J.W. Wilmink

FOLFIRINOX in Locally Advanced and Metastatic Pancreatic Cancer: A Single Centre Cohort Study

Introduction: FOLFIRINOX is emerging as new standard of care for fit patients with locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC). However, some of the physicians are reluctant to use FOLFIRINOX due to high toxicity rates reported in earlier studies. We reviewed our experience with FOLFIRINOX in LAPC and MPC, focussing on dose adjustments, toxicity and efficacy. Methods: We reviewed all patients with LAPC or MPC treated with FOLFIRINOX in our institution between April 2011 and December 2015. Unresectability (stage III and IV) was determined by the institutions multidisciplinary team for pancreatic cancer. Results: Fifty patients (18 LAPC and 32 MPC) were enrolled, with a median age of 55 years (IQR 49-66) and WHO performance status of 0/1. FOLFIRINOX was given as first-line treatment in 82% of patients. Dose modifications were applied in 90% of patients. The median number of completed cycles was 8 (IQR 5-9). Grade 3-4 toxicity occurred in 52% and grade 5 toxicity in 2%. The response rate was 25% (12% in LAPC, 32% in MPC). Median overall survival and progression-free survival were 14.8 and 10.3 months in LAPC, and 9.0 and 5.9 months in MPC, respectively. Overall 1- and 2-year survival was 65% and 10% in LAPC and 40% and 5% in MPC. Within the LAPC group, 6 patients (33%) underwent local ablative therapy and 1 patient (6%) a resection, leading to a median survival of 21.8 months. Conclusion: FOLFIRINOX treatment with nearly routine dose modification was associated with acceptable toxicity rates, relatively high response rates and an encouraging overall survival.

Induction Chemotherapy Followed by Resection or Irreversible Electroporation in Locally Advanced Pancreatic Cancer (IMPALA): A Prospective Cohort Study

BackgroundFollowing induction chemotherapy, both resection or irreversible electroporation (IRE) may further improve survival in patients with locally advanced pancreatic cancer (LAPC). However, prospective studies combining these strategies are currently lacking, and available studies only report on subgroups that completed treatment. This study aimed to determine the applicability and outcomes of resection and IRE in patients with nonprogressive LAPC after induction chemotherapy.MethodsThis was a prospective, single-center cohort study in consecutive patients with LAPC (September 2013 to March 2015). All patients were offered 3xa0months of induction chemotherapy (FOLFIRINOX or gemcitabine depending on performance status), followed by exploratory laparotomy for resection or IRE in patients with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 nonprogressive, IRE-eligible tumors.ResultsOf 132 patients with LAPC, 70% (nxa0=xa093) started with chemotherapy (46% [nxa0=xa061] FOLFIRINOX). After 3xa0months, 59 patients (64%) had nonprogressive disease, of whom 36 (27% of the entire cohort) underwent explorative laparotomy, resulting in 14 resections (11% of the entire cohort, 39% of the explored patients) and 15 IREs (11% of the entire cohort, 42% of the explored patients). After laparotomy, 44% (nxa0=xa016) of patients had Clavien–Dindo grade 3 or higher complications, and 90-day all-cause mortality was 11% (nxa0=xa04). With a median follow-up of 24xa0months, median overall survival after resection, IRE, and for all patients with nonprogressive disease without resection/IRE (nxa0=xa030) was 34, 16, and 15xa0months, respectively. The resection rate in 61 patients receiving FOLFIRINOX treatment was 20%.ConclusionInduction chemotherapy followed by IRE or resection in nonprogressive LAPC led to resection or IRE in 22% of all-comers, with promising survival rates after resection but no apparent benefit of IRE, despite considerable morbidity. Registered at Netherlands Trial Register (NTR4230).

Volume matters in the systemic treatment of metastatic pancreatic cancer: a population-based study in the Netherlands.

