Red-flag Signs and Symptoms for Earlier Diagnosis of Early-Onset Colorectal Cancer

Cassandra D. L. Fritz, MD, MPHS; Ebunoluwa E. Otegbeye, MD, MPHS; Xiaoyu Zong, MPH; Joshua Demb, PhD, MPH; Katelin B. Nickel, MPH; Margaret A. Olsen, PhD, MPH; Matthew Mutch, MD; Nicholas O. Davidson, MD, DSc; Samir Gupta, MD, MSCS; Yin Cao, ScD, MPH

Disclosures

J Natl Cancer Inst. 2023;115(8):909-916.

Abstract and Introduction

Abstract

Background: Prompt detection of colorectal cancer (CRC) among individuals younger than age 50 years (early-onset CRC) is a clinical priority because of its alarming rise.

Methods: We conducted a matched case-control study of 5075 incident early-onset CRC among US commercial insurance beneficiaries (113 million adults aged 18–64 years) with 2 or more years of continuous enrollment (2006–2015) to identify red-flag signs and symptoms between 3 months to 2 years before the index date among 17 prespecified signs and symptoms. We assessed diagnostic intervals according to the presence of these signs and symptoms before and within 3 months of diagnosis.

Results: Between 3 months and 2 years before the index date, 4 red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia) were associated with an increased risk of early-onset CRC, with odds ratios (ORs) ranging from 1.34 to 5.13. Having 1, 2, or at least 3 of these signs and symptoms were associated with a 1.94-fold (95% confidence interval [CI] = 1.76 to 2.14), 3.59-fold (95% CI = 2.89 to 4.44), and 6.52-fold (95% CI = 3.78 to 11.23) risk (P _trend < .001), respectively, with stronger associations for younger ages (P _interaction< .001) and rectal cancer (

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Characteristics of early-onset colorectal cancer and controls, IBM MarketScan (2006–2015)
Characteristics	Cases No. (%) (n = 5075)	Controls No. (%) (n = 22 378)
Age at the index date, mean (SD), y	43.2 (5.6)	42.8 (5.9)
Sex
Female	2442 (48.1)	10 781 (48.2)
Male	2633 (51.9)	11 597 (51.8)
Duration of insurance enrollment, mean (SD), y	4.0 (1.7)	3.9 (1.7)
≥2 years of prescription coverage	3956 (78.0)	17 297 (77.3)
Geographical region
South	2220 (43.7)	9745 (43.5)
Northeast	776 (15.3)	3497 (15.6)
North Central	1193 (23.5)	5160 (23.1)
West	801 (15.8)	3617 (16.2)
Unknown	85 (1.7)	359 (1.6)
Residence
Urban	4250 (83.7)	18 810 (84.1)
Rural	744 (14.7)	3218 (14.4)
Unknown	81 (1.6)	350 (1.6)
Full-time employment	2606 (51.3)	10 961 (49.0)
Health plan
Preferred provider organization	3299 (65.0)	14 156 (63.3)
Health maintenance organization	646 (12.7)	3084 (13.8)
Other	1130 (22.3)	5138 (23.0)
Charlson Comorbidity Index, mean (SD)^a	0.18 (0.64)	0.1 (0.44)
Family history of gastrointestinal cancer^a	62 (1.2)	211 (0.9)
Obesity^a	279 (5.5)	1069 (4.8)
Tobacco use^a	194 (3.8)	929 (4.2)
No. of clinical visits, mean (SD)^a
Outpatient office visits^b	3.5 (4.2)	3.1 (3.8)
Urgent care	0.09 (0.58)	0.07 (0.46)
Emergency room	0.29 (0.79)	0.25 (0.74)
Hospitalization	0.09 ( 0.35)	0.08 (0.36)
Tumor site
Colon cancer	3201 (63.1)	—
Rectal cancer	1860 (36.7)	—

^aBetween 3 months and 2 years prior to the index date.
^bOutpatient office visits from internal medicine, family practice, obstetrics and gynecology, gastroenterology, and colorectal surgery.

