Toshifusa Nakajima

Five-Year Outcomes of a Randomized Phase III Trial Comparing Adjuvant Chemotherapy With S-1 Versus Surgery Alone in Stage II or III Gastric Cancer

PURPOSE The first planned interim analysis (median follow-up, 3 years) of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer confirmed that the oral fluoropyrimidine derivative S-1 significantly improved overall survival, the primary end point. The results were therefore opened at the recommendation of an independent data and safety monitoring committee. We report 5-year follow-up data on patients enrolled onto the ACTS-GC study. PATIENTS AND METHODS Patients with histologically confirmed stage II or III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive S-1 after surgery or surgery only. S-1 (80 to 120 mg per day) was given for 4 weeks, followed by 2 weeks of rest. This 6-week cycle was repeated for 1 year. The primary end point was overall survival, and the secondary end points were relapse-free survival and safety. RESULTS The overall survival rate at 5 years was 71.7% in the S-1 group and 61.1% in the surgery-only group (hazard ratio [HR], 0.669; 95% CI, 0.540 to 0.828). The relapse-free survival rate at 5 years was 65.4% in the S-1 group and 53.1% in the surgery-only group (HR, 0.653; 95% CI, 0.537 to 0.793). Subgroup analyses according to principal demographic factors such as sex, age, disease stage, and histologic type showed no interaction between treatment and any characteristic. CONCLUSION On the basis of 5-year follow-up data, postoperative adjuvant therapy with S-1 was confirmed to improve overall survival and relapse-free survival in patients with stage II or III gastric cancer who had undergone D2 gastrectomy.

Gastric cancer treatment guidelines in Japan

Abstract.Recent developments in treatment modalities for gastric cancer have allowed the selection of a variety of treatments, and this has resulted in some confusion in daily practice. The Japan Gastric Cancer Association issued the first edition of Gastric cancer treatment guidlelines in March, 2001 to provide a common basis of understanding of the extent of disease and selection of proper treatment among doctors, patients, and their families.

Benefit of adjuvant chemotherapy for resectable gastric cancer: A meta-analysis

CONTEXT Despite potentially curative resection of stomach cancer, 50% to 90% of patients die of disease relapse. Numerous randomized clinical trials (RCTs) have compared surgery alone with adjuvant chemotherapy, but definitive evidence is lacking. OBJECTIVES To perform an individual patient-level meta-analysis of all RCTs to quantify the potential benefit of chemotherapy after complete resection over surgery alone in terms of overall survival and disease-free survival, and to further study the role of regimens, including monochemotherapy; combined chemotherapy with fluorouracil derivatives, mitomycin C, and other therapies but no anthracyclines; combined chemotherapy with fluorouracil derivatives, mitomycin C, and anthracyclines; and other treatments. DATA SOURCES Data from all RCTs comparing adjuvant chemotherapy with surgery alone in patients with resectable gastric cancer. We searched MEDLINE (up to 2009), the Cochrane Central Register of Controlled Trials, the National Institutes of Health trial registry, and published proceedings from major oncologic and gastrointestinal cancer meetings. STUDY SELECTION All RCTs closed to patient recruitment before 2004 were eligible. Trials testing radiotherapy; neoadjuvant, perioperative, or intraperitoneal chemotherapy; or immunotherapy were excluded. Thirty-one eligible trials (6390 patients) were identified. DATA EXTRACTION As of 2010, individual patient data were available from 17 trials (3838 patients representing 60% of the targeted data) with a median follow-up exceeding 7 years. RESULTS There were 1000 deaths among 1924 patients assigned to chemotherapy groups and 1067 deaths among 1857 patients assigned to surgery-only groups. Adjuvant chemotherapy was associated with a statistically significant benefit in terms of overall survival (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.76-0.90; P < .001) and disease-free survival (HR, 0.82; 95% CI, 0.75-0.90; P < .001). There was no significant heterogeneity for overall survival across RCTs (P = .52) or the 4 regimen groups (P = .13). Five-year overall survival increased from 49.6% to 55.3% with chemotherapy. CONCLUSION Among the RCTs included, postoperative adjuvant chemotherapy based on fluorouracil regimens was associated with reduced risk of death in gastric cancer compared with surgery alone.

