Treatment Of Metastatic Pancreatic Cancer Research Articles

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.

Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the ‘burden of therapy’ method

BackgroundTargeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non–small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. Patients and methodsPatients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the ‘Burden of Therapy/Toxicity’ (BOTh) for each patient on every day during the clinical study. ResultsOne hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). ConclusionThe addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period.The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77).

Genomic biomarker discovery of first-line gemcitabine/nabpaclitaxel treatment in Chinese advanced pancreatic carcinoma patients.

436 Background: Pancreatic carcinoma is one of the most lethal malignancies worldwide and is characterized by extremely poor prognosis. Gemcitabine plus Nab-paclitaxel (GNp) has been recommended by international guidelines for first-line treatment of locally advanced or metastatic pancreatic carcinoma. However, exploration into molecular biomarkers of GNp treatment is still limited. This study aims to observe and evaluate the efficacy and safety of first-line GNp treatment of pancreatic carcinoma, and to explore potential predictive and prognostic biomarkers to screen advantageous population. Methods: From December 20, 2018 to July 6, 2020, patients with metastatic pancreatic carcinoma, who received first-line GNp treatment, were enrolled. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events (AE). Patients were collected formalin fixed paraffin embedded (FFPE) samples and sequenced by a next-generation sequencing (NGS)-based 450 gene panel carried out by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: In this study, tissue samples from 101 patients were assessed by NGS, including 58 (57.4%) primary tissues and 43 (42.6%) metastasis tissues. So far, 72 patients were available for efficacy analysis, the ORR and DCR were 38.2% and 77.9%, respectively, and were similar between patients sampled from primary lesions and metastasis lesions. The PFS and OS were 176 days and 308 days, respectively. The most frequently mutated genes were KRAS (91.9%), TP53 (76.8%), CDKN2A (32.3%) and SMAD4 (26.3%). Germline pathogenic BRCA2 mutations were detected in 3 (3.0%) patients, while somatic mutations of BRCA2 were found in 2 (2.0%) patients. For KRAS, missense mutations resulted in single amino acid substitutions primarily at G12 (88.1%), and lower frequencies at Q61 (4.0%) and V14 (1.0%). At G12, five different amino acid substitutions have been identified, with G12D (37.6%) the predominant mutation, G12V (32.7%), G12R (11.9%), G12C (3.0%) and G12A (1.0%). The ORR to AG treatment was significantly higher in TP53-alteration (-alt, 47.1%) than in TP53-wild-type (-WT, 11.1%) subgroups (p=0.01). Median OS times in CDKN2B-alt and CDKN2B-WT patients were 180 days and 323 days (p=0.029), respectively. Conclusions: Current evidence indicates that GNp is a valuable option for the first-line treatment of metastatic pancreatic cancer. TP53 may serve as a novel response-predictive gene for GNp treatment in pancreatic carcinoma. Overall survival was significantly prolonged in CDKN2B-WT patients compared with CDKN2B-alt patients. This study provided insights in identifying patients who might potentially benefit from GNp therapy. Clinical trial information: NCT03768687.

FOLFIRINOX in advanced pancreatic cancer patients with the double-variant type of UGT1A1 *28 and *6 polymorphism: a multicenter, retrospective study

BackgroundUGT1A1 *28 and *6 polymorphism is associated with reduced enzyme activity and severe toxicities of irinotecan, especially in patients with homozygous or heterozygous for UGT1A1*28 or *6 polymorphism for both UGT1A1*28 and *6 (double-variant-type of UGT1A1 polymorphism, UGT1A1-DV). FOLFIRINOX is one of the standard treatments for metastatic pancreatic cancer (PC). The optimal dose of irinotecan as a component of the FOLFIRINOX has not been established yet for patients with UGT1A1-DV.Patients and methodsAdvanced PC patients with UGT1A1-DV who had received at least one cycle of FOLFIRINOX from December 2013 to March 2016 were collected retrospectively conducted at multicenter in Japan. We evaluated the patient characteristics, efficacy and safety of FOLFIRINOX and investigate the optimal initial dose of irinotecan in Japanese advanced PC patients with UGT1A1-DV.ResultsA total of 31 patients were enrolled. Grade 4 neutropenia was seen more frequently (67%; 4/6) in patients who had received irinotecan at an initial dose of ≥ 150 mg/m2 than in those who had received the drug at an initial dose of ≤ 120 mg/m2 (20%; 5/24). The response rate (RR) and progression-free survival (PFS) in patients given irinotecan of ≤ 120 mg/m2 were 21.4% and 8.1 months, respectively, which were consistent with previous report for patients without UGT1A1-DV.ConclusionBased on our findings, we recommend that in Japanese advanced PC patients with UGT1A1- DV treated with FOLFIRINOX, irinotecan be administered at an initial dose of ≤ 120 mg/m2.

