The impact of microscopic versus macroscopic extranodal extension in oral cavity squamous cell carcinoma: National cancer database analysis and review of the literature.

OBJECTIVE: To analyze the prognostic significance of microscopic vs macroscopic extranodal extension and to assess the impact of chemoradiation on overall survival among patients with oral cavity squamous cell carcinoma and varying degrees of extranodal extension. METHODS: Utilizing the National Cancer Database, we performed a retrospective cohort study of 7975 patients with oral cavity squamous cell carcinoma and varying degrees of extranodal extension who underwent primary surgical intervention. Propensity-score matched models following Cox regression analyses allowed us to assess the impact of adjuvant radiation alone vs adjuvant chemoradiation on overall survival in patients with microscopic extranodal extension and macroscopic extranodal extension. RESULTS: 7975 patients with oral cavity squamous cell carcinoma were included in the final analysis. Within this cohort, 25.4% had microscopic extranodal extension and 5.2% had macroscopic extranodal extension. On univariate analysis, we found that microscopic and macroscopic extranodal extension were associated with decreased overall survival when compared to those with positive nodes without extranodal extension (HR = 1.67; 95% CI 1.56, 1.79 and HR = 1.88; 95% CI 1.66, 2.14, respectively). On multivariate analysis after propensity-score matching, we found no significant difference in overall survival in patients who received adjuvant radiation alone vs. adjuvant chemoradiation for both microscopic and macroscopic extranodal extension. CONCLUSION: Our data suggest that microscopic extranodal extension in oral cavity squamous cell carcinoma is associated with worse overall survival than patients without extranodal extension following primary surgical intervention with neck dissection. The results of this study also suggest that the addition of chemotherapy to adjuvant radiation may not provide a significant survival benefit in patients with oral cavity squamous cell carcinoma with microscopic and macroscopic extranodal extension. Comprehensive assessment of the benefits of adjuvant chemoradiation in the setting of microscopic vs macroscopic extranodal extension would need to be studied in a randomized controlled trial.

Novel Peptide NIRF Optical Surgical Navigation Agents for HNSCC.

Head and neck squamous cell carcinoma (HNSCC) survival rates have not improved in a decade, with a 63% 5-year recurrence rate after surgery, making HNSCC a compelling indication for optical surgical navigation (OSN). A promising peptide, HN1, targeted and internalized in human HNSCC cells in multiple laboratories, but was slow (24 h) to accumulate. We modified HN1 and explored structural variables to improve the uptake kinetics and create IRdye800 adducts useful for OSN. Eleven new molecules were synthesized and characterized chemically, in human HNSCC cells (Cal 27), and in HNSCC xenograft mice. Cal 27 flank xenografts in Balb/c nude mice were imaged for 3-48 h after 40 nmol intravenous doses of IR800-labeled molecules. Cell uptake kinetics in the 1-2 h window incubated at 1-10 µM were independent of the dye label (FITC, Cy5, or IR800), but increased markedly with additional N-terminal lipophilic substitution, and after resequencing the peptide to separate polar amino acids and move the lysine-dye more centrally. Microscopy confirmed the strong Cal 27 cell binding and demonstrated primarily cytosolic and membrane localization of the fastest peptide, 4Iphf-HN17. 4Iph-HN17-IR800 showed 26-fold greater rate of uptake in cells than HN1-IR800, and far stronger OSN imaging intensity and tumor to background contrast in mice, suggesting that the new peptide is a promising candidate for OSN of HNSCC.

Salivary gland sparing and improved target irradiation by conformal and intensity modulated irradiation of head and neck cancer.

The goals of this study were to facilitate sparing of the major salivary glands while adequately treating tumor targets in patients requiring comprehensive bilateral neck irradiation (RT), and to assess the potential for improved xerostomia. Since 1994 techniques of target irradiation and locoregional tumor control with conformal and intensity modulated radiation therapy (IMRT) have been developed. In patients treated with these modalities, the salivary flow rates before and periodically after RT have been measured selectively from each major salivary gland and the residual flows correlated with glands' dose volume histograms (DVHs). In addition, subjective xerostomia questionnaires have been developed and validated. The pattern of locoregional recurrence has been examined from computed tomography (CT) scans at the time of recurrence, transferring the recurrence volumes to the planning CT scans, and regenerating the dose distributions at the recurrence sites. Treatment plans for target coverage and dose homogeneity using static, multisegmental IMRT were found to be significantly better than standard RT plans. In addition, significant parotid gland sparing was achieved in the conformal plans. The relationships among dose, irradiated volume, and the residual saliva flow rates from the parotid glands were characterized by dose and volume thresholds. A mean radiation dose of 26 Gy was found to be the threshold for preserved stimulated saliva flow. Xerostomia questionnaire scores suggested that xerostomia was significantly reduced in patients irradiated with bilateral neck, parotid-sparing RT, compared to patients with similar tumors treated with standard RT. Examination of locoregional tumor recurrence patterns revealed that the large majority of recurrences occurred inside targets, in areas that had been judged to be at high risk and that had received RT doses according to the perceived risk. Tangible gains in salivary gland sparing and target coverage are being achieved, and an improvement in some measures of quality of life is suggested by our findings. Additional reduction of xerostomia may be achieved by further sparing of the salivary glands and the non-involved oral cavity. A mean parotid gland dose of < or = 26 Gy should be a planning objective if significant parotid function preservation is desired. The pattern of recurrence suggests that careful escalation of the dose to areas judged to be at highest risk may improve tumor control.