Disparities in Advanced Stage Colorectal Cancer Outcomes in Appalachia: A Comprehensive Review

Appalachia Overview

The Appalachian region consists of 423 counties across thirteen states: Alabama, Georgia, Kentucky, Maryland, Mississippi, New York, North Carolina, Ohio, Pennsylvania, South Carolina, Tennessee, Virginia, and West Virginia. One-fourth of counties in Appalachia are classified as rural, defined as being neither part of nor adjacent to a metropolitan area. ¹ As of 2023, over 26 million Americans live in Appalachia, with almost 2.5 million living in rural Appalachia. ¹ Disparities in social determinants of health (SDOH) and health care outcomes in the Appalachian region demonstrate the necessity to investigate and address the needs of these communities.

Social determinants of health encompasses various aspects of the environment one lives in, and various trends in SDOH within Appalachia portend poorer health outcomes. Regarding economic stability, the median Appalachian household income is $56,780, sitting at almost $13,000 below the national median. ² The overall poverty rate is 14.5% in Appalachia, compared to the national rate of 12.6%. ² Geographic isolation also increases reliance on personal vehicles for long distance travel, ³ which is a known risk factor for obesity. ⁴ Food insecurity in rural Appalachia reaches rates of 26%, more than double the national rate of 11%. ⁵ Smoking rates are also high in Appalachia, with almost 50% of individuals under the age of 45 reporting as current smokers, and almost 60% of individuals with an annual income of less than $10,000. ⁶ Stigma toward seeking health care is another factor that leads to worsened health outcomes. For example, it has been shown that women in Appalachia uphold stigmas against mental health treatment, leading to an increased rate of depression within Appalachian women. ⁷ Lastly, adult literacy rates are also lower in rural areas such as the Appalachian region.^8,9

These trends in SDOH lead to poorer health outcomes and increased vulnerability to disease in the Appalachian population. Rates of diabetes are generally higher in Appalachia than the national average, with areas such as southeastern Ohio having a diabetes prevalence of over double the national average of 9.4%. ¹⁰ Furthermore, Appalachian residents are also being diagnosed with diabetes at a younger age. ¹¹ Obesity rates are nearly 44% of the entire Appalachian population, ¹² with adolescent obesity rates at 13.1%, more than double the national adolescent rates. ¹³ Hypertension rates in rural areas are more than 10% higher than urban areas. ¹⁴ Overall stroke rates are also higher than the national average and occur at younger ages within the Appalachian population. ¹⁵ Prevalence of chronic cardiac disease and its associated mortality are also higher in Appalachian region.^15,16 While this increase in cardiac disease is likely due to both SDOH and higher comorbidity burdens as mentioned above, it has also been shown that adolescents who are current smokers are less likely to believe that smoking is unhealthy. ¹⁷

The combination of SDOH and comorbid health conditions also increases the risk of cancer in the Appalachian population. Not only is the risk of cancer increased, but cancer mortality is also higher in comparison to non-Appalachian regions. ¹⁸ Furthermore, there exists a difference between rural and urban Appalachia, with rural Appalachia having persistently higher cancer incidence and mortality rates than that of urban regions. ¹⁹ For example, lung cancer incidence ²⁰ and mortality ¹⁸ have been shown to be elevated in Appalachian regions relative to the rest of the nation. In addition, many Appalachian regions have extensive coal mining industries, and residents from those regions have even worse lung cancer outcomes compared to the rest of the Appalachian population. ²⁰ Prior studies have also demonstrated that there is an increased incidence of cervical, ²¹ breast,^22-24 penile, ²⁵ prostate, ²⁶ colorectal, ²⁷ and head and neck ²⁸ cancers. This paints a picture of the dire need for interventions targeted towards reducing health disparities, and specifically cancer disparities, in Appalachian populations.

This review aims to summarize the current understanding of advanced stage colorectal cancer and its impact on Appalachian populations. We also strive to highlight prior efforts to reduce disparities within this vulnerable population and emphasize the importance of collaboration between medical centers in these regions to create and implement feasible interventions.

Advanced Stage Colorectal Disease Overview

Advanced stage colorectal cancer is defined by the presence of metastatic disease with an American Joint Committee on Cancer (AJCC) TNM stage of IVA, IVB, or IVC that is largely based upon the site of distant disease spread. In general, the most common locations for solid organ metastases include the liver and lungs (stage IVA if spread is isolated to one distant organ or IVB if affecting more than one distant organ). Peritoneal metastasis of colorectal cancer (stage IVC) represents a unique patient population, as although the peritoneum is a common site for metastatic disease, management differs from those patients with IVA or IVB disease.

