Geriatric nutritional risk index as a prognostic marker of pTNM-stage I and II esophageal squamous cell carcinoma after curative resection

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Abstract

The geriatric nutritional risk index (GNRI) is associated with mortality in several malignancies. We retrospectively analyzed whether the GNRI can predict long-term outcomes in 191 patients with esophageal squamous cell carcinoma (ESCC) after curative esophagectomies by evaluating their cancer-specific survival (CSS). In multivariate analyses, serum albumin (hazard ratio [HR], 2.498; p = 0.0043), GNRI (HR, 1.941; p = 0.0181), pathological tumor-node-metastasis (pTNM) stage (HR, 3.884; p < 0.0001), and tumor differentiation (HR, 2.307; p = 0.0066) were independent prognostic factors for CSS.

In pTNM stage I, multivariate analysis identified C-reactive protein (HR, 7.172; p = 0.0483) and GNRI (HR, 5.579; p = 0.0291) as independent prognostic factors for CSS. In univariate analyses in pTNM stages II and III, only low GNRI ( p = 0.0095) and low serum albumin levels ( p = 0.0119), respectively, were significantly associated with worse CSS. In patients with low GNRI, CSS was significantly worse than in those with normal GNRI ( p = 0.0011), especially in pTNM stages I ( p = 0.0044) and II ( p = 0.0036) groups, but not in stage III group ( p = 0.5099).

Preoperative GNRI may sort patients into low- or high-risk groups for shorter CSS, especially in those with pTNM stage I and II ESCC.

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Geriatric Nutritional Risk Index: a new index for evaluating at-risk elderly medical patients.

Olivier Bouillanne, Gilles Morineau, Claire Dupont … (2006)

Patients at risk of malnutrition and related morbidity and mortality can be identified with the Nutritional Risk Index (NRI). However, this index remains limited for elderly patients because of difficulties in establishing their normal weight. Therefore, we replaced the usual weight in this formula by ideal weight according to the Lorentz formula (WLo), creating a new index called the Geriatric Nutritional Risk Index (GNRI). First, a prospective study enrolled 181 hospitalized elderly patients. Nutritional status [albumin, prealbumin, and body mass index (BMI)] and GNRI were assessed. GNRI correlated with a severity score taking into account complications (bedsores or infections) and 6-mo mortality. Second, the GNRI was measured prospectively in 2474 patients admitted to a geriatric rehabilitation care unit over a 3-y period. The severity score correlated with albumin and GNRI but not with BMI or weight:WLo. Risk of mortality (odds ratio) and risk of complications were, respectively, 29 (95% CI: 5.2, 161.4) and 4.4 (95% CI: 1.3, 14.9) for major nutrition-related risk (GNRI: <82), 6.6 (95% CI: 1.3, 33.0), 4.9 (95% CI: 1.9, 12.5) for moderate nutrition-related risk (GNRI: 82 to <92), and 5.6 (95% CI: 1.2, 26.6) and 3.3 (95% CI: 1.4, 8.0) for a low nutrition-related risk (GNRI: 92 to < or =98). Accordingly, 12.2%, 31.4%, 29.4%, and 27.0% of the 2474 patients had major, moderate, low, and no nutrition-related risk, respectively. GNRI is a simple and accurate tool for predicting the risk of morbidity and mortality in hospitalized elderly patients and should be recorded systematically on admission.

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Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: part 2

Yuko Kitagawa, Takashi Uno, Tsuneo Oyama … (2018)

