Esophagectomy after definitive chemoradiation in esophageal cancer: a safe therapeutic strategy.

The standard treatment regimen for esophageal cancer is chemoradiation followed by esophagectomy. However, the use of neoadjuvant chemoradiotherapy damages the surrounding tissue, which potentially increases the risk of postoperative complications, including anastomotic leakage. The impact of definitive chemoradiotherapy (dCRT, 50.4 Gy radiotherapy) compared to the standard neoadjuvant scheme (nCRT, 41.4 Gy radiotherapy) prior to surgery on the incidence of anastomotic leakage remains poorly understood. To study this, all patients who received dCRT between 2011 and 2021 followed by esophagectomy were included. For each patient, two patients who received nCRT were selected as matched controls. Outcomes included postoperative anastomotic leakage, pulmonary and other complications, anastomotic stenosis, pulmonary and other postoperative complications (Clavien Dindo Classification ≥1), and overall survival. One hundred and eight patients were included with a median follow-up of 28 months. The time between neoadjuvant treatment and surgery was longer in the dCRT group compared to the nCRT group (65 vs. 48 days, P < 0.001). Postoperatively, significantly more patients in the dCRT group suffered from anastomotic leakage (11% vs. 1%, P = 0.04) and anastomotic stenosis (42% vs. 17%, P < 0.01). No differences were found for other complications or overall survival between both groups. In conclusion, preoperative dCRT is associated with a higher risk of anastomotic leakage and stenosis. These complications, however, can be treated effectively. Therefore, esophagectomy after dCRT is considered to be an appropriate treatment strategy in a selected patient group.

N3 Disease in Esophageal Cancer: Results from a Nationwide Registry.

BACKGROUND: Patients with extensive lymph node metastases have a poor prognosis. Clinical staging of lymph node metastases poses significant challenges given the limited sensitivity and specificity of imaging techniques. The aim of this study was to investigate the overall survival (OS) of patients with N3 disease in a real-world Dutch population and the added value of surgery in these patients. METHODS: Patients with cN3M0 esophageal or gastroesophageal cancer were identified from the Netherlands Cancer Registry (2012-2019). Treatment consisted of neoadjuvant chemo(radio)therapy followed by resection or chemo(radio)therapy, radiotherapy, or esophagectomy alone. OS was calculated using the Kaplan-Meier method. RESULTS: Some 21,566 patients were diagnosed with esophageal cancer of whom 359 (1.7%) had cN3M0 disease. Median OS of these patients was 12.5 months (95% CI: 10.7-14.3). Median OS following chemoradiotherapy alone and neoadjuvant therapy plus surgery was 13.3 months (95% CI: 10.7-15.9) and 23.7 months (95% CI: 18.3-29.2), respectively. Of all patients who underwent esophagectomy, 391 (2.8%) had (y)pN3 disease, and median OS was 16.1 months (95% CI: 14.8-17.4). Twenty-one patients (5.4%) were correctly classified as cN3, and 3-year OS was 21%. CONCLUSION(S): Clinical staging appears to be difficult, apparently in patients with N3 esophageal cancer. Surgery seems to be of benefit to these patients. More research is required to address the ongoing challenges in clinical staging and the best neoadjuvant therapy.

Improvement of perioperative outcomes of gastric gastrointestinal stromal tumour (GIST) resections and the influence of minimal invasive surgery.

BACKGROUND: Safety of minimally invasive surgery (MIS) for gastrointestinal stromal tumours (GISTs) is still under debate since it might increase the risk of tumour rupture, especially in larger tumours. The aim of this study was to investigate trends in treatment and perioperative outcomes of patients undergoing resections of gastric GISTs over time. METHODS: This was a multicentre retrospective study of consecutive patients who underwent wedge resection or partial gastrectomy for localized gastric GIST at five GIST reference centres between January 2009 and January 2022. To evaluate changes in treatment and perioperative outcomes over time, patients were divided into four equal periods. Perioperative outcomes were analysed separately and as a novel composite measure textbook outcome (TO). RESULTS: In total 385 patients were included. Patient and tumour characteristics did not change over time, except for median age (62-65-68-68 years, p = 0.002). The proportion of MIS increased (4.0%-9.8%-37.4%-53.0 %, p < 0.001). Postoperative complications (Clavien Dindo ≥2; 22%-15%-11%-10 %, p = 0.146), duration of admission (6-6-5-4 days, p < 0.001) and operating time (92-94-77-73 min, p = 0.007) decreased over time while TO increased (54.0%- 52.7%-65.9%-76.0 %, p < 0.001). No change was seen in perioperative ruptures (6.0%- 3.6%-1.6%-3.0 %, p = 0.499). MIS was correlated with less CD ≥ 2 complications (p = 0.006), shorter duration of admission (p < 0.001) and more TO (p < 0.001). Similar results were observed in tumours ≤5 cm and >5 cm. CONCLUSION: A larger percentage of gastric GIST were treated with MIS over time. MIS was correlated with less complications, shorter duration of admission and more TO. Tumour rupture rates remained low over time.

