Publications by authors named "Hanneke W M van Laarhoven"

272 Publications

Personalized versus standard cognitive behavioral therapy for fear of cancer recurrence, depressive symptoms or cancer-related fatigue in cancer survivors: study protocol of a randomized controlled trial (MATCH-study).

Trials 2021 Oct 12;22(1):696. Epub 2021 Oct 12.

Department of Medical Psychology, Cancer Center Amsterdam, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Background: Fear of cancer recurrence, depressive symptoms, and cancer-related fatigue are prevalent symptoms among cancer survivors, adversely affecting patients' quality of life and daily functioning. Effect sizes of interventions targeting these symptoms are mostly small to medium. Personalizing treatment is assumed to improve efficacy. However, thus far the empirical support for this approach is lacking. The aim of this study is to investigate if systematically personalized cognitive behavioral therapy is more efficacious than standard cognitive behavioral therapy in cancer survivors with moderate to severe fear of cancer recurrence, depressive symptoms, and/or cancer-related fatigue.

Methods: The study is designed as a non-blinded, multicenter randomized controlled trial with two treatment arms (ratio 1:1): (a) systematically personalized cognitive behavioral therapy and (b) standard cognitive behavioral therapy. In the standard treatment arm, patients receive an evidence-based diagnosis-specific treatment protocol for fear of cancer recurrence, depressive symptoms, or cancer-related fatigue. In the second arm, treatment is personalized on four dimensions: (a) the allocation of treatment modules based on ecological momentary assessments, (b) treatment delivery, (c) patients' needs regarding the symptom for which they want to receive treatment, and (d) treatment duration. In total, 190 cancer survivors who experience one or more of the targeted symptoms and ended their medical treatment with curative intent at least 6 months to a maximum of 5 years ago will be included. Primary outcome is limitations in daily functioning. Secondary outcomes are level of fear of cancer recurrence, depressive symptoms, fatigue severity, quality of life, goal attainment, therapist time, and drop-out rates. Participants are assessed at baseline (T0), and after 6 months (T1) and 12 months (T2).

Discussion: To our knowledge, this is the first randomized controlled trial comparing the efficacy of personalized cognitive behavioral therapy to standard cognitive behavioral therapy in cancer survivors. The study has several innovative characteristics, among which is the personalization of interventions on several dimensions. If proven effective, the results of this study provide a first step in developing an evidence-based framework for personalizing therapies in a systematic and replicable way.

Trial Registration: The Dutch Trial Register (NTR) NL7481 (NTR7723). Registered on 24 January 2019.
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http://dx.doi.org/10.1186/s13063-021-05657-zDOI Listing
October 2021

Phase I/II Study of LDE225 in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Cancer.

Cancers (Basel) 2021 Sep 28;13(19). Epub 2021 Sep 28.

Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, 1012 Amsterdam, The Netherlands.

Background: Desmoplasia is a central feature of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. We investigated the combined use of LDE225 and chemotherapy to treat PDAC patients.

Methods: This was a multi-center, phase I/II study for patients with metastatic PDAC establishing the maximum tolerated dose of LDE225 co-administered with gemcitabine and nab-paclitaxel (phase I) and evaluating the efficacy and safety of the treatment combination after prior FOLFIRINOX treatment (phase II). Tumor microenvironment assessment was performed with quantitative MRI using intra-voxel incoherent motion diffusion weighted MRI (IVIM-DWI) and dynamic contrast-enhanced (DCE) MRI.

Results: The MTD of LDE225 was 200 mg once daily co-administered with gemcitabine 1000 mg/m and nab-paclitaxel 125 mg/m. In phase II, six therapy-related grade 4 adverse events (AE) and three grade 5 were observed. In 24 patients, the target lesion response was evaluable. Three patients had partial response (13%), 14 patients showed stable disease (58%), and 7 patients had progressive disease (29%). Median overall survival (OS) was 6 months (IQR 3.9-8.1). Blood plasma fraction (DCE) and diffusion coefficient (IVIM-DWI) significantly increased during treatment. Baseline perfusion fraction could predict OS (>222 days) with 80% sensitivity and 85% specificity.

Conclusion: LDE225 in combination with gemcitabine and nab-paclitaxel was well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Quantitative MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline tumor perfusion.
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http://dx.doi.org/10.3390/cancers13194869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507646PMC
September 2021

Reply to C. Pöttgen et al and Y.-H. Lin et al.

J Clin Oncol 2021 Sep 23:JCO2101980. Epub 2021 Sep 23.

Maarten C. C. M. Hulshof, PhD, MD, Department of Radiotherapy, Amsterdam UMC, Amsterdam, the Netherlands and Hanneke W. M. van Laarhoven, PhD, MD on behalf of the ARTDECO study group, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1200/JCO.21.01980DOI Listing
September 2021

The role of transforming growth factor β in upper gastrointestinal cancers: A systematic review.

Cancer Treat Rev 2021 Nov 2;100:102285. Epub 2021 Sep 2.

Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, De Boelelaan 1117-1118, 1081 HV Amsterdam, The Netherlands.

Esophageal and gastric malignancies are associated with poor prognosis, in part due to development of recurrences or metastases after curative treatment. The transforming growth factor β (TGF-β) pathway might play a role in the development of treatment resistance. In this systematic review, we provide an overview of preclinical studies investigating the role of TGF-β in esophageal and gastric malignancies. We systematically searched MEDLINE/PubMed and EMBASE for eligible preclinical studies describing the effect of TGF-β or TGF-β inhibition on hallmarks of cancer, such as proliferation, migration, invasion, angiogenesis and immune evasion. In total, 2107 records were screened and 45 articles were included, using mouse models and 45 different cell lines. TGF-β failed to induce apoptosis in twelve of sixteen tested cell lines. TGF-β could either decrease (five cell lines) or increase proliferation (seven cell lines) in gastric cancer cells, but had no effect in esophageal cancer cells. In all esophageal and all but two gastric cancer cell lines, TGF-β increased migratory, adhesive and invasive capacities. In vivo studies showed increased metastasis in response to TGF-β treatment. Additionally, TGF-β was shown to induce vascular endothelial growth factor production and differentiation of cancer-associated fibroblasts and regulatory T-cells. In conclusion, we found that TGF-β enhances hallmarks of cancer in most gastric and esophageal cancer cell lines, but not in all. Therefore, targeting the TGF-β pathway could be an attractive strategy in patients with gastric or esophageal cancer, but additional clinical trials are needed to define patient groups who would benefit most.
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http://dx.doi.org/10.1016/j.ctrv.2021.102285DOI Listing
November 2021

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk.

