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Racial Differences in Stage IV Colorectal Cancer Survival in Younger and Older Patients
Original Study
Racial Differences in Stage IV Colorectal Cancer Survival in Younger and Older Patients Kristin Wallace,1,2 Allan DeToma,1,2 David N. Lewin,1,3 Shaoli Sun,1,3 Don Rockey,4 Carolyn D. Britten,1,5 Jennifer D. Wu,1,6 Aissatou Ba,1 Anthony J. Alberg,1,2 Elizabeth G. Hill1,2 Abstract African Americans (AAs) compared to European Americans (EAs) have poorer stage specific survival from colorectal cancer (CRC), especially among younger patients. We used population-based Surveillance, Epidemiology, and End Results (SEER) registry data to evaluate the impact of race, age on advanced stage CRC survival. We found that younger AAs (vs. EAs) had a significantly higher risk of death which was attenuated in older patients. Introduction: African Americans (AAs) compared with European Americans (EAs) have poorer stage-specific survival from colorectal cancer (CRC). Recent reports have indicated that the racial difference in survival has worsened over time, especially among younger patients. To better characterize this association, we used population-based Surveillance, Epidemiology, and End Results registry data to evaluate the effect of race on stage IV CRC survival in patients aged < 50 and 50 years. Patients and Methods: The population included 16,782 patients diagnosed with stage IV colon and rectal adenocarcinoma from January 1, 2004 and December 31, 2011. Cox proportional hazards regression was used to evaluate the association between race and other prognostic factors and the risk of death in each age group. Results: Younger AAs compared with EAs had a greater prevalence of proximal CRC at diagnosis, a factor associated with a significantly greater risk of death in both races. Among patients < 50 years old, AAs had a greater risk of death compared with EAs (hazard ratio, 1.35; 95% confidence interval, 1.20-1.51), which was attenuated in patients 50 years of age (hazard ratio, 1.10; 95% confidence interval, 1.04-1.16); P for interaction ¼ .01. Conclusion: The results revealed poor overall survival for AAs compared with EAs, especially for those < 50 years of age. The greater prevalence of proximal CRC at diagnosis among younger AAs (vs. EAs) might contribute to the racial difference in survival. Future studies are needed to understand how the colonic location affects the efficacy of treatment regimens. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Colon cancer, Early onset, Metastatic, Race, Survival
Introduction African Americans (AAs) compared with European Americans (EAs) have a greater colorectal cancer (CRC) incidence and poorer stage-specific survival.1,2 For most Americans, survival has improved 1
Hollings Cancer Center Department of Public Health Sciences Department of Pathology and Laboratory Medicine 4 Department of Medicine 5 Division of Hematology and Oncology, Department of Medicine 6 Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 2 3
Submitted: Jul 21, 2016; Revised: Sep 24, 2016; Accepted: Nov 14, 2016 Address for correspondence: Kristin Wallace, PhD, Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425 E-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2016.11.006
significantly during the past 20 years; however, for AAs, the rates have improved more slowly, especially for those with advanced disease stages.2,3 Also, younger AAs appear to be more vulnerable to CRC, because the relative difference in survival by race has been more pronounced in younger than in older patients.4-6 A primary reason for the improvement in stage IV CRC survival has been the better treatment options available. Since the introduction of combination chemotherapy and biologic agents in 2004, the median survival for stage IV CRC has increased from approximately 10 months in the mid-1990s to 20 months in 2008.7,8 In our previous study,4 we found that the racial disparity in advanced CRC had worsened over time, especially among younger age AAs compared with EAs with a diagnosis of CRC after 2003. One of the reasons for the poorer survival for AAs compared with EAs might be
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Race and Colorectal Cancer Survival because of the greater prevalence of proximal neoplasia in AAs,9-14 which is often associated with worse survival,15-18 especially in the context of metastatic disease. A recent investigation has found that treatment with biologic agents appears to be less effective in patients with proximal CRC compared with distal or rectal cancer.19 In our previous study, we had a limited number of cases < 50 years old and only 2 years of CRC case data after the introduction of the biologic therapies. Therefore, in the present analysis, we took advantage of the population-based Surveillance, Epidemiology, and End Results (SEER) registry data to investigate racial differences in CRC survival in younger (< 50 years) and older ( 50 years) patients with stage IV CRC diagnosed after 2003. Our analysis focused on stage IV cases from 2004 to 2011 for several reasons, including similar standard recommended treatment guidelines, a large relative difference in survival by race in stage IV CRC, and a high proportion of patients dying of CRC, rather than of competing causes. We also investigated whether clinical or pathologic factors at diagnosis (colonic location, histologic type, grade, elevated carcinoembryonic antigen [CEA]) differ by race and help to explain the differences observed in survival.
Patients and Methods Study Population The SEER Program of the National Cancer Institute is a population-based data system that collects cancer incidence in 18 regions within the United States. The mortality data reported by SEER are provided by the National Center for Health Statistics. For our analysis, the study population included adults ( 18 years old) with pathologically documented colon and rectal adenocarcinoma in the SEER registry diagnosed from January 1, 2004 to December 31, 2011 with positive follow-up time (> 0 days). SEER codes the cancer stage using the SEER staging criteria, defined as local, regional, or distant disease. We further limited the study population to include only patients who presented with distant disease (equivalent to TNM stage IV), which includes disease detected in the lymph nodes or other distant sites. We used the following additional case selection criteria to further define the study population: single primary tumor only; AA or EA race; tumor histologic type reported as adenocarcinoma not otherwise specified, mucinous adenocarcinoma, or signet ring cell adenocarcinoma; tumor grade reported as well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated (grade I, II, III, or IV, respectively); colonic location proximal (cecum, ascending colon, or hepatic flexure transverse colon); distal (splenic flexure, descending colon, or sigmoid colon); or rectal (rectosigmoid or rectum); and CEA serum level at diagnosis, either normal or elevated. Patients with variable values other than those specified (including missing or unknown values) were excluded from the final analysis set (Figure 1).
Statistical Analysis
2
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Statistical analysis was performed using SAS, version 9.4, and R, version 3.1.2.20 All analyses were performed using data stratified by age at diagnosis (< 50 vs. 50 years) and gender, with the primary comparisons within strata being those between EA and AA patients. Univariate associations of demographic and clinical characteristics with race were evaluated using Wilcoxon rank-sum tests for continuous variables and c2 tests for categorical variables.
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Overall survival was calculated as the interval in months from diagnosis of distant stage CRC to death from any cause. The survival times for patients alive as of December 31, 2011 were censored at the end of the follow-up period. Kaplan-Meier methods were used to estimate the median survival time, 5-year survival probabilities, and corresponding 95% confidence intervals (CIs). Comparisons between survival curves were performed using log-rank tests. The factors’ associations with survival were evaluated by fitting Cox proportional hazards (CPH) regression models. Because of the significant interaction between age category and race, we fit separate CPH regression models for the 2 age groups. The P value for interaction for both univariate and multivariable CPH models was 0.01. We first fit univariate CPH models to investigate the unadjusted associations between demographic and clinical characteristics and survival. We then fit multivariable CPH models with the independent variables of age (as a continuous variable), race, and gender (model 1) and, also with the colonic location, tumor grade, histologic type, and CEA elevation status (model 2). Finally, we further stratified by gender and fit all univariate and multivariable CPH models described (with gender removed as an independent variable). The associations were summarized using hazard ratios (HRs) and the corresponding 95% CIs.
Results The population included 14,182 EA patients (85%) and 2600 AA patients (15%), for 16,782 patients with data available for analysis. Of the 2735 patients aged < 50 years, 82% were EAs and 18% AAs. Of the 14,047 patients aged 50, 85% were EAs and 15% AAs. Also, of the 8932 men, 86% were EAs and 14% AAs, and of the 7750 women, 83% were EAs and 17% AAs. Overall, the survival was better for the younger than for the older patients, irrespective of race. Among the AA group, those aged < 50 years had a median survival of 20 months (range, 18-22 months) compared with 13 months (range, 12-14 months) for those aged 50 years. Similarly, in the EA group, the median survival for the younger group was 25 months (range, 24-26 months) compared with 14 months (range, 14-15 months) for the older group.
