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Newly updated guidelines from the American Society for Radiation Oncology (ASTRO) capture the World Health Organization (WHO)’s 2021 reclassification of glioblastoma as grade 4 adult-type diffuse gliomas. 

The new ASTRO guidelines and the WHO reclassification incorporate newly discovered molecular markers with histologic findings, which allow clinicians to more precisely diagnose and treat these tumors. The term glioblastoma now refers only to IDH wild-type gliomas, which grow more quickly and are more aggressive that IDH mutant gliomas. The guidelines also incorporate the use of newer imaging techniques.

The ASTRO guidelines were last updated in 2016.

According to guideline co-author Steve E. Braunstein, MD, PhD, the treatment of older and/or medically frail patients was one of the topics the guidelines task force spent the most time discussing.

Despite “dozens and dozens of high-quality clinical trials that have been done, there are still areas where we don’t have a clear consensus or a clear, high-level evidence-based approach for treating those patients…who are somewhat older or more medically frail,” Braunstein told Medscape Medical News in an interview. The task force observed that even assessing two or three factors like performance status and age doesn’t really capture the patient and how they’re going to best respond to therapy.

The guidelines offer suggested dose-fractionation regimens for radiation therapy (RT) guided by the patient’s age and functional status with shorter courses conditionally recommended for older patients and those with indications of frailty. Supportive care is conditionally recommended in lieu of chemoradiation for patients with markers of severe frailty, who are often at an increased risk for complications from intensive treatments. However, for both groups — older/more frail and severely frail patients — the appropriate treatment approach should flow from a multidisciplinary, patient-centered discussion. 

“We recognize that we need to do more to understand these patients in a deeper way in order to bestow upon them appropriate personalized recommendations,” said Braunstein, who is also vice chair of radiation oncology at the University of California San Francisco.

Reirradiation Conditionally Recommended for WHO Grade 4 Diffuse Glioma

The task force conditionally recommended reirradiation for WHO grade 4 diffuse glioma recurrence for selected adult patients with good functional status, following a multidisciplinary, patient-centered discussion. This discussion would address indications and techniques for reirradiation, specifically diagnostic and treatment considerations and systemic therapy in the reirradiation setting.

At least one expert interviewed by Medscape Medical News questioned this recommendation. 

“For recurrent glioblastomas, they suggest that reirradiation is an option…the endorsement of that approach is fairly significant,” said Patrick Y. Wen, MD, is director of the Center for Neuro-Oncology at Dana-Farber/Brigham and Women’s Cancer Center and Harvard Medical School in Boston. “In fact, we actually don’t know if reirradiation works.” 

He added that the guidelines could be more balanced in outlining the limitations of reirradiation. “We all do it because there’s nothing else to do, but that doesn’t mean it’s a great choice.”

Wen, who was not involved in the development of the guidelines, said there has only been one randomized trial, which compared Avastin [bevacizumab], which is standard of care, with bevacizumab and radiation. Although patients who received the combination had decreased progression-free survival, there was no improvement in overall survival.

Wen noted that there has only been one randomized trial, which compared Avastin [bevacizumab], which is standard of care, with bevacizumab and radiation. Although patients who received the combination had improved progression-free survival, there was no improvement in overall survival. 

“So you could interpret that as the only randomized study out there…showing no survival benefit.” There is a trial being conducted by the European Organisation for Research and Treatment of Cancer, the LEGATO trial, that is currently evaluating whether reirradiation and lomustine improves survival compared with standard lomustine chemotherapy alone.

The data that do exist supporting the use of reirradiation come entirely from retrospective studies, he added. “There’s huge selection bias with retrospective data because the patients, who you would radiate are the ones that have small tumors and that are probably in decent shape, so they’re going to do better.”

In addition to making the conditional recommendation for reirradiation, the task force acknowledged care disparities for patients from diverse backgrounds. 

More Studies Needed to Examine Barriers to Access, Clinical Trial Enrollment 

“There are great disparities in the care of patients, who are coming from different backgrounds,” said Braunstein. “Those are a function of things that could include age, geography, insurance status, ethnic background, and race, among others. We really want to ensure that we’re giving every patient with this terrible diagnosis, the opportunity to have the best care possible.”

As part of the discussion, the task force reviewed the literature on health disparities and adult high-grade glioma, calling to attention the need for more studies that examine barriers to access and the need to increase clinical trial enrollment for underserved populations.

Other key recommendations for patients with grade 4 adult-type diffuse gliomas include:

• Fractionated RT for those who have undergone biopsy or resection; optimal timing and fractionation schedules for adjuvant RT are included.
• Concurrent temozolomide chemotherapy and RT are recommended following biopsy or resection. Alternating electric field therapy — a cancer treatment using low-intensity, intermediate frequency electrical fields — is conditionally recommended following RT for those with tumors in the upper regions of the brain (ie, supratentorial disease).

Braunstein reported relationships with Elekta GT Medical Tech (consultant) and Icotec Medical (honoraria, travel expenses). 

Wen has reported relationships with AstraZeneca, Bayer, Merck, Novartis, and others.