Comprehensive treatment of esophageal cancer and rational drug use Xiaobing Chen, Department of Internal Medicine, Henan Cancer Hospital In China, surgery is still the main treatment for esophageal cancer, but the importance of drug treatment cannot be ignored for patients with middle and advanced esophageal cancer. Based on the fact that adenocarcinoma is predominant in esophageal cancer in foreign countries and >90% is squamous cancer in China; most of the foreign clinical trials are based on adenocarcinoma or combined gastroesophageal cancer, therefore NCCN guidelines are not fully applicable to clinical practice of esophageal cancer in China. For squamous esophageal cancer, there is no standard protocol in China. The TNM stage is one of the main bases to decide the clinical treatment plan for esophageal cancer, and both the 2013 NCCN and domestic esophageal cancer standardization guidelines recommend esophageal Ultrasound endoscopy (EUS) combined with PET-CT is recommended to improve the accuracy of clinical staging. The treatment of esophageal cancer should follow the principle of multidisciplinary comprehensive treatment. Neoadjuvant chemotherapy is meaningful for reducing tumor grade, shrinking primary tumor volume, controlling and eliminating micro metastases, evaluating the sensitivity of chemotherapy drugs in vivo, improving surgical resection rate and increasing long-term survival rate after surgery. Preoperative neoadjuvant chemotherapy is currently recommended to be considered for patients with locally advanced esophageal cancer beyond T2 and any positive lymph nodes. Cisplatin (DDP) and fluorouracil (5-Fu) based preoperative combination chemotherapy regimens are now the standard with an efficiency of 40%-58% and a pathologic complete remission (pCR) rate of 2.5%-5.0%. With the development and application of new generation chemotherapeutic drugs such as paclitaxel (PTX), doxorubicin (TXT), irinotecan (CPT-11), nedaplatin (NDP), and vincristine (NVB), they are also used in neoadjuvant chemotherapy of esophageal cancer. At present, the commonly used chemotherapy regimens: DDP+5-Fu/Calcium folinic acid (CF), PTX/CPT-11+DDP, NDP+Tegafur (FT207)/5-Fu+CF. 2 cycles of chemotherapy are recommended, then the efficacy is evaluated, and for patients who are suitable for surgery, an interval of 2-4 weeks can be used for surgery. The population for neoadjuvant radiotherapy should be selected from stage IIB and III patients with lymph node metastasis and late local staging. Current studies have confirmed that preoperative radiotherapy can improve the 1-year survival rate, help reduce the postoperative local recurrence rate, do not increase the incidence of surgical complications, and synchronous radiotherapy is better than sequential radiotherapy. The guidelines recommend the main chemotherapy drug regimen for neoadjuvant chemoradiotherapy: DDP+5-FU or capecitabine (CAP), PTX/carboplatin (CBP), oxaliplatin (OXA)/5-Fu (5-FU or CAP); CBP/5-FU, CPT-11/DDP, TXT or PTX/5-Fu (5-FU or CAP). 3 weeks repeated once for 2 courses ; concurrent radiotherapy with radiation dose: clinical target area (CTV) dose 40Gy (36-46Gy). It should be noted that neoadjuvant therapy may miss the best time to remove local lesions, especially when treatment failure results in metastatic expansion. Therefore, multidisciplinary consultation before treatment to develop a treatment plan; timely assessment during treatment, timely interventions, and multidisciplinary consultation to adjust the treatment plan should be conducted in an effort to maximize the benefit to patients. The main reasons for failure of postoperative adjuvant therapy for esophageal cancer include: potential micro metastases before surgery; incomplete resection and lymph node dissection during surgery; postoperative patients’ immune function is reduced; postoperative tumor cells may enter the proliferation cycle in large quantities due to negative feedback, resulting in recurrence and metastasis. Adjuvant therapy is aimed at: preventing tumor recurrence and distant metastasis; and prolonging OS and PFS in postoperative patients. it is now commonly accepted that postoperative adjuvant therapy is preferred for patients with high-risk factors (young, hypofractionated, positive stump, positive lymph nodes, etc.). The common regimens recommended for postoperative adjuvant chemotherapy are DDP/5-FU, DDP/CF/5-FU, and DDP/PTX (or TXT), typically with 4-6 cycles. For those who have received chemotherapy or chemoradiotherapy before surgery, the effectiveness of preoperative chemotherapy or chemoradiotherapy needs to be judged according to the degree of cancer residual after surgery, and then decide whether to use the original treatment regimen or replace it with a new regimen for postoperative