BackgroundNeoadjuvant treatment for pancreatic ductal adenocarcinoma (PDAC) has increased, necessitating histopathologic confirmation of cancer. This study evaluates the performance of endoscopic... Show moreBackgroundNeoadjuvant treatment for pancreatic ductal adenocarcinoma (PDAC) has increased, necessitating histopathologic confirmation of cancer. This study evaluates the performance of endoscopic tissue acquisition (TA) procedures for borderline resectable and resectable PDAC.MethodsPathology reports of patients included in two nationwide randomized controlled trials (PREOPANC and PREOPANC-2) were reviewed. The primary outcome was sensitivity for malignancy (SFM), considering both “suspicious for” and “malignant” as positive. Secondary outcomes were rate of adequate sampling (RAS) and diagnoses other than PDAC.ResultsOverall, 892 endoscopic procedures were performed in 617 patients, including endoscopic ultrasonography (EUS)-guided TA in 550 (89.1%), endoscopic retrograde cholangiopancreatography (ERCP)-guided brush cytology in 188 (30.5%), and periampullary biopsies in 61 patients (9.9%). The SFM was 85.2% for EUS, 88.2% for repeat EUS, 52.7% for ERCP, and 37.7% for periampullary biopsies. The RAS ranged 94–100%. Diagnoses other than PDAC were other periampullary cancers in 24 (5.4%), premalignant disease in five (1.1%), and pancreatitis in three patients (0.7%).ConclusionsEUS-guided TA of patients with borderline resectable and resectable PDAC included in RCTs had an SFM above 85% for both first and repeat procedures, meeting international standards. Two percent had false positive result for malignancy and 5% had other (non-PDAC) periampullary cancers. Show less
BackgroundSurgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic... Show moreBackgroundSurgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach.MethodsThis multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and & LE; 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m(2), leucovorin 400 mg/m(2), irinotecan 150 mg/m(2) at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m(2)). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized.DiscussionThe multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. Show less
va't Land, F.R.; Latifi, D.; Moskie, M.; Homs, M.Y.V.; Bosscha, K.; Bonsing, B.A.; ... ; South West Pancreatic Canc Care SW 2023
Background and purpose: In this phase I/II trial, non-progressive locally advanced pancreatic cancer (LAPC) patients after (modified)FOLFIRINOX therapy were treated with stereotactic body... Show moreBackground and purpose: In this phase I/II trial, non-progressive locally advanced pancreatic cancer (LAPC) patients after (modified)FOLFIRINOX therapy were treated with stereotactic body radiotherapy (SBRT) combined with heat-killed mycobacterium (IMM-101) vaccinations. We aimed to assess safety, feasibility, and efficacy of this treatment approach.Materials and methods: On five consecutive days, patients received a total of 40 Gray (Gy) of SBRT with a dose of 8 Gy per fraction. Starting two weeks prior to SBRT, they in addition received six bi-weekly intradermal vaccinations with one milligram of IMM-101. The primary outcomes were the number of grade 4 or higher adverse events and the one-year progression free-survival (PFS) rate. Results: Thirty-eight patients were included and started study treatment. Median follow-up was 28.4 months (95 %CI 24.3 - 32.6). We observed one grade 5, no grade 4 and thirteen grade 3 adverse events, none related to IMM-101. The one-year PFS rate was 47 %, the median PFS was 11.7 months (95 %CI 11.0 - 12.5) and the median overall survival was 19.0 months (95 %CI 16.2 - 21.9). Eight (21 %) tumors were resected, of which 6 (75 %) were R0 resections. Outcomes were comparable with the outcomes of the patients from the previous LAPC-1 trial, in which LAPC patients were treated with SBRT, without IMM-101.Conclusion: Combination treatment with IMM-101 and SBRT was safe and feasible for non-progressive locally advanced pancreatic cancer patients after (modified)FOLFIRINOX. No improvement in the progression-free survival could be demonstrated by adding IMM-101 to SBRT.(c) 2023 Published by Elsevier B.V. Radiotherapy and Oncology 183 (2023) 109541 Show less
Eijck, C.W.F. van; Koning, W. de; Sijde, F. van der; Moskie, M.; Koerkamp, B.G.; Homs, M.Y.V.; ... ; Mustafa, D.A.M. 2023