Patients Aged < 50 Years
Overall, 19% of the AA patients with CRC were < 50 years old compared with 16% of the EA patients (Table 1). In those aged < 50 years, several pathologic features differed significantly at diagnosis by race. These included tumor location, tumor grade, and CEA level. Specifically, the prevalence of proximal CRC was 17% greater in AA women than in EA women and 9% greater in AA men than in EA men. In contrast, the incidence of rectal cancer was 10% lower in AA women than in EA women and 9% lower in AA men than in EA men. CEA positivity was 6% greater in both AA men and women than in EA men and women. The prevalence of high-grade tumors in AA and EA men was 24% and 33%, respectively. No significant differences were observed in histologic types. The median survival was lower in AAs than in EAs (Table 2, Figure 2). Relative to EA women, AA women had significantly worse survival (18 months vs. 25 months) and lower 5-year survival rates (0.12 vs. 0.18; log-rank P < .0001). For both AA
Kristin Wallace et al Figure 1 Flowchart Detailing Exclusion Criteria and Number of Patients Dropped for Each Clinical or Pathologic Variable
Pa ents ≥18 yrs of age w/Stage IV Colorectal Cancer w/posi ve follow-up me diagnosed between years 2004-2011
Black or White
NO
YES
3,965
44,678
Posi ve Histology w/one primary tumor
NO
YES
11,237
33,441
Adenocarcinoma (NOS, Mucinous, Signet- Cell)
NO
YES
29,054
4,387
Grades I-IV
NO
YES
4,213
24,841
CEA level at diagnosis
NO
8,059
YES Study Popula on 16,782
< 50 years of age 2,735
≥ 50 years of age 14,047
Abbreviations: CEA ¼ carcinoembryonic antigen; NOS ¼ not otherwise specified.
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Race and Colorectal Cancer Survival Table 1 Univariate Associations of Demographic and Clinical Characteristics With Gender and Race Stratified by Age Characteristic
Male
P Valuea
Female
P Valuea
Age <50-y group Patients (n)
1467
1268
EA
1204
1033
AA
263
Age (y) 44 (18-49)
44 (18-49)
AA
45 (19-49)
44 (21-49)
416 (35)
432 (42)
AA
91 (35)
83 (35)
281 (23)
272 (26)
AA
85 (32)
100 (43)
507 (42)
329 (32)
AA
87 (33)
52 (22)
Tumor grade
.005 708 (69)
AA
200 (76)
172 (73)
EA
396 (33)
325 (31)
AA
63 (24)
Adeno NOS 1073 (89)
919 (89)
AA
235 (89)
213 (91)
86 (7)
74 (7)
AA
19 (7)
17 (7)
45 (4)
AA
9 (3)
CEA
5 (2) .05
Normal EA
240 (20)
216 (21)
AA
36 (14)
36 (15)
EA
964 (80)
817 (79)
AA
227 (86)
199 (85)
Patients
7565
6482
EA
6534
5411
AA
1031
Elevated
Age 50-y group
4
-
1071 <.0001
Age (y)
<.0001
EA
65 (50-98)
69 (50-103)
AA
62 (50-94)
65 (50-108)
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2607 (48)
AA
447 (43)
572 (53)
EA
2006 (31)
1269 (23)
AA
251 (24)
178 (17) <.0001
<.0001
EA
4623 (71)
3649 (67)
AA
793 (77)
829 (77)
EA
1911 (29)
1762 (33)
AA
238 (23)
242 (23) <.0001
.10
EA
5913 (91)
4852 (90)
AA
977 (95)
965 (90)
EA
477 (7)
453 (8)
AA
43 (4)
95 (9)
EA
144 (2)
106 (2)
AA
11 (1)
11 (1) <.0001
<.0001
EA
1293 (20)
1024 (19)
AA
136 (13)
128 (12)
EA
5241 (80)
4387 (81)
AA
895 (87)
943 (88)
Elevated
40 (4) .02
2499 (38)
Normal
Signet cell EA
EA
CEA
Mucinous EA
321 (30)
Signet cell .43
EA
1535 (28)
333 (32)
Mucinous
63 (27) .97
2029 (31)
AA
Adeno NOS
High
Histologic type
EA
Histologic type
Low 808 (67)
<.0001
High
.16
EA
P Valuea
Low
Rectal EA
<.0001
Tumor grade
Proximal EA
Female
Rectal
Distal EA
P Valuea
Distal
<.0001
.004
Male
Colonic location
.14
EA Colonic location
Characteristic
Proximal
235 .51
Table 1 Continued
Data presented as median (range) or n (%); column percentages might not total 100% because of rounding. Abbreviations: AA ¼ African American; Adeno ¼ adenocarcinoma; CEA ¼ carcinoembryonic antigen; EA ¼ European American; NOS ¼ not otherwise specified. a P value derived from Wilcoxon’s rank sum test for ageerace association and c2.test for all others.
and EA women, the median survival was lowest for those with proximal neoplasia (Table 2). AA women with distal and rectal disease experienced worse survival than EA women (21 vs. 27 months with distal disease; 17 vs. 29 months with rectal disease). Using stratified Cox regression analysis (Table 3), AA women had a significantly greater risk of death compared with EA women (HR, 1.48; 95% CI, 1.25-1.75). Adjustment for clinicopathologic covariates slightly attenuated the risk (HR, 1.39; 95% CI, 1.17-1.65). Overall, young AA men experienced worse survival compared with young EA men (log-rank P ¼ .006), with lower median survival
Kristin Wallace et al Table 2 Kaplan-Meier Median Survival Time and Survival Probability Estimates Stratified by Age, Gender, Colonic Location, and Race Age
Gender
Colonic Location
Male
Distal
Race
Patients (n)
Events (n)
Prevalence (%)
EA AA EA AA EA AA EA AA EA AA EA AA EA AA EA AA
416 91 281 85 507 87 1204 263 432 83 272 100 329 52 1033 235
241 65 191 60 312 60 744 185 257 58 196 69 188 41 641 168
35 35 23 32 42 33
EA AA EA AA EA AA EA AA EA AA EA AA EA AA EA AA
2029 333 2499 447 2006 251 6534 1031 1535 321 2607 572 1269 178 5411 1071
1450 250 1957 358 1407 186 4814 794 1107 237 2079 450 942 134 4128 821
31 32 38 43 31 24
Median Survival (mo)
5-y Survival Probability (%)
<50 y
Proximal Rectal Overall Female
Distal Proximal Rectal Overall
42 35 26 43 32 22
26 25 19 18 26 21 24 22 27 21 17 15 29 17 25 18
(23-31) (20-31) (16-23) (15-25) (23-29) (14-23) (23-26) (19-24) (25-32) (18-27) (14-20) (12-20) (27-33) (15-22) (24-27) (16-20)
0.20 0.02 0.16 0.09 0.18 0.14 0.18 0.07 0.17 0.14 0.17 0.09 0.21 0.12 0.18 0.12
(0.15-0.27) (0.00-0.14) (0.11-0.22) (0.03-0.22) (0.14-0.24) (0.06-0.31) (0.15-0.22) (0.04-0.14) (0.13-0.23) (0.07-0.28) (0.12-0.23) (0.04-0.23) (0.16-0.29) (0.05-0.27) (0.15-0.22) (0.08-0.19)
19 14 12 11 18 15 16 13 17 16 10 13 14 15 13 14
(17-20) (12-18) (11-12) (9-13) (17-20) (11-17) (15-16) (11-14) (16-19) (12-20) (9-11) (11-14) (13-16) (11-21) (12-13) (12-15)
0.12 0.10 0.08 0.05 0.11 0.08 0.10 0.07 0.13 0.07 0.09 0.07 0.10 0.07 0.10 0.07
(0.10-0.14) (0.06-0.15) (0.07-0.10) (0.03-0.09) (0.09-0.13) (0.04-0.13) (0.09-0.11) (0.05-0.10) (0.11-0.15) (0.04-0.13) (0.08-0.11) (0.05-0.11) (0.08-0.13) (0.03-0.16) (0.09-0.11) (0.05-0.10)
50 y Male
Distal Proximal Rectal Overall
Female
Distal Proximal Rectal Overall
28 30 48 53 23 17
Data in parentheses are 95% confidence intervals. Abbreviations: AA ¼ African American; EA ¼ European American.
(22 vs. 25 months) and 5-year survival probabilities (0.07 vs. 0.18; Table 2). Similar to women, the young men of both races with proximal CRC had the lowest survival. In young men, the greatest difference in survival was observed with rectal cancer when comparing AA and EA men (21 vs. 26 months). Stratified Cox regression analysis revealed that AA men had a greater risk of mortality than EA men (HR, 1.25; 95% CI, 1.06-1.47; Table 3), even after adjustment for clinical covariates (HR, 1.29; 95% CI, 1.10-1.52).
