BACKGROUND Head and neck cancers can arise in the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, thyoroid, and salivary glands

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1 HEAD AND NECK CANCERS Updated May 2017 by Dr. Di (Maria) Jiang (PGY-5 Medical Onclgy Resident, University f Trnt) DISCLAIMER: The fllwing are study ntes cmpiled by the abve PGY-5 medical nclgy residents and reviewed by a staff medical nclgist. They reflect what we feel is relevant knwledge fr graduating medical nclgy residents preparing fr their final examinatin. The infrmatin has nt been surveyed r ratified by the Ryal Cllege. BACKGROUND Head and neck cancers can arise in the ral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, thyrid, and salivary glands Oral cavity Lips Buccal mucsa Anterir tngue Flr f the muth Hard palate Upper and lwer gingiva Pharynx Naspharynx Orpharynx: include base f tngue Hyppharynx: pyrifrm sinuses, pstcrid larynx, pharyngeal walls Larynx: Supraglttic Glttic larynx: true vcal crds Subglttic larynx Nasal cavity and the paranasal sinuses: maxillary, ethmid, sphenid, and frntal Majr (partid, submandibular, sublingual) and minr salivary glands NOTE: Head and neck squamus cell carcinma (HNSCC) and EBV-related naspharyngeal carcinma (NPC) are very different and will be discussed separately A) PUBLIC HEALTH EPIDEMIOLOGY (1) - Incidence: In 2010 ver 4000 Canadians were diagnsed with HNSCC HPV-assciated HNSCC usually diagnsed at a yunger age Increasing incidence f HPV-assciated HNSCC (primarily rpharyngeal) while tbacc related incidence is declining (2) Male:Female > 3:1 depending n anatmical site - Mrtality: In 2010 ver 1500 Canadians died frm HNSCC RISK FACTORS

2 Smking HPV EtOH HPV infectin fr rpharyngeal cancer (base f the tngue and tnsils) EBV infectin fr naspharyngeal cancer HIV PREVENTION & SCREENING - Preventin: Smking and EtOH cessatin HPV vaccine and methds t reduce HPV expsure - Screening: N screening recmmendatins in Canada r United States. B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - Cmmn Symptms: Palpable mass r lymph nde Patients with HPV psitive rpharyngeal cancers ften present with cystic neck masses. Weight lss Often depends n primary, fr example: Laryngeal: harseness r ther changes in the vice, cugh, difficult r nisy breathing Orpharyngeal: sre thrat lasting lnger than a few weeks, feeling that smething is stuck in the thrat, difficult r painful swallwing, ear pain, OSA Oral cavity: nn-healing ulcer r mass INVESTIGATIONS - Physical exam: Oral cavity Head and neck lymph ndes Cranial nerve exam - Labratry: Rutine BW, hepatitis screen - Diagnstic Imaging: CT head and neck MRI neck fr rpharyngeal, may be necessary fr ther sites CT chest (stage II r higher) PET scan nt rutinely dne, fr HNSCC primary unknwn CT abdmen and bne scan are nt rutinely perfrmed - Diagnstic Prcedures: Endscpy and bipsy Cnsider FNA f suspicius lymph ndes fr staging - Other: Ensure wmen with HPV+

3 HNSCC have rutine surveillance fr cervical cancer pelvic exam and pap smear. PATHOLOGY & MOLECULAR BIOLOGY - Cmmn Histlgy: Vast majrity are squamus cell carcinma and discussin in this chapter pertains t SCC. Differential includes adencarcinma, melanma, sarcma, lymphma - Cmmn Metastatic Sites: Lcal recurrence and lymph ndes Lung Bne - Relevant Mlecular Bilgy: HPV testing using IHC fr p16(3) STAGING Staging fr HNSCC is cmplex as it is different fr each anatmical site. General rules t fllw: N1 = ne LN less than 3 cm N2a = ne LN >3 cm and < 6 cm N2b = multiple ipsilateral LN; all < 6 cm N2c = bilateral r cntralateral LN; all <6cm N3 = LN > 6cm T1-3 N1 = Stage III T1-3 N2-3 = Stage IV T4 any N = Stage IV Any distant metastatic site = Stage IVC NOTE: New staging recmmendatins fr HPV+ rpharyngeal cancer t be published in 2016 (4) C) TREATMENT EARLY STAGE - Bttm Line General Apprach: Primary surgery r radical radiatin alne N rle fr chemtherapy - Prgnsis: 5-yr OS 56-90% depending n lcatin f the tumr LOCALLY ADVANCED