Introduction: 5-fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) is promising in treating patients with pancreatic ductal adenocarcinoma. However, many patients and physicians... Show moreIntroduction: 5-fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) is promising in treating patients with pancreatic ductal adenocarcinoma. However, many patients and physicians are reluctant to start FOLFIRINOX due to its high toxicity and limited clinical response rates. In this study, we investigated the effect of a single FOLFIRINOX cycle, in combination with a granulocyte colony-stimulating factor, on the blood immune transcriptome of patients with pancreatic ductal adenocarcinoma. We aimed to iden-ify an early circulating biomarker to predict the lack of FOLFIRINOX response. Methods: Blood samples of 68 patients from all disease stages, who received at least four FOLFIRINOX cycles, were collected at baseline and after the first cycle. The response to treatment was radiologically evaluated following the Response Evaluation Criteria in Solid Tumours criteria 1.1. Targeted immune-gene expression profiling (GEP) was performed using Nano-String technologies. To predict the lack of FOLFIRINOX response, we developed a FOLFIRINOX delta GEP (FFX-Delta GEP) score. Results: A single FOLFIRINOX cycle significantly altered 395 genes, correlating to 30 significant alterations in relative immune cell abundances and pathway activities. The eight-gene (BID, FOXP3, KIR3DL1, MAF, PDGFRB, RRAD, SIGLEC1 and TGFB2) FFX-Delta GEP score predicted the lack of FOLFIRINOX response with a leave-one-out cross-validated area under the curve (95% confidence interval) of 0.87 (0.60-0.98), thereby outperforming the predictiveness of absolute and proportional Delta carbohydrate antigen19-9 values. Conclusions: A single FOLFIRINOX cycle, combined with granulocyte colony-stimulating factor, alters the peripheral immune transcriptome indisputably. Our novel FFX-Delta GEP is, to our knowledge, the first multigene early circulating biomarker that predicts the lack of FOLFIRINOX response after one cycle. Validation in a larger independent patient cohort is crucial before clinical implementation. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Sijde, F. van der; Dik, W.A.; Mustafa, D.A.M.; Vietsch, E.E.; Besselink, M.G.; Debets, R.; ... ; Eijck, C.H.J. van 2022
BackgroundBiomarkers predicting treatment response may be used to stratify patients with pancreatic ductal adenocarcinoma (PDAC) for available therapies. The aim of this study was to evaluate the... Show moreBackgroundBiomarkers predicting treatment response may be used to stratify patients with pancreatic ductal adenocarcinoma (PDAC) for available therapies. The aim of this study was to evaluate the association of circulating cytokines with FOLFIRINOX response and with overall survival (OS). MethodsSerum samples were collected before start and after the first cycle of FOLFIRINOX from patients with PDAC (n=83) of all disease stages. Overall, 34 circulating cytokines were analyzed with a multiplex immunoassay. In addition, changes in peripheral blood immune cell counts were determined by flow cytometry to correlate with differences in cytokine levels. Chemotherapy response was determined by CT scans with the RECIST 1.1 criteria, as disease control (n=64) or progressive disease (n=19) within eight cycles of FOLFIRINOX. ResultsPatients with high serum IL-1RA concentrations after one cycle of chemotherapy were less likely to have tumor progression during FOLFIRINOX (OR 0.25, P=0.040). Increase of circulating IL-1RA concentrations correlated with increase of total, classical (CD14+CD16-), and non-classical monocytes (CD14-CD16+), and dendritic cells. In multivariable cox regression, including the variables chemotherapy response outcome and baseline CA19-9 level, serum concentrations of IL-7 (HR 2.14, P=0.010), IL-18 (HR 2.00, P=0.020), and MIP-1 beta (HR 0.51, P=0.025) after one cycle of FOLFIRINOX showed correlations with OS. ConclusionsCirculating IL-1RA, IL-7, IL-18, and MIP-1 beta concentrations are biomarkers associated with FOLFIRINOX response in PDAC patients, suggesting an important role for specific immune cells in chemotherapy response and PDAC progression. Cytokine-based treatment might improve patient outcome and should be evaluated in future studies. Show less
Lau, S.P.; Land, F.R. van 't; Burg, S.H. van der; Homs, M.Y.V.; Lolkema, M.P.; Aerts, J.G.J.V.; Eijck, C.H.J. van 2022
Introduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy... Show moreIntroduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy may complement our current treatment strategies. We previously demonstrated that the combination of an allogeneic tumour-lysate dendritic cell (DC) vaccine with an anti-CD40 agonistic antibody resulted in robust antitumour responses with survival benefit in a murine PDAC model. In the Rotterdam PancrEAtic Cancer Vaccination-2 trial, we aim to translate our findings into patients. This study will determine the safety of DC/anti-CD40 agonistic antibody combination treatment, and treatment-induced tumour-specific immunological responses. Methods and analysis In this open-label, single-centre (Erasmus Univsersity Medical Center, Rotterdam, Netherlands), single-arm, phase I dose finding study, adult patients with metastatic pancreatic cancer with progressive disease after FOLFIRINOX chemotherapy will receive monocyte-derived DCs loaded with an allogeneic tumour lysate in conjunction with a CD40 agonistic antibody. This combination-immunotherapy regimen will be administered three times every 2 weeks, and booster treatments will be given after 3 and 6 months following the third injection. A minimum of 12 and a maximum of 18 patients will be included. The primary endpoint is safety and tolerability of the combination immunotherapy. To determine the maximum tolerated dose, DCs will be given at a fixed dosage and anti-CD40 agonist in a traditional 3+3 dose-escalation design. Secondary endpoints include radiographic response according to the RECIST (V.1.1) and iRECIST criteria, and the detection of antitumour specific immune responses. Ethics and dissemination The Central Committee on Research Involving Human Subjects (CCMO; NL76592.000.21) and the Medical Ethics Committee (METC; MEC-2021-0566) of the Erasmus M.C. University Medical Center Rotterdam approved the conduct of the trial. Written informed consent will be required for all participants. The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Show less
Lau, S.P.; Land, F.R. van 't; Burg, S.H. van der; Homs, M.Y.V.; Lolkema, M.P.; Aerts, J.G.J.V.; Eijck, C.H.J. van 2022
Introduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy... Show moreIntroduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy may complement our current treatment strategies. We previously demonstrated that the combination of an allogeneic tumour-lysate dendritic cell (DC) vaccine with an anti-CD40 agonistic antibody resulted in robust antitumour responses with survival benefit in a murine PDAC model. In the Rotterdam PancrEAtic Cancer Vaccination-2 trial, we aim to translate our findings into patients. This study will determine the safety of DC/anti-CD40 agonistic antibody combination treatment, and treatment-induced tumour-specific immunological responses.Methods and analysis In this open-label, single-centre (Erasmus Univsersity Medical Center, Rotterdam, Netherlands), single-arm, phase I dose finding study, adult patients with metastatic pancreatic cancer with progressive disease after FOLFIRINOX chemotherapy will receive monocyte-derived DCs loaded with an allogeneic tumour lysate in conjunction with a CD40 agonistic antibody. This combination-immunotherapy regimen will be administered three times every 2 weeks, and booster treatments will be given after 3 and 6 months following the third injection. A minimum of 12 and a maximum of 18 patients will be included. The primary endpoint is safety and tolerability of the combination immunotherapy. To determine the maximum tolerated dose, DCs will be given at a fixed dosage and anti-CD40 agonist in a traditional 3+3 dose-escalation design. Secondary endpoints include radiographic response according to the RECIST (V.1.1) and iRECIST criteria, and the detection of antitumour specific immune responses.Ethics and dissemination The Central Committee on Research Involving Human Subjects (CCMO; NL76592.000.21) and the Medical Ethics Committee (METC; MEC-2021-0566) of the Erasmus M.C. University Medical Center Rotterdam approved the conduct of the trial. Written informed consent will be required for all participants. The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Show less
