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Proton therapy for pediatric brain tumors yields better cognitive outcomes than X-ray therapy

Proton therapy appeared associated with better neuropsychological outcomes than X-ray radiation therapy among children with brain tumors, according to a study presented at American Society for Radiation Oncology Annual Meeting.

“Based on radiation dose profiles, we have always anticipated that children with brain tumors would derive cognitive benefits of proton therapy relative to conventional X-ray therapy,” Vinai Gondi, MD, radiation oncologist and director of research and education at Northwestern Medicine Chicago Proton Center, said in a press release. “This study provides our first and most compelling clinical evidence of the importance of using proton therapy to spare as much normal brain tissue as possible.”

Researchers evaluated 125 pediatric patients (median age at diagnosis, 7 years) who were treated for tumors in the supratentorial (17.6%), midline (28.8%) or posterior fossa (53.6%) regions of the brain. Median time from treatment to last evaluation was 4 years.

All children underwent age-appropriate neuropsychological assessments, including standardized tests of IQ, processing speed, visual motor integration and parent-reported functioning, which were standardized with a mean of 100 (standard deviation, 15). They also received scaled digit and memory tests, which were scaled with a mean of 10 (standard deviation, 3).

The researchers conducted univariate and multivariate linear regression analyses to identify factors predictive of neuropsychological outcomes.

Children who underwent proton therapy had higher socioeconomic status, differing distributions of race and tumor locations and shorter median time from conclusion of treatment to last neurological assessment (2.6 years vs. 6.6 years; P < .001) than children treated with X-ray radiotherapy.

Univariate analyses revealed children who received proton therapy had higher mean verbal IQ (99.6 vs. 92.9; P = .03), full-scale IQ (99.6 vs. 88.6; P = .02), processing speed (86.9 vs. 80; P = .03), visual motor integration (87.1 vs. 80.8; P = .04), general adaptive composite (91.4 vs. 80.7; P = .04), conceptual function (94.6 vs. 84.1; P = .002), social function (94.8 vs. 86.2; P =.002). and practical function (91.1 vs. 78.9; P = .002).

Digit span and long-term memory did not differ significantly between the two treatment groups.

Multivariate analyses, including tests for interaction with follow-up time, showed that children treated with proton therapy outperformed the X-ray radiotherapy group in full-scale IQ (B = 10.6 points/year; P = .048), processing speed (B =12.6; P =.02), and parent-reported practical function (B = 13.8; P = .049). Children who underwent craniospinal irradiation had lower processing speed (B= -15.9; P =.04) and visual motor integration (B = -14; P = .006). Older children had a higher verbal IQ (B = 0.84; P =.02) and full-scale IQ (B = 1.02; P = .01).

Visual motor integration was higher among children from families with a higher socioeconomic status (B = 1.2 points/$10,000 household income, P = .04) and lower after

administration of vincristine chemotherapy (B = -16.6; P = .01). Children with posterior fossa tumors had lower parent-reported practical function (B = -10.8; P = .048).

Subgroup analyses showed proton therapy, compared with X-ray radiation, appeared associated with higher full-scale IQ (B = 17.2; P = .02) following craniospinal irradiation or whole ventricular radiation therapy (n = 76) and higher processing speed (B = 22.6; P = .01) after partial brain radiation therapy (n= 49).

“We still have much to learn about the dose tolerances of key neuroanatomic structures for performance on specific neuropsychologic domains,” study author Jeffrey Gross, MD, MS, resident in the department of radiation oncology at Northwestern University’s Feinberg School of Medicine, told HemOnc Today. “In our study, children receiving partial brain proton therapy have better preservation of processing speed compared [with] their peers treated with X-rays. We hypothesize this may be due to sparing of the central white matter tracts.”

“Children receiving craniospinal proton therapy had better preservation of full-scale IQ compared to similar children treated with X-rays,” Gross added. “We hypothesize this may be due to decreased dose to the temporal lobes and hippocampi in the boost portion of treatment for children receiving proton therapy.”