Randomized Trial of Adjuvant Chemotherapy With Mitomycin, Fluorouracil, and Cytosine Arabinoside Followed by Oral Fluorouracil in Serosa-Negative Gastric Cancer: Japan Clinical Oncology Group 9206–1

PURPOSE To evaluate the survival benefit of adjuvant chemotherapy after curative resection in serosa-negative gastric cancer patients (excluding patients who were T1N0), we conducted a multicenter phase III clinical trial in which 13 cancer centers in Japan participated. PATIENTS AND METHODS From January 1993 to December 1994, 252 patients were enrolled into the study and allocated randomly to adjuvant chemotherapy or surgery alone. The chemotherapy comprised intravenous mitomycin 1.33 mg/m2, fluorouracil (FU) 166.7 mg/m2, and cytarabine 13.3 mg/m2 twice weekly for the first 3 weeks after surgery, and oral FU 134 mg/m2 daily for the next 18 months for a total dose of 67 g/m2. The primary end point was relapse-free survival. Overall survival and the site of recurrence were secondary end points. RESULTS Ninety-eight percent of patients underwent gastrectomy with D2 or greater lymph node dissection. There were no treatment-related deaths and few serious adverse events. There was no significant difference in relapse-free and overall survival between the arms (5-year relapse-free survival 88.8% chemotherapy v 83.7% surgery alone; P =.14 and 5-year survival 91.2% chemotherapy v 86.1% surgery alone; P =.13, respectively). Nine patients (7.1%) in the chemotherapy arm and 17 patients (13.8%) in the surgery-alone arm had cancer recurrence. CONCLUSION There was no statistically significant relapse-free or overall survival benefit with this adjuvant chemotherapy for patients with macroscopically serosa-negative gastric cancer after curative resection, and there was no statistical difference between the two arms relating to the types of cancer recurrence. We do not recommend adjuvant chemotherapy with this regimen for this population in clinical practice.

Anatomical major resection versus nonanatomical limited resection for liver metastases from colorectal carcinoma

BACKGROUND Although systematic anatomical hepatic resection has been reported to improve patient survival in hepatocellular carcinoma, principles of hepatectomy procedure have not been clearly demonstrated in secondary hepatic malignancy. The purpose of the present study was to determine whether selection of surgical procedures for liver resection is associated with the pattern of tumor recurrence or patient survival. METHODS During the period of 1980 through 1999, 174 cases underwent liver resection for hepatic metastasis from colorectal cancer. Of these, 96 underwent systematic anatomical major hepatic resection (anatomical group) and 78 cases underwent nonanatomical limited resection (nonanatomical group). Subset analysis of 115 patients with unilobar single or double tumors was also conducted. RESULTS The overall 5-year survival rate of 174 patients was 43.2%. Univariate analysis did not show a significant difference in patient survival according to surgical procedure (anatomical group versus nonanatomical group). Operative morbidity and mortality rates were slightly higher in anatomical group. From the subset analysis in unilobar single or double tumors, anatomical major hepatectomy was unnecessary in 80.4% of the cases if the tumors were resectable by nonanatomical limited resection. Ninety percent of the ipsilateral recurrence, which could have been avoided if the first operation was anatomical hemihepatectomy, could undergo second hepatectomy with 5-year survival rate of 58.3%. CONCLUSIONS There was not a significant difference in patient survival according to surgical procedure. To minimize surgical stress and operative risk, nonanatomical limited liver resection should be a basic surgical procedure for colorectal metastases.

Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial

BACKGROUND To study the survival benefit of adjuvant chemotherapy in gastric cancer, seven cancer centres in Japan carried out a phase III clinical trial of adjuvant chemotherapy after curative gastrectomy for macroscopically serosa-negative gastric cancer. METHODS 579 patients were enrolled in the study, stratified by disease stage (T1, n=188; T2, n=323), and allocated randomly adjuvant chemotherapy or no further treatment. 285 of 288 cases in the treatment group and 288 of 291 in the control group were eligible. Six cases were excluded because they did not fulfill the entry criteria. The treatment group had intravenous mitomycin (1.4 mg/m2) and fluorouracil (166.7 mg/m2) twice weekly for 3 weeks after surgery, and oral UFT (uracil plus tegafur, 300 mg daily) for 18 months. Analyses were by intention to treat. FINDINGS No serious toxic effects were observed in the treatment group. At median follow-up of 72 months, 59 patients in the control group and 47 in the treatment group had died. There was no significant difference in survival between the groups (5-year survival 82.9% control vs 85.8% treated; hazard ratio 0.738 [95% CI 0.498-1.093]). 5-year survival of patients with T1 (mucosal or submucosal) cancer in the control and treatment groups was 94.9% versus 92.0%, and that of patients with T2 (muscularis propria or subserosa) cancer was 76.9% versus 83.0%. However, a test for heterogeneity and interaction over T1 and T2 subgroups revealed no significant difference in terms of drug response. INTERPRETATION There was no survival benefit with this adjuvant therapy regimen for patients with macroscopically serosa-negative gastric cancer (T1 and T2) after curative gastrectomy. Patients with T1 cancer can be excluded from future trials, because curative surgery alone yielded a very good survival rate and there seemed no need for adjuvant therapy.

State of the art in the treatment of gastric cancer: from the 71st Japanese Gastric Cancer Congress

Abstract:The recent literatures has few reports of the state of the art and latest results in the treatment of gastric cancer, although such information is necessary for conducting new clinical trials and for obtaining informed consent from patients. In the panel discussions at the 71st Gastric Cancer Congress of Japan (held in Tokyo, June 1999), 18 representative institutions and hospitals in Japan reported their latest results for the surgical treatment of gastric cancer, indicating the state of the art in the treatment of gastric cancer. Here we report a summary of these sessions.

Predictors of Successful Hepatic Resection: Prognostic Usefulness of Hepatic Asialoglycoprotein Receptor Analysis