PurposeIn pancreatic surgery, a relation between surgical volume and postoperative mortality and overall survival (OS) has been recognized, with high-volume centers reporting significantly better survival rates. We aimed to explore the influence of hospital volume on administration of palliative chemotherapy and OS in the Netherlands.MethodsPatients diagnosed between 2007 and 2011 with metastatic pancreatic cancer were identified in the Netherlands Cancer Registry. Three types of high-volume centers were defined: high-volume (1) incidence center, based on the number of patients diagnosed with metastatic pancreatic cancer, (2) treatment center based on number of patients with metastatic pancreatic cancer who started treatment with palliative chemotherapy and (3) surgical center based on the number of resections with curative intent for pancreatic cancer. Independent predictors of administration of palliative chemotherapy were evaluated by means of logistic regression analysis. The multivariable Cox proportional hazard model was used to assess the impact of being diagnosed or treated in high-volume centers on survival.ResultsA total of 5385 patients presented with metastatic pancreatic cancer of which 24xa0% received palliative chemotherapy. Being treated with chemotherapy in a high-volume chemotherapy treatment center was associated with improved survival (HR 0.76, 95xa0% CI 0.67–0.87). Also, in all patients with metastatic pancreatic cancer, being diagnosed in a high-volume surgical center was associated with improved survival (HR 0.74, 95xa0% CI 0.66–0.83).ConclusionsHospital volume of palliative chemotherapy for metastatic pancreatic cancer was associated with improved survival, demonstrating that a volume–outcome relationship, as described for pancreatic surgery, may also exist for pancreatic medical oncology.

Metformin Use During Treatment of Potentially Curable Esophageal Cancer Patients is not Associated with Better Outcomes

BackgroundMetformin use has been associated with a dose-dependent increased response to neoadjuvant chemo(radio)therapy in esophageal cancer patients. However, no association between metformin use and overall survival has been reported yet. The purpose of our study was to investigate the effect of metformin use on pathological response as well as overall and disease-free survival in patients with resectable esophageal cancer.MethodsBetween March 1994 and September 2013, all patients undergoing an esophagectomy for esophageal and gastroesophageal junction cancer after neoadjuvant chemo(radio)therapy with curative intent were included in a prospective database. A complete pathological response was defined as ypT0N0M0, Mandard 1. Kaplan–Meier curves with log-rank testing were performed for overall survival and disease-free survival.ResultsA total of 461 patients were included with a median follow-up of 24xa0months (range 1–228); 43 patients were diagnosed with diabetes mellitus type II (9.3xa0%) of whom 32 patients used metformin (74xa0%). A total of 94 (20xa0%) patients had a complete pathological response, which did not differ between metformin users (19xa0%) and non-metformin users (21xa0%, pxa0=xa00.99). We did not observe a statistically significant difference between metformin users and non-metformin users for median overall survival (43.6 vs. 42.8xa0months, pxa0=xa00.66) or for median disease-free survival (31.1 vs. 47.0xa0months, pxa0=xa00.68). A subgroup analysis in patients with diabetes mellitus type II showed a nonsignificant increase in median overall survival for metformin users (43.6xa0months) compared with non-metformin users (21.4xa0months, pxa0=xa00.44). For median disease-free survival, a similar nonsignificant increase was observed for metformin users (31.1xa0months) compared with non-metformin users (20.1xa0months, pxa0=xa00.31).ConclusionsThe use of metformin did not result in higher pathological response rates or improved overall survival or disease-free survival compared with non-metformin use in patients receiving neoadjuvant chemo(radio)therapy for resectable esophageal cancer. In contrast to what has been postulated for other tumor types, metformin may not have a beneficial effect in esophageal cancer.

Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer: Upfront surgery versus neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer

Studies comparing upfront surgery with neoadjuvant treatment in pancreatic cancer may report only patients who underwent resection and so survival will be skewed. The aim of this study was to report survival by intention to treat in a comparison of upfront surgery versus neoadjuvant treatment in resectable or borderline resectable pancreatic cancer.

