Therapeutic strategies vary according to factors such as the location of the esophageal lesion, extent of the lesion, depth of invasion, presence/absence of metastasis, general condition of the patient, and the institution that provides the treatment. There are many treatment options available. Some treatments are already formulated and used commonly in daily clinical practice. Some other treatments are in the clinical research phase and in the process of expanded use, although lacking in solid supportive evidence.
With regard to surgical treatment, there are various options depending on the institution as to the width of the resection margin, extent of lymph node dissection, the organ and route used for reconstruction, multimodality therapy including adjuvant therapy, and salvage surgery following definitive (chemo-) radiotherapy. Therefore, it is difficult to choose the currently most appropriate standard therapy based on evidence.
The esophagus extends anatomically from the cervical through the thoracic region into the abdominal region. It is surrounded by various organs according to its location. Although therapeutic strategies vary widely according to the location of the tumor, stage, and general condition of the patient, surgery remains the mainstay of treatment. In general, absolute indications for endoscopic treatment are carcinomas with a depth of invasion classified as EP or LPM. However, esophagectomy and reconstruction not accompanied by lymph node dissection may be indicated as a comprehensive judgment for extensive early carcinomas without clinical lymph node metastasis. For lesions reaching up to the muscularis mucosa, the frequency of lymph node metastasis is about 9.3 %. This percentage increases as the depth of invasion increases. For lesions invading deeper into the submucosal tissue, the rate of metastasis is about 50 %. In general, if there is reasonable ground for suspecting lymph node metastasis, lymph node dissection should be carried out even for superficial lesions in the treatment of T2 or deeper carcinomas. Surgery may be considered in patients with T4 lesions, only when curative resection is judged to be applicable. Basically, surgery is not chosen as the initial treatment when there is metastasis to distant lymph nodes or other organs.
At present, efforts are focused on the establishment of surgical treatments by the formulation and standardization of surgical techniques represented by three-field lymph node dissection (cervical, thoracic, and abdominal) for cases of thoracic esophageal carcinoma, as well as the introduction and promotion of endoscopic surgery (video-assisted surgery) based on established surgical treatments and minimization of surgical invasion through the use of limited surgery. However, supportive evidence to promote these actions still remains inadequate.
Surgery for cervical esophageal carcinoma
The anatomical structure and physiological functions of the hypopharynx to the cervical esophagus are complicated. Because the loss of vocal function by combined laryngectomy greatly affects the postoperative QOL of the patient, the surgical procedure should be determined carefully, after due consideration given to the balance between the radicality of the treatment and the QOL.
Carcinoma of the cervical esophagus is often advanced at diagnosis, with a high incidence of lymph node metastasis and infiltration into other organs. However, lymph node metastasis is mainly restricted to the cervical region, and radical surgery is often applicable. Patients who have extensive distant metastases and metastasis to a number of superior mediastinal lymph nodes are usually not suitable candidates for radical resection.
This operation is indicated for patients in whom the tumor has not invaded the larynx or trachea and in whom the proximal end of the tumor remains inferior to the esophageal orifice.
Larynx-conserving surgery is divided into larynx-conserving cervical esophagectomy and larynx-conserving total esophagectomy according to the necessity for thoracic esophagectomy. Concomitant resection of the thoracic esophagus may be performed when the tumor has invaded the thoracic esophagus, when there are multiple lesions not amenable to endoscopic resection, or when it is difficult to perform reconstruction requiring microvascular anastomosis. This surgery may be indicated for patients in whom preoperative therapy results in tumor shrinkage.
Laryngopharyngoesophagectomy (combined laryngectomy)
Laryngopharyngoesophagectomy is indicated for patients with tumors invading the larynx, trachea, and hypopharynx, or those in whom sufficient preservation of the cervical esophagus to perform anastomosis is difficult.
This type of surgery is divided into laryngopharyngectomy plus cervical esophagectomy and laryngopharyngectomy plus total esophagectomy according to the necessity for thoracic esophagectomy. Resection of the thoracic esophagus may be combined when the tumor has invaded the thoracic esophagus, when there are multiple lesions not suitable for endoscopic resection, or when it is difficult to perform reconstruction requiring microvascular anastomosis.
