Marshall R. Posner, MD Dana-Farber Cancer Institute New Paradigms to Improve Outcomes in Head and Neck Cancer The Evolving Roles of Induction Chemotherapy, Chemoradiotherapy, and Sequential Therapy Marshall R. Posner, MD Dana-Farber Cancer Institute

Case 1: T3N1 Supraglottic Tumor No Significant Co-Morbidities Patient is a 56 year old male Presents with hoarseness, left ear pain, 3 months duration, treated with antibiotics for 1 month 40 pack-year smoking history, quit 3 years ago Wine on weekends Bank mortgage officer MI with stent 3 years ago Mild hypertension well controlled Exam shows tumor of the left supraglottic larynx, paralyzed left vocal cord, 2.5 cm left level 2 lymph node T3N1, stage III

Case 1: T3N1 Supraglottic Tumor No Significant Co-Morbidities This patient has resectable stage III larynx cancer, good performance status, and minimal co-morbidities Which treatment option would you recommend? Total laryngectomy Organ preservation – chemoradiotherapy Organ preservation – induction chemotherapy followed by radiotherapy Organ preservation – sequential therapy: induction chemotherapy followed by chemoradiotherapy Estimated 5-year survival is 50%-60%

Case 1 B Alternative Patients with the Same Tumor The patient has the same presentation, but now has a heavy, active alcohol and smoking history with cirrhosis and minimal ascites In this circumstance laryngectomy would be favored because of the underlying risk of severe toxicity from chemotherapy The patient is 85 years old with moderate congestive heart failure and hypertension and is on diuretics

Case 1 B Alternative Patients with the Same Tumor The patient is 85 years old with moderate congestive heart failure and hypertension and is on diuretics Which treatment option would you recommend? Cetuximab plus radiotherapy Concurrent carboplatin Carboplatin plus cetuximab Carboplatin plus paclitaxel plus cetuximab Other

Case 2: T3N2b Tumor of the Oropharynx No Significant Co-Morbidities Patient is a 52 year old male Presents with a painless right neck mass of 4 months duration 5 pack-year smoking history, quit 30 years ago Wine on weekends A malpractice litigation lawyer Exam shows tumor of the right base of tongue and a 5 cm right, cystic level 2 mass of lymph nodes T3 n2b - stage IVA The tumor abuts the midline of the tongue base and is not adjacent to the larynx It is resectable with a total glossectomy and might be resectable with a partial glossectomy

Case 2: T3N2b Tumor of the Oropharynx No Significant Co-Morbidities This patient has marginally resectable stage IV oropharynx cancer, good performance status, and minimal co-morbidities Which treatment option would you recommend? Total or partial glossectomy (indeterminate until surgery is performed) Organ preservation – chemoradiotherapy Organ preservation – induction chemotherapy followed by radiotherapy Organ preservation – sequential therapy: induction chemotherapy followed by chemoradiotherapy Estimated 5-year survival is 35%-50% with standard surgery and radiotherapy

Case 3: T3N3 Tumor of the Hypopharynx No Significant Co-Morbidities Patient is a 63 year old male Presents with hoarseness, left ear pain and a left neck mass for 2 months 65 pack-year smoking history, quit 3 months ago Wine on weekends Retired malpractice attorney Hypertension, mild COPD Exam shows tumor of the left pyriform sinus with extension into the larynx, a paralyzed left vocal chord, and a 7.5 cm right, cystic level 2 mass of lymph nodes fixed to the neck T3N3, stage IVB On CT imaging the tumor surrounds the internal carotid It is unresectable

Case 3: T3N3 Tumor of the Hypopharynx No Significant Co-Morbidities This patient has unresectable stage IVB hypopharynx cancer, good performance status, and minimal co-morbidities Surgery is not an option Estimated 5 year survival is 20%-30% with radiotherapy and there is a high rate of distant metastases

Case 3: T3N3 Tumor of the Hypopharynx No Significant Co-Morbidities This patient has unresectable stage IVB hypopharynx cancer, good performance status, and minimal co-morbidities Which treatment option would you recommend? Chemoradiotherapy Induction chemotherapy, followed by radiotherapy Sequential therapy: induction chemotherapy followed by chemoradiotherapy

Marshall R. Posner, MD Dana-Farber Cancer Institute New Paradigms to Improve Outcomes in Head and Neck Cancer The Evolving Roles of Induction Chemotherapy, Chemoradiotherapy, and Sequential Therapy Marshall R. Posner, MD Dana-Farber Cancer Institute