Table 2. Signs and symptoms (3 months to 2 years prior to the index date) and risk of colorectal cancer by age of onset
Signs and symptoms^a	Cases No. (%)	Controls No. (%)	OR (95% CI)^b	OR (95% CI)^c
Early-onset, younger than 50 y
Abdominal pain	588 (11.6)	1714 (7.7)	1.36 (1.22 to 1.52)	1.34 (1.19 to 1.49)
Rectal bleeding	363 (7.2)	287 (1.3)	5.25 (4.47 to 6.17)	5.13 (4.36 to 6.04)
Malaise and/or fatigue	324 (6.4)	1230 (5.5)	1.02 (0.89 to 1.16)	1.01 (0.88 to 1.15)
Nausea and vomiting	143 (2.8)	525 (2.3)	0.89 (0.72 to 1.09)	0.86 (0.70 to 1.06)
Diarrhea	140 (2.8)	308 (1.4)	1.47 (1.18 to 1.83)	1.43 (1.14 to 1.78)
Iron deficiency anemia	117 (2.3)	193 (0.9)	2.11 (1.65 to 2.71)	2.07 (1.61 to 2.66)
Constipation	106 (2.1)	244 (1.1)	1.28 (1.00 to 1.64)	1.27 (0.99 to 1.63)
Other deficiency anemias	102 (2.0)	314 (1.4)	1.16 (0.91 to 1.47)	1.16 (0.91 to 1.48)
Average-onset, 50–64 y
Abdominal pain	1362 (8.0)	5036 (7.1)	1.07 (1.01 to 1.15)	1.07 (1.00 to 1.15)
Malaise and/or fatigue	869 (5.1)	3607 (5.1)	0.98 (0.90 to 1.05)	0.98 (0.90 to 1.06)
Rectal bleeding	772 (4.5)	1333 (1.9)	2.46 (2.25 to 2.70)	2.49 (2.27 to 2.73)
Nausea and vomiting	365 (2.1)	1338 (1.9)	1.07 (0.95 to 1.21)	1.01 (0.89 to 1.14)

^aSigns and symptoms with at least 2% prevalence in cases between 3 months and 2 years prior to the index date. Other signs and symptoms (not shown) with less than 2% prevalence include abdominal mass, anal or rectal pain, anorexia, bowel habit change, bowel obstruction, gas or bloating, heartburn, incontinence of feces, and weight loss. CI = confidence interval; OR = odds ratio.
^bAdjusted for matching factors: age (years), sex (female, male), duration of insurance enrollment (years), prescription coverage (yes, no), and geographical region (south, northeast, north central, west, unknown) before the index date.
^cIn addition to matching factors, the model was additionally adjusted for full-time employment (yes, no), residence (urban, rural, unknown), health insurance plan (preferred provider organization, health maintenance organization, others), and the following factors between 3 months and 2 years prior to the index date: Charlson Comorbidity Index (continuous), family history of gastrointestinal neoplasm (yes, no), obesity (yes, no), tobacco use (yes, no), outpatient office visits (0, 1–3, ≥4 times), urgent care visit (yes, no), emergency room visit (yes, no), hospital admission (yes, no).

