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

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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.

Main findings

  • Little is known about the pathogenesis, which underlies lymphedema and fibrosis in patients with head and neck cancer, although both animal and human data suggest the involvement of a range of pro inflammatory cytokines ,including tumor necrosis factor a (TNFa), transforming growth factor (TGF)-b, interleukin (IL)-10, IL-1, IL-6, and IL-8.
  • Physical examination findings for fibrosis were documented using Common Toxicity Criteria for Adverse Events (CTCAE) Fibrosis Scale.
  • Biomarkers investigated in this study. TNF-a, IL-1b, IL-10, IL-6, and IL-8 were analyzed using a sensitive flow cytometric bead array (Becton Dickinson) assay that allows multiple cytokine analyses of a single sample
  • The research results support the notion that an association exists between the levels of selected proinflammatory cytokines and the risk and course of clinically significant lymphedema and fibrosis among patients being treated with conventional regimens for cancers of the head and neck.
  • IL-6 levels were significantly higher at the immediate end-of-treatment for those who developed moderate–severe external and internal lymphedema and fibrosis compared with individuals with none– mild trajectories.
  • IL-6 is s a regulator of both adipose disposition and hemostasis in human lymphedema and IL-6 is an activate agent in collagen production.
  • Proinflammatory processes clearly contribute to the development of lymphedema/fibrosis in patients who have experienced cancer of the head and neck. The processes continue well past end of treatment. The strongest evidence for the interrelationships of biomarkers with the overall and trajectory patterns of the severity of lymphedema–fibrosis was observed for IL-6, IL-1b, TNFa, TGFb1, and MMP-9.
  • Given the pathogenesis of tissue injury in response to radiation-based protocols (as well as with cytotoxic chemotherapy) and the pivotal role thought to be played by activation of NF-jB, the cytokines noted in this study are consistent with their roles in driving toxicity phenotypes. This finding reinforces the future consideration of using cytokines as dynamic biomarkers for lymphedema and fibrosis. The use of such biomarkers could facilitate identification of patients at high risk for severe lymphedema and fibrosis and pave the way for preventive interventional clinical trials.