Background
Postoperative intra-abdominal infectious complication (PIIC) after gastrectomy for gastric cancer worsens in-hospital death or long-term survival. However, the methodology for PIIC ...preoperative risk assessment remains unestablished. We aimed to develop a preoperative risk model for postgastrectomy PIIC.
Methods
We collected 183,936 patients’ data on distal or total gastrectomy performed in 2013–2016 for gastric cancer from the Japanese National Clinical Database and divided into development (2013–2015;
n
= 140,558) and validation (2016;
n
= 43,378) cohort. The primary outcome was the incidence of PIIC. The risk model for PIIC was developed using 18 preoperative factors: age, sex, body mass index, activities of daily living, 12 comorbidity types, gastric cancer stage, and surgical procedure in the development cohort. Secondarily, we developed another model based on the new scoring system for clinical use using selected factors.
Results
The overall incidence of PIIC was 4.7%, including 2.6%, 1.7%, and 1.3% in anastomotic leakage, pancreatic fistula, and intra-abdominal abscess, respectively. Among the 18 preoperative factors, male odds ratio, (OR) 1.92, obesity (OR, 1.52–1.96), peripheral vascular disease (OR, 1.55), steroid use (OR, 1.83), and total gastrectomy (OR, 1.89) strongly correlated with PIIC incidence. The entire model using the 18 factors had good discrimination and calibration in the validation cohort. We selected eight relevant factors to create a simple scoring system, using which we categorized the patients into three risk groups, which showed good calibration.
Conclusion
Using nationwide clinical practice data, we created a preoperative risk model for postgastrectomy PIIC for gastric cancer.
Background
To evaluate the feasibility and accuracy of diagnosis using sentinel node (SN) biopsy in T1 gastric cancer, a multicenter trial was conducted by the Japan Clinical Oncology Group (JCOG).
...Methods
Sentinel node biopsy with indocyanine green (ICG) was performed in patients with T1 gastric cancer. Green-stained nodes (GNs), representing SNs, were removed first, and gastrectomy with lymphadenectomy was then performed. GNs in one plane (with the largest dimension) were histologically examined intraoperatively by frozen section with hematoxylin and eosin (H&E) stain. All harvested lymph nodes (GNs and non-GNs) were histologically examined by paraffin section after surgery. The primary endpoint was to determine the proportion of false negatives, which was defined as the number of patients with negative GNs by frozen section divided by those with positive GNs and/or positive non-GNs by paraffin section. The sample size was set at 1,550, based on the expected and threshold value as 5 and 10 % in the proportion of false negatives.
Results
Accrual was suspended when 440 patients were enrolled because the proportion of false negatives was high. In the primary analysis, the proportion of false negatives was 46 % (13/28) after a learning period with 5 patients for each institution. Seven of 13 patients had nodal metastases outside the lymphatic basin. False negatives remained at 14 % (4/28) even by examining additional sections of GNs by paraffin section.
Conclusions
The proportion of false negatives was much higher than expected. Intraoperative histological examination using only one plane is not an appropriate method for clinical application of SN biopsy in gastric cancer surgery.
Background
Adjuvant therapy for gastric cancer is a standard among the world with no regimen selection criteria. Also, prognostic factors except for tumor staging have not been established. We aimed ...to identify prognostic and predictive markers for gastric cancer adjuvant therapy from large randomized controlled trials with standard lymph node dissection.
Methods
Three studies: ACTS-GC, CLASSIC, and SAMIT were found and selected for a pooled analysis, following PRISMA guideline. The integrity of individual participant data (IPD) was verified in the eligible 3527 patients registered, and fixed-effect model was used. The primary endpoint was relapse-free survival (RFS) and the secondary endpoint was overall survival (OS).
Results
Age was a significant prognostic factor in addition to tumor stages both in “surgery alone” and “adjuvant” groups. Adjuvant therapy was effective for every TN stage; however, it tended to be more effective in T1–2 than in T3–4. Also, it was more effective in low- or middle-BMI than in high-BMI group with Hazard ratio HRs: 0.58, 0.58, and 1.05, respectively. Capecitabine plus oxaliplatin (CAPOX) was more effective than S-1 for T1–2, N2–3, and differentiated type with HRs between 0.59 and 0.70, but with no difference among TNM stages. Combining histology to TN; the HRs in differentiated T1–2 N1–3 groups were between 0.29 and 0.45. For T3–4 N0–1 group, S-1 was likely to be effective, not significant.
Conclusions
Age is a significant prognostic factor both in surgery alone and adjuvant group. CAPOX is more effective for differentiated T1–2 tumors with lymph node metastasis.
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.
