Daniel M. Keller, PhD

May 01, 2012

May 1, 2012 (Miami, Florida) — For patients with brain metastases from non–small cell lung cancer (NSCLC), the risk for leukoencephalopathy was much lower if they were treated with stereotactic radiosurgery (SRS) alone than if SRS was combined with whole-brain radiation therapy (WBRT) in a study reported here.

Edward Monaco III MD, PhD, a sixth-year resident in the Department of Neurological Surgery at the University of Pittsburgh in Pennsylvania, reported at the American Association of Neurological Surgeons (AANS) 80th Annual Scientific Meeting that 36 of 37 patients (97.3%) treated with SRS plus WBRT developed leukoencephalopathy compared with only 1 of 31 patients (3.2%) treated with SRS alone (P < .001).

WBRT can improve survival from about 1 month without treatment to 3 to 7 months, but this latter figure has not changed much over the past 25 years, Dr. Monaco noted. During that time, SRS has emerged as a safe and effective treatment for brain metastases.

As survival times with lung cancer have improved, the toxicity of treatments has become a concern. WBRT is associated with diffuse white-matter changes, and leukoencephalopathy is thought to be linked to neurocognitive dysfunction.

To investigate a possible association of WBRT and leukoencephalopathy, Dr. Monaco and colleagues retrospectively examined prospectively collected data. Sixty-eight patients met the inclusion criteria of survival for more than 1 year and evaluable imaging (WBRT + SRS: n = 37; SRS only: n = 31).

The groups were similar in their exposure to chemotherapy but differed in the number of metastases treated by SRS, with more treated initially and overall in the WBRT + SRS group (both P < .01). The median marginal SRS radiation dose was slightly lower in the WBRT + SRS group than in the SRS group (18 Gy vs 20 Gy, respectively; P < .001).

Median survival was marginally longer for the SRS group (28.2 months vs 25.1 months; P = .05).

SRS was provided by using Gamma Knife radiosurgery. Time to imaging was determined from the first WBRT or SRS treatment.

The investigators took into account age, sex, chemotherapy, the WBRT regimen, number of SRS procedures, and the total number of metastases treated with SRS to evaluate their effects on white-matter changes. White-matter changes on magnetic resonance imaging were graded from 0 (little or no white-matter hyperintensity, in particular surrounding the ventricles) to 3 (diffuse white-matter hyperintensity extending into the subcortical white matter).

Large Increase in Leukoencephalopathy in First Year With WBRT

"After 1 and 2 years, the proportion of patients who had a therapy that included whole brain radiation therapy had a marked increase in the changes of their white matter over time," Dr. Monaco said. Before any radiation therapy, 92% of patients in the WBRT + SRS group had normal white matter, but at 1 year, "92% had changes to their white matter," he noted. At 2 years, 70% of these patients had grade 3 white-matter changes.

"In contrast, patients who had had stereotactic radiosurgery alone had only 1 patient over the entire follow-up [who] demonstrated any white matter change, and that was only to grade 2," he said. For the 2 groups, the tumor burden had no effect on white-matter changes when patients with fewer than 10 metastases were compared with those who had 10 or more metastases.

Dr. Monaco concluded that WBRT and not SRS alone is strongly correlated with progressive, irreversible white-matter changes, adding to mounting evidence that the 2 modalities have differential effects on normal brain tissue structure and function. Until results from a planned prospective evaluation of leukoencephalopathy and its effect on neurocognitive function are available, he said that on the basis of the vast experience from the Pittsburgh group, they favor "initially withholding or even completely avoiding whole brain radiation therapy in treating patients with brain metastases except in cases of miliary disease or carcinomatous meningitis."

Phillip Tibbs, MD, professor and chairman of the Department of Neurosurgery at the University of Kentucky College of Medicine in Lexington, Kentucky, discussed the study, calling it "an outstanding contribution to a very important topic." He said in the era before SRS, WBRT was shown to prevent recurrences and remote metastases and to lengthen survival after tumor resection. And he raised the question of whether SRS is more like surgery, and if so, whether it can substitute for WBRT. SRS is appealing to patients because it can be performed in a single session, is well tolerated, and offers decreased neurotoxicity; in addition, patients do not lose their hair.

Dr. Tibbs cited as a strength of the study its focus on a single tissue type of tumor, NSCLC. Its biggest limitation is that it is retrospective. Furthermore, there was bias in which technique was chosen when there were more metastases, using WBRT + SRS for a larger tumor burden. Moreover, the imaging intervals and radiation doses were not standardized and varied widely.

The biggest issue Dr. Tibbs identified was whether radiographic changes correlate with neurocognitive changes and whether such changes would be important to a patient with a limited life expectancy. These issues were not addressed in the study.

Finally, he cited a paper by Ayoama and colleagues in JAMA (2006;295:2483-2491) showing a 12-month recurrence rate of 76.4% for SRS alone vs 46.8% for WBRT + SRS (P < .001). In terms of neurotoxicity, Dr. Tibbs said, "Disease in the brain is neurotoxic.... Recurrent cancer in the brain is bad for the brain. It's also bad for neurocognitive function." He said in his view "tumor recurrence causes a decrement in neuropsychological functioning that is worse than any change due to whole brain radiation therapy." He expressed the view that standards of care established through class I evidence "should not be abandoned or overturned without additional class I evidence."

Dr. Tibbs is of the opinion that SRS could be considered an alternative to craniotomy for metastases rather than an alternative to WBRT. He said the neurotoxicity of WBRT is often transient "and pales beside the neurotoxicity of uncontrolled or recurrent metastases."

Dr. Monaco has disclosed no relevant financial relationships. Disclosure information has been requested of Dr. Tibbs but has not yet been received.

American Association of Neurological Surgeons: 80th Annual Scientific Meeting; Abstract #612. Presented April 16, 2012.

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