Measurement of metabolite levels and treatment-induced changes in hepatic metastases of gastro-esophageal cancer using 7-T phosphorus magnetic resonance spectroscopic imaging.

Methods for early treatment response evaluation to systemic therapy of liver metastases are lacking. Tumor tissue often exhibits an increased ratio of phosphomonoesters to phosphodiesters (PME/PDE), which can be noninvasively measured by phosphorus magnetic resonance spectroscopy (31P MRS), and may be a marker for early therapy response assessment in liver metastases. However, with commonly used 31P surface coils for liver 31P MRS, the liver is not fully covered, and metastases may be missed. The objective of this study was to demonstrate the feasibility of 31P MRS imaging (31P MRSI) with full liver coverage to assess 31P metabolite levels and chemotherapy-induced changes in liver metastases of gastro-esophageal cancer, using a 31P whole-body birdcage transmit coil in combination with a 31P body receive array at 7 T. 3D 31P MRSI data were acquired in two patients with hepatic metastases of esophageal cancer, before the start of chemotherapy and after 2 (and 9 in patient 2) weeks of chemotherapy. 3D 31P MRSI acquisitions were performed using an integrated 31P whole-body transmit coil in combination with a 16-channel body receive array at 7 T, with a field of view covering the full abdomen and a nominal voxel size of 20-mm isotropic. From the 31P MRSI data, 12 31P metabolite signals were quantified. Prior to chemotherapy initiation, both PMEs, that is, phosphocholine (PC) and phosphoethanolamine (PE), were significantly higher in all metastases compared with the levels previously determined in the liver of healthy volunteers. After 2 weeks of chemotherapy, PC and PE levels remained high or even increased further, resulting in increased PME/PDE ratios compared with healthy liver tissue, in correspondence with the clinical assessment of progressive disease after 2 months of chemotherapy. The suggested approach may present a viable tool for early therapy (non)response assessment of tumor metabolism in patients with liver metastases.

31 P MR Spectroscopy in the Pancreas: Repeatability, Comparison With Liver, and Pilot Pancreatic Cancer Data.

BACKGROUND: Non-invasive evaluation of phosphomonoesters (PMEs) and phosphodiesters (PDEs) by 31-phosphorus MR spectroscopy (31 P MRS) may have potential for early therapy (non-)response assessment in cancer. However, 31 P MRS has not yet been applied to investigate the human pancreas in vivo. PURPOSE: To assess the technical feasibility and repeatability of 31 P MR spectroscopic imaging (MRSI) of the pancreas, compare 31 P metabolite levels between pancreas and liver, and determine the feasibility of 31 P MRSI in pancreatic cancer. STUDY TYPE: Prospective cohort study. POPULATION: 10 healthy subjects (age 34 ± 12 years, four females) and one patient (73-year-old female) with pancreatic ductal adenocarcinoma. FIELD STRENGTH/SEQUENCE: 7-T, 31 P FID-MRSI, 1 H gradient-echo MRI. ASSESSMENT: 31 P FID-MRSI of the abdomen (including the pancreas and liver) was performed with a nominal voxel size of 20 mm (isotropic). For repeatability measurements, healthy subjects were scanned twice on the same day. The patient was only scanned once. Test-retest 31 P MRSI data of pancreas and liver voxels (segmented on 1 H MRI) of healthy subjects were quantified by fitting in the time domain and signal amplitudes were normalized to γ-adenosine triphosphate. In addition, the PME/PDE ratio was calculated. Metabolite levels were averaged over all voxels within the pancreas, right liver lobe and left liver lobe, respectively. STATISTICAL TESTS: Repeatability of test-retest data from healthy pancreas was assessed by paired t-tests, Bland-Altman analyses, and calculation of the intrasubject coefficients of variation (CoVs). Significant differences between healthy pancreas and right and left liver lobes were assessed with a two-way analysis of variance (ANOVA) for repeated measures. A P-value <0.05 was considered statistically significant. RESULTS: The intrasubject CoVs for PME, PDE, and PME/PDE in healthy pancreas were below 20%. Furthermore, PME and PME/PDE were significantly higher in pancreas compared to liver. In the patient with pancreatic cancer, qualitatively, elevated relative PME signals were observed in comparison with healthy pancreas. DATA CONCLUSION: In vivo 31 P MRSI of the human healthy pancreas and in pancreatic cancer may be feasible at 7 T. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

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.

