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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

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SLIDE 1

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

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SLIDE 2

Altered fractionation in HNSCC ?

Objective = increase the « dose - intensity » of RT Accelerated RT Hyperfractionated RT

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SLIDE 3

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 »

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SLIDE 4

Accelerated RT ?

Protracting RT Detrimental Accelerated RT Beneficial ??

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SLIDE 5

Purpose : To test whether altered fractionated RT may improve survival

as compared to conventional RT

Meta-Analysis of Radiotherapy in Carcinomas of Head & neck

MARCH

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SLIDE 6

Eligibility criteria (1)

Trials properly randomized Performed between 1970 and 1998

R

Conventional RT Hyperfractionated or accelerated RT

IGR 09.02

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SLIDE 7

50 Gy 60 Gy 70 Gy 80 Gy

7 weeks 6 weeks 5 weeks 4 weeks 3 weeks 2 weeks

Acceleration Total dose

Reference

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SLIDE 8

50 Gy 60 Gy 70 Gy 80 Gy

7 weeks 6 weeks 5 weeks 4 weeks 3 weeks 2 weeks

Total dose decreased Total the same

(+/- 4%)

Total dose increased

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SLIDE 9

50 Gy 60 Gy 70 Gy 80 Gy

7 weeks 6 weeks 5 weeks 4 weeks 3 weeks 2 weeks

lower dose, shorter time Same dose, shorter time same time higher dose

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SLIDE 10

50 Gy 60 Gy 70 Gy 80 Gy 7 wks. 6 wks 5 wks 4 wks 3 wks 2 wks CHART TROG 91-01 GORTEC 94-02 Vienna RTOG 73-01 Vancouver DAHANCA RTOG 90-03 Oro 93 EORTC22851 CAIR

KBN79

Rio RTOG 90-03 EORTC22791 +Toronto) RTOG 90-03

19% 54% 27%

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SLIDE 11

Data collection and checking

Updated individual data collected for all random ized patients from published and unpublished trials Extensive checking and validation to ensure integrity of random ization and follow -up and im prove accuracy

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SLIDE 12

Results

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SLIDE 13

Overall survival (all 3 groups)

  • Alt. fractionated RT

Conventional RT

Survival (% ) 20 40 60 80 100 Time from randomisation (Years) 1 2 3 4 5 6 ≥ 7

5 7 .4 % 3 9 .7 % 5 4 .1 % 3 6 .3 %

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SLIDE 14

Non cancer and cancer death (all 3 groups)

Survival (% ) 20 40 60 80 100 Time from randomisation (Years) 1 2 3 4 5 6 ≥7

2 0 6 0 1 0 0

6 3 .2 % 5 0 .5 % 5 9 .1 % 4 6 .2 % 9 0 .5 % 7 8 .4 % 9 1 .7 % 7 8 .9 % Cancer death Non cancer death

  • Alt. fractionated RT

Conventional RT

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SLIDE 15

Overall survival

  • Alt. fractionated RT

Conventional RT

20 40 60 80 100 1 2 3 4 5 6 3 6 .7 % 2 8 .5 % Survival (% ) 20 40 60 80 100 Time from randomisation (Years) 1 2 3 4 5 6 ≥7 20 40 60 80 100 1 2 3 4 5 6 4 4 .4 % 4 2 .4 % Survival (% ) 20 40 60 80 100 1 2 3 4 5 6 Time from randomisation (Years) ≥7 20 40 60 80 100 1 2 3 4 5 6 3 1 .9 % 3 0 .2 % Survival (% ) 20 40 60 80 100 1 2 3 4 5 6 Time from randomisation (Years) ≥7 Survival (% ) 100 100 20 40 60 80 1 2 3 4 5 6 3 9 .7 % 3 6 .3 % 20 40 60 80 1 2 3 4 5 6 20 40 60 80 100 1 2 3 4 5 6 Time from randomisation (Years) ≥7

Hyperfractionation

Acceleration w / o total dose reduction Acceleration with total dose reduction All 3 groups