Effects of Chemotherapy on Survival at 5 Years From the Meta-Analysis Trial Category No. of Trials No. Patients Difference (%) P value All trials 65 10,850 +4 <0.0001 Adjuvant 8 1854 +1 0.74 Induction 31 5269 +2 0.10 PF 15 2487 +5 0.01 Other Chemo 16 2782 0 0.91 Concomitant 26 3727 +8 <0.0001 Monnerat, et al. Annals of Oncology, 13: 995-1006, 2002

PF Induction Chemotherapy is Effective for Improving Survival and Organ Preservation for Locally Advanced SCCHN Meta – Analysis 2000, 2004, 2005 Phase III Trials – Survival Studio Trial 1994, 2004 GETTEC Oropharynx Trial 2000 Phase III Trials – Organ Preservation VA Larynx Trial 1991 EORTC Hypopharynx Trial 1994, 2004 Intergroup 91-11 Trial 2003, 2006

Overall Survival GETTEC Patients at risk 161 157 137 138 101 105 65 86 48 59 28 33 16 19 7 Percent Years No chemotherapy Chemotherapy 40 20 60 80 100 1 2 3 4 5 6 8 Domenge C, et al. Br J Cancer. 2000;83:1594-1598.

Calais Chemoradiotherapy Regimen 1 2 3 4 Weeks Carboplatin 70 mg/m2 /day x 4 days QD Radiotherapy 200 cGy/ Fx 5-FU 600 mg/m2/days x 4 days 5 6 7 J Natl Cancer Inst. 1999;91:2081-2086.

Calais Chemoradiotherapy Study 5-Year Survival 20 40 60 80 100 6 12 18 24 30 36 42 48 54 66 72 Survival (%) Months CRT XRT Conclusions: Borderline statistically significant (P = .05) better overall survival with CRT (22% vs 16%) Absolute 6% improvement Better LRC (48% vs 25%), No change in DM (20%) CRT is better then XRT alone for oropharynx cancer Denis, F et al. JCO. 2004.

RTOG 91-11 Phase III Trial of Larynx Preservation RANDOMIZE A P XRT F B C Surgery ± Surgery 547 pts Stage III/IV glottic, supraglottic intermed. stage Forastiere, NEJM, 2003 Forastiere AA, et al. ASCO 2006. Abstract 5517

RTOG 91-11:Phase III Trial of Larynx Preservation: 5-Year Update PF CRT XRT LFS 44.6% 46.6% 33.9% P < .011 LRC 54.9%* 68.8%* 51% P < .0018 DM 14.3% 13.2% 22.3% DFS 38.6%* 39% 27.3%* P < .0016 Survival 59.2% 54.6% 53.5% PF was equivalent to CRT for LFS CRT had better LRC than PF DFS was identical but overall survival favored PF Did patients fare better with PF because they had subtle improvements in function Forastiere AA, et al. ASCO 2006. Abstract 5517

Induction Chemotherapy Pros High dose treatment, systemic exposure, transient toxicity Improved nutrition and PS Reduced tumor volume Better preparation for definitive radiotherapy and IMRT planning Improved function Established efficacy in resectable disease and organ preservation Improved survival Intermediate assessment of response/prognosis Adjusted intensity of post-induction therapy Cons Systemic toxicity increased Survival improvement may be site and stage related Increased duration of therapy, change in tumor biology No improvement in local/regional dose intensity Cisplatin-based PF was the only effective chemotherapy regimen

Chemoradiotherapy Pros Cons Improved local regional intensity Shortened treatment time Efficacy in unresectable disease Efficacy in organ preservation Effective post-operative therapy Cons Local toxicity increased Long-term toxicity not defined Esophageal stenosis, swallowing impaired Mortality from unrecognized toxicity Increased systemic toxicity Induction of systemic chemotherapy resistance No acceptable standard Assessment of response/prognosis compromised No effect on distant metastases in advanced disease IMRT planning difficult

TPF Induction Chemotherapy has Proven Superior to PF in Multiple Phase III Trials Organ Preservation GORTEC Hypopharynx and Larynx Trial , 2006 Locally Advanced Resectable and Unresectable TAX 324 (2006) Unresectable Disease TAX 323 (2004, 2006)

