Treatment Of Metastatic Pancreatic Cancer Research Articles

Addition and timing of surgery in multiagent chemotherapy treatment of metastatic pancreatic cancer

Background: Most pancreatic cancer patients have metastasis at diagnosis and even limited metastatic burden is considered a contraindication to surgery. Modern multiagent chemotherapy regimens have challenged the dogma of unresectable disease in locally advanced pancreatic cancer. We aimed to evaluate survival in surgically treated metastatic pancreatic cancer with preoperative versus postoperative multiagent chemotherapy using data from the National Cancer Database.

Plasma anthocyanins and their metabolites reduce in vitro migration of pancreatic cancer cells, PANC-1, in a FAK- and NF-kB dependent manner: Results from the ATTACH-study a randomized, controlled, crossover trial in healthy subjects

Pancreatic cancer is primarily considered to be a metastatic disease with a low 5-year survival rate. We aimed to detect if plasma-isolated anthocyanins and their metabolites (PAMs) modulate pancreatic cancer cells migration and to describe molecular targets of PAMs in this process. Plasma metabolites were isolated by solid-phase extraction before and after a 28-days intervention trial involving 35 healthy subjects comparing effects of a daily anthocyanin-rich juice intake vs. placebo. Plasma extracts were used for migration and mechanistic in vitro studies as well as for metabolomic analysis. Pancreatic PANC-1 and AsPC-1 were used for migration studies in a Boyden chamber co-cultured with endothelial cells. Expression of adhesion molecules on cancer and endothelial cells were determined by flow cytometry and NF-kB (nuclear factor-kappa B) p65 and focal adhesion kinase activation were measured by immunoassays. UHPLC-MS/MS metabolomics was done in plasma and urine samples. Plasma extracts isolated after the intake of the anthocyanin-rich juice significantly reduced PANC-1 migration, but not AsPC-1 migration. In PANC-1, and to a lower extent in endothelial cells, plasma extracts after juice intake decreased the expression of ß1- and ß4-integrins and intercellular adhesion molecule-1. Pooled plasma from volunteers with the highest inhibition of PANC-1 migration (n = 10) induced a reduction of NF-kB-p65 and FAK-phosphorylation in cancer and in endothelial cells. Concerning metabolites, 14 were significantly altered by juice intervention and PANC-1 migration was inversely associated with the increase of o-coumaric acid and peonidin-3-galactoside. PAMs were associated with lower PANC-1 cell migration opening new strategies for metastatic pancreatic cancer treatment.

The effectiveness of nab-paclitaxel plus gemcitabine and gemcitabine monotherapy in first-line metastatic pancreatic cancer treatment: A real-world evidence.

Pancreatic cancer is one of the most lethal malignancies with a rise in mortality rates. FOLFIRINOX and nab-paclitaxel plus gemcitabine demonstrated a survival benefit compared to gemcitabine alone. Both protocols are now considered the standard of first-line treatment with no significant difference between them, primarily based on observational studies. Although new therapeutic options have emerged recently, the prognosis remains poor. We conducted a retrospective single-center study on 139 patients treated for metastatic pancreatic adenocarcinoma (mPDAC) with gemcitabine monotherapy (Gem) or nab-paclitaxel + gemcitabine (Nab-P/Gem) in the first line. The aim of our study was to evaluate the effectiveness in terms of overall survival (OS) and progression-free survival (PFS) as well as the influence of patient and disease characteristics on outcomes. Nab-P/Gem resulted in OS of 13.87 months compared to 8.5 months in patients receiving Gem. The same trend was achieved in PFS, 5.37 versus 2.80 months, respectively, but without reaching statistical significance. Furthermore, the 6-month survival in the Nab-P/Gem group was also higher, 78.1% versus 47.8%. In terms of survival, the group of elderly patients, patients of poorer performance, with higher metastatic burden and liver involvement, benefited the most from combination therapy. In our analysis ECOG performance status (p.s.), previous primary tumor surgery, and liver involvement were found to be independent prognostic factors. The addition of nab-paclitaxel to gemcitabine resulted in a significant improvement in the OS of patients with mPDAC. Subgroup analysis demonstrated that patients with some unfavorable prognostic factors benefited the most.

Meta-analysis of gemcitabine plus nab-paclitaxel combined with targeted agents in the treatment of metastatic pancreatic cancer.

