Head and Neck Cancers

Transcription

1 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) Head and Neck Cancers Version NCCN.g Continue Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

2 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Panel Members * David G. Pfister, MD Þ/Chair Memial Sloan-Kettering Cancer Center Robert I. Haddad, MD Dana-Farber/Brigham and Women s Cancer Center Harlan A. Pinto, MD Þ Stanfd Cancer Institute * Kie-Kian Ang, MD, PhD The University of Texas MD Anderson Cancer Center * David M. Brizel, MD Duke Cancer Institute Barbara A. Burtness, MD Fox Chase Cancer Center Paul M. Busse, MD, PhD Massachusetts General Hospital Cancer Center Anthony J. Cmelak, MD Vanderbilt-Ingram Cancer Center A. Dimitrios Colevas, MD Stanfd Cancer Institute Frank Dunphy, MD Duke Cancer Institute David W. Eisele, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Jill Gilbert, MD Vanderbilt-Ingram Cancer Center * Maura L. Gillison, MD, PhD The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Medical oncology Surgery/surgical oncology Radiation oncology Otolaryngology Þ Internal medicine * Writing Committee Member Bruce H. Haughey, MBChB, MS Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine Wesley L. Hicks, Jr., MD Roswell Park Cancer Institute Ying J. Hitchcock, MD Huntsman Cancer Institute at the University of Utah Merrill S. Kies, MD The University of Texas MD Anderson Cancer Center * William M. Lydiatt, MD UNMC Eppley Cancer Center at The Nebraska Medical Center Ellie Maghami, MD City of Hope Comprehensive Cancer Center Renato Martins, MD, MPH Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance Thomas McCaffrey, MD, PhD H. Lee Moffitt Cancer Center & Research Institute Bharat B. Mittal, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Continue NCCN Guidelines Panel Disclosures John A. Ridge, MD, PhD Fox Chase Cancer Center Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. Sandeep Samant, MD St. Jude Children's Research Hospital/ University of Tennessee Cancer Institute David E. Schuller, MD The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute * Jatin P. Shah, MD, PhD Memial Sloan-Kettering Cancer Center Sharon Spencer, MD University of Alabama at Birmingham Comprehensive Cancer Center * Andy Trotti, III, MD H. Lee Moffitt Cancer Center & Research Institute Randal S. Weber, MD The University of Texas MD Anderson Cancer Center Gregy T. Wolf, MD University of Michigan Comprehensive Cancer Center Frank Wden, MD University of Michigan Comprehensive Cancer Center Sue S. Yom, MD, PhD UCSF Helen Diller Family Comprehensive Cancer Center NCCN Lauren Gallagher, RPh, PhD Miranda Hughes, PhD Nicole McMillian, MS

3 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. NCCN Guidelines Version Sub-Committees Mucosal Melanoma William M. Lydiatt, MD /Lead UNMC Eppley Cancer Center at The Nebraska Medical Center Jatin P. Shah, MD, PhD Memial Sloan-Kettering Cancer Center Andy Trotti, III, MD H. Lee Moffitt Cancer Center & Research Institute Principles of Systemic Therapy A. Dimitrios Colevas, MD Stanfd Cancer Institute Frank Dunphy, MD Duke Cancer Institute Renato Martins, MD, MPH Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance Principles of Nutrition A. Dimitrios Colevas, MD /Lead Stanfd Cancer Institute Paul M. Busse, MD, PhD Massachusetts General Hospital Cancer Center Ying J. Hitchcock, MD Huntsman Cancer Institute at the University of Utah Gregy T. Wolf, MD University of Michigan Comprehensive Cancer Center Principles of Radiation Therapy Sharon Spencer, MD /Lead University of Alabama at Birmingham Comprehensive Cancer Center Andy Trotti, III, MD /Lead H. Lee Moffitt Cancer Center & Research Institute Kie-Kian Ang, MD, PhD The University of Texas MD Anderson Cancer Center David Brizel, MD Duke Cancer Institute Paul M. Busse, MD, PhD Massachusetts General Hospital Cancer Center Anthony J. Cmelak, MD Vanderbilt-Ingram Cancer Center Ying J. Hitchcock, MD Huntsman Cancer Institute at the University of Utah Bharat B. Mittal, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Continue NCCN Guidelines Panel Disclosures Principles of Surgery Gregy T. Wolf, MD /Lead University of Michigan Comprehensive Cancer Center David M. Brizel, MD Duke Cancer Institute David W. Eisele, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins William M. Lydiatt, MD UNMC Eppley Cancer Center at The Nebraska Medical Center John A. Ridge, MD, PhD Fox Chase Cancer Center Sandeep Samant, MD St. Jude Children's Research Hospital/ University of Tennessee Cancer Institute David E. Schuller, MD The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Randal S. Weber, MD The University of Texas MD Anderson Cancer Center Medical oncology Surgery/Surgical oncology Radiation oncology Otolaryngology Þ Internal medicine Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

4 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Table of Contents NCCN Head Neck Cancers Panel Members NCCN Head and Cancers Sub-Committee Members Summary of the Guidelines Updates Multidisciplinary Team Approach and Suppt Services (TEAM-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) Cancer of the Nasopharynx (NASO-1) Cancer of the Glottic Larynx (GLOT-1) Cancer of the Supraglottic Larynx (SUPRA-1) Ethmoid Sinus Tums (ETHM-1) Maxillary Sinus Tums (MAXI-1) Very Advanced Head and Neck Cancer (ADV-1) Recurrent/Persistent Head and Neck Cancer (ADV-2) Occult Primary (OCC-1) Salivary Gland Tums (SALI-1) Mucosal Melanoma (MM-1) Follow-up Recommendations (FOLL-A) Principles of Surgery (SURG-A) Radiation Techniques (RAD-A) Principles of Systemic Therapy (CHEM-A) Principles of Nutrition: Management and Supptive Care (NUTR-A) Clinical Trials: NCCN believes that the best management f any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at NCCN Member Institutions, click here: nccn.g/clinical_trials/physician.html. NCCN Categies of Evidence and Consensus: All recommendations are Categy 2A unless otherwise specified. See NCCN Categies of Evidence and Consensus. Staging (ST-1) The NCCN Guidelines are a statement of evidence and consensus of the auths regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care treatment. The National Comprehensive Cancer Netwk (NCCN) makes no representations warranties of any kind regarding their content, use application and disclaims any responsibility f their application use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Netwk. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any fm without the express written permission of NCCN Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

5 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Updates Updates in Version of the NCCN Guidelines f Head and Neck Cancer from Version include: Global Changes The term excision was changed to resection throughout the guidelines. A Principles of Nutrition: Management and Supptive Care section was developed that includes recommendations f Assessment and Management (nutritional, speech and swallowing) and Use of Alternative Routes f Nutrition (NG and PEG Tubes) f head and neck cancer patients. ( NUTR-A) The Principles of Radiation page f each cancer site was revised extensively. Cancer of the Lip LIP-2 T1-2, N0: Treatment of Primary and Neck: The recommendation External beam RT to primary site ± brachytherapy changed to Definitive RT to primary site. (Also f OR-2) LIP-3 T3,T4a, N0; Any T, N1-3; Treatment of Primary and Neck: The recommendation External beam RT ± brachytherapy Chemo/RT changed to Definitive RT Chemo/RT. LIP-A A new section on brachytherapy (including low-dose rate and high-dose rate) was added. (Also f OR-A) Footnotes 2 and 3 regarding brachytherapy are new to the algithm. (The same footnotes were added to OR-A) Cancer of the Oral Cavity OR-1 Clinical Staging; Bottom pathway: Changed to T4b, Any N, Unresectable nodal disease Unfit f surgery. (Also f ORPH-1, HYPO-1, GLOT-1, SUPRA-1, ADV-1) OR-2 T1-2, N0: Treatment of Primary and Neck: The recommendation External beam RT to primary site ± brachytherapy changed to Definitive RT. OR-3 T3, N0;T4a, Any N; T1-3, N1-3;Treatment of Primary and Neck: N0, N1, N2a-b,N3 pathway: After the recommendation Resection of primary ipsilateral bilateral neck dissection, the following phrase was removed, guided by tum thickness, extent of disease. Cancer of the Oropharynx ORPH-1 Wkup; Third bullet: Tum HPV testing suggested changed to Tum HPV testing recommended. Footnote a was revised as follows, Either immunohistochemistry f analysis of p16 expression HPV in situ hybridization f detection of HPV DVA in tum cell nuclei is recommended. Although not used to guide treatment, HPV testing is valuable prognostically... ORPH-2 Adjuvant Treatment f T1-2, N0-1 tums: F patients with adverse features and positive margins after resection, the following recommendation was added as an option, Consider chemo/rt (f T2 only). ORPH-A The statement IMRT is a preferred technique f cancers of the opharynx in der to minimize dose to critical structures, changed to Either IMRT 3-D confmal RT are recommended f cancers of the opharynx in der to minimize dose to critical structures, especially the parotid glands. A comparable change was also made to other cancer sites within the Guidelines (NASO-A, ETHM-A, MAXI-A, OCC-A). Footnote 3: The first sentence changed to, Based on published data, concurrent chemadiation most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m2 2-3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG 0522). Also f HYPO-A, GLOT-A, SUPRA-A, ADV-A, OCC-A) Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. Continued UPDATES 1 of 4

6 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Updates Cancer of the Hypopharynx HYPO-1 Under Clinical Staging: Advanced cancer requiring total laryngectomy changed to Advanced cancer requiring pharyngectomy with total laryngectomy. HYPO-2 Most T1, N0, selected T2, N0 (not requiring total laryngectomy); Adjuvant treatment: F patients with adverse features and positive margins after surgery, the following recommendation was added as an option, Consider chemo/rt (f T2 only). Cancer of the Nasopharynx NASO-A The statement IMRT is a preferred technique f cancers of the nasopharynx to minimize dose to critical structures, changed to Either IMRT 3-D confmal RT is recommended f cancers of the nasopharynx in der to minimize dose to critical structures. Cancer of the Glottic Larynx GLOT-6--continued T4a, Any N pathway: Adjuvant Treatment: The recommendation Chemo/RT (categy 1) changed to RT Consider chemo/rt Observation f highly selected patients. A cresponding footnote l was also added regarding good risk features f favable T4a patients who could be observed after surgery. Cancer of the Supraglottic Larynx SUPRA-1 Under Clinical Staging: First pathway changed to Not requiring total laryngectomy (Most T1-2, N0; Selected T3). SUPRA-8 T4a, N0-N3 Top pathway; Treatment of Primary Neck: Laryngectomy, ipsilateral thyroidectomy... changed to Laryngectomy, appropriate thryoidectomy... Cancer of the Glottic Larynx Ethmoid Sinus Tums GLOT-1 ETHM-A Clinical Staging; Second pathway: Total laryngectomy not Footnote 4 regarding the avoidance of critical neural structures in required changed to Total laryngectomy not required (T1-T2 the paranasal sinus area is new to the page. (Also f MAXI-A) Select T3). GLOT-2 Very Advanced Head and Neck Cancer Treatment of Primary and Neck ADV-2 Carcinoma in situ: The recommendation Clinical trial was Recurrent Persistent disease; Distant metastases; Standard removed. therapy; PS 0-1: Platinum + 5-FU + cetuximab (categy 1) was Total laryngectomy not required (T1-T2 select T3) pathway: added as a treatment option. After Partial laryngectomy... three new pathways regarding ADV-A adverse features and adjuvant treatment were added. Chemadiation: First sentence changed to, Based on published GLOT-6 data, concurrent chemadiation most commonly uses conventional T4a, Any N pathway: fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 After Treatment of Primary and Neck: The recommendation weeks with single-agent cisplatin given every 3 weeks at 100 mg/m 2; Laryngectomy with ipsilateral thyroidectomy... changed to Total 2-3 cycles of chemotherapy are used depending on the radiation laryngectomy with thyroidectomy as indicated... fractionation scheme. A section on postoperative radiation therapy dosing was added to the page. Footnote 2 regarding re-irradiation is new to the algithm. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. Continued UPDATES 2 of 4

7 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Updates Occult Primary OCC-1 Neck mass; Second column: Recommendation changed to read, H&P and complete head and neck exam with attention to skin; palpation of the base of tongue and opharynx; mirr and fiberoptic examination... Third column: Fine-needle aspiration (preferred) Open biopsy changed to Fine-needle aspiration. Squamous cell carcinoma, adenocarcinoma, and anaplastic epithelial tums; Wkup: The third bullet changed to PET/CT scan as indicated (befe exam under anesthesia). Footnote d that states, Strongly consider referral to highvolume multidisciplinary cancer center, is new to the algithm. OCC-3 Poly differentiated nonkeratinizing squamous cell NOS anaplastic (not thyroid) Squamous cell carcinoma; Definitive treatment: The option of Surgery changed to Surgery (preferred f < N2 disease). The option of RT (categy 3) changed to RT f < N2 (categy 2B). The option of Chemotherapy/RT (categy 2B) changed to Chemotherapy f N2 (categy 2B). OCC-4 Post neck dissection; N1 without extracapsular spread: Level I only; Treatment; RT recommendation: Waldeyer s ring was removed. Level II, III, upper level V; Treatment; RT recommendation: Nasopharynx and Hypopharynx were added. Level IV only; Treatment; RT recommendation: Waldeyer s ring was removed. Oropharynx was added. Footnote c was revised as follows: Whether HPV EBV positive status may help to define the radiation fields is being investigated. Occult Primary---continued OCC-5 Post neck dissection; N2, N3 without extracapsular spread: Level I only; Treatment; RT recommendation: Waldeyer s ring was removed. Level IV only; Treatment; RT recommendation: Waldeyer s ring was removed. Oropharynx was added. OCC-6 Post neck dissection; Extracapsular spread: Level I only; Treatment; RT recommendation: Waldeyer s ring was removed. Level IV only; Treatment; RT recommendation: Waldeyer s ring was removed. Oropharynx was added. OCC-A A section on postoperative radiation therapy dosing was added to the page. Salivary Gland Tums SALI-1 Wkup; Last bullet: The recommendation Open biopsy consider fine-needle aspiration (may not be necessary in incompletely resected patients) changed to Fine-needle aspiration biopsy. SALI-2 Clinically benign carcinoma, T1, T2 pathway; Pathology result; Low grade: The recommendation If tum spillage, consider RT changed to If tum spillage perineural invasion, consider RT. SALI-3 Cancer site: Parotid gland changed to Parotid and sub-mandibular gland. SALI-4 Locegional recurrence without pri RT pathway; After Completely resected : The pathway f Adenoid cystic disease was removed. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. Continued UPDATES 3 of 4

8 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Updates FOLL-A Follow-up Recommendations The page title changed to, Follow-up Recommendations (based on risk of relapse, second primaries, treatment sequalae and toxicities). Histy and physical exam: Year 2, every 2-4 mo changed to...every 2-6 mo Years 3-5, every 4-6 changed to...every 4-8 mo > 5 years, every 6-12 mo changed to...every 12 mo Third bullet; Chest imaging...: A link to the NCCN Guidelines f Lung Cancer Screening was added. SURG-A Principles of Surgery This section was revised extensively. CHEM-A Principles of Systemic Therapy A new section of bulleted statements was added regarding standard therapy f locally advanced disease. Squamous Cell Cancers; Primary systemic therapy + concurrent RT: F non-nasopharyngeal cancers, Carboplatin/infusional 5-FU was changed from categy 2A to categy 1. F non-nasopharyngeal cancers: Paclitaxel/cisplatin/infusional 5-FU was added as an Induction/Sequential chemotherapy regimen. A new section denoting Induction/Sequential chemotherapy f nasopharynx cancers was added as follows: Induction/Sequential chemotherapy Docetaxel/cisplatin/5-FU Cisplatin/5-FU Cisplatin/epirubicin/paclitaxel Following induction, agents to be used with concurrent chemadiation typically include weekly cisplatin carboplatin. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. UPDATES 4 of 4

9 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Team Approach Head and neck surgery Radiation oncology Medical oncology Plastic and reconstructive surgery Specialized nursing care Dentistry/prosthodontics Physical medicine and rehabilitation Speech and swallowing therapy Clinical social wk Nutrition suppt MULTIDISCIPLINARY TEAM The management of patients with head and neck cancers is complex. All patients need access to the full range of suppt services and specialists with expertise in the management of patients with head and neck cancer f optimal treatment and follow-up. Pathology (including cytopathology) Diagnostic radiology Adjunctive services Neurosurgery Ophthalmology Psychiatry Addiction services Audiology Palliative care SUPPORT AND SERVICES Follow-up should be perfmed by a physician and other health care professionals with expertise in the management and prevention of treatment sequelae. It should include a comprehensive head and neck exam. The management of head and neck cancer patients may involve the following: General medical care Pain and symptom management Nutritional suppt Enteral feeding Oral supplements Dental care f radiation therapy effects Xerostomia management Smoking and alcohol cessation Speech and swallowing therapy Audiology Tracheotomy care Wound management Depression assessment and management Social wk and case management Supptive care (See NCCN Guidelines f Palliative Care) Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. TEAM-1

10 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Lip WORKUP CLINICAL STAGING Histy and physical (H&P) including a complete head and neck exam; mirr and fiberoptic examination as clinically indicated Biopsy Chest imaging As indicated f primary evaluation Panex Computed tomography (CT)/magnetic resonance imaging (MRI) of primary and neck as indicated Preanesthesia studies Dental evaluation T1-2, N0 T3, T4a, N0 Any T, N1-3 Surgical candidate Po surgical risk See Treatment of Primary and Neck (LIP-2) See Treatment of Primary and Neck (LIP-3) Definitive RTa to primary and nodes Chemo/RTb Follow-up (See FOLL-A) Multidisciplinary consultation as indicated T4b, any N, unresectable nodal disease See Treatment of Very Advanced Head and Neck Cancer (ADV-1) asee Principles of Radiation Therapy (LIP-A). bsee Principles of Systemic Therapy (CHEM-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. LIP-1

11 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Lip CLINICAL STAGING TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT FOLLOW-UP T1-2, N0 Surgical resection (preferred) (elective neck dissection not recommended) d Positive margins, perineural/vascular/ lymphatic invasion No adverse pathologic findings Re-resection RTa e Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Definitive RT to primary sitea,c Residual recurrent tum post-rt Surgery d/ reconstruction asee Principles of Radiation Therapy (LIP-A). cno elective treatment to neck is preferred f the T1-2, N0. dsee Principles of Surgery (SURG-A). econsider re-resection to achieve negative margins, if feasible. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. LIP-2

12 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Lip CLINICAL STAGING: T3,T4a, N0; Any T, N1-3 TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT FOLLOW-UP N0 Resection of primary ± ipsilateral bilateral neck dissection d N0 Surgeryd (preferred) Definitive RTa Chemo/RT b N1 N2a-b, N3 N2c (bilateral) Resection of primary, ipsilateral neck dissection ± contralateral neck dissection d Resection of primary, ipsilateral neck dissection ± contralateral neck dissection d Resection of primary and bilateral neck dissection d Treatment of Primary and Neck (LIP-4) One positive node without adverse features f Adverse features f Extracapsular spread and/ positive margin Other risk features RT a (optional) Chemo/RT b preferred (categy 1) Re-resectione RTa RT a Consider chemo/rt b Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) asee Principles of Radiation Therapy (LIP-A). bsee Principles of Systemic Therapy (CHEM-A). dsee Principles of Surgery (SURG-A). e Consider re-resection to achieve negative margins, if feasible. fadverse features: extracapsular nodal spread, positive margins, multiple positive nodes, perineural/lymphatic/vascular invasion. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. LIP-3

13 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Lip CLINICAL STAGING: T3, T4a, N0; Any T, N1-3 TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT FOLLOW-UP Primary site: Complete clinical response (N0 at initial staging) Definitive RTa Chemo/RTb Primary site: Complete clinical response (N+ at initial staging) Primary site: < complete clinical response Residual tum in neck Complete clinical response of neck Salvage surgery + neck dissection as indicated d Post-treatment evaluation g Negative Positive Neck dissection d Observe Neck dissection d Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) asee Principles of Radiation Therapy (LIP-A). bsee Principles of Systemic Therapy (CHEM-A). dsee Principles of Surgery (SURG-A). gsee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. LIP-4

14 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Lip PRINCIPLES OF RADIATION THERAPY 1 DEFINITIVE: RT Primary and gross adenopathy: Conventional fractionation: Gy (2.0 Gy/fraction; daily Monday-Friday) in 7 weeks External-beam RT (EBRT) ± brachytherapy2,3 Brachytherapy Interstitial brachytherapy is considered f selected cases. 2,3 -Low-dose rate (LDR) brachytherapy: Consider LDR boost Gy if combined with 50 Gy EBRT Gy over several days if using LDR as sole therapy -High-dose rate (HDR) brachytherapy: Consider HDR boost 21 Gy at 3 Gy/fraction if combined with Gy EBRT Gy at 3-6 Gy/fraction if using HDR as sole therapy. Neck Uninvolved nodal stations: Gy ( Gy/fraction) POSTOPERATIVE: RT Primary: Gy (2.0 Gy/fraction) Neck Involved nodal stations: Gy (2.0 Gy/fraction) Uninvolved nodal stations: Gy ( Gy/fraction) 1 See Radiation Techniques (RAD-A) and. 2Brachytherapy should be perfmed at centers where there is expertise in this modality. ( Nag S, Cano ER, Demances DJ, et al. The American Brachytherapy Society recommendations f high-dose-rate brachytherapy f head-neck carcinomas. Int J Radiat Oncol Biol Phys 2001;50: ; and Mazeron JJ, Ardiet JM, Hale- Meder C, et al. GEC-ESTRO recommendations f brachytherapy f head and neck squamous cell carcinoma. Radiother Oncol 2009; 91: ) 3The interval between EBRT and brachytherapy should be as sht as possible (1-2 weeks) depending on recovery from acute toxicity. The interval between HDR fractions should be at least 6 hours. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. LIP-A

15 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Oral Cavity Buccal mucosa, flo of mouth, anteri tongue, alveolar ridge, retromolar trigone, hard palate WORKUP CLINICAL STAGING H&P including a complete head and neck exam; mirr and fiberoptic examination as clinically indicated Biopsy Chest imaging CT with contrast and/ MRI with contrast of primary and neck as indicated Consider positron emission tomography (PET)-CT f stage III-IV diseasea Examination under anesthesia (EUA) with endoscopy, if indicated Preanesthesia studies Dental/prosthodontic evaluation, including jaw imaging as indicated Nutrition, speech and swallowing evaluation/therapy as indicatedb Multidisciplinary consultation as indicated T1-2, N0 T3, N0 T1-3, N1-3 T4a, any N T4b, any N, Unresectable nodal disease Unfit f surgery See Treatment of Primary and Neck (OR-2) See Treatment of Primary and Neck (OR-3) See Treatment of Primary and Neck (OR-3) See Treatment of Primary and Neck (OR-3) See Treatment of Very Advanced Head and Neck Cancer (ADV-1) a See. b See Principles of Nutrition: Management and Supptive Care (NUTR-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OR-1

16 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Oral Cavity Buccal mucosa, flo of mouth, anteri tongue, alveolar ridge, retromolar trigone, hard palate CLINICAL STAGING TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT FOLLOW-UP No adverse features e T1 2, N0 Resection of primary (preferred) ± ipsilateral bilateral neck dissection (guided by tum thickness) c Definitive RT d One positive node without adverse features e RTd optional (categy 2B) Adverse features e Other risk features No residual disease Residual disease Extracapsular spread and/ positive margin Chemo/RTd,f (preferred) (categy 1) Re-resectiong RTd RT d Consider chemo/rt d,f Salvage surgery Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) csee Principles of Surgery (SURG-A). dsee Principles of Radiation Therapy (OR-A). eadverse risk features: extracapsular nodal spread, positive margins, pt3 pt4 primary, N2 N3 nodal disease, nodal disease in levels IV V, perineural invasion, vascular embolism ( See ). fsee Principles of Systemic Therapy (CHEM-A). gconsider re-resection to achieve negative margins, if feasible. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OR-2

17 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Oral Cavity Buccal mucosa, flo of mouth, anteri tongue, alveolar ridge, retromolar trigone, hard palate CLINICAL STAGING TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT FOLLOW-UP N0, N1, N2a-b, N3 Resection of primary, ipsilateral bilateral neck dissection c No adverse features e RT d (optional) T3,N0; T4a, Any N; T1-3, N1-3 Surgery c N2c (bilateral) Resection of primary and bilateral neck dissection c Adverse features e Extracapsular spread and/ positive margin Other risk features Chemo/RT (preferred) d,f (categy 1) Re-resectiong RTd RT d Consider chemo/rtd,f Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) csee Principles of Surgery (SURG-A). dsee Principles of Radiation Therapy (OR-A). eadverse risk features: extracapsular nodal spread, positive margins, pt3 pt4 primary, N2 N3 nodal disease, nodal disease in levels IV V, perineural invasion, vascular embolism ( See ). fsee Principles of Systemic Therapy (CHEM-A). gconsider re-resection to achieve negative margins, if feasible. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OR-3

18 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Oral Cavity PRINCIPLES OF RADIATION THERAPY 1 DEFINITIVE: RT Primary and gross adenopathy: Conventional fractionation: Gy (2.0 Gy/fraction; daily Monday-Friday) in 7 weeks Altered fractionation: 2.0 Gy/fraction; 6 fractions/week accelerated; Gy to gross disease; Gy to subclinical disease. Concomitant boost accelerated RT: 72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) Brachytherapy Interstitial brachytherapy is considered f selected cases. 2,3 -LDR brachytherapy: Consider LDR boost Gy if combined with 50 Gy EBRT Gy over several days if using LDR as sole therapy. -HDR brachytherapy: Consider HDR boost 21 Gy at 3 Gy/fraction if combined with Gy EBRT Gy at 3-6 Gy/fraction if using HDR as sole therapy. Neck Uninvolved nodal stations: Gy ( Gy/fraction) F unresectable disease ( See ADV-1) POSTOPERATIVE: RT Preferred interval between resection and postoperative RT is 6 weeks. Primary: Gy (2.0 Gy/fraction) Neck Involved nodal stations: Gy (2.0 Gy/fraction) Uninvolved nodal stations: Gy ( Gy/fraction) Postoperative chemadiation Concurrent single-agent cisplatin at 100 mg/m2 every 3 weeks is recommended See Radiation Techniques (RAD-A) and. 2Brachytherapy should be perfmed at centers where there is expertise in this modality. (Nag S, Cano ER, Demances DJ, et al. The American Brachytherapy Society recommendations f highdose-rate brachytherapy f head-neck carcinomas. Int. J. Radiat Oncol Biol Phys. 2001;50: ; and Mazeron JJ, Ardiet JM, Hale-Meder C, et al.,gec-estro recommendations f brachytherapy f head and neck squamous cell carcinoma. Radiother Oncol 2009;91: ) 3The interval between EBRT and brachytherapy should be as sht as possible (1-2 weeks) depending on recovery from acute toxicity. The interval between HDR fractions should be at least 6 hours. 4Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with without concomitant chemotherapy f locally advanced head and neck cancer. N Engl J Med 2004;350: Cooper JS, Pajak TF, Fastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy f high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350(19): Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27: Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OR-A

19 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Oropharynx Base of tongue/tonsil/posteri pharyngeal wall/soft palate WORKUP CLINICAL STAGING H&P including a complete head and neck exam; mirr and fiberoptic examination as clinically indicated Biopsy Tum human papilloma virus (HPV) testing recommendeda Chest imaging CT with contrast and/ MRI with contrast of primary and neck Consider PET-CTb f stage III-IV disease Dental evaluation, including panex as indicated Nutrition, speech and swallowing evaluation/therapy and audiogram as indicated c Examination under anesthesia with endoscopy as indicated Preanesthesia studies Multidisciplinary consultation as indicated T1-2, N0-1 T3-4a, N0-1 Any T, N2-3 T4b, any N, Unresectable nodal disease Unfit f surgery See 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 Very Advanced Head and Neck Cancer (ADV-1) aeither immunohistochemistry f analysis of p16 expression HPV in situ hybridization f detection of HPV DNA in tum cell nuclei is recommended. Although not used to guide treatment, HPV testing is valuable prognostically. The results of HPV testing should not change management decisions except in the context of a clinical trial. banatomical imaging is also recommended. c See Principles of Nutrition: Management and Supptive Care (NUTR-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ORPH-1

20 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Oropharynx Base of tongue/tonsil/posteri pharyngeal wall/soft palate CLINICAL TREATMENT OF PRIMARY AND NECK STAGING Complete clinical response Definitive RT d Residual disease ADJUVANT TREATMENT Salvage surgery No adverse features g T1-2, N0-1 Resection of primary ± ipsilateral bilateral neck dissection e F T2, N1 only, RT d + systemic therapy f (categy 2B f systemic therapy) One positive node without adverse features g Adverse features g Other risk features Complete clinical response Residual disease Extracapsular spread ± positive margin Positive margin Consider RT d Chemo/RT d,f (categy 1) Re-resectionh RT d Consider chemo/rt (f T2 only) RT d Consider chemo/rt d,f Salvage surgery dsee Principles of Radiation Therapy (ORPH-A). esee Principles of Surgery (SURG-A). fsee Principles of Systemic Therapy (CHEM-A). gadverse features: extracapsular nodal spread, positive margins, pt3 pt4 primary, N2 N3 nodal disease, nodal disease in levels IV V, perineural invasion, vascular embolism ( See ). hconsider re-resection to achieve negative margins, if feasible. Note: All recommendations are categy 2A unless otherwise indicated. Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ORPH-2

21 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Oropharynx Base of tongue/tonsil/posteri pharyngeal wall/soft palate CLINICAL STAGING TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT Concurrent systemic therapy/rt, d,f cisplatin (categy 1) preferred Complete clinical response Residual disease No adverse features g Salvage surgery RT g T3-4a, N0-1 Surgery f primary and neck e Induction chemotherapy (categy 3) f,i followed by RTd chemo/rtd Adverse features g Complete clinical response Residual disease Extracapsular spread and/ positive margin Other risk features Chemo/RT d,f (categy 1) RT d Consider chemo/rt d,f Salvage surgery Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Multimodality clinical trials See Principles of Radiation Therapy (ORPH-A). See Principles of Surgery (SURG-A). See Principles of Systemic Therapy (CHEM-A). Adverse features: extracapsular nodal spread, positive margins, pt3 pt4 primary, N2 N3 nodal disease, nodal disease in levels IV V, perineural invasion, vascular embolism ( See ). See on induction chemotherapy. d e f g i Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ORPH-3

22 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Oropharynx Base of tongue/tonsil/posteri pharyngeal wall/soft palate CLINICAL STAGING Any T, N2-3 TREATMENT OF PRIMARY AND NECK Concurrent systemic therapy/rt, d,f cisplatin (categy 1) preferred Induction chemotherapyf,i (categy 2B) followed by RT chemo/rt Surgery: e Primary and neck N1 N2a-b N3 N2c Primary site: Complete clinical response Primary site: Residual tum Residual tum in neck Complete clinical response of neck Resection of primary, ipsilateral bilateral neck dissection e Resection of primary and bilateral neck dissection e Negative Positive Salvage surgery + neck dissection as indicated e No adverse features g Adverse features g Extracapsular spread and/ positive margin Note: All recommendations are categy 2A unless otherwise indicated. ADJUVANT TREATMENT Neck dissection e Observe Neck dissection e RT d Multimodality clinical trials Other risk See Principles of Radiation Therapy (ORPH-A). features Consider See Principles of Surgery (SURG-A). chemo/rt d,f See Principles of Systemic Therapy (CHEM-A). Adverse features: extracapsular nodal spread, positive margins, pt3 pt4 primary, N2 N3 nodal disease, nodal disease in levels IV V, perineural invasion, vascular embolism ( See ). See on induction chemotherapy. See Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). d e f g i j Post-treatment evaluation j Chemo/RT d,f (categy 1) Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ORPH-4

