Neoadjuvant Therapy For Pancreatic Cancer Research Articles

The complement C3a/C3aR pathway is associated with treatment resistance to gemcitabine-based neoadjuvant therapy in pancreatic cancer

Gemcitabine is a standard first-line drug for pancreatic cancer chemotherapy. Nevertheless, gemcitabine resistance is common and significantly limits its therapeutic efficacy, impeding advancements in pancreatic cancer treatment. In this study, through a comprehensive analysis of gemcitabine-resistant cell lines and patient samples, 39 gemcitabine resistance-associated risk genes were identified, and two distinct gemcitabine response-related phenotypes were delineated. Through a combination of bioinformatics analysis and in vivo and in vitro experiments, we identified the C3a/C3aR signaling pathway as a pivotal player in the development of gemcitabine resistance in pancreatic cancer. We found that activation of the C3a/C3aR signaling pathway promoted the proliferation, migration and gemcitabine resistance of pancreatic cancer cells, while the C3aR antagonist SB290157 effectively counteracted these effects by impeding the activation of the C3a/C3aR pathway. Our study reveals the fundamental role of complement C3a in the progression of pancreatic cancer, suggesting that complement C3a may serve as a promising biomarker in pancreatic cancer.

A Calculator Approach to Select Neoadjuvant Therapy in Pancreatic Cancer

A Calculator Approach to Select Neoadjuvant Therapy in Pancreatic Cancer

Identification of tumour regression in neoadjuvantly treated pancreatic cancer is based on divergent and nonspecific criteria.

Following the increased use of neoadjuvant therapy for pancreatic cancer, grading of tumour regression (TR) has become part of routine diagnostics. However, it suffers from marked interobserver variation, which is mainly ascribed to the subjectivity of the defining criteria of the categories in TR grading systems. We hypothesized that a further cause for the interobserver variation is the use of divergent and nonspecific morphological criteria to identify tumour regression. Twenty treatment-naïve pancreatic cancers and 20 pancreatic cancers treated with neoadjuvant chemotherapy were reviewed by three experienced pancreatic pathologists who, blinded for treatment status, categorized each tumour as treatment-naïve or neoadjuvantly treated, and annotated all tissue areas they considered showing tumour regression. Only 50%-65% of the cases were categorized correctly, and the annotated tissue areas were highly discrepant (only 3%-41% overlap). When the prevalence of various morphological features deemed to indicate TR was compared between treatment-naïve and neoadjuvantly treated tumours, only one pattern, characterized by reduced cancer cell density and prominent stroma affecting a large area of the tumour bed, occurred significantly more frequently, but not exclusively, in the neoadjuvantly treated group. Finally, stromal features, both morphological and biological, were investigated as possible markers for tumour regression, but failed to distinguish TR from native tumour stroma. There is considerable divergence in opinion between pathologists when it comes to the identification of tumour regression. Reliable identification of TR is only possible if it is extensive, while lesser degrees of treatment effect cannot be recognized with certainty.

Impact of Neoadjuvant Therapy for Pancreatic Cancer: Transatlantic Trend and Postoperative Outcomes Analysis.

The introduction of modern chemotherapy a decade ago has led to increased use of neoadjuvant therapy (NAT) in patients with pancreatic ductal adenocarcinoma (PDAC). A recent North American study demonstrated increased use of NAT and improved operative outcomes in patients with PDAC. The aims of this study were to compare the use of NAT and short-term outcomes in patients with PDAC undergoing pancreatoduodenectomy (PD) among registries from the US and Canada, Germany, the Netherlands, and Sweden. Databases from 2 multicenter (voluntary) and 2 nationwide (mandatory) registries were queried from 2018 to 2020. Patients undergoing PD for PDAC were compared based on the use of upfront surgery vs NAT. Adoption of NAT was measured in each country over time. Thirty-day outcomes, including the composite measure (ideal outcomes), were compared by multivariable analyses. Sensitivity analyses of patients undergoing vascular resection were performed. Overall, 11,402 patients underwent PD for PDAC with 33.7% of patients receiving NAT. The use of NAT increased steadily from 28.3% in 2018 to 38.5% in 2020 (p < 0.0001). However, use of NAT varied widely by country: the US (46.8%), the Netherlands (44.9%), Sweden (11.0%), and Germany (7.8%). On multivariable analysis, NAT was significantly (p < 0.01) associated with reduced rates of serious morbidity, clinically relevant pancreatic fistulae, reoperations, and increased ideal outcomes. These associations remained on sensitivity analysis of patients undergoing vascular resection. NAT before PD for pancreatic cancer varied widely among 4 Western audits yet increased by 26% during 3 years. NAT was associated with improved short-term outcomes.