4 - Bttm Line General Apprach: Management depends n a number f factrs including anatmical site, size, invasin, c-mrbidities, patient preference, etc: Cnsider discussin at a multi-disciplinary tumr bard Often: Oral cavity: primary surgery fllwed by radiatin +/- chemtherapy Orpharyngeal, laryngeal, hyppharyngeal: Radiatin +/- chemtherapy, surgery fr salvage therapy nly - If ges fr primary radiatin +/- cncurrent chemtherapy Radiatin: 70Gy/35# Cisplatin 100mg/m2 d1, 22, 43 (5) 50% f patients d nt get third dse Cnsider RT + weekly cisplatin 40mg/m2 fr less well patients If cisplatin cntraindicated cnsider RT + cetuximab 400mg/m2 lad (ne week prir t RT) then 250mg/m2 weekly during radiatin (6) N clear benefit fr patients ver 71 years f age area f nging research. Onging trials investigating whether less intense chemtherapy is effective fr patients with HPV+ HNSCC (7) If ges fr primary surgery then pst-perative management: N adjuvant treatment if lw-risk (n intermediate r high-risk features) Intermediate risk: adjuvant RT alne 66Gy/33# >T2 Clse margins PNI LVI N2 r greater Level IV r V ndes High-risk (8): adjuvant CRT with high-dse cisplatin 100mg/m2 d1, 22, 43 Psitive margins Extracapsular spread Nte: Begin within 11 weeks f surgery - Prgnsis: Lcally advanced: 40% lng term survival Better with HPV+ nn-smkers(9) High-risk fr secndary malignancy (usually due t life-style i.e. smking) - Fllw-up: Imaging ~2 mnths after treatment - Imprtant Phase III Clinical Trials: Cncurrent chemtherapy

5 RTOG Cncurrent chemtherapy and raditherapy fr rgan preservatin in advanced laryngeal cancer. Frastiere et al. NEJM UPDATED: Lng-Term Results f RTOG 91-11: A Cmparisn f Three Nnsurgical Treatment Strategies t Preserve the Larynx in Patients With Lcally Advanced Larynx Cancer. Frastiere et al. JCO Regimen 1. Inductin cisplatin 100mg/m2 d1 plus 5-FU 1000mg/m2/d d1-5 q3w x 3 cycles fllwed by RT 70Gy/35# 2. Cncurrent cisplatin 100mg/m2 d1, 22, 43 and RT 3. RT alne Primary Endpint Laryngectmy-free survival Inclusin/Exclusin Previusly untreated stage III/IV HNSCC f the larynx Criteria T1 and T4 excluded Karnfsky PPS >= 60 Size (N) 518 Results Laryngectmy-Free Survival: Cncurrent CRT significantly imprved LFS HR 0.58 (95% CI , p=0.005) Overall Survival:N difference althugh trend twards wrse with cncurrent CRT HR 1.25 (95% CI , p=0.08) cmpared t inductin chemtherapy Txicity Cncurrent CRT mre txic: stmatitis (43% vs 20%), esphagitis (35% vs 19%), nausea/vmiting (20% vs 14%) Cnclusin Cncurrent CRT imprved laryngectmy-free survival with n imprvement in OS Other Cmments 70% f patients in cncurrent CRT arm received 3 cycles f cisplatin (mre than real-wrld numbers) Raditherapy plus cetuximab fr squamus-cell carcinma f the head and neck. Bnner et al. NEJM Regimen 1. RT alne, 70-76Gy 2. RT plus Cetuximab (400mg/m2 lad 1 week prir t RT then 250mg/m2 weekly during RT) Primary Endpint Lcreginal cntrl Inclusin/Exclusin Previusly untreated stage III/IV nn-metastatic HNSCC f the Criteria rpharynx, hyppharynx r larynx Karnfsky PPS >= 60 Nrmal hematpietic, hepatic and renal functin Size (N) 424 Results Lcreginal cntrl: RT+cetux significantly imprved lcreginal prgressin median 24.4m vs 14.9m, HR 0.68 (95% CI , p=0.005) Overall Survival:RT+cetux significantly imprved median survival 49.0 vs 29.3 m (p=0.03), 3-y OS 55% vs 45% (p=0.05), HR 0.74 (95% CI ) Txicity acneifrm rash: 87% vs 10% all grades, 17% gr 3-5 infusin reactin: 15% vs 2% all grades, 3% vs 0% gr 3-5 ther mild side effects f cetuximab: weight lss, headache, nausea Cnclusin RT+cetux imprves lcreginal cntrl and verall survival cmpared t RT alne