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SLIDE 16

Overall survival

  • Alt. fractionated RT

effect w ith p = 0 .0 0 3

( 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 ]

Total (a ... c) 2313/ 3650 2235/ 3423

  • 98.5

1122.9

  • Alt. fractionated RT
  • No. Events / No. Entered

Control O-E Variance HR of death ( Alt. fractionated RT / Control) HR ( 9 5 % CI )

Test for heterogeneity:

2 16

= 38.07 p = 0.001 Test for interaction:

2 2 = 7.52

p = 0.02

0 .9 2 [ 0 .8 6 - 0 .9 7 ]

  • Alt. fractionated RT better

|

Control better

0.0 0.5 1.0 1.5 2.0

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SLIDE 17

Loco regional control (all 3 groups)

Risk of recurrence (% ) 20 40 60 80 100 Time from randomisation (Years) 1 2 3 4 5 6 ≥7

4 6 .5 % 5 2 .9 % Absolute difference at 5 years: 6 .4 ± 1 .3 %

  • Alt. fractionated RT

Conventional RT

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SLIDE 18

Loco regional control

  • Alt. fractionated RT

Conventional RT

Risk of recurrence (% ) 20 40 60 80 100 Time from randomisation (Years) 1 2 3 4 5 6 ≥7 20 40 60 80 100 1 2 3 4 5 6 4 8 .5 % 5 7 .9 % Risk of recurrence (% ) 20 40 60 80 100 1 2 3 4 5 6 4 0 .2 % 4 7 .5 % 20 40 60 80 100 1 2 3 4 5 6 ≥7 Time from randomisation (Years) 100 20 40 60 80 1 2 3 4 5 6 5 7 .5 % 5 9 .8 % 20 40 60 80 100 1 2 3 4 5 6 Risk of recurrence (% ) Time from randomisation (Years) ≥7 20 40 60 80 100 1 2 3 4 5 6 4 6 .5 % 5 2 .9 % All the 3 groups together 20 40 60 80 100 1 2 3 4 5 6 20 40 60 80 1 2 3 4 5 6 Risk of recurrence (% ) Time from randomisation (Years) ≥7 Absolute difference at 5 years: 6.4 ± 1.3%

Hyperfractionation

Acceleration w / o total dose reduction Acceleration with total dose reduction

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SLIDE 19

Loco regional control

  • Alt. fractionated RT

effect w ith p < 0 .0 0 0 1

( a) Hyperfractionation

EORTC 227913 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 ]

Total (a ... c) 1610/ 3650 1741/ 3423 -165.0 828.7

  • Alt. fractionated RT
  • No. Events / No. Entered

Control O-E Variance HR of recurrence ( Alt. fractionated RT / Control) HR ( 9 5 % CI )

Test for heterogeneity:

2 16

=28.57 p = 0.03 Test for interaction:

2 2 = 3.8

p = 0.15

0 .8 2 [ 0 .7 7 - 0 .8 8 ]

  • Alt. fractionated RT better

| Control better 0.0 0.5 1.0 1.5 2.0

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SLIDE 20

Local control

  • Alt. fractionated RT

effect w ith p < 0 .0 0 0 1

( 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 ]

Total (a ... c) 1180/ 3318 1347/ 3092

  • 164.8

624.4

Category/ Study

  • Alt. fractionated RT
  • No. Events / No. Entered

Control O-E Variance HR of local recurrence ( Alt. fractionated RT / Control) HR ( 9 5 % CI ) Test for heterogeneity:

2 13= 21.83

p = 0.06 Test for interaction:

2 2 = 1.4

p = 0.5

0 .7 7 [ 0 .7 1 - 0 .8 3 ]