Efficacy of liver metastasectomy in pancreatic cancer

Background: Standard treatment for metastatic pancreatic cancer is systemnic chemotherapy. Significance of liver metastasectomy in pancreatic cancer remains unknown. This study aims to investigate efficacy of liver metastasectomy in pancreatic cancer. Methods: Between 2001 and 2019, 14 cases who underwent liver metastasectomy for pancreatic cancer at Tohoku University Hospital, including 7 synchronous metastasis cases and 7 metachronous metastasis cases, were retrospectively investigated. Results: Synchronous metastasis: Simultaneous resection of primary pancreatic tumor and liver metastases was performed in 5 cases, including 4 cases with neoadjuvant therapy and one cases with upfront surgery. Two-stage resection, which means prior metastasectomy and subsequent resection of primary tumor after chemotherapy, was performed in 2 cases. The number of metastatic tumors was within 3 in 6 cases. Median survival time (MST) after surgery, which was calculated from the primary tumor resection date in two-stage resection, was 12.5 months. One case with two-stage resection has been alive without recurrence for 81 months after surgery. Metachronous metastasis: The median time between primary tumor resection and liver metastases was 10.7 months. All cases were treated with systemic chemotherapy before liver metastasectomy. Duration of chemotherapy before metastasectomy was 3 months in 1 case, 6-12 months in 4 cases, and 12-24 months in 2 cases. The number of metastatic tumors was within 2 in all cases. MST after metastasectomy was 19.8 months. Conclusion: There are cases who has benefit of metastasectomy in liver metastasis of pancreatic cancer.

Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer

The safety of oncolytic adenovirus-mediated suicide and interleukin-12 (IL12) gene therapy was evaluated in metastatic pancreatic cancer patients. In this phase I study, a replication-competent adenovirus (Ad5-yCD/mutTKSR39rep-hIL-12) expressing yCD/mutTKSR39 (yeast cytidine deaminase/mutant S39R HSV-1 thymidine kinase) and human IL-12 (IL12) was injected into tumors of 12 subjects with metastatic pancreatic cancer (T2N0M1-T4N1M1) at escalating doses (1 × 1011, 3 × 1011, or 1 × 1012 viral particles). Subjects received 5-fluorocytosine (5-FC) therapy for 7 days followed by chemotherapy (FOLFIRINOX or gemcitabine/albumin-bound paclitaxel) starting 21 days after adenovirus injection. The study endpoint was toxicity through day 21. Experimental endpoints included measurements of serum IL12, interferon gamma (IFNG), and CXCL10 to assess immune system activation. Peripheral blood mononuclear cells and proliferation markers were analyzed by flow cytometry. Twelve patients received Ad5-yCD/mutTKSR39rep-hIL-12 and oral 5-FC. Approximately 94% of the 121 adverse events observed were grade 1/2 requiring no medical intervention. Ad5-yCD/mutTKSR39rep-hIL-12 DNA was detected in the blood of two patients. Elevated serum IL12, IFNG, and CXCL10 levels were detected in 42%, 75%, and 92% of subjects, respectively. Analysis of immune cell populations indicated activation after Ad5-yCD/mutTKSR39rep-hIL-12 administration. The median survival of patients in the third cohort is 18.1 (range, 3.5–20.0) months. The study maximum tolerated dose (MTD) was not reached.

PET-CT monitoring in the treatment of pancreatic cancer

Pancreatic cancer is a disease characterized by low visualization, high metastasis, and lethality. The average life expectancy for this nosology is less than 1 year. Early diagnosis of pancreatic cancer is difficult due to the lack of specific symptoms. As a rule, at the time of tumor visualization, every third patient has regional lymph nodes involved in the process, and every second patient already has distant metastases. We present a clinical case of a 73-year-old patient with a diagnosis of: cancer of the pancreatic head St IV, T4N1M1. The woman's primary positron emission tomography (PET-CT) revealed a metabolically active lesion with a size of 26 х 21 х 32 mm. After the combined multistage therapy under the control of PET-CT, it was possible to achieve complete leveling of the primary tumor focus and a relapse-free course of the disease for 11 months. Our clinical observation showed the effectiveness of dynamic control (using PET-CT) treatment of metastatic pancreatic cancer, which influenced the patient's treatment strategy. Conclusion. Patients with pancreatic adenocarcinoma ECOG ≥ 3, despite the prevalence of the process, should be offered comprehensive treatment.