Discussion.

Discussion.

Clinical and pathological factors associated with survival in patients with pancreatic cancer who receive adjuvant therapy after neoadjuvant therapy: A retrospective multi-institutional analysis

BackgroundNeoadjuvant therapy is being increasingly used for patients with pancreatic cancer. The role of adjuvant therapy in these patients is unclear. The purpose of this study was to identify clinical and pathologic characteristics that are associated with longer overall survival in patients with pancreatic cancer who receive adjuvant therapy after neoadjuvant therapy. MethodsThis study was conducted using multi-institutional data. All patients underwent surgery after at least 1 cycle of neoadjuvant therapy for pancreatic cancer. Patients who died within 3 months after surgery and were known to have distant metastasis or macroscopic residual disease were excluded. Mann–Whitney U test, χ2 analysis, Kaplan–Meier plot, and univariate and multivariate Cox regression analysis were performed as statistical analyses. ResultsIn the present study, 529 patients with resected pancreatic cancer after neoadjuvant therapy were reviewed. For neoadjuvant therapy, 177 (33.5%) patients received neoadjuvant chemotherapy, and 352 (66.5%) patients received neoadjuvant chemoradiotherapy. The median duration of neoadjuvant therapy was 7.0 months (interquartile range, 5.0–8.7). Patients were followed for a median of 23.0 months after surgery. Adjuvant therapy was administered to 297 (56.1%) patients and was not associated with longer overall survival for the entire cohort (24 vs 22 months, P = .31). Interaction analysis showed that adjuvant therapy was associated with longer overall survival in patients who received less than 4 months neoadjuvant therapy (hazard ratio 0.40; 95% confidence interval 0.17–0.95; P = .03) or who had microscopic margin positive surgical resections (hazard ratio 0.56; 95% confidence interval 0.33–0.93; P = .03). ConclusionIn this retrospective study, there was a survival benefit associated with adjuvant therapy for patients who received less than 4 months of neoadjuvant therapy or had microscopic positive margins.

Tumor necrosis as a biomarker for response to neoadjuvant therapy in pancreatic cancer

Tumor necrosis as a biomarker for response to neoadjuvant therapy in pancreatic cancer

Modern radiological assessment after neoadjuvant therapy in pancreatic cancer: an overview

This narrative review provides an overview of the current radiological assessment of pancreatic cancer after neoadjuvant treatment. The current literature was searched for evidence of the different radiological quantitative imaging modalities to stage pancreatic cancer. An overview is given in a narrative method. The quantitative imaging modalities comprise computed tomography (CT) perfusion, dual-energy CT, magnetic resonance imaging, and fluorodeoxyglucose positron emission tomography (FDG-PET)/CT. Radiomics analysis can be used to further characterize the tumors and to reflect the complex tumor microstructure before and after neoadjuvant treatment. Exact extension of the tumor and infiltration of the surrounding tissue is of utter importance to decide, whether the neoadjuvant treatment leads to a resectability or not. There is increasing evidence of the importance of quantitative imaging modalities to assess treatment response in patients with pancreatic cancer after neoadjuvant treatment. Prospective studies employing these modalities are needed to further investigate the benefit for the patients.

Perioperative and long-term survival outcomes of pancreatectomy with arterial resection in borderline resectable or locally advanced pancreatic cancer following neoadjuvant therapy: a systematic review and meta-analysis.

