The treatments and postoperative complications of esophageal cancer: a review

Radical surgical treatment is an ideal treatment for early esophageal cancer, and the postoperative survival rate is more than 90%. In 2009, the global collaboration on esophageal cancer (WEOC) published the results of 7884 esophagectomy cases of esophageal cancer from 13 participating institutions, in which 4725 have not received AC nor radiotherapy. After 30 days, 1 year, 5 years and 10 years, the overall survival rates were 98, 78, 42 and 31%, respectively [39]. The death risk is higher in the first 2 years after esophagectomy, and then declines at a constant rate of 5.9% per year [40]. Saddoughi et al. [40] conducted a retrospective analysis of 3500 cases of esophagectomy from 1985 to 2013, and found that 52 cases (1.5%) of patients with stage IV esophageal cancer received surgical resection, with the 1-year and 5-year survival rate of 29 and 6%, respectively. Thus, esophagectomy should not be performed for stage IV disease, and the palliative treatment may be more suitable.

Surgical treatment is utilized in the treatment of esophageal cancer at the present time,while the simple surgical treatment is not effective and the survival rate is also low. Meanwhile, most patients are already in the middle and late stages of the disease when they are diagnosed, with being often accompanied by local or different parts of the body metastasis. Since the symptoms of early esophageal cancer patients are insidious and difficult to be found. Hence, the simple surgery is difficult to obtain sufficient clinical effect. Neoadjuvant therapy prior to esophagectomy is the standard treatment for locally advanced and operable esophageal cancer. Neoadjuvant chemotherapy, which is also known as initial chemotherapy, refers to the reduction of tumor size through chemotherapy before surgery, this can reduce tumor load and control distant metastasis as early as possible. Existing studies have shown that preoperative neoadjuvant chemotherapy can significantly improve the short-term and long-term survival rate of patients [48, 49]. Fluorouracil and paclitaxel combined with platinum and platinum, respectively, are two commonly used chemotherapy regimens for esophageal cancer [49]. Stiles et al. [50] reviewed the survival status of 238 patients who received neoadjuvant therapy or chemotherapy and radiotherapy before resection during 1987–2013. Results showed that 15% (n = 36) died within 1 year after esophagectomy, and 69% died in documented recurrence of cancer. Saddoughi et al. [40] analyzed the causes of esophagectomy after neoadjuvant therapy and believed that the performance state, poor tumor differentiation and lack of response to neoadjuvant therapy were risk factors leading to early death. Tong et al. [51] performed multivariate scores on 175 patients who received surgery after neoadjuvant chemoradiotherapy, and suggested a high percentage of remaining active tumor cells in the primary tumor, moreover, the positive lymph node was an independent predictor of poor prognosis. Neoadjuvant chemoradiotherapy has the characteristics of double-edged sword. Sufficient responders may have better survival in the long term, while the diseases may occur in the process of neoadjuvant therapy for the patients with adverse reactions. It is, therefore, meaningful to determine the clinical, biochemical and molecular predictors of tumor regression after neoadjuvant therapy [49].

In general, some patients with esophageal cancer also need to remove the gastric wall, or even a part of the stomach, when removing the esophagus. Since the esophagus is connected with the stomach, with the mutual influences on the function. The resection of esophageal cancer is prone to gastric movement disorders, thereby leading to obstacle of empty of function of bosom stomach and bringing about content of a large number of stomach to detain. It is reported that more than 50% of patients after esophagectomy have FDGE symptoms [52]. Different anastomotic modes are correlated with the occurrence of FDGE [53]. Gender differences, longer operation time and hospital stay are also have the probability of becoming factors contributing to FDGE [54]. In addition, a study of 285 patients undergoing esophagectomy suggests that the incidence of FDGE was 18.2%, and gastric size (gastric tube versus the whole stomach) was the only significant factor influencing the incidence of FDGE among perioperative factors [55]. The previous research showed that gastric tube was significantly better than the whole stomach in reducing the incidence of postoperative gastric emptying disorder (PDGE) [56].

Reflux esophagitis is a common postoperative complication of esophageal cancer, it is mainly manifested as body flexion after the meal or acid liquid and food reflux from the stomach and esophagus to the pharynx or mouth when patients sleep in bed at night. This is also accompanied by symptoms such as post-sternal burning, pain, difficulty in swallowing and so on. The occurrence of this symptom may be related to vagotomy and gastrin concentration [57]. Besides, anastomosis level is correlated with reflux esophagitis. In the investigation of 53 patients who have thoracic esophageal cancer and underwent root canal esophagectomy, gastric tube reconstruction and neck anastomosis, results showed that anastomosis degree of gastric tube reconstruction after esophageal cancer was associated with the incidence of reflux esophagitis [58].

