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NCCN Jatin P. Shah, MD, PhD; Sharon Spencer, MD; Andrea Trotti, III, MD; Randal S. Weber, MD; Gregory Wolf, MD; Mucosal Melanoma and Frank Worden, MD of the Head and Neck Overview Mucosal melanoma (MM) is a rare, very aggres- Clinical Practice Guidelines in Oncology sive noncutaneous melanoma that affects the upper David G. Pfister, MD; Kie-Kian Ang, MD, PhD; David M. Brizel, MD; aerodigestive tract, genitourinary tract, and anal/rec- Barbara Burtness, MD; Anthony J. Cmelak, MD; tal region.1 This portion of the NCCN Clinical Prac- A. Dimitrios Colevas, MD; Frank Dunphy, MD; David W. Eisele, MD; Jill Gilbert, MD; Maura L. Gillison, MD, PhD; tice Guidelines in Oncology (NCCN Guidelines) Robert I. Haddad, MD; Bruce H. Haughey, MBChB, MS; for Head and Neck (H&N) Cancers only describes Wesley L. Hicks, Jr., MD; Ying J. Hitchcock, MD; MMs of the H&N, which constitute fewer than 10% Merrill S. Kies, MD; William M. Lydiatt, MD; Ellie Maghami, MD; of melanomas of the H&N.1,2 Note that a separate Renato Martins, MD, MPH; Thomas McCaffrey, MD, PhD; Bharat B. Mittal, MD; Harlan A. Pinto, MD; NCCN Guideline is available for cutaneous melano- John A. Ridge, MD, PhD; Sandeep Samant, MD; ma (see NCCN Guidelines for Melanoma, available Giuseppe Sanguineti, MD; David E. Schuller, MD; in this issue and online at www.NCCN.org).

NCCN Clinical Practice Guidelines in Please Note Oncology for Mucosal Melanoma of the The NCCN Clinical Practice Guidelines in Oncology ® Head and Neck (NCCN Guidelines ) are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or Key Words consult the NCCN Guidelines® is expected to use indepen- NCCN Clinical Practice Guidelines, NCCN Guidelines, muco- dent medical judgment in the context of individual clinical sal melanoma, head and neck cancer, biopsy, neck dissec- circumstances to determine any patient’s care or treatment. tion, adjuvant therapy, radiation therapy, chemotherapy, The National Comprehensive Cancer Network® (NCCN®) pathology(JNCCN 2012;10:320–338) makes no representation or warranties of any kind regarding NCCN Categories of Evidence and Consensus their content, use, or application and disclaims any respon- Category 1: Based upon high-level evidence, there is uniform sibility for their applications or use in any way. NCCN consensus that the intervention is appropriate. © National Comprehensive Cancer Network, Inc. Category 2A: Based upon lower-level evidence, there 2012, All rights reserved. The NCCN Guidelines and the is uniform NCCN consensus that the intervention is illustrations herein may not be reproduced in any form appropriate. without the express written permission of NCCN. Category 2B: Based upon lower-level evidence, there is Disclosures for the NCCN Mucosal Melanoma NCCN consensus that the intervention is appropriate. of the Head and Neck Panel Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is At the beginning of each NCCN Guidelines panel meeting, panel appropriate. members disclosed any financial support they have received from industry. Through 2008, this information was published in an All recommendations are category 2A unless otherwise aggregate statement in JNCCN and online. Furthering NCCN’s noted. commitment to public transparency, this disclosure process has Clinical trials: NCCN believes that the best management for now been expanded by listing all potential conflicts of interest any cancer patient is in a clinical trial. Participation in clinical respective to each individual expert panel member. trials is especially encouraged. Individual disclosures for the NCCN Mucosal Melanoma of the Head and Neck Panel members can be found on page 338. (The most recent version of these guidelines and accompany- ing disclosures, including levels of compensation, are available on the NCCN Web site at www.NCCN.org.)

These guidelines are also available on the Internet. For the latest update, visit www.NCCN.org.

© JNCCN–Journal of the National Comprehensive Cancer Network | Volume 10 Number 3 | March 2012 321 NCCN Guidelines® Mucosal Melanoma of the Journal of the National Comprehensive Cancer Network Head and Neck

The full NCCN Guidelines for H&N Cancers Management Approaches address tumors arising in the upper aerodigestive The staging system for MM begins with stage III dis- tract (i.e., lip, oral cavity, pharynx, larynx, paranasal ease, which is the most limited form of disease for MM sinuses; see Figure 1). Occult primary cancer, salivary (see Workup and Staging, page 333).4 Surgery (with gland cancer, and MM are also addressed.3 Many of or without radiation therapy [RT]) is the primary the approaches for managing H&N cancer are also treatment for stage III MM, whereas surgery followed applicable to MM (e.g., multidisciplinary team, sur- by RT or systemic therapy is the primary treatment for gical principles). To view the full NCCN Guidelines stage IV MM, depending on systemic involvement. for H&N Cancers, visit the NCCN Web site at www. NCCN.org. By definition, the NCCN Guidelines cannot in- Multidisciplinary Team Involvement corporate all possible clinical variations and are not The initial evaluation and development of a plan intended to replace good clinical judgment or individ- for treating patients with MM require a multidisci- ualization of treatments. Exceptions to the rule were plinary team of health care providers with expertise discussed among the members of the NCCN H&N in caring for these patients. Similarly, managing Cancers Panel while developing these guidelines. and preventing sequelae of radical surgery, RT, and Text continues on p. 332

