1. Multimodality treatment of head and neck SCC R5 林育靖 / P 洪瑞隆

4. Anatomy

6. T stage of oropharyngeal cancer T1 T2 T3 T4a T4b Invade to adjacent tissue, less extensive Invade to adjacent tissue, more extensive

7. Ipsilateral Contralateral N1 Single,< 3 cm Single ipsilateral, < 3cm

8. N2a Single ipsilateral, 3-6cm Contralateral Ipsilateral Single, 3-6 cm

9. N2b Multiple ipsilateral, < 6cm Ipsilateral < 6 cm Contralateral

10. N2c Bilateral or contralateral, < 6cm Ipsilateral < 6 cm Contralateral

11. N3 Any LN > 6cm Ipsilateral > 6 cm Contralateral

12. Staging M0 N3 Any T M1 Any N Any T Stage IVc M0 Any N T4b Stage IVb M0 N2 T4a M0 N2 T3 M0 N2 T2 M0 N2 T1 M0 N1 T4a M0 N0 T4a Stage IVa M0 N1 T3 M0 N1 T2 M0 N1 T1 M0 N0 T3 Stage III M0 N0 T2 Stage II M0 N0 T1 Stage I

16. Intergroup 0034 Laramore GE et al. Int J Radiat Oncol Biol Phys 1992; 23: 705-713 442 pts, resectable, III/IV, SCC C/T x 3 Surgery XRT XRT Cisplatin 100mg/m2, D1 5-FU 1000mg/m2/d IVF 24hrs, D1-D5 q3w Compliance of adjuvant C/T: 63% Surgery 30% Larynx 17% Hypopharynx 26% 27% Oropharynx Oral NS 38% 46% DFS NS 44% 46% OS 0.03 NS p 23% 15% Dist Mets 24% RT 19% CT/RT LRR 4 yrs

17. NCI 443 pts, resectable, III/IV, SCC C/T x 1 XRT XRT Surgery C/T x 6 XRT Surgery C/T x 1 Surgery Cisplatin 100mg/m2, D1 Bleomycin 15mg/m2, D3-D7 Cisplatin 80mg/m2, monthly Compliance: 9% complete 6 cycles 27% complete > 3 cycles 45% received none A B C Cancer 1987; 60: 301-311 J Clin Oncol 1990; 8: 838-847 19% Larynx 35% Hypopharynx 46% Oral NS 45% 37% 35% OS NS 64% 49% 55% DFS 22% 42% B 0.011 (C vs A) NS p 13% 24% Dist Mets 30% C 41% A LRR 5 yrs

19. British Journal of Cancer 2000; 83: 1594-1598 GETTEC, French 318, HNSCC, oropharynx stage II-IV Induction C/T Cisplatin 100mg/m2, D1 5-FU 1000mg/m2, D1-D5 q3w, 3 cycles Operable: Surgery  RT Inoperable: RT Operable: Surgery  RT Inoperable: RT

20. chemotherapy No chemotherapy Overall survival p=0.03 chemotherapy No chemotherapy Dz-free survival p=0.11 GETTEC, French

21. Journal of the National Cancer Institute 1994; 86: 265-272 Journal of the National Cancer Institute 2004; 96: 1714-1717 GSTTC, Italy 237, HNSCC, stage III/IV Induction C/T Operable: Surgery  RT Inoperable: RT Cisplatin 100mg/m2, D1 5-FU 1000mg/m2, D1-D5 q3w, 4 cycles Operable: Surgery  RT Inoperable: RT A B Oral cavity Para-nasal sinus Hypopharynx Oropharynx 73% 71% Inoperable 29% A 27% Operable B

22. All pts Operable group Inoperable group Overall survival Overall survival Overall survival 3-yr distant metastasis rate 0.01 31% 3% Operable 0.04 p value 42% B 24% A Inoperable

23. SWOG 158, Head Neck epidermoid carcinoma, stage III/IV Induction C/T Surgery  RT Cisplatin 50mg/m2, D1 MTX 40mg/m2, D1 Bleomycin 15U/m2, D1, D8 Vincristine 2mg, D1 Q3w, 3 cycles A B Laryngoscope 1988; 98: 1205 Surgery  RT  No survival benefit 21% 16% 28% 35% Oral cavity Larynx Hypopharynx Oropharynx 0.07 28% 49% Distant mets 48% 40% Local recur 23% 31% DFS p 38% 40% OS 24% B 14% A Regional recur 4yr

