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Komiya et al. J Cancer Metastasis Treat 2020;6:4 I http://dx.doi.org/10.20517/2394-4722.2019.41 Page 5 of 7

ES-SCLC patients with BMs in the real-world setting do not benefit from clinical trials that do not include
BM cases. New therapeutic interventions for these patients are unlikely to develop while they remain
ignored by researchers. Expanding eligibility criteria to include patients with BMs would provide benefits in
several aspects. In a population with a high incidence of BMs such as ES-SCLC, efficacy and safety effects
unique to patients with BMs may exist. If the efficacy and safety of an investigational agent is assessed at an
early phase, late phase studies may enroll patients to assess central nervous system (CNS) penetration along
with related efficacy and safety. A successful example is a phase III trial comparing alectinib vs. crizotinib
in advanced non-small cell lung cancer where alectinib demonstrated a CNS response rate of 81% in
[12]
a population with 40% BM at baseline . ASCO and Friends of Cancer Research strongly recommend
investigation in patients with BMs in the setting of prospective trials rather than relying on post-marketing
[4]
experience . They state that previously treated and radiographically stable BM cases for at least four weeks
should be included in prospective trials of all phases, whereas active/progressive BMs may require a study-
to-study approach. A group from the FDA supports their recommendation by suggesting exclusion of only
[13]
those who are symptomatic or are taking medications with known drug interactions .

Current staging methods of SCLC includes CT scans of chest/abdomen/pelvis, positron emission
tomography scan, mediastinal staging procedures via bronchoscopy, and MRI of the brain. Lesions in the
CNS have been previously assessed only clinically in early ages, while CT of the head came of use in the
1980s-early 1990s. With the now more recent use of MRI, more asymptomatic BM cases are presumably
detected, likely explaining the increase of the conditional group as commented above. However, radiographic
screening of BM was mandated only in 32% of studies overall, and 23% of studies published in the 2010s (data
not shown). Changes in the management of BMs may also explain the trend over the decades. As stereotactic
radiosurgery became available for small CNS lesions, more cases were identified that were previously treated
with radiation therapy. In fact, the cases in the conditional group have grown over the decades [Table 2].
They also include asymptomatic cases, those previously treated with radiation or surgery, and those in
stable condition without the need for high dose steroids.

We are aware that removing restrictions in eligibility criteria may not necessarily result in rapid increases in
enrollment of the previously-excluded population. For instance, a recent trial in extensive-stage SCLC that
allowed the presence of BMs accrued a very limited number of patients . Attitudes of investigators will
[15]
hopefully change as ASCO/Friends recommendations become more appreciated in the next several years.

We acknowledge limitations in this study. With a retrospective search, there might be studies not covered
by our search strategy. Studies not available in English publication were excluded, indicating potential
publication bias. The articles in the earlier years had limited space to provide information such as detailed
eligibility criteria, whereas recent articles can be more informative with online supplemental datasets.
Information regarding eligibility of patients with leptomeningeal metastases were not available in most
studies. Few agents with specific concerns on CNS disease such as anti-angiogenesis drugs have been tested
in a limited number of trials. These potential biases may need to be considered for the interpretation of this
study.

In conclusion, a significant number of ES-SCLC trials continue to exclude patients with BM, although
conditional allowance has increased over the decades. Future studies need to further ease eligibility
regarding BM according to ASCO/Friends recommendations.

DECLARATIONS
Acknowledgments
We thank the Parkview Research Center for administrative support.