Neoadjuvant chemotherapy followed by surgery as standard treatment for stage II + III thoracic esophageal squamous cell carcinoma in Japan

In Japan, the overall 5-year survival rates after surgery alone for thoracic esophageal squamous cell carcinoma are 88% in patients with stage I and 52% in patients with stage II + III disease. Because of the poor outcome of stage II + III patients, multimodality approaches based on chemotherapy or chemoradiotherapy have been evaluated as adjuvant therapy. Neoadjuvant chemoradiotherapy has mainly been evaluated in the USA, while adjuvant chemotherapy for systemic effects has mainly been evaluated in Japan. In 2003, the results of a randomized study (Japan Clinical Oncology Group [JCOG] 9204) comparing surgery alone with postoperative chemotherapy with cisplatin and fluorouracil were reported, confirming that adjuvant chemotherapy prevents relapse in patients with esophageal cancer after surgery. In 2008, another study (JCOG 9907) comparing postoperative and preoperative chemotherapy was reported, and those results showed that preoperative chemotherapy induced downstaging and R0 reduction and improved overall survival without additional serious adverse events. Preoperative chemotherapy with cisplatin and fluorouracil followed by surgery can be regarded as the standard treatment for stage II + III thoracic esophageal squamous cell carcinoma in Japan.     

Future perspectives on the standardization of surgical treatment for esophageal cancer

The Japanese Society for Esophageal Diseases published guidelines for the treatment of esophageal cancer in December 2002. Radical surgery is indicated for T1N1 and T2,3 disease without M1 metastasis to other organs, which consists of transthoracic esophagectomy through the right chest with mediastinal and abdominal (two-field), and cervical if necessary (three-field) resection, lymphadenectomy, and esophageal reconstruction by pulling up the stomach. The survival benefit of cervical lymphadenectomy remains controversial. A randomized, controlled trial (RCT) comparing two-field and three-field resection is needed to evaluate the efficacy of cervical lymphadenectomy. In the West, especially in the USA, surgeons prefer transhiatal esophagectomy, which is illogical in cancer surgery, rather than transthoracic esophagectomy. A recent Dutch RCT comparing transhiatal and transthoracic esophagectomy reported lower morbidity and a trend toward improved long-term survival in the transhiatal group. Minimally invasive surgery for esophageal cancer is common in clinical practice today. However, there is little evidence showing that less-invasive procedures are superior to radical surgery. Further investigation is needed to determine the efficacy of thoracoscopic esophagectomy and laparoscopic mobilization of the stomach for esophageal replacement. The efficacy of neoadjuvant chemotherapy and chemoradiotherapy also remains controversial. However, the effectiveness of adjuvant chemotherapy after surgery on disease-free survival was confirmed by the Japanese Clinical Oncology Group RCT.     

Surgical treatment for esophageal cancer. Current issues

Esophageal cancer is one of the most difficult malignancies to cure. The prognosis remains unsatisfactory despite significant advances in surgical techniques and perioperative management. The optimal treatment strategy for localized esophageal cancer has not yet been established. Surgical resection remains the mainstay of treatment for esophageal cancer, and curative resection is the most important surgery. Extended esophagectomy with three-field lymphadenectomy provides the highest quality of tumor clearance and prolongation of patient survival. There has been intense effort in developing novel strategies to treat patients with resectable esophageal cancer. Various combined-modality approaches have been attempted to improve treatment outcomes. Definitive chemoradiotherapy has an impact on long-term survival in patients with resectable esophageal cancer. Accordingly, there are three main combined-modality approaches: esophagectomy with adjuvant chemotherapy or chemoradiotherapy; primary definitive chemoradiotherapy with or without salvage esophagectomy, and preoperative chemoradiotherapy followed by planned esophagectomy. Recently, owing to the remarkable advances in optical technology, minimally invasive esophagectomy using endoscopic instruments has been introduced into esophageal cancer surgery. This article reviews recent changes in the treatment of esophageal cancer surgery, and considers the role of esophagectomy.     

Three-field dissection for squamous cell carcinoma in the thoracic esophagus.