Although proton therapy may not be a realistic option in all cases, it is a valuable treatment that is becoming more widely adopted, Gross said.

“At the present time, there are 28 proton therapy facilities in operation in the United States, with more being built or in planning stages,” Gross said. “Although sometimes it is not practically feasible for pediatric brain tumor patients and their families to travel to receive proton therapy, our bias is that when available, it should be offered. However, the benefits of neuropsychological preservation are only realized years after treatment; therefore, patients who will have long-term survival stand to benefit the most.” – by Jennifer Byrne

For more information:

Gross J, et al. Abstract 103. Presented at: ASTRO Annual Meeting; Oct. 21-24, 2018; San Antonio.

Disclosure: Gondi is a partner in Radiation Oncology Consultants Ltd. and co-principal investigator for NRG Oncology. Gross reports no relevant disclosures. Please see the abstract for all other authors’ relevant financial disclosures.

Proton therapy appeared associated with better neuropsychological outcomes than X-ray radiation therapy among children with brain tumors, according to a study presented at American Society for Radiation Oncology Annual Meeting.

“Based on radiation dose profiles, we have always anticipated that children with brain tumors would derive cognitive benefits of proton therapy relative to conventional X-ray therapy,” Vinai Gondi, MD, radiation oncologist and director of research and education at Northwestern Medicine Chicago Proton Center, said in a press release. “This study provides our first and most compelling clinical evidence of the importance of using proton therapy to spare as much normal brain tissue as possible.”

Researchers evaluated 125 pediatric patients (median age at diagnosis, 7 years) who were treated for tumors in the supratentorial (17.6%), midline (28.8%) or posterior fossa (53.6%) regions of the brain. Median time from treatment to last evaluation was 4 years.

All children underwent age-appropriate neuropsychological assessments, including standardized tests of IQ, processing speed, visual motor integration and parent-reported functioning, which were standardized with a mean of 100 (standard deviation, 15). They also received scaled digit and memory tests, which were scaled with a mean of 10 (standard deviation, 3).

The researchers conducted univariate and multivariate linear regression analyses to identify factors predictive of neuropsychological outcomes.

Children who underwent proton therapy had higher socioeconomic status, differing distributions of race and tumor locations and shorter median time from conclusion of treatment to last neurological assessment (2.6 years vs. 6.6 years; P < .001) than children treated with X-ray radiotherapy.

Univariate analyses revealed children who received proton therapy had higher mean verbal IQ (99.6 vs. 92.9; P = .03), full-scale IQ (99.6 vs. 88.6; P = .02), processing speed (86.9 vs. 80; P = .03), visual motor integration (87.1 vs. 80.8; P = .04), general adaptive composite (91.4 vs. 80.7; P = .04), conceptual function (94.6 vs. 84.1; P = .002), social function (94.8 vs. 86.2; P =.002). and practical function (91.1 vs. 78.9; P = .002).

Digit span and long-term memory did not differ significantly between the two treatment groups.

Multivariate analyses, including tests for interaction with follow-up time, showed that children treated with proton therapy outperformed the X-ray radiotherapy group in full-scale IQ (B = 10.6 points/year; P = .048), processing speed (B =12.6; P =.02), and parent-reported practical function (B = 13.8; P = .049). Children who underwent craniospinal irradiation had lower processing speed (B= -15.9; P =.04) and visual motor integration (B = -14; P = .006). Older children had a higher verbal IQ (B = 0.84; P =.02) and full-scale IQ (B = 1.02; P = .01).

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Visual motor integration was higher among children from families with a higher socioeconomic status (B = 1.2 points/$10,000 household income, P = .04) and lower after

administration of vincristine chemotherapy (B = -16.6; P = .01). Children with posterior fossa tumors had lower parent-reported practical function (B = -10.8; P = .048).

Subgroup analyses showed proton therapy, compared with X-ray radiation, appeared associated with higher full-scale IQ (B = 17.2; P = .02) following craniospinal irradiation or whole ventricular radiation therapy (n = 76) and higher processing speed (B = 22.6; P = .01) after partial brain radiation therapy (n= 49).

