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Contains fulltext : 239076.pdf (Publisher’s version ) (Closed access) OBJECTIVE: This study compared median OS after resection of LAPC after upfront FOLFIRINOX versus a propensity-score matched cohort of LAPC patients treated with FOLFIRINOX-only (ie, without resection). BACKGROUND: Because the introduction of FOLFIRINOX chemotherapy, increased resection rates in LAPC patients have been reported, with improved OS. Some studies have also reported promising OS with FOLFIRINOX-only treatment in LAPC. Multicenter studies assessing the survival benefit associated with resection of LAPC versus patients treated with FOLFIRINOX-only are lacking. METHODS: Patients with non-progressive LAPC after 4 cycles of FOLFIRINOX treatment, both with and without resection, were included from a prospective multicenter cohort in 16 centers (April 2015-December 2019). Cox regression analysis identified predictors for OS. One-to-one propensity score matching (PSM) was used to obtain a matched cohort of patients with and without resection. These patients were compared for OS. RESULTS: Overall, 293 patients with LAPC were included, of whom 89 underwent a resection. Resection was associated with improved OS (24 vs 15 months, P < 0.01), as compared to patients without resection. Before PSM, resection, Charlson Comorbidity Index, and Response Evaluation Criteria in Solid Tumors (RECIST) response were predictors for OS. After PSM, resection remained associated with improved OS [Hazard Ratio (HR) 0.344, 95% confidence interval (0.222-0.534), P < 0.01], with an OS of 24 versus 15 months, as compared to patients without resection. Resection of LAPC was associated with improved 3-year OS (31% vs 11%, P < 0.01). CONCLUSIONS: Resection of LAPC after FOLFIRINOX was associated with increased OS and 3-year survival, as compared to propensity-score matched patients treated with FOLFIRINOX-only.

Contains fulltext : 239059.pdf (Publisher’s version ) (Closed access) BACKGROUND AND OBJECTIVES: Patients with locally advanced pancreatic cancer (LAPC) are increasingly treated with FOLFIRINOX, resulting in improved survival and resection of tumors that were initially unresectable. It remains unclear, however, which specific patients benefit from FOLFIRINOX. Two nomograms were developed predicting overall survival (OS) and resection at the start of FOLFIRINOX for LAPC. METHODS: From our multicenter, prospective LAPC registry in 14 Dutch hospitals, LAPC patients starting first-line FOLFIRINOX (April 2015-December 2017) were included. Stepwise backward selection according to the Akaike Information Criterion was used to identify independent baseline predictors for OS and resection. Two prognostic nomograms were generated. RESULTS: A total of 252 patients were included, with a median OS of 14 months. Thirty-two patients (13%) underwent resection, with a median OS of 23 months. Older age, female sex, Charlson Comorbidity Index ≤1, and CA 19.9 1, involvement of the superior mesenteric artery, celiac trunk, and superior mesenteric vein ≥ 270° were independent factors decreasing the probability of resection (c-index: 0.79). CONCLUSIONS: Two nomograms were developed to predict OS and resection in patients with LAPC before starting treatment with FOLFIRINOX. These nomograms could be beneficial in the shared decision-making process and counseling of these patients.

Introduction Chemotherapy is the mainstay of systemic treatment of biliary tract cancer (BTC). However, the treatment response to chemotherapy varies between patients. Currently, no prognostic biomarkers for chemotherapy efficacy have been considered for use in clinical practice. A systematic review was conducted to evaluate the prognostic value of immunohistochemical biomarkers for chemotherapy in patients with resected as well as with advanced BTC. Method Medline and EMBASE databases were searched up to March 2017 for studies that evaluated biomarker expression by immunohistochemistry in resected or advanced BTC patients treated with chemotherapy. The primary endpoints were overall survival (OS) and disease or progression free survival (DFS or PFS). Result Twenty-six studies, including a total of 1348 patients and 26 different biomarkers, met the inclusion criteria and were included in this review. The most frequently studied prognostic biomarkers in BTC were the human Equilibrative Nucleoside Transporter 1 (hENT1), Ribonucleotide Reductase M1 (RRM1), and excision repair cross-complementation 1 (ERCC1). In the meta-analysis of patients treated with gemcitabine-based chemotherapy, high hENT1 expression was associated with longer OS (HR 0.43, 95% CI: 0.28 to 0.64) and DFS/PFS (HR 0.45, 95% CI: 0.33 to 0.61). Conclusion hENT1 is a promising prognostic biomarker for gemcitabine-based chemotherapy in resected as well as in advanced BTC and should be further validated for the selection of patients for chemotherapy.