NCCN Mucosal Melanoma of the Head and City of Hope Comprehensive Cancer Center Renato Martins, MD, MPH† Neck Panel Members Fred Hutchinson Cancer Research Center/ *David G. Pfister, MD/Chair†Þ Seattle Cancer Care Alliance Memorial Sloan-Kettering Cancer Center Thomas McCaffrey, MD, PhDζ *Kie-Kian Ang, MD, PhD§ H. Lee Moffitt Cancer Center & Research Institute The University of Texas MD Anderson Cancer Center Bharat B. Mittal, MD§ *David M. Brizel, MD§ Robert H. Lurie Comprehensive Cancer Center of Duke Cancer Institute Northwestern University Barbara Burtness, MD† Harlan A. Pinto, MD†Þ Fox Chase Cancer Center Stanford Comprehensive Cancer Center John A. Ridge, MD, PhD¶ Anthony J. Cmelak, MD§ Fox Chase Cancer Center Vanderbilt-Ingram Cancer Center Sandeep Samant, MD¶ A. Dimitrios Colevas, MD† St. Jude Children’s Research Hospital/ Stanford Comprehensive Cancer Center University of Tennessee Cancer Institute Frank Dunphy, MD† Giuseppe Sanguineti, MD§ Duke Cancer Institute The Sidney Kimmel Comprehensive Cancer Center at David W. Eisele, MD¶ Johns Hopkins UCSF Helen Diller Family Comprehensive Cancer Center David E. Schuller, MD¶ Jill Gilbert, MD† The Ohio State University Comprehensive Cancer Center – Vanderbilt-Ingram Cancer Center James Cancer Hospital and Solove Research Institute *Maura L. Gillison, MD, PhD¶ *‡Jatin P. Shah, MD, PhD¶ The Ohio State University Comprehensive Cancer Center – Memorial Sloan-Kettering Cancer Center James Cancer Hospital and Solove Research Institute Sharon Spencer, MD§ Robert I. Haddad, MD† University of Alabama at Birmingham Dana-Farber/Brigham and Women’s Cancer Center Comprehensive Cancer Center ‡ Massachusetts General Hospital Cancer Center * Andrea Trotti, III, MD§ H. Lee Moffitt Cancer Center & Research Institute Bruce H. Haughey, MBChB, MS¶ Randal S. Weber, MD¶ Siteman Cancer Center at Barnes-Jewish Hospital and The University of Texas MD Anderson Cancer Center Washington University School of medicine Gregory Wolf, MD¶ζ Wesley L. Hicks, Jr., MD¶ University of Michigan Comprehensive Cancer Center Roswell Park Cancer Institute Frank Worden, MD¶† Ying J. Hitchcock, MD§ University of Michigan Comprehensive Cancer Center Huntsman Cancer Institute at the University of Utah NCCN Staff: Miranda Hughes, PhD, and Nicole McMillian, MS Merrill S. Kies, MD† KEY: The University of Texas MD Anderson Cancer Center *‡William M. Lydiatt, MD¶ζ *Writing Committee Member ‡ UNMC Eppley Cancer Center at Mucosal Melanoma Subcommittee Member. The Nebraska Medical Center Specialties: †Medical Oncology; ÞInternal Medicine; §Radiation Ellie Maghami, MD¶ζ Oncology; ¶Surgery/Surgical Oncology; ζOtolaryngology

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PRESENTATION WORKUP PRIMARY ADJUVANT TREATMENT TREATMENT

Strongly consider Stage III Wide surgical resection of primarya postoperative RT to primary siteb

Postoperative RT T4a, N0 Wide surgical resectiona to primary siteb

Recurrent or Persistent disease Follow-up (see the NCCN Clinical Practice Postoperative RT (see page 325) Wide surgical resection Sinus or nasal cavity T3-T4a, N1 to primary site and Guidelines in Oncology (NCCN + neck dissection of positive necka mucosal melanoma neckb Guidelines) for [cutaneous] Melanoma, elsewhere in this issue and online at www.NCCN.org)

Clinical trial (preferred) • H&P including complete head and neck or exam; mirror and fiberoptic examination Stage IVB Primary RTb as clinically indicated or Biopsy c Verification of pathology using appropriate Systemic therapy confirms • staining (HMB-45, S-100, Melan-A) diagnosis of CT and/or MRI to determine anatomic malignant • mucosal extent of disease, particularly for sinus melanoma disease • Chest imaging as indicated • Consider PET-CT scan to rule out Clinical trial (preferred) metastatic disease or Best supportive care Stage IVC or Primary RTb or c Oral cavity, oropharynx, Systemic therapy See Primary larynx, or hypopharynx Treatment (page 324) mucosal melanoma

aSee Principles of Surgery (pages 326-329). bSee Principles of Radiation Therapy (page 330). cSee Systemic Therapy Options forAdvanced or Metastatic Melanoma in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for [cutaneous] Melanoma, elsewhere in this issue and online at www.NCCN.org.

Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are category 2A unless otherwise indicated.

Mucosal Melanoma of the Head and Neck Version 1.2012

PRESENTATION WORKUP PRIMARY ADJUVANT TREATMENT TREATMENT

Strongly consider Stage III Wide surgical resection of primarya postoperative RT to primary siteb

Postoperative RT T4a, N0 Wide surgical resectiona to primary siteb

Version 1.2012, 11-16-11 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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PRIMARY ADJUVANT FOLLOW-UP PRIMARYTHERAPY FOR OCCULTPRIMARY- MELANOMA TREATMENT TREATMENT

Wide surgical resection, Strongly consider Stage III elective neck dissectiona postoperative RTb

Level V, Posterior lateral See NCCN occipital node node dissection Guidelines for Recurrent [cutaneous] Follow-up ±Adjuvant systemic therapy, per Wide surgical resection b or Melanoma, Stage IVA a Postoperative RT (see page d,e NCCN Guidelines for [cutaneous] + neck dissection Persistent elsewhere in ± RT to nodal bed 325) Melanoma, elsewhere in this issue and disease this issue and online at www.NCCN.org Oral cavity, online at oropharynx, larynx, www.NCCN.org or hypopharynx All other Neck dissectiona mucosal melanoma Clinical trial (preferred) nodal sites or Stage IVB Primary RTb and/or Systemic therapyc

