Chemotherapy Intensification by Interval Compression in Localized
Ewing Sarcoma Family Tumors (ESFT)
RB Womer, DC West, MD Krailo, PS Dickman, B Pawel,
for the Children’s Oncology Group AEWS0031 Committee
AEWS0031 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 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 CharacteristicsCharacteristics Standard
(N=284)Intensive(N=284)
Age at Study Entry Median (Range) 12 (0-33) 13 (0-45)
Gender
Male 154 (54%) 154 (54%)
Female 130 (46%) 130 (46%)
Race
White 252 (89%) 250 (88%)
Black 8 (3%) 6(2%)
Other 14 (5%) 16 (6%)
Not Reported 10 (4%) 12 (4%)
Laboratory Information
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 Characteristics 2Characteristics Standard
(N=284)Intensive(N=284)
Primary tumor site
Skull, maxilla, mandible 15 (5.5%) 12 (4.3%)
C, T, L Vertebrae 11 (3.9%) 28 (9.9%)
Sacrum 16 (5.6%) 8 (2.8%)
Ribs, Sternum 29 (10.3%) 25 (8.9%)
Scapula, clavicle 14 (4.9%) 14 (5.0%)
Humerus 13 (4.6%) 12 (4.2%)
Ulna, Radius 7 (2.5%) 7 (2.5%)
Phalanges (Fingers) 0 (0%) 1 (0.4%)
Pelvis 31 (11%) 33 (11.6%)
Femur 32 (11.3%) 27 (9.5%)
Patella 1 (0.4%) 1 (0.4%)
Tibia, fibula 40 (14.1%) 33 (11.1%)
Bones of feet 8 (2.9%) 7 (2.5%)
Soft Tissue 67 (23.6%) 76 (26.8%)
Fracture at primary site 9 (3.5%) 14 (5.5%)
AEWS0031Chemotherapy Cycle Lengths
Standard (A) Intensive (B)
Mean (days) 23.3 18.5
Median (days) 21 15
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
By RegimenEFS for All Eligible Patients
p=0.029
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
By RegimenSurvival for All Eligible Patients
p=0.026
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
-4
5-9
10-14
15+
Age Group
By Age at DxEFS for All Eligible Patients
0.00
0.25
0.50
0.75
1.00
Est
imat
ed P
ropo
rtio
n S
urvi
ving
0 2 4 6Years
-45-910-1415+
Age Group
By Age at DxSurvival for All Eligible Patients
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
-17 Years18+ Years
Age Group
By Age Group at EnrollmentEFS for All Eligible Patients
AEWS0031 Regimens and Age0.
000.
250.
500.
751.
00
Est
imat
ed P
ropo
rtio
n E
vent
-Fre
e
0 2 4 6Years
-17 Years
18+ Years
Age Group
Reg B
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
-17 Years
18+ Years
Age Group
Reg B
Reg A
AEWS0031 Infectious ToxicitiesToxicity Type Randomized Treatment Assignment
Standard Intensive
Percent
Number of Courses with Toxicity
Total Number of
Courses Percent
Number of Courses
with Toxicity
Total Number of
Courses
Wound-infectious 1.0 35 3614 0.7 27 3623
Colitis 0.2 8 3614 0.1 5 3623
Typhlitis 0.0 1 3614 0.3 11 3623
Catheter-related infection 1.5 54 3614 1.0 38 3623
Febrile neutropenia (fever of unknown origin) 6.1 221 3614 7.4 269 3623
Infection with grade 3 or 4 neutropenia 4.6 166 3614 4.8 173 3623
Infection with unknown ANC 0.2 6 3614 0.1 2 3623
Infection without neutropenia 2.2 80 3614 2.0 72 3623
Infection/Febrile Neutropenia - Other 0.3 11 3614 0.3 11 3623
AEWS0031 Other Toxicities
Toxicity Type
Randomized Treatment Assignment
Standard Intensive
Percent
Number of Course
with Toxicit
y
Total Nu
mber of Courses
Percent
Number of
Course
with Toxicity
Total Number of
Courses
Transfusion: Platelets 2.6 93 3614 4.8 173 3623
Transfusion: pRBCs 5.6 201 3614 8.9 322 3623
Cardiac left ventricular function
0.0 1 3623
Hypotension 0.8 29 3614 0.5 18 3623
Fatigue (lethargy, malaise, asthenia) 0.3 12 3614 0.2 6 3623
Fever (in the absence of neutropenia) 0.1 4 3614 0.1 4 3623
Weight loss 0.1 4 3614 0.1 3 3623
Constitutional Symptoms - Other 0.1 2 3614 0.1 2 3623
Hand-foot skin reaction
0.2 9 3623
Radiation dermatitis 0.4 13 3614 0.2 7 3623
Rash/desquamation 0.1 3 3614 0.2 8 3623
Wound-infectious 1.0 35 3614 0.7 27 3623
Wound-non infectious 0.1 4 3614 0.1 2 3623
AEWS0031 Hospital Days by Regimen
Treatment p-value1
Standard(n=237)
Intensive(n=239)
Mean (SD) 68.5 (26.9) 69.9 (29.1) 0.46
Median (Range) 66 (5, 178) 67 (5, 267)
AEWS0031 Events
• 123 relapses• 13 SMN (7 Regimen A, 6 Regimen B)
– 9 secondary AML/MDS• 4 Regimen A, 5 Regimen B
– 3 secondary OS– 1 Diffuse large B cell lymphoma
• 1 toxic death• 1 narcotic overdose• 4 other deaths as first event
– Incomplete data or not evaluated
AEWS0031 Conclusions So Far
• Every-two-week chemotherapy is more effective than every three week chemotherapy for localized Ewing sarcoma, with similar toxicity– Unless one is 18 or older
AEWS0031 Things to Do (1)
• Data cleanup– Check deaths as first events– Review soft tissue primary sites– Check sites of first relapse– Compile interval compression data
AEWS0031 Things to Do (2)• Analyses
– Bone v. soft tissue• Overall• By regimen• Bone surface ES?
– Regimen and primary site– Primary tumor treatment– Dose intensification achieved
• Relationship to outcome– Patterns of relapse
• Relationship to regimen
• Correlative biology– ~160 patients on AEWS0031 and bio studies
AEWS0031 Study Committee
Rick WomerDan WestMark KrailoKaren AlbrittonChristie Lee PowellChris DennyMeeni DevidasPaul DickmanDoug HawkinsBruce PawelJohn DormansJohn Healey
Carol Kotsubo Karen MarcusKathleen PattersonScott SailerTed ZwerdlingLoreen MacIsaacBrenda EnnisMark GebhardtHolcombe GrierJames MeyerGreg GriffinLinda Granowetter
Special thanks to Chris Williams-Hughes, Celeste Sabinske,Biljana Georgievska and Steven Jong.
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