5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer.

BACKGROUND: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is the standard treatment for pathological stage II gastric cancer. The phase III trial (JCOG1104) investigating the non-inferiority of four courses of S-1 to eight courses was terminated due to futility at the first interim analysis. To confirm the primary results, we reported the results after a 5-years follow-up in JCOG1104. METHODS: Patients histologically diagnosed with stage II gastric cancer after radical gastrectomy were randomly assigned to receive S-1 for eight or four courses. In detail, 80 mg/m2/day S-1 was administered for 4 weeks followed by a 2-week rest as a single course. RESULTS: Between February 16, 2012, and March 19, 2017, 590 patients were enrolled and randomly assigned to 8-course (295 patients) and 4-course (295 patients) regimens. After a 5-years follow-up, the relapse-free survival at 3 years was 92.2% for the 8-course arm and 90.1% for the 4-course arm, and that at 5 years was 87.7% for the 8-course arm and 85.6% for the 4-course arm (hazard ratio 1.265, 95% CI 0.846-1.892). The overall survival at 3 years was 94.9% for the 8-course arm, 93.2% for the 4-course arm, and that at 5 years was 89.7% for the 8-course arm, and 88.6% for the 4-course arm (HR 1.121, 95% CI 0.719-1.749). CONCLUSIONS: The survival of the four-course arm was slightly but consistently inferior to that of the eight-course arm. Eight-course S-1 should thus remain the standard adjuvant chemotherapy for pathological stage II gastric cancer.

Association of D-dimer level with thrombotic events, bleeding, and mortality in Japanese patients with solid tumors: a Cancer-VTE Registry subanalysis.

BACKGROUND: The D-dimer test is a simple test frequently used in routine clinical screening for venous thromboembolism (VTE). The Cancer-VTE Registry was a large-scale, multicenter, prospective, observational study in Japanese patients with cancer. This study aimed to clarify the relationship between D-dimer level at cancer diagnosis (baseline) and the incidence of events during cancer treatment (1-year follow-up period). METHODS: This was a post hoc sub-analysis of patients from the Cancer-VTE Registry whose D-dimer levels were measured at baseline. The incidence of events during the 1-year follow-up period was evaluated stratified by baseline D-dimer level. Adjusted hazard ratios for D-dimer level and events during the follow-up period were evaluated. RESULTS: Among the total enrolled patients, baseline D-dimer level was measured in 9020 patients. The mean ± standard deviation baseline D-dimer level was 1.57 ± 3.94 µg/mL. During the follow-up period, the incidence of VTE, cerebral infarction/transient ischemic attack (TIA)/systemic embolic events (SEE), bleeding, and all-cause death increased with increasing baseline D-dimer level. The incidence of all-cause death increased with increasing D-dimer level regardless of cancer stage. The adjusted hazard ratio of all-cause death was 1.03 (95% confidence interval: 1.02-1.03) per 1.0-µg/mL increase in baseline D-dimer level. CONCLUSIONS: Increases in D-dimer levels were associated with a higher risk of thrombotic events, such as VTE and cerebral infarction/TIA/SEE, during cancer treatment. Furthermore, higher D-dimer levels at cancer diagnosis were associated with a higher mortality rate, regardless of cancer stage.

Incidence and risk factors for venous thromboembolism in the Cancer-VTE Registry stomach cancer subcohort.

BACKGROUND: The Cancer-VTE Registry was a large-scale, multicenter, prospective registry designed to investigate real-world data on venous thromboembolism (VTE) incidence and risk factors in adult Japanese patients with solid tumors. This pre-specified subgroup analysis aimed to estimate the incidence of VTE, including VTE types other than symptomatic VTE, and identify risk factors of VTE in stomach cancer from the Cancer-VTE Registry. METHODS: Stage II-IV stomach cancer patients who planned to initiate cancer therapy and underwent VTE screening within 2 months before registration were enrolled. RESULTS: Of 1,896 patients enrolled, 131 (6.9%) had VTE at baseline, but 96.2% were asymptomatic. Female sex, age ≥ 65 years, VTE history, and D-dimer > 1.2 µg/mL were independent risk factors of VTE at baseline. Notably, patients with D-dimer > 1.2 µg/mL at the time of cancer diagnosis had an approximately 20-fold risk of VTE. During follow-up, event incidences were symptomatic VTE, 0.3%; incidental VTE requiring treatment, 1.1%; composite VTE, 1.4%; bleeding, 1.6%; cerebral infarction/transient ischemic attack/systemic embolic events, 0.7%; and all-cause death, 15.0%. The incidence of all-cause death was higher in patients with VTE vs without VTE at baseline (adjusted hazard ratio 1.67; 95% confidence interval 1.21-2.32; p = 0.002). CONCLUSIONS: VTE prevalence at the time of cancer diagnosis was not negligible and was extremely high when the patients had high D-dimer. VTE screening by D-dimer before starting cancer treatment is advisable, even for asymptomatic patients, regardless of whether the patient is undergoing surgery or chemotherapy. TRIAL REGISTRATION: UMIN000024942.