Clinical trial (preferred) or FOLLOW-UP RECOMMENDATIONS Best supportive care (based on risk of relapse, second primaries, treatment sequelae, and toxicities) Stage IVC or Primary RTb or • History and physical examf: Systemic therapyc ➤ Year 1, every1-3 mo ➤ Year 2, every2-6 mo ➤ Years3-5,every 4-8mo ➤ >5years, every12mo • Posttreatment baselineimaging of primary(and neckif treated) recommended within 6mooftreatmentg (category2B) ➤ Further reimaging as indicated based on signs/symptoms; not routinely recommended forasymptomatic patients • Chestimaging as clinically indicated • Thyroid-stimulating hormone (TSH)every 6-12 mo if neck irradiated • Speech/hearing and swallowing evaluation and rehabilitation as clinically indicated • Smoking cessation and alcohol counselingasclinically indicated • Dental evaluation ➤ Recommended for oral cavity ➤ As indicated for oropharynx, hypopharynx, and nasopharynx ➤ As indicated for other sites, if significant intraoral radiation

aSee Principles of Surgery(pages 326-329). dAdjuvant radiotherapy:30Gy/5fraction (fx) over 2.5 weeks(6.0Gy/fx). Careful attention to dosimetry is necessary.(AngKK, Peters LJ,Weber RS,et al. aSee Principles of Surgery (pages 326-329). Postoperativeradiotherapy forcutaneous melanomaofthe head and neckregion. IntJRadiat OncolBiol Phys 1994;30:795-798). b See Principles of Radiation Therapy (page 330). eRT is indicated forsatellitosis, positive nodes,orextracapsular spread. c See Systemic Therapy Options for Advanced or Metastatic Melanoma in the NCCN Clinical Practice Guidelines in Oncology (NCCN fFor mucosal melanoma, physical exam should include endoscopic inspection for paranasal sinus disease. Guidelines) for [cutaneous] Melanoma, elsewhere in this issue and online at www.NCCN.org. gFor cancer of the oropharynx, hypopharynx, glottic larynx, supraglottic larynx, and nasopharynx: imaging recommended for T3-4 or N2-3 disease only.

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Wide surgical resection, Strongly consider Stage III elective neck dissectiona postoperative RTb

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Evaluation Primary Tumor Resection All patients should be evaluated by a head and neck surgical oncologist before treatment to: Review the adequacy of biopsy material, review staging and imaging to determine the extent of disease, exclude the The resection of advanced tumors of the oral cavity, oropharynx, hypopharynx, larynx, or paranasal sinus will presence of a synchronous primary tumor, assess current functional status, and evaluate for potential surgical vary in extent depending on the structures involved. The primary tumor should be considered surgically curable salvage if initial treatment is nonsurgical. through appropriate resection using accepted criteria for adequate excision, depending on the region involved. Participate in the multidisciplinary team discussions regarding patient treatment options with the goal of maximizing survival with preservation of form and function. En bloc resection of the primary tumor should be attempted whenever feasible. Develop a prospective surveillance plan that includes adequate dental, nutritional, and health behavior evaluation and In continuity neck dissection is necessary when there is direct extension of the primary tumor into the neck. intervention and any other ancillary evaluations that would provide for comprehensive rehabilitation. Surgical resection should be planned based on the extent of the primary tumor as ascertained by clinical Develop and design the surgical procedure, margins, and reconstructive plan to resect all gross tumor with adequate examination and careful interpretation of appropriate radiographic images. tumor-free surgical margins for.patients undergoing surgery The surgical procedure should not be modified based on For oral cavity cancers, as thickness of the lesion increases, so does the risk of regional metastases and the any response observed as a result of prior therapy except in instances of tumor progression that mandates a more need for adjuvant elective neck dissection. extensive procedure to encompass the tumor at the time of definitive resection. Perineural invasion should be suspected when tumors are adjacent to motor or sensory nerves. When invasion is suspected, the nerve should be dissected both proximally and distally and should be resected to Integration of Therapy obtain clearance of disease. Frozen section determination of the proximal and distal nerve margins may prove It is critical that multidisciplinary evaluation and treatment be coordinated by all modalities involved in patient care helpful to facilitate tumor clearance. before the initiation of any treatment. Partial or segmental resection of the mandible may be necessary to encompass adequately the cancer with adequate tumor-free margins.Adequate resection may require partial, horizontal, or sagittal resection of the Assessment of Resectability mandible for tumors involving or adherent to mandibular periosteum. Segmental resection should be 1 Tumor involvement of the following sites is associated with poor prognosis or function or with T4b cancer considered in tumors that grossly involve mandibular periosteum (as determined by tumor fixation to the (i.e., unresectable based on technical ability to obtain clear margins): mandible) or show evidence of direct tumor involvement of the bone at the time of operation or through Involvement of the pterygoid muscles particularly when associated with severe trismus or pterygopalatine fossa preoperative imaging.The extent of mandibular resection will depend on the degree of involvement accessed 1 involvement with cranial neuropathy clinically and in the operating room. Gross extension of tumor into the skull base (e.g., erosion of the pterygoid plates or sphenoid bone, widening of the For tumors of the larynx, the decision to perform either total laryngectomy or conservation laryngeal surgery foramen ovale) (e.g., transoral resection, hemilaryngectomy, supraglottic laryngectomy) will be decided by the surgeon but Direct extension to superior nasopharynx or deep extension into the eustachian tube and lateral nasopharyngeal walls should adhere to the principles of complete tumor extirpation with curative intent. Invasion (encasement) of the common or internal carotid artery. Encasement is usually assessed radiographically and For maxillary sinus tumors, note that “Ohngren's line" runs from the medial canthus of the eye to the angle of defined as tumor surrounding the carotid artery 270° the mandible, helping to define a plane passing through the maxillary sinus.Tumors "below" or "before" this Direct extension of neck disease to involve the skin1 line involve the maxillary infrastructure. Those "above" or "behind" Ohngren's line involve the suprastructure. Direct extension to mediastinal structures, prevertebral fascia, or cervical vertebrae1 Presence of subdermal metastases

1In selected cases, surgery might still be considered.

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1In selected cases, surgery might still be considered.

