Proton Beam in Medulloblastoma: 'New Benchmark'

Roxanne Nelson, BSN, RN

February 04, 2016

For children with medulloblastoma, proton-beam radiotherapy should be considered an "attractive alternative" to conventional radiotherapy, the authors of a new study conclude.

Proton-beam therapy "is effective in decreasing many of the late side effects of treatment," said lead author Torunn Yock, MD, director of pediatric radiation oncology at the Massachusetts General Hospital in Boston. "When possible and available, it should be considered an attractive alternative to [conventional] photon radiotherapy."

The study was published online January 29 in the Lancet Oncology.

The goal of the clinical trial was to assess ototoxicity, late complications, acute adverse effects, and survival and, although not part of the actual study design, the authors did discuss how their results compare with historic control subjects who were treated with conventional photon-based radiotherapy.

They found that both groups had similar survival rates. But importantly, the findings (from a median follow-up of 7 years) suggest that proton radiotherapy results in fewer late effects than standard radiotherapy.

Although the children treated with proton-beam radiotherapy did experience adverse effects, including serious hearing loss in 16%, growth hormone deficit in 55%, and decreases in neurocognitive functions, these rates were somewhat lower than those observed in the literature for conventional radiotherapy.

No cardiac, pulmonary, or gastrointestinal toxic effects — common in patients treated with conventional radiotherapy — were observed in the children treated with proton-beam radiotherapy.

New Benchmark

"This study sets a new benchmark for the treatment of pediatric medulloblastoma and alludes to the clinical benefits of advanced radiation therapies," David R. Grosshans, MD, from the Department of Radiation Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, writes in an accompanying comment.

He notes that there are many researchers in this field who have "voiced concerns that radiation oncology is becoming stagnant" and that the specialty is reluctant to integrate findings from other fields into their treatment paradigms.

"In some sense this might be true, and radiation oncology should embrace change," Dr Grosshans notes.

Medulloblastoma has become the "poster child disease" when it comes to integrating genomics and molecular subtyping into treatment regimens, he points out, and thus it will be "increasingly important for radiation oncologists to take these findings into account in the design of new prospective studies."

But although these data "offer a glimpse of the benefits of the low-dose sparing afforded by proton therapy," further improvements are possible.

"Hearing outcomes, when compared with studies of photons, were slightly improved," Dr Grosshans notes. "With newer delivery techniques for proton therapy, including spot scanning proton therapy for the craniospinal component of treatment, further improvements may be expected, because cochlear doses will be reduced."

The authors also report a significant decrease in neurocognitive function, driven primarily by outcomes for patients younger than 8 years of age at treatment. "Practitioners should remind families that they are, out of necessity, treating the entire brain and that this exposure can be associated with cognitive impairment," he emphasizes, although these results were more favorable than those from previous studies of conventional radiotherapy.

"I believe that radiation oncologists have always understood that our treatments are associated with the potential for severe adverse effects," Dr Grosshans concludes. "I also believe that many in radiation oncology embrace new technology, not simply to have the latest and greatest innovations, but rather to reduce the effect of radiation therapy on patients' quality of life. Nowhere in oncology is this more important than for pediatric cancers."

Likely to Benefit Pediatric Cancers

The use of proton-beam radiotherapy has been controversial, primarily because of the costs involved and the lack of conclusive data that it is superior to less-expensive therapies. In particular, there has been criticism of the use of proton-beam radiotherapy for prostate cancer.

But pediatric malignancies might be a different story. "Proton radiotherapy is likely to be beneficial when employed in children with high rates of cure and who are still growing and developing," Dr Yock told Medscape Medical News. "Any tissue, brain, muscle, bone, etc., will not continue to grow and develop as well as it would have if it receives radiation. The effects are worse with increasing dose, increasing volume, and decreasing age."

Therefore, children with curable brain tumors (other than medulloblastoma) will probably benefit because it is likely there will be a decrease in neurocognitive adverse effects, she pointed out. This is the subject of current ongoing protocols.