An esophageal cancer has frequent metastasis in the cervical and upper mediastinal lymph nodes, in particular along the recurrent nerves. Cervicothoracoabdominal three-field dissection is the most radical and rational lymphadenectomy procedure based on this evidence. During three-field dissection, the nodes along the recurrent nerves from the neck to the mediastinum are more meticulously resected than during any other procedure of radical lymphadenectomy. A consensus has been obtained that complete resection of the recurrent nerve nodes improves the survival rates of patients with cancer in each of the various locations of the thoracic esophagus, and that resection of the supraclavicular and internal jugular nodes improves the survival rates of patients with cancer in the upper thoracic esophagus. There is, however, still some controversies over whether or not resection of the supraclavicular and internal jugular nodes improves the survival rates of patients with cancer in the middle or lower thoracic esophagus. Moreover, there remains many controversies over the indication for three-field dissection regarding metastasis-positivity in the lymph nodes, the numbers of the metastasis-positive nodes, the stage, surgical risks and other aspects. Large randomized prospective studies are needed to accumulate conclusive evidence for the benefits of three-field dissection.     

Esophageal cancer surgery in 2005

Surgery for esophageal cancer remains a cornerstone for early stage disease. The treatment of more advanced locoregional disease is quite controversial. Efforts to improve survival in more advanced stages include using chemoradiotherapy alone without operation, using induction or adjuvant therapy in conjunction with resection, and performing a more radical resection by an en-bloc approach and/or a three-field lymph node dissection. The actual approach to esophagectomy in an individual patient is very controversial and seems to be mostly surgeon and institution dependent. There is a paucity of large, adequately powered randomized clinical trials to guide surgical care of patients with esophageal cancer. Accordingly, the numerous aspects of care of the patient are quite varied with little consensus reached among surgeons. There is increasing evidence that the care of the patient requiring an esophagectomy be performed in an institution and by a surgeon with a relatively high volume.     

Mortality and morbidity rates, postoperative course, quality of life, and prognosis after extended radical lymphadenectomy for esophageal cancer. Comparison of three-field lymphadenectomy with two-field lymphadenectomy.

PURPOSE: The authors evaluated the efficacy of extended radical (three-field) lymphadenectomy for esophageal cancer compared with less radical (two-field) lymphadenectomy. STUDY SUBJECTS AND ANALYTIC METHODS: The mortality and morbidity rates, postoperative courses, and survival rates were compared between 63 patients who underwent three-field lymph node dissection and 65 who underwent two-field lymph node dissection at Kurume University Hospital from 1986 to 1991. Long-term quality of life after surgery was compared between 37 patients who underwent three-field dissection and 35 who underwent two-field dissection from 1980 to 1991. RESULTS: Three-field dissection resulted in better survival for patients with positive lymph node metastasis from a carcinoma in the upper thoracic or midthoracic esophagus compared with two-field dissection. The mortality rates, postoperative courses and quality of life were the same for both procedures. CONCLUSIONS: Three-field dissection is preferred for upper thoracic or midthoracic esophageal cancer because of improved survival, acceptable mortality and morbidity rates, and good postoperative course and quality of life.     

胸段食管鳞癌的多学科综合治疗

食管癌患者就诊时大多已为中晚期,第七版UICC食管癌新分期Ⅲ期以上肿瘤单纯手术切除往往疗效不满意,系统性的多学科治疗至关重要.越来越多的证据表明术前同期放化疗是最为有效的诱导治疗方式,可使肿瘤降期并提高根治性切除率;针对食管鳞癌中常见的多组、多野淋巴结转移患者,术前诱导化疗不失为可行的选择.对于已根治性手术切除的局部进展期肿瘤,术后辅助放疗或有助于弥补手术清扫范围的不足以加强局控;术后辅助化疗的作用亦有待进一步深入研究.胸段食管鳞癌与西方国家常见的食管下段腺癌有本质的不同,需要积累更多的前瞻性临床研究,以形成适合我国食管癌患者的综合治疗模式.     

