Multimodal Therapy Versus Primary Surgery for Gastric and Gastroesophageal Junction Diffuse Type Carcinoma, with a Focus on Signet Ring Cell Carcinoma: A Nationwide Study.

BACKGROUND: Diffuse type adenocarcinoma and, more specifically, signet ring cell carcinoma (SRCC) of the stomach and gastroesophageal junction (GEJ) have a poor prognosis and the value of neoadjuvant chemo(radio)therapy (nCRT) is unclear. METHODS: All patients who underwent surgery for diffuse type gastric and GEJ carcinoma between 2004 and 2015 were retrospectively included from the Netherlands Cancer Registry. The primary outcome was overall survival after surgery. Kaplan-Meier curves were plotted. Furthermore, multivariable Poisson and Cox regressions were performed, correcting for confounders. To comply with the Cox regression proportional hazard assumption, gastric cancer survival was split into two groups, i.e. <90 days and >90 days, postoperatively by adding an interaction variable. RESULTS: Analyses included 2046 patients with diffuse type cancer: 1728 gastric cancers (50% SRCC) and 318 GEJ cancers (39% SRCC). In the gastric cancer group, 49% received neoadjuvant chemotherapy (nCT) and 51% received primary surgery (PS). All-cause mortality within 90 days postoperatively was lower after nCT (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.20-0.44; p < 0.001). Also after 90 days, mortality was lower in the nCT group (HR for the interaction variable 2.84, 95% CI 1.87-4.30, p < 0.001; total HR 0.29*2.84 = 0.84). In the GEJ group, 38% received nCT, 22% received nCRT, and 39% received PS. All-cause mortality was lower after nCT (HR 0.63, 95% CI 0.43-0.93; p = 0.020) compared with PS. The nCRT group was removed from the Cox regression analysis since the Kaplan-Meier curves of nCRT and PS intersected. The results for gastric and GEJ carcinomas were similar between the SRCC and non-SRCC subgroups. CONCLUSION: For gastric and GEJ diffuse type cancer, including SRCC, nCT was associated with increased survival.

Impact of 18FFDG-PET/CT and Laparoscopy in Staging of Locally Advanced Gastric Cancer: A Cost Analysis in the Prospective Multicenter PLASTIC-Study.

BACKGROUND: Unnecessary D2-gastrectomy and associated costs can be prevented after detecting non-curable gastric cancer, but impact of staging on treatment costs is unclear. This study determined the cost impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG-PET/CT) and staging laparoscopy (SL) in gastric cancer staging. MATERIALS AND METHODS: In this cost analysis, four staging strategies were modeled in a decision tree: (1) 18FFDG-PET/CT first, then SL, (2) SL only, (3) 18FFDG-PET/CT only, and (4) neither SL nor 18FFDG-PET/CT. Costs were assessed on the basis of the prospective PLASTIC-study, which evaluated adding 18FFDG-PET/CT and SL to staging advanced gastric cancer (cT3-4 and/or cN+) in 18 Dutch hospitals. The Dutch Healthcare Authority provided 18FFDG-PET/CT unit costs. SL unit costs were calculated bottom-up. Gastrectomy-associated costs were collected with hospital claim data until 30 days postoperatively. Uncertainty was assessed in a probabilistic sensitivity analysis (1000 iterations). RESULTS: 18FFDG-PET/CT costs were €1104 including biopsy/cytology. Bottom-up calculations totaled €1537 per SL. D2-gastrectomy costs were €19,308. Total costs per patient were €18,137 for strategy 1, €17,079 for strategy 2, and €19,805 for strategy 3. If all patients undergo gastrectomy, total costs were €18,959 per patient (strategy 4). Performing SL only reduced costs by €1880 per patient. Adding 18FFDG-PET/CT to SL increased costs by €1058 per patient; IQR €870-1253 in the sensitivity analysis. CONCLUSIONS: For advanced gastric cancer, performing SL resulted in substantial cost savings by reducing unnecessary gastrectomies. In contrast, routine 18FFDG-PET/CT increased costs without substantially reducing unnecessary gastrectomies, and is not recommended due to limited impact with major costs. TRIAL REGISTRATION: NCT03208621. This trial was registered prospectively on 30-06-2017.

Evaluation of the Implementation of FDG-PET/CT and Staging Laparoscopy for Gastric Cancer in The Netherlands.

