Neoadjuvant sintilimab and chemotherapy in patients with resectable esophageal squamous cell carcinoma: A prospective, single-arm, phase 2 trial

Background Immunotherapy (Programmed cell death 1 blockade) has entered the ranks of advanced esophageal cancer first-line treatment; however, little is known about the efficacy of PD-1 inhibitor as neoadjuvant therapy in resectable esophageal squamous cell carcinoma (ESCC). We aim to evaluate the activity and safety of the neoadjuvant sintilimab combined with chemotherapy in the treatment of resectable thoracic ESCC. Methods The enrolled patients with resectable (clinical stage II to IVA) ESCC received neoadjuvant sintilimab injection (200 mg/time, day 1), paclitaxel liposomes (135 mg/m2, day 1), and carboplatin (area under curve of 5 mg/mL/min, day 1) every 21 days for 2 cycles, and esophagectomy was performed within 3-6 weeks after the 2 cycles of treatment. The primary endpoint of the study was the pathological complete response (PCR) rate. Results From July 2019 to March 2021, a total of 47 patients were enrolled, of which 33 patients (70.2%) had clinical stage III disease. All patients completed the full two-cycle treatment and forty-five patients received radical surgery, including 44 (97.8%) R0 resections. Ten (22.2%) of 45 patients had a PCR, and the major pathological response (MPR) rate was 44.4% (20/45). The grade 3–4 treatment-related adverse events (TRAEs) were mainly neutropenia (6 of 47,12.8%) and leucopenia (8 of 47,17.0%). One (2.1%) patient occurred postoperative immune-associated encephalitis. No delays in surgery were observed. Conclusions sintilimab combined with paclitaxel liposome and carboplatin, as demonstrated in this phase II trial to exhibit a relatively high PCR rate and acceptable safety, warrants additional investigation in resectable ESCC. Trial Registration http://www.chictr.org.cn/, ChiCTR1900026593.

(b). Esophageal lesion (Unmeasurable lesion) Evaluation standard (Modified from "Efficacy Evaluation Criteria of Esophageal Barium Swallowing Radiography at the End of Radiotherapy for Esophageal Cancer in Japan") Complete Response (CR) The lesion disappeared completely, the esophageal wall was soft, and no tumor remained. Partia l Remission (PR) Along the long axis of the esophagus, the length of the lesion subsided by more than 50%, but not completely, and the esophageal lumen stenosis improved. Stable Disease (SD) In the long axis of the esophagus, the length of the lesion was less than 50%, or regardless of tumor changes, lumen stenosis of the esophagus is evident but does not progress.
Progressive Disease (PD) The length of lesions increased by more than 20%, and esophageal lumen stenosis was more obvious than before.
(c). Comprehensive evaluation lymph node esophageal lesion supplemental file 2 Dose adjustment principle All patients were given the planned chemotherapy dose in principle, and the dose could be adjusted if necessary according to the most serious hematological or other toxicity. Any patient requiring a dose reduction will continue to receive the reduced dose for subsequent treatment cycles. If a patient presents with multiple toxicities and the principles of dose adjustment differ from one another, the lowest dose is selected. If ANC ≤ 1.5 x 109/L and platelets <100 x 109/L on day 1 of the course of treatment, the medication was suspended for one week. Except for alopecia, nausea and vomiting, other non-hematological toxicities of grade II and above should be recovered to grade 0 to 1 before the next course of treatment can be performed. Recovery of hematologic and non-hematologic toxicities can be delayed up to 14 days. A maximum of two decrements are allowed. Dose reductions should be based on the grade of the most severe toxicity from the previous course of treatment. Cisplatin and carboplatin were adjusted to 75% of the original dose for the first time, and to 50% of the original dose for the second time. Paclitaxel was adjusted to 80% of the original dose for the first time, and adjusted to 60% of the original dose for the second time, and the dose adjustment scheme was adjusted according to the following. 1. Paclitaxel and DDP were both reduced: Grade III/IV neutropenia accompanied (≥38.3°C or 38.0°C for 1 hour). Grade IV neutropenia persisting for ≥7 days; other investigators believe that dose reduction is warranted. 2. Cisplatin dose reduction: Adjust the dose of DDP according to the renal function.
When 45ml/min≤ creatinine clearance (CCI) <60ml/min, the DDP dose is reduced by 25%; when 30ml/min ≤ creatinine clearance (CCI) <45ml/min, the DDP dose is reduced by 50%; when creatinine clearance (CCI) <30ml/min, the medication should be suspended. The next cycle of treatment cannot be started until recovery to level 0-1. 3. Paclitaxel dose reduction: For severe peripheral neuropathy, the dose should be adjusted or discontinued according to the total dose principle.
Note: DDP is only decremented once when both 1 and 2 are present; Paclitaxel was reduced only once when both 1 and 3 occurred. supplemental file 4 ROC curves of serum inflammatory indexes predicting ability of pathological curative effect (G): the therapeutic efficacy was categorized into pathological tumor regression grades 0, 1 (MPR) and grade 2, 3 (non-MPR). Cutoff = 4.19, Sensitivity = 0.45, Specificity = 0.88