Multimodal treatment for resectable esophageal cancer

Surgical resection has been traditionally the mainstay of treatment for localized esophageal cancers. However, survival after surgery alone for advanced esophageal cancer is not satisfactory. In Japan, the development of multimodal therapy for esophageal cancers has centered mainly on systemic chemotherapy plus surgery to control distant metastasis. Based on the results of the recent Japan Clinical Oncology Group (JCOG) 9907 study, preoperative chemotherapy (consisting of 5-FU and cisplatin) followed by surgery has emerged as the standard treatment. In Western countries, where chemoradiotherapy followed by surgery has been mainly explored for patients with resectable esophageal cancers, two large controlled trials that evaluated the effectiveness of preoperative chemotherapy reported conflicting results. However, a recent meta-analysis reported significant survival benefits for preoperative chemotherapy in patients with adenocarcinoma of the esophagus. We need to find new effective preoperative chemotherapeutic regimens, including molecular target agents, with response rates higher than that of the conventional chemotherapy of 5-FU and cisplatin. However, we also must compare the survival benefits of preoperative chemotherapy with preoperative chemoradiotherapy.     

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.     

Preoperative concurrent chemotherapy and radiation therapy followed by surgery for esophageal cancer.

Currently, the most promising strategy to improve the prognosis of advanced esophageal cancer is preoperative chemoradiation (CRT) followed by surgery. The superiority of CRT over radiation therapy alone has been demonstrated by several randomized studies. Many phase II studies of CRT followed by surgery have shown that the pathologic complete response (CR) rate ranges from 17 to 40%, and the median survival time (MST) is 12 to 31.3 months. Five randomized trials have compared preoperative CRT followed by surgery with surgery alone for resectable esophageal cancer, and four of them did not find any significant survival benefit for the combined treatment group. There are several issues in interpreting these findings, such as the quality of the surgery, the accuracy of the preoperative staging, the statistical power and design of the trials. Until comprehensive evaluation can be done, the standard therapy for resectable esophageal cancer should be considered to be surgery alone. The histological response in the resected specimen correlates well with the prognosis. Patients with pathologic CR display significantly better survival than those with microscopic residual cancer cells in the resected specimens. These findings suggest that more potent regimens leading to higher pathologic CR rates should improve the prognosis. Chemotherapy or radiation therapy sensitivity testing needs to be established. If accurate prediction of the response is possible prior to therapy, non-responders can be excluded. Cell cycle-related genes, apoptosis-related genes, and drug metabolizing genes have been investigated in many pilot studies and need to be evaluated by large-scale clinical studies. At present, pathologic CR can not be accurately diagnosed before surgery. Endoscopic biopsy is also unreliable for the diagnosis. In the future, new diagnostic tools such as positron emission tomography scanning, a sensitivity test or molecular markers may enable accurate diagnosis of pathologic CR to guide the choice of treatment strategies for individual patients.     

日本食管癌外科发展简述

食管癌外科起源于20世纪初,但真正意义的经胸入路食管癌切除并消化道重建始于20世纪30年代。几乎同一时期,日本与西方国家同步开始了食管癌的外科探索。亚洲食管癌病理学类型以鳞状细胞癌为主,其肿瘤生物学特点和治疗策略不同于以腺癌为主的欧美患者。历经八十余年的发展,日本食管癌外科治疗从初始尝试、深耕实践到追求卓越,探索出一套较为先进的外科技术和诊疗规范,在国际上独树一帜。日本学者在成立日本食管学会的基础上,制订且不定期更新《日本食管癌诊疗规约》,出版学会专业学术期刊Esophagus。日本临床肿瘤协作组开展了诸多食管癌三期临床研究,为食管鳞状细胞癌的诊治提供了强有力证据。本文针对日本食管癌外科的起源、发展、现状及未来,通过文献查证、资深专家访谈及《食管癌外科治疗热点问题-日本专家问卷调查》收集信息,对日本食管癌外科发展进行简述。     

Release of band cells from the bone marrow is impaired by preoperative chemoradiation in patients with esophageal carcinoma: increased risk of postoperative pneumonia

