Upfront Radiotherapy Tied to Better Outcomes for Brain Metastases in EGFR-Mutant NSCLC

By Will Boggs MD

February 06, 2017

NEW YORK (Reuters Health) - Stereotactic radiosurgery followed by treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor appears to provide the best survival for patients with brain metastases from EGFR-mutant non-small-cell lung cancer (NSCLC), according to new findings.

"Clearly given the selection bias that patients with more worrisome CNS burden of disease were the ones getting radiosurgery or whole-brain radiotherapy (WBRT) as first line, we really expected to find that those getting TKI alone upfront should have had better survival," said Dr. Veronica L. Chiang from Yale University in New Haven, Connecticut.

"The fact that even the WBRT group (with highest burden of CNS disease) had a survival advantage was very much the most surprising finding," she told Reuters Health by email.

Because of the significant improvements in overall survival with EGFR-TKI therapy in these patients, there has been an interest in assessing the effectiveness of upfront EGFR-TKI and withholding local therapies for brain tumors - stereotactic radiosurgery (SRS), WBRT and surgical resection - until progression of intracranial disease.

Dr. Chiang and colleagues from six academic centers analyzed their combined experience to determine the optimal management of patients with EGFR-mutant NSCLC who developed brain metastases and had not yet received EGFR-TKI.

Among the 351 patients included in the study, 131 (37%) received EGFR-TKI followed by SRS or WBRT at intracranial progression, 120 (34%) received WBRT followed by EGFR-TKI, and 100 (29%) received SRS followed by EGFR-TKI.

Patients who received upfront EGFR-TKI were less likely to have symptomatic brain metastases and more likely to have small metastases, whereas those who received upfront WBRT were more likely to have a less favorable prognosis and to have >10 brain metastases, the researchers report in the Journal of Clinical Oncology, online January 23.

With a median follow-up of 22 months, the median overall survival after brain metastases was 30 months.

Median overall survival was best for the upfront SRS group (46 month), followed by the upfront WBRT group (30 months) and the upfront EGFR-TKI group (25 months, log-rank p<0.001).

After adjustment for other variables, upfront SRS was independently associated with improved overall survival relative to EGFR-TKI (adjusted hazard ratio, 0.39; p<0.001), as was upfront WBRT (aHR, 0.70; p=0.039).

The median time to intracranial progression was significantly shorter for upfront EGFR-TKI (17 months) than for upfront SRS (23 months) or WBRT (24 months).

Patients fared best with upfront SRS whether they had a more favorable or less favorable prognosis (as measured by the disease-specific Graded Prognosis Assessment).

"Medical oncologists have been very excited over the past few years to learn that TKIs cross the blood brain barrier and have demonstrable efficacy in the brain," Dr. Chiang explained. "Because of this, patients are being offered medical therapy only as first-line treatment for their cancer, including for their brain metastases, without full discussion of standard radiation options. This study suggests that upfront use of radiation needs to continue to be considered despite its side effect profile, and maybe we should not be so willing yet to accept this recent change in practice."

"Management of patients with brain metastases today requires a knowledgeable and coordinated multidisciplinary team at every stage in their potentially long clinical course," she concluded. "The question each member of the team should ask is not whether their options should be used, but rather when and in what sequence in relationship to the options available through the other members of the team and relative to the patient's course. Many patients will live long enough to potentially need all available options."

Dr. You Lu from Sichuan University in Chengdu, China, who coauthored an accompanying editorial, told Reuters Health by email, "This retrospective analysis indeed provided us with important evidence for the superiority of upfront brain radiotherapy, particularly for upfront WBRT. However, it seems to me that the upfront brain radiotherapy would be still a controversial issue in altering current clinical practice for the treatment of patients with EGFR-mutated NSCLC with brain metastases."

"As our editorial mentioned, we need to consider the benefits of deferring or withholding WBRT in the era of targeted therapies," he said. "In addition, enthusiasm for the benefits of up-front SRS could be appropriately balanced. Of course, multidisciplinary discussion is always required, and prospective data will be the key solution to these questions."

Dr. Lizza E. L. Hendriks from Maastricht University Medical Center in the Netherlands, who has researched various aspects of NSCLC brain metastases and their treatment, told Reuters Health by email, "One should be less strict in deferring (radiotherapy) in an EGFR-mutated patient with brain mets; however, I think what really should be done is a prospective randomized trial, as the authors also stated."

"Another trial that resembles the proposal of the authors was closed because of poor accrual (French trial, upfront WBRT followed by EGFR-TKI vs. EGFR-TKI followed by WBRT upon cranial progressive disease, NCT01363557), and I think oncologists and radiation oncologist should really put effort into completing these kinds of trials, as this is the only way to get a really reliable answer to a very important question," she said.

SOURCE: http://bit.ly/2kZlos3 and http://bit.ly/2l4mte4

J Clin Oncol 2017.