ASCO Highlights Head and Neck Cancer

ASCO Highlights Head and Neck Cancer Anne S. Tsao, M.D. Director, Mesothelioma Program Assistant Professor July 11, 2009 The University of Texas MD ANDERSON CANCER CENTER Department of Thoracic/Head & Neck Medical Oncology

Outline HPV Abstract 6001 HPV and tobacco Abstract 6002 HPV RTOG0129 Abstract 6004 HPV/p16 phase III EGFR Biomarkers Abstract 6005 EXTREME / EGFR FISH Abstract 6000 Mass Spectrometry ChemoXRT Abstract 6007 Darbepoetin alpha Neoadjuvant Abstract 6009 Phase III CRT vs neoadjuvant chemo-crt (PF, TPF) Thyroid Abstract 6003 Phase II Braf mutations and sorafenib

Abstract 6001: tobacco and HPV outcomes UMMC 0221 UMMC 9921 Retrospective review of tumor tissue from 124 pts with stage III/IV oropharynx cancer from 2 phase II chemoxrt trials. Objectives: 1) Evaluate association of HPV status and long-term outcomes 2) Evaluate effect of tobacco use on long-term outcomes in HPV positive patients Worden et al. Abstract #6001, ASCO 2009

Worden et al. Abstract #6001, ASCO 2009 Definitions HPV analysis: pre-treatment biopsies tested for HPV DNA by multiplex pcr/mass spect analysis (detects 15 subtypes) (Sequenome) Smoking status: determined by chart review and self-reporting Never tobacco: < 100 cigarettes per lifetime, never used any chewing tobacco/cigars/pipes Current smoker: present, including those who quit < 1 year prior to diagnosis Former smoker: Quit > 1 year prior to diagnosis

Patient characteristics Characteristic N=124 Male 83% Age 57 HPV (+) 82% HPV (+) never tobacco 27% HPV (+) any tobacco 56% HPV (-) never tobacco 0% HPV (-) any tobacco 18% Primary oropharynx site: BOT Tonsil other Stage III Stage IVA Stage IVB 50% 46% 4% 14% 74% 12% Tobacco status HPV (+) HPV (-) N=102 N=22 Never (n=33) 32% 0% Former (n=52) 45% 28% Current (n=39) 23% 72% Worden et al. Abstract #6001, ASCO 2009

Worden et al. Abstract #6001, ASCO 2009 DFS by HPV status and Treatment Efficacy by HPV status OS by HPV status and Treatment TTR by HPV status and Treatment HPV (+) status leads to improved DFS, OS, and time to disease recurrence regardless of treatment.

Worden et al. Abstract #6001, ASCO 2009 HPV status by tobacco usage Time to recurrence In HPV (+) pts by tobacco usage Risk of recurrence in HPV (+) patients HR P-value Current vs never 5.2 0.038 Former vs never 2.9 0.18 Current vs Former 1.8 0.24 P=0.063 for overall effect of tobacco Smoking while HPV (+) leads to a worse time to recurrence.

Worden et al. Abstract #6001, ASCO 2009 Disease specific survival (DSS) Disease specific survival by tobacco usage DSS in HPV (+) pts HR P-value Current vs never 7.2 0.07 Former vs never 3.6 0.24 Current vs Former 1.99 0.22 P=0.064 for overall effect of tobacco Smoking while HPV (+) leads to a worse DSS.

Worden et al. Abstract #6001, ASCO 2009 Summary Abstract 6001 In this retrospective analysis, HPV (+) tumors have better OS and DSS and less risk of recurrence than HPV (-) tumors. Patients with HPV (+) disease and current tobacco users have an increased risk of disease recurrence compared to HPV (+) never tobacco users.

Gillison et al. Abstract #6003, ASCO 2009 Abstract #3 Survival outcomes by HPV status in oropharynx cancer patients in RTOG 0129 Lab methodology: HPV 16 in situ hybridization (ISH) HPV 16 negative wide spectrum ISH (HPV18, 31, 33, 35, 39, 45, 52, 56. 59, 68) P16 IHC Primary endpoint: Correlate HPV to OS, PFS