adjuvant therapy. Currently, studies on postoperative radiotherapy for esophageal cancer are mostly retrospective analyses with small sample size, and there is a lack of results of phase III clinical studies. For those with intraoperative lymph node metastasis or deep tumor infiltration, it may be more reasonable to adopt postoperative radiotherapy mode. Treatment of unresectable esophageal cancer unresectable esophageal cancer includes patients with T4b, N3 and stage IV (AJCC2009). Esophageal cancer not suitable for surgical treatment includes patients with severe heart, lung, liver and kidney dysfunction, hematopoietic system diseases, immune system diseases and cachexia that cannot tolerate surgery. For the above two categories of patients, the treatment methods include: comprehensive treatment, palliative treatment and supportive treatment. Concurrent radiotherapy for T4b and N3 patients can enhance local tumor control and reduce distant metastasis of esophageal cancer and improve patients’ survival rate. For patients with unresectable tumors in stage T4 who choose to be treated by other modalities, the preferred treatment is to give 50-50.4Gy radiotherapy and concurrent chemotherapy with 5-FU+DDP. A recent study has shown that simultaneous radiotherapy with Tegeo (S-1)/DDP has better clinical efficacy, prolonged survival and tolerable adverse effects in the treatment of advanced cervical esophageal cancer, and has the potential to replace conventional surgical treatment. IV. Treatment of locally recurrent esophageal cancer For patients with local recurrence, if radiotherapy or chemotherapy has not been applied previously, radiotherapy synchronized with 5-FU+DDP chemotherapy and other options, including endoscopic treatment, are preferred. For patients with anastomotic recurrence, re-excision may be considered. Local recurrence after radiotherapy should be judged as to whether the patient can tolerate surgery and whether the recurrence site is resectable. If these criteria are met, surgical resection is feasible. If recurrence occurs after surgery, the patient should be considered for palliative care. Patients with recurrence that cannot tolerate surgery or is unresectable after radiotherapy may be given brachytherapy, laser therapy, photodynamic therapy, or other supportive therapy, including esophageal dilatation. V. Palliative treatment for advanced metastatic esophageal cancer For patients with stage IV esophageal cancer, only palliative treatment is suitable, aiming to relieve symptoms, especially to relieve dysphagia and improve quality of life and prolong survival. Whether to give best supportive care alone or add chemotherapy should be based on the patient’s PS status. patients with KPS score ≤ 60 or ECOG score ≥ 3 are given best supportive care. patients with fair PS score can be given best supportive care alone or add chemotherapy. If chemotherapy is applied for palliative care, patients should be encouraged to participate in a clinical trial. Patients not participating in clinical trials choosing chemotherapy based on 5-FU, DDP or PTX regimens may be given both regimens in sequence. Radiotherapy alone should only be used for patients who cannot receive chemotherapy or as palliative treatment. There is no standard protocol for palliative chemotherapy for esophageal cancer. Single-agent chemotherapy for esophageal cancer has a low efficiency ( RR 15 % ~ 30 %) and a short remission period (<4< span="">months). Therefore, many investigators are trying combination studies and new drug applications. Most of the existing chemotherapy regimens are composed of single agents such as DDP, NDP, PTX, TXT, CPT-11, NVB, 5-Fu, epothilone (EPI), gemcitabine (GEM), and other drugs that are effective in treating esophageal cancer. Among them, the more studied cases and more widely used is the 5-FU and DDP-based regimen, with an efficiency rate of 25%-35% for the combination of the two . In the absence of large samples and randomized studies to confirm which palliative treatment regimen is effective, in order to achieve the goals of symptom relief, improvement of quality of life, control of tumor development and prolongation of survival with tumor, patients may benefit from the entire treatment process, which is carefully divided into first-line treatment, second-line treatment and supportive treatment to maximize the role of palliative treatment, according to the specific status of each patient. The options mostly chosen in China are: DDP + 5-Fu, DDP + CF + 5-Fu, NDP + 5-Fu, PTX /DOC + DDP, CPT-11 + DDP, etc. These options have larger samples, more certain efficacy, longer survival, better tolerability, easier dosing method and better efficacy for squamous carcinoma, or effective for both squamous carcinoma and adenocarcinoma, so