There have been remarkable changes in gastric cancer treatments in Japan, resulting in superb improvement of prognosis in patients with this disease. In this paper, the last 50 years have been ...divided into three eras: before 1990; the 1990s; and the era of evidence, which means after 2000. Changes of treatments and prognosis were analyzed by several factors, such as surgery, chemotherapy, informed consent, clinical trials, and others, as improvement of prognosis is not due to one factor but several ones influencing each other.
We made large progress in the treatment of gastric cancer since the establishment of “Japanese Research Society for the Study of Gastric Cancer” in 1964. History of these developments was described in various aspects.
Purpose
Prior to publication of the Clavien-Dindo classification in 2004, there were no grading definitions for surgical complications in either clinical practice or surgical trials. This report ...establishes supplementary criteria for this classification to standardize the evaluation of postoperative complications in clinical trials.
Methods
The Japan Clinical Oncology Group (JCOG) commissioned a committee. Members from nine surgical study groups (gastric, esophageal, colorectal, lung, breast, gynecologic, urologic, bone and soft tissue, and brain) specified postoperative complications experienced commonly in their fields and defined more detailed grading criteria for each complication in accordance with the general grading rules of the Clavien-Dindo classification.
Results
We listed 72 surgical complications experienced commonly in surgical trials, focusing on 17 gastroenterologic complications, 13 infectious complications, six thoracic complications, and several other complications. The grading criteria were defined simply and were optimized for surgical complications.
Conclusions
The JCOG postoperative complications criteria (JCOG PC criteria) aim to standardize the terms used to define adverse events (AEs) and provide detailed grading guidelines based on the Clavien-Dindo classification. We believe that the JCOG PC criteria will allow for more precise comparisons of the frequency of postoperative complications among trials across many different surgical fields.
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 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.
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.
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.
Background
Esophagogastric junction (EGJ) carcinoma has attracted considerable attention because of the marked increase in its incidence globally. However, the optimal extent of esophagogastric ...resection for this tumor entity remains highly controversial.
Methods
This was a questionnaire-based national retrospective study undertaken in an attempt to define the optimal extent of lymph node dissection for EGJ cancer. Data from patients with EGJ carcinoma, less than 40 mm in diameter, who underwent R0 resection between January 2001 and December 2010 were reviewed.
Results
Clinical records of 2807 patients without preoperative therapy were included in the analysis. There are distinct disparities in terms of the nodal dissection rate according to histology and the predominant tumor location. Nodal metastases frequently involved the abdominal nodes, especially those at the right and left cardia, lesser curvature and along the left gastric artery. Nodes along the distal portion of the stomach were much less often metastatic, and their dissection seemed unlikely to be beneficial. Lower mediastinal node dissection might contribute to improving survival for patients with esophagus-predominant EGJ cancer. However, due to low dissection rates for nodes of the middle and upper mediastinum, no conclusive result was obtained regarding the optimal extent of nodal dissection in this region.
Conclusions
Complete nodal clearance along the distal portion of the stomach offers marginal survival benefits for patients with EGJ cancers less than 4 cm in diameter. The optimal extent of esophageal resection and the benefits of mediastinal node dissection remain issues to be addressed in managing patients with esophagus-predominant EGJ cancers.
OBJECTIVE:To clarify the role of splenectomy in total gastrectomy for proximal gastric cancer.
BACKGROUNDS:Splenectomy in total gastrectomy is associated with increased operative morbidity and ...mortality, but its survival benefit is unclear. Previous randomized controlled trials were underpowered and inconclusive.
METHODS:We conducted a multiinstitutional randomized controlled trial. Proximal gastric adenocarcinoma of T2-4/N0-2/M0 not invading the greater curvature was eligible. During the operation, surgeons confirmed that R0 resection was possible with negative lavage cytology, and patients were randomly assigned to either splenectomy or spleen preservation. The primary endpoint was overall survival (OS) and the secondary endpoints were relapse-free survival, operative morbidity, operation time, and blood loss. The trial was designed to confirm noninferiority of spleen preservation to splenectomy in OS with a noninferiority margin of the hazard ratio as 1.21 and 1-sided alpha of 5%.
