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Page 6 of 11 Kepka. J Cancer Metastasis Treat 2019;5:53 I http://dx.doi.org/10.20517/2394-4722.2018.114

in the concomitant arm had a higher rate of myelosuppression . Thus, the available evidence is insufficient
[31]
to determine the effectiveness of chemotherapy for the treatment of BM from SCLC. We have no evidence
that chemotherapy improves brain tumor control and overall survival in those patients. However, when BM
are accompanied by systemic progression and the option of giving chemotherapy for a specific patient exists,
chemotherapy is given based on the recognized chemo-responsiveness of this SCLC.

Although WBRT remains the standard therapeutic strategy for these patients, this approach is not based on
the results of randomized trials. In addition, the effectiveness of WBRT in patients with widespread metastatic
disease is debatable. We cannot exclude that some of these patients may be treated with chemotherapy
alone. Another dubious indication for WBRT in these patients involves BM in RTOG RPA class 3, that is,
patients with poor performance status (KPS < 70). In one retrospective analysis of 132 patients with BM
from SCLC who received WBRT, the median survival for 27 (20%) patients from RPA class 3 was 2 months ;
[2]
similarly, in another trial that included 154 such patients, the median survival for 51 (33%) patients from
RPA class 3 was 2.3 months . With such a short survival, the benefit of WBRT is doubtful. One prospective
[3]
trial that also included patients with SCLC histology aimed to determine whether WBRT had any benefit
in terms of symptoms palliation in 91 RTOG RPA class 3 patients. All patients received WBRT and were
asked to complete a questionnaire about their symptoms before and 1 month after WBRT. Only 43 (47%)
patients completed the questionnaire after WBRT, the other patients died or were not able to respond to
the survey questions because of further deterioration of performance and/or neurological status. In the
group of patients who completed both questionnaires, the intensity of symptoms of the disease significantly
increased after WBRT. This result challenges the value of WBRT for patients with poor performance status .
[32]
Recently, the limited value of WBRT in patients with BM from NSCLC who were unsuitable for resection or
radiosurgery in terms of survival, quality of life, and reduction of the dose of steroids was demonstrated in a
large randomized trial . Taking into account, the short survival of patients with BM from SCLC, the value
[33]
of considering WBRT in these patients as a standard of care should be subject to further research.

Radiotherapy for BM that occur after PCI
PCI reduces the risk of BM in both LS SCLC and ES SCLC, as shown in a meta-analysis and prospective
randomized trials [6,8,27] . Nevertheless, a substantial proportion of patients still develop brain failure after
PCI. The 3-year BM rate after PCI was 33% vs. 59% without PCI in a meta-analysis of 987 patients from
seven randomized trials that compared treatment of SCLC with and without PCI . In ES SCLC, the risk of
[6]
symptomatic BM after PCI was 15% vs. 40% without PCI . In a Japanese prospective trial that compared
[8]
treatment with and without PCI with staging and strict surveillance with brain MRI, the 1-year BM rate
was as high as 33% with PCI vs. 59% in patients without PCI . These results indicate that 15%-30% of
[27]
patients will still develop BM after PCI. Such failure represents a special therapeutic challenge, because
reirradiation of the whole brain that has already received a biological dose of ~ 30 Gy risks meaningful
neurotoxicity. On the other hand, the short survival of such patients may prevent them from the occurrence
of late toxic effects, and in the short term, reirradiation at moderate doses may be beneficial, especially
in symptomatic patients, taking into account the radio-sensitivity of SCLC. Even if localized treatment
options like radiosurgery or less often resection appear as appropriate strategies in the irradiated region,
most of these patients recur as multifocal BM that are unsuitable for radiosurgery. At the 2018 IASLC World
Conference on Lung Cancer, one study reported that 60% of 32 patients who recurred in the brain after
PCI were unsuitable for radiosurgery and WBRT may be considered for such patients . There are very few
[34]
reports about whole brain reirradiation after PCI. The largest series of patients treated with brain radiation
after PCI with a median time of 14 months (range, 4-42 months) demonstrated that in 76 patients receiving a
PCI dose of 30 Gy in 15 fractions, repeat WBRT with doses of 20-30 Gy in fractional doses of 2 Gy was given to
66 (88%) patients and radiosurgery of 18-24 Gy in a single fraction to 13 (18%) patients. Median survival after
repeat WBRT and radiosurgery was 3 months and 5 months, respectively, with a range of 0-12 months for both
treatment types; 40% of 44 symptomatic patients improved after reirradiation. No serious, grade > 2 toxicity
was observed in these patients . These results indicate that WBRT with moderate doses may be beneficial in
[35]