Multimodular treatment in Head and Neck Squamous Cell Carcinoma (HNSCC)

Multimodular treatment in Head and Neck Squamous Cell Carcinoma (HNSCC) Amanda Psyrri, MD,FACP Attikon University Hospital Athens, Greece

Learning objectives After reading and reviewing this material, the participant should be able to: Evaluate the role of induction, definitive concurrent chemotherapy and sequential therapy in locally advanced HNSCC Describe organ preservation strategies Discuss the common indications for postoperative chemoradiation Define the role of bioradiotherapy with cetuximab Understand HPV-associated oropharyngeal cancers

Outline Introduction Concurrent chemoradiotherapy Induction chemotherapy Sequential therapy Bioradiotherapy with cetuximab HPV-associated oropharyngeal cancers Surgical management of the neck

Many subsites Heterogeneous group of tumours of varying primary sites 95% are HNSCC Oral cavity Oropharynx/hypopharynx Larynx Nasopharynx Other anatomic sites Paranasal sinuses Salivary glands Lip Image courtesy of Massachusetts General Hospital Cancer Center

Etiology Traditionally, tobacco and alcohol use account for the majority of HNSCC A growing proportion of oropharyngeal squamous cell carcinomas is caused by high-risk Human Papillomaviruses (HPV), especially HPV16

Incidence in the USA In 2015, 45,780 new cases of oral cavity and pharynx cancer and 8,650 deaths are expected to occur in the United States Oral cavity and pharynx Stage distribution by race United States 2004 2010 5-year relative survival rates by race and stage United States 2004 2010 100 80 60 40 20 31 32 20 47 47 49 18 16 27 All races White Black 100 80 60 40 20 83 83 77 61 62 42 37 38 24 63 64 44 0 Localised Regional Distant 0 Localised Regional Distant All stages Redrawn from Siegel MPH, et al. CA Cancer J Clin 2015;65:5 29

Incidence and Mortality Worldwide WHO Europe region (adults) 15 th most common cancer in Europe 1 Estimated numbers (x100) Lip and oral cavity cancer in Europe (2012): 61,400 new cases diagnosed (2% total) ~34,100 cases of other pharyngeal cancer diagnosed (1% total cancer cases) 1 Highest World age-standardised incidence rates in Hungary (both men and women); lowest rates in Greece for men and Cyprus for women Worldwide (2012): >142,000 cases of other pharyngeal cancer diagnosed (1% total cancer cases) Lip and oral cavity cancer incidence rates highest in Melanesia and lowest in Western Africa, partly reflecting varying data quality worldwide Incidence rates of other pharyngeal cancer highest in Western Europe and lowest in Western Africa 1 1. Ferlay J, et al. GLOBOCAN 2012 v1.0. Available from: http://globocan.iarc.fr, accessed December 2013 2. Ferlay J, et al. Eur J Cancer 2013;49:1374 1403

Epidemic of HPV-associated OPC* Incidence rates for overall oropharyngeal cancer, HPV-positive oropharyngeal cancer, and HPV-negative oropharyngeal cancer from 1988 to 2004 in Hawaii, Iowa, and Los Angeles Estimated age-standardised incidence of human papillomavirus (HPV)-positive and HPV-negative tonsillar cancer squamous cell carcinoma cases per 100,000 person-years, Stockholm, Sweden, 1970-2006 Chaturvedi AK, et al. J Clin Oncol 2011;29:4294 301. Reprinted with permission. 2011 American Society of Clinical Oncology. All rights reserved Error bars indicate 95% CI. Näsman A, et al. Int J Cancer 2009;125:362 6. Reproduced with permission from Wiley

Staging overview Stage TNM Stage 0 T is N 0 M 0 Stage I T 1 N 0 M 0 Stage II T 2 N 0 M 0 Stage III T 3 N 0, T 1-3 N 1, M 0 Stage IVA T 4a N 0-2,M 0, T 1-3 N 2,M 0 Stage IVB Stage IVC T and N stages vary by anatomic site N2 or T4 tumours locoregionally advanced (Stage IV) Typically T1: 2 cm, T2: 2-4 cm, T3: 4 cm, T4: invades adj. structures N1: single LN 3 cm, N2: LN 2 cm or several LN, N3: >6 cm TNM: tumour nodes metastases Any T, N 3, M 0, T 4b, Any N, M 0 M 1, any T or N Patel SG, et al. CA Cancer J Clin 2005;55;242-258

