Racial Disparities in Recurrence and Overall Survival in Patients With Locoregional Colorectal Cancer

Rebecca A. Snyder, MD, MPH; Chung-Yuan Hu, MPH, PhD; Syed Nabeel Zafar, MBBS, MPH; Amanda Francescatti, MS; George J. Chang, MD, MS

Disclosures

J Natl Cancer Inst. 2021;113(6):770-777. 

In This Article

Discussion

In this study of a real-world population of US patients with locoregional CRC, statistically significant racial disparities in recurrence and survival were identified. Black patients with colon cancer appeared to receive equivalent or superior quality of care compared with their White counterparts, measured by increased adjuvant chemotherapy use among stage III patients and higher rates of overall GCC. However, despite receiving equivalent or superior quality of care, rates of recurrence were higher among Black compared with White patients, and OS was worse. There were measurable differences in socioeconomic status between Black and White patients, including insurance status and household income; however, even after controlling for these differences, Black patients were still at higher risk for recurrence and mortality. To our knowledge, this is the first report of racial differences in CRC recurrence rates within the routine, clinical practice setting.

These findings are consistent with secondary analyses of patients enrolled in clinical trials in the United States, which have also found shorter time to recurrence, worse disease-free survival, and worse OS in Black patients.[8–10] In a secondary analysis of patients with stage III colon cancer enrolled on the Alliance N0147 clinical trial and treated with 5-FU, leucovorin, and oxaliplatin (FOLFOX) chemotherapy, Black patients younger than 50 years had a shorter disease-free survival compared with White patients (HR = 2.84, 95% CI = 1.73 to 4.66), as did those with N1 disease (HR = 1.54, 95% CI = 1.04 to 2.29).[9] A pooled analysis of over 14 000 patients with stage II and III colon cancer enrolled in 12 randomized adjuvant chemotherapy trials also demonstrated worse recurrence-free survival in Black compared with White patients (3-year recurrence-free survival = 64.4% vs 72.1%, HR = 1.14, 95% CI = 1.04 to 1.24).[10]

In this study, the finding that Black patients with colon cancer were more likely to receive GCC than White patients was unexpected. Most prior studies have demonstrated persistent racial disparities in CRC treatment, including lower rates of surgery for stage I and stage IV CRC, adjuvant chemotherapy for stage III colon cancer, radiation for stage II or III rectal cancer, and targeted therapy for stage IV CRC.[11–15] The cohort of Black patients treated at CoC sites and included in this study was more often from a metro area (87.5% vs 75.1) and more likely to receive care at an academic or research facility than White patients (31.2% vs 16.0%), which could explain higher rates of GCC. It is certainly possible that this finding is not generalizable to patients treated at non-CoC sites.

Because Black patients experience higher recurrence rates and worse survival even in the context of randomized controlled trials in which patients receive standard therapy, it has been suggested that underlying differences in tumor biology may be responsible for disparate outcomes. Recent evidence suggests that KRAS mutation rates differ by race, with a higher proportion of KRAS codon 13 mutations among Black patients.[16,17] Additionally, in a secondary analysis of the CALGB/SWOG 80405 randomized trial in metastatic CRC patients, a higher rate of extended RAS mutations (noncodon 12 or 13) was identified in Black compared with White patients, and these extended mutations were associated with worse OS.[17] Correlative studies of patients with metastatic CRC treated in the CALGB/SWOG 80405 randomized trial recently investigated the association of consensus molecular subtypes and tumor mutational burden with OS and progression-free survival (PFS).[18,19] Although consensus molecular subtypes and tumor mutational burden are prognostic for survival, the specific profiles of each did not differ by race ; however, this was not the primary focus of either analysis.

Several studies have recently demonstrated an association between patient race and tumor sidedness. A Surveillance, Epidemiology, and End Results Program analysis of stage IV CRC patients found that right-sided cancers were more common in Black compared with White patients (odds ratio = 1.45, 95% CI = 1.33 to 1.58) and that right-sided cancers were associated with a greater risk of death (HR = 1.27, 95% CI = 1.22 to 1.32).[20] Several smaller state or hospital-based cohort studies also found higher rates of proximal cancers in Black compared with White patients.[21–23] In this study, a statistically significant difference in the frequency of proximal tumors between White and Black patients was not seen (48.8% vs 51.8%, respectively, P = .11). However, based on recent data as well as the findings presented in this study, further study of potential differences in tumor biology appears warranted.

