WHEN TO USE WBRT

Although the "sun is setting" on the use of whole brain radiation (WBRT) for brain metastases, it appears that the conversation is not quite over. In fact, it continues in two viewpoint articles published online January 5 in JAMA Oncology, in which experts debate the merits and shortcomings of WBRT and whether it still has a role in the treatment of brain metastases.

With the advent of stereotactic radiosurgery (SRS), which is seen by many as a more precise, convenient, and less toxic modality, some experts believe that WBRT should no longer be the standard treatment for all patients.

In fact, as part of their second Choosing Wisely campaign, the American Society for Radiation Oncology (ASTRO) recommended that oncologists should not routinely add adjuvant WBRT to SRS for limited brain metastases because for most of these patients SRS alone is sufficient.

This is also the argument expressed in the viewpoint article that argues for a limited role of WBRT, authored by Jing Li, MD, PhD, from The University of Texas MD Anderson Cancer in Houston, and Paul D. Brown, MD, from the Mayo Clinic, Rochester, Minnesota.

Several phase 3 trials have provided level 1 evidence supporting SRS used alone in patients with limited (one to three lesions) metastases, they point out. In addition, emerging evidence suggests that SRS may be effective and appropriate in patients with four or more lesions.

WBRT has not been shown to improve overall survival and is associated with impaired cognitive function and quality of life (QOL), they comment.

There are patients who can benefit from WBRT, Dr Brown commented in an interview with Medscape Medical News. "These include patients with numerous — such as 10 or more — metastases, or resected brain metastases where local control is of the utmost importance and the patient and physician are willing to take on the risks to cognitive function and quality of life."

Other patients who may be appropriate candidates are those with large lesions that are not amenable to surgery or radiosurgery, Dr Brown added. "Although some use fractionated radiosurgery for these large lesions."

"WBRT is also often utilized as salvage treatment, if there is recurrence of multiple lesions after radiosurgery," he said.

The authors cite evidence from four randomized phase 3 trials that did not find an overall survival benefit when WBRT was added to SRS in patients with one to three lesions. There was, however, improvement in intracranial control.

The most recent study, the N0574 trial (JAMA. 2016;316:401-409), "settled a long-standing debate" on what benefit adjuvant WBRT given after SRS might confer. There was no survival benefit (median overall survival was 7.4 months for WBRT plus SRS vs 10.4 months SRS alone; hazard ratio, 1.02; P = .92), even though patients in the WBRT group did have improvements in intracranial control.

There are a few potential reasons for the lack of survival benefit from WBRT, the authors speculate, one being the "success of salvage therapy at the time of intracranial progression.

Another reason for the lack of survival benefit may be the 4- to 6-week interruption of systemic therapy for WBRT; this has long been suspected of being a contributing factor.

As for patients with more than three lesions, there has been a shift toward using SRS, the authors note, with the intention of avoiding WBRT for as long as possible.

The question of whether SRS can be expanded to patients with 4 or more lesions has been addressed in several retrospective and one prospective observational study, which compared outcomes for patients with patients with 2 to 4 vs 5 to 10 lesions (Lancet Oncol. 2014;15:387-395).

In this study, the use of SRS for patients with 5 to 10 lesions was not inferior to the other intervention in terms of multiple endpoints, including overall survival (10.8 vs 10.8 months).

"SRS is at least equal or more effective than WBRT for local control of the treated metastases," said Dr Brown. "However, WBRT decreases the development of new brain metastases while SRS has no impact on the development of new brain metastases."

"To my knowledge there has not been a phase 3 trial comparing WBRT to SRS for more than 4 brain metastases," he added.

In the viewpoint, the authors also note that recent advancement in systemic therapy with central nervous system penetration may further diminish the role of WBRT. With new targeted therapy and immunotherapy, controlling microscopic disease with WBRT is being increasingly questioned.

One emerging approach is using SRS to treat gross disease and then using targeted agents and/or immunotherapy to control microscopic disease. This strategy may delay the need for WBRT for as long as possible or even avoid its use.

Dr Brown believes that WBRT use will be further reduced as systemic therapies are increasingly used to treat both the extracranial disease and microscopic intracranial disease. "This will push the use of WBRT more towards the end of the disease course, as opposed to in the past, when WBRT was frequently utilized early in the disease course."

