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altered fractionated RT in HNSCC :

what is the magnitude of the benefit ?

Jean Bourhis, MD PhD

Institute 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 ??

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

Eligibility criteria (1)

Trials properly randomizedPerformed between 1970 and 1998

RConventional RT

Hyperfractionated or accelerated RT

IGR 09.02

50 Gy 60 Gy 70 Gy 80 Gy

7 weeks

6 weeks

5 weeks

4 weeks

3 weeks

2 weeks

Acceleration

Total dose

Reference

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

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

50 Gy 60 Gy 70 Gy 80 Gy

7 wks.

6 wks

5 wks

4 wks

3 wks

2 wksCHART

TROG 91-01

GORTEC 94-02

Vienna

RTOG 73-01

Vancouver

DAHANCARTOG 90-03

Oro 93

EORTC22851

CAIRKBN79

RioRTOG 90-03

EORTC22791

+Toronto)RTOG 90-03

19%

54%

27%

Data collection and checking

Updated individual data collected for all randomized patientsfrom published and unpublished trials

Extensive checking and validation to

ensure integrity of randomization

and follow-up and improve accuracy

Results

Overall survival (all 3 groups)

Alt. fractionated RT

Conventional RTSurv

ival

(%)

0

20

40

60

80

100

Time from randomisation (Years)0 1 2 3 4 5 6 ≥

7

57.4%

39.7%54.1%

36.3%

Non cancer and cancer death (all 3 groups)

Surv

ival

(%)

0

20

40

60

80

100

Time from randomisation (Years)0 1 2 3 4 5 6 ≥7

0

20

60

100

63.2%

50.5%59.1%

46.2%

90.5%

78.4%

91.7%

78.9%

Cancer death

Non cancer death


Conventional RT

Overall survival


Conventional RT

0

20

40

60

80

100

0 1 2 3 4 5 6

36.7%

28.5%

Surv

ival

(%)

0

20

40

60

80

100


0

20

40

60

80

100

0 1 2 3 4 5 6

44.4%

42.4%Surv

ival

(%)

0

20

40

60

80

100

0 1 2 3 4 5 6Time from randomisation (Years)

≥7

0

20

40

60

80

100

0 1 2 3 4 5 6

31.9%

30.2%

Surv

ival

(%)

0

20

40

60

80

100


≥7

Surv

ival

(%)

100100

0

20

40

60

80

0 1 2 3 4 5 6

39.7%

36.3%

0

20

40

60

80

0 1 2 3 4 5 60

20

40

60

80

100


≥7

HyperfractionationAcceleration w / ototal dose reduction

Accelerationwith total dose reduction

All 3 groups

Overall survival


effect with p = 0.003

(a) HyperfractionationEORTC 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 0.78 [0.69-0.89]

(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 13.1DAHANCA 9 422/755 413/730 -5.0 208.6

Oro 9301 10 51/65 48/63 4.8 24.4

CAIR 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 0.97 [0.89-1.05]

(c) Accelerated fractionation with 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 0.94 [0.84-1.05]

Total (a ... c) 2313/3650 2235/3423 -98.5 1122.9


No. Events / No. Entered

ControlO-E Variance HR of death

(Alt. fractionated RT / Control)HR (95% CI)

Test for heterogeneity:216

=38.07 p = 0.001

Test for interaction:22

= 7.52 p = 0.02

0.92 [0.86-0.97]

Alt. fractionated RT better | Control better0.0 0.5 1.0 1.5 2.0

Loco regional control (all 3 groups)

Ris

kof re

curr

ence

(%)

0

20

40

60

80

100


46.5%

52.9%

Absolute difference at 5 years:6.4 ±

1.3%


Conventional RT

Loco regional control


Conventional RT

Ris

kof

recu

rren

ce(%

)

0

20

40

60

80

100


0

20

40

60

80

100

0 1 2 3 4 5 6

48.5%

57.9%

Ris

kof

recu

rren

ce(%

)

0

20

40

60

80

100

0 1 2 3 4 5 6

40.2%

47.5%

0

20

40

60

80

100

0 1 2 3 4 5 6 ≥7 Time from randomisation (Years)

100

0

20

40

60

80

0 1 2 3 4 5 6

57.5%

59.8%

0

20

40

60

80

100

0 1 2 3 4 5 6

Ris

kof

recu

rren

ce(%

)

Time from randomisation (Years)≥7

0

20

40

60

80

100

0 1 2 3 4 5 6

46.5%

52.9%

All the 3 groups together0

20

40

60

80

100

0 1 2 3 4 5 60

20

40

60

80

0 1 2 3 4 5 6

Ris

kof

recu

rren

ce(%

)

Time from randomisation (Years)≥7

Absolute differenceat 5 years:6.4 ± 1.3%

Hyperfractionation Acceleration w / ototal dose reduction

Acceleration withtotal dose reduction

Loco regional control

Alt. fractionated RTeffect with p < 0.0001

(a) HyperfractionationEORTC 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 0.76 [0.66-0.89](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

CAIR 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 0.79 [0.72-0.87]


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 0.90 [0.80-1.02]

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

Alt. fractionated RTNo. Events / No. Entered

Control O-E VarianceHR of recurrence



=28.57 p = 0.03Test for interaction:

22= 3.8 p = 0.15

0.82 [0.77-0.88]


Local control

Alt. fractionated RT effect with p < 0.0001

(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 0.75 [0.63-0.89]


