Biomarkers Associated with Lymphedema and Fibrosis in Patients with Cancer of the Head and Neck
Sheila H. Ridner, PhD, RN, FAAN,1 Mary S. Dietrich, PhD,1,2 Stephen T. Sonis, DMD, DMSc,3 and Barbara Murphy, MD4
Background: This study examined interrelationships of selected interleukins (ILs), tumor growth factors, matrix metalloproteinases (MMPs), and C-reactive protein, interferon-gamma (IFN-c), and tumor necrosis factor a (TNF-a) 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-1b, TNF-a, TGF-b1, 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-1b trajectories converged with external lymphedema trajectories and all lymphedema–ﬁbrosis AUCs. TNF-a and TGF-b1 converged most strongly with ﬁbrosis in terms of trajectory patterns. However TNF-a demonstrated stronger association with lymphedema–ﬁbrosis AUC (ﬁbrosis: rs=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.