of other adverse features. Paranasal sinus tumors The NCCN guidelines for ethmoid and maxillary sinus cancer apply for squamous cell carcinoma, adenocarcinoma, minor salivary gland tumor, esthesioneuroblastoma, undifferentiated carcinoma, and sinonasal neuroendocrine carcinoma. Ethmoid sinus Surgical resection is the preferred treatment option for newly diagnosed T1 to T4a cancers, and all cases diagnosed after incomplete resection (polypectomy) with gross residual disease. 1 Definitive RT is a treatment option in T1 to T2 cancers and concurrent chemoradiation in T3 to T4a cancers. 29 31 In T4b cancers, treatment options include concurrent chemoradiation or RT alone, preferably in the setting of a clinical trial. 1,32 Adjuvant RT is recommended for all patients after surgery, with the exception of an option for observation in T1 cancers with negative margins, central tumor location, and low grade histology (category 2B). 1 Adjuvant chemoradiation carries with it a category 2B recommendation for patients with positive margins and/or intracranial extension. 1 Maxillary sinus The guidelines do not recommend definitive RT as a primary treatment option for T1 to T4a tumors. For T4b tumors, treatment options include definitive RT, concurrent chemoradiation, or treatment in the setting of a HEAD & NECK DOI 10.1002/HED JULY 2016 989

GOOI ET AL. clinical trial. 32 For T1 to T2, N0 maxillary sinus adenoid cystic carcinomas, adjuvant RT is recommended after surgical resection for suprastructure tumors and may also be considered for infrastructure tumors. 1 For T1 to T2, N0 with other histologies, adjuvant RT or chemoradiation (category 2B) is recommended for perineural invasion or positive margins. For T3 to T4a, N0 cancers, adjuvant RT is recommended for positive margins, squamous cell carcinomas, adenoid cystic carcinomas, and undifferentiated tumors. For T1 to T4a, N-positive cancers, adjuvant RT is always recommended. Adjuvant chemoradiation may be considered (category 2B) for patients with positive margins or extracapsular nodal spread. 1,29 31 Very advanced head and neck cancer These recommendations are for very advanced head and neck cancers, including newly diagnosed T4b, any N, any M status, unresectable nodal disease, or patients deemed unfit for surgery. For patients with M0 status, the guidelines state a preference for enrollment into a clinical trial. When standard therapy is used, recommendations are based on patient s performance status (PS) graded by the Eastern Cooperative Oncology Group guidelines. For PS 0 to 1, recommended RT strategies include concurrent chemoradiation with high-dose cisplatin (category 1 recommendation) or induction chemotherapy followed by radiation (category 3 recommendation). 23,33,34 For PS 2, definitive radiation may be offered with or without concurrent systemic therapy. 1 For patients with PS 3, RT may be offered for palliative intent. In the setting of M1 disease, the guidelines make recommendations for clinicians to consider locoregional treatment based on primary site algorithms. 1 RT may be offered in a subset of patients with PS 0 to 1 with limited metastases either in combination with surgery or systemic therapy. Radiation is not a treatment option for patients with M1 disease and PS 2 or 3. 1 For locoregional recurrence without prior RT that is resectable, surgery or chemoradiation are possible treatment recommendations. If surgery is utilized, adjuvant radiation or chemoradiation may be considered according to the General principles. In patients with locoregional recurrence or second primary and no distant metastasis who have received prior RT, treatment recommendations vary depending on whether the disease is considered resectable. 1 If resectable, surgery with or without reirradiation or systemic therapy is recommended in the setting of a clinical trial. If not resectable, reirradiation can be considered if the following criteria are met: (1) a time period of 6 months have passed since initial RT; (2) the patient is able to receive an additional dose of at least 60 Gy; and (3) the patient is able to tolerate concurrent chemotherapy. 1,35 The guidelines further state that organs at risk should be carefully analyzed through review of dose volume histograms, and dosing should be based on factors to include time interval since initial RT, treatment volumes, and life expectancy of the patient. 1 When recurrent or persistent disease occurs in the setting of distant metastasis, the NCCN guidelines state a preference for further treatment to be conducted in the setting of a clinical trial. 1 If standard systemic therapy is used, the combination of platinum, 5-fluorouracil, and cetuximab carries with it a category 1 recommendation for patients with a PS of 0 to 1. 1 RT is an alternative treatment recommendation in this scenario for selected patients with limited metastases, but is not a treatment option in patients with PS 2 to 3 status. 