Background: The impact of pancreatic and periampullary cancer treatment on health-related quality of life (HRQoL) is unclear.Methods: This study merged data from the Netherlands Cancer Registry... Show moreBackground: The impact of pancreatic and periampullary cancer treatment on health-related quality of life (HRQoL) is unclear.Methods: This study merged data from the Netherlands Cancer Registry with EORTC QLQ-C30 and-PAN26 questionnaires at baseline and three-months follow-up of pancreatic and periampullary cancer patients (2015-2018). Propensity score matching (1:3) of group without to group with treatment was performed. Linear mixed model regression analyses were performed to investigate the association between cancer treatment and HRQoL at follow-up.Results: After matching, 247 of 629 available patients remained (68 (27.5%) no treatment, 179 (72.5%) treatment). Treatment consisted of resection (n = 68 (27.5%)), chemotherapy only (n = 111 (44.9%)), or both (n = 40 (16.2%)). At follow-up, cancer treatment was associated with better global health status (Beta-coefficient 4.8, 95% confidence-interval 0.0-9.5) and less constipation (Beta-coefficient -7.6, 95% confidence-interval -13.8-1.4) compared to no cancer treatment. Median overall survival was longer for the cancer treatment group compared to the no treatment group (15.4 vs. 6.2 months, p < 0.001).Conclusion: Patients undergoing treatment for pancreatic and periampullary cancer reported slight improvement in global HRQoL and less constipation at three months-follow up compared to patients without cancer treatment, while overall survival was also improved. Show less
PURPOSE: The benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a... Show morePURPOSE: The benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a statistically significant overall survival (OS) benefit. The long-term results are reported. METHODS: In this multicenter, phase III trial, patients with resectable and borderline resectable pancreatic cancer were randomly assigned (1:1) to neoadjuvant chemoradiotherapy or upfront surgery in 16 Dutch centers. Neoadjuvant chemoradiotherapy consisted of three cycles of gemcitabine combined with 36 Gy radiotherapy in 15 fractions during the second cycle. After restaging, patients underwent surgery followed by four cycles of adjuvant gemcitabine. Patients in the upfront surgery group underwent surgery followed by six cycles of adjuvant gemcitabine. The primary outcome was OS by intention-to-treat. No safety data were collected beyond the initial report of the trial. RESULTS: Between April 24, 2013, and July 25, 2017, 246 eligible patients were randomly assigned to neoadjuvant chemoradiotherapy (n = 119) and upfront surgery (n = 127). At a median follow-up of 59 months, the OS was better in the neoadjuvant chemoradiotherapy group than in the upfront surgery group (hazard ratio, 0.73; 95% CI, 0.56 to 0.96; P = .025). Although the difference in median survival was only 1.4 months (15.7 months v 14.3 months), the 5-year OS rate was 20.5% (95% CI, 14.2 to 29.8) with neoadjuvant chemoradiotherapy and 6.5% (95% CI, 3.1 to 13.7) with upfront surgery. The effect of neoadjuvant chemoradiotherapy was consistent across the prespecified subgroups, including resectable and borderline resectable pancreatic cancer. CONCLUSION: Neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves OS compared with upfront surgery and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer. Show less
PURPOSEThe benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a... Show morePURPOSEThe benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a statistically significant overall survival (OS) benefit. The long-term results are reported.METHODSIn this multicenter, phase III trial, patients with resectable and borderline resectable pancreatic cancer were randomly assigned (1:1) to neoadjuvant chemoradiotherapy or upfront surgery in 16 Dutch centers. Neoadjuvant chemoradiotherapy consisted of three cycles of gemcitabine combined with 36 Gy radiotherapy in 15 fractions during the second cycle. After restaging, patients underwent surgery followed by four cycles of adjuvant gemcitabine. Patients in the upfront surgery group underwent surgery followed by six cycles of adjuvant gemcitabine. The primary outcome was OS by intention-to-treat. No safety data were collected beyond the initial report of the trial.RESULTSBetween April 24, 2013, and July 25, 2017, 246 eligible patients were randomly assigned to neoadjuvant chemoradiotherapy (n = 119) and upfront surgery (n = 127). At a median follow-up of 59 months, the OS was better in the neoadjuvant chemoradiotherapy group than in the upfront surgery group (hazard ratio, 0.73; 95% CI, 0.56 to 0.96; P = .025). Although the difference in median survival was only 1.4 months (15.7 months v 14.3 months), the 5-year OS rate was 20.5% (95% CI, 14.2 to 29.8) with neoadjuvant chemoradiotherapy and 6.5% (95% CI, 3.1 to 13.7) with upfront surgery. The effect of neoadjuvant chemoradiotherapy was consistent across the prespecified subgroups, including resectable and borderline resectable pancreatic cancer.CONCLUSIONNeoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves OS compared with upfront surgery and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer. Show less