25. Concurrent chemoradiotherapy

26. 859 pts, HNSCC stage III/IV HFxRT Conventional RT Sanchiz F et al. Int J Radiat Oncol Biol Phys. 1990; 19: 1347-1350 CCRT (conventional RT) 60Gy/30fx, 2Gy/d 70.4Gy, 1.1Gy bid 5FU 250mg/m2, qod <0.01(A v B) <0.01(A v C) <0.01(A v B) <0.01(A v C) p 96.3% 90% 67.8% RR 37% 31% 17% 10yr DFS 42% C: CCRT 40% B: HFxRT 17% A: RT 10yr OS 36% Larynx 10% Other 14% Hypopharynx 11% Nasopharynx 29% Oral cavity

27. Journal of Clinical Oncology 1994; 12: 2648-2653 175 pts, HNSCC T3/T4 RT alone CCRT Identical RT in both arms RT: 60Gy/30fx, conventional C/T: 5-FU 1200mg/m2/d, infusion D1-D3, D22-D24 More mucositis, weight loss, and skin toxicity in CCRT arm Browman GP et al 0.04 56% 68% Complete response 0.08 42% 58% 3yr OS 0.057 p value 30% RT 40% CCRT 3yr PFS 27% Larynx 5% Other 14% Hypopharynx 42% Oropharynx 12% Oral cavity

28. 100 pts, HNSCC stage III/IV RT alone CCRT RT: 66-72Gy, conventional, 1.8-2Gy/fx Aldelstein DJ et al Cancer 2000; 88: 876-883 Cisplatin: 20mg/m2/d 5FU: 1000mg/m2/d Infusion, D1-D4 D22-D25 Primary site resection +/- neck dissection Residual dz or recurrence Survival benefit from better local control <0.001 77% 45% Local control without resection 0.004 42% 34% OS with primary site preserve 75% 51% 48% RT 0.55 50% OS 0.09 84% Dist. Mets-free survival 0.04 p value 62% CCRT RFS 5yr 36% Larynx 16% Hypopharynx 44% Oropharynx 4% Oral cavity

29. Journal of National Cancer Institute 1999; 91:2081-2086 GORTEC 226 pts, oropharynx III/IV RT alone CCRT Identical RT in both arms RT: 7000cGy/35fx, conventional Dose delivery q3w, 3 cycles Carbo 70mg/m2/d, D1-D4 5FU 600mg/m2/d, D1-D4 0.02 42% 66% LR control 0.04 20% 31% DFS NS 11% 11% Dist. mets 0.02 p value 42% RT 51% CCRT OS 3yr 6960 cGy CCRT 6920 cGy RT dose RT 67% 66% 3rd 88% 86% 2nd 1st 98% 5FU 98% Carbo

30. Journal of Clinical Oncology 2000; 18: 1458-1464 130 pts, HNSCC stage III/IV HFxRT alone CCRT (HFxRT) Identical RT in both arms RT: 77Gy/70fx/35d, 1.1Gy bid C/T: 5FU 6mg/m2/d, 5days/wk Similar stomatitis, esophagitis in both arm, more leukopenia and thrombocytopenia in CCRT arm Jeremic B et al, Japan 0.0013 57% 86% Dist. Mets-PFS 0.0075 25% 46% OS 0.041 36% 50% Local recur.-PFS 0.0068 p value 25% RT 41% CCRT PFS 5yr 17% Larynx 9% Nasophaynx 16% Hypopharynx 37% Oropharynx 21% Oral cavity

31. Journal of Clinical Oncology 2003; 21: 92-98 ECOG RTOG 295 pts, HNSCC unresectable III/IV A: RT alone B: CCRT surgery Cisplatin 100mg/m2, D1, D22, D43 C: CCRT (RT 3000cGy) CR or unresectable CCRT (RT 4000cGy) PR CCRT (RT 3000cGy) Cisplatin 75mg/m2, D1 5FU 1000mg/m2/d x 4d q4w x 3 RT: 7000cGy/35fx, conventional identical in three arms 9% Larynx 19% Hypopharynx 59% Oropharynx 13% Oral cavity 0.001(A vs C) 0.05(B vs C) 73% 85.1% 92.6% Treatment compliance NS 0.014 (A vs B) p 27% 37% 23% 3y OS 19.1% 21.8% 17.9% Dist. Mets as first site C B A