23 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Oropharynx 1See Radiation Techniques (RAD-A) and. 2See Principles of Systemic Therapy (CHEM-A). 3Based on published data, concurrent chemadiation most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m2 2-3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG 0522). Other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing schedules of cisplatin altered fractionation with chemotherapy are efficacious, and there is no consensus on the optimal approach. In general, the use of concurrent chemadiation carries a high toxicity burden; altered fractionation multiagent chemotherapy will likely further increase the toxicity burden. F any chemadiation approach, close attention should be paid to published repts f the specific chemotherapy agent, dose, and schedule of administration. Chemadiation should be perfmed by an experienced team and should include substantial supptive care. PRINCIPLES OF RADIATION THERAPY 1 DEFINITIVE: RT Conventional fractionation: Gy (2.0 Gy/fraction; daily Monday-Friday) in 7 weeks Altered fractionation: 2.0 Gy/fraction; 6 fractions/week accelerated; Gy to gross disease; Gy to subclinical disease. Concomitant boost accelerated RT: 72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) Neck Uninvolved nodal stations: Gy ( Gy/fraction) Concurrent chemadiation2 Conventional fractionation: 3 Primary and gross adenopathy: typically 70 Gy (2.0 Gy/fraction) Neck Uninvolved nodal stations: Gy ( Gy/fraction) Note: All recommendations are categy 2A unless otherwise indicated POSTOPERATIVE: RT Preferred interval between resection and postoperative RT is 6 weeks. Primary: Gy (2.0 Gy/fraction) Neck Involved nodal stations: Gy (2.0 Gy/fraction) Uninvolved nodal stations: Gy ( Gy/fraction) Postoperative chemadiation Concurrent single-agent cisplatin at 100 mg/m2 every 3 weeks is recommended. 4-6 Either intensity-modulated RT (IMRT) 3-D confmal RT is recommended f cancers of the opharynx in der to minimize dose to critical structures, especially the parotid glands. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with without concomitant chemotherapy f locally advanced head and neck cancer. N Engl J Med 2004;350: Cooper JS, Pajak TF, Fastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy f high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350: Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ORPH-A

24 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Hypopharynx WORKUP CLINICAL STAGING H&P including a complete head and neck exam; mirr and fiberoptic examination as clinically indicated Biopsy Chest imaging CT with contrast and/ MRI with contrast of primary and neck Consider PET-CTa f stage III-IV disease Examination under anesthesia with endoscopy Preanesthesia studies Nutrition, speech and swallowing evaluation/therapy and audiogram as indicatedb Dental evaluation Consider videostrobe f select patients Multidisciplinary consultation as indicated Most T1, N0, selected T2, N0 (not requiring total laryngectomy) Advanced cancer requiring pharyngectomy with total laryngectomy T4b, any N Uresectable nodal disease Unfit f surgery T1, N+; T2-3, Any N T4a, Any N See Treatment of Primary and Neck (HYPO-2) See Treatment of Primary and Neck (HYPO-3) See Treatment of Primary and Neck (HYPO-5) See Treatment of Very Advanced Head and Neck Cancer (ADV-1) a Anatomical imaging is also recommended. b See Principles of Nutrition: Management and Supptive Care (NUTR-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. HYPO-1

25 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Hypopharynx CLINICAL STAGING TREATMENT OF PRIMARY AND NECK Primary site: Complete clinical response ADJUVANT TREATMENT Definitive RT c Most T1, N0, selected T2, N0 (not requiring total laryngectomy) Surgery: Partial laryngopharyngectomy (open endoscopic) + ipsilateral bilateral neck dissection d Primary site: Residual tum No adverse features e Adverse features e Salvage surgery + neck dissection as indicated d Extracapsular spread ± positive margin Positive margins Chemo/RT c,f (categy 1) Re-resectiong RTc Consider chemo/rt (f T2 only) Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Other risk features RT c Consider chemo/rt c,f csee Principles of Radiation Therapy (HYPO-A). dsee Principles of Surgery (SURG-A). e Adverse features: extracapsular nodal spread, positive margins, pt3 pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism ( See ). fsee Principles of Systemic Therapy (CHEM-A). gconsider re-resection to achieve negative margins, if feasible. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. HYPO-2

26 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Hypopharynx CLINICAL STAGING TREATMENT OF PRIMARY AND NECK Induction chemotherapy f,h See Response After Induction Chemotherapy (HYPO-4) ADJUVANT TREATMENT Selected T2, N0 (requiring laryngectomy) T1, N+; T2-3, any N (if pharyngectomy with total laryngectomy required) Laryngopharyngectomy + neck dissection, d including level VI Concurrent systemic therapy/rt (cisplatin preferred) c,f No adverse features e Adverse features f Primary site: complete clinical response Primary site: residual tum Extracapsular spread and/ positive margin Other risk features Residual tum in neck Complete clinical response of neck Post-treatment evaluation i Salvage surgery + neck dissection as indicated d Chemo/RT c,f (categy 1) RT c Consider chemo/rt c,f Neck dissection d Negative Positive Observe Neck dissection d Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Multimodality clinical trials See Principles of Radiation Therapy (HYPO-A). See Principles of Surgery (SURG-A). Adverse features: extracapsular nodal spread, positive margins, pt3 pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism (See ). See Principles of Systemic Therapy (CHEM-A). In randomized clinical trials, assessment of response has been done after 2 3 cycles. See Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). c d e f h i Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. HYPO-3

27 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Hypopharynx RESPONSE ASSESSMENT Primary site: Complete response (CR) Definitive RT c (categy 1) Consider chemo/rtc,f (categy 2B) Residual tum in neck Complete clinical response of neck Post-treatment evaluation i Neck dissection d Negative Positive Observe Neck dissection d Response after induction chemotherapy f,h Primary site: Partial response (PR) Chemo/RT c,f (categy 2B) CR Residual disease Observe Salvage surgery Follow-up (See FOLL-A) Primary site: < PR Surgery d No adverse features e Adverse features e Extracapsular spread and/ positive margin Other risk features Chemo/RT c,f (categy 1) csee Principles of Radiation Therapy (HYPO-A). Consider chemo/rtc,f dsee Principles of Surgery (SURG-A). eadverse features: extracapsular nodal spread, positive margins, pt3 pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism (See ). fsee Principles of Systemic Therapy (CHEM-A). hin randomized clinical trials, assessment of response has been done after 2 3 cycles. isee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). Note: All recommendations are categy 2A unless otherwise indicated. RT c RT c Recurrent Persistent Disease (See ADV-2) Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. HYPO-4

28 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Hypopharynx CLINICAL TREATMENT OF PRIMARY AND NECK STAGING Surgery + neck dissectiond (preferred) T4a, any N Induction chemotherapyf,h (categy 3) Concurrent systemic therapy/rtc,f (categy 3) j Primary site: CR PR and stable disease in neck Primary site: < PR progression in neck Primary site: Complete clinical response F CR: RT consider chemo/rt; c,f F PR: Chemo/RTc,f Primary site: Complete clinical response Primary site: Residual tum Primary site: residual tum Residual tum in neck Complete clinical response of neck Residual tum in neck Complete clinical response of neck ADJUVANT TREATMENT c RT Chemo/RTc,f Neck dissection d Salvage surgery + neck dissection as indicated d RTc Salvage surgery + neck dissectiond as indicated Chemo/RTc,f Neck dissection d Post-treatment evaluation i Post-treatment evaluation h Negative Positive Salvage surgery + neck dissection as indicated d Negative Positive Observe Neck dissection d Observe Neck dissection d Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Multimodality clinical trials csee Principles of Radiation Therapy (HYPO-A). dsee Principles of Surgery (SURG-A). fsee Principles of Systemic Therapy (CHEM-A). hin randomized clinical trials, assessment of response has been done after 2 3 cycles. isee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). jsee on induction chemotherapy. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. HYPO-5

29 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Hypopharynx Concurrent chemadiation3 Conventional fractionation4 Primary and gross adenopathy: typically 70 Gy (2.0 Gy/fraction) Neck Uninvolved nodal stations: Gy ( Gy/fraction) 1 See Radiation Techniques (RAD-A) and. 2 3See Principles of Systemic Therapy (CHEM-A). 4 Particular attention to speech and swallowing is needed during therapy. Based on published data, concurrent chemadiation most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with singleiagent cisplatin given every 3 weeks at 100 mg/m 2; 2-3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG 0522). Other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing schedules of cisplatin; altered fractionation with chemotherapy are efficacious, and there is no consensus on the optimal approach. In general, the use of concurrent chemadiation carries a high toxicity burden; altered fractionation multiagent chemotherapy will likely further increase the toxicity burden. F any chemadiation approach, close attention should be paid to published repts f the specific chemotherapy agent, dose, and schedule of administration. Chemadiation should be perfmed by an experienced team and should include substantial supptive care. PRINCIPLES OF RADIATION THERAPY 1,2 Note: All recommendations are categy 2A unless otherwise indicated. DEFINITIVE: POSTOPERATIVE: RT RT Primary and gross adenopathy: Preferred interval between resection and postoperative RT Conventional fractionation: Gy (2.0 Gy/fraction; daily is 6 weeks. Monday-Friday) in 7 weeks Primary: Gy (2.0 Gy/fraction) Altered fractionation: Neck 2.0 Gy/fraction; 6 fractions/week accelerated; Involved nodal stations: Gy (2.0 Gy/fraction) Gy to gross disease; Gy to subclinical disease. Uninvolved nodal stations: Gy ( Gy/fraction) Concomitant boost accelerated RT: 72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as Postoperative chemadiation second daily fraction during last 12 treatment days) Concurrent single-agent cisplatin at 100 mg/m2 every 3 weeks is Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) recommended. 5-7 Neck Uninvolved nodal stations: Gy ( Gy/fraction) 5Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with without concomitant chemotherapy f locally advanced head and neck cancer. N Engl J Med 2004;350: Cooper JS, Pajak TF, Fastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy f high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350: Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. HYPO-A

30 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Nasopharynx WORKUP CLINICAL STAGING H&P including a complete head and neck exam; mirr and fiberoptic examination as clinically indicated Nasopharyngeal exam and biopsy Chest imaging MRI with gadolinium of nasopharynx and base of skull to clavicles and CT (as indicated) with contrast Consider PET-CT f stage III-IV disease Dental evaluation as indicated Nutrition, speech and swallowing evaluation/therapy, and audiogram as indicateda Imaging f distant metastases (ie, chest, liver, bone) f Wld Health Organization ( WHO) class 2-3/N2-3 disease (may include PET scan and/ CT) Multidisciplinary consultation as indicated T1, N0, M0 T1, N1-3; T2-T4, Any N Any T, Any N, M1 See Treatment of Primary and Neck (NASO-2) See Treatment of Primary and Neck (NASO-2) See Treatment of Primary and Neck (NASO-2) a See Principles of Nutrition: Management and Supptive Care (NUTR-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. NASO-1

31 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. CLINICAL STAGING Cancer of the Nasopharynx TREATMENT OF PRIMARY AND NECK FOLLOW-UP T1, N0, M0 Definitive RT to nasopharynx and elective RT to neck b T1, N1-3; T2-T4, any N Concurrent chemo/rt (categy 1) b,c Induction chemotherapy (categy 3) followed by chemo/rt Adjuvant chemotherapy c d Neck: Residual tum Neck: Complete clinical response Neck dissection f Observe Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Any T, any N, M1 Platinum-based combination chemotherapy c Concurrent chemo/rt b,c,e RTb to primary and neck Chemo/RTc as clinically indicated bsee Principles of Radiation Therapy (NASO-A). csee Principles of Systemic Therapy (CHEM-A). dsee on induction chemotherapy. ecan be used f select patients with distant metastasis in limited site with small tum burden, f patients with symptoms in the primary any nodal site. fsee Principles of Surgery (SURG-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. NASO-2

32 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Nasopharynx PRINCIPLES OF RADIATION THERAPY 1 Definitive RT: Primary and gross adenopathy: Gy (2.0 Gy/fraction; daily Monday-Friday) in 7 weeks Neck Uninvolved nodal stations: Gy ( Gy/fraction) Concurrent Chemadiation: Conventional fractionation: Primary and gross adenopathy: 70 Gy (2.0 Gy/fraction) Neck Uninvolved nodal stations: Gy ( Gy/fraction) Either IMRT 3-D confmal RT is recommended in cancer of the nasopharynx to minimize dose to critical structures. 1 See Radiation Techniques (RAD-A) and. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. NASO-A

33 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. WORKUP a Cancer of the Glottic Larynx CLINICAL STAGING TREATMENT OF PRIMARY AND NECK Carcinoma in situ See Treatment (GLOT-2) H&P including a complete head and neck exam; mirr and fiberoptic examination as clinically indicated Biopsy Chest imaging CT with contrast and thin cuts through larynx and/ MRI of primary and neck Consider PET-CT f stage III-IV disease Examination under anesthesia with endoscopy Preanesthesia studies Dental/evaluation as indicated Nutrition, speech and swallowing evaluation/therapy, and audiogram as indicatedb Consider videostrobe f select patients Multidisciplinary consultation as indicated Total laryngectomy not required (T1-T2 Select T3) T3 requiring total laryngectomy (N0-1) T3 requiring total laryngectomy (N2-3) T4a disease T4b, any N Unresectable nodal disease Unfit f surgery See Treatment (GLOT-2) See Treatment of Primary and Neck (GLOT-3) See Treatment of Primary and Neck (GLOT-4) See Treatment of Primary and Neck (GLOT-6) See Treatment of Very Advanced Head and Neck Cancer (ADV-1) a Complete wkup is not indicated f Tis, T1. b See Principles of Nutrition: Management and Supptive Care (NUTR-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. GLOT-1

34 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Glottic Larynx CLINICAL STAGING TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT FOLLOW-UP Carcinoma in situ Endoscopic resection RT c RTc Total laryngectomy not required (T1-T2 select T3) Partial laryngectomy/ endoscopic open resectiond as indicated N0 no adverse features e Observe Note: All recommendations are categy 2A unless otherwise indicated. Follow-up (See FOLL-A) c See Principles of Radiation Therapy (GLOT-A). d See Principles of Surgery (SURG-A). eadverse features: extracapsular nodal spread, positive margins, pt3 pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism ( See ). fsee Principles of Systemic Therapy (CHEM-A). g Consider re-resection to achieve negative margins, if feasible. One positive node without adverse features e Adverse features e Extracapsular spread ± positive margin Positive margins Other risk features Consider RT c Chemo/RT c,f (categy 1) Re-resection RTc Consider chemo/rtc,f (f T2 patients) RT c Consider chemo/rt c,f g Recurrent Persistent Disease (See ADV-2) Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. GLOT-2

35 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Glottic Larynx CLINICAL STAGING T3 requiring total laryngectomy (N0-1) TREATMENT OF PRIMARY AND NECK Concurrent systemic therapy/rt, c,f cisplatin ( categy 1) preferred RTc if patient not candidate f systemic therapy/rt N0 Primary site: Complete clinical response (N0 at initial staging) Primary site: Complete clinical response (N+ at initial staging) Primary site: Residual tum Laryngectomy with ipsilateral thyroidectomy d Residual tum in neck Complete clinical response of neck Post-treatment evaluation h Salvage surgery + neck dissection as indicated d Negative Positive ADJUVANT TREATMENT Neck dissection d Observe Neck dissection d Follow-up (See FOLL-A) Surgery d N1 Laryngectomy with ipsilateral thyroidectomy, ipsilateral neck dissection bilateral neck dissectiond No adverse features i Adverse features i Extracapsular spread and/ positive margin Other risk features csee Principles of Radiation Therapy (GLOT-A). dsee Principles of Surgery (SURG-A). fsee Principles of Systemic Therapy (CHEM-A). hsee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). i Adverse features: extracapsular nodal spread, positive margins, pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism ( See ). Note: All recommendations are categy 2A unless otherwise indicated. Chemo/RT c,f (categy 1) RT c Consider chemo/rt c,f Recurrent Persistent Disease (See ADV-2) Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. GLOT-3

36 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. CLINICAL STAGING Cancer of the Glottic Larynx TREATMENT OF PRIMARY AND NECK Concurrent systemic therapy/rt, c,f cisplatin (categy 1) preferred Primary site: Complete clinical response Primary site: Residual tum Residual tum in neck Complete clinical response of neck T3 requiring total laryngectomy (N2-3) Surgery d Laryngectomy with ipsilateral thyroidectomy, ipsilateral bilateral neck dissection d Induction chemotherapy (categy 3) j f See Response Assessment (GLOT-5) Post-treatment evaluation h Salvage surgery + neck dissection as indicated d No adverse features i Adverse features i Other risk features Negative Positive Extracapsular spread and/ positive margin ADJUVANT TREATMENT Neck dissection d Observe Neck dissection d Chemo/RT c,f (categy 1) RT c Consider chemo/rt c,f Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) csee Principles of Radiation Therapy (GLOT-A). dsee Principles of Surgery (SURG-A). fsee Principles of Systemic Therapy (CHEM-A). hsee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). iadverse features: extracapsular nodal spread, positive margins, pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism ( See ). jsee on induction chemotherapy. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. GLOT-4

37 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Glottic Larynx RESPONSE ASSESSMENT Primary site: CR Definitive RT c (categy 1) Consider chemo/rtc,f (categy 2B) Residual tum in neck Complete clinical response of neck Post-treatment evaluation h Neck dissection d Negative Positive Observe Neck dissection d Response after induction chemotherapy f,k Primary site: PR Chemo/RT c,f (categy 2B) CR Residual disease Observe Salvage surgery Follow-up (See FOLL-A) Primary site: < PR Surgery d No adverse features i Adverse features i Extracapsular spread and/ positive margin Other risk features Chemo/RT c,f (categy 1) RT c Consider chemo/rt c,f csee Principles of Radiation Therapy (GLOT-A). dsee Principles of Surgery (SURG-A). fsee Principles of Systemic Therapy (CHEM-A). hsee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). iadverse features: extracapsular nodal spread, positive margins, pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism ( See ). kin randomized clinical trials, assessment of response has been done after 2 3 cycles. Note: All recommendations are categy 2A unless otherwise indicated. RT c Recurrent Persistent Disease (See ADV-2) Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. GLOT-5

38 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Glottic Larynx CLINICAL STAGING T4a, Any N Selected T4a patients who decline surgery TREATMENT OF PRIMARY AND NECK Total laryngectomy with thyroidectomy as indicated N0 ± unilateral bilateral neck dissectiond Surgery d N1 N2-3 Consider concurrent chemadiation c,f Clinical trial f function-preserving surgical nonsurgical management Induction chemotherapy (categy 2B) j Total laryngectomy with thyroidectomy as indicated, ipsilateral neck dissection ± contralateral neck dissection d Total laryngectomy with thyroidectomy as indicated, ipsilateral bilateral neck dissection d f Primary site: Complete clinical response Primary site: Residual tum csee Principles of Radiation Therapy (GLOT-A). dsee Principles of Surgery (SURG-A). fsee Principles of Systemic Therapy (CHEM-A). hsee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). jsee on induction chemotherapy. Residual tum in neck Complete clinical response of neck See Response Assessment (GLOT-5) Post-treatment evaluation h Negative Positive Salvage surgery + neck dissection as indicated d Note: All recommendations are categy 2A unless otherwise indicated. ADJUVANT TREATMENT RT Consider chemo/rtc,f Observation f highly selected patientsl Neck dissection d Observe Neck dissection d Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) l Good risk features f favable T4a patients who could be observed after surgery include: Indolent histopathology: papillary variant of squamous cell carcinoma, verrucous carcinoma. Widely negative margins, pn0 neck, especially central compartment (Level VI) without perineural invasion, lymphovascular invasion. Low-volume disease with microscopic extralaryngeal extension beyond the laryngeal skeleton and widely negative margins. pn0, Broders grade I-II, subglottic extension < 1 cm. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. GLOT-6

39 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Glottic Larynx Concurrent chemadiation2 Conventional fractionation: 3 Primary and gross adenopathy: typically 70 Gy (2.0 Gy/fraction) Neck Uninvolved nodal stations: Gy ( Gy/fraction) Note: All recommendations are categy 2A unless otherwise indicated. PRINCIPLES OF RADIATION THERAPY 1 DEFINITIVE: POSTOPERATIVE: RT RT Tis, N0: Gy in Gy/fraction Preferred interval between resection and postoperative RT T1, N0: Gy in Gy/fraction is 6 weeks. T2, N0: >66 Gy using conventional fractionation (2.0 Gy/fraction) Primary: Gy (2.0 Gy/fraction) T2 and gross adenopathy: Neck Conventional fractionation: Gy (2.0 Gy/fraction; daily Involved nodal stations: Gy (2.0 Gy/fraction) Monday-Friday) in 7 weeks Uninvolved nodal stations: Gy ( Gy/fraction) Altered fractionation: 2.0 Gy/fraction; 6 fractions/week accelerated Postoperative chemadiation Gy to gross disease, Concurrent single-agent cisplatin at 100 mg/m2 every 3 weeks is Gy to subclinical disease. recommended. 4-6 Concomitant boost accelerated RT: 72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) Hyperfractionation: Gy/7 weeks (1.2 Gy/fraction, twice daily) Neck Uninvolved nodal stations: Gy ( Gy/fraction) 1See Radiation Techniques (RAD-A) and. 4 2See Principles of Systemic Therapy (CHEM-A). 3Based on published data, concurrent chemadiation most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m 2 ; 2-3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG 0522). Other fraction sizes (eg, 1.8 Gy, N Engl J Med 2004;350: conventional), multiagent chemotherapy, other dosing schedules of cisplatin, altered 6 fractionation with chemotherapy are efficacious, and there is no consensus on the optimal approach. In general, the use of concurrent chemadiation carries a high toxicity burden; altered fractionation multiagent chemotherapy will likely further increase the toxicity burden. F any chemadiation approach, close attention should be paid to published repts f the specific chemotherapy agent, dose, and schedule of administration. Chemadiation should be perfmed by an experienced team and should include substantial supptive care. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with without concomitant chemotherapy f locally advanced head and neck cancer. N Engl J Med 2004;350:1945- Cooper JS, Pajak TF, Fastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy f high-risk squamous-cell carcinoma of the head and neck. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. GLOT-A

40 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Supraglottic Larynx WORKUP CLINICAL STAGING Not requiring total laryngectomy (Most T1-2, N0; Selected T3) See Treatment of Primary and Neck (SUPRA-2) H&P including a complete head and neck exam; mirr and fiberoptic examination as clinically indicated Biopsy Chest imaging CT with contrast and thin cuts through larynx and/ MRI of primary and neck Consider PET-CT f stage III-IV disease Examination under anesthesia with endoscopy Preanesthesia studies Dental evaluation as indicated Nutrition, speech and swallowing evaluation/therapy, and audiogram as indicateda Consider videostrobe f select patients Multidisciplinary consultation as indicated Requiring total laryngectomy (T3, N0) T4a, N0 Node-positive disease See Treatment of Primary and Neck (SUPRA-3) See Treatment of Primary and Neck (SUPRA-8) See Clinical Staging (SUPRA-4) T4b, any N Unresectable nodal disease Unfit f surgery See Treatment of Very Advanced Head and Neck Cancer (ADV-1) a See Principles of Nutrition: Management and Supptive Care (NUTR-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SUPRA-1

41 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Supraglottic Larynx CLINICAL STAGING TREATMENT OF PRIMARY AND NECK PATHOLOGY STAGE ADJUVANT TREATMENT FOLLOW-UP Node negative, (T1-T2, N0) One positive node without other adverse features Consider RT c Not requiring total laryngectomy (Most T1-2, N0; Selected T3 patients) Endoscopic resection ± neck dissectionb Open partial supraglottic laryngectomy ± neck dissectionb Definitive RTc Positive node; Adverse features: positive margins Adverse features: extracapsular nodal spread d Re-resection RTc Consider chemo/rtc,e (categy 2B) Chemo/RTc,e (categy 1) RT c (categy 2B f select patients) Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Node negative, (T3-T4a, N0) See Treatment (SUPRA-3) and (SUPRA-8) bsee Principles of Surgery (SURG-A). csee Principles of Radiation Therapy (SUPRA-A). dconsider re-resection to achieve negative margins, if feasible. esee Principles of Systemic Therapy (CHEM-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SUPRA-2

42 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Supraglottic Larynx CLINICAL STAGING Requiring total laryngectomy (T3, N0) TREATMENT OF PRIMARY AND NECK Concurrent systemic therapy/rt, c,e cisplatin (categy 1) preferred Laryngectomy, ipsilateral thyroidectomy with ipsilateral bilateral neck dissection b RTc if patient not medical candidate f concurrent systemic therapy/rt Primary site: Complete clinical response Primary site: Residual tum N0 one positive node without adverse features g Adverse features g Other risk features Salvage surgery + neck dissection as indicated c Extracapsular spread and/ positive margin ADJUVANT TREATMENT RTc optional Chemo/RT c,e (categy 1) RT c Consider chemo/rt c,e Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) bsee Principles of Surgery (SURG-A). csee Principles of Radiation Therapy (SUPRA-A). esee Principles of Systemic Therapy (CHEM-A). Induction chemotherapye (categy 3) f See Response Assessment (SUPRA-7) fsee on induction chemotherapy. g Adverse features: extracapsular nodal spread, positive margins, pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism ( See ). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SUPRA-3

43 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Supraglottic Larynx CLINICAL STAGING Not requiring total laryngectomy (T1-2, N+ and selected T3, N1) See Treatment of Primary and Neck (SUPRA-5) Requiring total laryngectomy (Most T3, N2-3) See Treatment of Primary and Neck (SUPRA-6) Node positive disease T4a, N1-N3 See Treatment of Primary and Neck (SUPRA-8) T4b, any N Unresectable nodal disease Unfit f surgery See Treatment of Head and Neck Cancer (ADV-1) Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SUPRA-4

44 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Supraglottic Larynx CLINICAL STAGING Not requiring total laryngectomy (T1-2, N+ and selected T3, N1) TREATMENT OF PRIMARY AND NECK Concurrent systemic therapy/rt, c,e cisplatin (categy 1) preferred Definitive RT c Partial supraglottic laryngectomy and neck dissection(s) b Primary site: Complete clinical response Primary site: Residual tum No adverse features g Adverse features g Residual tum in neck Complete clinical response of neck Post-treatment evaluation h Salvage surgery + neck dissection as indicated b Extracapsular spread and/ positive margin ADJUVANT TREATMENT Neck dissection b Observe RT c Chemo/RT c,e (categy 1) Negative Positive Observe Neck dissection b Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Induction chemotherapy (categy 3) f e See Response Assessment (SUPRA-7) Other risk features RT c Consider chemo/rt c,e bsee Principles of Surgery (SURG-A). csee Principles of Radiation Therapy (SUPRA-A). esee Principles of Systemic Therapy (CHEM-A). fsee on induction chemotherapy. gadverse features: extracapsular nodal spread, positive margins, pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism ( See ). hsee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SUPRA-5

45 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Supraglottic Larynx CLINICAL STAGING TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT Concurrent systemic therapy/rt, c,e cisplatin (categy 1) preferred Primary site: Complete clinical response Residual tum in neck Complete clinical response of neck Neck dissection b Post-treatment evaluation h Negative Positive Observe Neck dissection b Requiring total laryngectomy (Most T3, N2-N3) Laryngectomy, ipsilateral thyroidectomy with neck dissection b Induction chemotherapy (categy 2B) e,f Primary site: Residual tum No adverse features g Adverse features g Salvage surgery + neck dissection as indicated b Extracapsular spread and/ positive margin Other risk features RT c Chemo/RT c,e (categy 1) RT c Consider chemo/rt c,e See Response Assessment (SUPRA-7) Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) bsee Principles of Surgery (SURG-A). csee Principles of Radiation Therapy (SUPRA-A). esee Principles of Systemic Therapy (CHEM-A). fsee on induction chemotherapy. g hsee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). Adverse features: extracapsular nodal spread, positive margins, pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism ( See ). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SUPRA-6

46 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Supraglottic Larynx RESPONSE ASSESSMENT Primary site: CR Definitive RT c (categy 1) Consider chemo/rtc,e (categy 2B) Residual tum in neck Complete clinical response of neck Post-treatment evaluation h Neck dissection b Negative Positive Observe Neck dissection b Response after induction chemotherapy e,i Primary site: PR Primary site: < PR Chemo/RT c,e (categy 2B) Surgery b CR Residual disease No adverse features g Adverse features g Extracapsular spread and/ positive margin Other risk features bsee Principles of Surgery (SURG-A). csee Principles of Radiation Therapy (SUPRA-A). esee Principles of Systemic Therapy (CHEM-A). g hsee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). i In randomized clinical trials, assessment of response has been done after 2 3 cycles. Observe Salvage surgery Chemo/RT c,e (categy 1) RT c Consider chemo/rt c,e Note: All recommendations are categy 2A unless otherwise indicated. RT c Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Adverse features: extracapsular nodal spread, positive margins, pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism ( See ). Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SUPRA-7

47 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Supraglottic Larynx CLINICAL STAGING TREATMENT OF PRIMARY AND NECK ADJUVANT TREATMENT T4a, N0-N3 Laryngectomy, appropriate thyroidectomy with ipsilateral bilateral neck dissection b Extracapsular spread and/ positive margin g Chemo/RT c,e (categy 1) Other risk features g RTc Consider chemo/rtc,e T4a, N0-N3 patients who decline surgery Consider concurrent chemadiationc,e Clinical trial Primary site: Complete clinical response Primary site: Residual tum Residual tum in neck Complete clinical response of neck Post-treatment evaluation h Negative Positive Salvage surgery + neck dissection as indicated b Neck dissection b Observe Neck dissection b Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Induction chemotherapy (categy 2B) e,f See Response Assessment (SUPRA-7) bsee Principles of Surgery (SURG-A). csee Principles of Radiation Therapy (SUPRA-A). esee Principles of Systemic Therapy (CHEM-A). fsee on induction chemotherapy. gadverse features: extracapsular nodal spread, positive margins, pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism (See ). hsee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SUPRA-8

48 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Cancer of the Supraglottic Larynx DEFINITIVE: RT T1-2, N0: Gy conventional (2.0 Gy/fraction) T2-3, N0-1: Conventional fractionation: Primary and gross adenopathy: Gy (2.0 Gy/fraction), Gy (2.0 Gy/fraction; daily Monday-Friday) in 7 weeks Neck, uninvolved nodal stations: Gy ( Gy/fraction) Altered fractionation: 2.0 Gy/fraction; 6 fractions/week accelerated; Gy to gross disease; Gy to subclinical disease. Concomitant boost accelerated RT: 72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction twice daily) Neck Uninvolved nodal stations: Gy ( Gy/fraction) Concurrent chemadiation2 Conventional fractionation3 Primary and gross adenopathy: typically 70 Gy (2.0 Gy/fraction) Neck Uninvolved nodal stations: Gy ( Gy/fraction) PRINCIPLES OF RADIATION THERAPY 1 POSTOPERATIVE: RT Preferred interval between resection and postoperative RT is 6 weeks. Primary: Gy (2.0 Gy/fraction) Neck Involved nodal stations: Gy (2.0 Gy/fraction) Uninvolved nodal stations: Gy ( Gy/fraction) Postoperative chemadiation Concurrent single-agent cisplatin at 100 mg/m2 every 3 weeks is recommended See Radiation Techniques (RAD-A) and. 4Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with without 2See Principles of Systemic Therapy (CHEM-A). concomitant chemotherapy f locally advanced head and neck cancer. N Engl J Med 2004;350: Based on published data, concurrent chemadiation most commonly uses 5 conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 wks with Cooper JS, Pajak TF, Fastiere AA, et al. Postoperative concurrent radiotherapy and single-agent cisplatin given every 3 weeks at 100 mg/m2; 2-3 cycles of chemotherapy chemotherapy f high-risk squamous-cell carcinoma of the head and neck. are used depending on the radiation fractionation scheme (RTOG 0522). Other fraction N Engl J Med 2004;350: sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing schedules of Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and cisplatin, altered fractionation with chemotherapy are efficacious, and there is no neck cancers: A comparative analysis of concurrent postoperative radiation plus consensus on the optimal approach. In general, the use of concurrent chemadiation chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck carries a high toxicity burden; altered fractionation multiagent chemotherapy will 2005;27: likely further increase the toxicity burden. F any chemadiation approach, close attention should be paid to published repts f the specific chemotherapy agent, dose, and schedule of administration. Chemadiation should be perfmed by an experienced team and should include substantial supptive care. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SUPRA-A

49 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Ethmoid Sinus Tums CLINICAL PRESENTATION WORKUP PATHOLOGY Unresected mass Incompletely resected mass H&P including a complete head and neck exam; mirr and fiberoptic examination as clinically indicated CT and/ MRI Chest imaging Biopsy unless pri tissue available Squamous cell carcinoma Adenocarcinoma Min salivary gland tum Sarcoma (non-rhabdomyosarcoma) Esthesioneuroblastomas Undifferentiated carcinoma (sinonasal undifferentiated carcinoma [SNUC], small cell neuroendocrine) a Mucosal melanoma (See NCCN Guidelines f Mucosal Melanoma MM-1) See Primary Treatment (ETHM-2) Lymphoma ( See NCCN Guidelines f Non-Hodgkin's Lymphoma) a F sinonasal undifferentiated carcinoma (SNUC) and small cell neuroendocrine histologies, systemic therapy should be a part of the overall treatment. Consider referral to a maj medical center that specializes in these diseases. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ETHM-1