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Margins Neck Management Frozen section margin assessment is always at the discretion of the surgeon and should be considered when it will facilitate The surgical management of regional lymphatics is dictated by the extent of tumor at initial tumor staging. These guidelines complete tumor removal. The achievement of adequate margins may require resection of an adjacent structure in the oral cavity apply to the performance of neck dissections as part of treatment of the primary tumor. In general, patients undergoing surgery or laryngopharynx (such as the base of tongue and/or anterior tongue, mandible, larynx, or portions of the cervical esophagus). for resection of the primary tumor will undergo dissection of the ipsilateral side of the neck that is at greatest risk for metastases. Adequate resection is defined as clear resection margins with at least enough clearance from gross tumor to obtain clear frozen section and permanent margins (often 1.5-2 cm of visible and palpable normal mucosa). In general, frozen section Tumor sites that frequently have bilateral lymphatic drainage (e.g., base of tongue, palate, supraglottic larynx, deep space examination of the margins will usually be undertaken intraoperatively and, importantly, when a line of resection has uncertain pre-epiglottic involvement) should often have both sides of the neck dissected with the extent of dissection determined as clearance because of indistinct tumor margins or there is suspected residual disease (e.g., soft tissue, cartilage, carotid artery, suggested below. For patients with tumors at or approaching the midline, both sides of the neck are at risk for metastases, or mucosal irregularity). and bilateral neck dissections should be performed. Elective neck dissection may not be recommended if postoperative The details of resection margins should be included in the operative dictation. The margins may be assessed on the resected radiation is planned. specimen or alternatively from the surgical bed with proper orientation. Aclear margin is defined as the distance from the invasive tumor front that is 5 mm from the resected margin. Patients with advanced lesions involving the anterior tongue or floor of mouth which approximate or cross the midline should Aclose margin is defined as the distance from the invasive tumor front to the resected margin that is < 5 mm. undergo contralateral submandibular dissection as necessary to achieve adequate tumor resection. The primary tumor should be marked in a fashion adequate for orientation by the surgical pathologist. The neck dissection should be oriented or sectioned to identify levels of lymph nodes encompassed in the dissection. Elective neck dissection should be based on risk of occult metastasis in the appropriate nodal basin. ➤ Reconstruction of surgical defects should be performed using conventional techniques at the discretion of the surgeon. In general, elective neck dissections are not performed for mucosal melanoma, except for the oral cavity. ➤ In mucosal melanoma, no evidence shows that the depth of invasion predicts occult metastatic disease, although the risk Primary closure is recommended when appropriate but should not be pursued at the expense of obtaining wide, tumor-free likely does increase with increasing depth. margins. Reconstructive closure with local/regional flaps, free tissue transfer, or split-thickness skin or other grafts with or Elective dissections are generally selective, preserving all major structures, unless operative findings dictate otherwise. without mandibular reconstruction is performed at the discretion of the surgeon.

Surgical Management of Cranial Nerves VII, X (Including the Recurrent Laryngeal Nerve), XI, and XII Management of Recurrences Operative management of the facial nerve and other major cranial nerves during primary or regional node resection is influenced Surgically resectable primary cancers should be re-resected with curative intent if feasible, and recurrences in a previously by the preoperative clinical function of the nerve. treated neck should also undergo surgical salvage. Neck disease in an untreated neck should be addressed by formal neck dissection or modification depending on the clinical situation. Nonsurgical therapy may also be used as clinically appropriate. When the nerve is functioning, thorough efforts should be made to preserve the structure and function of the nerve (main trunk and/or branches) even if otherwise adequate tumor margins are not achieved—recognizing that the surgeon should leave no Surveillance gross residual disease. All patients should have regular follow-up visits to assess for symptoms and possible tumor recurrence, health behaviors, Adjuvant postoperative radiation or chemoradiation is generally prescribed when microscopic residual or gross residual tumor nutrition, dental health, and speech and swallowing function. is suspected. Direct nerve invasion by tumor and/or preoperative paralysis of the nerve may warrant segmental resection (and sometimes Tumor evaluations must be performed by specialists skilled in head and neck clinical examination. nerve grafting) at the discretion of the surgeon if tumor-free margins are assured throughout the remainder of the procedure. The frequency of evaluation is summarized in Follow-up Recommendations (page 325).

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PRINCIPLES OF RADIATION THERAPY1 RADIATION TECHNIQUES1-8

RT for unresectable locally advanced melanoma: Target delineation and optimal dose distribution require experience in head and neck imaging, and a thorough understanding of 66-74 Gy patterns of disease spread. Standards for target definition, dose specification, fractionation (with and without concurrent Palliative RT dose and schedule may be considered chemotherapy), and normal tissue constraints are still evolving. IMRT, 3D, and 2D conformal techniques may be used as appropriate depending on the stage, tumor location, physician training/experience, and available physics support. Close interplay Postoperative RT exists between radiation technology, techniques, fractionation, and chemotherapy options, resulting in a large number of Primary site resection: combinations that may impact toxicity or tumor control. Close cooperation and interdisciplinary management are critical to Paranasal sites: treatment planning and radiation targeting, especially in the postoperative setting or after induction chemotherapy.9 RT to primary site + 2- to 3-cm margins or to anatomic compartment Oral cavity, oropharynx, and hypopharynx sites: Intensity-Modulated Radiotherapy (IMRT) RT to primary site (+ 2- to 3-cm margins or anatomic zone) and elective treatment to neck IMRT has been shown to be useful in reducing long-term toxicity in oropharyngeal, paranasal sinus, and nasopharyngeal cancers (unless negative pathology findings of neck dissection) by reducing the dose to salivary glands, temporal lobes, auditory structures (including cochlea), and optic structures. The Also strongly consider radiation to primary site for any locally recurrent disease after previous resection application of IMRT to other sites (e.g., oral cavity, larynx, hypopharynx, salivary glands) is evolving and may be used at the discretion of treating physicians. Neck/nodal basin dissection: High-risk features: IMRT and Fractionation10,11 2 nodes Several ways exist to integrate IMRT, target volume dosing, and fractionation. The Simultaneous Integrated Boost (SIB) technique Single node 3 cm uses differential “dose painting” (66-74 Gy to gross disease; 50-60 Gy to subclinical disease) for each fraction of treatment 4 Extracapsular nodal disease throughout the entire course of radiation. SIB is commonly used in conventional (5 fractions/wk) and the “6 fractions/wk 5 Node resection (alone) with no further basin dissection accelerated” schedule. The sequential (SEQ) IMRT technique typically delivers the initial (lower-dose) phase (weeks 1-5) followed Recurrence in nodal basin after previous surgery by the high-dose boost volume phase (weeks 6-7) using 2-3 separate dose plans, and is commonly applied in standard fractionation and hyperfractionation. The Concomitant Boost Accelerated schedule may use a“modified SEQ” dose plan by Dose and fractionation: delivering the dose to the subclinical targets once a day for 6 weeks, and a separate boost dose plan as a second daily fraction for 6 Primary and neck (high-risk sites): 60-66 Gy (2.0 Gy/fx) or 70 Gy for gross disease the last 12 treatment days. Low-risk, undissected, or uninvolved portions of neck: 50-60 Gy (2 Gy/fx)