Identifying Risk Factors of Complications following Total Gastrectomy for Gastric Cancer: Comparison between Splenectomy and Spleen-Preserving Surgery - A Supplementary Analysis of JCOG0110.

INTRODUCTION: Splenectomy for proximal gastric cancer was found to offer no survival benefit in a randomized trial clarifying the role of splenectomy (JCOG0110 study). Although many studies have explored risk factors for morbidities following total gastrectomy, none have assessed the risk factors for postoperative complications in spleen-preserving total gastrectomy. METHODS: Using data from 505 patients enrolled in a previous randomized trial, risk factors for postoperative complications were identified by multivariable logistic regression analysis. Then, the risk factors were assessed separately between splenectomy and spleen-preserving total gastrectomy. RESULTS: Postoperative complications were identified in 119 patients (23.6%) and were more common following splenectomy than following spleen-preserving surgery (30.7% and 16.1%, respectively, p < 0.01). Multivariable analysis revealed that age ≥65 years (p = 0.032), body mass index ≥25 (p = 0.003), and blood loss ≥350 (p = 0.019) were independent risk factors for postoperative complications in the entire cohort. Among them, only body mass index was a significant independent risk factor for complications in both spleen preservation (p = 0.047) and splenectomy groups (p = 0.017). CONCLUSION: Risk factors for postoperative complications were essentially the same between splenectomy and spleen preservation. Being overweight increased the risk of postoperative complications.

Five-year follow-up of a randomized clinical trial comparing bursectomy and omentectomy alone for resectable gastric cancer (JCOG1001).

BACKGROUND: Bursectomy, the total resection of the bursa omentalis, is a standard procedure in gastrectomy for resectable gastric cancer. A phase III trial (JCOG1001) comparing bursectomy and omentectomy alone was terminated early at the interim analysis. The final results of the updated analysis after a minimum follow-up of 5 years are reported here. METHODS: Patients with histologically proven adenocarcinoma of the stomach (cT3-T4a) were randomized (1 : 1) during surgery to bursectomy or omentectomy-alone groups and then underwent D2 gastrectomy. The primary endpoint was overall survival, analysed on an intention-to-treat basis. RESULTS: A total of 1204 patients (602 bursectomy and 602 omentectomy alone) were enrolled between June 2010 and March 2015. The bursectomy group had a significantly higher incidence of Clavien-Dindo grade III-IV intra-abdominal abscess than the omentectomy-alone group (5.5 versus 2.5 per cent respectively; P = 0.008). The updated 5-year overall survival rates were 74.9 (95 per cent c.i. 71.2 to 78.2) per cent in the bursectomy group and 76.5 (72.8 to 79.7) per cent in the omentectomy-alone group; the adjusted HR for death in the bursectomy group was 1.03 (95 per cent c.i. 0.83 to 1.27) (1-sided P = 0.598). Bursectomy did not decrease peritoneal recurrence (12.1 versus 12.3 per cent respectively; P = 1.000). In a multivariable analysis, old age (above 65 years), tumour located in the lower third or posterior wall of the stomach, macroscopic type 3/5, total gastrectomy, and cT4a were independent predictors of poor overall survival, but omentectomy alone was not. CONCLUSION: In D2 gastrectomy, bursectomy is not recommended as a standard procedure for cT3-T4a gastric cancer. Registration number: UMIN000003688 (https://www.umin.ac.jp/ctr/).

The Amount and Concentration of Drain Amylase Together Predict Postoperative Pancreatic Fistula after Gastric Cancer Surgery More Accurately than the Concentration Alone.