50 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Ethmoid Sinus Tums CLINICAL PRESENTATION Newly diagnosed; T1, T2 Newly diagnosed; T3, T4a Newly diagnosed, T4b patient declines surgery Diagnosed after incomplete resection (eg, polypectomy, endoscopic procedure) and gross residual disease Diagnosed after incomplete resection (eg, polypectomy, endoscopic procedure) and no residual disease on physical exam, imaging, and/ endoscopy PRIMARY TREATMENT Surgical resection b (preferred) Definitive RT d Surgical resection b (preferred) Chemo/RT c,d Chemo/RTc,d RTd Clinical trial (preferred) Surgery b (preferred), if feasible RTd Chemo/RTc,d RT d Surgery, b if feasible (See newly diagnosed T1,T2) bsee Principles of Surgery (SURG-A). e csee Principles of Systemic Therapy (CHEM-A). dsee Principles of Radiation Therapy (ETHM-A). F min salivary gland tums, f see SALI-A. ADJUVANT TREATMENT RTd Observatione f T1 only (categy 2B) Consider chemo/rt c,d (categy 2B) if adverse featuresf RTd Consider chemo/rt c,d (categy 2B) if adverse featuresf RTd Consider chemo/rt c,d (categy 2B) if adverse featuresf RTd Observatione f T1 only (categy 2B) Pathologic features: negative margins, favable histology, central tums, low-grade tums. Adverse features include positive margins and intracranial extension ( See ). Note: All recommendations are categy 2A unless otherwise indicated. FOLLOW-UP Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ETHM-2

51 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Ethmoid Sinus Tums PRINCIPLES OF RADIATION THERAPY 1 DEFINITIVE: RT Primary and gross adenopathy: Conventional fractionation: Gy (2.0 Gy/fraction; daily Monday-Friday) in 7 weeks Altered fractionation: 2.0 Gy/fraction; 6 fractions/week accelerated; Gy to gross disease; Gy to subclinical disease. Concomitant boost accelerated RT: 72 Gy/6 weeks (2 Gy once daily and then 1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) Neck Uninvolved nodal stations: Gy ( Gy/fraction) 2 POSTOPERATIVE: RT Primary: Gy (2.0 Gy/fraction) Neck Involved nodal stations: Gy (2.0 Gy/fraction) Uninvolved nodal stations: Gy ( Gy/fraction) 2 Primary and gross adenopathy: Preferred interval between resection and postoperative RT is 6 weeks Postoperative chemadiation Concurrent single-agent cisplatin at 100 mg/m2 every 3 weeks is recommended. Concurrent chemadiation3 Primary and gross adenopathy: typically 70 Gy (2.0 Gy/fraction; daily Monday-Friday) in 7 weeks4 Neck: Uninvolved nodal stations: Gy ( Gy/fraction) 2 Either IMRT 3-D confmal RT is recommended f maxillary sinus paranasal/ethmoid sinus tums to minimize dose to critical structures. 1 See Radiation Techniques (RAD-A) and. 2 Treatment to uninvolved nodal stations is not consistently perfmed at all institutions. 3See Principles of Systemic Therapy (CHEM-A). 4 In the paranasal sinus area, care should be taken to avoid critical neural structures in the volume; therefe, 1.8 Gy/fraction can be considered. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ETHM-A

52 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Maxillary Sinus Tums WORKUP PATHOLOGY H&P including a complete head and neck exam; mirr and fiberoptic examination as clinically indicated Complete head and neck CT with contrast and/ MRI Dental/prosthetic consultation as indicated Chest imaging Biopsy a Squamous cell carcinoma Adenocarcinoma Min salivary gland tum Sarcoma (nonrhabdomyosarcoma) Esthesioneuroblastoma Undifferentiated carcinoma (SNUC, small cell neuroendocrine) b Mucosal melanoma (See Guidelines f Mucosal Melanoma MM-1) Lymphoma T1-2, N0 All histologies T3-4, N0, Any T, N+ All histologies See NCCN Guidelines f Non-Hodgkin s Lymphoma See Primary Treatment (MAXI-2) See Primary Treatment (MAXI-3) a Biopsy: Preferred route is transnasal. Needle biopsy may be acceptable. Avoid canine fossa puncture Caldwell-Luc approach. b F sinonasal undifferentiated carcinoma (SNUC) and small cell neuroendocrine histologies, systemic therapy should be a part of the overall treatment. Consider referral to a maj medical center that specializes in these diseases. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MAXI-1

53 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Maxillary Sinus Tums STAGING PRIMARY TREATMENT ADJUVANT TREATMENT FOLLOW-UP Margin negative T1-2, N0 All histologies except adenoid cystic Surgical resection c Perineural invasion Margin positive Consider RTd Consider chemo/rtd,e (categy 2B) Surgical re-resection, f if possible Margin negative Margin positive Consider RT d Chemo/RTd,e (categy 2B) Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) T1-2, N0 Adenoid cystic Surgical resection c Suprastructure c Infrastructure c RT g Observation RT g csee Principles of Surgery (SURG-A). dsee Principles of Radiation Therapy (MAXI-A). e See Principles of Systemic Therapy (CHEM-A). fconsider re-resection to achieve negative margins, if feasible. g F adenoid cystic tums and min salivary gland tums, see (SALI-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MAXI-2

54 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Maxillary Sinus Tums STAGING PRIMARY TREATMENT ADJUVANT TREATMENT FOLLOW-UP T3-T4a, N0 Adverse features h Complete surgical resection c RTd,g to primary and neck (categy 2B No adverse features h Chemo/RTd,e to primary and neck (categy 2B) f neck) (f squamous cell carcinoma and undifferentiated tums) T4b, any N Clinical trial Definitive RTg Chemo/RTd,e Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) T1-T4a, N+ Adverse features h Surgical resection + neck dissection c No adverse RTd,g to primary + neck features h Chemo/RTd,e to primary and neck (categy 2B) csee Principles of Surgery (SURG-A). dsee Principles of Radiation Therapy (MAXI-A). e See Principles of Systemic Therapy (CHEM-A). gf adenoid cystic tums and min salivary gland tums, see (SALI-A). hadverse features include positive margins extracapsular nodal spread ( See ). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MAXI-3

55 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Maxillary Sinus Tums PRINCIPLES OF RADIATION THERAPY 1 DEFINITIVE: POSTOPERATIVE: RT RT Conventional fractionation: Gy (2.0 Gy/fraction; daily Primary: Gy (2.0 Gy/fraction) Monday-Friday) in 7 weeks Neck Altered fractionation: Involved nodal stations: Gy ( 2.0 Gy/fraction) 2.0 Gy/fraction; 6 fractions/week accelerated; Uninvolved nodal stations: Gy ( Gy/fraction) Gy to gross disease; Primary and gross adenopathy: Preferred interval between resection and postoperative RT Gy to subclinical disease Concomitant boost accelerated RT: 72 Gy/6 weeks (2 Gy once is 6 weeks daily and then 1.8 Gy/fraction, large field; 1.5 Gy boost as second Postoperative chemadiation daily fraction during last 12 treatment days) Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) Concurrent single-agent cisplatin at Neck 100 mg/m2 every 3 weeks is recommended. Uninvolved nodal stations: Gy ( Gy/fraction) 2 Concurrent chemadiation3 Primary and gross adenopathy: typically 70 Gy (2.0 Gy/fraction; daily Monday-Friday) in 7 weeks4 Neck: Uninvolved nodal stations: Gy ( Gy/fraction) 2 Either IMRT 3-D confmal RT is recommended f maxillary sinus paranasal/ethmoid sinus tums to minimize dose to critical structures. 1 See Radiation Techniques (RAD-A) and. 2 Treatment to uninvolved nodal stations is not consistently perfmed at all institutions. (Le QT, Fu KK, Kaplan MJ, et al. Lymph node metastasis in maxillary sinus carcinoma. Int J Radiat Oncol Biol Phys 2000;46: ) 3See Principles of Systemic Therapy (CHEM-A). 4In the paranasal sinus area, care should be taken to avoid critical neural structures in the volume; therefe, 1.8 Gy/fraction can be considered. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MAXI-A

56 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Very Advanced Head and Neck Cancer DIAGNOSIS TREATMENT OF HEAD AND NECK CANCER Newly diagnosed (M0); T4b, any N, Unresectable nodal disease Unfit f surgery Clinical trial preferred Standard therapy PS 0-1 PS 2 Concurrent systemic therapy/rt, cisplatin a,b (categy 1) preferred Induction chemotherapy b (categy 3) followed by RTc chemadiation Definitive RTc ± concurrent systemic therapyb c Residual neck disease + primary site controlled: Neck dissection, d if feasible Follow-up (See FOLL-A) PS 3 RTc Single-agent chemotherapy b Best supptive care Recurrent Persistent Disease (See ADV-2) PS = Perfmance Status (Eastern Cooperative Oncology Group [ECOG]) athe single-agent cisplatin carboplatin chemadiotherapy regimens have not been compared in randomized trials. Therefe, no optimal standard regimen is defined. Combination chemotherapy regimens are me toxic and have not been directly compared to single-agent regimens. bsee Principles of Systemic Therapy (CHEM-A). csee Principles of Radiation Therapy (ADV-A). dsee Principles of Surgery (SURG-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ADV-1

57 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Very Advanced Head and Neck Cancer DIAGNOSIS Locegional recurrence without pri RT Resectable TREATMENT OF HEAD AND NECK CANCER Surgery d Chemo/RT b,c No adverse features e Adverse features e Extracapsular spread and/ positive margin Other risk features Observe Follow-up (See FOLL-A) Chemo/RT b,c (categy 1) RTc Consider chemo/rt b,c Recurrent Persistent disease Locegional recurrence Second primary with pri RT Distant metastases Unresectable Resectable Unresectable Clinical trial preferred PS 0-1 See Treatment of Very Advanced Head and Neck Cancer (ADV-1) Surgery d ± reirradiation ± chemotherapy, clinical trial preferred Reirradiation ± chemotherapy, clinical trial preferred Chemotherapy (see distant metastases pathway) Platinum + 5-FU + cetuximab (categy 1) Combination chemotherapyb Single-agent chemotherapyb Salvage therapy f persistent disease as indicated Chemotherapy, clinical trial preferred Best supptive care Standard therapy b PS 2 Single-agent chemotherapyb Best supptive care Best supptive care bsee Principles of Systemic Therapy (CHEM-A). csee Principles of Radiation Therapy (ADV-A). PS 3 Best supptive care PS = Perfmance Status (ECOG) dsee Principles of Surgery (SURG-A). eadverse features: extracapsular nodal spread, positive margins, pt3 pt4 primary, N2 N3 nodal disease, perineural invasion, vascular embolism ( See ). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ADV-2

58 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Very Advanced Head and Neck Cancer PRINCIPLES OF RADIATION THERAPY 1,2 CONCURRENT CHEMORADIATION (preferred): Conventional fractionation: Primary and gross adenopathy: typically 70 Gy (2.0 Gy/fraction) Neck Uninvolved nodal stations: Gy ( Gy/fraction) CHEMORADIATION Based on published data, concurrent chemadiation most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m 2; 2-3 cycles of chemotherapy are used depending on the radiation fractionation scheme. 4 Other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing schedules of cisplatin; altered fractionation with chemotherapy are efficacious, and there is no consensus on the optimal approach. In general, the use of concurrent chemadiation carries a high toxicity burden; altered fractionation multiagent chemotherapy will likely further increase the toxicity burden. F any chemadiation approach, close attention should be paid to published repts f the specific chemotherapy agent, dose, and schedule of administration. Chemadiation should be perfmed by an experienced team and should include substantial supptive care. 3 DEFINITIVE RT: Conventional fractionation: Primary and gross adenopathy: Gy (2.0 Gy/fraction; daily Monday-Friday) in 7 weeks Neck Uninvolved nodal stations: Gy ( Gy/fraction) Altered fractionation: 2.0 Gy/fraction; 6 fractions/week accelerated; 70 Gy to gross disease; 50 Gy to subclinical disease. Concomitant boost accelerated RT: 72 Gy/6 weeks (1.8 Gy/fraction, large field; 1.5 Gy boost as second daily fraction during last 12 treatment days) Hyperfractionation: 81.6 Gy/7 weeks (1.2 Gy/fraction, twice daily) Modified fractionation total dose > 70 Gy and treatment course < 7 weeks POSTOPERATIVE: RT Preferred interval between resection and postoperative RT is 6 weeks. Primary: Gy (2.0 Gy/fraction) Neck Involved nodal stations: Gy (2.0 Gy/fraction) Uninvolved nodal stations: Gy ( Gy/fraction) Postoperative chemadiation Concurrent single-agent cisplatin at 100 mg/m2 every 3 weeks is recommended. 5-7 Footnotes and references on next page. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. Continue ADV-A 1of2

59 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Very Advanced Head and Neck Cancer PRINCIPLES OF RADIATION THERAPY (References) 1 See Radiation Techniques (RAD-A) and. 2In general, the reirradiated population of head and neck cancer patients as described in the current literature represents a diverse but highly selected group of patients treated in centers where there is high level of expertise and systems in place f managing acute and long-term toxicities. When the goal of treatment is salvage and surgery is not an option, reirradiation strategies can be considered f patients who: develop failures second primaries at 6 months after the initial radiotherapy; can receive additional doses of radiotherapy of at least 60 Gy without exceeding the spinal cd limit of 50 Gy, (ie, total combined doses of pri radiotherapy and anticipated radiotherapy); and can tolerate concurrent chemotherapy ( McDonald M, Lawson J, Garg M, et al. ACR appropriateness criteria retreatment of recurrent head and neck cancer after pri definitive radiation. Expert panel on radiation oncology-head and neck cancer. Int J Radiat Oncol Biol Phys 2011;80: ). 3See Principles of Systemic Therapy (CHEM-A). 4RTOG 0522: a randomized phase III trial of concurrent accelerated radiation and cisplatin versus concurrent accelerated radiation, cisplatin, and cetuximab [followed by surgery f selected patients] f stage III and IV head and neck carcinomas. Clin Adv Hematol Oncol 2007;5: Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with without concomitant chemotherapy f locally advanced head and neck cancer. N Engl J Med 2004;350: Cooper JS, Pajak TF, Fastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy f high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350: Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27: Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ADV-A 2of2

60 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Occult Primary PRESENTATION Neck mass H&P and Complete head and neck exam with attention to skin; palpation of the base of tongue and opharynx; mirr and fiberoptic examination as indicated to visualize nasopharynx, opharynx, hypopharynyx, and larynx Fine needle aspiration (FNA) a Squamous cell carcinoma, adenocarcinoma, and anaplastic epithelial tums b Lymphoma Thyroid WORKUP Chest imaging CT with contrast MRI with gadolinium (skull base through thacic inlet) PET/CT scan as indicated (befe exam under anesthesia) HPV, Epstein-Barr virus (EBV) testing suggested f squamous cell undifferentiated histologyc Thyroglobulin and calcitonin staining f adenocarcinoma and anaplastic undifferentiated tums See NCCN Guidelines f Non-Hodgkin s Lymphomas See NCCN Guidelines f Thyroid Carcinoma Note: All recommendations are categy 2A unless otherwise indicated. See Wkup and Treatment (OCC-2) Systemic wk-up per See Primary Melanoma NCCN Guidelines f Melanoma Therapy f Melanoma Skin exam, note regressing lesions (MM-4) a Repeat FNA, ce, open biopsy may be necessary f uncertain non-diagnostic histologies. Patient should be prepared f neck dissection at time of open biopsy, if indicated. bdetermined with appropriate immunohistochemical stains. cwhether HPV EBV positive status may help to define the radiation fields is being investigated ( See ). dstrongly consider referral to a high-volume, multidisciplinary cancer center. Primary found Primary not found d Treat as appropriate (See Guidelines Index) Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OCC-1

61 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Occult Primary PATHOLOGIC FINDINGS WORKUP DEFINITIVE TREATMENT Primary found Treat as appropriate (See Guidelines Index) Node level I, II, III, upper V Node level IV, lower V EUA Palpation and inspection Biopsy of areas of clinical concern and tonsillectomy Direct laryngoscopy and nasopharynx survey EUA including direct laryngoscopy, esophagoscopy Chest/abdominal/ pelvic CT ( PET-CT if not previously perfmed) Adenocarcinoma of neck node, thyroglobulin negative, calcitonin negative Levels I-III Levels IV, V Poly differentiated nonkeratinizing squamous cell not otherwise specified (NOS) anaplastic (not thyroid) of neck node Squamous cell carcinoma of neck node e Neck dissection + parotidectomy, if indicated f Evaluate f infraclavicular primary See Definitive Treatment (OCC-3) g RT to neck ± parotid bed Neck dissection, f if indicated ehpv and EBV testing are suggested if not yet done. fsee Principles of Surgery (SURG-A). gsee Principles of Radiation Therapy (OCC-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OCC-2

62 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Occult Primary HISTOLOGY DEFINITIVE TREATMENT Surgeryf (preferred f < N2 disease) Neck dissection f N1 without extracapsular spread N2, N3 without extracapsular spread Extracapsular spread See OCC-4 See OCC-5 See OCC-6 Poly differentiated nonkeratinizing squamous cell NOS anaplastic (not thyroid) Squamous cell carcinoma RTg f < N2 (categy 2B) Chemotherapy/RTg,h f N2 (categy 2B) Induction chemotherapyh,i (categy 3) followed by chemo/rtg,h RT Complete clinical response Residual tum in neck Post-treatment evaluation j Neck dissection f Negative Positive Observe Neck dissection f fsee Principles of Surgery (SURG-A). gsee Principles of Radiation Therapy (OCC-A). hsee Principles of Systemic Therapy (CHEM-A). isee on induction chemotherapy. jsee Post Chemadiation RT Neck Evaluation (SURG-A 7 of 7). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OCC-3

63 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Occult Primary TREATMENT Level I only RTg to al cavity, opharynx, and bilateral neck (block RT to the larynx) Observation Post neck dissection N1 without extracapsular spread Level II, III, upper level V Level IV only Lower level V RTc,g to opharynx, nasopharynx, hypopharynx, and bilateral neck Observation RTg to opharynx, larynx, hypopharynx, and bilateral neck Observation RTg to larynx, hypopharynx, and bilateral neck Observation Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) cwhether HPV EBV positive status may help to define the radiation fields is being investigated gsee Principles of Radiation Therapy (OCC-A). ( See ). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OCC-4

64 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Occult Primary TREATMENT Level I only RTg to al cavity, opharynx, and bilateral neck (block RT to the larynx) Chemotherapy/RT g,h (categy 2B) RTg to neck only (categy 3) Post neck dissection N2, N3 without extracapsular spread Level II, III, upper level V Level IV only Lower level V RTc,g to nasopharynx, bilateral neck, hypopharynx, larynx, and opharynx Chemotherapy/RT g,h (categy 2B) RTg to neck only (categy 3) RTg to opharynx, larynx, hypopharynx, and bilateral neck Chemotherapy/RT g,h (categy 2B) RTg to neck only (categy 3) RTg to larynx, hypopharynx, and bilateral neck Chemotherapy/RT g,h (categy 2B) RTg to neck only (categy 3) Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) cwhether HPV EBV positive status may help to define the radiation fields is being investigated gsee Principles of Radiation Therapy (OCC-A). hsee Principles of Systemic Therapy (CHEM-A). ( See ). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OCC-5

65 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Occult Primary TREATMENT Level I only Chemotherapy/RT g,h (categy 1) with RTg to al cavity, opharynx, and bilateral neck (block RT to the larynx) RTg to neck only (categy 3) Post neck dissection Extracapsular spread Level II, III, upper level V Level IV only Lower level V Chemotherapy/RT g,h (categy 1) with RTc,g to nasopharynx, bilateral neck, hypopharynx, larynx, and opharynx RTg to neck only (categy 3) Chemotherapy/RT g,h (categy 1) with RTg to opharynx, larynx, hypopharynx, and bilateral neck RTg to neck only (categy 3) Chemotherapy/RT g,h (categy 1) with RTg to larynx, hypopharynx, and bilateral neck RTg to neck only (categy 3) Follow-up (See FOLL-A) Recurrent Persistent Disease (See ADV-2) cwhether HPV EBV positive status may help to define the radiation fields is being investigated gsee Principles of Radiation Therapy (OCC-A). hsee Principles of Systemic Therapy (CHEM-A). ( See ). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OCC-6

66 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Occult Primary DEFINITIVE RT: Conventional fractionation: Gross adenopathy: Gy (2.0 Gy/fraction; daily Monday-Friday) in 7 weeks Mucosal dosing: Gy (2.0 Gy/ fraction) to putative mucosal sites, depending on field size. Consider higher dose to Gy to particularly suspicious areas Neck: Uninvolved nodal stations: Gy ( Gy/fraction) PRINCIPLES OF RADIATION THERAPY 1,2 POSTOPERATIVE: RT Conventional fractionation: Mucosal dose: Gy (2.0 Gy/ fraction) to putative mucosal sites, depending on field size. Consider higher dose to Gy to particularly suspicious areas Neck: Uninvolved nodal stations: Gy ( Gy/fraction) Involved nodal stations: Gy (2.0 Gy/fraction) Concurrent Chemadiation: 3 Conventional fractionation: 4 Postoperative chemadiation Gross adenopathy: typically 70 Gy (2.0 Gy/fraction) Concurrent single-agent cisplatin at 100 mg/m2 every 3 weeks is Mucosal dosing: Gy (2.0 Gy/fraction) to putative recommended. 5-7 mucosal primary sites, depending on field size and use of chemotherapy. Consider higher dose to Gy to particularly suspicious areas Neck: Uninvolved nodal stations: Gy ( Gy/fraction) Either IMRT 3-D confmal RT is recommended when targeting the opharynx to minimize the dose to critical structures, especially the parotid glands. 1F squamous cell carcinoma, adenocarcinoma, and poly differentiated carcinoma. 2See Radiation Techniques (RAD-A) and. 3See Principles of Systemic Therapy (CHEM-A). 4Based on published data, concurrent chemadiation most commonly uses conventional fractionation at 2.0 Gy per fraction to a typical dose of 70 Gy in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m2 ; 2-3 cycles of chemotherapy are used depending on the radiation fractionation scheme (RTOG 0522). Other fraction sizes (eg, 1.8 Gy, conventional), multiagent chemotherapy, other dosing schedules of cisplatin, altered fractionation with chemotherapy are efficacious, and there is no consensus on the optimal approach. In general, the use of concurrent chemadiation carries a high toxicity burden; altered fractionation multiagent chemotherapy will likely further increase the toxicity burden. F any chemadiation approach, close attention should be paid to published repts f the specific chemotherapy agent, dose, and schedule of administration. Chemadiation should be perfmed by an experienced team and should include substantial supptive care. 5Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with without concomitant chemotherapy f locally advanced head and neck cancer. N Engl J Med 2004;350: Cooper JS, Pajak TF, Fastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy f high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350: Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). Head Neck 2005;27: Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. OCC-A

67 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Salivary Gland Tums CLINICAL PRESENTATION WORKUP Unresected salivary gland mass Parotid Submandibular Min salivary glanda H&P including a complete head and neck exam; mirr and fiberoptic examination as clinically indicated CT/MRI, if clinically indicatedb Chest imaging FNA biopsy Clinically benignc Carcinoma See SALI-2 Incompletely resected salivary gland mass Lymphoma See NCCN Guidelines f Non-Hodgkin s Lymphomas asite and stage determine therapeutic approaches. bf advanced cancer, this includes CT/MRI: base of skull to clavicle. ccharacteristics of a benign tum include mobile superficial lobe, slow growth, painless, VII intact, and no neck nodes. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SALI-1

68 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Salivary Gland Tums Clinically benignc carcinoma, T1, T2 Complete surgical resection d PATHOLOGY RESULT Benign Low grade Adenoid cystic; Intermediate high grade If tum spillage perineural invasion, consider RT e Consider RTe (categy 2B f T1) Follow-up as clinically indicated Follow-up (See FOLL-A) Recurrent Persistent Disease (See SALI-4) Benign Follow-up as clinically indicated T3, T4a Surgical evaluation Parotid gland T4b Cancer site No surgical resection possible surgical resection not recommended Other salivary glands See Treatment (SALI-3) Definitive RTe Chemo/RT (categy 2B) Follow-up (See FOLL-A) ccharacteristics of a benign tum include mobile superficial lobe, slow growth, no pain, VII intact, and no neck nodes. dsurgical resection of a clinically benign tum includes: no enucleation of lateral lobe and intraoperative communication with pathologist if indicated. esee Principles of Radiation Therapy (SALI-A). Recurrent Persistent Disease (See SALI-4) Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SALI-2

69 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Salivary Gland Tums CANCER SITE TREATMENT f Parotid and submandibular gland Clinical N0 Clinical N+ Parotidectomy with complete resection of tum ± neck dissectiong f high-grade and high-stage tums Parotidectomy + neck dissection g Completely resected No adverse features Adenoid cystic Follow-up (See FOLL-A) Adverse features: Intermediate high grade Close positive margins Neural/perineural invasion Lymph node metastases Lymphatic/vascular invasion Recurrent Persistent Disease (See SALI-4) RT e (categy 2B) Adjuvant RT e Consider chemo/rt (categy 2B) Other salivary gland sites Clinical N0 Clinical N+ Complete tum resection g Complete tum resection and lymph node dissectiong Incompletely resected, gross residual disease Surgical resection, g if possible No further surgical resection possible Definitive RTe Chemo/RT (categy 2B) esee Principles of Radiation Therapy (SALI-A). fthe facial nerve should be preserved if possible. gsee Principles of Surgery (SURG-A). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SALI-3

70 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Salivary Gland Tums RECURRENCE TREATMENT FOR RECURRENCE RT e Follow-up, (See FOLL-A) Locegional recurrence without pri RT Resectable Completely resected Adverse features: Intermediate high grade Close positive margins Neural/perineural invasion Lymph node metastases Lymphatic/vascular invasion Adjuvant RT e Consider chemo/rt (categy 2B) Unresectable RTe Chemo/RT (categy 2B) Follow-up (See FOLL-A) Locegional recurrence second primary with pri RT Resectable Unresectable g Surgery (preferred) Reirradiation ± chemotherapy, clinical trial preferred Reirradiation ± chemotherapy, clinical trial preferred Chemotherapy (see Distant metastases pathway below) Distant metastases Clinical trial preferred Standard therapy PS 0-2 Chemotherapy Expectant management (with slow-growing disease) Selected metastasectomy (categy 3) esee Principles of Radiation Therapy (SALI-A). gsee Principles of Surgery (SURG-A). PS 3 Best supptive care PS = Perfmance Status (ECOG) Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SALI-4

71 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Salivary Gland Tums PRINCIPLES OF RADIATION THERAPY 1 DEFINITIVE RT: Photon photon/electron therapy neutron therapy Dose Primary and gross adenopathy: Gy ( Gy/fraction) ngy (1.2 ngy/fraction) Neck Uninvolved nodal stations: Gy ( Gy/fraction) ngy (1.2 ngy/fraction) POSTOPERATIVE RT: Photon photon/electron therapy neutron therapy Dose Primary: 60 Gy ( Gy/fraction) 2 18 ngy (1.2 ngy/fraction) Neck Uninvolved nodal stations: Gy ( Gy/fraction) ngy (1.2 ngy/fraction) 1 See Radiation Techniques (RAD-A) and (). 2 Range based on grade/natural histy of disease (eg, 1.8 Gy fraction may be used f slower growing tums). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SALI-A

72 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRESENTATION WORKUP Mucosal Melanoma TREATMENT Biopsy confirms diagnosis of mucosal malignant melanoma H&P including complete head and neck exam; mirr and fiberoptic examination as clinically indicated Verification of pathology using appropriate staining (HMB-45, S-100, Melan-A) CT and/ MRI to determine anatomic extent of disease, particularly f sinus disease Chest imaging as indicated Consider PET-CT scan to rule out metastatic disease Sinus nasal cavity mucosal melanoma Oral cavity, opharynx, larynx, hypopharynx mucosal melanoma See Primary Treatment (MM-2) See Primary Treatment (MM-3) Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MM-1

73 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Mucosal Melanoma PRIMARY TREATMENT ADJUVANT TREATMENT Stage III Wide surgical resection of primary a Strongly consider postoperative RT to primary site b Sinus nasal cavity mucosal melanoma T4a, N0 T3-T4a, N1 Wide surgical resection a Postoperative RT to primary site b Postoperative RT Wide surgical resection + neck dissection of positive neck a to primary site and neck b Follow-up (See FOLL-A) Recurrent Persistent Disease See NCCN Melanoma Guidelines Stage IVB Clinical trial (preferred) Primary RTb Systemic therapyc Stage IVC Clinical trial (preferred) Best supptive care Primary RTb Systemic therapyc asee Principles of Surgery (SURG-A). bsee Principles of Radiation Therapy (MM-A). csee Principles of Systemic Therapy f Advanced Metastatic Melanoma page ME-D from the NCCN Melanoma Guidelines. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MM-2

74 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Mucosal Melanoma PRIMARY TREATMENT ADJUVANT TREATMENT FOLLOW-UP Stage III Wide surgical resection, elective neck dissection a Strongly consider postoperative RT b Oral cavity, opharynx, larynx, hypopharynx mucosal melanoma Stage IVA Stage IVB Wide surgical resection + neck dissection a Postoperative RT b Clinical trial (preferred) Primary RTb and/ Systemic therapyc Follow-up (See FOLL-A) Recurrent Persistent Disease See NCCN Melanoma Guidelines Stage IVC Clinical trial (preferred) Best supptive care Primary RTb Systemic therapyc asee Principles of Surgery (SURG-A). bsee Principles of Radiation Therapy (MM-A). csee Principles of Systemic Therapy f Advanced Metastatic Melanoma page ME-D from the NCCN Melanoma Guidelines. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MM-3

75 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Mucosal Melanoma PRIMARY THERAPY FOR OCCULT PRIMARY- MELANOMA Level V, occipital node Posteri lateral node dissection ± RT to nodal bed d,e ± Adjuvant systemic therapy, per NCCN Guidelines f Melanoma All other nodal sites Neck dissection a asee Principles of Surgery (SURG-A). dadjuvant 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 f cutaneous melanoma of the head and neck region. International Journal of Radiation Oncology, Biology, Physics 1994;30: ). ert is indicated f satellitosis, positive nodes, extracapsular spread. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MM-4

76 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Mucosal Melanoma PRINCIPLES OF RADIATION THERAPY 1 RT f Unresectable Locally Advanced Melanoma: Gy Palliative RT dose and schedule may be considered Postoperative RT: Primary site resection: Paranasal sites: RT to primary site cm margins to anatomic compartment Oral cavity, opharynx, and hypopharynx sites: RT to primary site (+ 2-3 cm margins anatomic zone) and elective treatment to neck (unless negative pathology findings of neck dissection) Also strongly consider radiation to primary site f any locally recurrent disease after previous resection. Neck/nodal basin dissection: High-risk features: 2 nodes Single node 3 cm Extracapsular nodal disease N ode resection (alone) with no further basin dissection Recurrence in nodal basin after previous surgery. Dose and fractionation: Primary and neck (high-risk sites): Gy (2.0 Gy/fraction) 70 Gy f gross disease Low-risk, undissected, uninvolved ptions of neck: Gy (2 Gy/fraction) 1 See Radiation Techniques (RAD-A) and (). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MM-A

77 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. FOLLOW-UP RECOMMENDATIONS (based on risk of relapse, second primaries, treatment sequalae, and toxicities) H&P exam 1: Year 1, every 1-3 mo Year 2, every 2-6 mo Years 3-5, every 4-8 mo >5 years, every 12 mo Post-treatment baseline imaging of primary (and neck, if treated) recommended within 6 mo of treatment 2 (categy 2B) Further reimaging as indicated based on signs/symptoms; not routinely recommended f asymptomatic patients Chest imaging as clinically indicated ( See NCCN Guidelines f Lung Cancer Screening) Thyroid-stimulating hmone (TSH) every 6-12 mo if neck irradiated Speech/hearing and swallowing evaluation and rehabilitation as clinically indicated Smoking cessation and alcohol counseling as clinically indicated Dental evaluation Recommended f al cavity As indicated f opharynx, hypopharynx, and nasopharynx As indicated f other sites, if significant intraal radiation Consider EBV moniting f nasopharynx 1 2 F mucosal melanoma, a physical exam should include endoscopic inspection f paranasal sinus disease. F cancer of the opharynx, hypopharynx, glottic larynx, supraglottic larynx, and nasopharynx: imaging is recommended f T3-4 N2-3 disease only. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. FOLL-A