Endoscopic treatment Summary Endoscopic resection (ER) includes endoscopic mucosal resection (EMR), wherein the affected mucosal lesion is held or aspirated and resected with a snare, and endoscopic submucosal dissection (ESD), which refers to en bloc resection of an extensive lesion using an IT knife or hook knife [1–4]. Other endoscopic treatments available include photodynamic therapy (PDT), argon plasma coagulation (APC), and electromagnetic coagulation therapy. General remarks Indications for endoscopic resection Among lesions in which the depth of invasion does not extend beyond the mucosal layer (T1a), those confined within the mucosal EP or the LPM are only extremely rarely associated with lymph-node metastasis; therefore, endoscopic resection is a sufficiently radical treatment for these lesions. Lesions extending up to the muscularis mucosae or slightly infiltrating the submucosa (up to 200 μm) are also amenable to mucosal resection; however, they are associated with an elevated risk of lymph-node metastasis. Therefore, these represent relative indications [5, 6]. Furthermore, about 50% of the lesions that show deeper (more than 200 μm) invasion into the submucosa (T1b) are associated with metastasis, and in such cases, even if they are classified as superficial carcinomas, should be treated in the same manner as advanced carcinomas. Mucosal resection covering 3/4 of the entire circumference is likely to be associated with postoperative cicatricial stenosis. Therefore, sufficient explanation should be given to the patient prior to the operation and preventive measures must be taken [7, 8]. Diagnosis by histopathology of the resected tissue specimens There are limitations to all the modes of diagnosis of the depth of tumor invasion prior to treatment. It is also difficult to accurately determine the depth of invasion of extensive lesions. Furthermore, preoperative diagnosis of the histologic type of the invasive tumors or that of vascular invasion is impracticable. Histopathologic examination of the resected tissue specimens is, therefore, important for determining whether an additional treatment is required or not, and diagnosis of tissue specimens obtained by en bloc resection is indispensable. Treatment of lesions not amenable to endoscopic resection Insufficient elevation of the mucosa after submucosal injection may pose difficulty in additional ER of residual marginal lesions after ER, or ER after radiotherapy or chemoradiotherapy. These cases and cases with a bleeding tendency are not suitable for ER, and other treatment options such as PDT [9] and APC would need to be considered. Superiority of en bloc resection En bloc resection is desirable for histologic diagnosis of the resected specimens. ESD enables en bloc resection of lesions that were formerly subjected to fractional resection. Further development of equipment and spread of improved techniques are anticipated. Complications Various complications, including bleeding (0.2%), esophageal perforation (1.9%), and post-resection cicatricial stenosis (6.0–16.7%), have been reported in association with ER [10]. Sufficient explanation should be provided to the patients, and measures must be taken for prevention/treatment of these complications. CQ18: is additional treatment recommended in cases detected to have pT1a-MM lesion following endoscopic treatment for superficial esophageal cancer? Recommendation statement There is strong evidence to recommend an additional treatment in patients identified as having a pT1a-MM lesion with positive vascular invasion after endoscopic treatment (rate of consensus: 85% [17/20]; strength of evidence: D). Explanatory note There are no reports of randomized comparative or case–control studies demonstrating the usefulness of additional treatment in patients in whom the resected specimens collected at endoscopic treatment are histopathologically diagnosed as pT1a-MM lesions. According to the reports based on the results of surgical treatment, the frequency of lymph-node metastasis in resected specimens obtained from patients with pT1a-MM squamous cell carcinoma was 0–27%, and summarization and analysis of data from major reports revealed that it was present in 30/210 cases (14.2%; 95% CI 9.85–19.76) [11–18]. There are few or no reports on the frequency of metastasis in pT1a-MM adenocarcinoma cases, however, that in cases of pT1a adenocarcinomas is reported to be in the range of 0–5%; summarization and analysis of data from major reports revealed that it was presented in 91/1882 cases (4.9%; 95% CI 3.95–5.9) [19–21]. Meanwhile, the frequency of recurrent lymph-node metastasis in cases diagnosed from the resected specimens collected at endoscopic treatment as pT1a-MM disease was 0–4.2% for squamous cell carcinoma, with a tallied frequency of 5/223 (2.24%; 95% CI 0.73–5.15) [5, 17, 22], and 0% for adenocarcinoma [23]. For squamous cell carcinomas, in particular, the frequency of lymph-node metastasis differed markedly between cases with pT1a-MM disease identified in surgical specimens and that identified in endoscopically resected specimens. This difference in the frequency of lymph-node metastasis is considered to be mainly attributable to the difference in the method of histopathologic diagnosis between surgical specimens and endoscopically resected specimens. As surgical specimens are larger in size as compared to endoscopically resected specimens, the possibility of cases diagnosed as pT1a-MM disease of including pT1b cases cannot be ruled out. As a ground for this presumption, it has been reported that the frequency of lymphatic invasion in pT1a-MM cases substantially differs between cases who have undergone endoscopic resection and those who have undergone surgery (pT1a-MM in endoscopically resected cases: 0–8.1% [5, 17]; surgically treated cases: 18.2–41.2% [11–14, 17]). Reports of studies conducted to identify the risk factors for lymph-node metastasis in cases with superficial cancer of the esophagus limited to pT1a-MM cases are scarce. It was from the analysis of the data of 50 pT1a-MM cases in one study, that the frequency of lymph-node metastasis significantly differed between lymphatic invasion-negative cases and lymphatic invasion-positive cases (negative cases: 4/38 (10.5%); positive cases: 5/12 (41.7%) [14]. Multivariate analysis to identify the risk factors for lymph-node metastasis revealed an odds ratio for positive lymphatic invasion of 3.63–6.11 for T1 cases overall [15, 16], 3.83 for pT1a-MM/pT1b-SM1 cases [14], and 7.333 when the analysis was limited to pT1a-MM cases [17]. Assessment of the risk factors for metachronous metastasis in cases treated by endoscopic resection revealed a frequency of lymph-node or distant metastasis of 3.73% (15/402) for the pT1 cases overall, 0.36% (1/280) for pT1a-EP/LPM cases, 4.29% (3/70) for pT1a–MM cases, 11.7% (2/17) for pT1b-SM1 cases, and 25.7% (9/35) for pT1b–SM2 cases; hence, the frequency increased progressively with advancing depth of invasion, and multivariate analysis identified depth of invasion as the sole significant risk factor, with a hazard ratio of 13.1 (95% CI 1.3–133.7, p = 0.03) for pT1a-MM vs. pT1a-EP/LPM [22]. For superficial carcinomas overall, on the other hand, positive lymphatic invasion failed to be identified as a significant risk factor for metachronous metastasis; however, when the analysis was limited to only pT1a cases, the 5-year cumulative incidence of metastasis was significantly higher in the lymphatic metastasis-positive cases as compared to the lymphatic metastasis-negative cases (46.7% vs. 0.7%, p < 0.0001) [22]. Cases diagnosed as having pT1a-MM cases after endoscopic resection had a greater risk of recurrence of metastasis as compared to those diagnosed as having pT1a-EP/LPM disease and positive lymphatic invasion may be cited as a risk factor, although it is difficult to arrive at a conclusion, because all the papers reviewed represented retrospectively accumulated case reports and an additional treatment mainly consisting of chemoradiotherapy was administered to lymphatic invasion-positive cases among the patients treated by endoscopic resection. Surgical treatment or chemoradiotherapy is considered as a radical additional treatment in patients diagnosed by histopathology of the endoscopically resected specimens as having pT1a-MM disease. Gratifying therapeutic results in surgically treated T1a patients have been reported, with a reported 5-year disease-specific survival rate of 98–100% and overall survival rate 82–100% [17, 18, 20]. Meanwhile, the mortality rate from postoperative complications has been reported to be in the range of 0.2–3.6% [14, 18, 21, 24]. In regard to the results of chemoradiotherapy for cStage I (cT1N0M0) disease, the reported 4-year overall survival rate was 80.5%, 5-year overall survival rate was 66.4%, and 5-year disease-specific survival rate was 76.8%, despite the inclusion of a significant proportion of cT1b cases (85.2% for cT1a cases) [25, 26]. Esophageal fistula (3.2%), esophagostenosis (3.2%), Grade 3 cardiac ischemia (1%), and respiratory failure (2.8%) were reported as serious late complications, but there has been no report of treatment-related death [25, 26]. In patients given additional chemoradiotherapy after endoscopic resection, the 5-year overall survival rate and disease-specific survival time were both 100% among pT1a-MM cases as well as T1b-SM1 cases, and the 3-year survival rate was 92.9% for pT1a-MM cases, although the sample sizes in the studies were small; neither report contained any detailed description on adverse events, although there were no cases of serious adverse events or treatment-related death [5, 27]. Taking into consideration the benefit–risk balance, the additional treatment may be useful for patients diagnosed by histopathology of the endoscopically resected specimens as having pT1a-MM disease, who are at a high risk of recurrence. From the above results, the strength of evidence was rated as D, considering that most of the reports cited represented retrospective case accumulations, and no recommendation based on high-level evidence has been made yet. Chemoradiotherapy, which is the mainly adopted modality for additional treatment, is covered by the national health insurance. Taking into account the benefit–risk balance, strength of evidence, and patient preferences, we conclude that there is strong evidence to recommend additional treatment in patients identified as having a pT1a-MM lesion with positive vascular invasion after endoscopic treatment. Surgical treatment Surgery for cervical esophageal carcinoma Summary In the treatment of cervical esophageal carcinoma, simultaneous laryngectomy is often required; therefore, preoperative chemoradiotherapy or definitive chemoradiotherapy is often undertaken in an attempt to conserve the larynx. Larynx-preserving surgery enables conservation of vocal function, although it is associated with an increased risk of aspiration and pneumonia, necessitating the need for caution while selecting this treatment. Lowering of the QOL due to the loss of vocal function poses a serious problem in patients who have undergone combined laryngectomy. No significant difference in the post-treatment prognosis has been reported so fact between cervical esophageal carcinoma patients treated by surgery and radical chemoradiotherapy. The appropriate treatment in these patients should be selected with due consideration given to the QOL, etc. General remarks Since cervical esophageal carcinoma develops in a region densely packed with important structures such as the trachea, large blood vessels, nerves, and the thyroid, it is frequently associated with malignant invasions of the adjacent organs. Lymph-node metastasis is also frequently encountered; therefore, it is not uncommon for the malignancy to be at an advanced stage at diagnosis. There are a significant number of cases in which surgery is indicated inasmuch as widespread metastasis is uncommon, unlike the case in thoracic esophageal cancer. A major problem in surgery for cervical esophageal cancer is that simultaneous laryngectomy is also indicated in many cases. Under these circumstances, surgery may be performed after tumor shrinkage is obtained by preoperative chemoradiotherapy in an effort to preserve the larynx, or radical chemoradiotherapy may be administered, followed by salvage surgery in the event of detection of residual disease or recurrence. Larynx-preserving surgery is indicated for patients in whom the tumor has not invaded the pharynx, larynx, or trachea. Conservation of vocal function is the utmost benefit of this option, although it is associated with the risk of aspiration or pneumonia; not uncommonly, primary tracheotomy is required. Therefore, sufficient consideration should be given as to the indication and choice of operative procedure, e.g., an additional aspiration-preventive measure such as laryngeal elevation could be employed. Combined laryngectomy (laryngopharyngoesophagectomy) is indicated for patients with tumors invading the pharynx, larynx, and trachea. The procedure may even be indicated for patients without direct pharyngeal invasion, in whom sufficient preservation of the esophagus to perform anastomosis with intestinal graft is difficult. Marked lowering of QOL due to loss of vocal function poses a serious problem in patients who have undergone combined laryngectomy. Reconstruction after surgical resection of cervical esophageal carcinoma is frequently performed using a free jejunal graft [28] or a gastric tube [29]. The method of first choice is reconstruction using a free jejunal graft, although reconstruction using a gastric tube is chosen for cases in which the disorder is complicated by thoracic esophageal cancer or in which the cervical esophageal cancer extends caudad to involve the thoracic esophagus. The frequency of lymph-node metastasis in cases of cervical esophageal cancer is relatively high, although it is confined in most cases to the cervical region and a part of the upper mediastinum; therefore, lymph-node dissection is primarily targeted at lymph nodes in these regions. Nevertheless, reports on the outcomes of lymphadenectomy in patients with cervical esophageal cancer are few as yet, and further investigation is needed. No significant difference in the post-treatment prognosis has been reported until date between cervical esophageal carcinoma patients treated by surgery alone and those treated by radical chemoradiotherapy. Selection among the available treatment options should be made with due consideration given to the post-treatment QOL, etc. Surgery for thoracic esophageal carcinoma Summary Thoracic esophageal carcinoma is often accompanied by extensive lymph-node metastasis in the cervical, thoracic, and abdominal regions. Therefore, it is a common practice that, in T1b-SM 2, 3 or more advanced cases regarded as advanced cancer cases, a right thoracotomy with esophagectomy and lymphadenectomy of the cervical, mediastinal, and upper abdominal regions is carried out. According to the revision of the Japanese Classification of Esophageal Cancer, supraclavicular lymph nodes [#104] are classified in Group 2, to ensure 3-fields’ lymphadenectomy for D2 resection in the surgical treatment of middle thoracic esophageal carcinoma. In thoracoscopic surgery, thoracic manipulations are currently also carried out with the patient in the prone position, whilst, previously, thoracic manipulations were predominantly undertaken with the patient in the left-lateral decubitus position. This is still at the stage of clinical research. A randomized comparative study to compare the long-term outcomes of this type of surgery vs. conventional standard surgery with thoracotomy has been started (JCOG1409 Study), and the results are awaited. General remarks Thoracic esophageal carcinoma is frequently associated with extensive lymph-node metastasis in the cervical, mediastinal, and upper abdominal regions. Therefore, it is common practice to perform a right thoracotomy to meet the need for adequate dissection of the mediastinal lymph nodes, along with esophagectomy and lymphadenectomy in lymph-node stations of the cervical, thoracic and abdominal regions to complete the entire extent of resection. Depth of invasion beyond T1a-MM is a predictor of lymph-node metastasis, and stage T1b-SM 2, 3 lesions should be counted as advanced carcinomas [17, 30]. The extent of lymph-node dissection should be determined according to individual cases after preoperative evaluation of the location, size, and depth of invasion of the main lesion by imaging modalities such as CT, ultrasonography (US), magnetic resonance imaging (MRI), and PET, because the distribution and incidence of lymph-node metastasis vary with the aforementioned parameters. Based on the analysis of data from a nationwide registry conducted by the Japan Esophageal Society [31], the supraclavicular lymph nodes [#104] are placed in Group 2, to ensure three fields’ lymph-node dissection for D2 dissection in the treatment of middle thoracic esophageal carcinoma in the 11th edition of the Japanese Classification of Esophageal Cancer. It is not feasible to dissect the supraclavicular lymph nodes [#104] via thoracic manipulation, and a cervical approach is necessary for secure lymph-node dissection in this region. It is common practice that radical surgery for thoracic esophageal carcinoma is usually accomplished using a combination of three approaches: the cervical, thoracic, and abdominal approaches. The mediastinal approach has also been proposed as an alternative to the cervical approach for dissection of the cervical paraesophageal lymph nodes [#101]. Thoracoscopy-assisted esophagectomy with esophageal reconstruction has been reported as promising surgical procedures, in view of its minimal invasiveness, radical curability, and favorable long-term outcomes, although studies are ongoing. Various procedures such as endoscopy/laparoscopy-assisted esophagectomy with esophageal reconstruction and mediastinoscopy- or laparoscopy-assisted transhiatal esophagectomy (blunt resection of the esophagus) have been reported, and analysis of the reported cases during the 2011–2013 period in the National Clinical Database (NCD) revealed that 37.6% of the patients underwent endoscopy/laparoscopy-assisted surgery, which was reported as a safe approach with a mortality rate of 2.44%, against an overall mortality rate of 3.03%. The indications for this approach vary among institutions; it has been adopted even for cT3 cases at some institutions, and in patients who have received preoperative chemoradiotherapy at other institutions. Some techniques have been introduced for ensuring safe endoscopic surgery with a reduced operation time and improved accuracy of lymph-node dissection, including direct manipulations through a small incision via a minor thoracotomy, video-assisted thoracoscopic surgery (VATS) with minor thoracotomy, and hand-assisted laparoscopic surgery (HALS) involving manipulation with one hand inserted into the abdomen. While thoracic manipulations have been predominantly carried out with the patient in the left-lateral decubitus position, complete endoscopic thoracic manipulations have been increasingly performed with the patient placed in the prone position in recent years. Mediastinal lymph-node dissection using a mediastinoscope inserted via a cervical incision and laparoscopic transhiatal lymph-node dissection are some of the other procedures described. Reports have suggested that endoscopy/laparoscopy-assisted surgery enables conservation of the vasculature and nerves while confirming the microanatomy, and also increases the accuracy of lymph-node dissection, as it allows higher power visualization. A randomized comparative study to assess the long-term outcomes of this type of surgery as compared to the conventional standard surgery with a thoracotomy has been initiated (JCOG1409 Study), and the results are awaited [32]. Surgery for carcinoma of the esophagogastric junction (abdominal esophageal carcinoma) Summary There is no unanimity of opinions as to treatment policy and surgical procedures for carcinoma of the esophagogastric junction, particularly adenocarcinoma according to Nishi’s classification or Siewert type II carcinoma. Based on a retrospective analysis, the Japanese Gastric Cancer Association—Japan Esophageal Society Joint Working Group proposed the optimal extent of lymph-node resection for esophagogastric junction carcinomas measuring ≤4 cm in diameter. Prospective clinical studies to determine the optimal extent of lymph-node resection for more advanced tumors are currently in progress. General remarks For definition of carcinoma of the esophagogastric junction, Siewert’s classification is used overseas, whereas, in Japan, Nishi’s classification is adopted by both the Japanese Gastric Cancer Association and the Japan Esophageal Society. In Siewert’s classification, type I lesions are often handled as carcinomas of the thoracic esophagus and type III lesions as cardiac carcinomas. Squamous cell carcinomas in Nishi’s classification, on the other hand, are often treated as thoracic esophageal cancers. Opinions are still divided as to treatment policy and surgical procedures for adenocarcinomas in Nishi’s classification and Siewert type II carcinoma. Carcinoma of the esophagogastric junction may be associated with extremely extensive lymph-node metastasis involving the cervical region, mediastinum, upper abdomen, and areas circumjacent to the abdominal aorta, and no unified view has been reached in regard to the appropriate extent of lymph-node dissection. The Japanese Gastric Cancer Association—Japan Esophageal Society Joint Working Group has laid down recommendations in respect of the extent of lymphadenectomy on the grounds of the dissection effect index (rate of metastasis × 5-year survival rate of patients with metastasis) derived from retrospective analysis of data from surgically treated cases. The efficacy of lymphadenectomy in accordance with this scheme is expected to be verified by future accumulation of cases. Nevertheless, the problems with retrospective analysis of tumors is that the patients are confined to those with tumors measuring ≤4 cm in diameter and that the subject population includes only a small number of cases with dissection of the lymph nodes in the upper and middle mediastinal regions and areas circumjacent to the abdominal aorta. A prospective clinical study to evaluate the outcomes depending on the extent of lymphadenectomy for more advanced tumors is currently in progress. The Japanese Gastric Cancer Association—Japan Esophageal Society Joint Working Group has proposed a definition of the esophagogastric junction based on endoscopic findings. In the algorithm used as a guide for the extent of lymph-node dissection, as well, lesions are defined according to the principal location of the center of the tumor, i.e., whether it is located proximal or distal to the junction. In the clinical practice setting, however, the junction can scarcely be identified by endoscopy in cases of advanced carcinoma, and that frequent, concurrent hiatal herniation interferes with positional estimation of the junction even by fluoroscopic exploration or CT. Thus, it may be said that only but an obscure judgment about the location of the junction can be obtained in the clinical setting. The extent of resection of the esophagus and stomach is determined in accordance with the extent of lymph-node dissection, and the range of operative procedures available extend from total esophagogastrectomy to lower third esophagectomy plus proximal gastrectomy. In surgery for carcinoma of the esophagogastric