BACKGROUNDGemcitabine plus nab-paclitaxel (GA) is a commonly used first-line treatment regimen for metastatic pancreatic cancer, and many studies will add a novel targeted agent to this regimen for improving patient survival rate. However, the clinical effectiveness of GA is the most controversial issue. AIMTo compare the efficacy and safety of GA regimen with a targeted agent and GA regimen.METHODSUp to 1 December 2021, the eligible randomized controlled trials (RCTs) relating to GA and GA with a targeted agent were searched on PubMed, EMBASE and Cochrane Library for eligible data. We screened out appropriate studies for overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and toxicity, which had been pooled and finally analyzed by using Stata version 15.1. In addition, we use Reference Citation Analysis (https://www.referencecitationanalysis.com/) to collect the latest related literature to improve the latest cutting-edge research results.RESULTSSeven RCTs involving 1544 patients (848 men and 696 women) were included. There were no significant differences between GA with a targeted agent and GA in PFS [hazard ratio (HR): 1.18 95% confidence interval (CI): 0.91-1.53], OS (HR: 1.12 95%CI: 0.99-1.27), and ORR (HR: 0.96 95%CI: 0.71-1.29). There was no notable difference in the two groups in grade 3/4 toxicity (fatigue, anemia, vomiting and neutropenia), whereas the incidence of grade 3/4 diarrhea considerably increased in GA with a targeted drug.CONCLUSIONAdding a novel targeted agent to the GA regimen did not improve survival rate of patients with metastatic pancreatic cancer.

Evaluation of Serum microRNA Let-7c and Let-7d as Predictive Biomarkers for Metastatic Pancreatic Cancer

Background:First-line treatments for metastatic pancreatic cancer are chemotherapy regimens consisting of 5-fluorouracil or gemcitabine; however, there are no biomarkers to help determine which patients might benefit from which treatment regimens. We aimed to show that microRNAs let-7c and 7d can be used as independent predictive biomarkers for metastatic pancreatic cancer.Methods:A total of 55 patients who had first-line chemotherapy with FOLFIRINOX or gemcitabine + capecitabine were included. Patients were divided into groups based on let-7c and let-7d levels and chemotherapy treatment as let-7c-7d high FOLFIRINOX, let-7c-7d high gemcitabine + capecitabine, let-7c-7d low FOLFIRINOX, and let-7c-7d low gemcitabine + capecitabine. Blood samples were taken from patients before chemotherapy for microRNA let-7c and 7d analysis. MicroRNA isolation was performed using a miRNeasy Serum/Plasma Kit and identified using spectrophotometric measurements. After isolation, microRNA was converted to cDNA using a microRNA cDNA Synthesis Kit with poly (A) polymerase tailing. The expression of microRNA was examined using quantitative real-time polymerase chain reaction.Results:The overall survival of patients who received FOLFIRINOX treatment with a high let-7c-7d level was statistically significantly longer than those who received gemcitabine + capecitabine with a high let-7c-7d level. In addition, patients with low let-7c expression receiving FOLFIRINOX progressed significantly 2.104 times earlier than patients with high let-7c expression receiving FOLFIRINOX.Conclusion:The serum MicroRNA let-7c level was found to be an independent predictive biomarker in the FOLFIRINOX treatment group.

Treatment of metastatic pancreatic cancer

Pancreatic cancer is the 4th most common cause of cancer death in Germany and continues to be associated with apoor prognosis. Aprerequisite for chemotherapy or radiotherapy is always the pathohistological (or cytological) confirmation of the tumor disease. Molecular diagnostics include analysis of DNA mismatch repair in the tumor and of the germline mutations in BRCA 1/2 (gBRCA mutation). Systemic chemotherapy remains the mainstay in the management of locally advanced and metastatic disease. If agBRCA mutation is detected, platinum-based therapy should be used. Patients with good performance status benefit from second-line therapy. Immunotherapy with checkpoint inhibitors (not yet approved) may be considered in pretreated patients with evidence of deficient DNA mismatch repair or microsatellite instability.

MO6-1 Real-world treatment outcomes of metastatic pancreatic cancer in Japan: Tokushukai REAl-world Data project 03 (TREAD 03)

Gemcitabine (GEM) plus nub-paclitaxel (GnP) and FOLFIRINOX (FFX) have become established treatment for metastatic pancreatic cancer (mPC). The aim of this study was to investigate prognostic factors and temporal trends in treatment pattern for overall survival (OS) in a real-world setting.