European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4).

INTRODUCTION: The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD). METHODS: Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD. RESULTS: Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended. DISCUSSION: These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.

Outcomes of liver surgery: A decade of mandatory nationwide auditing in the Netherlands.

BACKGROUND: In 2013, the nationwide Dutch Hepato Biliary Audit (DHBA) was initiated. The aim of this study was to evaluate changes in indications for and outcomes of liver surgery in the last decade. METHODS: This nationwide study included all patients who underwent liver surgery for four indications, including colorectal liver metastases (CRLM), hepatocellular carcinoma (HCC), and intrahepatic- and perihilar cholangiocarcinoma (iCCA - pCCA) between 2014 and 2022. Trends in postoperative outcomes were evaluated separately for each indication using multilevel multivariable logistic regression analyses. RESULTS: This study included 8057 procedures for CRLM, 838 for HCC, 290 for iCCA, and 300 for pCCA. Over time, these patients had higher risk profiles (more ASA-III patients and more comorbidities). Adjusted mortality decreased over time for CRLM, HCC and iCCA, respectively aOR 0.83, 95%CI 0.75-0.92, P < 0.001; aOR 0.86, 95%CI 0.75-0.99, P = 0.045; aOR 0.40, 95%CI 0.20-0.73, P < 0.001. Failure to rescue (FTR) also decreased for these groups, respectively aOR 0.84, 95%CI 0.76-0.93, P = 0.001; aOR 0.81, 95%CI 0.68-0.97, P = 0.024; aOR 0.29, 95%CI 0.08-0.84, P = 0.021). For iCCA severe complications (aOR 0.65 95%CI 0.43-0.99, P = 0.043) also decreased. No significant outcome differences were observed in pCCA. The number of centres performing liver resections decreased from 26 to 22 between 2014 and 2022, while median annual volumes did not change (40-49, P = 0.66). CONCLUSION: Over time, postoperative mortality and FTR decreased after liver surgery, despite treating higher-risk patients. The DHBA continues its focus on providing feedback and benchmark results to further enhance outcomes.

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.

Trends and overall survival after combined liver resection and thermal ablation of colorectal liver metastases: a nationwide population-based propensity score-matched study.

BACKGROUND: In colorectal liver metastases (CRLM) patients, combination of liver resection and ablation permit a more parenchymal-sparing approach. This study assessed trends in use of combined resection and ablation, outcomes, and overall survival (OS). METHODS: This population-based study included all CRLM patients who underwent liver resection between 2014 and 2022. To assess OS, data was linked to two databases containing date of death for patients treated between 2014 and 2018. Hospital variation in the use of combined minor liver resection and ablation versus major liver resection alone in patients with 2-3 CRLM and ≤3 cm was assessed. Propensity score matching (PSM) was applied to evaluate outcomes. RESULTS: This study included 3593 patients, of whom 1336 (37.2%) underwent combined resection and ablation. Combined resection increased from 31.7% in 2014 to 47.9% in 2022. Significant hospital variation (range 5.9-53.8%) was observed in the use of combined minor liver resection and ablation. PSM resulted in 1005 patients in each group. Major morbidity was not different (11.6% vs. 5%, P = 1.00). Liver failure occurred less often after combined resection and ablation (1.9% vs. 0.6%, P = 0.017). Five-year OS rates were not different (39.3% vs. 33.9%, P = 0.145). CONCLUSION: Combined resection and ablation should be available and considered as an alternative to resection alone in any patient with multiple metastases.

Evolution in Laparoscopic Gastrectomy From a Randomized Controlled Trial Through National Clinical Practice.

