Small-cell lung cancer (SCLC) exhibits several characteristics that distinguish it from other types of lung cancer, namely the risk of early hematogenous dissemination, its marked sensitivity to chemotherapy and radiation therapy and its particular propensity to metastasize to the brain. The frequency of brain metastases in SCLC at diagnosis is ~10%; however, brain metastases may occur in >50% of 2-year survivors (1). As cytotoxic drugs have difficulty crossing the blood-brain barrier, the effectiveness of chemotherapy for brain metastases is unsatisfactory.

To evaluate the effectiveness of prophylactic cranial irradiation (PCI) to control micrometastases to the brain, a number of clinical trials have been performed (2–4). A meta-analysis demonstrated that, in patients with limited disease (LD) who achieved a complete response (CR) with initial chemoradiotherapy (CRT), PCI decreased the risk of brain metastases (from 58.8 to 33.3% at 3 years) and increased the 3-year survival rate (from 15.3% in the control group to 20.7%) (5). Therefore, PCI has been established as a part of standard therapy for LD-SCLC. Furthermore, the European Organization for Research and Treatment of Cancer (EORTC) trial reported that PCI decreased the risk of symptomatic brain metastases and prolonged overall survival in extensive disease (ED) that responded to chemotherapy (6). A pooled analysis reported that PCI was associated with a significant survival benefit in LD-SCLC as well as ED-SCLC patients (7). Based on the results of those studies, PCI is currently considered a part of standard therapy for ED-SCLC. However, hair loss, skin erythema, headache, nausea and vomiting, appetite loss, fatigue, dizziness and drowsiness have been reported as early adverse effects due to PCI, while muscle weakness, dementia, gait disturbance and leukoencephalopathy have been reported as late PCI-associated adverse toxicities. The number of studies that have attempted to evaluate the effect of PCI on neurocognitive functioning (NCF) and other quality-of-life (QOL) markers is currently limited. Therefore, the aim of this study was to investigate the effect of PCI on NCF in patients with SCLC.

In this retrospective study, the PCI-related neurotoxicities following standard treatment for SCLC were reviewed, with a median follow-up time of 22 months. Following PCI, dementia occurred in 42% of all patients without brain metastases, whereas gait disturbances appeared in 25% of all patients. Patients who received PCI were significantly more likely to develop dementia and gait disturbances compared with patients who did not receive PCI. Among patients treated with PCI, those aged >65 years were significantly more likely to develop dementia and gait disturbances.

The number of studies evaluating the effect of PCI on NCF and other QOL markers is currently limited. It remains controversial whether the neurotoxicities following PCI are clinically significant. Certain previous studies concluded that PCI caused no significant increase in the incidence of neurotoxicities. Grosshans et al (12) reported the results of neuropsychological tests prospectively conducted prior to and following PCI in 37 patients. In their study, there was no convincing evidence for long-term PCI-related neurotoxic effects (median follow-up, 23 months; range, 6–120 months). The median age of the patients enrolled in that study was 59 years. Arriagada et al conducted a prospective study of 300 SCLC patients randomly assigned to the PCI or non-PCI groups (2). A neuropsychological examination and a computed tomography scan of the brain were performed at the time of random assignment and repeatedly assessed after 6, 18, 30 and 48 months. There were no significant differences between the two groups in terms of neuropsychological function or abnormalities indicated by computed tomography brain scans. The mean age of the patients in the non-PCI and PCI groups was 56 and 57 years, respectively.

However, other studies reported that PCI possibly decreased NCF and that neurotoxicities were more common in older patients. Gondi et al reported that PCI was associated with a higher risk of decline in self-reported cognitive functioning and the Hopkins Verbal Learning Test-Recall and -Delayed Recall at 6 and 12 months in the pooled analysis of two Radiation Therapy Oncology Group trials (13). The median age of the study patients was 62 years. Moreover, a prospective study from Germany reported that patients aged ≥65 years who received PCI exhibited a trend towards distinct changes in the white matter on brain magnetic resonance imaging (11). These analyses did not include East-Asian patients, although the life expectancy of the general population is quite long in Japan.

Our study demonstrated that PCI-related neurotoxicities were also more common among older patients in Japan. However, there were several limitations to our study. First, there were not enough baseline evaluations in terms of HDS-R, as this was a retrospective analysis. However, it was confirmed that all the patients had sufficient preserved NCF to understand the risks and the schedule of the treatment prior to receiving PCI. Thus, the dementia and gait disturbances observed in this study were not present prior to PCI. Second, this study included cases treated with various radiation doses for PCI. At present, the standard dose of PCI for LD-SCLC is considered to be 25 Gy/10 fr, based on the results of a previous trial in which 25 Gy achieved significantly better survival compared with 36 Gy (14). Our study included old cases, prior to the establishment of the standard radiation dose in PCI. As a result, there were no significant differences in neurotoxicities among radiation doses in this analysis. In addition, this was a retrospective study with a small sample size. A prospective study with a large sample size is required to confirm our findings.

In conclusion, the adverse effects of PCI on NCF, particularly the risk of dementia and gait disturbances, tend to appear frequently in older patients. The treatment for SCLC in older patients should be designed considering the balance between benefits and risks, including late toxicities caused by PCI.