Time dependent ethnic convergence in colorectal cancer survival in hawaii

After lung, prostate, and breast cancer, colorectal cancer ranks as a leading source of cancer mortality.[1] Nationally, although death rates have been declining since the mid-1980s, this trend is not consistent across all ethnic groups.[2] Specifically, in the past 10 years the death rate for Caucasians has been decreasing at nearly twice the rate as that for African Americans, and for Native Americans the rate has actually been increasing.[3, 4] Among Asian ethnic groups, Chinese and Filipinos suffer a higher death rate than do the Japanese.[5] These ethnic disparities appear largely driven by differential stage distribution (e.g., more advanced stage cases at presentation). Underutilization of cancer screening appears a key factor.[6] However, studies have found that even after controlling for stage at diagnosis, significant ethnic differences remain.[7]

How can one explain cancer survival differences that persist after adjustment for stage? Biological theories suggest that members of certain ethnic groups are genetically predisposed to more aggressive forms of the disease, differ in host-tumor interactions, or are more likely to have contributing comorbid conditions. Wudel et al. (2002) recently reported that colorectal cancer survival differences between Caucasians and African Americans could not be explained by measurable differences in treatment.[8] Neuhausen has proposed a multi-factorial biology-utilization model.[9] Environmental theories propose that behavioral or socioeconomic factors leading to differential utilization of medical care are responsible. Varying utilization of, as well as access to health care has been reported as an explanation. [10–12] Schrijvers et al. (1997) have described a relation between socioeconomic status and comorbidity.[13] Evidence of interaction between age and socioeconomic status has also been reported.[14]

Hawaii's diverse ethnic composition combined with its long-standing statewide cancer registry, the Hawaii Tumor Registry (HTR), offer an ideal setting for examining ethnic differences in cancer survival. Previous research has documented significant survival disparities among the major ethnic groups (Caucasian, Japanese, Hawaiian, Filipino, and Chinese) in the state. In 1978, Nomura et al. found that Japanese patients had a nearly one-third higher survival rate than Caucasians.[15] Hirohata et al. (1977) described better survival rates among Japanese and Caucasians than among Filipinos and Hawaiians, even after adjusting for age, gender, and extent of disease at diagnosis.[16] Wegner et al. (1982) analyzed HTR data from 1960–1974 and found the same pattern of differences, which also could not be explained by any of the available covariates.[17]

The goal of the present study is to examine trends in recent survival rates. The HTR data that was incorporated in the Wegner (1982) study is still available as is more recent data up to the year 2000, allowing for an examination of survival patterns over time. Improved survival rates for cancer patients were observed by Hinds et al. (1983) during the years 1960–1974.[18] More recently, Maskarinec et al. (1999) have described improved breast cancer survival among all ethnic groups for 1970–1990.[19] Also, for the years 1995–1998 it was found that all ethnic disparities in breast cancer survival were eliminated once TNM Stage had been controlled.[20] These findings largely fail to support purely biologic explanations of disparate colorectal cancer survival. Differential utilization of health care or access to health care appears more important.

In Hawaii, the passage of time has brought general improvements in medical care and also narrowed disparities in access to medical care. Utilization of screening procedures continues to vary among ethnic groups, however. At the onset of this study, we hypothesized that, over the past 30 years, improved cancer screening and treatment, as well as better access to medical care across all ethnic groups has both improved survival rates and reduced ethnic differences in colorectal cancer survival. We further predicted that stage at diagnosis, age, and gender could explain most remaining survival differences, although we questioned the role of other factors such as treatment utilization and co-morbid disease.

