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

definitive chemoradiotherapy with baseline brain MRI, 25 (21%) harbored BM on pre-PCI MRI, and 23 were
asymptomatic. The duration of chemo-radiotherapy was the only prognostic factor for occurrence of pre-PCI
BM. Patients with BM in pre-PCI MRI and duration of chemo-radiotherapy that exceeded 4.5 months had
significantly shorter survival . These findings are in line with modeling radiobiological studies that sought
[25]
to elucidate dose-response relationship for PCI in SCLC as a function of time interval between time of
treatment of primary tumor and initiation of PCI. The nearly linear dose-response relationship for reduction
in BM was demonstrated for “early PCI” (up to 60 days from the start of treatment of the primary tumor) in
doses of 0-35 Gy given in 2-Gy fractions. When PCI was delayed for over 60 days, a significant threshold in
dose-response was observed, which is consistent with a fast growth rate of untreated subclinical BM from
SCLC . Thus, it is important to initiate PCI early from the start of treatment. However, the guidelines
[26]
do not recommend the concomitant use of PCI with chemotherapy because of apprehension concerning
the toxicity of such an approach. What we learn from these studies is that every effort should be made to
avoid unnecessarily prolonging chemo-radiotherapy for SCLC and to start PCI as quickly as possible after
the end of treatment of the primary tumor. Pre-PCI MRI and higher WBRT dose not change a prognosis
of asymptomatic patients in which progression in the brain occurs during initial therapy. However, in
some patients with ES SCLC without BM on pre-PCI MRI, MRI surveillance without baseline PCI may be
recommended as in a Japanese trial, in which patients with MRI surveillance did not have a survival benefit
with the addition of PCI . Pre-PCI MRI is also a pre-requisite for PCI with hippocampal avoidance.
[27]

TREATMENT OF BM WITH METACHRONOUS PRESENTATION
Despite a high initial response rate on chemotherapy, the majority of patients with LS SCLC and practically all
with ES SCLC will relapse within the first year after treatment. After first-line chemotherapy, only extremely
limited therapeutic options exist. Median survival after second-line chemotherapy is 3-6 months in clinical
trials . In addition, BM occur rarely as a sole event. The majority of patients with BM simultaneously have
[28]
extracranial disease progression . The limited therapeutic options and poor survival after relapse determine
[4]
the poor outcome of treatment of metachronous BM. Thus, a metachronous presentation, that is, occurrence
after first-line treatment, appears as an adverse prognostic factor [13,14] . Treatment strategies for BM that occur
at the relapse differ with regard to the earlier use or not of PCI.

Radiotherapy for BM that occur without prior PCI
When the use of chemotherapy for asymptomatic BM that occur simultaneously with the diagnosis of primary
is not debatable, the use of chemotherapy for metachronous BM is conditioned by a number of factors, such
as the site of progression, brain only vs. brain and extracranial site, previous response to chemotherapy,
the time interval from the last line of chemotherapy, the extent of extracranial disease, and performance
status. We have no strong evidence for the use of chemotherapy for BM from SCLC. In the Cochrane
Database of Systematic Reviews, only three small randomized trials involving 192 participants that dealt
with chemotherapy for BM from SCLC were identified . In one study, 120 patients with BM and concurrent
[29]
systemic failure were randomized to receive teniposide with and without WBRT. Patients in the combined
modality arm had higher RR in the brain (57%) than patients treated with teniposide alone (22%), (P < 0.001).
Patients who received WBRT also had longer time to progression in the brain than patients treated with
chemotherapy alone, (P = 0.005). Overall survival did not differ greatly between the groups (median survival:
3.5 months in the combined modality arm and 3.2 months for chemotherapy alone arm; P = 0.087) . Only one
[5]
trial compared chemotherapy with no chemotherapy; 33 patients received WBRT for BM from SCLC (first
line, n = 5; recurrence, n = 28) and were randomized to WBRT alone vs. WBRT plus topotecan. No significant
difference in survival was found between these two groups . The Cochrane Database of Systematic Reviews
[30]
identified one other chemotherapy trial that compared two schedules - sequential and concomitant-of
combination chemotherapy (teniposide plus cisplatin) with WBRT. This trial included only 39 patients and no
difference in overall survival and response rate for either combination was demonstrated, although patients