Progressive Decrease in Mortality of Post-Induction Marrow-Ablative Chemotherapy with Autologous Hematopoetic Cell Rescue for Young Children with Newly-Diagnosed Malignant Central Nervous System Tumors: The “Head Start” I-III (HSI-III) Trials, 1991-2009

Introduction: Since 1991, three sequential prospective multi-national clinical trials (including 39 participating institutions) have been conducted by the “Head Start” Consortium for young children newly-diagnosed with malignant brain tumors, designed to improve both the cure rate and quality of survival of such children through replacement (<6yo) or reduction in dosage of brain irradiation (6-10yo) by a single cycle of marrow-ablative chemotherapy with autologous hematopoieic cell rescue as consolidation following initial induction chemotherapy. We present data documenting progressively decreasing morbidity and mortality of the marrow-ablative consolidation phase of treatment as well as the improvement in disease-specific survival.  Methods: Overall treatment design has remained unchanged throughout the 3 prospective trials; 5 cycles of induction chemotherapy (vincristine, cisplatin, etoposide, cyclophosphamide with/without high-dose methotrexate (HD-MTX) over 4 days each 21-28 days cycle (HSI-II) or 3 cycles of the prior regimen + HD-MTX alternating with 2 cycles of vincristine, oral etoposide, temozolomide and cyclophosphamide) were followed –for patients with minimal residual, non-progressive tumor - by a single marrow-ablative cycle consisting of thiotepa (300mg/M2/day x 3 days), etoposide (250mg/M2/day x 3 days) on days -5 to -3, preceded by carboplatin (500mg/M2/day or AUC of 6/day by Calvert formula, whichever was the lower of the methods of dosing) on days -8 to -6. Bone Marrow (HSI) or leukapheresed peripheral blood hematopoietic cells under Neupogen stimulation (HSII-III) were obtained following recovery from the first and/or second induction cycles. Radiotherapy was reserved for patients with residual tumor following completion of induction or >6yo. Results: A total of 216 children were enrolled on 3 consecutive HS trials with medulloblastoma, other primitive neuro-ectodermal tumors, ependymoma, atypical teratoid/rhabdoid tumors, malignant glial tumors and other malignant CNS tumors and underwent marrow-ablative chemotherapy, the 100 day toxic mortality for whom steadily declined from HSI (3/37=8.1%; 1 day +4 hepato-renal failure; 1 day +26 viral pneumonitis post-multi-organ system failure; 1 day +21 post-respiratory arrest due to  oropharyngeal mucositis) through HSII (1/46=2.2%; pseudomonas aerugenosa sepsis) to HSIII (1/131 = 0.8%; VOD day +21). Data on time to engraftment, transplant-related morbidities and long-term disease-specific survival will also be presented. Conclusions: Increasing experience with the marrow-ablative chemotherapy regimen, combined with improved leukapheresis and post-reinfusion supportive care techniques, have likely contributed to the steady decline in transplant-related mortality in this patient population and contributed towards improved overall survival.