  • Alt. fractionated RT better

| Control better 0.0 0.5 1.0 1.5 2.0

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SLIDE 21

Regional control

  • Alt. fractionated RT

effect w ith p = 0 .0 1

( a) Hyperfractionation

EORTC 22791 3 28/ 180 38/ 176

  • 6.8

16.4 PMH Toronto 5 58/ 172 58/ 164

  • 2.8

28.9 RTOG 9003 HF 6 60/ 276 67/ 279

  • 5.2

31.7

Subtotal (a) 146/ 628 163/ 619

  • 14.8

77.0

0 .8 3 [ 0 .6 6 - 1 .0 3 ]

( b) Accelerated fractionation w / o total dose reduction

EORTC 22851 7 58/ 257 73/ 255

  • 9.8

32.6 RTOG 9003 S 6 66/ 281 67/ 279

  • 2.1

33.2 RTOG 9003 B 6 70/ 277 67/ 279 0.2 34.2 BCCA 9113 8 17/ 41 10/ 41 3.6 6.7 DAHANCA 9 91/ 755 100/ 730

  • 6.8

47.7 Oro 9301 10 21/ 65 26/ 63

  • 1.7

11.7 CAI R 11 6/ 51 9/ 49

  • 2.3

3.6 KBN PO 79 12 3/ 196 2/ 199 0.6 1.2

Subtotal (b) 332/ 1923 354/ 1895

  • 18.4

171.0

0 .9 0 [ 0 .7 7 - 1 .0 4 ]

( c) Accelerated fractionation w ith total dose reduction

CHART 14 135/ 552 84/ 366 2.7 52.4 Vienna 15 25/ 78 41/ 81

  • 7.6

16.5 GORTEC 9402 17 58/ 137 69/ 131

  • 9.0

31.5

Subtotal (c) 218/ 767 194/ 578

  • 13.9

100.3

0 .8 7 [ 0 .7 2 - 1 .0 6 ]

Total ( a ... c) 6 9 6 / 3 3 1 8 7 1 1 / 3 0 9 2

  • 4 7 .1

3 4 8 .3

  • Alt. fractionated RT
  • No. Events / No. Entered

Control O-E Variance HR of regional recurrence ( Alt. fractionated RT / Control) HR ( 9 5 % CI ) Test for heterogeneity: 2 13 = 11.8 p = 0.54 Test for interaction: 2 2= 0.38 p = 0.83

0 .8 7 [ 0 .7 9 - 0 .9 7 ]

  • Alt. fractionated RT better

| Control better 0.0 0.5 1.0 1.5 2.0

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SLIDE 22

Subgroup analyses

Category

  • No. Deaths / No. Entered
  • Alt. fractionated RT

Control O-E Variance Hazard Ratio I nteraction test

  • Alt. fractionated RT better

| Control better 0.0 0.5 1.0 1.5 2.0 Age

50 or less 374/ 680 394/ 631

  • 45.6

184.5 51-60 736/ 1172 719/ 1128

  • 19.4

355.5 61-70 785/ 1221 736/ 1125

  • 29.3

371.4 71 or over 408/ 561 376/ 524 14.2 191.0

p = 0 .0 2

Sex

Male 1916/ 3005 1839/ 2777

  • 93.6

924.9 Female 388/ 630 387/ 632

  • 6.0

187.1

p = 0 .3 9

Perform ance status

1017/ 1878 1030/ 1802

  • 64.2

507.0 1 959/ 1348 900/ 1235

  • 8.4

454.6 2 or 3 297/ 367 269/ 326

  • 14.0

124.2

p = 0 .2 3

Stage

I-II 397/ 950 355/ 862

  • 2.8

184.2 III 639/ 1024 681/ 1000

  • 62.4

321.8 IV 1265/ 1655 1189/ 1542

  • 43.4

602.4

p = 0 .1 0

Site

Oral cavity 282/ 370 278/ 346

  • 15.7

134.9 Oropharynx 1150/ 1673 1127/ 1576

  • 53.9

561.2 Larynx 586/ 1231 553/ 1142

  • 19.9

276.8 Hypopharynx 235/ 297 227/ 282

  • 12.3

110.7 Others 52/ 69 45/ 72 8.9 19.6

p = 0 .2 0

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SLIDE 23

Meta-analysis on fractionation : less or no benefit in older patients

50 or less 768 / 1 311 51-60 1 455 / 2 300 61-70 1521 / 2 346 71 + 784 / 1 085 Total 4 528 / 7 042 Category No. Events / No. Entered Hazard ratio (Alt. fractionated RT/Control)