Front Genet 2021 30;12:693933. Epub 2021 Aug 30.

Blood Transfusion Service, Azienda Ospedaliero-Universitaria Meyer, Children's Hospital, Florence, Italy.

Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case-Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07-1.17, = 3.03 × 10 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of , a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.
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http://dx.doi.org/10.3389/fgene.2021.693933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435735PMC
August 2021

First- and Second-Line Palliative Systemic Treatment Outcomes in a Real-World Metastatic Pancreatic Cancer Cohort.

J Natl Compr Canc Netw 2021 Aug 27:1-8. Epub 2021 Aug 27.

1Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam.

Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor survival rate, which can be improved by systemic treatment. Consensus on the most optimal first- and second-line palliative systemic treatment is lacking. The aim of this study was to describe the use of first- and second-line systemic treatment, overall survival (OS), and time to failure (TTF) of first- and second-line treatment in metastatic PDAC in a real-world setting.

Patients And Methods: Patients with synchronous metastatic PDAC diagnosed between 2015 and 2018 who received systemic treatment were selected from the nationwide Netherlands Cancer Registry. OS and TTF were evaluated using Kaplan-Meier curves with log-rank test and multivariable Cox proportional hazard analyses.

Results: The majority of 1,586 included patients received FOLFIRINOX (65%), followed by gemcitabine (18%), and gemcitabine + nab-paclitaxel (13%) in the first line. Median OS for first-line FOLFIRINOX, gemcitabine + nab-paclitaxel, and gemcitabine monotherapy was 6.6, 4.7, and 2.9 months, respectively. Compared to FOLFIRINOX, gemcitabine + nab-paclitaxel showed significantly inferior OS after adjustment for confounders (hazard ratio [HR], 1.20; 95% CI, 1.02-1.41), and gemcitabine monotherapy was independently associated with a shorter OS and TTF (HR, 1.98; 95% CI, 1.71-2.30 and HR, 2.31; 95% CI, 1.88-2.83, respectively). Of the 121 patients who received second-line systemic treatment, 33% received gemcitabine + nab-paclitaxel, followed by gemcitabine (31%) and FOLFIRINOX (10%).

Conclusions: Based on population-based data in patients with metastatic PDAC, treatment predominantly consists of FOLFIRINOX in the first line and gemcitabine with or without nab-paclitaxel in the second line. FOLFIRINOX in the first line shows superior OS compared with gemcitabine with or without nab-paclitaxel.
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http://dx.doi.org/10.6004/jnccn.2021.7028DOI Listing
August 2021

Informing Patients With Esophagogastric Cancer About Treatment Outcomes by Using a Web-Based Tool and Training: Development and Evaluation Study.

J Med Internet Res 2021 Aug 27;23(8):e27824. Epub 2021 Aug 27.

Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.

Background: Due to the increasing use of shared decision-making, patients with esophagogastric cancer play an increasingly important role in the decision-making process. To be able to make well-informed decisions, patients need to be adequately informed about treatment options and their outcomes, namely survival, side effects or complications, and health-related quality of life. Web-based tools and training programs can aid physicians in this complex task. However, to date, none of these instruments are available for use in informing patients with esophagogastric cancer about treatment outcomes.

Objective: This study aims to develop and evaluate the feasibility of using a web-based prediction tool and supporting communication skills training to improve how physicians inform patients with esophagogastric cancer about treatment outcomes. By improving the provision of treatment outcome information, we aim to stimulate the use of information that is evidence-based, precise, and personalized to patient and tumor characteristics and is communicated in a way that is tailored to individual information needs.

Methods: We designed a web-based, physician-assisted prediction tool-Source-to be used during consultations by using an iterative, user-centered approach. The accompanying communication skills training was developed based on specific learning objectives, literature, and expert opinions. The Source tool was tested in several rounds-a face-to-face focus group with 6 patients and survivors, semistructured interviews with 5 patients, think-aloud sessions with 3 medical oncologists, and interviews with 6 field experts. In a final pilot study, the Source tool and training were tested as a combined intervention by 5 medical oncology fellows and 3 esophagogastric outpatients.

Results: The Source tool contains personalized prediction models and data from meta-analyses regarding survival, treatment side effects and complications, and health-related quality of life. The treatment outcomes were visualized in a patient-friendly manner by using pictographs and bar and line graphs. The communication skills training consisted of blended learning for clinicians comprising e-learning and 2 face-to-face sessions. Adjustments to improve both training and the Source tool were made according to feedback from all testing rounds.

Conclusions: The Source tool and training could play an important role in informing patients with esophagogastric cancer about treatment outcomes in an evidence-based, precise, personalized, and tailored manner. The preliminary evaluation results are promising and provide valuable input for the further development and testing of both elements. However, the remaining uncertainty about treatment outcomes in patients and established habits in doctors, in addition to the varying trust in the prediction models, might influence the effectiveness of the tool and training in daily practice. We are currently conducting a multicenter clinical trial to investigate the impact that the combined tool and training have on the provision of information in the context of treatment decision-making.
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http://dx.doi.org/10.2196/27824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433928PMC
August 2021

The association between effectiveness of first-line treatment and second-line treatment in gastro-oesophageal cancer.

Eur J Cancer 2021 Oct 20;156:60-69. Epub 2021 Aug 20.

Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Background: Population-based predictive factors for the effectiveness of second-line palliative systemic therapy in gastro-oesophageal cancer are not available. This study investigates the predictive value of effectiveness of first-line treatment for second-line treatment outcomes in gastro-oesophageal cancer in a real-world setting.

Methods: Patients with metastatic gastro-oesophageal cancer diagnosed in 2010-2017 who were treated with second-line therapy after disease progression on first-line therapy were identified from the Netherlands Cancer Registry. Patients were divided into four groups as per duration of time to treatment failure (TTF) of the first line (0-3, 3-6, 6-9 and >9 months), and the association with overall survival (OS) and second-line TTF was assessed using Kaplan-Meier curves and two-sided multivariable regression models.

Results: Median OS since the start of the second line of patients (n = 611) with first-line TTF of 0-3, 3-6, 6-9 and >9 months was 4.0, 4.1, 5.5 and 7.1 months, respectively (P < 0.001). Median second-line TTF of patients with first-line TTF of 0-3, 3-6, 6-9 and >9 months was 2.8, 2.4, 3.0 and 4.5 months, respectively (P < 0.001). Patients with first-line TTF of >9 months showed a longer OS than patients with first-line TTF of 0-3 months (adjusted hazard ratio (HR) 1.90; 95% confidence interval (CI) 1.46-2.47), 3-6 months (adjusted HR 1.88; 95% CI 1.47-2.39) and 6-9 months (adjusted HR 1.31; 95% CI 1.04-1.65). Results for second-line TTF were similar.

