Blacks bear a disproportionate burden of cancers. Blacks have the lowest survival rate and the highest death rate in comparison to other racial or ethnic groups for most cancer types (1). Socioeconomic status (SES), such as income status, education level, and medical insurance, plays the most critical role in leading to these racial inequalities (1–5). Blacks have a higher rate with stage IV cancer, and the risk of cancer-related death is higher when compared with Whites because more Blacks are uninsured than Whites (6–11). Previous studies reported that the 5-year survival rate of lung cancer is lower in Blacks than those in Whites (1). In addition to socioeconomic status, curative-intent surgery also plays a vital role in survival. Blacks diagnosed with early-stage lung cancer are less likely to perform radical surgery than Whites even after considering the impact of socioeconomic factors (1, 12, 13). While the roles of race and SES disparity have been well-studied in various cancer care settings, their roles and interplay in stage IV SCLC remains primarily unknown. SCLC accounts for 10-15% of all lung cancers, and the prognosis for SCLC patients is poor (14–16). More than 60% of SCLC patients present with stage IV disease at diagnosis (17, 18). Differences in lung cancer incidence still exist among different ethnic groups, with Blacks having a significantly higher lung cancer rate than Whites and Blacks who are diagnosed with more stage IV cancers than Whites (1). In comparison, the incidence of SCLC decreases among all races, and there is no significant difference in stage distributions between Blacks and Whites from 2006 to 2010 (19).

NCDB is a prospectively maintained registry database covering 70% of newly diagnosed cancer cases in the nation (20). It includes 82% of lung cancer cases with an annual follow-up of at least 90% of the patients (21). In this current study, we analyzed the survival differences in stage IV SCLC patients between Blacks and Whites, considering various variables available in NCDB. We also investigated the characteristics of various clinical and treatment-related features among Blacks and Whites and the potential impact on clinical outcomes.

SCLC cases diagnosed between 2004 and 2014 were obtained from the National Cancer Database (22). The histology codes were mainly based on the International Agency for Research on Cancer (IARC) classifications: small cell carcinoma [International Classification of Diseases for Oncology Third Edition (ICD-O-3) codes 8002, 8041–8045)]. We identified 214,096 cases with TNM staging data, excluding stage I, II, III, and the stage unknown cases. The final study cohort consisted of 119,611 stage IV SCLC patients, including 110,696 White patients and 8,915 Black patients.

Study subjects were included in the study from the date of diagnosis and were followed until the end of the study period, the date of the last contact, or death, whichever came first. The primary outcome measure in our study was overall survival (OS) (20). Baseline demographic features including sex, age, education, census median income quartiles, insurance, living area, geographic region, distance to treating facility (great circle distance, distance in miles between patient’s residence based on ZIP code centroid or city to street address of treating facility); clinical characteristics including the time of diagnosis, tumor size, Charlson-Deyo score, and treatments including radiation therapy, chemotherapy, immunotherapy, palliative care, facility procedure volume, academic/research program between Blacks and Whites were studied. Patients with missing information were excluded from the analysis. Predictors included age (<60, 60-69, 70-79, >=80), insurance at the time of diagnosis (private, government, no insurance, missing), percentage of without high school degree 2007-2012 (<7%, 7-12.9%, 13-20.9%, >=21%), census median income quartile 2007-2012 (<$38,000, $38,000-$47,999, $48,000-$62,999, >$63,000) and Charlson-Deyo comorbidity score (0, 1, 2, >=3). A modified Charlson-Deyo score was calculated from preexisting comorbidities, which up to six conditions (23).