Implementation of Best Practices in Pancreatic Cancer Care in the Netherlands: A Stepped-Wedge Randomized Clinical Trial.

Importance: Implementation of new cancer treatment strategies as recommended by evidence-based guidelines is often slow and suboptimal. Objective: To improve the implementation of guideline-based best practices in the Netherlands in pancreatic cancer care and assess the impact on survival. Design, setting, and participants: This multicenter, stepped-wedge cluster randomized trial compared enhanced implementation of best practices with usual care in consecutive patients with all stages of pancreatic cancer. It took place from May 22, 2018 through July 9, 2020. Data were analyzed from April 1, 2022, through February 1, 2023. It included all patients in the Netherlands with pathologically or clinically diagnosed pancreatic ductal adenocarcinoma. This study reports 1-year follow-up (or shorter in case of deceased patients). Intervention: The 5 best practices included optimal use of perioperative chemotherapy, palliative chemotherapy, pancreatic enzyme replacement therapy (PERT), referral to a dietician, and use of metal stents in patients with biliary obstruction. A 6-week implementation period was completed, in a randomized order, in all 17 Dutch networks for pancreatic cancer care. Main Outcomes and Measures: The primary outcome was 1-year survival. Secondary outcomes included adherence to best practices and quality of life (European Organisation for Research and Treatment of Cancer [EORTC] global health score). Results: Overall, 5887 patients with pancreatic cancer (median age, 72.0 [IQR, 64.0-79.0] years; 50% female) were enrolled, 2641 before and 2939 after implementation of best practices (307 during wash-in period). One-year survival was 24% vs 23% (hazard ratio, 0.98, 95% CI, 0.88-1.08). There was no difference in the use of neoadjuvant chemotherapy (11% vs 11%), adjuvant chemotherapy (48% vs 51%), and referral to a dietician (59% vs 63%), while the use of palliative chemotherapy (24% vs 30%; odds ratio [OR], 1.38; 95% CI, 1.10-1.74), PERT (34% vs 45%; OR, 1.64; 95% CI, 1.28-2.11), and metal biliary stents increased (74% vs 83%; OR, 1.78; 95% CI, 1.13-2.80). The EORTC global health score did not improve (area under the curve, 43.9 vs 42.8; median difference, -1.09, 95% CI, -3.05 to 0.94). Conclusions and Relevance: In this randomized clinical trial, implementation of 5 best practices in pancreatic cancer care did not improve 1-year survival and quality of life. The finding that most patients received no tumor-directed treatment paired with the poor survival highlights the need for more personalized treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT03513705.

Minimum and Optimal CA19-9 Response After Two Months Induction Chemotherapy in Patients With Locally Advanced Pancreatic Cancer: A Nationwide Multicenter Study.

OBJECTIVE: This nationwide multicenter study aimed to define clinically relevant thresholds of relative serum CA19-9 response after 2 months of induction chemotherapy in patients with locally advanced pancreatic cancer (LAPC). BACKGROUND: CA19-9 is seen as leading biomarker for response evaluation in patients with LAPC, but early clinically useful cut-offs are lacking. METHODS: All consecutive patients with LAPC after 4 cycles (m)FOLFIRINOX or 2 cycles gemcitabine-nab-paclitaxel induction chemotherapy (±radiotherapy) with CA19-9 ≥5 U/mL at baseline were analyzed (2015-2019). The association of CA19-9 response with median OS (mOS) was evaluated for different CA19-9 cut-off points. Minimum and optimal CA19-9 response were established via log-rank test. Predictors for OS were analyzed using COX regression analysis. RESULTS: Overall, 212 patients were included, of whom 42 (19.8%) underwent resection. Minimum CA19-9 response demonstrating a clinically significant median OS difference (12.7 vs. 19.6 months) was seen at ≥40% CA19-9 decrease. The optimal cutoff for CA19-9 response was ≥60% decrease (21.7 vs. 14.0 mo, P =0.021). Only for patients with elevated CA19-9 levels at baseline (n=184), CA19-9 decrease ≥60% [hazard ratio (HR)=0.59, 95% CI, 0.36-0.98, P =0.042] was independently associated with prolonged OS, as were SBRT (HR=0.42, 95% CI, 0.25-0.70; P =0.001), and resection (HR=0.25, 95% CI, 0.14-0.46, P <0.001), and duration of chemotherapy (HR=0.75, 95% CI, 0.69-0.82, P <0.001). CONCLUSIONS: CA19-9 decrease of ≥60% following induction chemotherapy as optimal response cut-off in patients with LAPC is an independent predictor for OS when CA19-9 is increased at baseline. Furthermore, ≥40% is the minimum cut-off demonstrating survival benefit. These cut-offs may be used when discussing treatment strategies during early response evaluation.

