Symptoms and early-onset colorectal cancer: red flags are common flags!

The incidence and mortality associated with early-onset colorectal cancer (EoCRC), or CRC diagnosed at younger than age 50 years, has been increasing (1). In response, multiple professional organizations (2-4) lowered the age to begin screening in those at average risk (no symptoms, no family history) from 50 years to 45 years. However, one-half of EoCRC is diagnosed in patients younger than 45 years, and therefore would not be detected through screening (5). Thus, in addition to improving screening, the current approach to improving early detection of EoCRC also includes optimizing earlier screening in those with a family history of CRC or advanced polyps (2,3) and prompt evaluation of red flag signs and symptoms. The principal challenges in operationalizing “prompt evaluation of signs and symptoms” are to 1), understand which signs and symptoms should trigger diagnostic evaluation, 2), what that diagnostic evaluation should entail, and 3) the timeframe within which this evaluation should be completed to avoid upstaging of disease due to diagnostic delays.

We read with great interest the article in this issue of the Journal by Fritz et al. (6), who used the IBM Marketscan Database, which includes 113 million adults in the United States from 2006 to 2015, to assess 17 red flag signs and symptoms for EoCRC between 3 and 24 months before diagnosis of EoCRC. They included 5075 EoCRC patients and 22 378 controls, matched on the basis of age, sex, geography, insurance, and prescription drug enrollment. Investigators found that 68.6% of EoCRC patients presented with red flag signs and symptoms, as early as 24 months preceding their cancer diagnoses. Red flags included abdominal pain (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.19 to 1.49), rectal bleeding (OR = 5.13, 95% CI = 4.36 to 6.04), diarrhea (OR = 1.43, 95% CI = 1.14 to 1.78), and iron deficiency anemia (OR = 2.07, 95% = 1.61 to 2.66). Those who had 3 or more signs and symptoms had 6.52 times (95% CI= 3.78 to 11.23 times) the likelihood of EoCRC. This association was more pronounced in those with rectal cancer and the younger age groups. A total of 19.3% of EoCRC cases were diagnosed between 3 months and 2 years after first sign or symptom, with a median time to diagnosis of 8.7 months.

It is important to note that this commercial insurance database does not include Medicare, Medicaid, veteran, or indigent patients, and those with health maintenance organization insurance and from rural locales comprised a minority of the overall cohort, thus limiting generalizability to these populations. The results rely on diagnostic codes entered for symptoms and thus may not be generalizable to all individuals who have these symptoms or mention them to their providers. The database also lacked data on race, ethnicity, and preferred languages, factors known to affect EoCRC presentation and outcomes (7,8). Finally, data on cancer stage were unavailable; thus, this study neither clarifies whether delayed diagnoses are associated with more advanced stages of EoCRC, nor informs the optimal timeframe within which diagnostic testing must be completed to avoid upstaging of disease. Acknowledging these limitations, this study reproduces prior work (9) showing that rectal bleeding and iron deficiency anemia are strongly associated with development of EoCRC. Although a more attenuated association, this study also found that abdominal pain and diarrhea are associated with EoCRC, and harboring multiple symptoms compounds risk.

Understanding risk factors associated with EoCRC, particularly among those not yet eligible for screening, is critically important to selecting those who need diagnostic testing to evaluate for EoCRC. Multiple professional societies recommend colonoscopy for those with unexplained red flags such as hematochezia or iron deficiency (3,10). Unfortunately, gastrointestinal symptoms such as abdominal pain, hematochezia, altered bowel patterns, and iron deficiency are very common in the general population, and it is not likely feasible to offer colonoscopy to all of these individuals. For instance, a survey of more than 70 000 individuals in the United States found that 24.8% had abdominal pain and 20.2% had diarrhea (11). The National Health and Nutrition Examination survey reported that 5.6% of the US population has anemia (12). Of approximately 140 million adults aged 18 to 49 years living in the United States (13), this would amount to more than 34 million patients with abdominal pain, 28 million with diarrhea, and almost 8 million with anemia. Based on the odds ratios of EoCRC associated with abdominal pain (OR = 1.34) and diarrhea (OR = 1.43) reported in this study and the EoCRC incidence rate of 8.8/100 000 (14), 59 856 colonoscopies would be required to diagnose 2 cases of EoCRC on the basis of those symptoms (Figure 1). If we were to limit colonoscopies to those with 3 or more red flags (OR = 6.52) or the authors’ proposed weighted symptoms score of at least 2 (OR = 7.51), this would require 2060 or 1747 colonoscopies, respectively, to diagnose 1 case of EoCRC. Even if we had unlimited, immediate, and equitable access to colonoscopy, successfully navigating the sheer volume of young patients with these symptoms to colonoscopy would require massive multilevel and systematic approaches, ranging from public health awareness campaigns to leveraging electronic health records to identify and navigate patients to closed-loop evaluations (15).