A total of 119,611 stage IV SCLC patients, including 110,696 White patients and 8,915 Black patients, were included in this study. The median follow-up is 8.18 months (range 2.37-15.84 months). Patients’ demographic, clinical, and treatment features were compared between Blacks and Whites ( Tables 1 – 3 ). Blacks were more likely to be male, younger, with lower education and lower annual income than Whites on the logistic regression model. They also had shorter travel distances to their treatment site. The median travel distance between the patient’s primary residence and treatment site was 13.8 vs. 24.9 miles in Blacks versus Whites (P<0.0001). Blacks were found to have larger tumors (mean tumor size 58 vs. 54.2 mm, p <0.0001) and were more likely to receive radiation therapy (41.6% vs. 38.9%, p<0.0001) and treatment in academic centers (41.4% vs. 24.7%, p<0.0001) than Whites. In addition, Blacks were less likely to receive palliative therapy than Whites (20.7% vs. 21.7%, p = 0.03). Among stage IV SCLC patients who received the treatments, 7.7% of Blacks and 6.3% of Whites received radiation therapy alone (p<0.0001), 36.2% of Blacks and 38.2% of Whites received chemotherapy alone (p<0.0001), and 33.3% of Blacks and 32% of Whites received both chemotherapy and radiation therapy (p<0.0001, Supplementary Table 1 ). Among the patients who received radiation therapy and chemotherapy, 60.5% of Black and 62.6% White patients received chemotherapy first, followed by radiation therapy (p = 0.0299). In addition, more Blacks were found brain metastasis than Whites (27.7% vs. 24.6%, p<0.0001). The incidence of stage IV SCLC increased from 2004 to 2014 in both Blacks and Whites, although the distribution was slightly different. No significant differences were found between Blacks and Whites in insurance status, living area, geographic region, diagnostic confirmation method, Charlson-Deyo score, chemotherapy, immunotherapy, and treatment facility volume.

Although the overall distribution was consistent regarding the patients’ and tumor’s characteristics, some differences were noticed. Among those with stage IV SCLC, the proportion of female patients was lower than male patients in both Whites (48.8% versus 51.2%) and Blacks (48.3% versus 51.7%) ( Figure 1A ). The total number of White stage IV SCLC patients increased by 27.9% in 2014 compared to 2004 (8,393 patients in 2004 and 11,639 patients in 2014). The number of Black stage IV SCLC patients increased by 32.7% in 2014 compared to 2004 (645 in 2004 and 958 in 2014). The percentage of stage IV SCLC among all patients with SCLC had also increased significantly from 2004 to 2014 in both Whites and Blacks, and the increases in Whites were more than those in Blacks ( Figure 1B ). The median overall survival time of stage IV SCLC in Blacks was 6.57 months, higher than 6.21 months in Whites (p<0.001). The 6 months, 12 months, 18 months and 24 months’ survivals were 51.0%, 23.6%, 11.5%, 6.9% for Whites and 52.4%, 25.7%, 13.2%, 7.9% for Blacks (p<0.01) ( Figure 1C ).

We next used the Cox proportional hazards multivariable model to analyze the potential predictors of overall survival of patients with stage IV SCLC. Black was independently associated with a decreased hazard of death in Cox proportional hazards modeling after controlling for demographic and clinical factors (HR=0.911; 95%CI: 0.884-0.938; P<0.0001). Other favorable factors associated with improved OS included female (HR=0.852; 95% CI: 0.839-0.864, P<0.0001), greater distance to treatment center (HR=0.988; 95%CI: 0.983-0.993, P<0.0001), higher income particularly income>63,000 (HR=0.929; 95% CI: 0.901-0.958, P<0.0001), private insurance (HR=0.888; 95% CI: 0.835-0.945, P<0.0001), radiation therapy (HR=0.774; 95% CI: 0.762-0.787, P<0.0001), chemotherapy (HR=0.406; 95%CI:0.397-0.414, P<0.0001), and receiving treatment in academic/research center (HR=0.978; 95% CI: 0.96-0.997, P=0.02) ( Figure 2 ). Treatment with Chemotherapy appeared to be the most favorable predictor of survival in patients with stage IV SCLC. By contrast, factors associated with decreased OS included increase in age (HR=1.136; 95% CI: 1.126-1.147, P<0.0001), high education (HR=1.05; 95% CI: 1.017-1.085, P=0.0029), living in Rural (HR=1.055; 95% CI: 1.005-1.108, P = 0.0315), high Charlson-Deyo score (HR=1.537; 95% CI: 1.481-1.596, P < 0.0001), increase in tumor size (HR=1.007; 95% CI: 1.006-1.009, P<0.0001) and palliative care (HR=1.225; 95% CI: 1.202-1.247, P<0.0001).

