Nobutoshi Ando

Surgery Plus Chemotherapy Compared With Surgery Alone for Localized Squamous Cell Carcinoma of the Thoracic Esophagus: A Japan Clinical Oncology Group Study—JCOG9204

PURPOSE We performed a multicenter randomized controlled trial to determine whether postoperative adjuvant chemotherapy improves outcome in patients with esophageal squamous cell carcinoma undergoing radical surgery. PATIENTS AND METHODS Patients undergoing transthoracic esophagectomy with lymphadenectomy between July 1992 and January 1997 at 17 institutions were randomly assigned to receive surgery alone or surgery plus chemotherapy including two courses of cisplatin (80 mg/m2 of body-surface area x 1 day) and fluorouracil (800 mg/m2 x 5 days) within 2 months after surgery. Adaptive stratification factors were institution and lymph node status (pN0 versus pN1). The primary end point was disease-free survival. RESULTS Of the 242 patients, 122 were assigned to surgery alone, and 120 to surgery plus chemotherapy. In the surgery plus chemotherapy group, 91 patients (75%) received both full courses of chemotherapy; grade 3 or 4 hematologic or nonhematologic toxicities were limited. The 5-year disease-free survival rate was 45% with surgery alone, and 55% with surgery plus chemotherapy (one-sided log-rank, P =.037). The 5-year overall survival rate was 52% and 61%, respectively (P =.13). Risk reduction by postoperative chemotherapy was remarkable in the subgroup with lymph node metastasis. CONCLUSION Postoperative adjuvant chemotherapy with cisplatin and fluorouracil is better able to prevent relapse in patients with esophageal cancer than surgery alone.

Improvement in the Results of Surgical Treatment of Advanced Squamous Esophageal Carcinoma During 15 Consecutive Years

ObjectiveTo document the clinicopathologic characteristics and survival of patients undergoing esophagectomy for squamous carcinoma of the thoracic esophagus, and to examine the factors contributing to improvements in outcome noted in patients with advanced carcinoma. Summary Background DataJapanese and some Western surgeons recently have reported that radical esophagectomy with extensive lymphadenectomy conferred a survival advantage to patients with esophageal carcinoma. The factors contributing to this improvement in results have not been well defined. MethodsFrom 1981 to 1995, 419 patients with carcinoma of the thoracic esophagus underwent esophagectomy at the Keio University Hospital. The clinicopathologic characteristics and survival of patients treated between 1981 and 1987 were compared with those of patients treated between 1988 and 1995. Multivariate analysis using the Cox regression model was carried out to evaluate the impact of 15 variables on survival of patients with p stage IIa to IV disease. Several variables related to prognosis were examined to identify differences between the two time periods. ResultsThe 5-year survival rate for all patients was 40.0%. The 5-year survival rate was 17.7% for p stage IIa to IV patients treated during the earlier period and 37.6% for those treated during the latter period. The Cox regression model revealed seven variables to be important prognostic factors. Of these seven, three (severity of postoperative complications, degree of residual tumor, and number of dissected mediastinal nodes) were found to be significantly different between the earlier and latter periods. ConclusionsThe survival of patients undergoing surgery for advanced carcinoma (p stage IIa to IV) of the thoracic esophagus has improved during the past 15 years. The authors’ data suggest that this improvement is due mainly to advances in surgical technique and perioperative management.

A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: The Japan clinical oncology group study

OBJECTIVE To determine whether postoperative adjuvant chemotherapy confers a survival benefit on patients with esophageal squamous cell carcinoma undergoing radical surgery, we undertook a cooperative, prospective randomized controlled trial. METHODS A total of 205 patients underwent transthoracic esophagectomy with lymphadenectomy at eleven institutions between December 1988 and July 1991. These patients were prospectively randomized into two groups (100 patients underwent surgery alone and 105 patients had additional two courses of combination chemotherapy with cisplatin (70 mg/m2) and vindesine (3 mg/m2). The two groups did not differ with respect to sex, age, location of tumor, and distributions of pT, pN, pM, or p stage. RESULTS The 5-year survival was 44.9% in the surgery alone group and 48.1% in the surgery plus chemotherapy group. The relative risk was estimated to be 0.89 (95% confidence interval, 0.61 to 1.31) in the surgery plus chemotherapy group compared with the surgery alone group. No significant differences in survival were detected between the two groups, even with lymph node stratification. CONCLUSION Postoperative adjuvant chemotherapy with cisplatin and vindesine has no additive effect on survival in patients with esophageal cancer compared with surgery alone.