To test the clinical usefulness of hepatic asialogycoprotein receptor analysis in liver surgery, we have conducted univariate and multivariate analysis for the detection of cirrhotic patients and prediction of morbidity after hepatic resection. Liver scintigraphy using technetium 99m-labeled asialoglycoprotein analog (TcGSA), ICG test, and CT hepatic volumetry were undertaken in 158 surgical patients including 111 who underwent hepatic resection. Hepatic functional parameters including Child-Pugh score, indocyanine green retention at 15 minutes (ICG-R15), clearance index (HH15), receptor index (LHL15), receptor concentration ([R]0), total hepatic receptor amount (R0) and hepatic parenchymal volume (HPV) were compared among patients with normal, cirrhotic, and non-cirrhotic damaged liver. Preoperative hepatic functional parameters, resected parenchymal fraction (RPf), operative blood loss, and total receptor amount of the remnant liver (R0-remnant) were compared between patients with and without signs of postoperative liver failure. All parameters but HPV were significantly different among patients with normal, cirrhotic, and noncirrhotic damaged liver. The multivariate analysis selected two significant (p<0.05) parameters, [R]0 and Child-Pugh score for the detection of liver cirrhosis. Of the 111 patients who underwent resection, 14 developed transient signs of postoperative liver failure. Of the parameters tested, presence of liver cirrhosis, LHL15, R0, intraoperative blood loss, and R0-remnant were significantly different between patients with and without signs of postoperative liver failure (p<0.05). The multivariate logistic regression analysis selected only R0-remnant as a significant (p=0.022) parameter for the prediction of liver failure. The morbidity rate in patients with R0-remnant under 0.05 µmoles was 100%, and the rate decreased in inverse proportion to R0-remnant. in conclusion, combining the ASGP-R concentration ([R]0) and the Child-Pugh score best detected liver cirrhosis in surgical candidates. Cirrhotic patients and patients with a low R0-remnant are at higher risk for postoperative liver failure. The present study confirms the usefulness of hepatic asialogycoprotein receptor analysis in liver surgery.RésuméAfin de tester l’utilité clinique de l’analyse des récepteurs asialogycoprotéiniques (RAGP) en chirurgie hépatique, nous avons mené une étude mono et multivariée pour détecter les patients cirrhotiques et pouvoir savoir si elle pouvait prédire la morbidité après résection hépatique. On a exploré 158 patients chirurgicaux, dont 111 qui ont eu une résection hépatique, par une scintigraphie à l’analogue d’asialoglycoprotéine marqué au technetium-99m (TcGSA), le test de rétention du vert d’indigocyanine (ICG), et la volumétrie hépatique par tomodensitométrie. Pour les patients ayant un foie normal, cirrhotique et non-cirrhotique, on a comparé les paramètres fonctionnels hépatiques comprenant le score de Child-Pugh, la rétention d’ICG à 15 minutes (ICG-R15), l’indexe de clairance (HH15), l’indexe de récepteur (LHL15), la concentration en récepteur ([R]0), la quantité totale de récepteur hépatique (RO) et le volume parenchymateux hépatique (VPH). Les paramètres préopératoires hépatiques fonctionnels, la fraction de parenchyme réséquée (RPf), les pertes sanguines opératoires, et la quantité totale de récepteurs RAGP dans le foie restant (R0-remnant) ont été comparés entre les patients avec et sans insuffisance hépatique postopératoire. Tous les paramètres sauf le VPH ont différé de façon significative entre les patients à foie normal, cirrhotique et non-cirrhotique. En analyse multivariée deux facteurs sont restés significatifs (p<0.05) pour la détection de cirrhose hépatique, la [R]0 et le score de Child-Pugh. Parmi les 111 cas réséqués, 14 ont développé des signes transitoires d’insuffisance hépatique postopératoire. Parmi les paramètres testés, la présence de cirrhose hépatique, de LHL15, de [R]0, les pertes sanguines et le facteur «R0-remnant» différaient de façon significative entre les patients avec ou sans signes d’insuffisance hépatique postopératoire (p<0.05). L’analyse multivariée par régression logistique a retrouvé que le moignon R0 (p=0.022) était prédictif de l’insuffisance hépatique. Le taux de morbidité chez les patients ayant un R0-remnant en dessous des 0.05 µmoles a été de 100% et ce taux a diminué en sens inverse par rapport au taux R0-remnant. En conclusion, la meilleure prédiction de cirrhose hépatique chez les candidats à la chirurgie est fournie par la combinaison de concentrations en RAGP, le ([R]0) et le score de Child-Pugh. Les patients cirrhotiques et les patients ayant un taux R0-remnant bas sont à haut risque d’insuffisance hépatique postopératoire. Cette étude confirme l’utilité de l’analyse des RAGP hépatiques dans la chirurgie hépatique.ResumenPara comprobar la utilidad del análisis del receptor de la asialoglicoproteína hepática en cirugía de hígado, realizamos una serie de análisis uni y multivariantes para su detección en pacientes cirróticos, así como para evaluar su capacidad pronóstica por lo que a la morbilidad, tras resección hepática, se refiere. En 158 paciente quirúrgicos incluidos 111 sometidos a resección hepática se realizaron las siguientes pruebas: escintigrafía con tecnecio 99 marcado con un análago de asialoglicoproteína (TcGSA), test de ICG y volumetría hepática mediante tomografía axial computarizada (CT). Se compararon, entre pacientes con hígado normal, cirrótico y patológico por causas no cirróticas, los siguientes parámetros funcionales hepáticos: Valoración Child-Pugh, retención a los 15 minutos de ICG (ÏCG-R15), índice de aclaramiento (HH15), índice receptor (LHL15), concentración de receptor ([R]0), cantidad de recepción hepática total [R0] y volumen del parénquima hepático (HPV). Entre pacientes con y sin signos de fracaso hepático postoperatorio se compararon los siguiente parámetros: Función hepática preoperatoria, fracción parenquimatosa resecada (RPf), hemorragia y cantidad total de receptores en el remanente hepático (R0-remanent). Todos los parámetros, excepto el HPV, fueron significativamente diferentes entre pacientes con hígado normal, cirrótico y lesión hepática no cirrótica. El análisis multivariante seleccionó dos, muy significativos (p<0.05) para el diagnóstico de cirrosis: [R]0 y la valoración de Child-Pugh. 14, de los 111 casos con resección hepática, desarrollaron síndrome transitorio de fracaso hepático postoperatorio. De los parámetros estudiados: la cirrosis, LHL15, R0, hemorragia intraoperatoria y remanente R0, mostraron diferencias significativas (p<0.05) entre pacientes con o sin signos de fracaso hepático postoperatorio. El análisis de regresión logística multivariable demostró que el parámetro pronóstico más significativo de fracaso hepático es el remanente-R0 (p=0.022). La tasa de morbilidad en pacientes con un remanente-R0 inferior a 0.05 µmoles fue del 100%, disminuyendo en sentido inverso al tamaño del remanente-R0. Conclusión: las pruebas más eficaces para detectar la cirrosis hepática en posibles candidatos a tratamiento quirúrgico son: la ASGP-R concentración ([R]0) y la clasificación de Child-Pugh. Enfermos cirróticos y con un pequeño remanente-R0 son los que conllevan un mayor riesgo de fracaso hepático postoperatorio. El presente estudio confirma la utilidad, en cirugía hepática, del análisis del receptor hepático de asialoglicoproteína.

Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: A randomised trial

BACKGROUND There is conflicting evidence on the efficacy of regional adjuvant chemotherapy, via portal-vein infusion (PVI), after resection of colorectal cancer. We undertook a randomised controlled multicentre trial to investigate the efficacy of PVI (500 mg/m2 fluorouracil plus 5000 IU heparin daily for 7 days). METHODS 1235 of about 1500 potentially eligible patients were randomly assigned surgery plus PVI or surgery alone (control). The patients were followed up for a median of 63 months, with yearly screening for recurrent disease. The primary endpoint was survival; analyses were by intention to treat. FINDINGS 619 patients in the control group and 616 in the PVI group met eligibility criteria. 164 (26%) control-group patients and 173 (28%) PVI-group patients died. 5-year survival did not differ significantly between the groups (73 vs 72%; 95% Cl for difference -6 to 4). The control and PVI groups were also similar in terms of disease-free survival at 5 years (67 vs 65%) and the number of patients with liver metastases (79 vs 77%). INTERPRETATION PVI of fluorouracil, at a dose of 500 mg/m2 for 7 days, cannot be recommended as the sole adjuvant treatment for high-risk colorectal cancer after complete surgical excision. However, these results cannot eliminate a small benefit when PVI is used at a higher dosage or in combination with mitomycin.

How extensive should lymph node dissection be for cancer of the thoracic esophagus

From 1985 to 1992, 171 patients with cancer of the thoracic esophagus underwent esophagectomy with systematic dissection of regional lymph nodes including cervical nodes. The hospital mortality rate was 5.3%. The dissected nodes were classified into four groups: the deep cervical (C), upper mediastinal and cervical paratracheal (U), middle and lower mediastinal (L), and upper perigastric (G) groups. The U group mainly consisted of nodes beside the recurrent laryngeal nerves. The phase of cancer infiltration of lymph nodes was evaluated by the total number and the distribution of involved nodes. Of cases with nodal involvement, only 37% were in the late phase, in which more than seven nodes or in which the U, L, and G groups were all involved. Of cases in the earliest phase in which only one node was involved, 93% had either the U or G group involved. The C group of nodes was infrequently involved until the late phase. Cancer had metastasized to the U and G groups across a considerable anatomic distance even in earlier phases. Outcomes of the cases with nodal involvement not in the late phase were satisfactory; the cumulative survival was 60% at 3 years and 54% at 5 years. Systematic nodal dissection would benefit even cases with nodal involvement, unless the disease is in the late phase. Nodes beside the recurrent nerves and upper perigastric nodes should be dissected with higher priority, though they are located anatomically distant.