6 Meta-analysis f chemtherapy in head and neck cancer (MACH-NC): An update n 93 randmised trials and 17,346 patients. Pignn et al. Raditherapy and Onclgy Methds: Individual patient data frm trials cmparing lc-reginal treatment f radiatin with r withut chemtherapy (inductin, cncurrent, r adjuvant) Results 87 trials with 16,485 individual patients included HR fr death = 0.88 (p < ) fr additin f any chemtherapy t lcreginal teratment, 5-year abslute survival benefit f 4.5% (p < ) Cncurrent CRT better than RT alne HR fr death = 0.81 fr cncurrent CRT, 5-year abslute survival benefit = 6.5% Decreasing benefit with age, particularly >70y N benefit bserved in thse ver age 70 years Bttm-line Significant benefit f cncurrent CRT Cnsider RT alne fr patients >70y Ntes Trials f NPC nly were excluded Meta-analysis f chemtherapy in head and neck cancer (MACH-NC): A cmprehensive analysis by tumur site. Blanchard et al. Raditherapy and Onclgy Methds: Individual patient data frm trials cmparing lc-reginal treatment f radiatin with r withut chemtherapy Patients divided int 4 tumr lcatins: ral cavity, rpharynx, hyppharynx and larynx Other tumr lcatins were excluded Results 87 trials with 16,192 individual patients included Additin f chemtherapy beneficial fr all sites Cncurrent CRT better than RTl statistically fr rpharyngeal and laryngeal nly. 5-year OS benefits f cncurrent vs sequential: 8.9% ral cavity (p = 0.15) 8.1% rpharynx (p < ) 5.4% larynx (p = 0.05) 4% hyppharynx (p = 0.31) Bttm-line Significant benefit f chemtherapy fr all anatmical sites Cncurrent better fr rpharyngeal and laryngeal and likely als fr ral cavity and hyppharynx althugh nt statistically significant Defining risk levels in lcally advanced head and neck cancers: A cmparative analysis f cncurrent pstperative radiatin plus chemtherapy trials f the EORTC (#22931) and RTOG (#9501). Bernier et al. Head & Neck Methds: Analysis f pled data frm EORTC (10) and RTOG 9501 (11,12). Bth studies cmpared pst-surgery adjuvant radiatin t adjuvant chemradiatin with high-dse cisplatin (100mg/m2 d1,22,43) in patients with high-risk features. Results

