1. Neoadjuvant Chemotherapy in Locally Advanced Squamous Cell Cancer of Head and Neck Mei Tang, MD

2. Head and Neck Cancer Worldwide New cases : 644,000 New cases : 644,000 Cancer deaths: 350,000 Cancer deaths: 350,000 About 5% of all cancers About 5% of all cancers Local Recurrence: 40% - 60% Local Recurrence: 40% - 60% Distant metastatic disease: 20 - 30% Distant metastatic disease: 20 - 30%

3. SCCHN

4. The Role of Concomitant Chemotherapy in Locally Advanced SCCHN The Lancet March 18, 2000

5. MACH-NC 2000 63 trials (10,741 patients) 63 trials (10,741 patients) 1965 – 1993 1965 – 1993 Cancers of oropharynx, oral cavity, larynx, and hypopharynx Cancers of oropharynx, oral cavity, larynx, and hypopharynx Many countries contributed to this report Many countries contributed to this report

6. Overall Survival Benefit of Chemotherapy

7. Timing of Chemotherapy Neoadjuvant/induction chemotherapy Neoadjuvant/induction chemotherapy Concomitant chemotherapy (chemoradiotherapy, CRT) Concomitant chemotherapy (chemoradiotherapy, CRT) Adjuvant chemotherapy Adjuvant chemotherapy

8. Timing of Chemotherapy

9. Concomitant chemoradiotherapy is the current standard therapy for stage III and IV who do not undergo surgery

10. Induction Chemotherapy: an attractive option To allow the assessment of tumor response To allow the assessment of tumor response To select appropriate patient for organ preservation To select appropriate patient for organ preservation To improves local control To improves local control To reduce distant metastases To reduce distant metastases

11. Chemotherapy in Newly Diagnosed vs Recurrent Disease patients Response Rate Chemotherapy New Diagnosis Recurrence DDP/Bleo71%33% DDP/Bleo/Vinbl74%45% DDP/MTX/Bleo88%25% Bleo/MTX/VCR71%43%

12. Evidence supporting induction chemotherapy The VA trial No. 268 CT-RT vs Surg.-RT (P) The VA trial No. 268 CT-RT vs Surg.-RT (P) The EORTC trials in early 1990s (PF) The EORTC trials in early 1990s (PF) Intergroup trial 91-11(PF) Intergroup trial 91-11(PF) 1. A higher organ preservation or as good as concomitant CRT 2. A lower rate of distant failure 3. A trend toward improved survival, particularly in unresectable patients

13. Adding Taxanes into induction regimen (TPF – RT) High complete response rate: 80-100% Local failure rate: 31% Distant failure rate: 6% Toxicity: Less nausea, mucositis, G-3 hearing loss, trombocytopenia and treatment related death. Higher neutropenic fever,

14. Dosage in Chemo- regimens TPF (q3wk) PF(q3wk) Docetaxol (T) 75 mg/m2 N/A Cisplatin (P) 75 mg/m2 100 mg/m2 5-FU (F) 1000 mg /m2 day 1-4 1000 mg/m2 day 1-5

15. Timing of Chemotherapy

16. Limitations of the Data Trials between 1965-1993 Trials between 1965-1993 Different chemotherapy regimens (drug/schedules) Different chemotherapy regimens (drug/schedules) Platinum and 5-FU regimens are associate with 5% survival benefit at 5 years Platinum and 5-FU regimens are associate with 5% survival benefit at 5 years Response to chemotherapy was not taken into account Response to chemotherapy was not taken into account

17. 5-FU/Cisplatin in Previously Untreated Patients No.PatientsResponse(%) Complete Response (%) RTOG84’239139 Rooney85’619354 VALCSG91’1668531 Paccagnella94’1188031 Athanasiadis97’718332

18. Rationales of Induction Chemotherapy 1. There is increased responsiveness in previously untreated patients 2. Possible improvement in survival Improve locoregional control Decrease distant metastases 3. Surgical modification/organ preservation

20. Patient Selection 1

21. Patient Selection 2

22. TPF Improves PFS and OS When It Was Compared to PF in Induction TFP has better local control but no significant benefit in control of distant disease comparing to PF. OSPFS

25. Patient Selection Outside Clinical Trials Young (55 yo) Young (55 yo) PS 0-1 PS 0-1 No majoy comorbilities (RI, uncontrolled DM, recent heart attached..) No majoy comorbilities (RI, uncontrolled DM, recent heart attached..) Large primary: T3 or T4 Large primary: T3 or T4 Extensive LN involvement (N2b or above) Extensive LN involvement (N2b or above) Good nutrition standard Good nutrition standard

26. Targeted Therapy in SCCH-NC Cetuximab-RT vs. RT: Cetuximab-RT vs. RT: PF vs. PF + Cetuximab PF vs. PF + Cetuximab It seems safe and effective: Carboplatin (AUC 2)/Taxol (135 mg/m2)/Cetuximab Carboplatin (AUC 2)/Taxol (135 mg/m2)/Cetuximab TPF/Cetuximab TPF/Cetuximab TPF-RT+cetuximab TPF-RT+cetuximab

27. Targeted Therapy in SCCH-NC Everolimus: mTOR inhibitor Everolimus: mTOR inhibitor Panitumumab + chemo Panitumumab + chemo Nimotumumab (EGFR ab) Nimotumumab (EGFR ab)

28. Is it time to change treatment paradigm? No direct comparison of induction chemotherapy to concomitant treatment using the newer regimen No direct comparison of induction chemotherapy to concomitant treatment using the newer regimen Induction chemotherapy has no defined role in definitive treatment strategies

29. Summary Chemotherapy has established role in locally adv. SCCHN Chemotherapy has established role in locally adv. SCCHN TPF – CRT is an alternative treatment options besides the standard concomitant chemoradiotherapy. TPF – CRT is an alternative treatment options besides the standard concomitant chemoradiotherapy. CRT, not RT after TPF. Carboplatin CRT, not RT after TPF. Carboplatin TPF is better than PF in induction. It is possible but not proven that TPF-CRT is better than CRT with cisplatin. TPF is better than PF in induction. It is possible but not proven that TPF-CRT is better than CRT with cisplatin.

30. Dosage of Cisplatin in CRT 80% of pts tolerated > or = 6 doses of 30 mg/m2 weekly. Total: 180-210 mg 80% of pts tolerated > or = 6 doses of 30 mg/m2 weekly. Total: 180-210 mg 50% of pts tolerated 100 mg/m2 X 2. Total: 200 mg 50% of pts tolerated 100 mg/m2 X 2. Total: 200 mg Weekly is flexibl. The goal is to continue XRT with delay or dose reduction. Weekly is flexibl. The goal is to continue XRT with delay or dose reduction. No G-3 or 4 renal toxicity in weekly dose. No G-3 or 4 renal toxicity in weekly dose.

31. SCCH-N in GBMC 2009 Total 238 cases of head neck cancer Eighty cases of cancers in oral cavity, oropharynx, larynx and hypopharynx Stage I: 22 Stage II: 9 Stage III: 14 Stage IV: 28 Unknown or Stage 0: 7