Abstract 1243: Identification of aneuploidy biomarkers associated with response to first-line treatment of metastatic pancreatic cancer

Abstract Background: NCCN guidelines for first-line treatment of patients with metastatic pancreatic cancer includes either FOLFIRINOX or gemcitabine plus paclitaxel; however, these two treatment regimens have not been compared in a randomized clinical trial. In this study, we investigated genomic predictors of treatment response to guide this treatment decision. Methods: We selected 1,250 patients with metastatic pancreatic cancer who were treated with first-line FOLFIRINOX (FOLF, n = 588) or gemcitabine plus paclitaxel (G+P, n = 662) within the nationwide de-identified Flatiron Health-Foundation Medicine clinico-genomic database (CGDB). The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care). Comprehensive genomic profiling was performed by Foundation Medicine on tumor samples from each patient as part of the standard of care. Gain/loss status as well as loss of heterozygosity (LOH) status of each chromosome arm was assessed using a custom research-use only algorithm that utilizes copy number model calls for each segment and SNP MAF information from sequencing data. Univariable Cox proportional hazards regression was used to identify chromosome arm-level aneuploidies associated with survival in patients treated with first-line FOLF or G+P. In each treatment cohort, a multivariable Cox model was built using the bidirectional stepwise regression procedure to select aneuploidy features associated with survival. A binary risk score was calculated based on the linear predictor of the multivariable Cox model and categorized as high vs low using a median threshold. Results: Among the FOLF-treated cohort, we identified six aneuploidy features associated with survival (Bonferroni adjusted p < 0.05). FOLF-treated patients with a low FOLF risk score had better survival compared to those with a high FOLF risk score (HR: 0.46, 95%CI: 0.34-0.61, p = <0.001). This association was not observed among G+P-treated patients (HR: 0.86, 95%CI: 0.66-1.11, p = 0.25). Among the G+P treated cohort; eight aneuploidy features were associated with survival (Bonferroni adjusted p < 0.05). G+P-treated patients with a low G+P risk score had better survival compared to patients with a high G+P risk score (HR: 0.43, 95%CI: 0.33-0.57, p = <0.001). This association was not observed among FOLF-treated patients (HR: 0.86, 95%CI: 0.66-1.12, p = 0.25). These findings remained after adjusting for clinical features including surgery and ECOG performance status (HRG+P: 0.52, p = <0.001; HRFOLF: 0.5, p = <0.001). Conclusions: In metastatic pancreatic cancer, we found different chromosome arm-level aneuploidies were associated with survival for FOLF and G+P regimens which suggests an aneuploidy-based risk score may have utility in choosing first-line treatment. Citation Format: Kuei-Ting Chen, Radwa Sharaf, Garrett Frampton, Lee Albacker, Ericka Ebot. Identification of aneuploidy biomarkers associated with response to first-line treatment of metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1243.

Sequential first-line treatment with gemcitabine plus nab-paclitaxel (GA) followed by FOLFIRINOX (FFX) versus FFX alone in patients with metastatic pancreatic cancer (PC): GABRINOX-2 randomized phase 2 trial.