Gillison et al. Abstract #6003, ASCO 2009 Baseline Lab analysis 323 patients had oropharynx primary and HPV determination 206 (64%) were HPV-positive, 96% of which were HPV-16 P16 positive P16 negative HPV positive 192 (96%) 7 (4%) HPV negative 22 (19%) 94 (81%) Characteristic HPV + HPV - P-value Treatment 51.5% 50.4% 0.86 Age 53.5 57 0.02 Caucasian 92.2% 75.2% <0.001 PS 68.4% 56.4% 0.03 Stage IV 87.9% 83.8% 0.3 T stage 75.2% 60.7% 0.008 N stage 30.1% 38.5% 0.14 Pack years < 20 51% 22.2% <0.001

Overall Survival by HPV Status Variable at 2 years HPV + HPV - P-value OS rate 87.9% 65.8% <0.001 PFS rate 71.8% 50.4% <0.001 Local-regional control 13.6% 24.8% 0.004 Distant mets 9.7% 12.9% 0.26 Second primary 3.9% 11.1% 0.01 Aerodigestive SPT 2.9% 7.7% 0.04 Gillison et al. Abstract #6003, ASCO 2009

OS by HPV and Pack Years Gillison et al. Abstract #6003, ASCO 2009 OS HR 95% CI HPV +, < 20 pack years 1 - HPV +, > 20 pack years 1.91 1.2-3.05 HPV-, < 20 pack years 2.25 1.44-3.5 HPV-, > 20 pack years 4.3 2.3-7.71

Gillison et al. Abstract #6003, ASCO 2009 Survival outcomes by HPV or p16 status Overall Survival HR 95% CI HPV-positive tumor 0.44 0.29-0.69 p16 positive tumor 0.35 0.23-0.54 Progression-free survival HR 95% CI HPV-positive tumor 0.58 0.39-0.87 P16-positive tumor 0.46 0.31-0.68

Gillison et al. Abstract #6003, ASCO 2009 Summary Abstract #6003 Positive tumor HPV status predicts for improved OS and PFS in patients with oropharynx cancer, with less local-regional recurrence rates (but not distant recurrence). P16 IHC correlates with HPV tumor status and is a reasonable surrogate. Tobacco use modifies biological behavior of HPV positive tumors and leads to a worse outcome. Future trials in oropharyngeal HNSCC need to stratify patients by HPV status or p16 IHC.

Rischin et al. Abstract #6004, ASCO 2009 Abstract 6004 p16/hpv in phase III Retrospective review of tumor tissue from pts with stage III/IV oropharynx cancer from Phase III HeadSTART trial. HeadSTART showed no survival benefit to adding tirapazamine to cisplatin-xrt but major XRT violations were reported. Objectives: 1) Determine the prognostic significance of HPV and p16 in oropharyngeal patients from an international phase III trial

Rischin et al. Abstract #6004, ASCO 2009 Lab correlates HPV16/18 ISH (DAKO Genpoint Tyamide Signal Amplification System) using biotinylated probes for HPV16/18 p16 IHC (DAKO autostainer using p16 INK4a (Clone 16PO4) mouse monoclonal antibody. Nuclear and cytoplasmic staining intensity of tumor cells scored as grade 0-3 with grades 2-3 as positive.

Patient characteristics Characteristic HPV (+) HPV (-) P16 (+) P16 (-) n=55 N=140 N=108 N=78 Male 91% 83% 87% 81% Median Age 55 56 54 58 T stage 3-4 74% 75% 63% 84% N stage 2-3 87% 73% 86% 65% PS 0 76% 65% 79% 57% Current smoker 15% 37% 15% 45% HPV and p16 positive patients have higher N-stage, are less likely to be current smokers, and had an improved PS compared to HPV/p16 negative patients (p<0.05) Rischin et al. Abstract #6004, ASCO 2009

Rischin et al. Abstract #6004, ASCO 2009 Overall Survival by HPV status HPV positive patients had improved OS. HPV (-) patients who received TPZ had a slight improvement in OS when compared to HPV (-) patients who received cisplatin alone.