7 Patients wh benefit frm additin f adjuvant high-dse cisplatin t radiatin include thse with features f psitive margins and/r extracapsular extensin frm lymph ndes Patients withut these features had n survival advantage with additin f chemtherapy Bttm-line Patients with psitive margins and/r extracapsular extensin have imprved survival with additin f cisplatin t radiatin. Other Imprtant Published Data fr HNSCC: Pstperative Treatment Pstperative chemraditherapy is generally restricted t patients thught t be at high risk f lcreginal recurrence (psitive margins, extracapsular extensin) RT alne remains an alternative fr patients with intermediate levels f increased risk (PNI, LVI, LN 2, T3/T4) r fr thse wh cannt tlerate cncurrent chemtherapy Factrs assciated with an increased risk f lcreginal recurrence after surgery include: Advanced tumr (T) stage (T3/T4) Psitive resectin margins r tumr clse t the resectin margin Tumr extensin thrugh the lymph nde capsule (extracapsular extensin) May nt be a negative prgnstic factr in HPV-assciated tumrs Tw r mre psitive lymph ndes (N2/N3) Perineural invasin Lymphvascular space invasin Adjuvant treatment begins within 11 weeks f surgery EORTC : n=334 resected high risk HN randmized t RT alne (66Gy/#33) vs CRT with high dse cisplatin High-risk disease was defined as a T3 r T4 primary with any ndal stage (except T3N0 laryngeal cancer), psitive surgical margins, extracapsular extensin, perineural invasin, vascular invasin, r ral cavity/rpharyngeal primary sites with invlvement f level IV r V lymph ndes. CRT imprved 5yr PFS (47 vs 36%), OS (53 vs 40%) RTOG : n=459 resected high risk HN randmized t RT alne (60-66Gy/#30-33) vs CRT with high dse cisplatin High-risk patients were limited t thse with psitive resectin margins, invlvement f tw r mre lymph ndes, r extracapsular ndal extensin. 10 yr update: n difference in lcreginal cntrl, DFS, r OS. There were statistically significant differences bserved in patients with extracapsular spread r psitive margins fr lcreginal cntrl and disease-free survival and a trend fr better verall survival in an unplanned subgrup analysis. Bernier et al 2005: pled data frm EORTC and RTOG 9501, bth studies cmpared adjuvant RT t adjuvant CRT with high dse cisplatin 100mg/m2 D1, D22, D43 in patients with high risk features Patients wh benefited frm adjuvant CRT vs RT alne include thse with psitive margins and/r extracapsular extensin frm LN à survival benefit

8 adjuvant chemraditherapy may nt prvide greater benefit than RT alne in the HPV psitive rpharyngeal cancer patient, and is being evaluated in a prspective trial pstperative RT alne: nly small studies and retrspective review T3 r T4 disease withut any ther high risk features Irradiatin f the neck fllw the same indicatins as fr neck dissectin inductin chemtherapy with cisplatin + 5FU + dcetaxel fllwed by definitive RT respnsiveness t inductin therapy prvides predictive and prgnstic infrmatin Inductin chemtherapy cntrversial due t cnflicting results. TAX 324: n=501 randmized t inductin TPF r PF x 3 cycles fllwed by CRT with cncurrent carbplatin OS better with PF, 5yr OS 52% vs 42% Significant txicity with TPF EORTC 24971/TAX 323: n=358 randmized t inductin inductin TPF at lwer dse r PF x 4 Median OS better with TPF 18.8 vs 14.5 m Spanish TTCC 2014: n=439 stage III/IV HNSCC randmized t CRT r inductin TPF x 3 cycles fllwed by CRT. N difference in PFS, TTF r OS Italian Ghi 2014 (abstract nly): n=421 HNSCC randmized t CRT r inductin TPF x 3 fllwed by CRT. Within each grup secnd randmizatin t CRT with cncurrent PF x 2 r cetuximab Inductin chem imprved median OS 54 vs 30 mnths, 3yr OS 58% vs 46%, HR 0.72 Imprved PFS DeCIDE trial 2014 (abstract nly): n=280 HNSCC N2, N3 randmized t inductin TPF x 2 fllwed by CRT r CRT alne with cncurrent dcetaxel, 5FU and hydrxyurea Underpwered, n OS, DFS benefit De-escalatin in HPV Psitive Tumurs Subject f nging research HPV-psitive T1-3 with N0-2a and < 10 pack-year, N2b sub- grups have minimal risk f distant metastasis O Sullivan JCO 2013: HPV+ T1-3 N0-2a and <10 pack year N2b subgrups have minimal risk f distant metastases irrespective f treatment appraches Use cetuximab instead f cisplatin Use less RT Use less chem

