Comparison of Three Radiation Dose Levels
after EBVP Regimen in Favorable
Supradiaphragmatic Clinical Stages I-II
Hodgkin’s Lymphoma (HL):
Preliminary Results of the EORTC-GELA H9-F Trial
H. Eghbali, P. Brice, G.Y. Creemers, M. van Marwijk Kooij,
P. Carde, M. van’t Veer, E. Lugtenburg, A. Sonnet, C. Sebban,
M. Blanc, J.M. Raemaekers, L. Voillat, C. Rieux, E. Noordijk,
and M. Henry-Amar
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Objectives
1 To compare in a randomized fashion two dose
levels for radiotherapy in favorable group HL in
complete remission after chemotherapy
1 To demonstrate that in this subset of patients
radiotherapy could be omitted
1 To reduce late toxicity and maintain the failurefree survival rate for these patients
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Eligibility criteria
! Favorable subgroup based on retrospective analysis of previous trials
CS I-II supradiaphragmatic HL with no adverse factors:
and
and
and
•
•
•
•
age < 50 years
A + ESR < 50 mm or B + ESR < 30 mm
1 to 3 nodal areas involved
no mediastinal involvement or M/T ratio < 0.35
! Age 15 - 49 years
! WHO performance status 0-2
! Informed consent
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
EORTC – GELA H9 Trial
S
T
R
A
T
I
F
I
C
A
T
I
O
N
HLP – nodular
H9 – U
CR + CRu
> 1 risk factor
H9 - F
Registration
EBVP x 6
R
A
N
D
O
M
PR
No risk factors
NC + PD
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
IF-RT 36 Gy
IF-RT 20 Gy
No RT
IF-RT 36 Gy
+ boost 4 Gy
off protocol
Design
Equivalence trial with a one-sided test
End point: 5-year cumulative proportion of relapses in
patients who achieved a complete remission
Hypothesis
True 5-year cumulative proportion of failures = 10%, δ = 10%
α = 0.05, β = 0.20, one final comparison, 20% lost to FU
Total to be accrued: 139 x 3 x √3 x 1/0.80 = 903
H9-F stopping rules
♦ Proportion of CR/CRu rate after EBVP < 70%
♦ Proportion of early adverse effects ≥ 20%: early death,
severe (Grade 3-4) treatment-related toxicity within 1.5 year
after randomization, treatment discontinued for any reason
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
EORTC - GELA H9-F Trial
H9-F TRIAL ACCRUAL
(EORTC # 20982)
Accrual period: 9/1998 - 5/2004
600
Las t H9-F patie nt
rando miz e d to
no -RT: May 3, 2002
400
200
Closure of trial
May 14, 2004
09
-2
00
3
05
-2
00
4
09
-2
00
2
09
-2
00
1
09
-2
00
0
0
09
-1
99
9
Update as of November 1, 2005
Cumulative number
Analysis on an intent-to-treat basis
783 patients
enrolled
800
09
-1
99
8
Patients enrolled: 783 in 10 countries
1000
Time since trial start
Observed Follow-up
time since registration to last examination / death
median: 37 months (7 to 78)
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Staging procedures
• At entry
- Clinical staging
- ESR, CBC, blood chemistry
- Chest X-ray (MT ratio), CT scans thorax, abdomen
- Bone marrow biopsy
- Ann Arbor classification
• Evaluation of response
- Restaging after 6 courses of EBVP
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
EBVP chemotherapy regimen
Protocol derived from ABVD with
epirubicin replacing doxorubicin
and
prednisone replacing dacarbazine
Epirubicin
Bleomycin
Vinblastin
Prednisone
d1
d1
d1
d1-d5
1 course
6 courses
60 mg/m²
10 mg/m²
6 mg/m²
40 mg/m²
360 mg/m²
60 mg/m²
36 mg/m²
1200 mg/m²
Every 3 weeks, 6 courses
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Response to EBVP chemotherapy
CR / CRu
randomized for
not randomized
N = 600 77%
IF RX - 36 Gy
IF RX - 20 Gy
no radiotherapy
239 pts
209 pts
130 pts
Refusal, violation, other
Toxicity
PR / Progression
N = 162
21%
No data
N = 21
2%
13 pts
9 pts
(95% CI: 18-24%)
Total enrolled
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
783 pts
Patient characteristics
%
IF-RT 36 Gy
IF-RT 20 Gy
No RT
No Random.
