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Updated individual data collected for all randomized patientsfrom published and unpublished trials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
Alt. fractionated RT
Conventional RT
Overall survival
Alt. fractionated RT
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
Time from randomisation (Years)0 1 2 3 4 5 6 ≥7
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
0 1 2 3 4 5 6Time from randomisation (Years)
≥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
0 1 2 3 4 5 6Time from randomisation (Years)
≥7
HyperfractionationAcceleration w / ototal dose reduction
Accelerationwith total dose reduction
All 3 groups
Overall survival
Alt. fractionated RT
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
Alt. fractionated RT
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
Time from randomisation (Years)0 1 2 3 4 5 6 ≥7
46.5%
52.9%
Absolute difference at 5 years:6.4 ±
1.3%
Alt. fractionated RT
Conventional RT
Loco regional control
Alt. fractionated RT
Conventional RT
Ris
kof
recu
rren
ce(%
)
0
20
40
60
80
100
Time from randomisation (Years)0 1 2 3 4 5 6 ≥7
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]
(c) Accelerated fractionation with 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 0.90 [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
(Alt. fractionated RT / Control)HR (95% CI)
Test for heterogeneity:216
=28.57 p = 0.03Test for interaction:
22= 3.8 p = 0.15
0.82 [0.77-0.88]
Alt. fractionated RT better | Control better0.0 0.5 1.0 1.5 2.0
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]
(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
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]
(c) Accelerated fractionation with 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 0.83 [0.71-0.96]
Total (a ... c) 1180/3318 1347/3092 -164.8 624.4
Category/Study
Alt. fractionated RTNo. Events / No. Entered
Control O-E Variance
HR of local recurrence
(Alt. fractionated RT / Control)HR (95% CI)
Test for heterogeneity:213= 21.83 p = 0.06
Test for interaction:22= 1.4 p = 0.5
0.77 [0.71-0.83]
Alt. fractionated RT better | Control better0.0 0.5 1.0 1.5 2.0
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]
(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
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]
(c) Accelerated fractionation with 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 0.87 [0.72-1.06]
Total (a ... c) 696/3318711/3092 -47.1 348.3
Alt. fractionated RT
No. Events / No. Entered
ControlO-E Variance
HR of regional recurrence
(Alt. fractionated RT / Control)HR (95% CI)
Test for heterogeneity:213
=11.8 p = 0.54Test for interaction:
22=0.38 p = 0.83
0.87 [0.79-0.97]
Alt. fractionated RT better | Control better0.0 0.5 1.0 1.5 2.0
Subgroup analysesCategory No. Deaths / No. Entered
Alt. fractionated RT ControlO-E Variance Hazard Ratio Interaction test
Alt. fractionated RT better | Control better0.0 0.5 1.0 1.5 2.0
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]
(c) Accelerated fractionation with 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 0.90 [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
(Alt. fractionated RT / Control)HR (95% CI)
Test for heterogeneity:216
=28.57 p = 0.03Test for interaction:
22= 3.8 p = 0.15
0.82 [0.77-0.88]
Alt. fractionated RT better | Control better0.0 0.5 1.0 1.5 2.0
Artscan
Meta-analysis on fractionation : survival
Alt. fractionated RT
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
Alt. fractionated RT
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
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
Top Related