Phase I Trial of Liquid Nitrogen Spray Cryotherapy concurrent with neoadjuvant chemoradiation for Locally Advanced Esophageal Cancer: Dose Escalation and Long-Term Overall Survival

Background: Spray cryotherapy (LNSC) is hypothesized to increase effectiveness of neoadjuvant chemoradiation (CRT). We aimed to determine safety of multiple cryotherapy sessions prior to and concurrent with CRT in locally advanced esophageal cancer. Methods: “3+3” phase 1 dose frequency escalation trial. Primary outcome was safety; secondary outcomes were Quality of Life (QoL) complete clinical response (cCR), survival, and immunogenic cell death (change in serum HMGB1). Results: There was no treatment related grade 2 or 3 adverse events when LNSC was administered before or concurrent with CRT (n =13). Maximum Tolerated Dose was 3 sessions (2 prior to CRT, 1 during CRT). Mean QoL score improved from 37 at baseline to 31, 29, and 34 after the 1st, 2nd, and 3rd sessions (p-value 0.002, 0.004, and 0.4 respectively). CR with LNSC + CRT occurred in 70%. Over median follow-up of 36 months, overall survival was 40%. 38% showed >25% decrease in HMGB1 within 30 days. Discussion: No patient experienced dose limiting toxicity. LNSC was safely administered during CRT, improved QoL and high cCR rates were observed. These results support proceeding with a phase 2 trial.