BACKGROUND: The role of 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT) and staging laparoscopy (SL) has increased in the preoperative staging of gastric cancer. Dutch national guidelines have recommended the use of FDG-PET/CT and SL for patients with locally advanced tumors since July 2016. OBJECTIVE: The aim of this study was to evaluate the implementation of FDG-PET/CT and SL in The Netherlands. METHODS: Between 2011 and 2018, all patients who underwent surgery for gastric cancer were included from the Dutch Upper GI Cancer Audit. The use of FDG-PET/CT and SL was evaluated before and after revision of the Dutch guidelines. Outcomes included the number of non-curative procedures (e.g. palliative and futile procedures) and the association of FDG-PET/CT and SL, with waiting times from diagnosis to the start of treatment. RESULTS: A total of 3310 patients were analyzed. After July 2016, the use of FDG-PET/CT (23% vs. 61%; p < 0.001) and SL (21% vs. 58%; p < 0.001) increased. FDG-PET/CT was associated with additional waiting time to neoadjuvant therapy (4 days), as well as primary surgical treatment (20 days), and SL was associated with 8 additional days of waiting time to neoadjuvant therapy. Performing SL or both modalities consecutively in patients in whom it was indicated was not associated with the number of non-curative procedures. CONCLUSION: During implementation of FDG-PET/CT and SL after revision of the guidelines, both have increasingly been used in The Netherlands. The addition of these staging methods was associated with increased waiting time to treatment. The number of non-curative procedures did not differ after performing none, solely one, or both staging modalities.

Worldwide Practice in Gastric Cancer Surgery: A 6-Year Update.

OBJECTIVES: The aim of the study was to evaluate the current status of gastric cancer surgery worldwide and update the changes compared to a previous survey in 2014. METHODS: A cross-sectional survey was sent to surgical members of the International Gastric Cancer Association, pilot centers of the World Organization for Specialized Studies on Diseases of the Esophagus, and the Australian and New Zealand Gastric and Oesophageal Surgeons Association in addition to participants of the 2019 International Gastric Cancer and European Society for Diseases of the Esophagus congresses. Topics addressed included hospital volume, staging, perioperative treatment, surgical approach, anastomotic techniques, lymphadenectomy, and palliative management. RESULTS: Between June 2019 and January 2020, 165 respondents from 44 countries completed the survey. In total, 80% worked in a hospital performing >20 gastrectomies annually. Staging laparoscopy and 18F-fluorodeoxyglucose positron emission tomography with computed tomography were preferred by 68 and 26% for advanced cancer, and 90% offered perioperative chemo(radio)therapy to patients. For early cancer, a minimally invasive surgical approach was preferred by 65% for distal and by 50% for total gastrectomy. For advanced cancer, this was preferred by 39% for distal and by 33% for total gastrectomy. And 84% favored a stapled anastomosis, and 14% created a jejunal pouch as reconstruction during total gastrectomy. A D2 lymphadenectomy was preferred for distal as well as for total gastrectomy, in both early (62 and 71%) and advanced (84 and 89%) cancer. CONCLUSION: This international survey demonstrates that perioperative chemotherapy and a D2 lymphadenectomy have now become the preferred treatment for gastric cancer. A minimally invasive surgical approach has gained popularity.

Identification of the clinically most relevant postoperative complications after gastrectomy: a population-based cohort study.

BACKGROUND: Postoperative complications frequently occur after gastrectomy for gastric cancer and are associated with poor clinical outcomes, such as mortality and reoperations. The aim of study was to identify the clinically most relevant complications after gastrectomy, using the population-attributable fraction (PAF). METHODS: Between 2011 and 2017, all patients who underwent potentially curative gastrectomy for gastric adenocarcinoma were included from the Dutch Upper GI Cancer Audit. Postoperative outcomes (morbidity, mortality, recovery and hospitalization) were evaluated. The prevalence of postoperative complications (e.g., anastomotic leakage and pneumonia) and of the study outcomes were calculated. The adjusted relative risk and Confidence Interval (CI) for each complication-outcome pair were calculated. Subsequently, the PAF was calculated, which represents the percentage of a given outcome occurring in the population, caused by individual complications, taking both the relative risk and the frequency in which a complication occurs into account. RESULTS: In total, 2176 patients were analyzed. Anastomotic leakage and pulmonary complications had the greatest overall impact on postoperative mortality (PAF 29.2% [95% CI 19.3-39.1] and 21.6% [95% CI 10.5-32.7], respectively) and prolonged hospitalization (PAF 12.9% [95% CI 9.7-16.0] and 14.7% [95% CI 11.0-18.8], respectively). Anastomotic leakage had the greatest overall impact on re-interventions (PAF 25.1% [95% CI 20.5-29.7]) and reoperations (PAF 30.3% [95% CI 24.3-36.3]). Intra-abdominal abscesses had the largest impact on readmissions (PAF 7.0% [95% CI 3.2-10.9]). Other complications only had a small effect on these outcomes. CONCLUSION: Surgical improvement programs should focus on preventing or managing anastomotic leakage and pulmonary complications, since these complications have the greatest overall impact on clinical outcomes after gastrectomy.