Meta-analysis of chemotherapy in HNC (MACH-NC) 63 randomised trials (1965-1993) n = 10,717 pts with SCC of the oropharynx, oral cavity, larynx, or hypopharynx Comparison of locoregional treatment with and without chemotherapy Median follow-up: 6 years Overall benefit 4% at 5 years (32% vs. 36%) Trials N RR P value Absolute benefit (5 Yrs), % Adjuvant 8 1854 0.98 NS 1 Induction 31 5245 0.95 NS 2 Concomitant 26 3727 0.81 < 0.0001 8 HNC, head and neck cancer; MACH-NC, meta-analysis of chemotherapy in head and neck cancer; SCC, squamous cell carcinoma; ORR, overall risk reduction; RR, relative risk. Pignon JP, et al. Lancet 2000;355:949-955

MACH-NC: An Update 24 added trials 87 studies, 16,485 patients MACH-HN I: 8% absolute benefit concurrent-no significant effect of IC No significant difference (p = 0.19) was seen between mono-chemotherapy (HR 0.84) and poly-chemotherapy (HR 0.78) In the mono-chemotherapy group, the effect of chemotherapy was significantly higher (p = 0.006) with platin than with other types of mono-chemotherapies Age matters Younger than 50 years of age: 24% increased survival Older than 70 years of age: 3% increased survival MACH-NC, meta-analysis of chemotherapy in head and neck cancer; IC: induction chemotherapy Pignon JP, et al. Radiother Oncol 2009;92:4-14

Pluses and minuses of chemoradiation Improves locoregional control Facilitates organ preservation Beneficial impact on survival Doubles the rate of severe acute mucositis Use may be excessive based on stage Long-term functional deficits in speech, swallowing, mobility

Randomised trials of induction PF ± taxane Study Eligibility N T + PF CR/PR, n/n (%) PF CR/PR, n/n (%) TPF/PF PFS, Mos TPF/PF OS, Mos P Value (HR) Hitt JCO 2005 Stage III-IV 38 2 33/47 (80) 14/54 (68) 20 12 43 37 2 yrs: 66%/61%.035 (0.67) TAX 323 NEJM 2007 Unresectable 35 8 (68) (54) 11 8 18.6 14.2 3 yrs: 24%/18%.005 (0.71) Gortec ASCO 2006 L/HP II-IV 20 5 43/39 (82) 30/30 (60) LP: 63%/41%.036 TAX 324 NEJM 2007 III-IV 50 1 17/55 (72) 15/49 (64) 2-yr PFS: 53%/42% 70 30 3 yrs: 62%/48%.006 (0.7) CR, complete response; HP, hypopharynx; HR, hazard ratio; L, larynx; LP, larynx preservation; OS, overall survival; PF, cisplatin, 5-fluorouracil; PFS, progression-free survival; PR, partial response; T, docetaxel; TPF, docetaxel, cisplatin, 5-fluorouracil.

Randomised trials of sequential therapy*: Definitive chemo RT ± induction Trial Eligibility Target N* Control Tx Exp Tx OS DeCIDE U Chicago N2-3 400 285 DHFX TPF x 2 DHFX NS Paradigm DFCI Stages III-IV 300 145 Cisplatin CB-RT TPF x 3 Carbo-RT or D-CB-RT NS SWOG Oropharynx 400 Cisplatin RT TPF x 1-3 surgery or cisplatin-rt Carbo, carboplatin; CB, concomitant boost; chemort, chemoradiation therapy; DFCI, Dana-Farber Cancer Institute; RT, radiation therapy; TPF, docetaxel, cisplatin, 5-fluorouracil. DHFX, docetaxel, fluorouracil, and hydroxyurea *All powered to show survival difference of 10% to 15%.