Figure 1 presents the survivor function plots (stratified by ethnicity) for each cohort and for each cause of death category (controlled for stage at diagnosis, year of diagnosis, age, and sex). The corresponding five-year survivor estimates with 95% confidence intervals are shown in Table 3, and the parameter estimates for each Cox regression model are provided in Table 4. Unadjusted five-year survival rates for each ethnic group were 80.5% for Japanese, 79.4% for Caucasian, 78.8% for Chinese, 76.4% for Filipino, and 72.5% for Hawaiian. The test of the validity of the proportional hazards assumption with the variable [log _e (time)-0.52] indicated no violation [χ² (1) = 0.13, p = 0.72].

When an event was considered death by colorectal cancer, significant ethnic differences were found for all three cohorts [Likelihood Ratio χ² (4) = 20.0, 23.1, and 12.0; p < .001, p < .001, and p < .05 respectively]. An examination of the confidence intervals for cohort 1 indicated that Japanese and Caucasian patients had significantly longer five-year survival than Filipino and Hawaiian patients. For the second cohort, the confidence intervals indicated that Caucasians had a significantly longer survival time than Filipinos; and in the third cohort, Hawaiians had significantly shorter survival time than all other ethnic groups. When an event was considered any death not caused by colorectal cancer, significant ethnic differences were again found for all three cohorts [Likelihood Ratio χ² (4) = 46.3, 73.3, and 57.9; p < .0001 for all]. Confidence intervals indicated that the Japanese always had a significantly higher survival rate than at least one other ethnic group.

Results were largely consistent with our hypothesis, but with one major exception: the persistently low Hawaiian colorectal cancer survival in cohort 3. This unpredicted finding led to post hoc analyses that were identical to the previous Cox regression models, but included the available treatment variables (surgery, chemotherapy, radiation, and hormone therapy) as additional predictors. Table 5 provides the percentages of each ethnic group receiving a given treatment by stage. With the inclusion of treatment variables, ethnic differences were no longer significant in the third cohort, but remained significant in the first two [Likelihood Ratio χ² (4) = 25.3, 29.1, and 8.2; p < .0001, p < .0001, and p = .08 respectively]. See Figure 2.

Additionally, we tested the post hoc hypothesis that Hawaiians have lower survival because they were both younger and diagnosed at a more advanced stage than the other groups. If advanced disease is more aggressive in young people, this could explain why the Hawaiians had lower survival. An interaction term between age and stage at diagnosis was created and added to the models run previously. However this interaction term did not show statistical significance, failing to support the post hoc hypothesis.

At least for cohort 3, our data also allowed us to compare the predictive value of the SEER staging variable (local, region, and distant) with that of the more comprehensive TNM staging variable. TNM staging provided significantly improved predictive value over SEER staging [Likelihood Ratio χ² (1) = 126.4; p < .0001]. However, inclusion of TNM staging did not eliminate the Hawaiian ethnic disparity in outcome [Likelihood Ratio χ² (4) = 11.7, p < .05], again suggesting that stage at diagnosis alone does not account for the persistently low survival among Hawaiians.

With few exceptions, results clearly supported the stated hypothesis that ethnic disparities in colorectal cancer survival have been diminishing over time. Figure 1, showing the convergence of survival over time, best exemplifies this. The one discrepancy in this overall trend is the unchanged life expectancy for the Hawaiian group in cohort 3. A comparison with the survival curves for other causes of death within cohort 3 reveals that this effect is specific to colorectal cancer and does not reflect a general tendency for Hawaiians to die sooner.

One possible explanation for this is that Hawaiians were not utilizing medical care to treat colorectal cancer to the same degree as other ethnic groups. Our post hoc analyses did demonstrate that ethnic disparities were no longer statistically significant after controlling for treatment differences. Interestingly, however, Hawaiians did not appear to be receiving less treatment; and with respect to chemotherapy and radiation, appear to have been receiving more than the other ethnic groups. One possible explanation for this is that treatment is causing adverse effects and death. Another is that doctors see prognostic signs of severe disease that are not measured by our covariates, and therefore prescribe more treatment. That is, Hawaiians may have more advanced disease than staging alone indicates.