Purpose To examine the difference in hematological data and postsurgical course after esophagectomy between patients receiving preoperative chemoradiation and patients without preoperative treatment.Methods Twenty-two patients with squamous cell carcinoma of the esophagus who underwent esophagectomy during the past 2 years were retrospectively analyzed in the study. Six patients had preoperative chemoradiation (CRT group) and 16 patients had no preoperative treatment (non-CRT group). The hematological data, postoperative course, and surgical complications were compared between the two groups.Results Patients in the CRT group were given cisplatin and 5-FU (143 and 6,000 mg on average, respectively) plus an average of 35 Gy of radiation. Although the neutrophil count did not show a significant difference between the two groups, the band cell count was lower in the CRT group compared with the non-CRT group on postoperative day 1 (P<0.05). Postoperative pneumonia was detected in three patients (50%) from the CRT group versus none of the non-CRT group.Conclusion Preoperative CRT may be a risk factor for postoperative pneumonia in patients with esophageal carcinoma who undergo esophagectomy. The normal bone marrow response of releasing band cells from the postmitotic marrow pool after surgery could be disturbed by CRT, which might contribute to an increase in later pulmonary complications.     

MDTģʽ�����ٰ��������������ת��

??The mode of MDT gives rise to the concept modification about surgical treatments of pancreatic carcinoma YANG Yin-mo. Department of Surgery??Peking University First Hospital??Beijing 100034??China
Abstract Pancreatic carcinoma has the poorest prognosis in all the digestive cancers??and the management is still challenging. Nowadays the treatment strategy of pancreatic carcinoma has been changed from “surgery first” into the mode of multi-disciplinary team(MDT). Preoperative therapy is recommended for patients with borderline resectable pancreatic carcinoma so as to increase the R0 rates and improve the prognosis. However??there continues to be a blurring about the definitions of borderline resectability??which are all too often institution and operator dependent. Randomized clinical trials are needed to further evaluate the clinical outcome of preoperative therapy. Both the resectable and borderline resectable tumors could be defined as potentially curable pancreatic cancer. The definition change reflects the conversion from the mode of morphology and surgery to biology and oncology.     

New strategies in the treatment of esophageal cancer

Esophageal cancer is uncommon, but its incidence is rapidly increasing in the Western countries because of the high incidence of the cardia esophageal adenocarcinoma. Notwithstanding the encouraging results achieved with surgical procedures, esophageal carcinoma has a poor prognosis with 5-year survival in 10% of cases without differences between both squamous and adenocarcinoma histologies. Almost 50% of esophageal cancer patients have unresectable disease at presentation; in the past years combined modality treatments, using chemotherapy and/or radiotherapy with or without surgery, have been evaluated to reduce the risk of local and/or distant recurrences. Ongoing regimens with new agents (Taxanes, Vinorelbine, Irinotecan), in association or not with platinum compounds, show good antitumor efficacy and tolerability, even in the metastatic disease. Preoperative strategies with radiation only did not give any advantage compared to surgery alone, instead, controversial results were obtained, with a minimal advantage, using chemotherapy. Combined chemotherapy and radiation, in suitable candidates for resection has shown an improvement of complete pathological responses, in both the histologies, but with superior toxicities when compared to chemotherapy or radiation therapy alone. Postoperative adjuvant therapies as radiation, chemotherapy or both, have not led to a marked improvement in overall survival and should be performed only in clinical trials. The use of chemoradiotherapy showed a clear advantage versus radiotherapy alone and in many cases equivalent to regimens plus surgery even if control studies haven't been performed. Clinical trials with novel biologic agents, in combination to chemotherapy or alone, against cell growth arrest, neoagiongenesis and tumor metastasis invasion process are currently under evaluation. In the coming years new markers as antigen Ki-67 determination, p53 mutation or high levels activity of thymidylate synthase and novel staging techniques as PET could be precious to identify the better treatment for each patient.     

