New details from a clinical trial showing negative effects of whole-brain radiotherapy combined with stereotactic radiosurgery (SRS) in the treatment of brain cancer — and no improvement in overall survival — further call into question the use of the approach in the treatment of patients with one to three brain metastases.

“We think this study represents the end of an era in neuro-oncology,” presenter Anthony L. Asher, MD, a neurosurgeon with the Department of Neurological Surgery at Carolina Neurosurgery and Spine Associates, Charlotte, North Carolina, told Medscape Medical News.

“The number one goal of cancer therapy is to help patients live longer and better, and if we can’t help them live longer, then we absolutely have to help them live better — it’s our solemn oath not to worsen their quality of life,” he said.

In a talk presented here at the American Association of Neurological Surgeons (AANS) 84th Annual Meeting, Dr Asher presented updated data from N0574, a clinical trial of 213 patients with one to three brain metastases who were randomly assigned to stereotactic radiosurgery (SRS) alone or radiosurgery combined with whole-brain radiotherapy.

As first reported at the 2015 American Society of Clinical Oncology Meeting, the trial results at 3 months showed significantly greater cognitive deterioration in the whole-brain radiotherapy group compared with radiosurgery alone (91.7% vs 63.5%; P < .007).

The greater deterioration in the whole-brain radiotherapy group included the specific domains of immediate memory (30.4% vs 8.2%; P = .004), delayed memory (51.1% vs 19.7%; P .001), and verbal fluency (18.6% vs 1.9%; P = .010).

Whole-brain radiotherapy treatment was also associated with greater deterioration of quality-of-life measures, including in functional well-being (P = .006) and overall quality of life (P = .001).

Consistent with previous studies that have supported its continued use, whole-brain radiotherapy did show greater improvement in intracranial tumor control at 3 months, with improvement of 93.7% vs 75.3% with SRS alone (P < .001).

Importantly, however, the difference in median overall survival (OS) between the two groups was not statistically significant, with OS of 7.4 months for whole-brain radiotherapy and 10.4 months for radiosurgery alone (hazard ratio, 1.02; P = .92).

In expanding on those findings, Dr Asher reported additional data on 34 long-term survivors who were alive 12 months after entering the study, including 15 who received SRS alone and 19 with SRS plus whole-brain radiotherapy.

Among those patients, cognitive deterioration in the whole-brain radiotherapy group was greater at 3 months (94.1% vs 45.5%; P = .007), 6 months (72.2% vs 50%; P = .27), 9 months (76.9% vs 50%; P = .24), and 12 months (94.4% vs 60%; P = .04).

“Executive function was specifically impaired at 12 months,” Dr Asher said.

Dr Asher added that acute radiation side effects were also significantly higher at 6 weeks after whole-brain radiotherapy, including more alopecia (P = .01) and dermatitis (P = .06).

The late radiation side effect of central nervous system necrosis was similar between the two groups (6.8% for SRS vs 4.3% for SRS plus whole-brain radiotherapy; P = .72).

Of note, the study is the first to take a comprehensive look at the broad effects of whole-brain radiotherapy on the quality of life in what is typically patients’ last months of life, Dr Asher said.

“N0574 is the first trial to adequately and simultaneously assess the impact of whole brain radiotherapy on both quality of life and cognitive function,” he said.

“As such, it is the first study to comprehensively address the clinical outcomes most likely influenced by adjuvant radiation therapies in this patient population.”

“Specifically, in light of the results presented here, the routine use of whole-brain radiotherapy for newly diagnosed oligometastases is no longer justified,” he emphasized.

“‘[This study] has the potential to substantively impact the care of tens of thousands of patients with cancer.”

In fact, as many as 200,000 patients in the United States alone continued to receive whole-brain radiotherapy each year, Dr Asher noted, and the latest National Comprehensive Cancer Network guidelines still described stereotactic radiosurgery plus whole-brain radiotherapy as a category 1 recommendation for treatment of solitary brain metastases.

“The issue of whole-brain radiotherapy as adjuvant to SRS in the routine treatment of patients with oligo-cerebral metastases appears to be far from resolved in the general oncology community,” he said.

“This condition makes the results of our analysis even more pertinent to daily management of patients with systemic cancer.”

Dr Asher noted that a sensitivity analysis of N0574 did show that the factors affecting overall survival include age, number of metastases, and extent of extracranial disease, and the researchers are examining the effect of the factors on the primary outcomes.

In terms of patients with one to three metastases, however, “we observed that the use of SRS alone, compared with SRS combined with whole-brain radiotherapy, resulted in less cognitive deterioration and superior quality of life, despite improved overall brain control in the whole-brain radiotherapy group.”

“Future trials will need to evaluate the relative impact of SRS vs SRS plus whole-brain radiotherapy on the treatment of patients with more numerous (eg, 5 to 10 or greater) brain metastases.”

In looking at specific approaches in which whole-brain radiotherapy’s benefits may still outweigh the harms, some have suggested hippocampal-sparing approaches or disease-specific benefits, but Dr Asher underscored that much larger studies will be needed to find those answers.

“If we’re really going to address this issue to everyone’s satisfaction and break this down to the level of certain histologies, we are ultimately going to need very large registries capturing thousands of patients because it’s often hard to accrue these studies. And since there is already such a heavy lean to SRS alone, that randomization could be very difficult.”

In a separate session highlighting some of the year’s most important neurosurgery research in press, Daniel P. Cahill, MD, from Massachusetts General Hospital in Boston, called the findings “practice-changing.”

Commenting on the study for Medscape Medical News, neurosurgeon Brian V. Nahed, MD, an assistant professor also with the Massachusetts General Hospital and Harvard Medical School, said these results help improve the understanding of the effects of whole-brain radiotherapy.

“The findings confirm our general belief that when possible, it’s better to target lesions individually with SRS and to save whole-brain radiation therapy for widely spread or disseminated disease,” he said.