5/20/ ) Haffty GB: Concurrent chemoradiation in the treatment of head and neck cancer. Hematol. Oncol. Clin: North Am.

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1 Prague, April 29 ALTERNATING CHEMORADIATION: FOR WHOM? M. Merlano MD Holy Cross Gen. Hospital Cuneo - Italy ALTERNATING CHEMORADIATION: FOR WHOM? Definition of alternating chemoradiation Targets of alternating chemoradiation Comparison of alternating vs concurrent chemoradiation Efficacy Toxicity Selection of patients alternating chemoradiation A minor variation of concurrent chemoradiation aimed at minimizing toxicity (1) 1) Haffty GB: Concurrent chemoradiation in the treatment of head and neck cancer. Hematol. Oncol. Clin: North Am. 1999;13:

2 Split course? No, thanks! Tumor repopulation Tumor repopulation Split course? No, thanks! CT CT CT CT What is the real principle? The uninterrupetd radiotherapy Or The uninterrupted tumor treatment? Alternating radiotherapy and chemotherapy produces less acute mucosal toxicity than synchronous therapy but may prolong the overall treatment time Although longer treatment times adversely affect efficacy in programs of standard alone due to tumor repopulation, the significance of overall treatment time in a continuous course of alternating and CT is controversial. Some investigators have suggested that the usual time-dose relationship do not apply ppy (1) From: David M. Brizel: The Role of Combined Radiotherapy and Chemotherapy in the Management of Locally Advanced Squamous Carcinoma of the Head and Neck. In Perez and Brady's Principles and Practice of Radiation Oncology (Editors Edward C. Halperin MD, MA, FACR, Carlos A. Perez MD, Luther W. Brady MD ). V Ed. p.87. Lippincott Williams & Wilkins December 27. (1) Wong WW et al time-dose relationship for local control following alternate week concomitant radiation and chemotherapy of advanced head and neck cancer Int. J Radiat. Oncol. Biol. Phys. 1994;29:

3 QuickTime e un decompressore TIFF (LZW) sono necessari per visualizzare quest'immagine. 5/2/29 alternating chemoradiation A minor variation of concurrent chemoradiation aimed at minimizing toxicity (1) The alternating chemoradiation allows uninterrupted (continuous) treatment of the tumor, with radiotherapy administered during the pauses between courses of chemotherapy (2) Preclinical studies support the hypothesis that alternating chemoradiation could preserve efficacy without significantly increasing toxicity (3) 1) Haffty GB: Concurrent chemoradiation in the treatment of head and neck cancer. Hematol. Oncol. Clin: North Am. 1999;13: ) Merlano M: Alternating chemotherapy and radiotherapy in locally advanced head and neck cancer: am alternative? The Oncologist 26;11: ) Looney WB et al: Alternation of chemotherapy and radiotherapy in cancer management. III. Results in experimental solid tumors systems and their relationship to clinical studies. Cancer Treat. Rep. 1986;7: Targets of alternating chemoradiation To preserve increased efficacy of chemoradiation without paying the cost of the increased toxicity RAPIDLY ALTERNATING CT/ (1,2,3) Weeks Chemotherapy Radiotherapy Chemotherapy: cisplatin, 2 mg/m 2 /die, days 1 to 5; fluorouracil bolus i.v., 2 mg/m 2 /die, days 1 to 5 Radiation: 2 cgy/die, 1 fraction per day, 5 fractions per week 1) Merlano M, et al. N Engl J Med 1992;327: ; J.Natl.Cancer Inst. 1996;88: ) Corvò R et al: Cancer 21;92: ) Lefebvre J-L et al: J. Natl Cancer Inst 29;11:

4 Alternating chemoradiation vs radiotherapy Merlano M et al: N Engl J Med 1992;327: ALT pts 8 77 CR (%) deaths On tretment 7 6 p Overall survival Corvò R et al: Cancer 21;92: ALT PA- pts 7 66 CR (%) deaths On tretment 7 8 p Overall survival Alternating chemoradiation vs induction CT and radiotherapy ORGAN PRESERVATION EOC Lefebvre J.L. et al: J Natl Cancer Inst 29;11: Can we say that alternating chemoradiation is superior to radiation alone? 1) median OS by study Merlano 17 m 11 m P =.1 Corvò 24 m 19 m P = NS Lefebvre 5.1 yrs 4.4 yrs P = NS Keane Corvò 21 Merlano 1996 Total 1) Not platinum based 4

