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%