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The most common red flag signs and symptoms of early-onset colorectal cancer (CRC) included hematochezia, abdominal pain, and altered bowel habits, according to a systematic review and meta-analysis.

Of nearly 25 million patients younger than 50 in 81 studies, the most common presenting signs and symptoms of early-onset CRC were hematochezia (pooled prevalence 45%, 95% CI 40-50), abdominal pain (pooled prevalence 40%, 95% CI 35-45), and altered bowel habits (pooled prevalence 27%, 95% CI 22-33), reported Joshua Demb, PhD, MPH, of the University of California San Diego, and colleagues.

In addition, hematochezia (relative estimate range 5.2-54.0), abdominal pain (relative estimate range 1.3-6.0), and anemia (relative estimate range 2.1-10.8) were associated with higher likelihood of early-onset CRC compared with no CRC, they noted in .

"These findings underscore the need for clinicians to consider early-onset CRC as part of the differential diagnosis for patients presenting with potential red flag signs and symptoms, and to follow up through either confirmation of diagnosis and sign or symptom resolution when a benign cause is suspected, or colonoscopy referral to rule out CRC based on sign or symptom severity or absence of diagnosis or sign or symptom resolution after initial workup and management for a suspected benign cause," Demb and team wrote.

It took a mean 6.4 months (range 1.8-13.7) and a median 4 months (range 2.0-8.7) for patients to receive a diagnosis of CRC after signs and symptoms first occurred.

"Delayed diagnosis may be a result of late patient presentation and lack of clinician knowledge of common CRC symptoms, such as hematochezia or abdominal and pelvic pain, and signs, such as iron deficiency anemia," the authors noted in their introduction. "Patients and clinicians alike may downplay symptom severity and fail to recognize key red flags and clinical cues that should trigger suspicion of CRC."

Reid M. Ness, MD, MPH, of Vanderbilt-Ingram Cancer Center in Nashville, who was not involved in the study, agreed that since these symptoms are so common overall, "they are frequently ignored by providers as trivial."

Hematochezia and unexplained iron deficiency anemia in particular, however, "should always generate a colonoscopy request if one has not been performed very recently," Ness said. "Patients with hematochezia must be evaluated for possible underlying colorectal malignancy regardless of age."

In terms of the differential for abdominal pain, Ness described three categories: chronic pain, lasting more than 3 months; acute pain, lasting less than 2 weeks; and subacute pain, lasting 2 weeks to 3 months. "I am most concerned about the patient with subacute pain as a possible indicator of underlying malignancy," he noted.

A challenge of early-onset CRC is a lack of non-invasive screening options as the incidence rises, said Ajay Goel, PhD, of City of Hope in Duarte, California.

"More and more people are getting this disease when they're in their 20s, 30s and 40s, and screening doesn't even begin until 45," at which point compliance with colonoscopies is poor, Goel told 乌鸦传媒. "For this particular clinical challenge, we basically need better tests -- inexpensive, non-invasive tests we can start running on people much younger than age 45 if we're to tackle this issue."

Of note, an FDA panel on Thursday endorsed a blood-based test for CRC screening in adults 45 years and older at average risk for the disease, despite concerns over the test's low sensitivity for precancerous lesions.

Demb and team used PubMed/Medline, Embase, the Cumulative Index to Nursing & Allied Health, and Web of Science from the start of each database through May 2023 to find any studies reporting on signs and symptoms of CRC in patients younger than 50 who were ultimately diagnosed with non-hereditary CRC. Outcomes of interest included pooled proportions of the signs and symptoms in patients with early-onset CRC; estimates for associations between each sign or symptom and risk of CRC; and the time from sign or symptom presentation to diagnosis.

Among 12,859 studies initially identified, the authors included 81 studies with a total of 24,908,126 patients. Studies were excluded if they had fewer than 15 patients, had patients younger than 18, or if more than half the study period occurred before 1996, when incidence of early-onset CRC began rising.

Most of the included studies (n=76) were cross-sectional studies, four were case-control studies, and one was a cohort study. They were somewhat evenly distributed between North America, Europe, and Asia/Middle East, with 12 others from Africa, South America, and Oceania combined. Most of the studies (83%) were determined to have low risk of bias.

Among the 78 studies that reported on 17 signs and symptoms at presentation, the three most commonly presenting signs/symptoms of hematochezia, abdominal pain, and changes in bowel habits, such as constipation, diarrhea, alternating bowel habits, or alternating diarrhea or constipation, remained the top three both in the U.S. and in other countries and in the studies with populations both 50 and younger and 40 and younger.

Loss of appetite and obstruction were the only common symptoms in the studies with moderate or high risk of bias.

Demb and colleagues said that there was significant heterogeneity across the included studies, which affected their ability to meta-analyze some of the results. "This was most significant in assessment of the associations of signs and symptoms with early-onset CRC, where a lack of a consistent comparator group hindered our ability to pool estimates for the associations," they wrote.

In addition, they were unable to compare early-onset CRC risk against other potential outcomes, "which might have better contextualized the relative risk," they noted.

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