Incidence, Stage, Treatment, and Survival of Noncardia Gastric Cancer.

Importance: Gastric cancer is the fifth most common cancer worldwide, and investigating its incidence, characteristics, treatment, and outcomes over the past decades can help in selecting clinical strategies and future research directions. Objective: To analyze the trends in incidence, staging, and treatment of gastric cancer. Design, Setting, and Participants: This nationwide, population-based cohort study included patients diagnosed with noncardia gastric cancer (NCGC) between 1989 and 2021 in the Netherlands. Main Outcomes and Measures: Differences in tumor characteristics, treatment, and survival were analyzed per fixed time periods (1989-1993, 1994-1998, 1999-2003, 2004-2008, 2009-2013, 2014-2018, and 2019-2021). Results: In total, 47 014 patients (median [IQR] age, 73 [64-80] years; 28 032 [60%] male patients) were identified with mostly adenocarcinomas of the antrum region (when location was known). Age-standardized incidence decreased from 20.3 to 6.1 per 100 000 person-years between 1989 and 2021. During the study period, unknown T and N stages were recorded less frequently, and metastatic disease was diagnosed more frequently (1989-1993: 2633 of 9493 patients [28%]; 2019-2021: 1503 of 3200 patients [47%] in 2019-2021). Over time, fewer patients with metastatic disease underwent surgery with or without other treatment modalities (68% in 1989-1993 vs 64% in 2019-2021), and palliative chemotherapy in metastatic NCGC increased from 9% to 40%. For patients with nonmetastatic disease, 5-year relative survival improved from 28% (95% CI, 26.5%-29.2%) to 36% (95% CI, 33.5%-37.6%) between 1989 and 2021. For patients with nonmetastatic disease undergoing a resection, 5-year survival increased from 40% (95% CI, 38.3%-41.8%) to 51% (95% CI, 47.9%-53.3%). For patients with metastatic disease, 1-year relative survival increased from 10% (95% CI, 8.7%-11.1%) to 19% (95% CI, 17.2%-21.6%), but 3-year relative survival remained poor at 5% (95% CI, 3.6%-7.5%). Conclusions and Relevance: In this nationwide cohort study involving 47 014 patients diagnosed with NCGC (1989-2021), the results showed a decrease in incidence, more accurate staging, a shift in treatment modalities, and improved patient survival.

Long-term health-related quality of life in patients with advanced esophagogastric cancer receiving first-line systemic therapy.

PURPOSE: To investigate the effect of systemic therapy on health-related quality of life (HRQoL) in patients with advanced esophagogastric cancer in daily clinical practice. This study assessed the HRQoL of patients with esophagogastric cancer during first-line systemic therapy, at disease progression, and after progression in a real-world context. METHODS: Patients with advanced esophagogastric cancer (2014-2021) receiving first-line systemic therapy registered in the Prospective Observational Cohort Study of Oesophageal-gastric cancer (POCOP) were included (n = 335). HRQoL was measured with the EORTC QLQ-C30 and QLQ-OG25. Outcomes of mixed-effects models were presented as adjusted mean changes. RESULTS: Results of the mixed-effect models showed the largest significant improvements during systemic therapy for odynophagia (- 18.9, p < 0.001), anxiety (- 18.7, p < 0.001), and dysphagia (- 13.8, p < 0.001) compared to baseline. After progression, global health status (- 6.3, p = 0.002) and cognitive (- 6.2, p = 0.001) and social functioning (- 9.7, p < 0.001) significantly worsened. At and after progression, physical (- 9.0, p < 0.001 and - 8.8, p < 0.001) and role functioning (- 15.2, p = 0.003 and - 14.7, p < 0.001) worsened, respectively. Trouble with taste worsened during systemic therapy (11.5, p < 0.001), at progression (12.0, p = 0.004), and after progression (15.3, p < 0.001). CONCLUSION: In general, HRQoL outcomes in patients with advanced esophagogastric cancer improved during first-line therapy. Deterioration in outcomes was mainly observed at and after progression. IMPLICATIONS FOR CANCER SURVIVORS: Identification of HRQoL aspects is important in shared decision-making and to inform patients on the impact of systemic therapy on their HRQoL.