The implications of these findings are important. If differential screening constitutes the primary reason for ethnic survival disparities, it should be possible to achieve equally favorable outcomes in all ethnic groups. With the exception of the Hawaiians, the evidence presented here reflects a convergence in terms of screening, medical care, and colorectal cancer survival among all ethnic groups. Further efforts are needed to examine why Hawaiians do not follow the overall trend, and how to make improvements. In this regard, a Native Hawaiian cancer network called the Imi Hale is attempting, along with support from the National Cancer Institute, to increase screening for colorectal cancer in Native Hawaiians.[27]

One limitation of this study is that data are restricted to the state of Hawaii. However, even though there are clearly potential regional differences in ethnic patterns of survival, the results of this study could be important beyond Hawaii. For example, in national studies, it has been shown that African-Americans are less likely than others to receive adjuvant chemotherapy.[28] Differential treatment utilization may drive ethnic outcome disparities. The role of individual patient choice and the role of complicating co-morbid conditions in treatment selection probably play some role, and another limitation of our study is not having access to this information. In future studies, however, we hope to elucidate the impact of such factors.

To this end, an important area for future research is detailed analysis of specific treatments received by cancer patients. For example, beginning in 1988 (the start of the third cohort in the present study) colorectal cancer survival has been improved through the use of 5-fluorouracil-leucovorin as adjuvant chemotherapy.[29] This factor, as well as improving stage distribution through screening, has undoubtedly contributed to the greatly improved colorectal cancer survival rates in the third cohort. Unfortunately, the HTR does not provide adequate detail with respect to specific chemotherapy treatments, so this hypothesis could not be examined here. However, future studies incorporating expanded data sources should examine whether Hawaiians have been receiving adjuvant 5-FU-leucovorin to the same degree as others, and if not, why not (e.g., access, informed choice with refusal of recommended treatment, or co-morbid disease).

Conversely, if Hawaiians receive apparently similar adjuvant therapy (i.e., same agents, dosage, number of courses, etc.), do they benefit to the same degree as others? Also, do they show a similar degree of treatment compliance? These issues may be of particular relevance, because results from this study suggest that Hawaiians are equally likely, if not more likely, to receive treatments.

Hawaiians have been reported to have relatively high rates of diabetes, renal and vascular disease, and tend to be afflicted at a younger age. Perhaps an interaction between cancer treatment and comorbid conditions is having a negative effect on Hawaiians. We speculate that co-morbid illness might play a role in treatment selection for some individuals with colorectal cancer. Collection of ICD-9 diagnosis codes from non-HRT sources with appropriate record linkage would allow us to study this.

Other results from this study indicate that age at diagnosis is another significant predictor of survival, with older individuals having a shorter life expectancy after diagnosis. However, a comparison of hazard ratios by cause of death showed that the values were much lower for death due to colorectal cancer than for other causes. This suggests that, while age is clearly related to overall survival, it is less relevant to colorectal cancer survival. That is, colon cancer is not more deadly for older individuals than for younger ones. Similarly, sex appears to predict colorectal cancer survival. A small beneficial effect was observed for women when considering death due to colorectal cancer, but a strong effect when considering death due to other causes. The impact of co-morbid disease on survival might explain these age and gender differentials.

Stage at diagnosis represents the most important prognostic variable. In this study the SEER staging system was used so that identical analyses could be performed across all three cohorts. However, for the most recent cohort (cohort 3), TNM staging clearly improved survival predictions over the less comprehensive SEER staging. In future studies, we will use TNM staging whenever possible.

This study provided longitudinal evidence in support of non-biologic explanations for ethnic disparities in colorectal cancer survival. Specifically, the present analysis suggests that observed ethnic differences result from differential screening. In Hawaii, ethnic disparities in colorectal cancer survival have narrowed considerably over the past 30 years. However, Hawaiian patients did not experience the same degree of improvement in survival as the other ethnic groups.