INTRODUCTION: The drain amylase concentration (dAmy-C) is a useful marker for predicting pancreatic fistula after gastric cancer surgery. However, dAmy-C might be reduced in cases of high drainage volume. Therefore, we hypothesized that we could accurately assess the amount of amylase leaked from the pancreas by multiplying dAmy-C by the daily drainage volume. In this study, we investigated the clinical utility of the amount of drain amylase (A-dAmy: concentration × volume) for predicting pancreatic fistula. We investigated the clinical utility of the combination of dAmy-C and A-dAmy for predicting pancreatic fistula. METHODS: We investigated patients who underwent gastrectomy for gastric cancer at Yodogawa Christian Hospital between 2012 and 2020. The optimal cutoff levels of dAmy-C and A-dAmy on postoperative day 1 for predicting Clavien-Dindo (CD) grade II or higher pancreatic fistula was calculated using receiver operating characteristic (ROC) curves. We calculate the positive predictive value and negative predictive value for predicting pancreatic fistula using these cutoff levels. RESULTS: A total of 448 patients were eligible for analysis. Twenty-two patients experienced CD grade II or higher pancreatic fistula. ROC curves identified 1,615 IU/L as the optimal cutoff level of dAmy-C, predicting pancreatic fistula. When the simple cutoff level of dAmy-C was 1,600 IU/L, the positive predictive value for was 22.8%, and the negative predictive value was 99.7%. ROC curves identified 177.52 IU as the optimal cutoff level of A-dAmy predicting pancreatic fistula. When the simple cutoff level of A-dAmy was 177 IU, the positive predictive value was 21.2%, and the negative predictive value was 99.7%. Using these two cutoff levels together, the positive predictive value was 34.4%, and the negative predictive value was 99.7%. CONCLUSION: A-dAmy could predict and exclude pancreatic fistula after gastrectomy as with dAmy-C. The combination of dAmy-C and A-dAmy predict pancreatic fistula more accurately than dAmy-C alone.

Negative impact of intraoperative blood loss on long-term outcome after curative gastrectomy for advanced gastric cancer: exploratory analysis of the JCOG1001 phase III trial.

BACKGROUND: Recent retrospective studies have shown that increased intraoperative blood loss (IBL) during curative gastrectomy for patients with advanced gastric cancer is a negative prognostic indicator for recurrence. However, there are no reliable reports assessing this with a large-scale prospective cohort. This study aimed to evaluate the impact of IBL on long-term outcomes using data from the JCOG1001 phase III trial, which was designed to determine if bursectomy led to improved survival vs. nonbursectomy in patients with cT3/4a gastric cancer. METHODS: This study included 1203 of the 1204 patients enrolled in the JCOG1001. From the tertiles of IBL (196 ml, 400 ml), we divided the patients into three groups: IBL < 200 ml representing small blood loss (SBL, n = 404), 200 ml ≤ IBL < 400 ml representing medium blood loss (MBL, n = 393), and IBL ≥ 400 ml representing large blood loss (LBL, n = 406). The impact of IBL on relapse-free survival (RFS) was evaluated with univariable comparisons and multivariable Cox regression analyses. RESULTS: Three-year RFS after SBL, MBL, and LBL was 81.7%, 74.8%, and 70.6%, respectively. Multivariable analysis identified IBL, Eastern Cooperative Oncology Group performance status, pT, pN, and postoperative adjuvant chemotherapy as independent predictors of RFS. Compared with SBL as a reference, the hazard ratios of MBL and LBL were 1.461 (P = 0.012) and 1.520 (P = 0.009), respectively. CONCLUSIONS: Based on the analysis of data from a large-scale prospective study, an IBL of ≥ 200 ml after curative surgery for patients with cT3/4a gastric cancer was an independent predictor of reduced RFS.

Impact of tumor-related factors and inter-institutional heterogeneity on preoperative T staging for gastric cancer.

Background: To improve the diagnostic accuracy of preoperative T staging in gastric cancer, the authors evaluated tumor-related factors that might affect the diagnosis. Materials & methods: The authors analyzed the data of cT2-4b gastric cancer patients enrolled in the prospective, multicenter JCOG1302A study. They used contrast-enhanced computed tomography to analyze the association between tumor-related factors and the diagnostic accuracy of T3-4b staging for gastric cancer. Results: Among 876 cT3-4b tumors, the diagnostic accuracy was relatively low in the lower third of the stomach compared with those in the upper or middle. A multivariable analysis revealed that accuracy was higher in the lesser curvature or entire circumference region than in other areas (p < 0.001), in macroscopic types 3/5 than in types 0/1/2 (p = 0.003) and in the undifferentiated histological type than in the differentiated type (p = 0.011). Conclusion: The authors found tumor-related factors affecting preoperative T staging by enhanced computed tomography.

