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© 2003 American Society for Clinical Oncology Prognosis After Rectal Cancer in Blacks and Whites Participating in Adjuvant Therapy Randomized Trials
From the Department of Health Studies, University of Chicago and University of Chicago Cancer Research Center, Chicago, IL; National Surgical Adjuvant Breast and Bowel Project (NSABP) Biostatistical Center and Department of Biostatistics, University of Pittsburgh; NSABP Operations Center and Allegheny General Hospital, Pittsburgh, PA and Cancer Center, Aultman Hospital, Canton, OH. Address reprint requests to James J. Dignam, PhD, Department of Health Studies, 5841 South Maryland Avenue MC2007, The University of Chicago, Chicago, IL 60637; email: jdignam{at}health.bsd.uchicago.edu.
Purpose: National health statistics indicate that blacks have lower survival rates from colorectal cancer than do whites. This disparity has been attributed to differences in stage at diagnosis and other disease features, extent and quality of treatment, and socioeconomic factors. We evaluated outcomes for blacks and whites with rectal cancer who participated in randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP). The randomized trial setting enhances uniformity in disease stage and treatment plan among all participants. Patients and Methods: The study included black (N = 104) or white (N = 1,070) patients from two serially conducted NSABP randomized trials for operable rectal cancer. Recurrence-free survival and survival were compared using statistical modeling to account for differences in patient and disease characteristics between the groups. Results: Blacks and whites had largely similar disease features at diagnosis. After adjustment for patient and tumor prognostic covariates, the black/white recurrence hazard ratio (HR) was 1.25 (95% confidence interval [CI], 0.94 to 1.66). The mortality HR was somewhat larger at 1.45 (95% CI = 1.09 to 1.93). Outcomes were improved for both groups in the more recent trial, which employed systemic adjuvant chemotherapy in all treatment arms. Conclusion: Recurrence-free survival was modestly less favorable for blacks, whereas overall survival was more disparate. Outcomes between groups were more comparable than those noted in national health statistics surveys and other studies. Adequate treatment access and the identification of new prognostic factors that can identify patients at high risk of recurrence are needed to ensure optimal outcomes for rectal cancer patients of all racial/ethnic backgrounds.
RECTAL CARCINOMA is a moderate contributor to total cancer incidence in the United States as the ninth most frequent cancer, with 41,000 cases (3% of all new cancers) expected in 2002.1 Mortality is relatively high for rectal cancer that has progressed beyond the local stage. For example, the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program data for years 1989 to 1995 indicated 5-year relative survival rates (adjusted for age- and race-specific life expectancy) of 85.7% for localized disease, 56.9% for regional disease, and only 6.4% for rectal cancer that has progressed to distant metastatic sites.2 These survival percentages are lower than those reported for colon carcinoma, a cancer site with which rectal cancer is often grouped in cancer statistics summaries. The two sites combined will constitute the third most common source of both cancer incidence and mortality in United States men and women in 2002.1 Numerous candidate prognostic factors for rectal cancer have been investigated. Surgery-related factors, which include the type of operation, status of margins after surgery, extent of lymph node examination, and even aspects of the surgeon’s skill and experience, have been found to be associated with disease recurrence and mortality.3–7 In many of these studies, investigators have sought to identify those patients in need of adjuvant therapy after surgery to reduce risk of local recurrence, in recognition of the primacy of local disease control in successful rectal cancer treatment.3,8 Clinical and pathologic disease features, such as stage, lymphatic, and blood vessel invasion, and pathologic cell type have also been studied to determine recurrence risk after surgery and to aid in making decisions such as to administer adjuvant treatment.9–13 More recently, a number of molecular tumor markers and biologic activity indicators have been investigated in relation to prognosis and treatment response14–18 (see review in19). In addition to disease features, factors potentially related to rectal cancer prognosis include patient age, sex, and socioeconomic factors, including quality and extent of medical care.13,20–25 Race/ethnicity has been examined in relation to rectal cancer prognosis, with results showing that white Americans have had more favorable survival than black Americans during the last several decades.2,21,26–28 Examining recent data, the 1995 SEER report yields 5-year relative survival rates for all stages of rectal cancer of 60.2% for whites and 51.2% for blacks.2 Although the major explanatory factor for survival disparities by race in many cancers is later stage at diagnosis for blacks, the SEER report shows a similar distribution of stage for whites and blacks over these years and poorer stage-specific 5-year survival for blacks with localized and regional disease. Other studies have shown both a later stage at diagnosis and poorer stage-specific survival for blacks with rectal cancer.21,29–31 In this study, we examined survival and related outcomes after rectal cancer among blacks and whites (from the United States and Canada) who participated in randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP). In randomized trials, the extent of disease (stage and other characteristics) is restricted and therapy is mandated to be delivered according to a prescribed plan, and thus additional determinants of prognosis can be investigated in the absence of confounding by these factors. In a previous investigation, we found similar recurrence-free survival but slightly increased mortality among blacks relative to whites who participated in NSABP colon cancer trials.32