Pancreatic cancer frequently involves the surrounding major arteries, preventing surgeons from making a radical excision. Neoadjuvant therapy (NAT) can lessen the size of local tumors and eliminate potential micrommetastases. However, systematic and evidence-based recommendations for the treatment of arterial resection (AR) after NAT in pancreatic cancer are scarce. A computerized search of the Medline, Embase, Cochrane Library databases, and Clinicaltrials was performed to identify studies reporting the outcomes of patients who underwent pancreatectomy with AR and NAT for pancreatic cancer. Studies that reported perioperative and/or long-term results after pancreatectomy with AR and NAT were eligible for inclusion. The quality of the evidence was assessed with Newcastle-Ottawa Quality Assessment Form of bias tool. Data were pooled and analyzed by Stata 14.0 software. Nine studies with an overall sample size of 215 met our eligibility criteria and were included in the meta-analysis. All studies were retrospective studies, and the methodological quality was moderate. The pooled morbidity and mortality rates were 51% (95% CI: 41-61%; I²= 0.0%) and 2% (95% CI: 0-0.08; I²=33.3%), respectively. Meta-analysis showed that the overall R0 resection rate was 79% (CI: 70-86%, I²=15.5%). Comparative data on R0 rates of patients who underwent pancreatectomy with and without NAT showed a significant difference in favor of the former group with moderate statistical heterogeneity (Relative risk=1.21; 95% CI: 0.776-1.915; I²=48.0%). The median 1-, 2-, 3-, and 5-year survival rates of patients who had AR were 92.3% (range: 72.7-100%), 64.8% (range: 25-78.8%), 51.6% (range: 16.7-63.6%), and 14% (range: 0-41.1%), respectively. Data on median progression-free survival ranged from 5.25 to 36.3 months, and the median overall survival ranged from 17 to 44.9 months. Pancreatectomy with major AR following NAT has the potential to enhance the survival rate of patients with unresectable pancreatic cancer involving the arteries by achieving R0 resection, despite a significant risk of postoperative complications. However, to validate the feasibility and effectiveness of this procedure, prospective controlled studies are necessary to address limitations arising from small sample sizes and potential biases inherent in retrospective studies.

Diffusion-weighted imaging for determining response to neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis

ObjectivesTo determine the role of diffusion-weighted imaging (DWI) for predicting response to neoadjuvant therapy (NAT) in pancreatic cancer.Materials and methodsMEDLINE, EMBASE, and Cochrane Library databases were searched for studies evaluating the performance of apparent diffusion coefficient (ADC) to assess response to NAT. Data extracted included ADC pre- and post-NAT, for predicting response as defined by imaging, histopathology, or clinical reference standards. ADC values were compared with standardized mean differences. Risk of bias was assessed using the Quality Assessment of Diagnostic Studies (QUADAS-2).ResultsOf 337 studies, 7 were included in the analysis (161 patients). ADC values reported for the pre- and post-NAT assessments overlapped between responders and non-responders. One study reported inability of ADC increase after NAT for distinguishing responders and non-responders. A correlation with histopathological response was reported for pre- and post-NAT ADC in 4 studies. DWI’s diagnostic performance was reported to be high in three studies, with a 91.6–100% sensitivity and 62.5–94.7% specificity. Finally, heterogeneity and high risk of bias were identified across studies, affecting the domains of patient selection, index test, reference standard, and flow and timing.ConclusionDWI might be useful for determining response to NAT in pancreatic cancer. However, there are still too few studies on this matter, which are also heterogeneous and at high risk for bias. Further studies with standardized procedures for data acquisition and accurate reference standards are needed.Clinical relevance statementDiffusion-weighted MRI might be useful for assessing response to neoadjuvant therapy in pancreatic cancer. However, further studies with robust data are needed to provide specific recommendations for clinical practice.Key Points•The role of DWI with ADC measurements for assessing response to neoadjuvant therapy in pancreatic cancer is still unclear.•Pre- and post-neoadjuvant therapy ADC values overlap between responders and non-responders.•DWI has a reported high diagnostic performance for determining response when using histopathological or clinical reference standards; however, studies are still few and at high risk for bias.

