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Kepka. J Cancer Metastasis Treat 2019;5:53 I http://dx.doi.org/10.20517/2394-4722.2018.114 Page 3 of 11

on the rationale that due to rapid progression, the subclinical disease foci exist in the whole brain at the onset
of macroscopic BM. On the other hand, published data indicate that also in the case of SCLC, biological
behavior may differ in a single BM compared with multiple BM. Thus, a disease that occurs with single or
oligo- brain metastases may have different, more favorable prognosis than poly-metastatic brain disease at
its onset. The latter would have greater inherent aggressiveness. However, we cannot exclude that in the case
of less advanced brain involvement, more aggressive treatment strategies are employed. In the retrospective
analysis of 52 patients who received WBRT for single BM, the use of surgery in combination with WBRT was
related to improved survival compared with WBRT alone, with median overall survival of 19 and 5 months,
respectively (P = 0.03) . In the largest retrospective study on patients with BM from SCLC that included 229
[12]
patients treated with WBRT, the number of BM did not retain prognostic significance. Apart from the factors
included in the RTOG RPA score, the time of occurrence of BM in relation to the diagnosis of the primary
(synchronous vs. metachronous BM) and initial response to chemotherapy had a significant impact on
survival. Patients presenting with synchronous BM and initial good response to chemotherapy had improved
overall survival compared with patients presenting with metachronous BM and non-/poor responders to
initial chemotherapy . The authors proposed a new BM from SCLC score (BMS-score), which included
[13]
RTOG RPA class and synchronous vs. metachronous BM presentation. Initial response to chemotherapy was
not included in the score, because the evaluation of the response to chemotherapy may not be practical and as
a result may prevent the use of the score on a large scale .
[14]

Concluding the discussion of the issue of prognostic factors in BM from SCLC, we should emphasize
the unquestioned value of the RTOG RPA classes. The role of the number of BM should be reconfirmed,
especially in the era of rapid expansion of local treatment of BM, also in SCLC. The timing of occurrence of
BM, that is, synchronous vs. metachronous presentation, and the initial response to chemotherapy require
further evaluation.

TREATMENT OF BM WITH SYNCHRONOUS PRESENTATION
BM that occur synchronously with primary diagnosis of SCLC represent different clinical scenarios
and require different management compared with BM that are diagnosed metachronously, that is, at the
relapse of SCLC. We may distinguish four categories of this synchronous presentation that require different
management.

BM diagnosed during an initial staging of SCLC
When asymptomatic BM are part of the dissemination of SCLC, either as a sole distant site or as one of
many distant locations, treatment usually starts with chemotherapy. The efficacy of chemotherapy for BM
was questioned in the past, because the brain was considered a pharmacological sanctuary due to the brain-
blood barrier (BBB) that prevented drugs from penetration into the brain. However, tumor invasion likely
disrupts the BBB, because there are many clinical observations of the efficacy of chemotherapy in BM from
SCLC. Pooled data from five studies reported a 66% response rate (RR) in 64 patients with synchronous
BM . However, there are also contrary data indicating that the RR in the brain is lower than the systemic
[15]
RR; with 27% vs. 73% RR for brain and extracranial sites, respectively, in 24 asymptomatic patients with
BM from SCLC who received cyclophosphamide, doxorubicine, and vincristine . However, an aggressive
[16]
and rapid disease course prompts the initiation of systemic therapy so as not to miss the opportunity to
administer chemotherapy that may stop extracranial systemic and local disease progression that causes
bothersome and/or life threatening symptoms.

The question remains, whether chemotherapy should be followed by WBRT in such patients, even if the use
of chemotherapy results in a complete response in the brain. We have no prospective data on this point.
However, one randomized trial compared the use of teniposide alone vs. teniposide + WBRT 30 Gy in 120