The toll of not screening for colorectal cancer

KEYWORDS:

• Colorectal cancer
• screening
• colonoscopy
• sigmoidoscopy
• fecal occult blood test
• incidence
• mortality

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer mortality worldwide. Each year, 1.4 million people are diagnosed with CRC, representing 10% of the total global cancer incidence, and 700,000 people die as a result of the disease [1]. Although more cases continue to occur in high-income countries, CRC incidence has been rising rapidly in many less developed countries, such as Brazil, Philippines, and Bulgaria [2]. A large proportion of these cancers, however, develop slowly from removable colorectal adenomas over many years [3], and when detected and treated at early stages, the disease is mostly curable. Patients with CRC detected in a localized stage have a 5-year survival rate exceeding 90%, whereas 5-year survival still hardly exceeds 10% for patients with metastatic CRC [4].

These features make CRC a most suitable target for screening. Through early detection and removal of nonmalignant precancerous lesions and early cancers, screening tests can effectively reduce the incidence of advanced carcinoma and thus lead to a reduction in CRC mortality. A growing body of joint evidence from randomized controlled trials (RCTs) and observational studies have well established the effectiveness of screening by fecal occult blood test (FOBT), sigmoidoscopy, and colonoscopy in the prevention of CRC occurrence and deaths [5,6]. Population-based epidemiological analyses showed that recent colonoscopy use among around one-third of the screening-eligible population in the USA had avoided approximately 10,000 CRC deaths in 1 year, and about twice as many deaths could theoretically have been prevented if perfect adherence (100%) were achieved [7]. The considerable declines in CRC incidence and mortality observed in the USA over the past decade, in fact, are believed to be largely attributed to the increased awareness about the disease and the relatively high adherence to screening, especially colonoscopy screening [8]. Likewise, in Germany, a substantial and accelerating decrease in CRC incidence and mortality was observed between 2003 and 2012, the first 10 years since the implementation of screening colonoscopy. This decrease was selectively observed in the age groups for whom screening colonoscopy is offered (55+) [9].

Although CRC screening requires initial investments, modeling studies have consistently shown that CRC screening is cost-effective (if not cost-saving) in the long run, and comparable effectiveness and cost-effectiveness can be achieved through different strategies, such as annual FOBT, sigmoidoscopy every 5 years with annual FOBT, and colonoscopy every 10 years [10].

Because of the large potential in reducing disease burden, CRC screening has been recommended in many guidelines for average-risk persons aged over 50 years. However, only a few countries currently have screening programs in place or are in the process of implementation, and screening programs are essentially restricted to some of the more developed countries in North America, Europe, and Asia [11]. Even in countries where screening tests are routinely offered, such offers often do not reach the entire population and uptake rates often remain suboptimal, leaving much of the potential impact of screening programs unutilized.

Most population-based organized screening programs employ a two-step approach, starting with a noninvasive stool test, usually guaiac-based FOBT (gFOBT) or (increasingly) fecal immunochemical test (FIT), and following up with colonoscopy for those with positive results. Due to the need for repeated testing annually or biennially, one of the challenges these programs face is how to keep up the good compliance among initially screened persons in the following rounds of screening [12]. Sustained participation is essential for screening efficacy and should be an equally important indicator for program evaluation. Experience from the Netherlands and Finland shows that sustained high participation rates can be achieved by well-organized screening programs [13,14]. In some affluent countries where CRC screening is mostly opportunistic and delivered through physician recommendation, such as the USA, the predominantly used strategy is screening colonoscopy every 10 years. Seemingly more flexible for the target population, such strategy also has adherence that falls below the desirable levels – about one-third of age-eligible US residents were not up to date with screening in 2012 [15].

Multiple factors from individual, healthcare provider and organizational levels have been reported to be associated with screening compliance, such as patient socioeconomic status and knowledge of CRC screening, physician recommendation and provider-patient communication, as well as health insurance coverage and distribution of endoscopists [16,17]. To increase adherence and reduce disparities, efforts should focus on targeted intervention programs or strategies that can effectively remove barriers to CRC screening and facilitate the use. For example, intervention studies showed that intensive interactions between patients and healthcare providers or educators could lead to an absolute increase of up to 42% in screening uptake [16]. In addition, reminder systems, enhanced information leaflets, along with a number of other interventions that address barriers from various levels have all shown positive results [16,18]. Nonetheless, how to incorporate a specific intervention into existing screening program requires careful consideration in the context of target population preference, health system structure, and available resources, among others. Improving use of already established screening programs should be a priority not only for practice, but also for research, apart from other key research topics like continued search for enhanced noninvasive diagnostic tests, monitoring of screening program quality, as well as the evaluation and improvement of screening performance in real-world settings.

