Practice Guidelines in Oncology - Head and Neck Cancers - Oralmax.it

NCCN Clinical Practice Guidelines in OncologyHead and NeckCancersV.1.2007Continuewww.nccn.org

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesNCCN Head and Neck Cancers Panel Members* Arlene A. Forastiere, MD/Chair †The Sidney Kimmel ComprehensiveCancer Center at Johns HopkinsKie-Kian Ang, MD, PhD §The University of Texas M. D. AndersonCancer CenterDavid Brizel, MD §Duke Comprehensive Cancer CenterBruce E. Brockstein, MD †ÞRobert H. Lurie Comprehensive CancerCenter of Northwestern UniversityFrank Dunphy, MD †Duke Comprehensive Cancer CenterDavid W. Eisele, MD UCSF Comprehensive Cancer CenterHelmuth Goepfert, MD The University of Texas M. D. AndersonCancer CenterWesley L. Hicks, Jr., MD Roswell Park Cancer InstituteMerrill S. Kies, MD †The University of Texas M. D. AndersonCancer CenterWilliam M. Lydiatt, MD UNMC Eppley Cancer Center at TheNebraska Medical CenterEllie Maghami, MD City of Hope Cancer CenterThomas McCaffrey, MD, PhD H. Lee Moffitt Cancer Center & ResearchInstitute at the University of South FloridaBharat B. Mittal, MD §Robert H. Lurie Comprehensive CancerCenter of Northwestern UniversityDavid G. Pfister, MD †ÞMemorial Sloan-Kettering Cancer CenterHarlan A. Pinto, MD †ÞStanford Comprehensive Cancer CenterMarshall R. Posner, MD †ÞDana-Farber/Brigham and Women’sCancer Center | Massachusetts GeneralHospital Cancer CenterJohn A. Ridge, MD, PhD Fox Chase Cancer CenterSandeep Samant, MD St. Jude Children's ResearchHospital/University of Tennessee CancerInstituteContinueDavid E. Schuller, MD Arthur G. James Cancer Hospital &Richard J. Solove Research Institute atThe Ohio State UniversityJatin P. Shah, MD Memorial Sloan-Kettering Cancer CenterSharon Spencer, MD §University of Alabama at BirminghamComprehensive Cancer CenterAndy Trotti, III, MD §H. Lee Moffitt Cancer Center & ResearchInstitute at the University of SouthFloridaGregory T. Wolf, MD University of Michigan ComprehensiveCancer CenterFrank Worden, MD †University of Michigan ComprehensiveCancer CenterBevan Yueh, MD, MPH Fred Hutchinson Cancer ResearchCenter/Seattle Cancer Care Alliance† Medical Oncology Surgery/Surgical oncology§ Radiation oncology/ Radiotherapy OtolaryngologyÞ Internal medicine* Writing Committee MemberVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesTable of ContentsNCCN Head and Neck Cancers Panel Members Multidisciplinary Team Approach (TEAM-1) Support Modalities (TEAM-1)Ethmoid Sinus Tumors (ETHM-1)Maxillary Sinus Tumors (MAXI-1)Salivary Gland Tumors (SALI-1)Cancer of the Lip (LIP-1)Cancer of the Oral Cavity (OR-1)Cancer of the Oropharynx (ORPH-1)Cancer of the Hypopharynx (HYPO-1)Occult Primary (OCC-1)Cancer of the Glottic Larynx (GLOT-1)Cancer of the Supraglottic Larynx (N0) (SUPRA-1)Cancer of the Supraglottic Larynx (N+) (SUPRA-5)Cancer of the Nasopharynx (NASO-1)Unresectable Head and Neck Cancer (ADV-1)Recurrent Head and Neck Cancer (ADV-2)Guidelines IndexPrint the Head and Neck Cancers GuidelineFor help using thesedocuments, please click hereStagingManuscriptReferencesThis manuscript is beingupdated to correspondwith the newly updatedalgorithm.Clinical Trials: The NCCNbelieves that the best managementfor any cancer patient is in a clinicaltrial. Participation in clinical trials isespecially encouraged.To find clinical trials online at NCCNmember institutions, click here:nccn.org/clinical_trials/physician.htmlNCCN Categories of Consensus:All recommendations are Category2A unless otherwise specified.See NCCN Categories of ConsensusSummary of Guidelines UpdatesThese guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinicianseeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances todetermine any patient’s care or treatment. The National Comprehensive Cancer Network makes no representations or warranties of any kind,regarding their content use or application and disclaims any responsibility for their application or use in any way. These guidelines are copyrightedby National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any formwithout the express written permission of NCCN. ©2007.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesSummary of the Guidelines updatesSummary of changes in the 1.2007 version of the Head andNeck Cancer guidelines from the 1.2006 version include:Global Changes The risk categorization defining the indications for postoperativechemoradiation has been modified. Postoperative chemoradiation isindicated for "one or both major risk features or two or more minorrisk features". Major risk features are positive margins and/orextracapsular spread. Minor risk features are pT3 or pT4 primary(excluding T3, N0 laryngeal cancer);N2 or N3 nodal disease, nodaldisease in levels IV or V with oral cavity or oropharyngeal primary,perineural invasion, and vascular embolism. The terminology used to define nodal stations in the Principles ofRadiation Therapy sections was changed to "involved" or"uninvolved". The qualifier of "selective versus comprehensive" was removedafter the category 3 designation in the neck management afterprimary systemic therapy.Ethmoid Sinus Tumors The treatment option of chemoradiation was added as aconsideration for adjuvant therapy for patients with adversecharacteristics ( ETHM-2).Cancer of the Hypopharynx The recommendation for laryngopharyngectomy was clarified as"open or endoscopic" ( HYPO-2).Cancer of the Oropharynx Cisplatin is listed as the preferred agent if using the treatmentoption of concurrent systemic therapy/RT ( ORPH-3, ORPH-4).Cancer of the Hypopharynx Cisplatin is listed as the preferred agent if using the treatmentoption of concurrent systemic therapy/RT ( HYPO-3).Cancer of the Glottic Larynx Cisplatin is listed as the preferred agent if using the treatmentoption of concurrent systemic therapy/RT ( GLOT-3). The recommendations for Definitive RT have been modified andare based on T and N classification and adenopathy ( GLOT-A).Cancer of the Supraglottic Larynx The category of "Adverse feature: positive margin" was separatedout from extracapsular spread, with the treatmentrecommendations of "Further surgery or RT". The treatment option"RT" was added for "Adverse features: extracapsular nodalspread:” with a category 2B designation ( SUPRA-2). Cisplatin is listed as the preferred agent if using the treatmentoption of concurrent systemic therapy/RT ( SUPRA-3,SUPRA-6SUPRA-7).Unresectable Head and Neck Cancer A category 1 designation was added to the recommendation of"concurrent cisplatin- or carboplatin-based chemotherapy + RT".The recommendation for "induction chemotherapy followed by RT"was changed to "..followed by chemoradiation" ( ADV-1).Advanced Head and Neck Cancer The recommendation of Definitive RT + cetuximab was added forpatients not able to tolerate cytotoxic chemotherapy. ( ADV-A).Principles of Systemic Therapy Cetuximab was added as a systemic therapy option withconcurrent RT ( CHEM-A).Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.UPDATES

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersTeam ApproachGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesMULTIDISCIPLINARY TEAMThe management of patients with head and neck cancers is complex. Allpatients need access to the full range of specialists and support services withexpertise in the management of patients with head and neck cancer for optimaltreatment and follow-up. Head and neck surgery Clinical Social work Radiation oncology Nutrition support Medical oncology Pathology Plastic and reconstructive surgery Diagnostic radiology Specialized nursing care Adjunctive services Dentistry/prosthodontics Neurosurgery Physical medicine and Ophthalmologyrehabilitation Psychiatry Speech and swallowing therapy Addiction ServicesSUPPORT AND SERVICESFollow-up should be performed by a physician with expertise in the management andprevention of treatment sequelae. It should include a comprehensive head and neckexam. The management of head and neck cancer patients may involve the following: Pain and symptom management Nutritional support Enteral feeding Oral supplements Dental care for RT effects Xerostomia management Smoking cessation Tracheotomy care Social work and Case management Supportive Care (See NCCN Palliative Care Guideline)Back to Head and NeckTable of ContentsNote: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.TEAM-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersEthmoid Sinus TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesWORKUPUntreated H&P CT and/orMRI Chest x-rayBiopsyMalignantSee Primary Treatmentand Follow-up (ETHM-2)Ethmoid sinus: Squamous cell carcinoma Undifferentiatedcarcinoma Adenocarcinoma Salivary gland tumor Esthesioneuroblastomas Sarcoma (nonrhabdomyosarcoma)LymphomaDiagnosedwith incompleteexcisionSee NCCN Non-Hodgkin’sLymphoma Guidelines H&P CT and/orMRI Pathologyreview Chest x-raySee Primary Treatmentand Follow-up (ETHM-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ETHM-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersEthmoid Sinus TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICALPRESENTATIONPRIMARY TREATMENTADJUVANT TREATMENTFOLLOW-UPNewly diagnosed;T1, T2Complete surgicalresection (preferred)orRTorConsider Chemo/RT a (category 2B)if adverse characteristicsbDefinitive RTNewly diagnosed;T3, T4a resectableNewly diagnosed,unresectableDiagnosed after incompleteexcision (eg, polypectomy,endoscopic procedure) andgross residual diseaseCompletesurgical resectionChemo/RTaorRTorClinical trial (preferred)Surgery (preferred), if feasibleorRTorChemo/RT aRTorConsider Chemo/RT a (category 2B)if adverse characteristicsbRTorConsider Chemo/RT a (category 2B)if adverse characteristicsb Physical exam: Year 1,every 1–3 mo Year 2,every 2–4 mo Years 3–5,every 4–6 mo > 5 years,every 6–12 mo Chest imaging asclinically indicated TSH every 6-12 mo ifneck irradiated CT scan/MRI- baseline(category 2B)Diagnosed after incompleteexision (eg, polypectomy,endoscopic procedure) and nodisease on physical exam,imaging, and/or endoscopyRTorSurgery, if feasibleRTRecurrence(see ADV-2)aSee Principles of Systemic Therapy (CHEM-A).bAdverse characteristics include positive margins and perineural invasion.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ETHM-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersMaxillary Sinus TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesWORKUPPATHOLOGYLymphomaSee NCCN Non-Hodgkin’sLymphoma Guidelines H&P Complete head andneck CT withcontrast and/or MRI Dental/prostheticconsultation asindicated Chest x-rayBiopsy aMalignant Squamous cell carcinoma Undifferentiated carcinoma Adenocarcinoma Salivary gland tumor Esthesioneuroblastoma Sarcoma (nonrhabdomyosarcoma)T1-2, N0All histologiesT3-4, N0, Any T, N+All histologiesSee PrimaryTreatment (MAXI-2)See PrimaryTreatment (MAXI-3)a Biopsy: Preferred route is transnasal. Needle biopsy may be acceptable. Avoid canine fossa puncture or Caldwell-Luc approach.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MAXI-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersMaxillary Sinus TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesSTAGINGPRIMARY TREATMENTADJUVANT TREATMENTFOLLOW-UPT1-2, N0All histologiesexceptadenoid cysticT1-2, N0Adenoid cysticCompletesurgicalresectionCompletesurgicalresectionMarginnegativePerineuralinvasionMarginpositiveConsider RTborConsider chemo/RT(category 2B)Surgical reresection,if possibleRT bMarginnegativeMarginpositiveConsider RT bChemo/RT(category 2B) Physical exam: Year 1,every 1–3 mo Year 2,every 2–4 mo Years 3–5,every 4–6 mo > 5 years,every 6–12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiated CT/MRI- baseline(category 2B)bSee Principles of Radiation Therapy (MAXI-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MAXI-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersMaxillary Sinus TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesSTAGINGPRIMARY TREATMENTADJUVANT TREATMENTFOLLOW-UPT3, N0Operable T4a,all histologiesT4b, N any, allhistologiesT any, N+,resectableCompletesurgicalresectionClinical trialorDefinitive RTborChemo/RTbSurgicalexcision+ neckdissectionAdversecharacteristics cNo adversecharacteristics cAdversecharacteristics cNo adversecharacteristics cChemo/RT toprimary and neck(category 2B)RT to primary and neck (category 2B forneck) (for squamous cell carcinoma andundifferentiated tumors)Chemo/RT toprimary and neck(category 2B)RT to primary + neck Physical exam: Year 1,every 1–3 mo Year 2,every 2–4 mo Years 3–5,every 4–6 mo > 5 years,every 6–12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiated CT/MRI- baseline(category 2B)bSee Principles of Radiation Therapy (MAXI-A).cAdverse characteristics include positive margins, perineural invasion, or extracapsular nodal spread.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MAXI-3

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersMaxillary Sinus TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF RADIATION THERAPYDefinitive RT Primary and gross adenopathy: 66 Gy (2.0 Gy/day) NeckUninvolved nodal stations: 50 Gy (2.0 Gy/day)Postoperative RT Primary: 60 Gy (2.0 Gy/day) Neck Involved nodal stations: 60 Gy (2.0 Gy/day) Uninvolved nodal stations: 50 Gy (2.0 Gy/day)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MAXI-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersSalivary Gland TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICAL PRESENTATIONWORKUPTREATMENTUntreatedresectableSee Workup and PrimaryTreatment (SALI-2)Salivary glandmass Parotid Submaxillary Minor salivaryglandaPreviouslytreatedincompletelyresected H&P CT/MRI Pathologyreview Chest x-rayNegativephysicalexam andimagingGross residualdisease onphysicalexam or imagingSurgicalresection,if possibleNo surgicalresectionpossibleAdjuvant RT bAdjuvant RT bDefinitive RTborChemo/RT(category 2B)See Followup(SALI-4)Not resectableFine-needleaspiration orOpen biopsyDefinitive RTborChemo/RT(category 2B)aSite and stage determine therapeutic approaches.bSee Principles of Radiation Therapy (SALI-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SALI-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersSalivary Gland TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesWORKUPPRIMARY TREATMENTUntreated resectable,clinically benign, c< 4 cm (T1, T2)Completesurgicalexcision dBenign orlow gradeAdenoid cystic;Indeterminateor high gradeFollow-upRT (category 2Bfor T1)BenignFollow-upUntreatedresectable, clinicallysuspicious forcancer,> 4 cm or deep lobeCT/MRI:base ofskull toclavicleConsiderfine-needleaspirationLymphomaSurgicalresectionCancerParotidsuperficiallobeParotiddeep lobeSee Treatment(SALI-3)See Treatment(SALI-3)See NCCN Non-Hodgkin’sLymphoma GuidelinesOthersalivaryglandtumorsSee Treatment(SALI-3)cCharacteristics of benign tumor include mobile superficial lobe, slow growth, painless, VII intact, and no neck nodes.dSurgical excision of clinically benign tumor: no enucleation of lateral lobe, intraoperative communication with pathologist if indicated.Back to Head and NeckTable of ContentsNote: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SALI-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersSalivary Gland TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesTREATMENTParotidsuperficiallobeParotiddeep lobeClinical N0Clinical N+Clinical N0Clinical N+ParotidectomyParotidectomy +comprehensiveneck dissectionTotalparotidectomyTotalparotidectomy +comprehensiveneck dissectionCompletelyexcisedIncompletelyexcised grossresidual diseaseNo further surgicalresection possibleNo adverse characteristics Intermediate or high grade oradenoidcystic Close or positive margins Neural/perineural invasion Lymph node metastases Lymphatic/vascular invasionSee Followup(SALI-4)Adjuvant RT borConsiderChemo/RT(category 2B)Definitive RTbor Chemo/RT(category 2B)OthersalivaryglandtumorsClinical N0Clinical N+Complete glandexcisionComplete glandexcision andlymph nodedissectionNo adverse characteristics Intermediate or high grade oradenoidcystic Close or positive margins Neural/perineural invasion Lymph node metastases Lymphatic/vascular invasionSee Followup(SALI-4)Adjuvant RT borConsiderChemo/RT(category 2B)b See Principles of Radiation Therapy (SALI-A).Follow-up andRecurrence(see SALI-4)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SALI-3

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersSalivary Gland TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesFOLLOW-UPRECURRENCE Physical exam: Year 1, every 1–3 mo Year 2, every 2–4 mo Years 3–5, every 4–6 mo > 5 yr, every 6–12 mo Chest imaging as clinicallyindicated TSH every 6-12 mo, if neckirradiatedLocoregional ordistant disease;ResectableLocoregionaldisease;Not resectableSurgery or selectedmetastasectomy (category 3)RTborChemo/RT (category 2B)orChemotherapyorBest supportive careRTb See Principles of Radiation Therapy (SALI-A).Back to Head and NeckTable of ContentsNote: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SALI-4

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersSalivary Gland TumorsGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF RADIATION THERAPYDefinitive RTUnresectable disease or gross residual disease Photon/electron therapy or neutron therapy Dose Primary and gross adenopathy: 70 Gy (1.8-2.0 Gy/day) 1 or19.2 nGy (1.2 nGy/day) Uninvolved nodal stations:45-54 Gy (1.8-2.0 Gy/day) 1 or13.2 nGy (1.2 nGy/day)Postoperative RT Photon/electron therapy or neutron therapy Dose Primary: 60 Gy (1.8-2.0 Gy/day) 1or 18 nGy (1.2 nGy/day) Neck: 45-54 Gy (1.8-2.0 Gy/day) 1or 13.2 nGy (1.2 nGy/day)1 Range based on grade/natural history of disease (eg, 1.8 Gy fraction may be used for slower growing tumors).Back to Workup andPrimary Treatment(SALI-1)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SALI-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the LipGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesWORKUPCLINICAL STAGINGT1-2, N0See Treatment of Primary and Neck (LIP-2) H&P Biopsy Chest x-ray As indicated forprimary evaluation Panorex CT/MRI Preanesthesia studies Dental evaluationMultidisciplinaryconsultation asindicatedResectableT3, T4a, N0Any T, N1-3SurgicalcandidatePoorsurgicalriskSee Treatment of Primary and Neck (LIP-3)Definitive RTatoprimary and nodesFollow-uporChemo/RTbUnresectableSee Treatment of Head and Neck Cancer (ADV-1)aSee Principles of Radiation Therapy (LIP-A).bSee Principles of Systemic Therapy (CHEM-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.LIP-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the LipGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICAL STAGINGTREATMENT OF PRIMARY AND NECKADJUVANT TREATMENTFOLLOW-UPPositive marginsReexcisionorRTaorChemo/RTb(category 3)T1–2, N0Surgical excisionorPerineural/vascular/lymphatic invasionNo adversepathologic findingsRTaorChemo/RTb(category 3)Physical exam: Year 1,every 1–3 mo Year 2,every 2–4 mo Years 3–5,every 4–6 mo >5yr,every 6–12 moExternal-beam RT 50 Gy+ brachytherapyorBrachytherapy aloneorExternal-beam RT 66 GyResidual orrecurrent tumorpost-RTSurgery/reconstructionRecurrence (see ADV-2)aSee Principles of Radiation Therapy (LIP-A).bSee Principles of Systemic Therapy (CHEM-A).Back to Head and NeckTable of ContentsNote: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.LIP-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the LipGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICAL STAGING:RESECTABLE T3, T4a, N0; Any T, N1-3TREATMENT OF PRIMARY AND NECKADJUVANTTREATMENTFOLLOW-UPSurgicalcandidateSurgeryN0External RT a ±brachytherapyN1,N2a–b,N3N2c(bilateral)Excision of primary ±unilateral or bilateralselective neck dissection(reconstruction as indicated)Excision of primary, ipsilateralcomprehensive neckdissection ± contralateralselective neck dissection(reconstruction as indicated)Excision of primary andbilateral comprehensive neckdissection (reconstruction asindicated)Primary site:CompleteresponsePrimary site:< completeresponseResidualtumorCompleteresponseof neckOne positive nodewithout adversefeatures c,dAdversefeaturesN1(initialstage)N2-3(initialstage)Salvage surgery + neckdissection as indicatedMajor riskfeatures cMinor riskfeatures dNeck dissection(category 3)ObserveObserveorNeck dissection(category 3)aSee Principles of Radiation Therapy (LIP-A).bSee Principles of Systemic Therapy (CHEM-A).cExtracapsular nodal spread and/or positive margins.dMinor risk features: multiple positive nodes (without extracapsular nodal spread) or perineural/lymphatic/vascular invasion.RTaoptionalChemo/RT bRT aorChemo/RTb(multiple positivenodes only)(category 2B)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Physical exam: Year 1,every 1–3 mo Year 2,every 2–4 mo Years 3–5,every 4–6 mo >5yr,every 6–12 moRecurrence (see ADV-2)Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.LIP-3

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the LipGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF RADIATION THERAPYDefinitive RT Primary and gross adenopathy: 66 Gy (2.0 Gy/day)External-beam RT 50 Gy +brachytherapy or brachytherapy alone NeckUninvolved nodal stations: 50 Gy (2.0 Gy/day)Postoperative RT Primary: 60 Gy (2.0 Gy/day) Neck Involved nodal stations: 60 Gy (2.0 Gy/day) Uninvolved nodal stations: 50 Gy (2.0 Gy/day)Back to ClinicalStaging (LIP-1)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.LIP-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Oral CavityBuccal mucosa, floor of mouth, anterior tongue, alveolar ridge, retromolar trigone, hard palateGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesWORKUPCLINICAL STAGINGT1–2, N0See Treatment of Primary and Neck (OR-2) H&P Biopsy Chest x-rayor Chest CTa As indicated forevaluation Panorex CT/MRI Examination underanesthesia, if indicated Preanesthesia studies Dental evaluationMultidisciplinaryconsultation as indicatedT3, N0T1–3, N1–3T4a, any NSee Treatment of Primary and Neck (OR-2)See Treatment of Primary and Neck (OR-3)See Treatment of Primary and Neck (OR-4)UnresectableSee Treatment of Head and Neck Cancer (ADV-1)a Chest CT should be considered for patients at high risk for thoracic metastases.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OR-1