junction, the surgical invasiveness is affected not only by the extent of resection, but also by the surgical approach; therefore, the treatment selection must be approached by taking into consideration the balance between the surgical invasiveness and curability of the adopted procedure. Perioperative management and clinical path Summary Various improvements have been made to the clinical path system for esophageal cancer at facilities overseas and in Japan, in an effort to implement safe perioperative management with a reduced incidence of complications; however, convincing evidence is still to be presented. The clinical significance of the new concept of perioperative management introduced in recent years; namely, Enhanced Recovery after Surgery (ERAS) or fast-track surgery in surgical resection of the esophagus has drawn increasing attention. General remarks A clinical path is a standard medical practice plan containing information on the patient’s condition, goals of medical practice, and relevant evaluations and records, and represents a procedure for improving the quality of medical care through analysis of deviations from the standard. With the introduction of the Diagnosis-Related Group/Prospective Payment System (DRG/PPS) in the 1980s, clinical paths aimed primarily at shortening the length of hospitalization and reducing the medical fees were introduced [33]. In Japan, introduction of clinical paths for many disorders began in the 1990s concurrently with the introduction of the Diagnosis Procedure Combination (DPC) system. Clinical paths are generally thought to be important for promoting patient-centered collaborative (team) medical care, including perfection of informed consent as well as for improving the quality of medical care and education of personnel. Various improvements have been made in the clinical path system for esophageal cancer at facilities overseas and in Japan, in an effort to implement safe perioperative management, with a reduced incidence of complications. It has generally been recognized that preparation of a simple clinical path for esophageal cancer entails greater difficulty as compared to that for carcinomas of other digestive organs, because of the diversity and interinstitutional inequity of procedures and perioperative management techniques, and because of individual differences in the reaction to invasiveness. An increasing number of facilities have been introducing a clinical path for esophageal cancer for safe perioperative management, in parallel with the introduction of minimally invasive operations including endoscopy-aided surgery; however, convincing evidence demonstrating its clinical usefulness is still awaited [34, 35]. In recent years, the new concept of Enhanced Recovery after Surgery (ERAS) or fast-track surgery has been introduced for perioperative management in Europe and the United States. The ERAS Group organized in 2001 under the European Society for Clinical Nutrition and Metabolism (ESPEN) published an ERAS protocol for colectomy in 2004 [36], which has since been applied to perioperative management for various surgeries. Fast-track surgery is a multimodal rehabilitation program with integrated introduction of evidence-based procedures as an approach to patient care to expedite recovery after surgery. Currently, this term is essentially synonymous with ERAS. The Clinical significance of ERAS and fast-track surgery in cases of esophagectomy has recently been investigated, with the results indicating reductions in the incidence of complications, duration of hospitalization, and mortality rate, even though the level of evidence is still not high at present [37–40]. Perioperative management of patients with esophageal cancer has, heretofore, been assessed by comparative evaluation of the usefulness of clinical paths established at individual facilities from their independent standpoints. From now on, however, the clinical significance of ERAS/fast-track surgery as perioperative management procedures needs to be verified. Chemotherapy for unresectable advanced/recurrent esophageal cancer Summary Chemotherapy is used as the only systemic therapy modality under various settings in the treatment of esophageal cancer. Chemoradiotherapy and preoperative chemotherapy are used for cStage I–Stage IV local esophageal cancer, and chemotherapy is also used for unresectable advanced/recurrent esophageal cancer. Combination therapy with cisplatin + 5-FU is used for unresectable advanced/recurrent esophageal cancer, although there is no clear evidence of its ability to prolong the survival. Taxanes and other drugs are used as the second-line therapy in patients who become refractory to the first-line therapies, but these have only been reported in phase II studies involving a small number of patients, and should be used carefully. General remarks Systemic chemotherapy is used as the standard therapy for unresectable advanced/recurrent esophageal cancer. Although no comparative study with untreated controls has clearly demonstrated the ability of chemotherapy alone to prolong the survival, both the efficacy of monotherapy and combination therapy has been reported, and chemotherapy is used as standard therapy. Drugs and drug combinations that have been shown to be effective as the first-line therapy Monotherapy with 5-FU, platinum drugs, taxanes, vinca alkaloids, etc., has been reported to be associated with a response rate of 15–40% and a median survival duration of approximately 3–10 months. Combination therapy has been shown to be associated with even higher response rates (20–60%) than monotherapy (Table 1) [41–43]. Many studies have reported the efficacies of combination therapy with 2 or 3 drugs, whereas only one study has compared the efficacy of combination therapy versus monotherapy. Most of these studies were phase II studies involving a small number of patients. As two-drug combination therapies, the combination of cisplatin and 5-FU, which are expected to have a synergistic effect, and the combination of nedaplatin and 5-FU are used. Combined therapy with cisplatin + 5-FU is considered to be the standard therapy for patients with unresectable advanced/recurrent esophageal cancer. A three-drug combination therapy, a taxane given in combination with cisplatin + 5-FU, has been shown to be highly effective, with a reported response rate of 60% [44, 45], but it is unknown whether this therapy can prolong the survival. Therefore, at present, it is considered desirable to use this three-drug combination therapy in clinical studies. A comparative study of combined cisplatin + 5-FU therapy and 2-weekly docetaxel combined with cisplatin + 5-FU is currently ongoing (JCOG1314 Study), and the results of the study are awaited. Table 1 Reports of the first-line therapy for unresectable advanced/recurrent esophageal cancer Regimen N Response rate (%) Progression-free survival (month) Median survival (month) Cisplatin 100 mg/m2 on day 15-FU 1000 mg/m2/day on days 1–5/every 3 weeks SCC44 35 6.2 7.6 Cisplatin 70 mg/m2 on day 15-FU 700 mg/m2/day on days 1–5/every 3 weeks SCC39 35.9 Patients with response3.5 Patients with response9.5 Nedaplatin 90 mg/m2 on day 15-FU 800 mg/m2/day on days 1–5/every 4 weeks SCC42 39.5 2.5 8.8 Doxorubicin 30 mg/m2/day on day 15-FU 700 mg/m2/day on days 1–5Cisplatin 14 mg/m2/day on days 1–5/every 4 weeks SCC41 43.9 5.0 10.1 Docetaxel 30 to 40 mg/m2/day on days 1 and 155-FU 800 mg/m2/day on days 1–5Cisplatin 80 mg/m2 on day 1/every 4 weeks SCC55 62 5.8 11.1 SCC squamous cell carcinoma Drugs and combination therapies shown to be effective as the second-line therapy In regard to the second-line therapy for patients who become refractory to cisplatin + 5-FU, no drugs have been clearly shown to prolong the survival. Drugs that are likely to show efficacy other than fluoropyrimidines and platinum drugs should be used, but the benefit–harm (toxicity) balance should be carefully considered (Table 2). Monotherapy with taxanes, such as docetaxel and paclitaxel, is often used [46, 47]. The significance of readministration of drugs used in the first-line therapy and combination therapy [48] for these patients has not been established. Table 2 Reports of second- or subsequent-line therapy for unresectable advanced/recurrent esophageal cancer Regimen N Response rate (%) Progression-free survival (month) Median survival (month) Docetaxel 70 mg/m2 every 3 weeks SCC 46a AC 3Others 2 20 2.3 8.1 Paclitaxel 100 mg/m2 on days 1, 8, 15, 22, 29, and 35/every 7 weeks SCC52 44.2 3.9 10.4 Docetaxel 30 mg/m2/day on day 1Nedaplatin 50 mg/m2 on day 1/every 2 weeks SCC48 27.1 3.1 5.9 Nivolumab 3 mg/kg/every 2 weeks SCC64 17 1.5 10.8 SCC squamous cell carcinoma, AC adenocarcinoma aIncluding 14 patients with the initial treatment Although there have been a few reports on molecular-targeted drugs, epidermal growth factor receptor (EGFR) inhibitors have been reported to be associated with response rates in the range of 10–20%. A comparative study of an EGFR inhibitor gefitinib and placebo in patients receiving the second-line therapy for esophageal cancer, including adenocarcinoma, failed to demonstrate any usefulness of gefitinib [49]. In the future, development of biomarkers, etc., may allow the usefulness of EGFR inhibitors to be demonstrated in particular subsets of subjects, but, at present, their usefulness in the treatment of esophageal cancer remains unknown. Drugs and combination therapies shown to be effective as the third-line therapy For patients who become refractory or intolerant to the first- and second-line therapies, no drugs have been demonstrated to be effective, and palliative symptomatic treatment is recommended. A phase II study reported the efficacy of nivolumab, an immune checkpoint inhibitor with a new mechanism of action [50], but a phase III comparative study is required to validate its applicability in clinical practice. Radiotherapy Summary For definitive radiotherapy, concurrent chemoradiotherapy is recommended. The potential usefulness of preoperative chemoradiotherapy for resectable advanced cancer is being investigated in an ongoing clinical study. Chemoradiotherapy or radiotherapy alone is indicated for unresectable patients according to the PS. Palliative radiotherapy is considered for cStage IVb esophageal cancer patients presenting with obstruction. A total dose of 60 or 50.4 Gy is often prescribed for chemoradiotherapy, and it is considered that unnecessary prolongation of the treatment duration should be avoided. General remarks Randomized comparative studies and their meta-analyses have demonstrated that concurrent chemoradiotherapy is more effective than radiotherapy alone for definitive treatment of esophageal cancer [51, 52]. Therefore, concurrent chemoradiotherapy is considered preferable, unless its use is precluded by factors such as advanced age, presence of complications, or any other reasons. Radiotherapy is indicated for patients with residual lesions in the local or regional lymph nodes. An additional (chemo-) radiotherapy is considered when there is residual cancer after endoscopic treatment for T1a or T1b cancer, or when the patient is suspected to have lymph-node metastasis. Preoperative chemotherapy is the standard treatments for resectable advanced cancer in Japan. Patients who are not suitable for surgery or who do not wish to undergo surgery are given definitive chemoradiotherapy. In addition, preoperative chemoradiotherapy for these patients is being investigated in an ongoing clinical study. Chemoradiotherapy is indicated for unresectable cancer patients with a good PS, and subsequently, surgery may be considered. Radiotherapy alone may be considered for patients with a poor PS. Palliative radiotherapy may be considered for cStage IVb esophageal cancer patients presenting with obstruction. Radiotherapy may be used not only in patients with postoperative residual lesions and untreated patients, but also in those with postoperative recurrence without distant metastasis. At present, in most facilities, CT-based three-dimensional treatment planning is performed, which allows optimization of the doses to the tumor and risk organs, enabling highly accurate treatment. When radiotherapy alone is performed, since the local control rate may decrease due to accelerated repopulation of the tumor cells, it is considered that unnecessary prolongation of the treatment duration should be avoided [53]. In regard to the optimal total dose for definitive treatment, a randomized comparative study of chemoradiotherapy at a total dose of 50.4 Gy versus 64.8 Gy, conducted mainly by the US Radiation Therapy Oncology Group (RTOG), failed to demonstrate the superiority of the higher dose [54]. In Japan, chemoradiotherapy mainly using 60 Gy has been reported, but clinical studies using 50.4 Gy have also been reported, expecting reduction of the late toxicities of chemoradiotherapy and salvage surgery after definitive radiation. In clinical practice, the dose should be determined considering the several factors such as the patient’s general condition, tumor volume, irradiation area, and doses to the risk organs. When radiotherapy alone is performed, a total dose of 60–70 Gy is commonly prescribed. Multidisciplinary treatment Preoperative/postoperative adjuvant therapy Summary At present, the standard treatment for cStage II and III thoracic esophageal cancer in Japan is preoperative chemotherapy with cisplatin + 5-FU, followed by surgery. On the other hand, in Europe and North America, the standard treatment is preoperative chemoradiotherapy followed by surgery. A randomized comparative study to confirm the superiority of preoperative docetaxel + cisplatin + 5-FU (DCF) therapy and that of preoperative chemoradiotherapy (cisplatin + 5-FU, radiotherapy at 41.4 Gy) over the currently used preoperative regimen of cisplatin + 5-FU (JCOG1109 Study) is ongoing. General remarks In recent years, multidisciplinary treatment, including chemotherapy, radiotherapy, and surgery, has been used for esophageal cancer. The JCOG9204 Study conducted in Japan compared the outcomes of surgery alone with those of surgery plus postoperative chemotherapy with cisplatin and 5-FU [55]. While no significant difference in the overall survival were observed between the two groups, the 5-year disease-free survival (DFS) was significantly better in the surgery plus postoperative chemotherapy group (55%) than in the surgery alone group (45%); furthermore, this improved prognosis was particularly evident in the pathological lymph-node metastasis-positive cases. As a result, surgery plus postoperative chemotherapy became the standard treatment in Japan for patients with histopathologically diagnosed lymph-node metastasis after surgical resection. Subsequently, the JCOG9907 Study investigated the optimal timing, in relation to surgery, of adjuvant chemotherapy with cisplatin + 5-FU, and showed that 5-year overall survival was significantly better in the preoperative chemotherapy plus surgery group (55%) than in the surgery plus postoperative chemotherapy group (43%) [56]. Thereafter, preoperative adjuvant chemotherapy with cisplatin + 5-FU followed by radical surgery came to be adopted as the standard of care for cStage II and III thoracic esophageal cancer patients in Japan. On the other hand, in Europe and North America, preoperative chemoradiotherapy followed by radical surgery is used as the standard treatment. Preoperative chemoradiotherapy yields a higher local control rate than preoperative chemotherapy alone, but may also increase the risk of perioperative complications and surgery-related mortality. So far, in Japan, local control is achieved by accurate lymph-node dissection during surgery, and preoperative radiotherapy has been thought to be unnecessary. In Europe and North America, several randomized comparative studies investigating the usefulness of preoperative chemoradiotherapy have been reported [57], because adequate local control has not yet been achieved by surgery. The CROSS trial, which is a large-scale randomized comparative study conducted in the Netherlands, showed that the overall survival was significantly longer in the preoperative chemoradiotherapy + surgery group than in the surgery alone group (median overall survival, 49.4 vs. 24.0 months) [58]. On the other hand, there were no significant differences in the incidence of postoperative complications between the two groups. The results of a subgroup analysis in the JCOG9907 Study suggested that the additive effect of the currently used preoperative chemotherapy with cisplatin + 5-FU may be insufficient for improving the prognosis in patients with cStage III thoracic esophageal cancer, and that either preoperative chemotherapy with a more intensive regimen or preoperative chemoradiotherapy may need to be attempted in the future, aimed at better local control. Taxane antitumor agents (paclitaxel/docetaxel) are thought to be effective in patients with esophageal cancer. Recently, DCF therapy, in which docetaxel is added to cisplatin + 5-FU therapy has attracted attention. The JCOG1109 Study, which was started in 2012, is a randomized comparative study performed to confirm the superiority of preoperative DCF therapy and that of preoperative chemoradiotherapy (cisplatin + 5-FU, radiotherapy at 41.4 Gy) over the currently used preoperative regimen of cisplatin + 5-FU, and the results of the study are awaited, so that the standard treatment for cStage II and III thoracic esophageal cancer can be established in Japan [59]. Chemoradiotherapy Summary Chemoradiotherapy has been demonstrated to yield a greater prolongation of the survival than radiotherapy alone in patients with locally advanced esophageal cancer. It is considered as the standard of care in non-surgical treatment, and chemoradiotherapy aimed at complete cure is indicated for cStage 0 to IVa cancer. Although a study comparing chemoradiotherapy and surgery alone in resectable cases reported that chemoradiotherapy can be expected to have equivalent efficacy to surgery, no studies have directly compared the two, and it is speculated that the standard treatment, namely, preoperative chemotherapy + surgical treatment, would yield better results in patients with cStage II and III cancer. Therefore, chemoradiotherapy is considered as one of the options in patients who are intolerant to surgery or refuse surgery. It is important to select the appropriate radiation dose, irradiation area, and chemotherapy regimen while considering a treatment strategy, and also consider the salvage treatments for residual and recurrent lesions after chemoradiotherapy (Table 3). Table 3 Summary of prospective clinical studies of chemoradiotherapy Study name Histological type studied Regimen Radiation dose (Gy) Complete response rate (%) Survival (%) JCOG9708 cStage IbSCC Cisplatin 70 mg/m2 on days 1 and 365-FU 700 mg/m2 on days 1–4 and 36–39 60 87.5 4-year survival80.5 RTOG85-01 cStage I, II, IIISCC, AC Radiotherapy alone 64 NA 5-year survival0 Cisplatin 75 mg/m2 on days 1 and 295-FU 1000 mg/m2 on days 1–4 and 29–32 50 NA 5-year survival27 RTOG94-05 cStage I, II, IIISCC, AC Cisplatin 75 mg/m2 on days 1 and 295-FU 1000 mg/m2 on days 1–4 and 29–32 50.4 NA 2-year survival40 Cisplatin 75 mg/m2 on days 1 and 295-FU 1000 mg/m2 on days 1–4 and 29–32 64.8 NA 2-year survival31 JCOG9906 cStage II, IIISCC Cisplatin 40 mg/m2 on days 1, 8, 36 and 435-FU 400 mg/m2 on days 1–5, 8–12, 36–40, and 43–47 60 62.2 3-year survival44.7 mRTOG cStage II, IIISCC Cisplatin 75 mg/m2 on days 1 and 295-FU 1000 mg/m2 on days 1–4 and 29–32 50.4 70.6 3-year survival63.8 JCOG9516 Unresectable localSCC Cisplatin 70 mg/m2 on days 1 and 365-FU 700 mg/m2 on days 1–4 and 36–39 60 15 2-year survival31.5 JCOG0303 Unresectable localSCC Cisplatin 70 mg/m2 on days 1 and 295-FU 700 mg/m2 on days 1–4 and 29–32 60 0 3-year survival25.9 Cisplatin 4 mg/m2/5 doses weekly for 6 weeks5-FU 200 mg/m2/5 doses weekly for 6 weeks 60 1.4 3-year survival25.7 KROSG0101/JROSG021 cStage II, IVAlocal SCC Cisplatin 70 mg/m2 on days 1 and 295-FU 700 mg/m2 on days 1–5 and 29–33 60 NA 2-year survival46 Cisplatin 7 mg/m2 on days 1–5, 8–12, 29–33 and 36–405-FU 250 mg/m2 on days 1–14 and 29–42 60 NA 2-year survival44 KDOG0501 Unresectable localSCC Cisplatin 40 mg/m2 on days 1, 15, 29, and 435-FU 400 mg/m2 on days 1–5, 15–19, 29–33, and 43-47Docetaxel 20–40 mg/m2 on days 1, 15, 29, and 43 61.2 42.1 1-year survival63.2 SCC squamous cell carcinoma, AC adenocarcinoma, 5-FU 5-fluorouracil, NA not available General remarks Chemoradiotherapy for cStage 0 and I disease Chemoradiotherapy is indicated for lesions covering ≥ 3/4th of the circumference, which are difficult to treat endoscopically, and those invading up to the submucosa or deeper. The JCOG9708 Study showed good results, with a complete response rate of 87.5% and a 4-year survival rate of 80.5% [26]. Although 9 patients (12.5%) had residual cancer and 30 (41%) developed recurrence after treatment, many of these lesions could be completely cured by endoscopic treatment or surgical resection, and only 9 patients had lesions that could not be radically resected at recurrence. cStage I patients are known to frequently develop recurrent or metachronous multiple lesions in the esophagus after complete response [60], and it is important to perform CT and endoscopy every 3–4 months for at least 2 years after complete response is obtained, and subsequently every 6 months, for detecting recurrent or metachronous multiple lesions at a sufficiently early stage as to allow the lesions to be treated endoscopically. In addition, it has been reported that 10–50% of patients with obvious submucosal invasion or intramucosal lesions with vascular invasion after endoscopic treatment develops lymph-node metastasis, and these patients were likely to have non-curative resection [61]. For additional treatment of these patients, radical surgery with lymph-node dissection is currently used as the standard of care, while one report has suggested the usefulness of prophylactic chemoradiotherapy in combination with cisplatin + 5-FU for regional lymph nodes [62]. In the JCOG0508 Study, cT1bN0 esophageal cancer with a limited depth of invasion (up to SM2), which was estimated to be treatable endoscopically, was treated endoscopically, and patients with pathologically confirmed complete resection who had pT1a with positive vascular invasion or pT1b received prophylactic chemoradiotherapy. With such treatment, these patients showed a 3-year survival rate (primary endpoint of the study) of 90.7% (90% CI 84.0–94.7). On the other hand, 3 (20%) of the 15 patients who had positive surgical margins after endoscopic treatment and received definitive chemoradiotherapy died of the disease. It should be carefully investigated as to which subpopulation of patients with cT1bN0 disease would be suitable candidates for this treatment. The clinical study was presented at the Annual Meeting of the American Society of Clinical Oncology in June 2016, and its publication is awaited. Chemoradiotherapy for cStage II and III disease According to one report, chemoradiotherapy was equivalent to surgery alone for cStage II and III cancer [63]. However, according to the JCOG9906 study, chemoradiotherapy was associated with a complete response rate of 62.2%, 3-year survival rate of 44.7%, and 5-year survival rate of 36.8%, which were considered to be inferior results to those of preoperative chemotherapy + surgery in the same subject population (5-year survival rate of 55%, JCOG9907 Study), although no direct comparison can be made. Therefore, chemoradiotherapy is recommended for patients who refuse surgery or are intolerant to surgery, as a treatment with