RESULTS:Between June 2002 and March 2009, 505 patients (254 splenectomy, 251 spleen preservation) were enrolled from 36 institutions. Splenectomy was associated with higher morbidity and larger blood loss, but the operation time was similar. The 5-year survivals were 75.1% and 76.4% in the splenectomy and spleen preservation groups, respectively. The hazard ratio was 0.88 (90.7%, confidence interval 0.67–1.16) (<1.21); thus, the noninferiority of spleen preservation was confirmed (P = 0.025).
CONCLUSIONS:In total gastrectomy for proximal gastric cancer that does not invade the greater curvature, splenectomy should be avoided as it increases operative morbidity without improving survival.
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.
Backgrounds
No confirmatory randomized controlled trials (RCTs) have evaluated the efficacy of laparoscopy-assisted distal gastrectomy (LADG) compared with open distal gastrectomy (ODG). We performed ...an RCT to confirm that LADG is not inferior to ODG in efficacy.
Methods
We conducted a multi-institutional RCT. Eligibility criteria included histologically proven gastric adenocarcinoma in the middle or lower third of the stomach, clinical stage I tumor. Patients were preoperatively randomized to ODG or LADG. This study is now in the follow-up stage. The primary endpoint is relapse-free survival (RFS) and the primary analysis is planned in 2018. Here, we compared the surgical outcomes of the two groups. This trial was registered at the UMIN Clinical Trials Registry as UMIN000003319.
Results
Between March 2010 and November 2013, 921 patients (LADG 462, ODG 459) were enrolled from 33 institutions. Operative time was longer in LADG than in ODG (median 278 vs. 194 min,
p
< 0.001), while blood loss was smaller (median 38 vs. 115 ml,
p
< 0.001). There was no difference in the overall proportion with in-hospital grade 3–4 surgical complications (3.3 %: LADG, 3.7 %: ODG). The proportion of patients with elevated serum AST/ALT was higher in LADG than in ODG (16.4 vs. 5.3 %,
p
< 0.001). There was no operation-related death in either arm.
Conclusions
This trial confirmed that LADG was as safe as ODG in terms of adverse events and short-term clinical outcomes. LADG may be an alternative procedure in clinical IA/IB gastric cancer if the noninferiority of LADG in terms of RFS is confirmed.
Some patients develop recurrence after curative resection and adjuvant chemotherapy. S-1, an oral fluoropyrimidine, is one of the standard regimens in adjuvant chemotherapy, and is also used in ...first-line treatment for advanced/metastatic gastric cancer. It is controversial as to whether the same treatment strategy can be applied for patients who develop recurrence after adjuvant chemotherapy and those who did not receive adjuvant chemotherapy. To investigate this issue, we compared the outcomes of patients who developed recurrences after treatment with or without adjuvant chemotherapy using the results of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC).
Patients who had confirmed recurrence in the ACTS-GC trial were analyzed. We defined 2 independent cohorts. Cohort 1 patients were divided by whether they received adjuvant chemotherapy (adjuvant S-1 group and surgery-only group). Cohort 2 patients were divided by whether they received a regimen including S-1 (IS) or not including S-1 (NIS) after recurrence.
A total of 375 patients experienced recurrence (160 in the adjuvant S-1 group and 215 in the surgery-only group). In cohort 1, the median time from recurrence to death (TFRD) was 11.4 months (95% confidence interval CI, 8.4-13.9) in the adjuvant S-1 group and 11.3 months (95% CI, 9.7-13.1) in the surgery-only group (hazard ratio HR, 1.05; 95% CI, 0.84-1.31). In cohort 2, 292 patients received chemotherapy after recurrence and were divided into the IS (n = 189) or the NIS group (n = 103). The median TFRD was 13.9 months (95% CI, 12.7-15.6) in the IS group and 8.1 months (95% CI, 6.6-9.7) in the NIS group (HR, 0.59; 95% CI, 0.45-0.76), and there was no significant interaction between the adjuvant S-1 group and surgery-only group.
Adjuvant chemotherapy with S-1 prolonged overall survival without influencing the TFRD. The same treatment strategy may be applied for patients who develop recurrence after adjuvant chemotherapy and those who did not receive adjuvant chemotherapy.
NCT00152217 . First Posted on September 9, 2005.
Background
Neoadjuvant chemotherapy (NAC) followed by radical surgery is a promising strategy to improve survival of patients with stage III gastric cancer, but is associated with the risk of ...preoperative overdiagnosis by which patients with early disease may receive unnecessary intensive chemotherapy.