Patient Selection and Description The NSABP is a National Cancer Institute-sponsored cooperative clinical trials group that has evaluated surgical procedures, radiotherapy, chemotherapy, immunotherapy, and endocrine therapy for the treatment and prevention of breast and colorectal cancer for more than 40 years. Beginning in 1977, a series of trials evaluating adjuvant therapies for colon and rectal cancer has been conducted. In this investigation, we examined data from two serially conducted trials for operable rectal cancer that enrolled patients between 1977 and 1992. The first trial (protocol R-01) was designed to determine whether the addition of the three-drug regimen methyl-lomustine, vincristine, and fluorouracil (MOF) or radiation therapy after surgery improved outcomes over surgery alone. From 1977 to 1986, a total of 574 patients were accrued. The second trial (protocol R-02) evaluated radiation therapy when added to chemotherapy and compared the efficacy of the MOF regimen to fluorouracil plus leucovorin (FU+LV). Patients were randomly assigned to receive radiation or no radiation following surgery. Males were also randomly assigned to receive either MOF or FU+LV. Because of the observation in protocol R-01 that females did not benefit from MOF, the study design for R-02 mandated that all females be assigned to FU+LV. A total of 741 patients were accrued from 1987 to 1992. Eligibility criteria for the trials were similar. Patients must have undergone a curative abdominoperineal resection (APR) or anterior resection (AR) for Dukes’ stage B (T3 to T4, N0, M0 according to tumor node metastasis [TNM] classification33) or stage C (TNM T1 to T4, N1 to N3, M0) adenocarcinoma of the rectum. For these trials, rectal tumors were defined as those in which opening of the pelvic peritoneum was necessary to define the distal extent of the tumor. Patients with contained perforation or obstruction were eligible, but those whose tumors demonstrated free perforation were not. Patients must have had an Eastern Cooperative Oncology Group performance status score of 2 or less and adequate renal and hepatic functions. All patients consented to participate, and the trials were reviewed and approved by institutional review boards at participating centers. Further details of the study designs can be found in published reports of primary findings.34,35 The NSABP quality-assurance program monitors all aspects of conduct of these trials. An independent medical review was conducted at the NSABP for primary eligibility and adequacy of surgery. A similar review was conducted for radiotherapy. Serious adverse events and all endpoints were centrally reviewed. An institutional site visit program is in place to evaluate study protocol compliance and confirm source documentation. We selected for inclusion in this analysis all protocol-eligible patients with follow-up information whose race was reported as either white or black. Eligibility violations were most often caused by errors in staging before random assignment, and the proportions of protocol-ineligible patients did not differ by race. For the two trials combined, 1,070 white and 104 black patients were included.
Study Endpoints and Statistical Methods Estimates of event time distributions and black/white failure hazard ratios were computed separately for each trial. Subsequently, data from the two trials were combined. To compute event time distributions among patients from both trials, combined, direct adjustment was used to produce estimates that took into account the unequal proportions of blacks and whites represented in the individual trials.38,39 The prognostic influence of patient/disease characteristics was assessed by computing average annual rates of failure in different categories (eg, age groups, stage groups) and by hazard ratio estimates via the Cox proportional hazards model.40 The Cox model was also used to compute relative hazard of failure for blacks versus whites, controlling for the confounding influence of other prognostic covariates. The proportional hazards assumption for the black/white hazard ratio was satisfied over the follow-up period examined. Analyses of race and other prognostic factors were conducted on combined data using a stratified Cox model, which allows for a separate baseline failure risk by trial. P values from all analyses are two-sided. For comparability of data from the two trials, follow-up is administratively censored at 5 years. This investigation reflects data reported to the NSABP Biostatistical Center through September 30, 1998, for protocol R-01 and through December 31, 1998, for Protocol R-02.