EGFR as a molecular target in HNSCC EGFR expression linked to poorer outcome 1 and reduced response to radiotherapy 2,3 Psyrri A, Presented at ASCO 2013 Lecture: EGFR, new data and best use of inhibitors (adapted from http://www.slideshare.net/melodyhsiao/scchn-cancer-report 1. Psyrri A, et al. Clin Can Res 2005;11:5856-62; 2. Baumann M, Krause M. Radiother Oncol 2004;72:257 266; 3.Ang KK, et al. Cancer Res 2002;62:7350 7356

Cetuximab Cetuximab IgG 1 mab Chimeric protein Specifically binds with high affinity to FcγRI (EC50 = 0.13 nm) and FcγRIIIa (EC50 = 6 nm) Induces apoptosis and ADCC* Preclinical synergistic activity in combination with chemotherapy and radiotherapy *ADCC: antibody dependent cellular cytotoxicity EGFR, epidermal growth factor receptor; mab Li S, et al. Cancer Cell 2005;7:301 311 Figure courtesy of Psyrri A. Presented at ASCO 2013; adapted from Vermorken JB, MCO 2011; ESO-ESMO Masterclass in Clinical Oncology www.slideshare.net

Phase III Study Design Eligibility Patients with locoregionally advanced squamous cell carcinoma of either the oropharynx, hypopharynx, or larynx Stratified by Karnofsky score: 90-100 vs. 60-80 Regional nodes: Negative vs. positive Tumour stage: AJCC T1-3 vs. T4 RT fractionation: Concomitant boost vs. once daily vs. twice daily R A N D O M I S E Arm 1 (RT) Radiation therapy Primary endpoints: Overall survival, locoregional control Arm 2 (RT + C) Radiation therapy + cetuximab wkly Bonner JA, et al. N Engl J Med 2006;354:567-578

Most common adverse events Toxicity, % RT (n = 212) RT + C (n = 208) All Grades Grades 3/4 All Grades Grades 3/4 Skin reaction 91 18 97 34 Mucositis/stomatitis 93 52 91 54 Dysphagia 63 30 64 25 Xerostomia 70 3 64 4 Fatigue/malaise 50 5 52 4 Infusion reaction* -- 14 3 *Listed for its relationship to cetuximab; P < 0.05; P < 0.001, Fisher s exact test. Bonner JA, et al. N Engl J Med 2006;354:567-578

Probability of overall survival ERBITUX + RT: Overall survival 5 year update ERBITUX + RT improves significantly long term survival, with nearly half of the patients alive at 5 years 1.0 0.9 0.8 0.7 0.6 0.5 0.4 ERBITUX + RT RT p-value 5-year OS rate 46% 36% 0.02 ERBITUX + RT 0.3 0.2 0.1 HR=0.73 (0.56 0.95) p = 0.02 RT 0.0 0 10 20 30 40 50 60 70 Months Treatment Total Dead Alive Median Erbitux + RT 211 110 101 49.0 RT 213 130 83 29.3 Bonner JA, et al. Lancet Oncol 2010;1:21 28. Reprinted from The Lancet, Copyright (2010). With permission from Elsevier

RTOG 9111: Larynx Preservation Trial Phase III larynx preservation trial: induction chemotherapy and radiation therapy vs. concomitant chemotherapy and radiation therapy vs. radiation therapy alone S T R A T I F Y Location 1. Glottic 2. Supraglottic T Stage 1. T2 2. T3, fixed cord 3. T3, no cord fixation 4. T4, with base of tongue 1 cm N Stage 1. N0, N1 2. N2, N3 R A N D O M I S E Arm 1: Arm 2: Arm 3: CR, PR x 3 d cycle RT CDDP/5-FU x 2 cycles NR surgery RT Radiation therapy + CDDP Radiation therapy Chemotherapy Arm 1: cisplatin 100 mg/m 2 /5-FU 1 gm/m 2 /24 hrs CVI x 120 o q3wks x 3 Arm 2: cisplatin 100 mg/m 2 Days 1, 22, 43 of RT Forastiere AA, et al. N Engl J Med 2003;349:2091-2098