Conclusions: This study shows a positive correlation between effectiveness of first-line therapy and outcomes of second-line therapy in gastro-oesophageal cancer. Physicians should take duration of the first line into account when considering second-line palliative systemic therapy.
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http://dx.doi.org/10.1016/j.ejca.2021.07.026DOI Listing
October 2021

Evaluation of the Khorana, PROTECHT, and 5-SNP scores for prediction of venous thromboembolism in patients with cancer.

J Thromb Haemost 2021 Aug 19. Epub 2021 Aug 19.

Department of Vascular Medicine, Amsterdam Cardiovascular Science, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.

Background: The Khorana score is a validated tool to identify cancer patients at higher risk of venous thromboembolism (VTE).

Objective: We compared its predictive performance to that of the clinical PROTECHT and the polygenic 5-SNP scores in patients who participated in the Dutch CPCT-02 study.

Patients/methods: Data on VTE and its risk factors were retrospectively collected for 2729 patients with advanced stage solid tumors planned for systemic cancer treatment. Patients were followed for 6 months. Overall discriminatory performance of the scores was evaluated by time-dependent c-indices. The scores were additionally evaluated dichotomously in competing risk models.

Results: A total of 160 (5.9%) patients developed VTE during follow-up. Time-dependent c-indices at 6 months for the Khorana, PROTECHT, and 5-SNP scores were 0.57 (95% confidence interval [CI]: 0.55-0.60), 0.60 (95% CI: 0.57-0.62), and 0.54 (95% CI: 0.51-0.57), respectively. The dichotomous scores classified 9.6%, 16.8%, and 9.5% as high-risk, respectively. VTE risk was about 2-fold higher among high-risk patients than low-risk patients for the Khorana (subdistribution hazard ratio [SHR] 1.9, 95% CI: 1.3-3.0), PROTECHT (SHR 2.1, 95% CI: 1.5-3.0), and 5-SNP scores (SHR 1.7, 95% CI: 1.03-2.8). The sensitivity at 6 months was 16.6% (95% CI: 10.5-22.7), 28.9% (95% CI: 21.5-36.3), and 14.9% (95% CI: 8.5-21.2), respectively.

Conclusions: Performance of the PROTECHT or 5-SNP score was not superior to that of the Khorana score. The majority of cancer patients who developed VTE during 6-month follow-up were not identified by these scores. Future directions for studies on cancer-associated VTE prediction may include combined clinical-genetic scores.
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http://dx.doi.org/10.1111/jth.15503DOI Listing
August 2021

Sex differences in tumor characteristics, treatment, and outcomes of gastric and esophageal cancer surgery: nationwide cohort data from the Dutch Upper GI Cancer Audit.

Gastric Cancer 2021 Aug 7. Epub 2021 Aug 7.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Background: Sex differences in clinicopathological characteristics, treatment, and postoperative outcomes of gastric and esophageal cancer are largely undefined. This study aimed to compare tumor and treatment characteristics and outcomes of gastric and esophageal cancer surgery between male and female patients.

Methods: Patients after elective surgery for primary esophageal (EAC) or gastric adenocarcinoma (GAC) registered in the Dutch Upper GI Cancer Audit between 2011 and 2016 were included. The primary endpoint, 5-year relative survival with relative excess risk (RER), i.e., adjusted for the normal life expectancy, was compared between male and female patients with EAC and GAC.

Results: In total, 4937 patients were included (75% male) with a mean age of 66 years. cT and cN-stages showed a similar distribution in male and female patients. In females, antrum GAC was more frequent (47% vs. 38%, p < 0.001). Female patients with EAC less frequently received neo-adjuvant treatment (OR = 0.60, 95% CI 0.38-0.96, p = 0.033). For GAC, less postoperative morbidity (33% vs. 38% p = 0.017) and less re-interventions (12% vs. 16%, p = 0.008) were observed in females, although they had inferior 5-year relative survival (49% vs. 56%, RER = 1.31, 95% CI 1.09-1.58, p = 0.004). No differences in relative survival of EAC were observed.

Conclusions: In addition to significant sex differences in tumor location, female patients with esophageal adenocarcinoma less frequently received neo-adjuvant therapy, and female patients with gastric adenocarcinoma had inferior relative survival. Further consideration and exploration of sex differences in surgical treatment and outcomes are necessary to improve tailored treatment and outcomes.
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http://dx.doi.org/10.1007/s10120-021-01225-1DOI Listing
August 2021

Presentation, Treatment, and Prognosis of Esophageal Carcinoma in a Nationwide Comparison of Sweden and the Netherlands.

Ann Surg 2021 11;274(5):743-750

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Objective: This population-based study aimed to compare presentation, treatment allocation and survival of potentially curable esophageal cancer patients between Sweden and the Netherlands.

Summary Of Background Data: Identification of inter-country differences in treatment allocation and survival may be used for targeted esophageal cancer care improvement.

Methods: Nationwide datasets were acquired from a Swedish cohort study and the Netherlands Cancer Registry. Patients with potentially curable (cT1-T4a/Tx, cN0/+, cM0/x) esophageal adenocarcinoma or squamous cell carcinoma (SCC) diagnosed in 2011-2015 were included. Multivariable logistic regression provided odds ratios (OR) for treatment allocation, and multivariable Cox model provided hazard ratios (HR) for overall survival, all with 95% confidence intervals (CI), adjusted for age, sex, year, tumor sub-location and stage.

Results: Among 1980 Swedish and 7829 Dutch esophageal cancer patients, Swedish patients were older (71 vs 69 years, P <0.001) and had higher cT-stage (cT3: 49% vs 46%, P <0.001). After adjustment for confounders, Swedish patients were less frequently allocated to curative treatment (adenocarcinoma: OR=0.31, 95%CI 0.26-0.36; SCC: OR=0.28, 95%CI 0.22-0.36). Overall survival was lower in Swedish patients (adenocarcinoma: HR=1.36, 95%CI 1.27-1.46; SCC: HR=1.38, 95%CI 1.24-1.53), also when allocated to curative treatment (adenocarcinoma: HR=1.12, 95%CI 1.01-1.24; SCC: HR=1.34, 95%CI 1.14-1.59).

Conclusion: Swedish patients with potentially curable esophageal cancer were less frequently allocated to curative treatment, and showed lower survival compared to Dutch patients. The less pronounced inter-country survival difference after curative treatment suggests that the overall survival difference could at least partly be due to relative undertreatment of Swedish patients. Shared curative treatment thresholds across Europe may help improve survival of esophageal cancer patients.
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http://dx.doi.org/10.1097/SLA.0000000000005127DOI Listing
November 2021

Repeated use of rich pictures to explore changes in subjective experiences over time of patients with advanced cancer.

