Rectal Cancer

Historically, blacks have had a shorter survival following a diagnosis of rectal and other cancers compared with whites. Possible contributing factors include socioeconomic issues and inherent biological differences in tumor characteristics, but research thus far has failed to elucidate the reasons. A new study looking at these racial differences following a diagnosis of rectal cancer shows that the gap in recurrence-free survival between blacks and whites appears to be narrowing but that whites have improved overall survival compared with blacks. The study, published in the February 1st issue of the Journal of Clinical Oncology (2003:21:433–440), however, does not shed more light on why the racial survival difference persists.Figure: James J. Dignam, PhD: “We can say with certainty that blacks and whites are becoming more similar with respect to disease-free survival, but overall survival still seemed to differ. We would have liked to see even less of a difference in survival following rectal cancer in this study.”Lead author James J. Dignam, PhD, Assistant Professor in the Department of Health Studies at the University of Chicago and a statistician with the National Surgical Adjuvant Breast and Bowel Project (NSABP), said in an interview, “It is possible that other causes of death played a role in poorer survival for blacks. The National Center for Health Statistics shows a shorter life expectancy for blacks than whites—about a six-year difference, and a three-year difference in life expectancy favoring whites in those surviving to age 50.” Retrospective Study The study included black and white patients enrolled in two serially conducted NSABP randomized controlled trials of operable rectal cancer. There were 1,070 whites and 104 blacks, which is similar to the proportion of blacks in the United States (about 10%), but nevertheless is a small number of blacks, Dr. Dignam said. The first trial compared surgery alone with adjuvant chemotherapy or radiation therapy, while patients in the second trial all received adjuvant chemotherapy, reflecting changing treatment standards for the time periods during which the trials were conducted. Dr. Dignam explained that he and his coinvestigators—Yunrong Ye, Linda Colangelo, Roy Smith, Eleftherios P. Mamounas, H. Samuel Wieand, and Norman Wolmark—chose to have a retrospective look at prognostic factors from these two trials because the conditions of a randomized clinical trial provide an ideal environment for such a study. This is because these trials are restricted as far as extent of disease, characteristics of the study population, and treatment offered, enabling comparison of other determinants of prognosis without confounding by these factors. Comparison of patient characteristics by race showed that whites were slightly older, with 31.8% age 65 or older compared with 22.1% of blacks.Figure: Joel E. Tepper, MD: “Investigating the issue as a population-based study should eliminate many of the biases inherent in a study that requires entry onto a formal clinical trial, where the criteria for study entry could affect the results.”There were more males in the white group (60.8% vs 53.8%, respectively). More whites had node-negative disease than blacks (34.3% vs 27.9%, respectively). However, among lymph-node positive patients, the number of positive nodes was similar for both races. Blacks were more likely to have undergone a curative abdominoperineal resection compared with whites (67.3% vs 46.8%, respectively). Patients in the two studies either underwent abdominoperineal resection or a less extensive procedure called anterior resection, a newer procedure that is thought to require more expertise, but both procedures have similar outcomes, he said. “We have to assume the surgeries are done correctly, but different institutions have different resources, and thus may favor one or another procedure. We didn't see dramatic differences between institutions vis vis surgical procedures.” A substantial portion of the anterior resections were performed in Canadian research hospitals, he noted. “Perhaps this may reflect the fact that Canadians are less conservative about adopting a newer procedure, as they were with lumpectomy for breast cancer.” Study Outcome For the first study, the five-year recurrence-free survival rate was 36.9% for blacks and 44.6% for whites. The five-year disease-free survival rate was 30.5% for blacks compared with 38% for whites. The overall five-year survival rates were 37.2% for blacks and 50.3% for whites. For the second study, which included a greater proportion of patients undergoing adjuvant therapy with or without radiation following surgery, the five-year recurrence-free survival rate was 53.7% for blacks and 60.8% for whites. The five-year disease-free survival rate was similar as well, with 51.1% of blacks and 56.1% of whites remaining event-free. The overall survival rate at five years was 60% for blacks and 68% for whites. “The outcomes were better in the second trial,” Dr. Dignam said. “This suggests that new treatments that are benefiting whites are also benefiting blacks—that is, adjuvant therapy with or without radiation therapy. The numbers are too small for treatment-specific comparisons within groups.” Remaining Questions “We can say with certainty that blacks and whites are becoming more similar with respect to disease-free survival but overall survival still seemed to differ,” he continued. “We would have liked to see even less of a difference in survival following rectal cancer in this study.” Dr. Dignam acknowledged that the study was unsatisfactory in terms of revealing the reasons for the survival difference. More details about surgery and follow-up care may have shed some light on the differences, and it is possible that molecular and biological characteristics of rectal tumors “might provide a payoff,” he said, as such factors do in breast cancer.Figure: Robert J. Mayer, MD: “For rectal cancer, the assumption would be that quality of care for blacks is not as good