A double aging is taking place in Europe and the incidence of pancreatic cancer is highest in the elderly. Although very few elderly patients with pancreatic cancer are receiving chemotherapy, older age and a less favourable performance status are prognostic for poor outcomes in many randomised and non-randomised studies. In elderly patients, physical fitness is being overestimated by performance status alone in comparison with a Comprehensive Geriatric Assessment (CGA). Studies investigating CGA and chemotherapy-treatment specifically in elderly patients with pancreatic cancer are scarce.

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all common cancers. However, divergent outcomes exist between patients, suggesting distinct underlying tumor biology. Here, we delineated this heterogeneity, compared interconnectivity between classification systems, and experimentally addressed the tumor biology that drives poor outcome. RNA-sequencing of 90 resected specimens and unsupervised classification revealed four subgroups associated with distinct outcomes. The worst-prognosis subtype was characterized by mesenchymal gene signatures. Comparative (network) analysis showed high interconnectivity with previously identified classification schemes and high robustness of the mesenchymal subtype. From species-specific transcript analysis of matching patient-derived xenografts we constructed dedicated classifiers for experimental models. Detailed assessments of tumor growth in subtyped experimental models revealed that a highly invasive growth pattern of mesenchymal subtype tumor cells is responsible for its poor outcome. Concluding, by developing a classification system tailored to experimental models, we have uncovered subtype-specific biology that should be further explored to improve treatment of a group of PDAC patients that currently has little therapeutic benefit from surgical treatment.

BACKGROUND Duodenal adenocarcinoma (DA) and intestinal-type papilla of Vater adenocarcinoma (it-PVA) are rare malignancies of the gastrointestinal tract. Current therapeutic options are translated nowadays from treatment strategies for patients with colorectal cancer due to histopathological similarities. AIM To retrospectively investigate the clinical outcome of patients with DA and it-PVA. METHODS All patients with DA and it-PVA diagnosed between 2000 and 2017 were included at two academic centers in the Netherlands. All patients with histopathologically-confirmed DA or it-PVA were eligible for inclusion. Clinical outcome was compared between DA and it-PVA per disease stage. In the subgroup of stage IV disease, survival after local treatment of oligometastases was compared with systemic therapy or supportive care. RESULTS In total, 155 patients with DA and it-PVA were included. Patients with it-PVA more often presented with stage I disease, while DA was more often diagnosed at stage IV (P < 0.001). Of all patients, 79% were treated with curative intent. The median survival was 39 mo, and no difference in survival was found for patients with DA and it-PVA after stratification for disease stage. Seven (23%) of 31 patients with synchronous stage IV disease underwent resection of the primary tumor, combined with local treatment of oligometastases. Local treatment of metastases was associated with an overall survival of 37 mo, compared to 14 and 6 mo for systemic therapy and supportive care, respectively. CONCLUSION Survival of patients with DA and it-PVA is comparable per disease stage. These results suggest a potential benefit for local treatment strategies in selected patients with oligometastases, although additional prospective studies are needed.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.