Cancer Rep (Hoboken) 2021 Jul 26:e1428. Epub 2021 Jul 26.

Center for Education Development and Research in Health Professions, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: The combination of verbal and visual tools may help unravel the experiences of advanced cancer patients. However, most previous studies have focused on a specific symptom, at only one moment in time. We recently found that a specific visual tool, originating from systems thinking, that is, rich pictures (RPs), could provide a more comprehensive view of the experiences of patients with advanced cancer.

Aims: To examine whether the repeated use of RPs can make changes in subjective experiences of patients living with advanced cancer visible over time.

Methods And Results: We performed a prospective study with a generic qualitative approach that was mostly informed by the process of grounded theory. We invited patients to make an RP twice, at the start of the study, and again after 2 months. Both RP drawing sessions were directly followed by a semi-structured interview. Patients with all types of solid tumors, above the age of 18, and with a diagnosis of advanced, incurable cancer, were eligible. Eighteen patients participated and 15 patients were able to draw an RP twice. In eight RP-sets, considerable differences between the first and second RP were noticeable. Two patterns were distinguished: (1) a change (decline or improvement) in physical health (five patients), and/or (2) a change in the way patients related to cancer (three patients).

Conclusion: RPs are a valuable qualitative research method that can be used to explore the experiences of patients with advanced cancer, not only at a single point in time but also over time.
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http://dx.doi.org/10.1002/cnr2.1428DOI Listing
July 2021

SOURCE-PANC: A Prediction Model for Patients With Metastatic Pancreatic Ductal Adenocarcinoma Based on Nationwide Population-Based Data.

J Natl Compr Canc Netw 2021 07 21. Epub 2021 Jul 21.

Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam.

Background: A prediction model for overall survival (OS) in metastatic pancreatic ductal adenocarcinoma (PDAC) including patient and treatment characteristics is currently not available, but it could be valuable for supporting clinicians in patient communication about expectations and prognosis. We aimed to develop a prediction model for OS in metastatic PDAC, called SOURCE-PANC, based on nationwide population-based data.

Materials And Methods: Data on patients diagnosed with synchronous metastatic PDAC in 2015 through 2018 were retrieved from the Netherlands Cancer Registry. A multivariate Cox regression model was created to predict OS for various treatment strategies. Available patient, tumor, and treatment characteristics were used to compose the model. Treatment strategies were categorized as systemic treatment (subdivided into FOLFIRINOX, gemcitabine/nab-paclitaxel, and gemcitabine monotherapy), biliary drainage, and best supportive care only. Validation was performed according to a temporal internal-external cross-validation scheme. The predictive quality was assessed with the C-index and calibration.

Results: Data for 4,739 patients were included in the model. Sixteen predictors were included: age, sex, performance status, laboratory values (albumin, bilirubin, CA19-9, lactate dehydrogenase), clinical tumor and nodal stage, tumor sublocation, presence of distant lymph node metastases, liver or peritoneal metastases, number of metastatic sites, and treatment strategy. The model demonstrated a C-index of 0.72 in the internal-external cross-validation and showed good calibration, with the intercept and slope 95% confidence intervals including the ideal values of 0 and 1, respectively.

Conclusions: A population-based prediction model for OS was developed for patients with metastatic PDAC and showed good performance. The predictors that were included in the model comprised both baseline patient and tumor characteristics and type of treatment. SOURCE-PANC will be incorporated in an electronic decision support tool to support shared decision-making in clinical practice.
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http://dx.doi.org/10.6004/jnccn.2020.7669DOI Listing
July 2021

A systematic review of HER2 blockade for the curative treatment of gastroesophageal adenocarcinoma: Successes achieved and opportunities ahead.

Cancer Treat Rev 2021 Sep 16;99:102249. Epub 2021 Jun 16.

Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Electronic address:

Introduction: Despite multimodality treatment for curatively-treated gastroesophageal adenocarcinoma (GEA), prognosis remains dismal. The benefit of adding trastuzumab to chemotherapy for advanced Human Epidermal Growth Factor 2 (HER2) positive GEA has been established in the ToGA trial. However, it remains unclear if HER2 inhibition might also be beneficial in the curative setting. Therefore, we conducted a systematic review to investigate the role of HER2 inhibitors for the curative treatment of GEA.

Methods: A systematic literature search was performed in PubMed, EMBASE, CENTRAL, and clinicaltrials.gov to identify clinical trials investigating HER2 inhibition for the curative treatment of GEA. Study quality was assessed using the GRADE methodology.

Results: From the 1825 studies retrieved, 17 were included (seven published articles; three published conference abstracts; seven ongoing studies). From the published studies, eight studies investigated single-agent HER2 inhibition. Four studies had a nonrandomized design, and two were randomized controlled trials. Two published studies were assessed as high-quality. The addition of single-agent HER2 inhibition to chemo(radio)therapy showed a pathological complete response rate (pCR) of 22.2% (range, 9.6-25%) and dual HER2 inhibition of 34.5% (34-35%). Two-year disease-free survival (DFS) was 51.0% (40-71%) with single-agent and 70.0% (70-70%) with dual HER2 therapy.

Discussion: Dual-agent HER2 inhibition showed promising pCR rates and DFS. Given the limited additional toxicity of the addition of HER2 targeting agents and the potential benefit of dual-targeting, further investigation is required in a phase III randomized clinical trial. Next steps include combining checkpoint inhibitors and HER2 blockade given the suggested synergism, as well as investigating new anti-HER2 agents.
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http://dx.doi.org/10.1016/j.ctrv.2021.102249DOI Listing
September 2021

Response shift after coronary revascularization.

Qual Life Res 2021 Jun 22. Epub 2021 Jun 22.

Department of Medical Psychology, Amsterdam University Medical Centers, Amsterdam Public Health Research Institute, University of Amsterdam, Amsterdam, Netherlands.

Purpose: The aims of this study were to investigate (1) the extent to which response shift occurs among patients with coronary artery disease (CAD) after coronary revascularization, (2) whether the assessment of changes in health-related quality of life (HRQoL), controlled for response shift, yield more valid estimates of changes in HRQoL, as indicated by stronger associations with criterion measures of change, than without controlling for response shift, and (3) if occurrences of response shift are related to patient characteristics.

Methods: Patients with CAD completed the SF-36 and the Seattle Angina Questionnaire (SAQ7) at baseline and 3 months after coronary revascularization. Sociodemographic, clinical and psychosocial variables were measured with the patient version of the New York Heart Association-class, Subjective Significance Questionnaire, Reconstruction of Life Events Questionnaire (RE-LIFE), and HEXACO personality inventory. Oort's Structural Equation Modeling (SEM) approach was used to investigate response shift.