5 Can we say that alternating chemoradiation is superior to radiation alone? Total dose (median) Median OS ALT- ALT- Merlano Corvò Lefebvre y 4.4 y Tab. 1 Selected randomized clinical trials of chemo-radiation Author # pts CT daily fraction 3-yrs OS 3-yrs OS Control arm p Fu (1987) 14 B Standard 43% 24%.16 Browman (1994) 175 F Standard 52% 37%.76 Corvò (21) 136 CF standard 37% 29%.2 Merlano (1996) 157 CF Standard 41% 23%.1 Adelstein (23) 295 C Standard 37% 23%.14 Brizel (1998) 116 CF Wendt (1998) 298 CF MFD 55% 34%.7 MFD 48% 24%.3 Huguenin (24) 224 C MFD 59% 49%.147 CT=chemotherapy; =radiotherapy; OS=overall survival; V=vinblastine; B=bleomycin; M=methotrexate; F=fluorouracil; C=cisplatin; MFD=multiple fractions per day modified from: Merlano M, Polla Mattiot V: future chemotherapy and radiotherapy options in head and neck cancer Expert Rev Anticancer Ther 26;6(3) Targets of alternating chemoradiation To preserve increased efficacy of chemoradiation ALT CT > evidence level I (meta-analysis) analysis) ALT CT = Concurrent CT/ not evidence based (lack of direct comparison) 5

6 Targets of alternating chemoradiation To preserve increased efficacy of chemoradiation without paying the cost of the increased toxicity Toxicity analysis From: Alternating and CT compared with alone in treatment of unresectable SCC-HN Merlano M et al: JNCI 1996;88:583-9 (modified) 157 pts WHO G. III-IV IV mucositis 19% vs 18% Toxicity related treatment delay: Alt. CT/ 1 week 21% 32% 2 weeks 11% 11% 3 weeks 4% 14% Overall 36% 47% From: Alternating chemoradiotherapy vs partly accelerated radiotherapy in locally advanced SCC-HN Corvò R et al: Cancer 21;92: (modified) Acute mucosal reaction observed in the treatment groups according to the objective OG Scale Combined treatment (n = 63) Radiotherapy (n = 64) Reaction n % n % Enanthema Patchy mucositis Confluent mucositis Hemorragic mucositis

7 From: Alternating chemoradiotherapy vs partly accelerated radiotherapy in locally advanced SCC-HN Corvò R et al: Cancer 21;92: (modified) Late effects (grade 2+) observed in 32 long surviving patients, disease free at 3 years Effect Combined treatment (n n = 2)(%) Radiotherapy (n n = 12)(%) P value Xerostomia 5 (25) 2 (17) NS Mucosal atrophy Subcutaneous fibrosis Larynx stricture 1 (5) 5 (42).1 4 (2) 8 (67).1 4 (2) 3 (25) NS Dysphagia 1 (5) 1 (8) NS Overall 1pts (5) 11pts (92).2 EOC OG Alternating CT / Sequential CT Sequential CT Concurrent CT - pts Hypoph. larynx 51% 49% % 1% F.U. Lar. Pres. (5 yrs) Ov. Surv. (5 yrs) 6.5 yrs med. 6.7 yrs med. (ASCO 6) ) Lefebvre J-L et al: J. Natl Cancer Inst 29;11: ) Forastiere AA et al: N Engl J Med 23;349:291-8; updated ASCO 26 Effects Mucositis % G 2 G 3-4 Late toxicities % EOC OG Alternating CT / P <.1 Sequential CT Sequential CT Concurrent CT (fib.) 41 (fib.) P <.29 P not reported P not reported 1) Lefebvre J-L et al: J. Natl Cancer Inst 29;11: ) Forastiere AA et al: N Engl J Med 23;349:291-8; updated ASCO 26 3) Data at two years 7