"Similarly, many tumors outside of the brain, such as neuroblastoma and sarcomas, are well treated with the highly focused proton beam, which can spare normal critical structures often better than photon radiotherapy," Dr Yock said. "This allows better growth and development for these normal tissue too, which leads to fewer late effects of treatment."

She added that her group is currently prospectively enrolling patients with these sarcomas and neuroblastomas in proton-treatment protocols to help define the benefits.

Reduction in Late Toxic Effects

In their phase 2 nonrandomized trial, Dr Yock and her colleagues assessed late complications, acute adverse effects, and survival associated with proton radiotherapy in children with medulloblastoma.

Of the 59 patients enrolled from May 2003 to December 2009, 39 had standard-risk disease, six had intermediate-risk disease, and 14 had high-risk disease.

All patients had received chemotherapy, and the median follow-up of survivors was 7 years.

Fifty-eight patients (98%) underwent a resection of the primary posterior fossa tumor, and 55 underwent a near or gross total resection.

Every patient in the cohort also received the intended doses of proton radiotherapy; the median craniospinal irradiation dose was 23.4 GyRBE and the median boost dose was 54.0 GyRBE.

Median age at the time proton radiotherapy was administerd was 6.6 years. Thirteen patients died during the trial (12 from disease and one from traumatic brain injury).

In the standard-risk group, 5-year progression-free survival was 85% and overall survival was 86%, which are similar to the results from two cooperative group studies, at 81% to 83% for progression-free survival and 85% to 86% for overall survival (Lancet Oncol. 2006;7:813-820; J Clin Oncol. 2006;24:4202-4208).

The primary outcome was the cumulative incidence of ototoxicity at 3 years, graded on the Pediatric Oncology Group ototoxicity scale. The results show that four of 45 evaluable patients (9%) had grade 3/4 ototoxicity, according to that measure, in both ears at follow-up. In addition, three patients (7%) developed grade 3/4 ototoxicity in one ear, although ototoxicity later reverted to grade 2 in one patient. Overall, the cumulative incidence of grade 3/4 hearing loss at 3 years was 12%; at 5 years, this had increased to 16%.

The authors note that this is less than the 24% to 25% of patients suffering hearing loss reported in studies using conventional radiotherapy, although the comparisons are "imperfect" because of differences in radiation boost volumes.

Cognitive capacity was assessed by the Full Scale Intelligence Quotient, which decreased by 1.5 points per year after a median follow-up of 5.2 years. This was driven mostly by declines in processing speed and verbal comprehension index. In contrast, perceptual reasoning index and working memory were not significantly affected, the authors note.

Compared with previously reported findings, the estimated mean average loss of intelligence quotient points per year was lower in the proton cohort than in several different photon-treated groups, despite a younger median age and a mixed standard- and high-risk population, the authors point out.

Seven years after the beginning proton radiotherapy, the cumulative incidence of any hormone deficit was 63%, and a deficit in growth hormone was the most common (55%). Overall, 36 patients (61%) developed one or more endocrine deficit, 31 of whom developed growth hormone deficits during follow-up.

The cumulative incidence of neuroendocrine deficits at 5 years in patients who received 40 GyRBE or more to the hypothalamus was 73%, compared with 44% in patients who received less than 40 GyBRE. But this difference was not significant, the authors note.

Of importance, there were no cardiac effects, pulmonary disorders, gastrointestinal effects, new seizure disorders, esophageal strictures, chest wall abnormalities, or cases of dry mouth, the authors note.

This study was funded by the National Cancer Institute and Massachusetts General Hospital. Coauthor Nancy Tarbell, MD, from Massachusetts General Hospital, reports owning stock options in ProCure. Dr Grosshans has disclosed no relevant financial relationships.

Lancet Oncol. Published online January 29, 2016. Abstract, Comment

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