n = 239
n = 209
n = 130
n = 205
55 / 45
30 (15-49)
37/43/20
95
5
53
1
2
54 / 46
31 (15-49)
44/40/16
93
7
48
2
2
56 / 44
32 (16-49)
28/48/24
92
8
68
4
3
Sex M/F
56 / 44
31 (15-49)
Age, median (range)
CS I – II2 – II3 *
42/38/20
A + ESR < 50
92
B + ESR < 30
8
Mediastinum involved * 49
Bulky disease **
3
E lesion
0
* No CR v. CR-CRu, P < 0.01;
** nodal masses ≥ 100 mm
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Response to treatment
after
EBVP
CR
CRu
PR
NC, Prog.
Unspecified
51%
26%
18%
3%
2%
at the end of treatment
Random. No random.
76%
22%
0%
1%
1%
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
28%
33%
23%
15%
1%
Progressions – Relapses
36 Gy
20 Gy
no RT
no CR /
no random.
Number of events
21
21
36
48
Prog. under treat.
Relapse
3
18
4
17
1
35
27
21
Prog + Rel Prog + Rel Prog + Rel
Involved, unirrad.
Involved, irradiated
Extra-nodal relapse
Unspecified
2 + 12
1+4
0+1
0+1
1+3
1+6
2+7
0+1
1 + 30
0+1
0+4
–
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Prog + Rel
21 + 5
5+5
3+9
–
Proportion Relapse-Free
EORTC-GELA H9-F trial
relapse-free survival
1.0
0.8
0.6
6 EBVP-IF RT 36Gy (239)
6 EBVP-IF RT 20Gy (209)
6 EBVP-no RT (130)
0.4
0.2
5-yr rate P value
89%
86%
70%
<0.001
final value 1-β ' = 77%
November 2005
0.0
0
12
24
36
48
60
Time since EBVP start, mo
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Proportion Failure-Free
EORTC-GELA H9-F trial
treatment failure-free survival
1.0
0.8
0.6
5-yr rate P value
6 EBVP-IF RT 36Gy (239)
89%
6 EBVP-IF RT 20Gy (209)
86%
6 EBVP-no RT (130)
70%
6 EBVP-no random. (205)
71%
<0.001
0.4
0.2
November 2005
0.0
0
12
24
36
48
Time since EBVP start, mo
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
60
Deaths
36 Gy
20 Gy
no RT
no CR /
no random.