®NCCNCLINICALSTAGINGPractice Guidelinesin Oncology – v.1.2007TREATMENT OF PRIMARY AND NECKHead and Neck CancersCancer of the Oral CavityBuccal mucosa, floor of mouth, anterior tongue, alveolar ridge, retromolar trigone, hard palateNo adverse features b,cADJUVANT TREATMENTGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesFOLLOW-UPT1–2, N0T3, N0Excision of primary(preferred) ± unilateralor bilateral selectiveneck dissectionorExternal-beam RT ±brachytherapy 70 Gy to primary 50 Gy to neck at riskExcision of primaryand reconstructionas indicated andunilateral or bilateralselective neckdissectionOne positive node withoutadverse features b,cAdversefeaturesResidual diseaseNo adverse features b,cAdversefeaturesOne or both major riskfeatures or 2 minorrisk featuresb,c 2 minor riskfeatures cNo residual diseaseOne or both major riskfeatures or 2 minorrisk featuresb,c 2 minor riskfeatures cRTdoptionalChemo/RT d,e(category 1)RT dSalvagesurgeryRT d (optional)Chemo/RT d,e(category 1)RT d Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 yr,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiated Speech andswallowingevaluation andrehabilitation asindicatedbMajor risk features: positive margins and/or extracapsular nodal spread.cMinor risk features: pT3 or pT4 primary; N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism.dSee Principles of Radiation Therapy (OR-A).eSee Principles of Systemic Therapy (CHEM-A).Recurrence (see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OR-2

®NCCNCLINICALSTAGINGPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Oral CavityBuccal mucosa, floor of mouth, anterior tongue, alveolar ridge, retromolar trigone, hard palateTREATMENT OF PRIMARY AND NECKADJUVANTTREATMENTGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesFOLLOW-UPT1-3, N1-3SurgeryN1,N2a-b,N3N2c(bilateral)Excision of primary,ipsilateralcomprehensive neckdissection ± contralateralselective neck dissection(reconstruction asindicated)Excision of primary andbilateral comprehensiveneck dissection(reconstruction asindicated)No adversefeatures b,cAdversefeaturesOne or bothmajor riskfeatures or 2minor riskfeaturesb,c 2 minor riskfeatures cRTdoptionalChemo/RT d,e(category 1)RT d Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 yr,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiated Speech andswallowingevaluation andrehabilitation asindicatedbMajor risk features: positive margins and/or extracapsular nodal spread.cMinor risk features: pT3 or pT4 primary; N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism.dSee Principles of Radiation Therapy (OR-A).eSee Principles of Systemic Therapy (CHEM-A).Recurrence (see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OR-3

®NCCNCLINICALSTAGINGPractice Guidelinesin Oncology – v.1.2007Buccal mucosa, floor of mouth, anterior tongue, alveolar ridge, retromolar trigone, hard palateTREATMENT OF PRIMARY AND NECKHead and Neck CancersCancer of the Oral CavityGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesFOLLOW-UPSurgery (preferredfor bone invasion)Chemotherapy/RTd,e(category 1)T4a, Any NorConcurrentsystemictherapy/RTe(category 3)Primary site:CompleteresponseResidualtumorCompleteresponseof neckN1 (initialstage)N2-3 (initialstage)Neck dissection(category 3)ObserveObserveorNeck dissection(category 3) Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 yr,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiated Speech andswallowingevaluation andrehabilitation asindicatedPrimary site:residualtumorSalvage surgery + neckdissection as indicatedd See Principles of Radiation Therapy (OR-A).e See Principles of Systemic Therapy (CHEM-A) .Recurrence (see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OR-4

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Oral CavityGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF RADIATION THERAPYDefinitive RT Primary and gross adenopathy: 70 Gy (2.0 Gy/day)External-beam RT 50 Gy ± brachytherapy NeckUninvolved nodal stations: 50 Gy (2.0 Gy/day)Postoperative RT Primary: 60 Gy (2.0 Gy/day) Neck Involved nodal stations: 60 Gy (2.0 Gy/day) Uninvolved nodal stations: 50 Gy (2.0 Gy/day)Any one minor risk feature: pT3 or pT4 primary; N2 or N3 nodal disease, nodaldisease in levels IV or V, perineural invasion, vascular embolism.Postoperative chemoradiation for high pathologic risk features 1,2,3 One or both major risk features or two or more minor risk features. Concurrent single agent cisplatin at 100 mg/m2every 3 wks is recommended.1Bernier J, Domenge C, Ozsahin M et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med2004;350:1945-1952.2Cooper JS, Pajak TF, Forastiere AA et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N EnglJ Med 2004;350(19):1937-1944.3Bernier J, Cooper JS, Pajuk TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation pluschemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OR-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Base of tongue/tonsil/posterior pharyngeal wall/soft palateWORKUPHead and Neck CancersCancer of the OropharynxCLINICAL STAGINGGuidelines IndexHead and Neck Cancers TOCStaging, MS, References H&P Biopsy Chest x-rayor Chest CTa CT with contrast or MRIrecommended for primary andneck Panorex as indicated Dental evaluation as indicated Speech & swallowingevaluation as indicated Examination under anesthesiawith laryngoscopy Preanesthesia studiesMultidisciplinary consultation asindicatedT1-2, N0-1T3-4a, N0Any T, N2-3T3-4a, N+UnresectableSee Treatment of Primary and Neck (ORPH-2)See Treatment of Primary and Neck (ORPH-3)See Treatment of Primary and Neck (ORPH-4)See Treatment of Headand Neck Cancer (ADV-1)a Chest CT should be considered for patients at high risk for thoracic metastases.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ORPH-1

®NCCNCLINICALSTAGINGT1-2,N0-1Practice Guidelinesin Oncology – v.1.2007Base of tongue/tonsil/posterior pharyngeal wall/soft palateTREATMENT OF PRIMARY AND NECKDefinitive RTbpreferred(category 2B)orExcision of primary ±unilateral or bilateralneck dissectionorHead and Neck CancersCancer of the OropharynxPrimary controlledResidual diseaseNo adverse features c,dOne positive node withoutadverse features c,dAdversefeaturesOne or both major riskfeatures or 2 minorrisk featuresc,d 2 minor riskfeatures dADJUVANTTREATMENTSalvagesurgeryConsider RT bChemo/RT b,e(category 1)RT bGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesFOLLOW-UP Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 yr,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo, ifneck irradiated Speech and swallowingevaluation andrehabilitation asindicatedFor T1-T2, N1 only RT+ systemic therapye(category 3)Primary controlledResidual diseaseSalvagesurgeryRecurrence (see ADV-2)bSee Principles of Radiation Therapy (ORPH-A).cMajor risk features: positive margins and/or extracapsular nodal spread.dMinor risk features: pT3 or pT4 primary; N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism.eSee Principles of Systemic Therapy (CHEM-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ORPH-2

®NCCNCLINICALSTAGINGPractice Guidelinesin Oncology – v.1.2007Base of tongue/tonsil/posterior pharyngeal wall/soft palateTREATMENT OF PRIMARY AND NECKHead and Neck CancersCancer of the OropharynxADJUVANTTREATMENTGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesFOLLOW-UPT3-4a, N0Concurrent systemic therapy/RTb,ecisplatin (category 1) preferredorSurgeryorInduction chemotherapyfollowed by chemo/RToff protocol (category 3)orMultimodality clinical trials thatinclude function evaluationPrimary controlledResidual diseaseNo adverse features c,dAdversefeaturesOne or both major riskfeatures or 2 minorrisk featuresc,d 2 minor riskfeatures dPrimary controlledResidual diseaseSalvagesurgeryRT bChemo/RT b,e(category 1)RT bSalvagesurgery Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 yr,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo, ifneck irradiated Speech andswallowing evaluationand rehabilitation asindicatedRecurrence (see ADV-2)bSee Principles of Radiation Therapy (ORPH-A).cMajor risk features: positive margins and/or extracapsular nodal spread.dMinor risk features: pT3 or pT4 primary; N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, vascular embolism.eSee Principles of Systemic Therapy (CHEM-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ORPH-3

®NCCNCLINICALSTAGINGPractice Guidelinesin Oncology – v.1.2007Base of tongue/tonsil/posterior pharyngeal wall/soft palateTREATMENT OF PRIMARY AND NECKHead and Neck CancersCancer of the OropharynxADJUVANTTREATMENTGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesFOLLOW-UPAny T3-4a,N+ orAny T, N2-3Concurrent systemictherapy/RTb,ecisplatin (category 1)preferredorInduction chemotherapyfollowed by chemo/RToff protocol (category 3)orSurgery:primary andneckorN1N2a–bN3N2cMultimodality clinical trials thatinclude function evaluationPrimary site:completeresponsePrimary site:residual tumorResidualtumorCompleteresponseof neckN1(initialstage)N2-3(initialstage)Salvage surgery + neckdissection as indicatedExcision of primary, ipsilateralcomprehensive neck dissection(reconstruction as indicated)Excision of primary and bilateralcomprehensive neck dissection(bilateral is category 3 if necknodes contralateral only)(reconstruction as indicated)Neck dissection(category 3)ObserveObserveorNeck dissection(category 3)RT borChemo/RTb,e(category 1) Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 yr,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo, ifneck irradiated Speech andswallowing evaluationand rehabilitation asindicatedb See Principles of Radiation Therapy (ORPH-A).e See Principles of Systemic Therapy (CHEM-A) .Recurrence (see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ORPH-4

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the OropharynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesSelected T1-2, N0 Conventional fractionation:70 Gy (2.0 Gy/day)Selected T1, N1; T2, N0-1 Altered fractionation (preferred): Concomitant boost accelerated RT:72 Gy/6 weeks (1.8 Gy/fraction, large field;1.5 Gy boost as second daily fraction duringlast 12 treatment days) Hyperfractionation:81.6 Gy/7 weeks (1.2 Gy/fraction BID)Postoperative RTPrimary: 60 Gy (2.0 Gy/day) Neck Involved nodal stations: 60 Gy (2.0 Gy/day) Uninvolved nodal stations: 50 Gy (2.0 Gy/day)Any one minor risk feature: pT3 or pT4 primary;N2 or N3 nodal disease, nodal disease in levelsIV or V, perineural invasion, vascular embolism.PRINCIPLES OF RADIATION THERAPYT2-4a, N0-3 Concurrent chemoradiationConventional fractionation: 1 Primary and gross adenopathy 70 Gy (2.0 Gy/day) NeckUninvolved nodal stations:44-50 Gy (2.0 Gy/day)Postoperative chemoradiation for highpathologic risk features2,3,4 One or both major risk features, or twoor more minor risk features. Concurrent single agent cisplatin at100 mg/m2every 3 wks isrecommended.Radiation Techniques3D conformal techniques may be useddepending on the stage, tumor location,physician training/experience andavailable physics support. IMRTtechniques are an area of activedevelopment among the NCCNinstitutions and others. Targetdelineation and optimal dosedistribution require special training inhead and neck imaging, a thoroughunderstanding of patterns of diseasespread, and special training in IMRTtechniques. Standards for targetdefinition, dose specification,fractionation (with and withoutconcurrent chemotherapy), and normaltissue constraints should emerge withinthe next few years.1The majority of the published experience with concurrent chemoradiation has utilized conventional fractionation at 2.0 g per fraction to 70 Gy in 7 wks with singleagent cisplatin given every 3 wks at 100 mg/m 2. Use of other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, or altered fractionation withchemotherapy has been evaluated with no consensus on the optimal approach. In general, the use of concurrent chemoradiation carries a high toxicity burden--alteredfractionation or multiagent chemotherapy will likely further increase toxicity burden. For any chemoradiation approach, close attention should be paid to publishedreports for the specific chemotherapy agent, dose, and schedule of administration. Chemoradiation should be performed by an experienced team and includesubstantial supportive care.2Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med2004;350:1945-1952.3Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.N Engl J Med 2004;350:1937-1944.4Bernier J, Cooper JS, Pajuk TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation pluschemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ORPH-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the HypopharynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesWORKUPCLINICAL STAGING H&P Biopsy Chest x-rayor Chest CTa CT with contrast or MRI ofprimary and neckrecommended Examination underanesthesia with laryngoscopyand esophagoscopy Preanesthesia studies Dental evaluationEarly T stage not requiringtotal laryngectomy Most T1, N0-1; small T2, N0Resectable advanced cancerrequiring total laryngectomy T1, N2-3; T2-4a, Any N(Participation in clinicaltrials preferred)T1, N2-3;T2-3, Any NT4a, Any NSee Treatment of Primary andNeck (HYPO-2)See Treatment of Primary andNeck (HYPO-3)See Treatment of Primary andNeck (HYPO-5)Multidisciplinary consultationas indicatedUnresectableSee Treatment of Head andNeck Cancer (ADV-1)a Chest CT should be considered for patients at high risk for thoracic metastases.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.HYPO-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the HypopharynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICALSTAGINGTREATMENT OF PRIMARY AND NECKADJUVANT TREATMENTFOLLOW-UPEarly T stage(not requiringtotallaryngectomy) Most T1, N0-1,small T2, N0Definitive RT borSurgery: Partiallaryngopharyngectomy(open or endoscopic)+ ipsilateral or bilateralselective neck dissection(N0); Comprehensive neckdissection levels 1-5 (N1)Primary site:completeresponsePrimary site:residualtumorResidualtumorCompleteresponseof neckSalvage surgery+ neck dissectionas indicatedNo adverse features c,dAdversefeaturesOne or both major riskfeatures or 2 minorrisk featuresc,d 2 minor riskfeatures dNeck dissection(category 3)ObserveChemo/RT b,e(category 1)RT b Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 yr,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiatedb See Principles of Radiation Therapy (HYPO-A).cMajor risk features: positive margins and/or extracapsular nodal spread.dMinor risk features: pT3 or pT4 primary; N2 or N3 nodal disease, perineural invasion, vascular embolism.eSee Principles of Systemic Therapy (CHEM-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.HYPO-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the HypopharynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICALSTAGINGTREATMENT OF PRIMARY AND NECKInduction chemotherapy x 2cycles (category 1)See Response After InductionChemotherapy (HYPO-4)ADJUVANT TREATMENTFOLLOW-UPT1, N2-3;T2-3, any N(if totallaryngectomyrequired)orLaryngopharyngectomy+ selective (N0) orcomprehensive (N+)neck dissectionorConcurrent systemictherapy/RTb,ecisplatin preferred(category 2B)orNo adversefeatures c,dAdversefeaturesPrimary site:completeresponsePrimary site:residual tumorResidualtumorRT bOne or both major riskfeatures or 2 minorrisk featuresc,d 2 minor riskfeatures dCompleteresponseof neckN1(initial stage)N2-3(initial stage)Salvage surgery + neckdissection as indicatedChemo/RT b,e(category 1)RT bNeck dissection(category 3)ObserveObserveorNeck dissection(category 3) Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 yr,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiatedMultimodality clinicaltrials that includefunction evaluationb See Principles of Radiation Therapy (HYPO-A).cMajor risk features: positive margins and/or extracapsular nodal spread.dMinor risk features: pT3 or pT4 primary; N2 or N3 nodal disease, perineural invasion, vascular embolism.eSee Principles of Systemic Therapy (CHEM-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.HYPO-3

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the HypopharynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesRESPONSE AFTER INDUCTION CHEMOTHERAPYFOR T1, N2-3; T2-3, ANY N TUMORSADJUVANTTREATMENTFOLLOW-UPResidualtumorNeck dissection(category 3)Primary site:CompleteresponsePrimary site:Partial response(evaluation mayrequireendoscopy)Primary site:< PartialresponseChemotherapyx 1 cycleSurgeryDefinitive RT bPrimary site:CompleteresponsePrimary site:residualtumorCompleteresponseof neckSalvagesurgeryNo adversefeatures c,dAdversefeaturesN1(initialstage)N2-3(initialstage)ObserveObserveorNeck dissection(category 3)RT bOne or both majorrisk features or 2minor riskfeaturesc,dChemo/RT b,e(category 1) Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 yr,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiated 2 minor riskfeatures dRT bb See Principles of Radiation Therapy (HYPO-A).cMajor risk features: positive margins and/or extracapsular nodal spread.dMinor risk features: pT3 or pT4 primary; N2 or N3 nodal disease, perineural invasion, vascular embolism.eSee Principles of Systemic Therapy (CHEM-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.HYPO-4

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the HypopharynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICALSTAGINGTREATMENT OF PRIMARY AND NECKADJUVANT TREATMENTFOLLOW-UPSurgery + comprehensiveneck dissection (preferred)Chemo/RTb,e(category 1)T4a, any NorConcurrent systemictherapy/RTb,e(category 3)orPrimary site:completeresponsePrimary site:residual tumorResidualtumorCompleteresponseof neckN1(initialstage)N2-3(initialstage)Salvage surgery + neckdissection as indicatedNeck dissection(category 3)ObserveObserveorNeck dissection(category 3) Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 yr,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiatedMultimodality clinicaltrials that includefunction evaluationb See Principles of Radiation Therapy (HYPO-A).e See Principles of Systemic Therapy (CHEM-A) .Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.HYPO-5

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the HypopharynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF RADIATION THERAPYDefinitive RT Primary and gross adenopathy: 70 Gy (2.0 Gy/day) NeckUninvolved nodal stations: 50 Gy (2.0 Gy/day)Postoperative RT Primary: 60 Gy (2.0 Gy/day) Neck Involved nodal stations: 60 Gy (2.0 Gy/day) Uninvolved nodal stations: 50 Gy (2.0 Gy/day)Any one minor risk feature: pT3 or pT4 primary; N2 or N3 nodal disease,perineural invasion, vascular embolism.Postoperative chemoradiation for high pathologic risk features1,2,3 One or both major risk features or two or more minor risk features. Concurrent single agent cisplatin at 100 mg/m2every 3 wks is recommended.1Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced headand neck cancer. N Engl J Med 2004;350:1945-1952.2Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cellcarcinoma of the head and neck. N Engl J Med 2004;350:1937-1944.3 Bernier J, Cooper JS, Pajuk TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis ofconcurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850.Back to ClinicalStaging (HYPO-1)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.HYPO-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersOccult PrimaryGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRESENTATIONWORKUPSquamous cellcarcinoma,adenocarcinoma,and anaplasticepithelial tumors bLymphoma Complete head and neck examwith attention to skin, includingnasopharyngoscopy Chest x-ray CT with contrast or MRI withgadolinium (skull base throughthoracic inlet) PET scan only if other tests donot identify a primarySee NCCN Non-Hodgkin’sLymphoma GuidelinesSee Workup and PrimaryTreatment (OCC-2)Neck massFine-needleaspiration aThyroidSee NCCN ThyroidCarcinoma GuidelinesMelanomaSystemic work-up perNCCN Melanoma Guidelines skin exam, note regressinglesionsSee Primary Therapy forMelanoma (OCC-5)a Repeat FNA, core or open biopsy may be necessary for uncertain histologies. Patient should beprepared for neck dissection at time of biopsy, if necessary.b Determined with appropriate immunohistochemical stains.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OCC-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersOccult PrimaryGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPATHOLOGICFINDINGSWORKUPPRIMARY TREATMENTPrimaryfoundTreat as appropriate(See Guidelines Index)Adenocarcinoma(levels I–III)Comprehensiveneck dissection+ parotidectomy,if indicatedRT to neck ±parotid bedN1 with FNAorConsider RTas per OCC-3Node levelI, II, III,upper VNode levelIV, lower V Examination underanesthesia Palpation and inspection Biopsy of areas of clinicalconcern, includingtonsillectomy Direct laryngoscopy andnasopharynx survey Direct laryngoscopy,bronchoscopy,esophagoscopy Chest/abdominal/pelvic CTSquamous cellcarcinomaPoorlydifferentiatedorNonkeratinizingsquamous cellor NOS orAnaplastic(Not thyroid)SurgeryorRT c (category 3)orChemotherapy/RTd(category 3)Comprehensiveneck dissection(levels I–V)No residualtumorResidualtumorSee N1 with openbiopsy (OCC-3)orExtracapsular spreador N2, N3 (OCC-4)ObserveorConsider neck dissectionfor initial stage N3Comprehensiveneck dissectionPrimaryfoundTreat as appropriate(See Guidelines Index)cSee Principles of Radiation Therapy (OCC-A).dSee Principles of Systemic Therapy (CHEM-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OCC-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersOccult PrimaryGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPOSTSURGICAL TREATMENT FOR SQUAMOUS CELL CARCINOMA;NOS OR ANAPLASTICLevel I onlyRTcto neck only (category 3)orRTcto oral cavity, Waldeyer’s ring, oropharynx,both sides of the neck (block RT to the larynx)N1 with openbiopsyLevel II, III, upper level VLevel IV onlyRTcto neck only (category 3)orRTcto nasopharynx, both sides of the neck,hypopharynx, larynx, oropharynxRTcto neck only (category 3)orRTcto Waldeyer’s ring, larynx,hypopharynx, both sides of the neckLower level VRTcto neck only (category 3)orRTcto larynx, hypopharynx,both sides of the neckc See Principles of Radiation Therapy (OCC-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OCC-3

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersOccult PrimaryGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPOSTSURGICAL TREATMENT FOR SQUAMOUS CELL CARCINOMA;NOS OR ANAPLASTICLevel I onlyRTcto neck only (category 3)orRTcto oral cavity, Waldeyer’s ring, oropharynx,both sides of the neck (block RT to the larynx)orChemotherapy/RT d (category 2B)ExtracapsularspreadorN2, N3Level II, III, upper level VLevel IV onlyRTcto neck only (category 3)orRTcto nasopharynx, both sides of the neck,hypopharynx, larynx, oropharynxorChemotherapy/RT d (category 2B)RTcto neck only (category 3)orRTcto Waldeyer’s ring, larynx,hypopharynx, both sides of the neckorChemotherapy/RT d (category 2B)Lower level VRTcto neck only (category 3)orRTcto larynx, hypopharynx, bothsides of the neckorChemotherapy/RT d (category 2B)cSee Principles of Radiation Therapy (OCC-A).dSee Principles of Systemic Therapy (CHEM-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OCC-4

