Multimodality treatment of esophageal cancer

Stage specific management of non-small cell lung cancer is widely accepted. The use of pretreatment disease stage to guide therapy for esophageal cancer is an intellectually appealing concept. To date, there isa relative lack of data upon which one may base stage specific treatment decisions for esophageal carcinoma. This is because thorough pretreatment TNM staging is not universally practiced. As a result, stage-specific treatment varies widely. Based upon the available data, surgery alone may be appropriate for resectable, node-negative disease. In the case of clearly un-resectable disease, definitive chemoradiation is indicated.The value of neoadjuvant or adjuvant treatment modalities in the case of clearly resectable node-negative disease (TlN0 or T2N0) is questionable;however, in the presence of lymph node involvement (N1), or in the case of a marginally resectable primary tumor (T3 or T4), neoadjuvant chemoradiation is probably indicated. Although the achievement ofa complete pathologic response following chemoradiation may obviate surgical resection, even microscopic residual cancer can result in local recurrence. To date, there is no reliable method of ascertaining a complete pathologic response before surgical resection. Therefore, when feasible, the addition of surgical resection following chemoradiation is warranted.Future treatment trials for esophageal cancer should include rigorous pretreatment staging protocols to elucidate stage-specific results of therapy.     

胰腺癌新辅助化疗进展

胰腺癌目前仍然是临床非常棘手的问题,但在一些胰腺外科中心通过手术切除改善了胰腺癌的预后.目前已有结果提示新辅助治疗对胰腺癌患者安全,且能够显著提高手术切除率.但新辅助治疗与手术治疗、术后辅助治疗及姑息治疗相比较其疗效如何,到目前为止,尚缺少高质量的循证医学证据,也没有关于胰腺癌新辅助化疗或放化疗与外科手术后系统化疗间比较的随机对照研究.需要设计完善的随机对照研究对比新辅助化疗和手术治疗,以此来评价新辅助化疗在胰腺癌多种治疗方案中的价值.     

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.     

Primary Chemotherapy of Resectable Breast Cancer

Abstract: Primary chemotherapy (the administration of chemotherapy prior to definitive locoregional therapy) of breast cancer has numerous potential advantages and several identified disadvantages. While primary chemotherapy has been used widely in the treatment of locally advanced and inflammatory breast cancers, interest is now turning to its use in resectable breast cancers. Within the last five years, several trials of primary chemotherapy in the treatment of resectable breast cancer, both randomized and non-randomized, have been published. Although preliminary reports suggest that primary chemotherapy may be advantageous, the results from definitive randomized trials are not yet available. Until they are, this approach, although promising, remains in the investigational stages.     

Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Review of Meta-Analyses

Background  

Most randomized controlled trials (RCTs) that have compared neoadjuvant chemoradiation followed by surgery with surgery alone for locally advanced esophageal cancer have shown no difference in survival between the two treatments. Meta-analyses on neoadjuvant chemoradiation in esophageal cancer, however, are discordant.     

Non-invasive monitoring of tissue oxygenation during laparoscopic donor nephrectomy

Background

A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial.

Methods/design

The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm. The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up.

Discussion

This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen.

Trial registration

ISRCTN80832026     

A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer

BACKGROUND: Esophagectomy is a standard treatment for resectable esophageal cancer but relatively few patients are cured. Combining neoadjuvant chemoradiation with surgery may improve survival but treatment morbidity is a concern. We performed a meta-analysis of randomized controlled trials (RCTs) that compared the use of neoadjuvant chemoradiation and surgery with the use of surgery alone for esophageal cancer. METHODS: Medline and manual searches were done to identify all published RCTs that compared neoadjuvant chemoradiation and surgery with surgery alone for esophageal cancer. A random-effects model was used and the odds ratio (OR) was the principal measure of effect. Systematic quantitative review was done for outcomes unique to the neoadjuvant chemoradiation treatment group, such as pathological complete response. RESULTS: Nine RCTs that included 1,116 patients were selected with quality scores ranging from 1 to 3 (5-point Jadad scale). Odds ratio (95% confidence interval [CI]; P value), expressed as chemoradiation and surgery versus surgery alone (treatment versus control; values <1 favor chemoradiation-surgery arm), was 0.79 (0.59, 1.06; P = 0.12) for 1-year survival, 0.77 (0.56, 1.05; P = 0.10) for 2-year survival, 0.66 (0.47, 0.92; P = 0.016) for 3-year survival, 2.50 (1.05, 5.96; P = 0.038) for rate of resection, 0.53 (0.33, 0.84; P = 0.007) for rate of complete resection, 1.72 (0.96, 3.07; P = 0.07) for operative mortality, 1.63 (0.99, 2.68; P = 0.053) for all treatment mortality, 0.38 (0.23, 0.63; P = 0.0002) for local-regional cancer recurrence, 0.88 (0.55, 1.41; P = 0.60) for distant cancer recurrence, and 0.47 (0.16, 1.45; P = 0.19) for all cancer recurrence. A complete pathological response to chemoradiation occurred in 21% of patients. The 3-year survival benefit was most pronounced when chemotherapy and radiotherapy were given concurrently (OR 0.45, 95% CI 0.26 to 0.79, P = 0.005) instead of sequentially (OR 0.82, 95% CI 0.54 to 1.25, P = 0.36). CONCLUSIONS: Compared with surgery alone, neoadjuvant chemoradiation and surgery improved 3-year survival and reduced local-regional cancer recurrence. It was associated with a lower rate of esophageal resection, but a higher rate of complete (R0) resection. There was a nonsignificant trend toward increased treatment mortality with neoadjuvant chemoradiation. Concurrent administration of neoadjuvant chemotherapy and radiotherapy was superior to sequential chemoradiation treatment scheduling.     