TPS4190 Background: PC is a major health concern worldwide and a deadly disease due to its high metastatic behavior. In recent years, incremental progresses have been made with the use of new chemotherapy (CT) regimen in the metastatic setting. Thus, both PRODIGE 4/ACCORD11 (Conroy T, et al. 2011) and MPACT (Von Hoff D, et al. 2013) phase III trials established 2 new standard-of-care in the first line treatment of metastatic PC (mPC), demonstrating a survival benefit over gemcitabine monotherapy, with the use of FFX or GA. In the phase I/II GABRINOX trial (Assenat E, et al. ESMO Open 2021), we reported that sequential GA followed by FFX provided a high overall response rate (ORR) (64.9%) and a promising median progression-free survival (PFS, 10.5 months) and median overall survival (OS, 15.1 months), together with acceptable toxicity and remarkably low severe neurotoxicity rate (gr.3: 5.3%). To follow up these encouraging results in a controlled study, we aimed at comparing our experimental GABRINOX regimen to control FFX in the GABRINOX-2 randomized phase 2 trial (NCT05065801). Our primary objective is PFS, and our secondary objectives are tolerance, ORR, disease-control rate, OS, and Quality-of-life. Methods: Main inclusion criteria were as follows: Patients (pts) in good condition (ECOG PS ≤ 1), aged from 18 to 75 yo, with histologically or cytological proven mPC and at least one measurable metastatic target. Pts should have not been treated with (adjuvant) chemotherapy in the last 6 months. Eligible pts are randomized (ratio 1:1) either in the standard FFX group or in the experimental GABRINOX group where a GA (gemcitabine 1000 mg/m² and Nab-paclitaxel 125 mg/m², day 1-8-15) cycle alternates after a 2-weeks rest with a FFX cycle. To detect an increase in median PFS from 6.4 to 10.5 months (HR = 0.61) with a 80% power and a 5% α risk, 130 events are required among a total population of 210 pts. PFS was defined as the length of time between randomization and the onset of 1st documented progression (RECIST 1.1 criteria) or death. The study of quality of life will use the EORTC QLQ-C30 and QLQ-PAN26 self-reported questionnaires at baseline and every 2 months up to 12 months and then at 16, 20 and 24 months. Circulating DNA tests will be carried out at baseline and every 2 months until progression. All numerical variables will be expressed as medians and 95% CI, while PFS and OS will be estimated using Kaplan-Meier method. Multivariate analyses will use Cox proportional hazard model. Enrolment started in late 2021 and 3 patients were included so far. Clinical trial information: NCT05065801.

An Impossible Decision–the Life Interrupted by Uncertainty

The play tries to describe making important–life & death–medical decisions under uncertainty. While the overarching goal is to arrive at the most optimal, rational solution, the process of decision-making inherently involves human interactions – here between the patient, her husband, the doctor- fraught with emotions and navigated within immediate familiar and larger social and medical settings in the attempt to provide best possible and compassionate help to a human being afflicted with a life-threatening disease. The play revolves around the optimal choice of treatment for metastatic pancreatic cancer that a young 45-year-old woman and her family face: from not being treated to standard treatment to enrollment in various experimental studies. By covering most scientific concepts using dialogues between the real-life protagonists, the play attempts to show–and educate the broader public–how scientific progress is inevitably made because individuals (“made of flesh and blood”) have consented to participate in medical research while searching for the best solution for them as individuals. It uses a real-life example to answer an elusive ethical “triple aim”- arriving at a decision that respects the right of a person to decide as an autonomous human being, has the best possible chances to personally benefit from the treatments under consideration while contributing to knowledge that can help others in the future. Act 1: uncertainty about the diagnosis. Act 1, Scene 2: uncertainty about treatment (doctor’s office, after biopsy). Act 2,1: uncertainty about treatment (discussion at home). Act2, 2: decision. The annotations (endnotes) provide further explanations of the theoretical and philosophical concepts that were converted into the real-life drama of a patient facing a life-threatening disease. It attempts to demonstrate the central role of uncertainty that shape these decisions calling on science to help address them. The main goal of the play is to illustrate the applicability of many theoretical concepts of the science of uncertainty to real-life decision-making to show that they do matter to all of us individually and collectively. The author hopes that by converting the scientific, philosophical, and technical writings into this play, the public would benefit more from this text than hundreds of other scientific articles he has written on the topic.).

Human CPTP promotes growth and metastasis via sphingolipid metabolite ceramide and PI4KA/AKT signaling in pancreatic cancer cells.

Pancreatic cancer (PC) is a devastating solid malignancy with a dismal prognosis. The treatment of metastatic PC is a current challenge for medical oncologists due to a lack of early detection, drug resistance, and relapse. Therefore, potential biomarkers and effective therapeutic targets for PC are urgently required. Ceramide-1-phosphate transfer protein (CPTP) is a member of the glycolipid transfer protein family, which is associated with autophagy and inflammation regulation. The roles and mechanisms of CPTP in PC have not been clarified. In this study, by RT-qPCR and immunohistochemistry analysis, we found that CPTP is highly expressed in PC and is associated with a poor prognosis in PC patients. By using cell counting kit-8, colony formation, transwell and matrigel assays in vitro, as well as xenograft model assays in vivo, we further proved that CPTP enhanced PC cells growth and metastasis. In PC cells, human CPTP promotes growth and metastasis via sphingolipid metabolite ceramide and PI4KA/AKT signaling. Sp (specific protein)-1 and Sp3 transcription factors also act as upstream positive regulators of CPTP expression in PC cells. Collectively, these findings suggested that CPTP may function as a pro-tumorigenic gene in PC cells and could be a promising therapeutic target in PC.