Figure 1.

A representation of the approximately 59 856 adults aged 18-49 years in the United States with abdominal pain or diarrhea on the basis of a national survey by Almario et al. (11). Based on an annual early-onset colorectal cancer (EoCRC) incidence rate of 8.8/100 000 of EoCRC (14) and the odds ratio of EoCRC for those with abdominal pain and diarrhea presented by Fritz et al. (6), approximately 2 of the 59 856 individuals may have EoCRC. If the performance of quantitative fecal immunochemical testing (FIT) with a threshold of 10 µg/g reported by D’Souza et al. (21) is similar in those aged 18-49 years, applying FIT to the 59 856 individuals with abdominal pain and diarrhea would likely capture both patients with EoCRC (sensitivity of >90%) and require a total of 12 colonoscopies.

The reality is that we do not have unlimited, immediate, or equitable access to colonoscopy. Only 50% of those aged 50-54 years in the United States are up-to-date on CRC screening (16), up to 62% of individuals with a family history are not up-to-date on age-appropriate screening, and there is a burgeoning population of individuals entering polyp surveillance programs (17). The mismatch in colonoscopy availability and demand disproportionately affects underserved populations such as Black patients, Non-White Hispanic patients, and Alaska Native patients (18), populations that are devastatingly affected by EoCRC with earlier ages of diagnosis, later stages at diagnosis, and higher mortality (8). It is hard to imagine that expanding diagnostic colonoscopy to all individuals with the symptoms presented by Fritz et al. (6) can be accomplished in a systematic or equitable way, particularly because underrepresented groups are more likely to be diagnosed with these red flags in emergency room or urgent care settings (19), where the presentation may not be recognized as a red flag for EoCRC and patients may not be navigated to stable outpatient care.

This study, along with a growing body of literature on risk factors for EoCRC, presents a mandate for us to refine our approach to risk stratification to direct limited colonoscopy resources toward those at highest risk of harboring cancer, with the goal of avoiding the increased morbidity and mortality from upstaging of disease caused by diagnostic delays. Even with restricting colonoscopy to those with multiple symptoms or a weighted symptom score threshold, it is likely that patients with symptom codes entered during medical encounters (such as in this study) are a more risk-saturated population than those who may mention these symptoms to clinicians. Thus, it is critically important to entertain more objective risk stratification tools that can be applied to those with symptoms to truly identify the patients at highest risk for CRC. Although it would be ideal to apply a model, such as a polygenic risk score along with symptoms, the current evidence on polygenic risk scores is largely drawn from individuals of European ancestry (20) and thus unclear if generalizable to the diverse US population. Another potential approach is to use quantitative fecal immunochemical testing to risk stratify those with symptoms. D’Souza et al. (21) investigated this approach in more than 9000 patients from 50 National Health Services facilities who presented with symptoms, where 3.3% were diagnosed with CRC. A hemoglobin cutoff of 10 µg/g of stool had a CRC sensitivity of 91%, negative predictive value of 99.6%, and a number needed to colonoscope of 6.2 to detect 1 cancer. The number of EoCRC patients in this cohort was limited; thus, it is unclear if these results can be generalized to younger individuals. If results are reproduced in younger populations, quantitative fecal immunochemical testing, a widely available and affordable test, can potentially provide the objective risk stratification to truly cull the patients who need timely colonoscopy (Figure 1).

Although this study does not elucidate the timeframe within which a diagnostic test needs to be completed to avoid upstaging, investigators demonstrated that symptoms are present up to 24 months before diagnosis, and there is a 9-month delay in diagnosis for those who have had symptoms for 3-24 months. These results are congruent with prior literature and our EoCRC patients’ experiences. To begin to understand the impact of diagnostic delays, we need to standardize systematic collection of time of symptom onset and time of first presentation to medical care for symptoms. With this information, we will begin to understand how duration of symptoms and delays in seeking and getting care affect disease stage. There are multitude quality measures that are tracked with new cancer (22), and an assessment of delays in diagnosis can fit into this type of quality reporting to inform the different interventions required for delays from symptom onset to symptom report (public health education, decreasing barriers to accessing care) versus from symptom report to diagnosis (provider education of red flags, improving access to colonoscopy).

We applaud the investigators for bringing attention to the critically important topic of how to better identify those at risk for EoCRC. We must continue our efforts in refining our approach to risk stratification to efficiently and objectively apply scarce colonoscopy resources to avoid inequitable delays in diagnosis and upstaging of disease.

Data availability

No new data were generated or analyzed for this editorial.

Author contributions

Timothy Yen, MD (Conceptualization; Writing – original draft; Writing – review & editing), Swati G. Patel, MD MS (Conceptualization; Supervision; Writing – original draft; Writing – review & editing).

Funding

No funding was use for this editorial.

Conflicts of interest

Timothy Yen has no disclosures.

Swati G. Patel has received research support from Olympus America.