The history of surgical treatment for esophageal carcinoma in the 20th century in Japan

In the 20th century surgical results in the treatment of esophageal carcinomas significantly improved in Japan. For the reason, I review the trends in esophageal cancer surgery in Western countries and discuss the reasons for the choice of surgical procedures. In Japan, esophageal cancer surgery was initiated with the reports of surgical results presented by Professors Seo and Osawa at the Congress of the Japan Surgical Society held in 1933. Subsequently, the results in esophageal cancer patients undergoing surgical resection were improved with the progress in anesthesia. Subsequent to the establishment of the Japan Society of Esophageal Diseases in 1965, any institutes performed esophagectomy for esophageal carcinomas, and the procedure accounted for less than 2% of all operative deaths in Japan. The main reason for this reduction in the number of surgical deaths was improved perioperative care for major complications (cardiopulmonary failure and anastomotic leakage). In particular, the surgical procedure for curative lymphadenectomy called three-field dissection significantly improved surgical prognosis. In the last 10 years, the relationship between the number of positive lymph nodes and surgical prognosis was demonstrated in advanced esophageal cancers, while endoscopic mucosal resection was also performed for early esophageal cancers as a curative treatment. In the next century, better treatment should be designed for individual patients based on fundamental studies and clinical trials.     

Long-Term Survival After Salvage Resection of Recurrent Esophageal Cancer with Anterior Mediastinal Lymph Node Involvement: Report of a Case

A 55-year-old man underwent subtotal esophagectomy with extended three-field lymph node dissection for squamous cell carcinoma of the middle thoracic esophagus (histological stage pT3N4(3b)M0, pStage IVa). About 9 months later, contrast-enhanced computed tomography showed recurrence in several lymph nodes in the anterior mediastinum and the right side of the neck. We treated the recurrence by dissecting the affected nodes, followed by chemoradiotherapy. At the time of writing, 5 years later, the patient was well, without any further evidence of recurrence. Although the indications for resection of recurrent esophageal cancer are controversial and we cannot generalize about the best treatment for these patients, this case highlights the possibility of using salvage surgical resection to treat recurrent esophageal cancer with anterior mediastinal lymph node involvement in selected patients.     

Treatments for esophageal cancer: a review

Esophageal cancer is the eighth most common form of cancer worldwide. The treatments for esophageal cancer depend on its etiology. For mucosal cancer, endoscopic mucosal resection and endoscopic submucosal dissection are standard, while for locally advanced cancer, esophagectomy remains the mainstay. The three most common techniques for thoracic esophagectomy are the transhiatal approach, the Ivor Lewis esophagectomy (right thoracotomy and laparotomy), and the McKeown technique (right thoracotomy followed by laparotomy and neck incision with cervical anastomosis). Surgery for carcinoma of the cervical esophagus requires an extensive procedure with laryngectomy in many cases. When the tumor is more advanced, neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy is added. The theoretical advantages of adding chemotherapy to the treatment of esophageal cancer are potential tumor down-staging prior to surgery, as well as targeting micrometastases and, thus, decreasing the risk of distant metastasis. Cisplatin- and 5-fluorouracil-based regimes are used worldwide. Chemoradiotherapy is the standard for unresectable esophageal cancer and could also be considered as an option for resectable tumors. For patients who are medically or technically inoperable, concurrent chemoradiotherapy should be the standard of care. Although neoadjuvant chemoradiotherapy followed by surgery or salvage surgery after definitive chemoradiotherapy is a practical treatment; judicious patient selection is crucial. It is important to have a thorough understanding of these therapeutic modalities to assist in this endeavor.     

Sentinel node navigation surgery for esophageal cancer

Although sentinel node (SN) biopsy has been utilized to predict regional lymph node metastasis in patients with melanoma and breast cancer, the validity of the SN hypothesis is still controversial in regard to esophageal cancer. SN mapping for esophageal cancer is relatively complicated compared to that for gastric cancer, and the number of early-stage esophageal cancers is limited. Therefore, only a few studies have demonstrated the feasibility and validity of the SN concept for esophageal cancer. Nevertheless, our preliminary studies showed that SN mapping may be feasible in patients with early-stage esophageal cancer. Transthoracic extended esophagectomy with three-field radical lymph node dissection has been recognized as a curative procedure for thoracic esophageal cancer in Japan. However, uniform application of this highly invasive procedure might increase the morbidity and markedly reduce quality of life (QOL) after surgery. Although further accumulation of evidence based on multicenter clinical trials using standard protocol is required, SN mapping would provide significant information on individualized selective lymphadenectomy, which might reduce the morbidity and retain the patients' QOL.     