Clinical value of ctDNA in upper-GI cancers: A systematic review and meta-analysis

BACKGROUNDnThe recent expanding technical possibilities to detect tumor derived mutations in blood, so-called circulating tumor DNA (ctDNA), has rapidly increased the interest in liquid biopsies. This review and meta-analysis explores the clinical value of ctDNA in malignancies of the upper gastro-intestinal tract.nnnMETHODSnPubMed, Cochrane and Embase databases were searched to identify studies reporting the diagnostic, prognostic or predictive value of ctDNA in patients with esophageal, gastric and pancreatic cancer, until January 2017. The diagnostic accuracy and, using random-effect pair-wise meta-analyses, the prognostic value of ctDNA was assessed.nnnRESULTSnA total of 34 studies met the inclusion criteria. For esophageal and gastric cancer, amplification of oncogenes in blood, such as HER2 and MYC, can be relevant for diagnostic purposes, and to predict treatment response in certain patient subpopulations. Given the limited number of studies assessing the role of ctDNA in esophageal and gastric cancer, the meta-analysis estimated the diagnostic accuracy and predictive value of ctDNA in pancreatic cancer only (n=10). The pooled sensitivity and specificity of ctDNA as a diagnostic tool in pancreatic cancer were 28% and 95%, respectively. Patients with pancreatic cancer and detectable ctDNA demonstrated a worse overall survival compared to patients with undetectable ctDNA (HR 1.92, 95% confidence interval (CI) 1.15-3.22, p=0.01).nnnCONCLUSIONnThe presence of ctDNA is significantly associated with a poor prognosis in patients with pancreatic cancer. The use of ctDNA in clinical practice is promising, although standardization of sequencing techniques and further development of high-sensitive detection methods is needed.

Nationwide trends in chemotherapy use and survival of elderly patients with metastatic pancreatic cancer

Despite an aging population and underrepresentation of elderly patients in clinical trials, studies on elderly patients with metastatic pancreatic cancer are scarce. This study investigated the use of chemotherapy and survival in elderly patients with metastatic pancreatic cancer. From the Netherlands Cancer Registry, all 9407 patients diagnosed with primary metastatic pancreatic adenocarcinoma in 2005–2013 were selected to investigate chemotherapy use and overall survival (OS), using Kaplan–Meier and Cox proportional hazard regression analyses. Over time, chemotherapy use increased in all age groups (<70 years: from 26 to 43%, 70–74 years: 14 to 25%, 75–79 years: 5 to 13%, all P < 0.001, and ≥80 years: 2 to 3% P = 0.56). Median age of 2,180 patients who received chemotherapy was 63 years (range 21–86 years, 1.6% was ≥80 years). In chemotherapy‐treated patients, with rising age (<70, 70–74, 75–79, ≥80 years), microscopic tumor verification occurred less frequently (91‐88‐87‐77%, respectively, P = 0.009) and OS diminished (median 25‐26‐19‐16 weeks, P = 0.003). After adjustment for confounding factors, worse survival of treated patients ≥75 years persisted. Despite limited chemotherapy use in elderly age, suggestive of strong selection, elderly patients (≥75 years) who received chemotherapy for metastatic pancreatic cancer exhibited a worse survival compared to younger patients receiving chemotherapy.

Ablation with irreversible electroporation in patients with advanced perihilar cholangiocarcinoma (ALPACA): a multicentre phase I/II feasibility study protocol

