Esophageal cancer is the seventh most common cancer and the sixth most common cause of cancer related death worldwide. Globally, there were 604,000 new cases of esophageal cancer and 544,000 deaths in 2020. China is in the high incidence area of esophageal cancer, with 253,000 new cases of esophageal cancer and 194,000 deaths in 2016. Esophageal cancer has become a malignant disease that seriously endangers the health and social development.~Squamous cell carcinoma and adenocarcinoma are common pathological types of esophageal cancer. The main risk factors for esophageal squamous cell carcinoma are smoking and alcohol consumption. Esophageal squamous cell carcinoma is the most important pathological type of esophageal cancer in China, accounting for more than 90% of esophageal cancer.~The prognosis of esophageal cancer is very poor, most patients are in the middle and advanced stages at the time of diagnosis. The natural course of the disease is only 6-8 months, and the 5-year survival rate is less than 20%. In addition, 90% of patients undergoing surgery may have recurrent metastasis, and even those with very early staging (T1) still have the risk of relapse or metastasis within 5 years. Therefore, in recent years, scholars from various countries have continued to explore effective treatment methods in order to improve the quality of life and prolong the survival of esophageal cancer patients.~Palliative chemotherapy is the mainstay of treatment for advanced metastatic esophageal cancer including paclitaxel, platinum, fluorouracil, or irinotecan. Multiple phase III clinical studies have shown that PD-1 antibodies in addition to PF (fluorouracil plus cisplatin) or TP (paclitaxel plus cisplatin) regimens can improve the effective rate and prolong PFS and OS. Therefore, PD-1 antibody combined with chemotherapy has become the new standard first-line treatment for patients with advanced esophageal cancer.~Prior to the advent of PD-1 antibodies, the second-line regimen for advanced esophageal cancer was to select drugs that were not used in first-line chemotherapy, such as taxans or irinotecans. Keynote181, Attraction-03, and ESCORT studies have suggested that PD-1 antibody monotherapy is superior to standard chemotherapy in the second-line treatment of advanced esophageal cancer. In ESCORT studies, PD-1 antibodies and conventional chemotherapy (docetaxel or irinotecan) were 20.2 percent and 6.4 percent effective, median PFS at 1.9 months, and median OS at 8.3 months and 6.2 months, respectively. Based on the above research results, China's Food and Drug Administration has approved PD-1 antibody for the second-line treatment of advanced esophageal cancer.~Therefore, we intend to design a prospective, multicenter, randomized controlled clinical study based on the characteristics of esophageal cancer in China, explore the efficacy and safety of PD-1 antibody combined with mXELIRI compared with mXELIRI in the second-line treatment of metastatic esophageal squamous cell carcinoma. We will further analyze the significance of cross-line use of PD-1 antibody and analyze the possible benefit population.
This trial is a prospective, multicenter, randomized controlled trial. The sample size was 380. Patients with advanced or metastatic esophageal squamous cell carcinoma will be randomized to receive PD1 antibody combined with mXELIRI or mXELIRI regimens in a 1:1 ratio. The stratification factors include PS status (0 vs 1), PFS of first-line treatment (PFS < 3 months versus PFS ≥3 months) . Six cycles of chemotherapy are planned every 3 weeks, for a total of 18 weeks, after which the investigator can decide whether to provide capecitabine with or without PD1 antibody maintenance therapy. Efficacy assessments were performed every 6 weeks before disease progression during treatment. Survival status was followed every 3 months after disease progression.