Management of esophageal adenocarcinoma

The incidence of esophageal adenocarcinoma is increasing in Western countries with a tendency to exceed that of squamous-cell carcinoma. Prognosis is unfavorable with 5-year survival less than 15%, irrespective of treatment and the stage. At the time of diagnosis, more than two thirds of patients have a non-operable cancer because of extension or associated co-morbidities. Most studies have included different tumoral locations (esophagus and stomach) and different histological types (adenocarcinoma and squamous-cell carcinoma), making it difficult to interpret results. Surgery is currently the standard treatment for small tumors. Surgery should be preceded by neo-adjuvant treatment for patients with locally advanced resectable tumors, either preoperative chemotherapy or preoperative chemoradiation therapy. The therapeutic choice should be decided during multidisciplinary meetings according to patient and tumor characteristics and the expertise of the center. For patients with contraindications to surgery, exclusive chemoradiation therapy is recommended. Herein we reviewed and synthesized the different therapeutic strategies for esophageal adenocarcinoma.     

Current Status of Neoadjuvant Therapy for Adenocarcinoma of the Distal Esophagus

Prospective studies dealing with preoperative therapy in adenocarcinoma of the esophagus alone are rare. The interpretation of the preferential phase II trials and a few phase III trials is complicated, as most studies include adenocarcinoma of the esophagus (i.e., Barretts carcinoma), adenocarcinoma of the esophagogastric junction (including cardia carcinoma and subcardia carcinoma), or squamous cell carcinoma. Preoperative chemotherapy, generally well tolerated, cannot decrease the incidence of local failure beyond the level achieved with surgery alone, but it might delay systemic relapse. Preoperative radiotherapy can enhance local control, but it fails to improve overall survival. Neoadjuvant chemoradiation was demonstrated in only one randomized trail to have a survival benefit, but survival in the surgery-alone group was unusually low. Generally, survival was ameliorated in patients responding to neoadjuvant treatment. However, preoperative chemoradiation was often accompanied by a remarkable increase in postoperative morbidity and mortality. Nonresponding patients have, in this respect, a worse prognosis than responders after resection. The prediction of responding patients to neoadjuvant therapy as well as the early identification of patients who will not respond is of utmost clinical importance. Today, there is no absolute evidence that neoadjuvant treatment for patients with potentially resectable Barretts cancer prolongs survival. In patients with locally advanced, presumably not completely resectable adenocarcinoma of the esophagus, preoperative treatment appears to increase the chance for a curative resection and enhance survival in responding patients. Neoadjuvant treatment of adenocarcinoma of the esophagus, as a consequence, is currently not the standard treatment and should be performed only within controlled clinical trials.     

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。     

Clinical aspects of multimodality therapy for resectable locoregional esophageal cancer.

Radical resection has been considered the only possible way to save the lives of patients with esophageal cancer. Therefore, tremendous efforts have been made in order to improve the surgical results for resectable locoregional esophageal cancer. Various surgical approaches have been developed. Combination therapies such as neoadjuvant, adjuvant chemotherapy, and neoadjuvant chemoradiation have been extensively investigated in numerous randomized clinical trials. Due to insufficient surgical results and high postoperative mortality rates, definitive chemoradiation has been studied as alternative treatment in selected patients, based on the concept that combined-modality therapy allows simultaneous treatment of locoregional disease and systemic micrometastases. Chemoradiation has shown survival rates equivalent to surgery in some non-randomized comparative studies. Presently, concerns appear to be shifting to the question of whether definitive chemoradiation could be an alternative to surgery in the primary treatment of resectable locoregional esophageal cancer. Recently, 2 randomized trials, comparing definitive chemoradiation with chemoradiation and surgery were published. These trials seem to show at first glance that definitive chemoradiation can achieve results comparable to surgery with neoadjuvant chemoradiation. More sophisticated trials should be conducted as treatment modalities used in these trials are far from routine.     