Longitudinal immune monitoring of patients with resectable esophageal adenocarcinoma treated with Neoadjuvant PD-L1 checkpoint inhibition.

The analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry holds promise as a platform for immune checkpoint inhibition (ICI) biomarker identification. Our aim was to characterize the systemic immune compartment in resectable esophageal adenocarcinoma patients treated with neoadjuvant ICI therapy. In total, 24 patients treated with neoadjuvant chemoradiotherapy (nCRT) and anti-PD-L1 (atezolizumab) from the PERFECT study (NCT03087864) were included and 26 patients from a previously published nCRT cohort. Blood samples were collected at baseline, on-treatment, before and after surgery. Response groups for comparison were defined as pathological complete responders (pCR) or patients with pathological residual disease (non-pCR). Based on multicolor flow cytometry of PBMCs, an immunosuppressive phenotype was observed in the non-pCR group of the PERFECT cohort, characterized by a higher percentage of regulatory T cells (Tregs), intermediate monocytes, and a lower percentage of type-2 conventional dendritic cells. A further increase in activated Tregs was observed in non-pCR patients on-treatment. These findings were not associated with a poor response in the nCRT cohort. At baseline, immunosuppressive cytokines were elevated in the non-pCR group of the PERFECT study. The suppressive subsets correlated at baseline with a Wnt/ß-Catenin gene expression signature and on-treatment with epithelial-mesenchymal transition and angiogenesis signatures from tumor biopsies. After surgery monocyte activation (CD40), low CD8+Ki67+ T cell rates, and the enrichment of CD206+ monocytes were related to early recurrence. These findings highlight systemic barriers to effective ICI and the need for optimized treatment regimens.

A population-based comparison of patients with metastatic esophagogastric carcinoma between Japan and the Netherlands.

PURPOSE: Differences exist between Asian and Western patients with esophagogastric cancer, for example in terms of histological subtype and treatment strategies. This study aimed to compare characteristics and treatment between patients with metastatic esophagogastric cancer from Japan and the Netherlands using nationwide cancer registry data. METHODS: Patients diagnosed with metastatic esophageal or gastric cancer were included from the nationwide national cancer registry of Japan (2016-2019) and the Netherlands (2015-2020). Treatment strategies were analyzed using chi-squared tests. RESULTS: The proportion of patients with metastatic esophageal (16.0% vs 34.2%) and gastric cancer (14.9% vs 45.2%) were lower in Japan compared to the Netherlands. Japanese patients with metastatic esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC) or gastric cancer (GC) were more often male and older compared to Dutch patients. Proportion of patients with metastatic disease who received surgical resection was higher in Japan compared to the Netherlands (EAC 9.3 vs 1.4%, p < 0.001; ESCC 10.7% vs 2.3%, p < 0.001; GC 12.0% vs 3.6% p < 0.001). Proportion of patients who received systemic therapy was also higher (EAC 44.8% vs 30.4%, p < 0.001; ESCC 26.6% vs 12.0%, p < 0.001; GC 50.7% vs 35.8% p < 0.001). CONCLUSIONS: Japanese patients less often presented with metastatic esophagogastric cancer and more often underwent surgical resection or received systemic therapy compared to Dutch patients. Further investigation should elucidate what the deliberations are in both Japan and the Netherlands and if more patients in the Netherlands could benefit from surgical resection or systemic therapy and whether this would translate in better survival and quality of life.

