Transcript Change in Anatomic Distribution of Relapses with Accelerated Chemotherapy in Ewing Sarcoma

Change in Anatomic Distribution of
Relapses with Accelerated
Chemotherapy in Ewing Sarcoma
RB Womer, AR Weiss, DC West, MD Krailo,
PS Dickman, B Pawel,
for the Children’s Oncology Group
AEWS0031 Committee
INT-0091: Design
R
A
N
D
O
M
I
Z
E
VDC
VDC
+
I/E
L
O
C
A
L
C
O
N
T
R
O
L
VDCA
VDCA
+
I/E
INT-0091: Addition of IE Improved EFS
Grier et al., NEJM 348:698, 2003
INT-0091: IE Decreased Local Relapses
Grier et al., NEJM 348:699, 2003
AEWS0031 Design
Regimen A
R
A
N
D
O
M
I
Z
E
VCR
Dox
CPM
IFOS
ETOP
Local
Control
q3w x 2
VCR
Dox
CPM
IFOS
ETOP
q3w x 5
Regimen B
VCR
Dox
CPM
q2w x 3
IFOS
ETOP
Local
Control
VCR
Dox
CPM
q2w x 4
IFOS
ETOP
AEWS0031 Accrual
 Open May 2001-August 2005
 Localized ESFT, age <50 years
 Total 587 patients enrolled


19 ineligible
− 12 wrong diagnosis
− 4 metastases at diagnosis
− 3 treatment before enrollment or randomization
Thus 568 eligible patients
AEWS0031 Accrual by Strata*
Stratum
Stratum name
Accrual
1
< 17y, non-pelvic
419
2
< 17y, pelvic
93
3
> 18y, non-pelvic
57
4
> 18y, pelvic
18
*ineligible patients included
AEWS0031 Randomization
Age Group | Standard Intensive |
Total
-----------+----------------------+----------17 |
253
248 |
501
18+ |
31
36 |
67
-----------+----------------------+---------Total |
284
284 |
568
| Standard Intensive |
Total
-----------+----------------------+---------Non-Pelvic |
237
243 |
480
Pelvic |
47
41 |
88
-----------+----------------------+---------Total |
284
284 |
568
AEWS0031 Patient Characteristics
Characteristics
Standard
(N=284)
Intensive
(N=284)
Age at Study Entry Median (Range)
12 (0-33)
13 (0-45)
Male
154 (54%)
154 (54%)
Female
130 (46%)
130 (46%)
White
252 (89%)
250 (88%)
Black
8 (3%)
6 (2%)
Other
14 (5%)
16 (6%)
Race Not Reported
10 (4%)
12 (4%)
31.4 (32.2)
32.9 (28.3)
448.2 (414.0)
451.5 (437.2)
Pleural Effusions at Diagnosis
19 (8%)
21 (9%)
Gross tumor resection prior to start of chemotherapy
47 (17%)
48 (17%)
ESR (mm/hr)
LDH (IU/l)
AEWS0031 Patient Characteristics 2
Primary Site
Standard
(N=284)
Intensive
(N=284)
Skull, maxilla, mandible
15 (5.5%)
12 (4.3%)
C, T, L Vertebrae
11 (3.9%)
28 (9.9%)
Ribs, Sternum
29 (10.3%)
25 (8.9%)
Sacrum
16 (5.6%)
8 (2.8%)
Pelvis
31 (11%)
33 (11.6%)
Scapula, clavicle
14 (4.9%)
14 (5.0%)
Upper limbs
20 (6.9%)
19 (6.7%)
Lower limbs
81 (28.7%)
68 (22.5%)
Soft Tissue
67 (23.6%)
76 (26.8%)
Total flat bones
116 (41.2%)
120 (42.5%)
Total long bones
101 (35.6%)
87 (30.6%)
9 (3.5%)
14 (5.5%)
Fracture at primary site
AEWS0031: Primary Tumor Treatment
Percentages of patients who had:
Standard (A)
Intensive (B)
All
Surgery only
49
47
48
Radiation only
18
24
21
Surgery + radiation
33
27
29
No primary treatment
1
2
1.5
Estimated Proportion Event-Free
0.00
0.25
0.50
1.00
0.75
AEWS0031: EFS for all eligible patients
Regimen
Standard
Intensive
p=0.023
0
2
Years
4
6
Estimated Proportion Surviving
0.50
0.25
0.75
1.00
AEWS0031: OS for all eligible patients
Regimen
Standard
Intensive
0.00
p=0.026
0
2
Years
4
6
AEWS0031: Events
 126 relapses
74 Standard, 52 Intensive
 15 SMN (8 Reg. A, 7 Reg. B)
 11 secondary AML/MDS
− 5 Standard, 6 Intensive
 3 secondary OS
 1 Diffuse large B cell lymphoma
 1 toxic death (Intensive)
 1 narcotic overdose (recreational)

AEWS0031: Patterns of Relapse
123 Relapses*
72 Standard
18 Local
only
39 Distant
only
51 Intensive
15 Combined
54 Distant
20 Lung 16 Bone 11 Other 7 Multiple
16 Local
only
27 Distant
only
8 Combined
35 Distant
11 Lung 15 Bone 6 Other
3 Multiple
AEWS0031: Patterns of Relapse
123 Relapses*
72 Standard
18 Local
only
39 Distant
only
51 Intensive
15 Combined
54 Distant
20 Lung 16 Bone 11 Other 7 Multiple
16 Local
only
27 Distant
only
8 Combined
35 Distant
11 Lung 15 Bone 6 Other
3 Multiple
AEWS0031: “Other” Sites of Relapse
Standard
Intensive
CNS
(Brain, spinal cord)
7
0
Miscellaneous
4
(pleura, nodes, soft
tissue, liver)
6
(pleura, mediastinum,
marrow)
A few statistics
 P (local recurrence) Reg. A v. Reg B: 0.86
 P (distant recurrence) Reg A. v. Reg B: 0.06
 P (distant or combined) Reg A v. Reg B: 0.017
 P (CNS recurrence) Reg A v. Reg B: 0.02
AEWS0031: Conclusions
 Accelerated chemotherapy reduces lung and “other”
(especially CNS) relapses
 It has no effect on local or skeletal relapses
AEWS0031: Implications of Relapse Patterns
 Either accelerated (q2w) chemotherapy is particularly
effective against micrometastases in the lungs and CNS,
 Or there is a biologically distinct group of Ewing
sarcomas with a particular propensity for lung and CNS
relapse, that is especially sensitive to accelerated
chemotherapy
 Or both,
 Or neither
VDC/IE Regimens for ESFT
Regimen
Years
EFS
95% Intervals
INT-0091 B
1988-92
(CCG-7881/POG-8850)
69%
66-72%
INT-0154 A, B
1995-98
(CCG-7942/POG-9354)
71%
67-75%
AEWS0031 A (q3w)
70%
63-75%
2001-2005