Proton Radiotherapy Reduces Adverse Effects, Novel Agent Offers Hope in Medulloblastoma

Zosia Chustecka

June 06, 2010

June 6, 2010, Chicago — Two separate presentations here at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting offer hope in the treatment of medulloblastoma, the most common malignant brain tumor in children.

Some 400 to 500 cases of medulloblastoma are diagnosed in children every year in the United States. Treatment with radiation and chemotherapy "can cure these cases, but the treatments leave a lot of long-term side effects. If we can minimize them, we can allow these children to grow up and go to school and college and enjoy the normal life that we all take for granted," said one of the presenters, Amar Gajjar, MD, cochair of the Department of Oncology at St. Jude Children's Research Hospital in Memphis, Tennessee.

Dr. Torunn Yock

One approach to reducing adverse effects is to use proton radiotherapy instead of conventional radiotherapy. A presentation of data on 59 children followed for a median 2 years showed that there is less toxicity. The reduction in toxicity seen is "very promising," said lead author Torunn Yock, MD, from the Massachusetts General Hospital in Boston, which has 1 of only 7 proton radiotherapy centers in the United States.

So far, she said, the results show no significant effect on several measures of neurocognitive functioning, including full scale IQ, and show a lower rate of ototoxicity and endocrine deficiencies than what has been reported with conventional radiotherapy.

Elaborating in an interview with Medscape Oncology, Dr. Yock said that the best data for photon radiotherapy, using intensity-modulated radiotherapy, showed grade 3/4 ototoxicity in 25% of patients, whereas her team's data for proton radiotherapy found a rate of 16%. Photon radiotherapy, especially in younger children, can result in a decline in IQ of about 2 to 4 points per year (an IQ of 100 is average and an IQ below 80 indicates special needs), but her team found no statistically significant decline after proton radiotherapy. In addition, conventional radiotherapy results in 1 or more endocrine deficiencies in more than 50% of patients, whereas proton radiotherapy was associated with such problems in about 29%.

Endocrine deficiencies can include problems with growth and in puberty, resulting from radiation damage to the pituitary and hypothalamus, she explained.

There is a fundamental difference in the dose distribution of proton radiation and photon radiation, Dr. Yock explained. Conventional radiotherapy has both an entrance and an exit dose, whereas proton radiotherapy enters with a lower dose and dissipates all the energy in the tumor in the "Bragg peak," so that there is no exit dose. "This means that the radiotherapy is not damaging the tissue that lies behind the tumor, so it spares more of the normal tissue from unnecessary radiation," she said.

Control of disease was similar with the 2 different radiotherapy approaches, but from the perspective of adverse effects, the proton approach "wins hands down," Dr. Yock said. She told Medscape Oncology that she would recommend this approach in favor of conventional radiotherapy for all children with medulloblastoma, and said that patients have traveled from various parts of the world to receive this treatment at their center.

Self-Selected Patient Population?

Because proton-beam radiotherapy is not a readily available technology and many of the patients have to travel to receive this treatment, this is a fairly selected patient population, so it might not be entirely typical, said Lisa Diller, MD, from the Dana-Farber Cancer Center in Boston, who was approached for comment. One hint of this is the baseline IQ levels, which were higher than would be expected, she added.

Dr. Yock agreed, and said that the average baseline IQ was 107 in this study, whereas in literature children with brain tumors score in the range of 93 to 97. She also agreed that the fact that many families have to travel to receive this treatment does select the patient population — parents often find out about the therapy over the Internet, and then have to fund their own travel and accommodations for around 8 weeks to receive the full course of treatment.

Another caveat is that the comparison between proton radiotherapy and conventional approaches is based on historic controls, Dr. Diller noted, although she said that, so far, the data look promising. It does look as if the proton approach has fewer adverse effects — as one would expect from first principles with irradiating less of a developing brain — but she cautioned that this is "not proven and more follow-up is needed."

Novel Agent

Another new approach to the treatment of medulloblastoma was highlighted at an ASCO press briefing, even though the data were very preliminary, and came from a pilot trial in 12 patients, of whom only 2 had the specific abnormality that was targeted with a novel therapy.

The drug, GDC-0449 (under development by Genentech), targets the sonic hedgehog pathway, which is activated in about 20% of patients with medulloblastoma.

Dr. Amar Gajjar

Dr. Gajjar presented results from a trial of the drug in 12 children with relapsed medulloblastoma who had progressed after conventional therapy. Two of these children showed activation of the sonic hedgehog pathway: 1 progressed after 5 months on the new drug, and the other is still taking the drug and has remained progression-free for more than a year.

Dr. Gajjar said this was "promising" because medulloblastomas that have progressed have a "dismal prognosis," and only 5% of children are expected to survive; most die in 12 to 18 months, he said.

The drug was very well tolerated, and "some children benefited tremendously," he said. There are now plans for a phase 2 trial in children (up to 22 years of age) with recurrent medulloblastomas, but only in those who show activation of the sonic hedgehog pathway.

Lynn Schuchter, MD, moderator of the press conference and professor of medicine at the Abramson Cancer Center, University of Pennsylvania, in Philadelphia, explained that this abstract was highlighted even though the data are preliminary because it shows a "proof of principle of targeting this important pathway in cancer." She added that it also appears to be important in other cancers.

There has already been quite a bit of excitement among cancer researchers about this sonic hedgehog pathway and the potential for clinical benefit from drugs that target this pathway, even though the clinical results so far come from very small numbers of patients, as reported previously by Medscape Oncology.

Dr. Yock and coauthors report having served as consultants or advisors to IBA and Procure. Dr. Gajjar has disclosed no relevant financial relationships, but one of his coauthors reports acting in a consultancy or advisory role for Genentech, and stock ownership of Curis. Dr. Schuchter reports receiving research funding from Pfizer.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract CRA9501, presented June 5, 2010; abstract CRA9507, presented June 6, 2010.


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