Results: 191 patient completed questionnaires at baseline and at 3 months after treatment. The SF-36 showed recalibration and reprioritization response shift and the SAQ7 reconceptualization response shift. Controlling for these response shift effects did not result in more valid estimates of change. One significant association was found between reprioritization response shift and complete integration of having CAD into their life story, as indicated by the RE-LIFE.

Conclusion: Results indicate response shift in HRQoL following coronary revascularization. While we did not find an impact of response shift on the estimates of change, the SEM approach provides a more comprehensive insight into the different types of change in HRQoL following coronary revascularization.
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http://dx.doi.org/10.1007/s11136-021-02902-5DOI Listing
June 2021

Narrative recognition and identification: a qualitative pilot study into reading literary texts with advanced cancer patients.

J Cancer Surviv 2021 Jun 15. Epub 2021 Jun 15.

Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.

Purpose: Patients with advanced cancer can experience their disease as a contingent life event. The sudden interruption of their life stories can obscure life goals and disrupt meaning making. In the context of the research project "In search of stories," we aim to investigate the reading and discussion of selected stories which present ways of dealing with a contingent life event. In addition, we examine the use of a newly developed guide for reading these exemplary texts together with advanced cancer patients.

Methods: This qualitative study describes the experiences of five patients with advanced cancer who participated in a guided reading and discussion about selected literary texts. The intervention consisted of reading a selected story, after which each patient was interviewed, using the reading guide as a conversation template. The interviews were then thematically analyzed for their conceptual content using a template analysis.

Results: All five conversations showed some form of recognition in reaction to the chosen text, which led to personal identification of experiences of contingency, such as loss of life goals, impending death, or feelings of uncertainty. Besides the important role of identification, revealed by the responses to the questions in the reading guide, the discussion of the text helped them articulate their own experience and sources of meaning. Diverse worldviews came to the fore and concepts of meaning such as fate, life goals, quality of life, and death.

Conclusions: First experiences with our newly developed reading guide designed to support a structured reading of stories containing experiences of contingency suggest that it may help patients to express their own experiences of contingency and to reflect on these experiences.

Implications For Cancer Survivors: The intervention tested in this study may contribute to supportive care for survivors with advanced cancer, but further research is needed to evaluate its effect on quality of life.
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http://dx.doi.org/10.1007/s11764-021-01048-0DOI Listing
June 2021

The association between wearable activity monitor metrics and performance status in oncology: a systematic review.

Support Care Cancer 2021 Nov 12;29(11):7085-7099. Epub 2021 Jun 12.

Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.

Purpose: The expanding armamentarium of wearable activity monitors (WAMs) offers new opportunities to supplement physician-assessed performance status (PS) with real-life patient activity data. These data could guide clinical decision making or serve as a measure of treatment outcome. However, information on the association between physical activity (PA) and sedentary behavior (SB) monitored with wearables (i.e., WAM metrics) and PS in patients with cancer is needed. Therefore, we conducted a systematic review to examine the association between WAM metrics and PS in patients with cancer.

Methods: We searched MEDLINE and Embase for studies that assessed the association between WAM metrics and performance status among adults with cancer. We extracted information on study design and population, WAM type and different activity metrics, outcome definitions, and results. Included studies were subjected to risk of bias assessment and subsequent best evidence synthesis.

Results: Fourteen studies were included in this review. All studies reported on different combinations of WAM metrics including: daily steps (n = 8), SB (n = 5), mean activity counts (n = 4), dichotomous circadian rest-activity index (n = 3), and time spent in moderate-to-vigorous PA (MVPA) (n = 3). Much heterogeneity was observed regarding study population, WAM used, and reporting of results. We found moderate evidence for a positive weak-to-moderate association between WAM-assessed PA and PS and a weak-to-moderate negative association between WAM-assessed SB metrics and PS.

Conclusion: Weak-to-moderate associations between WAM metrics and PS suggest that WAM data and physician-assessed PS cannot be used interchangeably. Instead, WAM data could serve as a dynamic and objective supplement measurement of patients' physical performance.
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http://dx.doi.org/10.1007/s00520-021-06234-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464563PMC
November 2021

Improved unsupervised physics-informed deep learning for intravoxel incoherent motion modeling and evaluation in pancreatic cancer patients.

Magn Reson Med 2021 10 9;86(4):2250-2265. Epub 2021 Jun 9.

Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Purpose: Earlier work showed that IVIM-NET , an unsupervised physics-informed deep neural network, was faster and more accurate than other state-of-the-art intravoxel-incoherent motion (IVIM) fitting approaches to diffusion-weighted imaging (DWI). This study presents a substantially improved version, IVIM-NET , and characterizes its superior performance in pancreatic cancer patients.

Method: In simulations (signal-to-noise ratio [SNR] = 20), the accuracy, independence, and consistency of IVIM-NET were evaluated for combinations of hyperparameters (fit S0, constraints, network architecture, number of hidden layers, dropout, batch normalization, learning rate), by calculating the normalized root-mean-square error (NRMSE), Spearman's ρ, and the coefficient of variation (CV ), respectively. The best performing network, IVIM-NET was compared to least squares (LS) and a Bayesian approach at different SNRs. IVIM-NET 's performance was evaluated in an independent dataset of 23 patients with pancreatic ductal adenocarcinoma. Fourteen of the patients received no treatment between two repeated scan sessions and nine received chemoradiotherapy between the repeated sessions. Intersession within-subject standard deviations (wSD) and treatment-induced changes were assessed.

Results: In simulations (SNR = 20), IVIM-NET outperformed IVIM-NET in accuracy (NRMSE(D) = 0.177 vs 0.196; NMRSE(f) = 0.220 vs 0.267; NMRSE(D*) = 0.386 vs 0.393), independence (ρ(D*, f) = 0.22 vs 0.74), and consistency (CV (D) = 0.013 vs 0.104; CV (f) = 0.020 vs 0.054; CV (D*) = 0.036 vs 0.110). IVIM-NET showed superior performance to the LS and Bayesian approaches at SNRs < 50. In vivo, IVIM-NET showed significantly less noisy parameter maps with lower wSD for D and f than the alternatives. In the treated cohort, IVIM-NET detected the most individual patients with significant parameter changes compared to day-to-day variations.

Conclusion: IVIM-NET is recommended for accurate, informative, and consistent IVIM fitting to DWI data.
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http://dx.doi.org/10.1002/mrm.28852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362093PMC
October 2021

Randomized Study on Dose Escalation in Definitive Chemoradiation for Patients With Locally Advanced Esophageal Cancer (ARTDECO Study).