Patients Aged 50 Years The personal characteristics and clinical and pathologic features assessed at diagnosis differed by race in those aged 50 years (Table 1). The average age at diagnosis was 3 years younger for the AA men and 4 years younger for the AA women compared with EA men and women, respectively. Similar to observations in patients aged < 50 years, the older AA men and women were more likely to
have proximal tumors and greater CEA positivity but less likely to have high-grade lesions. Older AA women had a 5% greater prevalence of proximal tumors than did EA women. However, this difference was appreciably lower than the 17% difference observed in the younger cohort. Overall, the median survival was slightly greater for older EA patients than for AA patients (Table 2, Figure 2). Most of the racial difference in survival in those aged > 50 years was confined to the men. For example, the median survival did not differ by race in women aged > 50 years (13 months in EA women vs. 14 months in AA women). The 5-year survival probability was only slightly greater in older EA women relative to AA women (0.10 vs. 0.07). Furthermore, the risk of death did not differ significantly by race in older women (HR, 1.03; 95% CI, 0.95-1.11; Table 3). Adjustment for the multiple prognostic factors at diagnosis increased the risk by 6% (HR, 1.09; 95% CI, 1.01-1.18).
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Race and Colorectal Cancer Survival Figure 2 Survival Distributions Were Analyzed Using Survival Probability in Months From Diagnosis for (A) Men Aged < 50 Years, (B) Women Aged < 50 Years, (C) Men Aged ‡ 50 Years, and (D) Women Aged ‡ 50 Years
Abbreviations: AA ¼ African American; EA ¼ European American.
In contrast, the median survival for older AA men was poorer than that for EA men (13 months vs. 16 months). Likewise, the 5-year survival probability was lower for older AA men than for EA men (0.07 vs. 0.10). From the stratified CPH regression models, the univariate analysis revealed a greater risk of death for older AA men than for EA men (HR, 1.18; 95% CI, 1.09-1.27; Table 3). Adjustment for covariates led to an increase in this racial difference (HR, 1.24; 95% CI, 1.15-1.34).
Discussion
6
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Our analysis using the population-based SEER registry data revealed poorer stage-specific survival for AA patients than for EA patients, especially for those aged < 50 years. Overall, we observed that CRC was diagnosed in 19% of AA patients who were aged < 50 years compared with 16% of EA patients. Significantly worse survival was observed for AA men in both younger and older age groups; however, the largest racial difference in survival was found for AA women aged < 50 years, who had a 48% greater risk of death than younger EA women. In contrast, survival was poor for all women 50 years old. The prevalence of several poor prognostic factors at diagnosis differed by race, age, and gender and appears to explain some of the reasons for the differences in survival when stratified by race and age. AA patients of all ages had a greater
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prevalence of proximal tumors and higher CEA level compared with EA patients but a lower prevalence of high-grade tumors. Much of the difference in CRC survival by race in younger women appeared to result from the difference in the prevalence of proximal neoplasia at diagnosis. In summary, our findings highlight the importance of considering the patient’s age, gender, and colonic location when assessing the differences by race in stage IV CRC outcomes. CRC is the second leading cause of cancer-related death yet one of the most preventable and treatable cancers when identified in the early stages, with 90% survival at 5 years compared with < 20% for stage IV cases. Despite recommendations by some physician organizations to begin screening earlier in AAs,21,22 others have argued that efforts should be directed toward increasing the screening rates in those aged 50 years,23 because of the scarcities of resources and the much greater prevalence of disease in older patients. In the case of the present SEER cohort with stage IV CRC, approximately one sixth of the cases were diagnosed before 50 years of age. Moreover, the average age at diagnosis for the younger patients was 45 years for AA men, 44 years for EA men, and 44 years for both AA and EA women. From a public health perspective, screening younger AAs should be considered, regardless of the underlying etiology, given the poor survival and high prevalence of poor prognostic factors such as a proximal location.
Kristin Wallace et al Table 3 Summary of Results From Cox Proportional Hazards Regression Models Age <50 y Male (n [ 1467) Variable Agea
Model 1
Model 2
Age ‡50 y Female (n [ 1268)
Model 1
Male (n [ 7565)
Model 2
Model 1
Model 2
Female (n [ 6482) Model 1
Model 2
0.89 (0.80-1.00) 0.94 (0.84-1.05) 0.96 (0.86-1.07) 0.97 (0.87-1.08) 1.33 (1.30-1.37) 1.34 (1.30-1.37) 1.39 (1.35-1.42) 1.37 (1.34-1.42)
Race EA AA
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.25 (1.06-1.47) 1.29 (1.10-1.52) 1.48 (1.25-1.75) 1.39 (1.17-1.65) 1.18 (1.09-1.27) 1.24 (1.15-1.34) 1.03 (0.95-1.11) 1.09 (1.01-1.18)
Colonic location Distal
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
Proximal
1.30 (1.10-1.54) 1.17 (0.99-1.40) 1.46 (1.24-1.72) 1.34 (1.13-1.58) 1.36 (1.28-1.45) 1.27 (1.19-1.35) 1.35 (1.26-1.44) 1.17 (1.09-1.25)
Rectal
1.05 (0.90-1.22) 1.07 (0.92-1.24) 0.96 (0.81-1.14) 1.01 (0.85-1.19) 0.98 (0.92-1.05) 1.04 (0.97-1.11) 1.06 (0.98-1.15) 1.03 (0.95-1.12)
Grade Low High
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.63 (1.42-1.86) 1.56 (1.35-1.79) 1.49 (1.29-1.72) 1.36 (1.17-1.59) 1.46 (1.38-1.55) 1.40 (1.32-1.49) 1.48 (1.40-1.58) 1.48 (1.39-1.57)
Histologic type Adeno NOS
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
Mucinous
1.32 (1.04-1.67) 1.30 (1.02-1.66) 1.11 (0.86-1.43) 1.06 (0.82-1.37) 0.98 (0.89-1.09) 0.93 (0.84-1.03) 0.98 (0.88-1.08) 0.93 (0.84-1.03)
Signet cell
2.48 (1.84-3.35) 2.05 (1.49-2.82) 2.16 (1.55-2.99) 1.90 (1.35-2.68) 1.80 (1.52-2.14) 1.51 (1.27-1.80) 1.41 (1.16-1.72) 1.22 (1.00-1.50)
CEA Normal Elevated
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.37 (1.15-1.62) 1.55 (1.30-1.85) 1.67 (1.38-2.01) 1.70 (1.41-2.05) 1.43 (1.34-1.54) 1.55 (1.45-1.67) 1.57 (1.45-1.70) 1.71 (1.58-1.85)
Data presented as hazard ratio (95% confidence interval). Abbreviations: AA ¼ African American; Adeno ¼ adenocarcinoma; CEA ¼ carcinoembryonic antigen; EA ¼ European American; Model 1 ¼ univariate; Model 2 ¼ multivariable (covariates included age, race, colonic location, tumor grade, histologic type, and CEA); NOS ¼ not otherwise specified. a Hazard ratio and 95% confidence interval for age correspond to 10-y increment.