  • Alt. fractionated RT effect p=0.02
  • Alt. Frac. RT better |

Control better Test of interaction: p = 0.02 Test for trend: p = 0.007 0.0 0.5 1.0 1.5 2.0 0.78 [0.65 - 0.94] 0.95 [0.83 - 1.09] 0.92 [0.81 - 1.06] 1.08 [0.89 - 1.30] HR [95% CI] 0.92 [0.86 - 0.97]

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SLIDE 24

The more dose-intensity, the better ? where are the limits ?

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SLIDE 25

Gortec randomized trial

N = 268 T3-T4 HNSCC 70 Gy / 7 weeks 64 Gy / 3.5 weeks

IIIII IIIII IIIII IIIII IIIII IIIII IIIII IIIII IIIII IIIII II IIIII IIIII IIIII II

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SLIDE 26

50 Gy 60 Gy 70 Gy 80 Gy

7 weeks 6 weeks 5 weeks 4 weeks 3 weeks 2 weeks

Very accelerated Moderately accelerated Hyperfractionated

64.8 Gy

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SLIDE 27

Radio-induced mucositis : 64 Gy / 3 weeks

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SLIDE 28

No increase in late toxicity grade III / IV

(Bourhis et al JCO 2006)

Accelerated Conventional Mucosa 24% 19% NS Neck fibrosis 20.3% 10%

p = 0.2

Larynx 8.4% 5.6% NS Other 28% 31% NS

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SLIDE 29

7 11 19 33 37 59 137 2 9 13 17 23 49 129

0,00 0,20 0,40 0,60 0,80 1,00 1 2 3 4 5 6

Years from randomization

Very accelerated RT (n=137) Conventional RT (n=129)

logrank test p = 0.0087

At risk

LOCO-REGIONAL CONTROL

Bourhis et al JCO 2005

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SLIDE 30

Effect on local control

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SLIDE 31

50 Gy 60 Gy 70 Gy 80 Gy

7 weeks 6 weeks 5 weeks 4 weeks 3 weeks 2 weeks

Very accelerated Moderately accelerated Hyperfractionated

68 Gy

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SLIDE 32

Swedish randomized study : to markedly increase the dose intensity via a very strong acceleration of RT, keeping the total dose the same

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SLIDE 33

ARTSCAN loco-regional control : small effect depsite the very strong acceleration

  • Loco-regional control at 2

years: AF: 70.8 % CF: 66.7 %

AF CF p=0.50

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SLIDE 34

Are the results of ARTSCAN compatible with the benefit previously observed with accelerated RT in HNSCC ?

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SLIDE 35

Meta-analysis on fractionation : local regional control

  • Alt. fractionated RT

effect w ith p < 0 .0 0 0 1

( a) Hyperfractionation

EORTC 227913 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 ]

Total (a ... c) 1610/ 3650 1741/ 3423 -165.0 828.7

  • Alt. fractionated RT
  • No. Events / No. Entered

Control O-E Variance HR of recurrence ( Alt. fractionated RT / Control) HR ( 9 5 % CI )

Test for heterogeneity:

2 16

=28.57 p = 0.03 Test for interaction:

2 2 = 3.8

p = 0.15

0 .8 2 [ 0 .7 7 - 0 .8 8 ]

  • Alt. fractionated RT better

| Control better 0.0 0.5 1.0 1.5 2.0

Artscan

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SLIDE 36

Meta-analysis on fractionation : survival

  • Alt. fractionated RT

effect w ith p = 0 .0 0 3

( 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 ]

Total (a ... c) 2313/ 3650 2235/ 3423

  • 98.5

1122.9

  • Alt. fractionated RT
  • No. Events / No. Entered

Control O-E Variance HR of death ( Alt. fractionated RT / Control) HR ( 9 5 % CI )