Impact of sarcopenia on biliary drainage during neoadjuvant therapy for pancreatic cancer.

Since the usefulness of neoadjuvant chemo(radiation) therapy (NAT) for pancreatic cancer has been demonstrated, recurrent biliary obstruction (RBO) in patients with pancreatic cancer with a fully covered self-expandable metal stent (FCSEMS) during NAT is expected to increase. This study investigated the impact of sarcopenia on RBO in this setting. Patients were divided into normal and low skeletal muscle index (SMI) groups and retrospectively analyzed. Patient characteristics, overall survival, time to RBO (TRBO), stent-related adverse events, and postoperative complications were compared between the two groups. A Cox proportional hazard model was used to identify the risk factors for short TRBO. A few significant differences were observed in patient characteristics, overall survival, stent-related adverse events, and postoperative complications between 38 patients in the normal SMI group and 17 in the low SMI group. The median TRBO was not reached in the normal SMI group and was 112 days in the low SMI group (p=0.004). In multivariate analysis, low SMI was the only risk factor for short TRBO, with a hazard ratio of 5.707 (95% confidence interval, 1.148-28.381; p=0.033). Sarcopenia was identified as an independent risk factor for RBO in patients with pancreatic cancer with FCSEMS during NAT.

Biliary Adverse Events During Neoadjuvant Therapy for Pancreatic Cancer.

To describe a high-volume experience with biliary drainage before neoadjuvant therapy (NAT) for patients with operable pancreatic cancer (PC) and characterize the association between biliary adverse events (BAEs) and patient outcome. Patients with PC presenting with biliary obstruction require durable decompression before NAT. Patients with operable PC and tumor-associated biliary obstruction were examined and grouped by the presence or absence of a BAE during NAT. The incidence, timing, and management of BAEs are described, and outcomes, including the completion of all treatment and overall survival (OS), were compared. Of 426 patients who received pretreatment biliary decompression, 92 (22%) experienced at least 1 BAE during NAT, and 56 (13%) required repeat intervention on their biliary stent. The median duration of NAT was 161 days for all patients and was not different in the group that experienced BAEs. The median time from initial stent placement to BAE was 64 days. An interruption in the delivery of NAT (median 7 days) occurred in 25 (6%) of 426 patients. Among 426 patients, 290 (68%) completed all NAT, including surgery: 60 (65%) of 92 patients with BAE and 230 (69%) of 334 patients without BAE ( P =0.51). Among 290 patients who completed NAT and surgery, the median OS was 39 months, 26 months for the 60 patients with BAE, and 43 months for the 230 patients without BAE ( P =0.02). During extended multimodal NAT for PC, 22% of patients experienced a BAE. Although BAEs were not associated with a significant interruption of treatment, patients who experienced a BAE had worse OS.

Neoadjuvant therapy for pancreatic cancer.

Patients with localized pancreatic ductal adenocarcinoma (PDAC) are best treated with surgical resection of the primary tumour and systemic chemotherapy, which provides considerably longer overall survival (OS) durations than either modality alone. Regardless, most patients will have disease relapse owing to micrometastatic disease. Although currently a matter of some debate, considerable research interest has been focused on the role of neoadjuvant therapy for all forms of resectable PDAC. Whilst adjuvant combination chemotherapy remains the standard of care for patients with resectable PDAC, neoadjuvant chemotherapy seems to improve OS without necessarily increasing the resection rate in those with borderline-resectable disease. Furthermore, around 20% of patients with unresectable non-metastatic PDAC might undergo resection following 4-6 months of induction combination chemotherapy with or without radiotherapy, even in the absence of a clear radiological response, leading to improved OS outcomes in this group. Distinct molecular and biological responses to different types of therapies need to be better understood in order to enable the optimal sequencing of specific treatment modalities to further improve OS. In this Review, we describe current treatment strategies for the various clinical stages of PDAC and discuss developments that are likely to determine the optimal sequence of multimodality therapies by integrating the fundamental clinical and molecular features of the cancer.