9 METASTATIC - Bttm Line General Apprach: Cnsider salvage surgery r radiatin First-line is cisplatin 75mg/m2 d1 and 5-FU 1000mg/m2/d d1-4 q3-4w Cnsider splitting cisplatin 25mg/m2/d d1-3 Other first-line regimens: weekly cisplatin, carbplatin + paclitaxel Cetuximab added t platinum + 5-FU in sme places based n EXTREME trial(13) but nt funded in Ontari N evidence fr survival fr secnd-line treatments but reasnable ptin is dcetaxel Evidence fr nivlumab in secnd line will be available in Prgnsis: Median OS 6-9 mnths, better in HPV-related disease - Imprtant Phase III Clinical Trials: EXTREME Trial Platinum-Based Chemtherapy plus Cetuximab in Head and Neck Cancer. Vermrken et al. NEJM Regimen Platinum (cis r carb) plus 5-FU with r withut cetuximab (400mg/m2 lad then 250mg/m2 weekly) MOA f EGFR inhibitr Experimental Drug Primary Endpint OS Inclusin/Exclusin Recurrent r metastatic HNSCC Criteria Karnfsky PS >=70 Size (N) 442 Results Survival:Cetuximab imprved median OS by 2.5 mnths (10.1 vs 7.4, p=0.04), HR fr death 0.80 PFS:Cetuximab imprved median PFS (5.6 vs 3.3 mnths, p<0.001) Respnse Rate:Cetuximab imprved RR (36% vs 20%, p<0.001) Txicity Cetuximab arm had 9% grade 3 rash, therwise similar txicity Cnclusin Additin f cetuximab t first-line platinum based chemtherapy fr patients with metastatic HNSCC prvides a small but significant increase in OS, PFS and RR. Other Cmments Similar study with panitumumab was negative(14) Cetus nt funded in this setting in ntari SPECTRUM 2013: similar trial with Pmab neg Trend tward better OS with Pmab 11 mnths vs 9 Unlike EXTREME, crssver was allwed Cisplatin vs Carbplatin N adequately pwered trials Althugh carbplatin is ften cnsidered t be less effective than cisplatin in head and neck cancer, there is little direct evidence Secnd Line

10 Platinum refractry = prgressin within 6 mnths Immuntherapy Checkmate 141 Ferris NEJM 2016 (phase III): n=361 recurrent/metastatic platinum refractry SCC f ral cavity, pharynx, larynx (excluded NPC), 2:1 randmizatin t nivlumab 3mg/kg q2w r dealer s chice (weekly MTX, dcetaxel, cetux). 60% had PDL1 expressin >1% Median OS benefit 7.5 vs 5.1 mnths, HR 0.70; 1yr OS 36% vs 16.6% Median PFS similar 2.0 vs 2.3 mnths ORR 13.3% vs 5.8% QL favr nivlumab Explratry analyses Benefit in p16 + (9.1 vs 4.4m, HR 0.56) and n benefit in HPV negative tumrs 7.5 vs 5.8m. PDL1 >1% psitive benefit larger (8.7 vs 4.6 m, HR 0.55). OS similar in patients with PDL1 <1% Keynte (phase II): n=171 after platinum and cetux failure, treated with pembrlizumab 200mg q3w 82% PDL1 psitive, 22% HPV psitive ORR 16%. Respnse rates similar regardless f HPV and PDL1 status Median duratin f respnse 8 mnths Phase II trials with pembr, durvalumab nging Cnventinal Chemtherapy N evidence f survival benefit in secnd line, ORR ~10% Dcetaxel MTX Cetuximab SUPPORTIVE MEASURES - Cnsults: All patients shuld be referred t a dietitian and cnsidered fr a feeding tube Assess weight prir t each chem dse, >10% weight lss is cncerning à feeding tube SLP Dentistry Smking cessatin Cnsider hearing test - Hydratin Risk Reductin Patients n high-dse cisplatin require significant hydratin at hme r sme centres chse t admit patients t hspital Smking cessatin and alchl abstinence.