The results of the present investigation mirror earlier reports showing that the survival differences were most pronounced by race for younger patients.4,5,24 In our earlier investigation, using the South Carolina Central Cancer Registry data, we explored the associations between race, age, and clinicopathologic features and stage IV CRC survival. The multivariable proportional hazards regression analysis showed that AA patients compared with EA patients had a significantly greater risk of death after controlling for age, gender, year of diagnosis, and first-line chemotherapy use. Just as in the present analysis, we observed a significant interaction between race and age (P ¼ .04) on survival. Among AA patients versus EA patients aged < 50 years, the adjusted HR was 1.34 (95% CI, 1.061.71). The magnitude of the HR for patients aged < 50 years was similar to the adjusted HR found in the present study (HR, 1.33; 95% CI, 1.18-1.49). The reason for the greater risk of death in younger patients is clearly complex but was due, at least in part, to the greater prevalence of proximal CRC in younger AA patients compared with younger EA patients (Table 2). Similar to these results, many others25-29 have reported a greater prevalence of proximal or advanced proximal neoplasia, especially microsatellite stable CRC in AA patients compared with EA patients. A proximal colonic location outside of the context of microsatellite instability-high CRC has been associated with greater mortality, especially among stage IV CRC patients.15,17,30,31 Recent evidence has also documented a poorer response to treatment in patients with proximal CRC.19 The racial difference in survival by race and gender differed in the younger and older patients. As reported, a marked difference was
found in the prevalence of proximal CRC in women aged < 50 years (þ17% for AA women) but only a 5% difference by race was found for those aged 50 years. The reasons for the racial difference in survival among the younger women are not known but might reflect differences in the hormonal signatures by race. Younger EA women compared with younger AA women have higher estrogen levels,32-34 which could contribute to a lower prevalence of proximal neoplasia in younger women. Recently, a large prospective study reported a strong inverse association between endogenous estrogen levels and the risk of CRC, especially for colon cancer compared with rectal cancer.35 One possibility is that estrogen receptor expression loss results in more aggressive tumor behavior. In a murine model, the loss of estrogen receptor expression in the proximal colon led to crypt fission and reduced wound healing,36 factors associated with increased tumor prevalence and growth. Moreover, poorer survival has been observed in younger AA women compared with EA women with breast cancer, which might be explained by the greater proportion of poor prognostic ER breast cancer tumors in AA women.37 The poorer survival in younger AA women in the present study was similar to what we observed in our previous analysis.4 Racial differences in initiation and adherence to standard treatment of CRC might contribute to the stage-specific survival differences. AA patients historically have been less likely to receive the standard recommended therapy and to refuse therapy at a greater rate.38 Although data on systemic therapy use are not available from the SEER data set, the available agents (capecitabine, 5-fluorouracil,
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Race and Colorectal Cancer Survival irinotecan, oxaliplatin, bevacizumab, cetuximab) for the treatment of stage IV CRC remained consistent from 2004 to 2011, aside from the addition of panitumumab in 2006 and, more importantly, the restriction of epidermal growth factor receptoretargeted therapies to KRAS wild-type tumors by 2008.39 AA patients are more likely than EA patients to have KRAS mutant tumors6,29 and as a whole would be expected to derive less benefit from epidermal growth factor receptoretargeted therapies. However, no notable differences in HRs for race were observed when we analyzed the study periods separately (ie, 2004-2007 vs. 2008-2011). AA patients are less likely than EA patients to undergo surgical interventions for nonmetastatic colon and rectal cancer,38,40,41 raising the possibility that metastectomy rates might differ by race. To our knowledge, only 1 previous study has evaluated metastectomy rates by race and reported no differences.42 However, 2 large studies42,43 found that AA patients had significantly lower response rates to therapy, which could reduce the likelihood of undergoing resection. The strengths of our study included the study of a large, racially diverse population of patients with advanced-stage CRC with careful characterization of the demographic and pathologic characteristics and vital status. However, we also recognize its limitations. First, we had no data on patient-level factors (eg, comorbid conditions or lifestyle and behaviors) or treatment regimen data, which could have confounded or modified the association between race and CRC survival. These results point to the need for detailed studies identifying the risk factors for poor prognostic signatures and patient-level, clinical, molecular, and treatment-related data to help advance our understanding of the racial disparity in CRC survival.
Conclusion Using the large population-based SEER data set, we have shown that AA patients with stage IV CRC have greater mortality than EA patients, in particular, those aged < 50 years. These data suggest greater emphasis is needed for CRC screening of younger AA individuals and, further, raise the possibility that national guidelines for CRC screening should be modified, especially for AA women.
Clinical Practice Points Several previous investigations have detailed a racial disparity in
8
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CRC survival, yet the reasons for this remain incompletely understood. The greater rates of death for AA compared with EA patients have persisted despite adjustment for common confounding variables such as gender, age, and socioeconomic status. Our results suggest that the racial difference in survival might be influenced by differences in the prevalence of proximal and rectal CRC at diagnosis, because survival among both AA patients and EA patients with proximal stage IV CRC disease is poor. Future research is needed to understand why AAs develop proximal neoplasia at a younger age; we found a 17% difference in the prevalence of proximal CRCs in younger AA women compared with younger EA women but only a 5% difference by race among women aged 50 years. A better understanding of how to improve the treatment response in patients with stage IV proximal CRC is also needed.
Clinical Colorectal Cancer Month 2016
Acknowledgments This work was supported by the National Cancer Institute (NCI) by way of the Hollings Cancer Center NCI Cancer Center Support Grant (grant P30 CA138313) and a K07 Career Development Award to K.W. (grant K07CA151864-01A1).
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin 2014; 64:104-17. 2. Robbins AS, Siegel RL, Jemal A. Racial disparities in stage-specific colorectal cancer mortality rates from 1985 to 2008. J Clin Oncol 2012; 30:401-5. 3. Soneji S, Iyer SS, Armstrong K, Asch DA. Racial disparities in stage-specific colorectal cancer mortality: 1960-2005. Am J Public Health 2010; 100:1912-6. 4. Wallace K, Hill EG, Lewin DN, et al. Racial disparities in advanced-stage colorectal cancer survival. Cancer Causes Control 2013; 24:463-71. 5. Andaya AA, Enewold L, Zahm SH, et al. Race and colon cancer survival in an equalaccess health care system. Cancer Epidemiol Biomarkers Prev 2013; 22:1030-6. 6. Yoon HH, Shi Q, Alberts SR, et al. Racial differences in BRAF/KRAS mutation rates and survival in stage III colon cancer patients. J Natl Cancer Inst 2015; 107. http://dx.doi.org/10.1093/jnci/djv186. 7. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med 2005; 352:476-87. 8. Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 2009; 27:3677-83. 9. Shavers VL. Racial/ethnic variation in the anatomic subsite location of in situ and invasive cancers of the colon. J Natl Med Assoc 2007; 99:733-48. 10. Thornton JG, Morris AM, Thornton JD, Flowers CR, McCashland TM. Racial variation in colorectal polyp and tumor location. J Natl Med Assoc 2007; 99:723-8. 11. Lieberman DA, Holub JL, Moravec MD, Eisen GM, Peters D, Morris CD. Prevalence of colon polyps detected by colonoscopy screening in asymptomatic black and white patients. JAMA 2008; 300:1417-22. 12. Sharma S, O’Keefe SJ. Environmental influences on the high mortality from colorectal cancer in African Americans. Postgrad Med J 2007; 83:583-9. 13. Ashktorab H, Nouraie M, Hosseinkhah F, Lee E, Rotimi C, Smoot D. A 50-year review of colorectal cancer in African Americans: implications for prevention and treatment. Dig Dis Sci 2009; 54:1985-90. 14. Wallace K, Grau MV, Ahnen D, et al. The association of lifestyle and dietary factors with the risk for serrated polyps of the colorectum. Cancer Epidemiol Biomarkers Prev 2009; 18:2310-7. 15. Meguid RA, Slidell MB, Wolfgang CL, Chang DC, Ahuja N. Is there a difference in survival between right- versus left-sided colon cancers? Ann Surg Oncol 2008; 15: 2388-94. 16. O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004; 96:1420-5. 17. Wray CM, Ziogas A, Hinojosa MW, Le H, Stamos MJ, Zell JA. Tumor subsite location within the colon is prognostic for survival after colon cancer diagnosis. Dis Colon Rectum 2009; 52:1359-66. 18. Kalady MF, de Campos-Lobato LF, Stocchi L, et al. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg 2009; 250:582-9. 19. Boisen MK, Johansen JS, Dehlendorff C, et al. Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer. Ann Oncol 2013; 24:2554-9. 20. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2014. 21. Rex DK, Johnson DA, Anderson JC, et al. American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol 2009; 104:739-50. 22. Qaseem A, Denberg TD, Hopkins RH Jr, et al. Screening for colorectal cancer: a guidance statement from the American College of Physicians. Ann Intern Med 2012; 156:378-86. 23. Ahnen DJ, Wade SW, Jones WF, et al. The increasing incidence of young-onset colorectal cancer: a call to action. Mayo Clin Proc 2014; 89:216-24. 24. Wallace K, Sterba KR, Gore E, et al. Prognostic factors in relation to racial disparity in advanced colorectal cancer survival. Clin Colorectal Cancer 2013; 12:287-93. 25. Corley DA, Jensen CD, Marks AR, et al. Variation of adenoma prevalence by age, sex, race, and colon location in a large population: implications for screening and quality programs. Clin Gastroenterol Hepatol 2013; 11:172-80. 26. Lebwohl B, Capiak K, Neugut AI, Kastrinos F. Risk of colorectal adenomas and advanced neoplasia in Hispanic, black and white patients undergoing screening colonoscopy. Aliment Pharmacol Ther 2012; 35:1467-73. 27. Lieberman DA, Williams JL, Holub JL, et al. Race, ethnicity, and sex affect risk for polyps >9 mm in average-risk individuals. Gastroenterology 2014; 147:351-8.