Call for better response evaluation after neoadjuvant therapy in pancreatic cancer.

Call for better response evaluation after neoadjuvant therapy in pancreatic cancer.

Total neoadjuvant therapy for pancreatic cancer: Just what are we talking about?

Background: Neoadjuvant therapy (NT) has increasingly gained popularity over upfront surgery for pancreatic adenocarcinoma (PDAC). Within this conceptual framework, administration of the complete chemotherapy course prior to surgery is considered optimal. This notion of “total” application of anti-oncologic therapy – so far referred to as Total Neoadjuvant Therapy (TNT) – appears to be, hitherto, an amalgam of different definitions, regimens and timing uniquely ascribed and executed by individual institutions. This review critically examines TNT’s reported efficacy for pancreatic cancer with an aim towards improving standardization of its nomenclature and clinical application.

Neoadjuvant therapy in pancreatic cancer: a review and update on recent trials.

Neoadjuvant therapy (NAT) has been enthusiastically embraced for patients with operable pancreatic cancer (PDAC) in hopes of improving survival. However, the rapid integration of clinical trial data has made it difficult to discern optimal treatment strategies. The goal of this review is to summarize notable recent trials and their contributions to the field. The results of ESPAC-5F, NEOLAP-AIO-PAK-0113, SWOG1505, PREOPANC, HyperAcutePancreas, and ALLIANCE A021501 are reviewed in detail. These studies sequentially evaluate the different neoadjuvant treatment strategies, use of neoadjuvant chemoradiation, and immunotherapy in resectable, borderline-resectable, and locally advanced PDAC. Resection rate ranged from 24.4 to 95.7% (median 64.9%). These trials demonstrate median survival ranging from 14.9 to 41.0 months with progression-free survival ranging from 7.7 to 24.2 months. Survival results may be confounded by ability to reach resection, use of modern chemotherapy vs. gemcitabine monotherapy, and inclusion of locally advanced PDAC. Several upcoming trials will directly examine efficacy of NAT vs. adjuvant therapy, chemoradiation in the NAT setting, and molecular testing-driven chemotherapy selection. NAT is associated with improved survival for patients with borderline resectable PDAC but broader efficacy for resectable PDAC and optimal treatment strategy have yet to be defined.

ASO Author Reflections: Neoadjuvant Therapy for Pancreatic Cancer may Reduce Microscopic Venous Invasion, Which is an Independent Prognostic Factor Associated with Liver Recurrence.

ASO Author Reflections: Neoadjuvant Therapy for Pancreatic Cancer may Reduce Microscopic Venous Invasion, Which is an Independent Prognostic Factor Associated with Liver Recurrence.

Evidenz für neoadjuvante Chemotherapie beim resektablen Pankreaskarzinom

Pancreatic cancer could be the second leading cause of cancer death in 2030. Even though 5-year survival rates remain poor, substantial progress has been made in recent decades. The use of adjuvant chemotherapy after resection has prolonged survival and neoadjuvant concepts have been introduced to allow proportionately more resections in initially borderline resectable or locally advanced disease. Currently, there is an ongoing debate about the use of neoadjuvant therapy in both resectable and borderline resectable disease, whereas in locally advanced cancer, the use of neoadjuvant therapies is unquestionable. High-level evidence in this area remains scarce, despite numerous studies that have recently been published or are currently recruiting. A key problem is the definition of resectability which was - traditionally - based on anatomical criteria; however, it has become clear that this definition is not adequate as tumour biology as well as patient-related prognostic factors are not taken into consideration. A second unsolved problem is the difficulty to standardise neoadjuvant therapy as - in contrast to the adjuvant setting, where large randomised controlled trials have set clear standards - multiple protocols are used around the world. This does not allow us to give any clear recommendation on which therapy protocol should be chosen for a specific patient if neoadjuvant therapy is considered. Furthermore, success control under neoadjuvant treatment is not effectively defined - usually only CA 19-9 as the most common marker can aid in clinical decision making, as imaging often fails to show actual response. With regard to present guidelines, patients with resectable disease should not be treated with neoadjuvant therapy outside clinical studies, whereas for borderline resectable disease, recommendations vary between different countries and societies.This review summarises the present literature on the topic of neoadjuvant therapy in pancreatic cancer with a focus on resectable disease stage.

