CHEMOTHERAPY INTENSIFICATION BY INTERVAL COMPRESSION

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 Regimen A R A N D O M I Z E VCR Dox CPM q3w x 2 IFOS ETOP Local Control VCR Dox CPM q3w x 5 IFOS ETOP 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 2 3 4 < 17y, non-pelvic < 17y, pelvic > 18y, non-pelvic > 18y, pelvic 419 93 57 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 Age at Study Entry Median (Range) Gender Standard (N=284) 12 (0-33) Intensive (N=284) 13 (0-45) Male Female Race 154 (54%) 130 (46%) 154 (54%) 130 (46%) White Black Other 252 (89%) 8 (3%) 14 (5%) 250 (88%) 6(2%) 16 (6%) Not Reported Laboratory Information ESR (mm/hr) 10 (4%) 12 (4%) 31.4 (32.2) 32.9 (28.3) LDH (IU/l) Pleural Effusions at Diagnosis 448.2 (414.0) 19 (8%) 451.5 (437.2) 21 (9%) Gross tumor resection prior to start of chemotherapy 47 (17%) 48 (17%) AEWS0031 Patient Characteristics 2 Characteristics Primary tumor site Standard (N=284) Intensive (N=284) Skull, maxilla, mandible C, T, L Vertebrae Sacrum 15 (5.5%) 11 (3.9%) 16 (5.6%) 12 (4.3%) 28 (9.9%) 8 (2.8%) Ribs, Sternum Scapula, clavicle Humerus 29 (10.3%) 14 (4.9%) 13 (4.6%) 25 (8.9%) 14 (5.0%) 12 (4.2%) Ulna, Radius Phalanges (Fingers) Pelvis 7 (2.5%) 0 (0%) 31 (11%) 7 (2.5%) 1 (0.4%) 33 (11.6%) Femur Patella Tibia, fibula Bones of feet Soft Tissue 32 (11.3%) 1 (0.4%) 40 (14.1%) 8 (2.9%) 67 (23.6%) 27 (9.5%) 1 (0.4%) 33 (11.1%) 7 (2.5%) 76 (26.8%) Fracture at primary site 9 (3.5%) 14 (5.5%) AEWS0031 Chemotherapy Cycle Lengths Standard (A) Mean (days) 23.3 Intensive (B) 18.5 Median (days) 21 15 EFS for All Eligible Patients 1.00 By Regimen 0.75 0.50 Regimen Standard Intensive 0.25 p=0.029 0.00 0 2 Years 4 6 Survival for All Eligible Patients 1.00 By Regimen 0.75 0.50 Regimen Standard Intensive 0.25 p=0.026 0.00 0 2 Years 4 6 EFS for All Eligible Patients By Age at Dx 1.00 Estimated Proportion Event-Free 0.25 0.50 0.75 Age Group -4 5-9 10-14 15+ 0.00 0 2 Years 4 6 Survival for All Eligible Patients By Age at Dx 1.00 Estimated Proportion Surviving 0.25 0.50 0.75 Age Group -4 5-9 10-14 15+ 0.00 0 2 Years 4 6 EFS for All Eligible Patients 1.00 By Age Group at Enrollment 0.75 0.50 Age Group -17 Years 18+ Years 0.00 0.25 0 2 Years 4 6 AEWS0031 Regimens and Age 1.00 Estimated Proportion Event-Free 0.75 Reg B Reg A Age Group 0.50 -17 Years 18+ Years 0.00 0 0.25 2 4 6 Years AEWS0031 Infectious Toxicities Toxicity Type Randomized Treatment Assignment Standard Number of Courses with Toxicity Total Number of Courses Intensive Number of Courses with Toxicity Total Number of Courses Percent Wound-infectious Percent 1.0 35 3614 0.7 27 3623 Colitis Typhlitis Catheter-related infection Febrile neutropenia (fever of unknown origin) Infection with grade 3 or 4 neutropenia Infection with unknown ANC Infection without neutropenia Infection/Febrile Neutropenia - Other 0.2 0.0 1.5 8 1 54 3614 3614 3614 0.1 0.3 1.0 5 11 38 3623 3623 3623 6.1 4.6 0.2 2.2 0.3 221 166 6 80 11 3614 3614 3614 3614 3614 7.4 4.8 0.1 2.0 0.3 269 173 2 72 11 3623 3623 3623 3623 3623 AEWS0031 Other Toxicities Randomized Treatment Assignment Standard Total Nu mbe r of Cou rses Intensive Number of Cou rse with Toxi city Total Num ber of Cour ses Toxicity Type Perce n t Number of Course with Toxicit y Perce n t Transfusion: Platelets Transfusion: pRBCs Cardiac left ventricular function 2.6 5.6 93 201 3614 3614 4.8 8.9 173 322 3623 3623 0.0 Hypotension 1 18 3623 3623 0.8 29 3614 0.5 Fatigue (lethargy, malaise, asthenia) Fever (in the absence of neutropenia) 0.3 0.1 12 4 3614 3614 0.2 0.1 6 4 3623 3623 Weight loss Constitutional Symptoms - Other Hand-foot skin reaction 0.1 0.1 4 2 3614 3614 0.1 0.1 3 2 3623 3623 0.2 Radiation dermatitis 9 7 3623 3623 0.4 13 3614 0.2 Rash/desquamation Wound-infectious 0.1 1.0 3 35 3614 3614 0.2 0.7 8 27 3623 3623 AEWS0031 Hospital Days by Regimen Treatment Standard (n=237) Intensive (n=239) p-value1 Mean (SD) Median (Range) 68.5 (26.9) 66 (5, 178) 69.9 (29.1) 67 (5, 267) 0.46 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 Womer Dan West Mark Krailo Karen Albritton Christie Lee Powell Chris Denny Meeni Devidas Paul Dickman Doug Hawkins Bruce Pawel John Dormans John Healey Carol Kotsubo Karen Marcus Kathleen Patterson Scott Sailer Ted Zwerdling Loreen MacIsaac Brenda Ennis Mark Gebhardt Holcombe Grier James Meyer Greg Griffin Linda Granowetter Special thanks to Chris Williams-Hughes, Celeste Sabinske, Biljana Georgievska and Steven Jong.