The added value of capecitabine to adjuvant gemcitabine monotherapy (GEM) in pancreatic ductal adenocarcinoma (PDAC) was shown by the ESPAC-4 trial. Real-world data on the effectiveness of... Show moreThe added value of capecitabine to adjuvant gemcitabine monotherapy (GEM) in pancreatic ductal adenocarcinoma (PDAC) was shown by the ESPAC-4 trial. Real-world data on the effectiveness of gemcitabine plus capecitabine (GEMCAP), in patients ineligible for mFOLFIRINOX, are lacking. Our study assessed whether adjuvant GEMCAP is superior to GEM in a nationwide cohort. Patients treated with adjuvant GEMCAP or GEM after resection of PDAC without preoperative treatment were identified from The Netherlands Cancer Registry (2015-2019). The primary outcome was overall survival (OS), measured from start of chemotherapy. The treatment effect of GEMCAP vs GEM was adjusted for sex, age, performance status, tumor size, lymph node involvement, resection margin and tumor differentiation in a multivariable Cox regression analysis. Secondary outcome was the percentage of patients who completed the planned six adjuvant treatment cycles. Overall, 778 patients were included, of whom 21.1% received GEMCAP and 78.9% received GEM. The median OS was 31.4 months (95% CI 26.8-40.7) for GEMCAP and 22.1 months (95% CI 20.6-25.0) for GEM (HR: 0.71, 95% CI 0.56-0.90; logrank P = .004). After adjustment for prognostic factors, survival remained superior for patients treated with GEMCAP (HR: 0.73, 95% CI 0.57-0.92, logrank P = .009). Survival with GEMCAP was superior to GEM in most subgroups of prognostic factors. Adjuvant chemotherapy was completed in 69.5% of the patients treated with GEMCAP and 62.7% with GEM (P = .11). In this nationwide cohort of patients with PDAC, adjuvant GEMCAP was associated with superior survival as compared to GEM monotherapy and number of cycles was similar. Show less
Sijde, F. van der; Homs, M.Y.V.; Bekkum, M.L. van; Bosch, T.P.P. van den; Bosscha, K.; Besselink, M.G.; ... ; Dutch Pancreatic Canc Grp 2021
In this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in... Show moreIn this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 132 PDAC patients of all disease stages were included in this study, of whom 25% showed progressive disease during FOLFIRINOX according to the RECIST criteria. MiRNA expression was analyzed in serum collected before the start and after one cycle of chemotherapy. In the discovery cohort (n = 12), a 352-miRNA RT-qPCR panel was used. In the validation cohorts (total n = 120), miRNA expression was detected using individual RT-qPCR miRNA primers. Before the start of FOLFIRINOX, serum miR-373-3p expression was higher in patients with progressive disease compared to patients with disease control after FOLFIRINOX (Log2 fold difference (FD) 0.88, p = 0.006). MiR-194-5p expression after one cycle of FOLFIRINOX was lower in patients with progressive disease (Log2 FD -0.29, p = 0.044). Both miRNAs were predictors of early tumor progression in a multivariable model including disease stage and baseline CA19-9 level (miR-373-3p odds ratio (OR) 3.99, 95% CI 1.10-14.49; miR-194-5p OR 0.91, 95% CI 0.83-0.99). MiR-373-3p and miR-194-5p did not show an association with OS after adjustment for disease stage, baseline CA19-9, and chemotherapy response. In conclusion, high serum miR-373-3p before the start and low serum miR-194-5p after one cycle are associated with early tumor progression during FOLFIRINOX. Show less
Sijde, F. van der; Azmani, Z.; Besselink, M.G.; Bonsing, B.A.; Groot, J.W.B. de; Koerkamp, B.G.; ... ; Eijck, C.H.J. van 2021
Background: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor... Show moreBackground: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS). Methods: Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control (n = 30) or progressive disease (n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria. Results: Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40-79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31-37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6-6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6-17.4 months). Conclusion: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort. Show less
