Saving Lives, Saving Neurons, the Head Start Consortium for Young Children with Malignant Central Nervous System Tumors

Update - 6/24:
Head Start III completed patient accrual, as anticipated, in December 2009, with a total of approximately 215 children enrolled from 38 participating centers in the USA, Canada, Australia, New Zealand and Switzerland.

Several presentations and papers based on the ALSF-supported clinical trial have appeared:

• Preliminary oral platform presentations were delivered at the annual ASCO meeting in 2011 for both medulloblastoma (Dhall et al) and CNS PNET (Davidson et al). Preliminary oral platform presentations were also delivered at SIOP (Brazil) on CNS ATRT (Finlay et al 2009) and at SNO on Ependymoma (Venkatramini et al, 2011).
• Peer-reviewed manuscripts have been published on HSIII data to date on ependymoma (Venkatramini et al 2013, Pediatric Blood & Cancer) and CNS ATRT. (Zaky et al 2014, Pediatric Blood. & Cancer)
• Manuscripts are close to submission on (1) medulloblastoma and (2) CNS PNET. 

Other Findings
In addition, we have now been able to generate molecular profiling of young children's medulloblastoma treated either on or similar to HSIII, demonstrating the superior outcome (>90% cure rate) of such children with the SHH (sonic hedgehog pathway activation) profile with our chemotherapy-only strategy, leading us to recommend reduced intensity therapy in our upcoming HS4 protocol. A manuscript describing these findings is currently under review.

Additional secondary publications have either recently emanated from the "Head Start" Consortium,or are currently in preparation, including prevalence of hearing loss, importance of second look surgical biopsy/resection of residual mass, and long term assessment of endocrine function. Finally, formal prospective neuropsychological and quality of life evaluations are still ongoing on our surviving children.

Background
Primary brain tumors are the second most common type of cancer in children and adolescents and are the major cause of cancer related death in this population. Embryonal tumors, which include medulloblastomas and the other primitive neuroectodermal tumors (PNET), atypical teratoid/rhabdoid tumors (AT/RT) and ependymomas comprise the most common group of malignant brain tumors and are particularly prevalent in patients with these malignancies. This goal is summarized by our mission statement “Saving Lives, Saving Neurons.”

The "Head Start" (HS) treatment protocols, which were developed by the Principal Investigator of this proposal, have utilized intensive chemotherapy, including myeloablative consolidation with autologous hematopoietic cell rescue (AuHCR). This strategy has resulted in approximately 50% EFS with maintenance of cognitive function in the normal range. However, as with other treatment regimens, a significant proportion of patients treated in the HS I and II studies continue to develop recurrent disease after having achieved a complete remission.

Project Goal
The HS III study, when completed, very likely will confirm that the major problem is recurrence from minimal residual disease. Thus, we hypothesize that the most fruitful strategy will be to incorporate post-consolidation therapy that targets minimal residual disease. This will be tested in our upcoming HS IV protocol. Our overall goals are to complete HS III, begin HS IV, and develop a HS-related tumor and normal cell bank for biological research.