which complete cure can be expected [64]. The RTOG9405/INT0123 study conducted by the US RTOG compared cisplatin (75 mg/m2 on days 1 and 29) + 5-FU (1000 mg/m2 on days 1–4 and 29–32) chemotherapy with radiotherapy at a radiation dose of 50.4 Gy, and the same chemotherapy with radiotherapy at a radiation dose of 64.8 Gy, and revealed that, while the survival was not prolonged any further, higher toxicity was obtained in the 64.8 Gy group [54]. Based on this, chemotherapy with cisplatin (75 mg/m2 on days 1 and 29) + 5-FU (1000 mg/m2 on days 1–4 and 29–32) combined with radiotherapy at a radiation dose of 50.4 Gy (RTOG regimen) is considered as one of the standard chemoradiotherapy treatment regimens. A phase II study of a modified RTOG (mRTOG) regimen in Japan reported that addition of prophylactic irradiation of the regional lymph nodes to the original RTOG regimen yielded good results, with a complete response rate of 70.6% and 3-year survival rate of 63.8% [65]. Late toxicity was reduced in the mRTOG regimen when the radiation dose of 50.4 Gy was used, as compared with that in the JCOG9906 study, in which the radiation dose used was 60 Gy. However, attention should be paid to the development of myelosuppression, mucositis, and gastrointestinal symptoms associated with the increased doses of the chemotherapeutic agents. In addition, active salvage treatment, described below, also contributed to the improved treatment outcomes, and it is necessary to consider treatment strategies including salvage treatments after chemoradiotherapy. Criteria for indications of the mRTOG regimen combined with salvage treatment and the safety of salvage treatment are under investigation in the JCOG0909 Study. Chemoradiotherapy for cStage IVa esophageal cancer When a lesion that is not amenable to surgical resection is limited to the irradiation area, chemoradiotherapy is used as a standard treatment. A single-center phase II study of cisplatin + 5-FU in combination with radiotherapy at a radiation dose of 60 Gy reported a complete response rate of 33% and a 3-year survival rate of 23%, and a multicenter study, the JCOG9516 Study, reported a complete response rate of 15% and a 2-year survival rate of 31.5% [66, 67]. As a result, chemoradiotherapy with cisplatin + 5-FU has come to be used as a standard treatment. Two randomized studies comparing standard chemotherapy with 5-FU (700 mg/m2 on days 1–4 and 29–32) + cisplatin (70 mg/m2 on days 1 and 29) and low-dose chemotherapy with 5-FU (200 mg/m2) + cisplatin (4 mg/m2) on days 1–5, 8–12, 15–19, 22–26, 29–33, and 36–40, both combined with radiation at the dose of 60 Gy, failed to find any clear advantage of the low-dose chemotherapy [68, 69]. A clinical study of DCF therapy, in which docetaxel is added to cisplatin + 5-FU, in combination with radiotherapy reported good results with a complete response rate of 42.1%; however, Grade 3–4 esophagitis or febrile neutropenia occurred in ≥ 30% of the subjects. Therefore, adoption of this treatment needs to be carefully considered [70]. Multidisciplinary treatment in which surgery or chemoradiotherapy is performed after intensive induction chemotherapy has been shown to yield good short-term results with a 1-year survival rate of 67.9% [71], and a comparative study (JCOG1510) is planned. Radiation dose and chemotherapy regimens used in chemoradiotherapy The RTOG8501 study recommended chemoradiotherapy as a standard treatment, because comparison of radiotherapy (64 Gy) alone and concurrent chemoradiotherapy (cisplatin + 5-FU + 50 Gy) for esophageal cancer revealed significantly superior treatment outcomes of chemoradiotherapy [72]. In addition, a meta-analysis of studies of chemotherapy and radiotherapy reported that concurrent chemotherapy and radiotherapy yielded a significantly greater prolongation of the survival than sequential chemotherapy and radiotherapy [73]. Furthermore, the above-mentioned RTOG9405/INT0123 study revealed no superior outcomes in terms of the survival or local control rate in the high-dose group, concluding that a radiation dose of 50.4 Gy should be used in combination with cisplatin (75 mg/m2 on days 1 and 29) + 5-FU (1000 mg/m2 on days 1–4 and 29–32) chemotherapy. Many studies in Japan have used a radiation dose of 60 Gy in combination with lower doses of the antitumor agents, such as cisplatin (70 mg/m2 on days 1 and 29) and 5-FU (700 mg/m2 on days 1–4 and 29–32) [74, 75]. For multidisciplinary treatment including salvage treatment, the mRTOG regimen has also been increasingly used, and its usefulness is now under investigation in the JCOG0909 Study. Adverse effects of radical chemoradiotherapy Adverse effects of chemoradiotherapy are mainly classified into acute and late toxicity. Acute toxicity occurs mainly during concurrent chemotherapy and radiotherapy, within 1–2 months after the start of treatment. Late toxicity is often associated with radiation and occurs a few months to a few years after completion of treatment. Symptoms of acute toxicity include gastrointestinal toxicity, nausea, vomiting, renal impairment, leukopenia, esophagitis, and dysphagia, and should be treated according to guidelines such as the “Guidelines for Proper Use of Antiemetics” and “Practical Guideline of Febrile Neutropenia (FN)”. Symptoms of late toxicity include radiation pneumonitis, pleural effusion, pericardial effusion, pericarditis constrictive, and hypothyroidism, which interfere with daily life in approximately 10% of patients [76–78]. Since late toxicity may be lethal, regular follow-up, medical interviews to obtain information on subjective symptoms such as dyspnea, and early treatment are important. Salvage treatment for local residual/recurrent lesions after radical chemoradiotherapy When there is a local residual or recurrent lesion after chemoradiotherapy for esophageal cancer, salvage surgery or endoscopic treatment may allow long-term survival. It has been reported that, in salvage surgery, R0 resection allows long-term survival, but, at the same time, increases the incidence of postoperative complications and in-hospital mortality [79–83]. When a residual lesion remains confined in the mucosa, salvage endoscopic treatment can be performed safely [84, 85]. Photodynamic therapy (PDT) has been reported to yield good results even in cases with suspected invasion of the submucosa or muscularis propria, and PDT is considered as one of the potentially useful treatment options [86]. Follow-up after treatment of esophageal cancer Summary The purpose of follow-up after treatment of esophageal cancer is (1) to detect and treat recurrence early, and (2) to detect and treat multiple/double cancers early. Furthermore, follow-up is also important from the standpoint of systemic management and knowing the QOL of the patients after treatment. Methods of follow-up after treatment of esophageal cancer vary depending on the type of initial treatment and on the stage of cancer progression at the time of the initial treatment. During follow-up, it is important to keep in mind that the early detection/treatment may allow long-term survival and to pay attention to the occurrence of metachronous multiple esophageal cancers and metachronous double cancers in other organs, mainly high-incidence cancers, i.e., gastric cancer and head and neck cancer. Establishment of a consensus-based follow-up system and verification of its effectiveness are required. General remarks Follow-up after endoscopic resection No certain method of follow-up after endoscopic resection has been established. Local recurrence often occurs within 1 year after the initial treatment, although it, sometimes, takes up to 2–3 years after the initial treatment, and long-term-follow-up is required [87, 88]. Esophagoscopy with iodine staining is mainly used to screen for local recurrence, and many studies have reported that screening for local recurrence is performed every 3 or 6 months for 1 year after resection [3, 4, 87–89]. Patients with piecemeal resection and those with multiple iodine-unstained areas have a high risk of local recurrence, requiring a more strict esophagoscopy protocol [3, 4, 87, 88, 90]. Lymph-node recurrence/organ recurrence may be detected 2–3 years later, and regular, long-term follow-up is required [5, 91]. In regard to the methods of examination, follow-up is usually performed every 6–12 months using several equipments such as contrast-enhanced thoracoabdominal CT and EUS [92]. For example, in the JCOG0508 Study “Single-arm confirmatory study on efficacy of combined treatment of endoscopic mucosal resection and chemoradiotherapy for clinical stage I esophageal carcinoma,” medical examinations and contrast-enhanced neck to abdominal CT and measurement of squamous cell carcinoma (SCC) antigen, a tumor marker, are to be performed every 4 months for 3 years after EMR. Follow-up after radical surgery Recurrence after radical surgery occurs in 29–43% of cases in Japan. Although, in approximately 85% of cases, the recurrences occur early, often within 2 years after surgery, in some cases, they occur much later, and this should be borne in mind [93–95]. The patterns of recurrence include lymph-node recurrence, local recurrence, organ recurrence and disseminated recurrence, and mixed type of recurrence [95]. The actual method of follow-up after radical resection of esophageal cancer is currently determined by each institution, and no studies have clarified the usefulness of regular follow-up or an effective method of follow-up. A nationwide survey conducted by the Guideline Committee [96] revealed that many institutions perform follow-up with tumor markers and diagnostic imaging, mainly CT, ≥ 4 times a year during the first 2 years after resection and at least twice a year from the third year until the fifth year, and that some institutions perform follow-up for up to 10 years. Mainly contrast-enhanced thoracoabdominal CT and upper gastrointestinal endoscopy are performed as follow-up examinations, and neck/abdominal US, bone scintigraphy and PET-CT are performed as necessary. CT is performed every 3–6 months in many institutions, and the frequency of CT often varies depending on the stage of cancer progression and on the number of years after surgery. Follow-up after radical chemoradiotherapy CT, esophagoscopy, and other examinations are usually used for follow-up after radical chemoradiotherapy, but there are no reports clarifying the optimal frequency of these examinations or the optimal follow-up period. According to a nationwide survey [96], follow-up is performed every 3 months during the first year after chemoradiotherapy at most institutions. For patients with cStage II or more advanced cancers, follow-up similar to that in the first year is performed up to the third year at many institutions, and follow-up is continued for at least 5 years after treatment at all the institutions surveyed. Primary esophageal lesions and lymph-node metastasis are commonly encountered as residual/recurrent lesions after chemoradiotherapy, and in most of these cases, these are detected within 1 to 2 years after the start of treatment. After definitive chemoradiotherapy for esophageal cancer, not only screening for detecting recurrence, but also follow-up for the early identification of the late effects of radiotherapy such as radiation pneumonitis, pleural effusion, and pericardial effusion is necessary [76]. These late effects may greatly impair the patients’ QOL, and patients could die of the late effects. Points to consider in patients with metachronous multiple esophageal cancers and double cancers in other organs Esophageal cancer is characterized by relatively frequent occurrence, metachronously, of multiple cancers in the esophagus. In addition, development of metachronous cancer in other organs, such as gastric cancer and head and neck cancer, is also not rare [97, 98]. Bearing this in mind, upper gastrointestinal endoscopy needs to be regularly performed to carefully observe the pharynx, entire esophagus (remnant esophagus in surgical cases), and stomach. Particular attention needs to be paid to the development of metachronous head and neck cancer in patients with multiple iodine-unstained areas and those with head and neck cancer [98, 99]. Magnifying endoscopy with narrow-band imaging (NBI) is useful for detecting superficial head and neck cancer [100]. Furthermore, attention also needs to be paid to the development of colorectal and other cancers. Treatment of recurrent esophageal cancer Summary Since there are a variety of initial treatments for esophageal cancer, such as endoscopic treatment, radical surgery, and definitive chemoradiotherapy, treatment for recurrent esophageal cancer needs to be considered individually according to the type of initial treatment. Furthermore, treatment varies depending on whether the pattern of recurrence is lymph-node recurrence, local recurrence, distant organ recurrence, or mixed recurrence, and the general condition of the patient at the time of recurrence also affects the choice of treatment. It is difficult to conduct large-scale clinical studies on the treatment of recurrent esophageal cancer, and there is currently little evidence of the usefulness of any type of treatment used. While cure may be achieved depending on the type of recurrence, for example, by salvage therapy after radical chemoradiotherapy, treatment for suppressing tumor exacerbation or improving QOL is also often used. General remarks Treatment of recurrence after endoscopic resection Local recurrence after endoscopic mucosal resection often develops within 1 year after the initial treatment, but may sometimes take until 2 to 3 years after the initial treatment. Recently, indications for endoscopic resection have been expanded in clinical studies. There are no certain indications for, or evidence for the type of additional treatment after endoscopic resection, and some patients receive follow-up alone (see Chapter “Endoscopic treatment”). Treatment of recurrence after radical surgery Recurrence after radical surgery for esophageal cancer has been reported to occur in 28–47% of cases in Japan [93, 101], while the reported recurrence rates of ≥ 50% are not rare in reports from Europe and North America [102, 103]. In regard to the patterns of recurrence, 22–68% of cases show lymph node/local recurrence, 12–51% show distant organ metastasis, and 7–27% show a mixture of both types of recurrence. Recurrence in the neck/superior mediastinum is common in cases of lymph-node recurrence, while, in cases of distant organ metastasis, the lung is the most common site of recurrence, followed in frequency by the liver, bone, and brain. Even metastases to the small intestine and colon have been reported. Patients with recurrence after radical resection for esophageal cancer have extremely poor survival rates, with a median survival duration of 5–10 months after diagnosis. On the other hand, cases of long-term survival and those of complete cure have also been reported, and active treatment for recurrent lesions should be considered [93, 101–113]. Treatment of recurrence after radical resection for esophageal cancer is selected according to the site, pattern, and extent of recurrence. Treatment varies depending on the condition in each individual, such as the general condition of the patient at the time of recurrence, whether recurrence is in the surgical area, and whether irradiation was given preoperatively or postoperatively. Therefore, there have been a few reports of large-scale studies of the treatment outcomes according to various pathological conditions. Treatment of recurrence developing after complete response to definitive chemoradiotherapy In recent years, definitive chemoradiotherapy has been increasingly chosen as the initial treatment, not only for unresectable esophageal cancer, but also for cases with esophageal cancer that is judged as being resectable. Although complete response has been achieved in many cases, recurrences, including local recurrence, are often encountered. The treatment of recurrence varies depending on the pathology and general condition of the patient, and no consensus has been reached. However, when the recurrence is localized, salvage treatment such as surgery and endoscopic resection may be adopted [79, 84, 85, 105, 114–117] (see chapter “Multidisciplinary treatment”, Chemoradiotherapy). Palliative care Summary While palliative care should be commonly provided for cancers at any site, in esophageal cancer patients, dysphagia, malnutrition, cough due to fistula formation with the airways, and other symptoms often decrease the QOL, and provision of treatment for relieving these symptoms and maintaining/improving the QOL of the patients should be considered from even the early stages of treatment. However, the method of palliation adopted is determined by the prevailing practice at individual institutions, and further evaluation is required. All medical professionals need to master the knowledge and skills needed in palliative care. General remarks The World Health Organization (WHO) (2002) defines palliative care as “an approach that improves the quality of life of patients and their families facing problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual.” The Second Basic Plan to Promote Cancer Control Programs in fiscal year 2012 states that “promotion of palliative care from the time of cancer diagnosis” is an issue that needs to be focused on. The above-mentioned palliative care is common to all cancer patients and provided in daily practice, not only the attending physicians and nurses, but also palliative care specialists, psycho-oncologists, clinical psychologists, dentists, pharmacists, certified social workers, physical therapists, and other professionals need to engage and provide team care. Methods based on the “Guidelines for Pharmacotherapy of Cancer Pain” established by the Japanese Society for Palliative Medicine are recommended for cancer pain. Patients with esophageal cancer often suffer from dysphagia and malnutrition due to esophageal obstruction, cough due to aspiration/fistula, and chest pain due to the tumor, resulting in a lowered QOL already at the time of diagnosis. Even while providing treatment for cure, it is important, from the early stage, to provide treatment for the relief of symptoms and for maintaining/improving the QOL of the patients [118]. In palliative care for patients with terminal esophageal cancer, problems that need to be handled are, in particular, dysphagia due to esophageal obstruction and malnutrition caused by dysphagia, symptoms caused by airway obstruction or fistula formation with the airway, cachexia, and other symptoms due to distant metastases and hypercalcemia. To improve the symptoms of esophageal obstruction and airway obstruction and those caused by fistula, palliative radiotherapy, chemoradiotherapy, esophageal stenting, airway stenting, esophageal bypass surgery, and/or other treatments may be used [119, 120] (see Chapter “Radiotherapy”; Chapter “Multidisciplinary Treatment”, Chemoradiotherapy). For improving dysphagia in unresectable esophageal cancer, a Cochrane Database Systematic Review in 2014 showed that self-expandable esophageal metallic stents are more effective and faster-acting than plastic stents and other methods [121]. However, it should be kept in mind that stenting may also cause complications, causing pain and further decreasing the QOL, and the treatment(s) should be undertaken after providing adequate explanation to the patient and obtaining informed consent. In addition to esophageal stenting, intracavitary irradiation, laser irradiation, hyperthermia, ethanol injection, etc., have been reported as treatments for providing relief from esophageal obstruction. While intracavitary irradiation may act more slowly in providing relief from esophageal obstruction than esophageal stenting, it could be a useful alternative treatment to esophageal stenting, as it is associated with a lower incidence of complications, provides more sustained relief from esophageal obstruction, and may be expected to prolong the survival and improve the QOL [121]. However, intracavitary irradiation alone is scarcely adopted as a treatment option in Japan (see Chapter “Radiotherapy”). Patients with tracheoesophageal fistula formation have a reduced QOL due to repeated episodes of aspiration and pneumonia, but placement of a covered self-expandable esophageal stent, and in some cases, placement of an airway stent in addition to the esophageal stent, have been reported to be effective [122]. In patients with severe obstruction who have already undergone definitive chemoradiotherapy or radiotherapy and in whom radical resection cannot be expected, if it is considered that esophageal stenting would be difficult or dangerous, a nutritional fistula may be created to allow the patient to be switched to home care. Percutaneous endoscopic gastrostomy, which can usually be performed using an endoscope, is effective, and may be performed even before the start of the multidisciplinary treatments in patients with severe obstruction [123]. In cases in which percutaneous endoscopic gastrostomy is difficult due to severe obstruction, such that even a small-diameter endoscope is difficult to negotiate through, or in patients with a history of abdominal surgery, open gastrostomy or jejunostomy may be performed. In addition, medical professionals involved in the treatment of esophageal cancer often encounter potentially fatal complications, such as sudden respiratory arrest due to airway obstruction and massive hematemesis due to aortic perforation. Since it is difficult to save the lives in most of these cases, it is important to provide a thorough explanation in advance, particularly to the patients’ families. Patients and their families are thus often forced to live in fear of sudden change/death, and psychological support and mental care for them are indispensable. Diagnosis and treatment of Barrett’s esophagus and Barrett’s carcinoma Summary An esophagus lined with Barrett’s mucosa is called Barrett’s esophagus [124]. Barrett’s mucosa is endoscopically recognizable columnar epithelium extending from the stomach to the esophagus and does not require histological confirmation of specific columnar epithelial metaplasia [125–129]. Identification of the esophagogastric junction is required for the diagnosis of Barrett’s mucosa, and the endoscopically identifiable distal end of the lower esophageal palisade vessels is defined, in principle, as the esophagogastric junction. Barrett’s mucosa is characterized by at least one of the following histological findings: (1) esophageal gland ducts in the mucosa beneath the columnar epithelium or esophageal glands proper in the submucosa; (2) squamous islands within the columnar epithelium; (3) double muscularis mucosae beneath the columnar epithelium. Barrett’s carcinoma is defined as adenocarcinoma arising from Barrett’s mucosa. Early, superficial, and advanced cancer are defined in the same manner as for the case of esophageal squamous cell carcinoma, in general, but the deep muscularis mucosae is handled as the genuine muscularis mucosae. Barrett’s carcinoma is treated in accordance with the treatment principles for esophageal squamous cell carcinoma at the cancer site. Endoscopic resection is currently indicated for lesions extending in depth down to the lamina propria (EP: remaining in the epithelium, non-invasive lesion; SMM [superficial muscularis mucosae]: remaining in the superficial muscularis mucosae; LPM [lamina propria mucosae]: not reaching the deep muscularis mucosae); however, accumulation of cases is necessary for establishing the optimal treatment.