Purpose Solutions to improve the implementation of shared decision making (SDM) in oncology often focus on the consultation, with limited effects. In this study, we used a service design... Show morePurpose Solutions to improve the implementation of shared decision making (SDM) in oncology often focus on the consultation, with limited effects. In this study, we used a service design perspective on the care path of locally advanced pancreatic cancer (LAPC). We aimed to understand how experiences of patients, their significant others, and medical professionals over the entire care path accumulate to support their ability to participate in SDM. Participants and methods We used qualitative interviews including design research techniques with 13 patients, 13 significant others, and 11 healthcare professionals, involved in the diagnosis or treatment of LAPC. The topic list was based on the literature and an auto-ethnography of the illness trajectory by a caregiver who is also a service design researcher. We conducted a thematic content analysis to identify themes influencing the ability to participate in SDM. Results We found four interconnected themes: (1) Decision making is an ongoing and unpredictable process with many decision moments, often unannounced. The unpredictability of the disease course, tumor response to treatment, and consequences of choices on the quality of life complicate decision making; (2) Division of roles, tasks, and collaboration among professionals and between professionals and patients and/or their significant others is often unclear to patients and their significant others; (3) It involves "work" for patients and their significant others to obtain and understand information; (4) In "their disease journey," patients are confronted with unexpected energy drains and energy boosts, that influence their level of empowerment to participate in SDM. Conclusion The service design perspective uncovered how the stage for SDM is often set outside the consultation, which might explain the limited effect currently seen of interventions focusing on consultation itself. Our findings serve as a starting point for (re)designing care paths to improve the implementation of SDM in oncology. Show less
Background Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo... Show moreBackground Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients.MethodsThis nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and <= 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as <= 90 degrees arterial and <= 270 degrees venous involvement without occlusion. Patients receive 8cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36Gy in 15 fractions) during the second cycle, followed by surgery and 4cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3years and 1.5years follow-up.DiscussionThe PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer.Trial registrationPrimary registry and trial identifying number: EudraCT: 2017-002036-17.Date of registration: March 6, 2018.Secondary identifying numbers: The Netherlands National Trial Register - NL7094, NL61961.078.17, MEC-2018-004. Show less
Background and purpose: A matched comparison of external beam radiotherapy (EBRT) versus brachytherapy recently demonstrated that EBRT appears at least as effective for palliating dysphagia in... Show moreBackground and purpose: A matched comparison of external beam radiotherapy (EBRT) versus brachytherapy recently demonstrated that EBRT appears at least as effective for palliating dysphagia in patients with incurable esophageal cancer. The aim of this analysis was to compare patient-reported outcomes (PROs) after EBRT versus brachytherapy.Materials and methods: In a multicenter prospective cohort study, patients with incurable esophageal cancer requiring palliation of dysphagia were included to undergo EBRT (20 Gy in 5 fractions). This EBRT cohort was compared to the single-dose 12 Gy brachytherapy cohort of the previously reported SIRECtrial. Propensity score matching was applied to adjust for baseline imbalances. The primary endpoint of dysphagia improvement was reported previously. PROs were secondary outcomes and assessed at