78 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF SURGERY Evaluation All patients should be evaluated by a head and neck surgical oncologist pri to treatment to assure the following: Review the adequacy of biopsy material, review staging and imaging to determine the extent of disease, exclude the presence of a synchronous primary tum, assess current functional status, and evaluate f potential surgical salvage if initial treatment is nonsurgical. Participate in the multidisciplinary team discussions regarding patient treatment options with the goal of maximizing survival with preservation of fm and function. Develop a prospective surveillance plan that includes adequate dental, nutritional, and health behavi evaluation and intervention and any other ancillary evaluations that would provide f comprehensive rehabilitation. F patients undergoing an operation, the surgical procedure, margins, and reconstructive plan should be developed and designed to resect all gross tums with adequate tum-free surgical margins. The surgical procedure should not be modified based upon any response observed as a result of pri therapy except in instances of tum progression that mandate a me extensive procedure in der to encompass the tum at the time of definitive resection. Integration of Therapy It is critical that multidisciplinary evaluation and treatment be codinated and integrated prospectively by all modalities involved in patient care befe the initiation of any treatment. Assessment of Resectability Tum involvement of the following sites is associated with po prognosis function1 with T4b cancer (ie, unresectable based on technical ability to obtain clear margins): Involvement of the pterygoid muscles, particularly when associated with severe trismus pterygopalatine fossa involvement with cranial neuropathy; 1 Gross extension of the tum to the skull base (eg, erosion of the pterygoid plates sphenoid bone, widening of the famen ovale); Direct extension to the superi nasopharynx deep extension into the Eustachian tube and lateral nasopharyngeal walls; Invasion (encasement) of the common internal carotid artery. Encasement is usually assessed radiographically and defined as a tum surrounding the carotid artery by 270 degrees greater; Direct extension of neck disease to involve the external skin; 1 Direct extension to mediastinal structures, prevertebral fascia, cervical vertebrae1 Presence of subdermal metastases. 1 In selected cases, surgery might still be considered. Continued on next page Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SURG-A 1of7

79 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF SURGERY Primary Tum Resection The resection of advanced tums of the al cavity, opharynx, hypopharynx, larynx, paranasal sinus will vary in extent depending on the structures involved. The primary tum should be considered surgically curable by appropriate resection using accepted criteria f adequate excision, depending on the region involved. En bloc resection of the primary tum should be attempted whenever feasible. In-continuity neck dissection is necessary when there is direct extension of the primary tum into the neck. Surgical resection should be planned based upon the extent of the primary tum as ascertained by clinical examination and careful interpretation of appropriate radiographic images. F al cavity cancers, as thickness of the lesion increases, the risk of regional metastases and the need f adjuvant elective neck dissection also increases. Perineural invasion should be suspected when tums are adjacent to mot sensy nerves. When invasion is suspected, the nerve should be dissected both proximally and distally and should be resected to obtain clearance of disease. Frozen section determination of the proximal and distal nerve margins may prove helpful to facilitate tum clearance. Partial segmental resection of the mandible may be necessary to adequately encompass the cancer with adequate tum-free margins. Adequate resection may require partial, hizontal, sagittal resection of the mandible f tums involving adherent to mandibular periosteum. Segmental resection should be considered in tums that grossly involve mandibular periosteum (as determined by tum fixation to the mandible) show evidence of direct tum involvement of the bone at the time of operation through preoperative imaging. The extent of mandibular resection will depend on the degree of involvement accessed clinically and in the operating room. F tums of the larynx, the decision to perfm either total laryngectomy conservation laryngeal surgery (eg, transal resection, hemilaryngectomy, supraglottic laryngectomy.) will be decided by the surgeon but should adhere to the principles of complete tum extirpation with curative intent. F maxillary sinus tums, note that Ohngren's line" runs from the medial canthus of the eye to the angle of the mandible, helping to define a plane passing through the maxillary sinus. Tums "below" "befe" this line involve the maxillary infrastructure. Those "above" "behind" Ohngren's line involve the suprastructure. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. Continued on next page SURG-A 2of7

80 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF SURGERY Margins An overarching goal of oncologic surgery is complete tum resection with histologic verification of tum-free margins. Margin assessment may be in real time by frozen section by assessment of fmalin-fixed tissues. Tum-free margins are an essential surgical strategy f diminishing the risk f local tum recurrence. Conversely, positive margins increase the risk f local relapse and are an indication f postoperative adjuvant therapy. Clinical pathologic studies have demonstrated the significance of close positive margins and their relationship with local tum recurrence. 2 When there is an initial cut-through with an invasive tum at the surgical margin, obtaining additional adjacent margins from the patient may also be associated with a higher risk f local relapse. Obtaining additional margins from the patient is subject to ambiguity regarding whether the tissue taken from the surgical bed cresponds to the actual site of margin positivity. 3 Frozen section margin assessment is always at the discretion of the surgeon and should be considered when it will facilitate complete tum removal. The achievement of adequate wide margins may require resection of an adjacent structure in the al cavity laryngopharynx such as the base of tongue and/ anteri tongue, mandible, larynx, ptions of the cervical esophagus. Adequate resection is defined as clear resection margins with at least enough clearance from the gross tum to obtain clear frozen section and permanent margins (often 1.5-2cm of visible and palpable nmal mucosa). In general, frozen section examination of the margins will usually be undertaken intraoperatively, and imptantly, when a line of resection has uncertain clearance because of indistinct tum margins, there is suspected residual disease (ie, soft tissue, cartilage, carotid artery, mucosal irregularity). The details of resection margins should be included in the operative dictation. The margins may be assessed on the resected specimen alternatively from the surgical bed with proper ientation. A clear margin is defined as the distance from the invasive tum front that is 5 mm me from the resected margin. A close margin is defined as the distance from the invasive tum front to the resected margin that is less than 5 mm. A positive margin is defined as carcinoma in situ as invasive carcinoma at the margin of resection. The primary tum should be marked in a fashion adequate f ientation by the surgical pathologist. The primary tum should be assessed histologically f depth of invasion and f distance from the invasive ption of the tum to the margin of resection, including the peripheral and deep margins. The pathology rept should be template driven and describe how the margins were assessed. The rept should provide infmation regarding the primary specimen to include the distance from the invasive ption of the tum to the peripheral and deep margin. If the surgeon obtains additional margins from the patient, the new margins should refer back to the geometric ientation of the resected tum specimen with a statement by the pathologist that this is the final margin of resection and its histologic status. The neck dissection should be iented sectioned in der to identify levels of lymph nodes encompassed in the dissection. Reconstruction of surgical defects should be perfmed using conventional techniques at the discretion of the surgeon. Primary closure is recommended when appropriate but should not be pursued at the expense of obtaining wide, tum-free margins. Reconstructive closure with local/regional flaps, free-tissue transfer, split-thickness skin other grafts with without mandibular reconstruction is perfmed at the discretion of the surgeon. 2 Looser KG, Shah JP, Strong EW. The significance of "positive" margins in surgically resected epidermoid carcinomas. Head Neck Surg. 1978;1: Scholl P, Byers RM, Batsakis JG, et al. Microscopic cut-through of cancer in the surgical treatment of squamous carcinoma of the tongue. Prognostic and therapeutic implications. Am J Surg. 1986;152: Continued on next page Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SURG-A 3of7

81 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF SURGERY Surgical Management of Cranial Nerves VII, X (including the recurrent laryngeal nerve), XI, and XII Operative management of the facial nerve and other maj cranial nerves during primary regional node resection is influenced by the preoperative clinical function of the nerve. When the nerve is functioning, though effts should be made to preserve the structure and function of the nerve (main trunk and/ branches)--even if otherwise adequate tum margins are not achieved--recognizing that the surgeon should leave no gross residual disease. Adjuvant postoperative radiation chemadiation is generally prescribed when a microscopic residual gross residual tum is suspected. Direct nerve invasion by a tum and/ preoperative paralysis of the nerve may warrant segmental resection (and sometimes nerve grafting) at the discretion of the surgeon if tum-free margins are assured throughout the remainder of the procedure. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. Continued on next page SURG-A 4of7

82 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF SURGERY Neck Management The surgical management of regional lymphatics is dictated by the extent of the tum at initial tum staging. These guidelines apply to the perfmance of neck dissections as part of treatment of the primary tum. In general, patients undergoing surgery f resection of the primary tum will undergo dissection of the ipsilateral side of the neck that is at greatest risk f metastases. Tum sites that frequently have bilateral lymphatic drainage (eg, base of tongue, palate, supraglottic larynx, deep space pre-epiglottic involvement) often should have both sides of the neck dissected with the extent of dissection determined as suggested below. F those patients with tums at approaching the midline, both sides of the neck are at risk f metastases, and bilateral neck dissections should be perfmed. Elective neck dissection may not be recommended if postoperative radiation is planned. Patients with advanced lesions involving the anteri tongue flo of the mouth that approximate cross the midline, should undergo contralateral submandibular dissection as necessary to achieve adequate tum resection. Elective neck dissection should be based on risk of occult metastasis in the appropriate nodal basin. F al cavity squamous cell carcinoma, the depth of invasion is currently the best predict of occult metastatic disease and should be used to guide decision making. F tums with a depth greater than 4 mm, elective dissection should be strongly considered if radiation therapy is not already planned. F a depth less than 2 mm, elective dissection is only indicated in highly selective situations. F a depth of 2 to 4 mm, clinical judgment (as to reliability of follow-up, clinical suspicion, and other facts) must be utilized to determine appropriateness of elective dissection. Elective dissections are generally selective, preserving all maj structures, unless operative findings dictate otherwise. The type of neck dissection (comprehensive selective) is defined accding to preoperative clinical staging, is determined at the discretion of the surgeon, and is based on the initial preoperative staging as follows: N0 Selective neck dissection -Oral cavity at least levels I-III -Oropharynx at least levels II-IV -Hypopharynx at least levels II-IV and level VI when appropriate. -Larynx at least levels II-IV and level VI when appropriate (See ) N1-N2a-c Selective comprehensive neck dissection N3 Comprehensive neck dissection Level VI neck dissections are perfmed f certain primary sites (such as the larynx and hypopharynx) as required to resect the primary tum and any clinically evident neck nodes. Elective dissection depends on primary tum extent and site. Subglottic laryngeal cancers are sites where elective level VI dissections are often considered appropriate. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. Continued on next page SURG-A 5of7

83 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF SURGERY Management of Recurrences Surgically resectable primary cancers should be re-resected with curative intent if feasible, and recurrences in a previously treated neck should undergo surgical salvage, as well. Neck disease in an untreated neck should be addressed by fmal neck dissection modification depending on the clinical situation. Non-surgical therapy may also be utilized as clinically appropriate. Surveillance All patients should have regular follow-up visits to assess f symptoms and possible tum recurrence, health behavis, nutrition, dental health, and speech and swallowing function. Tum evaluations must be perfmed by specialists skilled in head and neck clinical examination. The frequency of evaluation is summarized elsewhere in the NCCN Guidelines f ( See Follow-up Recommendations [FOLL-A]). F post chemadiation RT neck evaluations (See Principles of Surgery: [Post Chemadiation RT Neck Evaluation [SURG-A 7 of 7]). Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. Continued on next page SURG-A 6of7

84 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF SURGERY (POST CHEMORADIATION OR RT NECK EVALUATION) 1 Persistent disease Suspected progression CT and/ MRI with contrast (4-8 weeks) Consider PET/CT scan If diagnosis confirmed progression Neck dissection No lymph node node <1 cm; PET/CT negative3 Observe After chemo/rt RT 4-8 weeks clinical assessment as appropriate If response PET/CT 2 (suggest full dose CT + IV contrast) at minimum 12 weeks Lymph node <1 cm; PET/CT positive4 Lymph node >1 cm; PET/CT negative3 Lymph node >1 cm; PET/CT positive4 Individual decision: Observe Neck dissection Consider ultrasound FNA Observe Neck dissection: Consider ultrasound FNA Patient/surgeon decision Consider amount of nodal regression Neck dissection CT and/ MRI with contrast at 6 weeks (if PET unavailable) Imaging negative Imaging positive Observe Neck dissection 1 Adapted with permission from Kutler DI, Patel SG, Shah JP. The role of neck dissection following definitive chemadiation. Oncology 2004;18: ; discussion 999, ,1007. Review. 2 If a PET/CT is perfmed and negative f suspicion of persistent cancer, further cross-sectional imaging is optional. 3PET negative = No low-grade uptake, felt not suspicious f disease 4PET positive = PET suspicious f disease Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. SURG-A 7of7

85 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. RADIATION TECHNIQUES 1-8 Target delineation and optimal dose distribution require experience in head and neck imaging and a though understanding of patterns of disease spread. Standards f target definition, dose specification, fractionation (with and without concurrent chemotherapy), and nmal tissue constraints are still evolving. IMRT, 3-D, and 2-D confmal techniques may be used as appropriate depending on the stage, tum location, physician training/experience, and available physics suppt. Close interplay exists between radiation technology, techniques, fractionation, and chemotherapy options resulting in a large number of combinations that may impact toxicity tum control. Close cooperation and interdisciplinary management are critical to treatment planning and radiation targeting, especially in the postoperative setting after induction chemotherapy. 9 Intensity-Modulated Radiotherapy (IMRT) IMRT has been shown to be useful in reducing long-term toxicity in opharyngeal, paranasal sinus, and nasopharyngeal cancers by reducing the dose to salivary glands, tempal lobes, audity structures (including cochlea), and optic structures. The application of IMRT to other sites (eg, al cavity, larynx, hypopharynx, salivary glands) is evolving and may be used at the discretion of treating physicians. IMRT and Fractionation 10,11 A number of ways exist to integrate IMRT, target volume dosing, and fractionation. The Simultaneous Integrated Boost (SIB) technique uses differential dose painting (66-74 Gy to gross disease; Gy to subclinical disease) f each fraction of treatment throughout the entire course of radiation. 4 SIB is commonly used in the conventional (5 fractions/week) and the 6 fractions/week accelerated schedule. 5 The Sequential (SEQ) IMRT technique typically delivers the initial (lower dose) phase (weeks 1-5) followed by the high-dose boost volume phase (weeks 6-7) using 2-3 separate dose plans, and is commonly applied in standard fractionation and hyperfractionation. The Concomitant Boost Accelerated schedule may utilize a Modified SEQ dose plan by delivering the dose to the subclinical targets once a day f 6 weeks, and a separate boost dose plan as a second daily fraction f the last 12 treatment days. 6 1Dogan N, King S, Emami B, et al. Assessment of different IMRT boost delivery methods on target coverage and nmal-tissue sparing. Int J Radiat Oncol Biol Phys 2003;57(5): L ee NY, de Arruda FF, Puri DR, et al. A comparison of intensity-modulated radiation therapy and concomitant boost radiotherapy in the setting of concurrent chemotherapy f locally advanced opharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006;66(4): Lee NY, O'Meara W, Chan K, et al. Concurrent chemotherapy and intensity-modulated radiotherapy f locegionally advanced laryngeal and hypopharyngeal cancers. Int J Radiat Oncol Biol Phys 2007;69(2): Mohan R, Wu Q, Mris M, et al. Simultaneous Integrated Boost (SIB) IMRT of advanced head and neck squamous cell carcinomas dosimetric analysis. Int J Radiat Oncol Biol Phys 2001;51(3): Overgaard J, Hansen HS, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003;362(9388): Schoenfeld GO, Amdur RJ, Mris CG, et al. Patterns of failure and toxicity after intensitymodulated radiotherapy f head and neck cancer. Int J Radiat Oncol Biol Phys 2008;71(2): Epub 2007 Dec 31. 7Wolden SL, Chen WC, Pfister DG, et al. Intensity-modulated radiation therapy (IMRT) f nasopharynx cancer: update of the Memial Sloan-Kettering experience. Int J Radiat Oncol Biol Phys 2006;64(1): Wu Q, Manning M, Schmidt-Ullrich R, Mohan R. The potential f sparing of parotids and escalation of biologically effective dose with intensity-modulated radiation treatments of head and neck cancers: a treatment design study. Int J Radiat Oncol Biol Phys 2000;46(1): Salama JK, Haddad RI, Kies MS, et al. Clinical Practice Recommendations f Radiotherapy Planning following Induction Chemotherapy in Locegionally Advanced Head and Neck Cancer. Int J Radiat Oncol Biol Phys (3): Hartfd AC, Palisca MG, Eichler TJ, et al. American Society f Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guidelines f intensity-modulated radiation therapy (IMRT). Int J Radiat Oncol Biol Phys. 2009;73(1): IMRT Documentation Wking Group, Holmes T, Das R, Low D, et al. American Society of Radiation Oncology recommendations f documenting intensity-modulated radiation therapy treatments. Int J Radiat Oncol Biol Phys. 2009;74(5): Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. RAD-A

86 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF SYSTEMIC THERAPY The choice of chemotherapy should be individualized based on patient characteristics (perfmance status, goals of therapy). The standard therapy f fit patients with locally advanced disease remains concurrent cisplatin and radiotherapy. Cisplatin-based induction chemotherapy can be used, followed by radiation-based locegional treatment (ie, sequential chemort). However, an improvement in overall survival with the incpation of induction chemotherapy compared to proceeding directly to state of the art concurrent chemort (cisplatin preferred, categy 1) has not been established. Randomized phase III studies comparing sequential chemotherapy/rt to concurrent chemotherapy/rt alone are ongoing. Cisplatin-based induction chemotherapy followed by high-dose, every-3-week cisplatin chemadiotherapy is not recommended due to toxicity concerns. 1,2 After induction chemotherapy, multiple options can be used f the radiation-based ption of therapy. Radiotherapy alone versus radiotherapy plus cetuximab weekly carboplatin are among the options. Squamous Cell Cancers Lip, Oral Cavity, Oropharynx, Hypopharynx, Glottic Larynx, Supraglottic Larynx, Ethmoid Sinus, Maxillary Sinus, Occult Primary: Primary systemic therapy + concurrent RT Cisplatin alone 3,4 (preferred) (categy 1) Cetuximab 5 (categy 1) Carboplatin/infusional 5-FU (categy 1) 6,7 5-FU/hydroxyurea8 Cisplatin/paclitaxel8 Cisplatin/infusional 5-FU9 Carboplatin/paclitaxel 10 (categy 2B) Postoperative chemadiation Cisplatin alone (categy 1 f high risk) Nasopharynx: Chemadiation followed by adjuvant chemotherapy Cisplatin + RT followed by cisplatin/5-fu 15,16 (categy 1) Lip, Oral Cavity, Oropharynx, Hypopharynx, Glottic Larynx, Supraglottic larynx, Ethmoid Sinus, Maxillary Sinus, Occult Primary: Induction*/Sequential chemotherapy Docetaxel/cisplatin/5-FU (categy 1 if induction is chosen) Paclitaxel/cisplatin/infusional 5-FU20 Following induction, agents to be used with concurrent chemadiation typically include weekly carboplatin cetuximab. 21 Nasopharynx: Induction*/Sequential chemotherapy Docetaxel/cisplatin/5-FU22 Cisplatin/5-FU18 Cisplatin/epirubicin/paclitaxel Following induction, agents to be used with concurrent chemadiation typically include weekly cisplatin16 carboplatin. 21 *Induction chemotherapy should only be done in a tertiary setting. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. Continued on next page See References on page CHEM-A 3 of 3 CHEM-A 1of3

87 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF SYSTEMIC THERAPY The choice of chemotherapy should be individualized based on patient characteristics (perfmance status, goals of therapy). Recurrent, Unresectable, Metastatic (incurable) Combination therapy Cisplatin carboplatin + 5-FU + cetuximab (non-nasopharyngeal) 23 (categy 1) Cisplatin carboplatin + docetaxel24 paclitaxel25 Cisplatin/cetuximab (non-nasopharyngeal) 26 Cisplatin + 5-FU25,27 Single agents Cisplatin Carboplatin Paclitaxel Docetaxel 5-FU Methotrexate Ifosfamide Bleomycin Gemcitabine 28 (nasopharyngeal) Cetuximab (non-nasopharyngeal) 29 See References on page CHEM-A 3 of 3 Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CHEM-A 2of3

88 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. 1 PRINCIPLES OF SYSTEMIC THERAPY (REFERENCES) Lefebvre J, Pointreau Y, Rolland F, et al. Sequential chemadiotherapy (SCRT) f larynx preservation (LP): Results of the randomized phase II TREMPLIN study [abstract]. J Clin Oncol 2011;29: Abstract Adelstein DJ, Moon J, Hanna E, et al. Docetaxel, cisplatin, and fluouracil induction chemotherapy followed by accelerated fractionation/concomitant boost radiation and concurrent cisplatin in patients with advanced squamous cell head and neck cancer: A Southwest Oncology Group phase II trial (S0216). Head Neck. 2010;32: Fastiere A, Ma M, Weber R, et al. Long term results of Intergroup RTOG 91-11: A Phase III trial to preserve the larynx - Induction cisplatin/5-fu and radiation therapy versus concurrent cisplatin and radiation therapy versus radiation therapy [abstract]. J Clin Oncol 2006;24:Abstract Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemadiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21(1): Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab f locegionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11: Denis F, Garaud P, Bardet E, et al. Final results of the French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage opharynx carcinoma. J Clin Oncol 2004;22: Bourhis J, Sire C, Graff P, et al. Concomitant chemadiotherapy versus acceleration of radiotherapy with without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012;13: Garden AS, Harris J, Vokes EE, et al. Preliminary results of Radiation Therapy Oncology Group 97-03: A randomized phase II trial of concurrent radiation and chemotherapy f advanced squamous cell carcinomas of the head and neck. J Clin Oncol 2004;22: Tayl S, Murthy A, Vannetzel J, et al. Randomized comparison of neoadjuvant cisplatin and fluouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 1994;12: Suntharalingam M, Haas ML, Conley BA, et al. The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 2000;47: Cooper JS, Pajak TF, Fastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy f high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350: Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with without concomitant chemotherapy f locally advanced head and neck cancer. N Engl J Med 2004;350: Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: A comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27: Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined postoperative radiotherapy and weekly cisplatin infusion f locally advanced head and neck carcinoma: final rept of a randomized trial. Int J Radiat Oncol Biol Phys 1996 Dec 1;36: Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemadiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study J Clin Oncol 1998;16: Chan AT, Leung SF, Ngan RK, et al. Overall survival after concurrent cisplatinradiotherapy compared with radiotherapy alone in locegionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2005;97: Vermken JB, Remenar E, van Herpen C, et al; EORTC 24971/TAX 323 Study Group. Cisplatin, fluouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357(17): Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluouracil alone with docetaxel in head and neck cancer. N Engl J Med 2007;357(17): Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluouracil with without docetaxel f larynx preservation. J Natl Cancer Inst 2009;101: Hitt R, López-Pousa A, Martínez-Trufero J, et al. Phase III study comparing cisplatin plus fluouracil to paclitaxel, cisplatin, and fluouracil induction chemotherapy followed by chemadiotherapy in locally advanced head and neck cancer. J Clin Oncol. 2005;23: Chitapanarux I, Lvidhaya V, Kamnerdsupaphon P, et al. Chemadiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: Randomised, non-inferiity, open trial. Eur J Cancer 2007;43: Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CHEM-A 3of3

89 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF SYSTEMIC THERAPY (REFERENCES) 22Bae WK, Hwang JE, Shim HJ, et al. Phase II study of docetaxel, cisplatin and 5FU induction chemotherapy followed by chemadiotherapy in locegionally advanced npc. Cancer Chemother Pharmacol 2010; 65: Vermken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359: Samlowski WE, Moon J, Kuebler JP, et al. Evaluation of the combination of docetaxel/carboplatin in patients with metastatic recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group Phase II study. Cancer Invest 2007;25: Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): An Intergroup Trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2005;23: Burtness B, Goldwasser MA, Flood W, et al. Phase III randomized trial of cisplatin plus placebo versus cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Group Study. J Clin Oncol 2005;23: Fastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus flurouracil and carboplatin plus fluouracil versus methotrexate in advanced squamous cell carcinoma of the head and neck: A Southwest Oncology Group Study. J Clin Oncol 1992;10: Zhang L, Zhang Y, Huang PY, et al. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer Chemother Pharmacol 2008;61: Epub 2007 Mar Vermken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/ metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25: Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. CHEM-A 3of3

90 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF NUTRITION: MANAGEMENT AND SUPPORTIVE CARE Most head and neck cancer patients lose weight as a result of their disease, health behavis, and treatment-related toxicities. Nutritional management is very imptant in head and neck cancer patients to improve outcomes and to minimize significant tempary permanent treatment-related complications (eg, severe weight loss). It is recommended that the multidisciplinary evaluation of head and neck cancer patients include a registered dietitian and a speech-language/swallowing therapist. Assessment and Management Nutritional Close moniting of nutritional status is recommended in patients who have: (1) significant weight loss (>10% ideal body weight); and/ (2) difficulty swallowing because of pain tum involvement pri to treatment. All patients should be evaluated f nutritional risks and should receive nutrition counseling by a registered dietitian and/ indicated treatment with various nutrition interventions, such as feeding tubes (eg, nasogastric [NG] tubes, percutaneous endoscopic gastrostomy [PEG] tubes) intravenous nutrition suppt (but only if enteral suppt is not feasible). Pre- and post-treatment functional evaluation including nutritional status should be undertaken using either subjective objective assessment tools. All patients should receive dietary counseling with the initiation of treatment, especially with radiotherapy-based treatments. Follow-up with the registered dietitian should continue at least until the patient has achieved a nutritionally stable baseline following treatment. F some patients with chronic nutritional challenges, this follow-up should be ongoing. Speech and Swallowing A fmal speech and swallowing evaluation at baseline is recommended: (1) f patients with speech and/ swallowing dysfunction; (2) f patients whose treatment is likely to affect speech and/ swallowing. Patients with ongoing abnmal function should be seen regularly by speech-language pathologists. Dysphagia and swallowing function can be measured by clinical swallowing assessments by videofluoscopic swallowing studies. Patient quality-of-life evaluations should also include assessment f any changes in speech and communication; changes in taste; and assessment f xerostomia, pain, and trismus. Follow-up with the speech-language pathologist should continue at least until the patient has achieved a stable baseline following treatment. F some patients with chronic speech and swallowing challenges, this follow-up may need to be indefinite. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. NUTR-A 1of2

91 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. PRINCIPLES OF NUTRITION: MANAGEMENT AND SUPPORTIVE CARE Use of Alternative Routes f Nutrition (NG and PEG Tubes) The panel does not recommend prophylactic PEG NG tube placement in patients with very good perfmance status and without significant pretreatment weight loss, significant airway obstruction, severe dysphagia. However, these patients will need encouragement to monit their calic intake and to assess f changes in body weight during treatment. They also may need tempary tube feeding intervention during and/ after treatment. Prophylactic feeding tube placement should be strongly considered f patients with: Severe weight loss pri to treatment, 5% weight loss over pri 1 month, 10% weight loss over 6 months; Ongoing dehydration dysphagia, anexia, pain interfering with the ability to eat/drink adequately; Significant combidities that may be aggravated by po tolerance of dehydration, lack of calic intake, difficulty swallowing necessary medications; Severe aspiration; mild aspiration in elderly patients in patients who have compromised cardiopulmonary function; Patients f whom long-term swallowing disders are likely, including those anticipated to receive large fields of high-dose radiation to the mucosa and adjacent connective tissues. However, consideration of other risk facts f swallowing dysfunction must be taken into account as well. To maintain swallowing function during and following treatment (eg, radiation), patients who may have feeding tube placement should be encouraged to intake ally if they can swallow without aspiration any other compromises. Alterations in swallowing function can occur long after treatment (especially after radiation-based treatment) and should be monited f the lifetime of the patient. Note: All recommendations are categy 2A unless otherwise indicated. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. NUTR-A 2of2

92 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 1 American Joint Committee on Cancer (AJCC) TNM Staging Classification f the Lip and Oral Cavity (7th ed., 2010) (Nonepithelial tums such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included) Primary Tum (T) TX Primary tum cannot be assessed T0 No evidence of primary tum Tis Carcinoma in situ T1 Tum 2 cm less in greatest dimension T2 Tum me than 2 cm but not me than 4 cm in greatest dimension T3 Tum me than 4 cm in greatest dimension T4a Moderately advanced local disease* (lip) Tum invades through ctical bone, inferi alveolar nerve, flo of mouth, skin of face, that is, chin nose (al cavity) Tum invades adjacent structures (eg, through ctical bone [mandible maxilla] into deep [extrinsic] muscle of tongue [genioglossus, hyoglossus, palatoglossus, and styloglossus], maxillary sinus, skin of face) T4b Very advanced local disease Tum invades masticat space, pterygoid plates, skull base and/ encases internal carotid artery *Note: Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tum as T4. Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm less in greatest dimension N2 Metastasis in a single ipsilateral lymph node, me than 3 cm but not me than 6 cm in greatest dimension; in multiple ipsilateral lymph nodes, none me than 6 cm in greatest dimension; in bilateral contralateral lymph nodes, none me than 6 cm in greatest dimension N2a Metastasis in single ipsilateral lymph node me than 3 cm but not me than 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, none me than 6 cm in greatest dimension N2c Metastasis in bilateral contralateral lymph nodes, none me than 6 cm in greatest dimension N3 Metastasis in a lymph node me than 6 cm in greatest dimension Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Histologic Grade (G) GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poly differentiated G4 Undifferentiated Continued... Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. ST-1 Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

93 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 1 - Continued American Joint Committee on Cancer (AJCC) TNM Staging Classification f the Lip and Oral Cavity (7th ed., 2010) (Nonepithelial tums such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included) Anatomic Stage/Prognostic Groups Stage 0 Stage I Stage II Stage III Tis T1 T2 T3 T1 N0 N0 N0 N0 N1 M0 M0 M0 M0 M0 T2 N1 M0 T3 N1 M0 Stage IVA T4a T4a N0 N1 M0 M0 T1 N2 M0 T2 N2 M0 T3 N2 M0 T4a N2 M0 Stage IVB Any T T4b N3 Any N M0 M0 Stage IVC Any T Any N M1 Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. ST-2 Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

94 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 2: American Joint Committee on Cancer (AJCC) TNM Staging System f the Pharynx (7th ed., 2010) (Nonepithelial tums such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included) Primary Tum (T) TX Primary tum cannot be assessed T0 No evidence of primary tum Tis Carcinoma in situ Nasopharynx T1 T2 T3 T4 Tum confined to the nasopharynx, tum extends to opharynx and/ nasal cavity without parapharyngeal extension* Tum with parapharyngeal extension* Tum involves bony structures of skull base and/ paranasal sinuses Tum with intracranial extension and/ involvement of cranial nerves, hypopharynx, bit, with extension to the infratempal fossa/masticat space Hypopharynx T1 Tum limited to one subsite of hypopharynx and/ 2 cm less in greatest dimension T2 Tum invades me than one subsite of hypopharynx an adjacent site, measures me than 2 cm but not me than 4 cm in greatest diameter without fixation of hemilarynx T3 Tum me than 4 cm in greatest dimension with fixation of hemilarynx extension to esophagus T4a Moderately advanced local disease Tum invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, central compartment soft tissue** T4b Very advanced local disease Tum invades prevertebral fascia, encases carotid artery, involves mediastinal structures **Note: Central compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat. *Note: Parapharyngeal extension denotes posterolateral infiltration of tum. Oropharynx T1 Tum 2 cm less in greatest dimension T2 Tum me than 2 cm but not me than 4 cm in greatest dimension T3 Tum me than 4 cm in greatest dimension extension to lingual surface of epiglottis T4a Moderately advanced local disease Tum invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, mandible* T4b Very advanced local disease Tum invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, skull base encases carotid artery *Note: Mucosal extension to lingual surface of epiglottis from primary tums of the base of the tongue and vallecula does not constitute invasion of larynx. Continued... Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ST-3