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Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus April 2012 edited by the Japan Esophageal Society

Hiroyuki Kuwano, Yasumasa Nishimura, Tsuneo Oyama … (2014)

Introduction Purpose These guidelines are intended for doctors who are engaged in the diagnosis and treatment of esophageal carcinoma, for the following purposes: (1) to present the standard practice for the diagnosis and treatment of esophageal carcinoma with a high regard for the principles of evidence-based medicine (EBM); (2) to improve the safety and results of treatment, thereby reducing the difference in treatment results among different institutions; (3) to reduce unnecessary costs and efforts; (4) help enable people to undergo treatment without anxiety. These guidelines provide only guidance on the indications for treatment and do not restrict or prohibit the use of any treatment deviating from those described herein. Responsibilities The Japan Esophageal Society assumes responsibility for the content described in these guidelines. However, responsibility for the treatment results should be borne by the doctor providing the treatment and shall not rest with the Japan Esophageal Society. Basic principles adopted for the preparation of these guidelines These guidelines only present indications for the treatment procedures and do not address the technical problems of each treatment modality. The principles of presenting adequate treatment procedures include the following: (1) treatments are introduced in relation to the progression of carcinoma, without excess or deficiency; (2) the therapeutic efficacy is evaluated by evidence-based approaches; (3) the final evaluation of treatment procedures is based on the survival period, but remission of symptoms, reduction of tumor, and improvement of quality of life (QOL) are also taken into account; (4) evaluation is carried out depending on the location of the lesion. We propose to revise these guidelines continually along with advances in medical science. Choice of treatment and patients’ consent When choosing a treatment, regardless of whether it is made based on these guidelines or not, it is necessary that the doctors explain the details of the treatment, the reasons for choosing it, possible complications, treatment results, etc., to patients to obtain the patients’ understanding and informed consent. Level of recommendation “Clinical Questions” are attached to each item, and the levels of evidence/strength of recommendation for each item is indicated according to Minds (Medical Information Network Distribution System: http://minds.jcqhc.or.jp/n/) classification of recommendation grades (A, B, C1, C2, D), together with the recommendation grades of the Committee to Develop Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus. Algorithm for treatment of esophageal carcinoma (Fig. 1) Epidemiology, present status, and risk factors Summary With regard to the dynamic trends of esophageal carcinoma in Japan, the incidence rate1 has been increasing slowly in men, whereas it has been leveling off in women. The mortality has been leveling off in men, but has been decreasing in women. Fig. 1 Algorithm for treatment of esophageal carcinoma Currently, among patients with esophageal carcinoma, the percentage of males is higher, and the percentage of patients in their 60s to 70s is high. The carcinoma is most frequently located in the middle thoracic esophagus. Squamous cell carcinoma is the predominant histologic type. Esophageal carcinoma is frequently associated with synchronous or metachronous multiple carcinoma. The cited risk factors include smoking and alcohol drinking in the case of squamous cell carcinoma. In regard to the risk factors for adenocarcinoma, Barrett’s epithelium derived from persistent inflammation of the lower esophagus due to gastroesophageal reflux disease (GERD) has been reported to serve as the background mucosa for esophageal carcinoma in Europe and North America. In Japan, however, the risk associated with this factor remains unclear because of the scarcity of patients. Morbidity and mortality According to statistics issued by the Center for Cancer Control and Information, National Cancer Center based on cancer morbidity data derived from the Population-Based Cancer Registry, the estimated incidence rate in 2004 (crude incidence rate) was 24.4 persons per 100,000 population in men and 4.0 persons per 100,000 population in women. The age-adjusted incidence rate2 has been showing an upward trend in men, whereas there has been no particular pattern of increase or decrease recently in women. According to the vital statistics compiled by the Ministry of Health, Labour and Welfare, there were 11,746 deaths from esophageal carcinoma in 2008 (the crude mortality rate3 9.3 persons per 100,000), which accounted for 3.4 % of all deaths from malignant neoplasms. The crude mortality rate associated with esophageal carcinoma was 16.3 persons per 100,000 population in men, ranking after cancers of the lung, stomach, large intestine, liver, and pancreas. The corresponding rate was 2.7 persons per 100,000 population in women, ranking below the 10th place. The age-adjusted mortality rate4 of esophageal carcinoma has been leveling off in men and decreasing in women. Cancer mortality data from vital statistics and various graphs based on this data are available at the Center for Cancer Control and Information Services, National Cancer Center (http://ganjoho.jp/professional/statistics/index.html). Present status of esophageal carcinoma in Japan With regard to the present status of esophageal carcinoma in Japan, a nationwide survey conducted by the Japan Esophageal Society (2002) revealed that male patients outnumbered female patients, with a male–female ratio of about 6:1. Most patients were in their 60s or 70s, accounting for about 68 % of the patients overall. The carcinomas were predominantly located in the middle thoracic esophagus (51.6 %), followed in frequency by the lower thoracic esophagus (24.2 %), upper thoracic esophagus (13.4 %), abdominal esophagus (4.5 %), and cervical esophagus (4.0 %). Squamous cell carcinoma was the overwhelmingly frequent histologic type, accounting for 92.9 % of all cases, followed in frequency by adenocarcinoma (2.4 %). A family history of malignant tumor was found in 22.7 % of patients. A family history of esophageal carcinoma was present in 17 % of all cases with a family history of malignant tumor, although gastric cancer was the most frequent at 28.9 %. About 20 % of patients with esophageal carcinoma have synchronous or metachronous multiple cancer, which was the most frequently observed gastric cancer, followed by pharyngeal cancer, representing an important issue in the clinical diagnosis and treatment of esophageal carcinoma (see “Diagnosis and treatment of double carcinoma”). Risk factors The risk factors for esophageal carcinoma are alcohol drinking and smoking. Alcohol and smoking are important risk factors for squamous cell carcinoma, serving as risk factors in more than 90 % of all cases of esophageal carcinoma in Japan. It is known that the risk of developing esophageal carcinoma is increased by concomitant use of tobacco and alcohol. In October 2009, a working group of the World Health Organization prescribed that acetaldehyde associated with alcoholic beverages is a Group 1 carcinogen. In addition, in relation to dietary factors, poor nutritional status and vitamin deficiency due to inadequate intake of fruits and vegetables are also reported as risk factors. By contrast, intake of green and yellow vegetables and fruits are reported as preventive factors. Although adenocarcinoma accounts for only a small percentage of patients with esophageal carcinoma, the percentage is increasing in Europe and North America, accounting for about more than half of all the cases of esophageal carcinoma. Barrett’s epithelium caused by persistent inflammation of the lower esophagus due to gastroesophageal reflux disease (GERD) is known to serve as the background mucosa of the disease in Europe and America. GERD, high BMI, which serves as a risk factor for GERD, and smoking are involved in the development of the disease. In Japan, no clear evidence has been established because of the scarcity of cases. Diagnosis of esophageal carcinoma Diagnosis of the stage of carcinoma Summary The clinical stage of esophageal carcinoma is determined by various diagnostic imaging procedures in terms of the depth of tumor invasion, and presence/absence of lymph node metastasis and distant metastasis. Patients should be informed of the therapeutic strategies based on the assessment of the characteristic features of the lesion (grade of malignancy) and their general condition. Therapeutic strategies should be decided after explaining the basis for and process of diagnosis to patients, and obtaining their understanding, will, and consent (Fig. 2). Fig. 2 Algorithm for deciding the therapeutic strategies for esophageal carcinoma Evaluation of the general condition Radical surgery for esophageal carcinoma, particularly surgery accompanied by thoracolaparotomy, is the most invasive among various types of surgery for gastrointestinal carcinomas. Recent advances in surgical techniques, anesthetic procedures, postoperative management, etc., have led it to safer and more radical treatment for esophageal carcinoma. However, the incidences of postoperative complications and surgery-related mortality still remain higher than those for other diseases. It should also be noted that esophageal carcinoma occurs predominantly in people of advanced age, i.e., 65–70 years of age, and that people of this age group are more likely to have various lifestyle-related diseases (hypertension, diabetes mellitus, hyperlipidemia, etc.). Therefore, it is desirable that application of radical surgery be decided with due caution after evaluation of vital organ function. When applying chemotherapy, radiotherapy or chemoradiotherapy, it is desirable that the functions of vital organs meet certain criteria for implementation of the therapy. In this connection, several tests that are required for evaluating the general condition and function of major organs are described below, in addition to rough guides for judging the test results. However, therapy based on the patient’s general condition should follow comprehensive evaluation and it is not easy to establish accurate numerical standards. Performance status (PS) Performance status is a simple and useful index commonly used for comprehensive evaluation of the patient’s general condition (Table 1). Esophageal carcinoma patients with PS scores of 0–2, as described below, are generally considered as suitable candidates for radical surgery, chemotherapy, or radiotherapy. Table 1 Eastern Cooperative Oncology Group (ECOG) activity score PS 0 Fully active and able to carry out all pre-disease activities without restriction PS 1 Restricted in physically strenuous activities, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework and office work PS 2 Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50 % of waking hours PS 3 Capable of only limited self-care, confined to bed or chair more than 50 % of waking hours PS 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair Pulmonary function tests Aging and smoking history are risk factors in patients with carcinoma of the esophagus, and the prevalence of chronic obstructive lung disease is relatively high among these patients. Pulmonary function test results are important indices for deciding the advisability of thoracotomy. Whether or not thoracotomy is indicated should be judged comprehensively, taking into account the results of spirometry (%VC, FEV1.0 %, %RV/TLC), arterial blood gas analysis, chest radiography findings, CT findings, smoking history, and past medical history. Thoracotomy should be considered carefully if the values of %VC is 40 % or less, FEV1.0 % is 50 % or less, FEV1.0 is less than 1.5 L, and %RV/TLC is 56 % or more, respectively, and the arterial oxygen tension is 60 Torr or less. Cardiac function tests In principle, surgery is not indicated in patients with heart failure due to valvular disease or cardiomyopathy, severe arrhythmia, or myocardial infarction within 3 months prior to the onset. A resting or exercise electrocardiography (ECG) is carried out as a rule. If any abnormality is found, the patient should be subjected to Holter ECG monitoring, echocardiography, cardiac catheterization, or exercise stress perfusion imaging. It is desirable to consult with a cardiovascular internist if the patient has cardiac function abnormalities or has been on antiplatelet therapy or anticoagulant therapy before surgery. Hepatic function tests Surgical treatment is basically not indicated for severe hepatitis or fulminant hepatitis. In cases of chronic hepatitis or hepatic cirrhosis, surgical treatment should be considered based on a comprehensive evaluation of blood counts and the results of blood coagulation tests, blood biochemistry tests, ICG stress test (15 min), and hepatitis screening. Excluding special conditions, surgery is basically not performed in patients who have an ICG retention rate of 40 % or more at 15 min due to hepatic dysfunction. If the value is 20–40 %, application of minimally invasive surgery including reduction of operative radicality may be considered with due caution. It has been pointed out that systemic chemotherapy may cause reactivation of hepatitis B virus in HBs antigen-positive patients. Chemotherapy may also cause fulminant hepatitis in patients who have a history of hepatitis B virus infection (negative for HBs antigen and positive for HBc antibody or HBs antibody). Therefore, it is desirable to consult a hepatologist beforehand. Renal function tests Evaluation of renal function includes general urinalysis, serum creatinine, BUN, electrolytes, and creatinine clearance (Ccr). Although it is relatively rare for surgery to be ruled out only because of renal function deterioration, it is desirable to explain to the patient the possible need for dialysis therapy if the serum Cr level is 2.0 mg/dL or more and the Ccr is 30 % or less. Glucose tolerance test Perioperative blood glucose control should be implemented strictly in patients with diabetes or decreased glucose tolerance. Measurement of fasting blood glucose levels, the oral 75 g glucose tolerance test, measurement of HbA1c levels, quantitative urinary glucose measurement, and urinary ketone testing should be performed. Preoperative control is targeted at a fasting blood glucose of <140 mg/dl, daily urinary glucose excretion of ≤10 g, and negative test for urinary ketones. Other considerations Central nervous system function, including the presence/absence of mental disorders, should be evaluated comprehensively. In general, radical surgery is not indicated for patients with carcinoma of the esophagus when there is a concomitant acute-phase cerebrovascular disorder. It is desirable that patients with depression, anxiety, delirium, or dementia be referred for professional evaluation by a psychiatrist. Endoscopic treatment Summary The mainstay of endoscopic treatment is endoscopic resection (ER). Endoscopic resection includes conventional endoscopic mucosal resection (EMR), in which the affected mucosa is held or aspirated and resected with a snare, and endoscopic submucosal dissection (ESD), which refers to en bloc resection of an extensive lesion using an IT knife or a hook knife. Other available endoscopic treatments include photodynamic therapy (PDT),5 argon plasma coagulation therapy,6 and electromagnetic coagulation therapy. Indications for endoscopic resection (Fig. 3) Among lesions that do not exceed the mucosal layer (T1a), those remaining within the mucosal epithelium (EP) or the lamina propria mucosae (LPM) are extremely rarely associated with lymph node metastasis; therefore, endoscopic resection is a sufficiently radical treatment for these lesions. Lesions reaching the muscularis mucosae or slightly infiltrating the submucosa (up to 200 μm, T1b-SM1) are amenable to mucosal resection, but may have a risk of lymph node metastasis. Therefore, these cases represent relative indications. Furthermore, 50 % of lesions invading deeper (more than 200 μm) into the submucosa (T1b-SM2) are associated with metastasis, and even superficial carcinomas should be treated in the same manner as advanced carcinomas (carcinomas exceeding the muscularis propria). Fig. 3 Indications for endoscopic resection Mucosal resection covering 3/4 of the entire circumference is likely to be associated with postoperative cicatricial stenosis. Therefore, sufficient explanation should be given to the patient prior to the operation and preventive measures must be taken. In cases of superficially spreading carcinoma, deep infiltration may occur in several areas, necessitating careful diagnosis of the depth of invasion. Diagnosis of resected tissue specimens There are limitations to all modes of diagnosis of the depth of tumor invasion. It is also difficult to accurately determine the depth of invasion of extensive lesions. Thus, tissue specimens obtained by en bloc resection are necessary. Treatment of lesions not amenable to ER Elevation of the mucosa may pose difficulty in additional ER of lesions remaining marginally after ER or ER after radiotherapy or chemoradiotherapy. These cases and cases with a bleeding tendency are not amenable to ER, and consideration of other treatment options such as photodynamic therapy (PDT) and argon plasma coagulation (APC) is required. Superiority of en bloc resection En bloc resection is desirable for histologic diagnosis of resected specimens. Endoscopic submucosal dissection (ESD) enables en bloc resection of lesions which formerly were subjected to fractional resection. Further development of equipment and spread of improved techniques are anticipated. Complications Various complications, including bleeding, esophageal perforation, and cicatricial stenosis have been reported in association with ER, including ESD. The need for prevention, prophylactic measures, and treatment of these complications should be well recognized. There has been extensive discussion on the need for additional treatment after diagnosis of resected tissue. Indications for endoscopic resection Handling of resected specimens and evaluation of the integrity of treatment The rules for the handling of endoscopically resected specimens and the procedures for histopathological examination to help determine therapeutic strategies are as follows: Only specimens obtained by en bloc resection should be used for histopathological evaluation of the adequacy of resection. The following procedures should be undertaken when handling specimens, in accordance with the Guidelines for Clinical and Pathologic Studies on Carcinoma of the Esophagus, 10th edition. EMR and ESD specimens should be stretched out so that they are approximately the same size as in vivo, and the proximal and distal ends should be identified. Specimens should then be promptly fixed. Iodine staining is recommended before sectioning, to identify the iodine-unstained area. Specimens should be sectioned in a direction that allows accurate assessment of the resection margins. When the specimen has adequate resection margins, it should be sectioned transversely (perpendicular to the long axis) to obtain as much information as possible. When the specimen has small resection margins, it should be sectioned perpendicular to the tangent line at the smallest margin. The entire specimen should be continuously sectioned at 2–3 mm intervals. The cut surface should include the full thickness of the epithelium and the muscularis mucosae (Fig. 4). Fig. 4 Sectioning of specimens obtained by endoscopic resection. The specimen should be cut after the iodine-unstained area is identified by the staining The histopathological diagnosis should be made by examination of all the sections obtained by the above process. The objective of performing histopathological diagnosis of endoscopically resected specimens is to determine whether any additional treatment is necessary. The depth of invasion, presence/absence of lymphovascular invasion, and status of the resection margin should therefore be specified to determine whether the lesion has been completely removed and to assess the likelihood of metastasis. Surgical treatment Summary 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 Summary 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. Resection 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. Larynx-conserving surgery 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 [100], cervical paraesophageal lymph nodes [101], deep cervical lymph nodes [102], peripharyngeal lymph nodes [103], and supraclavicular lymph nodes [104]. The major thoracic lymph nodes are the recurrent laryngeal nerve lymph nodes [106-rec] and upper thoracic paraesophageal lymph nodes [105]. Among these, [101] and [106-rec] lymph nodes belong to group 1, and [102], [104] and [105] 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 Summary 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. Resection 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 [101]. 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 [101] 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 [104] 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) Table 2 Advantages and disadvantages of each route of reconstruction Route Antethoracic Retrosternal Posterior mediastinal Advantages 1. Proximal esophagectomy at a higher level is possible 1. Proximal esophagectomy at a higher level is possible 1. This route is the most original anatomic location 2. The anastomotic technique is simple 2. Reconstruction length is shorter than in the antethoracic route 2. The surgical stress is less 3. Treatment of anastomotic leakage is simple and safe 3. The procedure for treatment of anastomotic leakage, if any, is easier than in the case of intrathoracic anastomosis 3. The frequency of anastomotic leakage is low 4. Treatment of carcinoma occurring in the reconstructed organ is easy 4. Treatment of carcinoma occurring in the reconstructed organ is relatively easy Disadvantages 1. The reconstruction length is long 1. The reconstructed organ may compress the heart 1. Anastomotic leakage may become critical (particularly, in cases of intrathoracic anastomosis) 2. The frequency of anastomotic leakage is high 2. If the sternoclavicular joint part is narrow, pressure necrosis of the reconstructed organ may occur 2. There may be restrictions to proximal esophagectomy 3. The reconstructed organ is likely to be bent 3. Regurgitation occurs frequently 4. There are esthetic issues 4. Perforation or severe ulcers may occur 5. Blockage due to bending is apt to occur 5. Surgery for recurrent carcinoma in the reconstructed organ is difficult 6. Radiotherapy for recurrent disease may be difficult 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 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) Summary 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 [110], cardiac lymph nodes [1] [2], lesser curvature lymph nodes [3], left gastric artery lymph nodes [7], and celiac artery lymph nodes [9] 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 Summary 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. Transhiatal esophagectomy 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 Summary 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. Salvage surgery Summary 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. Definition 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. Indications 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. Neoadjuvant therapy Summary Neoadjuvant therapy (preoperative adjuvant therapy) has been compared with surgery alone or postoperative adjuvant therapy in cases of resectable Stage II or III thoracic esophageal carcinoma. The significance of neoadjuvant therapy for Stage I esophageal carcinoma has yet to be evaluated. Neoadjuvant chemotherapy The randomized controlled trial (JCOG9907 study) that compared neoadjuvant chemotherapy and postoperative chemotherapy with cisplatin + 5-FU in patients with resectable Stage II or III thoracic esophageal carcinoma (2002 UICC classification) revealed a significant improvement in the overall survival time in the patients given neoadjuvant chemotherapy. Based on this finding, neoadjuvant chemotherapy + radical surgery for resectable Stage II or III thoracic esophageal carcinoma was positioned as a standard treatment in Japan. Neoadjuvant chemoradiotherapy The results of a meta-analysis of randomized controlled trials performed in Europe and North America have indicated that neoadjuvant chemoradiotherapy combined with surgery has the potential to improve the long-term survival in patients undergoing surgical resection for esophageal carcinoma as compared to surgery alone. In Japan, this combination therapy is administered to patients with locally advanced carcinoma in some institutions, although, currently, there is no firm basis for its recommendation. An expected advantage of neoadjuvant therapy over postoperative adjuvant therapy is that it is easier to complete the protocol treatment when applied as neoadjuvant therapy. Neoadjuvant therapy is expected to improve the resection rate and long-term follow-up results by reducing the size of the primary lesion and controlling lymph node metastasis and micrometastasis. It is possible that neoadjuvant therapy allows assessment of the patients’ response to chemotherapy and radiotherapy to some extent by allowing histopathologic studies of the resected specimens. However, issues of concern include the following: drug resistance may be induced; local control may be delayed in ineffective cases, resulting in facilitation of metastatic spread of the disease; preoperative radiotherapy may make surgical manipulations more difficult and increase the postoperative risk. The multicenter clinical study JCOG9907 carried out by the Esophageal Oncology Group of the Japan