J Clin Oncol 2021 Sep 8;39(25):2816-2824. Epub 2021 Jun 8.

Department of Medical Oncology, Erasmus MC, Rotterdam, the Netherlands.

Purpose: To analyze the effect of radiation dose escalation to the primary tumor on local tumor control in definitive chemoradiation (dCRT) for patients with esophageal cancer.

Patients And Methods: Patients with medically inoperable and/or irresectable esophageal carcinoma, referred for dCRT, were randomly assigned between a standard dose (SD) of 50.4 Gy/1.8 Gy for 5.5 weeks to the tumor and regional lymph nodes and a high dose (HD) up to a total dose of 61.6 Gy to the primary tumor. Chemotherapy consisted of courses of concurrent carboplatin (area under the curve 2) and paclitaxel (50 mg/m) in both arms once a week for 6 weeks. The primary end point was local progression-free survival.

Results: Between September 2012 and June 2018, 260 patients were included. Squamous cell carcinoma (SCC) was present in 61% of patients, and 39% had adenocarcinoma (AC). Radiation treatment was completed by 94%, and 85% had at least five courses of chemotherapy. The median follow-up time for all patients was 50 months. The 3-year local progression-free survival (LPFS) was 70% in the SD arm versus 73% in the HD arm (not significant). The LPFS for SCC and AC was 75% versus 79% and 61% versus 61% for SD and HD, respectively (not significant). The 3-year locoregional progression-free survival was 52% and 59% for the SD and HD arms, respectively ( = .08). Overall, grade 4 and 5 common toxicity criteria were 12% and 5% in the SD arm versus 14% and 10% in the HD arm, respectively ( = .15).

Conclusion: In dCRT for esophageal cancer, radiation dose escalation up to 61.6 Gy to the primary tumor did not result in a significant increase in local control over 50.4 Gy. The absence of a dose effect was observed in both AC and SCC.
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http://dx.doi.org/10.1200/JCO.20.03697DOI Listing
September 2021

Pre-Operative Decitabine in Colon Cancer Patients: Analyses on WNT Target Methylation and Expression.

Cancers (Basel) 2021 May 13;13(10). Epub 2021 May 13.

Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

DNA hypermethylation is common in colon cancer. Previously, we have shown that methylation of WNT target genes predicts poor prognosis in stage II colon cancer. The primary objective of this study was to assess whether pre-operative treatment with decitabine can decrease methylation and increase the expression of WNT target genes , and in colon cancer patients. A clinical study was conducted, investigating these potential effects of decitabine in colon cancer patients (DECO). Patients were treated two times with 25 mg/m decitabine before surgery. Methylation and expression of and WNT target genes (primary outcome) and expression of endogenous retroviral genes (secondary outcome) were analysed in pre- and post-treatment tumour samples using pyrosequencing and rt-PCR. Ten patients were treated with decitabine and eighteen patients were used as controls. Decitabine treatment only marginally decreased methylation. More importantly, no differences in methylation or expression of WNT target or endogenous retroviral genes were observed. Due to the lack of an effect on primary and secondary outcomes, the study was prematurely closed. In conclusion, pre-operative treatment with decitabine is safe, but with the current dosing, the primary objective, increased WNT target gene expression, cannot be achieved.
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http://dx.doi.org/10.3390/cancers13102357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153633PMC
May 2021

Potential mechanisms of the fatigue-reducing effect of cognitive-behavioral therapy in cancer survivors: Three randomized controlled trials.

Psychooncology 2021 Sep 3;30(9):1476-1484. Epub 2021 May 3.

Department of Medical Psychology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.

Objective: Fatigue is a common symptom among cancer survivors that can be successfully treated with cognitive-behavioral therapy (CBT). Insights into the working mechanisms of CBT are currently limited. The aim of this study was to investigate whether improvements in targeted cognitive-behavioral variables and reduced depressive symptoms mediate the fatigue-reducing effect of CBT.

Methods: We pooled data from three randomized controlled trials that tested the efficacy of CBT to reduce severe fatigue. In all three trials, fatigue severity (checklist individual strength) decreased significantly following CBT. Assessments were conducted pre-treatment and 6 months later. Classical mediation analysis testing a pre-specified model was conducted and its results compared to those of causal discovery, an explorative data-driven approach testing all possible causal associations and retaining the most likely model.

Results: Data from 250 cancer survivors (n = 129 CBT, n = 121 waitlist) were analyzed. Classical mediation analysis suggests that increased self-efficacy and decreased fatigue catastrophizing, focusing on symptoms, perceived problems with activity and depressive symptoms mediate the reduction of fatigue brought by CBT. Conversely, causal discovery and post-hoc analyses indicate that fatigue acts as mediator, not outcome, of changes in cognitions, sleep disturbance and depressive symptoms.

Conclusions: Cognitions, sleep disturbance and depressive symptoms improve during CBT. When assessed pre- and post-treatment, fatigue acts as a mediator, not outcome, of these improvements. It seems likely that the working mechanism of CBT is not a one-way causal effect but a dynamic reciprocal process. Trials integrating intermittent assessments are needed to shed light on these mechanisms and inform optimization of CBT.
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http://dx.doi.org/10.1002/pon.5710DOI Listing
September 2021

Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial.

J Clin Oncol 2021 Jun 23;39(18):1995-2004. Epub 2021 Apr 23.

Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.

Purpose: Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen.

Methods: From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses.

Results: The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent ( value for interaction, = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13).

Conclusion: The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.
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http://dx.doi.org/10.1200/JCO.20.03614DOI Listing
June 2021

Fecal Microbiota Transplantation from Overweight or Obese Donors in Cachectic Patients with Advanced Gastroesophageal Cancer: A Randomized, Double-blind, Placebo-Controlled, Phase II Study.

Clin Cancer Res 2021 Jul 21;27(13):3784-3792. Epub 2021 Apr 21.

Department of Internal and Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Purpose: Cachexia is a multifactorial syndrome, associated with poor survival in patients with cancer, and is influenced by the gut microbiota. We investigated the effects of fecal microbiota transplantation (FMT) on cachexia and treatment response in patients with advanced gastroesophageal cancer.

Experimental Design: In a double-blind randomized placebo-controlled trial performed in the Amsterdam University Medical Center, we assigned 24 cachectic patients with metastatic HER2-negative gastroesophageal cancer to either allogenic FMT (healthy obese donor) or autologous FMT, prior to palliative chemotherapy (capecitabine and oxaliplatin). Primary objective was to assess the effect of allogenic FMT on satiety. Secondary outcomes were other features of cachexia, along with disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity. Finally, exploratory analyses were performed on the effect of FMT on gut microbiota composition (metagenomic sequencing) and metabolites (untargeted metabolomics).