Daily Radiotherapy: STD or ACB GORTEC:2000-01: A Phase III Trial of TPF vs PF Followed by Radiotherapy for Organ Preservation in Resectable Larynx and Hypopharynx Cancer T RANDOMIZE P Surgery F No Response Response P F Daily Radiotherapy: STD or ACB TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750CI- D1-5 Q 3 weeks x4 PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 3 Calais G, et al. ASCO 2006. Abstract 5506

GORTEC Phase III Larynx Preservation Trial Comparing TPF and PF Induction Therapy for Hypopharynx and Larynx Cancer Increase in Larynx Preservation with TPF vs PF Larynx preservation observed in 80% and 58% of patients following TPF and PF treatment, respectively (NR) Overall survival trend favors TPF over PF (P = .096) TPF (%) PF (%) P Value Larynx preserved (current rate) 63.2 41.4 .036 Response CR PR 82.8 43.4 39.4 60.8 30.4 .0013 Calais G, et al. ASCO 2006. Abstract 5506

Larynx Preservation (Months) GORTEC Phase III Larynx Preservation Trial Comparing TPF and PF Induction Therapy for Hypopharynx and Larynx Cancer 6 12 18 24 30 36 42 20 40 60 80 100 Percent (%) Larynx Preservation (Months) P (Log-rank test) = 0.036 Induction TPF (n=108) Induction PF (n=112) Calais et al. ASCO, 2006. Oral Presentation.

TAX 323: TPF vs PF Followed by Radiotherapy A Phase III Study in Unresectable SCCHN RANDOMIZE P F Daily Radiotherapy EUA T Surgery TPF: Docetaxel 75D1 + Cisplatin 75D1 + 5-FU 750CI- D1-5 Q 3 weeks x4 PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 4 Vermoken, ASCO, 2004

Log-Rank P = 0.0052 Hazard Ratio = 0.71 TAX 323: Survival Update Log-Rank P = 0.0052 Hazard Ratio = 0.71 Survival Time (months) Survival Probability (%) 6 12 18 24 30 36 42 48 54 60 66 72 10 20 40 50 70 80 90 100 TPF (n=177) PF (n=181) Patients at Risk TPF: PF: 177 163 127 91 74 64 43 26 16 7 181 150 98 77 57 47 39 33 25 15 8 4 Remenar, ASCO, 2006

TAX 323: Severe Adverse Events Chemotherapy Toxicity PF (n=179) TPF (n=174) > 3% of pts N (%) N (%) Alopecia 0 20 (11.5) Stomatitis / oral 20 (11.2) 8 (4.6) Infection 13 (7.3) 15 (8.6) Nausea 13 (7.3) 1 (0.6) Vomiting 9 (5.0) 1 (0.6) Diarrhea 8 (4.5) 5 (2.9) Dyspnea 8 (4.5) 6 (3.4) Dysphagia 5 (2.8) 6 (3.4) Pain 7 (3.9) 11 (6.3) Death 12 (6.6) 6 (3.4) Vermoken, ASCO, 2004

An Analysis of Failure in Phase II TPF Induction Trials* Three Cycles of Induction Therapy Followed by BID Radiotherapy Trials: TPF, TPFL5, TPFL4, op-TPFL Entered: 84* Local/Regional Failure: 26 (31%) Local/Regional and DM 5 (6%) DM only 0 *Excludes 17 Patients with NPC Haddad, Cancer, 2003

An Analysis of Failure in Phase III Chemoradiotherapy Trials* Trials: INT EORTC RTOG GORTEC LRF 22% 18% 16% 57% DM 23% 21% 20% 18% DM % of Failure 51% 54% 65% 32% The Rate of DM Was Not Reduced by CRT *Excludes Larynx Trial 91-11 Adelstein, JCO, 2003 Bernier, NEJM, 2005 Cooper, NEJM, 2005 Denis, JCO, 2005

Induction Chemotherapy and Chemoradiotherapy in Locally Advanced SCCHN PF induction chemotherapy results in a significant 5% (P <.01) improvement in 5-year survival in meta-analysis (Monnerat, annals of oncology, 2002) PF was the only induction regimen that was effective, TPF is better After induction chemotherapy and radiotherapy, failure is frequently local/regional (Haddad, cancer, 2003) CRT results in a significant 8% (P <.0001) improvement in 5 year survival in meta-analysis (Monnerat, Annals of Oncology, 2002) There is less local/regional failure, but relatively more distant metastases (Adelstein, JCO, 2003; Bernier, NEJM, 2005; Cooper, NEJM, 2005; Denis, JCO, 2005)