Kristin Wallace et al 28. Carethers JM, Murali B, Yang B, et al. Influence of race on microsatellite instability and CD8þ T cell infiltration in colon cancer. PLoS One 2014; 9:e100461. 29. Xicola RM, Gagnon M, Clark JR, et al. Excess of proximal microsatellite-stable colorectal cancer in African Americans from a multiethnic study. Clin Cancer Res 2014; 20:4962-70. 30. Benedix F, Kube R, Meyer F, et al. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum 2010; 53:57-64. 31. Suttie SA, Shaikh I, Mullen R, Amin AI, Daniel T, Yalamarthi S. Outcome of right- and left-sided colonic and rectal cancer following surgical resection. Colorectal Dis 2011; 13:884-9. 32. Kim C, Golden SH, Mather KJ, et al. Racial/ethnic differences in sex hormone levels among postmenopausal women in the Diabetes Prevention Program. J Clin Endocrinol Metab 2012; 97:4051-60. 33. Lamon-Fava S, Barnett JB, Woods MN, et al. Differences in serum sex hormone and plasma lipid levels in Caucasian and African-American premenopausal women. J Clin Endocrinol Metab 2005; 90:4516-20. 34. Randolph JF Jr, Sowers M, Gold EB, et al. Reproductive hormones in the early menopausal transition: relationship to ethnicity, body size, and menopausal status. J Clin Endocrinol Metab 2003; 88:1516-22. 35. Murphy N, Strickler HD, Stanczyk FZ, et al. A prospective evaluation of endogenous sex hormone levels and colorectal cancer risk in postmenopausal women. J Natl Cancer Inst 2015; 107. http://dx.doi.org/10.1093/jnci/djv210.
36. Hasson RM, Briggs A, Carothers AM, et al. Estrogen receptor alpha or beta loss in the colon of Min/þ mice promotes crypt expansion and impairs TGFbeta and HNF3beta signaling. Carcinogenesis 2014; 35:96-102. 37. Wray CJ, Phatak UR, Robinson EK, et al. The effect of age on race-related breast cancer survival disparities. Ann Surg Oncol 2013; 20:2541-7. 38. Esnaola NF, Gebregziabher M, Finney C, Ford ME. Underuse of surgical resection in black patients with nonmetastatic colorectal cancer: location, location, location. Ann Surg 2009; 250:549-57. 39. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359:1757-65. 40. Temple LK, Hsieh L, Wong WD, Saltz L, Schrag D. Use of surgery among elderly patients with stage IV colorectal cancer. J Clin Oncol 2004; 22:3475-84. 41. Esnaola NF, Stewart AK, Feig BW, Skibber JM, Rodriguez-Bigas MA. Age-, race-, and ethnicity-related differences in the treatment of nonmetastatic rectal cancer: a patterns of care study from the national cancer data base. Ann Surg Oncol 2008; 15: 3036-47. 42. Sanoff HK, Sargent DJ, Green EM, McLeod HL, Goldberg RM. Racial differences in advanced colorectal cancer outcomes and pharmacogenetics: a subgroup analysis of a large randomized clinical trial. J Clin Oncol 2009; 27:4109-15. 43. Polite BN, Dignam JJ, Olopade OI. Colorectal cancer and race: understanding the differences in outcomes between African Americans and whites. Med Clin North Am 2005; 89:771-93.
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Racial Differences in Stage IV Colorectal Cancer Survival in Younger and Older Patients Kristin Wallace,1,2 Allan DeToma,1,2 David N. Lewin,1,3 Shaoli Sun,1,3 Don Rockey,4 Carolyn D. Britten,1,5 Jennifer D. Wu,1,6 Aissatou Ba,1 Anthony J. Alberg,1,2 Elizabeth G. Hill1,2 Abstract African Americans (AAs) compared to European Americans (EAs) have poorer stage specific survival from colorectal cancer (CRC), especially among younger patients. We used population-based Surveillance, Epidemiology, and End Results (SEER) registry data to evaluate the impact of race, age on advanced stage CRC survival. We found that younger AAs (vs. EAs) had a significantly higher risk of death which was attenuated in older patients. Introduction: African Americans (AAs) compared with European Americans (EAs) have poorer stage-specific survival from colorectal cancer (CRC). Recent reports have indicated that the racial difference in survival has worsened over time, especially among younger patients. To better characterize this association, we used population-based Surveillance, Epidemiology, and End Results registry data to evaluate the effect of race on stage IV CRC survival in patients aged < 50 and 50 years. Patients and Methods: The population included 16,782 patients diagnosed with stage IV colon and rectal adenocarcinoma from January 1, 2004 and December 31, 2011. Cox proportional hazards regression was used to evaluate the association between race and other prognostic factors and the risk of death in each age group. Results: Younger AAs compared with EAs had a greater prevalence of proximal CRC at diagnosis, a factor associated with a significantly greater risk of death in both races. Among patients < 50 years old, AAs had a greater risk of death compared with EAs (hazard ratio, 1.35; 95% confidence interval, 1.20-1.51), which was attenuated in patients 50 years of age (hazard ratio, 1.10; 95% confidence interval, 1.04-1.16); P for interaction ¼ .01. Conclusion: The results revealed poor overall survival for AAs compared with EAs, especially for those < 50 years of age. The greater prevalence of proximal CRC at diagnosis among younger AAs (vs. EAs) might contribute to the racial difference in survival. Future studies are needed to understand how the colonic location affects the efficacy of treatment regimens. Clinical Colorectal Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Colon cancer, Early onset, Metastatic, Race, Survival
Introduction African Americans (AAs) compared with European Americans (EAs) have a greater colorectal cancer (CRC) incidence and poorer stage-specific survival.1,2 For most Americans, survival has improved 1
Hollings Cancer Center Department of Public Health Sciences Department of Pathology and Laboratory Medicine 4 Department of Medicine 5 Division of Hematology and Oncology, Department of Medicine 6 Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 2 3
Submitted: Jul 21, 2016; Revised: Sep 24, 2016; Accepted: Nov 14, 2016 Address for correspondence: Kristin Wallace, PhD, Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425 E-mail contact: [email protected]
1533-0028/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2016.11.006
significantly during the past 20 years; however, for AAs, the rates have improved more slowly, especially for those with advanced disease stages.2,3 Also, younger AAs appear to be more vulnerable to CRC, because the relative difference in survival by race has been more pronounced in younger than in older patients.4-6 A primary reason for the improvement in stage IV CRC survival has been the better treatment options available. Since the introduction of combination chemotherapy and biologic agents in 2004, the median survival for stage IV CRC has increased from approximately 10 months in the mid-1990s to 20 months in 2008.7,8 In our previous study,4 we found that the racial disparity in advanced CRC had worsened over time, especially among younger age AAs compared with EAs with a diagnosis of CRC after 2003. One of the reasons for the poorer survival for AAs compared with EAs might be
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Race and Colorectal Cancer Survival because of the greater prevalence of proximal neoplasia in AAs,9-14 which is often associated with worse survival,15-18 especially in the context of metastatic disease. A recent investigation has found that treatment with biologic agents appears to be less effective in patients with proximal CRC compared with distal or rectal cancer.19 In our previous study, we had a limited number of cases < 50 years old and only 2 years of CRC case data after the introduction of the biologic therapies. Therefore, in the present analysis, we took advantage of the population-based Surveillance, Epidemiology, and End Results (SEER) registry data to investigate racial differences in CRC survival in younger (< 50 years) and older ( 50 years) patients with stage IV CRC diagnosed after 2003. Our analysis focused on stage IV cases from 2004 to 2011 for several reasons, including similar standard recommended treatment guidelines, a large relative difference in survival by race in stage IV CRC, and a high proportion of patients dying of CRC, rather than of competing causes. We also investigated whether clinical or pathologic factors at diagnosis (colonic location, histologic type, grade, elevated carcinoembryonic antigen [CEA]) differ by race and help to explain the differences observed in survival.