32. Journal of Clinical Oncology 1994; 12: 385-395 215 pts, HNSCC stage III/IV, unresectable RT 70Gy/35fx C/T  RT (A) CCRT (B) Cisplatin 100mg/m2, D1 5-FU 1000mg/m2, D1-D5 Q3w x 3 Cisplatin 60mg/m2, D1 5-FU 800mg/m2, D1-D5 Qw x 7 Taylor SG et al NS p=0.011 11% Larynx 27% Hypopharynx 6% Nasopharynx 23% Oropharynx 32% Oral 1% Sinus 55% 41% 3-yr dz specific survival 42% 36% 3-yr OS 7% 10% Dist Mets 41% 55% LR recurrence B A 81% 79% 88% B No difference % RT delay 78% % RT(>65Gy) 97% % 5-FU 97% % Cisplatin A

34. J Clin Oncol. 1995; 13: 876-83 Annals of Oncology 2004; 15: 1179-1186 Brockstein B et al Induction C/T x 3 CCRT Intensified CCRT 164 pts 230 pts Cisplatin 100mg/m2, D1 5FU 640mg/m2/d, CVI, D1-D5 Leucovorin 100mg q4h po, D1-D6 INF- α 2MU/m2/d, D1-D6 q3w PFLI 5FU 800mg/m2/d x 5/wk Hydroxyurea 1000mg q12h, 11doses/wk RT 6000cGy/30fx FHX 5FU 800mg/m2/d x 5/wk Hydroxyurea 1000mg q12h, 11doses/wk RT 6000cGy/30fx Cisplatin 100mg/m2, D1 or Paclitaxel 100mg/m2, D1 q3w x 3 + PFLI-FHX (C/T)HF2X

35. Distant failure Locoregional failure Overall survival Progression-free survival J Clin Oncol. 1995; 13: 876-83 Annals of Oncology 2004; 15: 1179-1186

40. Journal of Clinical Oncology 2002; 20: 3964-3971 53 pts, HNSCC, oropharynx, stage III/IV C/T x 2 CCRT Carboplatin AUC 6 Paclitaxel 200mg/m2 q3w Non-responder Surgery  RT C/T x 2 Neck dissection N2/N3 dz University of Pennsylvania RT: 70Gy/35fx/7wk Paclitaxel 30mg/m2/wk CCRT: Historical control: similar pts, OP  RT, 3-yr dist.mets: 30% Am J Otolaryngol 2001; 22:329-335 Induction C/T: RR 89% C/T  CCRT: 90% CR 77% Organ preserve 19% Distant metastasis 17% Locoregional recurrence 70% OS 59% 3-yr EFS

42. Journal of Clinical Oncology 2004; 22: 4905(abstr 5508)

44. Journal of Clinical Oncology 2005; 23: 8636-8645 382 pts, HNSCC stage III/IV CF x 3 PCF x 3 Hitt R et al, Spain Paclitaxel 175mg/m2, D1 Cisplatin 100mg/m2, D2 5FU 500mg/m2/d, D2-D6 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d, D1-D5 q3w q3w CCRT Cisplatin 100mg/m2, q3w RT 7000cGy/35fx CR or PR>80% Poor responder Salvage surgery 30% Larynx 23% Hypopharynx 34% Oropharynx 13% Oral cavity 65% Unresectable 35% Resectable

45. Hitt R et al, Spain Journal of Clinical Oncology 2005; 23: 8636-8645 0.03 26m 36m Time to tx failure 0.03 37m 43m Median survival Induction <0.001 14% 33% CR <0.001 16% 53% mucositis p value 36% CF 37% PCF neutropenia Dose density <0.001 81% 91% Cisplatin 99% Paclitaxel <0.001 p value 91% CF 98% PCF 5FU

46. Ongoing trials HNSCC, locally advanced Induction C/T CCRT CCRT Journal of Clinical Oncology 2006; 24: 2624-2628

48. Post-op CCRT

51. N Eng J Med 2004; 350: 1945-1952 EORTC 22931 167 pts, HNSCC stage III/IV XRT Cisplatin + XRT Cisplatin 100mg/m2, D1, D22, D43 XRT 54Gy/27fx, Boost 12Gy/6fx Surgery Surgery pT3/T4 + any N pT1/T2 + N2/N3 pT1/T2 + N0/N1 + unfavorable patho 80% 20% Vascular embolism 43% 57% Extracapsular spread 2% 85% 13% Perineural invasion 1% Unknown 71% Negative 28% Positive Margin 1% Unknown 22% Larynx 20% Hypopharynx 30% Oropharynx 26% Oral cavity