OBJECTIVE: To examine the influence of the LOGICA RCT (randomized controlled trial) upon the practice and outcomes of laparoscopic gastrectomy within the Netherlands. BACKGROUND: Following RCTs the dissemination of complex interventions has been poorly studied. The LOGICA RCT included 10 Dutch centers and compared laparoscopic to open gastrectomy. METHODS: Data were obtained from the Dutch Upper Gastrointestinal Cancer Audit (DUCA) on all gastrectomies performed in the Netherlands (2012-2021), and the LOGICA RCT from 2015 to 2018. Multilevel multivariable logistic regression analyses were performed to assess the effect of laparoscopic versus open gastrectomy upon clinical outcomes before, during, and after the LOGICA RCT. RESULTS: Two hundred eleven patients from the LOGICA RCT (105 open vs 106 laparoscopic) and 4131 patients from the DUCA data set (1884 open vs 2247 laparoscopic) were included. In 2012, laparoscopic gastrectomy was performed in 6% of patients, increasing to 82% in 2021. No significant effect of laparoscopic gastrectomy on postoperative clinical outcomes was observed within the LOGICA RCT. Nationally within DUCA, a shift toward a beneficial effect of laparoscopic gastrectomy upon complications was observed, reaching a significant reduction in overall [adjusted odds ratio (aOR):0.62; 95% CI: 0.46-0.82], severe (aOR: 0.64; 95% CI: 0.46-0.90) and cardiac complications (aOR: 0.51; 95% CI: 0.30-0.89) after the LOGICA trial. CONCLUSIONS: The wider benefits of the LOGICA trial included the safe dissemination of laparoscopic gastrectomy across the Netherlands. The robust surgical quality assurance program in the design of the LOGICA RCT was crucial to facilitate the national dissemination of the technique following the trial and reducing potential patient harm during surgeons learning curve.

MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial.

BACKGROUND: Guidelines are inconclusive on whether contrast-enhanced MRI using gadoxetic acid and diffusion-weighted imaging should be added routinely to CT in the investigation of patients with colorectal liver metastases who are scheduled for curative liver resection or thermal ablation, or both. Although contrast-enhanced MRI is reportedly superior than contrast-enhanced CT in the detection and characterisation of colorectal liver metastases, its effect on clinical patient management is unknown. We aimed to assess the clinical effect of an additional liver contrast-enhanced MRI on local treatment plan in patients with colorectal liver metastases amenable to local treatment, based on contrast-enhanced CT. METHODS: We did an international, multicentre, prospective, incremental diagnostic accuracy trial in 14 liver surgery centres in the Netherlands, Belgium, Norway, and Italy. Participants were aged 18 years or older with histological proof of colorectal cancer, a WHO performance status score of 0-4, and primary or recurrent colorectal liver metastases, who were scheduled for local therapy based on contrast-enhanced CT. All patients had contrast-enhanced CT and liver contrast-enhanced MRI including diffusion-weighted imaging and gadoxetic acid as a contrast agent before undergoing local therapy. The primary outcome was change in the local clinical treatment plan (decided by the individual clinics) on the basis of liver contrast-enhanced MRI findings, analysed in the intention-to-image population. The minimal clinically important difference in the proportion of patients who would have change in their local treatment plan due to an additional liver contrast-enhanced MRI was 10%. This study is closed and registered in the Netherlands Trial Register, NL8039. FINDINGS: Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26-36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5-24·0]). INTERPRETATION: Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging. FUNDING: The Dutch Cancer Society and Bayer AG - Pharmaceuticals.

Time Trends in the Treatment and Survival of 5036 Uveal Melanoma Patients in The Netherlands over a 30-Year Period.

