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Limited radiation exposure preserves intellectual functioning in some children with medulloblastoma
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Reduced-dose craniospinal irradiation plus a tumor bed boost preserved intellectual functioning in children with wingless or Group 4 subtypes of medulloblastoma, according to research published in the Journal of Clinical Oncology.
Children with the sonic hedgehog (SHH) subtype appeared to have the most distinct functional and processing speed outcome, results also showed. Thus, subgroup-specific analyses should inform novel biologically based treatment protocols for patients with medulloblastoma, according to the researchers.
Craniospinal irradiation results in a decline in neuropsychological functioning overtime, and more than 90% of survivors require long-term special education services.
“Characterizing the intellectual implications of reducing treatment in patients who are candidates for therapy de-escalation (ie, wingless [WNT] and some Group 4 patients) is most immediately relevant to clinical practice,” Iska Moxon-Emre, BSc, MSc, MA, doctoral student in neurosciences and mental health at University of Toronto, and colleagues wrote. “However, it is also valuable to understand if patients in other subgroups can benefit from radiation dose de-escalation.”
Researchers had two primary goals in their analysis of four biologically distinct subgroups of medulloblastoma — WNT, SHH, Group 3 and Group 4.
“Our first aim was to compare the rate of change in intellectual functioning between patients in each subgroup while controlling for relevant medical and/or demographic features,” Moxon-Emre and colleagues wrote. “... Our second aim was to evaluate the impact of treatment with different radiation intensity protocols on intellectual outcome within medulloblastoma subgroups.”
Researchers evaluated data from 121 patients treated between 1991 and 2013 at children’s hospitals in Toronto, Washington, D.C., or Palo Alto, California. Researchers categorized patients as having WNT (n = 17), SHH (n = 28), Group 3 (n = 28) or Group 4 (n = 51) medulloblastoma subtypes. WNT and Group 4 patients were considered candidates for therapy de-escalation.
Researchers compared intellectual trajectories between subgroups. They also evaluated the effects of reduced-dose craniospinal irradiation (CSI) plus a tumor bed boost compared with higher CSI doses and larger boost volumes to the brain — which included standard-dose CSI with posterior fossa boost, reduced-dose CSI with posterior fossa boost and standard-dose CSI with tumor bed boost.
Each subgroup declined significantly for all measures of intellectual functioning (all P < .05). However, WNT patients did not demonstrate significant perceptional reasoning declines and had marginally significant declines in verbal comprehension and working memory (P = .05).
The SHH subgroup showed less declines in processing speed than Group 3 and Group 4, and less than Group 3 patients overall (all P < .05). The SHH subgroup also had the lowest incidence of cerebellar mutism and motor deficits.
In terms of radiation intensity, reduced-dose CSI (18-23.4 Gy) and tumor bed boost (45-55.4 Gy) preserved intellectual functioning in WNT and Group 4 patients. In contrast, WNT and Group 4 patients in the all other treatments group declined by at least 1.8 points per year across all measures of intellectual functioning (all P < .001).
Reduced-dose CSI plus tumor bed boost did not preserve intellectual function in Group 3 patients. Regardless of radiation intensity, patients showed declines in all measures (P < .05). However, among patients treated with reduced-dose CSI plus tumor bed boost, only the decline for verbal comprehension reached significance (P = 0.2).
SHH patients treated with reduced-dose CSI and tumor bed boost did not experience significant declines in Full Scale IQ, perceptual reasoning and processing speed; however, patients in all other treatment groups declined significantly (P < .05).
Moxon-Emre and colleagues acknowledged the radiation intensity analyses had small patient populations. Further, patients were treated on several different protocols and received various chemotherapy agents, and various IQ test versions were used.
Multisite collaborative studies are needed to confirm that reduced-dose CSI plus tumor bed boost confers favorable intellectual outcomes in larger cohorts of WNT and Group 4 patients separately, researchers wrote. Further, the association between tumor location and the incidence of cerebellar mutism/motor deficits in SHH patients warrants further evaluation.
