Kaichi Isono

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.

In order to determine the operative indications of three-field lymph node dissection of esophageal cancer, attempts were made to collect data concerning procedures performed between 1983 and 1989 in major institutions in Japan, and the results from institutions performing three-field or two-field lymph node dissection were compared. The treatment results of three-field lymph node dissection were better than those after two-field dissection, except for early or advanced cancer. The survival rate improved by the three-field as compared with the two-field lymph node dissection; however, since surgery was invasive, some complications such as recurrent nerve paralysis were frequent. The results show that the indication of three-field lymph node dissection has to be carefully determined for each patient.

Immunosuppressive activities of the newly discovered FK506, isolated from Streptomyces tsukubaensis, were examined by using cardiac allotransplantation in the rat, and the mechanisms underlying induction and maintenance of FK506-induced long-term allograft survival were studied. Male rats of WKA (RT1k) and F344 (RT1lvl) strains were used as recipients and donors, respectively, and those of BN (RT1n) strain were used as third-party donors. Treatment with FK506, beginning from the day of allografting for 14, 10, or as few as 4 days, prolonged allograft survival significantly across the major histocompatibility barrier. The minimum doses for prolonging graft survival were 0.1 mg/kg/day by intramuscular treatment and 1.0 mg/kg/day by oral treatment. Treatment with FK506 at a dose of 0.32 mg/kg/day from day 4 until day 10 resulted in all the grafts surviving indefinitely and from days 5 to 10, half the grafts survived indefinitely, suggesting that the agent inhibited ongoing rejection. On the other hand, cyclosporine treatment at a dose of 20 mg/kg/day from day 2 did not prolong graft survival time statistically significantly. Induction of prolonged graft survival was not obtained by pretreatment of the prospective donor or recipient; prolonging effects were observed only when the agent was administered after allografting. Thus, the primary effect of the agent is exerted on responder lymphocytes reacting to the donor antigens in the induction phase of long-term graft acceptance. The mechanisms underlying the maintenance of long-term grafts were analyzed by testing the capacity of lymphocytes or serum of long-term graft-bearing rats to inhibit graft rejection in irradiated grafted hosts. Transfer of 2 x 10(8) lymphocytes from FK506-induced long-term F344 graft-bearing WKA rats resulted in indefinite survival of F344 heart allografts, but it did not prolong survival of third-party BN hearts. Transfer of 2.5 ml serum from long-term graft-bearing rats also prolonged graft survival of F344 hearts, but not BN hearts. These results suggest that donor strain-specific suppressor cells and humoral factor(s) are induced by treatment with FK506 in the presence of allografts, and that they play at least partial roles in the maintenance of long-term allograft acceptance.

UNLABELLED: To evaluate glucose metabolism in esophageal cancer, 48 patients were studied using PET with 18F-2-fluoro-2-deoxy-D-glucose (FDG). METHODS: After transmission scans were obtained, 18F-FDG (148 MBq) was administered intravenously. In 11 patients, a dynamic study was performed to evaluate glucose metabolism. Using the changes of radioactivity in both plasma and tumor, rate constants (k1-k4) defined in the metabolic model for 18F-FDG were calculated. In 48 patients, static PET scans of the tumor (5-min scans) were obtained 60 min after administration. Fluorine-18-FDG activity within each tumor was corrected for physical decay and normalized by dose administration and patient weight to produce a standardized uptake value (SUV). RESULTS: Both the k3 value (n = 11) reflecting hexokinase activity and SUV (n = 13) were well correlated with hexokinase activity from the resected specimen (p < 0.05). Forty-seven of 48 patients before treatment revealed SUV greater than 2.0, but 10 normal control subjects and 1 esophageal benign tumor revealed less than 2.0 (accuracy rate 98.3%). Although clinicopathological findings did not correlate with SUV, except for two patients with carcinosarcoma, 23 patients with an SUV greater than 7.0 had a poor prognosis compared with 25 patients with SUVs less than 7.0. CONCLUSION: These findings suggest that 18F-FDG PET may be useful in distinguishing malignant tumors from benign lesions and in the preoperative evaluation of the prognostic factor.