1Dogan N, King S, Emami B, et al. Assessment of different IMRT boost delivery methods on target coverage and normal-tissue sparing. Int J Radiat Oncol Biol Phys 2003;57:1480-1491. 2Lee NY, de Arruda FF, Puri DR, et al. Acomparison of intensity-modulated radiation therapy and concomitant boost radiotherapy in the setting of concurrent chemotherapy for locally advanced oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006;66:966-974. 3Lee NY, O'Meara W, Chan K, et al. Concurrent chemotherapy and intensity-modulated radiotherapy for locoregionally advanced laryngeal and hypopharyngeal cancers. Int J Radiat Oncol Biol Phys 2007;69:459-468. 4Mohan R, Wu Q, Morris M, et al.“Simultaneous Integrated Boost” (SIB) IMRT of advanced head and neck squamous cell carcinomas—dosimetric analysis. Int J Radiat Oncol Biol Phys 2001;51:180–181. 5Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003;362:933-940. 6Schoenfeld GO, Amdur RJ, Morris CG, et al. Patterns of failure and toxicity after intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2008;71:377-385. 7Wolden SL, Chen WC, Pfister DG, et al. Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer: update of the Memorial Sloan-Kettering experience. Int J Radiat Oncol Biol Phys 2006;64:57-62. 8Wu Q, Manning M, Schmidt-Ullrich R, Mohan R. The potential for sparing of parotids and escalation of biologically effective dose with intensity- modulated radiation treatments of head and neck cancers: a treatment design study. Int J Radiat Oncol Biol Phys 2000;46:195-205. 9Salama JK, Haddad RI, Kies MS, et al. Clinical practice recommendations for radiotherapy planning following induction chemotherapy in locoregionally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 2009;75:725-733. 10Hartford AC, Palisca MG, Eichler TJ, et al. American Society forTherapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guidelines for intensity-modulated radiation therapy (IMRT). Int J Radiat Oncol Biol Phys. 2009;73:9-14. 1See Radiation Techniques (facing page) and Discussion. 11IMRT Documentation Working Group, Holmes T, Das R, Low D, et al. American Society of Radiation Oncology recommendations for documenting intensity-modulated radiation therapy treatments. Int J Radiat Oncol Biol Phys 2009;74:1311-1318.

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Mucosal Melanoma of the Head and Neck Text continued from p. 321 Comorbidity and Quality of Life

Comorbidity Nasal antrum Comorbidity refers to the presence of concomitant disease (in addition to MM) that may affect the diag- 8–10 Oral cavity nosis, treatment, and prognosis of the patient. Doc- Nasopharynx Lip Pharynx umentation of comorbidity is particularly important Buccal mucosa Alveolar ridge and in oncology to facilitate optimal treatment selection retromolar trigone Floor of mouth Oropharynx and estimates of prognosis. Comorbidity is known Hard palate Base of tongue Oral tongue Soft palate to be a strong independent predictor of mortality in (anterior) Tonsillar pillar 10–17 two-thirds) and fossa patients with H&N cancer, and comorbidity also Hypopharynx Larynx influences costs of care, use of treatment, and quality Supraglottis 18–20 False cords of life. Traditional indices of comorbidity include Arytenoids 9 Epiglottis the Charlson index and the Kaplan-Feinstein index Arytenoepiglottic fold 10,21 Glottis and its modifications. The Adult Comorbidity Subgliottis Esophagus Evaluation-27 (ACE-27) is specific for H&N cancer and has excellent emerging reliability and validity.22,23 Quality of Life Health-related quality-of-life issues are paramount Figure 1 Anatomic sites and subsites of the head and neck. Reprinted with permission, from CMP Healthcare Media. in H&N cancer and MM. These tumors affect basic Source: Cancer Management: A Multidisciplinary Approach, physiologic functions (e.g., ability to chew, swallow, 9th ed. Pazdur R, Coia L, Hoskins W, et al. (eds), Chapter 4. and breathe), the senses (e.g., taste, smell, hearing), Copyright 2005, All rights reserved. and uniquely human characteristics (e.g., appear- ance, voice). Health status describes an individual’s chemotherapy (e.g., pain, xerostomia, speech and physical, emotional, and social capabilities and limi- swallowing problems, depression) require profes- tations. Function and performance refer to how well an sionals familiar with the disease. Follow-up for these individual is able to perform important roles, tasks, sequelae should include a comprehensive H&N ex- or activities. The definition ofquality of life differs, amination. Adequate nutritional support can help because the central focus is on the value (determined to prevent severe weight loss in patients undergoing by the patient alone) that individuals place on their treatment for MM; therefore, patients should be en- health status and function.24 couraged to see a dietician.5 Patients should also be encouraged to stop smoking and to modify alcohol consumption if excessive, Mucosal Melanoma of because these habits may decrease the efficacy of treat- the Head and Neck 6,7 ment and adversely affect other health outcomes. MM of the H&N is a rare but highly aggressive neo- Programs using behavioral counseling combined with plasm with a poor prognosis. It may occur throughout medications that promote smoking cessation (ap- the upper aerodigestive tract. Most MM of the H&N proved by the FDA) can be very useful (http://www. (~70%) occurs in the nasal cavity or paranasal sinus re- ahrq.gov/clinic/tobacco/tobaqrg.htm). Specific com- gion, and approximately 25% develops in the oral cav- ponents of patient support and follow-up are listed ity (see Figure 2).4,25 The remainder develops in other in the algorithm (see Team Approach, in the NCCN sites (e.g., oropharynx, hypopharynx, larynx). Sinonasal Guidelines for H&N Cancers, available online at MM is typically confined to the primary site at presen- www.NCCN.org [TEAM-1]). Notably, patients with tation, and patients often present with symptoms (e.g., MM require timely diagnosis and management of de- nasal obstruction).2,26 Oral cavity MM more frequently pression. The H&N Cancers Panel also recommends presents with clinically apparent lymph node metastasis referring to the NCCN Guidelines for Palliative Care and is often asymptomatic.27 No etiologic risk factors are (to view the most recent version of these guidelines, yet apparent. MM occurs in a greater extent in Asians visit the NCCN Web site at www.NCCN.org). and less frequently in the Western population.28