Lymph node dissection
According to the 10th edition of the Japanese Classification of Esophageal Cancer, cervical lymph nodes include superficial cervical nodes of the neck , cervical paraesophageal lymph nodes , deep cervical lymph nodes , peripharyngeal lymph nodes , and supraclavicular lymph nodes . The major thoracic lymph nodes are the recurrent laryngeal nerve lymph nodes [106-rec] and upper thoracic paraesophageal lymph nodes .
Among these,  and [106-rec] lymph nodes belong to group 1, and ,  and  lymph nodes belong to group 2 in cases of cervical esophageal carcinoma. It is preferable to remove them.
Method of reconstruction
Although reconstruction using a free intestinal graft is common when the operation involves cervical manipulation alone, gastric tube reconstruction may be employed in some cases. Myocutaneous flaps or skin rolls may also be used for reconstruction. When concomitant thoracic esophagectomy is performed, the stomach or colon is used for reconstruction as in cases of usual reconstruction following resection of the thoracic esophageal carcinoma. However, a free jejunal graft may be added if the length of the organ prepared for reconstruction is not sufficient.
Surgery for thoracic esophageal carcinoma
Thoracic esophageal carcinoma is often accompanied by extensive lymph node metastasis in the cervical, thoracic, and abdominal regions. A right thoracotomy with total extirpation of the thoracoabdominal esophagus and lymph node dissection is generally carried out. The width of the resection margin of the tumor should be decided bearing in mind both the possibility of persistent carcinoma in the remaining esophageal wall and the extent of lymph node dissection.
In cases of thoracic esophageal carcinoma, the extent of lymph node dissection should be determined after preoperative evaluation of the location, size, and depth of invasion of the carcinoma by imaging modalities including computed tomography (CT), magnetic resonance imaging (MRI), and PET.
Three routes of reconstruction, i.e., antethoracic, retrosternal, and posterior mediastinal are available. Although each of these routes has its own advantages and disadvantages, the posterior mediastinal route has been most frequently employed recently. The stomach is the most common organ used for reconstruction.
Thoracic esophageal carcinoma is often accompanied by extensive lymph node metastasis in the cervical, thoracic, and abdominal regions. A right thoracotomy with total extirpation of the thoracoabdominal esophagus, and lymph node dissection of the lymph nodes in all the three regions (cervical, thoracic, and abdominal) is generally carried out.
The width of the margin of resection of the tumor should be decided bearing in mind both the possibility of persistent carcinoma in the remaining esophageal wall and the extent of lymph node dissection. Persistent carcinoma in the esophageal wall may result from intramural spread, intraepithelial spread, vascular invasion, or intramural metastasis. Submucosal spread increases according to the tumor depth, reportedly reaching 30 mm in cases of T2 carcinoma. There is no standard extent of resection established for all of the above cases, and a sufficient margin may not be available at the proximal end of the resection according to the location of the tumor. Thus, the extent of resection should be decided on the basis of the findings on preoperative esophagography and endoscopy, intraoperative rapid frozen-section diagnosis, and intraoperative macroscopic evaluation including close observation of the mucosal surface (and iodine application) under intraoperative esophagotomy.
Endoscopic esophagectomy and reconstruction
Thoracoscopy- or laparoscopy-assisted esophagectomy with esophageal reconstruction and mediastinoscopy- or laparoscopy-assisted transhiatal esophagectomy have been reported as promising surgical procedures, although they are still in the investigational stages, in view of the minimal invasiveness, radicality, and the long-term results. In Japan, endoscopic esophagectomy is almost always performed as a radical surgery which includes sufficient lymph node dissection comparable to open surgery. Indications for this operation vary among institutions and it is used for T3 cancer in some institutions. It has been reported that endoscopic esophagectomy is comparable to conventional standard surgery with open thoracotomy in terms of the operating time, amount of blood loss, and number of dissected lymph nodes, and is advantageous in terms of providing early relief from postoperative pain and rapid restoration of vital capacity, as long as it is carried out at institutions with accumulated clinical experience. On the negative side, recurrent laryngeal nerve paralysis is reported to occur more frequently after this procedure than after standard surgery via thoracotomy.
