altered fractionated RT in HNSCC : w hat is the m agnitude of the - PowerPoint PPT Presentation

altered fractionated RT in HNSCC : w hat is the m agnitude of the benefit ? Jean Bourhis, MD PhD I nstitute Gustave Roussy & ESTRO

Altered fractionation in HNSCC ? Objective = increase the « dose - intensity » of RT Accelerated RT Hyperfractionated RT

Hyperfractionation RT Dose / fraction = reduced (1.1 to 1.3 Gy) Spare normal tissues(from late effects) Total dose higher (80 Gy) Increased « dose - intensity »

Accelerated RT ? Protracting RT Detrimental Accelerated RT Beneficial ??

MARCH Meta-Analysis of Radiotherapy in Carcinomas of Head & neck Purpose : To test whether altered fractionated RT may improve survival as compared to conventional RT

Eligibility criteria (1) Trials properly randomized Performed between 1970 and 1998 Hyperfractionated or accelerated RT R Conventional RT IGR 09.02

7 weeks Reference 6 weeks Acceleration 5 weeks 4 weeks 3 weeks 2 weeks Total dose 50 Gy 60 Gy 70 Gy 80 Gy

Total dose increased 7 weeks 6 weeks Total the same (+/- 4%) 5 weeks 4 weeks Total dose 3 weeks decreased 2 weeks 50 Gy 60 Gy 70 Gy 80 Gy

7 weeks same time higher dose 6 weeks Same dose, shorter time 5 weeks 4 weeks lower dose, shorter time 3 weeks 2 weeks 50 Gy 60 Gy 70 Gy 80 Gy

RTOG 90-03 7 wks . Rio Oro 93 RTOG 90-03 EORTC 2279 1 RTOG 90-03 +Toronto ) 6 wks DAHANCA KBN79 CAIR 5 wks RTOG 73-01 27% EORTC 22851 Vancouver 4 wks TROG 91-01 GORTEC 94-02 3 wks 54% Vienna 2 wks CHART 19% 50 Gy 60 Gy 70 Gy 80 Gy

Data collection and checking Extensive checking Updated individual and validation to data collected for all ensure integrity of random ized patients random ization from published and and follow -up and unpublished trials im prove accuracy

Results

Overall survival (all 3 groups) 100 Alt. fractionated RT Conventional RT 80 Survival (% ) 5 7 .4 % 60 5 4 .1 % 3 9 .7 % 40 3 6 .3 % 20 0 ≥ 0 1 2 3 4 5 6 7 Time from randomisation (Years)

Non cancer and cancer death (all 3 groups) Alt. fractionated RT Conventional RT 100 1 0 0 9 1 .7 % 9 0 .5 % 7 8 .9 % 80 7 8 .4 % Non cancer 6 3 .2 % Survival (% ) death 60 6 0 5 0 .5 % 5 9 .1 % Cancer death 4 6 .2 % 40 20 2 0 0 0 ≥ 7 0 1 2 3 4 5 6 Time from randomisation (Years)

Overall survival 100 100 100 100 Acceleration w / o Hyperfractionation 80 80 80 80 total dose reduction Survival (% ) Survival (% ) 60 60 60 60 4 4 .4 % 3 6 .7 % 40 40 40 40 4 2 .4 % 2 8 .5 % 20 20 20 20 0 0 0 0 ≥ 7 ≥ 7 0 0 1 1 2 2 3 3 4 4 5 5 6 6 0 0 1 1 2 2 3 3 4 4 5 5 6 6 Alt. fractionated RT Time from randomisation (Years) Time from randomisation (Years) Conventional RT 100 100 100 100 100 All 3 groups Acceleration 80 80 80 80 80 with total dose reduction Survival (% ) Survival (% ) 60 60 60 60 60 3 9 .7 % 40 40 40 40 40 3 1 .9 % 3 6 .3 % 3 0 .2 % 20 20 20 20 20 0 0 0 0 0 ≥ 7 ≥ 7 0 0 1 1 2 2 3 3 4 4 5 5 6 6 0 0 0 1 1 1 2 2 2 3 3 3 4 4 4 5 5 5 6 6 6 Time from randomisation (Years) Time from randomisation (Years)