Prognostic significance of epidermal growth factor receptor in esophageal squamous cell carcinomas

The prognostic value of epidermal growth factor (EGF) receptor level was studied in 32 patients with esophageal squamous cell carcinoma. The EGF receptor levels of tumors were measured by iodine 125 (125I)‐EGF binding assay, and the patients subsequently were divided into two groups: a group with high EGF binding capacities (< 2.5% of input), and a group with low EGF binding capacities (<2.5% of input). The cumulative survival rates for the two groups were calculated by the Kaplan‐Meier method. The generalized Wilcoxon test indicated that the survival rate of the high EGF binding group was significantly lower than that of the low EGF binding group (P < 0.05). In tumors from two patients with the highest EGF receptor levels, EGF receptor gene amplification was observed. These patients developed mediastinal lymph node metastasis and died 4 and 11 months after surgery, respectively. These results suggest that elevated EGF receptor level is a significant prognostic indicator for esophageal squamous cell carcinoma.

Magnetic resonance imaging of esophageal squamous cell carcinoma using magnetite particles coated with anti-epidermal growth factor receptor antibody

A highly specific and effective magnetic resonance imaging (MRI) contrast agent was prepared by coating super‐paramagnetite particles with monoclonal antibodies (MAbs) directed against epidermal growth factor receptors (EGFRs), which are over‐expressed in esophageal squamous cell carcinoma. The preparation maintained both the immuno‐reactivity of the MAbs and the full relaxing capability of the magnetite particles. The particles of this EGFR‐specific contrast agent are 13.2 ± 1.9 nm in size, and thus, it is assumed that they are smaller than capillary pores and, hence, able to escape scavenging by reticulo‐endothelial system cells. The EGFR‐specific T2‐relaxing ability of this contrast agent was ascertained first in vitro, using the EGFR‐expressing cell line TE8 and the EGFR‐deficient cell line H69. The results in athymic rats bearing TE8 or H69 tumors revealed that the agent has EGFR‐specific MRI contrast capacity in vivo. The electron‐microscopic findings in TE8 tumor‐bearing rats revealed that the magnetite particles had been taken up by their lysosomes. In conclusion, immuno‐specific MRI using magnetite particles coated with MAbs against EGFR appears to be useful in the diagnosis of squamous cell carcinoma of the esophagus. Int. J. Cancer 75:626–634, 1998.

Epidermal Growth Factor Receptors in Cancer Tissues of Esophagus, Lung, Pancreas, Colorectum, Breast and Stomach

The levels of epidermal growth factor (EGF) receptors were investigated in surgically resected tumors of various origins including esophagus (n = 33), lung (n = 14), pancreas (n = 9), colorectum (n = 10), breast (n = 23) and stomach (n = 8). The 125I‐EGF binding capacities of squamous cell carcinomas of esophagus and lung were exceptionally higher than those of the other cancer tissues. Immunohistochemical staining with an anti‐EGF receptor monoclonal antibody detected EGF receptors in the basal cells and parabasal cells of normal esophageal epithelium and in all the cancer cells of squamous cell carcinoma tissues of esophagus and lung. DNA replicating cells were examined by the bromodeoxyuridine staining method and it was found that the basal cells and parabasal cells of normal epithelium and peripheral cells of cancer pearls are proliferating. Contrary to this, a tumor antigen TA‐4, known as a specific marker for squamous carcinoma, was detected in the differentiated cancer cells and in middle‐layer squamous cells. These results strongly suggest that the increase in EGF receptor levels may be associated with the development of human squamous cell cancers of esophagus and lung. Thus, measurement of EGF receptor expression in tumor tissues has diagnostic value and should prove useful for the development of new therapies.

Validation study of radio-guided sentinel lymph node navigation in esophageal cancer.