RTOG 9111: Larynx Preservation Trial The median follow-up among surviving patients, 3.8 years Demographics: median age 59 years; 94% KPS 80; 50% N0; 68% SGL; 28% N2-3 Arm cddp/5-fu RT RT/cDDP RT Enrolled, n (evaluable) 180 (173) 182 (172) 185 (173) 2-yr laryngectomy FS, % 59 66 53 5-yr DMFS, % 85 88 78 5-yr DFS, % 38 36 27 5-yr OS,% 55 54 56 Conclusions RT/cDDP: stat signif in LFS (P = 0.01) No SS diff in survival 5-FU, 5-fluorouracil; cddp, cisplatin; DFS, disease-free survival; DMFS, distant metastasis-free survival; FS, free survival; KPS, Karnofsky performance score; LFS, laryngectomy-free survival; OS, overall survival; RT, radiation therapy; SGL, supraglottal larynx; SS, statistically significant. Forastiere AA, et al. N Engl J Med 2003;349:2091-2098

(A) Laryngeal preservation, (B) laryngectomy-free survival, (C) overall survival, and (D) locoregional control according to treatment group; conc., concomitant; ind., induction; RT, radiation therapy P<0.001 P=0.02 P=0.53 P=0.0015 Forastiere AA, et al. J Clin Oncol 2013;31:845-852. Reprinted with permission. 2013 American Society of Clinical Oncology. All rights reserved

Survival, limited to (A) deaths from study cancer and (B) deaths not caused by study cancer according to treatment group; conc., concomitant; ind., induction; RT, radiation therapy P=0.03 Forastiere AA, et al. J Clin Oncol 2013;31:845-852. Reprinted with permission. 2013 American Society of Clinical Oncology. All rights reserved

Nonsurgical treatment options for locally advanced HNSCC 5-FU, 5-fluorouracil; CI, confidence interval; HR, hazard ratio; RT, radiation therapy; SCCHN, squamous cell carcinoma of the head and neck; TPF, docetaxel, cisplatin, 5-fluorouracil; Ctx: chemotherapy 1. Pignon JP, et al. Lancet 2000;355:949-955; 2. Bonner JA, et al. Lancet Oncol 2009;11:21-8; 3. Vermorken JB, et al. N Engl J Med. 2007;357:1695-1704; 4. Posner MR, et al. N Engl J Med 2007;357:1705-1715.

Adjuvant Trials: HNSCC RT ± CT (DDP) Trial RT (Gy) F/U, mos LRC, % DFS, % OS, % RTOG 9501 [1] 2 LN, ECE, + margins n = 459 (60-66) 46 81 vs. 70 (P = 0.01) 33 vs. 25 (P = 0.04) 45 vs. 38 (P = 0.19) EORTC 22931 [2] N2-3, ECE, + margins n = 350 (66) 60 82 vs. 69 (P = 0.007) 47 vs. 36 (P = 0.04) 53 vs. 40 (P = 0.002) Bachaud [3] + ECE n = 83 (> 60) 60 70 vs. 55 (P = 0.05) 45 vs. 23 (P < 0.02) 36 vs. 13 (P < 0.01) DDP, cisplatin; CT, chemotherapy; DFS, disease-free survival; ECE, extracapsular extension; F/U, follow-up; LN, lymph node; LRC, locoregional control; OS, overall survival; RT, radiation therapy; HNSSC, head and neck squamous cell carcinoma 1. Cooper JS, et al. N Engl J Med. 2004;350:1937-1944; 2. Bernier J, et al. N Engl J Med. 2004;350:1945-1952; 3. Bachaud JM, et al. Int J Radiat Oncol Biol Phys. 1991;20:243-246.

