Since stage at diagnosis plays a significant role in CRC survival, understanding which factors contribute to a more advanced stage at diagnosis is vital to improving overall survival. Potential factors include comorbidity, age, and race. These factors are known to influence cancer outcomes at least in terms of receipt of standard therapy, which in turn, likely influences survival [4-10]. While the relationship between delivery of treatment and these factors has been established, the association between comorbidity, age, race, and stage at diagnosis of CRC is less clear (Figure ​(Figure11).

A critical, comorbidity-related concern in cancer outcomes relates to how comorbidity influences survival among cancer patients. Comorbidity is already known to negatively influence the delivery of stage-appropriate treatment (Figure ​(Figure1),1), and not receiving appropriate therapy will negatively influence survival outcomes [23-29]. As the population ages, the increasing burden of comorbid illness will likely play a greater role in cancer treatment-related toxicity and outcomes. Higher comorbidity has been shown to broaden the survival disparity between blacks and whites with CRC [24]. Both comorbidity and advanced age have been associated with worse outcomes after surgery for CRC [23,25,26,29], decreased referral to a medical oncologist [23,28], and incomplete courses of adjuvant chemotherapy [27,30]. By best understanding where in the cancer care continuum comorbidity, age, and race exert their greatest influence, we can better determine how to improve care for patients with comorbid illnesses and CRC.

In the VA cohort, where increasing comorbidity was associated with earlier stage at diagnosis, patients with multiple comorbid illnesses might have more frequent health care contact and thus benefit from the greater clinical scrutiny it provides. Evidence demonstrates that VA patients are more likely to experience higher quality primary care than FFS patients; a corollary to increased access to primary care is an increase in routine chronic and preventive medical care that may be overlooked in commercial health systems with less access to primary care. In non-VA populations, FFS health care might lead to erratic interaction with the health care system as determined by ability to pay. For example, VA patients have been shown to do better with diabetes and hyperlipidemia control than patients in commercial health systems [15]. VA patients are more likely to report receiving diabetes education than those covered by private insurance [31]. Hence, the increased medical scrutiny inherent when a person has multiple comorbidities coupled with a health system that provides easy access to primary care providers might ensure delivery of age-appropriate screening or might lead to the incidental diagnosis of cancer through blood tests or studies ordered for other purposes.

Other factors may explain the relationship between comorbidity and stage observed in the VA cohort and not in the FFS cohort. Most notably, the difference might be due to differences in the two cohorts. The VA cohort was older, predominantly male, and carried a higher burden of comorbid illnesses than the FFS cohort. This difference between the VA and non-VA cohorts in our analysis is representative of the VA and non-VA populations as a whole [32-35]. The association might be influenced by the comorbid conditions themselves, leading to a varied influence of comorbidity on stage based more upon population and less on health system. For example, symptoms attributed to comorbid illnesses might actually be arising from a neglected, evolving malignancy [36]. Second, the pathophysiology of the comorbid illness or its treatment might contribute to the development or progression of the cancer. For example, a growing body of data has demonstrated an association between chronic insulin therapy and development of CRC among patients with type II diabetes mellitus [37]. Such factors might have diminished (in the VA group) or nullified (in the FFS group) the effect of comorbidity on stage at diagnosis.

Another factor may have been the definition of the FFS cohort. Eligible patients had metastatic disease during 2003–2006, although their prior non-metastatic period was also considered. As a result, the cohort was enriched with patients who were stage IV at diagnosis. This group may have less screening and healthcare involvement at baseline, and the impact of comorbidity status may have been diluted. Nonetheless, this group still had a quarter of patients who were non-metastatic at diagnosis.

In our analysis, race and age were not influential factors in the stage of CRC diagnosis. Age was not influential likely because numeric age is less important clinically when the degree of comorbidity is measured. In other words, older patients without significant comorbidity should have similar clinical outcomes than relatively younger patients without comorbidity. For instance, when older patients receive chemotherapy, they are able to tolerate and respond to treatment as well as their younger counterparts [38-41]. The lack of interaction with race and stage at diagnosis might be due to a similar process. Bach et al found that after controlling for population mortality (non-cancer related death), the difference in cancer-related mortality between blacks and white was diminished [24]. The racial differences in stage at diagnosis might be reduced when adjusted for comorbidity. We did not, however, account for differences in socioeconomic status, which might have also influenced the role of race.

In framing the significance of our findings, the limitations of this study must be discussed. First, in terms of categorizing comorbidity, we chose to use the Charlson index, which has been validated in the oncology setting. Despite being updated, the index was created in 1984 and based on admissions to a hospital over a one-month period [20,21], which brings into question the generalizability of the index to cancer diagnosis and treatment today [42]. The Charlson index does not grade severity of comorbidity, nor does it capture functional disability. It might not be measuring comorbid conditions that are most relevant to a cancer population. On the other hand, the ease of use, reliability, and content validity of the index make it a reasonable choice [42].

