Association of Oral Cavity and Oropharyngeal Cancer Biomarkers in Surgical Drain Fluid With Patient Outcomes

Abstract

Importance: Survival rates for head and neck cancer have been relatively stable for several decades. Individualized prognostic indicators are needed to identify patients at risk for poorer outcomes.

Objective: To determine whether biomarker levels in surgical drain fluid of patients with head and neck cancer are associated with poor cancer outcomes.

Design, setting, and participants: This prospective cohort study enrolled patients with squamous cell carcinoma (SCC) of the oral cavity and oropharynx who required surgical treatment from April 1, 2011, to February 1, 2016, at a tertiary or academic care center. Twenty patients, including 14 with stage IV disease, had complete specimen collection. Differences in cytokine and MMP levels by disease outcomes were evaluated.

Interventions: Patients underwent surgical treatment with drain placement as dictated by the standard of care. Drain fluid samples were collected every 8 hours postoperatively until drains were removed because of clinical criteria. Levels of cytokines and matrix metalloproteinases (MMPs) were measured using electrochemiluminescent, patterned array, multiplex technology.

Main outcomes and measures: The primary clinical outcome measures were survival outcome and recurrence. The biomarkers measured included the cytokines basic fibroblastic growth factor, vascular endothelial growth factor isoform A, soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PIGF) and MMP-1, MMP-3, and MMP-9. Other clinical and pathologic cancer characteristics were recorded.

Results: In this cohort of 20 patients with SCC (15 men and 5 women; mean [SD] age, 63.5 [9.9] years), a significant association with recurrence was found for levels of MMP-1 (relative difference between groups, 2.78; 95% CI, 1.23-6.29), MMP-3 (relative difference between groups, 5.29; 95% CI, 2.14-13.05), and sFlt-1 (relative difference between groups, 3.75; 95% CI, 1.84-7.65). No biomarkers were associated with disease outcome. Vascular endothelial growth factor isoform A was associated with nodal metastasis (relative difference between groups, 1.98; 95% CI, 1.12-3.51), and basic fibroblastic growth factor was associated with lymphovascular invasion (relative difference between groups, 1.74; 95% CI, 1.02-2.97).

Conclusions and relevance: In this pilot sample of patients with SCC of the oral cavity and oropharynx, MMP-1, MMP-3, and sFlt-1 levels in wound fluid were associated with poor clinical cancer outcomes in the form of recurrence. This finding is consistent with the literature of tumor microenvironment in saliva, serum, and tumor tissue biomarkers. To our knowledge, this report is the first of such findings in surgical drain fluid, an easily accessible means of cytokine measurement. Measurement of these biomarkers in surgical fluid potentially represents a novel means of assessing cancer prognosis in this population.

Figure 1.. Change in Biomarker Levels Associated With Survival

Graphs depict the geometric mean values of biomarkers by survival and 8-hour shift (every 8-hour period of sequential wound fluid collection was deemed to be a shift). None of the interaction assessments reached statistical significance for survival outcome. Error bars indicate 95% CIs. bFGF indicates basic fibroblastic growth factor; MMP, matrix metalloproteinase; NED, no evidence of disease; PIGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase 1; and VEGFA, vascular endothelial growth factor isoform A.

Figure 2.. Change in Biomarker Levels Associated With Recurrence

Graphs depict geometric mean values of biomarkers by presence (yes) or absence (no) of recurrence and 8-hour shift (every 8-hour period of sequential wound fluid collection was deemed to be a shift). Only the soluble fms-like tyrosine kinase 1 (sFlt-1) level had an interaction assessment that reached statistical significance for recurrence. Error bars indicate 95% CIs. bFGF indicates basic fibroblastic growth factor; MMP, matrix metalloproteinase; PIGF, placental growth factor; and VEGFA, vascular endothelial growth factor isoform A.