Clinical Oncology Group (JCOG) deserves special mention in the present revision of the guidelines, because its results provided the rationale for neoadjuvant chemotherapy to be established as the standard treatment for patients with no particular impediments to this treatment. Neoadjuvant chemotherapy A number of randomized controlled trials have been conducted in Europe and America addressing the possible beneficial effects of neoadjuvant chemotherapy on the survival rates of patients with esophageal carcinoma. According to the results of a meta-analysis of these randomized controlled trials, the effects of neoadjuvant chemotherapy on the survival of the patients varied according to the set end points. Therefore, the effects of neoadjuvant chemotherapy in resectable cases have not yet been established (T1-3N0, 1M0, UICC Classification, the 2002 edition). The 2007 Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus recommended the implementation of neoadjuvant chemotherapy particularly in patients with positive lymph node metastasis, on the basis of the results of the JCOG9204 study (1992–1997: postoperative adjuvant chemotherapy with cisplatin + 5-FU vs. surgery alone). At the time of revising the guidelines, the timing of adjuvant chemotherapy with cisplatin + 5-FU was examined in the JCOG9907 study (1999–2006), and it was found that neoadjuvant chemotherapy yielded significantly improved overall survival in comparison to postoperative chemotherapy. Therefore, in Japan, neoadjuvant chemotherapy with cisplatin + 5-FU followed by radical surgery is now regarded as the standard treatment for resectable Stage II or III thoracic esophageal carcinoma. Neoadjuvant chemoradiotherapy Neoadjuvant chemoradiotherapy is a treatment strategy premised on planned surgery and is distinguished from rescue treatment for residual or recurrent carcinoma following chemoradiotherapy aimed at radical cure. In recent years, this type of treatment is recognized as a tri-modality therapy involving a combination of chemotherapy, radiotherapy, and surgery rather than as neoadjuvant chemoradiotherapy. In some cases, a radiation dose of 50.4 Gy, which is the standard dose for definitive chemoradiotherapy, is used. In Europe and North America, a number of randomized controlled trials that verified the usefulness of neoadjuvant chemoradiotherapy have been reported since the latter half of the 1980s, because of the limitations of local control by surgery. Although neoadjuvant chemoradiotherapy did not contribute to overall survival in most of these studies, the pCR rate was generally higher in patients given neoadjuvant chemoradiotherapy. In addition, in a study of esophageal adenocarcinoma reported by Walsh et al. and in the CALGB9781 study, the postoperative survival rate was significantly higher in patients given neoadjuvant chemoradiotherapy than in those undergoing surgery alone. In a randomized controlled trial conducted by Bosset et al. in patients with squamous cell carcinoma, neoadjuvant chemoradiotherapy significantly improved the recurrence-free survival period, although there was no prolongation of overall survival. Many other randomized controlled trials have demonstrated prolongation of survival in patients receiving neoadjuvant chemoradiotherapy, although there was no significant influence in the overall survival rate. According to a meta-analysis that addressed surgery preceded by neoadjuvant chemoradiotherapy vs. surgery alone, when the 3-year survival rate was used as an end point, neoadjuvant chemoradiotherapy (20–45 Gy) in patients with resectable carcinoma was associated with a significant increase in operation-related mortality within 90 postoperative days. However, it resulted in a decrease in the local recurrence rate and significant increase of the 3-year survival rate. In meta-analyses carried out so far in Europe and North America, the patient characteristics (histologic type, stage, etc.) and chemoradiotherapy protocols have not been consistent. The radicality of surgery has been suggested to greatly influence the outcome. No randomized controlled trials of neoadjuvant chemoradiotherapy have been carried out to date in Japan, and thus at present there is no satisfactory rationale for recommending this therapy as effective preoperative therapy. Postoperative adjuvant therapy Summary Surgery combined with postoperative adjuvant therapy has been compared to surgery with or without preoperative adjuvant therapy in resectable cases or cases of Stage II or Stage III thoracic esophageal carcinoma judged as candidates for curative resection. However, to date, the value of postoperative adjuvant therapy for patients with Stage I esophageal carcinoma has not yet been studied. Postoperative chemotherapy: A randomized controlled trial (JCOG9204 study) comparing surgery with and without postoperative chemotherapy (cisplatin + 5-FU, 2 courses) carried out in Japan demonstrated that postoperative chemotherapy resulted in a significant increase in the disease-free survival rate as compared to surgery alone, although there was no significant difference in the overall survival rate. Analysis of subgroups from the JCOG9204 study demonstrated that the recurrence-preventive effect of 2 courses of cisplatin + 5-FU therapy administered postoperatively was observed only in patients with positive lymph node metastasis. Therefore, in clinical practice, postoperative adjuvant chemotherapy has been considered only after carefully considering the pathological diagnosis after radical surgery. However, in view of the results of the aforementioned JCOG9907 study, implementation of neoadjuvant chemotherapy has been positioned as a standard treatment after taking into account the general condition of the patient. Postoperative radiotherapy: The results of a randomized controlled trial of pre- and postoperative radiotherapy vs. postoperative radiotherapy alone carried out by the Esophageal Oncology Group of the JCOG showed that the overall survival rate was significantly higher in patients given postoperative radiotherapy alone when the analysis was focused only on eligible patients who received treatment according to the protocol. Based on this finding, preventive postoperative irradiation was formerly in wide use in Japan. However, in overseas randomized controlled trials that compared surgery with and without postoperative irradiation (usual fractionation; 45–60 Gy), postoperative irradiation was associated with a decrease in the local recurrence in the irradiated area, but without a significant increase in the survival rate. Therefore, there is little evidence for recommending postoperative irradiation after curative resection as a standard treatment. At present, the significance of postoperative (chemo-) radiotherapy is unclear. (Chemo-) radiotherapy has been employed in clinical practice and also reported to be effective in cases of non-curative resection or postoperative local recurrence. Although there is insufficient evidence, some local therapy may be necessary for patients who have undergone non-curative resection and who have macroscopic residual tumor without distant metastasis. (Chemo-) radiotherapy seems to be a useful treatment option for such patients. The rationale for implementing postoperative adjuvant therapy is its potential to control local residual tumor after surgical resection, lymph node metastasis outside the dissection area, and distant micrometastasis, and thereby to lead to improvement in long-term outcomes. The advantage of postoperative adjuvant therapy is that it is possible to implement treatment suited to the disease stage as determined at surgery. However, its disadvantages are that the absence of evaluable lesions makes it difficult to determine its efficacy and postoperative adjuvant therapy may be associated with a lower rate of completion of therapy than preoperative adjuvant therapy. The 2007 Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus stated that radical resection followed by postoperative chemotherapy was the most commonly employed treatment strategy in Japan. However, preoperative chemotherapy (neoadjuvant chemotherapy) is now regarded as a standard treatment on the basis of the results of the aforementioned JCOG9907 study (1999–2006: neoadjuvant chemotherapy vs. postoperative chemotherapy). Postoperative chemotherapy In a randomized controlled trial (JCOG8806) in patients with squamous cell carcinoma carried out by the Esophageal Oncology Group of the JCOG (comparison between surgery plus 2 courses of postoperative cisplatin + vindesine and surgery alone), addition of postoperative chemotherapy did not have any beneficial effect on survival and yielded no significant difference in the 5-year survival rate. Subsequently, another randomized controlled trial carried out in patients with esophageal squamous cell carcinoma using a different chemotherapy regimen (JCOG9204: comparison between surgery plus 2 courses of postoperative cisplatin + 5-FU and surgery alone) showed no clear intergroup difference in the overall survival rate. However, the disease-free survival time was significantly longer in patients given postoperative chemotherapy than in those treated by surgery alone. Thus, postoperative chemotherapy appeared to have a recurrence-preventive effect, particularly in patients with lymph node metastasis. By contrast, no such beneficial effect of postoperative adjuvant therapy was noted in patients without lymph node metastasis. A randomized controlled trial carried out in France comparing surgery with and without 6–8 courses of postoperative cisplatin + 5-FU included patients undergoing palliative resection who accounted for about half of all the subjects. There was no significant difference in the median survival time between the two groups, and the researchers concluded that postoperative adjuvant chemotherapy with cisplatin and 5-FU exerted no beneficial effect. A meta-analysis of these randomized controlled trials also showed no beneficial effect of adjuvant chemotherapy on the survival rate. The results of surgery with and even without adjuvant therapy obtained from all previous JCOG clinical studies were much better than the results of surgery plus postoperative adjuvant therapy reported by clinical studies conducted in Europe and North America. This may reflect the differences in the policy and accuracy of lymph node dissection between Japan and Western countries. This should be borne in mind when comparing the results of clinical studies carried out in Japan and those conducted in Europe and North America. Thus, there is not enough evidence to show that adjuvant chemotherapy improves the overall survival rate of patients undergoing curative resection. However, a Japanese randomized controlled study (JCOG9204) demonstrated a significant increase in the disease-free survival rate after adjuvant chemotherapy, showing the recurrence-preventive effect of this therapy, particularly in patients with lymph node metastasis. Considering the fact that the accuracy of lymph node dissection is characteristically high in Japan and placing weight on the evidence obtained from this country, adjuvant chemotherapy (cisplatin + 5-FU, 2 courses) seems to have a role in the prevention of postoperative recurrence in patients with lymph node metastasis in whom curative resection has been achieved without any preoperative therapy. Adjuvant radiotherapy Preoperative irradiation has long been considered a standard treatment in Japan. However, since there is no report definitively documenting that preoperative irradiation improves the survival rate, the Esophageal Oncology Group of the JCOG performed a randomized controlled trial from 1981 to 1984 to compare the outcomes of preoperative (30 Gy/15 fractions) plus postoperative (24 Gy/12 fractions) irradiation with postoperative irradiation alone (50 Gy/25 fractions). Since a number of cases were excluded from the analysis in this study because of non-curative resection or surgical complications, the results may be somewhat unreliable. However, when the analysis was confined to the eligible patients who received treatment as per protocol, the overall survival rate was significantly higher in the group administered postoperative irradiation alone. Based on this finding, prophylactic postoperative irradiation came to be used commonly in Japan. By contrast, 4 overseas randomized controlled trials comparing surgery with and without postoperative irradiation (usual fractionation, 45–60 Gy) demonstrated no significant increase in the survival rate, although the rate of local recurrence in the irradiated areas decreased in the group given postoperative irradiation. A meta-analysis based on these controlled studies also showed no increase in the survival rate in the group treated by postoperative irradiation. Therefore, there is little evidence for recommending postoperative radiotherapy following curative resection as a standard treatment. However, a subset analysis in a large-scale randomized controlled trial performed in China showed that postoperative radiotherapy led to a significant increase in the survival rate in Stage III patients alone. Therefore, postoperative radiotherapy may be of clinical value for selected patients. Chemotherapy Summary Chemotherapy in the treatment of esophageal carcinoma is usually combined with surgery or radiotherapy in the form of preoperative or postoperative adjuvant chemotherapy or chemoradiotherapy. The use of chemotherapy not combined with other modalities is limited to patients with distant metastasis (M1b) or postoperative distant recurrence. Currently, 5-FU + cisplatin is the most commonly used combination regimen for chemotherapy. However, since there is no definitive evidence of prolongation of the survival time, this therapy is regarded as a palliative treatment. Proven effective monotherapy drugs Many chemotherapeutic drugs, such as 5-FU, cisplatin, mitomycin C, bleomycin, vindesine, adriamycin, paclitaxel, docetaxel, vinorelbine, nedaplatin, irinotecan, and gemcitabine are known to be effective in the treatment of esophageal carcinoma (Table 3). However, while 15–44 % of patients have been estimated to respond to monotherapy, cases of complete response (CR) are rare and no monotherapy has been shown to have a survival-prolonging effect. At present, the most commonly used drugs are 5-FU and cisplatin. Basic studies have demonstrated that these two drugs are effective when used as monotherapy, and exert a synergistic effect when combined and a sensitizing effect when combined with radiotherapy. In clinical, many reports were published about good results of these drags combination therapy. These are the reasons for the wide use of these two drugs. At present (as of February 2012), the use of paclitaxel is not yet covered by the national health insurance in Japan, although public knowledge-based application of this drug has been approved. The use of vinorelbine, irinotecan, and gemcitabine for the treatment of esophageal carcinoma is also not covered by the national health insurance in Japan. Table 3 Efficacy of major monochemotherapeutic agents against carcinoma of the esophagus (drugs covered by the national health insurance in Japan) Drug Dose and schedule No. of cases Response rate (%) 5-FU 500 mg/m2/day × 5 days 26 15 Mitomycin C 20 mg/m2 every 4–6 weeks 24 42 Cisplatin 50 mg/m2 every 3 weeks 24 25 Vindesine 3–4.5 mg/m2 every week 23 18 Docetaxel 70 mg/m2 every 3 weeks 48 21 Nedaplatin 100 mg/m2 every 4 weeks 29 52 Paclitaxela 100 mg/m2 every week × 6, 2-week withdrawal 52 44 aThis drug is approved through public knowledge-based application (as of February 2012) Efficacy in combination therapy Although various combination therapies using cisplatin have been employed since this drug was introduced clinically (Table 4), the currently most commonly used combination regimen is 5-FU + cisplatin. In other countries, this combination therapy is usually administered as follows: continuous intravenous infusion of 5-FU at 1,000 mg/m2/day for 4–5 days, plus intravenous cisplatin at 100 mg/m2 on day 1. In contrast, a phase II clinical trial of 5-day continuous intravenous infusion of 5-FU at 700 mg/m2/day plus intravenous cisplatin at 70 mg/m2 on day 1 carried out in Japan showed a response rate of 36 %. A comparison between this combination therapy and best supportive care carried out overseas demonstrated no definite prolongation of survival in the former group. However, this study included many patients in whom this therapy was used mainly as adjuvant chemotherapy. However, it excluded those in whom the metastatic focus in the liver accounted for more than 30 % of the hepatic parenchyma and those who had peritoneal dissemination. Therefore, the effect of this combination therapy on survival remains unclear. Although in recent years, regimens containing paclitaxel, irinotecan, or gemcitabine have been tried overseas, and regimens using nedaplatin or docetaxel have been tried in Japan, no large-scale phase III trials of these regimens have been carried out. Thus, the merits of these regimens over the standard combination of 5-FU + cisplatin have yet to be demonstrated. Currently in Japan, the combination of 5-FU + cisplatin is commonly used as the first-line treatment, followed by docetaxel as a second-line treatment. In any event, the effect of the use of chemotherapy alone, regardless of whether it is combination therapy or monotherapy, is limited, and chemotherapy not combined with other treatment modalities is applied only to patients with unresectable metastatic lesions. Table 4 Efficacies of major combination therapies Drug Histologic type No. of cases Response rate (%) 5-FU + cisplatin Squamous cell carcinoma 39 36 Cisplatin + paclitaxela Squamous cell carcinoma/adenocarcinoma 32 44 Cisplatin + irinotecanb Squamous cell carcinoma/adenocarcinoma 35 57 Cisplatin + gemcitabineb Squamous cell carcinoma/adenocarcinoma 32 45 5-FU + nedaplatin Squamous cell carcinoma 38 40 aThis regimen is approved through public knowledge-based application (as of February 2012) bThis regimen is not approved for insurance coverage (as of February 2012) Cisplatin, a chemotherapeutic drug that is in wide use, is classified as a highly pro-emetic drug. Guidelines for appropriate use of antiemetic drugs recommend the triple-drug combination of a 5-HT3 receptor antagonist, corticosteroid, and aprepitant to prevent emesis while using cisplatin. For other drugs, it is necessary to check the risk of emesis against guidelines for appropriate use of antiemetic drugs and to take appropriate prophylactic measures. Radiotherapy Summary As compared to radiation monotherapy, concurrent chemoradiotherapy significantly increases the survival rate, although radiotherapy administered sequentially after induction chemotherapy does not. Concurrent chemoradiotherapy is indicated for patients with T1-4N0-3M0 carcinoma (UICC-TNM classification, 2009 edition) in good general condition and for those with locally advanced carcinoma up to metastasis to the supraclavicular lymph nodes (M1). However, the risk of serious complications such as fistula formation is high in cases of unresectable locally advanced carcinoma (T4). Because prolongation of the duration of irradiation decreases the local control rate of radiation monotherapy, it is important to complete irradiation using a definitive dose (66–68.4 Gy) within 7 weeks. In definitive concurrent chemoradiotherapy, the use of at least 50 Gy/25 fractions/5 weeks with a conventional fractionation protocol is necessary. The standard radiation dose for concurrent chemoradiotherapy in the USA is 50.4 Gy/28 fractions. In contrast, in Japan, the standard radiation dose is 60 Gy/30 fractions/6–8 weeks for concurrent chemoradiotherapy, and its safety has already been demonstrated. A randomized controlled trial carried out in Japan revealed that concomitant use of external beam radiation and intracavitary radiation is effective for patients with T1–2 esophageal carcinoma, a relatively early stage of the disease. However, recently chemoradiotherapy is used commonly, and the available evidence is not sufficient to recommend the addition of intracavitary radiation to chemoradiotherapy. Previously, radiotherapy was primarily used for patients who were not suitable candidates for surgery or endoscopic mucosal resection (EMR). However, in recent years, radiotherapy (in particular, chemoradiotherapy) has been widely used for both superficial carcinoma and locally advanced carcinoma, as definitive treatment. The standard radiotherapy used for esophageal carcinoma is in accordance with the Radiotherapy Planning Guidelines 2008 (ed. by Japanese College of Radiology, The Japanese Society for Therapeutic Radiology and Oncology, and Japan Radiological Society). The key points are described below. Definitive radiotherapy Indications A definitive radiotherapy protocol is used when control of all gross lesions leading to cure is expected. Definitive irradiation is the most suitable for cases with T1-4N0-3M0 carcinoma (UICC-TNM classification, 2009 edition) and cases with locally advanced disease up to metastasis to the supraclavicular nodes (M1). In patients with a favorable general condition allowing combined use of chemotherapy, the standard treatment is chemoradiotherapy rather than radiation monotherapy. Definitive chemoradiotherapy has been used for the treatment of postoperative recurrence in the regional lymph nodes in patients without distant metastasis or postoperative residual tumor, as well as for definitive irradiation in fresh cases. It has been shown to provide favorable therapeutic results. Target volume Gross tumor volume (GTV) GTV includes the esophageal primary foci (GTV primary) and metastatic lymph nodes (GTV nodal) as determined by endoscopy and CT. In cases of esophageal carcinoma, it is difficult to determine the presence of lymph node metastasis on the basis of the sizes of the lymph nodes. However, it has been reported to be relatively safe to treat lymph nodes measuring 5 mm or more in the minor axis as determined by CT or MRI, regarding them as metastatic foci, to decrease the percentage of false-negative cases. 18F-fluorodeoxyglucose (FDG)-PET is useful for staging because it allows the detection of hidden distant metastases. However, the sensitivity and specificity of this technique to detect metastatic lymph nodes are not always high in cases of esophageal carcinoma; therefore, it may not be reasonable to attempt to identify metastatic lymph nodes on the basis of PET findings alone for treatment planning. On the positive side, it has been reported that PET/CT can confirm the extent of the primary focus (GTV primary) better than those based on CT alone, if the threshold of FDG activity is set properly. Clinical target volume 1 (CTV1) CTV1 is defined as the entire circumference of the esophagus including the GTV primary on endoscopy or CT, as well as possible microscopic lesions within 3–4 cm cephalocaudally and regional lymph nodes. A study of resected specimens of esophageal squamous cell carcinoma in 34 patients showed that the mean extent of microscopic invasion from the GTV primary was 10.5 ± 13.5 mm. It has been reported that a CTV margin of 3 cm would cover the aforementioned extent of microscopic progression in 94 % of patients. However, because EP and LPM lesions in cases of T1a carcinoma rarely metastasize to the lymph nodes, irradiation of regional lymph nodes is not required. By contrast, lymph node metastasis is present in 10–50 % of cases of MM or SM superficial carcinomas. Therefore, prophylactic irradiation of the regional lymph nodes is required for these cases, as for cases of advanced esophageal carcinoma. Table 5 lists the standard CTV1 in relation to the site of the primary lesion. Currently, there is not enough evidence and there is no evidence-based consensus on which lymph node regions the CTV should extend to. The irradiation dose to these areas should be 40–46 Gy/20–23 fractions. In regard to chemoradiotherapy for superficial esophageal carcinoma (cT1N0M0), it has been reported that favorable therapeutic results can be obtained by localized irradiation, allowing a 3-cm margin inferiorly and superiorly, and a 1- to 2-cm margin anteriorly, posteriorly, and on both sides of the primary focus (GTV primary). Thus, extensive irradiation of regional lymph nodes may not be necessary for superficial esophageal carcinoma. Table 5 Standard lymph node regions in relation to the site of the primary focus (CTV1) Cervical esophagus (Ce) From the midsdle deep cervical lymph nodes [102-mid] to the lymph nodes at the tracheal bifurcation [107] Upper thoracic esophagus (Ut) From the supraclavicular lymph nodes [104] to the middle thoracic paraesophageal lymph nodes [108] Middle thoracic esophagus (Mt) a. From the supraclavicular lymph nodes [104] to the lower thoracic paraesophageal [110] or perigastric lymph nodesb. From the lymph nodes along the recurrent laryngeal nerve [106-rec] and upper thoracic paraesophageal lymph nodes [105] to the lower thoracic paraesophageal [110] or perigastric lymph nodes Lower thoracic esophagus (Lt) From the lymph nodes along the recurrent laryngeal nerve [106-rec] and upper thoracic paraesophageal lymph nodes [105] to the perigastric lymph nodes Patients of advanced age or with complications Only lymph node regions around the primary focus Locations of regional lymph nodes of the esophagus on CT images are shown in the 10th edition of the Japanese Classification of Esophageal Cancer Perigastric lymph nodes: Cardiac lymph nodes [1,2], lymph nodes along the lesser curvature [3], and lymph nodes along the left gastric artery [7] There is no consistent consensus on CTV1 in cases of primary carcinoma originating in the middle thoracic esophagus (Mt) Clinical target volume 2 (CTV2) CTV2 after irradiation of 40–46 Gy to CTV1 should cover the whole circumference of the esophagus including the GTV primary with addition of a margin of about 2 cm in the cephalocaudal direction and 0–0.5 cm in the lateral direction, and the area of metastatic lymph nodes (GTV nodal) with