Trends in best-case, typical and worst-case survival scenarios of patients with non-metastatic esophagogastric cancer between 2006 and 2020: A population-based study.

New treatment options and centralization of surgery have improved survival for patients with non-metastatic esophageal or gastric cancer. It is unknown, however, which patients benefitted the most from treatment advances. The aim of this study was to identify best-case, typical and worst-case scenarios in terms of survival time, and to assess if survival associated with these scenarios changed over time. Patients with non-metastatic potentially resectable esophageal or gastric cancer diagnosed between 2006 and 2020 were selected from the Netherlands Cancer Registry. Best-case (20th percentile), upper-typical (40th percentile), typical (median), lower-typical (60th percentile) and worst-case (80th percentile) survival scenarios were defined, and regression analysis was used to investigate the change in survival time for each scenario across years. For patients with esophageal cancer (N = 24 352) survival time improved on average 12.0 (until 2011), 1.5 (until 2018), 0.7, 0.4 and 0.2 months per year for the best-case, upper-typical, median, lower-typical and worst-case scenario, respectively. For patients with gastric cancer (N = 9993) survival time of the best-case scenario remained constant, whereas the upper-typical, median, lower-typical and worst-case scenario improved on average with 1.0 (until 2018), 0.5, 0.2 and 0.2 months per year, respectively. Subgroup analyses showed that, survival scenarios improved for nearly all patients across treatment groups and for patients with squamous cell carcinomas or adenocarcinomas. Survival improved for almost all patients suggesting that in clinical practice the vast majority of patients benefitted from treatment advances. The clinically most meaningful survival advantage was observed for the best-case scenario of esophageal cancer.

SOURCE beyond first-line: A survival prediction model for patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy.

Prior models have been developed to predict survival for patients with esophagogastric cancer undergoing curative treatment or first-line chemotherapy (SOURCE models). Comprehensive clinical prediction models for patients with esophagogastric cancer who will receive second-line chemotherapy or best supportive care are currently lacking. The aim of our study was to develop and internally validate a new clinical prediction model, called SOURCE beyond first-line, for survival of patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy. Patients with unresectable or metastatic esophageal or gastric adenocarcinoma (2015-2017) who received first-line systemic therapy (N = 1067) were selected from the Netherlands Cancer Registry. Patient, tumor and treatment characteristics at primary diagnosis and at progression of disease were used to develop the model. A Cox proportional hazards regression model was developed through forward and backward selection using Akaike's Information Criterion. The model was internally validated through 10-fold cross-validations to assess performance. Model discrimination (C-index) and calibration (slope and intercept) were used to evaluate performance of the complete and cross-validated models. The final model consisted of 11 patient tumor and treatment characteristics. The C-index was 0.75 (0.73-0.78), calibration slope 1.01 (1.00-1.01) and calibration intercept 0.01 (0.01-0.02). Internal cross-validation of the model showed that the model performed adequately on unseen data: C-index was 0.79 (0.77-0.82), calibration slope 0.93 (0.85-1.01) and calibration intercept 0.02 (-0.01 to 0.06). The SOURCE beyond first-line model predicted survival with fair discriminatory ability and good calibration.

Stereotactic radiotherapy or metastasectomy for oligometastatic esophagogastric cancer: A nationwide population-based cohort study.