95 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 2 - Continued American Joint Committee on Cancer (AJCC) TNM Staging System f the Pharynx (7th ed., 2010) (Nonepithelial tums such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included) Regional Lymph Nodes (N): Nasopharynx The distribution and the prognostic impact of regional lymph node spread from nasopharynx cancer, particularly of the undifferentiated type, are different from those of other head and neck mucosal cancers and justify the use of a different N classification system. NX N0 N1 N2 N3 N3a N3b Regional lymph nodes cannot be assessed No regional lymph node metastasis Unilateral metastasis in cervical lymph node(s), 6 cm less in greatest dimension, above the supraclavicular fossa, and/ unilateral bilateral, retropharyngeal lymph nodes, 6 cm less, in greatest dimension* Bilateral metastasis in cervical lymph node(s), 6 cm less in greatest dimension, above the supraclavicular fossa* Metastasis in a lymph node(s)* > 6 cm and/ to supraclavicular fossa Me than 6 cm in dimension Extension to the supraclavicular fossa** *Note: Midline nodes are considered ipsilateral nodes. **Supraclavicular zone fossa is relevant to the staging of nasopharyngeal carcinoma and is the triangular region iginally described by Ho. It is defined by three points: (1) the superi margin of the sternal end of the clavicle; (2) the superi margin of the lateral end of the clavicle, and (3) the point where the neck meets the shoulder. Note that this would include caudal ptions of levels IV and VB. All cases with lymph nodes (whole part) in the fossa are considered N3b. Regional Lymph Nodes (N) : Oropharynx and Hypopharynx NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm less in greatest dimension N2 Metastasis in a single ipsilateral lymph node, me than 3 cm but not me than 6 cm in greatest dimension, in multiple ipsilateral lymph nodes, none me than 6 cm in greatest dimension, in bilateral contralateral lymph nodes, none me than 6 cm in greatest dimension N2a Metastasis in a single ipsilateral lymph node me than 3 cm but not me than 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, none me than 6 cm in greatest dimension N2c Metastasis in bilateral contralateral lymph nodes, none me than 6 cm in greatest dimension N3 Metastasis in a lymph node me than 6 cm in greatest dimension Note: Metastases at level VII are considered regional lymph node metastases. Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Continued... Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ST-4

96 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 2 - Continued American Joint Committee on Cancer (AJCC) TNM Staging System f the Pharynx (7th ed., 2010) (Nonepithelial tums such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included) Anatomic Stage/Prognostic Groups: Nasopharynx Stage 0 Stage I Stage II Stage III Stage IVA Stage IVB Stage IVC Tis N0 M0 T1 N0 M0 T1 N1 M0 T2 N0 M0 T2 N1 M0 T1 N2 M0 T2 N2 M0 T3 N0 M0 T3 N1 M0 T3 N2 M0 T4 N0 M0 T4 N1 M0 T4 N2 M0 Any T N3 M0 Any T Any N M1 Anatomic Stage/Prognostic Groups: Oropharynx, Hypopharynx Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 T1 N1 M0 T2 N1 M0 T3 N1 M0 Stage IVA T4a N0 M0 T4a N1 M0 T1 N2 M0 T2 N2 M0 T3 N2 M0 T4a N2 M0 Stage IVB T4b Any N M0 Any T N3 M0 Stage IVC Any T Any N M1 Histologic Grade (G) GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poly differentiated G4 Undifferentiated Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ST-5

97 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 3 American Joint Committee on Cancer (AJCC) TNM Staging System f the Larynx (7th ed., 2010) (Nonepithelial tums such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included) Primary Tum (T) TX Primary tum cannot be assessed T0 No evidence of primary tum Tis Carcinoma in situ Supraglottis T1 Tum limited to one subsite of supraglottis with nmal vocal cd mobility T2 Tum invades mucosa of me than one adjacent subsite of supraglottis glottis region outside the supraglottis (eg, mucosa of base of tongue, vallecula, medial wall of pyrifm sinus) without fixation of the larynx T3 Tum limited to larynx with vocal cd fixation and/ invades any of the following: postcricoid area, pre-epiglottic space, paraglottic space, and/ inner ctex of thyroid cartilage T4a Moderately advanced local disease Tum invades through the thyroid cartilage and/ invades tissues beyond the larynx (eg, trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, esophagus) T4b Very advanced local disease Tum invades prevertebral space, encases carotid artery, invades mediastinal structures Continued on next page Glottis T1 T1a T1b T2 Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. T3 T4a T4b Subglottis T1 T2 T3 T4a T4b Tum limited to the vocal cd(s) (may involve anteri posteri commissure) with nmal mobility Tum limited to one vocal cd Tum involves both vocal cds Tum extends to supraglottis and/ subglottis, and/ with impaired vocal cd mobility Tum limited to the larynx with vocal cd fixation and/ invasion of paraglottic space, and/ inner ctex of the thyroid cartilage Moderately advanced local disease Tum invades through the outer ctex of the thyroid cartilage and/ invades tissues beyond the larynx (eg, trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, esophagus) Very advanced local disease Tum invades prevertebral space, encases carotid artery, invades mediastinal structures Tum limited to the subglottis Tum extends to vocal cd(s) with nmal impaired mobility Tum limited to larynx with vocal cd fixation Moderately advanced local disease Tum invades cricoid thyroid cartilage and/ invades tissues beyond the larynx (eg, trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, esophagus) Very advanced local disease Tum invades prevertebral space, encases carotid artery, invades mediastinal structures ST-6

98 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 3 - continued American Joint Committee on Cancer (AJCC) TNM Staging System f the Larynx (7th ed., 2010) (Nonepithelial tums such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included) Regional Lymph Nodes (N)* NX Regional lymph nodes cannot be assessed N0; no regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm less in greatest dimension N2 Metastasis in a single ipsilateral lymph node, me than 3 cm but not me than 6 cm in greatest dimension; in multiple ipsilateral lymph nodes, none me than 6 cm in greatest dimension; in bilateral contralateral lymph nodes, none me than 6 cm in greatest dimension N2a Metastasis in a single ipsilateral lymph node, me than 3 cm but not me than 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, none me than 6 cm in greatest dimension N2c Metastasis in bilateral contralateral lymph nodes, none me than 6 cm in greatest dimension N3 Metastasis in a lymph node, me than 6 cm in greatest dimension *Note: Metastases at level VII are considered regional lymph node metastases. Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Anatomic Stage/Prognostic Groups Stage 0 Stage I Stage II Stage III Stage IVA Stage IVB Stage IVC Tis N0 M0 T1 N0 M0 T2 N0 M0 T3 N0 M0 T1 N1 M0 T2 N1 M0 T3 N1 M0 T4a N0 M0 T4a N1 M0 T1 N2 M0 T2 N2 M0 T3 N2 M0 T4a N2 M0 T4b Any N M0 Any T N3 M0 Any T Any N M1 Histologic Grade (G) GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poly differentiated G4 Undifferentiated Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ST-7

99 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 4 American Joint Committee on Cancer (AJCC) TNM Staging System f the Nasal Cavity and Paranasal Sinuses (7th ed., 2010) (Nonepithelial tums such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included) Primary Tum (T) TX T0 Tis Primary tum cannot be assessed No evidence of primary tum Carcinoma in situ Maxillary Sinus T1 Tum limited to maxillary sinus mucosa with no erosion destruction of bone T2 Tum causing bone erosion destruction including extension into the hard palate and/ middle nasal meatus, except extension to posteri wall of maxillary sinus and pterygoid plates T3 Tum invades any of the following: bone of the posteri wall of maxillary sinus, subcutaneous tissues, flo medial wall of bit, pterygoid fossa, ethmoid sinuses T4a Moderately advanced local disease Tum invades anteri bital contents, skin of cheek, pterygoid plates, infratempal fossa, cribrifm plate, sphenoid frontal sinuses T4b Very advanced local disease Tum invades any of the following: bital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V 2), nasopharynx, clivus Nasal Cavity and Ethmoid Sinus Distant Metastasis (M) T1 Tum restricted to any one subsite, with without bony M0 No distant metastasis invasion M1 Distant metastasis T2 Tum invading two subsites in a single region extending to involve an adjacent region within the nasoethmoidal Continued on next page complex, with without bony invasion Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. ST-8 Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. T3 T4a T4b Tum extends to invade the medial wall flo of the bit, maxillary sinus, palate, cribrifm plate Moderately advanced local disease Tum invades any of the following: anteri bital contents, skin of nose cheek, minimal extension to anteri cranial fossa, pterygoid plates, sphenoid frontal sinuses Very advanced local disease Tum invades any of the following: bital apex, dura, brain, middle cranial fossa, cranial nerves other than (V 2), nasopharynx, clivus Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm less in greatest dimension N2 Metastasis in a single ipsilateral lymph node, me than 3 cm but not me than 6 cm in greatest dimension; in multiple ipsilateral lymph nodes, none me than 6 cm in greatest dimension; in bilateral contralateral lymph nodes, none me than 6 cm in greatest dimension N2a Metastasis in a single ipsilateral lymph node, me than 3 cm but not me than 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, none me than 6 cm in greatest dimension N2c Metastasis in bilateral contralateral lymph nodes, none me than 6 cm in greatest dimension N3 Metastasis in a lymph node, me than 6 cm in greatest dimension

100 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 4 - Continued American Joint Committee on Cancer (AJCC) TNM Staging System f the Nasal Cavity and Paranasal Sinuses (7th ed., 2010) (Nonepithelial tums such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included) Anatomic Stage/Prognostic Groups Stage 0 Stage I Stage II Stage III Stage IVA Stage IVB Stage IVC Tis N0 M0 T1 N0 M0 T2 N0 M0 T3 N0 M0 T1 N1 M0 T2 N1 M0 T3 N1 M0 T4a N0 M0 T4a N1 M0 T1 N2 M0 T2 N2 M0 T3 N2 M0 T4a N2 M0 T4b Any N M0 Any T N3 M0 Any T Any N M1 Histologic Grade (G) GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poly differentiated G4 Undifferentiated Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ST-9

101 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 5 American Joint Committee on Cancer (AJCC) TNM Staging System f the Maj Salivary Glands (Parotid, Submandibular, and Sublingual) (7th ed., 2010) Primary Tum (T) TX Primary tum cannot be assessed T0 No evidence of primary tum T1 Tum 2 cm less in greatest dimension without extraparenchymal extension* T2 Tum me than 2 cm but not me than 4 cm in greatest dimension without extraparenchymal extension* T3 Tum me than 4 cm and/ tum having extraparenchymal extension* T4a Moderately advanced disease Tum invades skin, mandible, ear canal, and/ facial nerve T4b Very advanced disease Tum invades skull base and/ pterygoid plates and/ encases carotid artery *Note: Extraparenchymal extension is clinical macroscopic evidence of invasion of soft tissues. Microscopic evidence alone does not constitute extraparenchymal extension f classification purposes. Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm less in greatest dimension N2 Metastasis in a single ipsilateral lymph node, me than 3 cm but not me than 6 cm in greatest dimension; in multiple ipsilateral lymph nodes, none me than 6 cm in greatest dimension; in bilateral contralateral lymph nodes, none me than 6 cm in greatest dimension N3 N2a N2b N2c Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Anatomic Stage/Prognostic Groups Stage I Stage II Stage III Stage IVA Stage IVB Stage IVC Metastasis in a single ipsilateral lymph node, me than 3 cm but not me than 6 cm in greatest dimension Metastasis in multiple ipsilateral lymph nodes, none me than 6 cm in greatest dimension Metastasis in bilateral contralateral lymph nodes, none me than 6 cm in greatest dimension Metastasis in a lymph node, me than 6 cm in greatest dimension T1 N0 M0 T2 N0 M0 T3 N0 M0 T1 N1 M0 T2 N1 M0 T3 N1 M0 T4a N0 M0 T4a N1 M0 T1 N2 M0 T2 N2 M0 T3 N2 M0 T4a N2 M0 T4b Any N M0 Any T N3 M0 Any T Any N M1 Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ST-10

102 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Staging Table 6 American Joint Committee on Cancer (AJCC) TNM Staging System f Mucosal Melanoma of the Head and Neck (7th ed., 2010) Primary Tum (T) T3 Mucosal disease T4a Moderately advanced disease Tum involving deep soft tissue, cartilage, bone, overlying skin T4b Very advanced disease Tum involving brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticat space, carotid artery, prevertebral space, mediastinal structures Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Regional lymph node metastases present Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Anatomic Stage/Prognostic Groups Stage III Stage IVA Stage IVB Stage IVC T3 N0 M0 T4a N0 M0 T3-T4a N1 M0 T4b Any N M0 Any T Any N M1 Histologic Grade (G) GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poly differentiated G4 Undifferentiated Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC (SBM). (F complete infmation and data suppting the staging tables, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. ST-11

103 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. NCCN Categies of Evidence and Consensus Categy 1: Based upon high-level evidence, there is unifm NCCN consensus that the intervention is appropriate. Categy 2A: Based upon lower-level evidence, there is unifm NCCN consensus that the intervention is appropriate. Categy 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Categy 3: Based upon any level of evidence, there is maj NCCN disagreement that the intervention is appropriate. All recommendations are categy 2A unless otherwise noted. Overview This discussion is being updated to crespond with the newly updated algithm. Last updated 05/23/11 The NCCN Head and Neck (H&N) Cancers guidelines address tums arising in the lip, al cavity, pharynx, larynx, and paranasal sinuses (see Figure 1); occult primary cancer, salivary gland cancer, and mucosal melanoma are also addressed. 1 A brief overview of the epidemiology and management of H&N cancer is provided. By definition, the NCCN practice guidelines cannot incpate all possible clinical variations and are not intended to replace good clinical judgment individualization of treatments. Exceptions to the rule were discussed among the members of the panel while developing these guidelines. A 5% rule (omitting clinical scenarios that comprise less than 5% of all cases) was used to eliminate uncommon clinical occurrences conditions from these guidelines. Incidence and Etiology It is estimated that about 49,260 new cases of al cavity, pharyngeal, and laryngeal cancers occurred in 2010, which account f about 3% of new cancer cases in the United States. An estimated 11,480 deaths from H&N cancers occurred during the same time period. 2,3 Squamous cell carcinoma a variant is the histologic type in over 90% of these tums. Alcohol and tobacco abuse are common etiologic facts in cancers of the al cavity, opharynx, hypopharynx, and larynx. Because the entire aerodigestive tract epithelium may be exposed to these carcinogens, patients with H&N cancer are at risk f developing second primary neoplasms of the H&N, lung, esophagus, and other sites that share these risk facts. Human papillomavirus (HPV) infection is now well accepted as a risk fact f the development of squamous cancers of the opharynx (particularly cancers of the lingual and palatine tonsils, and base of tongue) The overall incidence of HPV positive H&N cancer is increasing in the United States, while the incidence of HPV negative (primarily tobacco- and alcohol-related) cancer is decreasing. 11 A strong causal relationship has been established between the HPV type 16 and development of opharyngeal cancer (see HPV Testing in the opharyngeal section of this ). 4 It has not been demonstrated yet whether HPV vaccination will decrease the incidence of HPV positive opharyngeal cancer. Staging Stage at diagnosis predicts survival rates and guides management in patients with H&N cancer. The 2010 American Joint Committee on Cancer (AJCC) staging classification (7 th edition) was used as a basis f the NCCN's treatment recommendations f H&N cancer. 12,13 The 7 th edition of the AJCC staging guidelines became effective January 1, Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-1

104 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved The AJCC added staging criteria f mucosal melanoma in the 7 th edition. However, no maj changes in the T classification stage groupings f the other sites have been made in the revisions f the 7 th edition f H&N cancer; the min changes are described below. The TNM staging systems developed by the AJCC f the lip and al cavity, pharynx (nasopharynx, opharynx, and hypopharynx), larynx (glottis and supraglottis), paranasal sinuses (ethmoid and maxillary), maj salivary glands (parotid, submandibular, and sublingual), and mucosal melanoma are shown in Tables 1-6, respectively. 13 Definitions f regional lymph node (N) involvement and spread to distant metastatic sites (M) are unifm except f N staging of nasopharyngeal carcinoma (see Table 2). Definitions f staging the primary tum (T), based on its size, are unifm f the lip, al cavity, and opharynx. In contrast, T stage is based on subsite involvement and is specific to each subsite f the glottic larynx, supraglottic larynx, hypopharynx, and nasopharynx. In general, stage I II disease defines a relatively small primary tum with no nodal involvement. Stage III IV cancers include larger primary tums, which may invade underlying structures, and/ spread to regional nodes. Distant metastases are uncommon at presentation. Me advanced TNM stages are associated with wse survival. The anatomic criteria f definitions of T4a and T4b f the opharynx, hypopharynx, larynx, nasal cavity, paranasal sinuses, and maj salivary glands remain unchanged in the 7 th edition of the AJCC staging manual. However, the wds resectable (T4a) and unresectable (T4b) have been replaced by the terms moderately advanced (T4a) and very advanced (T4b). 12 These changes were deemed necessary, because a substantial proption of advanced stage malignancies of the H&N, although resectable, are being treated non-surgically. Furtherme, a clear consensus in criteria f resectability can be difficult to obtain. F example, some tums deemed unresectable are in fact anatomically resectable, but surgery is not pursued because of medical contraindications to surgery because it is anticipated that surgery will not improve prognosis (see Resectable versus Unresectable Disease in the Head and Neck Surgery section of this ). This change in terminology allows revising of stage IV disease into moderately advanced local/regional disease (stage IVA), very advanced local/regional disease (stage IVB), and distant metastatic disease (stage IVC) f many sites (i.e., lip, al cavity, opharynx, hypopharynx, larynx, paranasal sinuses, maj salivary glands, and mucosal melanoma). Of note, a designation of stage IV disease does not necessarily mean the disease is incurable, particularly in the absence of distant metastases. An algithm f mucosal melanoma was added to the NCCN 2010 H&N guidelines. Mucosal melanomas are rare, very aggressive tums that mainly affect the nasal cavity and paranasal sinuses. Thus, melanomas confined to the mucosa only are T3; those with moderately advanced lesions (involving underlying cartilage bone) are T4a, and very advanced primary tums are T4b. Min changes were made in the T staging categies f the nasopharynx in the 7 th edition of the AJCC (see Table 2). 12 Thus, fmer T2a lesions are now designated T1; therefe, fmer stage IIA is now stage I. Lesions previously staged as T2b are now T2; therefe, fmer stage IIB is now stage II. Regardless of unilateral bilateral location, retropharyngeal lymph nodes are considered N1. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-2

105 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Management Approaches Treating the patient with H&N cancer is complex. The specific site of disease, the extent of disease (stage), and the pathologic findings guide the appropriate surgical procedure, radiation targets, dose and fractionation, and indications f chemotherapy. Single-modality treatment with surgery radiotherapy is generally recommended f the approximately 30%-40% of patients who present with early stage disease (stage I stage II). The 2 modalities result in similar survival in these individuals. In contrast, combined modality therapy is generally recommended f the approximately 60% of patients with locally regionally advanced disease at diagnosis. The treatment of patients with locally advanced T4b unresectable nodal disease, metastatic disease, recurrent disease f the following sites (i.e., lip, al cavity, pharynx, larynx, paranasal sinus, and occult primary cancer) is addressed in the Very Advanced/Recurrent/Persistent H&N Cancers section of the H&N algithm. Participation in clinical trials is a preferred recommended treatment option in many situations. In fmulating these H&N guidelines, the panel has tried to make them evidence based while providing a statement of consensus as to the acceptable range of treatment options. Multidisciplinary Team Involvement The initial evaluation and development of a plan f treating the patient with H&N cancer require a multidisciplinary team of health care providers with expertise in caring f these patients. Similarly, managing and preventing sequelae of radical surgery, radiotherapy, and chemotherapy (e.g., pain, xerostomia, speech and swallowing problems, depression) require professionals familiar with the disease. Follow-up f these sequelae should include a comprehensive H&N examination. Adequate nutritional suppt can help to prevent severe weight loss in patients receiving treatment f H&N cancer; therefe, patients should be encouraged to see a dietician. 14 Patients should also be encouraged to stop smoking and to modify alcohol consumption if excessive, because these habits may decrease the efficacy of treatment and adversely affect other health outcomes. 15,16 Programs using behavial counseling combined with medications that promote smoking cessation (approved by the FDA [Food and Drug Administration]) can be very useful ( Specific components of patient suppt and follow-up are listed in the algithm. The panel also recommends referring to the NCCN Guidelines f Palliative Care. Combidity and Quality of Life Combidity Combidity refers to the presence of concomitant disease (in addition to H&N cancer) that may affect the diagnosis, treatment, and prognosis f the patient Documentation of combidity is particularly imptant in oncology to facilitate optimal treatment selection and estimates of prognosis. Combidity is known to be a strong independent predict f mtality in H&N cancer patients, and combidity also influences costs of care, utilization, and quality of life Traditional indices of combidity include the Charlson index 18 and the Kaplan-Feinstein index and its modifications. 19,30 The Adult Combidity Evaluation-27 (ACE-27) is specific f H&N cancer and has excellent emerging reliability and validity. 31,32 Quality of Life Health-related quality-of-life issues are paramount in H&N cancer. These tums affect basic physiological functions (i.e., the ability to chew, swallow, and breathe), the senses (taste, smell, and hearing), and uniquely human characteristics (i.e., appearance and voice). Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-3

106 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Health status describes an individual s physical, emotional, and social capabilities and limitations. Function and perfmance refer to how well an individual is able to perfm imptant roles, tasks, activities. Quality of life differs, because the central focus is on the value (determined by the patient alone) that individuals place on their health status and function. 33 A National Institutes of Health (NIH) sponsed conference 34 recommended the use of patient-completed scales to measure quality of life. F H&N cancer-specific issues, the 3 validated measures that have received the most widespread acceptance are: (1) the University of Washington Quality of Life scale (UW-QOL); 35 (2) the European Organization f Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-HN35); 36 and (3) the Functional Assessment of Cancer Therapy Head and Neck module (FACT-HN). 37 The Perfmance Status Scale f H&N cancer patients is a clinician-rated perfmance scale with a narrower focus than the previously mentioned Quality of Life scales that has also achieved widespread use. 38 Head and Neck Surgery Principles of Surgery All patients should be evaluated by an H&N surgical oncologist befe treatment. In addition, it is critical that multidisciplinary evaluation and treatment be well codinated. Evaluation, integration of therapy, assessment of resectability, primary tum resection, margins, surgical management of cranial nerves (VII, X-XII), neck management, management of recurrences, and surveillance (including post-treatment neck evaluation) are discussed in the Principles of Surgery in the H&N algithm. 1,39 Resectable disease, neck dissection, postoperative management, and salvage surgery of high-risk disease are discussed in the following sections. Resectable Versus Unresectable Disease The term unresectable has resisted fmal definition by H&N cancer specialists. The experience of the surgeon and the suppt available from reconstructive surgeons, physiatrists, and prosthodontists often strongly influence recommendations, especially in institutions where only a few patients with locally advanced H&N cancer are treated. The NCCN member institutions have teams experienced in the treatment of H&N cancer and maintain the multidisciplinary infrastructure needed f reconstruction and rehabilitation. A patient s cancer is deemed unresectable if H&N surgeons at NCCN member institutions do not think they can remove all gross tum on anatomic grounds if they are certain local control will not be achieved after an operation (even with the addition of radiotherapy to the treatment approach). Typically, these unresectable tums densely involve the cervical vertebrae, brachial plexus, deep muscles of the neck, carotid artery. Tum involvement of certain sites is associated with po prognosis (i.e., direct extension of neck disease to involve the external skin, direct extension to mediastinal structures, prevertebral fascia, cervical vertebrae). Unresectable tums (i.e., those tums that cannot be removed without causing unacceptable mbidity) should be distinguished from inoperable tums in those patients whose constitutional state precludes an operation (even if the cancer could be readily resected with few sequelae). Additionally, a subgroup of patients will refuse surgical management, but these tums should not be deemed unresectable. Although local and regional disease may be surgically treatable, patients with distant metastases are usually treated as though the primary tum was unresectable. Thus, patient choice a Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-4

107 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. physician s expectations regarding cure and mbidity will influence determine treatment. Patients with resectable tums who can also be adequately treated without surgery represent a very imptant group. Definitive treatment with radiation therapy (RT) alone RT combined with chemotherapy may represent equivalent preferable approaches to resection in these individuals. Although such patients may not undergo surgery, their tums should not be labeled as unresectable. Their disease is usually far less extensive than disease that truly cannot be removed. Neck Dissection Histically, cervical lymph node (i.e., neck) dissections have been classified as radical modified radical procedures. The less radical procedures preserved the sternocleidomastoid muscle, jugular vein, spinal accessy nerve, selective lymph node levels. The panel prefers to classify cervical lymphadenectomy using contempary nomenclature, thus classifying cervical lymph node dissections as either comprehensive selective. 40 A comprehensive neck dissection is one that removes all lymph node groups that would be included in a classic radical neck dissection. Whether the sternocleidomastoid muscle, jugular vein, spinal accessy nerve is preserved does not affect whether the dissection is classified as comprehensive. Depending on the site, comprehensive neck dissection is often recommended f N3 disease. Selective neck dissections have been developed based on an understanding of the common pathways f spread of H&N cancers to regional nodes (see Figure 2). 41,42 Depending on the site, selective neck dissection is often recommended f N0 disease. To remove the nodes most commonly involved with metastases from the al cavity, a selective neck dissection is recommended which includes the nodes found above the omohyoid muscle (levels I-III and sometimes the superi parts of level V). 40,43 Similarly, to remove the nodes most commonly involved with metastases from the pharynx and larynx, a selective neck dissection is recommended which includes the nodes in levels II-IV and level VI when appropriate. 40 Elective level VI dissections are often considered appropriate f infraglottic laryngeal cancers. H&N squamous cell cancer with no clinical nodal involvement rarely presents with nodal metastasis beyond the confines of an appropriate selective neck dissection (<10% of the time) The chief role of selective neck dissections in these NCCN H&N guidelines is to select patients f possible adjuvant therapy (i.e., chemo/rt RT), although selective neck dissections may be used as treatment when neck tum burden is low. 47 In general, patients undergoing selective neck dissection should not have clinical nodal disease; however, selective neck dissection may prevent mbidity in patients with nodal disease and may be appropriate in certain patients with N1-N2 disease In the guidelines, patients with cervical node metastases who undergo operations with therapeutic intent are generally treated with comprehensive neck dissections, because often they have disease outside the bounds of selective neck dissections. Determining whether an ipsilateral bilateral neck dissection is needed depends on tum thickness, the extent of the tum, and the site of the tum. 39 F example, bilateral neck dissection is often recommended f tums at near the midline and/ f tum sites with bilateral drainage. It is particularly imptant f nonsurgically treated patients to have careful and regular follow-up examinations by a trained H&N surgical oncologist so that any local regional recurrence is detected early, and salvage surgery (and neck dissection as indicated) is perfmed. After either RT chemadiation, post-treatment evaluation with Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-5

108 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. imaging (i.e., CT and/ MRI with contrast, PET-CT) guides the use of neck dissection If PET-CT is used f follow-up, the first scan should be perfmed at approximately 12 weeks after treatment to reduce the false-positive rate. 52,55 Note that a complete clinical response (i.e., clinically negative) may be defined as no visible palpable neck disease and no radiographic findings (i.e., the absence of either focally abnmal lymph nodes large nodes [> 1.5 cm]); 51,56 a complete pathologic response requires pathologic confirmation. If a complete clinical response has been achieved in patients who were N0 at initial staging, all of the panel members recommend observing the patient. 51,56,57 In patients who have a clinically negative neck, a negative PET-CT is 90% reliable and further imaging is optional Panelists also concur that any patient with residual disease suspected progression in the neck after radiotherapy chemadiation should undergo a neck dissection. 51 Postoperative Management of High-Risk Disease Many facts influence survival and locegional tum control in patients with H&N cancer. The role of chemotherapy in the postoperative management of the patient with adverse prognostic risk facts has been clarified by 2 separate multicenter randomized trials 61,62 and a combined analysis of data from the 2 trials f patients with high-risk cancers of the al cavity, opharynx, larynx, hypopharynx. 63 The US Intergroup trial the Radiation Therapy Oncology Group (RTOG) trial randomly assigned patients with 2 me involved nodes, positive margins, extracapsular nodal spread of tum to receive standard postoperative radiotherapy the same radiotherapy plus cisplatin 100 mg/m 2 every 3 weeks f 3 doses. 62 The European trial (i.e., European Organization f Research and Treatment of Cancer [EORTC] trial) was designed using the same chemotherapy treatment and similar RT dosing but also included as high-risk facts the presence of perineural perivascular disease and nodal involvement at levels 4 and 5 from an al cavity opharynx cancer. 61 The RTOG trial demonstrated statistically significant improvement in locegional control and disease-free survival but not overall survival, whereas the EORTC trial found significant improvement in survival and the other outcome parameters. A schedule using cisplatin at 50 mg IV weekly has also demonstrated improved survival in this setting in a randomized trial. 64 To better define risk, a combined analysis of prognostic facts and outcome from the 2 trials was perfmed. This analysis demonstrated that patients in both trials with extracapsular nodal spread of tum and/ positive resection margins benefited from the addition of cisplatin to postoperative radiotherapy. F those with multiple involved regional nodes without extracapsular spread, there was no survival advantage. 63 The NCCN panel noted that the combined analysis was considered explaty by the auths, because it was not part of the initial protocol design. 63 These publications fm the basis f the NCCN recommendations. In NCCN member institutions, patients with extracapsular nodal spread and/ positive surgical margins receive adjuvant chemadiotherapy after resection The presence of other adverse risk facts multiple positive nodes (without extracapsular nodal spread), vascular/lymphatic/perineural invasion, pt3 pt4 primary, and al cavity opharynx primary cancers with positive level 4 5 nodes are established indications f postoperative RT. Because patients with these other adverse features were also included in the EORTC trial that showed a survival advantage f patients receiving cisplatin Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-6

109 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. concurrent with postoperative radiotherapy compared to radiotherapy alone, the panel added consider chemadiation f these features. 61 Salvage Surgery Patients with advanced carcinoma (any T, N2-3) who undergo nonsurgical treatment, such as concurrent chemotherapy and RT, need very close follow-up both to evaluate f local recurrence and to assess f ipsilateral contralateral neck recurrence. The patients who do not have a complete clinical response to chemotherapy/rt require salvage surgery plus neck dissection as indicated. However, all panelists emphasized that it may be difficult to detect local regional recurrence due to radiation-related tissue changes, and this may result in a delayed diagnosis of persistent recurrent disease. The panelists also emphasized the increased risk of complications when salvage surgery is attempted. Some of these patients may require microvascular free flap reconstruction to cover the defects at the primary site. The patients undergoing neck dissection may develop complications related to delayed wound healing, skin necrosis, carotid exposure. Laryngectomy may be required to obtain clear surgical margins to prevent aspiration (e.g., in patients with advanced opharyngeal cancer). The patients requiring salvage laryngectomy may have high incidence of pharyngocutaneous fistula and may require either a free flap reconstruction of the laryngopharyngeal defect, a myocutaneous flap to buttress the suture line if the pharynx can be closed primarily. Head and Neck Radiotherapy In the NCCN H&N guidelines, the radiotherapy guidelines were revised f each site. Radiotherapy f H&N cancer has grown increasingly complex. The availability and technical precision of intensity modulated radiotherapy has markedly increased, perhaps beyond our confidence in estimating location of small subsites of microscopic disease. A though understanding of natural histy, anatomy, clinical circumstances, and imaging continue to guide the use of radiation as primary treatment as an adjuvant. The NCCN radiotherapeutic guidelines are not all inclusive. Although technical guidelines are rapidly evolving and becoming me specific, advanced technologies provide much opptunity f variations and individualization in targeting and dose delivery, challenging traditional notions of standard fields and targets. Radiation Doses Selection of radiation total dose depends on the primary tum and neck node size, fractionation, and clinical circumstances, including whether to use concurrent chemotherapy. In general, the primary tum and gross adenopathy require a total of Gy (2.0 Gy/fraction), and up to 81.6 Gy (1.2 Gy/fraction) in hyperfractionation. External radiation doses exceeding 75 Gy using conventional fractionation (2.0 Gy/fraction) may lead to unacceptable rates of nmal tissue injury. In contrast, elective irradiation to low and intermediate risk nodal stations in the neck requires Gy, depending on the estimated level of tum burden, and fraction size. Postoperative irradiation is recommended based on stage, histology, and surgical-pathological findings. In general, postoperative RT is recommended f selected risk facts, including advanced T-stage, depth of invasion, multiple positive nodes (without extracapsular nodal spread), perineural/lymphatic/vascular invasion. Higher doses of radiation alone (60-66 Gy), with chemotherapy, are recommended f the high-risk features of extracapsular disease and/ positive margins. The preferred interval between resection and commencement of postoperative RT is 6 weeks less. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-7