EORTC versus RTOG eligibility RTOG Stage III-IV OP, Ocw Level 4 or 5 pos. nodes Perineural Disease Vascular Embolisms Margins+ ECE 2+ pos. nodes EORTC Adapted from Bernier J, et al. Head and Neck Volume 27 Issue 5 Oct 2005

Refining adjuvant therapy Risk stratification Category Favourable Low Intermediate (ECE-/margin-) High (ECE+/margin+) Standard of care None 56-60 Gy 60-66 Gy 60-66 Gy + cisplatin Separate trials are currently designed for intermediate-risk and high-risk groups Cooper JS, et al. N Engl J Med 2004;350:1937-1944; Bernier J, et al. N Engl J Med 2004;350:1945-1952; Ang KK, et al. Int J Radiat Oncol Biol Phys 2001;51:571-578

Strategies to improve outcomes in HNSCC utilising EGFR inhibitors Treatment intensification of locally advanced HNSCC to improve OS Randomised trials: CRT+EGFR inhibitor versus CRT EGFR inhibition in the post-induction setting to reduce toxicity in sequential design Randomised phase II studies of induction chemotherapy followed by either chemoradiotherapy or cetuximab radiotherapy to reduce toxicity without compromising efficacy CRT: chemoradiotherapy; OS: overall survival

Randomised trials of EGFR inhibitor plus chemoradiation in HNSCC Author # pts Treatment Comparator Primary endpoint Setting S vs. E P value Giralt et al. 2012 150 C+EBRT+P C+ EBRT 2 yr LRC Locally advanced 68% vs. 61% 0.3 Martins et al. 2013 204 C+RT+ Erlotinib C+RT CRR Locally advanced 40% vs. 52% 0.08 Ang et al. 2011 895 C+RT+ cetuximab C+RT PFS Locally advanced 64% vs. 63% NS C: cisplatin; EBRT: external beam radiation therapy; RT: radiation therapy; S: standard, E: experimental arm; P: Panitumumab; CRR: complete response rate

EGFR inhibitor + chemoradiation: Toxicity Author Mucositis Toxicity Grade 3 Skin reactions Skin reactions out of field E S E S E S Ang 43% 33% 25% 15% 29% 1% Giralt 11% 5% 28% 13% 11% 0% Martins 48% 48% 13% 2% NR NR

The randomised Phase II Study: TREMPLIN Previously untreated SCC larynx/hypopharynx suitable for TL Primary endpoint: Larynx preservation 3 months after treatment Secondary endpoints: Larynx function preservation and survival 18 months after treatment PR 116 TPF (153 patients) 3 cycles, 1 cycle q3w T = 75 mg/m² on day 1 P = 75 mg/m² on day 1 F = 750 mg/m² on day 1 to 5 < PR 23 R Total laryngectomy + post-op RT 60 patients: RT 70 Gy Cisplatin 100 mg/m² on days 1, 22 and 43 56 patients: RT 70 Gy ERBITUX 400 mg/m² 1 wk prior to RT then 250 mg/m² weekly on wks 1 to 7 P: cisplatin; F: 5-fluorouracil; T: docetaxel; TL: total laryngectomy; PR: partial response ; RT: radiotherapy; CT: computed tomography; Tx: treatment Lefebvre JL, et al. J Clin Oncol 2013;31:853-859

Acute toxicity during RT Grade 3 mucositis Grade 4 mucositis Grade 3 in field skin toxicity Grade 4 in field skin toxicity Other toxicities, any grade, justifying a protocol modification Renal toxicity Hematological toxicity Poor general condition Infusion-related reaction Protocol modification due to acute toxicity Cisplatin n = 58 25 (43%) 2 14 (24%) 1 9 (15.5%) 8 (14.0%) 7 (12.0%) 0 ERBITUX n = 56 24 (43%) 1 29 (52%) 3 0 0 1 (1.7%) 3 (5.0%) p-value NS < 0.001 33 (57%) 19 (29%) 0.02 *2 patients did not start the treatment in the cisplatin arm Lefebvre JL, et al. J Clin Oncol 2013;31:853-859