“We have demonstrated that SHH patients have the most distinct functional and processing speed outcome and that only WNT and Group 4 patients appear to benefit clearly from limiting radiation exposure,” Moxon-Emre and colleagues wrote. “Our findings highlight the value of subgroup-specific analyses, and have the potential to inform current efforts to develop biologically based treatment protocols.” – by Chuck Gormley
Disclosure: Moxon-Emre reports no relevant financial disclosures. Other researchers report travel accommodations from Merck and one research reports royalties on patents from NanoString-based diagnostic panels.
Perspective
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Medulloblastoma — arising in the posterior fossa of infants, children and, less frequently, young adults — is the single most common form of childhood malignant brain tumor. Treatment, which includes craniospinal and primary site boost radiotherapy and chemotherapy in all but the youngest patients, has resulted, in a step-wise fashion, in improved outcome. Five-year PFS rates of over 80% are seen in subsets of patients, the majority of whom are cured of their disease.
An extremely vexing problem in the treatment of children with medulloblastoma, especially those aged 3 to 8 years, has been the quality of life of survivors. The majority of the younger children demonstrate impaired neurocognitive function. This is believed due, in great part, to the craniospinal radiation received and, to a lesser extent, possibly to the focal boost of radiation therapy and the chemotherapy employed. Other factors that have been shown to impact the degree and possibly the types of neurocognitive sequelae seen include age of the patient at the time of diagnosis, surgical complications like posterior-fossa mutism syndrome, and the degree of hydrocephalus at the time of diagnosis.
The biologic underpinnings of medulloblastoma have been rapidly unraveled over the past decade. Utilizing next-generation techniques, medulloblastoma is now considered to be comprised of at least four, and as many as eight, discernable molecular subtypes and possibly different diseases. These different molecular subtypes have corresponding differing prognoses, which has led to the consideration of treating children of different populations with medulloblastoma with molecular subset–specific dose intensities of radiation and chemotherapy. Even prior to the new molecular understandings of medulloblastoma, it has been shown that a reduction in the dose of craniospinal radiation therapy, when utilized with chemotherapy, can result in both improved survival and an amelioration of the severity of intellectual compromise.
The study by Moxon-Emre and colleagues from Toronto, Canada; Washington, D.C.; and Palo Alto, California has raised the possibility that intellectual outcome after treatment for medulloblastoma could also be affected by the molecular subgroup of the patient’s tumor. In those children who have now been identified as having the lowest molecular risk of tumor relapse, treatment with reduced-dose craniospinal radiation therapy and chemotherapy was associated with relatively preserved intellectual functioning. However, it should be pointed out that many of these children were somewhat older than others with medulloblastoma.
An interesting subgroup, those children with the Sonic Hedgehog (SHH) variant, were postulated to be more resistant to the neurocognitive sequelae of treatment. It is important to note that these patients, who more commonly have laterally placed cerebellar lesions, are also less likely to develop cerebellum mutism and have less postoperative motor deficits than other molecular subgroups. This, in some degree, may explain why they seem to be somewhat more resistant to the damage of radiation therapy. In contradistinction, some of the patients with the SHH variant have Gorlin’s syndrome and have more skin toxicity after radiotherapy. Thus, the rationale of why they would be more “resistant” to radiation-induced neurotoxicity is not completely clear.
As important as this paper is in demonstrating that children with medulloblastoma may be affected differently by treatment, the results need to be viewed cautiously. The review is retrospective, and the overall number of patients treated remains relatively small. The paper covers a wide time period, and reduced doses of craniospinal radiation therapy were utilized later in the study period. Further, the chemotherapy utilized varied over time.
The report does, however, give some credence to the clinical trials that are proscribing even further reduced doses of craniospinal radiotherapy and chemotherapy for some subsets of children with medulloblastoma. It also demonstrates how the new molecular understandings of the disease may lead to more rational and, in time, less toxic therapy. Prospective studies of larger cohorts of patients are required to confirm the associations suggested.
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