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersOccult PrimaryGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRIMARY THERAPY FOR OCCULT PRIMARY- MELANOMALevel V,occipital nodePosterior lateralnode dissection± RT to nodal bed d ± Adjuvant systemic therapy, perNCCN Melanoma GuidelinesAll othernodal sitesComprehensiveneck dissectiondAdjuvant radiotherapy: 30 Gy/5 fx over 2.5 weeks (6.0 Gy/fx). Careful attention to dosimetry is necessary.(Ang KK, Peters LJ, Weber RS, et al. Postoperative radiotherapy for cutaneous melanoma of the head and neck region.International Journal of Radiation Oncology, Biology, Physics 30:795-798, 1994).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OCC-5

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersOccult PrimaryGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF RADIATION THERAPYMucosal sites: 50-60 Gy (2.0 Gy/day) to mucosa, depending onfield size and use of chemotherapy. Considerboost to 60-64 Gy to particularly suspicious areasNeck Uninvolved nodal stations: 50 Gy (2.0 Gy/day) Involved nodal station(s):60-66 Gy * (2.0 Gy/day)* Up to 70 Gy in case of excision only for N1 neck.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.OCC-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Glottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesWORKUP aCLINICAL STAGINGTREATMENT OF PRIMARY AND NECK H&P Biopsy Chest x-rayor Chest CTb CT with contrast and thin cutsthrough larynx, or MRI ofprimary and neck recommended Examination under anesthesiawith laryngoscopy Preanesthesia studies Dental evaluation as indicated Speech & swallowing evaluationas indicatedMultidisciplinary consultation asindicatedSevere dysplasia/carcinoma in situ Total laryngectomynot required Most T1-2, any N Resectable Requiring totallaryngectomy Most T3, any NT4a diseaseSee Treatment and Follow-up (GLOT-2)See Treatment and Follow-up (GLOT-2)See Treatment and Follow-up (GLOT-3)See Treatment and Follow-up (GLOT-4)UnresectableSee Treatment of Head andNeck Cancer (ADV-1)a Complete workup not indicated for Tis, T1.b Chest CT should be considered for patients at high risk for thoracic metastases.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.GLOT-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Glottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICAL STAGINGTREATMENT OF PRIMARY AND NECKFOLLOW-UPSevere dysplasia/carcinoma in situ Total laryngectomynot required Most T1-2, any NClinical trialorEndoscopic removal(stripping/laser)orRT cRTcorPartial laryngectomy/endoscopic resection(selected superficial lesions)orOpen partial laryngectomyN0N+ (rare)ObserveNeck dissectionand/or RT c Physical exam: Year 1, every 1-3 mo Year 2, every 2-4 mo Years 3-5, every 4-6 mo > 5 years, every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo, ifneck irradiated Speech and swallowingevaluation andrehabilitation as indicatedc See Principles of Radiation Therapy (GLOT-A).Recurrence (see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.GLOT-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Glottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICALSTAGINGTREATMENT OF PRIMARY AND NECKADJUVANTTREATMENTFOLLOW-UP Resectable Requiringtotallaryngectomy Most T3,any NConcurrent systemictherapy/RTc,dcisplatin (category 1)preferredorSurgeryN0N1N2-3Primary site:CompleteresponsePrimary site:residualtumorResidualtumorCompleteresponseof neckLaryngectomy with ipsilateralthyroidectomy ± unilateral orbilateral selective neck dissection(reconstruction as indicated)Salvage surgery+ neck dissectionas indicatedLaryngectomy with ipsilateralthyroidectomy, ipsilateralcomprehensive neck dissection ±contralateral selective neck dissection(reconstruction as indicated)Laryngectomy with ipsilateralthyroidectomy, ipsilateral or bilateralcomprehensive neck dissection(reconstruction as indicated)c See Principles of Radiation Therapy (GLOT-A).dSee Principles of Systemic Therapy (CHEM-A).eMajor risk features: positive margins and/or extracapsular nodal spread.fMinor risk features: pT4 primary; N2 or N3 nodal disease, perineural invasion, vascular embolism.N1(initialstage)N2-3(initialstage)No adversefeatures e,fAdversefeaturesNeck dissection(category 3)ObserveObserveorNeck dissection(category 3 forselective vscomprehensive)One or bothmajor riskfeatures or 2 minor riskfeaturese,f 2 minor riskfeatures fChemo/RT c,d(category 1)RT c Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5, every 4-6mo > 5 years, every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo, ifneck irradiated Speech andswallowing evaluationand rehabilitation asindicatedRecurrence(see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.GLOT-3

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Glottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICALSTAGINGTREATMENT OF PRIMARY AND NECKADJUVANTTREATMENTT4adiseaseSelectedT4aConsider concurrentchemoradiationdorClinical trial forfunction preservingsurgical or nonsurgicalmanagementN0Primary site:CompleteresponsePrimary site:residualtumorResidualtumorCompleteresponseof neckLaryngectomy with ipsilateralthyroidectomy ± unilateral or bilateralselective neck dissection (reconstructionas indicated)Salvage surgery+ neck dissectionas indicatedN1(initialstage)N2-3(initialstage)Neck dissection(category 3)ObserveObserveorNeck dissection(category 3 forselective vscomprehensive) Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5, every 4-6 mo > 5 years, every 6-12mo Chest imaging asclinically indicated TSH every 6-12 mo, ifneck irradiated Speech and swallowingevaluation andrehabilitation asindicatedT4a, Any NN1Laryngectomy with ipsilateral thyroidectomy,ipsilateral comprehensive neck dissection ±contralateral selective neck dissection(reconstruction as indicated)Chemo/RTc,d(category 1)N2-3Laryngectomy with ipsilateral thyroidectomy,ipsilateral or bilateral comprehensive neckdissection (reconstruction as indicated)c See Principles of Radiation Therapy (GLOT-A).d See Principles of Systemic Therapy (CHEM-A) .Recurrence (see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.GLOT-4

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Glottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF RADIATION THERAPYDefinitive RT T1, N0: 63-66 Gy in 2.25-2.0 Gy/day T2 and gross adenopathy: 70 Gy (2.0 Gy/day) in 7 weeks 72 Gy in 6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second dailyfraction during last 12 treatment days) 79.2 - 81.6 Gy in 7 weeks (1.2 Gy/fraction, twice daily) Elective nodal RT > 50 Gy (2.0 Gy/day)Postoperative RT Primary: 60 Gy (2.0 Gy/day) Neck Involved nodal stations: 60 Gy (2.0 Gy/day) Uninvolved nodal stations: 50 Gy (2.0 Gy/day)Any one minor risk feature: pT4 primary; N2 or N3 nodal disease,perineural invasion, vascular embolism.Postoperative chemoradiation for high pathologic risk features1,2,3 One or both major risk features or two or more minor risk features. Concurrent single agent cisplatin at 100 mg/m2every 3 wks is recommended.1Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med2004;350:1945-1952.2Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. NEngl J Med 2004;350:1937-1944.3 Bernier J, Cooper JS, Pajuk TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation pluschemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.GLOT-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Supraglottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesWORKUPCLINICAL STAGING Not requiring totallaryngectomy Most T1–2, N0See Treatment of Primaryand Neck (SUPRA-2) H&P Biopsy Chest x-rayor Chest CTa CT with contrast and thin cutsthrough larynx or MRI of primaryand neck recommended Examination under anesthesiawith laryngoscopy Preanesthesia studies Dental evaluation as indicated Speech & swallowing evaluationas indicatedMultidisciplinaryconsultation as indicated Requiring laryngectomy T3, N0 T4a, N0 No cartilage destruction Low-volume base-oftongueinvolvement T4a, N0 Cartilage destruction Skin involvement High-volume invasionof base of tongueNode positive diseaseSee Treatment of Primaryand Neck (SUPRA-3)See Treatment of Primaryand Neck (SUPRA-4)See Workup and ClinicalStaging (SUPRA-5)UnresectableSee Treatment of Headand Neck Cancer (ADV-1)a Chest CT should be considered for patients at high risk for thoracic metastases.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SUPRA-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Supraglottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICAL STAGINGTREATMENT OF PRIMARY AND NECKADJUVANTTREATMENTFOLLOW-UP Not requiring totallaryngectomy Most T1–2, N0Endoscopic resection ±selective neck dissectionorOpen partial supraglotticlaryngectomy ± selectiveneck dissectionorDefinitive RT bOne positive nodewithout otheradverse featuresAdverse features:positive marginsAdverse features:extracapsular nodalspreadConsider RT bFurther surgeryorRT bChemo/RTb,c(category 2B)orRT b (category 2B) Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 years,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo, ifneck irradiated Speech and swallowingrehabilitation andtherapy as indicatedb See Principles of Radiation Therapy (SUPRA-A).c See Principles of Systemic Therapy (CHEM-A) .Recurrence (see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SUPRA-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Supraglottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICALSTAGINGTREATMENT OF PRIMARY AND NECKADJUVANTTREATMENTFOLLOW-UP Requiringlaryngectomy T3, N0 T4a, N0 No cartilagedestruction Low-volume base-oftongueinvolvementLaryngectomy,ipsilateralthyroidectomywith ipsilateral orbilateral selectiveneck dissectionorConcurrent systemictherapy/RTb,ccisplatin (category 1)preferredN0 or one positive nodewithout adverse features d,eAdversefeaturesPrimary site:CompleteresponsePrimary site:residualtumorOne or bothmajor riskfeatures or 2 minor riskfeaturesd,e 2 minor riskfeatures eSalvage surgery +neck dissectionas indicatedRTboptionalChemo/RT b,c(category 1)RT b Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 years,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo, ifneck irradiated Speech andswallowing evaluationand rehabilitation asindicatedRecurrence (see ADV-2)b See Principles of Radiation Therapy (SUPRA-A).cSee Principles of Systemic Therapy (CHEM-A).dMajor risk features: positive margins and/or extracapsular nodal spread.eMinor risk features: pT4 primary; N2 or N3 nodal disease, perineural invasion, vascular embolism.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SUPRA-3

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Supraglottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICAL STAGINGTREATMENT OF PRIMARY AND NECKADJUVANTTREATMENTFOLLOW-UP T4a, N0 Cartilage destruction Skin involvement High-volume invasionof base of tongueLaryngectomy, ipsilateralthyroidectomy withipsilateral or bilateralselective neck dissectionorClinical trialRT borChemo/RTb,c(category 1) Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 years,every 6-12 mo Chest imaging as clinicallyindicated TSH every 6-12 mo, if neckirradiated Speech and swallowing evaluationand rehabilitation as indicatedb See Principles of Radiation Therapy (SUPRA-A).c See Principles of Systemic Therapy (CHEM-A) .Recurrence (see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SUPRA-4

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Supraglottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesWORKUPCLINICAL STAGING Not requiring totallaryngectomy T1–2, N+ andselected T3–4aSee Treatment of Primaryand Neck (SUPRA-6)Node positivedisease H&P Biopsy Chest x-rayor Chest CTa CT with contrast and thincuts through larynx MRI of primary and neckrecommended Examination under anesthesiawith laryngoscopy Preanesthesia studies Dental evaluation as indicated Speech & swallowingevaluation as indicatedMultidisciplinaryconsultation as indicated Requiring totallaryngectomy Most T3–4a, N+ No cartilage destruction Low-volume base-oftongueinvolvement T4a, N+ Cartilage destruction Skin involvement High-volume invasionof base of tongueSee Treatment of Primaryand Neck (SUPRA-7)See Treatment of Primaryand Neck (SUPRA-8)Unresectable (T4b)See Treatment of Head andNeck Cancer (ADV-1)a Chest CT should be considered for patients at high risk for thoracic metastases.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SUPRA-5

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Supraglottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICALSTAGINGTREATMENT OF PRIMARY AND NECKADJUVANTTREATMENTFOLLOW-UPResidualtumorNeck dissection(category 3) Not requiringtotallaryngectomy T1–2, N+ andselectedT3–4aDefinitive RT borConcurrentsystemic therapy/RTcisplatin(category 1)preferred corPartial supraglotticlaryngectomy andcomprehensiveneck dissection(s)Primary site:CompleteresponsePrimary site:residualtumorNo adversefeatures d,eAdversefeaturesCompleteresponseof neckSalvage surgery+ neck dissectionas indicatedN1(initialstage)N2-3(initialstage)One or both major riskfeatures or 2 minorrisk featuresd,e 2 minor riskfeatures eObserveObserveor neckdissection(category 3)ObserveChemo/RT b,c(category 1)RT b Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 years,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiated Speech andswallowingevaluation andrehabilitation asindicatedRecurrence (see ADV-2)b See Principles of Radiation Therapy (SUPRA-A).cSee Principles of Systemic Therapy (CHEM-A).dMajor risk features: positive margins and/or extracapsular nodal spread.eMinor risk features: pT4 primary; N2 or N3 nodal disease, perineural invasion, vascular embolism.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SUPRA-6

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Supraglottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICAL STAGINGTREATMENT OF PRIMARY AND NECKADJUVANTTREATMENTFOLLOW-UP Requiring totallaryngectomy Most T3–4a, N+ No cartilagedestructionConcurrent systemictherapy/RTb,ccisplatin (category 1)preferredorLaryngectomy,ipsilateralthyroidectomy withcomprehensiveneck dissectionorPrimary site:CompleteresponsePrimary site:residualtumorNo adversefeatures d,eAdversefeaturesResidualtumorCompleteresponseof neckSalvage surgery +neck dissection asindicatedN1(initialstage)N2-3(initialstage)One or both majorrisk features or 2 minor riskfeaturesd,e 2 minor riskfeatures eNeck dissection(category 3)ObserveObserveorNeck dissection(category 3)RTChemo/RT b,c(category 1)RT b Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 years,every 6-12 mo Chest imaging asclinically indicated TSH every 6-12 mo,if neck irradiated Speech andswallowingevaluation andrehabilitation asindicatedInduction chemotherapyfollowed by chemo/RT(category 3) in selectedN2, N3 patientsRecurrence (see ADV-2)b See Principles of Radiation Therapy (SUPRA-A).cSee Principles of Systemic Therapy (CHEM-A).dMajor risk features: positive margins and/or extracapsular nodal spread.eMinor risk features: pT4 primary; N2 or N3 nodal disease, perineural invasion, vascular embolism.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SUPRA-7

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Supraglottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICAL STAGINGTREATMENT OFPRIMARY AND NECKADJUVANTTREATMENTFOLLOW-UPT4a, N+ Cartilage destruction Skin involvementLaryngectomy,ipsilateral thyroidectomywith ipsilateral or bilateralneck dissectionorClinical trialChemo/RTb,c(category 1) Physical exam: Year 1,every 1-3 mo Year 2,every 2-4 mo Years 3-5,every 4-6 mo > 5 years,every 6-12 mo Chest imaging as clinicallyindicated TSH every 6-12 mo, if neckirradiated Speech and swallowingevaluation and rehabilitation asindicatedb See Principles of Radiation Therapy (SUPRA-A).c See Principles of Systemic Therapy (CHEM-A) .Recurrence (see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SUPRA-8

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the Supraglottic LarynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF RADIATION THERAPYDefinitive RT Primary and gross adenopathy: 70 Gy (2.0 Gy/day) Neck Uninvolved nodal stations: 50 Gy (2.0 Gy/day)Postoperative RT Primary: 60 Gy (2.0 Gy/day) Neck Involved nodal stations: 60 Gy (2.0 Gy/day) Uninvolved nodal stations: 50 Gy (2.0 Gy/day)Any one minor risk feature: pT4 primary; N2 or N3 nodal disease,perineural invasion, vascular embolism.Postoperative chemoradiation for high pathologic risk features1,2,3 One or both major risk features or two or more minor risk features. Concurrent single agent cisplatin at 100 mg/m2every 3 wks is recommended.1Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced headand neck cancer. N Engl J Med 2004;350:1945-1952.2Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cellcarcinoma of the head and neck. N Engl J Med 2004;350:1937-1944.Back to Clinical Staging3 Bernier J, Cooper JS, Pajuk TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of Node negative (SUPRA-1)concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27:843-850. Node positive (SUPRA-5)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.SUPRA-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the NasopharynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesWORKUPCLINICAL STAGING H&P Nasopharyngeal exam and biopsy Chest x-rayor Chest CTa MRI with gadolinium ofnasopharynx and base of skull toclavicles and/or CT with contrast Dental evaluation as indicated Speech & swallowing evaluationas indicated Imaging for distant metastases(chest, liver, bone) for WHO class2-3/N2-3 disease (may includePET scan and/or CT)Multidisciplinary consultationT1, N0, M0 andT2a, N0, M0T1-T2a, N1-3;T2b-T4a, Any NAny T, Any N, M1See Treatment of Primaryand Neck (NASO-2)See Treatment of Primaryand Neck (NASO-2)See Treatment of Primaryand Neck (NASO-2)a Chest CT should be considered for patients at high risk for thoracic metastases.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.NASO-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the NasopharynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCLINICAL STAGINGTREATMENT OF PRIMARY AND NECKFOLLOW-UPT1, N0, M0 andT2a, N0, M0Definitive RTbtonasopharynx andelective RT to neckT1-T2a, N1-3;T2b-T4a, any NCisplatin, 100 mg/m2on days 1, 22, 43, +RT ( 70 Gy) toprimary and grossnodal disease(category 1) andbilateral neck: 50 GyCisplatin, 80 mg/m2day 1+ 5-FU, 1,000mg/m 2,CI x 4 days; repeatevery 4 wk x 3coursesNeck:residualtumorNeck:completeresponseNeckdissectionObserve Physical exam: Year 1, every 1–3 mo Year 2, every 2–4 mo Year 3–5, every 4–6mo > 5 years, 6–12 mo TSH every 6-12 mo, ifneck irradiated Speech and swallowingevaluation andrehabilitation asindicatedAny T, any N, M1Platinum-basedcombinationchemotherapyIf completeresponseDefinitive RTbto primaryand neckb See Principles of Radiation Therapy (NASO-A).Recurrence (see ADV-2)Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.NASO-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersCancer of the NasopharynxGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF RADIATION THERAPYDefinitive RT Primary and gross adenopathy: 70 Gy (2.0 Gy/day) Neck Uninvolved nodal stations: 50 Gy (2.0 Gy/day)Radiation TechniquesRadiation technique may play a critical role in reducing toxicityand enhancing tumor control in nasopharyngeal cancers. 3Dconformal techniques and IMRT techniques should be stronglyconsidered, though consensus on optimal technique has not yetemerged. IMRT techniques are an area of active developmentamong the NCCN institutions and others. Target delineation andoptimal dose distribution require special training in head and neckimaging, a thorough understanding of patterns of disease spread,and special training in IMRT techniques. Standards for targetdefinition, dose specification, fractionation (with and withoutconcurrent chemotherapy), and normal tissue constraints shouldemerge within the next few years.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.NASO-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersUnresectable Head and Neck CancerGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesDIAGNOSISTREATMENT OF HEAD AND NECK CANCERNewly diagnosedUnresectable(M0);T4b, N any, orunresectable N+Clinical trial preferredStandardtherapyPS 0-1PS 2Concurrent cisplatin or carboplatinbasedchemotherapy a + RTb(category 1)orInduction chemotherapycfollowedby chemoradiation (category 3)Induction chemotherapycfollowedby RT (category 3)orDefinitive RT b ± concurrentsystemic therapyResidual neck disease:Neck dissection, iffeasible + primary sitecontrolledPS 3Definitive RTborBest supportive careaThe single-agent cisplatin or carboplatin-based chemoradiotherapy regimens have not been compared in randomized trials. Therefore, no optimal standard regimenis defined. Combination chemotherapy regimens are more toxic and have not been directly compared to single-agent regimens.bSee Principles of Radiation Therapy (ADV-A).cCisplatin 100 mg/m2day 1 + 5-FU 1000mg/m 2/24 hrs continuous IV infusion for 120 hours for 3 cycles.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ADV-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersRecurrent Head and Neck CancerGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesDIAGNOSISTREATMENT OF HEAD AND NECK CANCERLocoregionalrecurrencewithoutprior RTResectableUnresectableSurgery RTbSee Treatment of Head andNeck Cancer (ADV-1)RecurrenceLocoregionalrecurrence orsecond primarywith prior RTResectableUnresectableSurgery ± reirradiation, clinical trial preferredReirradiation, clinical trial preferredorChemotherapy (see distant metastases pathway)DistantmetastasesClinical trial preferredStandardtherapy dPS 0–1PS 2Combination chemotherapyorSingle-agent chemotherapySingle- agent chemotherapyorBest supportive careChemotherapy onclinical trialorBest supportive careBest supportive carePS 3Best supportive carebSee Principles of Radiation Therapy (ADV-A).dSee Principles of Systemic Therapy (CHEM-A).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ADV-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersAdvanced Head and Neck CancerGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF RADIATION THERAPYConcurrent chemoradiation (preferred)Conventional fractionation: 1 Primary and gross adenopathy 70 Gy (2.0 Gy/day) NeckUninvolved nodal stations:44-50 Gy (2.0 Gy/day)Definitive RT without chemotherapy (for medically unfitor those who refuse chemotherapy)Altered fractionation (hyperfractionation or concomitantboost) regimens preferred for RT alone. Hyperfractionation:81.6 Gy/7 wks (1.2 Gy/fraction BID) Concomitant boost accelerated RT:72 Gy/6 wks (1.8 Gy/fraction, large field; 1.5 Gy boost assecond daily fraction during last 12 treatment days) Conventional fractionation: Primary and gross adenopathy: 70 Gy (2.0 Gy/day) NeckUninvolved nodal stations: 50 Gy (2.0 Gy/day)Radiation Techniques3D conformal techniques may be used depending on thestage, tumor location, physician training/experience andavailable physics support. IMRT techniques are an areaof active development among the NCCN institutions andothers. Target delineation and optimal dose distributionrequire special training in head and neck imaging, athorough understanding of patterns of disease spread,and special training in IMRT techniques. Standards fortarget definition, dose specification, fractionation (withand without concurrent chemotherapy), and normaltissue constraints should emerge within the next fewyears.Definitive RT + cetuximab (for patients not able to toleratecytotoxic therapy)1The majority of the published experience with concurrent chemoradiation has utilized conventional fractionation at 2.0 g per fraction to 70 Gy in 7 wks with singleagent cisplatin given every 3 wks at 100 mg/m 2. Use of other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy or altered fractionation withchemotherapy has been evaluated with no consensus on the optimal approach. In general, the use of concurrent chemoradiation carries a high toxicity burden--altered fractionation or multiagent chemotherapy will likely further increase toxicity burden. For any chemoradiation approach, close attention should be paid topublished reports for the specific chemotherapy agent, dose and schedule of administration. Chemoradiation should be performed by an experienced team andinclude substantial supportive care.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ADV-A

