1. Statements on Head and Neck Cancer 2006 Primary Radiochemotherapy Arlene A. Forastiere, M.D. Johns Hopkins University School of Medicine Department of Oncology

2. Concurrent Chemoradiotherapy as Standard of Care Based on Phase III Trials Organ PreservationRandomized Trials –Larynx INT R91-11 –OropharynxGORTEC Nasopharynx Trials in US & Asia Unresectable diseaseTrials in US & Europe Post-operative adjuvantEORTC & US trials

3. Standard of Care Options to Preserve the Larynx for locally advanced disease Conservation laryngeal surgery Concurrent RT and cisplatin 100 mg/m 2 x 3 RT alone

4. VA Laryngeal Cancer Study Group No difference in survival Larynx preserved in 64%; 2-year LFS rate 41% Pattern of failure (CT v S) – local, 12% v 2% – distant, 11% v 17% Risk factors for surgery –T4 or N2-3 –56% of T4 eventually required laryngectomy Induction CF - RT versus Surgery + RT NEJM 1991;324:1685-1690

5. INT R91-11 Trial to Preserve the Larynx Forastiere AA. NEJM 349:2091, 2003 Cisplatin/5-FU* x 2 Radiotherapy + cisplatin 100 mg/m 2 x 3 Radiotherapy RT 70 Gy/7 wks, 2 Gy/fx *cisplatin 100 mg/m 2 day 1 5-FU 1000 mg/m 2 CIVI days 1-5 cisplatin/5-FU RT surgery RT CR, PR NR

6. Eligibility Criteria Resectable SCC of the glottis or supraglottis requiring total laryngectomy Stage III or IV T1 excluded T4 excluded if tumor penetrated through cartilage or invaded > 1cm into base of tongue No distant metastases

7. Surgery Planned neck dissection –N2 or N3 at initial staging Total laryngectomy –Inadequate response (<PR) of primary to induction chemotherapy –Biopsy proven disease after completing RT –Laryngeal dysfunction or necrosis

8. Patient Characteristics, in % Induction N=173 Concurrent N=172 RT N=173 Supraglottis686672 T378 79 N0-1727368 Stage III646764

9. INT R91-11 Results: Larynx Preservation Intergroup R91-11: 43% absolute reduction in laryngectomy rate with RT/cisplatin No difference in survival (76% at 2-years)

10. Local-regional control ConcurrentInductionRT alone 78% 61% 56% Induction vs Concurrent p =0.0031 Induction vs RT alone p= 0.16 Concurrent vs RT alone p= 0.00002

11. ConcurrentInductionRT alone 61% 52% 44% I + RT vs CRT p= 0.64 I + RT vs RT p= 0.017 CRT vs RT p= 0.0053 Disease-free survival Laryngectomy- free survival 66% 59% 53% I + RT vs CRT p= 0.49 I + RT vs RT p= 0.08 CRT vs RT p= 0.01

12. Response and compliance after two cycles of induction chemotherapy CR 21%, PR 64%, total 85% 24 (15%) < PR –29% had laryngectomy per protocol –25% other chemo or unknown rx – 46% had RT with/without third cycle of CT; all achieved CR post XRT, one failed later

13. Results Forastiere AA. N Eng J Med 349:2091, 2003 Weber RS. Arch Otolaryngol Head Neck Surg 129:44, 2003 Chemotherapy suppressed metastasis –Concurrent 8% vs RT 16% Chemotherapy added toxicity –Gr 3-4 toxicity: chemotherapy 81%, 82% vs RT 61% Laryngectomy was required in 25% of all patients (16% chemorad, 28% induction, 32% RT alone)

14. InductionConcurrentRT alone 12 mos6%11%13% 24 mos3%6%8% Moderate impairment: unable to be understood on the telephone or worse Function and QOL Assessments: no difference in speech at 12 and 24 mos

15. Swallowing function at 12 mos: delay in recovery with concurrent treatment Swallowing function InductionConcurrentRT alone Soft foods, liquids only 9%23%15% Unable to swallow 03% No differences between treatment groups at 24 mos

16. 5-Year Update (ASCO 2006) Confirms the 2-year analysis Survival – no significant difference Function excellent – no significant difference Concurrent CRT is significantly better than RT alone for all endpoints except OS Induction was not better than RT alone for larynx preservation and LR control Concurrent CRT and induction were better than RT alone for laryngectomy-free survival and DFS

17. 5-year Update Analysis not yet complete –Late effects –Site of first failure –Cause of death

18. Implications for Patient Management For larynx preservation of T3 and low volume T4 disease, chemotherapy and RT should be given concurrently For high volume T4 disease –Glottic cancer or penetration through cartilage into soft tissues: surgery –Supraglottic cancer: option for concurrent chemoradiotherapy.

19. Implications for Patient Management RT alone for patients unable to tolerate the added toxicity of concurrent chemoradiotherapy No role for induction chemotherapy outside of a clinical trial

20. Concepts in Development Separate intermediate and advanced stages: improved survival as primary endpoint RT (altered fx or std) + biologic –Inhibitors of EGFR or angiogenesis Standard fx RT + cisplatin + biologic Induction followed by cisplatin/RT

21. Other Questions Alternative chemotherapy regimens Impact of changing epidemiology (human papilloma virus) and prevalence of oropharynx cancer Patient selection or therapeutic effect?