Study of Gemcitabine Plus Nab-Paclitaxel-Based Chemotherapy Regimen as First-Line Treatment in Metastatic Pancreatic Carcinoma.

Varun GoelBackground The purpose of this study was to study the effectiveness of gemcitabine and nab-paclitaxel combination as first-line chemotherapy regimen for the treatment of metastatic pancreatic cancer. There is scarcity of data regarding efficacy and toxicity profile of this combination in Indian population. Aims and Objectives The primary aim of this study was to assess efficacy of this regimen, for which evaluation done in terms of the objective response rate, progression-free survival (PFS), and overall survival. Safety data were also evaluated. Materials and Methods In this prospective study, gemcitabine plus nab-paclitaxel combination chemotherapy was given as first line in metastatic pancreatic carcinoma patients till progression or appearance of grade 3/4 toxicities with treatment. Results The study was performed in 30 patients comprising 18 (60%) males and 12 (40%) females. The median age was 60 years. Median number of cycles administered were six cycles per patient. Seventeen patients (56.67%) had a partial response and 0% had complete response. A total of seven (23.3%) patients progressed on chemotherapy and six (20%) had stable disease (SD). The disease control rate (responses and SD) was 76.7%. The median PFS was 5.75 months. There was no statistically significant difference in terms of response rates and baseline CA 19-9 levels. Most common toxicities were hematological toxicities with rates of grade 3/4 anemia and neutropenia of 20%. Among nonhematological toxicities, nausea (46.67%) and fatigue (30%) were the commonest. Conclusion Combination of gemcitabine and nab-paclitaxel is active and well tolerated in advanced pancreatic carcinoma. To the best of our knowledge, this is the first such study conducted in India.

Randomized Phase II Study of PARP Inhibitor ABT-888 (Veliparib) with Modified FOLFIRI versus FOLFIRI as Second-line Treatment of Metastatic Pancreatic Cancer: SWOG S1513.

PARP inhibitors synergize with topoisomerase inhibitors, and veliparib plus modified (m) FOLFIRI (no 5-FU bolus) had preliminary activity in metastatic pancreatic cancers. This study evaluated the safety and efficacy of second-line treatment with veliparib and mFOLFIRI versus FOLFIRI (control) for metastatic pancreatic cancer. This randomized phase II clinical trial led by the SWOG Cancer Research Network enrolled patients between September 1, 2016 and December 13, 2017. The median follow-up was 9 months (IQR 1-27). BRCA1/2 and homologous recombination DNA damage repair (HR-DDR) genetic defects were tested in blood and tumor biopsies. Patients received veliparib 200 mg twice daily, days 1-7 with mFOLFIRI days 3-5, or FOLFIRI in 14-day cycles. After 123 of planned 143 patients were accrued, an interim futility analysis indicated that the veliparib arm was unlikely to be superior to control, and the study was halted. Median overall survival (OS) was 5.4 versus 6.5 months (HR, 1.23; P = 0.28), and median progression-free survival (PFS) was 2.1 versus 2.9 months (HR, 1.39; P = 0.09) with veliparib versus control. Grade 3/4 toxicities were more common with veliparib (69% vs. 58%, P = 0.23). For cancers with HR-DDR defects versus wild-type, median PFS and OS were 7.3 versus 2.5 months (P = 0.05) and 10.1 versus 5.9 months (P = 0.17), respectively, with FOLFIRI, and 2.0 versus 2.1 months (P = 0.62) and 7.4 versus 5.1 months (P = 0.10), respectively, with veliparib plus mFOLFIRI. Veliparib plus mFOLFIRI did not improve survival for metastatic pancreatic cancer. FOLFIRI should be further studied in pancreatic cancers with HR-DDR defects.

Trends in use of one, two, and three-line NCCNcategory 1 regimens among Medicare fee-for-service (FFS) patients receiving treatment for metastatic pancreatic cancer.