Total observed
3
0
2
9
Progressive disease
2
–
1
6
Treatment-related
–
–
–
2
Intercurrent disease
1
–
–
–
Second cancer
–
–
1 (AL)
1 (NHL)
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
EORTC-GELA H9-F trial
overall survival
Proportion Surviving
1.0
0.8
0.6
6 EBVP-IF RT 36Gy (239)
6 EBVP-IF RT 20Gy (209)
6 EBVP-no RT (130)
0.4
5-yr rate P value
96%
100%
98%
0.248
0.2
November 2005
0.0
0
12
24
36
48
Time since EBVP start, mo
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
60
EORTC-GELA H9-F trial
overall survival
Proportion Surviving
1.0
0.8
5-yr rate P value
6 EBVP-IF RT 36Gy (239)
96%
6 EBVP-IF RT 20Gy (209)
100%
6 EBVP-no RT (130)
98%
0.0015
6 EBVP-no random. (205)
91%
0.6
0.4
0.2
November 2005
0.0
0
12
24
36
48
Time since EBVP start, mo
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
60
Conclusions (1)
" With the chosen chemotherapy so far there has been
no difference in clinical outcome between 20 and
36 Gy confirming the results of the GHSG HD10 trial
(4 ABVD + IF RX, 30 Gy v. 20 Gy)
" With the chosen chemotherapy the non-radiotherapy
arm failed
" Is this failure due to the nature of the chemotherapy
regimen or lack of any radiotherapy? The discussion
is open
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Conclusions (2)
" The next H10 trial addresses the same
question using ABVD which is considered as
the conventional chemotherapy regimen
" PET-scan will be used to assess early
complete remission (after 2 courses of ABVD)
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Four ABVD and Involved-field Radiotherapy in
Unfavorable Supradiaphragmatic Clinical
Stages (CS) I-II Hodgkin’s Lymphoma (HL):
Preliminary Results of the EORTC-GELA H9-U Trial
C. Fermé, M. Diviné, A. Vranovsky, F. Morschhauser,
R. Bouabdallah, J. Gabarre, A. Bastard-Stamatoullas,
R. Delarue, V. Zagonel, J. Jaubert, A. Hagenbeek,
M.H.H. Kramer, C. Rieux, J. Thomas, and M. Henry-Amar
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Objectives
•
To compare in unfavorable patients
6 x ABVD v. 4 x ABVD v. 4 x BEACOPP baseline
all followed by involved-field RT
•
To maintain the failure-free survival rate with
a reduction of the acute side effects and severe
late toxicity
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Eligibility criteria
! Unfavorable subgroup
CS I-II supradiaphragmatic HL with at least 1 adverse factor:
or
or
or
•
•
•
•
age > 50 years
A + ESR > 50 mm or B + ESR > 30 mm
> 4 nodal areas involved
M/T ratio > 0.35
! Age 15 - 70 years
! WHO performance status 0-2
! Informed consent
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
EORTC – GELA H9 Trial
S
T
R
A
T
I
F
I
C
A
T
I
O
N
HLP - nodular
Registration
H9 - F
No risk factors
H9 - U
> 1 risk factor
ABVD x 6
ABVD x 4
BEACOPP x 4
CR-CRu / PR
IF - RT
NC – PD
off protocol
BEACOPP baseline (Diehl V, GHSG 1997)
arms 2 & 3 common with that of the GHSG HD11 trial
Involved-field – RT
• CR / CRu after 4-6 courses
• PR after 4-6 courses
30 Gy
36 Gy + 4 Gy boost in PR areas
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Design
Equivalence trial with a one-sided test
End point: 5-year cumulative proportion of treatment failures
during or after initial treatment
Hypothesis
True 5-year cumulative proportion of failures = 10%,
δ = 10%, α = 0.05, β = 0.20, one final comparison
Total number of patients to be accrued: 139 x 3 x √3 = 723
H9-U stopping rules
♦ Failure rate ≥ 20% in any arm: partial or no response,
progressive disease after initial treatment, relapse after CR or CRu
♦
Proportion of early adverse effects ≥ 20%: early death,
severe (Grade 3-4) treatment-related toxicity within 1.5 year
after randomisation, treatment discontinued for any reason
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
EORTC - GELA H9-U Trial
EORTC-GELA H9-U TRIAL
Accrual period: 10/1998 - 9/2002
Analysis on an intent-to-treat basis
Update as of November 1, 2005