Some techniques have been suggested for performing carrying out implementing safe endoscopic surgery with reduced operating time and improved accuracy of node dissection. These techniques include for direct manipulations, via a minor thoracotomy, video-assisted thoracoscopic surgery (VATS) with minor thoracotomy and hand-assisted laparoscopic surgery (HALS), involving manipulation with one hand on the abdomen. Although thoracic manipulations have been predominantly carried out with the patient in the left lateral decubitus position, complete endoscopic thoracic manipulations with the patient in the prone position is becoming more and more frequent recently. Transhiatal esophagectomy with mediastinal dissection using a mediastinoscope inserted via a cervical incision or with mediastinal dissection via laparotomy has also been proposed. It is reported that endoscopic surgery allows node dissection with improved accuracy because of the higher-power visualization that allows observation of microanatomy. However, no definitive conclusions have been reached yet as to the long-term outcomes of this form of surgery as compared to those of conventional standard surgery with open thoracotomy and node dissection, and further investigation in randomized controlled trials is awaited.
Lymph node dissection
Thoracic esophageal carcinoma is commonly accompanied by lymph node metastasis in extensive areas from the cervical to the abdominal region. However, because the distribution and incidence of lymph node metastasis vary according to the location, size, and depth of invasion of the tumor, preoperative evaluation of individual patients by CT, US, MRI, and PET is important to determine the extent of lymph node dissection.
Radical surgery for thoracic esophageal carcinoma is accomplished ordinarily as a combination of three approaches, i.e., the cervical, thoracic, or abdominal approaches. The mediastinal approach has also been proposed as an alternative to the cervical approach for dissection of the cervical paraesophageal lymph nodes .
Upper thoracic esophageal carcinoma (Ut)
Patients with this type of lesion usually present with lymph node metastasis, mainly in the cervical to upper mediastinal region; thus, lymph node dissection should include the cervical region. Addition of median sternotomy or manubriotomy has also been suggested to allow a better field of view of the cervicothoracic junction region. Although metastasis to the lower mediastinal or abdominal lymph nodes occurs less frequently in cases of Ut, dissection should ordinarily cover all the three regions, i.e., cervical, thoracic, and abdominal regions, including the left gastric artery lymph nodes.
Middle thoracic esophageal carcinoma (Mt)
In general, metastatic lymph nodes in cases of Mt are relatively evenly distributed over the cervical to upper, middle, and lower mediastinal and abdominal regions. Because the involvement of cervical lymph nodes other than the cervical paraesophageal lymph nodes  is relatively rare, lymph node dissection via the intrathoracic approach instead of the cervical approach has also been proposed.
When the thoracic approach is judged to be inadequate based on the preoperative diagnosis of metastasis, it is important to add a cervical approach to dissect the lymph nodes surrounding the bilateral recurrent laryngeal nerve up to the inferior pole of the thyroid. In particular, the lymph nodes of 101L are difficult to be dissected thoroughly by thoracic manipulations alone, and additional dissection via a cervical incision is necessary. In addition, supraclavicular lymph nodes  cannot be dissected by thoracic manipulations, and a cervical approach is necessary for secure lymph node dissection in this region.
Lower thoracic esophageal carcinoma (Lt)
In cases of Lt, while lymph node metastasis mainly occurs in the mediastinal and abdominal regions, metastasis to the cervical lymph nodes may also occur, albeit at a lower frequency. The optimal approach for lymph node dissection remains under discussion; while some propose adding the cervical approach, similar to the case for Mt, others regard the thoracic approach as being superior. Because metastasis to the upper mediastinal lymph nodes is less frequent in cases of superficial carcinoma of the lower thoracic esophagus, there is a view that the extent of lymph node dissection could be minimized and that cervical lymph node dissection could be omitted altogether in some cases.
Method of reconstruction (Table 2)
Route of reconstruction
Three routes, i.e., the antethoracic, retrosternal, and posterior mediastinal (including intrathoracic) routes, are available for reconstruction. The route employed varies according to the case, and each route has its own advantages and disadvantages. Recently, the posterior mediastinal route is the most frequently used for reconstruction when high intrathoracic anastomosis is included. Because surgery for second primary cancer in the gastric tube is difficult after reconstruction via the posterior mediastinal route, the risk of carcinoma occurring in the gastric tube should be considered particularly when long survival is expected.
Organs used for reconstruction
Reconstruction using the stomach is the most common method. In patients with past history of gastrectomy, those with a concomitant gastric carcinoma, and those in whom the stomach needs to be preserved, colic and ileocolic or jejunal grafts may be used.
