Randomized study of preoperative chemotherapy in squamous cell cancer of the esophagus. CAO Esophageal Cancer Study Group]

Only 46 of 77 patients with potentially resectable squamous cell carcinoma of the esophagus who were asked to participate in a phase-III trial to be treated by either immediate surgery (n = 24) or surgery plus preoperative chemotherapy (n = 22) agreed to randomization. A priori 13 patients chose chemotherapy before surgery and 18 patients only surgery. The complete chemotherapy program consisted of three cycles with 5-FU (1g/m2/d x 5) and cisplatin (20 mg/m2/d x 5). The response rate (CR and PR) to chemotherapy was 47%. Side effects of therapy were higher than expected, based on results of previous phase-II studies. Two drug related deaths were observed. The resectability rate for patients in the operation-only group was 80 and 70% for patients receiving chemotherapy. The postoperative rate of septic complications (41 vs. 26%) and respiratory disorders (37 vs. 26%) were higher for patients with preoperative chemotherapy in comparison to the only surgically treated controls. Surgery related mortality was increased in the chemotherapy group (18%) compared to the controls (10%). Patients responding to preoperative chemotherapy had a prolonged survival (median 13 months) when compared with non-responders (median 5 months), but the median survival for the chemotherapy group and the only-surgery group was identical (10 months). We conclude, that the preoperative chemotherapy regime used in this multi-institutional trial neither influences resectability, nor increases overall survival of patients with localized esophageal cancer. However, preoperative chemotherapy was associated with considerable side effects and a high postoperative mortality.     

Immediate preoperative laparoscopic staging for squamous cell carcinoma of the esophagus

BACKGROUND: Conventional preoperative staging for esophageal carcinoma could be inaccurate. Laparoscopy has been applied for the staging of various upper gastrointestinal malignancies. It can identify peritoneal and liver deposits not shown by imaging, and could reduce the number of nontherapeutic laparotomies. This study aimed to evaluate the efficacy of laparoscopic staging for the management of squamous cell carcinoma involving the mid and distal esophagus. METHODS: A retrospective review was performed for all patients with esophageal cancer evaluated for surgical resection from January 1998 to January 2004. Laparoscopy was performed for all the patients with mid and distal esophageal cancer immediately before open gastric mobilization. The efficacy of laparoscopy for the management of squamous cell carcinoma of the esophagus was evaluated. RESULTS: Among the 63 patients with potentially resectable disease shown on conventional imaging, 54 (84%) underwent esophagectomy with curative intent after laparoscopic staging. Seven patients (11%) underwent laparoscopy alone because of abdominal metastases (n = 5) or other medical conditions (n = 2) that precluded esophagectomy. Two patients (3%) had exploratory right thoracotomy without esophagectomy despite normal laparoscopic findings. The sensitivity and specificity of laparoscopic staging were 100% in this series of patients (100% sensitivity and specificity means no false-positives or -negatives). CONCLUSION: Laparoscopic staging is valuable for the management of patients with mid and distal squamous cell carcinoma of the esophagus. Patients with metastatic disease and those with prohibitive surgical risk can thus avoid unnecessary laparotomy and be offered other treatment methods.     

Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus

Thirty-nine patients with potentially resectable cancer of the middle or lower esophagus who had not previously been treated were randomly assigned to receive either immediate operation (n = 20) or operation plus preoperative and postoperative therapy with cisplatin, vindesine, and bleomycin (n = 19). Patients were stratified by tumor size and location and by sex, with no significant differences appearing between the two treatment groups. Median follow-up for both groups was 30 months. The preoperative response rate to chemotherapy was 47%. The postoperative complication rate for patients in the operation-only group was 47%; it was 29% for patients receiving chemotherapy. The overall resectability rates were similar for the two groups. Patients responding to chemotherapy preoperatively had significantly prolonged survival (median greater than 20 months) when compared with either nonresponders (median 6.2 months) or patients receiving only operation (median 8.6 months). A highly significant correlation was noted between a weight loss of less than 10% and response to chemotherapy, which suggested that responses occurred in patients with less advanced disease. We conclude that preoperative and postoperative cisplatin, vindesine, and bleomycin chemotherapy has acceptable toxicity and does not increase the incidence of postoperative complications. The natural history of epidermoid carcinoma of the esophagus is altered and overall survival is prolonged for patients responding to preoperative chemotherapy. Potential responding patients can be identified by the degree of preoperative weight loss.     