BACKGROUND: Uveal melanoma (UM) is a rare intraocular tumor with a dismal prognosis once metastasized. This study provides a nationwide overview and time trends of patients diagnosed with primary UM in the Netherlands between 1989 and 2019. METHODS: A retrospective population-based cohort study based on patients with primary UM from the database of the Netherlands Cancer Registry (NCR), linked with the national population registry Statistics Netherlands on inhabitants' cause of death. Two time periods (1989-2004, 2005-2019) were compared with descriptive statistics. Kaplan-Meier and (multivariate) Cox proportional hazard models were used to assess changes over time for overall survival (OS) and cancer-specific survival (CSS). RESULTS: In total, 5036 patients were analyzed with a median age of 64.0 years at the time of diagnosis. The number of patients increased over time. In the first (1989-2004) and second (2005-2019) period, 32% versus 54% of the patients received radiotherapy (p < 0.001). The median FU time was 13.4 years. The median OS of the first and second periods was 9.5 (95% CI 8.7-10.3) versus 11.3 years (95% CI 10.3-12.3; p < 0.001). The median CSS was 30.0 years (95% CI NA) in the first period and not reached in the second period (p = 0.008). In multivariate analysis (MVA), female gender (HR 0.85; 95% CI 0.79-0.92, p < 0.001) and radiotherapy treatment (HR 0.73; 95% CI 0.64-0.83, p < 0.001) were associated with better OS. Radiotherapy treatment (HR 0.74; 95% CI 0.61-0.90, p = 0.002) was also associated with better CSS. The period of diagnosis was not associated with OS or CSS. CONCLUSIONS: In this study of patients with primary UM, there was a shift to the diagnosis of smaller tumors, possibly due to stage migration. There was also an increase in eye-preserving treatments over time. OS and CSS were modestly improved in the second time period; however, the time period was not associated with OS or CSS in multivariate analyses.

Esophageal cancer patients' need for information and support in making a treatment decision between standard surgery and active surveillance.

BACKGROUND: This study explores patients' need for information and support in deciding on esophageal cancer treatment, when experimental active surveillance and standard surgery are both feasible. METHODS: This psychological companion study was conducted alongside the Dutch SANO-trial (Surgery As Needed for Oesophageal cancer). In-depth interviews and questionnaires were used to collect data from patients who declined participation in the trial because they had a strong preference for either active surveillance (n = 20) or standard surgery (n = 20). Data were analyzed using both qualitative and quantitative techniques. RESULTS: Patients prefer to receive information directly from their doctors and predominantly rely on this information to make a treatment decision. Other information resources are largely used to confirm their treatment decision. Patients highly value support from their loved ones and appreciate emphatic doctors to actively involve them in the decision-making process. Overall, patients' needs for information and support during decision-making were met. CONCLUSIONS: The importance of shared decision-making and the role doctors have in this process is underlined. The role of doctors is essential at the initial phase of decision-making: Once patients seem to have formed their treatment preference for either active surveillance or surgery, the influence of external resources (including doctors) may be limited.

Prognostic Value of T-Cell Density in the Tumor Center and Outer Margins in Gastric Cancer.

Tumor-infiltrating lymphocytes are associated with the survival of gastric cancer patients. T-cell densities in the tumor and its periphery were previously identified as prognostic T-cell markers for resectable gastric cancer. Immunohistochemistry for 5 T-cell markers, CD3, CD45RO, CD8, FOXP3, and granzyme B was performed on serial sections of N = 251 surgical resection specimens of patients treated with surgery only in the D1/D2 trial. Positive T cells were digitally quantified into tiles of 0.25 mm2 across 3 regions: the tumor center (TC), the inner invasive margin, and the outer invasive margin (OIM). A classification and regression tree model was employed to identify the optimal combination of median T-cell densities per region with cancer-specific survival (CSS) as the outcome. All statistical tests were 2-sided. CD8OIM was identified as the most dominant prognostic factor, followed by FOXP3TC, resulting in a decision tree containing 3 prognostically distinct subgroups with high (Hi) or low (Lo) density of the markers: CD8OIMHi, CD8OIMLo/FOXP3TCHi, and CD8OIMLo/FOXP3TCLo. In a multivariable Cox regression analysis, which included pathological T and N stages, Lauren histologic types, EBV status, microsatellite instability, and type of surgery, the immune subgroups were independent predictors for CSS. CSS was lower for CD8OIMLo/FOXP3TCHi (HR: 5.02; 95% CI: 2.03-12.42) and for CD8OIMLo/FOXP3TCLo (HR: 7.99; 95% CI: 3.22-19.86), compared with CD8OIMHi (P < .0001). The location and density of both CD8+ and FOXP3+ T cells in resectable gastric cancer are independently associated with survival. The combination of CD8OIM and FOXP3TC T-cell densities is a promising stratification factor that should be validated in independent studies.

Local treatment in metastatic GIST patients: A multicentre analysis from the Dutch GIST Registry.