297 Background: There is limited research evaluating the share of patients (pts) with metastatic pancreatic cancer (m-PANC) treated according to NCCN guidelines. Methods: We identified pts with m-PANC using ICD-10 diagnosis codes in the 2016-2019 Medicare Parts A/B/D 100% Research Identifiable Files. Study pts had 2+ claims with a pancreatic cancer diagnosis and Medicare FFS coverage for 6 months pre- and 3 months post-metastatic disease diagnosis. A line of therapy (LOT) was assigned based on the order and number of therapies used. Pts with one, two, or three LOTs were defined as treated according to NCCN Category 1 guidelines if, in each LOT, pts used one of the following regimens: FOLFIRINOX (FFX), gemcitabine/nab-paclitaxel (gem/nab), gemcitabine + erlotinib, gemcitabine monotherapy, or 5-FU + leucovorin + liposomal irinotecan. Multi-drug LOTs were excluded from the analysis. Results: We identified 31,782 pts with m-PANC. 21,304 received one LOT, 7,352 received two LOTs, and 3,126 received three LOTs between 2016 and 2019. Among pts who received one or two LOTs, a higher portion were treated according to NCCN Category 1 guidelines in 2019 (72% and 43%, respectively) than in 2016 (64% and 33%, respectively). Among pts who received three LOTs, a higher portion were treated according to NCCN Category 1 guidelines in 2019 (17%) than in 2017 (12%); too few pts were treated in 2016 to make a comparison. From 2016 to 2019, FFX had the largest increase in share of pts receiving only one NCCN Category 1 LOT (11% to 27%) and gem-mono had the largest decrease (30% to 17%). Among pts receiving two NCCN Category 1 LOTs, gem/nab to liposomal irinotecan sequences had the largest increase in share of pts (18% to 32%) and gem/nab to FFX had the largest decrease (17% to 10%). Among pts receiving three NCCN Category 1 LOTs, patient share for FFX to gem/nab to Liposomal irinotecan was 35% in 2019, while gem/nab to FFX to Liposomal was 8%; pt counts in earlier years were too small to calculate patient share. Conclusions: The use of NCCN Category 1 therapies increased consistently from 2016 to 2019 among pts that received one, two, and three lines of therapy. FFX drove increases in NCCN Category 1 utilization among patients receiving one line of therapy, and gem/nab to liposomal irinotecan sequences were the primary drivers of the increase among patients receiving two lines of therapy. FFX to gem/nab to liposomal irinotecan was the primary driver of increase among patients receiving three lines of therapy.

1478P Trends in treatment patterns among Medicare fee-for-service (FFS) patients receiving treatment for metastatic pancreatic cancer

1478P Trends in treatment patterns among Medicare fee-for-service (FFS) patients receiving treatment for metastatic pancreatic cancer

A phase II trial combining tumor-targeting TP53 gene therapy with gemcitabine/nab-paclitaxel as a second-line treatment for metastatic pancreatic cancer.

4139 Background: Nearly all stage IV pancreatic adenocarcinoma (PAC) patients progress after first-line treatment, and second-line options are limited. SGT-53 is an investigational product for tumor-targeted TP53 gene therapy that has completed phase Ia/Ib trials [Senser et al (2013), Mol Ther 21:1096; Pirollo et al (2016) Mol Ther 24:1697]. Methods: Here we provide an interim analysis of a Phase II trial (SGT53-02-1; NCT02340117) combining SGT-53 with gemcitabine/nab-paclitaxel (GEM/ABX). Eligible were first-line patients or those who had progressed after FOLFIRINOX (FFX) and/or gemcitabine-based therapy (second-line). In a 7-week treatment cycle, SGT-53 (3.6 mg DNA) was given once or twice weekly with GEM/ABX (1000 mg/m2/wk and 125 mg/m2/wk, respectively, for 3 of 4 weeks). Progression-free survival (PFS) and objective response rate (ORR) are primary endpoints.Overall survival (OS) and PFS are estimated by Kaplan-Meier analysis. Results: Of all evaluable patients (n=20), best response in 7 patients was determined to be partial response (PR) and 13 had stable disease (SD); none had progressive disease. In the second-line patients (n=11) there were 5 PR and 6 SD after 9 had failed FFX treatment, 3 had failed gemcitabine-based treatment and 1 had failed both. For patients with elevated CA19-9, SGT-53 + GEM/ABX resulted in marked reductions in the tumor marker. Published data for patients with PAC after therapy failure [Mita et al (2019) J Clin Med 8: 761; Portal et al (2015) Br J Cancer 113:989; Wang-Gillam et al (2016) Lancet 387:545] are shown for comparison. Notably, mPFS in our second-line patients was 7.4 months versus 3.1 months for the approved second-line therapy [Wang-Gillam et al (2016)]. This improvement in PFS exceeds the benchmark proposed to predict a clinically meaningful Phase III trial [Rahib et al (2016) Lancet Oncol 2:1209]. Conclusions: Our data suggest a clinically meaningful benefit of adding SGT-53 to GEM/ABX particularly for second-line PAC patients, most of whom had failed prior FFX treatment. Clinical trial information: NCT02340117. [Table: see text]