Mucosal Melanoma of the Head and Neck

Workup and Staging Diagnosis of MM of the H&N can be difficult. The differential diagnosis of sinonasal MM includes lym- phoma, sarcoma, and olfactory neuroblastoma.29 Ide- ally, a combination of histology, immunohistochem- istry, and clinical features is used for diagnosis. MM is immunoreactive for S-100 and HMB-45 (and to a lesser extent for melan-A); however, MM is negative 2,29 for cytokeratin. II Workup for MM should include clinical examination and CT and/or MRI for paranasal sinus I disease, and appropriate imaging for other mucosal V sites. The physical examination should include en- III doscopic inspection for paranasal sinus disease. PET/ CT scanning may be considered to define the presence of distant disease in more advanced situations. IV The AJCC Staging Manual (7th edition) includes a staging system for MM (see Table 6 in the NCCN Guidelines for H&N, available online, at 4 www.NCCN.org [ST-11]) ; previous editions did not Figure 2 Level designation for cervical lymphatics in the right neck. have a classification for MM. The AJCC staging rec- Reprinted with permission, from CMP Healthcare Media. Source: ognizes 2 key factors specific to MM: 1) the disease Cancer Management: A Multidisciplinary Approach, 9th ed. Pazdur R, Coia L, Hoskins W, et al. (eds), Chapter 4. Copyright 2005, All rights still has a poor prognosis even with a limited primary reserved. burden of disease, and 2) there is still some grada- tion of survival based on the burden of disease, as for stage IVB or IVC disease.31 The panel strongly en- reflected in local, regional, and distant extent. courages clinical trials for all patients with MM to Thus, the AJCC staging system for MM begins better define treatment choices at all stages of disease. with stage III disease as the most limited form of In most case series, adjuvant RT seems effec- disease (similar to anaplastic thyroid carcinoma), tive in improving local control and survival.32 RT and breaks the disease down into stages reflecting is clearly indicated in more advanced cases as an local burden of disease and regional and distant adjunct to surgery (see the Principles of Radiation extent. Melanomas confined to the mucosa only Therapy on page 330 and in the NCCN Guidelines are T3, those with moderately advanced lesions for H&N Cancers, available online at www.NCCN. (involving underlying cartilage or bone) are T4a, org [RAD-A]).33 The role of radiation in stage III dis- and very advanced primary tumors are T4b. In ad- ease is not clear, but it can be considered and should dition, the AJCC staging system reflects the fact that MM occurs at all mucosal sites in the H&N. be determined on an individual basis by the treat- Therefore, rules for classifying and staging, and ing clinicians. However, survival rates after surgery surgical principles should be based on the ap- alone or surgery combined with radiation are better 30 propriate anatomic site of origin (see the NCCN than those after radiation alone. Guidelines for H&N Cancers, available online, at Treatment of the Neck www.NCCN.org). Neck dissection and postoperative radiation are rec- 34,35 Treatment of the Primary ommended for clinical nodal disease. The role of Although limited data are available on treatment elective neck treatment is unclear.36 The extension options, surgery is the primary treatment for MM of elective treatment to the neck seems unwarranted stage III through IVA (see Principles of Surgery on in most cases of N0 paranasal sinus MM. However, pages 326–329 and in the NCCN Guidelines for for oral cavity disease, the likelihood of positive dis- H&N Cancers, available online at www.NCCN.org ease is significantly higher and the treatment can [SURG-A]).30 However, surgery is not recommended be better localized to the ipsilateral neck with both