Salvage esophagectomy after definitive chemoradiotherapy

Salvage surgery is the sole curative-intent treatment option for patients with esophageal cancer after definitive chemoradiotherapy. The most significant factor associated with long-term survival appears to be RO resection. Patients who undergo salvage esophagectomy have high morbidity and mortality rates. Extended three-field lymphadenectomy should be limited in salvage surgery. Ischemic tracheobronchial lesions are serious complications of salvage esophagectomy. The right posterior bronchial artery should be preserved, and neck dissection should be avoided to preserve the blood supply from the inferior thyroidal artery to the trachea. The anastomotic leak rate is also significantly increased after salvage esophagectomy. Irradiation of the esophagus and stomach may affect the blood supply, which may then contribute to leakage. Gastric conduit necrosis in the posterior mediastinum can cause mortal mediastinitis, necessitating surgical modifications to reduce the impact of leaks into the thoracic cavity. The reconstruction route was changed to the anterior mediastinum with cervical anastomosis. Long-term or late cardiopulmonary toxicity cannot be ignored in patients who undergo salvage esophagectomy. A high morbidity rate is acceptable in view of the potential for long-term survival after salvage esophagectomy. Patients should be carefully selected for salvage esophagectomy after high-dose chemoradiotherapy at referral centers that specialize in esophageal cancer treatment.     

胸段食管癌隆突下淋巴结转移影响因素分析

目的探讨胸管食管癌隆突下淋巴结的转移规律及相关影响因素。方法回顾性分析安阳肿瘤医院2015-06—2018-05间1402例行食管癌根治术患者的病例资料(淋巴结清扫包括隆突下淋巴结)。结果胸段食管癌隆突下转移发生率为8.35%,与患者的性别、年龄、病理类型及手术方式等无关(P>0.05);与肿瘤部位、浸润深度、淋巴结转移程度、分化程度、TNM分期、脉管癌栓、神经侵犯及术前治疗方法等有关(P<0.05)。结论胸段食管癌隆突下淋巴结转移率较高,但食管胸上段癌、cT1期的食管癌患者隆突下淋巴结转移发生率较低,可行选择性清扫;胸中下段食管癌术中仍应作为淋巴结常规清扫部位。术前行放疗或同步放化疗后患者隆突下淋巴结转移发生明显降低,对局部晚期食管癌患者推荐术前放疗或同步放化疗。     

Multimodal Treatment for Lymph Node Recurrence of Esophageal Carcinoma After Curative Resection

Background  Although esophagectomy with extended lymph node dissection can improve survival of patients with esophageal carcinoma, lymph node metastasis has remained one of the main recurrence patterns. The aim of this study was to evaluate the outcome of intensive treatment for recurrent lymph node metastasis. Methods  Recurrent lymph node metastasis was detected in 68 patients with thoracic esophageal carcinoma after curative esophagectomy (R0, International Union Against Cancer criteria). Multimodal treatment was performed in 41 patients: 19 patients underwent lymphadenectomy with adjuvant therapy, and 22 received definitive chemoradiotherapy and repeated chemotherapy. The remaining 27 patients (40%) received chemotherapy or best supportive care. Results  Survival of the lymphadenectomy and the chemoradiotherapy groups was significantly better than that of the patients who received chemotherapy or best supportive care (P < .0001). Fifteen patients (79%) underwent curative lymph node dissection (R0) in the lymphadenectomy group. Complete response, partial response, and stable disease were obtained in 8 (37%), 10 (45%), and 4 (18%) patients who received chemoradiotherapy, respectively. There was no statistically significant difference in survival between the lymphadenectomy and the chemoradiotherapy groups. Although the location of lymph node metastasis did not influence survival significantly, seven patients with nodes around the abdominal aorta did not survive longer than 3 years. The most common repeat recurrence pattern was organ metastasis after the treatment. Multivariate analysis showed that the number of metastatic nodes and tumor marker were independent prognostic factors. Conclusion  Multimodal treatment including lymphadenectomy and chemoradiotherapy could improve survival of the patients with lymph node recurrence of esophageal carcinoma after curative resection.     