baseline and 3 months after treatment using EORTC QLQ-C30 and QLQ-OES18 questionnaires.Results: A total of 115 enrolled EBRT patients and 93 brachytherapy patients were eligible. After matching, 69 well-balanced pairs remained. At follow-up, significant deteriorations in functioning (i.e. physical, role, social), pain, appetite loss, and trouble with taste were observed after brachytherapy. In the EBRT group, such deterioration was observed only for role functioning, while significant improvements in trouble with eating and pain were found. Between-group comparison showed mostly comparable PRO changes, but significantly favored EBRT with regard to nausea, vomiting, pain, and appetite loss.Conclusion: Short course EBRT results in similar or better PROs at 3 months after treatment compared to single-dose brachytherapy for the palliation of malignant dysphagia. These findings further support its use and inclusion in clinical practice guidelines. (C) 2020 The Author(s). Published by Elsevier B.V. Show less
Background: The objective of this systematic review was to evaluate the performance of prognostic survival models for intrahepatic cholangiocarcinoma (iCCA) when validated in an external dataset.... Show moreBackground: The objective of this systematic review was to evaluate the performance of prognostic survival models for intrahepatic cholangiocarcinoma (iCCA) when validated in an external dataset. Furthermore, it sought to identify common prognostic factors across models, and assess methodological quality of the studies in which the models were developed.Methods: The PRISMA guidelines were followed. External validation studies of prognostic models for patients with iCCA were searched in 5 databases. Model performance was assessed by discrimination and calibration.Results: Thirteen external validation studies were identified, validating 18 different prognostic models. The Wang model was the sole model with good performance (C-index above 0.70) for overall survival. This model incorporated tumor size and number, lymph node metastasis, direct invasion into surrounding tissue, vascular invasion, Carbohydrate antigen (CA) 19-9, and carcinoembryonic antigen (CEA). Methodological quality was poor in 11/12 statistical models. The Wang model had the highest score with 13 out of 17 points.Conclusion: The Wang model for prognosis after resection of iCCA has good quality and good performance at external validation, while most prognostic models for iCCA have been developed with poor methodological quality and show poor performance at external validation. Show less
Background: Compliance with national guidelines on pancreatic cancer management could improve patient outcomes. Early compliance with the Dutch guideline was poor. The aim was to assess compliance... Show moreBackground: Compliance with national guidelines on pancreatic cancer management could improve patient outcomes. Early compliance with the Dutch guideline was poor. The aim was to assess compliance with this guideline during six years after publication.Materials and methods: Nationwide guideline compliance was investigated for three subsequent time periods (2012-2013 vs. 2014-2015 vs. 2016-2017) in patients with pancreatic cancer using five quality indicators in the Netherlands Cancer Registry: 1) discussion in multidisciplinary team meeting (MDT), 2) maximum 3-week interval from final MDT to start of treatment, 3) preoperative biliary drainage when bilirubin >250 mu mol/L, 4) use of adjuvant chemotherapy, and 5) chemotherapy for inoperable disease (non-metastatic and metastatic).Results: In total, 14 491 patients were included of whom 2290 (15.8%) underwent resection and 4561 (31.5%) received chemotherapy. Most quality indicators did not change over time: overall, 88.8% of patients treated with curative intent were discussed in a MDT, 42.7% were treated with curative intent within the 3-week interval, 62.7% with a resectable head tumor and bilirubin >250 mu mol/L underwent preoperative biliary drainage, 57.2% received chemotherapy after resection, and 36.6% with metastatic disease received chemotherapy. Only use of chemotherapy for non-metastatic, non-resected disease improved over time (23.4% vs. 25.6% vs. 29.7%).Conclusion: Nationwide compliance to five quality indicators for the guideline on pancreatic cancer management showed little to no improvement during six years after publication. Besides critical review of the current quality indicators, these outcomes may suggest that a nationwide implementation program is required to increase compliance to guideline recommendations. (C) 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved. Show less