Neoadjuvant Therapy for Pancreatic Cancer: Increased Use and Improved Optimal Outcomes.

The introduction of more effective chemotherapy a decade ago has led to increased use of neoadjuvant therapy (NAT) in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to assess the evolving use of NAT in individuals with PDAC undergoing pancreatoduodenectomy (PD) and to compare their outcomes with patients undergoing upfront operation. The American College of Surgeons NSQIP Procedure Targeted Pancreatectomy database was queried from 2014 to 2019. Patients undergoing pancreatoduodenectomy were evaluated based on the use of NAT versus upfront operation. Multivariable analysis was performed to determine the effect of NAT on postoperative outcomes, including the composite measure optimal pancreatic surgery (OPS). Mann-Kendall trend tests were performed to assess the use of NAT and associated outcomes over time. A total of 13,257 patients were identified who underwent PD for PDAC between 2014 and 2019. Overall, 33.6% of patients received NAT. The use of NAT increased steadily from 24.2% in 2014 to 42.7% in 2019 (p < 0.0001). On multivariable analysis, NAT was associated with reduced serious morbidity (odds ratio [OR] 0.83, p < 0.001), clinically relevant pancreatic fistulas (OR 0.52, p < 0.001), organ space infections (OR 0.74, p < 0.001), percutaneous drainage (OR 0.73, p < 0.001), reoperation (OR 0.76, p = 0.005), and prolonged length of stay (OR 0.63, p < 0.001). OPS was achieved more frequently in patients undergoing NAT (OR 1.433, p < 0.001) and improved over time in patients receiving NAT (50.7% to 56.6%, p < 0.001). NAT before pancreatoduodenectomy increased more than 3-fold over the past decade and was associated with improved optimal operative outcomes.

Baseline CT-based Radiomic Features Aid Prediction of Nodal Positivity after Neoadjuvant Therapy in Pancreatic Cancer.

Purpose To study the association between CT-derived textural features of pancreatic cancer and patient outcome. Materials and Methods This retrospective study evaluated 54 patients (median age, 62 years [range, 40-88 years]; 32 men) with pancreatic cancer who underwent chemoradiation followed by surgical resection and lymph node dissection from May 2012 to June 2016. Three-dimensional segmentation of the pancreatic tumor was performed on baseline dual-energy CT images: 70-keV pancreatic parenchymal phase (PPP) images and iodine material density images. Then, 15 and 19 radiomic features were extracted from each phase, respectively. Logistic regression with elastic net regularization was used to select textural features associated with outcome, and receiver operating characteristic analysis evaluated feature performance. Survival curves were generated using the Kaplan-Meier method. Results The feature of integral total (∫ T), representing the mean intensity in Hounsfield units times the contour volume in milliliters of PPP imaging (hereafter, "∫ T (HU·mL) (PPP)"), is inversely associated with posttherapy pathologic lymph node (ypN) category. A threshold ∫ T (HU·mL) (PPP) less than 507.85 predicted ypN1-2 classification with 96% sensitivity, 34% specificity, and area under the curve of 0.61. Patients with an ∫ T (HU·mL) (PPP) of less than 507.85 had decreased overall survival (median, 2.8 years) compared with patients with an ∫ T (HU·mL) (PPP) of 507.85 or greater (one event at 3.4 years) (P = .006). Patients with an ∫ T (HU·mL) (PPP) of less than 507.85 had decreased progression-free survival (median, 1.5 years) compared with patients with an ∫ T (HU·mL) (PPP) of 507.85 or greater (median, 2.7 years) (P = .001). Conclusion A CT-based radiomic signature may help predict ypN category in patients with pancreatic cancer. Keywords: CT-Dual Energy, Abdomen/GI, Pancreas, Tumor Response, Outcomes Analysis © RSNA, 2022 Supplemental material is available for this article.