Table 3. Number of red-flag signs and symptoms (3 months to 2 years prior to the index date) and risk of early-onset colorectal cancer overall and according to age groups
No. of red-flag signs and symptoms^a	Cases No. (%)	Controls No. (%)	OR (95% CI)^b	OR (95% CI)^c
All participants
0	4092 (80.7)	20 140 (90.0)	1 (Referent)	1 (Referent)
1	792 (15.6)	1998 (8.9)	1.97 (1.80 to 2.15)	1.94 (1.76 to 2.14)
2	159 (3.1)	217 (1.0)	3.66 (2.97 to 4.51)	3.59 (2.89 to 4.44)
≥3	32 (0.6)	23 (0.1)	6.96 (4.07 to 11.91)	6.52 (3.78 to 11.23)
Per each additional sign and symptom	–	–	1.94 (1.81 to 2.07)	1.91 (1.78 to 2.05)
P _trend	–	–	<.001	<.001
Age groups
18–34 y
0	326 (78.4)	1770 (90.5)	1 (Referent)	1 (Referent)
1	72 (17.3)	169 (8.7)	2.33 (1.72 to 3.16)	2.45 (1.75 to 3.42)
≥2	18 (4.3)	16 (0.8)	6.02 (3.03 to 11.96)	6.67 (3.19 to 13.96)
Per each additional sign and symptom	–	–	2.34 (1.86 to 2.95)	2.46 (1.89 to 3.21)
P _trend	–	–	<.001	<.001
35–44 y
0	1581 (78.9)	8031 (90.6)	1 (Referent)	1 (Referent)
1	336 (16.8)	746 (8.4)	2.33 (2.02 to 2.68)	2.36 (2.03 to 2.74)
≥2	86 (4.3)	89 (1.0)	5.08 (3.76 to 6.88)	4.99 (3.64 to 6.84)
Per each additional sign and symptom	–	–	2.20 (1.98 to 2.44)	2.19 (1.96 to 2.45)
P _trend	–	–	<.001	<.001
45–49 y
0	2185 (82.2)	10 339 (89.4)	1 (Referent)	1 (Referent)
1	384 (14.5)	1083 (9.4)	1.71 (1.51 to 1.94)	1.66 (1.45 to 1.90)
≥2	87 (3.3)	135 (1.2)	3.11 (2.36 to 4.10)	3.00 (2.26 to 3.98)
Per each additional sign and symptom	–	–	1.72 (1.57 to 1.89)	1.69 (1.53 to 1.87)
P _trend	–	–	<.001	<.001
P _interaction ^d	–	–	<.001	<.001

^aThe total number of red-flag signs and symptoms included the 4 red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia) statistically significantly associated with increased risk of early-onset colorectal cancer between 3 months and 2 years prior to the index date. CI = confidence interval; OR = odds ratio.
^bAdjusted for the same set of variables as in Table 2, model b.
^cAdjusted for the same set of variables as in Table 2, model c.
^d P _interaction was calculated for age at the index date (years) and the number of red-flag signs and symptom (continuous) using Wald test.

Authors and Disclosures

Cassandra D. L. Fritz, MD, MPHS^1,‡, Ebunoluwa E. Otegbeye, MD, MPHS^2,‡, Xiaoyu Zong, MPH³, Joshua Demb, PhD, MPH^4,5, Katelin B. Nickel, MPH⁶, Margaret A. Olsen, PhD, MPH^3,6, Matthew Mutch, MD⁷, Nicholas O. Davidson, MD, DSc¹, Samir Gupta, MD, MSCS^4,5,8,9,§ and Yin Cao, ScD, MPH^1,3,10,*^,§

¹Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
²Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
³Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
⁴Division of Gastroenterology, University of California San Diego, San Diego, CA, USA
⁵Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
⁶Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
⁷Section of Colon and Rectal Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
⁸Department of Internal Medicine, University of California San Diego, San Diego, CA, USA
⁹Veteran Affairs San Diego Healthcare System, Department of Medicine, Division of Gastroenterology, San Diego, CA, USA
¹⁰Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

*Correspondence to
Yin Cao, ScD, MPH, Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8100, St. Louis, MO 63110, USA (e-mail: yin.cao@wustl.edu).

^‡These authors contributed equally as the first authors.

^§These authors contributed equally as the senior authors.

Author contributions
Cassandra D. L Fritz, MD, MPHS (Conceptualization; Writing – original draft; Writing – review & editing), Ebunoluwa E. Otegbeye, MD, MPHS (Conceptualization; Formal analysis; Writing – original draft; Writing – review & editing), Xiaoyu Zong, MPH (Formal analysis; Writing – review & editing), Joshua Demb, PhD, MPH (Writing – review & editing), Katelin B Nickel, MPH (Data curation), Margaret A. Olsen, PhD, MPH (Data curation), Matthew Mutch, MD (Writing – review & editing), Nicholas O Davidson, MD, DSc (Writing – review & editing), Samir Gupta, MD, MSCS (Conceptualization; Writing – review & editing), and Yin Cao, ScD, MPH (Conceptualization; Formal analysis; Funding acquisition; Supervision; Writing – original draft; Writing – review & editing).

Conflicts of interest
The authors declared no competing interests.