Patients and Methods Study Population The SEER Program of the National Cancer Institute is a population-based data system that collects cancer incidence in 18 regions within the United States. The mortality data reported by SEER are provided by the National Center for Health Statistics. For our analysis, the study population included adults ( 18 years old) with pathologically documented colon and rectal adenocarcinoma in the SEER registry diagnosed from January 1, 2004 to December 31, 2011 with positive follow-up time (> 0 days). SEER codes the cancer stage using the SEER staging criteria, defined as local, regional, or distant disease. We further limited the study population to include only patients who presented with distant disease (equivalent to TNM stage IV), which includes disease detected in the lymph nodes or other distant sites. We used the following additional case selection criteria to further define the study population: single primary tumor only; AA or EA race; tumor histologic type reported as adenocarcinoma not otherwise specified, mucinous adenocarcinoma, or signet ring cell adenocarcinoma; tumor grade reported as well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated (grade I, II, III, or IV, respectively); colonic location proximal (cecum, ascending colon, or hepatic flexure transverse colon); distal (splenic flexure, descending colon, or sigmoid colon); or rectal (rectosigmoid or rectum); and CEA serum level at diagnosis, either normal or elevated. Patients with variable values other than those specified (including missing or unknown values) were excluded from the final analysis set (Figure 1).
Statistical Analysis
2
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Statistical analysis was performed using SAS, version 9.4, and R, version 3.1.2.20 All analyses were performed using data stratified by age at diagnosis (< 50 vs. 50 years) and gender, with the primary comparisons within strata being those between EA and AA patients. Univariate associations of demographic and clinical characteristics with race were evaluated using Wilcoxon rank-sum tests for continuous variables and c2 tests for categorical variables.
Clinical Colorectal Cancer Month 2016
Overall survival was calculated as the interval in months from diagnosis of distant stage CRC to death from any cause. The survival times for patients alive as of December 31, 2011 were censored at the end of the follow-up period. Kaplan-Meier methods were used to estimate the median survival time, 5-year survival probabilities, and corresponding 95% confidence intervals (CIs). Comparisons between survival curves were performed using log-rank tests. The factors’ associations with survival were evaluated by fitting Cox proportional hazards (CPH) regression models. Because of the significant interaction between age category and race, we fit separate CPH regression models for the 2 age groups. The P value for interaction for both univariate and multivariable CPH models was 0.01. We first fit univariate CPH models to investigate the unadjusted associations between demographic and clinical characteristics and survival. We then fit multivariable CPH models with the independent variables of age (as a continuous variable), race, and gender (model 1) and, also with the colonic location, tumor grade, histologic type, and CEA elevation status (model 2). Finally, we further stratified by gender and fit all univariate and multivariable CPH models described (with gender removed as an independent variable). The associations were summarized using hazard ratios (HRs) and the corresponding 95% CIs.
Results The population included 14,182 EA patients (85%) and 2600 AA patients (15%), for 16,782 patients with data available for analysis. Of the 2735 patients aged < 50 years, 82% were EAs and 18% AAs. Of the 14,047 patients aged 50, 85% were EAs and 15% AAs. Also, of the 8932 men, 86% were EAs and 14% AAs, and of the 7750 women, 83% were EAs and 17% AAs. Overall, the survival was better for the younger than for the older patients, irrespective of race. Among the AA group, those aged < 50 years had a median survival of 20 months (range, 18-22 months) compared with 13 months (range, 12-14 months) for those aged 50 years. Similarly, in the EA group, the median survival for the younger group was 25 months (range, 24-26 months) compared with 14 months (range, 14-15 months) for the older group.
Patients Aged < 50 Years
Overall, 19% of the AA patients with CRC were < 50 years old compared with 16% of the EA patients (Table 1). In those aged < 50 years, several pathologic features differed significantly at diagnosis by race. These included tumor location, tumor grade, and CEA level. Specifically, the prevalence of proximal CRC was 17% greater in AA women than in EA women and 9% greater in AA men than in EA men. In contrast, the incidence of rectal cancer was 10% lower in AA women than in EA women and 9% lower in AA men than in EA men. CEA positivity was 6% greater in both AA men and women than in EA men and women. The prevalence of high-grade tumors in AA and EA men was 24% and 33%, respectively. No significant differences were observed in histologic types. The median survival was lower in AAs than in EAs (Table 2, Figure 2). Relative to EA women, AA women had significantly worse survival (18 months vs. 25 months) and lower 5-year survival rates (0.12 vs. 0.18; log-rank P < .0001). For both AA
Kristin Wallace et al Figure 1 Flowchart Detailing Exclusion Criteria and Number of Patients Dropped for Each Clinical or Pathologic Variable
Pa ents ≥18 yrs of age w/Stage IV Colorectal Cancer w/posi ve follow-up me diagnosed between years 2004-2011
Black or White
NO
YES
3,965
44,678
Posi ve Histology w/one primary tumor
NO
YES
11,237
33,441
Adenocarcinoma (NOS, Mucinous, Signet- Cell)
NO
YES
29,054
4,387
Grades I-IV
NO
YES
4,213
24,841
CEA level at diagnosis
NO
8,059
YES Study Popula on 16,782
< 50 years of age 2,735
≥ 50 years of age 14,047
Abbreviations: CEA ¼ carcinoembryonic antigen; NOS ¼ not otherwise specified.
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Race and Colorectal Cancer Survival Table 1 Univariate Associations of Demographic and Clinical Characteristics With Gender and Race Stratified by Age Characteristic
Male
P Valuea
Female
P Valuea
Age <50-y group Patients (n)
1467
1268
EA
1204
1033
AA
263
Age (y) 44 (18-49)
44 (18-49)
AA
45 (19-49)
44 (21-49)
416 (35)
432 (42)
AA
91 (35)
83 (35)
281 (23)
272 (26)
AA
85 (32)
100 (43)
507 (42)
329 (32)
AA
87 (33)
52 (22)
Tumor grade
.005 708 (69)
AA
200 (76)
172 (73)
EA
396 (33)
325 (31)
AA
63 (24)
Adeno NOS 1073 (89)
919 (89)
AA
235 (89)
213 (91)
86 (7)
74 (7)
AA
19 (7)
17 (7)
45 (4)
AA
9 (3)
CEA
5 (2) .05
Normal EA
240 (20)
216 (21)
AA
36 (14)
36 (15)
EA
964 (80)
817 (79)
AA
227 (86)
199 (85)
Patients
7565
6482
EA
6534
5411
AA
1031
Elevated
Age 50-y group
4
-
1071 <.0001
Age (y)
<.0001
EA
65 (50-98)
69 (50-103)
AA
62 (50-94)
65 (50-108)
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2607 (48)
AA
447 (43)
572 (53)
EA
2006 (31)
1269 (23)
AA
251 (24)
178 (17) <.0001
<.0001
EA
4623 (71)
3649 (67)
AA
793 (77)
829 (77)
EA
1911 (29)
1762 (33)
AA
238 (23)
242 (23) <.0001
.10
EA
5913 (91)
4852 (90)
AA
977 (95)
965 (90)
EA
477 (7)
453 (8)
AA
43 (4)
95 (9)
EA
144 (2)
106 (2)
AA
11 (1)
11 (1) <.0001
<.0001
EA
1293 (20)
1024 (19)
AA
136 (13)
128 (12)
EA
5241 (80)
4387 (81)
AA
895 (87)
943 (88)
Elevated
40 (4) .02
2499 (38)
Normal
Signet cell EA
EA
CEA
Mucinous EA
321 (30)
Signet cell .43
EA
1535 (28)
333 (32)
Mucinous
63 (27) .97
2029 (31)
AA
Adeno NOS
High
Histologic type
EA
Histologic type
Low 808 (67)
<.0001
High
.16
EA
P Valuea
Low
Rectal EA
<.0001
Tumor grade
Proximal EA
Female
Rectal
Distal EA
P Valuea
Distal
<.0001
.004
Male
Colonic location
.14
EA Colonic location
Characteristic
Proximal
235 .51
Table 1 Continued
Data presented as median (range) or n (%); column percentages might not total 100% because of rounding. Abbreviations: AA ¼ African American; Adeno ¼ adenocarcinoma; CEA ¼ carcinoembryonic antigen; EA ¼ European American; NOS ¼ not otherwise specified. a P value derived from Wilcoxon’s rank sum test for ageerace association and c2.test for all others.
