Change in Anatomic Distribution Change in Anatomic Distribution of Relapses with Accelerated of Relapses with Accelerated Chemotherapy in Ewing SarcomaChemotherapy 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: DesignINT-0091: Design
RANDOMIZE
VDC
VDC+
I/E
LOCAL
CONTROL
VDCA
VDCA+
I/E
INT-0091: Addition of IE Improved INT-0091: Addition of IE Improved EFSEFS
Grier et al., NEJM 348:698, 2003
INT-0091: IE Decreased Local INT-0091: IE Decreased Local RelapsesRelapses
Grier et al., NEJM 348:699, 2003
AEWS0031 DesignAEWS0031 Design
RANDOMIZE
VCRDoxCPM
IFOSETOP
VCRDoxCPM
IFOSETOP
VCRDoxCPM
IFOSETOP
VCRDoxCPM
IFOSETOP
Regimen A
q3w x 2
Local Control
Local Control
q2w x 3
q3w x 5
q2w x 4
Regimen B
AEWS0031 AccrualAEWS0031 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*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 RandomizationAEWS0031 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 AEWS0031 Patient CharacteristicsCharacteristics
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%)
ESR (mm/hr) 31.4 (32.2) 32.9 (28.3)
LDH (IU/l) 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%)
AEWS0031 Patient AEWS0031 Patient Characteristics 2Characteristics 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%)
Fracture at primary site 9 (3.5%) 14 (5.5%)
AEWS0031: Primary Tumor AEWS0031: Primary Tumor TreatmentTreatment
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
Percentages of patients who had:
AEWS0031: EFS for all eligible AEWS0031: EFS for all eligible patientspatients
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n E
vent
-Fre
e
0 2 4 6Years
StandardIntensive
Regimen
p=0.023
AEWS0031: OS for all eligible AEWS0031: OS for all eligible patientspatients
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n S
urvi
ving
0 2 4 6Years
StandardIntensive
Regimen
p=0.026
AEWS0031: EventsAEWS0031: 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 AEWS0031: Patterns of RelapseRelapse
123 Relapses*
72 Standard 51 Intensive
18 Localonly
39 Distantonly
15 Combined 16 Localonly
27 Distantonly
8 Combined
54 Distant 35 Distant
20 Lung 16 Bone 11 Other 7 Multiple 11 Lung 15 Bone 6 Other 3 Multiple
AEWS0031: Patterns of AEWS0031: Patterns of RelapseRelapse
123 Relapses*
72 Standard 51 Intensive
18 Localonly
39 Distantonly
15 Combined 16 Localonly
27 Distantonly
8 Combined
54 Distant 35 Distant
20 Lung 16 Bone 11 Other 7 Multiple 11 Lung 15 Bone 6 Other 3 Multiple
AEWS0031: “Other” Sites of AEWS0031: “Other” Sites of RelapseRelapse
Standard Intensive
CNS (Brain, spinal cord)
7 0
Miscellaneous 4(pleura, nodes, soft tissue, liver)
6(pleura, mediastinum, marrow)
A few statisticsA 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: ConclusionsAEWS0031: Conclusions
Accelerated chemotherapy reduces lung and “other” (especially CNS) relapses
It has no effect on local or skeletal relapses
AEWS0031: Implications of Relapse AEWS0031: Implications of Relapse PatternsPatterns
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 ESFTVDC/IE Regimens for ESFT
Regimen Years EFS 95% Intervals
INT-0091 B(CCG-7881/POG-8850)
1988-92 69% 66-72%
INT-0154 A, B(CCG-7942/POG-9354)
1995-98 71% 67-75%
AEWS0031 A (q3w)
2001-2005 70% 63-75%