A Phase II Study of Allogeneic GM-CSF–Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer

This phase II study tested granulocyte-macrophage colony-stimulating factor (GM-CSF)-allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in the maintenance setting. Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8-12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for four doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms. Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median OS was 9.38 months [95% confidence interval (CI), 5.0-12.2] for Arm A and 14.7 months (95% CI, 11.6-20.0) for Arm B (HR, 1.75; P = 0.019). Using immune-related response criteria, two partial responses (5.7%) were observed in Arm A and four (13.8%) in Arm B. GVAX + ipilimumab promoted T-cell differentiation into effector memory phenotypes both in the periphery and in the tumor microenvironment and increased M1 macrophages in the tumor. GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.

Cost-effectiveness analysis of nab-paclitaxel plus gemcitabine versus folfirinox in the treatment of metastatic pancreatic cancer in china

ABSTRACT Objectives Nab-paclitaxel (Abraxane®) plus gemcitabine (AG) and Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) have shown significant clinical benefit and been widely used as 1st-line treatment of metastatic pancreatic cancer (mPC) in China. This study aims to compare the cost-effectiveness of AG versus FOLFIRINOX regimen for the treatment of mPC patients in China. Methods Markov model was developed with a lifetime survival projection in Microsoft Excel® to simulate the progression of the mPC over time. The quality-adjusted life years (QALYs), resource consumption in the health care sector and incremental cost-effectiveness ratios (ICERs) were reported. Uncertainty was assessed by one-way and probabilistic sensitivity analyses. Results AG regimen provided an effectiveness of 1.35 QALY at an average cost of USD 22,300 whereas FOLFIRINOX regimen brought 0.82 QALY at a cost of USD 22,980 in lifetime horizon. Therefore, AG regimen was dominant with an ICER of USD −1300 compared with FOLFIRINOX regimen. AG arm generated less drug cost, medical cost, hospitalization cost, and end-of-life cost than FOLFIRINOX arm did. Sensitivity analyses confirmed the robustness of base case findings. Conclusions AG is likely a cost-effective option for the 1st-line mPC treatment compared with FOLFIRINOX in China from the perspective of healthcare system.

First-line gemcitabine plus nab-paclitaxel for elderly patients with metastatic pancreatic cancer: Crossing the frontier of age?

BackgroundGemcitabine plus nab-paclitaxel (Gem-Nab) represents a standard first-line treatment for metastatic pancreatic cancer (mPC), but few data are available for elderly patients. We aimed to add evidence about safety and efficacy of Gem-Nab in this population. MethodsWe collected data of 156 patients with mPC aged ≥65 years receiving Gem-Nab. Patients were stratified according to age: <70 (group 1: 65 patients) and ≥70 years (group 2: 91 patients). ResultsThe median age was 71 years (range: 65–87 years). The toxicity profile was similar between group 1 and 2, except for all-grade anaemia (92.1% vs. 78.7%, respectively; p = 0.04) and neurotoxicity (61.9% vs. 40.4%, respectively; p = 0.02), also as a result of a lower dose intensity of nab-paclitaxel (83.3% vs. 90.5%, respectively; p = 0.04) administered to oldest patients. The response rate was 25.6% (group 1 vs. 2: 20.0% vs. 29.7%; p = 0.12). After a median follow-up of 26.5 months, median overall survival (OS) and progression-free survival (PFS) were similar between the groups (p > 0.05). The starting dose of Gem-Nab did not affect PFS and OS (p > 0.05). ConclusionGem-Nab is active and effective in older patients with mPC, with the results in line with the general mPC population enrolled in clinical trials. Mild dose modifications for elderly patients might be considered to improve safety without impairing efficacy.

P-188 Safety and efficacy of first-line gemcitabine plus nab-paclitaxel for elderly metastatic pancreatic cancer patients

Pancreatic cancer (PC) is a disease of the elderly since the average age at diagnosis is 71 years. Gemcitabine plus nab-paclitaxel (Gem-Nab) is a standard first-line treatment for metastatic pancreatic cancer (mPC), but few data about the safety and efficacy of this regimen are available for the elderly population, which is often underrepresented in randomized clinical trials.

PD-1 antibody combined with paclitaxel (albumin bound) and gemcitabine as first-line therapy in patients with metastatic pancreatic cancer.

