The incidence of esophageal cancer accounts for the sixth place of malignant tumor incidence worldwide, and its incidence has obvious regional characteristics. In some regions of China, esophageal cancer ranks first in incidence and mortality rate of malignant tumors, and China as a high incidence area of esophageal cancer has attracted worldwide attention. In recent years, although many advances have been made in tumor treatment, the prognosis of esophageal cancer is still very poor, and the overall 5-year survival rate is 10%-20%. Among them, 50% of patients have distant metastasis when they are diagnosed; and even for clinically advanced esophageal cancer, more than 50% of cases have distant metastasis and more than 70% have lymph node metastasis as confirmed by autopsy. Thus, esophageal cancer is not only a local regional disease but also a systemic disease. The conventional treatment of esophageal cancer is mainly surgery and radiotherapy, but the results are not satisfactory. Overseas retrospective survey reported that the 5-year survival rate of esophageal cancer treated by radiotherapy alone or surgery is 6% and 11% respectively; in China, Professor Huang Guojun et al. reported that the 5-year survival rate of 1373 cases of esophageal cancer treated by surgery alone is 29.6%, and postoperative recurrence or/and metastasis is the main reason affecting patients’ long-term survival. Therefore, finding effective drugs to control the systemic dissemination of esophageal cancer and exploring comprehensive treatment options are the keys to treat this deadly disease. This article reviews the latest advances in chemotherapeutic drug therapy for esophageal cancer to provide new ideas and approaches for the comprehensive treatment of esophageal cancer. The efficacy of monotherapy for esophageal cancer provides the basis for combination chemotherapy. in the 1960s and 1970s, chemotherapy for esophageal cancer was mainly monotherapy, and the commonly used drugs were bleomycin (BLM), mitomycin (MMC), 5-fluorouracil (5-FU), adriamycin (ADM), aminoglycoside (MTX), and onychomycin (VP-16), etc. The efficiency was about 15%, and no complete remission was No complete remission has been reported. Because of potential pulmonary toxicity, BLM is no longer used in combination chemotherapy for esophageal cancer abroad; MMC is also rarely used in combination chemotherapy for esophageal cancer because of cumulative bone marrow toxicity, and is more often replaced by 5-FU. Six reported single-agent cisplatin 50~120 mg/m2 every 3~4 weeks for the treatment of esophageal cancer, with an overall efficiency of 21%. Another reported that cisplatin 120 mg/m2 repeated every 2 weeks (d1, d15) treated 15 patients with preoperative chemotherapy, with an efficiency of 73%. Chemotherapeutic agents with less than 5% efficiency include isocyclophosphamide (IFO) and carboplatin. The phase II clinical study showed that carboplatin with vincristine treated 16 cases of esophageal cancer with no remission in 1 case. Therefore, carboplatin is not recommended to replace DDP in chemotherapy for esophageal cancer. The phytoalkaloid, norethindrone vincristine (NVB), acts on microtubules and inhibits microtubule equipping. It is reported by EORTC to be 20% effective in patients with esophageal cancer treated with initial chemotherapy; in combination with DDP, it is 32% effective. The most commonly used combination chemotherapy regimen for esophageal cancer is the combination of DDP and 5-FU, with an efficiency of 25%-35%. There is only one report of randomized comparison of DDP and DDP with continuous intravenous 5-FU combination, which is a phase II clinical study, with 92 cases, the efficiency of single-agent cisplatin group is 18%, and the efficiency of DDP + 5-FU group is 36%, and there is no significant difference in survival between the two groups; however, the toxicity of DDP + 5-FU group is greater, with 16% mortality associated with chemotherapy toxicity, while there is no treatment-related death in the single-agent cisplatin group. Another phase III clinical report randomly compared