Cancer screening, advances in surgery and radiation techniques, and developments of novel therapeutic agents have undoubtedly led to improved clinical outcomes in many cancer patients. However, new developments and advances are uneven among different cancer types, and disparities exist in clinical outcomes across multiple cancer types and some attributes to modifiable factors. Stage IV SCLC represented one of the most notorious cancers with only 2-4 months of survival in untreated patients. Chemotherapy using platinum‐based doublet remains a cornerstone of first-line treatment until the very recent breakthrough of adding the benefit of immunotherapy in combination with chemotherapy (24, 25). Although modest improvement in survival has been observed in patients with SCLC over time, the differences in clinical outcome, socioeconomic status, clinical features, and treatment patterns between races, particularly Blacks versus Whites, remain mostly unknown. Our current study represents the largest real-world analysis of stage IV SCLC patients to investigate the clinical outcomes, the impacts of SES, clinical and treatment factors among Blacks and Whites.

Multiple studies have examined the impact of race and ethnicity on overall lung cancer prognosis (26–28). These studies have demonstrated that non-Black patients have had favorable survival than Blacks over the last several decades. In fact, Blacks have been reported to have the lowest 1-year, and 3-year survival rates in patients with non-small cell lung cancer among all races (29), and the 5-year survival rate for lung cancer is lower in Blacks than in Whites (16% vs. 19%, respectively) (1). In a multivariate analysis of SCLC patients treated through Southwest Oncology Group trials, Whites were found associated with a more favorable clinical outcome than Blacks (26). A few factors such as differences in treatments, time of diagnosis, and possible biological variability were suspected of contributing to the difference observed in Whites versus non-Whites. By contrast, using the CALGB lung cancer database, Stock et al. found that the overall survival of Black patients was not significantly different from that of non–Black patients with or without adjustment for histology, treatment, and metastatic site, despite Black patients were more likely to present with worse performance status and lower socioeconomic condition (30). Both studies offered high-quality information built upon the constraints of clinical trial entry criteria, close follow-up, and relatively uniform treatment regimens through the studies. However, the overall numbers of SCLC patients remain relatively small, and the patients who enter the clinical studies may not best represent patients in the real world. Our study specifically focused on stage IV SCLC where the treatment regimens have been relatively uniform to control the potential confounding effects of stages on outcomes. Our study included a total of 119,611 stage IV SCLC patients. We demonstrated that Blacks with stage IV SCLC had improved overall survival compared to Whites (HR 0.91, CI: 0.884-0.938; P<0.0001). This finding is interesting as our analysis revealed that Blacks were more likely to be associated with unfavorable factors such as lower income levels and larger tumor size. Despite the lower socioeconomic status and larger tumor, Blacks’ one-year and two-year survival were qualitatively similar and statistically superior to Whites (25.7% versus 23.6% and 7.9% versus 6.9% respectively, p<0.01). This might be because more Black patients received radiation therapy (41.6% vs. 38.9%, p<0.0001), had a younger age at diagnosis, and received treatments in academic/research programs (41.4% vs. 24.7%, p<0.0001) than Whites.

Consolidative thoracic radiotherapy and prophylactic cranial irradiation (PCI) have been recommended in patients with stage IV SCLC based on improved overall survival (15, 31). Particularly, PCI has been recommended as the standard of care during our study period, although a recent study performed in Japan demonstrated inconsistent conclusions. Nevertheless, our data found that radiation therapy led to a 23% reduction in mortality (HR 0.77, CI: 0.762-0.787; P<0.0001) in patients with stage IV, and remained the second most favorable factor. It was not surprising to see that chemotherapy represented the most favorable factor in patients with stage IV SCLC (HR 0.41, CI: 0.397-0.414; P<0.0001). Our data suggested that the improved overall survival observed in Blacks than Whites might be related to more Blacks receiving radiation therapy than Whites. Unfortunately, we are unable to classify further the type of radiation (to the primary site vs prophylactic) and location of radiation therapy (thoracic, brain, or other organs) due to limitations of the NCDB dataset. Further studies in this regard are warranted and may be done through claims-based databases. Age was found to be an unfavorable prognosis factor in our study (HR 1.14, CI: 1.126-1.147; P<0.0001), and Blacks were more likely to be diagnosed at an age younger than 60 years (29% vs. 24.1%, p=0.0145). This finding is consistent with our previous findings in non-small cell lung cancer (20). It is also found Black patients have superior survival compared to White patients with multiple myeloma, particularly due to diagnosis in the younger population (22, 32).