or as modern or as effective as care offered to whites, particularly for a cancer where radiotherapy is a component, but this may be a simplistic interpretation.”Blacks typically have earlier onset of breast cancer and a higher proportion of estrogen-receptor-negative tumors; however, no meaningful racial differences in molecular or biological characteristics have been identified in colon cancer, he added. “In general, race alone is not a meaningful biological construct in studies of cancer disparities. Socioeconomic factors are confounding,” Dr. Dignam said. Additionally, he suggested that the next generation of studies include detailed information on causes of death to sort out mortality differences by race. “We need sufficiently detailed information on causes of death to understand mortality differences in rectal, colon, and breast cancer,” he said. “This is especially true in randomized controlled trials when the treatments are similar.” Another Perspective Asked for a comment, another colorectal cancer expert, Joel E. Tepper, MD, Professor and Chair of Radiation Oncology at the University of North Carolina School of Medicine, Chapel Hill, said, “As time goes on, the differences between blacks and whites with regard to rectal cancer have gotten smaller. This suggests that socioeconomic factors are a major cause of these differences. The study by Dr. Dignam et al shows that the differences are not as marked as has been thought and it raises the issue about which factors lead to poor outcomes in different patient groups.” Dr. Tepper said that a better way to look at the issue is a population-based study looking at the process of care, such as the CanCORS (Cancer Care Outcomes Research and Surveillance Consortium) study looking at colorectal and/or lung cancer, in which the University of North Carolina is participating. This study is investigating issues in the process of care that may impact outcome. “Doing this as a population-based study should eliminate many of the biases inherent in a study that requires entry onto a formal clinical trial, where the criteria for study entry could affect the results,” Dr. Tepper explained. Tumor characteristics and their effect on response to treatment are also important to study. Cooperative Groups such as Cancer and Leukemia Group B are beginning to evaluate biological tumor factors that may influence response in patients with gastric cancer, he said. “This study [by Dignam et al] showed that during the time the study was performed, mortality in blacks was worse than in whites but that the reasons for this were not clear. The study strongly suggests that socioeconomic factors may be a driving force in outcome, and could be more than the biological difference between the two populations. In order to investigate this, population-based studies are needed to discern the real differences between these patient populations,” concluded Dr. Tepper. Role of Biological Differences It is possible that differences in tumor biology account for the racial disparity in survival in patients with rectal cancer. Racial biological differences in tumor characteristics have been identified in breast and prostate cancers, noted GI cancer expert Robert J. Mayer, MD, Vice-Chairman for Academic Affairs in the Department of Medical Oncology at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School and a member of OT's Editorial Board. Breast tumors in black women have an earlier age of onset and are more likely to be hormone-receptor negative. In black men, prostate cancer is diagnosed at a younger age and is more likely to be hormone-refractory than in white men. “In the area of rectal cancer, the assumption would be that quality of care for blacks is not as good or as modern or as effective as care offered to whites, particularly for a cancer where radiotherapy is a component,” Dr. Mayer said. “This may be a simplistic interpretation. As we have learned in breast and prostate cancer, rectal cancer may be a different disease in blacks than in whites. The study by Dignam et al opens the door to studying this in rectal cancer in a prospective manner.” Harold Freeman: ‘Race Not Meaningful Biological Construct’ Asked to comment on the study, Harold Freeman, MD, Director of the NCI's Center to Reduce Cancer Health Disparities, said that the weight of evidence shows that equal treatment at the same stage of disease yields equal results for both rectal cancer and breast cancer, adding that Dr. Dignam drew this same conclusion as it relates to colorectal cancer in a previous paper. The new study showed that recurrence-free survival was almost equal in blacks and whites following a diagnosis of rectal cancer, yet there was a disparity with respect to survival, Dr. Freeman continued.Figure: Harold Freeman, MD“This finding [i.e., survival disparity] has little meaning unless one can determine causes of death in patients who died. In general, blacks have a higher rate of comorbidity.” Another limitation of the study, he pointed out, was the small number of black patients enrolled, making a meaningful comparison of blacks and whites stage for stage highly unlikely. Finally, Dr. Freeman said, ''racial categories are socially and politically determined and have no basis in biological science. “For this reason, when ‘race’ is used in scientific studies, there is a need for the author to indicate what is being measured. Race, for example, may be used as a proxy for economic status or presumed lifestyle factors.” For example, poverty and low education levels occur disproportionately in black compared with white Americans, and these factors lead to increased mortality and comorbidity. “The bottom line is the need to define the real variables that are the causes of the disparity rather than to assume or imply that ‘race’ in and of itself is the cause,” said Dr. Freeman, who is also a member of OT's Editorial Board. “The findings of Dr. Dignam et al in this article lead to a better understanding of these issues.”

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