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Page 2 of 7 Komiya et al. J Cancer Metastasis Treat 2020;6:4 I http://dx.doi.org/10.20517/2394-4722.2019.41

Conclusion: A significant number of ES-SCLC trials continues to exclude patients with BM. Future studies need to
ease eligibility regarding BM according to ASCO/Friends recommendations.

Keywords: Brain metastasis, small cell lung cancer, clinical trials

INTRODUCTION
Despite the introduction of cancer prevention, screening, and new treatment modalities, cancer remains
the leading cause of human mortality in both men and women worldwide. According to the National
Cancer Institute Surveillance, Epidemiology, and End Results Program, more than 600,000 people die
[1]
annually from cancer in the United States . To develop novel therapies and further improve outcomes,
well-designed clinical trials recruit candidates in numerous clinical settings. Although they are intended
to help physicians’ decision-making in future oncology patients, these trials are often restrictive in patient
selection. Patients with unfavorable risk factors are not permitted to participate due to fear of safety risks,
resulting in a lack of generalizability to the typical patient population.

In the real world, oncologists often face clinical scenarios that have not been addressed in previous trials.
Patients in oncology clinics may not have the same clinical characteristics that are required for participation
in trials, indicating potential discrepancies in patient populations between clinical trial and non-clinical
trial settings. In fact, a retrospective review of lung cancer cases at a Canadian institution showed that 73%
of their consecutive patients would have been trial-ineligible for their hypothetical trials with common
[2]
eligibility criteria . Due to lack of data in the trials, patients may develop unexpected outcomes with
newly-developed treatments or be undertreated because of the fear of unknown risk.

To address the lack of generalizability in oncology clinical trials, the American Society of Clinical Oncology
(ASCO) and Friends of Cancer Research proposed to the Food and Drug Agency (FDA) that clinical trials
must ease eligibility criteria and suggested re-considering several items commonly listed in exclusion
[3-6]
criteria . These include presence of brain metastases (BMs), history of HIV/Hepatitis B/C, minimum
age, organ dysfunction, and prior and concurrent malignancies. These items have been frequently listed
[3-6]
in exclusion criteria due to historical concerns without valid scientific analysis . Oncology patients with
any of these clinical characteristics tend to be excluded from clinical trials even though they account for a
significant proportion of all cancer cases in the real world.

In this study, we focused on the presence of BMs as an exclusion criterion in prospective clinical trials of
extensive-stage small cell lung cancer (ES-SCLC). Frequency of trial exclusion due to presence of BMs was
assessed to determine a trend over several decades.

METHODS
We conducted systematic screening to identify prospective clinical trials in ES-SCLC [Table 1]. The initial
screening used PubMed search with key words “small cell lung cancer” and “extensive”. Twenty journals
commonly publishing these studies were identified during the PubMed search: Journal of Clinical Oncology,
British Journal of Cancer, New England Journal of Medicine, Lancet, Lancet Oncology, Cancer Research,
Clinical Cancer Research, Annals of Oncology, Lung Cancer, Journal of Thoracic Oncology, Journal of National
Cancer Institute, Clinical Lung Cancer, Cancer, International Journal of Cancer, American Journal of Clinical
Oncology, European Journal of Cancer, Annals of Internal Medicine, The Oncologist, Cancer Chemotherapy
and Pharmacology, and Oncotarget. Online archives of these journals were investigated for additional