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF SYSTEMIC THERAPY (Page 1 of 2)The choice of chemotherapy should be individualized based on patient characteristics (performance status, goals of therapy).Squamous Cell CancersMaxillary Sinus, Ethmoid Sinus, Lip, Oral Cavity, Oropharynx,Hypopharynx, Glottic larynx, Supraglottic larynx, Occult PrimaryPrimary Systemic Therapy + concurrent RT Cisplatin alone 1,2 (preferred) 5-FU/hydroxyurea3 Cisplatin/paclitaxel3 Cisplatin/infusional 5-FU3,4 Carboplatin/infusional 5-FU5 Cetuximab6Postoperative Chemoradiation Cisplatin alone7-9Induction chemotherapy (followed by chemoradiation) Docetaxel/cisplatin/5-FU10,11NasopharynxChemoradiation followed by adjuvant chemotherapy Cisplatin + RT followed by Cisplatin/5-FU12Unresectable Recurrent Head and Neck CancersCombination therapy Cisplatin orcarboplatin + 5-FU4,13 Cisplatin orSingle agent Cisplatin Carboplatin Paclitaxel Ifosfamide Bleomycin Gemcitabinecarboplatin + taxane4 Docetaxel (nasopharyngeal) Cisplatin/cetuximab14 5-FU Cetuximab15 MethotrexateSee References on page CHEM-A 2 of 2Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.CHEM-A(1 of 2)

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesPRINCIPLES OF SYSTEMIC THERAPY (Page 2 of 2)REFERENCES1Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med2003;349:2091-8.2Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapyin patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21(1):92-98.3Garden AS, Harris J, Vokes EE, et al. Preliminary results of Radiation Therapy Oncology Group 97-03: A randomized phase II trial of concurrent radiationand chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol 2004;22:2856-2864.4Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neckcancer (E1395): An Intergroup Trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005;23(15):3562-3567.5Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparingradiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22(1):69-76.6Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous cell carcinoma of the head and neck. N Engl J Med 2006;354:567-78.7Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the headand neck. N Engl J Med 2004;350:1937-44.8Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer.N Engl J Med 2004;350:1945-52.9Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperativeradiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843-850.10 Schrijvers D, Van Herpen C, Kerger J, et al. Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer:a phase I-II feasibility study. Annals of Oncology 2004;15:638-645.11Vermorken JB, Remenar E, Van Herpen C, et al. Standard cisplatin/infusional 5-fluorouracil vs docetaxel plus PF as neoadjuvant chemotherapy fornonresectable locally advanced squamous cell carcinoma of the head and neck: A phase III trial of the EORTC Head and Neck Cancer Group. J ClinOncol 2004 Proc Amer Soc Clin Oncol;22(14S)[Abstr. 5508].12Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomizedIntergroup study 0099. J Clin Oncol 1998;16:1310-1317.13Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus flurouracil and carboplatin plus fluorouracil versus methotrexate inadvanced squamous cell carcinoma of the head and neck: A Southwest Oncology Group Study. J Clin Oncol 1992;10(8):1245-1251.14Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo versus cisplatin plus antiepidermal growth factor-receptorantibody cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Group Study. J Clin Oncol (In press).15Trigo J, Hitt R, Koralewski P, et al. Cetuximab monotherapy is active in patients with platinum-refractory recurrent/metastatic squamous cell carcinoma ofthe head and neck: results of a phase II study. J Clin Oncol 2004 Proc Amer Soc Clin Oncol ;22(14S)[Abstr. 5502].Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.CHEM-A(2 of 2)

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesStagingTable 12002 American Joint Committee on Cancer (AJCC)TNM Staging System for the Lip and Oral CavityPrimary Tumor (T)TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situT1T2T3T4(lip)T4aT4bTumor 2 cm or less in greatest dimensionTumormorethan2cmbutnotmorethan4cmingreatest dimensionTumor more than 4 cm in greatest dimensionTumor invades through cortical bone, inferior alveolarnerve, floor of mouth, or skin of face (ie, chin or nose)(oral cavity) Tumor invades adjacent structures (eg,through cortical bone, into deep [extrinsic] muscle oftongue [genioglossus, hyoglossus, palatoglossus, andstyloglossus], maxillary sinus, skin of face)Tumor invades masticator space, pterygoid plates, orskull base and/or encases internal carotid artery*Note: Superficial erosion alone of bone/tooth socket by gingival primaryis not sufficient to classify as T4.Regional Lymph Nodes (N)NX Regional nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm orless in greatest dimensionN2 Metastasis in a single ipsilateral lymph node, more than3 cm but not more than 6 cm in greatest dimension; or inmultiple ipsilateral lymph nodes, none more than 6 cm ingreatest dimension; or in bilateral or contralateral lymphnodes, none more than 6 cm in greatest dimensionN2a Metastasis in single ipsilateral lymph node more than 3cm but not more than 6 cm in greatest dimensionN2b Metastasis in multiple ipsilateral lymph nodes, noneN3N2cmore than 6 cm in greatest dimensionMetastasis in bilateral or contralateral lymph nodes,none more than 6 cm in greatest dimensionMetastasis in a lymph node more than 6 cm in greatestdimensionDistant Metastasis (M)MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasisStage GroupingStage 0Stage IStage IIStage IIITisT1T2T3T1N0N0N0N0N1M0M0M0M0M0T2 N1 M0T3 N1 M0Stage IVA T4aT4aN0N1M0M0T1 N2 M0T2 N2 M0T3 N2 M0T4a N2 M0Stage IVB Any TT4bN3Any NM0M0Stage IVC Any T Any N M1Histologic Grade (G)GX Grade cannot beassessedG1 Well differentiatedG2 ModeratelydifferentiatedG3 Poorly differentiatedUsed with the permission of the American Joint Committee on Cancer(AJCC), Chicago, Illinois. The original and primary source for thisinformation is the AJCC Cancer Staging Manual, Sixth Edition (2002)published by Springer-Verlag New York. (For more information, visitwww.cancerstaging.net.) Any citation or quotation of this material must becredited to the AJCC as its primary source. The inclusion of thisinformation herein does not authorize any reuse or further distributionwithout the expressed, written permission of Springer-Verlag New York,Inc.,onbehalfoftheAJCC.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ST-1

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesTable 22002 American Joint Committee on Cancer (AJCC)TNM Staging System for the Pharynx (Including Base of Tongue,Soft Palate, and Uvula)Primary Tumor (T)TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situNasopharynxT1T2T2aT3T4T2bOropharynxT1T2T3T4aT4bTumor confined to the nasopharynxTumor extends to soft tissuesTumor extends to the oropharynx and/or nasal cavitywithout parapharyngeal extension*Any tumor with parapharyngeal extension*Tumor invades bony structures and/or paranasal sinusesTumor with intracranial extension and/or involvement ofcranial nerves, infratemporal fossa, hypopharynx, orbit, ormasticator space*Note: Parapharyngeal extension denotes posterolateral infiltration oftumor beyond the pharyngobasilar fascia.Tumor 2 cm or less in greatest dimensionTumor more than 2 cm but not more than 4 cm in greatestdimensionTumor more than 4 cm in greatest dimensionTumor invades the larynx, deep/extrinsic muscle oftongue, medial pterygoid, hard palate, or mandibleTumor invades lateral pterygoid muscle, pterygoid plates,lateral nasopharynx, or skull base or encases carotidarteryHypopharynxT1 Tumor limited to one subsite of hypopharynx and 2 cm orless in greatest dimensionT2 Tumor invades more than one subsite of hypopharynx oran adjacent site, or measures more than 2 cm but notmore than 4 cm in greatest diameter without fixation ofhemilarynxT3T4aT4bRegional Lymph Nodes (N)NasopharynxThe distribution and the prognostic impact of regional lymph nodespread from nasopharynx cancer, particularly of the undifferentiatedtype, are different from those of other head and neck mucosalcancers and justify the use of a different N classification system.NXN0N1N2N3N3aN3bTumor more than 4 cm in greatest dimension or withfixation of hemilarynxTumor invades thyroid/cricoid cartilage, hyoid bone,thyroid gland, esophagus, or central compartment softtissue*Tumor invades prevertebral fascia, encases carotidartery, or involves mediastinal structures*Note: Central compartment soft tissue includes prelaryngeal strapmuscles and subcutaneous fat.Regional lymph nodes cannot be assessedNo regional lymph node metastasisUnilateral metastasis in lymph node(s), 6 cm or less ingreatest dimension, above the supraclavicular fossa*Bilateral metastasis in lymph node(s), 6 cm or less ingreatest dimension, above the supraclavicular fossa*Metastasis in a lymph node(s)* more than 6 cm and/or tosupraclavicular fossaMore than 6 cm in dimensionExtension to the supraclavicular fossa***Note: Midline nodes are considered ipsilateral nodes.**Supraclavicular zone or fossa is relevant to the staging ofnasopharyngeal carcinoma and is the triangular region originally describedby Ho. It is defined by three points: (1) the superior margin of the sternalend of the clavicle; (2) the superior margin of the lateral end of the clavicle,and (3) the point where the neck meets the shoulder. Note that this wouldinclude caudal portions of levels IV and V. All cases with lymph nodes(whole or part) in the fossa are considered N3b.Continued...Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ST-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesTable 2 - ContinuedOropharynx and HypopharynxNX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm or lessin greatest dimensionN2 Metastasis in a single ipsilateral lymph node, more than 3cm but not more than 6 cm in greatest dimension, or inmultiple ipsilateral lymph nodes, none more than 6 cm ingreatest dimension, or in bilateral or contralateral lymphnodes, none more than 6 cm in greatest dimensionN2a Metastasis in a single ipsilateral lymph node more than 3cm but not more than 6 cm in greatest dimensionN2b Metastasis in multiple ipsilateral lymph nodes, none morethan 6 cm in greatest dimensionN2c Metastasis in bilateral or contralateral lymph nodes, nonemore than 6 cm in greatest dimensionN3 Metastasis in a lymph node more than 6 cm in greatestdimensionDistant Metastasis (M)MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasisStage Grouping: NasopharynxStage 0Stage IStage IIAStage IIBTisT1T2aT1T2N0N0N0N1N1M0M0M0M0M0T2a N1 M0T2b N0 M0T2b N1 M0Stage III T1 N2 M0T2a N2 M0T2b N2 M0Stage IVAStage IVBStage IVCStage Grouping: Oropharynx, HypopharynxStage 0Stage IStage IIStage IIIStage IVAStage IVBStage IVCT3 N0 M0T3 N1 M0T3 N2 M0T4 N0 M0T4 N1 M0T4 N2 M0Any T N3 M0Any T Any N M1Tis N0 M0T1 N0 M0T2 N0 M0T3 N0 M0T1 N1 M0T2 N1 M0T3 N1 M0T4a N0 M0T4a N1 M0T1 N2 M0T2 N2 M0T3 N2 M0T4a N2 M0T4b Any N M0Any T N3 M0Any T Any N M1Histologic Grade (G) Oropharynx HypopharynxGX Grade cannot beassessedG1 Well differentiatedG2 ModeratelydifferentiatedG3 Poorly differentiatedUsed with the permission of the American Joint Committee on Cancer(AJCC), Chicago, Illinois. The original and primary source for thisinformation is the AJCC Cancer Staging Manual, Sixth Edition (2002)published by Springer-Verlag New York. (For more information, visitwww.cancerstaging.net.) Any citation or quotation of this material must becredited to the AJCC as its primary source. The inclusion of this informationherein does not authorize any reuse or further distribution without theexpressed, written permission of Springer-Verlag New York, Inc., on behalfof the AJCC.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ST-3

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesTable 32002 American Joint Committee on Cancer (AJCC)TNM Staging System for the LarynxPrimary Tumor (T)TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situSupraglottisT1 Tumor limited to one subsite of supraglottis with normalvocal cord mobilityT2 Tumor invades mucosa of more than one adjacent subsiteof supraglottis or glottis or region outside the supraglottis(eg, mucosa of base of tongue, vallecula, medial wall ofpyriform sinus) without fixation of the larynxT3 Tumor limited to larynx with vocal cord fixation and/orinvades any of the following: postcricoid area, preepiglottictissues, paraglottic space, and/or minor thyroidcartilage erosion (eg, inner cortex)T4a Tumor invades through the thyroid cartilage and/orinvades tissues beyond the larynx (eg, trachea, softtissues of neck including deep extrinsic muscle of thetongue, strap muscles, thyroid, or esophagus)T4b Tumor invades prevertebral space, encases carotidartery, or invades mediastinal structuresGlottisT1T1aT1bT2T3T4aTumor limited to the vocal cord(s) (may involve anterior orposterior commissure) with normal mobilityTumor limited to one vocal cordTumor involves both vocal cordsTumor extends to supraglottis and/or subglottis, and/orwith impaired vocal cord mobilityTumor limited to the larynx with vocal cord fixation and/orinvades paraglottic space, and/or minor thyroid cartilageerosion (eg, inner cortex)Tumor invades through the thyroid cartilage and/orinvades tissues beyond the larynx (eg, trachea, softtissues of neck including deep extrinsic muscle of theT4bSubglottisT1T2T3T4aT4btongue, strap muscles, thyroid, or esophagus)Tumor invades prevertebral space, encases carotidartery, or invades mediastinal structuresTumor limited to the subglottisTumor extends to vocal cord(s) with normal or impairedmobilityTumor limited to larynx with vocal cord fixationTumor invades cricoid or thyroid cartilage and/or invadestissues beyond the larynx (eg, trachea, soft tissues ofneck including deep extrinsic muscle of the tongue, strapmuscles, thyroid, or esophagus)Tumor invades prevertebral space, encases carotidartery, or invades mediastinal structuresRegional Lymph Nodes (N)NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm or lessin greatest dimensionN2 Metastasis in a single ipsilateral lymph node, more than 3cm but not more than 6 cm in greatest dimension; or inmultiple ipsilateral lymph nodes, none more than 6 cm ingreatest dimension, or in bilateral or contralateral lymphnodes, none more than 6 cm in greatest dimensionN2a Metastasis in single ipsilateral lymph node, more than 3cm but not more than 6 cm in greatest dimensionN2b Metastasis in multiple ipsilateral lymph nodes, none morethan 6 cm in greatest dimensionN2c Metastasis in bilateral or contralateral lymph nodes, nonemore than 6 cm in greatest dimensionN3 Metastasis in a lymph node, more than 6 cm in greatestdimensionDistant Metastasis (M)MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasisContinued...Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ST-4

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesTable 3 - ContinuedStage GroupingStage 0Stage IStage IIStage IIIStage IVAStage IVBStage IVCTis N0 M0T1 N0 M0T2 N0 M0T3 N0 M0T1 N1 M0T2 N1 M0T3 N1 M0T4a N0 M0T4a N1 M0T1 N2 M0T2 N2 M0T3 N2 M0T4a N2 M0T4b Any N M0Any T N3 M0Any T Any N M1Histologic Grade (G)GX Grade cannot beassessedG1 Well differentiatedG2 ModeratelydifferentiatedG3 Poorly differentiatedUsed with the permission of the American Joint Committee on Cancer(AJCC), Chicago, Illinois. The original and primary source for thisinformation is the AJCC Cancer Staging Manual, Sixth Edition (2002)published by Springer-Verlag New York. (For more information, visitwww.cancerstaging.net.) Any citation or quotation of this material must becredited to the AJCC as its primary source. The inclusion of this informationherein does not authorize any reuse or further distribution without theexpressed, written permission of Springer-Verlag New York, Inc., on behalfof the AJCC.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ST-5

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesTable 42002 American Joint Committee on Cancer (AJCC)TNM Staging System for the Major Salivary Glands (Parotid,Submandibular, and Sublingual)N3N2cMetastasis in bilateral or contralateral lymph nodes, nonemore than 6 cm in greatest dimensionMetastasis in a lymph node, more than 6 cm in greatestdimensionPrimary Tumor (T)TX Primary tumor cannot be assessedT0 No evidence of primary tumorT1 Tumor 2 cm or less in greatest dimension withoutextraparenchymal extension*T2 Tumor more than 2 cm but not more than 4 cm in greatestdimension without extraparenchymal extension*T3 Tumor more than 4 cm and/or tumor havingextraparenchymal extension*T4a Tumor invades skin, mandible, ear canal, and/or facialnerveT4b Tumor invades skull base and/or pterygoid plates and/orencases carotid artery*Note: Extraparenchymal extension is clinical or macroscopic evidence ofinvasion of soft tissues. Microscopic evidence alone does not constituteextraparenchymal extension for classification purposes.Regional Lymph Nodes (N)NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm or lessin greatest dimensionN2 Metastasis in a single ipsilateral lymph node, more than 3cm but not more than 6 cm in greatest dimension, or inmultiple ipsilateral lymph nodes, none more than 6 cm ingreatest dimension, or in bilateral or contralateral lymphnodes, none more than 6 cm in greatest dimensionN2a Metastasis in a single ipsilateral lymph node, more than 3cm but not more than 6 cm in greatest dimensionN2b Metastasis in multiple ipsilateral lymph nodes, none morethan 6 cm in greatest dimensionDistant Metastasis (M)Mx Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasisStage GroupingStage IStage IIStage IIIStage IVAStage IVBStage IVCT1 N0 M0T2 N0 M0T3 N0 M0T1 N1 M0T2 N1 M0T3 N1 M0T4a N0 M0T4a N1 M0T1 N2 M0T2 N2 M0T3 N2 M0T4a N2 M0T4b Any N M0Any T N3 M0Any T Any N M1Used with the permission of the American Joint Committee on Cancer(AJCC), Chicago, Illinois. The original and primary source for thisinformation is the AJCC Cancer Staging Manual, Sixth Edition (2002)published by Springer-Verlag New York. (For more information, visitwww.cancerstaging.net.) Any citation or quotation of this material must becredited to the AJCC as its primary source. The inclusion of this informationherein does not authorize any reuse or further distribution without theexpressed, written permission of Springer-Verlag New York, Inc., on behalfof the AJCC.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ST-6

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesTable 52002 American Joint Committee on Cancer (AJCC)TNM Staging System for the Nasal Cavity and Paranasal SinusesPrimary Tumor (T)TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situMaxillary SinusT1 Tumor limited to maxillary sinus mucosa with no erosionor destruction of boneT2 Tumor causing bone erosion or destruction includingextension into the hard palate and/or middle nasalmeatus, except extension to posterior wall of maxillarysinus and pterygoid platesT3 Tumor invades any of the following: bone of the posteriorwall of maxillary sinus, subcutaneous tissues, floor ormedial wall of orbit, pterygoid fossa, ethmoid sinusesT4a Tumor invades anterior orbital contents, skin of cheek,pterygoid plates, infratemporal fossa, cribriform plate,sphenoid or frontal sinusesT4b Tumor invades any of the following: orbital apex, dura,brain, middle cranial fossa, cranial nerves other thanmaxillary division of trigeminal nerve (V 2), nasopharynx,or clivusNasal Cavity and Ethmoid SinusT1 Tumor restricted to any one subsite, with or without bonyinvasionT2 Tumor invading two subsites in a single region orextending to involve an adjacent region within thenasoethmoidal complex, with or without bony invasionT3 Tumor extends to invade the medial wall or floor of theorbit, maxillary sinus, palate, or cribriform plateT4a Tumor invades any of the following: anterior orbitalcontents, skin of nose or cheek, minimal extension toanterior cranial fossa, pterygoid plates, sphenoid orfrontal sinusesT4bTumor invades any of the following: orbital apex, dura,brain, middle cranial fossa, cranial nerves other than(V 2), nasopharynx, or clivusRegional Lymph Nodes (N)NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm or lessin greatest dimensionN2 Metastasis in a single ipsilateral lymph node, more than 3cm but not more than 6 cm in greatest dimension, or inmultiple ipsilateral lymph nodes, none more than 6 cm ingreatest dimension, or in bilateral or contralateral lymphnodes, none more than 6 cm in greatest dimensionN2a Metastasis in a single ipsilateral lymph node, more than 3cm but not more than 6 cm in greatest dimensionN2b Metastasis in multiple ipsilateral lymph nodes, none morethan 6 cm in greatest dimensionN2c Metastasis in bilateral or contralateral lymph nodes, nonemore than 6 cm in greatest dimensionN3 Metastasis in a lymph node, more than 6 cm in greatestdimensionDistant Metastasis (M)MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasisContinued...Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ST-7