Characteristics of Blacks and Whites with Rectal Cancer Characteristics of the patients were similar between trials, with some exceptions (Table 1  ). More black patients were enrolled in protocol R-01 (11.5%) than protocol R-02 (6.8%). Patients in protocol R-01 had earlier-stage disease (38.5% Dukes’ B compared with 30.1% in R-02). More patients in protocol R-01 underwent APR (56.6%) compared with those in R-02 (42.4%).
When characteristics were compared by race, whites were slightly older, with 31.8% being 65 years of age or older, compared with 22.1% of blacks (P = .03). Whites were more often male (60.8%) than blacks (53.8%; P = .12). Whites more often had lymph node-negative disease (34.3%) than blacks (27.9%), but the number of positive lymph nodes among lymph node-positive patients was similar between blacks and whites. Blacks were more likely to have undergone APR (67.3%) compared with whites (46.8%; P = .0003).
Recurrence-Free Survival, Disease-Free Survival, and Survival
In protocol R-02, 5-year RFS was 53.7% for blacks and 60.8% for whites (P = .27; Fig 1  ). DFS was also similar, with 51.1% of blacks and 56.1% of whites event-free through 5 years (P = .34, not shown). Five-year survival was 60.0% for blacks and 68.0% for whites (P = .19).
Weighted estimates for the combined data, ignoring treatment and other prognostic covariates, yielded the following results: 5-year RFS was 53.7% for whites and 45.0% for blacks (P = .08); 5-year DFS was 48.2% for whites and 40.0% for blacks (P = .08); and 5-year survival was 60.3% for whites and 48.0% for blacks (P = .01; Fig 2
Race and Other Factors in Relation to Rectal Cancer Prognosis Factors in addition to race that may be associated with RFS or survival were investigated singly and in models containing all factors (Tables 2 and 3). Patients who were older at diagnosis had increased mortality risk, likely in part caused by the increased frequency of new primary cancers and noncancer deaths with increasing age. Males and females had similar RFS and survival. The presence and number of positive lymph nodes were strongly associated with increased risk of rectal cancer recurrence and mortality. Patients who underwent APR had somewhat higher recurrence risk and significantly greater mortality than did those who underwent AR. Patients with tumors in the recto-sigmoid area had slightly lower mortality rates than did those with tumors in the rectum. The prognostic influence of these covariates was similar when evaluated within individual trials (not shown).
Figure 3 shows black/white hazard ratios for rectal cancer recurrence and death, adjusted for treatment group, number of positive lymph nodes, age, sex, surgery type, and tumor location. Estimated hazard ratios are shown by trial and from the combined data using a stratified estimate, with the trial from which the patient originated as the stratification factor. Combined data results indicate a nonsignificant 25% excess risk of rectal cancer recurrence (P = .13) and a 45% excess risk of overall mortality (P = .01) for blacks (Fig 3).