Aside from the known general risk factors for development of colorectal cancer, there are specifically described risk factors related to development of advanced stage disease as previously described. Namely, the site of location of the primary tumor (ie, right-sided vs left-sided) can influence disease course due to the differences in tumor morphology and histology. In general, right-sided tumors are often sessile serrated adenomas and mucinous adenocarcinomas, while left-sided tumors tend to show tubulo-villous architecture and be typical adenocarcinomas. ²⁹ Therefore, right-sided invasive cancers can be harder to detect during earlier stages of tumorigenesis on colonoscopy given their flat morphology as compared to the polypoid morphology of left-sided tumors. ²⁹ Access to lower endoscopy, specifically screening colonoscopy, is another multifactorial consideration when stratifying the risk of presenting with advanced stage disease. Those patients with limited access due to socioeconomic and/or geographic disparities are more likely to have a delayed presentation as diagnostic workup is not initiated until there is a high symptom burden.

Treatment of advanced stage colon cancer takes a multi-disciplinary approach with both systemic treatment and surgery serving as mainstay pillars of therapy. Namely, advanced disease should be divided into metastases that are classified as resectable or unresectable. In those patients with a primary colon cancer and concomitant hepatic metastasis(es) where resection would leave an adequate future liver remnant, either neoadjuvant chemotherapy followed by surgery or upfront surgery are acceptable routes of treatment with similar outcomes. ³⁰ Surgery in this context can be accomplished via a single combined operation or as staged procedures with the decision individualized to each patient’s clinical gestalt. Similarly, pulmonary metastatectomy should also be considered as it has demonstrated a survival advantage in some studies. ³⁰ It should be acknowledged here that systemic chemotherapy and/or immunotherapy in conjunction with hepatic artery infusion of chemotherapy has the potential to increase the resectability of previously unresectable hepatic metastases. ³⁰ Patients with peritoneal disease that is determined to be resectable based upon calculation of the peritoneal carcinomatosis index (PCI) and without contraindications can undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for curative intent, long-term disease control, or both. General contraindications to CRS/HIPEC include hepatic or pulmonary metastases, any extra-abdominal metastasis, or decreased likelihood of achieving a complete gross cytoreduction, or completeness of cytoreduction (CC) score of 0. Systemic chemotherapy alone remains the standard of care initially for patients with multi-visceral metastasis that is diagnosed at the same time as the primary cancer or develops following resection of the primary cancer. ³⁰

Appalachian Experience With Advanced Stage Colorectal Disease

Patients with advanced stage colorectal disease are a uniquely vulnerable patient group that often require a multidisciplinary and personalized approach to care. Colorectal malignancy, like many other cancer types listed above, disproportionately affects Appalachian populations. It has been shown that age-adjusted colorectal cancer incidence in Appalachian regions was 120% that of non-Appalachian regions. ³¹ Colorectal cancer mortality is also higher in the Appalachian population.^31-33 Furthermore, more young patients are developing colorectal cancer in these regions, with the rate of early-onset colorectal cancer being 1.5 times higher than the national rate. ³⁴ Appalachian residents are also more likely to have a late-stage cancer diagnosis compared to non-Appalachians. ³²

Factors contributing to these disparities in colorectal cancer can be summarized in 2 groups: psychosocial and health systems risk factors. Psychosocial factors include educational level, basic literacy, tobacco use, obesity, diabetes, and social isolation. Within Appalachian counties, there is a strong negative correlation between rates of high school completion and colorectal cancer incidence and mortality. ³¹ Basic adult literacy, likely related to educational attainment, is likewise negatively correlated with colorectal cancer incidence and mortality. ³¹ And as previously described, basic literacy rates are lower in Appalachian regions relative to non-Appalachian areas.^8,9 Obesity, diabetes, and tobacco use were all shown to be risk factors for developing colorectal cancer at a younger age among Appalachian populations. ³⁴ Similarly, these are characteristics previously shown to be more prevalent in Appalachia. Colorectal cancer mortality has also been shown to be associated with social isolation in Appalachia. ³² Given the rural nature of Appalachia, a greater proportion of its population is more likely to experience social isolation. Health systems factors include screening, early interventions, and treatment options. Interestingly, it has been shown that women in rural Appalachia were adherent to breast cancer screening but not to colorectal cancer screening. ²² A logical consequence of lower screening rates is delayed treatment and decreased early interventions, which has also been shown to be common among Appalachian states. ³⁵ Even after the diagnosis is made, treatment options within Appalachian regions are often suboptimal. Guideline concordant chemotherapy rates in Appalachia were 62.9%, ³⁶ compared to 79.4% and 71.8% for patients on Medicaid and Medicare payers, ³⁷ respectively. Adjuvant radiation therapy rates were 56.0%, ³⁶ compared to 72.3% and 66.9% among Medicaid and Medicare payers, ³⁷ respectively. Lower volume hospitals or hospitals without Commission on Cancer designation in Appalachia were also less likely to perform guideline concordant lymph node assessments on their patients compared to other Appalachian hospitals with higher volume and/or Commission on Cancer designation. ³⁶