and EA women, the median survival was lowest for those with proximal neoplasia (Table 2). AA women with distal and rectal disease experienced worse survival than EA women (21 vs. 27 months with distal disease; 17 vs. 29 months with rectal disease). Using stratified Cox regression analysis (Table 3), AA women had a significantly greater risk of death compared with EA women (HR, 1.48; 95% CI, 1.25-1.75). Adjustment for clinicopathologic covariates slightly attenuated the risk (HR, 1.39; 95% CI, 1.17-1.65). Overall, young AA men experienced worse survival compared with young EA men (log-rank P ¼ .006), with lower median survival
Kristin Wallace et al Table 2 Kaplan-Meier Median Survival Time and Survival Probability Estimates Stratified by Age, Gender, Colonic Location, and Race Age
Gender
Colonic Location
Male
Distal
Race
Patients (n)
Events (n)
Prevalence (%)
EA AA EA AA EA AA EA AA EA AA EA AA EA AA EA AA
416 91 281 85 507 87 1204 263 432 83 272 100 329 52 1033 235
241 65 191 60 312 60 744 185 257 58 196 69 188 41 641 168
35 35 23 32 42 33
EA AA EA AA EA AA EA AA EA AA EA AA EA AA EA AA
2029 333 2499 447 2006 251 6534 1031 1535 321 2607 572 1269 178 5411 1071
1450 250 1957 358 1407 186 4814 794 1107 237 2079 450 942 134 4128 821
31 32 38 43 31 24
Median Survival (mo)
5-y Survival Probability (%)
<50 y
Proximal Rectal Overall Female
Distal Proximal Rectal Overall
42 35 26 43 32 22
26 25 19 18 26 21 24 22 27 21 17 15 29 17 25 18
(23-31) (20-31) (16-23) (15-25) (23-29) (14-23) (23-26) (19-24) (25-32) (18-27) (14-20) (12-20) (27-33) (15-22) (24-27) (16-20)
0.20 0.02 0.16 0.09 0.18 0.14 0.18 0.07 0.17 0.14 0.17 0.09 0.21 0.12 0.18 0.12
(0.15-0.27) (0.00-0.14) (0.11-0.22) (0.03-0.22) (0.14-0.24) (0.06-0.31) (0.15-0.22) (0.04-0.14) (0.13-0.23) (0.07-0.28) (0.12-0.23) (0.04-0.23) (0.16-0.29) (0.05-0.27) (0.15-0.22) (0.08-0.19)
19 14 12 11 18 15 16 13 17 16 10 13 14 15 13 14
(17-20) (12-18) (11-12) (9-13) (17-20) (11-17) (15-16) (11-14) (16-19) (12-20) (9-11) (11-14) (13-16) (11-21) (12-13) (12-15)
0.12 0.10 0.08 0.05 0.11 0.08 0.10 0.07 0.13 0.07 0.09 0.07 0.10 0.07 0.10 0.07
(0.10-0.14) (0.06-0.15) (0.07-0.10) (0.03-0.09) (0.09-0.13) (0.04-0.13) (0.09-0.11) (0.05-0.10) (0.11-0.15) (0.04-0.13) (0.08-0.11) (0.05-0.11) (0.08-0.13) (0.03-0.16) (0.09-0.11) (0.05-0.10)
50 y Male
Distal Proximal Rectal Overall
Female
Distal Proximal Rectal Overall
28 30 48 53 23 17
Data in parentheses are 95% confidence intervals. Abbreviations: AA ¼ African American; EA ¼ European American.
(22 vs. 25 months) and 5-year survival probabilities (0.07 vs. 0.18; Table 2). Similar to women, the young men of both races with proximal CRC had the lowest survival. In young men, the greatest difference in survival was observed with rectal cancer when comparing AA and EA men (21 vs. 26 months). Stratified Cox regression analysis revealed that AA men had a greater risk of mortality than EA men (HR, 1.25; 95% CI, 1.06-1.47; Table 3), even after adjustment for clinical covariates (HR, 1.29; 95% CI, 1.10-1.52).
Patients Aged 50 Years The personal characteristics and clinical and pathologic features assessed at diagnosis differed by race in those aged 50 years (Table 1). The average age at diagnosis was 3 years younger for the AA men and 4 years younger for the AA women compared with EA men and women, respectively. Similar to observations in patients aged < 50 years, the older AA men and women were more likely to
have proximal tumors and greater CEA positivity but less likely to have high-grade lesions. Older AA women had a 5% greater prevalence of proximal tumors than did EA women. However, this difference was appreciably lower than the 17% difference observed in the younger cohort. Overall, the median survival was slightly greater for older EA patients than for AA patients (Table 2, Figure 2). Most of the racial difference in survival in those aged > 50 years was confined to the men. For example, the median survival did not differ by race in women aged > 50 years (13 months in EA women vs. 14 months in AA women). The 5-year survival probability was only slightly greater in older EA women relative to AA women (0.10 vs. 0.07). Furthermore, the risk of death did not differ significantly by race in older women (HR, 1.03; 95% CI, 0.95-1.11; Table 3). Adjustment for the multiple prognostic factors at diagnosis increased the risk by 6% (HR, 1.09; 95% CI, 1.01-1.18).
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Race and Colorectal Cancer Survival Figure 2 Survival Distributions Were Analyzed Using Survival Probability in Months From Diagnosis for (A) Men Aged < 50 Years, (B) Women Aged < 50 Years, (C) Men Aged ‡ 50 Years, and (D) Women Aged ‡ 50 Years
Abbreviations: AA ¼ African American; EA ¼ European American.
In contrast, the median survival for older AA men was poorer than that for EA men (13 months vs. 16 months). Likewise, the 5-year survival probability was lower for older AA men than for EA men (0.07 vs. 0.10). From the stratified CPH regression models, the univariate analysis revealed a greater risk of death for older AA men than for EA men (HR, 1.18; 95% CI, 1.09-1.27; Table 3). Adjustment for covariates led to an increase in this racial difference (HR, 1.24; 95% CI, 1.15-1.34).
Discussion
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Our analysis using the population-based SEER registry data revealed poorer stage-specific survival for AA patients than for EA patients, especially for those aged < 50 years. Overall, we observed that CRC was diagnosed in 19% of AA patients who were aged < 50 years compared with 16% of EA patients. Significantly worse survival was observed for AA men in both younger and older age groups; however, the largest racial difference in survival was found for AA women aged < 50 years, who had a 48% greater risk of death than younger EA women. In contrast, survival was poor for all women 50 years old. The prevalence of several poor prognostic factors at diagnosis differed by race, age, and gender and appears to explain some of the reasons for the differences in survival when stratified by race and age. AA patients of all ages had a greater
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prevalence of proximal tumors and higher CEA level compared with EA patients but a lower prevalence of high-grade tumors. Much of the difference in CRC survival by race in younger women appeared to result from the difference in the prevalence of proximal neoplasia at diagnosis. In summary, our findings highlight the importance of considering the patient’s age, gender, and colonic location when assessing the differences by race in stage IV CRC outcomes. CRC is the second leading cause of cancer-related death yet one of the most preventable and treatable cancers when identified in the early stages, with 90% survival at 5 years compared with < 20% for stage IV cases. Despite recommendations by some physician organizations to begin screening earlier in AAs,21,22 others have argued that efforts should be directed toward increasing the screening rates in those aged 50 years,23 because of the scarcities of resources and the much greater prevalence of disease in older patients. In the case of the present SEER cohort with stage IV CRC, approximately one sixth of the cases were diagnosed before 50 years of age. Moreover, the average age at diagnosis for the younger patients was 45 years for AA men, 44 years for EA men, and 44 years for both AA and EA women. From a public health perspective, screening younger AAs should be considered, regardless of the underlying etiology, given the poor survival and high prevalence of poor prognostic factors such as a proximal location.