Additional chemotherapy before surgery is expected to have potentially beneficial effects on prognosis compared with chemotherapy only after surgery for advanced gastric cancer. The consideration of chemotherapy before surgery depends on preoperative diagnosis of the depth of tumor invasion in the stomach wall. Overdiagnosis of the depth of tumor invasion may lead to unnecessary administration of chemotherapy that is harmful to the patient. Tumor-related factors such as tumor location, macroscopic type and histological type may affect the diagnosis. Therefore, these factors should be considered with special care for the diagnosis, which may lead to higher accuracy in diagnosing the depth of tumor invasion in gastric cancer.

Association of renal function with the safety and efficacy of cisplatin plus S-1 therapy and docetaxel plus cisplatin plus S-1 therapy in patients with advanced gastric cancer: an exploratory analysis of JCOG1013.

BACKGROUND: Although cisplatin and 5-chloro-2,4-dihydropyrimidine (dihydropyrimidine dehydrogenase inhibitor contained in S-1) are excreted into the urine, it remains unknown how creatinine clearance (CrCl) affects the safety and efficacy of cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 in patients with advanced gastric cancer. METHODS: Among the 741 participants in JCOG1013 comparing cisplatin plus S-1 with docetaxel plus cisplatin plus S-1, 723 with serum creatinine levels ≤1.2 mg/dL were categorized into A1 (CrCl ≥ 80 mL/min), A2 (60 ≤ CrCl <80) and A3 (CrCl < 60) in the cisplatin plus S-1 arm and similarly B1, B2 and B3 in the docetaxel plus cisplatin plus S-1 arm. The initial dose modification by CrCl was pre-specified in the docetaxel plus cisplatin plus S-1 arm but not in the cisplatin plus S-1 arm. RESULTS: The numbers of patients categorized as A1/A2/A3 and B1/B2/B3 were 169/136/57 and 170/138/53, respectively. In the cisplatin plus S-1 arm, a lower CrCl was associated with higher incidences of grade 4 leukopenia (P = 0.006), neutropenia (P = 0.002), and grade 3/4 anorexia (P = 0.004) and febrile neutropenia (P = 0.049), whereas there was no association in the docetaxel plus cisplatin plus S-1 arm. No significant differences were observed according to CrCl in the overall survival [median: 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.886) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.719)], progression-free survival [median: 7.1/6.8/6.2 months in A1/A2/A3 (P = 0.884) and 7.5/7.2/7.8 months in B1/B2/B3 (P = 0.851)] and response rates [58.9/57.8/46.9% in A1/A2/A3 (P = 0.311) and 62.0/61.5/51.5% in B1/B2/B3 (P = 0.362)]. CONCLUSIONS: Renal impairment was associated with severe adverse events in cisplatin plus S-1 therapy but not with the efficacy in cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 therapy.

Is the ISGPS definition of pancreatic fistula applicable after gastrectomy?

BACKGROUND: Pancreatic fistula is one of the most common and potentially fatal surgical complications after radical gastrectomy. The purpose of this study was to assess the validity of extrapolating the definition of pancreatic fistula by the International Study Group on Pancreatic Surgery to include situations surrounding gastric cancer surgery. METHODS: The clinicopathological data of 443 patients who underwent elective gastrectomy with suprapancreatic lymph node dissection (D1+, D2, or D2+ dissection) without pancreatic resection were reviewed. The relationship between postoperative pancreas-related complications (PPRC) and laboratory data, including drain fluid amylase levels on postoperative day 1 (dAmy1) and day 3 (dAmy3), were investigated. RESULTS: Twenty-four patients (5.4%) developed PPRC of ≥ grade II according to Clavien-Dindo classification. Among them, 15 patients had dAmy3 levels ≥ 375 IU/L, while all 24 patients had dAmy1 levels ≥ 375 IU/L. None of the patients with dAmy1 levels < 375 IU/L developed PPRC. The area under the curve of dAmy1 and dAmy3, calculated by drawing receiver operating characteristic curves, were 0.896 and 0.791, respectively. Univariate and multivariate analyses demonstrated that both dAmy1 and dAmy3 were significant predictors of PPRC; however, dAmy1 (p < 0.001) was more strongly correlated with PPRC than dAmy3 (p = 0.049). CONCLUSIONS: DAmy1 is more sensitive than dAmy3 as an indicator of pancreatic fistula after gastric cancer surgery.