One of the most striking differences we noticed between Blacks and Whites was that Blacks were more likely to receive their treatments in academic/research programs than Whites. In our study, 41.4% of Black patients with stage IV SCLC received treatment at an academic/research program in contrast to 24.7% in White patients. Our study also demonstrated that treatment in academic/research centers was a favorable factor, therefore likely contributing to the improved survival in Blacks that we observed in our study. This data suggested receiving care at an academic/research center might mitigate the significant SES disadvantages in society and medical care as an actionable approach. This was similar to our previous study in NSCLC where we found the initial therapy at academic centers significantly improved clinical outcomes (20). Similarly, treatment at academic centers was also demonstrated independently associated with improved survival in patients with locally advanced head and neck cancer (22, 33). The underlying factors driving the improved outcomes are likely multifactorial. Academic/research centers more likely provide access to clinical trials, multi-disciplinary expertise, and ancillary services. Unfortunately, we cannot determine each factor’s exact impact on the survival of stage IV SCLC patients in our study due to the lack of such information in NCDB (34).

Consistent with previous studies performed in non-small cell lung cancers, our study demonstrated that Blacks were associated with lower socioeconomic status, including lower education and low annual incomes than Whites (20, 35–39). Interestingly, high education was found to not correlate with improved clinical outcomes. Instead, it was associated with worse clinical outcomes, although the difference was small (HR 1.05, CI: 1.017-1.085; P=0.0029). This is different from findings from other cancers, including non-small cell lung cancer, where a high level of education has been a beneficial factor for survival (34, 40, 41). This may be due to the ratio of no high school degree patients referred to the residential region rather than individual. Another reason might be that most Blacks are less educated and have better outcomes. Patients with high annual income, particularly those with > $ 63,000, were associated with favorable outcomes, likely due to more access to treatments. Similarly, females were also found to have better outcomes in our study, consistent with findings from other cancer types (39).

Not surprisingly, high comorbidity status was found closely correlated with poor prognosis. Palliative care was found to be associated with poor prognosis in our study. This may be because patients who received palliative care were more symptomatic and had lower tolerability to therapy. It has been noted previously that palliative care utilization is extremely low even amongst academic cancer centers, suggesting that its use is more associated with an alternative than an adjunct to active anticancer therapeutics (42). During this period of 2004 to 2014, the incidence of SCLC declined (43). However, the percentages of stage IV SCLC were increased in both White and Blacks, indicating potentially later diagnosis of this disease.

Our study demonstrated that Blacks were associated with significant socioeconomic disadvantages in comparison with Whites. However, despite these unfavorable factors, Blacks had survival outcomes qualitatively similar and statistically superior than those of Whites after co-variable adjustment. Blacks were found associated with younger age at diagnosis, a significantly higher chance of receiving radiation therapy and treatments at the academic/research program. This suggests the importance of radiotherapy and receiving care at an academic center could mitigate the known SES disadvantages in treating small cell lung cancer patients.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: National cancer database.

The studies involving human participants were reviewed and approved by Mayo Clinic IRB. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

HS and YL drafted the article. HS, KZ, and YL designed the study. JC and DH helped the statistical analysis. HS, KZ, HQ, AA, RM, YZ, AS, and YL give critical revision of the article for important intellectual content. All authors contributed to the article and approved the submitted version.

This work was supported by the National Institutes of Health [grant number is K12CA090628, YL].

YL: Advisory board: AstraZeneca, Novocure; Consultant: AstraZeneca; Honorarium: clarion health care; Research Funding Support: Merck, MacroGenics, Tolero Pharmaceuticals, AstraZeneca, Vaccinex, Blueprint Medicines, Harpoon Therapeutics, Sun Pharma Advanced Research, Bristol-Myers Squibb, Kyowa Pharmaceuticals, Tesaro, Bayer HealthCare. RM: Advisory board: AstraZeneca, Guardant Health, Novocure, Takeda; Consulting: AstraZeneca. AS is a consultant with Celgene, Takeda, Janssen, Amgen, AstraZeneca, Glaxo-Smithkline, and has received institutional research support from Pharmacyclics, Bristol Myers Squibb, Janssen, Amgen, Cellectar, Medimmune, and Ascentage.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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