Low-dose radiotherapy followed by chemoimmunotherapy in neoadjuvant treatment of locally advanced esophageal squamous cell carcinoma: A phase II STIMULATION-01 clinical trial.

348 Background: Neoadjuvant chemoimmunotherapy has shown promise in resectable esophageal squamous cell carcinoma (ESCC), yet its efficacy remains limited by relatively low pathologic complete response (pCR) rates. To address this, we proposed reprogramming the tumor immune microenvironment through the addition of low-dose radiotherapy, aiming to synergize with anti-PD-1 immunotherapy without increasing treatment-related toxicity. Methods: This phase II clinical trial was designed to enroll 30 participants. The key inclusion criteria for this study were as follows: Histologically (pathologically) confirmed thoracic esophageal squamous cell carcinoma with clinical stage: cT1b-cT2N1-2M0 or cT3-cT4aN0-2M0. The primary endpoint was pCR rate. During the neoadjuvant therapy phase, patients underwent two cycles of low-dose radiotherapy followed by chemotherapy and immunotherapy, with each cycle lasting 21 days. Patients were allocated into three treatment groups (4Gy/2f, 6Gy/3f, and 8Gy/4f). Tislelizumab, nab-paclitaxel and carboplatin were administered concurrently on the day following radiotherapy completion. Patients were scheduled for esophagectomy 6-8 weeks after the second neoadjuvant session. Blood and tumor tissue samples were collected before and after neoadjuvant therapy. Tumor tissue samples were collected for multi-omics sequencing. Blood samples were analyzed for ctDNA. Results: A total of 30 patients were included for final analysis, with 10 patients in each sub-group (4Gy/2f, 6Gy/3f, and 8Gy/4f) The results demonstrated that the pCR rate in the 8Gy/4f group was 70% (7/10), which was higher than that in the 4Gy/2f group (10%; p = 0.011) and the 6Gy/3f group (50%; p = 0.371). Furthermore, the ctDNA clearance rates in both the 8Gy/4f group (7/10) and the 6Gy/3f group (6/8) were numerically higher than that in the 4Gy/2f group (2/7), with P-values of 0.160 and 0.120, respectively. Among the 30 patients, 23 experienced treatment-related adverse events (TRAEs) of any grade, with the majority being mild (grade 1). Conclusions: The 8Gy/4f radiotherapy followed by chemoimmunotherapy significantly increased the anti-PD-1 immunotherapy efficacy without increasing the treatment-related adverse events or postoperative complications, highlighting promise as an effective neoadjuvant treatment modality. Clinical trial information: ChiCTR2400084438 . Baseline, pathological, and perioperative data of patients. All patients 4Gy/2f 6Gy/3f 8Gy/4f Number of Patients 30 10 10 10 Sex Female 6 2 1 3 Male 24 8 9 7 Age ≥65 14 4 4 6 <60 16 6 6 4 cTNM I 1 0 0 1 II 10 3 5 2 III 10 4 2 4 IV 9 3 3 3 ypTNM <jats:td colspan="1" ro