In addition to tumor biology, differences in socioeconomic status likely contribute to much of the racial disparity in CRC outcomes. A recent pooled analysis of randomized controlled trials in a variety of cancer types found that patients with Medicaid or without insurance did not receive the same benefit of experimental therapy as did patients with private insurance.[24] This would suggest that other unmeasured social determinants of health, such as financial strain or transportation access, for example, influence outcomes, even in the setting of equal access to high-quality treatment.[25] Many of the same social determinants of health that correlate with insurance status may also correlate with race and could affect multiple aspects of care delivery, such as treatment adherence or access to survivorship care, for example. Therefore, it is likely that the racial differences in recurrence rates and survival identified here also reflect unmeasured differences in socioeconomic conditions and health-care access. Prioritization of collecting better data specific to social determinants of health will be critical to make meaningful progress in cancer health disparities research.

Several studies have identified racial differences in response to therapy and treatment toxicity in both the locoregional and metastatic setting. In a large randomized controlled trial of patients with high-risk stage II or stage III colon cancer treated with 5-FU chemotherapy, African American patients had lower rates of treatment-related toxicity than Caucasian patients, including lower rates of diarrhea, nausea, vomiting, stomatitis, and overall toxicity (P < .05).[8] Similarly, a secondary analysis of the National Cancer Institute-sponsored (N9741) randomized trial of patients with metastatic CRC treated with standard chemotherapy found lower response rates in Blacks compared with Whites (28% vs 41%, P = .008) and lower rates of grade 3 or higher adverse events among Black patients (34% vs 48%, P = .004).[26] Finally, a prospective observational study of patients with metastatic CRC treated with bevacizumab also found lower response rates in Black compared with White patients (37.5% vs 46.3%; adjusted odds ratio = 0.67, 95% CI = 0.50 to 0.90).[27] Taken together, these findings seem to suggest racial differences in sensitivity to systemic therapy that deserve further investigation.

There are several limitations to this study. First, the purpose of the study was to measure differences in outcomes between Black and White patients; therefore, patients of other racial and ethnic groups were excluded (other race, n = 362; unknown race, n = 96). Because patients were not prospectively enrolled to include equal numbers of patients in each race category, the cohort size of Black patients (n = 811) was much smaller than the cohort of White patients (n = 7365). This resulted in a small number of Black patients with rectal cancer (n = 94), thereby limiting subgroup analysis. Differences were observed in measured socioeconomic factors between Black and White patients. Although these were included in the multivariable regression model, it is possible that other confounders related to social determinants of health, such as marital status, exist that were not available within the dataset. Because the study cohort is comprised of patients diagnosed in 2006–2007, these findings may not be representative of contemporary clinical outcomes. These dates were selected to allow at least 5 years of follow-up data for detection of recurrence. Because this is a retrospective study, it is possible that recurrence could be underestimated. To account for this, if patients sought treatment or follow-up at another institution, registrars were asked to collect these data for data completeness. Additionally, it would be expected that any variation in recurrence detection would be similar between racial groups and would be unlikely to alter the findings. Selection criteria for the study cohort could introduce potential bias, specifically the exclusion of patients who did not receive surveillance testing. However, the proportions of Black and White patients without any surveillance testing did not differ (21.9% vs 19.4%, P = .05). Additionally, the patient population within the NCDB consists of patients treated at CoC sites. It is possible that the observed racial differences in receipt of GCC are unique to the population of patients treated at CoC sites and may not be generalizable to patients treated in other clinical settings. Despite this limitation, because the NCDB represents 70% of newly diagnosed cancer cases nationwide, it is considered an acceptable representation of the national cancer patient population. Finally, NCDB does not capture data on performance status or response to therapy, which could result in unmeasured confounding. Despite receiving equivalent or superior quality of care, Black patients experience a higher risk of recurrence and worse OS compared with White patients.

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