Kuniyoshi Arai

D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer.

BACKGROUND Gastrectomy with D2 lymphadenectomy is the standard treatment for curable gastric cancer in eastern Asia. Whether the addition of para-aortic nodal dissection (PAND) to D2 lymphadenectomy for stage T2, T3, or T4 tumors improves survival is controversial. We conducted a randomized, controlled trial at 24 hospitals in Japan to compare D2 lymphadenectomy alone with D2 lymphadenectomy plus PAND in patients undergoing gastrectomy for curable gastric cancer. METHODS Between July 1995 and April 2001, 523 patients with curable stage T2b, T3, or T4 gastric cancer were randomly assigned during surgery to D2 lymphadenectomy alone (263 patients) or to D2 lymphadenectomy plus PAND (260 patients). We did not permit any adjuvant therapy before the recurrence of cancer. The primary end point was overall survival. RESULTS The rates of surgery-related complications among patients assigned to D2 lymphadenectomy alone and those assigned to D2 lymphadenectomy plus PAND were 20.9% and 28.1%, respectively (P=0.07). There were no significant differences between the two groups in the frequencies of anastomotic leakage, pancreatic fistula, abdominal abscess, pneumonia, or death from any cause within 30 days after surgery (the rate of death was 0.8% in each group). The median operation time was 63 minutes longer and the median blood loss was 230 ml greater in the group assigned to D2 lymphadenectomy plus PAND. The 5-year overall survival rate was 69.2% for the group assigned to D2 lymphadenectomy alone and 70.3% for the group assigned to D2 lymphadenectomy plus PAND; the hazard ratio for death was 1.03 (95% confidence interval [CI], 0.77 to 1.37; P=0.85). There were no significant differences in recurrence-free survival between the two groups; the hazard ratio for recurrence was 1.08 (95% CI, 0.83 to 1.42; P=0.56). CONCLUSIONS As compared with D2 lymphadenectomy alone, treatment with D2 lymphadenectomy plus PAND does not improve the survival rate in curable gastric cancer. (ClinicalTrials.gov number, NCT00149279.)

Left thoracoabdominal approach versus abdominal-transhiatal approach for gastric cancer of the cardia or subcardia: a randomised controlled trial

BACKGROUND Because of the inaccessibility of mediastinal nodal metastases, the left thoracoabdominal approach (LTA) has often been used to treat gastric cancer of the cardia or subcardia. In a randomised phase III study, we aimed to compare LTA with the abdominal-transhiatal approach (TH) in the treatment of these tumours. METHODS Between July, 1995, and December, 2003, 167 patients were enrolled from 27 Japanese hospitals and randomly assigned to TH (n=82) or LTA (n=85). The primary endpoint was overall survival, and secondary endpoints were disease-free survival, postoperative morbidity and hospital mortality, and postoperative symptoms and change of respiratory function. The projected sample size was 302. After the first interim analysis, the predicted probability of LTA having a significantly better overall survival than TH at the final analysis was only 3.65%, and the trial was closed immediately. Analysis was by intention to treat. This study is registered with , number NCT00149266. FINDINGS 5-year overall survival was 52.3% (95% CI 40.4-64.1) in the TH group and 37.9% (26.1-49.6) in the LTA group. The hazard ratio of death for LTA compared with TH was 1.36 (0.89-2.08, p=0.92). Three patients died in hospital after LTA but none after TH. Morbidity was worse after LTA than after TH. INTERPRETATION Because LTA does not improve survival after TH and leads to increased morbidity in patients with cancer of the cardia or subcardia, LTA cannot be justified to treat these tumours.

Gastric cancer treated in 1991 in Japan: data analysis of nationwide registry

The Japanese Gastric Cancer Association Registration Committee reported the treatment results and causes of death of patients with primary gastric cancer treated in 1991 at the leading hospitals in Japan. Data of 8851 patients with primary gastric cancer were collected from 113 hospitals, and data of 7935 patients with gastric resection were finally analyzed. The lost-to-follow-up rate was 6.9%; the direct death rate was 1.0%. The cumulative 5-year survival rate (5YSR) of all the patients was 68.2%; 89.9% for Stage I, 69.1% for Stage II, 43.5% for Stage III, and 9.9% for Stage IV. Characteristic findings of the analyzed data were (1) high proportion of early-stage cancer, (2) high resection rate, (3) low mortality rate, (4) low incidence of upper-third cancer, (5) poor treatment results in cases with scirrhous cancer, infiltrating growth, and marked lymphatic or venous invasion, and (6) predominance of systematic (D2) and extended lymphadenectomies possibly resulting in reducing local recurrence and improving survivals.