Background and purpose: This nationwide population-based study analyzed the outcomes of local treatment (i.e. stereotactic body radiotherapy [SBRT] or metastasectomy) or systemic therapy for oligometastatic disease (OMD) in patients with esophagogastric cancer in The Netherlands. Materials and methods: Between 2015 and 2016, all patients in The Netherlands with esophagogastric cancer and synchronous or metachronous OMD were eligible for inclusion. Patients who underwent local treatment of OMD (SBRT or metastasectomy) and/or systemic therapy were included. OMD was defined as distant metastases in 1 organ or 1 extra-regional lymph node region. The primary outcomes were overall survival (OS) and independent prognostic factors for OS. OS was calculated from diagnosis of OMD. Prognostic factors for OS were analyzed using a multivariable Cox proportional hazard model. Results: A total of 594 patients were included, of whom 83 underwent local treatment for OMD alone, 22 local treatment plus systemic therapy, and 489 systemic therapy alone. Median OS after local treatment for OMD alone was 16.0 months, local treatment plus systemic therapy 22.7 months, and after systemic therapy alone 8.5 months. Improved OS was independently associated with local treatment for OMD alone or combined with systemic therapy as compared with systemic therapy alone (hazard ratio [HR] 0.52, 95% CI: 0.31-0.90 and HR 0.42, 95% CI: 0.22-0.82, respectively) and a controlled primary tumor(HR 0.48, 95% CI: 0.27-0.86). Worse OS was independently associated with worse performance scores (HR 1.41, 95%: 1.32-1.75), poorly or undiffertumor as compared with good or moderadifferentiated tumor (HR 1.37, 95% CI: 1.06-1.76), and peritoneal as compared with lymph mode metastases (HR 1.39, 95% CI: 1.00-1.93). Conclusion: Local treatment of OMD alone or combined with systemic therapy was independently associated with improved OS as compared with systemic therapy alone in this population-based cohort study in The Netherlands. Randomized controlled trials are warranted to confirm these results.

Detecting Interval Distant Metastases With 18F-FDG PET/CT After Neoadjuvant Chemoradiotherapy for Locally Advanced Esophageal Cancer.

PURPOSE: Patients with esophageal cancer can develop distant metastases between the start of neoadjuvant chemoradiotherapy (nCRT) and planned surgery (ie, interval distant metastases). 18F-FDG PET/CT restaging after nCRT detects interval distant metastases in ~8% of patients. This study aimed to identify patients for whom 18F-FDG PET/CT restaging after nCRT could be omitted using an existing prediction model predicting for interval distant metastases or by using clinical stage groups. PATIENTS AND METHODS: Patients with locally advanced esophageal cancer who underwent baseline and restaging 18F-FDG PET/CT, nCRT, and were planned for esophagectomy between 2017 and 2021 were eligible for inclusion in this retrospective study. The primary outcome was the existing model's external performance (ie, discrimination and calibration) for predicting interval distant metastases. The existing model predictors included tumor length, cN status, squamous cell carcinoma histology, and baseline SUVmax. The secondary outcome determined the clinical stage groups (AJCC/UICC eighth edition) for adenocarcinoma and squamous cell carcinoma for which the incidence of interval distant metastases was <10%. RESULTS: In total, 127 patients were included, of whom 17 patients developed interval distant metastases (13%; 95% confidence interval [CI], 8%-21%) and 9 patients were deemed to have false-positive lesions on 18F-FDG PET/CT (7%; 95% CI, 2%-11%). Applying the existing model to this cohort yielded a discriminatory c-statistic of 0.56 (95% CI, 0.40-0.72). The calibration of the existing model was poor (ie, mostly underestimating the actual risk). The incidence of true-positive versus false-positive interval distant metastases for patients with clinical stage II disease was 5% versus 0%; clinical stage III, 14% versus 8%; and clinical stage IVa, 22% versus 9%. CONCLUSIONS: The existing prediction model cannot reliably identify patients at risk for developing interval distant metastases after nCRT for esophageal cancer. Omission of 18F-FDG PET/CT restaging after nCRT could be considered in patients with clinical stage II esophageal cancer.

A population-based study in synchronous versus metachronous metastatic esophagogastric adenocarcinoma.