Resection margin for squamous cell carcinoma of the esophagus.

OBJECTIVE: The safe resection margin in esophagectomy for esophageal squamous cell carcinoma (SCC) was determined based on the extent of epithelial and subepithelial accessory lesions from the main lesions of esophageal SCC. BACKGROUND: There have been many reports on the high incidence of a positive resection margin for esophageal cancer. Although there were some studies on the relationships of the proximal clearance to postoperative local recurrence, no pathologic study on the resection margin has been reported. METHODS: Four hundred twenty specimens of a whole resected esophagus were examined histopathologically and the longitudinal length from the main lesion to the five types of accessory lesions was measured on microscopic slides. RESULTS: Contiguous intraepithelial carcinoma existed in 69 (46%) of 150 sites of main lesions restricted to the mucosa or submucosa and subepithelial lesions existed in 131 (54%) of 245 sites and 82 (55%) of 150 sites of main lesions invading an adventitia and into neighboring structures, respectively. The risk of a positive resection margin due to subepithelial lesions was below 5% at 10 mm in the main lesion, restricted to the submucosa or the muscularis propria, and at 30 mm in the main lesion, invading the adventitia in the potentially curative operation cases. CONCLUSION: These clearances of the resection margin, in which the risk of a positive resection margin is below 5%, are acceptable, although these clearances should only be accepted after the extent of epithelial accessory lesions is accurately determined by the Lugol's stain method.     

Randomized trial of adjuvant chemotherapy after curative resection for gastric cancer

BACKGROUND: The aim of the study was to evaluate the efficacy of adjuvant chemotherapy on survival after resection for gastric cancer. METHODS: Patients were enrolled if they underwent resection of gastric cancer but had lymph node or serosal involvement or both. Surgical resection was either total or partial gastrectomy according to the site of the tumor, and surgeons were allowed to perform either D1 or D2 gastrectomy. The subjects were random assigned in two treatment groups as follows: surgery alone as the control group, or surgery and adjuvant chemotherapy. Nine cycles of 5 days protocol every 4 weeks was proposed to the patients of the chemotherapy group. The protocol included a daily administration of 200 mg/m(2) of folinic acid, 5-fluorouracil (375 mg/m(2) during the first session increasing 25 mg by session until reaching 500 mg/m(2)) and CDDP 15 mg/m(2). Two hundred patients were required. Kaplan-Meier survival curves were compared according to the log-rank and the Mantel-Haenszel methods. RESULTS: In all, 205 patients were enrolled in the study; 104 had surgery alone and 101 had surgery and adjuvant chemotherapy. The patients' characteristics were similar except for the mean age, which was 4 years less in the control group. Because of toxicity, 54% of the patients stopped the protocol before the end of the nine courses, and 46% of the patients received the nine courses including 32% with a decreased dose and 14% with a full dose. The 5-year survival rate was 39% in the control group and 39% in the chemotherapy group. CONCLUSIONS: This protocol of adjuvant chemotherapy failed to improve the 5-year survival after resection for gastric cancer.     

A new treatment for invasive squamous cell bladder cancer: the Nigro regimen: preoperative chemotherapy and radiation therapy

We report 5 cases of invasive squamous cell bladder cancer treated with preoperative mitomycin C and 5-fluorouracil in combination with preoperative external beam radiation therapy (the Nigro regimen), and the subsequent apparent cure of 3 of the 5 patients.     

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.     