Kristin Wallace et al Table 3 Summary of Results From Cox Proportional Hazards Regression Models Age <50 y Male (n [ 1467) Variable Agea
Model 1
Model 2
Age ‡50 y Female (n [ 1268)
Model 1
Male (n [ 7565)
Model 2
Model 1
Model 2
Female (n [ 6482) Model 1
Model 2
0.89 (0.80-1.00) 0.94 (0.84-1.05) 0.96 (0.86-1.07) 0.97 (0.87-1.08) 1.33 (1.30-1.37) 1.34 (1.30-1.37) 1.39 (1.35-1.42) 1.37 (1.34-1.42)
Race EA AA
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.25 (1.06-1.47) 1.29 (1.10-1.52) 1.48 (1.25-1.75) 1.39 (1.17-1.65) 1.18 (1.09-1.27) 1.24 (1.15-1.34) 1.03 (0.95-1.11) 1.09 (1.01-1.18)
Colonic location Distal
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
Proximal
1.30 (1.10-1.54) 1.17 (0.99-1.40) 1.46 (1.24-1.72) 1.34 (1.13-1.58) 1.36 (1.28-1.45) 1.27 (1.19-1.35) 1.35 (1.26-1.44) 1.17 (1.09-1.25)
Rectal
1.05 (0.90-1.22) 1.07 (0.92-1.24) 0.96 (0.81-1.14) 1.01 (0.85-1.19) 0.98 (0.92-1.05) 1.04 (0.97-1.11) 1.06 (0.98-1.15) 1.03 (0.95-1.12)
Grade Low High
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.63 (1.42-1.86) 1.56 (1.35-1.79) 1.49 (1.29-1.72) 1.36 (1.17-1.59) 1.46 (1.38-1.55) 1.40 (1.32-1.49) 1.48 (1.40-1.58) 1.48 (1.39-1.57)
Histologic type Adeno NOS
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
Mucinous
1.32 (1.04-1.67) 1.30 (1.02-1.66) 1.11 (0.86-1.43) 1.06 (0.82-1.37) 0.98 (0.89-1.09) 0.93 (0.84-1.03) 0.98 (0.88-1.08) 0.93 (0.84-1.03)
Signet cell
2.48 (1.84-3.35) 2.05 (1.49-2.82) 2.16 (1.55-2.99) 1.90 (1.35-2.68) 1.80 (1.52-2.14) 1.51 (1.27-1.80) 1.41 (1.16-1.72) 1.22 (1.00-1.50)
CEA Normal Elevated
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.37 (1.15-1.62) 1.55 (1.30-1.85) 1.67 (1.38-2.01) 1.70 (1.41-2.05) 1.43 (1.34-1.54) 1.55 (1.45-1.67) 1.57 (1.45-1.70) 1.71 (1.58-1.85)
Data presented as hazard ratio (95% confidence interval). Abbreviations: AA ¼ African American; Adeno ¼ adenocarcinoma; CEA ¼ carcinoembryonic antigen; EA ¼ European American; Model 1 ¼ univariate; Model 2 ¼ multivariable (covariates included age, race, colonic location, tumor grade, histologic type, and CEA); NOS ¼ not otherwise specified. a Hazard ratio and 95% confidence interval for age correspond to 10-y increment.
The results of the present investigation mirror earlier reports showing that the survival differences were most pronounced by race for younger patients.4,5,24 In our earlier investigation, using the South Carolina Central Cancer Registry data, we explored the associations between race, age, and clinicopathologic features and stage IV CRC survival. The multivariable proportional hazards regression analysis showed that AA patients compared with EA patients had a significantly greater risk of death after controlling for age, gender, year of diagnosis, and first-line chemotherapy use. Just as in the present analysis, we observed a significant interaction between race and age (P ¼ .04) on survival. Among AA patients versus EA patients aged < 50 years, the adjusted HR was 1.34 (95% CI, 1.061.71). The magnitude of the HR for patients aged < 50 years was similar to the adjusted HR found in the present study (HR, 1.33; 95% CI, 1.18-1.49). The reason for the greater risk of death in younger patients is clearly complex but was due, at least in part, to the greater prevalence of proximal CRC in younger AA patients compared with younger EA patients (Table 2). Similar to these results, many others25-29 have reported a greater prevalence of proximal or advanced proximal neoplasia, especially microsatellite stable CRC in AA patients compared with EA patients. A proximal colonic location outside of the context of microsatellite instability-high CRC has been associated with greater mortality, especially among stage IV CRC patients.15,17,30,31 Recent evidence has also documented a poorer response to treatment in patients with proximal CRC.19 The racial difference in survival by race and gender differed in the younger and older patients. As reported, a marked difference was
found in the prevalence of proximal CRC in women aged < 50 years (þ17% for AA women) but only a 5% difference by race was found for those aged 50 years. The reasons for the racial difference in survival among the younger women are not known but might reflect differences in the hormonal signatures by race. Younger EA women compared with younger AA women have higher estrogen levels,32-34 which could contribute to a lower prevalence of proximal neoplasia in younger women. Recently, a large prospective study reported a strong inverse association between endogenous estrogen levels and the risk of CRC, especially for colon cancer compared with rectal cancer.35 One possibility is that estrogen receptor expression loss results in more aggressive tumor behavior. In a murine model, the loss of estrogen receptor expression in the proximal colon led to crypt fission and reduced wound healing,36 factors associated with increased tumor prevalence and growth. Moreover, poorer survival has been observed in younger AA women compared with EA women with breast cancer, which might be explained by the greater proportion of poor prognostic ER breast cancer tumors in AA women.37 The poorer survival in younger AA women in the present study was similar to what we observed in our previous analysis.4 Racial differences in initiation and adherence to standard treatment of CRC might contribute to the stage-specific survival differences. AA patients historically have been less likely to receive the standard recommended therapy and to refuse therapy at a greater rate.38 Although data on systemic therapy use are not available from the SEER data set, the available agents (capecitabine, 5-fluorouracil,
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Race and Colorectal Cancer Survival irinotecan, oxaliplatin, bevacizumab, cetuximab) for the treatment of stage IV CRC remained consistent from 2004 to 2011, aside from the addition of panitumumab in 2006 and, more importantly, the restriction of epidermal growth factor receptoretargeted therapies to KRAS wild-type tumors by 2008.39 AA patients are more likely than EA patients to have KRAS mutant tumors6,29 and as a whole would be expected to derive less benefit from epidermal growth factor receptoretargeted therapies. However, no notable differences in HRs for race were observed when we analyzed the study periods separately (ie, 2004-2007 vs. 2008-2011). AA patients are less likely than EA patients to undergo surgical interventions for nonmetastatic colon and rectal cancer,38,40,41 raising the possibility that metastectomy rates might differ by race. To our knowledge, only 1 previous study has evaluated metastectomy rates by race and reported no differences.42 However, 2 large studies42,43 found that AA patients had significantly lower response rates to therapy, which could reduce the likelihood of undergoing resection. The strengths of our study included the study of a large, racially diverse population of patients with advanced-stage CRC with careful characterization of the demographic and pathologic characteristics and vital status. However, we also recognize its limitations. First, we had no data on patient-level factors (eg, comorbid conditions or lifestyle and behaviors) or treatment regimen data, which could have confounded or modified the association between race and CRC survival. These results point to the need for detailed studies identifying the risk factors for poor prognostic signatures and patient-level, clinical, molecular, and treatment-related data to help advance our understanding of the racial disparity in CRC survival.
Conclusion Using the large population-based SEER data set, we have shown that AA patients with stage IV CRC have greater mortality than EA patients, in particular, those aged < 50 years. These data suggest greater emphasis is needed for CRC screening of younger AA individuals and, further, raise the possibility that national guidelines for CRC screening should be modified, especially for AA women.
Clinical Practice Points Several previous investigations have detailed a racial disparity in
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CRC survival, yet the reasons for this remain incompletely understood. The greater rates of death for AA compared with EA patients have persisted despite adjustment for common confounding variables such as gender, age, and socioeconomic status. Our results suggest that the racial difference in survival might be influenced by differences in the prevalence of proximal and rectal CRC at diagnosis, because survival among both AA patients and EA patients with proximal stage IV CRC disease is poor. Future research is needed to understand why AAs develop proximal neoplasia at a younger age; we found a 17% difference in the prevalence of proximal CRCs in younger AA women compared with younger EA women but only a 5% difference by race among women aged 50 years. A better understanding of how to improve the treatment response in patients with stage IV proximal CRC is also needed.
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Acknowledgments This work was supported by the National Cancer Institute (NCI) by way of the Hollings Cancer Center NCI Cancer Center Support Grant (grant P30 CA138313) and a K07 Career Development Award to K.W. (grant K07CA151864-01A1).
Disclosure The authors have stated that they have no conflicts of interest.
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