BACKGROUND: The added value of local treatment in selected metastatic GIST patients is unclear. This study aims to provide insight into the usefulness of local treatment in metastatic GIST by use of a survey study and retrospective analyses in a clinical database. METHODS: A survey study was conducted among clinical specialists to select most relevant characteristics of metastatic GIST patients considered for local treatment, defined as elective surgery or ablation. Patients were selected from the Dutch GIST Registry. A multivariate Cox-regression model for overall survival since time of diagnosis of metastatic disease was estimated with local treatment as a time-dependent variable. An additional model was estimated to assess prognostic factors since local treatment. RESULTS: The survey's response rate was 14/16. Performance status, response to TKIs, location of active disease, number of lesions, mutation status, and time between primary diagnosis and metastases, were regarded the 6 most important characteristics. Of 457 included patients, 123 underwent local treatment, which was associated with better survival after diagnosis of metastases (HR = 0.558, 95%CI = 0.336-0.928). Progressive disease during systemic treatment (HR = 3.885, 95%CI = 1.195-12.627) and disease confined to the liver (HR = 0.269, 95%CI = 0.082-0.880) were associated with worse and better survival after local treatment, respectively. CONCLUSION: Local treatment is associated with better survival in selected patients with metastatic GIST. Locally treated patients with response to TKIs and disease confined to the liver have good clinical outcome. These results might be considered for tailoring treatment, but should be interpreted with care because only specific patients are provided with local treatment in this retrospective study.

Definition, diagnosis and treatment of oligometastatic oesophagogastric cancer: A Delphi consensus study in Europe.

BACKGROUND: Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. METHODS: In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%-75%) or consensus (≥75%). RESULTS: A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). CONCLUSION: The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials.

Cost-effectiveness of Laparoscopic vs Open Gastrectomy for Gastric Cancer: An Economic Evaluation Alongside a Randomized Clinical Trial.

Importance: Laparoscopic gastrectomy is rapidly being adopted worldwide as an alternative to open gastrectomy to treat gastric cancer. However, laparoscopic gastrectomy might be more expensive as a result of longer operating times and more expensive surgical materials. To date, the cost-effectiveness of both procedures has not been prospectively evaluated in a randomized clinical trial. Objective: To evaluate the cost-effectiveness of laparoscopic compared with open gastrectomy. Design, Setting, and Participants: In this multicenter randomized clinical trial of patients undergoing total or distal gastrectomy in 10 Dutch tertiary referral centers, cost-effectiveness data were collected alongside a multicenter randomized clinical trial on laparoscopic vs open gastrectomy for resectable gastric adenocarcinoma (cT1-4aN0-3bM0). A modified societal perspective and 1-year time horizon were used. Costs were calculated on the individual patient level by using hospital registry data and medical consumption and productivity loss questionnaires. The unit costs of laparoscopic and open gastrectomy were calculated bottom-up. Quality-adjusted life-years (QALYs) were calculated with the EuroQol 5-dimension questionnaire, in which a value of 0 indicates death and 1 indicates perfect health. Missing questionnaire data were imputed with multiple imputation. Bootstrapping was performed to estimate the uncertainty surrounding the cost-effectiveness. The study was conducted from March 17, 2015, to August 20, 2018. Data analyses were performed between September 1, 2020, and November 17, 2021. Interventions: Laparoscopic vs open gastrectomy. Main Outcomes and Measures: Evaluations in this cost-effectiveness analysis included total costs and QALYs. Results: Between 2015 and 2018, 227 patients were included. Mean (SD) age was 67.5 (11.7) years, and 140 were male (61.7%). Unit costs for initial surgery were calculated to be €8124 (US $8087) for laparoscopic total gastrectomy, €7353 (US $7320) for laparoscopic distal gastrectomy, €6584 (US $6554) for open total gastrectomy, and €5893 (US $5866) for open distal gastrectomy. Mean total costs after 1-year follow-up were €26 084 (US $25 965) in the laparoscopic group and €25 332 (US $25 216) in the open group (difference, €752 [US $749; 3.0%]). Mean (SD) QALY contributions during 1 year were 0.665 (0.298) in the laparoscopic group and 0.686 (0.288) in the open group (difference, -0.021). Bootstrapping showed that these differences between treatment groups were relatively small compared with the uncertainty of the analysis. Conclusions and Relevance: Although the laparoscopic gastrectomy itself was more expensive, after 1-year follow-up, results suggest that differences in both total costs and effectiveness were limited between laparoscopic and open gastrectomy. These results support centers' choosing, based on their own preference, whether to (de)implement laparoscopic gastrectomy as an alternative to open gastrectomy.