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesTable 5 - ContinuedStage GroupingStage 0Stage IStage IIStage IIIStage IVAStage IVBStage IVCTis N0 M0T1 N0 M0T2 N0 M0T3 N0 M0T1 N1 M0T2 N1 M0T3 N1 M0T4a N0 M0T4a N1 M0T1 N2 M0T2 N2 M0T3 N2 M0T4a N2 M0T4b Any N M0Any T N3 M0Any T Any N M1Histologic Grade (G)GX Grade cannot beassessedG1 Well differentiatedG2 ModeratelydifferentiatedG3 Poorly differentiatedUsed with the permission of the American Joint Committee on Cancer(AJCC), Chicago, Illinois. The original and primary source for thisinformation is the AJCC Cancer Staging Manual, Sixth Edition (2002)published by Springer-Verlag New York. (For more information, visitwww.cancerstaging.net.) Any citation or quotation of this material must becredited to the AJCC as its primary source. The inclusion of this informationherein does not authorize any reuse or further distribution without theexpressed, written permission of Springer-Verlag New York, Inc., on behalfof the AJCC.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.ST-8

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesManuscriptNCCN Categories of ConsensusOverviewThis manuscript is being updated to correspondwith the newly updated algorithm.Category 1: There is uniform NCCN consensus, based on high-levelevidence, that the recommendation is appropriate.Category 2A: There is uniform NCCN consensus, based on lowerlevelevidence including clinical experience, that therecommendation is appropriate.Category 2B: There is nonuniform NCCN consensus (but no majordisagreement), based on lower-level evidence including clinicalexperience, that the recommendation is appropriate.Category 3: There is major NCCN disagreement that therecommendation is appropriate.All recommendations are category 2A unless otherwise noted.The NCCN Head and Neck (H&N) Cancers guidelines addresstumors arising in the lip, oral cavity, oropharynx, hypopharynx,glottic and supraglottic larynx, paranasal (ethmoid and maxillary)sinuses, nasopharynx, and salivary glands, as well as occult primarycancer (see Figure 1). As background to the discussion of theseguidelines, a brief overview of the epidemiology and management ofH&N cancer is provided.Incidence and EtiologyApproximately 39,250 new cases of oral cavity, pharyngeal, andlaryngeal cancers are estimated to occur in 2005. This accounts forabout 3% of new cancer cases in the United States. An estimated111,090 deaths from H&N cancers will occur in 2005. Alcohol andtobacco abuse are common etiologic factors in cancers of the oralStagingManuscriptupdate inprogresscavity, oropharynx, hypopharynx, and larynx. Moreover, because theentire aerodigestive tract epithelium may be exposed to thesecarcinogens, patients with H&N cancer are at risk for developingsecond primary neoplasms of the H&N, lung, and esophagus.Stage at diagnosis is the most predictive factor of survival. The TNMstaging systems developed by the American Joint Committee onCancer (AJCC) for the lip and oral cavity, pharynx (nasopharynx,oropharynx, and hypopharynx), larynx, major salivary glands, andnasal cavity and paranasal sinuses are shown in Tables 1, 2, 3, 4,2and 5, respectively. The 2002 AJCC staging classification was usedas a basis for the NCCN's treatment recommendations for thepharynx (see Table 2). Definitions for regional lymph node (N)involvement and spread to distant metastatic sites (M) are uniformexcept for N staging of nasopharyngeal carcinoma. Definitions forstaging the primary tumor (T), based on its size, are uniform for thelip and oral cavity as well as the oropharynx. In contrast, T stage isbased on subsite involvement and is specific to each subsite for theglottic larynx, supraglottic larynx, hypopharynx, and nasopharynx.In general, stage I or stage II disease defines a relatively smallprimary tumor with no nodal involvement. Stage III and stage IVcancers include large primary tumors, which may invade underlyingstructures and/or spread to regional nodes. Distant metastases areuncommon at presentation. In general, the survival rate of patientswith locally advanced (stage III or stage IV) disease is less than50% of the survival rate of patients with early-stage disease.Management ApproachesTreating the patient with H&N cancer is complex. Each specific siteof disease, the extent of disease, and the pathologic findings dictatethe appropriate surgical procedure, radiation fields, dose andMS-1Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesfractionation, and indications for chemotherapy. Single modalitytreatment with surgery or radiotherapy is generally recommendedfor the approximately 40% of patients who present with early-stagedisease (stage I or stage II). The two modalities result in similarsurvival in these individuals. In contrast, for the 60% of patients withlocally advanced disease at diagnosis, combined modality therapy isgenerally recommended.As in other NCCN practice guidelines, participation in clinical trials isemphasized as a preferred or recommended treatment option,particularly for the population with locally advanced disease. Informulating these H&N guidelines, the panel has endeavored tomake them evidence based while providing a statement ofconsensus as to the acceptable range of treatment options.Multidisciplinary Team InvolvementThe initial evaluation and development of a plan for treating thepatient with H&N cancer require a multidisciplinary team of individualswith expertise in all aspects of the special care needs of thesepatients. Similarly, managing and preventing sequelae of radicalsurgery, radiotherapy, and chemotherapy require the involvement ofvarious health care professionals familiar with the disease. Followupfor these sequelae should include a comprehensive H&N examination.Adequate nutritional support can help to prevent severe3weight loss in patients receiving treatment for H&N cancer. Patientsshould also be encouraged to stop smoking, because smokingdecreases the efficacy of treatment.Manuscriptupdate inprogressSpecific components ofpatient support and follow-up are listed in the algorithm. Pain andsymptom management as well as social work and case managementare included in this list because of their importance in addressingthe late complications of disease and its therapy. The panel alsorecommends referring to the NCCN Guidelines for Supportive Care.4,5Comorbidity and Quality of LifeComorbidity. Comorbidity refers to the presence of concomitantdisease (in addition to H&N cancer) that may affect the diagnosis,treatment, and prognosis for the patient.Documentation ofcomorbidity is particularly important in oncology, because the failureto identify comorbid conditions (such as renal, heart, or liver failure)may result in inaccurate attribution of poor outcomes to the cancer.Comorbidity is known to be a strong independent predictor formortality in H&N cancer patients.Comorbidity has also beenshown to influence costs of care, utilization, and quality of life.Numerous indices of comorbidity have been developed. Traditional7indices include the Charlson index as well as the Kaplan-Feinsteinindex and its modifications.The Adult Comorbidity Evaluation-27(ACE-27) is specific for H&N cancer and has excellent emergingreliability and validity.20,21Quality of Life. Health-related quality-of-life issues are paramountin H&N cancer. These tumors have a tremendous effect on basicphysiological functions (such as the ability to chew, swallow, andbreathe), the senses (taste, smell, and hearing), and uniquelyhuman characteristics (such as appearance and voice). In informaluse, the terms health status, function, and quality of life arefrequently used interchangeably; however, these terms haveimportant distinctions. Health status describes an individual'sphysical, emotional, as well as social capabilities and limitations.Function and performance refer to how well an individual is able toperform important roles, tasks, or activities. On the other hand,quality of life differs, because the central focus is on the value(determined by the patient alone) that individuals place on theirhealth status and function.8,19A recent NIH-sponsored conferencerecommended the use of patient-completed scales to measure8-156-816-1822 23Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-2

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesquality of life. For H&N cancer-specific issues, the three validated doubt their ability to remove all gross tumor on anatomic grounds ormeasures that have received the most widespread acceptance are: if they are certain local control will not be achieved after an24(1) the University of Washington Quality of Life scale (UW-QOL); operation (even with the addition of radiotherapy to the treatment(2) the European Organization for Research and Treatment of approach). Typically, such tumors densely involve the cervical25Cancer Quality of Life Questionnaire (EORTC-HN35); and (3) the vertebrae, brachial plexus, deep muscles of the neck, or carotidFunctional Assessment of Cancer Therapy Head and Neck module artery. Unresectable tumors (ie, those tumors unable to be removed26(FACT-HN). A clinician-rated performance scale that has also without imposing unacceptable morbidity) should be distinguished27achieved widespread use is the Performance Status Scale.from those tumors in patients whose constitutional state precludesNumerous other instruments exist to measure generic cancer issues an operation (even if the cancer is readily resected with fewand other aspects of H&N cancer but are beyond the scope of this sequelae). Additionally, a subgroup of patients will refuse surgicaldiscussion.management, but these tumors should not be deemed unresectable.Although local and regional disease may be surgically treatable,Head and Neck SurgeryManuscriptupdate inprogresspatients with distant metastases are usually treated as though theprimary tumor were unresectable. Thus, patient choice or a doctor'sResectable Versus Unresectable Diseaseexpectations regarding cure and morbidity will influence orThe various site-specific sections of these H&N guidelines pertain to determine treatment.patients with resectable disease. The treatment of patients withPatients with resectable tumors who can also be adequately treatedlocally advanced unresectable disease, metastatic disease, orwithout an operation represent a very important group. Definitiverecurrent disease is addressed in the “Advanced Head and Necktreatment with radiation therapy (RT) alone or RT combined withCancer” section of these guidelines.chemotherapy may represent an equivalent or preferableThe term “unresectable” has resisted formal definition by H&N approaches to resection in these individuals. Although such patientscancer specialists for decades. No definition of surgicalmay not undergo surgery, their tumors should not be labeled asunresectability meets with universal approval. The experience of the unresectable. Their disease is usually far less extensive thansurgeon and the support available from reconstructive surgeons, disease that truly cannot be removed.physiatrists, and prosthodontists often strongly influenceCervical Lymph Node Dissectionsrecommendations. This is particularly common in institutions wherefew patients with locally advanced H&N cancer are treated. The Historically, cervical lymph node dissections have been classified asNCCN member institutions have teams experienced in the treatment “radical” or “modified radical” procedures. The less radicalof H&N cancer and maintain the multidisciplinary infrastructure procedures preserved the sternocleidomastoid muscle, jugular vein,needed for reconstruction and rehabilitation. A patient's cancer is and spinal accessory nerve. The panel prefers to classify cervicaldeemed unresectable if H&N surgeons at NCCN member institutions lymphadenectomy differently, classifying cervical lymph nodeVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-3

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesdissections as either “comprehensive” or “selective.”been administered in a preoperative setting to a patient with N2 orN3 disease in the neck. If a complete response has been achievedA comprehensive neck dissection is one that removes all lymphafter radiotherapy for N1 disease, all of the panel members arenode groups that would be included in a classic radical necksatisfied with the strategy of observing the patient. Many panelistsdissection. Whether the sternocleidomastoid muscle, jugular vein, orbelieve that any patient with a residual mass after radiotherapyspinal accessory nerve are preserved does not affect whether theshould undergo a comprehensive neck dissection, whereas a few ofdissection is comprehensive.the panelists believe that only removal of the residual mass isSelective neck dissections have been developed based on an necessary (category 3). Similarly, at some institutions, patients withunderstanding of the common pathways for spread of H&N cancers a complete response to radiation of N2 and N3 disease are28,29to regional nodes (see Figure 2). A supraomohyoid neckobserved, whereas at other institutions similar patients undergo adissection is designed to remove the nodes most commonlycomprehensive neck dissection (category 3). Opinions supportinginvolved with metastases from the oral cavity. A supraomohyoid both approaches were strong.neck dissection includes nodes found above the omohyoid muscle(level I, level II, level III, and the superior parts of level V). Similarly,a lateral neck dissection removes the nodes most commonlyinvolved with metastases from the pharynx and larynx. A lateral neckdissection includes nodes in level II, level III, and level IV. H&Nsquamous cell cancer with no clinical nodal involvement rarelypresents with nodal metastasis beyond the confines of anappropriate selective neck dissection (< 10% of the time).Manuscriptupdate inprogressThechief role of neck dissections in these NCCN H&N guidelines is toselect patients for possible adjuvant radiotherapy, although therehas been some enthusiasm for the use of selective neck dissectionsas treatment when neck tumor burden is low. In general, patientsundergoing selective neck dissection should not have clinical nodaldisease. In the guidelines, patients with cervical node metastaseswho undergo operations are generally treated with comprehensiveneck dissections, because often they have disease outside thebounds of selective neck dissections.The panelists do not agree entirely on the extent of neck dissectionneeded after definitive radiotherapy (without chemotherapy) has30-32Many factors influence survival and locoregional tumor control inpatients with H&N cancer. In most NCCN member institutions,patients with extracapsular nodal spread and/or positive surgicalmargins receive adjuvant chemoradiotherapy after resection.Many clinicians also believe that multiple positive nodes (withoutextracapsular nodal spread) or vascular/lymphatic/perineuralinvasion are minor adverse features. Patients with massive cancers(even if resected with a seemingly satisfying margin) or withlaryngeal tumors that require preoperative tracheotomy are usuallytreated with postoperative radiotherapy.Postoperative Management of High-Risk DiseaseThe role of chemotherapy in the postoperative management of thepatient with adverse prognostic risk factors has recently beenclarified by two separate multicenter randomized trialscombined analysis of data from the two trials.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.and aThe US Intergrouptrial R95-01 randomly assigned patients with two or more involvednodes, positive margins, or extracapsular spread of tumor to receivestandard postoperative radiotherapy or the same radiotherapy plus7068,6933-38MS-4

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, References2cisplatin 100 mg/m every 3 weeks for three doses. The European of radiation as primary treatment or as an adjuvant to surgery intrial was designed using the same treatment but also included as combination with chemotherapy for H&N cancer. The NCCNhigh-risk factors the presence of perineural or perivascular disease radiotherapeutic guidelines are not all inclusive. Much variation inand nodal involvement at levels 4 and 5 from an oral cavity orpractice exists among various countries and even within differentoropharynx cancer. The US trial demonstrated statisticallyinstitutions in the same country.significant improvement in locoregional control and disease-freesurvival but not overall survival, whereas the European trial foundsignificant improvement in survival as well as the other outcomeparameters. To better define risk, a combined analysis of prognosticfactors and outcome from the two trials was performed. Thisanalysis demonstrated that patients in both trials with either positiveresection margins or extracapsular spread of tumor benefited fromthe addition of cisplatin to postoperative radiotherapy, whereasthose with multiple involved regional nodes without extracapsularspread did not. These publications form the basis for the NCCNrecommendations in this updated guideline. Chemoradiation isdefinitely indicated for risk factors of a microscopic positive marginor extracapsular spread (category 1) and these define major riskfactors. The management of patients with multiple nodes only,without extracapsular spread or other adverse risk features wasdiscussed by the panel and a category 2B recommendation given forconsideration of chemoradiation. The panel noted that the combinedanalysis was considered exploratory by the authors because it wasnot part of the initial protocol design.Head and Neck RadiotherapyRadiotherapy for H&N cancer is extremely complex. Only a speciallytrained team consisting of a radiation oncologist, physicist,dosimetrist, and radiation technologist can achieve optimal results.In addition, modern radiotherapy equipment and techniques shouldbe used. Anatomic, tumor, and clinical circumstances dictate the useManuscriptupdate inprogressRadiation DosesSelection of radiation doses depends on the tumor and neck nodesize, location of the tumor, and clinical circumstances. In general,primary and gross adenopathy require a total of 70 Gy or more at adosage of 2.0 Gy/day. In contrast, radiation to low-risk nodalstations in the neck requires a total of 50 Gy or more, also at adosage of 2.0 Gy/day. Postoperative irradiation is recommendedbased on the tumor stage, tumor histology, and surgical findingsafter tumor resection. In general, postoperative RT is recommendedfor minor risk features, including multiple positive nodes (withoutextracapsular nodal spread) or perineural/lymphatic/vascularinvasion. Higher doses of radiation (60-65 Gy) are required formicroscopic disease to decrease the chances of locoregional failurebecause of interruption of the normal vasculature, scarring, andrelative hypoxia in the tumor bed.FractionationNo single fractionation schedule has proven to be best for alltumors. Historically, most radiation oncology departments in theUnited States deliver treatment once per day, 5 days per week, at1.8 to 2.0 Gy/fraction. In recent years, data strongly indicate somesquamous cancers can grow rapidly, especially in the face of celldepletion. The upper dose of 2.0 Gy/fraction, delivering 1000 cGy orgreater per week, is now the most commonly used dose among theNCCN member institutions. Thus, the guidelines have been revisedto indicate that the dose of 2.0 Gy/fraction is preferred, with theVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-5

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesexception of salivary gland tumors, which may have slower cell protocol 22791 compared hyperfractionation (1.15 Gy twice daily, or39-43kinetics. External radiation doses exceeding 75 Gy at80.5 Gy over 7 weeks) with conventional fractionation (2 Gy onceconventional fractionation of 1.8 to 2.0 Gy/day may lead todaily, or 70 Gy over 7 weeks) in the treatment of T2,T3,N0-1unacceptable normal tissue injury.oropharyngeal carcinoma. At 5 years, there was a statisticallysignificant increase in local control in the hyperfractionation armMost of the published studies with concurrent chemoradiation have47(38% versus 56%; P = .01) and no increase in late complications. Aused conventional fractionation at 2.0 Gy per fraction to 70 Gy orlong-term follow-up analysis has also demonstrated a small survivalmore in 7 weeks with single-agent cisplatin given every 3 weeks at48advantage for hyperfractionation ( P = .05). Another EORTC2100 mg/m . Use of other fraction sizes (eg, 1.8 Gy, conventional),protocol (22851) compared accelerated fractionation (1.6 Gy threemultiagent chemotherapy, or altered fractionation with chemotherapytimes daily, or 72 Gy over 5 weeks) with conventional fractionationhas been evaluated, but there is no consensus on the optimal(1.8-2.0 Gy once daily, or 70 Gy over 7-8 weeks) in variousapproach. In general, the use of concurrent chemoradiation carries aintermediate to advanced H&N cancers (excluding cancers of thehigh toxicity burden, and altered fractionation or multiagent chemotherapywill likely further increase the toxicity burden. For anyhypopharynx). Patients in the accelerated fractionation arm didsignificantly better with regard to locoregional control ( P = .02) at 5chemotherapeutic approach, close attention should be paid toyears. Disease-specific survival showed a trend ( P = .06) in favor ofpublished reports for the specific chemotherapy agent, dose, andthe accelerated fractionation arm. Acute and late toxicity wereschedule of administration. Chemoradiation should be performed byincreased in this fractionation arm, however, raising questions aboutan experienced team and should include substantial supportive care.49the net advantages of accelerated fractionation.Altered fractionation includes accelerated treatment delivering morethan 1000 cGy per week and hyperfractionation. The biologicalrationale for using hyperfractionation is based on the discovery byWithers and colleagues of a large, consistent difference in repaircapacity of late and early responding tissues.Manuscriptupdate inprogressAcceleratedschedules attempt to compensate for rapid tumor proliferation bycompressing the time-dose schedule. During the last decade, anumber of phase II trials have suggested an advantage to the use ofaltered fractionation schemes in various H&N cancers.Two large, randomized clinical trials have reported improvedlocoregional control using altered fractionation. The EuropeanOrganization for Research and Treatment of Cancer (EORTC)44,4546In the United States, the Radiation Therapy Oncology Group(RTOG) has reported preliminary results of a large phase III clinicaltrial (protocol 90-03) comparing hyperfractionation with two variantsof accelerated fractionation.After 2 years of follow-up, bothaccelerated fractionation with a concomitant boost andhyperfractionation were associated with improved locoregionalcontrol and disease-free survival compared with standardfractionation. However, acute toxicity was increased. No significantdifference was demonstrated in the frequency of grade 3 or worselate effects reported at 6 to 24 months after treatment start, amongthe various treatment groups. Consensus regarding alteredfractionation schedules with concomitant boost or hyperfractionationfor stage III or IV oral cavity, oropharynx, supraglottic larynx, andVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.50MS-6

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referenceshypopharyngeal squamous cell cancers has not yet emerged amongNCCN member institutions. Review of evidence supporting thistreatment is planned for the next full panel meeting.BrachytherapyBrachytherapy is used less often because of improved local controlobtained with concurrent chemo/RT. However, brachytherapy stillhas a role primarily for lip cancer, cancer of the oral cavity, andoropharynx. Several European and North American medical centershave had extensive experience with brachytherapy.The successof brachytherapy techniques is partly dependent on the training,experience, and skills of the implant team.Intensity-Modulated Radiation TherapyThe intensity of the radiation beam can be modulated in order todecrease doses to normal structures without compromising thedoses to the target. Intensity-modulated radiation therapy (IMRT) isan advanced form of 3-D conformal RT with enormous potential toprecisely target and to enable escalation of the radiation dose; thenet effect is decreased radiation exposure to normal structures.During the past several years, an exponential growth has occurredin the use of IMRT for various malignancies, in particular, prostateand H&N cancers.Several institutions have conducted phase II studies to explore theuse of beam modulation in H&N cancer. The objective data fromthese institutions consistently show a decrease in acute and latetoxicities without compromising tumor control.Manuscriptupdate inParanasal TumorsprogressHowever, nophase III studies have been done to substantiate the results fromphase II studies. The RTOG H-0022 and RTOG H-0225 are singlearmstudies exploring the feasibility of IMRT in the treatment oforopharyngeal and nasopharyngeal cancer. These trials are60-6751-59currently ongoing. At present, IMRT is not the standard of care forthe treatment of H&N cancers; however, selected patients maybenefit from this new technology if they are treated in centers thathave expertise in IMRT.3-D conformal techniques may be used depending on the stage,tumor location, physician training/experience, and available physicssupport. IMRT techniques are an area of active investigation amongthe NCCN institutions and others. Target delineation and optimaldose distribution require special training in H&N imaging, a thoroughunderstanding of patterns of disease spread, and special training inIMRT techniques. Standards for target definition, dose specification,fractionation (with and without concurrent chemotherapy), andnormal tissue constraints should emerge within the next few years.(Maxillary and Ethmoid Sinus Tumors)Tumors of the paranasal sinuses are rare and often asymptomaticuntil late in the course of their disease. Although the most commonhistology for these tumors is squamous cell carcinoma, multiplehistologies have been reported including sarcomas (excludingrhabdomyosarcoma), lymphomas, adenocarcinomas, salivary glandtumors, and esthesioneuroblastomas, and undifferentiatedcarcinomas. Locoregional control and incidence of distantmetastasis are dependent on both T stage and tumor histology.However, T stage remains the most reliable predictor of survival andlocal regional control (see Table 5).Management of Incompletely Excised Ethmoid CancerPatients with early-stage ethmoid cancer are asymptomatic. Theseneoplasms are often found after a routine nasal polypectomy orVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-7