WBRT Still Has a Role 

However, in the opposing viewpoint article, Minesh P. Mehta, MD, from Miami Cancer Institute, Florida, Hidefumi Aoyama, MD, from Niigata University, Niigata, Japan, and Vinai Gondi, MD, Northwestern Medicine, Cancer Center, Warrenville, Illinois, argue that it's not quite time for the sun to set on WBRT.

Instead, they argue, this modality still has a definite place in the treatment of brain metastases.

They discuss recent studies that have "raised important questions regarding WBRT," including the results of the QUARTZ trial (Lancet. 2016;388:2004-2014), which found no survival benefit for WBRT. In that study, 538 patients with non-small cell lung cancer that had metastasized to the brain were randomly assigned to WBRT or best supportive care.

In both groups, an 8- to 9-week median overall survival was observed. However, Mehta et al note that even though the obvious conclusion is that WBRT doesn't improve survival, the "caveat here is the dismal median [overall survival] of 8 to 9 weeks, implying selection of an extremely unfavorable cohort of patients, best considered for hospice."

Another caveat with the trial was that no differences were found in QOL, but the authors also emphasize that it takes weeks before WBRT will translate into a clinical benefit as well as improvements in QOL.

"When more than half the patients die within 8 weeks, there is not enough time for QOL benefit to manifest, underscoring the existing practice that for patients with poor performance status and short survival, best supportive care is ideal, not a practice-changing observation," write Dr Mehta and colleagues.

Another trial they highlight is the Alliance study (JAMA. 2016;316:401-409), which randomly assigned 213 patients with one to three lesions to SRS with or without WBRT. No differences were observed in median overall survival, which suggests that WBRT doesn't affect survival despite improved local control and should not be used.

But the "slippery slope" is that SRS has never shown a survival benefit, other than for patients with one lesion, even though it also improves local control. According to that logic, then, SRS should also not be used, they note.

A major drawback of WBRT is its association with increased neurocognitive dysfunction (NCDF). In the Alliance study, an NCDF increase of 0.65 was considered unacceptable, while an increase of 0.4 or better was acceptable.

The 3-month rate of NCDF with SRS was "unacceptably high at 63.5% (approaching the 0.65 'bad' rate for WBRT), but better than 91.7% for SRS and WBRT," they write. "The frightening conclusion is that SRS does not improve median [overall survival], results in an extremely high rate of brain failure (>50%), and is associated with early NCDF in almost two-thirds of patients."

However, they point out that proponents of SRS "would contend" that they generally do not see such a high rate of NCDF when SRS is used by itself. There are several possible explanations for this, but one could be that the use of an "exquisitely sensitive test battery," with a low threshold of only a 1–standard deviation change, would result in picking up a lot of "noise."

The "noise" or minor changes may not even be directly relevant to the patient, Dr Mehta and colleagues point out. But these small changes are detected all the same and labeled — in this case, as 60% of patients experiencing cognitive decline by 3 months. If instead a 1.5–standard deviation change had been used in the Alliance trial, the authors point out that the NCDF at 3 months would decrease to 19% for SRS and 45.8% for SRS and WBRT.

Taking it further, with a 2–standard deviation change, this declines further to 1.6% for SRS alone and 10.6% for SRS and WBRT, and "many SRS proponents would contend this to be reality; this reality would also suggest that with NCDF in about 10%, WBRT and SRS provides the most robust intracranial control and the lowest need for retreatment," they say.

So the question at hand is to figure out which threshold is clinically meaningful in this group of patients. "The clinical meaningfulness of a large decline in cognition is something that no one would argue about," the authors note.

Another question to be addressed is whether efforts should be focused on developing novel approaches to delivering WBRT in a way that will maximize intracranial control but with minimal cognitive dysfunction. Efforts are underway to investigate pharmacologic and technological innovations that will spare or conformally avoid memory-specific neural stem cell compartments.

Ultimately, the information must be presented in a way to the patient that will allow for an informed decision. "For patients with more than 4 [brain metastases], unless they have very low [disease-specific graded prognostic assessment] scores, or poor life expectancy, we recommend WBRT, SRS, or a combination, on a case-by-case basis, after appropriately counseling the patients," they conclude.

Dr Brown and Dr Li have disclosed no relevant financial relationships. Dr Mehta has consulting relationships with Varian, Agenus, Insys, IBA, and Remedy and has served on the data safety and monitoring board for Monteris. Dr Gondi has a consulting relationship with Insys and has received educational honoraria from US Oncology.