HPV and p16 Failure-free survival by p16 HPV (-) but p16 (+) found in 33% cases Possible explanation: -some cases may be due to other HPV subtypes. -lack of sensitivity of HPV ISH assay (PCR analysis underway) Rischin et al. Abstract #6004, ASCO 2009

LRF by HPV/p16 status Time to Locoregional failure by treatment HPV or p16 (+) pts had improved LRF. Patterns of Failure HPV or p16 (-) patients who received TPZ had an improvement in LRF when compared to HPV/p16 (-) patients who received cisplatin alone; suggesting a benefit to modifying hypoxia with tirapazamine in these patients. Rischin et al. Abstract #6004, ASCO 2009

Overall Survival multi-variate analysis Factor Overall survival HR P-value HPV (+) vs (-) 0.27 0.031 p16 (+) vs (-) 0.37 0.01 Stage III vs IV 0.34 0.28 PS 0 vs 1 0.57 0.12 Hgb high vs low 0.45 0.037 Rischin et al. Abstract #6004, ASCO 2009

Rischin et al. Abstract #6004, ASCO 2009 Summary Abstract 6004 HPV (+) oropharynx patients have an improved prognosis. p16 IHC may identify more patients than HPV ISH. Future trials need to stratify patients by HPV and p16 status The optimal treatment for HPV (+) patients is unknown but they should be treated differently than HPV (-) patients.

Metastatic or recurrent HNSCC excluding NP No prior chemo unless over 8 months prior for definitive therapy PS 0-2 Phase III EXTREME Trial Stratified by prior chemo, KPS (<80 vs > 80) Primary endpoint : OS R A N D O M I Z E Platinum 5-FU Maximum 6 chemo cycles No crossover allowed Platinum 5-FU Cetuximab Q3 weeks Cisplatin 100 mg/m 2 d1 or Carboplatin AUC 5 d1 5-FU 1000 mg/m 2 d1-4 Cetuximab Weekly Cetuximab loading dose 400 mg/m 2 IV times one followed by weekly infusions at 250 mg/m 2 Vermorken et al. NEJM 359:1116-1127, 2008

EXTREME Response Rate Vermorken et al. NEJM 359:1116-1127, 2008

EXTREME PFS Vermorken et al. NEJM 359:1116-1127, 2008

EXTREME Overall Survival platinum/5-fu/c225 platinum/5-fu Median OS 10.1 months 7.4 months HR 0.797 p=0.0362 Platinum/5-FU/C225 Platinum/5-FU Vermorken et al. NEJM 359:1116-1127, 2008

Summary EXTREME Trial Adding cetuximab to platinum/5-fu improved overall survival over platinum/5-fu in patients with metastatic HNSCC. This is the first systemic regimen in 25 years to show a benefit over platinum-based chemotherapy in HNSCC However, quality of life needs to be considered in these patients. There was more vomiting, infusion rxn, rash with cetuximab. Also, the optimal sequencing of agents remains unclear. Identifying a biomarker to predict for treatment response is critical for optimizing treatment. Vermorken et al. NEJM 359:1116-1127, 2008

Potential Ways of Assessing EGFR EGF Receptor (IHC) Gene Amplification (FISH) EGFR Mutation Downstream Signals / Events (eg, K-ras, B-raf, MAPKinase) Pao and Miller. JCO. 2005;23:2556-2568

Licitra et al. Abstract #6005, ASCO 2009 Abstract #6005 Biomarker potential of EGFR FISH in the phase III EXTREME study Retrospective analysis of FISH and cellular EGFR and CEP7 signals (Dakocytomation probe mix) 312 tumors of 442 patients evaluable (71% ITT) Baseline expression of EGFR and CEP7 were equal amongst the two arms

Colorado FISH+ definitions > 40% of cells displayed as > 4 EGFR counts or Gene amplification is present Presence of loose or tight EGFR gene clusters with > 4 copies EGFR gene to CEP7 ratio > 2 Or 15 copies of EGFR per cell in >10% of cells Licitra et al. Abstract #6005, ASCO 2009

EXTREME: Chemo + cetuximab patients Licitra et al. Abstract #6005, ASCO 2009 Colorado FISH status was not predictive for benefit to Cetuximab Did not influence OS, PFS, nor RR

Licitra et al. Abstract #6005, ASCO 2009 EXTREME: Chemo alone patients Colorado FISH status was not prognostic Did not influence OS, PFS, nor RR

FISH+ by Enrichment Model Licitra et al. Abstract #6005, ASCO 2009

Licitra et al. Abstract #6005, ASCO 2009 None of the Enrichment Models had correlation of FISH score with PFS Example Enrichment Model B and FISH Score Each star is a patient by PFS

None of the Enrichment Models had correlation of FISH score with OS Licitra et al. Abstract #6005, ASCO 2009 Example Enrichment Model B and FISH Score Each star is a patient by OS

Summary Abstract #6005 EGFR copy number by FISH was not predictive for response or survival to cetuximab-chemotherapy treatment. Additional studies for alternative biomarkers are needed: - K-ras mutations are negative predictors in colorectal cancer (CRYSTAL trial), but in HNSCC the incidence of K-ras mutations is < 3%. Also, HNSCC do not carry EGFR mutations. Other biomarkers are needed.