they are used as the main first-line treatment options Therefore, it is widely used in clinical practice. There is no consensus on the number of cycles of first-line chemotherapy for advanced and metastatic esophageal cancer. Because of the poor organism status and low immune function of these patients, too many cycles may not improve the disease control rate but may lead to toxic accumulation. According to clinical experience, 4 cycles are appropriate, and the maximum number of cycles should not exceed 6. Our proposition is: 1 ) After 2 cycles of chemotherapy, patients with shrinking or stable lesions will be treated with 2 cycles of chemotherapy according to the original regimen, for a total of 4 cycles, and if the lesions reach CR or PR, standardized chemotherapy will be stopped and maintenance therapy or biological therapy and herbal medicine will be used instead according to the principle of beat chemotherapy. Conduct follow-up observation in order to eliminate the toxic side effects of chemotherapy, restore the patient’s constitution, rebuild immune function, and once disease progression is detected, if the remission period exceeds 6 months, then carry out retreatment of first-line effective regimen or second-line treatment; if the lesion SD after 4 cycles of chemotherapy, adjust and change the first-line regimen or carry out second-line treatment; 2 ) If the disease progresses or toxicity cannot be tolerated after 2 cycles of chemotherapy review, it should be immediately change to adjust the first-line regimen or start second-line therapy. For refractory patients who have been previously treated with more standardized basic platinum-containing regimen chemotherapy for esophageal cancer and have failed chemotherapy or chemoradiotherapy treatment, if the organism status KPS score is greater than 60, the expected survival is greater than 3 months, and there is a willingness to receive second-line treatment, second-line single-agent chemotherapy can be selected from drugs that have shown some efficacy in first-line treatment and are not considered resistant or have not been used in first-line treatment. Intensive supportive therapy is a reasonable option for patients who cannot tolerate radiotherapy and cannot be surgically removed. The goal of optimal supportive care is to reduce the pain and burden of patients and improve the quality of life of patients and their relatives. With unresectable and locally progressive tumors, palliative interventions can alleviate symptoms and significantly improve the patient’s nutritional status, self-perception and overall quality of life. The composition of optimal supportive care should be determined by the patient’s symptoms. For patients with obstruction, endoesophageal stent placement, laser dissection and release, photodynamic therapy (PDT), radiation therapy, or a combination may be indicated as appropriate. For patients requiring nutritional support, parenteral nutrition needs to be ensured whenever possible, and radiotherapy plus analgesics may be applied for pain control. Similarly, surgery, radiotherapy and/or endoscopic treatment can be used as indications for tumor rupture and bleeding. Targeted therapy for esophageal cancer Targeted drugs in neoadjuvant treatment of esophageal cancer are mostly studied in phase I/II clinical settings, mostly in combination with radiotherapy and chemotherapy, which have better safety and certain objective efficacy. Several studies have confirmed that epidermal growth factor receptor 2 (HER-2) and vascular endothelial growth factor (VEGF) are closely related to the prognosis of esophageal cancer. Based on the results of the ToGA trial, a new standard regimen of trastuzumab in combination with DDP/5-Fu regimen for HER2/neu-positive locally advanced esophagogastric union cancer is recommended. In addition, several phase II clinical trials have evaluated the efficacy and safety of targeted therapeutics cetuximab, trastuzumab, gefitinib and bevacizumab in advanced esophageal cancer, which still need to be confirmed by further studies in multicenter phase III clinical trials. China belongs to a country with high incidence of esophageal cancer, and compared with esophageal cancer in western countries, there are great differences in many aspects such as etiology and pathogenesis, pathological types, surgical methods, etc. We must accelerate high-quality clinical studies, accumulate our own experience, explore treatment modes with Chinese characteristics, and improve the treatment level of esophageal cancer in China. Reference: Esophageal Cancer Professional Committee of China Anti-Cancer Association. Guidelines for standardized diagnosis and treatment of esophageal cancer. 2nd ed. Beijing: China Union Medical University Press,2013: 85-167.