Impact of Craniospinal Dose, Boost Volume, and Neurologic Complications on Intellectual Outcome in Patients With Medulloblastoma

Moxon‐Emre, Iska; Bouffet, Éric; Taylor, Michael D.; Laperrière, Normand; Scantlebury, Nadia; Law, Nicole; Spiegler, Brenda J.; Malkin, David; Janzen, Laura; Mabbott, Donald

doi:10.1200/jco.2013.52.3290

Cited by 195 publications

(157 citation statements)

References 29 publications

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“…While CSI is associated with side effects in all patients, children are particularly prone to long-term and deleterious morbidity from CSI. 20,21 Conversely, chemotherapy can be more toxic in adults than children, which may encourage less incorporation of chemotherapy for adult MB. Indeed, while the vast majority of pediatric MB patients receive adjuvant chemotherapy, 3 our analysis demonstrates that adjuvant chemotherapy is excluded in approximately one-third of adult MB patients receiving postoperative RT.…”

Section: Neurooncologymentioning

confidence: 99%

Adjuvant chemotherapy and overall survival in adult medulloblastoma

Kann¹,

Lester-Coll²,

Park³

et al. 2016

Neuro Oncol

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Medulloblastoma (MB) is the most common brain tumor in children. However, it is relatively rare in adults, with an estimated incidence of 0.6 per million. 1 The standardof-care management for pediatric MB is postoperative radiotherapy (RT) with craniospinal irradiation (CSI) and posterior fossa or resection bed boost followed by adjuvant chemotherapy. 2,3 Adoption of adjuvant chemotherapy in the pediatric setting has been associated with improved disease control and has allowed successful CSI dose deescalation in average-risk patients. [2][3][4][5] Even though chemotherapy is used routinely for pediatric patients, its benefit in adult MB is unclear. Data supporting adjuvant chemotherapy in the adult MB population are scarce. There are no randomized trials investigating the benefit of chemotherapy in adult MB, and evidence is generally limited to small retrospective series reported over several decades with conflicting results. [6][7][8][9] Furthermore, compared with children, adults may suffer less toxicity from CSI and greater morbidity from chemotherapy. This may lead to hesitancy in using postoperative chemotherapy, Adjuvant chemotherapy and overall survival in adult medulloblastoma AbstractBackground. Although chemotherapy is used routinely in pediatric medulloblastoma (MB) patients, its benefit for adult MB is unclear. We evaluated the survival impact of adjuvant chemotherapy in adult MB. Methods. Using the National Cancer Data Base, we identified patients aged 18 years and older who were diagnosed with MB in 2004-2012 and underwent surgical resection and adjuvant craniospinal irradiation (CSI). Patients were divided into those who received adjuvant CSI and chemotherapy (CRT) or CSI alone (RT). Predictors of CRT compared with RT were evaluated with univariable and multivariable logistic regression. Survival analysis was limited to patients receiving CSI doses between 23 and 36 Gy. Overall survival (OS) was evaluated using the Kaplan-Meier estimator, log-rank test, multivariable Cox proportional hazards modeling, and propensity score matching. Results. Of the 751 patients included, 520 (69.2%) received CRT, and 231 (30.8%) received RT. With median followup of 5.0 years, estimated 5-year OS was superior in patients receiving CRT versus RT (86.1% vs 71.6%, P < .0001). On multivariable analysis, after controlling for risk factors, CRT was associated with superior OS compared with RT (HR: 0.53; 95%CI: 0.32-0.88, P = .01). On planned subgroup analyses, the 5 year OS of patients receiving CRT versus RT was improved for M0 patients (P < .0001), for patients receiving 36 Gy CSI (P = .0007), and for M0 patients receiving 36 Gy CSI (P = .0008). Conclusions. This national database analysis demonstrates that combined postoperative chemotherapy and radiotherapy are associated with superior survival for adult MB compared with radiotherapy alone, even for M0 patients who receive high-dose CSI.

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Section: Neurooncologymentioning

confidence: 99%

Adjuvant chemotherapy and overall survival in adult medulloblastoma

Kann¹,

Lester-Coll²,

Park³

et al. 2016

Neuro Oncol

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“…El deterioro cognitivo comúnmente se observa como consecuencia del tratamiento multimodal para meduloblastoma, particularmente en niños más pequeños 45 . La hipoacusia se puede deber a la radioterapia o a los regímenes de quimioterapia con cisplatino 46 .…”

Section: Complicaciones Del Tratamientounclassified

Meduloblastoma: de la clasificación histológica a la molecular

Pabón

Hoyos

Restrepo

et al. 2018

MedUPB

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RESUMENEl meduloblastoma es un tumor frecuente en la población pediátrica, pero es raro en pacientes adultos. Es la segunda causa de muerte por cáncer en menores de 15 años. El hallazgo de una lesión tumoral cerebelosa mediana o paramediana que capta el medio de contraste y que a menudo comprime el cuarto ventrículo sugiere la presencia de este tumor. A través del uso de estudios de expresión génica y marcadores moleculares se ha generado una nueva aproximación a la clasificación del meduloblastoma. Así, se ha venido a entender el concepto de meduloblastoma no como una patología sino como un grupo de patologías distintas clínica y molecularmente. La resonancia magnética nuclear espinal y la punción lumbar deben ser realizadas en todos los pacientes como parte de la evaluación de la extensión de la enfermedad, debido a que las leptomeninges espinales son un sitio frecuente de diseminación. El tratamiento implica idealmente la interacción de un grupo interdisciplinario que pueda ofrecer al paciente: cirugía, radioterapia y quimioterapia. El pronóstico depende de variables como edad (menor de tres años), diseminación de la enfermedad, residuo tumoral posquirúrgico, variante histológica de células grandes/anaplásico, y pertenecer al grupo 3 (grupo de amplificacón del MYC).Palabras clave: cerebelo; meduloblastoma; expresión génica; clasificación. ABSTRACTMedulloblastoma is a common tumor in children, but is rare in adults. It is the second most common cause of cancer-related death in patients under 15 years. The presence of a median or paramedian enhancing cerebellar mass, often compressing the fourth ventricle may indicate the presence of this tumor. Genetic and molecular markers offer a new approach to the understanding and classification of medulloblastomas. Hence, we have come to understand medulloblastoma not as a sole disease but rather, as a group of clinically and molecularly distinct pathologies. Magnetic resonance imaging of the spine and lumbar puncture must be performed in all patients as part of the assessment of the extent of disease, since spinal leptomeninges are common sites for metastatic dissemination. Ideally, its treatmeant involves an interdisciplinary group that provides surgery, radiotherapy, and chemotherapy. Prognosis depends upon variables such as age (under three years), metastatic dissemination, residual tumor after surgery, large cell/ anaplastic histological variant, and group 3 tumor (MYC amplification group).

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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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Impact of Craniospinal Dose, Boost Volume, and Neurologic Complications on Intellectual Outcome in Patients With Medulloblastoma

Cited by 195 publications

References 29 publications

Adjuvant chemotherapy and overall survival in adult medulloblastoma

Adjuvant chemotherapy and overall survival in adult medulloblastoma

Meduloblastoma: de la clasificación histológica a la molecular

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma

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