From a broader perspective, there are additional structural factors that may affect translation of research findings in the implementation of most effective CRC screening. For example, much attention in the research community is being placed on continuously generating new evidence, especially for innovative diagnostic tools [16], while scientists are often less engaged and involved in disseminating this evidence to policy-makers and the public, and facilitating the implementation and proper use of screening. The latter field is often dominated by marketing strategies of manufacturers of novel tests, or by lobbying activities of professional groups who might benefit the most from pertinent screening offers which may go along with biased weighting of the evidence. For example, a novel test combining detection of specific genetic alterations with detection of hemoglobin in stool rapidly achieved widespread application in the USA, despite approximately 20-fold higher costs compared to FIT [6] that go along with an at best marginal if any advantage in diagnostic performance and major drawbacks in logistics [19].

Another example concerns the time course of creating evidence for the effectiveness of new screening modalities in reducing CRC incidence and mortality. There is common agreement that the most rigorous scientific evaluation may come from RCTs. However, given the very long-term, often decades-long development of most CRCs from their precursor lesions, it takes decades until the effects of novel screening modalities on CRC incidence and mortality can be fully disclosed by RCTs. Waiting for such results may lead to a large toll of CRC deaths in case of undue delay of implementation of the presumably most effective screening modalities. For example, while effectiveness of FOBT screening and screening sigmoidoscopy have long been demonstrated by RCTs, main results of RCTs specifically focusing on screening colonoscopy will be available around the year 2030 only. Given the long-standing, compelling evidence for the effectiveness of screening colonoscopy from observational studies in reducing incidence and mortality not only of distal but also (albeit to a lesser degree) of proximal CRC [5], the toll of delaying offering screening colonoscopy until the RCT results are available would be unacceptably high. For example, it has been estimated by model calculations that screening colonoscopies carried out in the initial 10 years of the German screening colonoscopy program (2003–2012) already resulted in the prevention of 180,000 new CRC cases [20]. Therefore, balanced weighting of evidence from both RCTs and observational studies is required to enable the most responsible decisions regarding implementation of screening programs.

Facing the burden of CRC, there is still much to be done. This includes not only increasing screening uptake through evidence-based interventions as discussed, but also ensuring screening quality by close and continued monitoring of program performance. With regard to opportunistic settings specifically, encouraging the use of the full range of tests is essential for further improvement in screening acceptance. An alternative stool test is always better than nothing when an endoscopic examination is refused. Additionally, it is time for high CRC incidence countries without screening programs to seriously consider the need and to decide the most suitable option, though for resource-constraint countries, such planning need to be based on competing disease burden and available resources and infrastructure. In particular, screening by a low-cost test, such as FOBT, may often be the only option in developing countries. Appropriate and high-quality screening service might be best delivered through organized population-based programs that include personal invitation, active follow-up, treatment for those with positive results, and rigorous quality control. Racial and socioeconomic disparities in screening can also be better addressed with organized programs, where the eligible population is provided with more equal access.

In conclusion, screening for CRC has been demonstrated by compelling evidence to be effective and cost-effective in reducing the disease incidence and mortality. Nevertheless, screening programs are currently only in place in a few countries and the uptake rates remain suboptimal. Multiple factors are associated with screening uptake, and interventions that can remove the barriers to CRC screening are a priority not only for practice, but also for research. Other key research topics include the continued search for novel noninvasive diagnostic tests, monitoring of screening program quality, as well as the monitoring, evaluation, and improvement of screening performance in real-world settings. To realize the full potential of CRC screening, more efforts need to be made to increase screening adherence and guarantee screening quality, and to implement such programs for high incidence countries where CRC screening is currently not routinely offered. Studies that demonstrated the effectiveness of screening, in fact, reveal an unsettling truth – a large proportion of the 700,000 CRC-related deaths every year should not occur. This is the toll of not screening for CRC. Underuse of CRC screening is a public health issue that patients, healthcare providers, scientists, and policy-makers all must work together to overcome.

Declaration of interest

H. Brenner has applied for a patent ‘Biomarker panel for diagnosing cancer’ (Application Number: EP 15161465.8 Priority Date: 27.03.2015). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Research on colorectal cancer screening conducted in the Division of Clinical Epidemiology and Aging Research at the German Cancer Institute has been partly funded by industrial research grants from Eiken Chemicals, Epigenomics, Roche Diagnostics and Applied Proteomics to the German Cancer Research Center.