Abstract 6000: Mass spectrometry profiling after EGFR inhibitor therapy Chung et al. Abstract #6000, ASCO 2009; Taguchi et al JNCI, 2007 MALDI is a proteomic profiling tool in serum and plasma. In NSCLC, a signature was developed that predicted for OS after EGFR TKI therapy. This profile called VeriStrat R contains 8 distinguishing mass spectrometry peaks. Theory: MS profile is reflective of EGFR dependency of the tumor regardless of histology and may predict OS in HNSCC.

Population Evaluated Control Cohorts N=78 HNSCC surgery N=34 HNSCC from 2 phase II trials treated with docetaxel/bortezomib or docetaxel/irinotecan EGFR Treated Cohorts N=55 Phase II gefitinib 250 mg daily N=32 Phase II erlotinib 150 mg po daily and bevacizumab 15 mg/kg every 3 wks N=21 cetuximab 400 mg/m 2 LD then 250 mg/m 2 weekly Chung et al. Abstract #6000, ASCO 2009

Patient Demographics Characteristic Gefitinib N=55 Erlotinib Bev N=34 C225 N=21 Control surgery N=78 Control No EGFRI N=34 Median Age 58 58 53 62.1 57 Male 45 27 16 55 26 Caucasian 49 9 20 72 NR PS 0 13 17 NR NR 7 Smoker 31 24 12 NR 27 Best response CR 0 1 PR SD 0 20 4 20 NR NR NR PD 31 9 NE 4 0 Chung et al. Abstract #6000, ASCO 2009

MALDI MS classification Cohorts Gefitinib N=55 Erlotinib Bev N=34 C225 N=21 Control surgery N=78 Control No EGFRI N=34 Good 56% 75% 76% 99% 65% Poor 42% 19% 24% 1% 35% Undefined 2% 3% 0% 0% 0% Failed MS 0% 3% 0% 0% 0% Chung et al. Abstract #6000, ASCO 2009

Overall Survival MS Profile Chung et al. Abstract #6000, ASCO 2009

Summary Abstract #6000 Preliminary studies suggest that MALDI- MS (VeriStrat R ) has predictive ability for OS in HNSCC patients treated with EGFR inhibitors. This is consistent with the group s prior NSCLC data. Profile is predictive for both EGFR TKI and monoclonal antibody work. Chung et al. Abstract #6000, ASCO 2009

Abstract 6007 Overgaard et al. Abstract #6007, ASCO 2009

Abstract 6007 DAHANCA 10 HNSCC, no NP Hgb < 9 mmol/l (14.5 g/dl) within 10 days of Tx PS 0-2 Radiotherapy + Darbepoetin Alpha Primary endpoint: LRC Secondary endpoint: Local control, DFS, OS, Hgb levels, early/late morbidity, compliance Stats: 80% power to detect 12% increase in LRC (n=600); interim analysis after 150 events; Due to planned interim analysis, trial stopped in Oct 2006 with 522 pts. Overgaard et al. Abstract #6007, ASCO 2009

Darbepoetin alpha Effect during XRT Darbepoetin alpha SAE Darbepoetin (n=260) Control (n=262) Thrombo-embolic 3% 1% Other 3% 2% Overgaard et al. Abstract #6007, ASCO 2009

Efficacy Overgaard et al. Abstract #6007, ASCO 2009 LRC OS Darbepoetin alpha Darbepoetin Aranesp led to a worse LRC and OS results.

Overgaard et al. Abstract #6007, ASCO 2009 Efficacy: DFS, cancer/non-cancer related Deaths DFS Deaths from cancer Darbepoetin alpha Darbepoetin alpha Darbepoetin led to worse DFS and more deaths from cancer. There was no difference in non-cancer related deaths. Non-cancer Related deaths

Overgaard et al. Abstract #6007, ASCO 2009 Subgroup analysis LRC There was no subgroup that benefited from darbepoetin

Overgaard et al. Abstract #6007, ASCO 2009 Summary Abstract 6007 Darbepoetin alpha should not be used concurrently with XRT in HNSCC patients it leads to a worse outcome and poorer tumor control. The reason remains unknown at this time.