22. ECOG 2399: Schema Primary endpoints: organ preservation rate, toxicity, assess utility of organ function instruments Median follow-up 33 months (11.8 months – 47 months)

23. TREATMENT DELIVERY (FEASIBILTY) Larynx (36) Oropharynx (69) Overall (105) # Induction Cycles unknown02 (4%)2 (3%) 103(4%)3(3%) 236 (100%)64 (93%)100 (95%) # Concurrent Cycles unknown03 (3%)3 (3%) 05 (14%)7 (10%)12 (12%) 407 (10%)7 (7%) 54 (11%)10 (15%)14 (13%) 6 6 (17%) 86%18 (26%)24 (23%) 721 (58%)24 (25%)45 (43%) 5, 6, or 7 cycles 83 (79%) Radiation (≥66Gy)315990 (87%)

24. SURGICAL INTERVENTIONS Larynx (n=36)Oro (n=69)Overall (n=105) Neck Dissection Only11 (31%)18 (26%)29 (28%) Primary Site Only7 (19%)6 (9%)13 (13%) Both 5 (14%)6 (9%)11 (11%) Primary Overall12 (33%)12 (18%)24 (23%)

25. Survival Time in Months Survival Probability 010203040 0.0 0.2 0.4 0.6 0.8 1.0 Oropharynx Larynx Overall Survival by Primary Site p=0.06 80% 58%

26. CONCLUSIONS Feasible regimen to deliver Surgical salvage rate for larynx cancer, 33% suggests: –that weekly paclitaxel concurrent with RT is not effective for LR control –Induction chemotherapy does not impact LR control or allow for a less intense concurrent chemoRT regimen DFS and OS results are excellent for OP (probable impact of HPV?) ASCO update in 2006

27. R99-14: Concomitant Boost RT + Concurrent Cisplatin 72 Gy/42 fx over 6 wks (daily for 3.5 wks then bid for 2.5 wks) + cisplatin 100 mg/m 2 day 1 & 22 76 analyzable pts –Median age 57 (range 40-76) –Stage IV 88%; T3-4 64%, N2-3 78% –Oral cavity9 (12%) –Oropharynx50 (66%) –Hypopharynx8 (11%) –Larynx9 (12%)

28. Ang, K. K. et al. J Clin Oncol; 23:3008-3015 2005 Overall survival, disease-free survival and relapse pattern

29. Ang, K. K. et al. J Clin Oncol; 23:3008-3015 2005 Cumulative incidence of all treatment-related late grade 3 to 5 and grade 4 to 5 toxicity Late Toxicity

30. R97-03: Randomized Ph II Concurrent Chemradiation RT – 70 Gy/35 fx Chemotherapy –Arm 1: cisplatin 10 mg/m 2 + 5-FU 400 mg/m 2 /d during last 10 days of RT –Arm 2: hydroxyurea + 5-FU + RT every other week (U. Chicago FHX) –Arm 3: cisplatin 20 mg/m 2 + paclitaxel 30 mg/m 2 weekly

31. R97-03: Randomized Phase II Concurrent Chemradiation 231 eligible pts randomized Median age 56 (range 21-83) T3-4 75%; N2-3 70% Primary site –Oral cavity 16% –Oropharynx67% –Hypopharynx17%

32. Garden, A.S. J Clin Oncol 22:2856-2864, 2004 Time to locoregional failure 41% 27.5% Estimated 2-yr LR failure rate

33. Garden, A.S. J Clin Oncol; 22:2856-2864, 2004 R97-03: Disease-free Survival Estimated 2-yr DFS 51% 49% 38%

34. ( R91-14: 2-yr survival 72% ) R97-03: Overall survival 2-yr rate 57% 69% 67%

35. Randomized trials needed RTOG H0129 Stage III/IV OC, OP, HP & Lx Accelerated fx/concomitant boost + cisplatin x 2 versus Standard fractionation + cisplatin x 3 RTOG H0522 Stage III/IV OC, OP, HP & Lx Accelerated fx/comcomitant boost + cisplatin 100 mg/m 2 x 2 +/- cetuximab

36. E1303: Non-operative rx for resectable patients (E2399 replacement) Induction paclitaxel + carboplatin + C225 (PCC) concurrent PCC + RT 70 Gy  Response assessment after induction and 50 Gy, surgery if < pCR after 50 Gy  Endpoints: 90% disease-free at completion of treatment

37. Phase II trial of C225 with RT and cisplatin in unresectable patients E3303: RT 70 Gy + C225 weekly + cisplatin 75 mg/m² days 1, 22 & 43 CR, PR, SD continue C225 for 6 mos Rationale: INT E1392 – improved 3-yr survival with RT/CDDP ( 37% vs 23%) Endpoints: PFS and survival, toxicity, molecular correlates Accrual: 68 pts to increase 2-yr PFS (35% to 50%)

38. Chemoradiotherapy Mixed site trials are useful for hypothesis generation and feasibility testing Efficacy for local-regional control may differ by primary site mandating site-specific trials –e.g. HPV related oropharynx cancer Alternative concurrent chemotherapy regimens to cisplatin 100 mg/m 2 or PF should not be assumed to have equivalent efficacy