Complete eradication of squamous cell carcinoma of the esophagus with combined chemotherapy and radiotherapy

Chemotherapy (with 5-fluorouracil and either mitomycin-C or cis-platinum) combined with radiotherapy was used either for palliation or as preoperative therapy in 67 patients with squamous cell carcinoma of the esophagus. In 25 patients having chemotherapy and 5000-6000 rads, good local palliation was obtained in 11 (49%) without surgery. In the remaining 25 patients, swallowing was restored with a variety of procedures (primarily Celestine tube or gastric bypass). The average survival time was seven months and two patients are still alive at 9 and 12.5 months. Of 42 patients receiving preoperative chemotherapy and radiotherapy, 35 had surgery. Of these, 13 (37%) had complete eradication of their tumors with no histologic evidence of carcinoma in the resected esophagus or associated lymph nodes. In another six (17%), the only evidence of tumor was small microscopic foci of cancer cells in the wall of the esophagus. The 6-, 12-, and 24-month survival rates for patients having surgery after the combined preoperative chemotherapy and radiotherapy were 83 per cent, 52 per cent, and 30 per cent, respectively. These results are far superior to those previously obtained.     

The effect of neoadjuvant chemotherapy on lymph node micrometastases in squamous cell carcinomas of the thoracic esophagus

BACKGROUND: Neoadjuvant chemotherapy (NACT) has been postulated but not yet proven to eradicate micrometastases and improve the prognosis of patients with advanced esophageal squamous cell carcinomas (ESCC). Cytokeratin immunohistochemistry of the lymph nodes of ESCC revealed immunohistochemical micrometastases (IHM) and cytokeratin deposits (CD), which are hyalinized denucleated particles considered to be cadavers of carcinoma cells. Successful chemotherapy should convert cancer cells from IHM to CD and improve the status of ESCC patients from systemic disease to regional disease. METHODS: Cytokeratin immunostaining of surgically removed lymph nodes was performed for 107 patients with node-positive ESCC, including 32 patients without preoperative treatment (Surgery group) and 75 patients undergoing NACT using CDDP, doxorubicin hydrochroride, and 5-fluorouracil (NACT group). Cytokeratin-positive staining was done for serial hematoxylin-eosin-stained sections and classified as pathologic metastasis, IHM, or CD. RESULTS: CD was observed less frequently in the Surgery group than in the NACT group (6% vs 43%, P < .0001), whereas IHM was more frequent in the former (47% vs 24%, P = .019). IHM was a poor prognostic factor in both groups, whereas CD was a favorable one in the NACT group. The effect of chemotherapy on IHM was classified as eradicated, IHM(-)/CD(+); persistent, IHM(+)/CD(+); no effect, IHM(+)/CD(-); or not informative, IHM(-)/CD(-). This classification correlated well with the clinical response of the primary neoplasm, number of pathologic metastases, and postoperative survival (3-year survival rates: 78%, 18%, 0%, and 38%). IHM/CD was found to be an independent prognostic factor together with the number of pathologic metastases in the multivariate analysis. CONCLUSIONS: Disappearance of IHM and the emergence of CD suggest the eradication of micrometastases by NACT. The clinical benefit of NACT was apparent for IHM(-)/CD(+) patients with node-positive ESCC.     

Preoperative chemotherapy, surgical resection, and selective postoperative therapy for squamous cell carcinoma of the esophagus

In an attempt to improve on the long-term survival rate of patients with esophageal squamous cell carcinoma, we designed a study in which treatment included preoperative chemotherapy with fluorouracil and cisplatin, surgical resection, and selective postoperative chemotherapy or radiation therapy. Between 1981 and 1986, 35 patients with potentially resectable lesions were entered into the study. After chemotherapy, 13 of 35 patients (37%) had a complete clinical response, 7 (20%) had a partial response, and 15 (43%) had no response. One patient sustained a serious toxic reaction (renal failure). Twenty-seven patients underwent surgical resection, with 1 hospital death (3.7%). Selective postoperative radiotherapy or chemotherapy was administered to 69%. The actuarial survival of all resected patients at 42 months was 54% (standard error, 10%). Multivariate analysis showed significant factors associated with 3-year survival were: (1) complete clinical response to chemotherapy; (2) absence of wall penetration in the specimen; and (3) microscopic or no disease in the specimen. We conclude that this multimodality treatment method improves the intermediate-term survival of patients with squamous cell carcinoma of the esophagus.     

Long-term results after esophagectomy for squamous cell carcinoma of the esophagus associated with head and neck cancer.