11 Screen fr thyrid functin q6-12 mnths fr patients treated with RT Dental care and cleaning at least q6mnths OSA screening Screen fr secndary malignancies Cnsider lw dse annual CT if smkers Cervical cancer in wmen

12 Naspharyngeal Carcinma A) PUBLIC HEALTH EPIDEMIOLOGY(1) - Incidence: Rare: <1:100,000/yr in Nrth America, up t 65:100,000 amng patients in Nrthern Africa, Suthern China and Sutheast Asia. In Canadians were diagnsed with NPC Male:Female = 2:1 - Mrtality: In Canadians died frm NPC RISK FACTORS - NPC Mst cmmn in Sutheast Asian and Chinese ancestry Epstein-Barr virus Salted fish and meat Smking PREVENTION & SCREENING - Preventin: Smking cessatin Reduce intake f salted fish and meat Reduce ccupatinal expsures - Screening: N screening recmmendatins in Canada r United States. B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - Cmmn Symptms: Palpable mass r lymphadenpathy Nasal symptms: nse bleeds r bldy discharge frm the nse, stuffiness r blckage in the nse Ear symptms: pain r blckage in ne ear, persistent infectins in ne ear, ringing in the ear, r tinnitus, hearing difficulties r hearing lss Eye symptms: bulging eye, diplpia trismus, sre thrat, facial pain, headache, cranial nerve deficits weight lss INVESTIGATIONS

13 - Physical exam - Labratry: Rutine BW, hepatitis screen EBV level - Diagnstic Imaging: CT head and neck MRI neck CT chest PET scan if n bvius metastases CT abdmen and bne scan are nt rutinely perfrmed - Diagnstic Prcedures: Endscpy Bipsy/FNA, EBER n tumr PATHOLOGY & MOLECULAR BIOLOGY - Cmmn Histlgy: Keratinizing squamus-cell carcinma (WHO type I) Differentiated nn-keratinizing carcinma (WHO type II) Strngest relatinship with EBV Undifferentiated carcinma (WHO type III) - Cmmn Metastatic Sites: Lcal recurrence Lung Bne - Relevant Mlecular Bilgy: STAGING C) TREATMENT LOCALIZED / ADJUVANT / RESECTABLE - Bttm Line General Apprach: Stage I Radiatin t primary (70Gy/35#) Stage II Radiatin plus high-dse cisplatin (100mg/m2) +/- adjuvant chemtherapy - Prgnsis: 5-yr OS 70-90%

14 - Imprtant Phase III Clinical Trials fr NPC: Cncurrent Chemraditherapy vs Raditherapy Alne in Stage II Naspharyngeal Carcinma: Phase III Randmized Trial. Chen et al. JNCI Regimen Raditherapy alne Raditherapy plus cisplatin 30mg/m2 weekly Primary Endpint OS Inclusin/Exclusin Chinese 1992 stage II NPC Criteria Size (N) 230 Results Survival:Chemtherapy HR fr death = 0.3 (95%CI , p=0.007), 5-yr OS abslute benefit f 8.7% (94.5% vs 85.8%) Txicity Increased early txicity (neutrpenia, nausea/vmiting, mucsitis) N difference in late txicity Cnclusin Additin f weekly cisplatin cncurrently with raditherapy imprves verall survival in patients with stage II NPC Other Cmments If reclassified t AJCC staging then abut 85% stage II, 15% stage III, slightly mre stage III were in the CRT grup LOCALLY ADVANCED / UNRESECTABLE - Bttm Line General Apprach fr NPC Stage III-IV: Cncurrent chemradiatin as per CCO guidelines(15) - Prgnsis: 5-yr OS: 45-62% Benefit f adjuvant chem in additin t CRT is currently being investigated with multiple nging phase III studies CRT and adjuvant chem: Radiatin: 70Gy/35#, cisplatin 100mg/m2 d1, 22, 43 then adjuvant chem 4 weeks pst-radiatin cisplatin 80mg/m2 d1 plus 5-FU 1000mg/m2/d d1-4, q28d x 3 cycles Cnsider CRT alne: Cisplatin 20mg/m2/d and 5-FU 400mg/m2/d cntinuus fr 96hrs d1-4 and Fllw-up: Imaging ~2 mnths after treatment Imprtant phase III clinical trials fr NPC: Intergrup 0099 Chemraditherapy versus raditherapy in patients with advanced naspharyngeal cancer: phase III randmized Intergrup study Al-Sarraf et al. J Clin Oncl Regimen RT 70Gy/35# +/- cisplatin 100mg/m2 d1,22,43 then pst-raditherapy cisplatin 80mg/m2 d1 and 5-FU 1000mg/m2/d d1-4 q4w x 3 cycles Primary Endpint PFS Inclusin/Exclusin Stage III-IV Criteria Size (N) 193 Results 3-yr PFS: imprved in chemtherapy arm (69% vs 24%, p<0.001) 3-yr OS: imprved in chemtherapy arm (78% vs 47%, p=0.005) Cnclusin Additin f chemtherapy t raditherapy significantly prlnged PFS and OS in patients with lcally advanced NPC