Cumulative number
Patients enrolled: 808
1000
Total enrolled: 808
800
600
400
200
0
09/98
09/99
09/00
09/01
09/02
09/03
Time since trial start
Observed Follow-up
time since registration to last examination / death
median: 42 months (1 to 83)
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
09/04
Treatment groups
6 x ABVD - IF RT
276 pts
4 x ABVD - IF RT
277 pts
4 x BEACOPP - IF RT
255 pts
Total enrolled
808 pts
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Patient characteristics
%
6 ABVD
4 ABVD
4 BEACOPP
20 (31)
22 / 58
20
A & ESR > 50 or B & ESR > 30
66
Mediastinum involved
87
39
M/T ratio > 0.35
Bulky disease *
43
E lesion **
12
Histological type NS / MC 82 / 17
20 (30)
23 / 58
19
68
84
38
42
6
85 / 15
21 (31)
21 / 62
17
60
87
43
45
8
89 / 10
Age > 50 (median)
CS I / II2-II3
CS II4 - II5
* M/T ratio ≥ 0.35 or nodal masses ≥ 100 mm
** P = 0.057
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Response to treatment (1)
At the end of chemotherapy
6 ABVD
4 ABVD
4 BEACOPP
CR / CRu
74%
71%
60%
PR
23%
28%
38%
No change
1%
1%
1%
Progression
2%
< 1%
-
Early death
-
-
< 1%
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Response to treatment (2)
At the end of treatment
6 ABVD
4 ABVD
4 BEACOPP
IF-RT
IF-RT
IF-RT
CR / CRu
87%
87%
86%
PR
8%
10%
11%
< 1%
< 1%
-
Progression
4%
3%
3%
Early death
< 1%
-
< 1%
No change
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Progressions – Relapses
6 ABVD 4 ABVD 4 BEACOPP
IF-RT
IF-RT
IF-RT
Number of events
17
25
20
Prog. under treat.
Relapse
8
9
6
19
6
14
Prog + Rel
Prog + Rel
Prog + Rel
2+3
0+4
6+1
0+1
1+4
5+6
0+8
0+1
1+4
3+3
2+7
-
Involved, unirrad.
Involved, irradiated
Extra-nodal relapse
Unspecified
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Proportion Failure-Free
EORTC-GELA H9-U trial
treatment failure-free survival
1.0
0.8
0.6
6 ABVD-IF RT (276)
4 ABVD-IF RT (277)
4 BEACOPP-IF RT (255)
0.4
5-yr rate P value
92%
89%
0.43
91%
0.2
November 2005
0.0
0
12
24
36
48
Time since Randomization, mo
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
60
EORTC-GELA H9-U trial
relapse-free survival
Proportion
Relapse-Free
1.0
0.8
0.6
6 ABVD-IF RT (244)
4 ABVD-IF RT (243)
4 BEACOPP-IF RT (214)
0.4
5-yr rate P value
96%
91%
0.122
95%
0.2
November 2005
0.0
0
12
24
36
48
Time since Randomization, mo
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
60
Deaths
Progressive disease
Treatment-related complication
20
14
pneumopathy (2), septicemia (4), bleeding (1)
severe pulmonary fibrosis (7)
Intercurrent disease
4
septicemia (2), pulmonary embolism (1)
suicide (1)
Second cancer
Unspecified
MDS (1), NHL (1)
Total observed
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
2
3
43
Proportion Surviving
EORTC-GELA H9-U trial
overall survival
1.0
0.8
0.6
6 ABVD-IF RT (276)
4 ABVD-IF RT (277)
4 BEACOPP-IF RT (255)
0.4
5-yr rate P value
91%
92%
0.97
91%
0.2
November 2005
0.0
0
12
24
36
48
Time since Randomization, mo
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
60
Conclusions (1)
" 4 ABVD + IF-RT 30 Gy can cure most of
patients with unfavorable early stage HL who
achieve CR / CRu after 4 courses
" BEACOPP baseline has no advantage over
ABVD in these patients
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Conclusions (2)
" The next H10-U trial using 4 x ABVD + IF-RT
as standard arm, addresses the question of
chemotherapy alone
" In this trial, early response to 2 courses of
ABVD will be evaluated using PET-scan
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)
Acknowledgements
• Participating investigators, physicians, radiotherapists, radiologists, data-managers, nurses
• Patients who participated in this European trial
• French Federation of Comprehensive Cancer
Centers (sponsor of the French centers)
• Supported by a grant from the French Ministry
of Health (PHRC 1998)
ASH – 2005 / Blood 2005;106(11):240a (Abstr. 813 & 814)