Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial

Gajjar, Amar; Chintagumpala, Murali; Ashley, David M.; Kellie, Stewart J.; Kun, Larry E.; Merchant, Thomas E.; Woo, S. L. C.; Wheeler, Greg; Ahern, V.; Krasin, Matthew J.; Fouladi, Maryam; Broniscer, Alberto; Krance, Robert A.; Hale, Gregory A.; Stewart, Clinton F.; Dauser, Robert C.; Sanford, Robert A.; Fuller, Christine; Lau, Ching C.; Boyett, James M.; Wallace, Dana; Gilbertson, Richard J.

doi:10.1016/s1470-2045(06)70867-1

Cited by 823 publications

(684 citation statements)

References 32 publications

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“…The conventional chemotherapy agents were vincristine, cisplatin, and lomustine or cyclophosphamide, similar to the treatment plan of a recently closed cooperative group study (8). High-dose chemotherapy was administered as part of a study and included high-dose cyclophosphamide, cisplatin, and vincristine or melphalan and cyclophosphamide (9,10).…”

Section: Chemotherapy Protocolsmentioning

confidence: 99%

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Changes Mimicking New Leptomeningeal Disease After Intensity-Modulated Radiotherapy for Medulloblastoma

Muscal

Jones

Paulino

et al. 2009

International Journal of Radiation Oncology*Biology*Physics

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Purpose-Acute and late changes in magnetic resonance imaging of the pediatric brain have been described after radiotherapy (RT). We report the post-RT neuroimaging changes in the posterior fossa after intensity-modulated RT (IMRT) in children with medulloblastoma and contrast them with those of leptomeningeal disease.Methods and Materials-We performed a retrospective review of 53 consecutive children with medulloblastoma who were treated with craniospinal RT followed by IMRT to the posterior fossa and chemotherapy between 1997 and 2006.Results-After IMRT to the posterior fossa, 8 (15%) of 53 patients developed increased fluidattenuated inversion-recovery signal changes in the brainstem or cerebellum and patchy, multifocal, nodular contrast enhancement at a median of 6 months. The enhancement superficially resembled leptomeningeal disease. However, the enhancement resolved without intervention at a median of 6 months later. The accompanying fluid-attenuated inversion-recovery signal changes occasionally preceded the enhancement, were often parenchymal in location, and resolved or persisted to a lesser degree. All 8 patients with transient magnetic resonance imaging changes in the posterior fossa were alive at last follow-up. In contrast, leptomeningeal disease occurred in 8 (15%) of our 53 patients at a median of 19.5 months after IMRT completion. Of these 8 patients, 7 demonstrated initial nodular enhancement outside the conformal field, and 7 patients died.Conclusion-Magnetic resonance imaging changes can occur in the posterior fossa of children treated with IMRT for medulloblastoma. In our experience, these transient changes occur at a characteristic time and location after RT, allowing them to be distinguished from leptomeningeal disease.

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Section: Chemotherapy Protocolsmentioning

confidence: 99%

“…Of the 53 patients, 18 received conventional chemotherapy and 33 high-dose chemotherapy with stem cell rescue (9,11). One patient received homeopathic therapy, and 1 patient died before receiving chemotherapy.…”

Section: Chemotherapy Protocolsmentioning

confidence: 99%

Changes Mimicking New Leptomeningeal Disease After Intensity-Modulated Radiotherapy for Medulloblastoma

Muscal

Jones

Paulino

et al. 2009

International Journal of Radiation Oncology*Biology*Physics

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“…Specifically, in the treatment of medulloblastoma, the most common malignant pediatric brain tumor, radiation, together with high-dose chemotherapy, has improved 5-year survival rates in patients (2). However, it also causes serious deleterious effects that include neurocognitive deficits, developmental problems, and secondary malignancies in the majority of survivors (3)(4)(5)(6). Identifying new approaches that would allow reduction of the total radiation dose in these treatments without compromising therapeutic efficacy is critical for improving tumor management and quality of life.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma

Markowitz

Powell

Tran

et al. 2016

Molecular Cancer Therapeutics

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Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient-derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patientderived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects.

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“…[11][12][13] Additionally, several recent studies have suggested that dose-escalation using tandem HDCT/auto-SCT might further improve outcomes in the treatment of recurrent or high-risk brain tumors. 14,15 In the present study, we prospectively evaluated the feasibility and effectiveness of tandem HDCT/auto-SCT in children o3 years of age with malignant brain tumors. RT was either not given or deferred until 3 years of age if the patient achieved CR after tandem HDCT/auto-SCT.…”

Section: Introductionmentioning

confidence: 99%

Tandem high-dose chemotherapy and auto-SCT for malignant brain tumors in children under 3 years of age

et al. 2013

Bone Marrow Transplant

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In an effort to improve survival and reduce late adverse effects of radiation therapy (RT), 25 children o3 years of age with malignant brain tumors received tandem high-dose chemotherapy (HDCT) and auto-SCT following six cycles of induction chemotherapy. RT was either not given or deferred until 3 years of age if the patient was in CR after tandem HDCT/auto-SCT. Tumors relapsed or progressed in nine patients (five during induction treatment), and two of these patients survived after receiving salvage treatment, including RT. Two patients died due to toxicities during tandem HDCT/auto-SCT. A total of 16 patients survived to a median follow-up period of 52 months (range 18-96) from the time of diagnosis. Four of these patients did not receive RT, two received local RT (L-RT), three received craniospinal RT (CSRT), and seven received both L-RT and CSRT. The 5-year OS and EFS rates were 67.8 ± 9.4% and 55.5 ± 10.0%, respectively. Neuroendocrine and neurocognitive functions evaluated 3 years after tandem HDCT/auto-SCT were acceptable. Our results indicate that tandem HDCT/auto-SCT may improve survival in young children with malignant brain tumors with an acceptable level of risk of long-term toxicity.

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Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial

Cited by 823 publications

References 32 publications

Changes Mimicking New Leptomeningeal Disease After Intensity-Modulated Radiotherapy for Medulloblastoma

Changes Mimicking New Leptomeningeal Disease After Intensity-Modulated Radiotherapy for Medulloblastoma

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma

Tandem high-dose chemotherapy and auto-SCT for malignant brain tumors in children under 3 years of age

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