Influence of Overweight on Surgical Complications for Gastric Cancer: Results From a Randomized Control Trial Comparing D2 and Extended Para-aortic D3 Lymphadenectomy (JCOG9501)

BackgroundThe impact of overweight on the outcome of gastrectomy with lymphadenectomy is controversial, and data from a well-controlled, randomized study are needed to identify a possible relationship.MethodsWe used data from 523 patients registered for a prospective randomized trial comparing D2 and extended para-aortic D3 lymphadenectomy to compare the effects of body mass index (BMI) and the extent of lymphadenectomy for the development of general or major surgical complications (anastomotic leakage, abdominal abscess, and pancreatic fistula).ResultsSeventy-seven patients were classified as overweight with BMI ≥ 25, and 38 and 39 of these patients underwent a D2 or D3 lymphadenectomy, respectively. Among the 446 patients classified as nonoverweight with BMI < 25, 225 received D2 and 221 received D3 lymphadenectomy. Surgical complications, operation time, and blood loss were statistically significantly associated with BMI, and logistic regression analysis revealed that overweight directly affected the occurrence of surgical complications even after considering operation time and blood loss as intermediate factors instead of outcome variables. Among patients undergoing D2 lymphadenectomy, being overweight increased the risk for surgical complications and blood loss, whereas overweight was associated with only blood loss and operation time among patients receiving D3 lymphadenectomy.ConclusionsOverweight increased the risk of surgical complications in patients undergoing gastrectomy both directly and indirectly through operation time and blood loss. The impact of overweight on surgical complications was more evident in patients undergoing a D2 dissection.

Lymph node metastasis and preoperative diagnosis of depth of invasion in early gastric cancer.

Background. No reports have, to date, focused on the relationship between preoperative determination of the depth of invasion and lymph node metastasis. The present study, under the leadership of the Japanese Gastric Cancer Association, was designed to form a basis for decision making in limited treatment for early gastric cancer (EGC). Methods. From eight major hospitals in Japan, 2672 gastric cancers whose preoperative depth of invasion was mucosal(M-cancer), and 6209 EGCs, consisting of 3584 mucosal(m-) and 2625 submucosal(sm-) cancers, were collected by questionnaire. All registered patients underwent gastrectomy with D1 or more extensive lymphadenectomy between 1985 and 1998. Results. The accuracy of preoperative diagnosis of depth of invasion of M-cancers was 80.2% (2144/2672). However, of the total of 2432 M-cancers in which no nodal involvement was observed intraoperatively (N0), histological examination of the resected specimens confirmed that lymph node metastasis was absent in 2353 (96.8%). The frequencies of lymph node metastasis in early gastric, m-, and sm-cancers were 8.9%, 2.5%, and 17.6%, respectively. Node involvement was associated with a higher frequency of undifferentiated than differentiated histology, as well as with greater tumor size. The incidences of lymph node metastasis in m-cancers with a diameter of less than 4 cm, and in sm-cancers with a diameter below 1 cm were 1.3% (37/2837) and 4.9% (4/82), respectively. These metastases rarely extended beyond the first tier. Conclusion. N0 and M-cancers, m-cancers less than 4 cm in diameter, and sm-cancers no larger than 1 cm in diameter may be appropriate indications for limited surgery.

Feasibility study of adjuvant chemotherapy with S-1 (TS-1; tegafur, gimeracil, oteracil potassium) for gastric cancer

BackgroundWe conducted a feasibility study using S-1, a novel oral derivative of 5-fluorouracil, as postoperative adjuvant chemotherapy for curatively resected gastric cancer patients.MethodsAdjuvant chemotherapy consisted of eight courses (4-week administration and 2-week withdrawal) of S-1, at 80–120 mg/body per day. Forty-one patients from 11 institutions were enrolled in this pilot study, from November 1999 to October 2000.ResultsThirty-five patients were eligible. In 7 patients, S-1 administration was discontinued due to recurrence. Among the 28 patients without recurrence, the planned eight courses of S-1 were administered to 17 patients (60.7%). In 4 patients, S-1 administration was discontinued due to subjective symptoms, such as anorexia, in the first course. Adverse reactions such as neutropenia, leukopenia, elevated total bilirubin, anorexia, general fatigue, diarrhea, nausea, and stomatitis were seen in more than half of the patients. Although grade 3 neutropenia (29.3%), leukopenia (9.8%), and diarrhea (9.8%) were observed, no grade 4 adverse effects appeared. Compared with the treatment of unresectable or recurrent gastric cancer with S-1, the incidence of adverse reactions in the adjuvant setting was slightly higher, probably due to the influence of gastrectomy.ConclusionExcept for the early development of anorexia, most likely due to adverse effects of surgery, postoperative administration of S-1 for 1 year seems feasible as adjuvant chemotherapy for gastric cancer.