Overall survival No. Events / No. Entered HR of death HR ( 9 5 % CI ) O-E Variance Alt. fractionated RT Control ( Alt. fractionated RT / Control) ( a) Hyperfractionation EORTC 22791 3 126/ 180 135/ 176 -17.2 64.2 RIO 4 41/ 52 47/ 51 -11.5 20.6 PMH Toronto 5 119/ 172 124/ 164 -13.8 59.6 RTOG 9003 HF 6 184/ 276 201/ 279 -15.9 95.9 Subtotal (a) 470/ 680 507/ 670 -58.4 240.4 0 .7 8 [ 0 .6 9 - 0 .8 9 ] ( b) Accelerated fractionation w / o total dose reduction EORTC 22851 7 171/ 257 164/ 255 -1.3 83.3 RTOG 9003 S 6 205/ 281 201/ 279 1.2 101.5 RTOG 9003 B 6 190/ 277 201/ 279 -9.0 97.6 BCCA 9113 8 30/ 41 23/ 41 4.8 13.1 DAHANCA 9 422/ 755 413/ 730 -5.0 208.6 Oro 9301 10 51/ 65 48/ 63 4.8 24.4 CAI R 11 19/ 51 37/ 49 -16.5 12.6 KBN PO 79 12 42/ 196 41/ 199 1.3 20.7 Subtotal (b) 1130/ 1923 1128/ 1895 -19.9 561.8 0 .9 7 [ 0 .8 9 - 1 .0 5 ] ( c) Accelerated fractionation w ith total dose reduction RTOG 7913 13 91/ 106 87/ 104 -2.9 44.1 CHART 14 359/ 552 227/ 366 5.7 140.2 Vienna 15 62/ 78 66/ 81 -3.1 31.9 TROG 9101 16 96/ 174 109/ 176 -9.4 51.1 GORTEC 9402 17 105/ 137 111/ 131 -10.5 53.4 Subtotal (c) 713/ 1047 600/ 858 -20.2 320.6 0 .9 4 [ 0 .8 4 - 1 .0 5 ] Alt. fractionated RT Total (a ... c) 2313/ 3650 2235/ 3423 -98.5 1122.9 effect w ith p = 0 .0 0 3 0 .9 2 [ 0 .8 6 - 0 .9 7 ] Test for heterogeneity: Test for interaction: 0.0 0.5 1.0 1.5 2.0 2 2 = 38.07 p = 0.001 2 = 7.52 p = 0.02 Alt. fractionated RT better | Control better 16

Loco regional control (all 3 groups) 100 Alt. fractionated RT Conventional RT 80 Absolute difference Risk of recurrence (% ) at 5 years: 6 .4 ± 1 .3 % 60 5 2 .9 % 4 6 .5 % 40 20 0 ≥ 7 0 1 2 3 4 5 6 Time from randomisation (Years)

Loco regional control 100 100 100 100 Acceleration w / o Hyperfractionation 80 80 Risk of recurrence (% ) 80 80 Risk of recurrence (% ) total dose reduction 5 7 .9 % 60 60 60 60 4 7 .5 % 4 8 .5 % 40 40 40 40 4 0 .2 % 20 20 20 20 0 0 0 0 ≥ 7 0 0 1 1 2 2 3 3 4 4 5 5 6 6 ≥ 7 0 0 1 1 2 2 3 3 4 4 5 5 6 6 Time from randomisation (Years) Time from randomisation (Years) Alt. fractionated RT 100 100 100 100 Conventional RT 80 80 80 80 80 Absolute difference Risk of recurrence (% ) Risk of recurrence (% ) at 5 years: 6.4 ± 1.3% 5 9 .8 % 60 60 60 60 60 5 2 .9 % 5 7 .5 % 40 40 4 6 .5 % 40 40 40 Acceleration with 20 20 20 20 20 total dose reduction All the 3 groups together 0 0 0 0 0 ≥ 7 ≥ 7 0 0 1 1 2 2 3 3 4 4 5 5 6 6 0 0 0 1 1 1 2 2 2 3 3 3 4 4 4 5 5 5 6 6 6 Time from randomisation (Years) Time from randomisation (Years)