Posttherapy topographical nodal status, ypN-site, predicts survival of patients who received neoadjuvant chemotherapy followed by curative surgical resection for non-type 4 locally advanced gastric cancer: supplementary analysis of JCOG1004-A.

BACKGROUND: Perioperative treatment is an accepted standard approach for treating locally advanced gastric cancer (LAGC). Histopathological tumor regression with < 10% residual tumor is a globally accepted prognosticator in LAGC patients who received neoadjuvant chemotherapy (NAC) and curative surgery. However, despite a response of the primary tumor, a significant percentage of patients dies from recurrence and identification of those at risk for relapse remains challenging. We re-estimated the value of histopathological tumor regression as a prognosticator alongside other factors, especially posttherapy topographical nodal status, ypN-site. PATIENTS AND METHODS: Individual patient data including clinicopathological variables were used from the four JCOG trials investigating NAC (JCOG0001, JCOG0002, JCOG0210, JCOG0405) for analyzing prognosticators in patients with curative surgery excluding those with type 4 AGC by univariable and multivariable Cox regression analyses. RESULTS: Among 85 patients, 5-year overall survival (OS) was 46.0% [95% confidence interval (CI) 35.0-56.4] with a median follow-up of 3.2 years. On univariable analysis, histopathological tumor regression with ≥ 10% residual tumor and ypN-site 2-3 were negatively associated with OS [≥ 10% residual tumor: hazard ratio (HR) 2.60; 95% CI 1.22-5.54; P = 0.014; ypN2-3: HR 3.59; 95% CI 1.60-8.06; P = 0.002). On multivariable analysis, only ypN-site 2-3 was predictive of OS (HR 3.67; 95% CI 1.55-8.69; P = 0.003), whereas histopathological tumor regression with ≥ 10% residual tumor was not (HR 2.24; 95% CI 0.98-5.10; P = 0.055). CONCLUSIONS: ypN-site may have greater impact on OS than histopathological tumor regression in patients who received NAC plus surgery for non-type 4 LAGC.

Gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer (JCOG0501): an open-label, phase 3, randomized controlled trial.

BACKGROUND: Specific treatment strategies are sorely needed for scirrhous-type gastric cancer still, which has poor prognosis. Based on the promising results of our previous phase II study (JCOG0210), we initiated a phase III study to confirm the efficacy of neoadjuvant chemotherapy (NAC) in type 4 or large type 3 gastric cancer. METHODS: Patients aged 20-75 years without a macroscopic unresectable factor as confirmed via staging laparoscopy were randomly assigned to surgery followed by adjuvant chemotherapy with S-1 (Arm A) or NAC (S-1plus cisplatin) followed by D2 gastrectomy plus adjuvant chemotherapy with S-1 (Arm B). The primary endpoint was overall survival (OS). RESULTS: Between October 2005 and July 2013, 316 patients were enrolled, allocating 158 patients to each arm. In Arm B, in which NAC was completed in 88% of patients. Significant downstaging based on tumor depth, lymph node metastasis, and peritoneal cytology was observed using NAC. Excluding the initial 16 patients randomized before the first revision of the protocol, 149 and 151 patients in arms A and B, respectively, were included in the primary analysis. The 3-year OS rates were 62.4% [95% confidence interval (CI) 54.1-69.6] in Arm A and 60.9% (95% CI 52.7-68.2) in Arm B. The hazard ratio of Arm B against Arm A was 0.916 (95% CI 0.679-1.236). CONCLUSIONS: For type 4 or large type 3 gastric cancer, NAC with S-1 plus cisplatin failed to demonstrate a survival benefit. D2 surgery followed by adjuvant chemotherapy remains the standard treatment.

Determinant Factors on Differences in Survival for Gastric Cancer Between the United States and Japan Using Nationwide Databases.

BACKGROUND: Although the incidence and mortality have decreased, gastric cancer (GC) is still a public health issue globally. An international study reported higher survival in Korea and Japan than other countries, including the United States. We examined the determinant factors of the high survival in Japan compared with the United States. METHODS: We analysed data on 78,648 cases from the nationwide GC registration project, the Japanese Gastric Cancer Association (JGCA), from 2004-2007 and compared them with 16,722 cases from the Surveillance, Epidemiology, and End Results Program (SEER), a United States population-based cancer registry data from 2004-2010. We estimated 5-year relative survival and applied a multivariate excess hazard model to compare the two countries, considering the effect of number of lymph nodes (LNs) examined. RESULTS: Five-year relative survival in Japan was 81.0%, compared with 45.0% in the United States. After controlling for confounding factors, we still observed significantly higher survival in Japan. Among N2 patients, a higher number of LNs examined showed better survival in both countries. Among N3 patients, the relationship between number of LNs examined and differences in survival between the two countries disappeared. CONCLUSION: Although the wide differences in GC survival between Japan and United States can be largely explained by differences in the stage at diagnosis, the number of LNs examined may also help to explain the gaps between two countries, which is related to stage migration.