Sequential Therapy for Head and Neck Cancer Induction Chemotherapy Chemoradiotherapy Surgery

Sequential Therapy for Head and Neck Cancer Induction chemotherapy High response rates, organ preservation, improved survival, systemic treatment Reduced tumor volume, better IMRT planning, improved functional outcome An intermediate assessment of response Chemoradiotherapy Increased local/regional dose intensity Adjustment based on response to induction therapy, potential toxicity, prognostic factors, and/or planned surgery Surgery Remove areas of initial bulk disease Preserve primary site

Takimoto & Rowinsky, JCO, 2003 A Cell Kinetic Model for Response and Survival: The Argument for Timing in Combined Modality Therapy Death Chemotherapy Treatment B Survival Treatment A Survival B A 1012 1011 1010 109 108 107 106 Tumor Cell Number Time Critical Time Frame Takimoto & Rowinsky, JCO, 2003

Sequential Combined Modality Therapy A Phase III Study: TAX 324 TPF vs PF Followed by Chemoradiotherapy T RANDOMIZE Carboplatin - AUC 1.5 Weekly P F EUA Surgery Daily Radiotherapy P F TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100D1 + 5-FU 1000CI-D1-5 Q 3 weeks x 3

TAX 324: Analysis Populations TPF PF ALL All Randomized 280 259 539 INTENT TO TREAT Population* 255 246 501 Treated With Chemotherapy 251 (98%) 243 (99%) 494 (98.6%) SAFETY Population TPF ( n=251) PF (n=243) ALL (n=494) Chemotherapy Treated 251 (100%) 243 (100%) 494 (100%) Receiving Chemoradiotherapy per Protocol 202 (81%) 184 (76%) 386 (78%) Not Receiving Chemoradiotherapy per Protocol 49 (19%) 59 (24%) 108 (22%) * ITT excludes 37 patients erroneously randomized and 1 patient with GCP compliance issue

TAX 324: Patients Characteristics (ITT) TPF (n=255) PF (n=246) Age (years): Median (Range)  65 years 55 (38 to 82) 34 (13%) 56 (33 to 80) 36 (15%) Gender Male 215 (84%) 204 (83%) PS (WHO) 0 1 142 (56%) 113 (44%) 126 (51%) 117 (48%) Anatomic site Oropharynx Larynx Hypopharynx Oral cavity 132 (52%) 48 (19%) 42 (17%) 33 (13%) 131 (53%) 34 (14%) 38 (15%) Clinical Stage III IV 41 (16%) 214 (84%) 46 (18%) 199 (81%) Reason Inoperable Technical Unresectability Low Surgical Curability Organ Preservation 92 (36%) 78 (31%) 85 (33%) 84 (34%) 75 (31%) 87 (35%)

TAX 324: Survival Intent to Treat Population TPF (n=255) PF (n=246) Median Survival (Mo) 95% CI 70.6 + 49 – NR 30.1 20.9 – 51.5 Died * 41% 53% Kaplan-Meir Survival 1–Year 2–Year 3–Year 80% [ 75.0 – 84.9] 67% [61.5 – 73.2] 62% [55.9 – 68.2] 69% [64.1 – 75.7] 54% [48.2 – 60.8] 48% [41.7 – 54.5] Hazard Ratio TPF:PF [95% CI] 0.70 [0.54 - 0.90] Log-Rank P Value 0.0058 *Cut-off: December 3, 2005; The median follow-up is 42 months

TAX 324: Survival TPF 67% TPF 62% PF 54% PF 48% Survival Time (months) Survival Probability (%) 6 12 18 24 30 36 42 48 54 60 66 72 10 20 40 50 70 80 90 100 TPF (n=255) PF (n=246) Number of patients at risk TPF: PF: 255 234 196 176 163 136 105 52 45 37 11 246 223 169 146 130 107 85 57 32 28 7 1 Log-Rank P = 0.0058 Hazard Ratio = 0.70 TPF 67% PF 54% TPF 62% PF 48%