Minimally Invasive Resection of Large Gastric Gastrointestinal Stromal Tumors.

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) frequently present as a large exophytically growing mass in the stomach, for which open partial gastrectomy is standard of care. The aim of this study was to evaluate the safety and feasibility of minimally invasive gastric resection (MIG) of large (>5 cm) GIST. METHODS: All patients who underwent MIG for a GIST in the University Medical Center Utrecht between 2011 and 2019 were included. Postoperative course and oncological outcomes were analyzed. RESULTS: Twenty-two patients with gastric GIST, median size 53 mm [20-175 mm], underwent MIG. In 4 patients, preoperative imatinib was given, aiming for tumor regression. Conversion from laparoscopic to open surgery occurred once (5%). An additional resection was performed in 3 patients (14%). In 2 patients (9%), an intraoperative complication occurred, consisting of tumor rupture in 1 patient (5%), and 6 patients (27%) developed postoperative complications. Median hospital stay was 5 days [3-7 days]. R0 resection was achieved in 96%. In 4 patients, adjuvant treatment was indicated. The median follow-up was 31 months, and 1-, 3- and 5-year disease-free survival were 94, 74 and 74%, respectively. One patient presented with local recurrence 2 years after the index resection. CONCLUSION: MIG for large GIST up to 17.5 cm in diameter is safe, feasible, and oncologically sound, allowing for a controlled resection and reduced patient morbidity.

Familial co-occurrence of congenital heart defects follows distinct patterns.

Aims: Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis. Methods and results: We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes. Conclusion: Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes.

Prognostic Value of [18F]FDG PET Radiomics to Detect Peritoneal and Distant Metastases in Locally Advanced Gastric Cancer-A Side Study of the Prospective Multicentre PLASTIC Study.

AIM: To improve identification of peritoneal and distant metastases in locally advanced gastric cancer using [18F]FDG-PET radiomics. METHODS: [18F]FDG-PET scans of 206 patients acquired in 16 different Dutch hospitals in the prospective multicentre PLASTIC-study were analysed. Tumours were delineated and 105 radiomic features were extracted. Three classification models were developed to identify peritoneal and distant metastases (incidence: 21%): a model with clinical variables, a model with radiomic features, and a clinicoradiomic model, combining clinical variables and radiomic features. A least absolute shrinkage and selection operator (LASSO) regression classifier was trained and evaluated in a 100-times repeated random split, stratified for the presence of peritoneal and distant metastases. To exclude features with high mutual correlations, redundancy filtering of the Pearson correlation matrix was performed (r = 0.9). Model performances were expressed by the area under the receiver operating characteristic curve (AUC). In addition, subgroup analyses based on Lauren classification were performed. RESULTS: None of the models could identify metastases with low AUCs of 0.59, 0.51, and 0.56, for the clinical, radiomic, and clinicoradiomic model, respectively. Subgroup analysis of intestinal and mixed-type tumours resulted in low AUCs of 0.67 and 0.60 for the clinical and radiomic models, and a moderate AUC of 0.71 in the clinicoradiomic model. Subgroup analysis of diffuse-type tumours did not improve the classification performance. CONCLUSION: Overall, [18F]FDG-PET-based radiomics did not contribute to the preoperative identification of peritoneal and distant metastases in patients with locally advanced gastric carcinoma. In intestinal and mixed-type tumours, the classification performance of the clinical model slightly improved with the addition of radiomic features, but this slight improvement does not outweigh the laborious radiomic analysis.

Refraining from resection in patients with potentially curable gastric carcinoma.

BACKGROUND: Surgical resection is the cornerstone of curative treatment for gastric cancer. The aim of this study was to evaluate reasons for and patient- and tumor characteristics that are associated with refraining from surgical resection in patients with potentially curable gastric cancer. MATERIALS AND METHODS: Between 2015 and 2017, all patients with potentially curable gastric adenocarcinoma (cT1-4a-x, cN0-3-x, cM0) were included from the Netherlands Cancer Registry (NCR). Patients were divided into a resection (RG) and a no-resection group (nRG). Reasons for not undergoing resection as registered by the NCR were evaluated. Using multivariable logistic regression analyses, patient and tumor characteristics associated with refraining from resection were assessed. RESULTS: Of the 1679 analyzed patients with potentially curable disease, 1127 patients (67%) underwent resection, and 552 patients (33%) did not. Most common registered reasons for refraining from surgery were patient refusal (25%), low performance status (23%), comorbidity and extent of disease (both 10%). Factors associated with not undergoing resection were: age ≥80 years (OR 4.77, [95%CI 2.27-10.06], p < 0.001), low Social-Economic-Status (SES) (OR 2.68 [95%CI 1.31-5.46], p = 0.007), WHO performance status 3-4 (OR 10.48 [95%CI 2.41-45.73], p = 0.002) with several accompanying comorbidities, unclassified Lauren classification (OR 3.93 [95%CI 1.61-9.56], p = 0.003) and overlapping/diffuse tumors (OR 3.51, [95%CI 1.54-8.05], p = 0.003). CONCLUSION: A third of patients with potentially curable gastric cancer did not undergo resection. Most frequent registered reasons for refraining from surgery were patient refusal, performance status, comorbidity and extent of disease. Additionally, multivariable analyses identified higher age, lower SES, and poor tumor characteristics as associated factors.