Induction Chemo HNSCC Trials Trial N Therapy Outcome TAX 323/EORTC 24971 NEJM 2007 TAX 324 NEJM 2007 Hitt, Madrid JCO 2005 GORTEC Calais 2006 358 TPF vs. PF 539 TPF vs. PF 382 Paclitaxel-PF vs. PF 220 TPF vs. PF OS benefit p=0.02 OS benefit P=0.006 OS benefit P=0.06 Larynx preservation 73% vs. 63% Paccagnella et al. ASCO 2008 abstract #6000: Induction chemo with chemoxrt versus chemoxrt alone.

ASCO 2009 Abstract 6009 Phase III Unresectable LAHNC No NP PS 0-1 Stage III or IV Neoadjuvant therapy x 3 Q3 wk Cisplatin 100 mg/m 2 day 1 5-FU 1000 mg/m 2 days 1-5 Cisplatin 75 mg/m 2 day 1 Docetaxel 75 mg/m 2 day 1 5-FU 750 mg/m 2 days 1-5 G-CSF primary prophylaxis ChemoXRT Cisplatin 100 mg/m 2 days 1, 22, 43 XRT to tumor 66-70 Gy once daily XRT to LN 60 Gy once daily Primary endpoint: TTF Secondary endpoint: LRC, TTP, OS, safety Stats: 80% power to detect 50% increase in median TTF Hitt et al. Abstract #6009, ASCO 2009

Patient Demographics Characteristics CRT PF + CRT (n=128) (n=156) TPF + CRT (n=155) Median age 56 57 58 Male 80% 93% 94% PS 0/1 26%/74% 31%/66% 29%/70% Primary tumor site Oropharynx 42% 43% 43% Hypopharynx 18% 18% 17% Larynx 20% 17% 19% Oral cavity 20% 22% 21% T4 stage 74% 80% 76% Hitt et al. Abstract #6009, ASCO 2009

Compliance Characteristics % received 3 cycles neoadjuvant chemo Median cycles of chemo during CRT CRT PF + CRT TPF + CRT (n=128) (n=156) (n=155) -- 76% 68% 3 2 2 % receiving protocol XRT 80% 68% 62% Hitt et al. Abstract #6009, ASCO 2009

Adverse Events Grade 3/4 Toxicity CRT (n=119) PF + CRT (n=156) TPF + CRT (n=153) Neutropenia 20% 38% 34% Febrile neutropenia* 1% 3% 18% Thrombocytopenia 4% 10% 10% Asthenia 3% 9% 14% Mucositis 31% 4% 42% XRT dermatitis 8% 11% 3% *Before GCSF amendment, 22% febrile neutropenia. After GCSF amendment, Incidence of febrile neutropenia was 11%. No GI, neuro, or renal toxicity reported. Hitt et al. Abstract #6009, ASCO 2009

TTF Hitt et al. Abstract #6009, ASCO 2009

TTP Hitt et al. Abstract #6009, ASCO 2009

Hitt et al. Abstract #6009, ASCO 2009 LCR Rate of surgery in CRT 50% and 25% in neoadjuvant chemo-crt

Efficacy Efficacy CRT (n=119) PF + CRT (n=123) TPF + CRT (n=111) Total neoadj chemo (n=234) Median TTF (months) Median TTP (months) Median OS (months) Deaths during neoadj chemo Deaths during CRT 5 12.3 13.4 13.1 18.5 20.4 27.1 33.6 37.2 12.5 HR 0.57 18.5 HR 0.79 37.1 HR 0.85 -- 2 pts 5 pts* 7 pts 2 pts 2 pts 2 pts* 4 pts *After GCSF amendment, only 1 pt treated on TPF arm died Hitt et al. Abstract #6009, ASCO 2009

Summary Abstract #6009 Neoadjuvant chemotherapy prior to chemoradiation is feasible and improves local-regional control. Although neoadjuvant chemo is becoming more popular, this trial does not definitive set neoadjuvant therapy as the new standard because of problems with the trial: No report on radiation quality or compliance. High rate of drop out rate from efficacy analysis (33, 44 pts missing! from neoadjuvant chemo arms). ITT analysis needs to be done. Incomplete toxicity report Efficacy report given during interim 2006 analysis reported that TPF was better than PF and CRT but now this is not the case and only 2 arms were reported on in this analysis. Hitt et al. Abstract #6009, ASCO 2009 Higher rate of deaths with chemo-crt. Emphasizes the need for patient selection and supportive therapy. A treatment benefit was seen in both neoadjuvant regimens - supports the point that it is not necessary to use TPF as neoadjuvant therapy. other options: cisplatin (75 mg/m 2 ) + docetaxel (75 mg/m 2 ) platinum + 5-FU or platinum + taxane Choice of population to treat with TPF remains to be decided.

