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Outcomes and acute toxicities of proton therapy for pediatric atypical teratoid/rhabdoid tumor of the central nervous system.

ABSTRACT: PURPOSE:Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system is a rare cancer primarily affecting children younger than 5 years old. Because patients are young and receive intensive chemotherapy, there is concern regarding late radiation toxicity, particularly as survival rates improve. Therefore, there is interest in using proton therapy to treat these tumors. This study was undertaken to investigate outcomes and acute toxicities associated with proton therapy for AT/RT. METHODS AND MATERIALS:The records of 31 patients with AT/RT treated with proton radiation from October 2008 to August 2013 were reviewed. Demographics, treatment characteristics, and outcomes were recorded and analyzed. RESULTS:Median age at diagnosis was 19 months (range, 4-55 months), with a median age at radiation start of 24 months (range, 6-62 months). Seventeen patients received local radiation with a median dose of 50.4 GyRBE (range, 9-54 GyRBE). Fourteen patients received craniospinal radiation; half received 24 GyRBE or less, and half received 30.6 GyRBE or more. For patients receiving craniospinal radiation, the median tumor dose was 54 GyRBE (range, 43.2-55.8 GyRBE). Twenty-seven patients (87%) completed the planned radiation. With median follow-up of 24 months for all patients (range, 3-53 months), median progression-free survival was 20.8 months and median overall survival was 34.3 months. Five patients (16%) developed clinical findings and imaging changes in the brainstem 1 to 4 months after radiation, consistent with radiation reaction; all cases resolved with steroids or bevacizumab. CONCLUSIONS:This is the largest report of children with AT/RT treated with proton therapy. Preliminary survival outcomes in this young pediatric population are encouraging compared to historic results, but further study is warranted.

SUBMITTER: McGovern SL

PROVIDER: S-EPMC4327980 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Outcomes and acute toxicities of proton therapy for pediatric atypical teratoid/rhabdoid tumor of the central nervous system.

McGovern Susan L SL Okcu M Fatih MF Munsell Mark F MF Kumbalasseriyil Nancy N Grosshans David R DR McAleer Mary F MF Chintagumpala Murali M Khatua Soumen S Mahajan Anita A

International journal of radiation oncology, biology, physics 20141011 5

<h4>Purpose</h4>Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system is a rare cancer primarily affecting children younger than 5 years old. Because patients are young and receive intensive chemotherapy, there is concern regarding late radiation toxicity, particularly as survival rates improve. Therefore, there is interest in using proton therapy to treat these tumors. This study was undertaken to investigate outcomes and acute toxicities associated with proton therapy for AT/R ...[more]

PMID: 25311260

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Project description:Despite intensifying multimodal treatments, children with central nervous system atypical teratoid/rhabdoid tumor (CNS ATRT) continue to endure unacceptably high mortality rates. At present, concerted efforts are focusing on understanding the characteristic INI1 mutation and its implications for the growth and survival of these tumors. Additionally, pharmaceutical pipeline libraries constitute a significant source of potential agents that can be taken to clinical trials in a timely manner. However, this process requires efficient target validation and relevant preclinical studies. As an initial screening approach, a panel of 129 small molecule inhibitors from multiple pharmaceutical pipeline libraries was tested against three ATRT cell lines by in vitro cytotoxicity assays. Based on these data, agents that have strong activity and corresponding susceptible cellular pathways were identified. Target modulation, antibody array analysis, drug combination and in vivo xenograft studies were performed on one of the pathway inhibitors found in this screening. Approximately 20% of agents in the library showed activity with IC(50) values of 1 μM or less and many showed IC(50) values less than 0.05 μM. Intra cell line variability was also noted among some of the drugs. However, it was determined that agents capable of affecting pathways constituting ErbB2, mTOR, proteasomes, Hsp90, Polo like kinases and Aurora kinases were universally effective against the three ATRT cell lines. The first target selected for further analysis, the inhibition of ErbB2-EGFR pathway by the small molecule inhibitor lapatinib, indicated inhibition of cell migration properties and the initiation of apoptosis. Synergy between lapatinib and IGF-IR inhibition was also demonstrated by combination index (CI) values. Xenograft studies showed effective antitumor activity of lapatinib in vivo. We present an experimental approach to identifying agents and drug combinations for future clinical trials and provide evidence for the potential of lapatinib as an effective agent in the context of the biology and heterogeneity of its targets in ATRT.

Dataset Information

Outcomes and acute toxicities of proton therapy for pediatric atypical teratoid/rhabdoid tumor of the central nervous system.

Publications

Outcomes and acute toxicities of proton therapy for pediatric atypical teratoid/rhabdoid tumor of the central nervous system.

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