Methods
We assessed the validity of a preoperative diagnostic criterion in a prospective multicenter study. Patients with gastric cancer with a clinical diagnosis of T2/T3/T4, M0, except for diffuse large tumors and extensive bulky nodal disease, were eligible. Prospectively recorded clinical diagnoses (cT category, cN category) were compared with postoperative pathological diagnoses (pT category, pN category, and pathological stage). The primary endpoint was the proportion of pathological stage I tumors among those diagnosed as cT3/T4, which we expected to be 5% or less.
Results
Data from 1260 patients enrolled from 53 institutions were analyzed. The proportion of pathological stage I tumors in those with a diagnosis of cT3/T4 (primary endpoint) was 12.3%, which was much higher than the prespecified value. The positive predictive value and the sensitivity for pathological stage III tumors were 43.6% and 87.8% respectively. The sensitivity and specificity of contrast-enhanced CT for lymph node metastasis were 62.5% and 65.7% respectively. After exploring several diagnostic criteria, we propose, for future NAC trials in Japan, a diagnosis of “cT3/T4 with cN1/N2/N3,” by which inclusion of pathological stage I tumors was reduced to 6.5%, although its sensitivity for pathological stage III tumors decreased to 64.5%.
Conclusion
Clinical diagnosis of T3/T4 tumors was not an optimal criterion to select patients for intensive NAC trials because more than 10% of patients with pathological stage I disease were included. We propose the criterion “cT3/T4 and cN1/N2/N3” instead.
Summary Background Historical data and recent studies show that standardised extended (D2) lymphadenectomy leads to better results than standardised limited (D1) lymphadenectomy. Based on these ...findings, the Dutch D1D2 trial, a nationwide prospectively randomised clinical trial, was undertaken to compare D2 with D1 lymphadenectomy in patients with resectable primary adenocarcinoma of the stomach. The aim of the study was to assess the effect of D2 compared with D1 surgery on disease recurrence and survival in patients treated with curative intent. Methods Between August, 1989, and July, 1993, patients were entered and randomised at 80 participating hospitals by means of a telephone call to the central data centre of the trial. The sequence of randomisation was in blocks of six with stratification for the participating centre. Eligibility criteria were a histologically proven adenocarcinoma of the stomach without evidence of distance metastasis, age younger than 85 years, and adequate physical condition for D1 or D2 lymphadenectomy. Patients were excluded if they had previous or coexisting cancer or had undergone gastrectomy for benign tumours. Strict quality control measures for pathological assessment were implemented and monitored. Analyses were by intention to treat. This study is registered with the NCI trial register , as DUT-KWF-CKVO-8905, EU-90003. Findings A total of 1078 patients were entered in the study, of whom 996 were eligible. 711 patients underwent the randomly assigned treatment with curative intent (380 in the D1 group and 331 in the D2 group) and 285 had palliative treatment. Data were collected prospectively and all patients were followed up for a median time of 15·2 years (range 6·9–17·9 years). Analyses were done for the 711 patients treated with curative intent and were according to the allocated treatment group. Of the 711 patients, 174 (25%) were alive, all but one without recurrence. Overall 15-year survival was 21% (82 patients) for the D1 group and 29% (92 patients) for the D2 group (p=0·34). Gastric-cancer-related death rate was significantly higher in the D1 group (48%, 182 patients) compared with the D2 group (37%, 123 patients), whereas death due to other diseases was similar in both groups. Local recurrence was 22% (82 patients) in the D1 group versus 12% (40 patients) in D2, and regional recurrence was 19% (73 patients) in D1 versus 13% (43 patients) in D2. Patients who had the D2 procedure had a significantly higher operative mortality rate than those who had D1 (n=32 10% vs n=15 4%; 95% CI for the difference 2–9; p=0·004), higher complication rate (n=142 43% vs n=94 25%; 11–25; p<0·0001), and higher reoperation rate (n=59 18% vs n=30 8%; 5–15; p=0·00016). Interpretation After a median follow-up of 15 years, D2 lymphadenectomy is associated with lower locoregional recurrence and gastric-cancer-related death rates than D1 surgery. The D2 procedure was also associated with significantly higher postoperative mortality, morbidity, and reoperation rates. Because a safer, spleen-preserving D2 resection technique is currently available in high-volume centres, D2 lymphadenectomy is the recommended surgical approach for patients with resectable (curable) gastric cancer. Funding Dutch Health Insurance Funds Council and the Netherlands Cancer Foundation.
PDF