Although the lung tissue was not resected in the surgery for esophageal cancer, the integrity of the thoracic wall and the intercostal muscles are damaged, especially for the integrity of the diaphragm, since the ventilation pump of the affected lung was severely damaged, respiratory tract infection is easy to occur. Patients may experience varying degrees of dyspnea and shortness of breath after surgery when pain from neck, chest, or upper abdominal incisions occurs, if the stomach is pulled into the chest to compress the lungs. The pathophysiological mechanisms lead to pulmonary infection including alveolar collapse, pulmonary edema, weakened pulmonary defense mechanisms, and poor ventilation [59]. Perioperative risk factors associated with postoperative pulmonary infection include chronic bronchitis, chronic cardiac insufficiency, and age ≥ 80 years [60].

The recent studies demonstrated that 28% of 2704 patients occurred severe respiratory complications, 15% appeared pneumonia, and 7% occurred respiratory failure [61]. Elliott et al. [62] analyzed the impacts of neoadjuvant therapy on postoperative pulmonary function, and found that neoadjuvant therapy altered pulmonary physiology, especially for the diffusion ability. These may lead to pulmonary complications, and also show a potentially modifiable risk index, which also demonstrates that neoadjuvant therapy is a potential risk factor for complications. Most of patients with esophageal cancer lung infection have postoperative pulmonary edema, which increase sputum production, ineffective cough and sputum cough. Assisting patients to effectively sputum cough is one of the main measures to treat pulmonary infection. Patients should be encouraged to drink water and give intravenous fluids to increase body hydration. However, for the patients with certain organic heart diseases, such as coronary heart disease and hypertension, infusion rates should be reduced based on the changes in heart rate and blood pressure in daily observation. Pain caused by chest wall incision and drainage tube can make patients worry about pain, reduce the depth of breathing, lead to rejection of cough or weak cough, and damage to the ipsilateral pulmonary ventilation function, which prevent effective release and relief of sputum cough. Meanwhile, the application of effective antibiotic therapy is undoubtedly one of the most effective methods to control pulmonary infection [63].

Postoperative chylothorax is still an important factor for reoperation and prolonged hospitalization after esophageal cancer. Chylothorax is potentially life-threatening and difficult to treat. It is an uncontrolled chylothorax caused by tissue damage to the thoracic duct during the operation process of esophageal cancer, and most often occurs between 2 and 10 days after surgery. Chylous drainage from catheter injury can lead to wound infection, skin flap necrosis, chylothorax, and other severe cases, it also can result in carotid artery exposure and rupture [64]. When this happens, closed thoracic drainage should be installed, and drainage volume should be closely observed, meanwhile, medium-chain triglyceride diet or total parenteral nutrition (TPN) nutrition improvement treatment should be given to maintain hydrolytic balance and supplement nutrition. In these conditions some patients may cure after treatment [65]. For the patients with large chylous flow, the chylous duct should be ligated immediately after thoracotomy [66]. Lin et al. [67] provided a method of intraoperative selective thoracic ligation of thoracic duct, which could reduce the incidence of postoperative chylothorax. Some studies reported that low fat-containing elemental formula is effective for postoperative recovery and potentially useful to prevent chyle leak [68]. Several cases take early intervention to reduce mortality after esophagectomy by conducting minimally invasive surgery [69].

Anastomotic fistula is a serious postoperative complication of esophageal cancer, with an incidence of 8.2–15% [70‐72]. The reasons are derived from the anastomotic mode, tension of the anastomotic site, secondary infection of the anastomotic site, and nutritional status of the patient before the operation. Neck anastomotic fistula is not easy to threaten the patient’s life, and can be healed by drainage. Intrathoracic anastomotic fistulas often occur 5–10 days after surgery. They can even lead to pleural membrane pollution and gastric necrosis when the condition worsens, causing a great threat to patients and a high mortality rate, even though some anastomotic fistulas are asymptomatic.

The surgical strategy of esophagectomy has been gradually improved, nevertheless, some potential risk factors still lead to postoperative anastomotic fistula. Anastomotic stoma or gastric stump fistula after esophageal cancer, leading to local inflammatory cell infiltration, poor mucosal healing, and further develop into fistula, mostly due to infiltration and infiltration of inflammatory substances in the suture plane, local erosion of digestive juice or bleeding in the suture plane. This is a process that gradually progresses from occult to fistula. According to the case analysis of this group, the fistula is mostly local inflammation or small rupture in the early stage, which is “occult”. The common reason is that the pressure of the stapling device or the closure device is uneven, resulting in local fracture and damage of the anastomotic mucosa layer. Another cause is that a hematoma is formed when the stump of the local gastric wall is closed, leading to poor blood flow in the suture plane, and poor local healing of the anastomosis or gastric stump. Because the fistula is small and there is only a small amount of digestive juice or gas in the gastrointestinal tract, patients often only have persistent sepsis such as elevated body temperature, increased heart rate, and fatigue. The location of the anastomotic site has a certain impact on the occurrence of anastomotic fistula. Neck anastomosis has a higher leakage rate (25–45%) compared with intrathoracic anastomosis (5–15%), which may lead to an increase in recurrent nerve palsy and longer hospital stay [73, 74]. Female patients with postoperative hypoproteinemia and renal insufficiency are more likely to have anastomotic fistula [75].