Proposed revision of the esophageal cancer staging system to accommodate pathologic response (pP) following preoperative chemoradiation (CRT)

OBJECTIVE: To determine the impact of pathologic response following preoperative chemoradiation (CRT) on the AJCC esophageal cancer staging system. SUMMARY BACKGROUND DATA: Increasing numbers of locoregionally advanced esophageal cancer patients are treated with preoperative CRT prior to surgical resection. METHODS: Five hundred ninety-three pts from 1985 to 2003 with esophageal cancer who underwent surgery with (n = 239) or without CRT (n = 354) were reviewed. Resected esophageal tumors were assessed for pathologic response by determining extent of residual tumor following CRT (P0, 0% residual; P1, 1%-50% residual; P2, >50% residual). RESULTS: After CRT down-staging, pTNM specific survival was similar, irrespective of treatment group (P = 0.98). The pTNM stage distribution was more favorable in the CRT group (P < 0.001) despite a more advanced initial cTNM stage distribution (P < 0.001). Following CRT, the pathologic response (pP) at the primary tumor as defined by extent of residual tumor predicted overall survival (3 years: P0, 0% residual = 74%; P1, 1%-50% residual = 54%; P2, >50% residual = 24%, P < 0.001) and stage specific survival with greater accuracy than pTNM stage alone. CONCLUSIONS: Our analyses demonstrate that following CRT, pTNM continues to predict survival. The extent of pathologic response following CRT is an independent risk factor for survival (pP) and should be incorporated in the pTNM esophageal cancer staging system to better predict patient outcome in esophageal cancer.     

Correlation between loss of Bcl-XL expression and improved prognosis in advanced esophageal cancer treated by preoperative chemoradiotherapy

We investigated the clinical significance of the apoptosis- related molecule expression of tumor cells in patients with advanced esophageal cancer treated with preoperative chemoradiotherapy (CRT). Preoperative CRT reduced Bcl-X(L) expression in a significant proportion of the group responding to CRT but not in the group resisting CRT, although Bcl-2 expression was reduced in both groups. The mean survival time of the patients with cancers that lost Bcl-X(L) following CRT was significantly longer compared to those with cancers expressing Bcl-X(L). These results suggested that CRT reduced Bcl-X(L) expression, and this decrease closely correlated with the prolonged survival of advanced esophageal cancer patients treated with preoperative CRT.     

Chemoradiation combined with total mesorectal excision for patients with locally advanced rectal cancer

Rectal cancer is characterized by a high rate of local recurrence. Although it is widely believed that local control results in improved patient outcome, its strategy is still controversial. In Japan, total mesorectal excision (TME) or tumor-specific mesorectal excision (TSME) with pelvic sidewall dissection is regarded as the standard procedure, while TME or TSME with preoperative chemoradiotherapy (CRT) is common in Western countries. Most clinical data have indicated that preoperative CRT is not associated with improved long-term survival but with a lower incidence of local recurrence. In addition, CRT is known to enhance the severity of impaired sphincter function. Currently, trials using CRT regimens with newly developed chemotherapy agents are ongoing to elucidate the effect on the control of distant metastasis. According to clinical reports, the prognosis of Japanese patients undergoing surgery alone is as favorable as that in patients undergoing surgery plus CRT in the West, which implies that CRT is not a necessary treatment but a selective option. The precise prediction of tumor response and advances in CRT regimens resulting in better survival may improve the treatment of rectal cancer in the future.     

Squamous cell carcinoma in an esophageal diverticulum below the aortic arch

INTRODUCTIONEsophageal diverticula frequently arise from pharyngoesophageal transition area, tracheal bifurcation and epiphrenic region. Carcinoma arising from esophageal diverticulum is rarely seen. We report a patient with a squamous cell carcinoma arising within an esophageal diverticulum below the aortic arch.PRESENTATION OF CASEA 70-year-old man was diagnosed to have a squamous cell carcinoma of the vocal cord with enlarged lymph nodes in the neck, as well as a squamous cell carcinoma arising within an esophageal diverticulum below the aortic arch. There have been no reported cases of esophageal cancer arising from a diverticulum below the aortic arch. Preoperative radiotherapy for the esophageal cancer and pharyngeal cancer was given, followed by surgery. The excised specimen of the esophageal diverticulum and its external appearance revealed that it lacked muscle fibers, with a type 0-IIa lesion arising from the diverticulum. Microscopic examination showed three lymph nodes at the superior mediastinum were positive for malignancy. Bilateral pleural dissemination was detected 7 months after esophagectomy.DISCUSSIONCancer arising from an esophageal diverticulum is mainly found at an advanced stage because of delayed diagnosis. The absence of muscularis propia may lead to early invasion. Thus, cancers within an esophageal diverticulum are considered to be at a more advanced stage than similar cancers arising elsewhere.CONCLUSIONFor detecting of cancer arising from an esophageal diverticulum, a high index of awareness is important. Delay in diagnosis makes surgical management difficult.     