TAX 324 : Progression-Free Survival Progression-Free Survival Time (months) Progression Free Survival Probability (%) 6 12 18 24 30 36 42 48 54 60 66 72 10 20 40 50 70 80 90 100 TPF (n=255) PF (n=246) Number of patients at risk TPF: PF: 255 198 150 135 121 73 39 35 26 16 5 246 183 125 104 92 57 38 25 14 8 2 Log-Rank P = 0.004 Hazard Ratio = 0.71 TPF 53% PF 42% TPF 49% PF 37%

TAX 324: Toxicity During Chemotherapy Number of Patients TPF (n=251) PF (n=243) NCIC-CTG Classification Grade 3/4 Any Event 65% 62% Stomatitis Nausea Lethargy Vomiting Diarrhea Anorexia 21% 14% 5% 8% 7% 12% 27% 10% 3%

TAX 324: Specific Safety During Chemotherapy TPF (n=251) PF (n=243) Neutropenia Grade 3/4 84% 56% Febrile Neutropenia Neutropenic Infection 12% 7% 9% Primary Prophylactic Antibiotics Were Given Per Protocol for TPF

TAX 324: Delays During Induction Chemotherapy TPF (n=251) PF (n=243) All (n=494) Treatment Delays 73 (29%) 157 (65%) 230 (47%) Hematologic 11 (4%) 108 (44%) 119 (24%) Neutropenia 2 (1%) 95 (39%) 97 (20%) Non-Hematologic 25 (10%) 22 (9.1%) 47 (10%) Other** 38 (15%) 40 (17%) 78 (16%) ** Logistic, Personal, Vacation

TAX 324: Exposure to Induction Chemotherapy TPF (n=251) PF (n=243) Median Cycles 3 Cumulative Dose (mg/m2) T P* F 224 299 11944 14760 Relative Median Dose Intensity .98 .99 .90 .88 *6 Patients in each Arm received carboplatin to replace cisplatin

TAX 324: Toxicity During Chemoradiotherapy Number of Patients TPF (n=203) PF (n=184) NCIC-CTG Grade 3/4 Any Event Stomatitis Dysphagia Mouth/Nose Dryness Nausea Rash/itch 65% 37% 23% 5% 6% 66% 38% 24% 4% 2%

TAX 324: Exposure to Study Treatment Chemoradiotherapy (CRT) TPF (n=202) PF (n=184) Median Dose Radiotherapy (Gy) Median Dose Carboplatinum (AUC) Median Duration CRT (Wks) 70 9.9 7.1 Chemoradiotherapy toxicity was not enhanced by prior doxetaxel in TPF

TAX 324: Analysis of Failure TPF (n=251) PF (n=243) All (n=494) Total Failures/Treated 88 (35%) 110 (45%) 198 (40%) LRF* 77 (31%) 93 (38%) 170 (34%) Primary 43 (17%) 49 (20%) 92 (19%) Neck 22 (9%) 33 (14%) 55 (11%) Both 12 (5%) 11 (5%) 23 (5%) Distant Metastases** 14 (6%) 21 (9%) 35 (7%) Distant Only 11 (4%) 17 (7%) 28 (6%) Distant and LRF 3 (1%) 4 (2%) 7 (1%) Second Primaries 9 (4%) 7 (3%) 16 (3%) *Hazard Ratio 0.73 (0.54-0.99), P = .03 **Hazard Ratio 0.60 (0.30-1.18), P = .18

TAX 324: Conclusions TPF significantly improves survival compared to PF There is a 14% absolute improvement in 3-year survival and a 30% reduction in mortality (P = 0.0058) for TPF 62% of TPF patients are alive at 3-years TPF significantly reduced local regional failure compared to PF Local regional failure was reduced by 27% (P= .03) Distant metastases were reduced 30% compared to PF (P = .18) TPF was less toxic than PF There were fewer treatment delays with TPF (30% vs 65%) More of planned TPF was delivered than PF

TAX 324: Conclusions Sequential therapy with TPF is tolerable and safe The toxicity of TPF is less than that of PF The toxicity of chemoradiotherapy after induction chemotherapy was acceptable and within expected range The toxicity of chemoradiotherapy was the same with TPF or PF Sequential therapy with TPF followed by carboplatin-based chemoradiotherapy represents a new, acceptable standard of care for locally advanced SCCHN Sequential therapy makes biological sense and is effective Ongoing Phase III trials will determine how TPF-based sequential therapy compares to chemoradiotherapy