8 Tab. 1 Selected randomized clinical trials of chemo-radiation Author # pts CT daily fraction Control arm Median OS (months) 3-yrs OS G.III-IV IV stomatitis Fu (1987) 14 B Standard Standard Not reported 43% vs 24% P =.16 75% vs 25% p<.1 52% vs 37% 32% vs 11% Browman (1994) 175 F Standard Standard 33 / 25 P =.76 P =.1 Concomitant 37% vs 29% 33% vs 49% Corvò (21) 136 CF standard Not reported boost - P =.2 P =.12 41% vs 23% 19% vs 18% Merlano (1996) 157 CF Standard Standard 16.5 / 11.7 P <.5 P = NS Lefebvre (29) (1) Standard 5.6 / % vs 62% 21% vs 32% 45 CF Standard (+ induction CT) (years) P =.4 P = % vs 33% 43% vs 32% Adelstein (23) 295 C Standard Standard 19.1 / 12.6 P =.14 P = NS 55% vs 34% 77% vs 77% Brizel (1998) 116 CF MFD MFD Not reported P =.7 P = NS 48% vs 24% 38% vs 16% Wendt (1998) 298 CF MFD MFD Not reported P <.3 P <.1 Favours chemoradiation Favours radiation equivalent CT=chemotherapy; =radiotherapy; OS=overall survival; V=vinblastine; B=bleomycin; M=methotrexate; F=fluorouracil; C=cisplatin; NS=not significant; MFD=multiple fractions per day 1) Organ preservation trial Author CT/ worse (p<.1) CT/ worse (p<.5) CT/ worse (non sign.) worse (non sign.) worse (p<.5) FU (B) Browman (F) Adelstein (C) Brizel (CF) Wendt (CF) Corvò (CF) Merlano (CF) Lefebvre (CF) Acute toxicity: grade III-IV IV mucositis Targets of alternating chemoradiation without paying the cost of the increased toxicity ALT CT < evidence level I (multiple phase III) Concurrent CT/ > evidence level I (multiple phase III) 8

9 1,9,8,7,6,5,4,3,2,1 Survival distribution fu S(mts,9,8,7,6,5,4,3,2,1 5/2/29 Pros and cons CONCURRENT CHEMORADIATION ALTERNATING CHEMORADIATION PROS CONS PROS CONS TREATMENT DURATION 7 WEEKS 1 WEEKS COMPLEXITY LOW HIGH ACUTE TOXICITY LATE TOXICITY HIGHER THAN INDUCTION CT FOLLOWED BY HIGHER THAN ALONE HIGHER (?) THAN INDUCTION CT FOLLOWED BY LOWER THAN INDUCTION CT FOLLOWED BY LOWER THAN ALONE LOWER THAN INDUCTION CT FOLLOWED BY LOWER THAN Age and chemo-radiation Variation of treatment effect according to age in the concomitant part of MACH - NC Concomitant CT + vs Age(y) No. of pts Hazard ratio (95% CI) Test for trend (p) ( ) (.7-.87) (.78-1.) Tot 928 pts > 6 y = 36.8% ( ) From: Pignon JP et al Int J Radiat Oncol Biol Phys 69 s112-s114, 27, modified Retrospective analysis of 151 pts treated in clinical practice at H. Cross Gen. among 1998 and 25 - treatment: ALT-CT/ Survival distribution func 1,9,8,7,6,5,4,3,2, S(mts 9

10 Holy Cross General Hospital data base # of PTS 151 Age 65 yrs 4 (36.3%) Age < 65 yrs 111 Stage III - IV 151 From the H.C.Gen. Data base Statistic Observed vacritical value p-value alpha Log-rank,318 3,841,573,5 Wilcoxon 1,343 3,841,246,5 Tarone-Ware,914 3,841,339,5 Prog. free Survival distribution function 1,9,8,7,6,5,4,3,2, PFS 1 From the H.C.Gen. Data base StatisticObserved v Critical valuep-value alpha Log-rank,298 3,841,585,5 Wilcoxon,899 3,841,343,5 Tarone-Ware,641 3,841,423,5 Survival distribution function 1,9,8,7,6,5,4,3,2, S(mts) <65 65> 1

11 ALTERNATING CHEMORADIATION: FOR WHOM? Elderly pts (over 65) could be treated with alternating chemordiation The treatment is superior to radiation The treatment is less toxic compared to radiation Pts unfit for concurrent chemoradiation should be evaluated for alternating chemoradiation Speculative, no data available THANK YOU 11