Whole-Brain Radiotherapy for Brain Metastases May Harm Quality of Life

Megan Brooks

December 12, 2012

In patients with a limited number of brain metastases from solid tumors after focal therapy, adjuvant whole-brain radiotherapy (WBRT) could have a negative impact on some aspects of health-related quality of life (HRQoL), including physical and cognitive functioning, at least transiently.

This finding comes from the European Organization for Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial. In 359 patients with 1 to 3 brain metastases from stable solid tumors, adjuvant WBRT was compared with observation using magnetic resonance imaging (MRI). HRQoL was a secondary end point in the trial.

The study was published online December 3 in the Journal of Clinical Oncology.

Maintenance of HRQoL was a primary objective "because the majority of patients with brain metastases still cannot be cured and treatments are directed toward palliation of symptoms," note Riccardo Soffietti, MD, from the University of Torino and San Giovanni Battista Hospital inn Turin, Italy, and colleagues.

There was a modest improvement in progression-free survival with WBRT, compared with observation, but this did not translate into an advantage in terms of HRQoL, the researchers report. Therefore, choosing observation with MRI initially, instead of adjuvant WBRT, "is not detrimental to HRQoL," they conclude.

Not Ready for Prime Time

What is clear from this and other trials is that WBRT is "not innocuous," said David Osoba, MD, FRCPC, medical oncologist and professor of medicine (retired) at the University of British Columbia in Vancouver, Canada, in a podcast posted December 3 on the journal Web site.

Pending further trials, "the routine use of WBRT for asymptomatic brain metastases is not yet ready for prime time," noted Dr. Osoba, who was not involved in the study.

"Few topics in oncology have stirred more controversy and partisanship than the appropriate use and role of WBRT in the modern practice of oncology," write Atif J. Khan, MD, from the Cancer Institute of New Jersey in New Brunswick, and Adam P. Dicker, MD, PhD, from the Kimmel Cancer Center in Philadelphia, Pennsylvania, in an accompanying editorial.

It "seems reasonable" to withhold WBRT in patients with 1 or a small number of metastases who receive stereotactic radiosurgery and have a low estimated risk for intracranial progression, they explain.

However, they note that early WBRT in addition to radiosurgery "may be warranted" in intermediate-risk patients with oligometastases (e.g., 2 to 7 metastases).

The primary results from this EORTC trial, published last year (J Clin Oncol. 2011;29:134-141), showed that adjuvant WBRT led to better progression-free survival than observation (4.6 vs 3.4 months), and a lower neurologic death rate (28% vs 44%). WBRT also improved lesion control at initial and new sites, compared with observation after surgery, and improved total intracranial control.

However, there was no difference in maintenance of performance status (the primary end point of the trial) or overall survival. In addition, roughly 70% of patients in the observation group were able to completely avoid WBRT. Serious adverse events were uncommon, but occurred slightly more often with WBRT (13 vs 3 events).

The secondary end point of HRQoL was assessed at baseline, at 8 weeks, and then every 3 months for 3 years using the EORTC Quality-of-Life Questionnaire C30 and Brain Cancer Module. Six primary HRQoL scales were considered: global health status; physical, cognitive, role, and emotional functioning; and fatigue.

Compliance with the HRQoL questionnaire was 88.3% at baseline, but dropped to 45.0% at 1 year; therefore, the researchers only analyzed HRQoL in the first year.

A Balancing Act

The researchers found that patients in the observation group reported better outcomes during the first 12 months of follow-up on 5 of the 6 primary HRQoL scales.

Specifically, there were significant and clinically relevant differences in global health status (10 point or greater) in favor of observation at 9 months (P = .0148), in physical functioning at 8 weeks (10.7 points), and in cognitive functioning at 12 months (10.7 points).

Patients receiving WBRT reported more fatigue at 8 weeks (difference of 11.9 points). WBRT also had an adverse effect on hair loss, appetite loss, constipation, nausea/vomiting, drowsiness, and social functioning.

In his podcast, Dr. Osoba explained that "the deleterious effects on neurocognitive function and other quality-of-life domains need to be balanced against the potential benefits, such as fewer patients requiring salvage therapy and reduced symptoms from the metastases. This is an important challenge to the decision-making surrounding these patients."

He added that it is "difficult to make any firm conclusions" from this analysis. "One obvious deficiency is that the completion rate of the [HRQoL] questionnaire was poor." Since [HRQOL] was an end point, albeit a secondary one, missing data is a serious drawback to the clear interpretation of the results," Dr. Osoba noted.

In their editorial, Drs. Khan and Dicker say the detriments in HRQoL with WBRT are "especially worrisome" when viewed in the context of improvements in progression-free survival and intracranial control seen in the WBRT group. "Surprisingly, these results suggest that WBRT seems to diminish QoL even while improving disease control," they write.

Clearly, more studies are needed. Until then, the "WBRT debate will continue," the editorialist conclude.

The study authors, Drs. Khan, Dr. Dicker, and Dr. Osoba have disclosed no relevant financial relationships.

J Clin Oncol. Published online December 3, 2012. Abstract, Editorial