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Optimized Radiation Treatment Schedule for Glioblastoma May Extend Survival

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Key Points

  • Radiation therapy can cause glioblastoma cells to revert to a state where they’re more like stem cells, and more resistant to radiation therapy.
  • Based on these findings, the investigators devised an optimum treatment schedule that administers the same total amount of radiation as the standard schedule, but in a different temporal order.
  • The new schedule led to superior survival in mouse models.

An altered radiation treatment schedule for glioblastoma, the most common and lethal form of brain cancer, extended the survival period of mice with the disease, according to a new study published in Cell. Because the research involved mice, the study does not recommend a specific new schedule for human patients, but the findings demonstrate that modifying the standard administration schedule of radiotherapy may make the treatment more effective, the authors noted.

“There have been many attempts over the years to develop a more effective radiation therapy schedule for patients with this disease, but none has proven superior to the standard approach, which has now been in use, essentially unchanged, for more than 50 years,” says Franziska Michor, PhD, principal investigator of the Physical Science – Oncology Center at Dana-Farber Cancer Institute, Boston, who is co–senior author of the study with Eric Holland, MD, PhD, of the Fred Hutchinson Cancer Research Center, Seattle. “An array of recent advances in the understanding of the basic biology of glioblastoma led us to try a fresh approach to the problem,” she said.

Glioblastoma treatment generally consists of surgery, chemotherapy, and radiation therapy. While the clinical management of the disease can extend patients’ lives, it is currently incurable: The median survival of treated patients is about 15 months.

Study Details

The new study was spurred by advances in three areas: the discovery of different subtypes of glioblastoma based on the abnormal genes within their cells; the development of better mouse models of the disease in humans; and the discovery that some of the cells in glioblastoma tumors are similar to stem cells, which can can withstand radiation therapy better than most glioblastoma cells can. Recently, scientists discovered that radiation therapy can cause glioblastoma cells to “de-mature”—to revert to a state where they’re more like stem cells, and more resistant to being killed by radiation.

“There’s a dynamic equilibrium within glioblastoma tumors in which cells are shifting between an immature and mature state,” Dr. Michor said. “We set out to see if we could use our understanding of this process to enhance the effectiveness of radiotherapy.”

For the current study, the investigators focused on a subtype of glioblastoma with an abnormal cell-signaling pathway that involves abnormal signaling induced by the platelet-derived growth factor. Such tumors account for about 30% of all glioblastomas.

New Treatment Schedule

The research team developed a mathematical model of the effect of radiation on glioblastoma cells—how quickly it prompts the cells to become more stem-like, how likely it is to kill cells, and how long these and other processes take. They then used the formulas to devise a treatment schedule that would, in theory, prolong survival.

“In radiotherapy, timing is everything,” Dr. Michor noted. “Irradiating too frequently would increase side effects and toxicity. Irradiating too infrequently would give the tumor cells too much opportunity to grow.”

The standard radiotherapy schedule for patients with glioblastoma is 2 Gy per day, 5 days a week, for 6 weeks. The researchers identified a schedule for delivering a total of 10 Gy that was predicted to produce better results in mice. This optimum schedule administers the same total amount of radiation, but in a different temporal order.

They tested the new schedule in mice with glioblastoma and found that they survived longer than similar mice treated under the standard schedule. The improvement was significant: Mice treated under the standard schedule survived a median period of 33 days, compared to 50 days for the mice treated under the new schedule.

Findings Could Lead to a Benefit for Humans

Because human glioblastoma patients usually receive a chemotherapy drug in conjunction with radiotherapy, and because the time scales of treatment response might be different from those in mice, the new schedule might not have an equally beneficial effect in patients, the authors stated, but studies are underway that more closely replicate the conditions of human treatment.

“Our model demonstrates that a revised dosing schedule can increase the number of stem-like cells in glioblastoma tumors and still slow the overall growth of the tumor and delay the time until tumor growth recurs,” Dr. Michor remarked. “The fact that we’ve accomplished this in animals raises the hope that we can achieve similar results in humans.”

Drs. Michor and Holland are the corresponding authors for the Cell article.

The study was funded by grants from the National Institutes of Health.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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