18F-Fludeoxyglucose-Positron Emission Tomography/Computed Tomography and Laparoscopy for Staging of Locally Advanced Gastric Cancer: A Multicenter Prospective Dutch Cohort Study (PLASTIC).

Importance: The optimal staging for gastric cancer remains a matter of debate. Objective: To evaluate the value of 18F-fludeoxyglucose-positron emission tomography with computed tomography (FDG-PET/CT) and staging laparoscopy (SL) in addition to initial staging by means of gastroscopy and CT in patients with locally advanced gastric cancer. Design, Setting, and Participants: This multicenter prospective, observational cohort study included 394 patients with locally advanced, clinically curable gastric adenocarcinoma (≥cT3 and/or N+, M0 category based on CT) between August 1, 2017, and February 1, 2020. Exposures: All patients underwent an FDG-PET/CT and/or SL in addition to initial staging. Main Outcomes and Measures: The primary outcome was the number of patients in whom the intent of treatment changed based on the results of these 2 investigations. Secondary outcomes included diagnostic performance, number of incidental findings on FDG-PET/CT, morbidity and mortality after SL, and diagnostic delay. Results: Of the 394 patients included, 256 (65%) were men and mean (SD) age was 67.6 (10.7) years. A total of 382 patients underwent FDG-PET/CT and 357 underwent SL. Treatment intent changed from curative to palliative in 65 patients (16%) based on the additional FDG-PET/CT and SL findings. FDG-PET/CT detected distant metastases in 12 patients (3%), and SL detected peritoneal or locally nonresectable disease in 73 patients (19%), with an overlap of 7 patients (2%). FDG-PET/CT had a sensitivity of 33% (95% CI, 17%-53%) and specificity of 97% (95% CI, 94%-99%) in detecting distant metastases. Secondary findings on FDG/PET were found in 83 of 382 patients (22%), which led to additional examinations in 65 of 394 patients (16%). Staging laparoscopy resulted in a complication requiring reintervention in 3 patients (0.8%) without postoperative mortality. The mean (SD) diagnostic delay was 19 (14) days. Conclusions and Relevance: This study's findings suggest an apparently limited additional value of FDG-PET/CT; however, SL added considerably to the staging process of locally advanced gastric cancer by detection of peritoneal and nonresectable disease. Therefore, it may be useful to include SL in guidelines for staging advanced gastric cancer, but not FDG-PET/CT.

Non-curative gastrectomy for advanced gastric cancer does not result in additional risk of postoperative morbidity compared to curative gastrectomy.

BACKGROUND: Non-curative gastrectomy (nCG) for gastric cancer can be considered in selected cases to relieve symptoms. The aim of this study was to evaluate postoperative morbidity and mortality in patients who underwent nCG and compare these results with an intended curative gastrectomy (CG). MATERIALS AND METHODS: All patients who underwent both nCG and CG in the Netherlands were included from the Dutch Upper GI Cancer Audit (2011-2016). In this population-based cohort study postoperative morbidity, mortality, readmissions and short-term oncological outcomes were appraised. Propensity score matching (PSM) was applied to create comparable groups of patients who underwent nCG versus CG, using patient and tumor characteristics. RESULTS: Of the 2202 eligible patients, 115 patients underwent nCG and 2087 underwent CG. After PSM, 115 nCG-patients were matched to 227 CG-patients. More conversions from laparoscopic to open surgery occurred during nCG (10·4 versus 2·6%, p = 0·007). Although postoperative mortality was higher after nCG in the original cohort (9·6 versus 4·8%, p = 0·026), after PSM there was no difference between groups (9·6 versus 7·0%, p = 0·415). Postoperative morbidity, re-interventions and readmission rates did not differ significantly between groups. Resection of additional organs (30·4 versus 11·5%, p < 0·001) and R+ resections (65·2 versus 12·3%, p < 0·001) occurred more frequently during nCG. CONCLUSIONS: nCG does not lead to additional postoperative risks compared to CG in patients with similar characteristics, and may be considered in fit patients with advanced gastric cancer. However, randomized trials evaluating potential (survival) benefits of nCG should be awaited.