Neoadjuvant chemoradiotherapy for advanced esophageal cancer

The limitations of surgical treatment for advanced esophageal cancer have been clarified, although esophagectomy with extended lymph node dissection has been widespread in Japan. Preoperative adjuvant therapy has been investigated in Western countries, and recently preoperative chemoradiotherapy (CRT) has been introduced for the treatment of resectable esophageal cancer. There are several reports of randomized controlled trials (RCTs) comparing CRT followed by surgery and surgery alone. According to the results of a meta-analysis, preoperative CRT is considered to be the standard therapy in Western countries. However, problems in the clinical heterogeneity of meta-analyses include: small number of patients in each RCT; differences in stage grouping; presence of both squamous cell carcinoma and adenocarcinoma; various surgical techniques used; and differences in the amount of radiation administered. Preoperative CRT appears to be a promising method for the treatment of potentially resectable advanced esophageal cancer patients with nodal metastasis. Currently, phase I and II trials of new anticancer agents or molecular targeting agents are ongoing. However, since the surgical procedure in the Western method is still being debated, well-designed RCTs are necessary, especially in esophageal squamous cell carcinoma. The effectiveness of CRT followed by surgery should be clarified based on excellent Japanese surgical techniques.     

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.     

Adjuvant treatment strategies for pancreatic cancer

Pancreatic cancer is a difficult and unsolved surgical problem. It remains one of the top five causes of cancer-related deaths and has the lowest 5-year survival of any cancer, largely due to late diagnosis, low resection rates, and local recurrence. Clinical trials examining the optimal timing and delivery of adjuvant therapies for pancreatic cancer have yielded controversial results. Although most experts agree that the addition of chemotherapy has survival benefit in patients with resectable pancreatic cancer, there is no consensus regarding the optimal therapeutic agents, timing (neoadjuvant versus adjuvant), and the addition of radiation therapy to the treatment regimen. Multiple phase III trials are in progress in efforts to examine these issues. Additionally, exciting progress has been made with novel chemotherapeutic combinations, and alternative treatment modalities including interferon-α, immunotherapy, and pancreatic cancer stem cells. Given the high failure pattern after surgical resection, with more than half of patients developing locoregional recurrence, all patients undergoing pancreaticoduodenectomy are candidates for adjuvant therapy.     

Controversies in the Multimodality Management of Locally Advanced Esophageal Cancer: Evidence-Based Review of Surgery Alone and Combined-Modality Therapy

Most patients with esophageal cancer present with locoregional disease, and the optimal initial management is controversial. The current National Comprehensive Cancer Network (NCCN) practice guidelines support diverse treatment options for locoregional disease, including surgical resection alone, definitive chemoradiation therapy, and preoperative combined-modality (neoadjuvant/trimodality) therapy. Many cancer centers worldwide favor a neoadjuvant approach, although the evidence supporting this practice is inconsistent. A concise review of the literature is presented. The topics discussed do not necessarily reflect each authors opinions or clinical practices.     

Standards of Outcome Reporting in Surgical Oncology: A Case Study in Esophageal Cancer

Background

Multimodal strategies before surgery are often used to improve outcomes, but disease progression (precluding surgical resection) and inoperability at planned surgery still occur following neoadjuvant treatment. The standards of reporting of these outcomes have not previously been considered. This study examined reporting of rates of progression to surgical resection and inoperability at planned surgery following neoadjuvant treatment in surgical oncology, using esophageal cancer as a case study.

Methods

A systematic review identified randomized trials and prospective nonrandomized studies reporting short-term outcomes of neoadjuvant treatment and surgery for esophageal cancer.