Unfortunately, there is a lack of literature examining the incidence and outcomes of advanced stage colorectal cancer. However, given the extensive risk factors prevalent in Appalachian populations and the inadequate health care infrastructures, it is reasonable to assume that advanced colorectal cancer disproportionately affects Appalachian residents.

Future Directions

Given everything presented in this review, it is clear that there is a tremendous need for interventions targeted towards reducing colorectal cancer incidence and mortality in Appalachian regions. It is also clear that there is a paucity of research examining how advanced stage colorectal cancer affects Appalachian populations, which is crucial in determining implementable changes.

First, it is critical to realize that many of these disparities in colorectal cancer arose from SDOH and lifestyle factors. Certain dietary changes, such as ketogenic diets ³⁸ and higher vegetable fat intake, ³⁹ have been shown to delay cancer progression and improve metastatic colorectal cancer outcomes. However, dietary resources for colorectal cancer patients are scarce. ⁴⁰ Therefore, interventions improving dietary resources and education would be crucial. In smaller scales, this could improve colorectal cancer outcomes in Appalachian residents who become diagnosed; in larger scales, this could lead to population improvements in diet and a decrease in colorectal cancer rates. While limited resources are always a practical concern, it has been shown that implementation of screening tools in an outpatient setting could help identify colorectal cancer patients at higher risk for malnutrition. ⁴¹ A step-by-step approach, such as starting with screening for malnutrition among colorectal patients, to screening all patients at outpatient clinics, to community-wide efforts to capture those uninvolved in the health care system, could be a feasible approach to using dietary modifications to improve colorectal cancer outcomes in Appalachia. Education is another area of focus that could improve colorectal cancer screening adherence and improve outcomes. For example, it has been shown that increased knowledge on colorectal cancer was associated with a significant decrease in psychological barriers to screening. ⁴² Community cancer coalitions have also been shown to be effective in increasing dissemination of colorectal cancer educational materials to rural Appalachian populations. ⁴³ An interesting study examining the role of fatalism in lack of screening adherence demonstrated that a community-based approach to promoting endoscopies could overcome colorectal cancer-associated fatalism and encourage more people to receive screening. ⁴⁴ Health care providers in these vulnerable locations could also assist in public education on colorectal cancer and increase screening. For example, a pilot study found that providers recommending take-home fecal immunochemical testing kits and provider telephone counseling could increase colorectal cancer screening in Appalachia. ⁴⁵ In addition, academic detailing has also been shown to be acceptable and feasible for primary care providers in rural Appalachia to increase colorectal cancer screening. ⁴⁶ This highlights the potential for interventions targeting SDOH such as diet, lifestyle, and education to improve colorectal cancer screening and outcomes.

While the prior section emphasized the importance and effectiveness of community outreach, there must also be interventions targeting access to high-volume centers for care. For advanced stage colorectal cancer, patients often need to travel to advanced medical centers to receive treatment. However, rural patients face many challenges in accessing the care they need. The long travel time, to those who can make the trip, was cited as a barrier to receiving care. ⁴⁷ Furthermore, those who had follow-ups in local providers often reported lack of availability and consistency in their care. ⁴⁷ This does not even consider those with advanced stage colorectal cancer who cannot access the care they need to begin with due to distance. Therefore, improving access to large medical centers is necessary in ensuring that rural Appalachian residents who do develop advanced colorectal cancer have access to the care they need.

In summary, the Appalachian population is at a higher risk of developing advanced colorectal cancer and having poor outcomes. Various factors contribute to this disparity, and many interventions are possible ranging from improving community-level education, promoting healthier diets, increasing local screening awareness, and increasing access to large volume centers for care. Therefore, it is imperative for medical institutions in and around the Appalachian region to collaborate. Collaborations between institutions could help increase investigation and knowledge into this vulnerable population, and to use the newfound knowledge to design implementable changes. Large institutions also are more likely have the resources and capabilities to reach rural communities and help improve smaller, local hospitals to better serve their population. Appalachian residents face drastic disparities in colorectal cancer rates and outcomes, but through a concerted effort among large medical institutions near the area, local hospitals and clinics, and outreach programs, this does not need to remain the case.