Prognostic Circulating Cytokine Panels for Metronomic Chemotherapy in Metastatic Gastrointestinal Cancer: Exploratory Pharmacodynamic Biomarker Analysis of the Phase II COMET Trial

Background/Objectives: Metronomic chemotherapy offers a well-tolerated option for heavily pretreated metastatic gastrointestinal cancer patients, but reliable prognostic biomarkers for patient selection are lacking. This study aimed to identify exploratory circulating cytokine signatures associated with outcomes in patients treated with metronomic chemotherapy. Methods: We analyzed plasma samples from 34 patients enrolled in the COMET trial (EudraCT 2007-000065-38), a phase II study of metronomic UFT, cyclophosphamide, and celecoxib. An 88-cytokine Luminex® (Luminex Corporation, Austin, TX, USA) panel was measured at baseline and at four treatment timepoints. Partial least squares discriminant analysis identified candidate biomarkers, followed by systematic combinatorial analysis using Manciu’s method to construct 3-cytokine composite risk scores. Results: Twenty-one patients (61.8%) experienced progressive disease and 13 (38.2%) achieved stable disease. Six biomarkers showed significant discriminative power: IL-16, MCP-4, THBS-2, Eotaxin-1, PDGF-AB/BB, and TRAIL. Three 3-cytokine panels achieved statistically significant risk stratification (all p < 0.05), with hazard ratios for overall survival ranging from 2.59 to 6.24. For the representative IL-16 + MCP-4 + THBS-2 panel, high-risk patients showed a median PFS of 2.0 vs. 4.0 months (HR 3.24, p = 0.0046) and a median OS of 5.8 vs. 11.1 months (HR 4.19, p = 0.0010). Conclusions: This exploratory pharmacodynamic biomarker analysis identifies three 3-cytokine panels associated with prognostic risk stratification in metronomic chemotherapy for metastatic gastrointestinal cancer. As this single-arm trial cannot distinguish prognostic from predictive value, findings are hypothesis-generating. Prospective external validation is required before clinical translation, and exploration in combination with immune checkpoint inhibitors is warranted.