Mild hyperthermia promotes immune checkpoint blockade-based immunotherapy against metastatic pancreatic cancer using size-adjustable nanoparticles

Immune checkpoint blockade treatment is one of the most promising immunotherapies, which exhibits promising therapeutic effects on inhibition of metastasis. However, immunotherapy has little effect on pancreatic cancer, due to its extensive fibrotic matrix and immunosuppressive tumor microenvironment. Mild hyperthermia induced by photothermal therapy (PTT) has been proven to activate the immune responses in the tumor microenvironment. Herein, we designed a combine strategy of mild hyperthermia and immune checkpoint blockade (BMS-202) treatment with size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL), in which BMS-202 loaded small-sized albumin nanoparticle (HSA-BMS) was encapsulated. Mild hyperthermia reduced the tumor hypoxia, relieved the interstitial pressure and increased the recruitment of endogenous immune cells in tumors. In the meantime, small-sized HSA-BMS was released from large-sized HSA-BMS@CAP-ILTSL in response to fibroblast activation protein-α (FAP-α) and near-infrared (NIR) laser, and enhanced the immunological responses by recovering the activity of T lymphocytes, accompanied by secreting relevant cytokines (TNF-α and IFN-γ). The combined therapy (HSA-BMS@CAP-ILTSL) could not only significantly suppress the tumor growth in vivo, but also decrease the amounts of metastatic nodules in distant organs. These results suggested that size-adjustable nanoparticles had a great potential in the treatment of metastatic pancreatic cancer. Statement of significanceThe desmoplastic stroma and hypoperfusion of pancreatic cancer imposed physical barriers to effective therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We constructed size-adjustable thermo- and fibrotic matrix- sensitive liposomes (HSA-BMS@CAP-ILTSL) with size around 120 nm, where small sized albumin nanoparticle (10 nm) of immune checkpoint inhibitor (HSA-BMS) were encapsulated inside. Mild hyperthermia not only contributed to release HSA-BMS for penetration (blocking the immunosuppressive signals deep in the tumor), but enhanced tumor blood perfusion for infiltration of endogenous immune cells. In the two-pronged treatment, the pancreatic cancer immunotherapy significantly enhanced and the risk of cancer metastasis was reduced. Overall, the strategy provides a promising approach to increase drug accumulation and improve the anti-tumor immune activity in pancreatic cancer.

Comparison between FOLFIRINOX and gemcitabine plus nab-paclitaxel including sequential treatment for metastatic pancreatic cancer: a propensity score matching approach

BackgroundFOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GnP) have been recommended as the first-line chemotherapy for metastatic pancreatic cancer (mPC). However, the evidence is lacking comparing not only two regimens, but also sequential treatment (FFX–GnP vs. GnP–FFX).MethodsData of 528 patients (FFX, n = 371; GnP, n = 157) with mPC were collected retrospectively. Propensity score matching was conducted to alleviate imbalance of the two groups. Overall survival (OS), progression free survival (PFS), and toxicity of patients were analyzed.ResultsIn the whole population, OS (12.5 months vs. 10.3 months, P = 0.05) and PFS (7.1 months vs. 5.8 months, P = 0.02) were longer in the FFX group before matching and after matching (OS: 11.8 months vs. 10.3 months, P = 0.02; PFS: 7.2 months vs. 5.8 months, P < 0.01). For sequential treatment, OS and PFS showed no significant difference. Interruptions of chemotherapy due to toxicities were more frequent (6.8 vs. 29.3%, P < 0.001) in the GnP group, and cessation of chemotherapy showed a significant association with mortality (z = − 1.94, P = 0.03).ConclusionsFFX achieved a longer overall survival than GnP in mPC, but not in the comparison for sequential treatment. More frequent adverse events followed by treatment interruptions during GnP might lead to a poor survival outcome. Therefore, FFX would be a better first-line treatment option than GnP for mPC.

