Higher IL-6, IL-17A Levels Linked to Persistent Fatigue in Patients With CRC

Patients with colorectal cancer (CRC) who had elevated levels of certain inflammatory biomarkers, particularly IL-6 and IL-17A, reported significantly higher fatigue for up to 3 years after diagnosis, according to a study recently published in Cancer Medicine.¹

Inflammation's Unclear Role in Cancer-Related Fatigue

Fatigue affects up to 90% of patients with cancer during chemotherapy and persists in roughly 30% after treatment ends, often described as unrelenting and disruptive to daily life. It is the most commonly reported symptom among people diagnosed with CRC, affecting between 70% and 82% of patients during treatment.²

Researchers have long suspected that systemic inflammation drives this symptom, but prior studies examining specific cytokines have produced inconsistent results.¹ To address these gaps, investigators analyzed whether inflammatory markers were longitudinally associated with fatigue in the first 3 years after CRC diagnosis and surgery. Given past findings, the study included a wider range of inflammatory markers, a comprehensive panel of 16.

The analysis focused on patients from the ColoCare Study, a prospective cohort of patients and survivors across 6 US sites and 1 German site. Specifically, it included 271 eligible patients with stage I to III CRC (mean age, 60.9 years) and 30 patients with stage IV disease. Fatigue was measured using the 3-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) subscale at baseline, before surgery, and at 3 subsequent points spanning up to 3 years post diagnosis; blood samples were analyzed for the 16 inflammatory and vascular biomarkers at each time point.

IL-6, IL-17A Emerged as Key Predictors of Persistent Fatigue

Among patients with stage I to III disease, mean fatigue peaked roughly 3 to 9 months after baseline (mean score, 36.9) then declined over the following 2 years. In linear mixed-effects models adjusting for age, sex, race, tumor site, stage, treatment, and other covariates, patients whose average IL-6 and IL-17A levels were twice as high as other participants' reported significantly higher fatigue scores over the study period (IL-6 estimate, 3.69 [95% CI, 1.65-5.73]; IL-17A estimate, 3.81 [95% CI, 1.58-6.05]). The researchers noted that these associations reflected differences between patients rather than fluctuations within an individual patient over time.

They also found that elevated IL-4, IL-17A, and tumor necrosis factor alpha (TNF-α) measured around 6 months post-surgery, when most patients were completing first-line treatment, were nominally associated with higher fatigue scores 2 years later; however, these associations did not survive correction for multiple testing. By contrast, biomarkers measured at baseline, before surgery, were not associated with fatigue at the 3-year mark.

Association Between Inflammation, Fatigue Varied by Sex

Effect modification by sex reached statistical significance for IL-2 after adjustment for multiple testing. When women had double their average IL-2 or IL-17A levels, they reported meaningfully higher fatigue (IL-2 estimate, 10.08 [95% CI, 3.40-16.75]; IL-17A estimate, 7.12 [95% CI, 2.47-11.77]), a magnitude that exceeded the threshold considered clinically meaningful for the EORTC-QLQ-C30 fatigue subscale. Men showed no such association, with the relationship trending in the opposite direction in some models.

The authors noted that female sex hormones are associated with greater production of pro-inflammatory cytokines, including IL-6 and IL-17A, which may partly explain the disparity. Another explanation could be the differences in how fatigue severity is perceived and reported by sex.

Further Research Needed to Validate Biomarker Associations

The researchers acknowledged several limitations of their study, one being that the EORTC QLQ-C30 does not assess multiple dimensions of fatigue. Also, due to the observational nature of the study, there were some missing data, which could contribute to unmeasured confounding. Because of this, they encouraged further research to verify and build upon their findings that higher levels of IL-4, IL-6, IL-17A, and TNF-α were associated with higher fatigue scores.

“With further validation, these markers may help to identify patients with CRC who are more susceptible to persistent fatigue after surgery,” the authors concluded. “These findings also support the need for further investigation into targeted interventions to reduce selected pro-inflammatory biomarkers to lower persistent fatigue in CRC survivors.”

References

1. Loroña NC, Liu L, Kazemian E, et al. Longitudinal associations between inflammatory biomarkers and fatigue in patients with colorectal cancer: a multicenter study. Cancer Medicine. 2026;15(7):e72135. doi:10.1002/cam4.72135
2. Denlinger CS, Barsevick AM. The challenges of colorectal cancer survivorship. J Natl Compr Canc Netw. 2009;7(8):883-893. doi:10.6004/jnccn.2009.0058