Reimagining external beam radiotherapy for glioblastoma: “old beam, new trick”

See the article by Almahariq et al. in this issue pp. 447–456.

“Pulsed radiation therapy for the treatment of newly diagnosed glioblastoma” by Almahariq et al., represents an important single institution, single-arm prospective trial of pulsed radiation therapy for glioblastoma multiforme demonstrating not only feasibility of a new technique for external beam radiation therapy (EBRT) in patients, but also represents a possible improvement in overall survival of patients without associated significant declines in quality of life and performance assessments.¹ These promising data establish the foundational basis of further evaluation, demonstrating the potential for superiority of pulsed radiation therapy in tumor control and improved normal tissue effects in larger, multi-institutional prospective randomized clinical trials. The importance of this pulsed radiation technique is that it carries the benefit of being both economically feasible and scalable within radiation oncology community practice, with most existing equipment able to immediately employ the methodology.

Radiation oncologists who devote their efforts to develop more effective radiation therapy strategies for the eradication of CNS neoplasms are often vexed by the dual realizations that that despite improvements in the past two decades, our treatment modalities are often not nearly effective enough, and those patients who are lucky enough to be long-term survivors may experience a risk of declines in neurocognitive function and quality of life.² EBRT in the upfront treatment of newly diagnosed glioblastoma in an adult is standardly delivered along with concurrent temozolomide to a total radiation dose of 60 Gy equally divided over 30 daily fractions. The daily dose of 2 Gy is delivered continuously at a constant dose rate, with 24-hour intervals between fractions. The time interval between fractions occurs not only for convenience, but allows for sublethal damage repair to occur, which is particularly important for the process of normal tissue recovery.³ Additionally, lower fraction sizes are associated with lower rates of long-term CNS toxicity, particularly when large volumes of brain are required to be fully treated in the radiation field.⁴ What Almahariq and colleagues suggest is providing scheduled interruptions in the delivery of the daily 2 Gy fraction by breaking the dose up into 0.2 Gy pulses, spaced at 3-minute intervals. Each 0.2 Gy pulse is the threshold above which ataxia-telangiectasia mutated kinase (ATM) activation and subsequent DNA repair is theoretically affected. The goal of pulsed radiation therapy is to induce enough DNA breaks to develop into a lethal event once cells progress through the cell cycle, but not enough to activate DNA repair.⁵ Therefore, disruption in the delivery of the daily radiation dose with pulsed dosing may provide an opportunity to promote damage to glioblastoma cells that are actively cycling, while protecting the largely quiescent normal tissue cell population in the normal brain.

This study is the first of its kind to demonstrate in a prospective fashion that modification of the continuous delivery of the daily fractions may enhance the biological effectiveness of radiation in therapy-resistant diseases. Prior attempts at pulsed dose-rate radiotherapy,⁶ low-dose rate,⁷ and dose escalation⁸ modifications to radiation delivery in the setting of glioblastoma have met with limited success. Given the lack of improvements in treatment in the past 15 years since the publication of the addition of temozolomide as a radiosensitizer,⁹ most radiotherapy trials have been performed in the recurrent setting as opposed to attempting to improve treatment in the upfront setting. It is important to consider when optimization of radiation treatment is likely to be most beneficial and to evaluate these novel modifications on the course of the natural history of the disease.

In the field of oncology, there is an understandable drive toward new and exciting innovations in the form of cutting-edge technologies, novel pharmaceuticals, and heavy particle treatments. However, while these approaches are essential in the improvement of cancer treatment, it is important to realize that a strategy that utilizes only these methods requires substantial time and resources and historically have often resulted only in achieving modest gains in survival, control, and minimization of toxicities. For those focused on the management of glioma, heavy particle treatments that cost hundreds of millions of dollars per facility, novel targeted agents, and immunotherapies that cost hundreds of thousands of dollars per year per patient to administer have demonstrated that new is not necessarily always better. Goals of radiation treatment in glioblastoma—to be able to improve survival and tumor control while simultaneously protecting the functioning of the normal brain—have proved to be exceedingly elusive. However, an often overlooked approach by radiation oncologists is modifying existing strategies and techniques from our radiobiological toolbox in order to maximize their effectiveness. As a field, there is a desperate need to reimagine and retool how we optimize the delivery of fractionated radiotherapy to its ideal radiobiological advantage for each treatment-resistant disease, especially when normal tissue injury mitigation is of concern. Because pulsed radiation therapy as described in this current manuscript does not require new authorizations or regulatory approvals, the economic benefits of this strategy that would make it more accessible and feasible to a greater population worldwide, with greater efficiency in speed of availability. While the potential for increased daily treatment time from pulsed techniques or from repeated setup verification may deter busier centers from employing such approaches, the ability to develop strategies with existing technologies may be especially appealing to radiation oncologists who have patient bases willing and appropriate for trials, but lack the access to perform research using more expensive therapies. More importantly, this study provides an important proof-of-principle that pulsed radiation therapy may also provide a benefit in other disease settings prospectively at the time of diagnosis, and there is no prohibition to this methodology being layered with concurrent radiosensitizers and with different ionizing radiation particles such as protons. As such, pulsed radiation therapy represents a win-win for both patients and providers, and results of upcoming studies employing pulsed radiation therapy in an expanded capacity should be viewed with eager anticipation.

Conflict of interest statement: None.