Biomarkers for selecting gastric cancer (GC) patients likely to benefit from sequential paclitaxel treatment followed by fluorinated-pyrimidine-based adjuvant chemotherapy (sequential paclitaxel) ...were investigated using tissue samples of patients recruited into SAMIT, a phase III randomized controlled trial. Total RNA was extracted from 556 GC resection samples. The expression of 105 genes was quantified using real-time PCR. Genes predicting the benefit of sequential paclitaxel on overall survival, disease-free survival, and cumulative incidence of relapse were identified based on the ranking of p-values associated with the interaction between the biomarker and sequential paclitaxel or monotherapy groups. Low VSNL1 and CD44 expression predicted the benefit of sequential paclitaxel treatment for all three endpoints. Patients with combined low expression of both genes benefitted most from sequential paclitaxel therapy (hazard ratio = 0.48 95% confidence interval, 0.30-0.78; p < 0.01; interaction p-value < 0.01). This is the first study to identify VSNL1 and CD44 RNA expression levels as biomarkers for selecting GC patients that are likely to benefit from sequential paclitaxel treatment followed by fluorinated-pyrimidine-based adjuvant chemotherapy. Our findings may facilitate clinical trials on biomarker-oriented postoperative adjuvant chemotherapy for patients with locally advanced GC.
Background & Aims Gastric cancer (GC) is a heterogeneous disease comprising multiple subtypes that have distinct biological properties and effects in patients. We sought to identify new, intrinsic ...subtypes of GC by gene expression analysis of a large panel of GC cell lines. We tested if these subtypes might be associated with differences in patient survival times and responses to various standard-of-care cytotoxic drugs. Methods We analyzed gene expression profiles for 37 GC cell lines to identify intrinsic GC subtypes. These subtypes were validated in primary tumors from 521 patients in 4 independent cohorts, where the subtypes were determined by either expression profiling or subtype-specific immunohistochemical markers (LGALS4, CDH17). In vitro sensitivity to 3 chemotherapy drugs (5-fluorouracil, cisplatin, oxaliplatin) was also assessed. Results Unsupervised cell line analysis identified 2 major intrinsic genomic subtypes (G-INT and G-DIF) that had distinct patterns of gene expression. The intrinsic subtypes, but not subtypes based on Lauren's histopathologic classification, were prognostic of survival, based on univariate and multivariate analysis in multiple patient cohorts. The G-INT cell lines were significantly more sensitive to 5-fluorouracil and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines. In patients, intrinsic subtypes were associated with survival time following adjuvant, 5-fluorouracil–based therapy. Conclusions Intrinsic subtypes of GC, based on distinct patterns of expression, are associated with patient survival and response to chemotherapy. Classification of GC based on intrinsic subtypes might be used to determine prognosis and customize therapy.
Background
Radical gastrectomy for gastric cancer is among the most invasive procedures in gastrointestinal surgery. Several studies have found that an enhanced recovery after surgery (ERAS) protocol ...is useful in patients who undergo colorectal surgery, but its value in gastric surgery remains uncertain. The aim of this study was to assess the usefulness of an ERAS protocol for gastric surgery.
Methods
We studied the clinical characteristics, oncological factors, surgical factors, and outcomes in patients who underwent elective radical gastrectomy for gastric cancer before and after the introduction of an ERAS protocol.
Results
The first days of oral intake, oral intake recovery, flatus, and defecation were significantly earlier in the ERAS group (
n
= 91) than in the conventional care (CONV) group (
n
= 100). Maximum pain evaluated on a visual analog scale and the number of additional analgesics on demand were significantly less in the ERAS group than in the CONV group. The ratio of the postoperative body weight at 1 week to the preoperative body weight was significantly higher in the ERAS group than in the CONV group (0.95 vs. 0.94, respectively,
P
= 0.01).
Conclusion
Our results suggest that the ERAS protocol is useful in patients who undergo elective radical gastrectomy.
Background
Biweekly irinotecan (CPT-11) plus cisplatin (CDDP) combination (BIRIP) and CPT-11 alone are both expectable options for treating advanced gastric cancer (AGC) in a second-line setting. We ...conducted a meta-analysis to compare the efficacy and safety of these two regimens in patients enrolled two randomized phase III trials.
Patients and methods
Individual patient-level data from two randomized phase III trials were collected for this study. In both trials, patients with AGC refractory to S-1-based chemotherapy were randomly allocated to BIRIP (CPT-11, 60 mg/m
2
; CDDP, 30 mg/m
2
, q2w) or to CPT-11 (150 mg/m
2
, q2w).