The Combined Use of Drainage Amylase Concentration and Serum C-reactive Protein as Predictors of Pancreas-Related Complications after Elective Gastrectomy.

INTRODUCTION: Postoperative pancreas-related complications (PPRC) can cause critical conditions, including sepsis and intra-abdominal bleeding. Thus, it is important to identify patients who are at risk of clinically significant PPRC as early as possible in the postoperative period. Some authors have reported the use of amylase concentration of the drainage fluid (dAmy) to predict PPRC. However, the positive predictive value of dAmy alone is not sufficient. OBJECTIVE: The aim of this study is to evaluate the predictive value of combined use of dAmy and serum C-reactive protein (sCRP) for PPRC. METHODS: The clinicopathological data of 327 patients who underwent elective gastrectomy for gastric cancer were reviewed. There were 18 patients who developed PPRC. Univariate and multivariate analyses were conducted to identify the risk factors of PPRC. Receiver operating characteristic curves were used to identify the cut-off values of dAmy and sCRP on postoperative day 3 (dAmy3 and sCRP3) to predict the risk of PPRC. RESULTS: In the multivariate analysis, splenectomy alone correlated with PPRC. The cut-off values of dAmy3 and sCRP3 were 761 IU/L and 15.15 mg/dL, respectively. Among the 17 patients with both dAmy3 and sCRP3 above the thresholds, 10 (58.8%) had PPRC with Clavien-Dindo classification (CD) ≥II and 7 (41.2%) had PPRC with CD ≥III. In contrast, among the 236 patients with both parameters below the thresholds, 233 (98.7%) did not develop PPRC, and only 1 (0.4%) had PPRC with CD ≥III. CONCLUSIONS: Splenectomy correlates with PPRC, which is consistent with results from large clinical trials. A combined use of dAmy3 and sCRP3 can be useful in predicting the risks of PPRC.

Long-term outcomes of preoperative docetaxel with cisplatin plus S-1 therapy for gastric cancer with extensive nodal metastasis (JCOG1002).

BACKGROUND: Preoperative chemotherapy with cisplatin plus S-1 (CS) followed by gastrectomy with D2 plus para-aortic lymph node (PAN) dissection is regarded as a standard treatment in Japan for advanced gastric cancer with bulky lymph node (BN) and/or PAN metastasis. In the JCOG1002, we added docetaxel to CS (DCS) to further improve long-term outcomes. However, the primary endpoint, clinical response rate (RR), did not reach the expected level (Ito et al. in Gastric Cancer 20:322-31, 2017). Herein, we report our long-term survival results. METHODS: Patients with BN and/or PAN metastasis received 2 or 3 cycles of DCS therapy (docetaxel at 40 mg/m2 and cisplatin at 60 mg/m2 on day 1 and S-1 at 80 mg/m2 per day for 2 weeks, followed by a 2-week rest) followed by gastrectomy with D2 plus PAN dissection and postoperative S-1 for 1 year. RESULTS: Between July 2011 and May 2013, 53 patients were enrolled. Clinically, 17.0% had both PAN and BN metastasis, and the rest had either PAN (26.4%) or BN (56.6%) metastasis. Among all eligible patients, the 5-year overall survival was 54.9% (95% confidence interval 40.3-67.3%) at the last follow-up in May 2018. Among 44 eligible patients with R0 resection, the 5-year relapse-free survival was 47.7% (95% confidence interval 32.5-61.5%). CONCLUSIONS: Adding docetaxel to CS in preoperative chemotherapy for extensive nodal metastasis improved neither short-term outcomes nor long-term survival. Preoperative chemotherapy with CS followed by D2 + PAN dissection and postoperative S-1 remains the standard of care for patients with extensive nodal metastasis.

Current status of perioperative chemotherapy for locally advanced gastric cancer and JCOG perspectives.