1 The NCCN guidelines make recommendations for consideration of palliative radiation with the purpose of relieving or preventing locoregional symptoms in the setting of unresectable disease, widely metastatic disease, or when patients are unsuitable for standard RT. Recommended palliative RT regimens include 50 Gy in 20 fractions, 37.5 Gy in 15 fractions, 30 Gy in 10 fractions, or 44.4 Gy in 12 fractions. 36 39 The guidelines state that severe RT toxicities should be avoided when treatment is for palliation. 1 Occult primary For patients with occult primary presenting with a neck mass, the NCCN gives detailed guidelines on appropriate workup and treatment recommendations based on histology and nodal levels of the neck mass if a primary site is not identified. 1 In squamous cell carcinoma, poorly differentiated carcinoma, not otherwise specified, or anaplastic (not thyroid) histologies, surgery is stated as the preferred modality for treatment of N1 disease with RT having a category 2B recommendation. 1 For N2 to N3 disease, treatment options include surgery, definitive chemoradiation (category 2B), or induction chemotherapy followed by either chemoradiation or RT (category 3). 1 For patients undergoing neck dissection, recommendations for adjuvant RT depend on N classification and the presence/ absence of extracapsular extension. 1 In N1 disease without extracapsular extension, either radiation or observation are management options. 1 When N2 to N3 disease without extracapsular extension is diagnosed, adjuvant RT alone or in combination with systemic therapy (category 2B) is recommended. 1 When extracapsular extension is present, adjuvant chemoradiation is recommended (category 1). 1 The target volume for RT in these scenarios is determined by tumor size, nodal stations, and HPV/ Epstein Barr virus status, although the guidelines go on to further clarify that HPV testing should not change management decisions except in the setting of a clinical trial. 1 Salivary gland The guidelines for treatment of salivary gland tumors apply for benign histology and carcinomas but do not apply for lymphomas. 1 Surgery is the recommended treatment modality for clinically benign tumors or T1 to T4a carcinomas. 1 For T1 to T2 carcinomas, adjuvant RT can be considered for intermediate/high-grade histology, adenoid cystic histology, or low-grade carcinomas with tumor spillage or perineural invasion. 1 After complete resection of T3 to T4 tumors, RT is recommended for intermediate/high-grade histology, adenoid cystic histology, close or positive margins, neural/perineural invasion, lymph node metastases, and lymphatic or vascular invasion. 1,40 43 Systemic therapy with RT in this scenario carries with it a category 2B recommendation. 1,44 Adjuvant 990 HEAD & NECK DOI 10.1002/HED JULY 2016

NCCN GUIDELINES ON RT FOR HEAD AND NECK CANCER RT is not recommended when no adverse features are encountered. 1 When the tumor is incompletely resected with gross residual disease and no further surgical resection is possible, definitive RT should be delivered, whereas RT with systemic therapy is a category 2B treatment option. 1 Mucosal melanoma Wide surgical resection is recommended for stage III and IVA mucosal melanoma, and primary RT is not a treatment option for these stages. Although treatment in the setting of a clinical trial is the preferred option for stage IVB and IVC mucosal melanoma, primary RT is an alternative treatment option. Adjuvant RT is to be strongly considered in stage III mucosal melanoma and is recommended in stage IVA mucosal melanoma. 45,47 CONCLUSIONS RT has a role in primary, adjuvant, and palliative treatment of all head and neck cancer subsites, although surgical excision remains the preferred option for primary treatment of resectable lip, oral cavity, paranasal sinus, salivary gland, and mucosal melanoma tumors. 1 IMRT and 3D conformal RT are the recommended techniques for delivery of RT to head and neck sites, with a preference for IMRT in paranasal and nasopharyngeal sites. Adjuvant RT is recommended for high-risk features to include advanced T stage, N2 or N3 nodal disease, perineural invasion, and lymphovascular invasion. 1 Adjuvant chemoradiation is recommended for extracapsular spread and/or positive margins. 1 Planning for RT should include assessment of nutritional status, speech and swallowing ability, and dentition, whereas follow-up of patients who have received RT should include reassessment of all of the above and thyroid function testing. REFERENCES 1. Pfister DG, Spencer S, Brizel DM, et al. Head and neck cancers, version 1.2015. J Natl Compr Canc Netw 2015;13:847 855; quiz 856. 2. Horiot JC, Le Fur R, N Guyen T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992;25:231 241. 3. Horiot JC, Bontemps P, van den Bogaert W, et al. 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