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesduring the course of a nasal endoscopic procedure. For a patientwith gross residual disease who has had a nasal endoscopicsurgical procedure, the preferred treatment is complete surgicalexcision of the residual tumor. This procedure often entails ananterior craniofacial resection to remove the Cribriform plate and toensure clear surgical margins. Most patients affected by ethmoidsinus cancer present after having had an incomplete excision. Thepatient who is diagnosed after incomplete excision (eg,polypectomy, endoscopic surgical procedure)---and has nodocumented residual disease on physical examination, imaging, andendoscopy---should be treated in a similar fashion if feasible. If noadverse pathologic factors are found, this treatment ensures clearsurgical margins and obviates the need for postoperativeradiotherapy. However, RT may be used as definitive treatment inpatients if pre-biopsy imaging studies and nasal endoscopydemonstrate that the superior extent of the disease does not involvethe skull base.Treatment of Maxillary Sinus TumorsComplete surgical resection for all T stages followed bypostoperative therapy remains a cornerstone of treatment. Inaddition, RT or chemotherapy/RT (category 2B) should beconsidered for T1-2, N0 tumors with perineural invasion. Neckdissection is indicated in the treatment of the clinically positive neck.Finally, a combination of chemotherapy and RT or definitive RTalone (without chemotherapy) may be used to treat surgicallyunresectable disease. Patients with maxillary sinus tumors whohave adverse characteristics (eg, positive margins, perineuralinvasion, or extracapsular nodal spread) should receive surgicalresection (if possible) followed by chemotherapy/RT to the primaryand neck (category 2B). Participation in clinical trials is favored forpatients with malignant tumors of the paranasal sinuses.Salivary Gland TumorsManuscriptupdate inprogressSalivary gland tumors can arise in the major salivary glands(parotid, submaxillary, or sublingual salivary gland glands) or in oneof the minor salivary glands, which are widely spread throughout theaerodigestive tract. Many minor salivary gland tumors are located onthe hard palate. Even though many salivary gland tumors aregenerally benign, approximately 20% of the parotid gland tumors aremalignant; the incidence of malignancy in submandibular and minorsalivary gland tumors is approximately 50% and 80%, respectively.These malignant tumors constitute a broad spectrum of histologictypes, including mucoepidermoid, acinic, adenocarcinoma, adenoidcystic carcinoma, malignant myoepithelial tumors, and squamouscarcinoma. The primary diagnosis of squamous carcinoma of theparotid gland is rare, because most of them are generally metastatictumors from skin cancers of the temple area. Prognosis andtendency to metastasize vary among these histologic types. Majorprognostic factors are histologic grade, tumor size, and localinvasion (see Table 4).TreatmentThe major therapeutic approach for salivary gland tumors isadequate and appropriate surgical resection. Surgical interventionrequires careful planning and execution, particularly in parotid tumorsurgery because of the presence of the facial nerve within the gland,which should be preserved if it is not directly involved by the tumor.Most of the parotid gland tumors are located in the superficial lobe,and if the facial nerve is functioning preoperatively, the nerve can bepreserved in most patients. The facial nerve should be sacrificed ifthere is preoperative facial nerve involvement with facial palsy or ifthere is direct invasion of the tumor into the nerve where the tumorcannot be separated from the nerve. Malignant deep lobe parotidVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-8

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencestumors are quite rare; however, they are generally a challenge for determined by anticipated functional and cosmetic results. Thethe surgeon where the patient may require superficial parotidectomy incidence of lymph node metastases, especially in early-stage loweras well as identification and retraction of the facial nerve to remove lip cancer, is low, averaging less than 10%. The risk of lymph nodedeep lobe parotid tumor.metastases is related to the location, size, and grade of the primarytumor. Elective neck dissection or neck irradiation can be avoided inMost malignant deep lobe parotid tumors will require postoperativepatients with early-stage disease and a clinically negative neck.RT because of the limitations of surgical margins in the resection ofTreatment recommendations are based on clinical stage, medicalthese tumors. RT is used in an adjuvant setting for tumors withstatus of the patient, and patient preference.adverse characteristics; chemotherapy/RT (category 2B) can alsobe considered. Adjuvant radiotherapy is indicated after resection if Workup and Stagingadverse characteristics are present, such as positive or closemargins, neural or perineural infiltration (often seen with adenoidcystic carcinomas), or lymph node metastases. Adjuvant RT is alsorecommended if the tumor is intermediate or high grade,lymphovascular invasion, or extracapsular spread is present.For unresectable tumors, RT alone (without chemotherapy) is usedas definitive treatment; however, chemoradiation (cisplatin) is alsoan option (category 2B). The panel was not in agreement regardingchemoradiation, because there are no published trials of thisapproach for unresectable salivary gland tumors. Chemotherapymay be used for palliation in advanced disease. Various agents (eg,paclitaxel) and combinations (eg, cisplatin, doxorubicin,cyclophosphamide; carboplatin and paclitaxel) have been shown insmall series to be active for some salivary gland malignanthistologies.Carcinoma of the LipThe guidelines for squamous cell carcinoma of the lip generallyfollow accepted clinical practice patterns established over severaldecades. No randomized clinical trials have been conducted thatcan be used to direct therapy. In general, treatment strategies areManuscriptupdate inprogressThe workup for patients with squamous cell carcinoma of the lipconsists of a physical examination, biopsy, and chest x-ray, A dentalPanorex and computerized tomographic (CT) scan or magneticresonance imaging (MRI) are done if bone invasion is suspected.The AJCC TNM staging system reflects tumor size, extension, andnodal disease (see Table 1). This system does predict the risk forlocal recurrence. The location of the primary tumor also ispredictive. Tumors in the upper lip and commissural areas have ahigher incidence of lymph node metastases at the time of diagnosis.Systemic dissemination is rare, occurring in approximately 10% to15% of patients, most often in those with uncontrolled locoregionaldisease.Treatment of the PrimaryThe treatment of lip cancer is governed by the stage of the disease.The choice of a local treatment modality is based on the expectedfunctional and cosmetic outcome. In early-stage cancers, surgeryand radiation are equivalent options in terms of local control. Somevery small or superficial cancers are managed more expeditiouslywith a surgical excision without resultant functional deformity or anundesired cosmetic result. On the other hand, a superficial cancerthat occupies most of the lower lip, for example, would be bestVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-9

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesmanaged with RT. Some advanced lip cancers can cause a great invasion (perineural, vascular, and/or lymphatic) and T1-2, N0 diseasedeal of tissue destruction and secondary deformity. Surgery is a can also be treated with chemotherapy/RT, although the panel disagreedabout this recommendation (category 3).more viable option in this clinical setting. Surgery is also the localmodality of choice for advanced cancers with extension into theFollow-up/Surveillancebone. Patients with resectable T3, N0; T4, N0; or any T, N1-3disease who are a poor surgical risk can be treated with definitiveFollow-up for patients with treated cancers of the lip relies solely onRT or chemotherapy/RT.periodic physical examinations every 1 to 3 months during year 1,every 2 to 4 months during year 2, every 4 to 6 months during yearsManagement of the Neck3 to 5, and every 6 to 12 months thereafter.The management of the neck is also governed by stage, but thelocation of the tumor should also be taken into account. Forexample, the lymphatics of the upper lip are very extensive. Thus,tumors in this location are more apt to spread to deep superiorjugular nodes. The position of the tumor along the lip also can behelpful in predicting the pattern of lymph node spread. A midlinelocation can place a patient at higher risk for contralateral disease.For patients with advanced disease and an N0 neck, the guidelinesrecommend a unilateral or bilateral selective neck dissection. Whena patient presents with palpable disease, care is taken to ensure allappropriate nodal levels are dissected.RadiationRadiotherapy, when used as definitive treatment, may consist ofexternal-beam RT or brachytherapy alone or in combination, dependingon the size of the tumor. The dose required also depends on tumorsize, but doses of 66 Gy or more are usually adequate to control thedisease. For T1 or T2 lesions, the total dose of external-beam RT maybe decreased when given in conjunction with brachytherapy. Whenradiotherapy is given in the adjuvant setting, doses of 60 Gy or moreare required, depending on the pathologic features. In both definitiveand adjuvant settings, the neck is treated with doses that addressmajor and minor risk features. Patients with positive margins orCancer of the Oral CavityManuscriptupdate inprogressThe oral cavity includes the following subsites: buccal mucosa,upper and lower alveolar ridge, retromolar trigone, floor of themouth, hard palate, and anterior two thirds of the tongue. There is arich lymphatic supply to the area, and initial regional nodedissemination is to nodal groups at level I, level II, and level III.Regional node involvement at presentation is evident inapproximately 30% of patients, but the risk varies according tosubsite. For example, primaries of the alveolar ridge and hard palateinfrequently involve the neck, whereas occult neck metastasis iscommon (50% to 60%) in patients with anterior tongue cancers.With the exception of patients with T1-2, N0 disease who are treatedwith definitive radiotherapy (without chemotherapy), all patientsundergo some type of neck dissection. The necessity of a bilateraldissection, instead of a unilateral dissection, depends on theassessment of risk of contralateral nodal involvement.Workup and StagingImaging studies to evaluate mandibular involvement and a carefuldental evaluation are particularly important for staging (see Table 1)and planning therapy for oral cavity cancers in addition to a physicalVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-10

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesexamination, biopsy, and chest x-ray; chest CT should beconsidered for patients at high risk for thoracic metastases.TreatmentSurgery and RT represent the standards of care for early-stage andlocally advanced resectable lesions in the oral cavity. The specifictreatment is dictated by the TN stage and, if N0 at diagnosis, by therisk of nodal involvement. Multidisciplinary team involvement isparticularly important for this site because of the critical physiologicfunctions of mastication, deglutition, and articulation of speech,which may be affected. Most panelists prefer surgical therapy forresectable oral cavity tumors. Advances in reconstruction usingmicrovascular techniques have led to improved functional outcomesfor patients with locally advanced disease.Postoperative chemotherapy/RT is recommended (category 1) forpatients who have oral cavity tumors that are T1-2, N0 with majoradverse features.68-70Major risk features include extracapsular nodalspread and/or positive margins. Patients with resectable T3, N0lesions or those with resectable T1-3, N1-3 lesions can receivepostoperative chemotherapy/RT (category 1) if they have majoradverse features. Treatment with either chemotherapy/RT or RTonly is reserved for patients with unresectable locally advanced,metastatic, or recurrent disease (see “Advanced Head and NeckCancer”). The concept of organ preservation using chemotherapy inthe initial management of locally advanced resectable disease hasnot been studied in trials specifically designed for this site.Chemotherapy/RT is included in the guidelines as a treatment optionfor patients with resectable T4, any N lesions; however, thisrecommendation is category 3 because of strong disagreementamong panel members.Manuscriptupdate inprogressFollow-up/SurveillanceFollow-up for patients with treated cancers of the oral cavity consistsof periodic physical examinations, chest imaging as clinicallyindicated, and, if the thyroid was irradiated, measurement of thethyrotropin (TSH) level every 6 to 12 months. Speech & swallowingevaluation and rehabilitation may be useful, as indicated.Cancer of the OropharynxThe oropharynx includes the base of the tongue, tonsils, soft palate,and posterior pharyngeal wall. The oropharynx is extremely rich inlymphatics. Depending on the subsite involved, 15% to 75% ofpatients present with lymph node involvement. Efforts to improve theoutcome of patients with locally advanced disease are ongoing.Participation in clinical trials is strongly recommended.Workup and StagingA multidisciplinary consultation is encouraged. Accurate stagingdepends on a thorough physical examination coupled withappropriate imaging studies. Chest CT should be considered forpatients at high risk for thoracic metastases. CT with contrast or MRIis recommended for the primary and the neck. Examination of theH&N region should include an examination under anesthesia withlaryngoscopy and pharyngoscopy. Bronchoscopy andesophagoscopy are also recommended because of the relativefrequency of simultaneous second primaries. A dental evaluation isrecommended, with Panorex studies as indicated. Speech andswallowing evaluation may be useful, as indicated.TreatmentThe treatment algorithm has been divided into three stagingcategories: (1) T1-2, N0-1; (2) T3-4, N0; and (3) any T3-4, N+ or anyVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-11

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesT, N2-3. Early-stage tumors (T1-2, N0-1) of the tonsil and base of neck disease who achieve a complete response should be observedtongue are treated with definitive radiotherapy withoutor undergo a planned neck dissection; both options are provided inchemotherapy (preferred [category 2B]), concurrentthe algorithm. There is major disagreement among panelistschemotherapy/RT (category 2B) for T1-T2, N1 only, or excision of regarding the type of neck dissection required (category 3 forprimary with or without unilateral or bilateral neck dissection; the selective versus comprehensive). Patients who achieve a completechoice of therapy depends on functional issues. Surgery is also response in the primary but have residual neck disease proceed toreserved for salvage in cases of residual or recurrent disease. neck dissection. Again, there is major disagreement amongRadiotherapy is an option for patients with one positive nodepanelists regarding the type of neck dissection to be performed(without adverse features). Chemotherapy/RT (eg, carboplatin and (category 3 for selective versus comprehensive). Patients with5-FU) is recommended (category 1) for major adverse features.Major risk features include extracapsular nodal spread and/orpositive margins.71Manuscriptupdate inprogressresidual tumor in the primary should be offered salvage surgery withneck dissection as indicated.Concurrent chemoradiotherapy is preferred (category 1) forMore advanced disease (T3-4, N0) in the absence of necktreatment of locally advanced (T3-4 or N2-3) cancer of theadenopathy can be approached using three pathways: (1)oropharynx. The status of induction chemotherapy added toconcurrent chemotherapy (eg, carboplatin plus 5-fluorouracil [5-FU]) chemoradiotherapy is an area of controversy for the NCCN panel.and radiotherapy (category 1) is preferred (salvage surgery is used The vast majority of randomized trials of induction chemotherapy71for managing residual or recurrent disease); (2) surgery plus followed by radiotherapy or surgery (which were published in thechemotherapy and radiotherapy for adverse features; or (3)1980s and 1990s) did not demonstrate a survival advantage.multimodality clinical trial of induction chemotherapy followed by Induction chemotherapy had no effect on local control; however, inconcurrent chemotherapy/RT that includes function evaluation or many trials, it did reduce the distant metastatic rate. A rationale forinduction chemotherapy followed by chemo/RT off protocolreevaluating induction chemotherapy added to concurrent71-73(category 3).chemoradiotherapy is to reduce distant metastases as a site offailure now that improved local control can be achieved withThree pathways are shown for patients with any T3-4 stage and withconcurrent chemoradiotherapy. Results from two phase III trials thatpositive nodes or any T, N2-3; concurrent chemotherapy/RTcompared induction cisplatin plus infusional 5-FU with or without the71(category 1) is preferred. For the concurrent chemotherapy/RTaddition of a taxane (docetaxel) showed significantly improvedapproach, all patients are evaluated for response in the primary site73,74response rates with the three drugs compared to two drugs.and in the neck. For patients who achieve a complete response inThus, improved chemotherapy regimens may be another reason tothe primary and the neck, the algorithm is divided into initial N1 andreevaluate this approach. The NCCN panel uniformly agreed thatinitial N2-3 neck disease. Patients with N1 disease are observed.clinical trials should be performed to directly answer the question ofThere is controversy about whether patients with more advancedwhether or not induction chemotherapy added to chemoradiotherapyVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-12

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesimproves survival in patients with locally advanced cancer of theoropharynx and other specified sites. Such trials are in progress,and the panel members uniformly agreed that patients should beenrolled in these trials. The panel members differed in their opinionas to whether or not this treatment should be considered a standardtreatment option off protocol. A small minority of panel members doadvocate this approach off protocol. This disagreement is reflectedby a category 3 recommendation in the algorithms.Altered fractionation is preferred when radiotherapy is useddefinitively for selected T1, N1 or T2, N0-1 tumors. For patients notreceiving concurrent chemoradiation, altered fractionation ispreferred. The recommended schedules are: (1) concomitant boostaccelerated radiotherapy consisting of 72 Gy delivered over 6 weeksusing 1.8 Gy/fractions to the large volume and 1.5 Gy boost as thesecond daily fraction 6 hours later during the last 12 treatments to asmaller volume; or (2) hyperfractionation consisting of 81.6 Gy givenin 7 weeks with 1.2 Gy/fractions twice daily 6 hours apart. Thischange from standard radiotherapy for large lesions was made onthe basis of the results of the RTOG 9003 protocol, which detected alocal control advantage for patients who were treated withhyperfractionation and concomitant boost versus those treated withstandard fractionation or accelerated fractionation with a break inthe treatment schedule.Manuscriptupdate inprogressIncreased acute toxicity was demonstratedin both altered fractionation schedules when compared withstandard radiotherapy. The concomitant boost schedule resulted inprolongation of acute symptoms 6 to 24 months after the initiation oftreatment, but no significant difference was demonstrated in thefrequency of late effects among schedules. In addition to the RTOGtrial, four other randomized trials have demonstrated improvedoutcomes with hyperfractionation.5047,75Salvage SurgeryPatients with advanced carcinoma of the oropharynx who undergononsurgical treatment, such as a combination of concurrent chemotherapyand RT, need very close follow-up both to evaluate theprimary for local recurrence and to assess for ipsilateral orcontralateral neck recurrence. The patients who do not respondcompletely to chemoradiation therapy require salvage surgery to theprimary and the neck. However, all the panelists emphasized thedifficulties in following these patients to detect local or regionalrecurrence. The radiation-related changes may mask local recurrence,resulting in a delay in diagnosing local or regional recurrence.All the panelists also emphasized the high incidence of complicationsrelated to salvage surgery and that laryngectomy is occasionallyrequired to obtain clear surgical margins or to prevent aspirationin patients with advanced oropharyngeal cancer. Some of thesepatients may require microvascular free flap reconstruction to coverthe defects at the primary site. The patients undergoing neck dissectionmay develop complications related to delayed wound healing,skin necrosis, or carotid exposure. The patients requiring salvagelaryngectomy may have high incidence of pharyngocutaneous fistulaand may require either a free flap reconstruction of thelaryngopharyngeal defect or if the pharynx can be closed primarily,buttressing the suture line with myocutaneous flap.Follow-up/SurveillanceThe follow-up of patients treated for oropharyngeal cancer continuesto rely on physical examination. Chest imaging is recommended asclinically indicated as surveillance for second primary tumors.Patients whose thyroid gland has been irradiated should have TSHlevels monitored every 6 to 12 months. Speech and swallowingevaluation and rehabilitation should be done as indicated.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-13

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCancer of the HypopharynxThe hypopharynx extends from the superior border of the hyoidbone to the lower border of the cricoid cartilage and is essentially amuscular, lined tube extending from the oropharynx to the cervicalesophagus. For staging purposes, the hypopharynx is divided intothree areas: (1) the pyriform sinus (the most common site of cancerin the hypopharynx); (2) the lateral and posterior pharyngeal walls;and (3) the postcricoid area.Workup and StagingA multidisciplinary consultation is encouraged. Accurate stagingdepends on a thorough physical examination coupled withappropriate imaging studies. Chest CT should be considered forpatients at high risk for thoracic metastases. Examination of theH&N region should include an examination under anesthesia withlaryngoscopy and pharyngoscopy. Bronchoscopy andesophagoscopy are also recommended because of the relativefrequency of simultaneous second primaries. A dental evaluation isrecommended, with Panorex studies as indicated. At the time ofdiagnosis, approximately 60% of patients with cancer of thehypopharynx have locally advanced disease with spread to regionalnodes. Furthermore, autopsy series have shown a high rate ofdistant metastases (60%) involving virtually every organ.Manuscriptupdate inprogressThus, theprognosis for patients with cancer of the hypopharynx is quite poor.Despite standard radical surgery and radiotherapy, the persistent orrecurrent locoregional disease, as well as distant dissemination,contribute to the poor outcome for these patients. Speech andswallowing evaluation should be performed in most patients.TreatmentPatients with resectable disease are divided into two groups: thosepatients with early-stage cancer (most T1, N0-1; small T2, N0) who76do not require a total laryngectomy and those patients withadvanced resectable cancer (T1, N2-3; T2-4, any N) who do requirelaryngectomy. The surgery and radiotherapy options for the formergroup represent a consensus among the panel members. Forpatients treated initially with definitive RT (without chemotherapy),surgery is indicated for residual neck disease (category 3recommendation for a selective versus comprehensive neckdissection). For patients with a complete response of the neck,observation is recommended.Patients with more advanced disease (defined as T1, N2-3; T2-3,any N) (see Table 2) requiring total laryngectomy and partial or totalpharyngectomy may be managed with (1) induction chemotherapy(category 1);(2) surgery; (3) concurrent chemoradiation (category2B); or (4) multimodality clinical trial of induction chemotherapyfollowed by concurrent chemoradiation that includes functionevaluation. The panel uniformly supports the recommendation ofinduction chemotherapy (category 1) followed by RT if a completeresponse is achieved at the primary site for patients with (1) T1, N2-773, or (2) T2-3, any N disease. Induction regimens include (1)docetaxel, cisplatin, and 5-FU (TPF);paclitaxel.or (2) carboplatin andGiven the functional loss resulting from this surgery andthe poor prognosis, participation in clinical trials is emphasized.The recommendation of the induction chemotherapy (cisplatin and5-FU)/definitive radiotherapy option is based on the results of anEORTC randomized trial.This trial enrolled 194 eligible patientswith stage II, stage III, or stage IV resectable squamous cellcarcinoma of the pyriform sinus (152 patients) and aryepiglottic fold(42 patients), excluding patients with T1 or N2c disease. Patientswere randomly assigned either to laryngopharyngectomy andpostoperative radiotherapy, or to chemotherapy with cisplatin and 5-Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.72777774,78MS-14