The randomized clinical trial setting offers a unique view into outcomes after cancer between racial/ethnic groups. Stage of disease at diagnosis is defined and limited by the protocol entry criteria, and treatment is administered according to a uniform standard, reducing the influence of two major factors that contribute to outcome disparities. In addition, important clinical and pathologic prognostic information is recorded for all patients. One limitation is the small number of participants of race groups other than those of the majority population, as, even if, for example, the number of black entrants to a trial were to meet proportional representation relative to the United States population, an approximate 9 : 1 ratio of whites to blacks would result. Another shortcoming of clinical trials is the lack of detailed socioeconomic information about patients, which may explain outcome disparities between patients of different racial/ethnic backgrounds. In the clinical trial setting, we might anticipate that the implicit standards the trial design imposes with respect to staging and treatment would render these influences less important than in other observational studies. However, there remains the likelihood that differences in ancillary care and environmental factors will contribute to poorer prognosis for some individuals within a clinical trial. On this latter point, some studies have found differences in extent of treatment between black and white colon and rectal cancer patients, with attendant poorer outcomes for blacks.22,41–42 Conversely, in studies among patients with relatively uniform care, outcomes were appreciably more similar.32,43–45 With uniform care for patients of a comparable disease stage, any residual differences in outcome might then be attributable to variations in disease characteristics within the broader stage characterization. Additional pathologic and clinical disease features that might impart poorer rectal cancer prognosis may be more frequent in blacks, but this question has yet to be investigated. In one large study of colon cancer, such differences were not found.46 This is unlike the case for breast and uterine cancer, in which frequency of unfavorable tumor characteristics is greater in blacks, even when disease stage is comparable.47,48 In this cohort of NSABP rectal cancer trial participants enrolled during the last 15 years, blacks and whites had largely similar characteristics at diagnosis. Stage was more similar than that seen in certain hospital and population-based surveys or studies,21,29–31 owing in part to the trial entry criteria. Tumor cell negative lymph nodes were somewhat more frequent among whites, whereas the number of positive lymph nodes among lymph node-positive patients was similar between blacks and whites. With respect to demographic characteristics, black patients tended to be younger at diagnosis and were more frequently female. One factor that was unequally distributed by race and was associated with mortality was type of surgery. An important factor in choice of procedure is tumor location, and black patients did somewhat more frequently have low-lying tumors that might not have been amenable to sphincter-sparing surgeries such as AR. Although tumor location was found to be strongly associated with choice of surgery, with nearly all AR surgeries being performed among patients with more proximal tumors, APR remained significantly more frequent among blacks after accounting for general location (rectum v. recto-sigmoid). Other specific features such as tumor position may also play a role, and other studies have shown variation in colorectal tumor location by patient demographic characteristics,49,50 but we suspected that choice of procedure could also have been influenced by other factors. Although AR and APR procedures have been shown to be comparable with respect to local recurrence rates,51 it has been noted that AR is more frequently performed in settings in which surgeons are more experienced or have been specifically trained in colorectal surgery,4 and that both the use and postoperative morbidity of AR are related to rectal surgery hospital caseload, an indirect measure of surgical expertise.52 The association of APR with both race and mortality in this study was more prominent in the older trial (R-01) and could reflect differences in the institutions where black and white patients were treated. To explore this, we examined race and surgery by institutions enrolling patients onto the trials and observed that a substantive proportion of AR procedures were performed at specific Canadian institutions that contributed large numbers of patients and that these institutions did not enroll black patients. In United States hospitals, the performance of AR versus APR did not seem strongly associated with institution (and consequently with race, as the proportional representation of blacks and whites differs by institution), but because the number of participating sites is large (more than 100), individual sites enroll too few patients to draw any conclusions about choice of surgery by patient race. Similar variations in procedures resulting from nonclinical aspects of cancer have been seen in the choice of breast-conserving surgery versus mastectomy in breast cancer.53–56 There may be additional unrecognized selection factors in the choice of procedure that are associated with higher mortality; a recent overview of trials conducted by the North Central Cancer Treatment Group also showed higher mortality among patients having undergone APR.7 We found that RFS was modestly less favorable for blacks than for whites, although survival differed significantly, possibly because of greater all-cause mortality and noncancer mortality, as well as shorter survival time after recurrence. The unadjusted absolute difference in 5-year survival was 12%. The adjusted mortality hazard ratio of 1.45 (95% CI, 1.09 to 1.93) was similar to or somewhat smaller than