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

CAIR 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 0.74 [0.67-0.83]


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 0.83 [0.71-0.96]

Total (a ... c) 1180/3318 1347/3092 -164.8 624.4

Category/Study


Control O-E Variance

HR of local recurrence


Test for heterogeneity:213= 21.83 p = 0.06

Test for interaction:22= 1.4 p = 0.5

0.77 [0.71-0.83]


Regional control

Alt. fractionated RT effect with p = 0.01

(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 0.83 [0.66-1.03]


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

CAIR 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 0.90 [0.77-1.04]


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 0.87 [0.72-1.06]

Total (a ... c) 696/3318711/3092 -47.1 348.3



ControlO-E Variance

HR of regional recurrence




22=0.38 p = 0.83

0.87 [0.79-0.97]


Subgroup analysesCategory No. Deaths / No. Entered

Alt. fractionated RT ControlO-E Variance Hazard Ratio Interaction test


Age50 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 = 0.02

SexMale 1916/3005 1839/2777 -93.6 924.9

Female 388/630 387/632 -6.0 187.1p = 0.39

Performance status0 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 = 0.23

StageI-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 = 0.10

SiteOral 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 = 0.20

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. EnteredHazard ratio

(Alt. fractionated RT/Control)

Alt. fractionated RT effect p=0.02

Alt. Frac. RT better | Control betterTest 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]

The more dose-intensity, the better ?

where are the limits ?

Gortec randomized trial

N = 268T3-T4HNSCC

70 Gy / 7 weeks

64 Gy / 3.5 weeks

IIIII IIIII IIIII IIIII IIIII IIIII IIIII

IIIII IIIII IIIII II IIIII IIIII IIIII II

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

Radio-induced mucositis : 64 Gy / 3 weeks

No increase in late toxicity grade III / IV (Bourhis et al JCO 2006)

Accelerated Conventional

Mucosa 24% 19% NSNeck fibrosis 20.3% 10% p = 0.2

Larynx 8.4% 5.6% NSOther 28% 31% NS

711193337591372913172349129

0,00

0,20

0,40

0,60

0,80

1,00

0 1 2 3 4 5 6Years 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

Effect on local control

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

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

same

ARTSCAN loco-regional control : small effect depsite the very

strong acceleration• Loco-regional control at 2

years:

AF: 70.8 % CF: 66.7 %

AF

CFp=0.50

Are the results of ARTSCAN compatible with the benefit previously observed with accelerated

RT in HNSCC ?

Meta-analysis on fractionation : local regional control

Alt. fractionated RTeffect with p < 0.0001

(a) HyperfractionationEORTC 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 0.76 [0.66-0.89](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

CAIR 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 0.79 [0.72-0.87]


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 0.90 [0.80-1.02]

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


Control O-E VarianceHR of recurrence




22= 3.8 p = 0.15

0.82 [0.77-0.88]


Artscan

Meta-analysis on fractionation : survival


effect with p = 0.003

(a) HyperfractionationEORTC 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 0.78 [0.69-0.89]


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 13.1DAHANCA 9 422/755 413/730 -5.0 208.6

Oro 9301 10 51/65 48/63 4.8 24.4

CAIR 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 0.97 [0.89-1.05]


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 0.94 [0.84-1.05]

Total (a ... c) 2313/3650 2235/3423 -98.5 1122.9



ControlO-E Variance HR of death



=38.07 p = 0.001

Test for interaction:22

= 7.52 p = 0.02

0.92 [0.86-0.97]


Artscan

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. EnteredHazard ratio

(Alt. fractionated RT/Control)

Alt. fractionated RT effect p=0.02

Alt. Frac. RT better | Control betterTest 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 age62 years

Tumour site

- Rate of HPV+ in these oroph. tumors ???

- This could well explain the excellent results of conventional RT in the oropharynx Sub group ??

Recruitment :1998-2006

QA

Radiotherapy QA

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

0

20

40

60

80

100

Estim

ated

per

cent

age

loco

regi

onal

fai

lure

-fre

e

0 1 2 3 4Years following end of radiotherapy

compliant plan by TMC

no adv impact

adv impact

2P < 0.0001

No deviation

Deviation

Magnitude of the benefit :

is it worthwhile ?

RTOG 90-03 : Local-Regional Control

Failed/Total

SFX 149/266

HFX 132/261 p=0.080

AFX-C 127/267 p=0.044

% C

ON

TRO

L

0

25

50

75

100

YEARS FROM RANDOMIZATION0 1 2 3 4 5 6 7 8 9 10

P < 0.04

1.00.90.80.70.60.50.40.30.20.10.0

Cetuximab + RT: Overall survival 5 year update

0 10 20 30 40 50 60 70Months

Pro

babi

lity

of O

vera

ll S

urvi

val

Treatment Total Death Alive Median

RT 213 130 83 29.3Cetuximab + 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

Altered fractionation+

chemotherapy ?

Effect of concomitant CT by type of radiotherapyMeta-Analy sis 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

80.5 Gy Hyperfractionated+ PF x 3 cycles concomitant

Random.

80.5 Gy Hyperfractionated

Bensadoun et al IJROBP 2005

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

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Quality of the data - videoserver1.iaea.orgvideoserver1.iaea.org/media/HHW/Radiotherapy/ICARO... · altered fractionated RT in HNSCC : what is the magnitude of the benefit ? Jean