Patient preferences for active surveillance vs standard surgery after neoadjuvant chemoradiotherapy in oesophageal cancer treatment: The NOSANO-study.

Active surveillance may be a safe and effective treatment in oesophageal cancer patients with a clinically complete response after neoadjuvant chemoradiotherapy (nCRT). In the NOSANO-study we gained insight in patients' motive to opt for either an experimental treatment called active surveillance or for standard immediate surgery. Both qualitative and quantitative analyses methods were used. Forty patients were interviewed about their treatment preference, 3 months after completion of nCRT (T1). Data were recorded, transcribed verbatim and analysed according to the principles of grounded theory. In addition, at T1 and T2 (12 months after completion of nCRT) questionnaires on health-related quality of life, coping, anxiety and decisional regret (only T2) were administered. Interview data analyses resulted in a conceptual model with 'dealing with threat of cancer' as the central theme. Patients preferring active surveillance tend to cope with this threat by confiding in their bodies and good outcomes. Their mind-set is one of 'enjoy life now'. Patients preferring surgery tend to cope by minimizing uncertainty and eliminating the source of cancer. Their mind-set is one of 'don't give up, act now'. Furthermore, questionnaire results showed that patients with a preference for standard surgery had a lower quality of life. Patient preferences are individualized and thus difficult to predict. Our model can help healthcare professionals to determine patient preferences for treatment. Coping style and mind-set seem to be determining factors here.

Risk of Lymph Node Metastasis in T1b Gastric Cancer: An International Comprehensive Analysis from the Global Gastric Group (G3) Alliance.

OBJECTIVE: We sought to define criteria associated with low lymph node metastasis risk in patients with submucosal (pT1b) gastric cancer from 3 Western and 3 Eastern countries. SUMMARY BACKGROUND DATA: Accurate prediction of lymph node metastasis risk is essential when determining the need for gastrectomy with lymph node dissection following endoscopic resection. Under present guidelines, endoscopic resection is considered definitive treatment if submucosal invasion is only superficial, but this is not routinely assessed. METHODS: Lymph node metastasis rates were determined for patient groups defined according to tumor pathological characteristics. Clinicopathological predictors of lymph node metastasis were determined by multivariable logistic regression and used to develop a nomogram in a randomly selected subset that was validated in the remainder. Overall survival was compared between Eastern and Western countries. RESULTS: Lymph node metastasis was found in 701 of 3166 (22.1%) Eastern and 153 of 560 (27.3%) Western patients. Independent predictors of lymph node metastasis were female sex, tumor size, distal stomach location, lymphovascular invasion, and moderate or poor differentiation. Patients fulfilling the National Comprehensive Cancer Network guideline criteria, excluding the requirement that invasion not extend beyond the superficial submucosa, had a lymph node metastasis rate of 8.9% (53/594). Excluding moderately differentiated tumors lowered the rate to 3.4% (10/296). The nomogram's area under the curve was 0.690. Regardless of lymph node status, overall survival was better in Eastern patients. CONCLUSIONS: The lymph node metastasis rate was lowest in patients with well differentiated tumors that were ≤3 cm and lacked lymphovascular invasion. These criteria may be useful in decisions regarding endoscopic resection as definitive treatment for pT1b gastric cancer.

Trends in Distal Esophageal and Gastroesophageal Junction Cancer Care: The Dutch Nationwide Ivory Study.