Results: Allogenic FMT did not improve any of the cachexia outcomes. Patients in the allogenic group ( = 12) had a higher DCR at 12 weeks ( = 0.035) compared with the autologous group ( = 12), longer median OS of 365 versus 227 days [HR = 0.38; 95% confidence interval (CI), 0.14-1.05; = 0.057] and PFS of 204 versus 93 days (HR = 0.50; 95% CI, 0.21-1.20; = 0.092). Patients in the allogenic group showed a significant shift in fecal microbiota composition after FMT ( = 0.010) indicating proper engraftment of the donor microbiota.

Conclusions: FMT from a healthy obese donor prior to first-line chemotherapy did not affect cachexia, but may have improved response and survival in patients with metastatic gastroesophageal cancer. These results provide a rational for larger FMT trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4918DOI Listing
July 2021

Perceptions of involvement in advance care planning and emotional functioning in patients with advanced cancer.

J Cancer Surviv 2021 06 10;15(3):380-385. Epub 2021 Apr 10.

Department of Research & Development, Netherlands Comprehensive Cancer Organization (IKNL), PO box 19079, 3501 DB, Utrecht, The Netherlands.

Purpose: Advance Care Planning (ACP) is positively associated with the quality of care, but its impact on emotional functioning is ambiguous. This study investigated the association between perceptions of ACP involvement and emotional functioning in patients with advanced cancer.

Methods: This study analyzed baseline data of 1,001 patients of the eQuiPe study, a prospective, longitudinal, multicenter, observational study on quality of care and quality of life in patients with advanced cancer in the Netherlands. Patients with metastatic solid cancer were asked to participate between November 2017 and January 2020. Patients' perceptions of ACP involvement were measured by three self-administered statements. Emotional functioning was measured by the EORTC-QLQ-C30. A linear multivariable regression analysis was performed while taking gender, age, migrant background, education, marital status, and symptom burden into account.

Results: The majority of patients (87%) reported that they were as much involved as they wanted to be in decisions about their future medical treatment and care. Most patients felt that their relatives (81%) and physicians (75%) were familiar with their preferences for future medical treatment and care. A positive association was found between patients' perceptions of ACP involvement and their emotional functioning (b=0.162, p<0.001, 95%CI[0.095;0.229]) while controlling for relevant confounders.

Conclusions: Perceptions of involvement in ACP are positively associated with emotional functioning in patients with advanced cancer. Future studies are needed to further investigate the effect of ACP on emotional functioning.

Trial Registration Number: NTR6584 Date of registration: 30 June 2017 IMPLICATIONS FOR CANCER SURVIVORS: Patients' emotional functioning might improve from routine discussions regarding goals of future care. Therefore, integration of ACP into palliative might be promising.
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http://dx.doi.org/10.1007/s11764-021-01020-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134301PMC
June 2021

Gender Differences in Treatment Allocation and Survival of Advanced Gastroesophageal Cancer: a Population-Based Study.

J Natl Cancer Inst 2021 Apr 10. Epub 2021 Apr 10.

Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Background: Biological sex and gender have been reported to impact incidence and overall survival (OS) of curatively treated gastroesophageal cancer. The aim of this study was to compare palliative treatment allocation and OS between women and men with advanced gastroesophageal cancer.

Methods: Patients with an unresectable (cT4b) or metastatic (cM1) esophageal (including cardia) adenocarcinoma (EAC) or squamous cell carcinoma (ESCC), or gastric adenocarcinoma (GAC) diagnosed in 2015-2018 were identified in the Netherlands Cancer Registry. Treatment allocation was compared using chi-squared tests and multivariable logistic regression analyses, and OS using the Kaplan-Meier method with log-rank test and Cox proportional hazard analysis. All statistical tests were 2-sided.

Results: Of patients with EAC (n = 3,077), ESCC (n = 794) and GAC (n = 1,836), 18.0%, 39.4% and 39.1% were women, respectively. Women received less often systemic treatment compared to men in EAC (42.7% vs. 47.4%, P = 0.045) and GAC (33.8% vs. 38.8%, P = 0.03), but not in ESCC (33.2% vs. 39.5%, P = 0.07). Women had a lower probability of receiving systemic treatment in GAC in multivariable analyses (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.62-1.00), but not in EAC (OR = 0.86, 95%CI = 0.69-1.06) and ESCC (OR = 0.81, 95%CI = 0.57-1.14). Median OS was lower in women with EAC (4.4 vs. 5.2 months, P = 0.04), but did not differ after adjustment for patient and tumor characteristics and systemic treatment administration.

Conclusion: We observed statistically significant and clinically relevant gender differences in systemic treatment administration and OS in advanced gastroesophageal cancer. Causes of these disparities may be sex-based, i.e. related to tumor biology, as well as gender-based, e.g. related to differences in treatment choices.
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http://dx.doi.org/10.1093/jnci/djab075DOI Listing
April 2021

A population-based study on incidence, treatment, and survival in ampullary cancer in the Netherlands.

Eur J Surg Oncol 2021 Jul 6;47(7):1742-1749. Epub 2021 Mar 6.

Department of Internal Medicine, Division of Medical Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, 6202 AZ, the Netherlands. Electronic address:

Introduction: Ampullary cancer is rare and as a result epidemiological data are scarce. The aim of this population-based study was to determine the trends in incidence, treatment and overall survival (OS) in patients with ampullary adenocarcinoma in the Netherlands between 1989 and 2016.

Methods: Patients diagnosed with ampullary adenocarcinoma were identified from the Netherlands Cancer Registry. Incidence rates were age-adjusted to the European standard population. Trends in treatment and OS were studied over (7 years) period of diagnosis, using Kaplan-Meier and Cox regression analyses for OS and stratified by the presence of metastatic disease.

Results: In total, 3840 patients with ampullary adenocarcinoma were diagnosed of whom, 55.0% were male and 87.1% had non-metastatic disease. The incidence increased from 0.59 per 100,000 in 1989-1995 to 0.68 per 100,000in 2010-2016. In non-metastatic disease, the resection rate increased from 49.5% in 1989-1995 to 63.9% in 2010-2016 (p < 0.001). The rate of adjuvant therapy increased from 3.1% to 7.9%. In non-metastatic disease, five-year OS (95% CI) increased from 19.8% (16.9-22.8) in 1989-1995 to 29.1% (26.0-31.2) in 2010-2016 (logrank p < 0.001). In patients with metastatic disease, median OS did not significantly improve (from 4.4 months (3.6-5.0) to 5.9 months (4.7-7.1); logrank p = 0.06). Cancer treatment was an independent prognostic factor for OS among all patients.