Perioperative treatment for locally advanced gastric cancer has been inconsistent between Japan and the Western countries. In Japan, D2 gastrectomy followed by adjuvant chemotherapy is regarded as standard treatment, while neoadjuvant or perioperative chemotherapy is considered to be a standard in the Western countries. Stomach Cancer Study Group of Japan Clinical Oncology Group (JCOG) has conducted many perioperative chemotherapy trials. After the publishing of positive results of ACTS-GC trial, stage-specific adjuvant chemotherapy protocols are planned. JCOG1104 was conducted as to demonstrate the non-inferiority of four courses of S-1 to standard eight courses of S-1, because the efficacy of S-1 appears to be sufficient in stage II. The trial failed to demonstrate the non-inferiority of four courses of S-1. S-1 for 1 year is still recognized to be a standard for stage II gastric cancer. For stage III, studies with more intensive treatments were planned as the efficacy of S-1 monotherapy seems to be insufficient. As in the Western countries, JCOG planned the perioperative chemotherapy. However, the clinical staging is a serious issue to select optimal patients for perioperative chemotherapy. JCOG conducted a prospective cohort study to evaluate the validity of clinical staging in JCOG1302A. From the results of this study, cT3-4 and cN1-3 are selected as optimal candidate for perioperative chemotherapy. JCOG1509 was conducted to demonstrate the superiority of perioperative chemotherapy to adjuvant chemotherapy in these cohorts. Perioperative chemotherapy for marginally resectable tumours such as linitis plastica or extensive nodal disease and special type of cancer like HER2 positive are also conducted.

Venous thromboembolism in cancer patients: report of baseline data from the multicentre, prospective Cancer-VTE Registry.

BACKGROUND: The Cancer-VTE Registry evaluates the occurrence and management of venous thromboembolism in Japanese participants with major solid tumors. Using Registry data, we evaluated the frequency of concurrent venous thromboembolism in cancer patients prior to treatment initiation by cancer type. METHODS: The Cancer-VTE Registry is an ongoing (March 2017-September 2020) prospective cohort study using a nationwide, multicentre clinical registry. Participants aged ≥20 years with colorectal, lung, stomach, pancreatic, breast or gynecologic cancer, confirmed staging, ≥6 months life expectancy post-registration and who had undergone venous thromboembolism screening were managed with routine clinical care. Venous thromboembolism frequency at registration was evaluated. RESULTS: Of 9735 participants, 571 (5.9%) had venous thromboembolism at baseline, including asymptomatic [5.5% (n = 540)] and symptomatic venous thromboembolism [0.3% (n = 31)]. Most participants with venous thromboembolism (n = 506, 5.2%) had deep vein thrombosis only; 65 (0.7%) had pulmonary embolism with/without deep vein thrombosis. The prevalence of distal and proximal deep vein thrombosis was 4.8% (n = 466) and 0.9% (n = 83), respectively. The highest prevalence of venous thromboembolism was for pancreatic cancer (8.5%) and the lowest for breast cancer (2.0%). Venous thromboembolism prevalence increased as cancer stage advanced. CONCLUSIONS: Although there was a marked difference in venous thromboembolism by cancer type, the data suggest that cancer stage is an important risk factor for venous thromboembolism. Thus, metastasis seems a critical risk factor for venous thromboembolism. This is the first demonstration of venous thromboembolism prevalence and risk factors in Japanese cancer patients prior to treatment. TRIAL REGISTRATION: UMIN000024942.

Survival Outcomes of Two Phase 2 Studies of Adjuvant Chemotherapy with S-1 Plus Oxaliplatin or Capecitabine Plus Oxaliplatin for Patients with Gastric Cancer After D2 Gastrectomy.

BACKGROUND: Two phase 2 trials of oxaliplatin-containing adjuvant therapy for patients with gastric cancer (GC) after D2 gastrectomy were conducted in Japan. The SOXaGC trial evaluated the tolerability and safety of adjuvant therapy with S-1 plus oxaliplatin (SOX), whereas the J-CLASSIC trial evaluated the feasibility of adjuvant therapy with capecitabine plus oxaliplatin (CAPOX). Because both were studies that did not evaluate survival results as study end points, the authors evaluated the survival outcomes for the patients in the two trials. METHODS: All 62 and 100 patients in the full analysis set of the SOXaGC and J-CLASSIC trials, respectively, were included in the current study. Their information about survival outcome was collected. The primary end point was relapse-free survival (RFS), and the secondary end point was overall survival (OS). RESULTS: For the pathologic stage (pStage 2) patients treated with CAPOX, the 3-year RFS rate was 87.8% and the 3-year OS rate was 92.7%. For the pStage 3 patients treated with SOX and CAPOX, the 3-year RFS rates were respectively 70.9% and 67.8% (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.50-1.72), whereas the 3-year OS rates were respectively 75.7% and 79.3% (HR, 1.10; 95% CI, 0.54-2.26). Subgroup analysis showed significant interactions between the treatment (SOX vs. CAPOX) and both sex (male vs. female; P = 0.024) and histologic type (diffuse vs. other, P = 0.069). CONCLUSIONS: This exploratory analysis demonstrated that SOX and CAPOX are suggested to have similar efficacy for pStage 3 GC patients after D2 gastrectomy. Differences in the treatment effect according to sex and histologic type warrant further evaluation.