Results
Cumulative data from 290 eligible patients were evaluated. The OS was 12.3 months 95% confidence interval (CI) 10.5–14.1 in the BIRIP group and 11.3 months (95% CI 10.0–13.2) in the CPT-11 group (hazard ratio 0.87; 95% CI 0.68–1.12,
P
= 0.272), while PFS was significantly longer in the BIRIP group (4.3 months 95% CI 3.5–5.1) than in the CPT-11 group (3.3 months 2.9–4.1; HR 0.77; 95% CI 0.61–0.98,
P
= 0.035). The response rate was 20.5% in the BIRIP group and 16.0% in the CPT-11 group (
P
= 0.361). However, the disease control rate was significantly better in the BIRIP group (72.1%) than in the CPT-11 group (59.2%) (
P
= 0.032). The two groups did not differ significantly in the incidences of grade 3 or worse adverse events.
Conclusions
Both BIRIP and CPT-11 may be good therapeutic options for patients with AGC as second-line treatment.
Clinical trial registration
UMIN 000025367.
Summary Background The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy. We did the Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) to ...assess the superiority of sequential treatment (paclitaxel then tegafur and uracil UFT or paclitaxel then S-1) compared with monotherapy (UFT or S-1) and also the non-inferiority of UFT compared with S-1. Methods We did this randomised phase 3 trial with a two-by-two factorial design at 230 hospitals in Japan. We enrolled patients aged 20–80 years with T4a or T4b gastric cancer, who had had D2 dissection and a ECOG performance score of 0–1. Patients were randomly assigned to one of four treatment groups with minimisation for tumour size, lymph node metastasis, and study site. Patients received UFT only (267 mg/m2 per day), S-1 only (80 mg/m2 per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m2 ) followed by either UFT, or S-1. Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups. The primary endpoint was disease-free survival assessed by intention to treat. We assessed whether UFT was non-inferior to S-1 with a non-inferiority margin of 1·33. This trial was registered at UMIN Clinical Trials Registry, number C000000082. Findings We randomly assigned 1495 patients between Aug 3, 2004, and Sept 29, 2009. 374 patients were assigned to receive UFT alone, 374 to receive S-1 alone, 374 to received paclitaxel then UFT, and 373 to receive paclitaxel then S-1. We included 1433 patients in the primary analysis after at least 3 years of follow-up (359, 364, 355, and 355 in each group respectively). Protocol treatment was completed by 215 (60%) patients in the UFT group, 224 (62%) in the S-1 group, 242 (68%) in the paclitaxel then UFT group, and 250 (70%) in the paclitaxel then S-1 group. 3-year disease-free survival for monotherapy was 54·0% (95% CI 50·2–57·6) and that of sequential treatment was 57·2% (53·4–60·8; hazard ratio HR 0·92, 95% CI 0·80–1·07, p=0·273). 3-year disease-free survival for the UFT group was 53·0% (95% CI 49·2–56·6) and that of the S-1 group was 58·2% (54·4–61·8; HR 0·81, 95% CI 0·70–0·93, p=0·0048; pnon-inferiority =0·151). The most common grade 3–4 haematological adverse event was neutropenia (41 11% of 359 patients in the UFT group, 48 13% of 363 in the S-1 group, 46 13% of 355 in the paclitaxel then UFT group, and 83 23% of 356 in the paclitaxel then S-1 group). The most common grade 3–4 non-haematological adverse event was anorexia (21 6%, 24 7%, seven 2%, and 18 5%, respectively). Interpretation Sequential treatment did not improve disease-free survival, and UFT was not non-inferior to S-1 (and S-1 was superior to UFT), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan. Funding Epidemiological and Clinical Research Information Network.
Background Irinotecan hydrochloride and S-1, an oral fluoropyrimidine, have shown antitumor activity against advanced gastric cancer as single agents in phase I/II studies. The combination of ...irinotecan and S-1 (IRI-S) is also active against advanced gastric cancer. This study was conducted to compare the efficacy and safety of IRI-S versus S-1 monotherapy in patients with advanced or recurrent gastric cancer. Methods Patients were randomly assigned to oral S-1 (80 mg/m² daily for 28 days every 6 weeks) or oral S-1 (80 mg/m² daily for 21 days every 5 weeks) plus irinotecan (80 mg/m² by intravenous infusion on days 1 and 15 every 5 weeks) (IRI-S). The primary endpoint was overall survival. Secondary endpoints included the time to treatment failure, 1- and 2-year survival rates, response rate, and safety. Results The median survival time with IRI-S versus S-1 monotherapy was 12.8 versus 10.5 months (P = 0.233), time to treatment failure was 4.5 versus 3.6 months (P = 0.157), and the 1-year survival rate was 52.0 versus 44.9%, respectively. The response rate was significantly higher for IRI-S than for S-1 monotherapy (41.5 vs. 26.9%, P = 0.035). Neutropenia and diarrhea occurred more frequently with IRI-S, but were manageable. Patients treated with IRI-S received more courses of therapy at a relative dose intensity similar to that of S-1 monotherapy. Conclusions Although IRI-S achieved longer median survival than S-1 monotherapy and was well tolerated, it did not show significant superiority in this study.
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