Association of Inflammatory Biomarkers With Survival Among Patients With Stage III Colon Cancer

Abstract

ImportanceThe association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited.ObjectiveTo assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer.Design, Setting, and ParticipantsThis cohort study was derived from a National Cancer Institute–sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020. A total of 1494 patients with plasma samples available for inflammatory biomarker assays were included. Data were analyzed from July 29, 2021, to February 27, 2022.ExposuresPlasma inflammatory biomarkers (interleukin 6 [IL-6], soluble tumor necrosis factor α receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles) that were assayed 3 to 8 weeks after surgery but before chemotherapy randomization.Main Outcomes and MeasuresThe primary outcome was disease-free survival, defined as time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios for the associations of inflammatory biomarkers and survival were estimated via Cox proportional hazards regression.ResultsOf 1494 patients (median follow-up, 5.9 years [IQR, 4.7-6.1 years]), the median age was 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, and 327 recurrences, 244 deaths, and 387 events for disease-free survival were observed. Plasma samples were collected at a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL) for IL-6, 2.9 × 103 pg/mL (IQR, 2.3-3.6 × 103 pg/mL) for sTNF-αR2, and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Compared with patients in the lowest quintile of inflammation, patients in the highest quintile of inflammation had a significantly increased risk of recurrence or death (adjusted hazard ratios for IL-6: 1.52 [95% CI, 1.07-2.14]; P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55]; P < .001 for trend; and for hsCRP: 1.65 [95% CI, 1.17-2.34]; P = .006 for trend). Additionally, a significant interaction was not observed between inflammatory biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival.Conclusions and RelevanceThis cohort study found that higher inflammation after diagnosis was significantly associated with worse survival outcomes among patients with stage III colon cancer. This finding warrants further investigation to evaluate whether anti-inflammatory interventions may improve colon cancer outcomes.Trial RegistrationClinicalTrials.gov Identifier: NCT01150045

Assessment and Prognostic Value of Inflammatory Biomarkers in Patients With Colon Cancer

“…The median (IQR) plasma concentration of IL-6 reported by Cheng et al (3.8 [2.3-6.2] pg/mL) is dissimilar to the median/mean values previously reported, with dissimilar prognostic threshold values used in previous studies of patients undergoing treatment for colorectal cancer (CRC) . With reference to sTNF-αR2, there are fewer studies to compare.…”

“…To the Editor We read the cohort study assessing the association of inflammatory biomarkers with survival among patients with stage III colon cancer by Cheng et al with some interest. This post hoc analysis of 1494 patients who underwent potentially curative surgical resection and adjuvant chemotherapy for TNM stage III colon cancer showed an association between inflammatory status, recurrence, and mortality.…”

“…Indeed, a meta-analysis of 10 000 patients with primary operable CRC reported that approximately 40% had a modified Glasgow prognostic score of 1 or greater (CRP >10 mg/L) . In contrast, Cheng et al reported a median (IQR) CRP level of 2.6 (1.2-5.6) mg/L and used a lower threshold (high-sensitivity CRP >3 mg/L). This would suggest that the cohort in the Cheng et al study had less systemic inflammation than cohorts in the existing literature.…”

Phase IIa Clinical Biomarker Trial of Dietary Arginine Restriction and Aspirin in Colorectal Cancer Patients

“…Results of the large phase III clinical trial results of C80702 (ClinicalTrials.gov Identifier: NCT01150045), which randomized stage III colon cancer patients to a 3 year intervention of celecoxib or placebo after 1st randomization to 3 vs. 6 mo adjuvant FOLFOX chemotherapy, revealed no difference in disease-free survival ascribed to celecoxib [ 48 ]. In a follow-up analysis of patients in this trial based on plasma inflammatory markers taken 3–8 weeks post-operatively (and prior to chemotherapy), higher inflammation postoperatively was associated with increased risk of recurrence or death [ 49 ]. Of note, analyses of the secondary clinical endpoints for C80702 (e.g., total adenoma recurrence, high-risk adenoma recurrence) have not yet been reported.…”

Assessment and Prognostic Value of Inflammatory Biomarkers in Patients With Colon Cancer—Reply

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COMMENT & RESPONSEIn Reply We thank McGovern et al for their interest in our analysis of inflammatory biomarkers and survival among patients with stage III colon cancer (CALGB/SWOG 80702). 1 In this cohort study, we reported the levels of plasma inflammatory biomarkers, including interleukin 6 (IL-6), soluble tumor necrosis factor α receptor 2 (sTNF-αR2), and high-sensitivity C-reactive protein (CRP). We found that higher inflammation after diagnosis was significantly associated with worse survival among patients with stage III colon cancer.McGovern et al pointed out that our study population may have less systematic inflammation.

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