Biomarkers Associated with Lymphedema and Fibrosis in Patients with Cancer of the Head and Neck

Background: This study examined interrelationships of selected interleukins (ILs), tumor growth factors, matrix metalloproteinases (MMPs), and C-reactive protein, interferon-gamma (IFN-γ), and tumor necrosis factor α (TNF-α) with lymphedema/fibrosis in patients with head and neck cancer (HNC). Methods and Results: Patients newly diagnosed with ≥Stage II HNC ( N = 100) were assessed for external/internal lymphedema and/or fibrosis before treatment, end-of-treatment, and at regularly established intervals through 72 weeks posttreatment and blood was drawn. Data from 83 patients were analyzed. Group-based trajectory modeling generated patient groups with similar longitudinal biomarker and lymphedema–fibrosis trajectories. Area-under-the-curve (AUC) values were also generated for each biomarker and severity of lymphedema–fibrosis. Associations among and between biomarkers and lymphedema–fibrosis trajectories and AUCs were tested (log-likelihood chi-square, correlations). The strongest evidence for the association of biomarkers with the overall and trajectory patterns and severity of lymphedema–fibrosis was observed for IL-6, IL-1β, TNF-α, TGF-β1, and MMP-9 (all p < 0.05). Convergence of joint trajectory patterns and AUC were observed with IL-6 with all lymphedema–fibrosis trajectories and internal lymphedema AUC. IL-1β trajectories converged with external lymphedema trajectories and all lymphedema–fibrosis AUCs. TNF-α and TGF-β1 converged most strongly with fibrosis in terms of trajectory patterns. However TNF-α demonstrated stronger association with lymphedema–fibrosis AUC (fibrosis: r s = 0.49). MMP-9 demonstrated convergence with lymphedema–fibrosis AUCs (lymphedema: 0.43–0.42; fibrosis: 0.35). Conclusion: Systemic levels of selected mediators of proinflammatory processes track with acute and chronic clinical phenotypes of lymphedema/fibrosis in HNC patients suggesting their potential role in the pathogenesis of these conditions.