Mucosal Melanoma of the Head and Neck

surgery and radiation (see Principles of Surgery on to 70 Gy for gross disease). Although the Australian- pages 326–329 and in the NCCN Guidelines for New Zealand randomized trial used 48 Gy in 20 frac- H&N Cancers, available online at www.NCCN.org tions (240 cGy per fraction) to neck, axilla, or groin,37 [SURG-A]). Therefore, elective treatment to the the NCCN H&N Cancers Panel prefers conventional neck for oral cavity MM seems justifiable. fractionation to somewhat higher total doses (60–66 Radiation Therapy Gy) in the neck because of concerns about late effects Prospective trials evaluating the role of RT in MM from larger dose per fraction, which may not be fully are lacking. However, recently reported results of a expressed for many years after treatment. randomized trial in cutaneous melanoma are con- Intensity modulated RT may be very helpful for sidered relevant to MM in the postoperative setting achieving homogenous dose distributions and spar- after neck dissection.37 Retrospective studies in MM ing of critical organs, especially in paranasal sinus 47–49 have shown local recurrence to be common after sur- sites (see Radiation Techniques on page 331). gery alone.30,38,39 After using postoperative radiation, Good outcomes have been reported with the use of lower rates of local and neck recurrence have been hypofractionation in cutaneous melanomas, which seen in historical comparison series.32,40 Reasonable has the advantage of convenience but no clear ad- local control outcomes using RT alone in unresect- vantage in cancer control. There is little experience able or medically inoperable cases have been report- using large dose per fraction in mucosal sites. Be- ed in small cohort series of MMs.30,41–44 cause of the proximity of neural structures and risk RT is often recommended in the postoperative of late effects, hypofractionation (if used) must be management of MMs. Primary size or thickness is carefully planned and delivered. not used as a risk factor when considering RT to the Systemic Therapy primary site; all invasive primaries are considered at Systemic therapy used for cutaneous melanoma (e.g., high risk for local recurrence. For sinonasal primary interleukin-2) is recommended for MM (see Sys- sites, target volumes may include the primary site temic Therapy Options for Advanced or Metastatic without elective treatment of the neck. Because oral Melanoma in the NCCN Guidelines for Melanoma, cavity primary sites are believed to be at a higher risk available in this issue on pages 378–380 and online at for failure in the neck, elective management with www.NCCN.org [ME-E]). Interferon and interleukin neck dissection and RT may be applied. have been used to treat MM.50 Data suggest that c-KIT Indications for postoperative radiation to the inhibitors (e.g., imatinib) may be useful in patients neck are generally extrapolated from cutaneous mel- with metastatic MM who have specificc-KIT muta- anoma. Recently, an Australian-New Zealand con- tions (i.e., exon 11 or 13 mutations).28,51 Therefore, sortium reported on a randomized trial (N = 250) of imatinib is reasonable to use in patients with MM postoperative RT versus observation in patients with who have c-KIT mutations.52 Although vemurafenib palpable adenopathy from cutaneous primaries. Post- is recommended for patients with cutaneous melano- operative RT was associated with a significant reduc- ma who have the V600E mutation of the BRAF gene, tion in relapse in the nodal basin (19% vs. 31%) and patients with MM rarely have this BRAF mutation.51 a significant improvement in lymph node field control.37 Only 20 patients experienced disease relapse Follow-Up Recommendations for surveillance are provided in who underwent postoperative RT, compared with 34 the algorithm (see Follow-Up Recommendations on patients who underwent observation only (P = .04). page 325). Note that physical examination should Considering this trial and retrospective studies in MM, the panel recommends postoperative RT for the include endoscopic inspection for paranasal sinus disease. Salvage surgery may be useful for patients with following high-risk features: extracapsular disease, in- 30 volvement of 2 or more neck or intraparotid nodes, MM; therefore, surveillance is important. any node 3 cm or greater, neck excision (alone) with Recurrent or Persistent Disease no further basin dissection, or recurrence in the neck For patients with MM who have recurrent or persistent or soft tissue after initial surgical resection.45,46 Con- disease, the NCCN H&N Cancers Panel recommends ventional fractionation is recommended (at 2 Gy per using the NCCN Guidelines for Melanoma (available fraction to a total postoperative dose of 60–66 Gy, or in this issue and online at www.NCCN.org).

Mucosal Melanoma of the Head and Neck

Principles of Surgery tients will refuse surgical management, but these tu- All patients should be evaluated by an H&N surgical mors should not be deemed unresectable. Although oncologist before being treated for MM. In addition, local and regional disease may be surgically treatable, multidisciplinary evaluation and treatment must patients with distant metastases are usually treated as be well coordinated. Many surgical principles de- though the primary tumor was unresectable. This is scribed in the NCCN Guidelines for H&N Cancers balanced by the potential to mitigate suffering from algorithm are applicable to MM (i.e., evaluation, local and regional disease. This may be particularly integration of therapy, assessment of resectability, true in MM. Thus, patient choice or a physician’s primary tumor resection, margins, management of expectations regarding cure and morbidity will influence or determine treatment. recurrences, and surveillance; see Principles of Sur- gery on pages 326–329 and in the NCCN Guidelines Neck Dissection for H&N Cancers, available online at www.NCCN. Historically, cervical lymph node (i.e., neck) dissec- org [SURG-A]).3,53 Resectable disease, neck dissections have been classified asradical or modified radi- tion, and salvage surgery of high-risk disease are dis- cal procedures. The less-radical procedures preserve cussed in the following sections. the sternocleidomastoid muscle, jugular vein, spinal accessory nerve, or selective lymph node levels. Resectable Versus Unresectable Disease The NCCN H&N Cancers Panel prefers to classify The term unresectable has resisted formal definition cervical lymphadenectomy using contemporary no- by H&N cancer specialists. The experience of the menclature, thus classifying cervical lymph node dis- surgeon and the support available from reconstruc- sections as either comprehensive or selective.54 A com- tive surgeons, physiatrists, and prosthodontists of- prehensive neck dissection is one that removes all ten strongly influence recommendations, especially lymph node groups that would be included in a clas- in institutions in which only a few patients with sic radical neck dissection. Whether the sternoclei- MM are treated. The NCCN Member Institutions domastoid muscle, jugular vein, or spinal accessory have teams experienced in the treatment of H&N nerve is preserved does not affect whether the dis- cancer and maintain the multidisciplinary infra- section is classified as comprehensive. Depending on structure needed for reconstruction and rehabilita- the site, comprehensive neck dissection is often rec- tion. A patient’s cancer is deemed unresectable if ommended for patients with positive nodal disease H&N surgeons at NCCN Member Institutions do MM (see Neck Management in Principles of Surgery not think they can remove all gross tumor on ana- on pages 326–329 and in the NCCN Guidelines for tomic grounds or if they are certain local control H&N Cancers, available online at www.NCCN.org will not be achieved after surgery (even with the [SURG-A]). In general, elective neck dissections for addition of RT to the treatment approach). Typi- melanoma are not performed, except for oral cavity. cally, these unresectable tumors densely involve the Currently, elective treatment of the neck tends to cervical vertebrae, brachial plexus, deep muscles of be reserved for when access to vessels is needed for the neck, or carotid artery (see Principles of Surgery microvascular anastomosis for free flaps and perhaps on pages 326–329 and in the NCCN Guidelines for in oral cavity primary MM. H&N Cancers, available online at www.NCCN.org For a therapeutic dissection, whether the neck [SURG-A]). Tumor involvement of certain sites is can be made more selective will depend on the pri- associated with poor prognosis (e.g., direct extension mary location of the tumor. Level I disease may be of neck disease to involve the external skin or to me- cleared with a selective neck dissection encompass- diastinal structures, prevertebral fascia, or cervical ing levels I through IV, and pharyngeal disease may vertebrae). not require a level I dissection.55,56 For example, to Unresectable tumors (i.e., those that cannot be remove the nodes most commonly involved with removed without causing unacceptable morbidity) metastases from the oral cavity, a selective neck dis- should be distinguished from inoperable tumors in section is recommended, which includes the nodes patients whose constitutional state precludes an op- found above the omohyoid muscle (levels I–III and eration (even if the cancer could be readily resected sometimes the superior parts of level V).54,57 Simi- with few sequelae). Additionally, a subgroup of pa- larly, to remove the nodes most commonly involved