BACKGROUND: Esophageal squamous cell carcinomas are frequently associated with head and neck cancers. The poor prognosis of each cancer, and their proximity, often limit the treatment options. This study was conducted to determine the characteristics and long-term outcome of such dual cancers. PATIENTS AND METHODS: We included 75 patients with esophageal carcinoma, of whom 25 had a synchronous head and neck malignancy. Curative treatment was possible in every case. The patients were divided into "solitary cancer" and "synchronous cancer" groups. RESULTS: The gender distribution, tumor location, and histological findings were similar in the two groups. Patients in the synchronous cancer group were younger than those in the solitary group (P < 0.0042). The operative mortality and pulmonary morbidity rates were not significantly different in the two groups. The rate of cervical anastomotic leaks was higher in the synchronous group (P < 0.05). The mean follow-up was 83 +/- 50 months. Five-year survival rates were not significantly different in the two groups (14.3% +/- 5.7% in the solitary group and 17.5% +/- 7.9% in the synchronous group). CONCLUSIONS: With aggressive treatment, the survival of patients with synchronous esophageal and head and neck cancers was similar to that of patients with isolated esophageal cancer.     

食管鳞癌切除术后切缘癌残留的影响因素及预后

目的 探讨食管鳞癌切除术后切缘癌残留的影响因素和预后,评价术后补救性治疗的价值.方法 回顾性总结中山大学肿瘤防治中心1997年1月至2003年6月连续收治的1074例行食管鳞癌切除术患者的临床与病理资料,分析肿瘤分化程度、部位、病变长度、切口选择、吻合位置、T分期、N分期与切缘癌残留发生率的关系,并通过生存分析探讨补救性治疗的方式.结果 本组44例（4.3%）出现切缘癌残留.食管端切缘癌残留在病变位于胸上段时发生率为6.5%;胃端切缘癌残留在病变位于胸下段时发生率为0.8%.切缘癌残留发生率随T分期和N分期的增加而升高（均P＜0.05）.Logistic回归分析显示,T分期和N分期是术后切缘癌残留发生的危险因素.切缘癌残留患者3年生存率为22.7%.生存时间（25.2±3.3）个月.术后行补救性治疗者20例（45.5%,其中行放疗18例,行联合放化疗2例）：另24例（54.5%）未行补救性治疗.术后行补救性治疗与未行补救性治疗患者的3年生存率分别为53.2%与7.8%（P=0.027）.结论 肿瘤浸润程度和淋巴结转移是食管鳞癌切除术后切缘癌残留发生的危险因素;术后行补救性治疗可明显提高生存率.     

Randomized trial of informed consent and recruitment for clinical trials in the immediate preoperative period.

BACKGROUND: The standard process of obtaining informed consent sometimes prevents physicians or patients from participating in clinical trials, partly because they are concerned about eventual treatment allocation or the physician is concerned the patient might harbor some uncertainty about the best treatment. Alternative randomization methods have been advocated that may address these and other concerns. METHODS: After institutional ethics committee gave its approval, the authors interviewed 770 patients before operation and asked them to consider enrolling in a mock anesthesia trial. Patients were allocated randomly to one of five methods of randomization and consent: one-sided informed consent (the most common approach), prerandomized consent to experimental treatment, prerandomized consent to standard treatment, one-sided physician-modified informed consent, or one-sided patient-modified informed consent. Recruitment rates were compared and sociodemographic and perioperative predictors of recruitment were identified. RESULTS: The randomization method did not result in any significant difference in recruitment rates: one-sided informed consent, 55.6%; prerandomized consent to experimental treatment, 53.3%; prerandomized consent to standard treatment, 53%; one-sided physician-modified informed consent, 60.7%; and one-sided patient-modified informed consent, 56.7% (P = 0.66). Multivariate predictors of recruitment were patient age >45 yr (odds ratio, 1.44; 95% confidence interval [CI], 1.08 to 1.93), English-speaking at home (1.49; 1.0 to 2.21), and male researcher-male patient interaction (1.37; 1.20 to 1.57). CONCLUSIONS: No evidence emerged that alternative randomization and consent designs resulted in increased recruitment rates compared with simple one-sided informed consent for a sham anesthesia trial in patients awaiting elective surgery. Older, male patients were more likely to provide consent.