110 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Fractionation in RT Alone No single fractionation schedule has proven to be best f all tums. Data strongly indicate squamous cancers of the H&N can grow rapidly, and may compensate f radiotherapy-induced cell loss through the mechanism of accelerated repopulation Especially in RT alone settings, schedules delivering at least 1000 cgy per week are recommended, with the exception of salivary gland tums, which may have slower cell kinetics. Trials in early stage glottic larynx cancer have shown higher recurrence rates with daily fraction sizes <200 cgy where the cumulative weekly dose is <1000 cgy. 79,80 Two large, randomized clinical trials from Europe have repted improved locegional control using altered fractionation. The EORTC protocol compared hyperfractionation (1.15 Gy twice daily, 80.5 Gy over 7 weeks) with conventional fractionation (2 Gy once daily, 70 Gy over 7 weeks) in the treatment of T2, T3, N0-1 opharyngeal carcinoma excluding base of tongue primaries. At 5 years, there was a statistically significant increase in local control in the hyperfractionation arm (38% versus 56%; P=.01) and no increase in late complications. 81 A long-term follow-up analysis has also demonstrated a small survival advantage f hyperfractionation (P=.05). 82 Another EORTC protocol (22851) compared accelerated fractionation (1.6 Gy 3 times daily, 72 Gy over 5 weeks) with conventional fractionation ( Gy once daily, 70 Gy over 7-8 weeks) in various intermediate to advanced H&N cancers (excluding cancers of the hypopharynx). Patients in the accelerated fractionation arm had significantly better locegional control at 5 years (P=.02). Disease-specific survival showed a trend in fav of the accelerated fractionation arm (P=.06). Acute and late toxicity were increased with acceleration, however, raising questions about the net advantages of accelerated fractionation. 83 The RTOG repted the initial 2-year results and subsequent mature results (after a median follow-up of 8.5 years) of a 4-armed phase III randomized clinical trial (protocol 90-03) comparing hyperfractionation and 2 variants of accelerated fractionation against standard fractionation. 84,85 After 2 years of follow-up, both accelerated fractionation with a concomitant boost (AFX-C) and hyperfractionation were associated with improved locegional control and disease-free survival compared with standard fractionation. However, acute toxicity was increased. No significant difference was demonstrated in the frequency of grade 3 wse late effects repted at 6 to 24 months after treatment start, among the various treatment groups. Long-term follow-up confirmed a statistically significant improvement in locegional control with either AFX-C hyperfractionation compared to standard fractionation. However, neither disease-free survival n overall survival were significantly improved. A meta-analysis of updated individual patient data from 15 randomized trials analyzing the effect of hyperfractionated accelerated radiotherapy on survival of patients with H&N cancer has been published. 86 Standard fractionation constituted the control arm in all of the trials in this meta-analysis. An absolute survival benefit of 3.4% at 5 years (HR 0.92; 95% CI, ; P=.003) was repted. This benefit, however, was limited to patients younger than 60 years of age. 86 Consensus regarding altered fractionation schedules with concomitant boost hyperfractionation f stage III IV al cavity, opharynx, supraglottic larynx, and hypopharyngeal squamous cell cancers has not yet emerged among NCCN member institutions Fractionation in Concurrent Chemadiation There is no consensus regarding the optimal radiation dose fractionation scheme when administered with concurrent chemotherapy. Most published studies have used conventional Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-8

111 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. fractionation at 2.0 Gy per fraction to 70 Gy me in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m 2. Other fraction sizes (e.g., 1.8 Gy, conventional), other dosing schedules of cisplatin, other single agents, multiagent chemotherapy, and altered fractionation with chemotherapy have been evaluated alone in combination. Numerous trials have shown that modified fractionation and concurrent chemotherapy are me efficacious than modified fractionation alone However, whether modified fractionation and concurrent chemotherapy is superi to standard fractionation and concurrent chemotherapy is unknown at this time. RTOG 0129 is assessing accelerated fractionation versus standard fractionation with concurrent cisplatin. Preliminary results suggest that accelerated fractionation does not improve survival over standard fractionation. 92 Concurrent chemadiation increases acute toxicity compared to radiation alone, although an increase in late toxicity beyond that caused by radiotherapy alone is less clear Altered fractionation and/ multiagent chemotherapy may further increase the toxicity burden. 96 F any chemotherapeutic approach, close attention should be paid to published repts f the specific chemotherapy agent, dose, and schedule of administration. Chemadiation should be perfmed by an experienced team and should include substantial supptive care. Radiation Techniques and IMRT The intensity of the radiation beam can be modulated in der to decrease doses to nmal structures without compromising the doses to the cancer targets 97,98 Intensity-modulated radiation therapy (IMRT) is an advanced fm of confmal RT permitting me precise cancer targeting while reducing dose to nmal tissues Xerostomia is a common long-term side effect of RT, which can be reduced with use of IMRT, drug therapy (e.g., pilocarpine, cevimeline), and other novel approaches (e.g., acupuncture) IMRT dose painting refers to the method of assigning different dose levels to different structures within the same treatment fraction (e.g., 2.0 to gross tum, 1.7 to microscopic tum, and <1.0 Gy to parotid gland) resulting in different total doses to different targets (e.g., 70 Gy, 56 Gy, <26 Gy). 108 Although dose painting has been used to simplify radiation planning, hot spots associated with higher toxicity can occur. 108,109 Alternatively, separate dose plans f the low versus higher dose targets can be delivered sequentially ( reduce target size and boost ) on the same day as separate fractions in twice a day schemas. 101,110 IMRT is now widely used in H&N cancer and is the predominant technique used at NCCN centers. It is useful in reducing long-term toxicity in opharyngeal, paranasal sinus, and nasopharyngeal cancers by reducing the dose to one me maj salivary glands, tempal lobes, mandible, audity structures (including cochlea), and optic structures. 103,104, However, overall survival is similar between patients treated with IMRT and those receiving conventional RT. 111,118,119 In-field recurrences, low-grade mucositis in areas away from the cancer targets, and posteri neck hair loss can occur with IMRT. 120,121 The application of IMRT to other sites (e.g., al cavity, larynx, hypopharynx, salivary glands) is evolving and may be used at the discretion of treating physicians. 122,123 Numerous phase II studies show a decrease in late toxicity (xerostomia) without compromising tum control f nasopharyngeal, sinonasal, and other sites. Me recently, 3 randomized trials have suppted the clinical benefits of IMRT in H&N cancer with regard to the reduction in xerostomia. Pow and colleagues evaluated treatment of early stage nasopharyngeal carcinoma with conventional radiotherapy Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-9

112 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. techniques versus with IMRT. 103 The results showed a statistical improvement in salivary flow and in patient-repted quality of life parameters. 103 In the study by Kam and colleagues, patients with nasopharyngeal carcinoma were randomized to either IMRT conventional 2-D radiotherapy. 104 At 1 year after treatment, patients in the IMRT arm had significantly lower rates of clinician-rated severe xerostomia than patients in the 2-D RT arm (39.3% versus 82.1%; P=.001). Salivary flow rates were also higher with IMRT. The mean parotid dose was 32 Gy in the IMRT group and 62 Gy in the conventional group. Although a trend f improvement in patient-repted dry mouth was observed after IMRT, recovery was incomplete and there was no significant difference in patient-repted outcomes between the 2 arms. The auths concluded that other salivary glands may also be imptant and merit protection. Recent data from the PARSPORT phase III randomized trial indicate that IMRT decreases xerostomia when compared with conventional RT in patients with non-nasopharyngeal carcinoma. 124,125 In this trial, patients with T1-T4, N0-N3, M0 disease were treated to a total dose of Gy in 30 fractions either with conventional RT (i.e., parallel opposed technique) with IMRT; 80 patients with opharyngeal and 14 patients with hypopharyngeal tums were included. Grade 2 wse (LENT-SOMA scale) xerostomia 1 year after treatment was seen in 74% of patients receiving conventional RT versus 38% of patients in the IMRT group (P =.003). No differences were seen in the rates of locegional control survival. Follow-up After RT F patients whose cancer has been treated with RT, the recommended follow-up includes an assessment of thyroid function (i.e., the thyroid stimulating hmone [TSH] level should be determined every 6 to 12 months). Increased TSH levels have been detected in 20% to 25% of patients who received neck irradiation. 126 Brachytherapy Brachytherapy is used less often in recent years because of improved local control obtained with concurrent chemadiation. However, brachytherapy still has a role f lip cancer. 127 Cancer of the Lip The guidelines f squamous cell carcinoma of the lip generally follow accepted clinical practice patterns established over several decades. No randomized clinical trials have been conducted that can be used to direct therapy. The incidence of lymph node metastases, especially in early stage lower lip cancer, is low, averaging less than 10%. The risk of lymph node metastases is related to the location, size, and grade of the primary tum. Elective neck dissection neck irradiation can be avoided in patients with early stage disease and a clinically negative neck. Treatment recommendations are based on clinical stage, medical status of the patient, anticipated functional and cosmetic results, and patient preference. Wkup and Staging The wkup f patients with squamous cell carcinoma of the lip consists of a complete H&N examination and other appropriate studies. A dental Panex (panamic x-ray), computerized tomographic (CT) scan, magnetic resonance imaging (MRI) are done as indicated to better assess soft tissue nodal spread if bone invasion is suspected. The AJCC TNM staging system reflects tum size, extension, and nodal disease (see Table 1). 12 This system does predict the risk f Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-10

113 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. local recurrence. The location of the primary tum also is predictive. Tums in the upper lip and commissural areas have a higher incidence of lymph node metastases at the time of diagnosis. Systemic dissemination is rare, occurring in approximately 10% to 15% of patients, most often in those with uncontrolled locegional disease. Treatment of the Primary The treatment of lip cancer is governed by the stage of the disease. The choice of a local treatment modality is based on the expected functional and cosmetic outcome. In early stage cancers (T1-2, N0), surgery is preferred and radiation is an option in terms of local control Some very small superficial cancers are managed me expeditiously with a surgical excision without resultant functional defmity an undesired cosmetic result. A superficial cancer that occupies most of the lower lip, however, would be best managed with RT. 131 Some advanced lip cancers can cause a great deal of tissue destruction and secondary defmity; surgery is preferred in this clinical setting. Surgery is also the local modality of choice f advanced cancers with extension into the bone. Patients with resectable T3-,T4a, N0; any T, N1-3 disease who are a po surgical risk can be treated with definitive RT (with without brachytherapy) with chemotherapy/rt. 131 In patients who appear to have a complete response after either RT chemadiation, post-treatment evaluation with imaging can be used to guide the use of neck dissection. Management of the Neck The management of the neck is also governed by stage, but the location of the tum should also be taken into account. F example, the lymphatics of the upper lip are very extensive. Thus, tums in this location are me apt to spread to deep superi jugular nodes. The position of the tum along the lip also can be helpful in predicting the pattern of lymph node spread. A midline location can place a patient at higher risk f contralateral disease. F patients with advanced disease (T3, T4a) and an N0 neck, an ipsilateral bilateral selective neck dissection is recommended. When a patient presents with palpable disease, care is taken to ensure all appropriate nodal levels are dissected. Radiation Therapy Radiotherapy, when used as definitive treatment, may consist of external-beam RT with without brachytherapy, depending on the size of the tum. The dose required also depends on tum size, but doses of Gy are adequate to control the disease. In the adjuvant setting, doses of Gy are required, depending on the pathologic features. In both definitive and adjuvant settings, the neck is treated with doses that address adverse features, such as positive margins invasion (perineural, vascular, and/ lymphatic). 132 Follow-up/Surveillance Recommendations f surveillance are provided in the algithm. Cancer of the Oral Cavity The al cavity includes the following subsites: buccal mucosa, upper and lower alveolar ridge, retromolar trigone, flo of the mouth, hard palate, and anteri two thirds of the tongue. There is a rich lymphatic supply to the area, and initial regional node dissemination is to nodal groups at levels I-III. Regional node involvement at presentation is evident in approximately 30% of patients, but the risk varies accding to subsite. F example, primaries of the alveolar ridge and hard palate infrequently involve the Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-11

114 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. neck, whereas occult neck metastasis is common (50% to 60%) in patients with anteri tongue cancers. In general, all patients undergo either ipsilateral bilateral selective neck dissection, which is guided by tum thickness. If definitive RT is chosen f treatment of T1-2, N0 disease, at least Gy is given to the neck. Wkup and Staging Imaging studies to evaluate mandibular involvement and a careful dental evaluation (including Panex, as indicated) are particularly imptant f staging (see Table 1) and planning therapy f al cavity cancers in addition to a complete H&N examination, biopsy, and other appropriate studies. F patients who appear to have stage III-IV disease, PET-CT may alter management by upstaging patients. 133 Treatment Surgery and RT represent the standards of care f early stage and locally advanced resectable lesions in the al cavity. The specific treatment is dictated by the TN stage and, if N0 at diagnosis, by the risk of nodal involvement. Multidisciplinary team involvement is particularly imptant f this site because of the critical physiologic functions of mastication, deglutition, and articulation of speech, which may be affected. Most panelists prefer surgical therapy f resectable al cavity tums, even f me advanced tums. The concept of gan preservation using chemotherapy in the initial management of these patients has received less attention in the management of al cavity cancers, because the functional outcome after primary surgical management is often quite good, given advances in reconstruction using microvascular techniques. Primary RT may be offered to select patients who are medically inoperable refuse surgery. Postoperative chemotherapy/rt (preferred, categy 1) re-excision of positive margins (if technically feasible) is recommended f all patients with resected al cavity cancers with the adverse pathologic features of extracapsular nodal spread and/ a positive mucosal margin F other risk features such as pt3 pt4 primary, N2 N3 nodal disease, nodal disease in levels IV V, perineural invasion vascular tum embolism clinical judgment should be utilized in the consideration of adding chemotherapy to RT treating with RT alone. Follow-up/Surveillance Recommendations f surveillance are provided in the algithm. Cancer of the Oropharynx The opharynx includes the base of the tongue, tonsils, soft palate, and posteri pharyngeal wall. The opharynx is extremely rich in lymphatics. Depending on the subsite involved, 15% to 75% of patients present with lymph node involvement. Effts to improve the outcome of patients with locally advanced disease are ongoing. Participation in clinical trials is strongly recommended. Wkup and Staging A multidisciplinary consultation is encouraged. Accurate staging (see Table 2) depends on complete H&N examination coupled with appropriate imaging studies. 12,134 Tum HPV testing is suggested f cancers of the opharynx given the established relationship between pri HPV infection and the development of a significant proption of opharyngeal cancers (see next section on HPV Testing ). HPV Testing A number of studies have recently documented an increase in the incidence of HPV-related cancer, now estimated to comprise up to 60% to 70% of newly diagnosed cancers of the opharynx in the United Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-12

115 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. States and parts of the European Union. 11,135,136 A strong causal relationship has been established particularly between HPV type 16 and development of opharyngeal cancer. 4 Prospective and retrospective analyses of clinical trials indicate that patients with HPV-positive cancers have improved response to treatment and improved survival and progression-free survival when compared with HPV-negative tums How this infmation should be used in routine clinical decision-making and in the design of clinical trials is currently a matter of intense investigation among NCCN centers. There is growing consensus that HPV status should be used as a stratification fact should be addressed in separate trials (HPV related versus unrelated disease) f which opharynx patients are eligible. With the exception of cancers of unknown primary (see Occult Primary Cancer in this ), the panel believes that HPV status should not be a routine consideration in treatment selection at this time. Additional studies are needed to better understand the effect of HPV status on response to different therapies, treatment outcome, and patterns of failure and in relation to other prognostic predictive facts such as smoking histy and stage. A number of clinical trial groups are repting retrospective analyses of response to therapy in HPV-related versus HPV-unrelated opharynx cancers ,141 The panel strongly urges that, where available, patients with HPV-related cancers be enrolled in clinical trials evaluating biological and treatment-related questions. HPV testing options in a clinical setting include HPV in situ hybridization [ISH]) and a surrogate marker, p16 immunohistochemistry (which is a me widely available test that has been shown in several studies to strongly crelate with HPV status and is similarly associated with improved prognosis) ,143 Sufficient pathologic material f HPV testing can be obtained by fine-needle aspiration (FNA). 144 The panel notes that HPV testing may prompt questions about prognosis (i.e., a favable, a less favable fecast) and sexual histy that the clinician should be prepared to address. Thus, without a specific reason f testing, HPV infmation may add anxiety and stress f some patients. Alternatively, gaining an understanding of the etiology f one s cancer can result in reduced anxiety f some patients. Treatment The treatment algithm has been divided into 3 staging categies: (1) T1-2, N0-1; (2) T3-4a, N0-1; and (3) any T, N2-3. Of note, T4b, N any, unresectable nodal disease is treated as advanced cancer. Early stage (T1-2, N0-1) opharyngeal cancers may be treated with primary surgery including neck dissection, as indicated, with definitive radiotherapy. The panel members felt that the third option of RT plus systemic therapy (categy 2B f systemic therapy) was only appropriate f T2, N1. Adjuvant chemotherapy/rt is recommended (categy 1) f adverse pathologic features of extracapsular nodal spread and/ positive mucosal margin F locally advanced resectable disease (T3-4a, N0-1; any T, N2-3), there are 3 treatment approaches in the algithms, in addition to enrollment in a multimodality clinical trial that includes function evaluation. The 3 approaches are: (1) concurrent systemic therapy/rt cisplatin (categy 1) (salvage surgery is used f managing residual recurrent disease); 93 (2) surgery with appropriate adjuvant therapy (chemo/rt RT); (3) induction chemotherapy followed by RT chemo/rt f which there was maj disagreement among panel members. Concurrent systemic therapy/rt with cisplatin alone (categy 1) is preferred f treatment of locally regionally advanced (T3-4a, N0-1, Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-13

116 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. any T, N2-3) cancer of the opharynx. Panel members differed in their opinion as to whether induction chemotherapy should be considered a standard treatment option f T3-4a, N0-1 disease. This disagreement is reflected by a categy 3 recommendation in the algithms (see next section on The Induction Chemotherapy Controversy ). 93, Of note, f patients with any T, N2-3 disease, the categy designation is 2B f induction chemotherapy because of the increased risk of distant metastases in patients with me advanced neck disease. The Induction Chemotherapy Controversy Defining the optimal role of induction chemotherapy in the management of locally regionally advanced H&N cancer has generated considerable discussion within the NCCN H&N Cancer Guidelines panel in recent years. The algithm f the management of advanced opharynx cancer illustrates well the lack of consensus among member institutions despite the extensive discussion. Thus, induction chemotherapy has a categy 3 ( maj disagreement ) designation f the management of T3-4a, N0-1 opharyngeal disease. In addition, induction chemotherapy has a categy 2B ( non-unifm consensus, no maj disagreement ) f any T, N2-3 opharyngeal disease. However, the lack of consensus is not unique to the opharyngeal cancer algithm; it is also apparent in other algithms where no better than a categy 2B designation occurs and categy 3 designations are common. Only f hypopharyngeal cancers less than T4a in extent (which if managed surgically would required total laryngectomy) is the use of induction chemotherapy utilized here as part of a larynx preservation strategy associated with a higher level of panel consensus (i.e., categy 2A). A brief review of the available data helps provide some perspective on the NCCN panel s deliberations. Most randomized trials of induction chemotherapy followed by radiotherapy and/ surgery compared to locegional treatment alone published in the 1980s and 1990s did not demonstrate an improvement in overall survival with the incpation of chemotherapy. 150 However, a change in the pattern of failure with less distant metastases was noted in some studies; 155 also, there appeared to be a crelation between response to induction chemotherapy and subsequent durable response to radiation. 155,156 Thus, the concept developed that in selected patients, induction chemotherapy could facilitate gan preservation, avoid mbid surgery, and improve overall quality of life of the patient even though overall survival was not improved. Because total laryngectomy is among the procedures most feared by patients, 157 larynx preservation was the focus of initial studies. Two randomized studies the Veterans Affairs (VA) Laryngeal Cancer Study Group trial in advanced larynx cancer and the EORTC trial predominantly in advanced hypopharynx cancer established the role of induction cisplatin/5-fu chemotherapy followed by definitive RT in responding patients as an alternative treatment to primary total laryngectomy and postoperative radiation, offering potential larynx preservation without compromise in survival (see, Cancer of the Larynx and Cancer of the Hypopharynx ). 155,156 Yet even in this setting, the role of induction chemotherapy decreased with time. Randomized trials and related meta-analyses indicated that concurrent chemadiotherapy (with cisplatin being the best studied agent) offered superi locegional tum control and survival compared to radiation alone, and shter duration of therapy compared to induction therapy followed by radiation. Meta-analyses repted that concurrent chemadiotherapy was me efficacious than an induction chemotherapy strategy. 150,154 In the larynx preservation setting, Intergroup compared radiation alone, concurrent Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-14

117 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. cisplatin/radiation, and induction cisplatin/5-fu followed by radiation, all with surgery f salvage. The concurrent arm had the highest larynx preservation rate (see, Cancer of the Larynx). 169 Nonetheless, there has been renewed interest in the role of induction chemotherapy f a few reasons. Given improvements in local/regional control now achieved with advances in surgery, RT, and concurrent chemotherapy/rt, the role of distant metastases as a source of treatment failure has increased and induction chemotherapy allows greater drug delivery f this purpose. 170 There has been growing concern regarding the long-term mbidity of concurrent chemadiotherapy and related increasing interest in expling alternative approaches that might have a different and hopefully me favable side-effect profile. Finally, a me effective triplet chemotherapy regimen has been identified compared to the standard cisplatin/5-fu used in induction trials of the 1980s and 1990s, and the related meta-analyses. Results from 3 phase III trials which compared induction cisplatin plus infusional 5-FU with without the addition of a taxane (docetaxel paclitaxel) followed by the same locegional treatment showed significantly improved outcomes (response rates, disease-free survival, overall survival depending on the trial) f patients in the 3-drug induction group compared to those receiving 2 drugs (cisplatin plus 5-FU). 147,149,152,153 A randomized trial in the larynx preservation setting similarly demonstrated superi larynx preservation outcome when induction docetaxel/cisplatin/5-fu (TPF) and cisplatin/5-fu were compared. 171 However, a clear advantage in overall survival from the addition of induction chemotherapy to concurrent chemadiation has not been demonstrated yet. A randomized phase II study in patients with stage III IV squamous cell H&N cancer of induction TPF followed by concurrent cisplatin/5-fu with RT versus concurrent cisplatin/5-fu with RT alone did rept a higher radiologic complete response rate with the incpation of induction chemotherapy. 172 However, a randomized 3-arm study comparing concurrent cisplatin/rt versus induction chemotherapy with TPF cisplatin/5-fu followed by concurrent cisplatin/rt repted a decrease in time to treatment failure with the incpation of induction therapy, but no difference in survival. Furtherme, approximately 3 times as many patients were not included in the efficacy assessments on the induction arms suggesting potential toxicity concerns. 173 There also remains considerable uncertainty and disagreement among panel members concerning which radiation chemadiation plan should follow induction. 174 Panel members agree that high-dose cisplatin (100 mg/m 2 every 21 days 3) may not be feasible f many patients in this setting, 173,175 raising concerns that any efficacy gains of induction may be offset by the use of better tolerated but potentially less effective concurrent programs poer patient compliance with the radiation-based part of treatment. There is no one preferred concurrent chemotherapy regimen to use. Panel members agreed that many different alternatives are reasonable (including concurrent low-dose weekly cisplatin, weekly taxanes, cetuximab, combinations thereof), but are inadequately studied, to be specifically recommended. 176 After induction chemotherapy, the use of cetuximab is suppted by data from the TREMPLIN study, in which patients with advanced laryngeal hypopharyngeal cancer who had a maj response to induction TPF were randomized to high-dose cisplatin f 3 cycles versus weekly cetuximab concurrent with RT. Patients on the cetuximab arm tolerated therapy better, had better compliance with drug delivery, and 3-month laryngeal preservation rates were similar to those observed on the cisplatin arm. 175 Some panel members Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-15

118 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. specifically considered exclusive use of low-dose weekly carboplatin in this setting to be inadequate. 177 There is some evidence suggesting that chemotherapy with weekly carboplatin might be equivalent to cisplatin; however, data are from the nasopharyngeal setting. 178 Other sequential induction-concurrent regimens, using less aggressive induction less intensive concurrent chemotherapy, appear to have higher compliance rates. 149,179 However, a definitive study has not been done comparing these newer strategies to concurrent chemadiotherapy alone. Because of these uncertainties, enrollment of patients in appropriate clinical trials is particularly encouraged. Outside of a clinical trial, proceeding directly to concurrent chemadiotherapy, cisplatin preferred, remains a standard treatment option f these patients, and is the preferred approach from the panel s perspective in several settings as indicated. When induction chemotherapy is used, randomized data have clearly proven that the addition of a taxane to cisplatin/5-fu, of which TPF is the most extensively studied, is me efficacious than cisplatin/5-fu. Radiation Therapy Fractionation Standard conventional fractionation is preferred when radiotherapy is used definitively f T1-2, N0 tums. Altered fractionation is appropriate f selected T1-2, N1 tums, particularly if concurrent chemotherapy is not used. The recommended schedules are shown in the Cancer of the Oropharynx section of the H&N algithm. Follow-up/Surveillance Recommendations f surveillance are provided in the algithm. Cancer of the Hypopharynx The hypopharynx extends from the superi bder of the hyoid bone to the lower bder of the cricoid cartilage and is essentially a muscular, lined tube extending from the opharynx to the cervical esophagus. F staging purposes, the hypopharynx is divided into 3 areas: (1) the pyrifm sinus (the most common site of cancer in the hypopharynx); (2) the lateral and posteri pharyngeal walls; and (3) the postcricoid area. Wkup and Staging A multidisciplinary consultation is encouraged. Accurate staging (see Table 2) depends on a complete H&N examination coupled with appropriate studies. 12 At the time of diagnosis, approximately 60% of patients with cancer of the hypopharynx have locally advanced disease with spread to regional nodes. Furtherme, autopsy series have shown a high rate of distant metastases (60%) involving virtually every gan. 180 Thus, the prognosis f patients with cancer of the hypopharynx can be quite po despite aggressive combined modality treatment. Treatment Patients with resectable disease are divided into 2 groups: 1) those patients with early stage cancer (most T1, N0; selected T2, N0) who do not require a total laryngectomy; and 2) those patients with advanced resectable cancer (T1, N+; T2-4a, any N) who do require laryngectomy. The surgery and radiotherapy options f the fmer group represent a consensus among the panel members. Patients with me advanced disease (defined as T1, N+; T2-3, any N) requiring total laryngectomy and partial total pharyngectomy may be managed with 3 approaches in addition to enrollment in multimodality Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-16

119 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. clinical trials: (1) induction chemotherapy followed by definitive RT if a complete response was achieved at the primary site 155 followed by other options depending on the response; (2) surgery with neck dissection and postoperative radiation chemadiation as dictated by pathologic risk features; (3) concurrent chemotherapy/rt, cisplatin preferred. Given the functional loss resulting from this surgery and the po prognosis, participation in clinical trials is emphasized. The recommendation of the induction chemotherapy/definitive radiotherapy option is based on the results of an EORTC randomized trial. 155 This trial enrolled 194 eligible patients with stage II, stage III, stage IV resectable squamous cell carcinoma of the pyrifm sinus (152 patients) and aryepiglottic fold (42 patients), excluding patients with T1 N2c disease. Patients were randomly assigned either to laryngopharyngectomy and postoperative radiotherapy, to chemotherapy with cisplatin and 5-FU f a maximum of 3 cycles, followed by definitive radiotherapy. In contrast to a similar approach used f laryngeal cancer, a complete response to induction chemotherapy was required in der to proceed with definitive radiotherapy. The published results showed equivalent survival, with median survival duration and 3-year survival rate of 25 months and 43%, respectively, f the surgery group versus 44 months and 57%, respectively, f the induction chemotherapy group. 155 A functioning larynx was preserved in 42% of patients who did not undergo surgery. Local regional failure rates did not differ between the surgery-treated patients and chemotherapy-treated patients, although the chemotherapy recipients did demonstrate a significant reduction in distant metastases as a site of first failure (P=.041). Adherence to the requirements f complete response to chemotherapy and f inclusion of only patients with the specified TN-stage is emphasized. A recently published randomized trial demonstrated that an alternating program of cisplatin/5-fu with RT yielded larynx preservation, progression-free interval, and overall survival rates equivalent to those obtained with induction platinum/5-fu followed by RT. 181 Given available randomized data demonstrating the superiity of TPF compared with PF f induction chemadiation, the triplet is now recommended as induction f this approach. 149,154,171 As noted in the algithm, surgery is recommended if less than a partial response occurs after induction chemotherapy. In this situation, when primary surgery is the selected management path, postoperative chemotherapy/rt is recommended (categy 1) f the adverse pathologic features of extracapsular nodal spread and/ positive mucosal margin. F other risk features, clinical judgment should be utilized when deciding to use RT alone when considering adding chemotherapy to RT. Options f patients with T4a, any N disease include surgery plus neck dissection (preferred) followed by adjuvant chemotherapy/rt RT, multimodality clinical trials, categy 3 recommendations. Follow-up/Surveillance Recommendations f surveillance are provided in the algithm. Cancer of the Nasopharynx Carcinoma of the nasopharynx is uncommon in the United States. Among H&N cancers, it has among the highest propensity to metastasize to distant sites. Nasopharyngeal cancer also poses a significant risk f isolated local recurrences after definitive radiation (without chemotherapy) f locally advanced disease Regional recurrences are uncommon in this disease, occurring in only 10% to 19% of patients. 185,186 Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-17

120 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. The NCCN H&N guidelines f the evaluation and management of carcinoma of the nasopharynx attempt to address risk f both local and distant disease. Stage is accepted as prognostically imptant. The prognostic significance of histology is still controversial. RT was the standard treatment f all stages of this disease, until the mid-1990s, when trial data showed improved survival f locally advanced tums treated with concurrent RT and cisplatin. 187 Wkup and Staging The wkup of nasopharyngeal cancer includes a complete H&N examination and other studies. These studies are imptant to determine the full extent of tum in der to assign stage appropriately and to design radiation pts that will encompass all the disease with appropriate doses. Multidisciplinary consultation is encouraged. The 2010 AJCC staging classification (7 th edition) is used as the basis f treatment recommendations (see Table 2). 12 Treatment Patients with T1, N0, M0 nasopharyngeal tums may be treated with definitive RT alone. F early stage cancer in this setting, radiation doses of Gy given with standard fractions are necessary f control of gross tum. The local control rate f these tums ranges from 80% to 90%, whereas T3-4 tums have a control rate of 30% to 65% with RT alone. 188,189 The combination of RT and concurrent platinum-based chemotherapy followed by adjuvant cisplatin/5-fu has been shown to increase the local control rate from 54% to 78%. The Intergroup trial 0099, which randomly assigned patients to chemotherapy plus external-beam RT versus external radiation alone, closed early when an interim analysis disclosed a significant survival and progression-free survival advantage faving the combined chemotherapy and radiation group. 187 The addition of chemotherapy also decreased local, regional, and distant recurrence rates. A similar randomized study conducted in Singape, which was modeled after the Intergroup treatment regimen, continued to show the benefit of the addition of chemotherapy to RT. Adjuvant chemotherapy after combined chemotherapy and radiation was also given in this trial. 190 In addition, the administration of the cisplatin dose was spread out over several days, and this regimen appeared to reduce toxicity while still providing a beneficial antitum effect. Another phase III randomized trial showed that concurrent chemo/rt (using weekly cisplatin) increased survival when compared with RT alone. 191 Five-year overall survival was 70% f the chemo/rt group versus 59% f the RT group. A randomized trial compared chemo/rt using cisplatin versus carboplatin and found that the 3-year overall survival rates were similar (78% versus 79%). 178 However, the NCCN guidelines recommend cisplatin f chemo/rt in patients who do not have a contraindication to the drug, because there are me randomized data suppting the use of cisplatin in this setting. The guidelines recommend concurrent chemotherapy (cisplatin) plus radiotherapy (categy 1) followed by adjuvant cisplatin/5-fu f T1, N1-3; and f T2-T4, any N lesions. Although an unusual occurrence, a patient with residual disease in the neck and a complete response at the primary should undergo a neck dissection. Initial therapy f patients who present with metastatic disease should consist of a platinum-based combination chemotherapy regimen. The management of patients with recurrent persistent nasopharyngeal cancer is described in the H&N algithm. When chemotherapy is indicated, commonly used active agents alone in Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-18