Radical lymph node dissection for cancer of the thoracic esophagus.

OBJECTIVE: The authors documented the localization and frequency of lymphatic spread in squamous cell carcinoma of the thoracic esophagus and evaluated the influence of radical systematic lymph node dissection on patient survival. SUMMARY BACKGROUND DATA: From accumulated surgical experience, it was suggested that some of the patients with lymph nodal involvement from cancer could be cured by its clearance. However, it is only recently that cancer of the esophagus has been evaluated in terms of analyzing lymphatic spread and results of lymphadenectomy. METHODS: Among 1298 patients admitted to the Toranomon Hospital between 1973 and 1993, 913 (70.3%) had resections, including curative and palliative procedures. For this study, 717 patients with TNM RO (resection with no residual tumor at operation in TNM classification) were analyzed. Survival was compared between groups of patients with less extensive thoracoabdominal (two-field) dissections and extensive collothoracoabdominal (three-field) dissections. RESULTS: Comparative study revealed that 5-year survival rate for TNM RO patients after free-field dissection (55.0%) was significantly better (log rank test, p = 0.0013) than the rate after two-field dissection (38.3%). The results were particularly significant in subgroups with stage III and IV (because of nodal factor). Overall 5-year survival rate after all resections was 42.4%. CONCLUSIONS: The role of radical lymph node dissection in cancer of the thoracic esophagus evaluated. Long-term survival was compared between two groups with two- and three-field dissection. It was concluded that survival rate was significantly better in patients with extensive three-field dissection.     

President’s address of the 65th annual scientific meeting of the Japanese Association for Thoracic Surgery: challenges for advanced esophageal cancer

Advanced esophageal tumors have been a challenge for surgery since the very beginning, and these challenges continue still today. In the early period of three-field lymphadenectomy (late 1980s), there was no special attention paid to tracheal necrosis after such an extended operation. In 1988, we reported functional mediastinal dissection preserving the right bronchial artery to prevent such complications. In 1993, we reported that the survival after three-field lymphadenectomy was better than that after en-bloc esophagectomy, and then the lymph node compartment classification based on the metastatic rate and the survival rate. This concept was introduced into the 9th edition of the Guidelines for Clinical and Pathologic Studies on Carcinoma of the Esophagus published in 1999. In early 1980s, combined resection of the neighboring organs was initiated for a locally advanced esophageal cancer. Almost all patients who underwent such an operation, however, died of metastasis in the short-term after surgery without any additional treatment. In 1987, we reported several types of tracheal repair using the latissimus dorsi muscle flap, as a less-invasive surgery that enabled adjuvant or additive therapy, after resection of the trachea involved by cancer. Then in 2004, we demonstrated that the canine aorta could be resected even immediately after aortic stenting. This suggests that an esophageal cancer involving the aorta can be resected using a new technique. To meet the challenges posed by advanced esophageal cancer, the help of other specialized fields besides esophageal surgery is needed: “The specialist must know everything of something, something of everything.”     

Perioperative therapy for esophageal cancer

Traditionally, surgery is considered the best treatment for esophageal cancer in terms of locoregional control and long-term survival, but survival after surgery alone for locally advanced esophageal cancer is not satisfactory. A multidisciplinary approach that includes surgery, radiotherapy, and chemotherapy, alone or in combination, has been developed to improve the prognosis. Multiple clinical trials have addressed the preferred treatment strategy, such as neoadjuvant or adjuvant and chemotherapy, radiotherapy, or chemoradiotherapy, in managing locally advanced esophageal cancer. In this review, we provide an update on treatment strategies for locally advanced esophageal cancers. Recent studies indicate that neoadjuvant chemoradiotherapy or chemotherapy has a survival benefit over surgery alone in this patient group. Neoadjuvant chemoradiotherapy is an accepted standard of care in the United States while neoadjuvant chemotherapy is regarded as standard treatment in Japan and the United Kingdom. The standard treatment differs among countries because two large randomized controlled trials that evaluated the effectiveness of neoadjuvant chemotherapy reported conflicting results and no trial has made a comparison between neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy directly. Future trials in locally advanced esophageal cancer should focus on identifying the optimum strategy and its regimen and aim to minimize treatment toxicities and effects on quality of life.     

