<h3>Purpose/Objective(s)</h3> The aim of this study was to evaluate patient outcomes and practice patterns among patients treated for non-melanomatous skin cancers of the head and neck with microscopic or clinical perineural invasion (PNI) using radiotherapy (RT) at a single institution. <h3>Materials/Methods</h3> To determine severe (grade 3+) toxicity and clinical outcomes, we reviewed the medical records of 283 patients who received primary RT or postoperative RT +/- chemotherapy between 1965 and 2019 for non-melanomatous skin cancers of the head and neck with PNI. Modalities included orthovoltage photons, megavoltage photons, and en face electrons with either daily (QD) or twice-daily (BID) fractionation. Field extent of the primary site was either local (2 cm margin), extended (>2 cm margin), or to the base of skull (BOS). <h3>Results</h3> The median age at the start of RT was 64 years old. Overall, 154 patients had microscopic PNI and 129 had clinical PNI. The median BID dose was 74.4 Gy (range, 32 – 79.2 Gy) and the median QD dose was 64 Gy (range, 15 – 79.5 Gy). Field extent was 25% local, 38% extended, and 37% BOS. Nodal involvement was seen in 17% of patients. Elective nodal irradiation was performed in 51% of node-negative patients. For patients with microscopic PNI, the 5- and 10-year rates of local control, local-regional control, disease-free survival, cause-specific survival, and overall survival were 85% and 80%, 78% and 74%, 76% and 72%, 80% and 79%, and 59% and 40%, respectively. For patients with clinical PNI, the 5- and 10-year rates of local control, local-regional control, disease-free survival, cause-specific survival, and overall survival were 59% and 57%, 57% and 55%, 54% and 52%, 68% and 58%, and 54% and 34%, respectively. In those with clinical PNI, T stage was associated with a statistically significant effect on local control and cause-specific survival on multivariable analysis (p = 0.01 and p = 0.03, respectively). Toxicities of grade 3 or higher occurred at rates of 12% in patients with microscopic PNI and 32% in those with clinical PNI. <h3>Conclusion</h3> Radiation therapy provides good long-term control rates in patients with microscopic PNI and patients with clinical PNI; nevertheless, clinical PNI remains a poor prognostic factor.
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