121 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. combination include gemcitabine, paclitaxel, docetaxel, cisplatin, carboplatin Cetuximab plus carboplatin has been studied f patients with recurrent metastatic nasopharyngeal cancer who have failed platinum-based therapy; 193 however, this regimen is not currently recommended in the NCCN guidelines. Follow-up/Surveillance Recommendations f surveillance are provided in the algithm. Cancer of the Larynx The larynx is divided into 3 regions: supraglottis, glottis, and subglottis. The distribution of cancers is as follows: 30% to 35% in the supraglottic region, 60% to 65% in the glottic region, and 5% in the subglottic region. The incidence and pattern of metastatic spread to regional nodes varies with the primary region. Me than 50% of patients with supraglottic primaries present with spread to regional nodes because of an abundant lymphatic netwk that crosses the midline. Bilateral adenopathy is not uncommon with early stage primaries. Thus, supraglottic cancer is often locally advanced at diagnosis. In contrast, the lymphatic drainage of the glottis is sparse and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic cancers are in an early stage at diagnosis. Thus, glottic cancers have an excellent cure rate in the range of 80% to 90%. Nodal involvement adversely affects survival rates. Wkup and Staging The evaluation of the patient to determine tum stage is similar f glottic and supraglottic primaries. Multidisciplinary consultation is critical f both sites because of the potential f loss of speech and, in some instances, f swallowing dysfunction. The 2010 AJCC staging classification (7 th edition) f laryngeal primary tums is determined by the number of subsites involved, vocal cd mobility, and the presence of metastases (see Table 3). 12 Treatment In the NCCN guidelines, the treatment of patients with laryngeal cancer is divided into 2 categies: (1) tums of the glottic larynx; (2) tums of the supraglottic larynx. Subglottic cancers are not discussed, because they are so uncommon. F patients with carcinoma in situ of the larynx, recommended treatment options include endoscopic removal (stripping, laser) RT. 197,198 F early stage glottic supraglottic cancers, surgery (partial laryngectomy through either endoscopic open approaches) and radiotherapy have similar effectiveness. 199 The choice of treatment modality depends on anticipated functional outcome, the patient s wishes, reliability of follow-up, and general medical condition. Management of the neck is dictated by the risk of occult nodal spread. Resectable, advanced-stage glottic and supraglottic primaries are usually managed with a combined modality approach. If treated with primary surgery, total laryngectomy is typically required, although selected cases can be managed with conservation surgical techniques that preserve vocal function. If surgical management would require totally laryngectomy but laryngeal preservation is desired, the preferred approach is concurrent chemotherapy (consisting of cisplatin [preferred] 100 mg/m 2 on days 1, 22, and 43) and radiotherapy (categy 1 f cisplatin). 169 Induction chemotherapy with management based on response is an option f all but T3, N0-1 glottic cancers, with panel consensus being categy 2B Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-19

122 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. 3, depending on the setting. Definitive RT (without chemotherapy) is an option f patients who are medically unfit refuse chemotherapy. Surgery is reserved f managing the neck as indicated, f those patients whose disease persists after chemo/rt radiotherapy, those patients who develop a subsequent locegional recurrence. The NCCN recommendations f managing locally advanced, resectable glottic and supraglottic cancers requiring laryngectomy with concurrent cisplatin and radiation reflect the results of Intergroup trial R Befe 2002, either induction chemotherapy with cisplatin/5-fu followed by radiotherapy (based on the results of the VA Laryngeal Cancer Study Group trial published in ) definitive radiotherapy alone (without chemotherapy) were the standard of care options recommended in the NCCN H&N guidelines. Currently, concurrent radiotherapy and cisplatin 100 mg/m 2 is the recommended option f achieving laryngeal preservation. 169 R91-11 was a success trial to the VA trial and compared 3 non-surgical regimens: (1) induction cisplatin/5-fu followed by RT (control arm and identical to that in the VA trial); (2) concurrent RT and cisplatin 100 mg/m 2 days 1, 22, and 43; and (3) RT alone. Radiotherapy was unifm in all 3 arms (70 Gy/7 weeks, 2 Gy/fraction), as was the option of surgery including total laryngectomy to salvage treatment failures in all arms. Stage III and IV (M0) patients were eligible, excluding T1 primaries and high-volume T4 primaries (tum extending me than 1 cm into the base of tongue tum penetrating through cartilage). The key findings of the R91-11 trial were 1) a statistically significant higher 2-year laryngeal preservation (local control) rate of 88% f concurrent RT with cisplatin, compared to 74% f induction chemotherapy and to 69% f RT alone; 2) no significant difference in laryngeal preservation between induction and RT alone treatments; and 3) similar survival f all treatment groups. These R91-11 results changed the preferred standard of care to concurrent RT and cisplatin (categy 1) f achieving laryngeal preservation f T3, N0 and T4a, N0 supraglottic cancers and f most T3, any N glottic cancers. 169 F patients with glottic and supraglottic T4a tums, the standard approach is a laryngectomy with ipsilateral thyroidectomy and neck dissection as indicated. F selected patients with T4a tums who decline surgery, the panel recommends (1) considering concurrent chemadiation; (2) clinical trials; (3) induction chemotherapy followed by chemo/rt (categy 2B). 169 Follow-up/Surveillance Recommendations f surveillance are provided in the algithm. Follow-up examinations in many of these patients may need to be supplemented with serial endoscopy high-resolution, advanced radiologic imaging techniques because of the scarring, edema, and fibrosis that occur in the laryngeal tissues and neck after high-dose radiation. Paranasal Tums (Maxillary and Ethmoid Sinus Tums) Tums of the paranasal sinuses are rare, and patients are often asymptomatic until late in the course of their disease. Tums of the maxillary sinus are me common than those of the ethmoid sinus nasal cavity. 12 Although the most common histology f these tums is squamous cell carcinoma, multiple histologies have been repted including adenocarcinoma, esthesioneuroblastoma (also known as olfacty neuroblastoma), sarcoma, and undifferentiated carcinoma (sinonasal undifferentiated carcinoma [SNUC], small cell neuroendocrine) Locegional control and incidence of distant metastasis are dependent on T stage, N stage, and tum histology. 204 Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-20

123 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. However, T stage remains the most reliable predict of survival and local regional control (see Table 4). 12 Note that mucosal melanoma also occurs in the paranasal sinus region, nasal cavity, and al cavity (see Mucosal Melanoma of the Head and Neck at the end of this ). Management of Ethmoid Sinus Cancer Patients with early stage cancer of the ethmoid sinus are typically asymptomatic. These neoplasms are often found after a routine nasal polypectomy during the course of a nasal endoscopic procedure. F a patient with gross residual disease who has had a nasal endoscopic surgical procedure, the preferred treatment is complete surgical excision of the residual tum. This procedure often entails an anteri craniofacial resection to remove the cribrifm plate and to ensure clear surgical margins. Most patients affected by ethmoid sinus cancer present after having had an incomplete excision. The patient who is diagnosed after incomplete excision (e.g., polypectomy, endoscopic surgical procedure) and has no documented residual disease on physical examination, imaging, and/ endoscopy should be treated with surgical resection if feasible. If no adverse pathologic facts are found, this treatment may obviate the need f postoperative radiotherapy in T1 patients only (categy 2B). However, RT may be used as definitive treatment in patients if pre-biopsy imaging studies and nasal endoscopy demonstrate that the superi extent of the disease does not involve the skull base. Systemic therapy should be part of the overall treatment f patients with SNUC small cell neuroendocrine histologies Surgery and RT have been used to treat patients with esthesioneuroblastomas; chemotherapy has also been incpated into the local/regional treatment Long-term follow-up is necessary f esthesioneuroblastomas, because recurrence can even occur after 15 years. 211,215 Treatment of Maxillary Sinus Tums Complete surgical resection f all T stages (except T4b, any N) followed by postoperative therapy remains a cnerstone of treatment f maxillary sinus tums Recent studies using IMRT have shown that it reduces the incidence of complications, such as radiation-induced ophthalmologic toxicity; however, the 5-year overall survival rate has not improved. 116,218, Participation in clinical trials is recommended f patients with malignant tums of the paranasal sinuses. Follow-up Recommendations f surveillance are provided in the algithm. Very Advanced Very advanced H&N cancers include newly diagnosed locally advanced T4b unresectable nodal disease, metastatic disease, recurrent disease. The treatment goal f patients with newly diagnosed but unresectable disease is cure (see discussion about unresectable disease in the Head and Neck Surgery section of this manuscript). F the recurrent disease group, the goal is cure (if surgery radiation remains feasible) palliation (if the patient has received previous radiotherapy and the disease is unresectable). The goal f patients with metastatic disease is palliation prolongation of life. Treatment Participation in clinical trials is preferred f all patients with very advanced H&N cancers. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-21

124 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Newly Diagnosed Advanced Disease F patients with a perfmance status (PS) of 0 1, the standard treatment of newly diagnosed, very advanced disease is concurrent cisplatin chemotherapy and radiotherapy (categy 1). 158 The panel had a maj disagreement regarding whether induction chemotherapy (TPF) followed by RT chemadiation should be used f patients with a PS of 0 1, which is reflected in the categy 3 recommendation (see also discussion about The Induction Chemotherapy Controversy in this manuscript). 149,153 Other options f patients with PS 2-3 are described in the algithm. Many randomized trials 64,90,91, and meta-analyses of clinical trials 150, demonstrate significantly improved overall survival, disease-free survival, and local control when a concomitant alternating chemotherapy and radiation regimen is compared with radiotherapy alone f advanced disease. All combined chemadiotherapy regimens are associated with various degrees of enhanced mucosal toxicities, which require close patient moniting, ideally provided by a team experienced in treating H&N cancer patients. Limited data are available comparing the efficacy of different chemadiotherapy regimens. Single-agent cisplatin plus RT is effective and relatively easy to administer and typically uses conventional fractionation at 2.0 Gy per fraction to 70 Gy me in 7 weeks with single-agent cisplatin given every 3 weeks at 100 mg/m Bonner and colleagues randomly assigned 424 patients with locally advanced and measurable stage III/IV squamous cell carcinomas of the H&N to receive definitive radiotherapy with without cetuximab. 223 Locegional control and median overall survival (49 months versus 29.3 months, P=.03) were significantly improved in patients treated with radiotherapy and cetuximab compared to radiotherapy alone. Radiotherapy and cetuximab may provide a therapeutic option f patients not considered medically fit f standard chemadiotherapy regimens. Other preferred chemadiation options were also identified by the panel. 224,225 Limited data are available comparing combination chemadiation versus using a single agent concurrently with RT. Recurrent Persistent Disease Surgery is recommended f resectable recurrent persistent locegional disease; adjuvant therapy depends on the risk facts. If the recurrence is unresectable and the patient did not have pri RT, then radiotherapy with concurrent systemic therapy is recommended, depending on the PS. F patients with recurrent disease not amenable to curative-intent radiation surgery, the treatment approach is the same as that f patients with metastatic disease; enrollment in a clinical trial is preferred. Metastatic Disease Palliative adjunctive measures include radiotherapy to areas of symptomatic disease, analgesics, and other measures to control other manifestations of disease spread (e.g., hypercalcemia). Single agents and combination systemic chemotherapy regimens are both used. Response rates to single agents range from 15% to 35%. The most active single agents include cisplatin, carboplatin, paclitaxel, docetaxel, 5-FU, methotrexate, ifosfamide, bleomycin, gemcitabine (f nasopharyngeal cancer), and cetuximab (f non-nasopharyngeal cancer). 194, Active combination regimens include (1) cisplatin carboplatin, plus 5-FU 229,230 with cetuximab (f non-nasopharyngeal cancer); 231 (2) cisplatin carboplatin, plus a taxane; 229,232 (3) cisplatin with cetuximab (f non-nasopharyngeal cancer), 233 4) cisplatin with 5-FU. 229,230 These regimens, on average, result in a doubling of response rates compared to single agents. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-22

125 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Randomized trials assessing a cisplatin-based combination regimen (such as cisplatin plus 5-FU) versus single-agent therapy with cisplatin, 5-FU, methotrexate have demonstrated significantly higher response rates f the combination regimen. No difference in overall survival, however, is demonstrable. 229,230, Histically, the median survival with chemotherapy is approximately 6 months, and the 1-year survival rate is approximately 20%. Achievement of a complete response is associated with longer survival and, although infrequent, has been repted me often with combination regimens. 230 A randomized phase III trial in patients with metastatic recurrent H&N cancer found no significant difference in survival when comparing cisplatin plus 5-FU with cisplatin plus paclitaxel. 229 The epidermal growth fact recept (EGFR) is a trans-membrane glycoprotein; activation of EGFR triggers a cascade of downstream intracellular signaling events imptant f regulation of epithelial cell growth. Overexpression of EGFR and/ common ligands has been observed in greater than 90% of squamous cell carcinomas of the H&N. This finding has led to the development of EGFR inhibits, such as the monoclonal antibody cetuximab and small molecule tyrosine kinase inhibits (i.e., erlotinib and gefitinib). Data from phase II studies indicate that in the cisplatin-refracty setting, the single-agent response rate of cetuximab is about 12% to 14%. Burtness and colleagues 233 compared cisplatin plus cetuximab versus cisplatin plus placebo as first-line treatment of recurrent disease; they repted a significant improvement in response rate with cetuximab (26% versus 10%, respectively). Of note, a phase III randomized trial (EXTREME) of 442 patients with recurrent metastatic squamous cell carcinoma found that cetuximab plus cisplatin/5-fu carboplatin/5-fu improved median survival when compared to the standard chemotherapy doublet (10.1 months versus 7.4 months, P=.04). 231 The response rate was also improved with cetuximab (20% to 36% [P<.001]). Available data f tyrosine kinase inhibits (such as erlotinib and gefitinib) have not established them as treatment options f recurrent metastatic H&N cancer outside of a clinical trial. In one randomized trial, treatment with 2 different dosing schedules of gefitinib offered no survival advantage compared to treatment with methotrexate. 237 The standard treatment of patients with incurable, recurrent, metastatic H&N cancer should be dictated, in large part, by the patient s PS. Patients should be fully infmed about the goals of treatment, cost of combination chemotherapy, and potential f added toxicity. Occult Primary Cancer When patients present with metastatic tum in a neck node and no primary site can be identified after appropriate investigation, the tum is defined as an occult unknown primary cancer; this is an uncommon disease, accounting f about 5% of patients presenting to referral centers. Although patients with very small tonsil and tongue base cancers frequently present with enlarged neck nodes and are classified as an unknown primary, most will be diagnosed by directed biopsy and tonsillectomy. H&N cancer of unknown primary site is a highly curable disease. After appropriate evaluation and treatment, most patients experience low mbidity and many will be cured. The primary tum becomes apparent on follow-up only in a few cases. Patients and oncologists are often concerned when the primary cancer 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 mass, prove to have metastatic cancer. The source of the lymphadenopathy is almost always discovered in the course of a complete H&N Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-23

126 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. examination, which should be perfmed on all patients with neck masses befe other studies are initiated. The following should be assessed during office evaluation: 1) risk facts (e.g., tobacco alcohol use); 2) antecedent histy of malignancy; and 3) pri excision, destruction, regression of cutaneous lesions. Wkup When patients present with a neck mass, they should have a complete H&N examination. FNA is preferred (over open biopsy), which generally guides management and treatment planning. Unless FNA is inconclusive, ce open biopsy should be avoided because it may alter interfere with subsequent treatment. Open biopsy should not be perfmed unless the patient is prepared f definitive surgical management of the malignancy as indicated, if documented in the operating room. This management may entail a fmal neck dissection. Therefe, an open biopsy of an undiagnosed neck mass should not be undertaken lightly, and patients should be thoughly apprised of treatment decisions and related sequelae. When a needle biopsy demonstrates squamous cell carcinoma, adenocarcinoma, anaplastic epithelial cancer and no primary site has been found, additional studies are needed. A PET/CT scan should only be done (befe biopsy) if other tests do not reveal a primary. HPV-16 and Epstein Barr Virus (EBV) testing are suggested f squamous cell undifferentiated histology. 194, HPV testing can be useful in wkup and management of cancers of the neck of unknown primary. An HPV-positive test strongly suggests an occult primary is located in the tonsil base of tongue regions, permitting one to customize radiation targets to these mucosal regions. 144 When the imaging studies and a complete H&N examination do not reveal a primary tum, then an examination under anesthesia should be perfmed. Mucosal sites should be inspected and examined. Appropriate endoscopies with directed biopsies of likely primary sites are recommended, but they seldom disclose a primary cancer. Many primary cancers are identified after tonsillectomy. However, the therapeutic benefit of this surgery is uncertain, because when patients have been treated without tonsillectomy, only a few develop a clinically significant primary tum. Treatment Neck dissection is recommended f all patients with thyroglobulinnegative and calcitonin-negative adenocarcinoma. If the metastatic adenocarcinoma presents high in the neck, parotidectomy may be included with the neck dissection. After neck dissection, management depends on the findings (i.e., N1 without extracapsular spread, N2 N3 without extracapsular spread, extracapsular spread). There is significant variation among NCCN member institutions regarding the management of patients with squamous cell carcinoma, poly differentiated nonkeratinizing squamous cell, anaplastic cancer (not thyroid) of unknown primary site, other uncommon histologies. Most members believe such patients should be managed with surgery and neck dissection (levels I-V) followed by RT chemo/rt. Others believe the following options can be used: (1) chemadiation (categy 2B); (2) primary RT (categy 3); (3) induction chemotherapy followed by chemadiation RT (categy 3). However, a neck dissection may be recommended after treatment, depending on the clinical response. After a neck dissection, NCCN institutions recommend either radiation that encompasses the potential primary sites as determined by the Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-24

127 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. neck node levels involved f N1 disease without extracapsular spread observation. Postoperative radiation concurrent chemadiation (categy 2B f chemadiation) is recommended f N2 N3 disease without extracapsular spread. Although some NCCN institutions would radiate the neck only (categy 3), most institutions would also radiate the likely occult primary sites based on the level of nodes involved. Extending the radiation field to encompass all possible mucosal primary sites is controversial and the source of disagreement. Little evidence suppts a survival benefit from radiation to all possible primary sites. F extracapsular spread, concurrent chemadiation is a categy 1 recommendation. 61,62 Salivary Gland Tums Salivary gland tums can arise in the maj salivary glands (parotid, submandibular, sublingual) in one of the min salivary glands, which are widely spread throughout the aerodigestive tract. 242 Many min salivary gland tums are located on the hard palate. Approximately 20% of the parotid gland tums are malignant; the incidence of malignancy in submandibular and min salivary gland tums is approximately 50% and 80%, respectively. These malignant tums constitute a broad spectrum of histologic types, including mucoepidermoid, acinic, adenocarcinoma, adenoid cystic carcinoma, malignant myoepithelial tums, and squamous carcinoma. The primary diagnosis of squamous carcinoma of the parotid gland is rare; however, the parotid is a frequent site of metastasis from skin cancer. 243 Prognosis and tendency to metastasize vary among these histologic types. Maj prognostic facts are histologic grade, tum size, and local invasion. Staging is done using the AJCC Cancer Staging Manual (7 th edition) (see Table 5). 12 Treatment The maj therapeutic approach f salivary gland tums is adequate and appropriate surgical resection Surgical intervention requires careful planning and execution, particularly in parotid tum surgery because the facial nerve is in the gland, which should be preserved if the nerve is not directly involved by the tum. Most parotid gland tums are located in the superficial lobe, and if the facial nerve is functioning preoperatively, the nerve can be preserved in most patients. The facial nerve should be sacrificed if there is preoperative facial nerve involvement with facial palsy if there is direct invasion of the tum into the nerve where the tum cannot be separated from the nerve. Malignant deep lobe parotid tums are quite rare; however, they are generally a challenge f the surgeon where the patient may require superficial parotidectomy and identification and retraction of the facial nerve to remove the deep lobe parotid tum. Most malignant deep lobe parotid tums will require postoperative RT because of adverse features such as the limitations of surgical margins in the resection of these tums. 244,246,248 RT is also used in an adjuvant setting f tums with other adverse features (e.g., intermediate high grade); 245 chemotherapy/rt (categy 2B) can also be considered. 249 Efficacy data f chemo/rt in this setting are limited. However, extensive safety data are available from the management of squamous cell H&N cancers. With regard to unresectable salivary gland tums, the panel was not in agreement regarding chemadiation, because there are limited published trials of this approach. However, there are data to suppt the use of neutron therapy. 250 Chemotherapy may be used f palliation in advanced disease. Various agents alone in combination (e.g., cisplatin, cyclophosphamide, doxubicin, mitoxantrone; carboplatin and vinelbine) and combinations of these Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-25

128 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. have been shown in small series to be active f some salivary gland malignant histologies Follow-up Recommendations f surveillance are provided in the algithm. Mucosal Melanoma of the Head and Neck Mucosal melanoma (MM) is a rare but highly aggressive neoplasm with a po prognosis. It may occur throughout the upper aerodigestive tract. Most MM (70%-80%) occurs in the nasal cavity paranasal sinus region, and most of the remainder develops in the al cavity. 255 Sinonasal MM is typically confined to the primary site at presentation. 256 Oral cavity MM me frequently presents with clinically apparent lymph node metastasis. 257 No etiological risk facts are yet apparent. Wkup and Staging Wkup f MM should include clinical examination and CT and/ MRI f paranasal sinus disease and appropriate imaging f other mucosal sites. PET-CT scanning may be considered to define the presence of distant disease in me advanced situations. The AJCC Cancer Staging Manual (7 th edition) includes a staging system f MM (see Table 6); 12 previous editions have not had a classification f MM. The AJCC staging recognizes 2 key facts specific to MM: 1) the po prognosis of the disease even with a limited primary burden of disease; and 2) there is still some gradation of survival based on the burden of disease as reflected in local, regional, and distant extent. Thus, the AJCC staging system f MM begins with stage III disease as the most limited fm of disease (similar to anaplastic thyroid carcinoma), and it breaks the disease down into stages reflecting local burden of disease, as well as regional and distant extent. In addition, the AJCC staging system reflects the fact that MM occurs at all mucosal sites in the H&N. Therefe, rules f classifying, staging, and surgical principles should be based on the appropriate anatomic site of igin. Treatment of the Primary Although limited data exist on treatment options, primary treatment should be surgical f stage III-IVA disease; however, surgery is not recommended f stage IVB-C disease. 258 Adjuvant radiation appears effective in improving local control and survival in most case series. 259 Radiation is clearly indicated in me advanced cases as an adjunct to surgery. 260 The role of radiation in stage III disease is not clear, but it can be considered and should be determined on an individual basis by the treating clinicians. The NCCN strongly encourages clinical trials f all patients with MM to better define treatment choices at all stages of the disease. Treatment of the Neck Neck dissection and postoperative radiation are recommended f clinical nodal disease. 261,262 The role of elective neck treatment is unclear. The extension of elective treatment to the neck seems unwarranted in most cases of N0 paranasal sinus MM. However, f al cavity disease, the likelihood of positive disease is significantly higher and the treatment can be better localized to the ipsilateral neck with both surgery and radiation. Therefe, elective treatment to the neck f al cavity MM appears justifiable. Radiation Therapy Prospective trials evaluating the role of radiotherapy in MM are lacking. However, recently repted results of a randomized trial in cutaneous melanoma are considered relevant to MM in the postoperative setting Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-26

129 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. after neck dissection (see third paragraph in this section). 263 Retrospective studies in MM have shown local recurrence to be common after surgery alone. 264 After using postoperative radiation, lower rates of local and neck recurrence have been seen in histical comparison series. 259,265 Reasonable local control outcomes using radiotherapy alone in unresectable medically inoperable cases have been repted in small coht series of MMs Radiotherapy is often recommended in the postoperative management of MMs. Primary size thickness is not used as a risk fact when considering radiotherapy to the primary site; all invasive primaries are considered at high risk f local recurrence. F sinonasal primary sites, target volumes may include the primary site without elective treatment of the neck. Because al cavity primary sites are felt to be at a higher risk f failure in the neck, elective management with neck dissection and RT may be applied. Indications f postoperative radiation to the neck are generally extrapolated from cutaneous melanoma. Recently, an Australian-New Zealand constium repted on a randomized trial (250 patients) of postoperative radiotherapy versus observation in patients with palpable adenopathy from cutaneous primaries. Postoperative radiotherapy was associated with a significant reduction in relapse in the nodal basin (19% versus 31%) and a significant improvement in lymph node field control. 263 Only 20 patients relapsed who received RT, whereas 34 patients relapsed who received observation only (P =.04). Considering this trial and retrospective studies in MM, the NCCN panel recommends postoperative radiotherapy f the following high-risk features: extracapsular disease, involvement of 2 me neck intraparotid nodes, any node 3 cm greater, neck excision (alone) with no further basin dissection, recurrence in the neck soft tissue after initial surgical resection. 269,270 Conventional fractionation is recommended (at 2 Gy per fraction to a total postoperative dose of Gy, to 70 Gy f gross disease). While the Australian-New Zealand randomized trial used 48 Gy in 20 fractions (240 cgy/fraction) to neck, axilla, groin, 263 the panel prefers conventional fractionation to somewhat higher total doses (60-66 Gy) in the neck because of concerns about late effects from larger dose per fraction, which may not be fully expressed f many years after treatment. IMRT may be very useful in helping to achieve homogenous dose distributions and sparing of critical gans, especially in paranasal sinus sites. 116,220 There are repts of good outcomes with the use of hypofractionation in cutaneous melanomas which carries the advantage of convenience, but no clear cancer control advantage. There is little experience using large dose per fraction in mucosal sites. Due to the close proximity of neural structures and risk of late effects, hypofractionation (if used) must be carefully planned and delivered. Systemic Therapy The role of systemic therapy is discussed in the NCCN [cutaneous] Melanoma Guidelines and should be consulted f management recommendations f systemic disease. Follow-up Recommendations f surveillance are provided in the algithm. Note that physical examination should include endoscopic inspection f paranasal sinus disease. Recommended Reading List Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemadiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003;21: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-27

130 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Adelstein DJ, Ridge JA, Gillison ML, et al. Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9-10, 2008, Washington, D.C. Head Neck. 2009;31: Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemadiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study J Clin Oncol. 1998;16: Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27: Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with without concomitant chemotherapy f locally advanced head and neck cancer. N Engl J Med. 2004;350: Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet. 2006;368: Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with without concurrent chemotherapy f locally advanced head and neck cancer. N Engl J Med. 1998;338: Colevas AD. Chemotherapy options f patients with metastatic recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2006;24: Cooper JS, Pajak TF, Fastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy f high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350: DeVita Jr. VT, Lawrence TS, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology, 8th edition. Philadelphia: Lippincott Williams & Wilkins; Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy f head and neck squamous cell carcinomas: first rept of RTOG Int J Radiat Oncol Biol Phys. 2000;48:7-16. Furniss CS, McClean MD, Smith JF, et al. Human papillomavirus 16 and head and neck squamous cell carcinoma. Int J Cancer. 2007;120: Gillison ML, Koch WM, Capone RB, et al. Evidence f a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92: Kutler DI, Patel SG, Shah JP. The role of neck dissection following definitive chemadiation. Oncology (Williston Park). 2004;18: ; discussion 999, , Laurie SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol. 2006;24: Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Larynx preservation in pyrifm sinus cancer: preliminary results of a European Organization f Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst. 1996;88: Piccirillo JF. Imptance of combidity in head and neck cancer. Laryngoscope. 2000;110: Pignon JP, Bourhis J, Domenge C, et al on behalf of the MACH-NC Collabative Group. Chemotherapy added to locegional treatment f head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. Lancet 2000;355: Rosenthal DI, Trotti A. Strategies f managing radiation-induced mucositis in head and neck cancer. Semin Radiat Oncol. 2009;19: Vermken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-28

131 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Figure 1 Anatomic sites and subsites of the head and neck Figure 2 Level designation f cervical lymphatics in the right neck Reprinted with permission, from CMP Healthcare Media. Source: Cancer Management: 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: Cancer Management: A Multidisciplinary Approach, 9th ed. Pazdur R, Coia L, Hoskins W, et al (eds), Chapter 4. Copyright 2005, All rights reserved. Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. MS-29

132 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. References 1. DeVita Jr. V, Lawrence T, Rosenberg S, eds. Cancer: Principles & Practice of Oncology, 8th edition. Philadelphia: Lippincott Williams & Wilkins; Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, CA Cancer J Clin 2010;60: Available at: 3. American Cancer Society. Cancer Facts & Figures Atlanta: American Cancer Society; Available at: 0.pdf. 4. Gillison ML, Koch WM, Capone RB, et al. Evidence f a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92: Available at: 5. Kreimer AR, Cliffd GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas wldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14: Available at: 6. Applebaum KM, Furniss CS, Zeka A, et al. Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. J Natl Cancer Inst 2007;99: Available at: 7. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and opharyngeal cancer. N Engl J Med 2007;356: Available at: 8. Schlecht NF, Burk RD, Adrien L, et al. Gene expression profiles in HPV-infected head and neck cancer. J Pathol 2007;213: Available at: 9. Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer 2007;110: Available at: Adelstein DJ, Ridge JA, Gillison ML, et al. Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9-10, 2008, Washington, D.C. Head Neck 2009;31: Available at: Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends f human papillomavirus-related and -unrelated al squamous cell carcinomas in the United States. J Clin Oncol 2008;26: Available at: Edge S, Byrd D, Compton C, et al. AJCC Cancer Staging Manual, 7th ed. New Yk: Springer; Greene F, Page D, Fleming I, et al. AJCC Cancer Staging Manual, 6th ed. New Yk: Springer-Verlag; Colasanto JM, Prasad P, Nash MA, et al. Nutritional suppt of patients undergoing radiation therapy f head and neck cancer. Oncology (Williston Park) 2005;19: Available at: Schnoll RA, Zhang B, Rue M, et al. Brief physician-initiated quitsmoking strategies f clinical oncology settings: a trial codinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2003;21: Available at: Gritz ER, Carr CR, Rapkin D, et al. Predicts of long-term smoking cessation in head and neck cancer patients. Cancer Epidemiol Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. REF-1

133 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Biomarkers Prev 1993;2: Available at: Feinstein AR. The pre-therapeutic classification of co-mbidity in chronic disease. Journal of Chronic Diseases 1970;23: Available at: Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic combidity in longitudinal studies: development and validation. J Chronic Dis 1987;40: Available at: Piccirillo JF. Imptance of combidity in head and neck cancer. Laryngoscope 2000;110: Available at: Piccirillo JF, Lacy PD, Basu A, Spitznagel EL. Development of a new head and neck cancer-specific combidity index. Arch Otolaryngol Head Neck Surg 2002;128: Available at: Piccirillo JF. Impact of combidity and symptoms on the prognosis of patients with al carcinoma. Arch Otolaryngol Head Neck Surg 2000;126: Available at: Chen AY, Matson LK, Roberts D, Goepfert H. The significance of combidity in advanced laryngeal cancer. Head Neck 2001;23: Available at: Singh B, Bhaya M, Stern J, et al. Validation of the Charlson combidity index in patients with head and neck cancer: a multiinstitutional study. Laryngoscope 1997;107: Available at: Hall SF, Rochon PA, Streiner DL, et al. Measuring combidity in patients with head and neck cancer. Laryngoscope 2002;112: Available at: Hall SF, Groome PA, Rothwell D. The impact of combidity on the survival of patients with squamous cell carcinoma of the head and neck. Head Neck 2000;22: Available at: Ribeiro KC, Kowalski LP, Latre MR. Impact of combidity, symptoms, and patients' characteristics on the prognosis of al carcinomas. Arch Otolaryngol Head Neck Surg 2000;126: Available at: de Graeff A, de Leeuw JR, Ros WJ, et al. Pretreatment facts predicting quality of life after treatment f head and neck cancer. Head Neck 2000;22: Available at: Funk GF, Karnell LH, Whitehead S, et al. Free tissue transfer versus pedicled flap cost in head and neck cancer. Otolaryngol Head Neck Surg 2002;127: Available at: Farwell DG, Reilly DF, Weymuller EA, et al. Predicts of perioperative complications in head and neck patients. Arch Otolaryngol Head Neck Surg 2002;128: Available at: Kaplan MH, Feinstein AR. The imptance of classifying initial combidity in evaluatin the outcome of diabetes mellitus. J Chronic Dis 1974;27: Available at: Bang D, Piccirillo J, Littenberg B, al e. The Adult Combidity Evaluation-27 (ACE-27) test: a new combidity index f patients with cancer [abstract]. J Clin Oncol Available at: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. REF-2