DDP+5-FU (CF), FAMTX (ADM+MTX+5-FU) and ELF (VP-16+CF+5-FU) for esophageal-gastric cancer with an efficiency of 10%-20% and a median survival of less than 8 months. Therefore, it has been suggested that the addition of 5-FU does not increase the efficacy of DDP. It can be seen that the efficacy of conventional chemotherapeutic drugs is not satisfactory, and the efficacy of new drugs in esophageal cancer needs to be evaluated. Ajani et al. firstly reported that single agent paclitaxel (PTX) 250 mg/m2 once every 3 weeks for 24 hours was used to treat 50 cases of advanced esophageal cancer with an efficiency of 32% and a median remission period of 17 weeks. Vander Gaast et al. reported a phase I clinical treatment of advanced esophageal cancer with PTX 100-160 mg/m2 combined with DDP 60 mg/m2 in a biweekly cycle in 31 cases, with an efficiency of 55% and good tolerability. Ilson et al. reported that PTX175mg/m23 hours was combined with DDP20mg/m2d1-5 and 5-FU1g/m2d1-5 in 21 days for 1 cycle, with an efficiency of 48%, median remission period of 5.7 months and median survival period of 10.8 months. In 30 patients with advanced esophageal cancer treated in Cancer Hospital of Chinese Academy of Medical Sciences, PTX 175mg/m2 d1 and DDP 40mg/m2d2, d3, 21 days for 1 cycle, the efficiency was 57.1%, among which 5 cases (17.9%) were in complete remission and 11 cases (39.3%) were in partial remission. It can be seen that the efficacy of the three-drug combination is not higher than that of the two-drug combination-PTX+DDP, and the addition of 5-FU only increases toxicity. The Eastern Cooperative Oncology Group (ECOG) reported that Tysodi was given in 1 cycle of 3 weeks for gastric cancer, in which 2 of 8 patients with esophageal cancer were in remission, with an efficiency of 25%. 3Cepto (CPT-11) CPT-11 is an inhibitor of topoisomerase II. Recently, it has been used in the treatment of esophageal and gastric cancer with good efficacy. 2 phase II clinical studies showed that single-agent CPT-11 weekly regimen (125 mg/m2/wk) treated esophageal cancer and esophagogastric cancer respectively with an efficiency of 15%. Another two phase II clinical studies evaluated the effect of the combination of CPT-11 weekly regimen with CF and 5-FU in 113 patients, with an efficiency of 22%. The efficiency was 57%. Govindan et al. reported that CPT-11160mg/m2 combined with Tysodex 60mg/m2 in a 3-week cycle was 30% effective in the treatment of initially treated advanced or recurrent esophageal cancer. Toxic side effects included 4th degree myelosuppression in 71% of patients and neutropenic fever in 43% of patients. Therefore, CPT-11 in combination with Tysodi is effective in the treatment of esophageal cancer, but the optimal dose needs to be continued to be explored. 4 Kinsei Kinsei (GEM) is a new antimetabolite, a derivative of cytarabine. kroep et al. reported that GEM 800mg/m2d2, d9, d16, combined with DDP 50mg/m2d1, d8, 28 days for 1 cycle, treated 36 cases of primary advanced esophageal cancer with 41% efficiency, 2 cases in complete remission and median survival time of 9.8 months. It shows that GEM combined with DDP may have good efficacy in the treatment of esophageal cancer. 5 Problems and summary The drug treatment of esophageal cancer is still stuck on cytotoxic drug-chemotherapy, focusing on exploring the best dose and method of administration and combination chemotherapy regimen. Combination chemotherapy is mainly DDP, and the combination with new drugs PTX, CPT-11, and GEM has shown good efficacy, but the number of cases of chemotherapy results in esophageal cancer is small, and most of the results are from phase II clinical studies, and there are few phase III randomized comparative results, and there is a need to compare the effect of DDP combined with new drugs and DDP combined with 5-FU. In addition, identification of specific tumor markers for esophageal cancer is the direction for research and treatment of esophageal cancer, and finding drug resistance related genes for esophageal cancer will improve the targeting of esophageal cancer treatment.