that observed in other studies. Dayal29 reported rectal cancer survival for patients from 11 United States cancer centers, and found an adjusted African American/white mortality relative risk of 1.44. Among a cohort of patients similarly treated at one institution from 1965 to 1981, Michelassi30 et al reported a stage-adjusted mortality relative risk of 1.75 for blacks versus whites. Five-year survival for stage B whites was 78% compared with 62% for blacks; for stage C patients, survival was 47% for whites and 25% for blacks. Ragland reported 51% mortality excess for black females and 14% mortality excess for black males.31 Because we observed overall mortality differences between blacks and whites though recurrence did not differ significantly, we speculated that mortality caused by other cancers or chronic diseases might be more frequent among blacks. Disease-free survival, which includes new primary cancers and deaths from noncancer causes as events, was also lower among blacks. When rates of events making up DFS were compared, blacks were slightly more likely to have died before rectal cancer recurrence, whereas the frequency of other primary cancers was similar. Thus far, we have not analyzed mortality according to cause for these studies, because detailed, reliable cause-of-death information was not ascertained and studies have indicated problems with using reported cause-of-death information without careful review.57,58 Such an analysis might be revealing, because life-expectancy differences between blacks and whites in the United States are substantial, with a current discrepancy of about 5.6 years overall and 3.4 years with the condition of survival to 50 years of age.59 Even if noncancer deaths did not differ, the presence of concurrent adverse health conditions, or comorbidity, has been shown to increase cancer mortality.24 The mortality rate following recurrence may be greater among blacks, but an analysis of postrecurrence survival had low statistical power and did not seem explanatory (nor did an analysis of survival censoring those deaths plausibly ruled not related to rectal cancer). In summary, the modest mortality differences between blacks and whites seen in this study remain unexplained, and with the limited number of patients and a lack of strong prognostic factor candidates for these studies, they may not be further resolved. It would be of interest to investigate this finding in other clinical trials data.
Because of the small number of blacks in each trial, we were unable to reliably evaluate the effect of adjuvant therapy separately among blacks and whites to determine whether benefits were similar. We also did not estimate treatment effects for the combined trial data because of interpretational limitations because of confounding between protocol and treatment regimen, in that not all treatment regimens are represented in both studies, and because additional unidentified factors may also have differed between trials. However, RFS and survival rates for both blacks and whites in protocol R-02 were considerably superior to those in protocol R-01, in both cases representing approximately 40% to 50% lower hazards for these endpoints (Fig 1 In the population at large, advanced stage at cancer diagnosis remains the major cause of poorer outcomes for blacks. The well-documented excess of more advanced cancers among blacks has been attributed to socioeconomic disparities (which affect the poor of any racial/ethnic group) and could likely be reduced by increased and targeted screening.23,64 Interestingly, in recent years there seems to be little difference in stage at rectal cancer diagnosis between blacks and whites.2 Furthermore, there has also been a shift toward earlier stage at diagnosis for both groups, as well as a general decline in the incidence of this disease among whites (where rates were consistently higher than for blacks until recently) and a constant to slightly increasing incidence among blacks.65 All of these trends could be indicative of increased screening and the preemptive treatment of premalignant conditions (in whites), suggesting a positive effect of more widespread and equitable screening practices. However, one recent study in an urban medical center continued to show underuse of rectal cancer screening (relative to recommended guidelines) by resident physicians.66 Since the late 1980s, diversity in clinical research participation has been enhanced through National Cancer Institute programs. Enrollment onto National Cancer Institute-sponsored trials was examined in the 1990s and was found to be proportionally representative of the population cancer burden for whites, blacks, and Hispanics.67 Nonetheless, increased efforts toward greater enrollment of blacks into randomized clinical trials will promote quality care in accordance with current treatment guidelines and broader access to potentially beneficial new agents, as well as provide the necessary data to identify and study variation in prognosis and response to therapies in specific patient populations.
We thank Carol Ursiny, CCRA, for maintaining the NSABP colon and rectal cancer trials database, and Barbara Good, PhD, for editorial assistance.
This investigation was supported by Public Health Service grants NCI-U10-CA-69651, NCI-U10-CA-12027, and NCI P30-CA-14599 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests computed over strata defined by the trial in which the patient was enrolled. Event time endpoints were recurrence-free survival (RFS) time, defined as time from surgery until rectal cancer recurrence, with other events treated as censored observations; disease-free survival (DFS) time, defined as time from surgery until either rectal cancer recurrence, new primary cancer, or death before these events; and survival time, defined as time from surgery until death from any cause. Distributions of RFS, DFS, and survival time were estimated using Kaplan-Meier curves and compared by log-rank tests.