Introduction: Short-course external beam radiotherapy (EBRT) and intraluminal brachytherapy are both accepted treatments for the palliation of dysphagia in patients with incurable esophageal cancer... Show moreIntroduction: Short-course external beam radiotherapy (EBRT) and intraluminal brachytherapy are both accepted treatments for the palliation of dysphagia in patients with incurable esophageal cancer. We compared the effects of both treatments from two prospective studies.Methods: We performed a multicenter prospective cohort study of patients with metastasized or otherwise incurable esophageal cancer requiring palliation of dysphagia from September 2016 to March 2019. Patients were treated with EBRT in five fractions of 4 Gy. Data were compared with all patients treated with a single brachytherapy dose of 12 Gy in the SIREC (Stent or Intraluminal Radiotherapy for inoperable Esophageal Cancer) trial, both between the original cohorts and between 1:1 propensity score-matched cohorts. The primary end point was an improvement of dysphagia at 3 months without reintervention. The secondary end points included toxicity and time-to-effect.Results: A total of 115 patients treated with EBRT and 93 patients who underwent brachytherapy were eligible for analysis. In the original cohorts, dysphagia improved after EBRT in 79% of patients compared with 64% after brachytherapy (p = 0.058). Propensity score matching resulted in 69 patients in each cohort well-balanced at baseline. Improvement of dysphagia was observed in 83% after EBRT versus 64% after brachytherapy (p = 0.048). In responding patients, improvement of dysphagia at 2 weeks was observed in 67% after EBRT compared with 35% after brachytherapy, and the maximum effect was reached after 4 weeks in 55% and 33%, respectively. Severe toxicity occurred in 3% of patients after EBRT compared with 13% after brachytherapy.Conclusions: Short-course EBRT appears at least as effective as brachytherapy in the palliation of dysphagia in patients with esophageal cancer. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. Show less
PURPOSE Preoperative chemoradiotherapy may improve the radical resection rate for resectable or borderline resectable pancreatic cancer, but the overall benefit is unproven.PATIENTS AND METHODS In... Show morePURPOSE Preoperative chemoradiotherapy may improve the radical resection rate for resectable or borderline resectable pancreatic cancer, but the overall benefit is unproven.PATIENTS AND METHODS In this randomized phase III trial in 16 centers, patients with resectable or borderline resectable pancreatic cancer were randomly assigned to receive preoperative chemoradiotherapy, which consisted of 3 courses of gemcitabine, the second combined with 15 x 2.4 Gy radiotherapy, followed by surgery and 4 courses of adjuvant gemcitabine or to immediate surgery and 6 courses of adjuvant gemcitabine. The primary end point was overall survival by intention to treat.RESULTS Between April 2013 and July 2017, 246 eligible patients were randomly assigned; 119 were assigned to preoperative chemoradiotherapy and 127 to immediate surgery. Median overall survival by intention to treat was 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P = .096). The resection rate was 61% and 72% (P = .058). The R0 resection rate was 71% (51 of 72) in patients who received preoperative chemoradiotherapy and 40% (37 of 92) in patients assigned to immediate surgery (P < .001). Preoperative chemoradiotherapy was associated with significantly better disease-free survival and locoregional failure-free interval as well as with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. Survival analysis of patients who underwent tumor resection and started adjuvant chemotherapy showed improved survival with preoperative chemoradiotherapy (35.2 v 19.8 months; P = .029). The proportion of patients who suffered serious adverse events was 52% versus 41% (P = .096).CONCLUSION Preoperative chemoradiotherapy for resectable or borderline resectable pancreatic cancer did not show a significant overall survival benefit. Although the outcomes of the secondary end points and predefined subgroup analyses suggest an advantage of the neoadjuvant approach, additional evidence is required. Show less