Docetaxel plus PF (TPF) and SCCHN TPF is the most effective combination regimen for induction chemotherapy* TPF regimens engender less toxicity and improved survival in locally advanced SCCHN compared to PF TPF is now the standard of care for induction chemotherapy TPF is an appropriate platform for curative therapy to which new molecularly targeted therapies should be added *Remenar, 2006, Posner, 2006, Calais, 2006

Sequential Therapy for Head & Neck Cancer Induction chemotherapy High response rates, organ preservation, improved survival, systemic treatment Reduced tumor volume, better function An intermediate assessment of response Chemoradiotherapy Increased local/regional dose intensity Adjustment based on response to induction therapy/ potential toxicity/prognostic factors/planned surgery Can chemoradiotherapy rescue non-responders to induction chemotherapy? Surgery Remove areas of initial bulk disease Preserve primary site

The Paradigm Study Sequential Therapy vs Chemoradiotherapy A Phase III Study of TPF/C-XRT vs P-ACBXRT RANDOMIZE P F XRT C Daily Radiotherapy 3 Cycles of Chemotherapy T Surgery Q 3 Weeks ACB Radiotherapy *T + ACB for Non-Responders T* ACB NR PR,CR

SWOG Phase III Oropharynx Trial: S0427 RANDOMIZE P F XRT Daily Radiotherapy T Surgery Q 3 Weeks <50% Response >50% Response 2 Cycles * Cisplatinum (P); Docetaxel (D); 5-Fuorouracil (F)

Italia Phase II/III TPF vs CRT Trial RANDOMIZE P F CRT Daily Radiotherapy T TPF: Docetaxel 75D1 + Cisplatin 80D1 + 5-FU 800CI- D1-4 Q 3 weeks x3 CRT PF: Cisplatin 20D1-4 + 5-FU 800CI-D1-4 Weeks 1,6 Pacagnella, ASCO, 2006

Case 1: T3N1 Supraglottic Tumor No Significant Co-Morbidities Patient is a 56 year old male Presents with hoarseness, left ear pain, 3 months duration, treated with antibiotics for 1 month 40 pack-year smoking history, quit 3 years ago Wine on weekends Bank mortgage officer MI with stent 3 years ago Mild hypertension well controlled Exam shows tumor of the left supraglottic larynx, paralyzed left vocal cord, 2.5 cm left level 2 lymph node T3N1, stage III

Case 1: T3N1 Supraglottic Tumor No Significant Co-Morbidities This patient has resectable stage III larynx cancer, good performance status, and minimal co-morbidities Which treatment option would you recommend? Total laryngectomy Organ preservation – chemoradiotherapy Organ preservation – induction chemotherapy followed by radiotherapy Organ preservation – sequential therapy: induction chemotherapy followed by chemoradiotherapy Estimated 5-year survival is 50%-60%

Case 1: T3N1 Supraglottic Tumor No Significant Co-Morbidities Total laryngectomy is an option Other options offer organ preservation with equivalent or better survival Bolus cisplatin-based CRT and PF-based induction chemotherapy are equivalent in terms of laryngectomy free survival Both are better than radiotherapy alone There is a suggestion that PF-based induction chemotherapy may improve survival compared to chemoradiotherapy TPF-based induction chemotherapy is better for organ preservation then PF-based induction chemotherapy TPF engenders less toxicity than PF Better planning for IMRT after induction therapy

Case 1 B Alternative Patients with the Same Tumor The patient has the same presentation, but now has a heavy, active alcohol and smoking history with cirrhosis and minimal ascites In this circumstance laryngectomy would be favored because of the underlying risk of severe toxicity from chemotherapy The patient is 85 years old with moderate congestive heart failure and hypertension and is on diuretics

Case 1 B Alternative Patients with the Same Tumor The patient is 85 years old with moderate congestive heart failure and hypertension and is on diuretics Which treatment option would you recommend? Cetuximab plus radiotherapy Concurrent carboplatin Carboplatin plus cetuximab Carboplatin plus paclitaxel plus cetuximab Other

Case 1 B Alternative Patients with the Same Tumor The patient is 85 years old with moderate congestive heart failure and hypertension and is on diuretics Cetuximab plus radiotherapy would be a reasonable choice here Concurrent carboplatin is untested and while less toxic than cisplatin, is not a standard therapy as sole treatment Carboplatin plus cetuximab is untested as a primary therapy Carboplatin plus paclitaxel plus cetuximab would be too toxic for this fragile elderly man at risk for aspiration pneumonia