UPCC 03305: Phase II single center trial of single-agent sorafenib in patients with thyroid cancer Brose et al. Abstract #6002, ASCO 2009 Sorafenib: VEGFR, PDGFR-b, BRAF, c-kit, RET Eligibility Criteria Metastatic thyroid cancer N=55 Sorafenib Continuous 28- day dosing 400 mg po BID Primary endpoint: overall response rate Secondary endpoints: survival, safety, duration of response, PK, genetic correlates Thyroid cancer: 44% PTC have BRAF V600E gene mutations 0% FTC have BRAF V600E gene mutations

UPCC 03305 Patient Demographics Characteristics (n=55) % pts Male 51% Histology Papillary thyroid FTC/Hurthle cell variant Medullary thyroid Anaplastic Poorly differentiated 47% 35% 4% 7% 5% Brose et al. Abstract #6002, ASCO 2009

Brose et al. Abstract #6002, ASCO 2009 UPCC03305 Grade 3+ Toxicity (n=30) Adverse event % pts Atrial fibrillation 3% Hand foot syndrome 7% Rash 7% Anxiety 3% Pruritis/skin discomfort 7% HTN 10% Vomiting 3% Diarrhea 7% LFT elevation (grade 5) 3%

UPCC 03305: Efficacy (n=46) Brose et al. Abstract #6002, ASCO 2009 Efficacy % pts PR 36% SD 46% Median PFS 63 wks Median OS DTC only 84 wks Median OS first 30 pts only 140 wks

Brose et al. Abstract #6002, ASCO 2009 UPCC 03305 BRAF V600E mutation PFS (n=22) There was a trend towards improved PFS in patients with BRAF V600E mutation but it was not statistically significant.

Brose et al. Abstract #6002, ASCO 2009 Summary Abstract #6002 Sorafenib has clinical activity in iodine refractory metastatic differentiated thyroid cancer. Patients with BRAFV600E mutations may have a trend towards improved PFS.

ASCO 2009 HNSCC Conclusions - Biomarkers HPV or p16 positive oropharynx HNSCC is a unique entity with an improved prognosis and may not need as aggressive treatment as HPV/p16 negative disease. Tobacco use and hypoxia may have an influential role in HPV/p16 positive disease. Currently, there are no tumor biomarkers available for predictive use in HNSCC with regard to EGFR inhibitors. (EGFR FISH in the EXTREME trial) Mass spectrometry proteomic profiling in plasma may be promising. In thyroid cancer, sorafenib has preliminary efficacy and may be especially beneficial in BRAF V600E mutation patients.

ASCO 2009 HNSCC Conclusions Concurrent and Neoadjuvant therapy Darbepoetin alpha use during concurrent chemoradiation is contraindicated. Although neoadjuvant chemotherapy is commonly being used, the phase III Hitt et al. trial had some flaws and did not establish this treatment strategy as a standard of care practice. However, additional studies are underway to elucidate this issue.

HNSCC Tsao s Neoadjuvant Recommendations Neoadjuvant therapy is becoming accepted in standard practice. However, the optimal regimen in the specific patient population remains unknown. Induction TPF followed by weekly platinum with XRT is reasonable however, it is not always necessary to use TPF, platinum-doublets can be utilized in the appropriate patient. Low N stage - Chemoradiation may be sufficient as distant disease recurrence is modest High T stage and/or High N stage May need induction chemo but not high dose chemo-xrt. N2C disease should probably receive induction chemo. N2B if large and bulky should also be considered. Optimal induction chemo regimen remains to be seen. Would avoid induction TPF then concurrent high dose cisplatin-xrt [in SWOG 0216, this was toxic with deaths and had a poor compliance (68%)]. Cetuximab with TPF or with platinum-docetaxel is under investigation.