Small-cell lung cancer (SCLC) has a strong tendency to metastasize to the brain, appearing in more than half of patients with a 2-year survival with SCLC. Because the blood-brain barrier greatly reduces the efficacy of many chemotherapy treatments, other approaches for controlling metastasis of SCLC to the brain are often required.1 Prophylactic cranial irradiation (PCI) is a technique that has been used with the goal of preventing development of SCLC-related brain metastases.2

PCI is a radiation-based treatment that has been in use since before surveillance by magnetic resonance imaging (MRI) became standard. In theory, the risks brought on by radiation have been thought to be outweighed by the opportunity to control the spread of this aggressive cancer into the brain.3

However, whether PCI provides a survival benefit has not been clear, and the possible influence of physician bias around recommending PCI was explored in 2 recently published reports.4,5 One, a report by Tyler P. Robin, MD, PhD, of University of Colorado, and colleagues, presented the results of their study based on email surveys of self-reported physician attitudes toward PCI and on a patient decision aid that the researchers developed and made available to the physicians in their study for feedback.4

The second, a perspective piece by Skyler B. Johnson, MD, PhD, and Roy H. Decker, MD, PhD, of Yale University School of Medicine, reviewed studies on PCI, including the report by Robin and colleagues.5

The decision to employ PCI for patients with limited-stage SCLC can be difficult, and “is best understood in the context of data surrounding disease outcomes and quality of life outcomes following the use of PCI,” stated Johnson and Decker in their perspective piece.5

According to Johnson and Decker, individual studies in limited-stage SCLC have shown no benefit to overall survival (OS) using PCI, but a meta-analysis of studies involving limited-stage disease did show a profound OS benefit with PCI.4 In this analysis, 3-year survival was significantly higher with PCI (20.7%) vs without it (15.3%; P =.01).6 Brain metastases also showed lower cumulative incidence at 3 years for patients who received PCI (33.3%) compared with those who did not (58.6%; P <.001).6

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Conflicting Study Results

Use of PCI in the context of extensive-stage SCLC has also shown mixed results.3,5 Two landmark studies of survival in patients with extensive-stage disease showed conflicting results with use of PCI.

In 2007, the European Organization for Research and Treatment of Cancer (EORTC) found that OS was better for patients with extensive-stage SCLC who underwent PCI (median 6.7 months) compared with those who did not (median 5.4 months; P =.003). One-year OS was 27.1% with PCI vs 13.3% without (P =.003), and 1-year cumulative risk of brain metastases was 14.6% with PCI vs 40.4% with observation (P <.001).7

These positive results in the EORTC trial with PCI in extensive-stage SCLC contrasted with those of a more recent multicenter trial in Japan, in which median OS was not significantly different with PCI (11.6 months) vs without PCI (13.7 months; P =.094).8

Results from these studies may have differed based on study design differences. The EORTC trial utilized brain scans less frequently (and only in the presence of neurologic symptoms) than did the Japanese study, which may have contributed to differences in application of salvage therapy between the 2 studies.5 Central nervous system staging may also have been determined differently between the studies, and therapy regimens may have differed in ways that contributed to disparate results.3

Beyond survival outcomes, a feature of PCI therapy is its risks to cognitive function. Different studies have shown varied outcomes for metrics of cognition, but pooled analysis indicated a more than three-fold worsening of cognitive function at both 6 and 12 months following PCI, with older patients showing more susceptibility.4,5 Quality of life also has been shown to suffer after PCI.5