Background The expanding armamentarium of wearable devices offers new opportunities to supplement physician-assessed performance status (PS) with continuously acquired real-life patient data. It is relevant to identify and characterize the level of association between wearable device physical activity (PA) metrics and PS in cancer patients as a first step into evaluating their potential combined utility in evaluating treatment outcomes and clinical decisions. Therefore, we conducted a systematic review to examine the association between wearable device PA metrics and PS in cancer patients. Methods We searched PubMed and EMBASE for studies that were conducted among adults with cancer, quantitatively assessed a relation between wearable device PA metrics and PS, and had a full text available in English. We extracted information on study design and population, wearable device type and PA metrics, outcome definitions, and results. Included studies were subjected to methodological quality assessment. Results Nine studies with a total of 574 patients were included in this review. Eight studies had a prospective observational study design and all studies reported on a different combination of wearable device PA metrics including: steps per day (n = 5), sedentary behavior (n = 5), and PA volume/intensity (n = 4). Much heterogeneity was observed regarding study population, wearable devices used, and reporting of results. None of the studies could be defined to be of ‘high methodological quality’ (≥ 70%): mean methodological quality was 47% and ranged from 40-60%. We found moderate evidence for a positive association between steps per day and PS, and for a negative association between sedentary behavior and PS. Conclusions Much heterogeneity was identified between studies with regards to study population, reported PA metrics, and used devices. Nevertheless, results of this study indicate that higher daily step count is associated with better PS in cancer patients. Whereas sedentary behavior is associated with worse PS. The next step into determining their potential combined utility in evaluating treatment outcomes and clinical decisions is to investigate the association between wearable device PA metrics and cancer outcomes. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure H.W. Wilmink: Advisory / Consultancy: Shire; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Halozyme; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Merck. H.W.M. van Laarhoven: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Philips. M. van Oijen: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Amgen. All other authors have declared no conflicts of interest.

A 60-year-old Ghanese woman was treated with radiotherapy and capecitabine for metastatic breast cancer. 6 weeks after starting capecitabine she developed palmar and plantar hyperpigmentation, which preceded symptoms of hand-foot syndrome, a known adverse effect of capecitabine. After a dose reduction, the hand-foot syndrome diminished but the hyperpigmentation remained. 8 months later the patient was well and stable.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) ranks 4th on the list of cancer-related deaths which is mostly due to therapy resistance. The tumor microenvironment is one of the main hallmarks to contribute to therapy resistance in which tumors are characterized by large amounts of stroma deposition, and hypovascularization. In this study we assess the use of non-invasive functional magnetic resonance imaging (MRI) for characterization of these tumor microenvironment characteristics and its prognostic and predictive role. Diffusion weighted (DWI) MRI and dynamic contrast enhanced (DCE)-MRI provide insight in stromal content and tumor vascularization. Subsequent correlation of imaging with immunohistochemical (IHC) stainings can validate the biological basis of these imaging modalities. Here, we propose a method to correlate functional MRI to corresponding histology derived tissue characteristics. Methods: Patients suffering from (borderline) resectable PDAC underwent DWI and DCE-MRI on a 3T Philips scanner prior to resection and/or neoadjuvant chemoradiation. DWI data were fitted with the intra voxel incoherent motion model to obtain, among others, the diffusion coefficient D, while DCE-MRI data were fitted according to the extended Tofts model to retrieve the volume transfer constant Ktrans. After resection, the tissue was sectioned in the axial plane and slices where photographed. One slice with evident tumor was selected for whole mount embedding. Whole mount sections were stained for stromal content (αSMA) and vascular density (CD31) The pancreas contour of the photographed tissue slices was manually outlined. Slices were aligned and stacked to form a 3D volume of the pancreas specimen, which was projected onto the MR images. Stained whole mount sections were aligned with the corresponding tissue photograph and transposed to the MRI accordingly to correlate pathology sections to imaging sections and validate parameters using IHC. Results: Sixteen patients were included in the study of which four patients have currently been analyzed. Tissue specimens after resection showed good visual agreement with MRI and could be matched using corresponding anatomical landmarks. In addition, Lower D-values, suggesting higher cell density, indeed corresponded with higher stromal content, while higher values on the Ktrans map, suggesting a higher tumor vascularity, corresponded with higher vessel density. Conclusion: With these preliminary data we demonstrated the feasibility of matching post-operative tissue slices to in vivo MRI of the pancreas. Matching stained whole mount sections to MRI images provides direct information on localization and local tumor heterogeneity for validation of functional MRI parameters. Expanding this work in a larger patient group will provide valuable insights on the underlying biology of functional MRI parameters in pancreatic cancer. Citation Format: Anne Steins, Remy Klaassen, Oliver Gurney-Champion, Maarten Bijlsma, Jan Paul Medema, Hessel Wijkstra, Geertjan van Tienhoven, Olivier Busch, Cornelis Punt, Marc Besselink, Hanneke Wilmink, Marc van de Vijver, Jaap Stoker, Aart Nederveen, Hanneke van Laarhoven. The role of the tumor microenvironment of pancreatic cancer to predict treatment outcome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 421. doi:10.1158/1538-7445.AM2015-421

