{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:56:09Z","timestamp":1791996969231,"version":"4.4.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["por-journal.com"],"crossmark-restriction":true},"short-container-title":["Pathol. Oncol. Res."],"abstract":"<jats:p>The randomized controlled pivotal phase 3 study evaluated efficacy and safety of neoadjuvant complex biologic, Leukocyte Interleukin Injection (LI), administered for 3 consecutive weeks pre-surgery, in treatment na\u00efve resectable locally advanced primary squamous cell carcinoma of oral cavity and soft palate. Randomization 3:1:3 to LI+\/-CIZ (cyclophosphamide, indomethacin, and zinc)+SOC, or SOC (standard of care) alone. LI-treated patients received 400\u00a0IU (as interleukin-2 equivalent; 200\u00a0IU peritumorally, 200\u00a0IU perilymphatically) sequentially, daily 5\u00a0days\/week for 3\u00a0weeks before surgery. All subjects were to receive SOC. Post-surgery, patients with low risk for recurrence were to receive radiotherapy, while those with high risk received concurrent chemoradiotherapy. Median follow-up was 56 months. There were 923 ITT (Intent-to-Treat) subjects (380 ITT low-risk and 467 ITT high-risk). Pre-surgery objective early response (45 objective early responders; 5 complete responses [CRs], 40 partial responses [PRs], confirmed by pathology at surgery. LI (+\/\u2212 CIZ) had 8.5% objective early responders (45\/529 ITT) and 16% objective early responders (34\/212 ITT low-risk) vs. no reported SOC objective early responders (0\/394 ITT). Objective early responders significantly lowered death rate to 22.2% (ITT LI-treated), 12.5% (ITT low-risk LI + CIZ + SOC), while the ITT low-risk SOC death rate was 48.7%. Thus, objective early response impacted overall survival (OS); proportional hazard ratios were 0.348 (95% CI: 0.152\u20130.801) for ITT low-risk LI-treated, 0.246 (95% CI: 0.077\u20130.787) for ITT low-risk LI + CIZ + SOC. ITT low-risk LI + CIZ + SOC demonstrated significant OS advantage vs. ITT low-risk SOC (unstratified log-rank p = 0.048; Cox hazard ratio = 0.68; 95% CI: 0.48\u20130.95, Wald p = 0.024 [controlling for tumor stage, tumor location, and geographic region]). Absolute OS advantage increased over time for ITT low-risk (LI + CIZ + SOC)-treated vs. ITT low-risk SOC: reaching 14.1% (62.7% vs. 48.6%) at 60\u00a0months, with 46.5\u00a0months median OS advantage (101.7\u00a0months vs. 55.2\u00a0months), respectively. Quality of life benefit for complete responders sustained for &amp;gt;3\u00a0years post LI treatment. Percent treatment-emergent adverse events were comparable among all treated groups. No excess safety issues were reported for LI over SOC alone post-surgery. 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