Isolated chylopericardium following radical esophagectomy: Report of a case

Chylopericardium after intrathoracic surgery is a rare clinical occurrence. To our knowledge, the incidence of isolated chylopericardium following esophagectomy has never previously been reported. We herein present a case of isolated chylopericardium following radical esophagectomy involving a right thoracotomy and a partial sternotomy. A 57-year-old man underwent radical esophagectomy with a three-field lymph node dissection for advanced cancer in the upper thoracic esophagus. After postoperative irradiation with adjuvant chemotherapy, chylopericardium developed. Pericardiocentesis was thus performed twice and resulted in a successful outcome.     

Surgical treatment for digestive cancer. Current issues - colon cancer

BACKGROUND: Due to the westernization of the diet in Japan, the incidence of colorectal cancer has increased 4.5 times in the last 25 years. In this review, the recent results of surgical treatment for colonic cancer and the future perspectives in Japan are described. MATERIALS AND METHODS: A multi-institutional registry of large bowel cancer in Japan of 10,809 patients with colonic cancer treated from 1991 to 1994 was investigated. The data have been published in the Guidelines of the Japanese Society for Cancer of the Colon and Rectum (2005). Regarding laparoscopic surgery, 1,495 patients with colon cancer were examined in a multicenter study between April 1993 and August 2002. RESULTS: Radical resection with a curative intent is appropriate for 83-99% of the patients with stage I-III localized colon carcinoma. Adequate lymphadenectomy, including paracolic, intermediate and principal node dissection (D3 lymphadenectomy), is of critical importance for both the accurate staging and local control of the disease. This treatment protocol has now been accepted as a 'standard' operation by Japanese colorectal surgeons. For patients undergoing a curative resection for colon cancer, the 5-year survival rates vary between 62 (stage III) and 91% (stage I). Adjuvant chemotherapy using 5-FU/leucovorin or oral compounds is commonly administered to patients with stage III disease. Laparoscopic surgery for colonic cancer yielded a comparable oncological outcome to that reported for conventional open surgery in the Japanese registry for all disease stages. CONCLUSION: Radical resection with a D3 lymphadenectomy provided satisfactory 5-year survival for patients with stage I-III colon cancer in Japan. However, the survival of patients with stage IV disease is still unsatisfactory (only a 14% 5-year survival). Any further improvements depend on both identifying such patients at an earlier stage as well as developing new and effective treatment modalities.     

腹腔镜根治手术在胃癌中应用的现状与争议

我国胃癌治疗效果仍不容乐观,我中心近年来由于规范的手术质量控制,胃癌尤其进展期Ⅲ期胃癌的治疗效果得到很大提高。全球多中心大样本的临床研究已明确了腹腔镜胃癌根治术治疗早期胃癌的安全性和有效性,中国和日本先后将腹腔镜手术确定为临床I期远端胃癌的推荐术式。腹腔镜根治手术治疗进展期胃癌,手术难度大、学习曲线长。目前,中国、日本和韩国等开展了多项临床研究评价腹腔镜根治手术治疗进展期胃癌的可行性、有效性,有望证实其长期疗效。随着手术技术进步、手术步骤优化、手术操作进一步熟练,腹腔镜根治手术治疗胃癌的适应证将不断扩大。腹腔镜手术可完成常规的淋巴结清扫,有经验的中心甚至可完成扩大清扫及脉络化清扫。进展期胃癌根治手术网膜囊切除存有争议,掌握技术,腹腔镜下网膜囊切除安全、可行,本文总结分享了我中心腹腔镜下胃癌根治网膜囊切除的经验。随着腹腔镜手术技术和设备的发展,以及经验的积累,腹腔镜手术在保证其安全性的前提下,完全可达到与开腹手术相当的根治程度。对于腹腔镜根治手术存在的争议,需开展相应的临床研究,以期进一步阐明腹腔镜根治手术在胃癌治疗中的优劣。