Loco regional control No. Events / No. Entered HR of recurrence HR ( 9 5 % CI ) O-E Variance Alt. fractionated RT Control ( Alt. fractionated RT / Control) ( a) Hyperfractionation EORTC 22791 3 78/ 180 99/ 176 -17.0 43.8 RIO 4 18/ 52 16/ 51 -1.4 8.2 PMH Toronto 5 91/ 172 101/ 164 -10.3 47.8 RTOG 9003 HF 6 123/ 276 147/ 279 -16.6 67.3 Subtotal (a) 310/ 680 363/ 670 -45.3 167.1 0 .7 6 [ 0 .6 6 - 0 .8 9 ] ( b) Accelerated fractionation w / o total dose reduction EORTC 22851 7 97/ 257 122/ 255 -16.0 54.6 RTOG 9003 S 6 143/ 281 147/ 279 -6.1 72.4 RTOG 9003 B 6 121/ 277 147/ 279 -16.4 66.9 BCCA 9113 8 25/ 41 21/ 41 2.2 11.5 DAHANCA 9 230/ 755 292/ 730 -37.6 130.4 Oro 9301 10 47/ 65 47/ 63 1.9 23.3 CAI R 11 13/ 51 31/ 49 -13.3 10.0 KBN PO 79 12 36/ 196 49/ 199 -6.1 21.2 Subtotal (b) 712/ 1923 856/ 1895 -91.5 390.3 0 .7 9 [ 0 .7 2 - 0 .8 7 ] ( c) Accelerated fractionation w ith total dose reduction RTOG 7913 13 77/ 106 74/ 104 -0.6 37.6 CHART 14 295/ 552 196/ 366 -1.8 117.4 Vienna 15 49/ 78 57/ 81 -4.6 26.4 TROG 9101 16 87/ 174 94/ 176 -3.3 45.2 GORTEC 9402 17 80/ 137 101/ 131 -17.9 44.6 Subtotal (c) 588/ 1047 522/ 858 -28.2 271.3 0 .9 0 [ 0 .8 0 - 1 .0 2 ] Alt. fractionated RT Total (a ... c) 1610/ 3650 1741/ 3423 -165.0 828.7 0 .8 2 [ 0 .7 7 - 0 .8 8 ] effect w ith p < 0 .0 0 0 1 Test for heterogeneity: Test for interaction: 2 0.0 0.5 1.0 1.5 2.0 2 =28.57 p = 0.03 2 = 3.8 p = 0.15 16 Alt. fractionated RT better Control better |

Local control HR of local recurrence Category/ Study No. Events / No. Entered HR ( 9 5 % CI ) Alt. fractionated RT Control Variance ( Alt. fractionated RT / Control) O-E ( a) Hyperfractionation EORTC 22791 3 74/ 180 95/ 176 -16.5 41.9 PMH Toronto 5 77/ 172 94/ 164 -12.8 42.6 RTOG 9003 HF 6 97/ 276 110/ 279 -10.1 51.6 Subtotal (a) 248/ 628 299/ 619 -39.4 136.0 0 .7 5 [ 0 .6 3 - 0 .8 9 ] ( b) Accelerated fractionation w / o total dose reduction EORTC 22851 7 82/ 257 108/ 255 -15.6 47.4 RTOG 9003 S 6 107/ 281 110/ 279 -4.6 54.2 RTOG 9003 B 6 89/ 277 110/ 279 -13.1 49.7 BCCA 9113 8 18/ 41 18/ 41 0.0 9.0 DAHANCA 9 183/ 755 253/ 730 -40.4 108.9 Oro 9301 10 36/ 65 38/ 63 0.4 18.4 CAI R 11 11/ 51 30/ 49 -13.1 9.5 KBN PO 79 12 33/ 196 48/ 199 -7.1 20.2 Subtotal (b) 559/ 1923 715/ 1895 -93.4 317.2 0 .7 4 [ 0 .6 7 - 0 .8 3 ] ( c) Accelerated fractionation w ith total dose reduction CHART 14 251/ 552 183/ 366 -11.2 103.8 Vienna 15 48/ 78 55/ 81 -4.0 25.7 GORTEC 9402 17 74/ 137 95/ 131 -16.8 41.7 Subtotal (c) 373/ 767 333/ 578 -32.0 171.2 0 .8 3 [ 0 .7 1 - 0 .9 6 ] Alt. fractionated RT Total (a ... c) 1180/ 3318 1347/ 3092 -164.8 624.4 0 .7 7 [ 0 .7 1 - 0 .8 3 ] effect w ith p < 0 .0 0 0 1 Test for heterogeneity: Test for interaction: 0.0 0.5 1.0 1.5 2.0 2 2 Alt. fractionated RT better 13 = 21.83 p = 0.06 | Control better 2 = 1.4 p = 0.5