Abstract IA09: Realizing the promise of prevention (at the personal and population levels)
Authors: Hawk Ernest T. 
Published: March 2017

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women, and the second leading cause of cancer death in Americans. However, both CRC incidence and mortality have been steadily declining since the 1980's. Lifestyle risk factors are well-established and it's estimated that half of all colorectal cancers could be prevented through diet, exercise and weight management alone. Screening and early detection have also contributed to reductions in CRC incidence and mortality, and further reductions in mortality are anticipated as current methods are refined, more widely implemented, and novel methods are established. Molecular prevention, particularly with nonsteroidal anti-inflammatory drugs (NSAIDs), also offers tremendous potential for prevention. But to realize the promise of these preventive strategies, consistent impactful action at both the personal and population levels are required.

Lifestyle risk factors play a significant role in colorectal cancer. In addition to age, BMI (RR: 1.02 (1.02-1.03, I2=59.9%, p=0.000)) , alcohol (RR: 1.11 (0.90-1.38, I2=76.6%, p=0.004)), and red and processed meats (RR: 1.16 (1.04-1.30, I2=47%, p= 0.06)) have all been shown to convincingly increase the risk of colorectal cancer, while physical activity has been shown to convincingly decrease risk (RR: 0.92(0.86-0.99, I2=80.3, p&lt;0.001)). In 2014, tobacco was also added to the list of established CRC risk factors, as the Surgeon General's report, “The Health Consequences of Smoking—50 Years of Progress”, concluded that the evidence was sufficient to infer a causal relationship between smoking and colorectal adenomatous polyps and colorectal cancers.

In addition to lifestyle factors, the presence of adenomas is a strong predictor of CRC risk, increasing risk as much as two-fold in the general population. However, screening rates remain below the national target of 80% established through Healthy People 2020, with just under 60% of age-eligible Americans screened with either FOBT or endoscopy. And while the U.S. lacks an organized national screening program, the National Colorectal Cancer Roundtable has launched the “80% by 2018” initiative to achieve 80% of adults aged 50 and older being regularly screened for colorectal cancer by 2018. If this goal is met, 277,000 new colorectal cancers and 203,000 deaths from CRC will be prevented by 2030. Preliminary data on the impact of the Affordable Care Act (ACA) suggests that it has led to small-to-moderate increases (4 percentage-point change) in CRC screening rates, particularly among hard-to-reach sectors of the population, such as the least educated (5.7–7.5 percentage-point change) or those with lower incomes (4.3–7.8 percentage point change).

In conjunction with screening, safe and effective molecular prevention efforts (i.e., cancer chemoprevention) are also anticipated to reduce CRC incidence and mortality. NSAIDs have shown great promise for CRC prevention through a large body of fairly concordant observational studies and clinical trials suggesting 15-30% reductions across the spectrum of colorectal neoplastic development (i.e., adenoma incidence, CRC incidence and mortality). Recently, the United States Preventive Services Task Force recommended the use of aspirin for colorectal cancer prevention (a “B” level recommendation) in the setting of increased cardiovascular risks. Additional ongoing trials are addressing the potential benefits and harms of aspirin in particular population subsets, such as the elderly, and across a spectrum of clinically-meaningful endpoints (e.g., cancer, cardiovascular events, functional disability/status). COX-2 selective inhibitors, such as celecoxib, have shown efficacy against colorectal adenoma development in RCTs involving high-risk groups, but their cardiovascular risks have thwarted widespread adoption in the clinic. In high-risk groups, sulindac has demonstrated largely positive results while calcium has demonstrated mixed effects. Most recently, agent combinations have shown significant promise. A trial of sulindac and eflornithine at sub-traditional doses given over three years involving 375 patients with prior adenomas resulted in 70% reductions in recurrent adenomas and greater than 90% reductions in multiple and advanced adenomas. More recently, erlotinib and sulidac were combined in an RCT of 92 patients with FAP demonstrating synergistic efficacy against duodenal adenomas which are typically more resistant to chemopreventive effects vs. colorectal disease. Confirmatory trials of these agent combinations, as well as RCTs of various other agent combinations are planned or underway.

While these actions are available for individuals to implement to reduce their risk of CRC, evidence-based programs are also needed to reinforce healthy lifestyle messages and to increase CRC screening at the population level. Interventions that have been shown effective in increasing CRC screening include provider assessment and feedback, provider and patient reminders, reducing structural barriers for patients, as well as small media promotion and one-on-one educational sessions discussing the indications for, benefits of, and ways to overcome screening barriers. CRC screening promotional programs in New York City and Delaware serve as excellent examples of the effectiveness of coordinated, multi-sectoral strategies to bolster community-wide CRC screening. Between 2001 and 2009 in Delaware, for example, the state eliminated long-standing disparities in CRC screening, equalized incidence and mortality rates between African-Americans and Caucasians, and substantially reduced the proportion of African-Americans with regional and distant disease. These programs, as well as the evidence of CRC outcomes in well-insured populations such as the U.S. military, demonstrate that disparities in CRC outcomes need not exist.

Going forward, although it is clear that treatment will always be needed, prevention is anticipated to become the dominant strategy by which we address CRC. However, the implementation, dissemination and cultural-tailoring of existing evidence-based interventions to address lifestyle risk factors across the lifespan, such as the Coordinated Approach to Child Health (CATCH) school-based obesity-prevention program, is urgently needed. Newer, less invasive tests, such as stool DNA testing, also have a role to play in increasing screening rates. Organized population-based screening efforts that connect patients to not only screening services, but also to essential downstream diagnostic and treatment services through patient navigation and reduced structural and cost barriers, can have a profound impact of both CRC incidence and mortality, as demonstrated in Delaware and NYC. Characterizing the pre-malignant genome of colorectal adenomas is a potential research strategy that could help realize the potential of molecular prevention, as the future discovery of the molecular underpinnings of colorectal neoplasia could allow for the development of tailored preventive agents that can reverse, inhibit or halt the progression towards cancer. Finally, another potential strategy for enhanced CRC prevention is to identify those at highest risk of CRC due to inherited cancer syndromes, such as Lynch Syndrome. Such an approach would likely have an immediate positive impact on affected individuals and their family members. The future of prevention in CRC will rely heavily upon enhanced implementation and dissemination of what we already know regarding lifestyle risk factors and screening, as well as more tailored molecular prevention approaches.

Citation Format: Ernest T. Hawk. Realizing the promise of prevention (at the personal and population levels). [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA09.