OBJECTIVE: This study evaluated the nationwide trends in care and accompanied postoperative outcomes for patients with distal esophageal and gastro-esophageal junction cancer. SUMMARY OF BACKGROUND DATA: The introduction of transthoracic esophagectomy, minimally invasive surgery, and neo-adjuvant chemo(radio)therapy changed care for patients with esophageal cancer. METHODS: Patients after elective transthoracic and transhiatal esophagectomy for distal esophageal or gastroesophageal junction carcinoma in the Netherlands between 2007-2016 were included. The primary aim was to evaluate trends in both care and postoperative outcomes for the included patients. Additionally, postoperative outcomes after transthoracic and tran-shiatal esophagectomy were compared, stratified by time periods. RESULTS: Among 4712 patients included, 74% had distal esophageal tumors and 87% had adenocarcinomas. Between 2007 and 2016, the proportion of transthoracic esophagectomy increased from 41% to 81%, and neo-adjuvant treatment and minimally invasive esophagectomy increased from 31% to 96%, and from 7% to 80%, respectively. Over this 10-year period, postoperative outcomes improved: postoperative morbidity decreased from 66.6% to 61.8% ( P = 0.001), R0 resection rate increased from 90.0% to 96.5% (P <0.001), median lymph node harvest increased from 15 to 19 ( P <0.001), and median survival increased from 35 to 41 months ( P = 0.027). CONCLUSION: In this nationwide cohort, a transition towards more neo-adju-vant treatment, transthoracic esophagectomy and minimally invasive surgery was observed over a 10-year period, accompanied by decreased postoperative morbidity, improved surgical radicality and lymph node harvest, and improved survival.

Recurrent Disease After Esophageal Cancer Surgery: A Substudy of The Dutch Nationwide Ivory Study.

OBJECTIVE: This study investigated the patterns, predictors, and survival of recurrent disease following esophageal cancer surgery. BACKGROUND: Survival of recurrent esophageal cancer is usually poor, with limited prospects of remission. METHODS: This nationwide cohort study included patients with distal esophageal and gastroesophageal junction adenocarcinoma and squamous cell carcinoma after curatively intended esophagectomy in 2007 to 2016 (follow-up until January 2020). Patients with distant metastases detected during surgery were excluded. Univariable and multivariable logistic regression were used to identify predictors of recurrent disease. Multivariable Cox regression was used to determine the association of recurrence site and treatment intent with postrecurrence survival. RESULTS: Among 4626 patients, 45.1% developed recurrent disease a median of 11 months postoperative, of whom most had solely distant metastases (59.8%). Disease recurrences were most frequently hepatic (26.2%) or pulmonary (25.1%). Factors significantly associated with disease recurrence included young age (≤65 y), male sex, adenocarcinoma, open surgery, transthoracic esophagectomy, nonradical resection, higher T-stage, and tumor positive lymph nodes. Overall, median postrecurrence survival was 4 months [95% confidence interval (95% CI): 3.6-4.4]. After curatively intended recurrence treatment, median survival was 20 months (95% CI: 16.4-23.7). Survival was more favorable after locoregional compared with distant recurrence (hazard ratio: 0.74, 95% CI: 0.65-0.84). CONCLUSIONS: This study provides important prognostic information assisting in the surveillance and counseling of patients after curatively intended esophageal cancer surgery. Nearly half the patients developed recurrent disease, with limited prospects of survival. The risk of recurrence was higher in patients with a higher tumor stage, nonradical resection and positive lymph node harvest.

Conventional regression analysis and machine learning in prediction of anastomotic leakage and pulmonary complications after esophagogastric cancer surgery.

BACKGROUND AND OBJECTIVES: With the current advanced data-driven approach to health care, machine learning is gaining more interest. The current study investigates the added value of machine learning to linear regression in predicting anastomotic leakage and pulmonary complications after upper gastrointestinal cancer surgery. METHODS: All patients in the Dutch Upper Gastrointestinal Cancer Audit undergoing curatively intended esophageal or gastric cancer surgeries from 2011 to 2017 were included. Anastomotic leakage was defined as any clinically or radiologically proven anastomotic leakage. Pulmonary complications entailed: pneumonia, pleural effusion, respiratory failure, pneumothorax, and/or acute respiratory distress syndrome. Different machine learning models were tested. Nomograms were constructed using Least Absolute Shrinkage and Selection Operator. RESULTS: Between 2011 and 2017, 4228 patients underwent surgical resection for esophageal cancer, of which 18% developed anastomotic leakage and 30% a pulmonary complication. Of the 2199 patients with surgical resection for gastric cancer, 7% developed anastomotic leakage and 15% a pulmonary complication. In all cases, linear regression had the highest predictive value with the area under the curves varying between 61.9 and 68.0, but the difference with machine learning models did not reach statistical significance. CONCLUSION: Machine learning models can predict postoperative complications in upper gastrointestinal cancer surgery, but they do not outperform the current gold standard, linear regression.