Background:Radio-guided detection of sentinel lymph nodes (SLN) has been used to predict regional lymph node metastasis in patients with melanoma and breast cancer. However, the validity of the SLN hypothesis is still controversial for esophageal cancer. The aim of this study is to evaluate the feasibility and accuracy of radio-guided SLN mapping for esophageal cancer. Methods:Seventy-five consecutive patients who were diagnosed preoperatively with T1N0M0 or T2N0M0 primary esophageal cancer were enrolled. Endoscopic injection of technetium-99m tin colloid was performed before surgery and radioactive SLNs were identified with preoperative lymphoscintigraphy and gamma probe. Standard radical esophagectomy with lymphadenectomy was performed in all patients and all resected nodes were evaluated by routine pathologic examination. Results:SLNs were identified successfully in 71 (95%) of 75 patients. The mean number of identified SLNs per case was 4.7. Twenty-nine (88%) of 33 cases with lymph node metastasis showed positive SLNs. The diagnostic accuracy based on SLN status was 94% (67/71). Distribution of identified SLNs was widely spread from the cervical to abdominal areas. Conclusions:This study reveals that radio-guided SLN mapping is an accurate diagnostic procedure for detecting lymph node metastasis in patients with early-stage esophageal cancer.

Evaluation of the accuracy of preoperative staging in thoracic esophageal cancer.

BACKGROUND Exact clinical staging before treatment of esophageal cancer has become increasingly important in the evaluation and comparison of the results of different treatment modalities, including surgery, chemotherapy, and radiotherapy. METHODS The accuracy of preoperative tumor staging by using an esophagography, esophagoscopy, percutaneous and endoscopic ultrasonography, and computed tomography was assessed in 224 patients with resectable esophageal cancer. The results of tumor staging by these tests were compared prospectively with the pathologic stage of the esophagectomy specimens with respect to the T and N categories defined by the International Union Against Cancer TNM classification. RESULTS For the T category, the overall accuracy was 80%. For the N category, overall accuracy was 72%, with a sensitivity of 78%, a specificity of 60%, and a positive predictive value of 78%. Overall, the accuracy of stage grouping was 56%. CONCLUSIONS Either the T or N categories can be predicted reliably by clinical staging techniques. However, the preoperative stage grouping might not be valid in resectable, localized esophageal cancer.

Intraoperative lymphatic mapping and sentinel lymph node sampling in esophageal and gastric cancer.

Recent studies for SN mapping of esophageal and gastric carcinoma show that the SN concept is valid even for upper GI cancers with multidirectional and complicated lymphatic flow. The relatively high incidence of anatomic skip metastasis can be attributed to aberrant distribution of SNs. An individualized and minimally invasive surgical approach can be applicable to management of esophageal and gastric carcinoma based on SN status. Although there are several issues to be resolved, this novel procedure has the potential for great benefit to improve quality control in the treatment of upper GI cancer. Well-designed clinical trials of lymphatic mapping for upper GI cancer will be essential to determine whether this technique is widely applicable in the management of these tumors.

An artificial esophagus constructed of cultured human esophageal epithelial cells, fibroblasts, polyglycolic acid mesh, and collagen.

We have been developing an artificial esophagus constructed of autologous esophageal component cells by cell culture. Because human esophageal epithelial cells are stratified in 20 layers, we attempted to construct an artificial esophageal epithelium 20 twenty layers thick. In in vitro experiments, we investigated how keratinocyte growth factor produced by fibroblasts accelerates the proliferation and differentiation of epithelial cells. Esophageal epithelial cells were cultured on collagen sheets in which dermal fibroblasts (0, 1, 4, 8 x 10(5) cells/ml of collagen) were embedded. In cultured epithelial cells on collagen gels without fibroblasts, 2.1 layer stratification was observed on the 21st day. With 1 x 10(5) fibroblasts/ml of collagen, 3.0 layer stratification was observed, 5.0 layers with 4 x 10(5) fibroblasts, and 18.1 layers with 8 x 10(5) fibroblasts. The degree of epithelial cell stratification was thus correlated with the number of embedded fibroblasts. Tubes constructed of a polyglycolic acid mesh frame, a collagen layer with esophageal fibroblasts, and an inner layer of esophageal epithelial cells were transplanted into muscle flaps of athymic rats. The luminal structures were observed to be patent without stenosis for 14 days. Histology of the epithelium revealed 20 layers of stratification. We thus succeeded in constructing epithelium similar to human esophageal epithelium. In the future we will attempt to use the tubular structures as a substitute for the esophagus after esophagectomy.