Results

Of 4,763 abstracts, 224 papers were retrieved and 76 studies included (8 randomized trials and 68 cohort studies of 19,441 esophagectomies). Articles reported outcomes of preoperative chemotherapy (n?=?33, 43.4?%), chemoradiotherapy (n?=?13, 17.1?%), or both within one paper (n?=?18, 23.7?%) and 12 (15.8?%) did not specify the type of neoadjuvant treatment. Also, 20 papers (26.3?%) reported numbers of patients not progressing to surgery after neoadjuvant treatment (with rates of nonprogression ranging between 2.0 and 35.3?%). In addition, 24 papers (31.6?%) reported rates of inoperability at planned surgery (with inoperability rates ranging between 0 and 26.2?%). More randomized controlled trials (RCTs) than observational studies reported nonprogression (4 randomized and 16 nonrandomized studies, 95?% CI ?9.6 to 62.6?%, p?=?0.108) and inoperability (6 randomized trials and 18 observational studies, 95?% CI 16.8?C80.3?%, p?=?0.005). Some 17 and 10 articles provided reasons for the observed rates of nonprogression and inoperability, respectively.

Conclusions

Reporting rates of progression to surgery after neoadjuvant treatment and inoperability at planned surgery for esophageal cancer were poor, limiting data synthesis and comparisons. It is suggested that core outcome sets for trials in surgical oncology are developed with inclusion of these important endpoints. Collaboration between medical and surgical oncologists is necessary to achieve this.     

Multimodal treatment of esophageal cancer

Background

The treatment of localized esophageal cancer has been debated controversially over the past decades. Neoadjuvant treatment was used empirically, but evidence was limited due to the lack of high-quality confirmatory studies. Meanwhile, data have become much clearer due to recently published well-conducted randomized controlled trials and meta-analyses.

Methods

Neoadjuvant and perioperative platinum fluoropyrimidine-based combination chemotherapy has now an established role in the treatment of stage II and stage III esophageal adenocarcinoma and cancer of the esophago-gastric junction. Neoadjuvant chemoradiation is now the standard of care for treating stage II and stage III esophageal squamous cell cancer and can also be considered for treating esophageal adenocarcinoma.

Results

Patients with esophageal squamous cell cancer treated with definitive chemoradiation achieve comparable long-term survival compared with surgery. Short-term mortality is less with chemoradiation alone, but local tumor control is significantly better with surgery.

Conclusion

This expert review article outlines current data and literature and delineates recommendable treatment guidelines for localized esophageal cancer.     

Surgical staging of esophageal cancer

The rising incidence of adenocarcinoma of the esophagus and the poor overall 5-year survival using current treatment regimens make it essential that clinical trials continue to search for more effective regimens for specific stages of esophageal cancer. It is clear from work in non-small cell lung cancer that clinical efficacy for platinum-based chemotherapeutic regimens has shown promise only in specific subsets of patients, such as those with stage IIIa tumors, but no benefit at all for earlier stages. In lung cancer, mediastinoscopy has been shown to be the most accurate method to stage locoregional lymph nodes and is considered to be the gold standard for clinical trials. In esophageal cancer, accurate surgical staging of all locoregional lymph nodes is more complex and may involve abdominal, thoracic, and cervical areas. Molecular evidence of lymph node involvement in esophageal cancer suggests that even histologically negative nodes may harbor micrometastases in a significant number of cases. Laparoscopy and thoracoscopy now offer a more accurate alternative to conventional staging of esophageal cancer. For distal esophageal cancers near the gastroesophageal junction, laparoscopic staging alone may suffice in most cases. Associated costs and the requirement for a surgical procedure should encourage the continued evaluation of new noninvasive modalities and the further evolution of endoscopic ultrasound. Currently, we recommend the application of minimally invasive surgical staging to assess new noninvasive technologies, such as PET scanning, and for use in clinical trials until the definitive approach to staging esophageal cancer is established. We are currently participating in an ongoing multicenter study of thoracoscopic and laparoscopic staging for esophageal cancer.     

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.     

Diagnosis and assessment of resectability for neoplasms of the pancreas and periampullary region

CT remains the initial study of choice for determining whether a patient has potentially resectable, locally advanced, or metastatic pancreatic cancer; such clinical staging is critical for accurate treatment planning. EUS has become the preferred method of tissue acquisition through the use of EUS-guided FNA biopsy. ERCP remains an important diagnostic tool, and endobiliary stenting is the preferred initial therapy for biliary obstruction. The extent to which laparoscopy should be used remains controversial. Laparoscopy is reasonable to consider before laparotomy (during the same anesthesia induction) in patients with biopsy-proven or suspected potentially resectable pancreatic cancer in whom a decision has been made to proceed with pancreatoduodenectomy.Pancreatoduodenectomy should be considered only in those patients whose tumors appear to be resectable based on high-quality CT and who have a good performance status. Furthermore, pancreatoduodenectomy should be part of a multimodality treatment program that includes preoperative or postoperative chemoradiation. Because of the modest survival rates associated with current treatments, the enrollment of all patients into clinical trials of new combinations of surgery, chemoradiation, and newly developed systemic drugs is strongly encouraged. Future progress in the treatment of pancreatic cancer will involve techniques for early diagnosis and effective systemic therapy. For now, the best results can be achieved by careful attention to patient selection, preoperative assessment of resectability, surgical technique, and postoperative care.     