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.     

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.     

Stomach carcinoma. Optimizing therapy by neoadjuvant or adjuvant therapy?]

Despite the decreasing frequency of gastric cancer in most Western countries prognosis could not be improved by surgery alone in the past. Advanced tumor stage due to late diagnosis is one of the reasons for this observation. Contrary to breast and colorectal cancer, postoperative chemotherapy failed to improve prognosis in gastric cancer. Small number of patients in Western studies, insufficient surgical procedures and the high frequency of locoregional relapse may be attributed for this observation. Intraperitoneal, adjuvant chemotherapy showed a positive impact on survival in Asian studies only, but was also used successfully as a part of a multimodality approach in Western phase II trials. Since neoadjuvant therapy proved to create downstaging of tumor size in some patients with advanced gastric cancer some working groups tried to influence prognosis of potentially resectable tumors by preoperative chemotherapy, surgical resection and postoperative, adjuvant therapy in the recent past. However, the efficacy of this therapeutic approach has to be reconfirmed in a controlled, phase III fashion.     

Endoscopic ultrasonography is useful for monitoring the tumor response of neoadjuvant chemoradiation therapy in esophageal squamous cell carcinoma

BackgroundRecently, neoadjuvant chemoradiation therapy (CRT) has been introduced for treatment of esophageal squamous cell carcinoma (ESCC). This study was performed to investigate the usefulness of endoscopic ultrasonography (EUS) in comparison with EUS findings before and after CRT, and histologic findings.MethodsThere were 33 patients with potentially resectable ESCC who underwent neoadjuvant CRT. Preoperative EUS and histologic findings were compared. EUS criteria were established on the basis of low and high echoic regions. Resected specimens were examined by hematoxylin-eosin, azan, and cytokeratin immunohistochemical staining.ResultsAzan and cytokeratin staining clearly delineated fibrous changes and residual tumor. Low echoic regions corresponded to residual tumor and high echoic spots corresponded to fibrosis. All 12 patients classified as grade 1 on EUS diagnosis had histologic grade 1 tumors. Nineteen of 21 cases that presented with high echo were grade 2 or 3. The prognosis according to EUS diagnosis was similar to the histologic effect.ConclusionsPreoperative EUS findings reflected the histologic effect after neoadjuvant CRT. EUS is a useful tool to assess the effect for CRT and to predict the prognosis in ESCC patients.     

Ösophagektomie als chirurgisches Therapieprinzip beim Plattenepithelkarzinom des Ösophagus

The fatalistic approach towards surgical therapy of esophageal squamous cell cancer has been replaced in recent years by a more differentiated view. This was triggered by the establishment of individualized therapeutic modalities based on tumor stage, tumor location, general patient status, and comorbidity. Despite advances in nonsurgical therapy of squamous cell esophageal cancer, esophagectomy remains the central therapeutic modality. Primary subtotal en-bloc esophagectomy with lymphadenectomy is the only curative option with a high likelihood of success for resectable tumors (uT1-3 categories) located below the level of the tracheal bifurcation and for early more proximal tumors. In patients with locally advanced tumors at or above the level of the tracheal bifurcation, surgical resection can still cure those who respond to neoadjuvant radiochemotherapy. Preoperative "conditioning" of risk patients, surgical safety strategies in risk situations, and standardization of both the operative procedure and the perioperative management have resulted in a marked reduction of the previously substantial postoperative mortality to below 3% in experienced centers. In our own experience of 900 esophagectomies for squamous cell esophageal cancer, the 5-year survival rate rose from about 20% to more than 50% in the last two decades. Esophagectomy thus has become a safe operation and remains the only therapeutic option offering cure for a substantial proportion of patients with squamous cell cancer of the esophagus.