Second, asymptomatic screening was not addressed as a variable in this study as patient screening information was not available for both patient cohorts. Patients with a high comorbidity index might be less likely to undergo cancer screening due to an increased risk for non-cancer-related mortality. If this were the case, the relationship between comorbidity and stage at diagnosis might be less important than the relationship between comorbidity and receipt of screening, as delayed screening could contribute to later stage at diagnosis. However, studies conducted in both VA and non-VA populations have shown that patients are screened for CRC regardless of comorbidity status, thereby suggesting that no relationship exists between degree of comorbidity and rates of asymptomatic screening [43-46]. If screening rates are not influenced by comorbidity, then stage at diagnosis becomes the next most important variable for investigation. Furthermore, if younger, healthier patients are more likely to be screened for CRC, then this analysis should have found that younger, healthier patients present with non-metastatic disease, and older, sicker patients present with metastatic disease. It did not.

This analysis does not explicitly address access to screening studies such as colonoscopy. Multiple factors have been associated with access or adherence to colorectal cancer screening, including age, education, insurance status, and a usual source of care [47]. Our presented data cannot address these characteristics completely, though the literature supports the assumption that VA patients enjoy greater access to many aspects of primary care than Medicare fee-for-service and privately insured patients [15,16,31]. While specific data is not available for our sample, the rate of CRC screening with endoscopy is fairly equivalent between VA and non-VA populations [48,49].

This study has strengths that overcome limitations of prior studies. First, we provide consistent data from two distinct health care systems. Our study is the first to examine the relationship between comorbidity, age and stage at diagnosis in the VA health system. As receipt of care in this system is less dependent on ability to pay, it serves as a useful control for the inability to access appropriate cancer care [50]. Second, this study does not dichotomize comorbidity, but models it as an integer-valued quantitative variable (0–≥ 3) with Charlson score ≥ 3 equated with severe comorbidity. A score of ≥ 3 predicts a significantly greater risk of non-cancer-related mortality over a one-year period [21]. A prior study demonstrated a slightly higher prevalence of comorbidity in patients diagnosed with early-stage (Dukes' A) CRC, but this study dichotomized comorbidity with a cut point of ≥ 1 [51]. A study by Gonzalez et al found the opposite: patients with any comorbid condition (Charlson score ≥ 1 vs. 0) were more likely to be diagnosed at late-stage, though interestingly, this finding did not persist with a Charlson score of ≥ 2 [52]. Based on these findings, we chose not to dichotomize comorbidity. This more quantitative use of the comorbidity index, as opposed to simply measuring presence versus absence of any comorbidity, might provide a more clinically-useful model when assessing the role of a comorbidity index on the diagnosis, treatment, and outcomes of cancer. A third strength of our study lies in our ability to measure comorbidity. Studies examining stage with larger cohorts obtained from cancer registries such as the Surveillance, Epidemiology, and End Results (SEER) database do not have access to comorbidity data.

Our exploratory results help to focus future efforts on improving CRC outcomes. As the association between comorbidity and cancer outcomes becomes clearer, future prospective studies should examine where in the patient's cancer care trajectory a specific comorbid illness might impact outcomes [53]. For example, among patients with breast cancer, studies have shown that only certain comorbid illnesses (such as diabetes) contribute to a later stage at diagnosis, while others (such as cardiovascular disease) do not [54]. Our exploratory findings should encourage further investigation into how comorbid illnesses, and not just comorbidity indices, impact diagnosis, treatment, and survival. If patients are even more likely to be diagnosed at early stage in the setting of comorbid illness, it becomes even more important to develop CRC treatment strategies that accommodate comorbidities. Future analysis will ask similar questions of the complete, multi-health system CanCORS sample, which includes approximately 10,000 lung and colorectal cancer patients. Socioeconomic characteristics, including income and education, should also be explored in conjunction with comorbidity. These factors cannot be appropriately investigated through SEER-Medicare linked datasets but can be explored via CanCORS.

As cancer treatment improves, more patients are living longer. As a result, more attention needs to be paid to the role of comorbidity and the patient's overall health as comorbidity might actually play a greater role in survival than the cancer, itself. Studies have shown that some cancer patients might be less likely to adopt diet, exercise and other healthy lifestyle changes after a cancer diagnosis [55]. Future interventional studies among cancer patients might investigate how better controlling health habits and comorbid illnesses might improve health-related quality of life and cancer-related survival outcomes. Data from this study suggests that the role of the health system and primary care provider may be an important influence in timing of diagnosis of CRC; similarly, access to primary and routine healthcare will be important for maintenance of health in the cancer survivorship period.