Anastomosis may be divided into cervical and intrathoracic depending on the site of anastomosis. This site of anastomosis is chosen according to the location of the tumor, the organ used for reconstruction, and the route of reconstruction. Intrathoracic anastomosis is associated with a high risk of serious complications in the event of anastomotic leakage. The anastomosis techniques include manual suture and mechanical suture. For intrathoracic anastomosis, mechanical suture using a circular stapler is frequently employed. Because anastomotic leakage and stricture exert a strong influence on the postoperative course and QOL of the patient, it is important to use appropriate anastomotic techniques tailored to individual patients.
Surgery for carcinoma of the esophagogastric junction (abdominal esophageal carcinoma)
Similar to the case for surgical treatment of thoracic esophageal carcinoma, various techniques are available for the surgical treatment of carcinoma of the esophagogastric junction (E, EG). These include a right thoracotomy with dissection including the upper mediastinal lymph nodes and reconstruction using a gastric tube, lower esophagectomy with proximal gastrectomy or lower esophagectomy with total gastrectomy via left thoracolaparotomy or serial left thoracic and abdominal incisions, and a transhiatal approach to the lower mediastinum without thoracotomy. Metastasis involving the lower paraesophageal to upper abdominal lymph nodes is frequent in these cases. The most commonly employed technique is intrathoracic anastomosis using a gastric tube or the jejunum.
Resection and lymph node dissection
The 10th edition of the Japanese Classification of Esophageal Cancer defines the esophagogastric junction region as the region within 2 cm above and below the esophagogastric junction, and esophagogastric junction carcinoma as that with its center located within this region. According to this definition, abdominal esophageal carcinoma is included in this category. In cases of esophagogastric junction carcinoma extending more to the esophageal side than to the gastric side (E, EG), right thoracotomy with dissection including the upper mediastinal lymph nodes and reconstruction using a gastric tube are frequently performed in the same manner as for cases of thoracic esophageal carcinoma. In some cases, lower esophagectomy with proximal gastrectomy or lower esophagectomy with total gastrectomy via left thoracolaparotomy or serial left thoracic and abdominal incisions may be carried out, considering that cervical or upper mediastinal lymph node dissection is of lesser significance. A transabdominal approach to the lower mediastinum via dilated esophageal hiatus without thoracotomy is also reported. Metastasis to the lower thoracic paraesophageal lymph nodes , cardiac lymph nodes  , lesser curvature lymph nodes , left gastric artery lymph nodes , and celiac artery lymph nodes  is frequent.
In cases of esophagogastric junction carcinoma extending more to the gastric side than to the esophageal side (G, GE), metastasis to the mediastinal lymph nodes is less frequent; thus dissection of these lymph nodes is of lesser consequence. Therefore, these lymph nodes are classified as group 3 in the 10th edition of the Japanese Classification of Esophageal Cancer.
Method of reconstruction
Intrathoracic anastomosis using a gastric tube, jejunal interposition by elevation of the jejunum, and intrathoracic anastomosis by the Roux-en-Y style are available. In cases of esophagogastric anastomosis following lower esophagectomy with proximal gastrectomy, postoperative reflux esophagitis is a potential problem and may require prophylactic measures.
Other surgical treatments
Although radical surgery for esophageal carcinoma basically consists of resection, lymph node dissection, and reconstruction, other treatments may be carried out if it is difficult or unnecessary to complete these procedures because of various factors such as the stage and malignancy grade of the carcinoma and the general condition of the patient. Transhiatal esophagectomy has been performed as a radical operation for mucosal carcinoma or abdominal esophageal carcinoma that is difficult to treat with an endoscopic procedure and that presumably requires no mediastinal lymph node dissection. This has also been used as a palliative operation for patients who are not suitable candidates for thoracotomy and mediastinal lymph node dissection because of poor pulmonary function or other reasons. However, indications for this procedure have recently become limited because of the expanding application of endoscopic treatment as esophagus-preserving therapy and the spread of multidisciplinary therapy including chemoradiotherapy.
Bypass surgery may be performed as a palliative treatment for patients who have difficulty in oral intake because of esophageal stenosis due to esophageal carcinoma or changes after treatment for esophageal carcinoma. However, the indications for bypass surgery have become limited because of the spread of esophageal stenting.