Background: Real-world data on treatment and outcomes in patients with synchronous metastatic disease compared with patients with metachronous metastatic disease in esophagogastric cancer have not been published before. The aim of our study was to explore treatment, overall survival (OS), and time to treatment fialure (TTF) in patients with synchronous and metachronous metastatic esophagogastric adenocarcinoma. Methods: Patients with synchronous metastatic disease (2015-2017) and patients with metachronous metastatic disease initially treated with curative intent for nonmetastatic disease (2015-2016) were selected from the Netherlands Cancer Registry. OS and TTF were assessed from metastatic diagnosis for patients with synchronous, early metachronous (⩽6 months) or late metachronous (>6 months) metastatic disease using Kaplan-Meier curves with two-sided log-rank test. Results: Median OS was 4.2, 2.1, and 4.4 months in patients with synchronous, early metachronous, and late metachronous metastatic disease, respectively (p < 0.001). The proportion of patients receiving systemic treatment was 41.3%, 21.5%, and 32.5% for synchronous, early metachronous, and late metachronous metastatic disease, respectively (p = 0.001). Among patients receiving systemic treatment, median OS was 8.8, 4.5, and 9.1 months (p < 0.001) and median TTF was 6.1, 3.8, and 5.7 months (p < 0.001) in synchronous, early metachronous, and late metachronous metastatic disease, respectively. Conclusion: Patients with early metachronous metastatic disease have a worse survival compared with patients with synchronous or late metachronous metastatic disease. These patients less often receive systemic treatment, and even when treated, survival is worse compared with patients with synchronous or late metachronous metastatic disease, suggesting a more aggressive tumor behavior.

A population-based study on treatment and outcomes in patients with gastric adenocarcinoma diagnosed with distant interval metastases.

BACKGROUND: In patients with gastric or gastroesophageal junction (GEJ) cancer treated with curative intent, distant interval metastases may be detected after start of neoadjuvant chemotherapy or during surgery. The aim of this study was to explore characteristics, allocated treatment and overall survival (OS) in gastric/GEJ cancer patients with interval metastases, and to compare OS with synchronous metastatic gastric/GEJ cancer patients who started palliative chemotherapy. METHODS: Patients with interval metastases were selected from the Netherlands Cancer Registry by including patients with potentially curable gastric/GEJ adenocarcinoma (2010-2018) who started chemotherapy without concurrent radiotherapy. The OS since start of neoadjuvant treatment of patients with interval metastases was compared with a propensity score-matched cohort of patients with synchronous metastases who received palliative systemic treatment. RESULTS: 164 patients with interval metastases diagnosed in 2010-2018 were included. Metastases were most frequently detected during surgery (83%) and most frequently located in the peritoneum (77%). Peritoneal interval metastases were observed in 63% and 80% of the patients who did and did not have a diagnostic laparoscopy prior to neoadjuvant treatment, respectively (P = 0.041). Median OS was 8.9 months (IQR 5.5-13.4), compared to 8.0 months (IQR 4.1-14.1) in matched synchronous metastatic patients calculated from start of neoadjuvant and palliative systemic treatment, respectively (P = 0.848). CONCLUSION: This population-based study shows that gastric/GEJ cancer patients who started neoadjuvant treatment and were diagnosed with interval metastases most frequently suffered from peritoneal metastases detected during (exploratory) surgery, even when a diagnostic laparoscopy was performed before start of treatment. OS was comparable to patients with synchronous metastatic gastric/GEJ cancer.

Detection, Treatment, and Survival of Pancreatic Cancer Recurrence in the Netherlands: A Nationwide Analysis.

OBJECTIVE: To evaluate whether detection of recurrent pancreatic ductal adenocarcinoma (PDAC) in an early, asymptomatic stage increases the number of patients receiving additional treatment, subsequently improving survival. SUMMARY OF BACKGROUND DATA: International guidelines disagree on the value of standardized postoperative surveillance for early detection and treatment of PDAC recurrence. METHODS: A nationwide, observational cohort study was performed including all patients who underwent PDAC resection (2014-2016). Prospective baseline and perioperative data were retrieved from the Dutch Pancreatic Cancer Audit. Data on follow-up, treatment, and survival were collected retrospectively. Overall survival (OS) was evaluated using multivariable Cox regression analysis, before and after propensity-score matching, stratified for patients with symptomatic and asymptomatic recurrence. RESULTS: Eight hundred thirty-six patients with a median follow-up of 37 months (interquartile range 30-48) were analyzed. Of those, 670 patients (80%) developed PDAC recurrence after a median follow-up of 10 months (interquartile range 5-17). Additional treatment was performed in 159/511 patients (31%) with symptomatic recurrence versus 77/159 (48%) asymptomatic patients (P < 0.001). After propensity-score matching on lymph node ratio, adjuvant therapy, disease-free survival, and recurrence site, additional treatment was independently associated with improved OS for both symptomatic patients [hazard ratio 0.53 (95% confidence interval 0.42-0.67); P < 0.001] and asymptomatic patients [hazard ratio 0.45 (95% confidence interval 0.29-0.70); P < 0.001]. CONCLUSIONS: Additional treatment of PDAC recurrence was independently associated with improved OS, with asymptomatic patients having a higher probability to receive recurrence treatment. Therefore, standardized postoperative surveillance aiming to detect PDAC recurrence before the onset of symptoms has the potential to improve survival. This provides a rationale for prospective studies on standardized surveillance after PDAC resection.