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesFU for a maximum of three cycles, followed by definitiveradiotherapy. In contrast to a similar regimen used for laryngealcancer, a complete response to induction chemotherapy wasrequired in order to proceed with definitive radiotherapy. Thepublished results showed equivalent survival, with median survivalduration and 3-year survival rate of 25 months and 43%,respectively, for the surgery group versus 44 months and 57%,respectively, for the induction chemotherapy group. A functioninglarynx was preserved in 42% of patients who did not undergosurgery. Local or regional failure rates did not differ between thesurgery-treated patients and chemotherapy-treated patients,although the chemotherapy recipients did demonstrate a significantreduction in distant metastases as a site of first failure ( P = .041).Adherence to the requirements for complete response tochemotherapy and for inclusion of only patients with the specifiedTN-stage are emphasized. As noted in the algorithm, surgery isrecommended if less than a partial response occurs after threecycles of induction chemotherapy. If there are no adverse features,then RT is recommended. Chemotherapy/RT (category 1) isrecommended for major adverse features (such as extracapsularnodal spread and/or positive margins). For minor risk features(multiple positive nodes or perineural/lymphatic/vascular invasion),RT or chemotherapy/RT (multiple positive nodes only [category 2B])is recommended. If a complete response is achieved, definitive RTis recommended. If a complete response is achieved after definitiveRT, observation is recommended.Options for patients with T4, any N disease include (1) surgeryfollowed by chemotherapy/RT (category 1) ;Manuscriptupdate inprogress(2) multimodalityclinical trial of induction chemotherapy followed by concurrentchemo/RT that includes function evaluation; or (3) concurrentchemoradiation (category 3).68-70Follow-up/SurveillanceThe recommended schedule of follow-up evaluations for patientswith cancer of the hypopharynx is the same as for patients withcancer of the oropharynx.Occult Primary CancerWhen patients present with metastatic tumor in a neck node and noprimary site can be identified after appropriate investigation, thetumor is defined as an “occult” or unknown primary cancer; this is anuncommon disease, accounting for about 5% of patients presentingto referral centers. H&N cancer of unknown primary site is a highlycurable disease. After appropriate evaluation and treatment, mostpatients experience low morbidity and many will be cured. Theprimary tumor becomes apparent on follow-up only in a few cases.Patients and oncologists are often concerned when the primarycancer cannot be found. This concern may lead to intensive,fruitless, and costly diagnostic maneuvers.Most patients older than 40 years who present with a neck massprove to have metastatic cancer. The source of thelymphadenopathy is almost always discovered in the course of acomplete H&N examination, which should be performed on allpatients with neck masses before other studies are initiated.Antecedent history of malignancy as well as prior excision,destruction, or regression of cutaneous lesions, should be assessedduring office evaluation.WorkupWhen patients present with a neck mass, fine-needle aspiration(FNA) should be the first study undertaken. Needle aspirationgenerally guides management and treatment planning. Core or openVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-15

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesbiopsy should be avoided, because it may alter or interfere withsubsequent treatment.When a needle biopsy demonstrates squamous cell carcinoma,adenocarcinoma, or anaplastic epithelial cancer and no primary sitehas been found, additional studies are needed.Nasopharyngolaryngoscopy, chest x-ray, and either CT scan withcontrast or MRI with gadolinium should be performed. A PET scanshould only be done if other tests do not reveal a primary. PET can beused to confirm clinical impressions, detect an unknown primary, andfor surveillance. Other imaging studies have very low yield and shouldnot be undertaken. If the FNA proves nondiagnostic, then core oropen biopsy may be needed. Open biopsy should not be performedunless the patient is prepared for definitive surgical management ofthe malignancy documented in the operating room. This managementmay entail a formal neck dissection. Therefore, an open biopsy of anundiagnosed neck mass should not be undertaken lightly, andpatients should be thoroughly apprised of the potential sequelae.When the imaging studies and thorough office examination (includingexamination of the nasopharynx, oropharynx, larynx, andhypopharynx as well as attention to the skin) do not reveal a primarytumor, then an examination under anesthesia should be performed.Mucosal sites should be inspected and examined. Appropriate endoscopieswith directed biopsies of likely primary sites are recommended,but they seldom disclose a primary cancer. Many primary cancers areidentified after tonsillectomy. However, the clinical significance of suchtumors is uncertain. When patients have been treated without tonsillectomy,only a few develop a clinically significant primary tumor.TreatmentComprehensive neck dissection (including level I through level V) isrecommended for all patients with squamous cell carcinoma andManuscriptupdate inprogressadenocarcinoma. If the metastatic adenocarcinoma presents high inthe neck, parotidectomy may be included with the neck dissection.NCCN member institutions have irreducible differences of opinionregarding the management of patients with poorly differentiated ornonkeratinizing squamous cell, anaplastic cancer of unknownprimary site, or other uncommon histologies. Some membersbelieve such patients should be managed with neck dissection,whereas others believe primary RT (category 3) or evenchemoradiation (category 3) should be used. If an N1 node wasexcised in an open biopsy, then all NCCN institutions use electiveradiation to the neck although some would radiate the neck only(category 3), whereas most institutions would also radiate the likelyoccult primary sites based on the level of nodes involved. Ifextracapsular nodal spread was present or if the patient presentedwith N2 or N3 disease, then all NCCN institutions use electiveradiation to the neck although some would radiate the neck only(category 3), whereas most institutions would also radiate the likelyoccult primary sites based on the level of nodes involved;chemotherapy/RT is also an option (category 2B). Additionaltreatment of possible mucosal primary sites is controversial and thesource of much disagreement. There is little evidence to support asurvival benefit from radiation to all possible primary sites.Cancer of the LarynxThe larynx is divided into three regions: supraglottis, glottis, andsubglottis. The distribution of cancers is as follows: 30% to 35% inthe supraglottic region, 60% to 65% in the glottic region, and 5% inthe subglottic region. The AJCC staging classification for laryngealprimary tumors is determined by the number of subsites involved,vocal cord mobility, and the presence of metastases (see Table 3).Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-16

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesThe incidence and pattern of metastatic spread to regional nodesvaries with the primary region. More than 50% of patients withsupraglottic primaries present with spread to regional nodesbecause of an abundant lymphatic network that crosses the midline.Bilateral adenopathy is not uncommon with early-stage primaries.Thus, supraglottic cancer is often locally advanced at diagnosis. Incontrast, the lymphatic drainage of the glottis is sparse and earlystageprimaries rarely spread to regional nodes. Becausehoarseness is an early symptom, most glottic cancers are in an earlystage at diagnosis. Thus, glottic cancers have an excellent curerate---in the range of 80% to 90%. As with other cancers of the H&N,nodal involvement decreases survival rates by approximately 50%.Workup and StagingThe evaluation of the patient to determine tumor stage is similar forglottic and supraglottic primaries. In both sites, the algorithms nowexplicitly recommend CT scan with contrast and thin cuts throughthe larynx, or MRI of the primary and neck. These imaging tests areconsidered particularly important to accurately stage the patient'stumor. Chest CT should be considered for patients at high risk forthoracic metastases. A barium esophagram is recommended forpatients with subglottic tumors; speech and swallowing evaluationas well as a dental evaluation should be done if indicated.Multidisciplinary consultation is particularly important for both sitesbecause of the potential for loss of speech and, in some instances,for swallowing dysfunction.TreatmentThe treatment of patients with laryngeal cancer is divided into threecategories: (1) tumors of the glottic larynx, (2) tumors of thesupraglottic larynx without positive nodes (N0), and (3) tumors of thesupraglottic larynx with positive nodes (N+).Manuscriptupdate inprogressFor patients with severe dysplasia or carcinoma in situ of the larynx,recommended treatment options include endoscopic removal(stripping, laser, or photodynamic therapy) or RT. NCCN alsoencourages participation in clinical trials. For invasive cancer,surgery (partial laryngectomy through either endoscopic or openapproaches) and radiotherapy are equally effective for early-stageglottic or supraglottic cancers. The choice of treatment modalitydepends on functional outcome, the patient's wishes, reliability offollow-up, and general medical condition.Management of the neck is dictated by the risk of occult nodalspread. Participation in clinical trials is preferred for patients withlocally advanced laryngeal cancer requiring total laryngectomy.Resectable, advanced-stage supraglottic and glottic primaries canbe managed surgically with a combined modality approachconsisting of either (1) total laryngectomy, or (2) concurrentchemoradiation (preferred, category 1).In patients with laryngealcancer, radiotherapy with concurrent administration of cisplatin issuperior either to induction chemotherapy followed by radiotherapyor to radiotherapy alone for laryngeal preservation and locoregionalcontrol.79Selected cases can be managed with conservationsurgical techniques that preserve vocal function.The panel recommends two nonsurgical approaches for patientswith locally advanced disease desiring laryngeal preservation. Thefirst option is treatment with concurrent chemotherapy consisting of2cisplatin 100 mg/m on days 1, 22, and 43 and radiotherapy; thesecond option is definitive RT (without chemotherapy) for patientswho are medically unfit or refuse chemotherapy.Surgery isreserved for managing the neck as indicated, for those patientswhose disease persists after radiotherapy, or those patients whodevelop a subsequent locoregional recurrence.7979Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-17

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesThe panel has updated its recommendations for managing locally indicated. For selected patients with glottic T4 tumors, the paneladvanced, resectable glottic and supraglottic cancers requiring recommends clinical trials testing function-preserving surgical orlaryngectomy to reflect the results of Intergroup trial R91-11.Before 2002, either induction chemotherapy with cisplatin/5-FUfollowed by radiotherapy or definitive radiotherapy alone (withoutchemotherapy) were the standard of care options recommended inthe NCCN H&N guidelines based on the results of the VeteransAdministration (VA) Laryngeal Cancer Study Group trial published in801991. In the 2002-2005 versions of the guidelines, concurrent2radiotherapy and cisplatin 100 mg/m is the recommended option forachieving laryngeal preservation. R91-11 was a successor trial tothe Veterans Administration trial and compared three non-surgicalregimens: (1) induction cisplatin/5-FU followed by RT (control armand identical to that in the VA trial); (2) concurrent RT and cisplatin2100 mg/m days 1, 22, and 43; and (3) RT alone. Radiotherapy wasuniform in all three arms, 70 Gy/7 wks, 2 Gy/fx. Laryngectomy wasused for salvage of treatment failures in all arms. Stage III and IV(M0) patients were eligible, excluding T1 primaries and high-volumeT4 primaries (tumor extending more than 1 cm into the base oftongue or tumor penetrating through cartilage). The key findings ofthe trial were a statistically significant higher 2-year laryngealpreservation (local control) rate for concurrent RT with cisplatin,88%, compared to 74% with induction chemotherapy and to 69%with RT alone; no significant difference in laryngeal preservationbetween induction and RT alone treatments; and similar survival forall treatment groups. These R91-11 results now change thestandard of care to concurrent RT and cisplatin (category 1,preferred) for achieving laryngeal preservation for most T3, N0 andT4, N0 supraglottic cancers and for most T3, any N glottic cancers.For patients with glottic T4 tumors, the standard approach is alaryngectomy with ipsilateral thyroidectomy and neck dissection as79Manuscriptupdate inprogressnonsurgical approaches.For managing T4 supraglottic primaries, the panel made adistinction between (1) high-volume, base-of-tongue involvement (>1 cm) or tumor penetration through cartilage; and (2) low-volumedisease with cartilage penetration on imaging or 1 cm or lessextension into the base of the tongue. This later category of T4supraglottic patients was eligible for Intergroup trial R91-11. Thecommittee prefers nonsurgical, larynx-preserving treatment withconcurrent RT and chemotherapy (category 1) for patients with lowvolumedisease whose tumor does not penetrate through cartilage.In contrast, the recommended options for those with high-volumeT4, N+ disease (eg, cartilage destruction, skin involvement, massiveinvasion of the base of the tongue) are either (1) laryngectomy,ipsilateral thyroidectomy with ipsilateral or bilateral neck dissection;or (2) a clinical trial. Definitive radiotherapy alone (withoutchemotherapy) is reserved for patients in the poor medical riskcategory.Follow-up/SurveillanceIt is particularly important for nonsurgically treated patients to havecareful and regular follow-up examinations by a trained H&Nsurgical oncologist so that any local or regional recurrence isdetected early, and salvage surgery (and neck dissection asindicated) is performed. Follow-up examinations in many of thesepatients need to be supplemented with serial endoscopy or highresolution,advanced radiologic imaging techniques because of thescarring, edema, and fibrosis that occur in the laryngeal tissues andneck after high-dose radiation. Speech & swallowing evaluation andrehabilitation may be useful, as indicated.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.7979MS-18

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesCarcinoma of the NasopharynxCarcinoma of the nasopharynx is uncommon in the United States.Among H&N cancers, it has the highest propensity to metastasize todistant sites. Nasopharyngeal cancer also poses a significant riskfor isolated local recurrences after definitive radiation (withoutchemotherapy) for locally advanced disease.Oddly enough,regional recurrences are uncommon in this disease, occurring inonly 10% to 19% of patients.The NCCN H&N guidelines for the evaluation and management of 3/N2-3 disease, imaging for distant metastases (ie, chest, liver,carcinoma of the nasopharynx attempt to address risk for both local bone) may include PET scan and/or CT.and distant disease. RT was the standard treatment for all stages ofthis disease, until the mid-1990s, when trial data showed improvedsurvival for locally advanced tumors treated with concurrent RT andcisplatin.85Stage is accepted as prognostically important. The prognosticsignificance of histology is still controversial. Several retrospectivereviews indicated local control and survival appear to depend onhistologic subtypes,84-8884,85between histology and these outcomes.whereas one study found no associationManuscriptupdate inprogressThe World HealthOrganization (WHO) classification for nasopharyngeal cancer isused most often. Type 1 represents well to moderately well--differentiated squamous cell cancers. Type 2 denotesnonkeratinizing tumors, including transitional carcinoma andlymphoepithelioma. Type 3 represents undifferentiated carcinomas,including lymphoepithelioma, anaplastic, clear cell, and spindle cellvariants.Workup and StagingThe workup of nasopharyngeal cancer includes a history, physicalexamination, nasopharyngeal examination and biopsy, dental8981-84evaluation, and appropriate diagnostic imaging studies (eg, MRIand/or CT with contrast). These studies are important to determinethe full extent of tumor in order to assign stage appropriately and todesign radiation ports that will encompass all the disease withappropriate doses. A chest x-ray should also be obtained. Chest CTshould be considered for patients at high risk for thoracicmetastases. Multidisciplinary consultation is encouraged. The 2002AJCC staging classification is used as the basis for treatmentrecommendations (see Table 2). For patients with WHO class 2-TreatmentTreatment options are subdivided according to T, N, and M status,rather than by stage alone. Patients with early-stagenasopharyngeal tumors (T1, N0, M0, and selected T2a, N0, M0tumors) may be treated with definitive RT alone (withoutchemotherapy) to the nasopharynx, with elective radiation to theneck. The local control rate for these tumors ranges from 80% to90%, whereas T3-4 tumors have a control rate of 30% to 65%.The combination of RT and platinum-based chemotherapy has beenshown to increase the local control rate from 54% to 78%. TheIntergroup trial 0099, which randomly assigned patients tochemotherapy plus external-beam RT versus external radiationalone, closed early when an interim analysis disclosed a significantsurvival and progression-free survival advantage favoring thecombined chemotherapy and radiation group.The addition ofchemotherapy also decreased local, regional, and distantrecurrence rates. A similar randomized study conducted inSingapore, which was modeled after the Intergroup treatmentregimen, continued to show the benefit of the addition of9186,90Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-19

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referenceschemotherapy to radiation therapy. Adjuvant chemotherapy after Speech & swallowing evaluation and rehabilitation may be useful, ascombined chemotherapy and radiation was also given in this trial.In addition, the administration of the cisplatin dose was spread outover several days, and this regimen appeared to reduce toxicitywhile still providing a beneficial antitumor effect.The guidelines recommend combined chemotherapy plusradiotherapy for T1, N1-3; and for T2b-4, any N lesions (stages IIB,III, IVA, IVB). The scheduling and doses of chemotherapy are thoseused in the intergroup trial 0099. Although an unusual occurrence, apatient with residual disease in the neck and a complete response atthe primary should undergo a neck dissection. Initial therapy forpatients who present with metastatic disease (stage IV) shouldconsist of a platinum-based combination chemotherapy regimen. If acomplete response is achieved, definitive RT alone (withoutchemotherapy) should be administered to the primary tumor andneck area. For early-stage cancer, radiation doses of at least 70 Gygiven with standard fractions are necessary for control of grosstumor. In patients with metastatic carcinoma who have failedplatinum-based therapy, a triplet-based combination usingpaclitaxel, carboplatin, and gemcitabine may be useful.Manuscriptupdate inprogressLikewise,cetuximab plus carboplatin may be useful for patients with recurrentor metastatic nasopharyngeal cancer who have failed platinumbasedtherapy;these patients.9495cetuximab monotherapy has also been used inFollow-up/SurveillanceFor patients whose nasopharyngeal cancer has been treated, therecommended follow-up includes periodic physical examination andan assessment of thyroid function (ie, the TSH level should bedetermined every 6 to 12 months). Increased TSH levels have beendetected in 20% to 25% of patients who received neck irradiation.939296indicated.Advanced Head and Neck CancerAdvanced H&N cancer includes newly diagnosed but unresectabledisease (see “Head and Neck Surgery”), recurrent disease, andmetastatic disease. The treatment goal for patients with newlydiagnosed but unresectable disease is cure. For the recurrentdisease group, the goal is cure (if surgery or radiation remainsfeasible) or palliation (if the patient has received previousradiotherapy and the disease is unresectable). The goal for patientswith metastatic disease is palliation or prolongation of life.TreatmentParticipation in clinical trials is preferred for all patients withadvanced H&N cancer. For patients with unresectable disease, suchtrials include testing altered fraction radiotherapy schedules,concurrent chemoradiotherapy, and novel radiosensitizers. Forpatients with recurrent disease not amenable to curative therapyand patients with metastatic disease, studies include trials of newagents and re-irradiation.Unresectable Disease. For patients with a performance status (PS)of 0 or 1, the standard treatment of newly diagnosed, unresectabledisease is concurrent cisplatin (single agent) or carboplatin-basedchemotherapy and radiotherapy.97The panel disagreed regardingwhether induction chemotherapy (cisplatin) followed by RT shouldbe used (category 3) for patients with a PS of 0 or 1. For those witha PS of 2, the recommended treatment is generally radiotherapyalone; again, the panel disagreed about using inductionchemotherapy followed by RT (category 3). For those with PS of 3,Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-20

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesthe recommended treatment is generally radiotherapy alone or, in used conventional fractionation at 2.0 g per fraction to 70 Gy orsome cases, best supportive care. Altered fractionationmore in 7 weeks with single-agent cisplatin given every 3 weeks at2(hyperfractionation or concomitant boost) regimens are preferred for 100 mg/m . Use of other fraction sizes (eg, 1.8 Gy, conventional),RT alone in patients who are medically unfit or who refusemultiagent chemotherapy, or altered fractionation withchemotherapy.chemotherapy has been evaluated, but there is no consensus on theMany randomized trialsand meta-analyses of clinical trialsdemonstrate significantly improved overall survival, disease-freesurvival, and local control when concomitant or alternatingchemotherapy and radiation is compared with radiotherapy alone.All combined chemoradiotherapy regimens are associated withvarious degrees of enhanced mucosal toxicities, which require closepatient monitoring, ideally provided by a team experienced intreating H&N cancer patients. The various single-agentchemoradiotherapy regimens have not been directly compared inrandomized trials. Therefore, no optimal standard regimen isdefined. Single-agent cisplatin plus RT is effective and relativelyeasy to administer.In a phase III randomized trial, cetuximabbasedchemoradiotherapy improved locoregional control and overallsurvival in patients with stage III/IV head and neck cancer.randomized phase II study in patients with advanced H&N (oralcavity, oropharynx, or hypopharynx) found that cisplatin pluspaclitaxel appeared to yield better overall survival than eithercisplatin plus 5-FU or hydroxyurea and 5-FU, although statisticalcomparisons were not possible.A study in patients with recurrent H&N found no difference insurvival when comparing cisplatin plus 5-FU versus cisplatin pluspaclitaxel.11297carboplatin plus 5-FU97-106 107-109111Other regimens using combination therapy includeand cetuximab plus cisplatin.113 114Most of the published studies with concurrent chemoradiation haveManuscriptupdate inprogress110Aoptimal approach. In general, the use of concurrent chemoradiationcarries a high toxicity burden, and altered fractionation or multiagentchemotherapy will likely further increase the toxicity burden. For anychemoradiation approach, close attention should be paid topublished reports for the specific chemotherapy agent, dose, andschedule of administration. Chemoradiation should be performed byan experienced team and should include aggressive supportivecare.Recurrent Disease. Surgery is recommended for resectablerecurrent disease, usually followed by radiation if it has not yet beenadministered. If the recurrence is unresectable and the patient didnot have prior RT, then radiotherapy with concurrent cisplatin orcarboplatin-based chemotherapy is recommended for patients withPS of 0 or 1. For patients with recurrent disease not amenable tocurative-intent radiation or surgery, treatment is similar to thetreatment for patients with metastatic disease. For select patients,re-irradiation in a clinical trial may be appropriate.Squamous cell carcinomas emerge after the accumulation of multiplegenomic events. In a multistep process, there appear to be essentialmolecular alterations, which confer a survival advantage for cancercells. The epidermal growth factor receptor (EGFR) is atransmembrane glycoprotein, activation of which triggers a cascade ofdownstream intracellular signaling events important for regulation ofepithelial cell growth. Overexpression of EGFR and/or common ligandshas been observed in greater than 90% of squamous cell carcinomasVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-21

