A Win for Protons in Pediatric Brain Tumors

Proton therapy for pediatric brain tumors led to significantly better longitudinal intelligence outcomes as compared with conventional radiation therapy, results of a matched-cohort study showed.

With a median follow-up of 4 to 5 years, children with medulloblastoma treated with proton therapy (PRT) had significantly better scores for global intelligence quotient (IQ), perceptual reasoning, and working memory (P<0.05). Treatment with photon therapy (XRT) was associated with significant declines in global IQ, working memory, and processing speed (P<0.05). In contrast, the proton therapy group had stable scores for all outcomes except processing speed, which declined significantly over time (P=0.003).

The results build on previous research suggesting a cognition-sparing benefit of proton therapy for treatment of pediatric brain tumors, reported Lisa S. Kahalley, PhD, of Texas Children’s Hospital (TCH) in Houston, and colleagues in the Journal of Clinical Oncology.

“It’s getting very difficult to argue that there isn’t a very strong clinical benefit associated with proton, so now it really becomes an access issue,” Kahalley told MedPage Today. “We have to think really hard about ways to improve access to families that aren’t located near proton centers.

“If there’s not a movement to build more proton centers, improve access, or figure out another way to transport patients so that they can have access elsewhere, then the really well-resourced families — the ones who have money and who can take off work for 6 weeks to relocate to a proton center for treatment — those are the ones who are going to get proton treatment. The families that don’t have the resources to do that, which would be the majority of America, those are the families that don’t end up getting what might be better treatment that is associated with better outcomes long term.”

Best Evidence Yet

Kahalley and colleagues previously reported favorable results with proton therapy in a heterogeneous population of patients with different types of brain tumors, treated at different times and with different protocols, and focused on the broader outcome parameter of IQ. The new study has several advantages that provide more confidence in the findings.

“This study has several important benefits,” said co-author Donald Mabbott, PhD, of the University of Toronto and the Hospital for Sick Children. “First, the two groups we studied had identical tumor (medulloblastoma) and treatment protocols (craniospinal radiation) during the same time period. The only difference was in proton versus photon radiation. In the 2016 paper, the proton group was compared to historical controls, the treatment protocols differed, and a mix of tumor diagnoses were compared. Further, the 2016 study included both cranial-spinal and focal radiation.

“Second, in the present study the groups were matched in terms of maternal and paternal education — which is known to impact intelligence outcomes. This was not evaluated in the 2016 study. Third, we observed more robust differences between the proton and photon groups in terms of changes in IQ outcomes, as compared to the 2016 paper, likely due to our more comparable groups.”

The careful matching of patients, tumor types, and treatment protocols “adds to the 2016 study results in that we now have more confidence that the differences in IQ we observed were due to the type of radiation therapy (proton versus photon), and not some other variable,” Mabbott added.

Multiple previous studies showed that proton radiotherapy may lessen the neuropsychological risk associated with cranial radiotherapy for pediatric brain tumors by reducing the radiation dose to normal brain tissue. Many of the studies were conducted prior to the introduction of modern photon radiotherapy (RT) protocols, such as intensity-modulated RT. As a result, no data exist to show that intellectual outcomes with proton therapy are superior to those of modern XRT protocols. Additionally, subsets of patients treated with proton therapy, notably younger patients and craniospinal irradiation (CSI), have increased intellectual risk, the authors noted.

Study, Key Findings

To address the gaps in knowledge, investigators searched records at two medical centers (Hospital for Sick Children and TCH) for patients with medulloblastoma treated with CSI during 2007 to 2018. They identified 79 patients, 42 treated with XRT at the Hospital for Sick Children, which did not have access to proton therapy, and 37 at TCH, where proton therapy was the standard for pediatric brain tumors throughout the study period.

The two cohorts were well matched with respect to sex (67% male), mean age at diagnosis (8.6 years), median CSI dose (23.4 Gy), mean length of follow-up (4.3 years), mean parental education (14.3 years), and baseline intelligence scores (global IQ, verbal reasoning, perceptual reasoning, working memory, and processing speed). The XRT cohort had a significantly greater boost dose to margin and total radiation dose to the tumor bed and margin (P=0.001, P=0.0001).

In an adjusted mixed-models analysis, patients treated with XRT differed significantly from the PRT cohort with respect to change over time (slope) in:

• Global IQ: -0.9 vs 0.3, P=0.011
• Perceptual reasoning: -0.8 vs 1.0, P=0.022
• Working memory: -2.2 vs 0.1, P=0.002

Both cohorts had a nonsignificant decline in verbal reasoning (-0.4, P=0.141) and a significant decline in processing speed (-0.9, P=0.003).

“To our knowledge, this study provides the strongest evidence to date demonstrating an intellectual advantage with PRT in the treatment of pediatric medulloblastoma,” the authors concluded. “Even in the context of CSI, patients treated with PRT exhibited stable intellectual outcomes in most domains and experienced significantly better long-term outcomes in global IQ, perceptual reasoning, and working memory compared with patients treated with XRT.

“Neurocognitive sparing did not come at the expense of disease control, with both groups experiencing comparable rates of relapse,” they added.

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