an additional margin of about 0–0.5 cm in the lateral direction. Planning target volume 1 (PTV1) The planning target volume at the beginning of radiotherapy (PTV1) should include CTV1 with an adequate margin (0.5–1.0 cm in the lateral direction and 1–2 cm in the cephalocaudal direction), allowing for respiratory movements and errors in reproducing the patient’s fixation. Because respiratory movements are particularly large in the case of lower thoracic esophageal carcinoma, a margin of 0.8 cm in the lateral direction and 1.8 cm in the cephalocaudal direction has been reported to be necessary. Planning target volume 2 (PTV2) The planning target volume for the reduced exposure field at 40–46 Gy (PTV2) should include CTV2 with an adequate margin (0.5–1.0 cm in the lateral direction and 1–2 cm in the cephalocaudal direction). Radiotherapy planning and the irradiation method Three-dimensional treatment planning based on CT images is recommended. This method allows an understanding of the 3-dimensional positional relationship between the target volume and the organs at risk, and is useful for implementing high-accuracy radiotherapy to minimize exposure of the organs at risk. If a lesion cannot be visualized by CT, as in the case of superficial carcinoma, clipping to the upper and lower parts of the lesion under endoscopic guidance is required prior to CT imaging. Organs at risk that require particular attention in treatment planning for esophageal carcinoma include the lung, heart, and spinal cord. The use of 6–10 MV X-rays is recommended for external irradiation. An appropriate point in the PTV is chosen as the dose assessment point. Irradiation should be applied while restricting the cumulative maximum dose to the spinal cord to 44–46 Gy or less by using the fixed multiple field technique or by changing the radiation field mid-course. Intensity-modulated radiotherapy (IMRT) may be used for the treatment of cervical esophageal carcinoma at facilities that have radiation oncologists and medical physicists who are familiar with treatment planning to secure adequate quality control of radiotherapy. Dose fractionation In general, the conventional fractionation method is used. The standard radiation dose for chemoradiotherapy used overseas is about 50 Gy/25–28 fractions/5–6 weeks. In contrast, in Japan, the standard radiation dose is about 60 Gy/30 fractions/6–8 weeks for chemoradiotherapy, and 60–70 Gy/30–35 fractions/6–7 weeks for radiation monotherapy. Chemoradiotherapy is described in detail in chapter XI. The overall treatment time is an important factor in radiotherapy for esophageal squamous cell carcinoma. The local control rate is known to decrease with increase in the overall treatment time of radiotherapy; therefore, in cases of radiation monotherapy, it is important to avoid prolongation of the overall treatment time as much as possible. Intracavitary radiation In Japan, superficial esophageal carcinoma is considered to be a suitable indication for intracavitary irradiation, because this technique of irradiation can deliver sufficient radiation dose to the superficial lesions. A retrospective analysis from a single institution indicated that a radiation boost by intracavitary irradiation for a superficial lesion of the esophagus yielded favorable therapeutic results. However, the report by Nemoto et al., who reviewed multicenter studies carried out in Japan, indicated that there was no difference in the survival rate between external radiation monotherapy and external radiotherapy combined with intracavitary irradiation in patients with superficial carcinoma of the esophagus. While randomized controlled trials focusing on superficial esophageal carcinoma have never been done, randomized controlled trials of intracavitary irradiation for esophageal carcinoma, including advanced cases in Japan, reported that intracavitary irradiation was effective for esophageal carcinomas measuring 5 cm or less in the major axis or those with a depth of invasion corresponding to T1 or T2. However, more recently, chemoradiotherapy has come to be used commonly, and the efficacy and safety of an additional intracavitary radiation boost to chemoradiotherapy are not necessarily clear. For intracavitary irradiation, a balloon applicator measuring 15–20 mm in diameter should be used to avoid uneven distribution of the radiation source. The point of dose assessment should be 5 mm lateral to the applicator surface (5 mm submucosal), and the dose on the mucosal surface should also be reported. Although there is no definite consensus about the optimal dose and fractionation of intracavitary irradiation because they are closely related to the combined external irradiation dose, the general practice is external irradiation at 50–60 Gy followed by intracavitary irradiation at 8–12 Gy/2–4 fractions (3–4 Gy per session). Because an increase in the fractional dose of intracavitary radiation is associated with an increased risk of late complications, such as esophageal ulcers and perforation, 1–2 sessions per week at a dose of 4 Gy or less per session for high-dose-rate irradiation, or at a dose of 6 Gy or less per session for low-dose-rate irradiation is recommended. Complications Major early adverse events include radiation dermatitis, radiation esophagitis, and radiation pneumonia. Radiation esophagitis is almost inevitable; however, the possibility of development of esophagomycosis or reflux esophagitis should also be borne in mind. Radiation pneumonia, which is sometimes a serious issue, requires differentiation from infectious pneumonia and carcinomatous lymphangitis. As late adverse events, esophageal perforation and bleeding occur in some patients treated by radiotherapy. The incidence rate of late adverse events is relatively increased in cases of T4 disease. In cases where high-dose intracavitary irradiation is employed, special caution concerning the occurrence of esophageal ulcers and perforation is necessary. The incidence of these conditions has been reported to be increased in patients given intracavitary irradiation after chemoradiotherapy. Esophageal stenosis may occur in patients with circumferential disease or those subjected to repeated EMR. Because radiation pneumonia may be fatal in patients of advanced age, it is necessary to reduce the exposure dose to the lung in treatment planning. The possibility of thoracic vertebral compression fracture within the radiation field requires particular attention and should be differentiated from bone metastasis. Pericardial effusion and constrictive pericarditis associated with radiation epicarditis and pleural effusion caused by radiation pleuritis have been reported to occur at high frequencies after chemoradiotherapy. Radiation myelitis is a serious and rare late complication. There are case reports of radiation myelitis developing even in cases with an exposure dose to the spinal cord of only 44 Gy, suggesting the need for particular vigilance regarding this complication. In addition, irradiation of the cervical area may cause hypothyroidism a few years post-irradiation. Because hypothyroidism may serve as a risk factor for radiation epicarditis and radiation pleuritis, regular monitoring of the thyroid functions is necessary in long-surviving patients. Radiotherapy for symptomatic relief This type of radiotherapy is aimed at improving the subjective symptoms and QOL and not at obtaining an anticancer effect. Radiotherapy may be used for the primary focus to improve dysphagia in patients with esophageal carcinoma, or for the treatment of distant metastases such as bone metastasis and brain metastasis. Although intracavitary irradiation monotherapy has been suggested to be useful for improving dysphagia, this radiotherapeutic technique is seldom used for the management of dysphagia associated with esophageal carcinoma in Japan. For palliative irradiation, it is important to set the minimum necessary radiation field and total dose to achieve the treatment objective. The treatment should be completed within as short a period of time as possible, considering the general condition of the patient. Chemoradiotherapy Summary Randomized controlled studies have demonstrated that chemoradiotherapy yields a significantly higher survival rate than radiation monotherapy in patients with esophageal carcinoma; therefore, this therapeutic modality is regarded as the standard therapy for patients with esophageal carcinoma when non-surgical treatment is the choice. Patients who can be the target of definitive chemoradiotherapy include T1-3N0-3M0 cases (UICC-TNM classification, 2009 edition), unresectable T4N0-3M0 cases, and cases with locally advanced disease up to metastasis to the supraclavicular nodes (M1). Some reports showed no significant difference in the overall survival and recurrence-free survival between patients with resectable lesions treated by chemoradiotherapy or by surgery alone. However, in Japan, neoadjuvant chemotherapy followed by surgery is considered to be superior to chemoradiotherapy in patients with Stage IB–III disease (UICC-TMN classification, 2009 edition), while the equivalence of chemoradiotherapy and surgery is considered in patients with Stage IA disease (T1N0M0, UICC-TNM classification, 2009 edition). Although the drug doses, radiation doses, and treatment schedules vary among different clinical studies, the most common protocol employed is combined chemotherapy with 5-FU plus cisplatin and concurrent radiotherapy at a total dose of 50-60 Gy. It is necessary to recognize that any of the reported treatment results can be reproducible only when the chemotherapy and radiotherapy defined in the study are adequately applied. Radiation dose in definitive chemoradiotherapy In a randomized controlled trial of radiation monotherapy (64 Gy) and concurrent chemoradiotherapy (5-FU + cisplatin + radiation 50 Gy) for T1-4N0-1M0 esophageal carcinoma (corresponding to UICC-TNM classification, 2002 edition) carried out by the US Radiation Therapy Oncology Group (RTOG), the 5-year survival rate was 0 % for the former and 26 % for the latter; the latter treatment yielded significantly better results (p < 0.0001). Thus, chemoradiotherapy is strongly recommended in non-surgical treatment. In regard of the timing of chemotherapy and radiotherapy, a meta-analysis showed that concurrent chemoradiotherapy is associated with a significantly lower mortality rate (p < 0.0001) than sequential chemoradiotherapy. In addition, a randomized controlled study (RTOG9405/INT0123) carried out succeedingly to RTOG 85-01 that compared chemoradiotherapy using standard-dose (50.4 Gy) and high-dose (64.8 Gy) radiation in patients with T1-4N0-1M0 esophageal carcinoma (corresponding to UICC-TNM classification, 2002 edition) revealed no superiority of high-dose radiation over standard-dose radiation in terms of the median survival time, the 2-year survival rate, and the local control rate, and concluded that the standard radiation dose for chemoradiotherapy using a combination of 5-FU plus cisplatin should be 50.4 Gy (1.8 Gy × 28 times). By contrast, a radiation dose of 60 Gy has been used predominantly in studies carried out in Japan. Although the standard radiation dose has not yet been established in Japan, change to 1.8 Gy/fraction × 28 times (total dose of 50.4 Gy) is now under review at some facilities. For information on the method of irradiation and dose fractionation, see “Radiotherapy”. Chemotherapy used in definitive chemoradiotherapy The standard chemotherapy regimen is 5-FU + cisplatin. In the aforementioned RTOG9405/INT0123 study, a course of 4 days’ continuous intravenous infusion of 5-FU at 1,000 mg/m2/day plus intravenous cisplatin at 75 mg/m2 on day 1 was repeated every 4 weeks up to a total of 4 courses (concurrent radiation was used in the initial 2 courses). In Japan, although use of the 5-FU + cisplatin regimen is variable, a phase II clinical study (JCOG9708) of chemoradiotherapy (5-FU + cisplatin + irradiation of 60 Gy) for cases of Stage I esophageal carcinoma (T1N0M0, UICC-TNM classification, 1997 edition [*corresponding to Stage IA: T1N0M0 in the 2009 edition]) conducted by the JCOG used 2 courses of 4 days’ continuous intravenous drip infusion of 5-FU at 700 mg/m2/day plus intravenous drip infusion of cisplatin at 70 mg/m2 on day 1 repeated every 4 weeks. In the JCOG9708 study, the complete response rate was 87.5 %, the 4-year survival rate was 80.5 %, and the 4-year progression-free survival rate was 68 %, suggesting results equivalent to those of surgery. Currently, a phase III clinical study (JCG0502) comparing chemoradiotherapy with surgery is underway. In another phase II JCOG study (JCOG9906) of chemoradiotherapy (5-FU + cisplatin + irradiation of 60 Gy) performed in cases of resectable Stage II–III esophageal carcinoma, a course of 5 days’ continuous intravenous infusion of 5-FU at 400 mg/m2/day for 2 weeks plus intravenous cisplatin at 40 mg/m2 on days 1 and 8 was repeated every 5 weeks for a total of 4 courses (the initial 2 courses were combined with concurrent irradiation). However, the use of chemotherapy according to the RTOG regimen is now under consideration in Japan. In any case, 2 courses of concurrent chemoradiotherapy are commonly administered. Although the use of additional chemotherapy after chemoradiotherapy is variable; 2 courses of additional chemotherapy are often administered for Stage II–III lesions. Table 6 shows the main schedules used in definitive chemoradiotherapy. Table 6 Main schedules used in definitive chemoradiotherapy Author Target stage Chemotherapy drugs Radiation dose 5-FU Cisplatin Period × No. of courses Single dose × No. of sessions Split RTOG T1-4N0, 1M0 1000 mg/m2/day × 4 days 75 mg/m2 every 4 weeks × 4 1.8 Gy × 28 None JCOG9708 T1N0M0 700 mg/m2/day × 4 days 70 mg/m2 every 4 weeks × 2 2.0 Gy × 30 1 week JCOG9906 T1N1M0 or T2-3N0-1M0 400 mg/m2/day × 10 days 40 mg/m2 × 2 every 4 weeks × 2 2.0 Gy × 30 2 week Ohtsu T4/M1/LYM 400 mg/m2/day × 10 days 40 mg/m2 × 2 every 5 weeks × 2 2.0 Gy × 30 2 weeks Nishimura T4M0 300 mg/m2/day × 14 days 10 mg/m2 every 4 week × 2 2.0 Gy × 30 1 week JCOG0303 T4/M1LYM 700 mg/m2/day × 4 days 70 mg/m2 every 4 weeks × 2 2.0 Gy × 30 1 week KROSG0101 Stage II–IVA 700 mg/m2/day × 5 days 70 mg/m2 every 4 weeks × 2 2.0 Gy × 30 1 week Nakajima Stage II/III 1,000 mg/m2/day × 4 days 75 mg/m2 every 4 weeks × 4 1.8 Gy × 28 None Schedules without radiation split are being adopted in several ongoing clinical trials in Japan Adverse events associated with definitive chemoradiotherapy Adverse events associated with chemoradiotherapy may be attributable to chemotherapy, radiotherapy, or both, and it is difficult to strictly distinguish among these causes. Major early adverse events include nausea, vomiting, myelosuppression, esophagitis, stomatitis, diarrhea, constipation, and radiation pneumonitis. In particular, radiation pneumonitis may be fatal, and it is desirable to identify factors that may predict the development of this condition. In this regard, it has been suggested that dose–volume histogram (DVH) parameters of irradiation may be useful. On the other hand, late adverse events include radiation pericarditis, radiation pleuritis, pleural effusion, and pericardial effusion. Hypothyroidism may occur in patients who have received radiation in the cervical area, which may also be accompanied by pleural effusion or pericardial effusion, necessitating caution. Although rare, the occurrence of thoracic vertebral compression fracture or radiation myelitis has also been reported (see “Radiotherapy”). In regard of the late toxic effects, it is considered that the radiation dose to organs at risk such as the lung and heart should be carefully considered. Use of a 3-dimensional radiation planning technique based on CT images aimed at reducing the toxic effects is now common. Among other possible adverse events during chemoradiotherapy for esophageal carcinoma, special attention should be paid to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) attributable to cisplatin and leukoencephalopathy attributable to 5-FU. Early detection and prompt medication, particularly prompt discontinuation of medication if the patient is on some drug therapy, are necessary. Follow-up after therapy Contrast-enhanced CT and endoscopic examination are generally used for follow-up observation after definitive chemoradiotherapy. Although there is no definitive evidence for the appropriate timing of the response evaluation and follow-up observation, patients are usually examined 3–4 weeks after completion of chemoradiotherapy at the end of each course of additional chemotherapy, and subsequently every 3 months during the first year, and every 4–6 months thereafter. Residual carcinoma or recurrence after chemoradiotherapy is found most frequently in the primary tumor in the esophagus and in the lymph nodes, usually within 1–2 years after the start of therapy. Therefore, if salvage therapy is considered, evaluation of the primary site is important. The initial endoscopic evaluation of the primary site within 75–90 days after the start of chemoradiotherapy, followed by a second evaluation within 1 month of the initial evaluation, is considered to be most effective in determining the presence/absence of exacerbation and judging whether a CR has been achieved. Because patients with esophageal carcinoma are known to show a relatively high likelihood of developing multiple carcinomas, with carcinomas developing de novo in other parts of the esophagus or in other organs (head and neck region, stomach, large intestine), careful follow-up observation and appropriate diagnostic measures are required. Salvage therapy for local remnant or recurrent lesions after definitive chemoradiotherapy Salvage therapy using endoscopy or surgery has recently been tried for the treatment of local remnant or recurrent lesions after definitive chemoradiotherapy (see “Salvage surgery”). As for salvage endoscopic treatment, endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and photodynamic therapy (PDT) have been tried, and favorable long-term results with acceptable safety have been reported. However, the indications for these treatments and selection of the appropriate treatment method have not yet been adequately evaluated. Salvage surgery (see “Salvage surgery”) provides cure in some cases; however, the incidence of operation-related adverse events and operation-related mortality is high, and the optimal surgical technique and extent of lymph node dissection have not yet been established. Therefore, salvage surgery is not employed in general practice. It has been reported that long-term survival may be achieved after salvage surgery when the depth of invasion of the residual or recurrent lesion is shallow, or when there is no residual or recurrent lymph node metastasis. To facilitate early detection of remnant or recurrence of the primary focus after definitive chemoradiotherapy, strict follow-up by endoscopy is necessary, bearing in mind the observations that the greater the T factor of the pretreatment staging, the more likely recurrence is, and that recurrence often occurs in the form of submucosal tumor-like elevation. Diagnosis and treatment of Barrett’s esophagus and Barrett’s carcinoma Summary Esophagus showing Barrett’s mucosa is called Barrett’s esophagus. Barrett’s mucosa refers to the columnar epithelial metaplasia that extends from the stomach to the esophagus in a continuous fashion and can be confirmed by endoscopy. Histological confirmation of specific columnar epithelial metaplasia is not required. Histologically, Barrett’s mucosa exhibits one of the following features: (1) proper esophageal glands or ducts beneath the overlying columnar epithelium; (2) squamous epithelial islets in the columnar epithelium; (3) double structure of the lamina muscularis mucosae. Barrett’s carcinoma is defined as adenocarcinoma occurring in Barrett’s mucosa. The definitions of early, superficial, and advanced carcinomas are the same as those of esophageal carcinoma, regarding the deep-seated lamina muscularis mucosae as the original lamina muscularis mucosae. Treatment of Barrett’s carcinoma is planned in accordance with the treatment of squamous cell carcinoma of the esophagus at the same location in the esophagus. Endoscopic resection is indicated for lesions confined to the lamina propria mucosae (EP, SMM, and LPM). Relative indications are currently under consideration. Diagnosis and treatment of double carcinoma (head and neck, stomach) Summary Patients with esophageal carcinoma frequently develop carcinoma of other organs, particularly of the upper aerodigestive tract, including head and neck carcinoma, gastric carcinoma, and lung carcinoma. Preoperative examination and postoperative follow-up must be carried out bearing in mind the possible presence of double/multiple lesions. Therapeutic strategies and problems involved in treatment vary widely according to the type, stage, and time of onset of the other lesions. It is important to select the surgical technique and the treatment method in a well-balanced manner, taking into consideration the general condition of the patient, and the prognosis of the esophageal lesions and second primary lesions. Double carcinoma is defined as the co-existence of two primary carcinomas in different organs. Patients with esophageal lesion are reported to show a higher incidence of double carcinoma as compared to the incidence of malignancy in the general population. This higher incidence of double carcinoma in esophageal carcinoma patients may be explained by the sharing of risk factors of carcinomas of the upper aerodigestive tract. We would also like to emphasize the concept of field cancerization here. The incidences and types of double carcinoma vary according to the year of survey, the duration of observation, and the specialization level of the facilities. According to the national registry of the Japan Esophageal Society, about 20 % of patients with esophageal lesion have a second primary lesion, being synchronous in 8 % and metachronous in 12.2 % of the cases. The most frequent type of double carcinoma was gastric lesions, followed by head and neck lesions (pharyngeal carcinoma), colorectal lesions and lung lesions, in descending order of frequency. In addition, according to the 2007 statistics of the Japanese Association for Thoracic Surgery, the incidence of double carcinoma, including second primary carcinomas preceding esophageal carcinoma but excluding the ones following esophageal carcinoma, was 12.9 %, with the proportion of synchronous double lesions at 7.45 %. The type of double lesions was most frequently gastric lesions, followed by head and neck lesions. From the viewpoint of diagnosis and treatment of esophageal lesions, the presence/absence of a second primary head and neck lesions is an important issue. A number of studies on double carcinoma in the esophagus and the head and neck region have so far been reported. Some reports claim that head and neck carcinomas may be the most frequently occurring second carcinoma in association with esophageal carcinoma. Among patients with esophageal lesions, most studies report a frequency of head and neck lesions of about 10 %, with pharyngeal lesions the most frequent type of head and neck lesions encountered in these cases. Some characteristic features that may help in predicting the presence of head and neck lesions in patients with esophageal lesions include the presence of multiple esophageal lesions and the existence of multiple zones in the esophagus showing negative iodine staining. In recent years, advances in endoscopic techniques, including magnifying endoscopy and image-enhanced endoscopy and increased attention to the head and neck region in patients with esophageal carcinoma, have increased the detection rate of head and neck carcinoma in the early stage by endoscopic examination of the upper gastrointestinal tract. Image-enhanced endoscopy has recently been introduced in the field of otorhinolaryngology, and the usefulness of this technique as compared to conventional white-light endoscopy has been reported. Although esophageal carcinoma and gastric carcinoma share few risk factors, smoking is said to be a common risk factor for both esophageal carcinoma and gastric carcinoma. The high prevalence of atrophy of the gastric mucosa due to Helicobacter pylori infection and the high morbidity rate of gastric carcinoma due to environmental factors in Japan may exert a great influence to incidence of concomitant gastric lesion with esophageal cancer. As a part of double/multiple carcinomas, carcinomas developing in the gastric tube after esophageal reconstruction pose another important problem. When carrying out pretreatment examination of patients with esophageal carcinoma, due caution is necessary, because double carcinomas frequently involve areas that may greatly influence the choice of the particular therapeutic strategies used. Follow-up observation after treatment of esophageal carcinoma The purposes of follow-up observation after treatment of esophageal carcinoma are (1) early detection and early treatment of recurrence and (2) early detection and early treatment of multiple esophageal carcinomas and double carcinomas involving other organs. In addition, follow-up observation is important from the point of view of general management of the patient after treatment and maintaining the patient’s QOL. The methods used for follow-up observation after treatment of esophageal carcinoma depend on the initial treatment employed and the stage of the disease at the time of the initial treatment. The patient follow-up is important for possible recurrence, bearing in mind the fact that early detection and early treatment of recurrence may allow prolongation of life. It is also important to exercise caution for the development of metachronous multiple esophageal carcinoma or metachronous multiple carcinoma of other organs, such as gastric carcinoma or head and neck carcinoma. Formulation of an effective follow-up protocol based on general agreements by many