In this method, the thoracic esophagus is detached and removed via the cervical and abdominal approaches without thoracotomy. This technique was first reported by Turner in 1933. Akiyama et al. introduced this method in Japan in 1971, and it has since come to be used widely in clinical practice in this country. This technique has been employed for resection and reconstruction in patients with cervical esophageal carcinoma, patients with thoracic or abdominal esophageal carcinoma who are not suitable candidates for thoracotomy because of severe pleural adhesions or poor pulmonary function, patients of advanced age, and patients with mucosal carcinoma not requiring lymph node dissection. Although this technique allows dissection of the abdominal to lower mediastinal lymph nodes to some extent, upper to middle mediastinal dissection is difficult.
Currently, the use of transhiatal esophagectomy has become rare because of the spread of chemoradiotherapy and endoscopic submucosal dissection.
Treatments for unresectable cases
Advanced esophageal carcinomas that are unresectable because of infiltration into other organs or distant metastasis are initially treated by radiotherapy, chemotherapy, or chemoradiotherapy. However, patients with esophageal stenosis or trachea–esophageal fistula not responding to these treatments suffer from difficulty in oral intake, resulting in a marked decrease in QOL. Bypass surgery is a palliative treatment used to achieve oral feeding in these cases of malignant esophageal stenosis or obstruction. Currently, indications for bypass surgery have become rare because of the spread of covered esophageal stent placement.
In bypass surgery, the thoracic esophagus is excluded from the continuity of the digestive tract and a new route of oral intake is made. The route of bypass is antethoracic or retrosternal. Because most patients have advanced carcinoma and a poor nutritional status, anastomotic leakage occurs frequently, necessitating caution. In recent years, this procedure has been also employed as a palliative operation in patients in whom major lesions are judged to be unresectable during salvage surgery following definitive chemoradiotherapy.
Perioperative management and clinical path
It was previously considered that introduction of the clinical path method would be difficult for perioperative management of esophageal carcinoma, because of the pathological features of this carcinoma and the diversity of surgical techniques available. In recent years, however, a clinical path for resection and reconstruction of the esophagus has been proposed by various institutions and has been applied in clinical practice. However, there has been only limited data from large-scale clinical studies evaluating the usefulness of a clinical path for perioperative management.
In recent years, an increasing number of institutions have included nutritional support teams (NST) for perioperative nutritional management of patients with esophageal carcinoma, facilitating early implementation of enteral nutrition. As an element of perioperative management, steroid administration is useful and recommended in postoperative management. Abstinence from smoking, respiratory physical therapy, and preoperative oral care are generally considered to be important for the prevention of postoperative complications.
Introduction of a clinical path in perioperative management of esophageal carcinoma
Clinical path is a treatment plan prepared to facilitate provision of safe team-approached medical care involving health-care professionals from multiple medical fields, including doctors, nurses, pharmacists, nutritionists, and physical therapists, with the aim of improving the quality of care through standardization of health care. In the USA, along with the introduction of the diagnosis-related group/prospective payment system (DRG/PPS) in 1983, the fixed charge system, replacing the fee-for-service system, came to be employed for inpatient hospital care and a clinical path was introduced mainly for the purpose of reducing the length of stay in the hospital of patients and to reduce health-care costs. In Japan, around the time of the introduction of the diagnosis procedure combination (DPC) system, clinical paths were introduced for the treatment of various diseases in the 1990s. The use of clinical paths has recently come to be considered to be important not only for improvement of the quality of health care and medical education to provide safe team health care, but also for enhancement of patient-centered health care, including promotion of obtainment of informed consent.
In patients with esophageal carcinoma, the general condition is greatly affected by the disease state and surgery. Perioperative management techniques in these patients, including the treatment of concomitant diseases, are diverse, with large differences among institutions. Therefore, preparation of a simple clinical path has been considered to be difficult, as reflected by the scarcity of reports documenting the clinical usefulness of a clinical path. The various clinical paths for esophageal carcinoma reported to date are those developed by institutions to achieve safe perioperative management of patients undergoing resection and reconstruction of the esophagus. It is currently difficult to find evidence comparing the usefulness of clinical paths.