Carcinologic events (ITT) Total of local (+/- regional) failures Feasible salvage total laryngectomy Successful salvage total laryngectomy At 18 months after end of treatment Last evaluation with a median follow-up of 36 months Cisplatin ERBITUX p-value Cisplatin ERBITUX p-value 5 (8.3%) 8 (14.3%) Log-rank: 0.30 7 (11.7%) 0/4* 7/8 0.01 1/6* 12 (21.4%) 9/12 (1 refused) 0/1 7/8 Log-rank: 0.14 Ultimate local failure rate 6 (10%)* 5 (8.9%) NS Regional failure alone 5 (8.3%) 5 (8.9%) NS 5 (8.3%) 5 (8.9%) NS Distant metastases 2 (3.3%) 2 (3.6%) NS Second primary tumour 3 (5.0%) 3 (5.3%) NS 0.04 *Data missing for 1 patient lost to follow-up at 5 months ITT: intention to treat Lefebvre JL, et al. J Clin Oncol 2013;31:853-859

Endpoints (ITT) Primary endpoint (3 months after end of Tx) Larynx preservation, n (%) (larynx in place without tumour) Cisplatin n = 60 ERBITUX n = 56 p-value 57 (95%) 52 (93%) 0.63 Secondary endpoints (18 months after end of Tx) Larynx function preservation, n (%) (larynx in place without tumour/trach/feeding tube) NB: At 18 months or at death Overall survival NB: Since randomisation Cisplatin n = 60 ERBITUX n = 56 p-value 52 (87%) 46 (82%) 0.68 92 % 89 % Log-rank: 0.44 NB: 1 pt lost to FU in the Cisplatin arm is considered as failure Lefebvre JL, et al. J Clin Oncol 2013;31:853-859

With permission of Maria Ghi, et al. ASCO 2012, abstract 5513 A phase II/III study comparing CRT to cetuximab/rt with or without induction TPF in locally advanced HNSCC

Skin rash any grade Grade 3-4 Nausea any grade Grade 3-4 Vomiting any grade Grade 3-4 Renal any grade Grade 3-4 Neurological any grade Grade 3-4 Neutropenia Grade 3-4 CT/RT (n=215)% 5 1 23 0 11 0 3 0 4 1 5 3 RT/cetuximab (n=133)% 55 8 10 0 7 0 0 0 2 1 2 1 p value <0.01 <0.01 <0.01 0.22 0.05 0.33 0.58 0.08 0.19 Febrile neutropenia 4 0 0.04 Mucositis any grade Grade 3 Grade 4 In-field skin toxicity any grade Grade 3 Grade 4 Maria Ghi, et al. ASCO 2012, abstract 5513 78 37 4 59 13 1 76 35 2 69 20 1 0.63 0.79 0.45 0.05 0.07 0.58

Oropharyngeal cancer disease variants: tobacco-related, HPV-related and mixed HPV+,p16+ p16- Weinberger PM, et al. J Clin Oncol 2006;24:736 47. Reprinted with permission. 2006 American Society of Clinical Oncology. All rights reserved Forastiere A, et al. N Engl J Med 2001;345:1890-1900; Koontongkaew S. J Cancer 2013;4:66-83. Available from http://www.jcancer.org/v04p0066.htm. CC BY-NC-ND 3.0

HPV and survival The relative survival for HPV positive patient is independent of therapy as long as this therapy is within the current standard of care Risk of death is consistently less than 60% that of HPV negative cancers across studies The absolute survival difference is consistently higher than 30%

Oropharynx: Classification of patients into risk-of-death categories Oropharyngeal cancer (n=266) HPV-positive (n=178) HPV-negative (n=88) 10 pack-years (n=88) >10 pack-years (n=90) 10 pack-years (n=23) >10 pack-years (n=65) N0-N2a (n=26) N2b-N3 (n=64) T2-T3 (n=15) T4 (n=8) 42.9% at low risk 3 year OS = 93.0% 29.7% at intermediate risk 3 year OS = 70.8% 27.4% at high risk 3 year OS = 46.2% Adapted from: Ang KK, et al. N Engl J Med 2010;363:24 35

Prognostic Grouping Model of HPV(+) OPC M1 disease considered Group IVB Too few cases to analyse; policies too varied Huang SH, et al. J Clin Oncol 2015;33:836 45. Reprinted with permission. 2015 American Society of Clinical Oncology. All rights reserved.