52. N Eng J Med 2004; 350: 1945-1952 EORTC 22931 0.61 25% 21% Dist Mets 0.007 31% 18% LRR 0.02 40% 53% 5yr OS 0.04 p value 36% RT 47% CCRT 5yr PFS 0.001 21% 41% Acute mucosa reaction - 16% Severe leukopenia 20% 14% Xerostomia p value 5% RT 10% CCRT Mucosa fibrosis 49% 3rd 66% 2nd 88% 1st C/T on time without delay

53. RTOG 9501 416 pts, HNSCC, high risk of recurrence XRT Cisplatin + XRT Cisplatin 100mg/m2, D1, D22, D43 XRT 60Gy/30fx, Boost 6Gy/3fx Surgery Surgery N Eng J Med 2004; 350: 1937-1944 83% LN>2 or extracapsular extension 17% Positive margin 21% Larynx 10% Hypopharynx 42% Oropharynx 27% Oral cavity

54. N Eng J Med 2004; 350: 1937-1944 45.9 months follow-up time hematological, mucosa, GI tract RTOG 9501 0.46 20% 23% Dist Mets as 1st event 0.01 30% 19% LRR 0.19 45% 52.5% OS 0.01 p value 30% RT 40% CCRT DFS 0.001 34% 77% Acute adverse effect 0.29 p value 17% RT 21% CCRT Late adverse effect

56. Organ preservation

59. New England Journal of Medicine 1991; 324: 1685-1690 Veterans Affairs Laryngeal Cancer Study Group 332 pts, laryngeal SCC stage III/IV Surgery Surgery +/- RT C/T x 2 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w RT: 5000cGy/25fx Adjuvant RT Definitive RT RT: 6600-7600cGy C/T x 1 Residual disease Poor respond 39% Laryngectomy-free survival 0.001 11% 17% Distant mets NS 8% 5% Recur at regional 0.001 12% 2% Recur at primary 0.98 68% 68% OS 0.12 p value 65% C/T  RT 75% Surgery DFS 2yr 26% T4 65% T3 9% T1/T2 63% Supraglottis 37% Glottis

61. Journal of National Cancer Institute 1996; 8: 890-899 EORTC 194 pts, hypopharynx SCC stage II/III/IV Surgery Surgery +/- RT C/T x 2 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w RT: 5000cGy/25fx Adjuvant RT Definitive RT RT: 7000cGy C/T x 1 Residual disease Poor respond 35% Laryngectomy-free survival 0.041 25% 36% Distant mets NS 19% 23% Recur at regional NS 12% 17% Recur at local NS 30% 35% OS NS p value 25% C/T  RT 32% Surgery DFS 5yr 5% T4 75% T3 20% T2 22% Aryepiglottic fold 78% Pyriform sinus

62. Oral Oncology 1998; 34: 224-228 GETTEC, French 68 pts, laryngeal SCC all T3 Surgery C/T x 3 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w RT: 5000cGy/25fx Adjuvant RT Definitive RT RT: 7000cGy Inferior outcome !! 28% Unknown 41% Glottis 31% Supraglottis 42% 8yr Laryngectomy-free survival 0.006 69% 84% 2yr OS 0.02 p value 62% C/T  RT 78% Surgery 2yr DFS

63. New England Journal of Medicine 2003; 349: 2091-2098 RTOG 91-11 518 pts, laryngeal SCC III/IV Surgery +/- RT C/T x 2 Cisplatin 100mg/m2, D1 5FU 1000mg/m2/d x 5d q3w CCRT RT CCRT: RT 7000cGy/35fx Cisplatin 100mg/m2, q3w C/T x 1 Residual disease Poor respond RT alone Speech/swallow : similar 0.004(B v C) 0.001(B v A) 61% 78% 56% LR control 0.03(B v A) 15% 12% 22% Distant mets 0.005(B v C) 0.001(B v A) 75% 88% 70% Intact larynx 56% 27% A: RT NS 55% 54% OS 0.02(C v A) 0.006(B v A) p 38% C: C/T  RT 36% B: CCRT DFS 5yr 10% T4 78% T3 12% T2 31% Glottis 69% Supraglottis