Background Patient-reported outcomes (PROs) are amongst the most relevant outcome measures in pancreatic cancer care and research. However, it is unknown which out of the numerous PROs are most important to patients and health care professionals (HCPs) in this setting. The aim of this study was to identify a core set of PROs to be incorporated in a nationwide prospective multidisciplinary pancreatic cancer registry. Patients and methods We performed a two-round Delphi survey among 150 patients diagnosed with pancreatic or periampullary cancer (treated either with curative intent or in palliative setting) and 78 HCPs (surgeons, medical oncologists, gastroenterologists, radiotherapists, nurses, and dietitians) in The Netherlands. In round 1, participants were invited to rate the importance of 53 PROs, which were extracted from 17 different PRO measures and grouped into global domains, on a 1–9 Likert scale. PROs rated as very important (score 7–9) by the majority (≥80%) of curative and/or palliative patients as well as HCPs were considered sufficiently important to be incorporated in the core set. PROs not fulfilling these criteria in round 1 were presented again to the participants in round 2 along with individual and group feedback. Results A total of 97 patients (94%) in curative-intent setting, 38 patients (81%) in palliative setting and 73 HCPs (94%) completed both rounds 1 and 2. After the first round, 7 PROs were included in the core set: general quality of life, general health, physical ability, satisfaction with caregivers, satisfaction with services and care organisation, coping and defecation. After the second round, 10 additional PROs were added: appetite, ability to work/do usual activities, medication use, weight changes, fatigue, negative feelings, positive feelings, fear of recurrence, relationship with partner/family, and pancreatic enzyme replacement therapy use. Conclusion This study provides a core set of PROs selected by patients and HCPs, which may be incorporated in pancreatic cancer care and research. Validation outside the Dutch context is recommended for generalisation and use in international studies.

Objectives Thymic malignancies are rare tumors on the superior anterior mediastinum. Treatment of advanced stages includes chemotherapy. The objective of this analysis was to review the treatment of this disease in the past decade. Methods This is a retrospective analysis of the results obtained in a total of 29 patients with advanced malignant thymomas who underwent systemic chemotherapy in the past 10 years at our institution. Sixteen received neoadjuvant chemotherapy in the attempt to shrink the tumor and then perform a radical operation. The others received chemotherapy as palliation. Platinum based chemotherapy was mainly used. Results The response rate to first-line chemotherapy was 50% in the neoadjuvant setting and 31% in the advanced setting. A better survival was observed in patients who underwent chemotherapy as part of their combined modality treatment, in patients with thymomas, and in patients without visceral metastases. Some patients responded to targeted therapies at relapse. Conclusions A better understanding of the biology of this rare tumor may allow in the future the development of better therapies for the more aggressive tumor types (WHO type C), which appear to be increasing in frequency.