直肠癌新辅助治疗后手术并发症

术前同步放化疗（新辅助治疗）已经成为局部进展期直肠癌综合治疗的标准模式。从临床应用以来，它对外科手术并发症（伤口愈合、吻合口漏等）的影响一直就受到关注。许多随机临床试验的结果认为，新辅助治疗并不显著增加术后伤口愈合、吻合口漏方面的风险，但仍不时有些回顾性研究得出相反的结果。虽然保肛手术后的括约肌功能与外科手术之间存在必然联系，但是不同形式的术前放疗也可能对其产生影响。当我们决定患者是否接受新辅助治疗时，不但要考虑肿瘤的TNM分期，也应该考虑放疗方式、与手术的间隔时间、化疗周期数等。     

围手术期胃癌放疗的相关问题

放疗作为胃癌综合治疗的组成部分,在近年来得到较多的关注和重视。可切除胃癌的术后辅助放化疔已在INT0116研究中得到证实．而且在实际治疗人群证实了术后辅助放化疗的获益。近期的ARTIST研究．在D,术后辅助放化疗的优势仅显示在淋巴结阳性患者中．而且另外两项ACT—GC和CLASSIC研究．报道的极低局部复发率．与实际临床的差异．使得这些研究结果在实际临床治疗的应用需要慎重。早期单纯放疗的新辅助治疗．在贲门癌中显示了疗效．随后的Ⅱ期新辅助放化疗研究均显示了较高的病理完全缓解率．但同期联合的化疗毒性较高．值得在降低不良反应同时,探索新辅助放化疗的作用。放疗新技术的应用对胃癌放疗提高肿瘤控制和减轻不良反应有重要价值。确立合适治疗人群、放疗敏感性筛选、联合化疗药物和靶向药物在胃癌放疗中的应用．是胃癌放疗的发展方向。     

Complementary use of local excision and transanal endoscopic microsurgery for rectal cancer after neoadjuvant chemoradiation

Background Neoadjuvant therapies have significantly improved local control and survival of patients with rectal cancer. Nevertheless, although a complete pathologic response can be achieved in 30% of cases, a transabdominal surgical resection is always required. This study aimed, for the first time, to test in the literature the feasibility of local excision combined with transanal endoscopic microsurgery (TEM) as a surgical option for patients treated with neoadjuvant chemoradiation. Methods Between July 1997 and December 2002, 30 patients with rectal cancer affected by an extraperitoneal tumor entered a protocol consisting of neoadjuvant chemoradiation followed by surgery. The surgical treatment, consisting of open surgery, local excision, or TEM, was planned according to the patient’s clinical response after chemoradiation and distance from the anal verge. Results A significant clinical downstaging was observed in eight patients. Five of these patients underwent TEM, and three had local excision. Consequently, open surgery was performed for 22 patients. Histology showed six cases of complete pathologic response: three in the open surgery group and three in the transanal excision group. After a mean follow-up period of 47 months, the disease-free survival rate was 77% in the open surgery group and 100% in TEM or local excision group. Conclusions The findings suggest the complementary feasibility of TEM and local excision after neoadjuvant chemoradiation. However, randomized trials are needed to confirm the oncologic safety of this approach.     

Adjuvant Therapy for Pancreatic Cancer

Pancreatic cancer is a major cause of cancer death; and despite advances in the standards of surgery and supportive care, the median and long-term survival rates have not shown similar dramatic improvements. Techniques such as radical surgery alone cannot guarantee a cure. Previous work with conventional chemotherapy and radiotherapy in patients with advanced pancreatic cancer has indicated a role for adjuvant therapy for patients with resectable tumors. The main modalities that have been assessed are based on the Gastrointestinal Tumour Study Group (GITSG) results using 5-fluorouracil chemotherapy, external beam radiation therapy (EBRT), or both. Alternative approaches such as neoadjuvant therapy have been used, which may increase the number of patients suitable for resection; and regional therapy techniques have been used to increase the therapeutic potential by concentrating agents to the tumor bed. The results of single or combination therapy do show some improvement in survival but have been limited in most cases to retrospective nonrandomized series of patients. Therefore the results must be assessed as such. There are several large randomized trials that will deliver definitive answers in the near future as to whether conventional adjuvant therapy is effective. New approaches using novel agents for advanced disease are currently being assessed, and they may eventually identify the most appropriate and effective agents to use for pancreatic cancer in the adjuvant setting.