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

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StandardIntensive

Regimen

By RegimenEFS for All Eligible Patients

p=0.029

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Regimen

By RegimenSurvival for All Eligible Patients

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10-14

15+

Age Group

By Age at DxEFS for All Eligible Patients

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Age Group

By Age at DxSurvival for All Eligible Patients

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0 2 4 6Years

-17 Years18+ Years

Age Group

By Age Group at EnrollmentEFS for All Eligible Patients

AEWS0031 Regimens and Age0.

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Age Group

Reg B

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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.