February 03, 2016
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Proton beam therapy reduces toxicity in treatment of pediatric medulloblastoma

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Proton radiotherapy appeared as effective as but less toxic than conventional photon radiotherapy for the treatment of children with medulloblastoma, according to the results of an open-label phase 2 study.

“Proton radiotherapy is still not widely available in the U.S. or around the world, but it is increasingly recognized for its potential to reduce the side effects of treatment, particularly in the pediatric population,” Torunn I. Yock, MD, associate professor of radiation oncology at Harvard Medical School and director of pediatric radiation oncology at Massachusetts General Hospital for Children, said in a press release. “At experienced centers, proton therapy has a proven track record of treatment success and safety.”

Conventional medulloblastoma treatment with photon radiotherapy and chemotherapy is associated with risk for neurocognitive, hearing and hormonal deficits, and can lead to toxic effects on the heart, lung, thyroid, vertebra and reproductive organs. These effects appear worse the younger a child is when treated.

Proton radiotherapy — also called proton beam therapy — irradiates less normal tissue than traditional photon radiotherapy, which may be associated with better health outcomes and fewer adverse events.

Thus, Yock and colleagues sought to observe late complications, adverse events and survival outcomes associated with proton radiotherapy in pediatric patients with medulloblastoma.

The cumulative incidence of ototoxicity at 3 years served as the primary endpoint. Key secondary endpoints included neuroendocrine toxicity and neurocognitive toxicity.

The study included data from 59 patients (median age, 6.6 years; interquartile range [IQR], 5.1-9.9; 56% boys). The majority of patients (n = 39) had standard-risk disease; the remainder had intermediate- (n = 6) or high-risk (n = 14) disease.

Researchers attempted resection of the primary posterior fossa tumor in 58 of the patients.

All patients received chemotherapy. They also underwent craniospinal irradiation of 18 to 36 Gy radiobiological equivalents (GyRBE) delivered at 1.8 GyRBE per fraction, followed by a boost dose.

The median time from surgery to proton radiotherapy was 30 days (IQR, 29-33). All patients received the intended doses of proton radiotherapy, with a median craniospinal irradiation dose of 23.4 GyRBE (IQR, 23.4-27) and median boost of 54 GyRBE (IQR, 54-54).

Median follow-up was 7 years (IQR, 5.2-8.6).

Fifty-five patients underwent baseline audiological assessments, 49 of whom had follow-up audiograms after a median of 5 years (IQR, 2.9-6.4).

Nine percent (n = 4) of patients developed grade 3 or grade 4 ototoxicity in both ears, with 7% (n = 3) developing ototoxicity in one ear. The researchers noted that one patient’s grade 3 ototoxicity later reverted to grade 2.

The cumulative incidence of grade 3 or grade 4 hearing loss at 3 years was 12% (95% CI, 4-25); it increased to 16% (95% CI, 6-29) at 5 years.

Further, in 35% of 98 ears tested (n = 34), the researchers observed a Pediatric Oncology Group hearing ototoxicity score at 5 years identical to baseline or improved by one point. Scores worsened by one point in 21% of ears (n = 21), by two points in 36% (n = 35), by three points in 6% (n = 6) and by four points in 2% (n = 2).

Median follow-up for assessment of neurocognitive effects in 43 children was 5.2 years (IQR, 2.6-6.4).

Overall, Full Scale Intelligence Quotient decreased 1.5 points (95% CI, 0.9-2.1) per year, largely driven by decrements in processing speed and verbal comprehension. The score decreased significantly among children aged younger than 8 years (mean change per year, –2; 95% CI, –2.7 to –1.3) but remained stable in older children.

The researchers did not observe significant changes in perceptual reasoning and working memory.

Seven years after the start of proton radiotherapy, the cumulative incidence of any hormone deficit was 63% (95% CI, 48-75).  Growth hormone deficit occurred in 55% (95% CI, 41-67) of patients.

The researchers did not report any late cardiac, pulmonary or gastrointestinal adverse events.

Eighty-three percent (95% CI, 71-90) of patients achieved 3-year PFS. A post-hoc analysis indicated 80% (95% CI, 67-88) of patients achieved 5-year PFS and 83% (95% CI, 70-90) achieved 5-year OS.

The researchers acknowledged their lack of a control group as a study limitation. However, they noted that randomized trials comparing photon and proton radiotherapy in children have been deemed unethical in the U.S. and abroad.

“Our results indicate that proton therapy maintains excellent cure rates in pediatric medulloblastoma while reducing long-term side effects, particularly in hearing and neurocognitive function, and eliminating cardiac, pulmonary, GI, and reproductive effects,” Yock said. “While we are currently investigating quality of life differences between proton and photon treatment, I truly believe that — particularly for the youngest children — the ability to offer them proton therapy can make a big difference in their lives.”

The adoption of proton therapy for medulloblastoma may represent a paradigm shift in pediatric radiation oncology, David R. Grosshans, MD, PhD, associate professor of radiation oncology at The University of Texas MD Anderson Cancer Center, wrote in an accompanying editorial.

“This study sets a new benchmark for the treatment of pediatric medulloblastoma and alludes to the clinical benefits of advanced radiation therapies,” Grosshans wrote. “Many researchers in the field have voiced concerns that radiation oncology is becoming stagnant and reluctant to integrate findings from other fields such as cancer genomics into their treatment paradigms. In some sense this might be true, and radiation oncology should embrace change.” – by Cameron Kelsall

Disclosure: One study researcher reports that an immediate family member owns stock in ProCure. Yock, the other researchers and Grosshans report no relevant financial disclosures.