Case 2: T3N2b Tumor of the Oropharynx No Significant Co-Morbidities Patient is a 52 year old male Presents with a painless right neck mass of 4 months duration 5 pack-year smoking history, quit 30 years ago Wine on weekends A malpractice litigation lawyer Exam shows tumor of the right base of tongue and a 5 cm right, cystic level 2 mass of lymph nodes T3 n2b - stage IVA The tumor abuts the midline of the tongue base and is not adjacent to the larynx It is resectable with a total glossectomy and might be resectable with a partial glossectomy

Case 2: T3N2b Tumor of the Oropharynx No Significant Co-Morbidities This patient has marginally resectable stage IV oropharynx cancer, good performance status, and minimal co-morbidities Which treatment option would you recommend? Total or partial glossectomy (indeterminate until surgery is performed) Organ preservation – chemoradiotherapy Organ preservation – induction chemotherapy followed by radiotherapy Organ preservation – sequential therapy: induction chemotherapy followed by chemoradiotherapy Estimated 5-year survival is 35%-50% with standard surgery and radiotherapy

Case 2: T3N2b Tumor of the Oropharynx No Significant Co-Morbidities Total or partial glossectomy is an option but the other 3 options offer organ preservation and better survival Functional organ preservation is an important goal in this setting Bolus cisplatin-based chemoradiotherapy has been the standard of care, carboplatin/5-FU chemoradiotherapy is a standard in Europe and PF-based induction chemotherapy has been used effectively With PF-based induction chemotherapy or chemoradiotherapy 5-year survival is 20%-50% TPF is reasonable treatment for this patient Sequential therapy with TPF followed by carboplatin-based chemoradiotherapy was also better than PF and has a 60% 3-year survival Induction chemotherapy with TPF followed by radiotherapy alone improved survival in unresectable patients compared to PF and was associated with a significantly improved quality of life

Case 3: T3N3 Tumor of the Hypopharynx No Significant Co-Morbidities Patient is a 63 year old male Presents with hoarseness, left ear pain and a left neck mass for 2 months 65 pack-year smoking history, quit 3 months ago Wine on weekends Retired malpractice attorney Hypertension, mild COPD Exam shows tumor of the left pyriform sinus with extension into the larynx, a paralyzed left vocal chord, and a 7.5 cm right, cystic level 2 mass of lymph nodes fixed to the neck T3N3, stage IVB On CT imaging the tumor surrounds the internal carotid It is unresectable

Case 3: T3N3 Tumor of the Hypopharynx No Significant Co-Morbidities This patient has unresectable stage IVB hypopharynx cancer, good performance status, and minimal co-morbidities Surgery is not an option Estimated 5 year survival is 20%-30% with radiotherapy and there is a high rate of distant metastases

Case 3: T3N3 Tumor of the Hypopharynx No Significant Co-Morbidities This patient has unresectable stage IVB hypopharynx cancer, good performance status, and minimal co-morbidities Which treatment option would you recommend? Chemoradiotherapy Induction chemotherapy, followed by radiotherapy Sequential therapy: induction chemotherapy followed by chemoradiotherapy

Case 3: T3N3 Tumor of the Hypopharynx No Significant Co-Morbidities Chemoradiotherapy Bolus cisplatin or carboplatin and 5-FU have been found to improve survival in unresectable SCCHN Induction chemotherapy, followed by radiotherapy Several studies have shown improved survival in unresectable tumors when PF is given followed by radiotherapy TPF has been shown to be more active than PF and result in a better quality of life Sequential therapy TPF followed by chemoradiotherapy has resulted in improved survival compared to PF and chemoradiotherapy. Sequential therapy and chemoradiotherapy have not been compared in Phase III trials Phase III trials are ongoing, early results suggest that sequential therapy is not worse than chemoradiotherapy

Head and Neck Cancer - 2006 Up to 70% of patients with advanced disease and without significant co-morbidities can be cured Sequential chemotherapy, chemoradiotherapy, postoperative chemoradiotherapy Better assessment of risk factors, extent of disease New agents to improve survival Therapy is long, difficult and requires considerable physician care and an experienced team New agents with reduced toxicity Improved interventions during therapy to reduce acute toxicity and improve late function

New Paradigms to Improve Outcomes in Head and Neck Cancer The Evolving Roles of Induction Chemotherapy, Chemoradiotherapy, and Sequential Therapy DISCUSSION