Mucosal Melanoma of the Head and Neck

with metastases from the pharynx and larynx, a se- 2000;126:1086–1088. lective neck dissection is recommended, which in- 13. Chen AY, Matson LK, Roberts D, Goepfert H. The significance of comorbidity in advanced laryngeal cancer. Head Neck cludes the nodes in levels II through IV and level 2001;23:566–572. 54 VI when appropriate. Selective neck dissections 14. Singh B, Bhaya M, Stern J, et al. Validation of the Charlson may be used as treatment when neck tumor burden comorbidity index in patients with head and neck cancer: a multi- is low.55,56 institutional study. Laryngoscope 1997;107:1469–1475. 15. Hall SF, Rochon PA, Streiner DL, et al. Measuring comorbidity in Salvage Surgery patients with head and neck cancer. Laryngoscope 2002;112:1988– Salvage surgery may be useful for patients with MM; 1996. therefore, surveillance is important.30 However, the 16. Hall SF, Groome PA, Rothwell D. 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Mucosal Melanoma of the Head and Neck Date Completed 5/11/11 10/7/11 4/11/11 6/8/11 6/8/11 10/13/11 10/7/11 6/22/11 5/3/11 6/8/11 3/4/11 6/8/11 10/6/11 2/22/11 5/2/11 6/7/11 3/21/11 4/7/11 10/7/11 7/27/11 6/1/11 11/9/11 5/31/11 11/20/09 6/8/11 6/3/11 8/15/11 3/28/11 5/3/11 10/6/11 9/23/11 Other None None None None None None None None None None None None None None None None None None None None None None None None National Cancer Institute None None None None None None

Patent, Equity, Patent, Equity, or Royalty None None None None None None None None None None None None None None None None None None None None None None None None None None None None None None None

Advisory Boards, Speakers Bureau, Expert Witness, or Speakers Bureau, Advisory Boards, Consultant Bristol-Myers Squibb Company; Eli Lilly and Company; GlaxoSmithKline; ImClone LLC; and sanofi-aventis U.S. LLC Siemens AG Amgen Inc.; Boehringer Ingelheim GmbH; GlaxoSmithKline plc; Merck & Co., Inc.; and Pfizer Inc. Amgen Inc. Bristol-Myers Squibb Company Amgen Inc. None None None None None None None None None None Eli Lilly and Company; Genentech, Inc. None None None Boehringer Ingelheim GmbH; and Bristol-Myers Squibb Company None None None None None None GlaxoSmithKline; and National Cancer Institute None IRX Therapeutics Bristol-Myers Squibb Company

Clinical Research Support Clinical Research None None Genentech, Inc.; Millennium Pharmaceuticals, and Pfizer Inc. None Bayer AG; Boehringer Ingelheim GmbH; Exelixis Inc.; Genentech, Inc.; GlaxoSmithKline plc; ActoGenix; Eastern Cooperative Oncology Group; NCI; and Radiation Therapy Group None None Eastern Cooperative Oncology Group None None None None None None None None Amgen Inc.; Bayer AG; Eisai Co., Ltd.; Eli Lilly and Company; Exelixis, Inc.; Genentech, Novartis AG; and Infinity Pharmaceuticals; and Pfizer Inc. None Genentech, Inc. AstraZeneca Pharmaceuticals LP; Eli Lilly and Company; Exelixis, Inc.; Genentech, ImClone LLC; and Novartis AG None None Methodist Healthcare Foundation None None None None GlaxoSmithKline plc; and EUSA Pharma None IRX Therapeutics Pfizer Inc. Individual Disclosures for the NCCN Guidelines Panel Mucosal Melanoma of Head and Neck Individual Disclosures Panel Member Kie-Kian Ang, MD, PhD David M. Brizel, MD Barbara Burtness, MD Anthony J. Cmelak, MD A. Dimitrios Colevas, MD MD Frank Dunphy, Eisele, MD David W. Jill Gilbert, MD Maura L. Gillison, MD, PhD Robert I. Haddad, MD MBChB, MS Bruce H. Haughey, MD L. Hicks, Jr., Wesley J. Hitchcock, MD Ying Merrill S. Kies, MD MD William M. Lydiatt, Ellie Maghami, MD Renato Martins, MD, MPH MD, PhD Thomas McCaffrey, Bharat B. Mittal, MD MD David G. Pfister, Harlan A. Pinto, MD John A. Ridge, MD, PhD Sandeep Samant, MD Giuseppe Sanguineti, MD MD David E. Schuller, Shah, MD, PhD Jatin P. MD Sharon Spencer, III, MD Andrea Trotti, MD Randal S. Weber, MD Gregory Wolf, MD Frank Worden, The NCCN guidelines staff have no conflicts to disclose. The NCCN guidelines staff