Clinical paths for diagnosis and treatment involving EMR and ESD, endoscopic treatment procedures for early esophageal carcinoma have already been developed and are in clinical use in many institutions. Clinical paths have also been introduced for thoracoscopy- or laparoscopy-assisted esophagectomy with reconstruction, which are used in high-volume centers treating a large number of patients.
Perioperative nutritional management of esophageal carcinoma
Nishi et al. have reported that spontaneous healing of anastomotic leakage after surgery for esophageal carcinoma requires a caloric intake of at least 45 kcal/kg/day, and that the serum albumin concentration must be maintained at 3.5 g/dL or more. It has been reported that enteral nutrition in the perioperative period is associated with a lower incidence of perioperative complications, due to reduced production of endotoxins and inflammatory cytokines, as compared to parenteral nutrition. In cases of radical surgery for esophageal carcinoma, perioperative management by aggressive use of enteral nutrition has been reported to be helpful.
In patients undergoing radical surgery for esophageal carcinoma, the digestive and absorptive capability of the small intestine is often maintained in a normal condition. Therefore, it has been considered that early enteral nutrition rather than central venous nutrition is desirable to enhance postoperative immunity, etc. An enteral feeding tube should be placed during surgery, and a liquid diet should be initiated by 1–3 days after surgery.
The definition of salvage surgery is often debated. In the narrow sense, salvage surgery is aimed at curative resection of residual or recurrent tumor after definitive chemoradiotherapy. In Japan, the experience of salvage surgery began to be reported in the early 2000s. Although its indication and role have not yet been established, salvage surgery is recognized to pose a greater risk than general surgery for esophageal carcinoma. It is also known that the frequency of noncurative resection is high, resulting in a poor prognosis. In contrast, cases of curative resection are accompanied by an improved prognosis. Currently, no treatment other than salvage surgery (including endoscopic resection) is accepted as curative treatment for residual or recurrent tumor. Salvage surgery must be implemented only with the informed consent of the patients obtained after explaining the risks and long-term outcomes, and thus requires cautious consideration.
The 10th edition of the Japanese Classification of Esophageal Cancer defines salvage surgery as that for residual or recurrent cancer after definitive (chemo-) radiotherapy. The variety of surgeries include resection of the esophagus, removal of lymph nodes (dissection), and endoscopic resection (for salvage endoscopic treatment, see XI. Chemoradiotherapy). Additional resection of residual or recurrent tumor after endoscopic treatment may also be referred to as salvage surgery, but this is not included in these guidelines.
The standard radiation dose for definitive chemoradiotherapy is 50.4 Gy in Europe and North America, on the basis of the results of the INT0123 study. However, in Japan, many institutions use 60 Gy or more as the radiation dose for definitive chemoradiotherapy. The Japan Esophageal Society defines surgery following irradiation of 50 Gy or more as salvage surgery. Although salvage surgery is aimed at achieving curative resection, it ends up in non-curative resection at times because of its nature as a rescue treatment. Therefore, curativity (i.e., R0 resection or not) is not included in its definition.
The indication for salvage surgery is determined by both tumor factors and patient factors. Tumor factors include the feasibility of radical resection and the long-term prognosis, whereas patient factors include the patient’s general ability to tolerate surgery, especially the functions of important organs such as the heart and lung.
The incidence of complications is higher in cases of salvage surgery than in patients treated by surgery alone or surgery combined with preoperative chemoradiotherapy (radiation dose less than 50 Gy). The reported incidence of respiratory complications such as pneumonia is 9–62 %, while that of anastomotic leakage is 14–39 %. In particular, it is of great concern that the incidence of serious complications due to tissue ischemia, such as tracheal necrosis, perforation, and necrosis of the reconstructed gastric tube, is higher after salvage surgery than that after usual surgery. The reported in-hospital mortality after salvage surgery is 7–22 %, indicating that this type of surgery is associated with a higher surgical risk than usual surgery. The high incidence of complications and high in-hospital mortality should be taken into account when considering the indications for salvage surgery.
With regard to the postoperative survival rate, the reported 5-year survival rate is 25–35 %. Long-term survival can be expected in patients only when curative resection is achieved. However, the rate of non-curative resection is high in salvage surgery, reported to be in the range of 12–50 %. Because the prognosis of patients with non-curative resection is extremely poor, careful judgment is required when determining the indications for salvage surgery.