Note that the optimal treatment for anastomotic leakage is unclear. Previous studies argued that conservative treatment, oral and intravenous antibiotics, drainage, and surgical and non-surgical treatment can be used according to the patient’s situation and treatment unit preference [76, 77]. Surgical repair can be tried and reinforced with greater omentum or intercostal muscle flap when the patients are in early anastomotic fistula, it should be noted that the mortality rate of the second operation is higher [78]. If the amount of leakage is small, endoscopic surgery can be performed [79], such as Endoscopic vacuum-assisted closure (EVAC) [80]. EVAC is based on the continuous negative pressure applied to the wound by sponge [81], so that the anastomotic site can be anastomosed again or the leakage site can be closed to achieve the purpose of treatment, which has the advantages of effectively attracting influenza dye and accelerating wound healing. In addition, a retrospective study of 70 patients, who have esophageal anastomotic leakage after Ivor Lewis esophagectomy treated by self-expanding metal stents (SEMS), found that the treatment of this method with SEMS was effective, safe and technically feasible [82]. At present, the application of SEMS in the treatment of anastomotic fistula after resection of esophageal cancer has become another mature treatment method [82‐84]. Embedding anastomosis with epiploon is an effective way to reduce the anastomotic fistula after esophagectomy, and it will not cause additional damage to cardiopulmonary function.

Prevention of anastomotic leakage should focus on preoperative nutritional status and intraoperative operations to minimize direct catheter trauma for the postoperative management. The longer time for gastric tube reconstruction are more likely to suffer from ischemia at its tip, as esophageal reconstruction mainly involves the stomach. It is therefore necessary to pay attention to the preoperative severing of gastric vessels. Furthermore, improving perioperative management and early postoperative enteral nutrition, pulmonary physiotherapy, prevention of hypoxemia and hypotension are all the important measures to reduce the incidence of anastomotic leakage [76]. Patient status should be closely monitored after surgery, and the patients with fever or leukocytosis should be vigilant. Atrial fibrillation may be a strong indicator of leakage, and the high levels of inflammatory markers in the blood are also possible indicators of leakage. Once the anastomotic fistula occurs, it should be diagnosed as soon as possible. Generally, the selected methods include esophagography, upper gastrointestinal endoscopic examination, computed tomography (CT), etc. In the early stage of postoperative microfistula, inflammatory reactants temporarily “closed” the fistula, and the gastric circumference became smaller after surgery. Especially for the tubular stomach, the contrast agent often passes through the digestive tract quickly, most of the contrast agent has no obvious extravasation, and it is easy to miss the diagnosis of intrathoracic fistula. If the stomach contents are not fully decompressed or given food, it is easy to enlarge the fistula and progress into a severe fistula. While the spiral CT examination is non-invasive and does not stimulate the wound margin, which can clearly show the hierarchical structure around the digestive tract in the chest. In recent years, particularly in thin-layer CT, scattered small gas or a small amount of uneven density of effusion around the anastomotic or gastric incision edge appear, and the presence of hidden thoracic fistula is often considered in the clinical manifestations of systemic poisoning. A prospective clinical study confirms that CT shows that small gas shadows around the thoracic and digestive tract are significantly superior in the sensitivity of the diagnosis of occult fistula in the chest, compared to the leakage of contrast agent in upper gastrointestinal angiography. And a set of CT-based predictive score has been proposed by some doctors to provide higher accuracy for the diagnosis of anastomotic fistula [85].

Anastomotic stenosis is a common complication after radical resection of esophageal cancer. Although postoperative anastomotic stenosis does not immediately endanger the life of patients, it seriously affects the quality of life of patients. Most of the anastomotic stenosis is caused by scar contraction, as results of too much anastomotic suture, the tight suture, and the not well matched mucosa. Anastomotic leakage, multi-layer anastomosis and long-term fluid diet are the high risk factors that can cause anastomotic stenosis after operation of esophageal cancer. Attention should be paid to avoid the occurrence of these factors before, during and after operation, which can effectively reduce the occurrence of anastomotic stenosis. Expanding narrow anastomotic stoma is a common method at early clinical stage. At this time, the scar is not firm and easy to expand, but expansion is prohibited within 1 month to prevent anastomotic leakage [86].

Esophageal cancer surgery may also lead to severe diarrhea by causing gastrointestinal dysfunction. Antidiarrheal drugs should be given actively, along with rehydration to prevent dehydration.