Determining prognostic factors for gastric cancer using the regression tree method

Abstract.Background: The regression tree method is a useful statistical technique that has been little used in the analysis of prognosis.Methods:The prognostic factors of gastric cancer were investigated, using the regression tree method, in 555 patients who had undergone curative resection for serosa-negative gastric cancer and who were enrolled in a randomized controlled trial of postoperative adjuvant chemotherapy (JCOG [Japan Clinical Oncology Group] 8801 study).Results:By the regression tree method, the first divided prognostic factor (the most important factor) was lymph node metastasis; in particular, extent of lymphatic spread had the greatest impact on prognosis. In addition, age, tumor size, depth of invasion, and individual dose intensity were found to be significant prognostic factors, whereas sex, tumor location, macroscopic tumor type, and extent of lymph node dissection were not. The resulting tree structure consisted of nine terminal nodes with different prognostic factors, and four clusters were obtained by the merging of terminal nodes that showed a similar prognosis. The cluster which showed the best survival rate (5-year survival rate, 0.986) consisted of two terminal nodes: node 12, which contained N0T1 patients who were younger than 62 years and had a tumor size of less than 7.5 cm, and node 14, which contained N1 patients who were younger than 46 years.Conclusion:In serosa-negative gastric cancer, lymph node metastasis was the most important prognostic factor. Utilization of the regression tree method enabled visual interpretation of the results of statistical analyses through the graphic representation of prognostic factors. It allowed the identification of the optimal combination of these prognostic factors that defined several groups of patients with distinct prognoses and may serve as a useful reference for the individualization of treatment strategy.

Phase I/II study of irinotecan (CPT-11) and S-1 in the treatment of advanced gastric cancer.

A phase I/II study to determine the recommended dose for combination therapy with CPT-11 (irinotecan hydrochloride) and S-1 (tegafur, gimestat and otastat potassium) for advanced or recurrent gastric cancer, and to assess the safety and efficacy of this therapy. In the phase I portion of the study, S-1 was administered from day 1 to 14 at a fixed dose approved in Japan (80 mg/m2/day), and CPT-11 was administered on days 1 and 8, with its dose being escalated to 100 from 80 mg/m2. This regimen was repeated at 3-week intervals. The phase II portion of the study assessed the efficacy and safety of this regimen at the recommended dose determined in the phase I portion of the study. Seven patients were enrolled in the phase I portion of the study. The dose-limiting toxicity was the delay of administration owing to adverse reactions (leucopenia and diarrhea). The maximum tolerated dose of CPT-11 was 100 mg/m2 and the recommended dose was determined to be 80 mg/m2. In the phase II portion of the study, 10 patients with no prior chemotherapy regimen were enrolled. The median number of treatment cycles given was 4.5, the response rate was 20.0% (2/10) in all patients, the tumor control rate stable disease or better response was 60% (6/10) and the mean survival time was 311 days. Major adverse reactions included a decreased hemoglobin level, diarrhea, nausea and anorexia of grade 3 or worse (each occurred in 10% of the patients). Other adverse reactions were slight and well tolerated. The present combination therapy with CPT-11 and S-1 produced a low response rate but a high tumor control rate (stable disease or better response) and slight prolongation of survival time. This is a well-tolerated ambulatory regimen for advanced gastric cancer.

Clinicopathological Characteristics of Cases with Metastasis to Lower Mediastinal Lymph Nodes and Treatment in Gastric Cancer with Esophageal Invasion

In 118 gastric cancer patients with esophageal invasion who had undergone lymphadenectomy in the lower mediastinum, a study was conducted to explore characteristics of positive lymph node metastasis. The patients with positive lymph node metastasis in the lower mediastinal area (29 cases) had larger tumor, a higher rate of peritoneal dissemination, and had more cases of type 3 and 4 than the negative group (89 cases). The former group also had more non curative resections and more undifferentiated tumors (p<0.01). The rate of mediastinal lymph node metastasis was 24.6%. The outcome was significantly worse in patients with positive mediastinal lymph node metastasis than in those without it.

Comparative Studies on Clinicopathological Characteristics and Surgical Results in Senile and Young Gastric Cancer.

80歳以上の高齢者および35歳以下の若年者胃癌を対象として臨床病理学的特徴と手術成績を比較検討した.5年ごとに両群の頻度をみると, 若年者群では増加傾向を示さないが, 高齢者群では最近の5年間で著明な増加を示した.臨床病理学的には, 高齢者は早期癌が19%と少なく, 進行癌は2型の癌が35%と多く, 4型は少なかった.手術術式はR1郭清, 胃亜全摘が多く, リンパ節転移は高齢者群でn1 (+) が多かった.組織型は分化型が77%と多くを占め, 若年者群では未分化型が88%であった.高齢者の早期癌は隆起型を主体とする分化型を示すのに対して, 若年者では陥凹型を中心とした未分化型であった.胃内の早期癌の多発病巣は高齢老に多かった.他病死を除いた高齢者の治癒切除例の5年生存率は63.3%で若年者の81.3%と比較し不良であった.死因をみると高齢者では他病死が多いのに対して若年者では癌死が多くを占めた.