An integrated analysis of two phase II trials (JCOG0001 and JCOG0405) of preoperative chemotherapy followed by D3 gastrectomy for gastric cancer with extensive lymph node metastasis.

BACKGROUND: Gastric cancer with extensive lymph node metastasis is commonly regarded as unresectable, while preoperative chemotherapy followed by gastrectomy has been tested since 2000 in JCOG (JCOG0001 and JCOG0405). The survivals were quite different between the trials despite the similar eligibility criteria. The aim of this study was to investigate if survival is still better in JCOG0405 after adjusting baseline factors and if there is any subset of patients who benefit more from either treatment. METHODS: Eligibility criteria for both trials included histologically proven gastric adenocarcinoma; bulky nodal involvement around the celiac artery and its major branches (bulky N) and/or para-aortic lymph node (PAN); cM0 (except PAN); negative lavage cytology; not linitis plastica type; PS of 0 or 1. Patients received two or three cycles of preoperative chemotherapy of irinotecan plus cisplatin in JCOG0001, or S-1 plus cisplatin in JCOG0405, followed by D3 gastrectomy. Multivariable analysis for overall survival adjusting baseline and treatment factors was performed with the Cox regression model. RESULTS: After adjusting baseline factors, S-1 plus cisplatin was superior to irinotecan plus cisplatin for overall survival (HR = 0.39: 95% CI 0.22-0.67). The 5-year overall survival was poor for patients with bulky N+/PAN+ (19.2%) compared with bulky N+/PAN- (50.7%) or bulky N-/PAN+ (43.5%). CONCLUSIONS: S-1 plus cisplatin was shown to be a favorable preoperative treatment for gastric cancer with extensive lymph node metastasis by multivariable analysis, while poor prognosis in patients having both bulky N+ and PAN+ may necessitate further treatment improvement.

Randomized phase III trial of gastrectomy with or without neoadjuvant S-1 plus cisplatin for type 4 or large type 3 gastric cancer, the short-term safety and surgical results: Japan Clinical Oncology Group Study (JCOG0501).

BACKGROUND: The prognosis of patients with linitis plastica (type 4) and large (≥ 8 cm) ulcero-invasive-type (type 3) gastric cancer is extremely poor, even after extended surgery and adjuvant chemotherapy. Given the promising results of our previous phase II study evaluating neoadjuvant chemotherapy (NAC) with S-1 plus cisplatin (JCOG0210), we performed a phase III study to confirm the efficacy of NAC in these patients, with the safety and surgical results are presented here. METHODS: Eligible patients were randomized to gastrectomy plus adjuvant chemotherapy with S-1 (Arm A) or NAC followed by gastrectomy + adjuvant chemotherapy (Arm B). The primary endpoint was the overall survival (OS). This trial is registered at the UMIN Clinical Trials Registry as C000000279. RESULTS: From February 2007 to July 2013, 300 patients were randomized (Arm A 149, Arm B 151). NAC was completed in 133 patients (88%). Major grade 3/4 adverse events during NAC were neutropenia (29.3%), nausea (5.4%), diarrhea (4.8%), and fatigue (2.7%). Gastrectomy was performed in 147 patients (99%) in Arm A and 139 patients (92%) in Arm B. The operation time was significantly shorter in Arm B than in Arm A (median 255 vs. 240 min, respectively; p = 0.024). There were no significant differences in Grade 2-4 morbidity and mortality (25.2% and 1.3% in Arm A and 15.8% and 0.7% in Arm B, respectively). CONCLUSIONS: NAC for type 4 and large type 3 gastric cancer followed by D2 gastrectomy can be safely performed without increasing the morbidity or mortality.