Cost-Effectiveness Analysis of Olaparib Maintenance Treatment for Germline BRCA-Mutated Metastatic Pancreatic Cancer.

Background: The PARP inhibitor olaparib has been shown to have clinical efficacy in patients with a germline BRCA mutation and ovarian or breast cancer. However, the high treatment cost associated with this drug limits its viability as a clinical treatment option. This work aims to evaluate the cost-effectiveness of olaparib as a maintenance treatment for metastatic pancreatic cancer from the perspective of the United States and China healthcare systems and provides valuable suggestions for clinical decision making. Method: A three-state Markov model (progression-free, progressed disease, death) was constructed using TreeAge Pro 2020 software to evaluate the economic value of olaparib vs. placebo maintenance treatment for metastatic pancreatic cancer based on the clinical data derived from phase III randomized controlled trial (POLO, ClinicalTrials.gov number, NCT02184195). Total costs, quality-adjusted life years and incremental cost-effectiveness ratio were used as economic indicators for this analysis. A 5-years horizon and 5%/year discount rates were used. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were performed to assess the model uncertainty. Results: The incremental cost-effectiveness ratios (ICERs) of the use of olaparib vs. placebo in China and the United States were $6,694/QALY and $13327/QALY, respectively. All ICERs were far below the thresholds of $30829 in China and $50000 in the United States. Sensitivity analysis confirmed a stable economic advantage in the use of olaparib vs. placebo as maintenance therapy in China and the United States. Conclusion: Olaparib was estimated to be more cost effective than placebo for the maintenance therapy of patients with a germline BRCA mutation and pancreatic cancer in China and the United States at thresholds of $30829 and $50000 per QALY, respectively.

Locoregional Treatment of Metastatic Pancreatic Cancer Utilizing Resection, Ablation and Embolization: A Systematic Review.

Simple SummaryMetastatic pancreatic ductal adenocarcinoma (mPDAC) has a dismal prognosis. In selected patients with limited metastatic disease, locoregional therapy, in addition to systemic chemotherapy, may improve survival. This systematic review sought to examine current evidence on the value of additional locoregional treatment, including resection, ablation and embolization, in patients with hepatic or pulmonary mPDAC. The results, although liable to substantial bias, demonstrated superior survival from metastatic diagnosis or treatment in a subset of patients after radical-intent local primary and metastatic treatment (hepatic mPDAC 7.8–19 months; pulmonary mPDAC 22.8–47 months) compared to chemotherapy or best supportive care (hepatic mPDAC 4.3–7.6 months; pulmonary mPDAC 11.8 months). However, as a consequence of the bias, definitive conclusions regarding the seemingly beneficial effect of locoregional treatment cannot be endorsed. Randomized controlled trials with strictly selected oligometastatic PDAC patients are required to deduce final recommendations on this notion.The prognosis of metastatic pancreatic ductal adenocarcinoma (mPDAC) remains universally poor, requiring new and innovative treatment approaches. In a subset of oligometastatic PDAC patients, locoregional therapy, in addition to systemic chemotherapy, may improve survival. The aim of this systematic review was to explore and evaluate the current evidence on locoregional treatments for mPDAC. A systematic literature search was conducted on locoregional techniques, including resection, ablation and embolization, for mPDAC with a focus on hepatic and pulmonary metastases. A total of 59 studies were identified, including 63,453 patients. Although subject to significant bias, radical-intent local therapy for both the primary and metastatic sites was associated with a superior median overall survival from metastatic diagnosis or treatment (hepatic mPDAC 7.8–19 months; pulmonary mPDAC 22.8–47 months) compared to control groups receiving chemotherapy or best supportive care (hepatic mPDAC 4.3–7.6 months; pulmonary mPDAC 11.8 months). To recruit patients that may benefit from these local treatments, selection appears essential. Most significant is the upfront possibility of local radical pancreatic and metastatic treatment. In addition, a patient’s response to neoadjuvant systemic chemotherapy, performance status, metastatic disease load and, to a lesser degree, histological differentiation grade and tumor marker CA19-9 serum levels, are powerful prognostic factors that help identify eligible subjects. Although the exact additive value of locoregional treatments for mPDAC patients cannot be distillated from the results, locoregional primary pancreatic and metastatic treatment seems beneficial for a highly selected group of oligometastatic PDAC patients. For definite recommendations, well-designed prospective randomized controlled trials with strict in- and exclusion criteria are needed to validate these results.