doctors in Japan and verification of its efficacy are required. Follow-up observation after endoscopic resection Because the indications and types of additional treatment after endoscopic resection vary, and a substantial number of patients undergo follow-up observation alone, there is no standard method for follow-up observation. Local recurrence after endoscopic resection is often seen within 1 year after the initial treatment, but may also occur after 2–3 years. Therefore, long-term follow-up is necessary. Esophageal endoscopy with iodine staining is mainly used for the detection of local recurrence. Although some reports propose examinations at 6-month intervals, other reports recommend examinations at 3-month intervals during the first year after resection. Patients who undergo fractional resection or who have multiple zones of negative iodine staining require more detailed endoscopic examination of the esophagus. Lymph node recurrence and organ recurrence may be found after 2–3 years; therefore, periodic long-term observation is necessary. Patients should be followed up at 6- to 12-month intervals by cervical and abdominal ultrasonography, thoracoabdominal contrast CT, and/or EUS. Follow-up methods after endoscopic resection suggested by JCOG0508 study (phase II study on efficacy of combined treatment of endoscopic mucosal resection [EMR] and chemoradiotherapy for clinical Stage I esophageal carcinoma [T1N0M0]) included clinical examination, cervical to abdominal contrast- enhanced CT, and measurement of the serum levels of the tumor marker SCC every 4 months until 3 years after EMR. Follow-up observation after radical surgery Recurrence after radical surgery has been reported to occur in 28–47 % of patients in Japan. A recurrence rate of 50 % or more is not rare in reports from Europe and North America. Among patients with recurrence, the timing of recurrence is within 1 year after surgery in 54–79 % of patients and within 2 years after surgery in 80–98 % of patients. Although rare, recurrence after more than 2 years can also occur, necessitating caution. The mode of recurrence may be lymph node metastasis, local recurrence, organ metastasis, or disseminated recurrence; a combination of these is also encountered frequently. Currently, the actual follow-up protocol employed after radical surgery for esophageal carcinoma is left to the discretion of the treating facility. There are no reports of the benefit of regular follow-up observations or of effective methods of follow-up observation. Examination for recurrence basically consists of head and neck US, thoracoabdominal contrast-enhanced CT, and bone scintigraphy. At many facilities, examination by US or CT is repeated every 3–6 months, often with some variations of the intervals according to the degree of progression and the number of years elapsed after surgery. Follow-up is generally carried out for 5 years, although some facilities continue to follow up their patients for 10 years. During the implementation of diagnostic imaging, many facilities add examination by interview, physical examination, and measurement of tumor markers. Follow-up observation after definitive chemoradiotherapy Although CT and esophageal endoscopy are usually employed for follow-up observation after definitive chemoradiotherapy, there have been no reports providing evidence for establishing the optimal frequency for such examinations or the duration of follow-up. In most cases, these examinations are performed at 3–4 weeks after the end of chemoradiotherapy and after the end of each course of additional chemotherapy. Thereafter, follow-up examinations are generally carried out every 3 months during the first year after therapy, and every 4–6 months from the second year onward after therapy. Residual carcinoma or recurrence after chemoradiotherapy is found frequently in the primary focus in the esophagus or in the regional lymph nodes, and in most cases recurrence occurs within 1–2 years after the start of therapy (see “Chemoradiotherapy”). After definitive chemoradiotherapy for esophageal carcinoma, observation for possible late adverse events related to radiotherapy such as radiation pneumonitis, pleural effusion, and pericardial effusion is necessary, in addition to examinations for recurrence. These aforementioned disorders may cause deterioration of a patient’s QOL, and radiotherapy-related late toxicity may even lead to death (see “Radiotherapy”). Surveillance for metachronous multiple esophageal carcinomas and multiple carcinomas arising from other organs Esophageal carcinoma is relatively frequently accompanied by metachronous multiple esophageal carcinoma. In addition, the occurrence of metachronous carcinomas in other organs, such as gastric carcinoma and cancer of the head and neck region, is not rare. Metachronous carcinoma of other organs has been reported as the predominant cause of postoperative death in pN0 patients. Bearing this in mind, it is necessary to perform endoscopic examination of the upper gastrointestinal tract and to observe the areas from the pharynx to the entire esophagus (remaining esophagus in resected cases) and the stomach regularly and carefully. Surveillance for the development of colorectal carcinoma or other carcinomas is also necessary. Treatment of recurrent esophageal carcinoma Summary The initial treatment for esophageal carcinoma is selected from a wide variety of options, including endoscopic treatment, radical surgery, and definitive chemoradiotherapy. Therefore, treatment of recurrent esophageal carcinoma should be determined according to the modality selected for the initial treatment. In addition, treatment of recurrent carcinoma varies according to the type of recurrence, i.e., lymph node metastasis, local recurrence, distant organ metastasis, or the combination of these. The general condition of the patient at the time of recurrence also exerts influence on the selection of treatment. Recurrence is not rare even in patients in whom the initial treatment has been properly implemented. Large-scale clinical trials to clarify issues related to treatment of recurrence are difficult to conduct. Recurrent carcinoma may be curable depending on the type of recurrence, and aggressive treatment may be desirable. Treatment, however, is often aimed at suppression of tumor aggravation and improvement of the QOL. Treatment of recurrence after endoscopic resection Although local recurrence after endoscopic mucosal resection most often occurs within 1 year after the initial treatment, it may even occur after 2–3 years in some cases. In recent years, the indications for endoscopic resection have been extended from the aspect of clinical research. The indications and types of additional treatment after endoscopic resection are variable, and quite a number of patients are followed up without any additional treatment. Treatment of recurrence after radical surgery Recurrence after radical surgery has been reported to occur in 28–47 % of patients in Japan. Reports of recurrence rates of 50 % or more are not rare from Europe and North America. In relation to the mode of recurrence, lymph node or local recurrence is found in 22–68 % of patients, and distant organ metastasis in 12–51 % of patients; the two types of recurrences have been reported to occur in combination in 7–27 % of patients. Lymph node recurrence usually involves the cervical or superior mediastinal lymph nodes, and distant organ recurrence most frequently involves the lung, followed by the liver, bone and brain, in descending order of frequency. Metastasis to the small intestine or colon has also been reported. The survival rate of patients with recurrence after radical resection of esophageal carcinoma is extremely poor, with the median survival time from the diagnosis of recurrence reported to be 5–10 months. However, long-surviving cases and cases of complete cure do exist; therefore, aggressive treatment is desirable. Treatment of recurrence after radical resection of esophageal carcinoma is selected on the basis of the site, type, and extent of recurrence. Treatment also depends on the general condition of the patient at the time of recurrence, whether the recurrence is within or outside the scope of surgical manipulation, and whether or not the patient has received radiation pre- or postoperatively. Therefore, there is little data on the treatment results from a large number of patients with various clinical conditions. Treatment of recurrence in cases showing CR after definitive chemoradiotherapy It has become more common in recent years to adopt definitive chemoradiotherapy as the initial treatment, not only for cases of unresectable esophageal carcinoma, but also for those with resectable esophageal carcinoma. Although this therapy yields a relatively high rate of CR, recurrences, including local ones, are frequently seen (see “Chemoradiotherapy”). Palliative medicine Summary Although palliative care should be provided in all fields of cancer, a decrease in the patient’s QOL is particularly common in patients with esophageal carcinoma, caused by the difficulty in swallowing, malnutrition, and/or cough due to fistula formation. Consideration of procedures for symptom relief and maintenance and improvement of the QOL is required from the initial stages of treatment. However, selection of such procedures is currently left to the discretion of the treating institution. Close investigation of this issue would be desirable in the future. All health-care providers should acquire the basic knowledge and skills involved in the field of palliative medicine. According to the WHO (2002), palliative care is defined as “an approach that improves the quality of life of patients and their families facing problems associated with life-threatening illness, through the prevention and relief of suffering by early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual.” Palliative care should ideally begin when a patient is diagnosed as having cancer. This type of care is needed by all cancer patients and is provided in daily clinical practice. Palliative care requires a team approach that includes not only the doctors in charge and nurses, but also psycho-oncology specialists, pharmacists, social workers, and physical therapists. It has been pointed out that in particular, the role of a specialist nurse as a team leader is important in the palliative care of patients with esophageal carcinoma. It is not rare, particularly in cases of esophageal carcinoma, that the patient has decreased QOL from the time of diagnosis because of difficulty in swallowing and malnutrition due to esophageal stenosis, cough due to mis-swallowing, or a fistula and chest pain due to the tumor. It is important to provide palliative care and treatment for the purpose of maintaining or improving QOL in parallel with the initial treatment that is aimed at cure of the disease. Important issues in the palliative care of patients with end-stage esophageal carcinoma include difficulty in swallowing due to esophageal stenosis and the resultant malnutrition, the symptoms arising from airway stenosis and fistula formation to the airway, and cachexia and other symptoms due to distant metastasis and hypercalcemia. Among these, relief of symptoms arising from esophageal stenosis, airway stenosis, or fistula formation may be attempted by palliative treatments such as radiotherapy, chemoradiotherapy, esophageal stent insertion, airway stent insertion, and esophageal bypass (see “Radiotherapy” and “Chemoradiotherapy”). Gastrostomy or enterostomy as well as intravenous hyperalimentation may be performed to deal with malnutrition. These palliative treatments are typically employed for patients with esophageal carcinoma. Correct decisions as to the method and timing of implementation of these treatments are critical in the provision of palliative care for patients with end-stage esophageal carcinoma. However, there have been few large-scale studies that have evaluated the efficacy and safety of various treatments and procedures in palliative medicine for patients with esophageal carcinoma. There have been no studies on the possibility of radiotherapy or chemotherapy providing survival advantage over best supportive care. However, it is a fact that in the actual clinical setting, a certain proportion of patients who have undergone these treatments have shown marked improvement in their QOL. Health-care providers should be skilled in palliative treatments and procedures specific to esophageal carcinoma, and the appropriate treatments should be employed proactively after obtaining informed consent from the patients. In addition, health-care providers who are engaged in the treatment of esophageal carcinoma often encounter fatal conditions, such as acute respiratory arrest due to airway obstruction or massive hematemesis due to perforation into the aorta. In many cases, rescue of the patient is difficult once these events occur. It is important to give adequate explanation in advance about the possible occurrence of such events, particularly to the patients’ families. Because the patients and their families have to live with the fear of sudden death or sudden change in clinical condition, provision of psychological support and mental care to both are indispensable. To treat carcinoma-related pain, procedures described in the Clinical Guideline for Pharmacological Management of Cancer Pain issued by the Japanese Society for Palliative Medicine are recommended. Therapeutic efficacy and guidelines in Europe and North America: including the results of prognostic studies based on national registries Summary Unlike the situation in Japan, in Europe and North America, adenocarcinomas originating in the lower esophagus account for a large proportion of esophageal lesions. Therefore, the methods of treatment and their results are not necessarily comparable to those in Japan. A simple comparison of endoscopic treatments in Japan and Western countries is precluded by differences in the criteria for selection of suitable candidates. There are no well-established guidelines. Transhiatal esophagectomy is common, reflecting the increase in the frequency of lower esophageal adenocarcinoma. The extent of lymph node dissection is often restricted to the middle and lower mediastinum. Although there are no large differences from Japan in terms of surgical indications in relation to the disease stage, the surgical results have not been satisfactory in Europe and North America. The reported efficacy of neoadjuvant chemotherapy varies between Europe and North America. US Guidelines restrict neoadjuvant chemotherapy to carcinomas of the lower esophagus and the esophagogastric junction, and recommend neoadjuvant chemoradiotherapy for carcinoma arising in other parts of the esophagus. The England/Wales and Scotland, guidelines recommend 2 courses of neoadjuvant chemotherapy for cases with resectable disease, but do not recommend neoadjuvant chemoradiotherapy. In regard to non-surgical treatment, as chemoradiotherapy has been shown to yield better results than radiation monotherapy; guidelines published in Europe and North America both recommend chemoradiotherapy as do those published in Japan. There are differences in the epidemiology of esophageal carcinoma between Japan and Europe/North America, which make it impractical to simply compare the methods and results of treatment between these regions. In regard to the histologic type, squamous cell carcinoma accounts for more than 90 % of all cases of esophageal carcinoma in Japan, whereas adenocarcinoma accounts for more than 50 %, and squamous cell carcinoma for less than 40 % of cases in Europe and North America. As for the location of the tumor, tumors arising in the middle thoracic esophagus are reported as the most frequent, accounting for more than 50 % of all cases in Japan, whereas lesions arising in the lower thoracic esophagus are reported to account for more than 50 % of the cases in Europe and North America. The past two decades have seen an increase in the frequency of adenocarcinoma in Western countries, and it is reported that Barrett’s esophagus developing from obesity and GERD have been reported as background factors for this increase. Therefore, these factors account for the differences in therapeutic strategies and treatment results between Japan and the US/Europe. Guidelines for the diagnosis and treatment of esophageal carcinoma have also been published in some Western countries. These include 4 comprehensive guidelines, i.e., 2 guidelines from the USA, 1 from the UK, and another from Scotland. In the USA, Physician Data Query (PDQ) from the National Cancer Institute (NCI) and information from the National Comprehensive Cancer Network (NCCN) are available on the Internet, and the information is updated continually, with data added from the latest literature. In particular, the NCCN guidelines provide an algorithm to facilitate selection of the appropriate treatment. The strength of recommendation is categorized according to the level of evidence. In the guidelines published in England/Wales and Scotland, the levels of evidence are specified as in the Japanese guidelines. They provide specific information on the epidemiology and pathogenesis, perioperative management, and postoperative complications as well as on the palliative treatment of esophageal carcinoma. Endoscopic treatment Although there are reviews on endoscopic treatment from Europe and North America, they differ from reports published in Japan in those cases of high-grade dysplasia are included as target lesions, and photodynamic therapy (PDT) is also included as a type of treatment. Therefore, a simple comparison with reports from Japan is not possible. The reported 5-year survival rate after EMR is 87.7 % in Japan, according to the national statistics published in 2002. It is rare in Western countries for esophageal carcinoma to be detected at an early stage; therefore, EMR is not commonly performed. Therefore, guidelines regarding endoscopic treatment are limited. Although the NCCN guidelines recommend EMR for mucosal carcinoma (Tis or T1a), the NCI guidelines recommend surgery for Stage 0 lesions. In the Scottish guidelines, EMR is recommended for carcinomas confined to the mucosal layer. The England/Wales guidelines contain no description of endoscopic resection. Surgery In the USA, transhiatal esophagectomy without thoracotomy is regarded as the standard surgical treatment technique for esophageal carcinoma for the following reasons: the results of resection are poor due to the prevalence of advanced carcinoma; surgical complications are frequent because of the high rate of high risk patients; carcinoma in the lower esophagus is frequent; no difference in the recurrence-free survival has been reported between transhiatal esophagectomy and subtotal esophagectomy via right thoracotomy accompanied by lymph node dissection and complications are less frequent with the former procedure. The extent of lymph node dissection is often restricted to the middle and lower mediastinum, and dissection covering all the three regions (cervical, thoracic, and abdominal) is not generally performed. Table 7 shows the results of randomized controlled trials of surgical treatment of esophageal carcinoma reported in and after 1990, and the 2002 Japanese national registry data. Although there are variations in the stages considered for resection among overseas studies, the reported 5-year survival rate is generally about 25 % or less, being significantly different from the corresponding rate of 44.1 % in all cases treated by resection in Japan. Table 7 Summary of randomized controlled trials of surgical treatment for esophageal carcinoma and national registry data of the Japan Esophageal Society Author Year Targeta Treatment No. of cases Histologic type S/A/O Resected cases Treatment-related deaths 2-year survival (%) 3-year survival (%) 5-year survival (%) MST (month) Bosset 1989–1995 Stage I–III, excluding T3N1 S 139 134/0/5 137 5 (3.6 %) About 42 About 35 About 25 18.6 CR + S 143 139/0/4 138 17 + 1 (12.6 %) About 48 About 35 About 25 18.6 Kelsen 1990–1995 Stage I–III S 234 110/124 217 13 (5.6 %) 35 19 7 16.1 C + S 233 103/120 171 5 + 10 (6.4 %) 31 18 6 14.9 MRCOCWP 1992–1998 Resectable cases S 402 124/268/10 386 40 (10 %) 34 About 25 About 15 13.3 C + S 400 123/265/12 361 36 + 8 (11 %) 43 About 32 About 25 16.8 Bedenne 1993–2000 T3N0-1M0 (Stage II–III) ditto CR cases CR + S 129 115/14 107 12 (9.3 %) 39.9 16.4 CR + C 130 115/15 1 1 (0.8 %) 35.4 14.9 Burmiester 1994–2000 Stage I–III, excluding T4 S 128 50/78/0 110 6 (5.4 %) 39.8 28.1 14.8 19.3 CR + S 128 45/80/3 105 5 (4.7 %) 45.3 32.8 16.4 22.2 Stahl 1994–2001 T3-4N0-1M0 S 86 86/0 51 11 (12.8 %) 39.9 31.3 16.4 CR + S 86 86/0 0 3 (3.5 %) 35.4 24.4 14.9 Japan Esophageal Society 2002 All resected cases S + α 1518 41 (4.5 %)b 62.2 53.6 44.1 About 44 Stage I S + α 361 88.5 82.7 71.2 About 53 Stage IIA S + α 290 66.6 60.7 49.2 About 46 Stage IIB S + α 211 64.9 55.7 42.8 About 20 Stage III S + α 494 44.4 33.7 27.7 S Surgery, C chemotherapy, R radiotherapy, +α regardless of whether or not adjuvant therapy was given, S squamous cell carcinoma, A adenocarcinoma, O other histologic type, MST Median survival time aClinical TNM classification bIn-hospital mortality (including direct surgical death and death from recurrence) According to the NCCN guidelines, surgery is indicated for Stage 0-III or resectable Stage IVA carcinoma of the esophagus. As for cases of cervical esophageal carcinoma, the NCCN guidelines state that definitive chemoradiotherapy should be administered for carcinomas in this region and those located less than 5 cm from the cricopharynx, with no consideration of surgery. Preoperative and postoperative adjuvant therapy Preoperative adjuvant therapy A meta-analysis of several randomized controlled trials performed in Europe and North America to examine the usefulness of neoadjuvant chemotherapy revealed no consistent benefit of neoadjuvant chemotherapy on survival. Thus, the efficacy of neoadjuvant chemotherapy for patients with resectable disease (T1-3N0, 1M0, UICC classification, 2002 edition) remains unclear. In addition, a meta-analysis reported in Australia in 2007 concluded that neoadjuvant chemoradiotherapy may have additional benefit in cases of esophageal adenocarcinoma, but is not effective for patients with squamous cell carcinoma, emphasizing the need to choose adjuvant therapy according to the histologic type of the disease. According to the NCCN guidelines, preoperative therapy is indicated for cases with T1b, N1, T2 to resectable T4, and resectable Stage IVA disease. Neoadjuvant chemotherapy is restricted to cases of adenocarcinoma located in the lower esophagus or the esophagogastric junction. Lesions in other parts of the esophagus are described as indications for neoadjuvant chemoradiotherapy, with the recommended drugs specified by category. The England/Wales and Scotland guidelines do not recommend neoadjuvant chemoradiotherapy, although they state that adjuvant chemotherapy with 2 courses of cisplatin + 5-FU should be considered for cases with resectable disease. Postoperative adjuvant therapy The NCCN guidelines recommend postoperative chemotherapy only for patients who have received neoadjuvant chemotherapy. Chemoradiotherapy is recommended for T2-3N0-1 adenocarcinoma or N1 adenocarcinoma cases with R0 resection. Some R1–2 cases may also be included. The Scottish guidelines do not recommend either postoperative chemotherapy or chemoradiotherapy, based on the results of randomized controlled trials for the former and the lack of data for the latter. The England/Wales guidelines also do not recommend postoperative chemotherapy. Chemoradiotherapy With regard to non-surgical treatment, conventional guidelines recommend the use of chemoradiotherapy, based on reports that chemoradiotherapy yielded better results when concurrent chemoradiotherapy was compared with radiation monotherapy. According to the 2002 national registry of the Japan Esophageal Society, the 5-year survival rate was 15.1 % in patients who received radiation monotherapy, whereas it was 22.9 % in those treated by chemoradiotherapy. The corresponding rates by disease stage were 32.5 vs. 52.0 % for Stage I–IIA cases and 4.2 vs. 14.9 % for Stage IIB-IVB cases, indicating the superiority of chemoradiotherapy over radiation monotherapy. The protocol recommended by the Radiation Therapy Oncology Group that is commonly employed in Europe and North America consists of irradiation using the multiple field technique at a total dose of 50.4 Gy administered in 28 fractions, with the exposure field covering the region within 5 cm above and below the tumor. This regimen is based on the results of a randomized controlled trial that found no difference in the survival period between standard-dose (50.4 Gy) and high-dose (64.8 Gy) chemoradiotherapy, and reached a negative conclusion about the benefit of increasing the total radiation dose. The NCCN guidelines specify that the radiation dose should be 50–50.4 Gy.

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Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Impact Journals LLC

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 21 July 2020

Publication date (Electronic): 21 July 2020

Volume: 11

Issue: 29

Pages: 2834-2846

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¹Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan

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Correspondence to: Noriyuki Hirahara, email : norinorihirahara@ 123456yahoo.co.jp

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Publisher ID: 27670

DOI: 10.18632/oncotarget.27670

PMC ID: 7381097

SO-VID: 49f9a194-5783-474e-9015-15e3a31568a4

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Copyright: Hirahara et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Geriatric nutritional risk index as a prognostic marker of pTNM-stage I and II esophageal squamous cell carcinoma after curative resection

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