Test for heterogeneity:

2 16

= 38.07 p = 0.001 Test for interaction:

2 2 = 7.52

p = 0.02

0 .9 2 [ 0 .8 6 - 0 .9 7 ]

  • Alt. fractionated RT better

|

Control better

0.0 0.5 1.0 1.5 2.0

Artscan

slide-37
SLIDE 37

Meta-analysis on fractionation : less or no benefit in older patients

50 or less 768 / 1 311 51-60 1 455 / 2 300 61-70 1521 / 2 346 71 + 784 / 1 085 Total 4 528 / 7 042 Category No. Events / No. Entered Hazard ratio (Alt. fractionated RT/Control)

  • Alt. fractionated RT effect p=0.02
  • Alt. Frac. RT better |

Control better Test of interaction: p = 0.02 Test for trend: p = 0.007 0.0 0.5 1.0 1.5 2.0 0.78 [0.65 - 0.94] 0.95 [0.83 - 1.09] 0.92 [0.81 - 1.06] 1.08 [0.89 - 1.30] HR [95% CI] 0.92 [0.86 - 0.97] Median age 62 years

slide-38
SLIDE 38

Tumour site

  • Rate of HPV+ in these oroph. tumors ???
  • This could well explain the excellent results
  • f conventional RT in the oropharynx

Sub group ?? Recruitment : 1998-2006

slide-39
SLIDE 39

QA

slide-40
SLIDE 40

Radiotherapy QA

slide-41
SLIDE 41

Major impact o the RT-QA on the outcome after RT : LR Failure according to RT deviations yes / no

(N= 820 patients randomized)

Lester Peters ICHNO 2009

20 40 60 80 100 Estimated percentage locoregional failure-free 1 2 3 4 Years following end of radiotherapy compliant plan by TMC no adv impact adv impact 2P < 0.0001

No deviation Deviation

slide-42
SLIDE 42

Magnitude of the benefit : is it worthwhile ?

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SLIDE 43

RTOG 90-03 : Local-Regional Control

Failed/Total SFX 149/266 HFX 132/261 p=0.080 AFX-C 127/267 p=0.044

% CONTROL 25 50 75 100 YEARS FROM RANDOMIZATION 1 2 3 4 5 6 7 8 9 10

P < 0.04

slide-44
SLIDE 44

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Cetuximab + RT: Overall survival 5 year update

10 20 30 40 50 60 70

Months Probability of Overall Survival

Treatment Total Death Alive Median

RT 213 130 83 29.3 Cetuximab + RT 211 110 101 49.0

ERBITUX + RT RT Cetuximab + RT RT

p-value

5-year OS rate 46% 36%

0.02 p = 0.02

ERBITUX + RT improves significantly long term survival, with nearly half of the patients alive at 5 years

HR=0.73 (0.56–0.95)

Bonner J.A, et al. as presented ASTRO 2008

slide-45
SLIDE 45

Altered fractionation

+

chemotherapy ?

slide-46
SLIDE 46

Effect of concomitant CT by type of radiotherapy

Meta-Analysis of Chemotherapy in Head & Neck Cancer

MACH-NC

21% + 7 17% + 3 27% + 5 1% + 13 RT-CT post-op

  • Convent. RT-CT
  • Fractionat. RT-CT

Mixed

slide-47
SLIDE 47

80.5 Gy Hyperfractionated + PF x 3 cycles concomitant

Random.

80.5 Gy Hyperfractionated

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SLIDE 48

Bensadoun et al IJROBP 2005

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SLIDE 49

Conclusion from the MARCh data base : magnitude of the benefit

  • Small but significant improvement in overall survival (3%) and

loco-regional control (6%) in favor of altered fractionation

  • The observed benefit may depend of the type of radiotherapy
  • The higher benefit was observed when total dose was increased

i.e. hyperfractionated RT: + 8% on survival and 9% on LRC