15 - Other Imprtant Published Data fr NPC: Cncurrent chemraditherapy plus adjuvant chemtherapy versus cncurrent chemraditherapy alne in patients with lcreginally advanced naspharyngeal carcinma: a phase 3 multicentre randmised cntrlled trial. Chen et al. Lancet Oncl Methds: Phase III RCT f cncurrent radiatin (66Gy/33#) plus weekly cisplatin (40mg/m2) with r withut adjuvant cisplatin (80mg/m2 d1) and 5-FU (800mg/m2/d d1-4) q4w x 3 cycles Primary end-pint was failure-free survival Results 508 patients enrlled N difference in 2-yr failure-free survival (86% vs 84%, p=0.13) N difference in txicity Bttm-line N benefit f adding adjuvant cisplatin and 5-FU t CRT fr lcally advanced NPC Nte Early results published, final results are pending Chemtherapy and raditherapy in naspharyngeal carcinma: an update f the MAC-NPC meta-analysis. Blanchard et al. Lancet Onclgy Methds: Individual patient data frm trials cmparing treatment f radiatin with r withut chemtherapy fr lcally advanced NPC, updated frm 2006 meta-analysis. Included interactin testing fr different schedules f chemtherapy Results 19 trials with 4806 individual patients included Pled HR fr death 0.79 (95%CI , p<0.0001) Abslute 5-yr OS benefit f chemtherapy is 6.3% Cncurrent chemtherapy with r withut adjuvant chemtherapy is better than adjuvant alne r inductin alne (p=0.01) Bttm-line Cncurrent chemradiatin significantly imprves OS, PFS and lcal cntrl in patients with lcally advanced NPC. Additin f adjuvant chemtherapy t chemradiatin f unclear benefit, nn-significant trend twards imprvement with adjuvant chemtherapy. Minimal r n benefit with inductin chemtherapy r adjuvant chemtherapy alne SUPPORTIVE MEASURES Refer t supprtive measures fr HNSCC METASTATIC - Bttm Line General Apprach: Cnsider salvage surgery r radiatin N randmized evidence, cnsider clinical trial Cisplatin and gemcitabine typically given as first-line, ne pssible regimen is: Cisplatin 70mg/m2 d1 and gemcitabine 1000mg/m2 d1 and 8 q21d Other first-line regimens: carbplatin and gemcitabine, cisplatin and 5-FU, cisplatin and paclitaxel, weekly cisplatin, capecitabine Immuntherapy trials nging - Prgnsis: 5-yr OS 20% - Other Imprtant Published Data fr NPC:

16 Cmparisn f five cisplatin-based regimens frequently used as the first-line prtcls in metastatic naspharyngeal carcinma. Jin et al. J Cancer Res Clin Oncl Methds: Retrspective review f 822 patients with metastatic r recurrent NPC Results Five cmmn treatments: cisplatin plus gemcitabine, cisplatin plus 5-FU, cisplatin plus paclitaxel, cisplatin plus paclitaxel plus 5-FU and cisplatin plus 5-FU plus blemycin. Highest RR with cis-gem (71.1%), statistically significant ver cis-5-fu (60.2%), p= N difference in PFS r OS. Mre txicity with three-drug regimens. Bttm-line Cis-gem, cis-5-fu and cis-paclitaxel are all active regimens fr metastatic NPC N benefit fr three drugs ver tw. D) REFERENCES 1. Canadian Cancer Sciety. Canadian Cancer Statistics 2015: Special tpic: Predictins f the future burden f cancer in Canada. 2015; 2. Frte T, Niu J, Lckwd GA, Bryant HE. Incidence trends in head and neck cancers and human papillmavirus (HPV)-assciated rpharyngeal cancer in Canada, Cancer Causes Cntrl Aug;23(8): Gilbert R, Winquist E, Waldrn J, Mcquestin M. The Management f Head and Neck Cancer in Ontari :Organizatinal and Clinical Practice Guideline Recmmendatins Kristina R. Dahlstrm, Garden AS, William N et al. Prpsed Staging System fr Patients With HPV-Related Orpharyngeal Cancer Based n Naspharyngeal Cancer N Categries. J Clin Oncl 34: Adelstein DJ, Li Y, Adams GL, Wagner H, Kish J a, Ensley JF, et al. An intergrup phase III cmparisn f standard radiatin therapy and tw schedules f cncurrent chemraditherapy in patients with unresectable squamus cell head and neck cancer. J Clin Oncl. 2003;21(1): Bnner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Chen RB, et al. Raditherapy plus Cetuximab fr Squamus-Cell Carcinma f the Head and Neck. N Engl J Med Feb 9;354(6): O Sullivan B, Huang SH, Siu LL, Waldrn J, Zha H, Perez-Ordnez B, et al. Deintensificatin candidate subgrups in human papillmavirus-related rpharyngeal cancer accrding t minimal risk f distant metastasis. J Clin Oncl Feb 10;31(5): Bernier J, Cper JS, Pajak TF, van Glabbeke M, Burhis J, Frastiere A, et al. Defining risk levels in lcally advanced head and neck cancers: a cmparative analysis f cncurrent pstperative radiatin plus chemtherapy trials f the EORTC (#22931) and RTOG (# 9501). Head Neck Oct;27(10): Ang KK, Harris J, Wheeler R, Weber R, Rsenthal DI, Nguyen-Tân PF, et al. Human papillmavirus and survival f patients with rpharyngeal cancer. N Engl J Med Jul 1;363(1): Bernier J, Dmenge C, Ozsahin M, Matuszewska K, Lefèbvre J-L, Greiner RH, et al. Pstperative irradiatin with r withut cncmitant chemtherapy fr lcally advanced head and neck cancer. N Engl J Med. 2004;350(19): Cper JS, Pajak TF, Frastiere AA, Jacbs J, Campbell BH, Saxman SB, et al. Pstperative cncurrent raditherapy and chemtherapy fr high-risk squamus-cell carcinma f the head and neck. N Engl J Med May 6;350(19): Cper JS, Zhang Q, Pajak TF, Frastiere AA, Jacbs J, Saxman SB, et al. Lng-term fllw-up f the RTOG 9501/intergrup phase III trial: pstperative cncurrent radiatin therapy and chemtherapy in high-risk squamus cell carcinma f the head and neck. Int J Radiat Oncl Bil Phys Dec 1;84(5): Vermrken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rttey S, et al. Platinum-based

17 chemtherapy plus cetuximab in head and neck cancer. N Engl J Med Sep 11;359(11): Vermrken JB, Stöhlmacher-Williams J, Davidenk I, Licitra L, Winquist E, Villanueva C, et al. Cisplatin and flururacil with r withut panitumumab in patients with recurrent r metastatic squamus-cell carcinma f the head and neck (SPECTRUM): an pen-label phase 3 randmised trial. Lancet Oncl Jul;14(8): Thephamngkhl K, Brwman G, Hdsn I, Oliver T, Zuraw L. A Quality Initiative f the Prgram in Evidence-based Care (PEBC), Cancer Care Ontari (CCO) Naspharyngeal Cancer