“We still have much to learn about the dose tolerances of key neuroanatomic structures for performance on specific neuropsychologic domains,” study author Jeffrey Gross, MD, MS, resident in the department of radiation oncology at Northwestern University’s Feinberg School of Medicine, told HemOnc Today. “In our study, children receiving partial brain proton therapy have better preservation of processing speed compared [with] their peers treated with X-rays. We hypothesize this may be due to sparing of the central white matter tracts.”

“Children receiving craniospinal proton therapy had better preservation of full-scale IQ compared to similar children treated with X-rays,” Gross added. “We hypothesize this may be due to decreased dose to the temporal lobes and hippocampi in the boost portion of treatment for children receiving proton therapy.”

Although proton therapy may not be a realistic option in all cases, it is a valuable treatment that is becoming more widely adopted, Gross said.

“At the present time, there are 28 proton therapy facilities in operation in the United States, with more being built or in planning stages,” Gross said. “Although sometimes it is not practically feasible for pediatric brain tumor patients and their families to travel to receive proton therapy, our bias is that when available, it should be offered. However, the benefits of neuropsychological preservation are only realized years after treatment; therefore, patients who will have long-term survival stand to benefit the most.” – by Jennifer Byrne

For more information:

Gross J, et al. Abstract 103. Presented at: ASTRO Annual Meeting; Oct. 21-24, 2018; San Antonio.

Disclosure: Gondi is a partner in Radiation Oncology Consultants Ltd. and co-principal investigator for NRG Oncology. Gross reports no relevant disclosures. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective
    Roshan Prabhu

    Roshan Prabhu

    The dosimetric advantages seen with proton vs. photon therapy for pediatric central nervous system tumors are compelling, and it is very unlikely that a randomized trial of these two modalities in the pediatric population would be conducted due to ethical considerations and lack of equipoise. Therefore, comparative cohort studies such as these are important to try to determine if there is a neurocognitive benefit for proton therapy and, if so, the magnitude.

    It was recently demonstrated that radiotherapy volume and technique do matter for neurocognitive outcomes after photon-based partial-brain radiotherapy in a randomized trial of children that showed smaller target volume and more conformal techniques resulted in significantly improved cognitive and endocrine function preservation. This would imply that greater sparing of intermediate- and low-radiotherapy dose to the brain with protons may further preserve these functions.

    We also know that many patient and tumor factors can predict for neurocognitive outcomes that are unrelated to radiotherapy modality. Despite the use of multivariable analysis, it is impossible to truly control for the effects of these confounding factors, which must be remembered when interpreting results.

    The MD Anderson group conducted a similar study that showed, despite significant differences in the baseline and last cognitive test results, there was no significant difference in the change over time for cognition between protons and photons.

    Gross and colleagues used different statistical methods, comparing last cognitive test results in a multivariable manner, which resulted in a different conclusion. This method does not account for baseline differences in cognition between patients and may not specifically address the underlying question, which is cognitive trajectory after radiotherapy, rather than absolute test results at a certain time point.

    Proton therapy for some children with CNS tumors very likely has advantages in cognition and endocrine function. The unaddressed question is which patients are most likely to benefit and therefore should undergo the hardship of travel and treatment at a proton center. My instinct is that younger patients, those with supratentorial tumors, or those with tumors near the hypothalamic-pituitary-adrenal axis or hippocampus are most likely to benefit, but this has yet to be shown.

    References:

    Conklin HM, et al. J Clin Oncol. 2008; doi:10.1200/JCO.2007.15.9970.

    Jalai R, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2017.0997.

    Kahalley LS, et al. J Clin Oncol. 2016; doi:10.1200/JCO.2015.62.1383.

    Moxon-Emre I, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.52.3290.


    • Roshan Prabhu, MD, MS
    • Levine Cancer Institute at Atrium Health

    Disclosures: Prabhu reports no relevant financial disclosures.

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