Introduction The majority of patients with perihilar cholangiocarcinoma (PHC) has locally advanced disease or distant lymph node metastases on presentation or exploratory laparotomy, which makes them not eligible for resection. As the prognosis of patients with locally advanced PHC or lymph node metastases in the palliative setting is significantly better compared with patients with organ metastases, ablative therapies may be beneficial. Unfortunately, current ablative options are limited. Photodynamic therapy causes skin phototoxicity and thermal ablative methods, such as stereotactic body radiation therapy and radiofrequency ablation, which are affected by a heat/cold-sink effect when tumours are located close to vascular structures, such as the liver hilum. These limitations may be overcome by irreversible electroporation (IRE), a relatively new ablative method that is currently being studied in several other soft tissue tumours, such as hepatic and pancreatic tumours. Methods and analysis In this multicentre phase I/II safety and feasibility study, 20 patients with unresectable PHC due to vascular or distant lymph node involvement will undergo IRE. Ten patients who present with unresectable PHC will undergo CT-guided percutaneous IRE, whereas ultrasound-guided IRE will be performed in 10 patients with unresectable tumours detected at exploratory laparotomy. The primary outcome is the total number of clinically relevant complications (Common Terminology Criteria for Adverse Events, score of≥3) within 90 days. Secondary outcomes include quality of life, tumour response, metal stent patency and survival. Follow-up will be 2 years. Ethics and dissemination The protocol has been approved by the local ethics committees. Data and results will be submitted to a peer-reviewed journal. Conclusion The Ablation with irreversible eLectroportation in Patients with Advanced perihilar CholangiocarcinomA (ALPACA) study is designed to assess the feasibility of IRE for advanced PHC. The main purpose is to inform whether a follow-up trial to evaluate safety and effectiveness in a larger cohort would be feasible.

Translating the ABC-02 trial into daily practice: outcome of palliative treatment in patients with unresectable biliary tract cancer treated with gemcitabine and cisplatin

Abstract Background: Biliary tract cancer (BTC) is an uncommon cancer with an unfavorable prognosis. Since 2010, the standard of care for patients with unresectable BTC is palliative treatment with gemcitabine plus cisplatin, based on the landmark phase III ABC-02 trial. This current study aims to evaluate the efficacy and safety of gemcitabine and cisplatin in patients with unresectable cholangiocarcinoma and gallbladder cancer in daily practice that meet the criteria for the ABC-02 trial in comparison to patients who did not. Methods: Patients diagnosed with unresectable BTC between 2010 and 2015 with an indication for gemcitabine and cisplatin were included. We divided these patients into three groups: (I) patients who received chemotherapy and met the criteria of the ABC-02 trial, (II) patients who received chemotherapy and did not meet these criteria and (III) patients who had an indication for chemotherapy, but received best supportive care without chemotherapy. Primary outcome was overall survival (OS) and secondary outcome was progression-free survival (PFS). Results: We collected data of 208 patients, of which 138 (66.3%) patients received first line chemotherapy with gemcitabine and cisplatin. Median OS of 69 patients in group I, 63 patients in group II and 65 patients in group III was 9.6 months (95%CIu2009=u20096.7–12.5), 9.5 months (95%CIu2009=u20097.7–11.3) and 7.6 months (95%CIu2009=u20095.0–10.2), respectively. Median PFS was 6.0 months (95%CIu2009=u20094.4–7.6) in group I and 5.1 months (95%CIu2009=u20093.7–6.5) in group II. Toxicity and number of dose reductions (pu2009= .974) were comparable between the two chemotherapy groups. Conclusion: First-line gemcitabine and cisplatin is an effective and safe treatment for patients with unresectable BTC who do not meet the eligibility criteria for the ABC-02 trial. Median OS, PFS and treatment side effects were comparable between the patients who received chemotherapy (group I vs. group II).

Tumoren van de galwegen

Carcinomen van de galwegen kunnen voorkomen in de lever (intrahepatisch cholangiocarcinoom), in de leverhilus (hilair cholangiocarcinoom) of in de ductus hepatocholedochus (mid- en distaal cholangiocarcinoom). De incidentie bedraag in Nederland 1-4 per 100.000. Er zijn drie verschillende typen: papillair, nodulair en diffuus periductaal. Primaire scleroserende cholangitis en een choledochuscyste zijn bekende risicofactoren. De meeste patienten presenteren zich met een pijnloze icterus, jeuk, gewichtsverlies en anorexia.