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135 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. 47. Ferlito A, Rinaldo A, Silver CE, et al. Elective and therapeutic selective neck dissection. Oral Oncol 2006;42: Available at: Schmitz S, Machiels JP, Weynand B, et al. Results of selective neck dissection in the primary management of head and neck squamous cell carcinoma. Eur Arch Othinolaryngol 2009;266: Available at: Patel RS, Clark J, Wyten R, et al. Squamous cell carcinoma from an unknown head and neck primary site: a "selective treatment" approach. Arch Otolaryngol Head Neck Surg 2007;133: Available at: Sivanandan R, Kaplan MJ, Lee KJ, et al. Long-term results of 100 consecutive comprehensive neck dissections: implications f selective neck dissections. Arch Otolaryngol Head Neck Surg 2004;130: Available at: Liauw SL, Mancuso AA, Amdur RJ, et al. Postradiotherapy neck dissection f lymph node-positive head and neck cancer: the use of computed tomography to manage the neck. J Clin Oncol 2006;24: Available at: Pceddu SV, Jarmolowski E, Hicks RJ, et al. Utility of positron emission tomography f the detection of disease in residual neck nodes after (chemo)radiotherapy in head and neck cancer. Head Neck 2005;27: Available at: Yao M, Smith RB, Hoffman HT, et al. Clinical significance of postradiotherapy [18F]-fluodeoxyglucose positron emission tomography imaging in management of head-and-neck cancer-a longterm outcome rept. Int J Radiat Oncol Biol Phys 2009;74:9-14. Available at: Lango MN, Myers JN, Garden AS. Controversies in surgical management of the node-positive neck after chemadiation. Semin Radiat Oncol 2009;19: Available at: Isles MG, McConkey C, Mehanna HM. A systematic review and meta-analysis of the role of positron emission tomography in the follow up of head and neck squamous cell carcinoma following radiotherapy chemadiotherapy. Clin Otolaryngol 2008;33: Available at: Cry J, Peters L, Fisher R, et al. N2-N3 neck nodal control without planned neck dissection f clinical/radiologic complete respondersresults of Trans Tasman Radiation Oncology Group Study Head Neck 2008;30: Available at: Lau H, Phan T, Mackinnon J, Matthews TW. Absence of planned neck dissection f the N2-N3 neck after chemadiation f locally advanced squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 2008;134: Available at: Ong SC, Schoder H, Lee NY, et al. Clinical utility of 18F-FDG PET/CT in assessing the neck after concurrent chemadiotherapy f Locegional advanced head and neck cancer. J Nucl Med 2008;49: Available at: Nayak JV, Walvekar RR, Andrade RS, et al. Deferring planned neck dissection following chemadiation f stage IV head and neck cancer: the utility of PET-CT. Laryngoscope 2007;117: Available at: Abgral R, Querellou S, Potard G, et al. Does 18F-FDG PET/CT improve the detection of posttreatment recurrence of head and neck squamous cell carcinoma in patients negative f disease on clinical follow-up? J Nucl Med 2009;50: Available at: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. REF-4

136 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. 61. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with without concomitant chemotherapy f locally advanced head and neck cancer. N Engl J Med 2004;350: Available at: Cooper JS, Pajak TF, Fastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy f high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350: Available at: Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27: Available at: Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined postoperative radiotherapy and weekly cisplatin infusion f locally advanced head and neck carcinoma: final rept of a randomized trial. Int J Radiat Oncol Biol Phys 1996;36: Available at: Shah JP, Cendon RA, Farr HW, Strong EW. Carcinoma of the al cavity. facts affecting treatment failure at the primary site and neck. Am J Surg 1976;132: Available at: Looser KG, Shah JP, Strong EW. The significance of "positive" margins in surgically resected epidermoid carcinomas. Head Neck Surg 1978;1: Available at: Johnson JT, Barnes EL, Myers EN, et al. The extracapsular spread of tums in cervical node metastasis. Arch Otolaryngol 1981;107: Available at: Feldman M, Fletcher GH. Analysis of the parameters relating to failures above the clavicles in patients treated by postoperative irradiation f squamous cell carcinomas of the al cavity opharynx. Int J Radiat Oncol Biol Phys 1982;8: Available at: Mirimanoff RO, Wang CC, Doppke KP. Combined surgery and postoperative radiation therapy f advanced laryngeal and hypopharyngeal carcinomas. Int J Radiat Oncol Biol Phys 1985;11: Available at: Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose f postoperative radiation therapy of head and neck cancer: first rept of a prospective randomized trial. Int J Radiat Oncol Biol Phys 1993;26:3-11. Available at: Thames HD, Jr., Withers HR, Peters LJ, Fletcher GH. Changes in early and late radiation responses with altered dose fractionation: implications f dose-survival relationships. Int J Radiat Oncol Biol Phys 1982;8: Available at: Withers H, Thames H, Peters L. Differences in the fractionation response of acutely and late-responding tissues In: Kaercher K, Kogelnik H, Reinartz G, eds, eds. Progress in Radio-Oncology II. Vol. 11. New Yk: Raven Press; 1982: Withers HR, Tayl JM, Maciejewski B. The hazard of accelerated tum clonogen repopulation during radiotherapy. Acta Oncol 1988;27: Available at: Harwood AR, Beale FA, Cummings BJ, et al. T4NOMO glottic cancer: an analysis of dose-time volume facts. Int J Radiat Oncol Biol Phys 1981;7: Available at: Amnmarn R, Prempree T, Viravathana T, et al. A therapeutic approach to early vocal cd carcinoma. Acta Radiol Oncol Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. REF-5

137 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. 1985;24: Available at: Schwaibold F, Scariato A, Nunno M, et al. The effect of fraction size on control of early glottic cancer. Int J Radiat Oncol Biol Phys 1988;14: Available at: Kim RY, Marks ME, Salter MM. Early-stage glottic cancer: imptance of dose fractionation in radiation therapy. Radiology 1992;182: Available at: Parson J. Time-dose-volume relationships in radiation therapy. In: Million R, Cassisi N, eds. Management of Head and Neck Cancer: A Multidisciplinary Approach, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1994: Yamazaki H, Nishiyama K, Tanaka E, et al. Radiotherapy f early glottic carcinoma (T1N0M0): results of prospective randomized study of radiation fraction size and overall treatment time. Int J Radiat Oncol Biol Phys 2006;64: Available at: Yu E, Shenouda G, Beaudet MP, Black MJ. Impact of radiation therapy fraction size on local control of early glottic carcinoma. Int J Radiat Oncol Biol Phys 1997;37: Available at: Hiot JC, Le Fur R, N'Guyen T, et al. Hyperfractionation versus conventional fractionation in opharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992;25: Available at: Hiot JC. [Controlled clinical trials of hyperfractionated and accelerated radiotherapy in othinolaryngologic cancers]. Bull Acad Natl Med 1998;182: ; discussion Available at: Hiot JC, Bontemps P, van den Bogaert W, et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC randomized trial. Radiother Oncol 1997;44: Available at: Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy f head and neck squamous cell carcinomas: first rept of RTOG Int J Radiat Oncol Biol Phys 2000;48:7-16. Available at: Trotti A, Fu K, Pajak T, et al. Long term outcomes of RTOG 90-03: A comparison of hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy f head and neck squamous cell carcinoma [Abstract]. Int J Radiat Oncol Biol Phys 2005;63:S70-S71. Available at: = Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368: Available at: Budach V, Stuschke M, Budach W, et al. Hyperfractionated accelerated chemadiation with concurrent fluouracil-mitomycin is me effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German Cancer Society Prospective Randomized Trial. J Clin Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. REF-6

138 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. Oncol 2005;23: Available at: Budach W, Hehr T, Budach V, et al. A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck. BMC Cancer 2006;6: Available at: Bensadoun R-J, Benezery K, Dassonville O, et al. French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC- GORTEC). Int J Radiat Oncol Biol Phys 2006;64: Available at: Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with without concurrent chemotherapy f locally advanced head and neck cancer. N Engl J Med 1998;338: Available at: Jeremic B, Shibamoto Y, Milicic B, et al. Hyperfractionated radiation therapy with without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 2000;18: Available at: Ang K, Zhang Q, Wheeler RH, et al. A phase III trial (RTOG 0129) of two radiation-cisplatin regimens f head and neck carcinomas (HNC): Impact of radiation and cisplatin intensity on outcome [abstract]. J Clin Oncol 2010;28(Suppl 15):Abstract Available at: Denis F, Garaud P, Bardet E, et al. Final results of the French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage opharynx carcinoma. J Clin Oncol 2004;22: Available at: Denis F, Garaud P, Bardet E, et al. Late toxicity results of the GORTEC randomized trial comparing radiotherapy with concomitant radiochemotherapy f advanced-stage opharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scing systems. Int J Radiat Oncol Biol Phys 2003;55: Available at: Bourhis J, Calais G, Lapeyre M, et al. Concomitant radiochemotherapy accelerated radiotherapy: analysis of two randomized trials of the French Head and Neck Cancer Group (GORTEC). Semin Oncol 2004;31: Available at: Machtay M, Moughan J, Trotti A, et al. Facts associated with severe late toxicity after concurrent chemadiation f locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol 2008;26: Available at: Hartfd AC, Palisca MG, Eichler TJ, et al. American Society f Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) Practice Guidelines f Intensity-Modulated Radiation Therapy (IMRT). Int J Radiat Oncol Biol Phys 2009;73:9-14. Available at: Holmes T, Das R, Low D, et al. American Society of Radiation Oncology recommendations f documenting intensity-modulated radiation therapy treatments. Int J Radiat Oncol Biol Phys 2009;74: Available at: Wu Q, Manning M, Schmidt-Ullrich R, Mohan R. The potential f sparing of parotids and escalation of biologically effective dose with intensity-modulated radiation treatments of head and neck cancers: a treatment design study. Int J Radiat Oncol Biol Phys 2000;46: Available at: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. REF-7

139 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved Chao KS, Majhail N, Huang CJ, et al. Intensity-modulated radiation therapy reduces late salivary toxicity without compromising tum control in patients with opharyngeal carcinoma: a comparison with conventional techniques. Radiother Oncol 2001;61: Available at: Dogan N, King S, Emami B, et al. Assessment of different IMRT boost delivery methods on target coverage and nmal-tissue sparing. Int J Radiat Oncol Biol Phys 2003;57: Available at: Li Y, Tayl JMG, Ten Haken RK, Eisbruch A. The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy. Int J Radiat Oncol Biol Phys 2007;67: Available at: Pow EHN, Kwong DLW, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy f early-stage nasopharyngeal carcinoma: initial rept on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66: Available at: Kam MKM, Leung S-F, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in earlystage nasopharyngeal carcinoma patients. J Clin Oncol 2007;25: Available at: Pfister D, Cassileth B, Deng G, et al. Acupuncture f pain and dysfunction after neck dissection: Results of a randomized controlled trial. J Clin Oncol 2010;28: Available at: Scarantino C, LeVeque F, Swann RS, et al. Effect of pilocarpine during radiation therapy: results of RTOG 97-09, a phase III randomized study in head and neck cancer patients. J Suppt Oncol 2006;4: Available at: Petrone D, Condemi JJ, Fife R, et al. A double-blind, randomized, placebo-controlled study of cevimeline in Sjogren's syndrome patients with xerostomia and keratoconjunctivitis sicca. Arthritis Rheum 2002;46: Available at: Galvin JM, De Neve W. Intensity modulating and other radiation therapy devices f dose painting. J Clin Oncol 2007;25: Available at: Lauve A, Mris M, Schmidt-Ullrich R, et al. Simultaneous integrated boost intensity-modulated radiotherapy f locally advanced head-and-neck squamous cell carcinomas: II--clinical results. Int J Radiat Oncol Biol Phys 2004;60: Available at: Schoenfeld GO, Amdur RJ, Mris CG, et al. Patterns of failure and toxicity after intensity-modulated radiotherapy f head and neck cancer. Int J Radiat Oncol Biol Phys 2008;71: Available at: Lee NY, de Arruda FF, Puri DR, et al. A comparison of intensitymodulated radiation therapy and concomitant boost radiotherapy in the setting of concurrent chemotherapy f locally advanced opharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006;66: Available at: de Arruda FF, Puri DR, Zhung J, et al. Intensity-modulated radiation therapy f the treatment of opharyngeal carcinoma: the Memial Sloan-Kettering Cancer Center experience. Int J Radiat Oncol Biol Phys 2006;64: Available at: Garden AS, Mrison WH, Wong P-F, et al. Disease-control rates following intensity-modulated radiation therapy f small primary opharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;67: Available at: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. REF-8

140 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved Eisbruch A, Levendag PC, Feng FY, et al. Can IMRT brachytherapy reduce dysphagia associated with chemadiotherapy of head and neck cancer? The Michigan and Rotterdam experiences. Int J Radiat Oncol Biol Phys 2007;69:S Available at: Wolden SL, Chen WC, Pfister DG, et al. Intensity-modulated radiation therapy (IMRT) f nasopharynx cancer: update of the Memial Sloan-Kettering experience. Int J Radiat Oncol Biol Phys 2006;64: Available at: Madani I, Bonte K, Vakaet L, et al. Intensity-modulated radiotherapy f sinonasal tums: Ghent University Hospital update. Int J Radiat Oncol Biol Phys 2009;73: Available at: Eisbruch A. Reducing xerostomia by IMRT: what may, and may not, be achieved. J Clin Oncol 2007;25: Available at: Hodge CW, Bentzen SM, Wong G, et al. Are we influencing outcome in opharynx cancer with intensity-modulated radiotherapy? An inter-era comparison. Int J Radiat Oncol Biol Phys 2007;69: Available at: Veldeman L, Madani I, Hulstaert F, et al. Evidence behind use of intensity-modulated radiotherapy: a systematic review of comparative clinical studies. Lancet Oncol 2008;9: Available at: Eisbruch A, Marsh LH, Dawson LA, et al. Recurrences near base of skull after IMRT f head-and-neck cancer: implications f target delineation in high neck and f parotid gland sparing. Int J Radiat Oncol Biol Phys 2004;59: Available at: Rosenthal DI, Trotti A. Strategies f managing radiation-induced mucositis in head and neck cancer. Semin Radiat Oncol 2009;19: Available at: Gomez DR, Zhung JE, Gomez J, et al. Intensity-modulated radiotherapy in postoperative treatment of al cavity cancers. Int J Radiat Oncol Biol Phys 2009;73: Available at: Lee NY, O'Meara W, Chan K, et al. Concurrent chemotherapy and intensity-modulated radiotherapy f locegionally advanced laryngeal and hypopharyngeal cancers. Int J Radiat Oncol Biol Phys 2007;69: Available at: Nutting CM, Mden JP, Harrington KJ, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol Available at: Nutting C, A'Hern R, Rogers MS, et al. First results of a phase III multicenter randomized controlled trial of intensity modulated (IMRT) versus conventional radiotherapy (RT) in head and neck cancer (PARSPORT: ISRCTN ; CRUK/03/005) [abstract]. J Clin Oncol 2009;27(Suppl 18):Abstract LBA6006. Available at: Posner MR, Ervin TJ, Miller D, et al. Incidence of hypothyroidism following multimodality treatment f advanced squamous cell cancer of the head and neck. Laryngoscope 1984;94: Available at: Pigneux J, Richaud PM, Lagarde C. The place of interstitial therapy using 192 iridium in the management of carcinoma of the lip. Cancer 1979;43: Available at: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN. REF-9

141 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved McCombe D, MacGill K, Ainslie J, et al. Squamous cell carcinoma of the lip: a retrospective review of the Peter MacCallum Cancer Institute experience Aust N Z J Surg 2000;70: Available at: de Visscher JG, van den Elsaker K, Grond AJ, et al. Surgical treatment of squamous cell carcinoma of the lower lip: evaluation of long-term results and prognostic facts--a retrospective analysis of 184 patients. J Oral Maxillofac Surg 1998;56: Available at: de Visscher JG, Botke G, Schakenraad JA, van der Waal I. A comparison of results after radiotherapy and surgery f stage I squamous cell carcinoma of the lower lip. Head Neck 1999;21: Available at: de Visscher JG, Grond AJ, Botke G, van der Waal I. Results of radiotherapy f squamous cell carcinoma of the vermilion bder of the lower lip. A retrospective analysis of 108 patients. Radiother Oncol 1996;39:9-14. Available at: Babington S, Veness MJ, Cakir B, et al. Squamous cell carcinoma of the lip: is there a role f adjuvant radiotherapy in improving local control following incomplete inadequate excision? ANZ J Surg 2003;73: Available at: Fleming AJ, Jr., Smith SP, Jr., Paul CM, et al. Impact of [18F]-2- fluodeoxyglucose-positron emission tomography/computed tomography on previously untreated head and neck cancer patients. Laryngoscope 2007;117: Available at: Branstetter BF, Blodgett TM, Zimmer LA, et al. Head and neck malignancy: is PET/CT me accurate than PET CT alone? Radiology 2005;235: Available at: Nasman A, Attner P, Hammarstedt L, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125: Available at: Hammarstedt L, Lindquist D, Dahlstrand H, et al. Human papillomavirus as a risk fact f the increase in incidence of tonsillar cancer. Int J Cancer 2006;119: Available at: Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with opharyngeal cancer. N Engl J Med 2010;363: Available at: Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100: Available at: Gillison ML, Harris J, Westra W, et al. Survival outcomes by tum human papillomavirus (HPV) status in stage III-IV opharyngeal cancer (OPC) in RTOG 0129 [abstract]. J Clin Oncol 2009;27(Suppl 15):Abstract Available at: Rischin D, Young R, Fisher R, et al. Prognostic significance of HPV and p16 status in patients with opharyngeal cancer treated on a large international phase III trial [abstract]. J Clin Oncol 2009;27(Suppl 15):Abstract Available at: Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of HPVassociated p16ink4a expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009;27: Available at: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.REF-10

142 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved Ragin CCR, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer 2007;121: Available at: Rischin D, Young RJ, Fisher R, et al. Prognostic significance of p16ink4a and human papillomavirus in patients with opharyngeal cancer treated on TROG phase III trial. J Clin Oncol 2010;28: Available at: Begum S, Gillison ML, Nicol TL, Westra WH. Detection of human papillomavirus-16 in fine-needle aspirates to determine tum igin in patients with metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2007;13: Available at: Vokes EE, Stenson K, Rosen FR, et al. Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluouracil, and hydroxyurea chemadiotherapy: curative and gan-preserving therapy f advanced head and neck cancer. J Clin Oncol 2003;21: Available at: Hitt R, Grau J, Lopez-Pousa A, et al. Phase II/III trial of induction chemotherapy (ICT) with cisplatin/5-fluouracil (PF) vs. docetaxel (T) plus PF (TPF) followed by chemadiotherapy (CRT) vs. CRT f unresectable locally advanced head and neck cancer (LAHNC) [abstract]. J Clin Oncol 2005;23(Suppl 16):Abstract Available at: Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing cisplatin plus fluouracil to paclitaxel, cisplatin, and fluouracil induction chemotherapy followed by chemadiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005;23: Available at: Hitt R, Grau J, Lopez-Pousa A, et al. Randomized phase II/III clinical trial of induction chemotherapy (ICT) with either cisplatin/5- fluouracil (PF) docetaxel/cisplatin/5-fluouracil (TPF) followed by chemadiotherapy (CRT) vs. crt alone f patients (pts) with unresectable locally advanced head and neck cancer (LAHNC) [abstract]. J Clin Oncol 2006;24(Suppl 18):Abstract Available at: Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluouracil alone with docetaxel in head and neck cancer. N Engl J Med 2007;357: Available at: Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locegional treatment f head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collabative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355: Available at: Paccagnella A, Orlando A, Marchii C, et al. Phase III trial of initial chemotherapy in stage III IV head and neck cancers: a study by the Gruppo di Studio sui Tumi della Testa e del Collo. J Natl Cancer Inst 1994;86: Available at: Lch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluouracil alone in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: longterm results of the TAX 324 randomised phase 3 trial. Lancet Oncol Available at: Vermken JB, Remenar E, van Herpen C, et al. Cisplatin, fluouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357: Available at: Pignon J-P, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.REF-11

143 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14. Available at: Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyrifm sinus cancer: preliminary results of a European Organization f Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996;88: Available at: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324: Available at: McNeil BJ, Weichselbaum R, Pauker SG. Speech and survival: tradeoffs between quality and quantity of life in laryngeal cancer. N Engl J Med 1981;305: Available at: Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemadiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21: Available at: Lo TC, Wiley AL, Jr., Ansfield FJ, et al. Combined radiation therapy and 5-fluouracil f advanced squamous cell carcinoma of the al cavity and opharynx: a randomized study. AJR Am J Roentgenol 1976;126: Available at: Sanchiz F, Milla A, Tner J, et al. Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 1990;19: Available at: Browman GP, Cripps C, Hodson DI, et al. Placebo-controlled randomized trial of infusional fluouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 1994;12: Available at: Smid L, Lesnicar H, Zakotnik B, et al. Radiotherapy, combined with simultaneous chemotherapy with mitomycin C and bleomycin f inoperable head and neck cancer--preliminary rept. Int J Radiat Oncol Biol Phys 1995;32: Available at: Merlano M, Benasso M, Cvo R, et al. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 1996;88: Available at: Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998;16: Available at: Munro AJ. An overview of randomised controlled trials of adjuvant chemotherapy in head and neck cancer. Br J Cancer 1995;71: Available at: El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region. A meta-analysis of prospective and randomized trials. J Clin Oncol 1996;14: Available at: Bourhis J, Amand C, Pignon J-P. Update of MACH-NC (Meta- Analysis of Chemotherapy in Head & Neck Cancer) database focused on concomitant chemadiotherapy [abstract]. J Clin Oncol Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.REF-12

144 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. 2004;22(Suppl 14):Abstract Available at: Pignon JP, le Maitre A, Bourhis J. Meta-Analyses of Chemotherapy in Head and Neck Cancer (MACH-NC): an update. Int J Radiat Oncol Biol Phys 2007;69:S Available at: Fastiere AA, Goepfert H, Ma M, et al. Concurrent chemotherapy and radiotherapy f gan preservation in advanced laryngeal cancer. N Engl J Med 2003;349: Available at: Argiris A, Haraf DJ, Kies MS, Vokes EE. Intensive concurrent chemadiotherapy f head and neck cancer with 5-Fluouracil- and hydroxyurea-based regimens: reversing a pattern of failure. Oncologist 2003;8: Available at: Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluouracil with without docetaxel f larynx preservation. J Natl Cancer Inst 2009;101: Available at: Paccagnella A, Ghi MG, Leggian L, et al. Concomitant chemadiotherapy versus induction docetaxel, cisplatin and 5 fluouracil (TPF) followed by concomitant chemadiotherapy in locally advanced head and neck cancer: a phase II randomized study. Ann Oncol 2010;21: Available at: Hitt R, Grau JJ, Lopez-Pousa A, et al. Final results of a randomized phase III trial comparing induction chemotherapy with cisplatin/5-fu docetaxel/cisplatin/5-fu follow by chemadiotherapy (CRT) versus CRT alone as first-line treatment of unresectable locally advanced head and neck cancer (LAHNC) [abstract]. J Clin Oncol 2009;27(Suppl 15):Abstract Available at: Salama JK, Haddad RI, Kies MS, et al. Clinical practice guidance f radiotherapy planning after induction chemotherapy in locegionally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2009;75: Available at: Lefebvre J, Pointreau Y, Rolland F, et al. Sequential chemadiotherapy (SCRT) f larynx preservation (LP): Preliminary results of the randomized phase II TREMPLIN study [abstract]. J Clin Oncol 2009;27(Suppl 15):Abstract Available at: Buiret G, Combe C, Favrel V, et al. A retrospective, multicenter study of the tolerance of induction chemotherapy with docetaxel, Cisplatin, and 5-Fluouracil followed by radiotherapy with concomitant cetuximab in 46 cases of squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2010;77: Available at: Nutting CM, Bhide SA, Harrington KJ. Treatment of head and neck cancer. N Engl J Med 2008;358: ; auth reply Available at: Chitapanarux I, Lvidhaya V, Kamnerdsupaphon P, et al. Chemadiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiity, open trial. Eur J Cancer 2007;43: Available at: Kies MS, Holsinger FC, Lee JJ, et al. Induction chemotherapy and cetuximab f locally advanced squamous cell carcinoma of the head and neck: results from a phase II prospective trial. J Clin Oncol 2010;28:8-14. Available at: Kotwall C, Sako K, Razack MS, et al. Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 1987;154: Available at: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.REF-13

145 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved Lefebvre JL, Rolland F, Tesselaar M, et al. Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst 2009;101: Available at: Cooper JS, del Rowe J, Newall J. Regional Stage IV carcinoma of the nasopharynx treated by aggressive radiotherapy. Int J Radiat Oncol Biol Phys 1983;9: Available at: Bailet JW, Mark RJ, Abemay E, et al. Nasopharyngeal carcinoma: treatment results with primary radiation therapy. Laryngoscope 1992;102: Available at: Johansen LV, Mestre M, Overgaard J. Carcinoma of the nasopharynx: analysis of treatment results in 167 consecutively admitted patients. Head Neck 1992;14: Available at: Sanguineti G, Geara FB, Garden AS, et al. Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control. Int J Radiat Oncol Biol Phys 1997;37: Available at: Wang C. Radiation Therapy f Head and Neck Neoplasms, 3rd ed. New Yk: Wiley-Liss; Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemadiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study J Clin Oncol 1998;16: Available at: Mesic JB, Fletcher GH, Goepfert H. Megavoltage irradiation of epithelial tums of the nasopharynx. Int J Radiat Oncol Biol Phys 1981;7: Available at: Hoppe RT, Goffinet DR, Bagshaw MA. Carcinoma of the nasopharynx. Eighteen years' experience with megavoltage radiation therapy. Cancer 1976;37: Available at: Wee J, Tan EH, Tai BC, et al. Randomized trial of radiotherapy versus concurrent chemadiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 2005;23: Available at: Chan AT, Leung SF, Ngan RK, et al. Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locegionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2005;97: Available at: Leong S-S, Wee J, Tay MH, et al. Paclitaxel, carboplatin, and gemcitabine in metastatic nasopharyngeal carcinoma: a Phase II trial using a triplet combination. Cancer 2005;103: Available at: Chan ATC, Hsu M-M, Goh BC, et al. Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent metastatic nasopharyngeal carcinoma. J Clin Oncol 2005;23: Available at: Zhang L, Zhang Y, Huang P-Y, et al. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer Chemother Pharmacol 2008;61: Available at: Ngan RKC, Yiu HHY, Lau WH, et al. Combination gemcitabine and cisplatin chemotherapy f metastatic recurrent nasopharyngeal Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.REF-14

146 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved. carcinoma: rept of a phase II study. Ann Oncol 2002;13: Available at: Ma BBY, Tannock IF, Pond GR, et al. Chemotherapy with gemcitabine-containing regimens f locally recurrent metastatic nasopharyngeal carcinoma. Cancer 2002;95: Available at: Rodel RM, Steiner W, Muller RM, et al. Endoscopic laser surgery of early glottic cancer: involvement of the anteri commissure. Head Neck 2009;31: Available at: Zouhair A, Azria D, Coucke P, et al. Decreased local control following radiation therapy alone in early-stage glottic carcinoma with anteri commissure extension. Strahlenther Onkol 2004;180: Available at: Silver CE, Beitler JJ, Shaha AR, et al. Current trends in initial management of laryngeal cancer: the declining use of open surgery. Eur Arch Othinolaryngol 2009;266: Available at: Katz TS, Mendenhall WM, Mris CG, et al. Malignant tums of the nasal cavity and paranasal sinuses. Head Neck 2002;24: Available at: Cohen ZR, Marm E, Fuller GN, DeMonte F. Misdiagnosis of olfacty neuroblastoma. Neurosurg Focus 2002;12:e3. Available at: Ejaz A, Wenig BM. Sinonasal undifferentiated carcinoma: clinical and pathologic features and a discussion on classification, cellular differentiation, and differential diagnosis. Adv Anat Pathol 2005;12: Available at: Iezzoni JC, Mills SE. "Undifferentiated" small round cell tums of the sinonasal tract: differential diagnosis update. Am J Clin Pathol 2005;124 Suppl: Available at: Dulguerov P, Jacobsen MS, Allal AS, et al. Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Cancer 2001;92: Available at: Lin EM, Sparano A, Spalding A, et al. Sinonasal undifferentiated carcinoma: a 13-year experience at a single institution. Skull Base 2010;20: Available at: Babin E, Rouleau V, Vedrine PO, et al. Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses. J Laryngol Otol 2006;120: Available at: Chen AM, Daly ME, El-Sayed I, et al. Patterns of failure after combined-modality approaches incpating radiotherapy f sinonasal undifferentiated carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2008;70: Available at: Mendenhall WM, Mendenhall CM, Riggs CE, Jr., et al. Sinonasal undifferentiated carcinoma. Am J Clin Oncol 2006;29: Available at: Kim BS, Vongtama R, Juillard G. Sinonasal undifferentiated carcinoma: case series and literature review. Am J Otolaryngol 2004;25: Available at: Smith SR, Som P, Fahmy A, et al. A clinicopathological study of sinonasal neuroendocrine carcinoma and sinonasal undifferentiated carcinoma. Laryngoscope 2000;110: Available at: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.REF-15

147 Printed by Gregio Sanchez Aniceto on 4/30/2012 4:38:52 PM. F personal use only. Not approved f distribution. Copyright 2012 National Comprehensive Cancer Netwk, Inc., All Rights Reserved Diaz EM, Johnigan RH, Pero C, et al. Olfacty neuroblastoma: the 22-year experience at one comprehensive cancer center. Head Neck 2005;27: Available at: McLean JN, Nunley SR, Klass C, et al. Combined modality therapy of esthesioneuroblastoma. Otolaryngol Head Neck Surg 2007;136: Available at: Ozsahin M, Gruber G, Olszyk O, et al. Outcome and prognostic facts in olfacty neuroblastoma: a rare cancer netwk study. Int J Radiat Oncol Biol Phys 2010;78: Available at: Sohrabi S, Drabick JJ, Crist H, et al. Neoadjuvant Concurrent Chemadiation f Advanced Esthesioneuroblastoma: A Case Series and Review of the Literature. J Clin Oncol Available at: t Bachar G, Goldstein DP, Shah M, et al. Esthesioneuroblastoma: The Princess Margaret Hospital experience. Head Neck 2008;30: Available at: Dirix P, Nuyts S, Geussens Y, et al. Malignancies of the nasal cavity and paranasal sinuses: long-term outcome with conventional three-dimensional confmal radiotherapy. Int J Radiat Oncol Biol Phys 2007;69: Available at: Hoppe BS, Stegman LD, Zelefsky MJ, et al. Treatment of nasal cavity and paranasal sinus cancer with modern radiotherapy techniques in the postoperative setting--the MSKCC experience. Int J Radiat Oncol Biol Phys 2007;67: Available at: Chen AM, Daly ME, Bucci MK, et al. Carcinomas of the paranasal sinuses and nasal cavity treated with radiotherapy at a single institution over five decades: are we making improvement? Int J Radiat Oncol Biol Phys 2007;69: Available at: Pceddu S, Martin J, Shanker G, et al. Paranasal sinus tums: Peter MacCallum Cancer Institute experience. Head Neck 2004;26: Available at: Dirix P, Vanstraelen B, Jissen M, et al. Intensity-modulated radiotherapy f sinonasal cancer: improved outcome compared to conventional radiotherapy. Int J Radiat Oncol Biol Phys 2010;78: Available at: Hoppe BS, Nelson CJ, Gomez DR, et al. Unresectable carcinoma of the paranasal sinuses: outcomes and toxicities. Int J Radiat Oncol Biol Phys 2008;72: Available at: Hoppe BS, Wolden SL, Zelefsky MJ, et al. Postoperative intensitymodulated radiation therapy f cancers of the paranasal sinuses, nasal cavity, and lacrimal glands: technique, early outcomes, and toxicity. Head Neck 2008;30: Available at: Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab f squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354: Available at: Garden AS, Harris J, Vokes EE, et al. Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase II trial of concurrent radiation and chemotherapy f advanced squamous cell carcinomas of the head and neck. J Clin Oncol 2004;22: Available at: Version , 04/26/12 National Comprehensive Cancer Netwk, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.REF-16

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