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Table 1. Selection of ES-SCLC trials
Inclusion criteria ES-SCLC
Publication in English literature
Publication by December 2018
Exclusion criteria Including NSCLC
Trials specific for BMs
Radiation therapy as primary intervention
Investigation period From January 2018 to June 2018
Search methods Pubmed search
Online journal website
Citation in review articles
ES-SCLC: extensive stage small cell lung cancer; NSCLC: non-small cell lung cancer; BMs: brain metastases

articles. Recently published clinical reviews about ES-SCLC were also identified and investigated for more
articles [7-10] .

Eligible studies must have enrolled primarily ES-SCLC and been published in English. Studies primarily
investigating brain/chest radiation and BM-specific trials were excluded. Studies were categorized into
allowed/undefined, conditional (e.g., only previously treated or asymptomatic BM are allowed), or complete
exclusion of BM. Chi-squire test was used for categorical group comparison. Two-sided P-values of less
than 0.05 were defined as statistically significant.

RESULTS
The screening for clinical trials in ES-SCLC identified 240, 198, and 53 distinct articles by PubMed, journal
website archives, and review articles, respectively. Characteristics of the trials are shown in Table 2. Most of
the studies are published in journals with impact factor < 10, publication year 2000 or later, non-US sites,
phases other than phase III, first-line setting, non-randomized, fewer than 100 patients, performance status
other than 0-1, and no age limit. Radiographic screening of BM by magnetic resonance imaging (MRI) or
computed tomography (CT) was mandated only in 32% (157 studies, data not shown). Anti-angiogenic
agents were used only in 19 studies.

Early publication year (1970-1999) and first-line/maintenance setting were significantly associated with
a higher incidence of complete exclusion of cases with BM (P < 0.0001 and 0.0233, respectively). The
complete exclusion was 20% in early vs. 10% in late publication years, and 16% in first-line/maintenance
vs. 8% in others. There was no correlation between the complete exclusion of BMs and other clinical
characteristics including journal impact factor, region, trial phase, randomization, sample size, patient
performance status, and age limit.

Studies in the 1990s had the highest incidence (27%) of complete exclusion, which decreased to 8% in the
2010s [Figure 1]. The conditional group increased from 25% in the 1970s to 34% in the 1990s and 79% in
the 2010s.

DISCUSSION
Lung cancer is the most common cause of cancer mortality in the United States. Small cell lung cancer
(SCLC), which accounts for approximately 15%-20% of all lung cancer cases, commonly presents with
BMs [11-13] . Clinical trials in ES-SCLC focusing on systemic therapy often exclude patients with BMs
primarily due to safety concerns; however, detailed incidence and trends in excluding BMs have not been
investigated. The current study demonstrated that 8% of ES-SCLC trials in the 2010s still completely
exclude patients with BM, whereas a recent analysis on non-small cell lung cancer trials at clinicaltrials.gov
[14]
reported a complete exclusion rate of 14% .