Prognosis of Interval Distant Metastases After Neoadjuvant Chemoradiotherapy for Esophageal Cancer.

BACKGROUND: In esophageal cancer patients, distant metastases develop between the start of neoadjuvant chemoradiotherapy and planned surgery, so-called interval metastases. The primary aim of this study was to assess management, overall survival (OS), and prognostic factors for OS in these patients. A secondary aim was to compare OS with synchronous metastatic patients. METHODS: Esophageal cancer patients with interval distant metastases were identified from the Netherlands Cancer Registry (2010 to 2017). Management was categorized into metastasis-directed therapy (MDT), primary tumor resection, or best supportive care (BSC). The OS was calculated from the diagnosis of the primary tumor. Prognostic factors affecting OS were studied using Cox proportional hazard models. Propensity score-matching (1:3) generated matched cases with synchronous distant metastases. RESULTS: In all, 208 patients with interval metastases were identified: in 87 patients (42%) MDT was initiated; in 10%, primary tumor resection only; in 7%, primary tumor resection plus MDT; and in 41%, BSC. Median OS was 10 months (interquartile range, 8.6 to 11.1). Compared with BSC, superior OS was independently associated with MDT (hazard ratio [HR] 0.36; 95% confidence interval [CI], 0.26 to 0.49), primary tumor resection (HR 0.55; 95% CI, 0.33 to 0.94), and primary tumor resection plus MDT (HR 0.20; 95% CI, 0.10 to 0.38). Worse OS was independently associated with signet ring cell carcinoma (HR 1.92; 95% CI, 1.12 to 3.28) and poor differentiation grade (HR 1.96; 95% CI, 1.35 to 2.83). The OS was comparable between matched patients with interval and synchronous distant metastases (10.2 versus 9.4 months, P = .760). CONCLUSIONS: In esophageal cancer patients treated with neoadjuvant chemoradiotherapy with interval distant metastases, the OS was poor and comparable to that of synchronous metastatic patients.

Preoperative predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma.

BACKGROUND: This study aimed to identify predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) resection with and without neoadjuvant therapy. METHODS: Included were patients who underwent PDAC resection (2014-2016). Multivariable multinomial regression was performed to identify preoperative predictors for manifestation of recurrence within 3, 6 and 12 months after PDAC resection. RESULTS: 836 patients with a median follow-up of 37 (interquartile range [IQR] 30-48) months and overall survival of 18 (IQR 10-32) months were analyzed. 670 patients (80%) developed recurrence: 82 patients (10%) <3 months, 96 patients (11%) within 3-6 months and 226 patients (27%) within 6-12 months. LogCA 19-9 (OR 1.25 [95% CI 1.10-1.41]; P < 0.001) and neoadjuvant treatment (OR 0.09 [95% CI 0.01-0.68]; P = 0.02) were associated with recurrence <3 months. LogCA 19-9 (OR 1.23 [95% CI 1.10-1.38]; P < 0.001) and 0-90° venous involvement on CT imaging (OR 2.93 [95% CI 1.60-5.37]; P < 0.001) were associated with recurrence within 3-6 months. A Charlson Age Comorbidity Index ≥4 (OR 1.53 [95% CI 1.09-2.16]; P = 0.02) and logCA 19-9 (OR 1.24 [95% CI 1.14-1.35]; P < 0.001) were related to recurrence within 6-12 months. CONCLUSION: This study demonstrates preoperative predictors that are associated with the manifestation of early and very early recurrence after PDAC resection. Knowledge of these predictors can be used to guide individualized surveillance and treatment strategies.

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.