Treatment deintensification Aims to reduce treatment-related morbidity and improve patient quality of life without compromising treatment effectiveness Patients with HPV+ OPSCC are younger and expected to live long; therefore, morbidity resulting from late toxicity is a concern in these patients Deintensification strategies include: administering radiotherapy alone, reducing the dose of radiotherapy and substituting chemotherapy with cetuximab

Radiation therapy oncology group 1016 : Study Design Stage III/IV Oropharynx p16+ R A N D O M I S E II: Accelerated IMRT 70 Gy/6 weeks (cetuximabx8) I: Accelerated IMRT 70 Gy/6 weeks (cisplatin 100 mg/m², d1, 22) Stratification factors: cn-stage (cn0-2a vs. cn2b- cn3), ct-stage (T1-2 vs.t3-4) Zuprod Performance Status (0 vs. 1), smoking history (<10py vs. >10py) Cmelak A, et al. ASCO 2014

ECOG 1308: Phase II Schema Eligibility OPSCC resectable HPV ISH + and / or p16+ Stage III, IVA Induction chemotherapy Cisplatin 75/m 2 d1 Paclitaxel 90/m 2 d1, 8, 15 Cetuximab 250/m 2 d1, 8, 15 Q 21 days for 3 cycles R E S P O N S E E V A L U A T I O N Concurrent chemoradiation CLINICAL CR Low dose IMRT 54 Gy / 27 fx* + Cetuximab qweek CLINICAL PR/SD Full dose IMRT 69.3 Gy / 33 fx* + Cetuximab qweek IMRT margins for primary: 1.0 to 1.5 cm around gross disease Nodal margin: 1 cm margin minimum, treat entire nodal level Primary Objective: 2-year PFS after low-dose IMRT (stat aim: 2-year 85% or better) IMRT: intensity modulated radiation therapy Cmelak A, et al. ASCO 2014

Endpoint: 2yr PFS and OS Cohort (n) 2 year PFS (90% CI) 2 year OS (90% CI) All low dose pts (62) 0.80 (0.70, 0.88) 0.93 (0.85, 0.97) T4a (7) 0.54 (0.19, 0.79) 0.86 (0.45, 0.97) Non-T4a (55) 0.84 (0.73, 0.91) 0.94 (0.86, 0.98) N2c (19) 0.77 (0.56, 0.89) 0.95 (0.76, 0.99) Non-N2c (43) 0.82 (0.69, 0.90) 0.93 (0.82, 0.97) Smoker >10 pk-yrs (22) 0.57 (0.35, 0.73) 0.86 (0.67, 0.94) Smoker 10 pk-yrs (40) 0.92 (0.81, 0.97) 0.97 (0.87, 0.995) Smoker 10 pk-yrs, <T4, N2c (27) 0.96 (0.82, 0.99) 0.96 (0.82, 0.99) All high-dose pts (15)* 0.65 (0.41, 0.82) 0.87 (0.63. 0.96) *3 high-dose pts did not go on to receive RT Cmelak A, et al. ASCO 2014

Neck dissection Always: Patients who have any clinically apparent residual disease after chemoradiotherapy If surgical salvage is necessary for the primary tumour, a neck dissection may be required to access the primary or for donor vessels for free flap reconstruction Observation is acceptable if: No lymph node or lymph node <1 cm at CT/MRI and negative PET/CT after chemoradiotherapy

Conclusions Cisplatin chemoradiotherapy remains the standard of care for locally advanced (LA) HNSCC Cetuximab is approved with radiation for LA-HNSCC but no prospective comparison with cisplatin-rt has been performed TPF is the preferred induction regimen Sequential therapy is not superior to chemoradiotherapy alone HPV-positive patients constitute a separate prognostic and therapeutic cohort Deintensification trials for HPV-associated oropharyngeal cancers are ongoing

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