Conclusion: Both incidence and OS of ampullary cancer increased from 1989 to 2016 which is most likely related to the observed increased resection rates and use of adjuvant therapy.
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http://dx.doi.org/10.1016/j.ejso.2021.02.028DOI Listing
July 2021

A Phase II Study Demonstrates No Feasibility of Adjuvant Treatment with Six Cycles of S-1 and Oxaliplatin in Resectable Esophageal Adenocarcinoma, with ERCC1 as Biomarker for Response to SOX.

Cancers (Basel) 2021 Feb 17;13(4). Epub 2021 Feb 17.

Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

We assessed the feasibility of adjuvant S-1 and oxaliplatin following neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Patients treated with nCRT (paclitaxel, carboplatin) and esophagectomy received six 21-day cycles with oxaliplatin (130 mg/m) on day 1 and S-1 (25 mg/m twice daily) on days 1-14. The primary endpoint was feasibility, defined as ≥50% completing treatment. We performed exploratory propensity-score matching to compare survival, ERCC1 and Thymidylate Synthase (TS) immunohistochemistry analyses, proteomics biomarker discovery and 5-FU pharmacokinetic analyses. Forty patients were enrolled and 48% completed all adjuvant cycles. Median dose intensity was 98% for S-1 and 62% for oxaliplatin. The main reason for early discontinuation was toxicity (67%). The median recurrence-free and overall survival were 28.3 months and 40.8 months, respectively (median follow-up 29.1 months). Survival was not significantly prolonged compared to a matched cohort ( = 0.09). Patients with ERCC1 negative tumor expression had significantly better survival compared to ERCC1 positivity ( = 0.01). Our protein signature model was predictive of survival [ = 0.04; Area under the curve (AUC) 0.80]. Moreover, 5-FU pharmacokinetics significantly correlated with treatment-related toxicity. To conclude, six cycles adjuvant S-1 and oxaliplatin were not feasible in pretreated esophageal adenocarcinoma. Although the question remains whether additional treatment with chemotherapy should be provided in the adjuvant setting, subgroups such as patients with ERCC1 negativity could potentially benefit from adjuvant SOX based on our exploratory biomarker research.
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http://dx.doi.org/10.3390/cancers13040839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922275PMC
February 2021

SOURCE: Prediction Models for Overall Survival in Patients With Metastatic and Potentially Curable Esophageal and Gastric Cancer.

J Natl Compr Canc Netw 2021 04 26;19(4):403-410. Epub 2021 Feb 26.

1Department of Medical Oncology, Cancer Center Amsterdam, and.

Background: Personalized prediction of treatment outcomes can aid patients with cancer when deciding on treatment options. Existing prediction models for esophageal and gastric cancer, however, have mostly been developed for survival prediction after surgery (ie, when treatment has already been completed). Furthermore, prediction models for patients with metastatic cancer are scarce. The aim of this study was to develop prediction models of overall survival at diagnosis for patients with potentially curable and metastatic esophageal and gastric cancer (the SOURCE study).

Methods: Data from 13,080 patients with esophageal or gastric cancer diagnosed in 2015 through 2018 were retrieved from the prospective Netherlands Cancer Registry. Four Cox proportional hazards regression models were created for patients with potentially curable and metastatic esophageal or gastric cancer. Predictors, including treatment type, were selected using the Akaike information criterion. The models were validated with temporal cross-validation on their C-index and calibration.

Results: The validated model's C-index was 0.78 for potentially curable gastric cancer and 0.80 for potentially curable esophageal cancer. For the metastatic models, the c-indices were 0.72 and 0.73 for esophageal and gastric cancer, respectively. The 95% confidence interval of the calibration intercepts and slopes contain the values 0 and 1, respectively.

Conclusions: The SOURCE prediction models show fair to good c-indices and an overall good calibration. The models are the first in esophageal and gastric cancer to predict survival at diagnosis for a variety of treatments. Future research is needed to demonstrate their value for shared decision-making in clinical practice.
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http://dx.doi.org/10.6004/jnccn.2020.7631DOI Listing
April 2021

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

Ann Thorac Surg 2021 Feb 18. Epub 2021 Feb 18.

Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.athoracsur.2021.01.061DOI Listing
February 2021

Impact of pathological tumor response after CROSS neoadjuvant chemoradiotherapy followed by surgery on long-term outcome of esophageal cancer: a population-based study.

Acta Oncol 2021 Apr 25;60(4):497-504. Epub 2021 Jan 25.

Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: With increasing interest in organ-preserving strategies for potentially curable esophageal cancer, real-world data is needed to understand the impact of pathological tumor response after neoadjuvant chemoradiotherapy (CRT) on patient outcome. The objective of this study is to assess the association between pathological tumor response following CROSS neoadjuvant CRT and long-term overall survival (OS) in a nationwide cohort.

Material And Methods: All patients diagnosed in the Netherlands with potentially curable esophageal cancer between 2009 and 2017, and treated with neoadjuvant CRT followed by esophagectomy were included. Through record linkage with the nationwide Dutch Pathology Registry (PALGA), pathological data were obtained. The primary outcome was pathological tumor response based on ypTNM, classified into pathological complete response (ypT0N0) and incomplete responders (ypT0N+, ypT+N0, and ypT+N+). Multivariable logistic and Cox regression models were used to identify predictors of pathological complete response (pCR) and survival.

Results: A total of 4946 patients were included. Overall, 24% achieved pCR, with 19% in adenocarcinoma and 42% in squamous cell carcinoma. Patients with pCR had a better estimated 5-year OS compared to incomplete responders (62% vs. 38%, < .001). Of the patients with incomplete response, ypT+N+ patients (32% of total population) had the lowest estimated 5-year OS rate, followed by ypT0N+ and ypT+ N0 (22%, 47%, and 49%, respectively, < .001). Adenocarcinoma, well to moderate differentiation, cT3-4, cN+, signet ring cell differentiation and lymph node yield (≥15) were associated with lower likelihood of pCR.

Conclusion: In this population-based study, pathological tumor response based on the ypTNM-stage was associated with different prognostic subgroups. A quarter of patients achieved ypT0N0 with favorable long-term survival, while one-third had an ypT+N+ response with very poor survival. The association between pathological tumor response and long-term survival could help in more accurate assessments of individual prognosis and treatment decisions.
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http://dx.doi.org/10.1080/0284186X.2020.1870246DOI Listing
April 2021
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