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesof the H&N. This finding has led to the development of EGFR inhibitors,such as the monoclonal antibody cetuximab and small molecule Single agents and combination systemic chemotherapy regimensinvestigational agents aimed at controlling locally advanced tumors.tyrosine kinase inhibitors (such as erlotinib and gefitinib).are both used. Response rates to single agents range from 15% to35%. The most active agents include cisplatin, carboplatin,In phase II trials, cetuximab was combined with cisplatin in treatingpaclitaxel, docetaxel, 5-FU, methotrexate, ifosfamide, bleomycin,115-117patients with tumors refractory to platinum-based chemotherapy.gemcitabine (for nasopharyngeal cancer), and cetuximab. The mostTumor responses have been observed in 12% to 14% of patients, aactive regimens include (1) cisplatin or carboplatin, plus 5-FU; or (2)striking result in this very poor prognostic group. Moreover, Trigocisplatin or carboplatin, plus a taxane. These regimens result inand colleagues have recently reported responses in 12.5% ofhigher response rates of 30% to 40%.patients, similarly platinum refractory, with cetuximab administered95as a single agent.Randomized trials assessing a combination of cisplatin plus 5-FUversus single-agent therapy with cisplatin, 5-FU, or methotrexateA randomized placebo-controlled trial assessed cisplatin andhave demonstrated significantly higher response rates for thecetuximab versus cisplatin in recurrent or metastatic squamous cellcombination regimen. No difference in overall survival, however, is114,118carcinomas of the H&N as first-line therapy. With 123 patients113,119-121demonstrable. The median survival with chemotherapy isenrolled, a 26% response rate was observed in the experimentalapproximately 6 months, and the 1-year survival rate isarm versus 10% in the controlled arm ( P = .029). Bonner andapproximately 20%. Achievement of a complete response iscolleagues have randomly assigned 424 patients with locallyassociated with longer survival and, although infrequent, has beenadvanced and measurable squamous cell carcinomas of the H&N toreported more often with combination regimens.110receive definitive radiotherapy with or without cetuximab.Locoregional control and survival were significantly improved in The standard treatment of patients with incurable, recurrent, orpatients treated with radiotherapy and cetuximab compared to metastatic H&N cancer should be dictated, in large part, by theradiotherapy alone.patient's PS. Individuals with a good PS (0-1) may be offeredcombination or single-agent chemotherapy. Patients should be fullyThis sequence of trials has provided data demonstrating the potentialefficacy for cetuximab in treating squamous cell carcinomas ofinformed about the goals of treatment and the cost of combinationchemotherapy as well as the potential for added toxicity. Forthe H&N. Radiotherapy and cetuximab may provide a therapeuticpatients with a PS of 2, single-agent chemotherapy or bestoption for patients not considered optimal candidates for standardsupportive care is most appropriate. For patients with a good PSchemoradiotherapy regimens. Certainly more study is needed.who relapse after first-line chemotherapy, second-line treatment in aMetastatic Disease. Palliative adjunctive measures includeclinical trial or best supportive care is appropriate. For patients withradiotherapy to areas of symptomatic disease, analgesics, and a PS of 3, best supportive care is appropriate.Manuscriptupdate inprogressVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-22

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesDisclosures for the NCCN Head and Neck Cancers GuidelinesPanelAt the beginning of each panel meeting to develop NCCNguidelines, panel members disclosed the names of companies,foundations, and/or funding agencies from which they receivedresearch support; for which they participate in speakers' bureau,advisory boards; and/or in which they have equity interest orpatents. Members of the panel indicated that they have receivedsupport from the following: Amgen Inc; AstraZeneca; Bristol Myers-Squibb; CEL-SCI; Eastern Collaborative Oncology Group; Eli Lilly;GEM Pharmaceuticals; Genentech Inc; GlaxoSmithKline; ImCloneSystems Inc; MedImmune Inc; NCI; NeoPharm Inc; NIAID; NPSPharmaceuticals; OSI Pharmaceuticals; Pfizer Inc; RochePharmaceuticals; and Sanofi-Aventis. Some panel members do notaccept any support from industry. The panel did not regard anypotential conflicts of interest as sufficient reason to disallowparticipation in panel deliberations by any member.Manuscriptupdate inprogressVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-23

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesFigure 1Anatomic sites and subsites of the head and neckFigure 2Level designation for cervical lymphatics in the right neckNasal antrumOral cavityLipBuccalmucosaAlveolar ridge andretromolar trigoneFloor of mouthHard palateOral tongue(anteriortwo thirds)LarynxSupraglottisFalse cordsArytenoidsEpiglottisArytenoepiglottic foldGlottisSubglottisNasopharynxOropharynxBase of tongueSoft palateTonsillar pillarand fossaHypopharynxEsophagusPharynxReprinted with permission, from CMP Healthcare Media. Source: CancerManagement: A Multidisciplinary Approach, 9th ed. Pazdur R, Coia L,Hoskins W, et al (eds), Chapter 4. Copyright 2005, All rights reserved.Reprinted with permission, from CMP Healthcare Media. Source: CancerManagement: A Multidisciplinary Approach, 9th ed. Pazdur R, Coia L,Hoskins W, et al (eds), Chapter 4. Copyright 2005, All rights reserved.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.MS-24

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, ReferencesReferences1. Jemal A, Murray T, Ward E, et al. Cancer Statistics, 2005. CACancer J Clin 2005;55:10-30.2. Greene FL, Page DL, Fleming ID, et al (eds). AJCC CancerStaging Manual, Sixth Edition Springer-Verlag: New York 2002.3. Colasanto JM, Prasad P, Nash MA, et al. Nutritional support ofpatients undergoing radiation therapy for head and neck cancer.Oncology 2005;19:371-382.4. Schnoll RA, Zhang B, Rue M, et al. Brief physician-initiated quitsmokingstrategies for clinical oncology settings: a trial coordinatedby the Eastern Cooperative Oncology Group. J Clin Oncol2003;21:355-365.5. Gritz ER, Carr CR, Rapkin D, et al. Predictors of long-termsmoking cessation in head and neck cancer patients. CancerEpidemiol Biomarkers Prev 1993;2:261-270.6. Feinstein AR. The pre-therapeutic classification of comorbidity inchronic disease. J Chron Dis 1970;23:455-469.Manuscriptupdate inprogress10. Piccirillo JF. Impact of comorbidity and symptoms on theprognosis of patients with oral carcinoma. Arch Otolaryngol HeadNeck Surg 2000126:1086-1088.11. Chen AY, Matson LK, Roberts D, et al. The significance of comorbidityin advanced laryngeal cancer. Head Neck 2001;23:566-572.12. Singh B, Bhaya M, Stern J, et al. Validation of the Charlsoncomorbidity index in patients with head and neck cancer: a multiinstitutionalstudy. Laryngoscope 1997;107:1469-1475.13. Hall SF, Rochon PA, Streiner DL, et al. Measuring comorbidity inpatients with head and neck cancer. Laryngoscope 2002;112:1988-1996.14. Hall SF, Groome PA, Rothwell D. The impact of comorbidity onthe survival of patients with squamous cell carcinoma of the headand neck. Head Neck 2000;22:317-322.15. Ribeiro KC, Kowalski LP, Latorre MR. Impact of comorbidity,symptoms, and patients' characteristics on the prognosis of oralcarcinomas. Arch Otolaryngol Head Neck Surg 2000;126:1079-1085.7. Charlson ME, Pompei P, Ales KL, et al. A new method ofclassifying prognostic comorbidity in longitudinal studies:development and validation. J Chronic Dis 1987;40:373-383.8. Piccirillo JF. Importance of comorbidity in head and neck cancer.Laryngoscope 2000;110:593-602.9. Piccirillo JF, Lacy PD, Basu A, et al. Development of a new headand neck cancer-specific comorbidity index. Arch Otolaryngol HeadNeck Surg 2002;128:1172-1179.16. de Graeff A, de Leeuw JR, Ros WJ, et al. Pretreatment factorspredicting quality of life after treatment for head and neck cancer.Head Neck 2000;22:398-407.17. Funk GF, Karnell LH, Whitehead S, et al. Free tissue transferversus pedicled flap cost in head and neck cancer. OtolaryngolHead Neck Surg 2002;127:205-212.18. Farwell DG, Reilly DF, Weymuller EA Jr., et al. Predictors ofperioperative complications in head and neck patients. ArchOtolaryngol Head Neck Surg 2002;128:505-511.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.REF-1

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®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, References65. Teh BS, Mai WY, Grant WH 3rd, et al. Intensity modulatedtherapy for advanced head and neck cancer. J Clin Oncolradiotherapy (IMRT) decreases treatment-related morbidity and 2003;21:320-326.potentially enhances tumor control. Cancer Invest 2002;20:437-451.73. Hitt R, Grau J, Lopez-Pousa A, et al. Phase II/III trial of induction66. Chen YJ, Kuo JV, Ramsinghani NS, et al. Intensity-modulated chemotherapy (ICT) with cisplatin/5-fluorouracil (PF) vs. docetaxelradiotherapy for previously irradiated, recurrent head-and-neck (T) plus PF (TPF) followed by chemoradiotherapy (CRT) vs. CRT forcancer. Med Dosim 2002;27:171-176.unresectable locally advanced head and neck cancer (LAHNC)(abstract). ASCO Annual Meeting Proceedings (post-meeting67. De Neve W, Duthoy W, Boterberg T, et al. Intensity Modulatededition).J Clin Oncol 2005;23:5578.Radiation Therapy: Results in Head and Neck cancer andImprovements ahead of us. Int J Radiat Oncol Biol Phys74. Vermorken JB, Remenar E, van Herpen C, et al. Standard2003;55:460.68. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiationwith or without concomitant chemotherapy for locally advancedhead and neck cancer. N Engl J Med 2004;350:1945-1952.69. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrentradiotherapy and chemotherapy for high-risk squamous-cell carcinomaof the head and neck. N Engl J Med 2004;350:1937-1944.70. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels inlocally advanced head and neck cancers: A comparative analysis ofManuscriptupdate inprogresscisplatin/infusional 5-fluorouracil (PF) vs docetaxel (T) plus PF(TPF) as neoadjuvant chemotherapy for nonresectable locallyadvanced squamous cell carcinoma of the head and neck (LA-SCCHN): a phase III trial of the EORTC Head and Neck CancerGroup (EORTC #24971) (abstract). ASCO Annual MeetingProceedings (post-meeting edition). J Clin Oncol 2004;22:5508.75. Pinto LJ, Canary PCV, Araujo CMM, et al. Prospectiverandomized trial comparing hyperfractionated versus conventionalradiotherapy in stages III and IV oropharyngeal carcinoma. Int JRadiat Oncol Biol Phys 1990;21:557-562.concurrent postoperative radiation plus chemotherapy trials of the76. Kotwall C, Sako K, Razack MS, et al. Metastatic patterns inEORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843-850.squamous cell cancer of the head and neck. Am J Surg71. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 1987;154:439-442.French Head and Neck Oncology and Radiotherapy Group77. Lefebvre J-L, Chevalier D, Luboinski B, et al. Larynxrandomized trial comparing radiotherapy alone with concomitantpreservation in pyriform sinus cancer: Preliminary results of aradiochemotherapy in advanced-stage oropharynx carcinoma. J ClinEuropean Organization for Research and Treatment of CancerOncol 2004;22:69-76. Epub 2003 Dec 02.phase III trial. J Natl Cancer Inst 1996;88:890-899.72. Vokes EE, Stenson K, Rosen FR, et al. Weekly carboplatin and78. Schrijvers D, Van Herpen C, Kerger J, et al. Docetaxel, cisplatinpaclitaxel followed by concomitant paclitaxel, fluorouracil, andand 5-fluorouracil in patients with locally advanced unresectablehydroxyurea chemoradiotherapy: curative and organ-preservingVersion 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.REF-5

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®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesor metastatic nasopharyngeal carcinoma. J Clin Oncol2005;23:3568-3576.for inoperable head and neck cancer: Preliminary report. Int J RadiatOncol Biol Phys 1995;32:769-775.95. Trigo J, Hitt R, Koralewski P, et al. Cetuximab monotherapy is 102. Bachaud J-M, Cohen-Jonathan E, Alzieu C, et al. Combinedactive in patients (pts) with platinum-refractory recurrent/metastatic postoperative radiotherapy and weekly cisplatin infusion for locallysquamous cell carcinoma of the head and neck (SCCHN): Results of advanced head and neck carcinoma: Final report of a randomizeda phase II study (abstract). ASCO Annual Meeting Proceedings trial. Int J Radiat Oncol Biol Phys 1996;36:999-1004.(post-meeting edition). J Clin Oncol 2004;22:5502.103. Merlano M, Benasso M, Corvo R, et al. Five-year update of a96. Posner MR, Ervin TJ, Miller D, et al. Incidence of hypothyroidism randomized trial of alternating radiotherapy and chemotherapyfollowing multimodality treatment for advanced squamous-cell compared with radiotherapy alone in treatment of unresectablecancer of the head and neck. Laryngoscope 1984;94:451-454.97. Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase IIIcomparison of standard radiation therapy and two schedules ofconcurrent chemoradiotherapy in patients with unresectablesquamous cell head and neck cancer. J Clin Oncol 2003:21:92-98.98. Lo TCM, Wiley AL Jr., Ansfield FJ, et al. Combined radiationtherapy and 5-fluorouracil for advanced squamous cell carcinoma ofthe oral cavity and oropharynx: A randomized study. Am JRoentgenol 1976;126:229-235.Manuscriptupdate inprogresssquamous cell carcinoma of the head and neck. J Natl Cancer Inst1996;88:583-589.104. Brizel DM, Albers ME Fisher SR, et al. Hyperfractionatedirradiation with or without concurrent chemotherapy for locallyadvanced head and neck cancer. N Engl J Med 1998;338:1798-Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.1804.105. Wendt TG, Grabenbauer GG, Rodel CM, et al. SimultaneousRadiochemotherapy versus radiotherapy alone in advanced headand neck cancer: A randomized multicenter study. J Clin Oncol1998;16:1318-1324.99. Sanchiz F, Milla A, Torner J, et al. Single fraction per day versustwo fractions per day vs. radiochemotherapy in the treatment of 106. Jeremic B, Shibamoto Y, Milicic N, et al. Hyperfractionatedhead and neck cancer. Int J Radiation Oncol Biol Physradiation therapy with or without concurrent low-dose daily cisplatin1990;19:1347-1350.in Iocally advanced squamous cell carcinoma of the head and neck:A prospective randomized trial. J Clin Oncol 2000;18:1458-1464.100. Browman GP, Cripps C, Hodson DI, et al. Placebo-controlledrandomized trial of infusional fluorouracil during standard107. Munro AJ. An overview of randomised controlled trials ofradiotherapy in locally advanced head and neck cancer. J Clin Oncol adjuvant chemotherapy in head and neck cancer. Br J Cancer1994;12:2648-2653.1995;71:83-91.101. Smid L, Lesnicar H, Zakotnik B, et al. Radiotherapy combined 108. El-Sayed S, Nelson N. Adjuvant and adjunctive Chemotherapywith simultaneous chemotherapy with mitomycin C and bleomycin in the management of squamous cell carcinoma of the head andREF-7

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, Referencesneck region: A meta-analysis of prospective and randomized trials. JClin Oncol 1996;14:838-847.109. Pignon JP, Bourhis J, Domenge C, et al on behalf of the MACH-NC Collaborative Group. Chemotherapy added to locoregionaltreatment for head and neck squamous-cell carcinoma: Three metaanalysesof updated individual data. Lancet 2000;355:949-955.antiepidermal growth factor-receptor antibody cetuximab inmetastatic/recurrent head and neck cancer: An Eastern CooperativeOncology Group Study. J Clin Oncol 2005;23:8646-8654.115. Herbst RS, Bunn PA, Jr. Targeting the epidermal growth factorreceptor in non-small cell lung cancer. Clin Cancer Res2003;9:5813-5824.110. Bonner JA, Harari PM, Giralt J, et al. Cetuximab prolongs 116. Herbst RS, Arquette M, Shin DM, et al. Phase II multicentersurvival in patients with locoregionally advanced squamous cell study of the epidermal growth factor receptor antibody cetuximabcarcinoma of head and neck: A phase III study of high dose radiation and cisplatin for recurrent and refractory squamous cell carcinomatherapy with or without cetuximab (abstract). ASCO Annual MeetingProceedings (post-meeting edition). J Clin Oncol 2004;22:5507.111. Garden AS, Harris J, Vokes EE, et al. Preliminary results ofRadiation Therapy Oncology Group 97-03: A randomized phase IItrial of concurrent radiation and chemotherapy for advancedsquamous cell carcinomas of the head and neck. J Clin Oncol2004;22:2856-2864.112. Gibson MK, Li Y, Murphy B, et al. Randomized phase IIIevaluation of cisplatin plus fluorouracil versus cisplatin plusManuscriptupdate inprogressof the head and neck. J Clin Oncol 2005;23:5578-5587.117. Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter studyof the antiepidermal growth factor receptor monoclonal antibodycetuximab in combination with platinum-based chemotherapy inpatients with platinum-refractory metastatic and/or recurrentsquamous cell carcinoma of the head and neck. J Clin Oncol2005;23:5568-5577.118. Burtness B, Li Y, Flood W, et al. Phase III trial comparingcisplatin (C) + placebo (P) to C+ anti-epidermal growth factorpaclitaxel in advanced head and neck cancer (E1395): an intergroup antibody (EGF-R) in patients (pts) with metastatic/recurrent headtrial of the Eastern Cooperative Oncology Group. J Clin Oncol and neck cancer (HNC) (abstract). Proc Am Soc Clin Oncol2005;23:3562-3567.2002;21:902.113. Forastiere AA, Metch B, Schuller DE, et al. Randomizedcomparison of cisplatin plus fluorouracil and carboplatin plusfluorouracil vs. methotrexate in advanced squamous-cell carcinomaof the head and neck: A Southwest Oncology Group study. J ClinOncol 1992;10:1245-1251.114. Burtness B, Goldwasser MA, Flood W, et al. Phase IIIrandomized trial of cisplatin plus placebo versus cisplatin plus119. Jacobs C, Lyman G, Velez-Garcia E, et al. A phase IIIrandomized study comparing cisplatin and fluorouracil as singleagents and in combination for advanced squamous cell carcinomaof the head and neck. J Clin Oncol 1992;10:257-263.120. Browman GP, Cronin L. Standard chemotherapy in squamouscell head and neck cancer: What we have learned from randomizedtrials. Semin Oncol 1994;21:311-319.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.REF-8

®NCCNPractice Guidelinesin Oncology – v.1.2007Head and Neck CancersGuidelines IndexHead and Neck Cancers TOCStaging, MS, References121. Clavel M, Vermorken JB, Cognetti F, et al. Randomizedcomparison of cisplatin, methotrexate, bleomycin and vincristine(CABO) vs. cisplatin and 5-fluorouracil (CF) versus cisplatin inrecurrent or metastatic squamous cell carcinoma of the head andneck. Ann Oncol 1994;5:521-526.Recommended ReadingColletier PJ, Garden AS, Morrison WH, et al. Postoperative radiationfor squamous cell carcinoma metastatic to cervical lymph nodesfrom an unknown primary site: Outcomes and patterns of failure.Head Neck 1998;20:674-681.Datta NR, Choudry AD. Twice a day versus once a day radiationtherapy in head and neck cancer. Int J Radiat Oncol Biol Phys1989;17:132.Davidson BJ, Spiro RH, Patel S, et al. Cervical metastases of occultorigin: The impact of combined modality therapy. Am J Surg1994;168:395-399.Greven KM, Keys JW Jr, Williams DW 3rd, et al. Occult primarytumors of the head and neck; lack of benefit from position emissiontomography imaging with 2-[F-18] fluoro-2-deoxy-D-glucose. Cancer1999;114-118.Jungehulsing M, Scheidhauer K, Damm M, et al. 2[F]-fluoro-2-deoxy-D-glucose position emission tomography is a sensitive toolfor the detection of occult primary cancer (carcinoma of unknownprimary syndrome) with head and neck lymph node manifestation.Otolaryngol Head Neck Surg 2000;123:294-301.Martin H, Morfit HM. Cervical lymph node metastasis as the firstsymptom of cancer. Surg Gynecol Obstet 1944;78:133-159.Mendenhall WM, Mancuso AA, Parsons JT, et al. DiagnosticManuscriptupdate inprogressevaluation of squamous cell carcinoma metastatic to cervical lymphnodes from an unknown head and neck primary site. Head Neck1998;20:739-744.Pignon JP, Bourhis J, Domenge C, et al on behalf of the MACH-NCCollaborative Group. Chemotherapy added to locoregionaltreatment for head and neck squamous-cell carcinoma: Three metaanalysesof updated individual data. Lancet 2000;355:949-955.Randall DA, Johnstone PA, Foss RD, et al. Tonsillectomy indiagnosis of the unknown primary tumor of the head and neck.Otolaryngol Head Neck Surg 2000;122:52-55.Shanta V, Krishnamurthi S. Combined bleomycin and radiotherapyin oral cancer. Clin Radiol 1980;31:617-620.Spaulding MD, Fisher SG, Wolf GT, et al. Cooperative laryngealcancer study group: Tumor response, toxicity, and survival afterneoadjuvant organ-preserving chemotherapy for advanced laryngealcarcinoma. J Clin Oncol 1994;12:1592-1599.Talmi YP, Wolf GT, Hazuka M, et al. Unknown primary of the headand neck. J Laryngol Otol 1996;110:353-356.Weissler MC, Melin S, Sailer SL, et al. Simultaneouschemoradiation in the treatment of advanced head and neck cancer.Arch Otolaryngol Head Neck Surg 1992;188:806-810.Wolf GT, Fisher SG. Effectiveness of salvage neck dissection foradvanced regional metastases when induction chemotherapy andradiation are used for organ preservation. Laryngoscope1992;102:934-939.Wolf GT, Hong WK, Fisher SF. Neoadjuvant chemotherapy for organpreservation: Current status. Proceedings of the 4th InternationalConference on Head and Neck Cancer 1996;4:89-97.Version 1.2007, 04/10/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.REF-9