TPS4665 Background: Pancreatic cancer is a malignant tumor with limited therapeutic strategies and poor prognosis. About 60% of the patients have metastasis disease at time of diagnosis and lose the opportunity for surgery. Thus, therapy based on drugs becomes a vital part in pancreatic cancer. In 2013, MPACT showed that albumin-bound paclitaxel combined with gemcitabine in the treatment of metastatic pancreatic cancer could increase the mOS from 6.6 months to 8.7 months (HR = 0.72, 95% CI: 0.62-0.83; P &lt; 0.001). Nowadays, the immunosuppressive checkpoint inhibitors acting on PD-1/PD-L1 pathway have shown a significant efficacy in enhancing tumor immune surveillance and anti-tumor immune response. In 2018, two studies reported in ASCO showed the preliminary efficacy of albumin paclitaxel, gemcitabine and PD-1 inhibitor in the treatment of advanced pancreatic cancer. Among patients who have not received treatment before, the disease control rate was even up to 100%. Therefore, this study will further explore the domestic PD-1 antibody combined with albumin-bound paclitaxel and gemcitabine as the first-line treatment of advanced pancreatic cancer among Chinese pancreatic cancer patients. Methods: This is a prospective, single-armed, exploratory, investigator initiated trial to explore the efficacy and safety of PD-1 antibody combined with albumin-bound paclitaxel and gemcitabine as first-line treatment of metastatic pancreatic cancer. This study is, to our knowledge, the first one to test the efficacy and safety of PD-1 antibody on metastatic pancreatic cancer patients among Chinese population. Survival index is median survival estimated by Kaplan-Meier and draw the survival curve. The response rate was compared by χ 2 test / Fisher test. All primary and secondary outcomes will be analyzed on the full analysis set. PD-1 antibody, 200mg, D1 administration; paclitaxel (albumin binding type), 125mg/m2, D1, 8 days administration; gemcitabine, 1000mg/m2, D1, 8 days administration, every 21 days as a cycle and PD-1 antibody (200mg, D1, every 21 days) single drug maintenance treatment is given after the completion of 6 cycle chemotherapy. Major eligibility criteria is that each participant must have metastatic pancreatic cancer confirmed by histology or cytology and has never received systemic anti-tumor therapy before. So far, 11 of planned 20 patients have been enrolled. Clinical trial information: NCT04181645 .

Choice of first line systemic treatment in pancreatic cancer among national experts

BackgroundTreatment options for patients with metastatic pancreatic cancer depend on various factors, including performance status, tumor burden and patient preferences. Metastatic pancreatic cancer is incurable and many systemic treatment options have been investigated over the past decades. This analysis of patterns of practice was performed to identify decision criteria and their impact on the choice of first-line management of metastatic pancreatic cancer. Materials and methodsMembers of the Swiss Group for Clinical Cancer Research (SAKK) Gastrointestinal Cancer Group were contacted and agreed to participate in this analysis. Decision trees for the first line treatment of metastatic pancreatic cancer from 9 centers in Switzerland were collected and analyzed based on the objective consensus methodology to identify consensus and discrepancies in clinical decision-making. ResultsThe final treatment algorithms included 3 decision criteria (comorbidities, performance status and age) and 5 treatment options: FOLFIRINOX, FOLFOX, gemcitabine + nab-paclitaxel, gemcitabine mono and best supportive care. ConclusionWe identified multiple decision criteria relevant to all participating centers. We found consensus for the treatment of young (age below 65) patients with good performance status with FOLFIRINOX. For patients with increasing age and reducing performance status there was a decreasing trend to use gemcitabine + nab-paclitaxel. Gemcitabine monotherapy was typically offered to patients in the presence of comorbidities. For patients with ECOG 3–4, most of the experts recommended BSC.

Efficacy and toxicity comparison of nab-paclitaxel plus S-1 and nab-paclitaxel plus gemcitabine as first-line chemotherapy for metastatic pancreatic cancer

Abstract To compare efficacy and safety of nab-paclitaxel plus gemcitabine (AG) with nab-paclitaxel plus S-1 (AS) as first-line treatment for metastatic pancreatic cancer, we conducted a retrospective analysis by reviewing medical records of 53 metastatic pancreatic cancer patients in our institution. They received either AG (nab-paclitaxel 125 mg/m2 on days 1, 8 and gemcitabine 1000 mg/m2 on days 1, 8) or AS (nab-paclitaxel 125 mg/m2 on days 1, 8 and S-1 80–120 mg on days 1–14) chemotherapy. We found that AS had higher objective response rate (36% vs 21.4%), better disease control rate (84% vs 75%), prolonged time to progression (TTP, 7.1 vs 5 months), and improved overall survival (OS, 15.3 vs 12 months) when compared with AG. In Cox proportional hazards model, sex was significantly associated with TTP (P value = .031) and metastatic sites plus treatment after progression were significantly associated with OS (P value = .028 and .01, respectively). The incidence rate of chemotherapy-related adverse events was similar in both groups. Neutropenia (50% and 60%, all grade; 21.4% and 36%, grade 3 or 4, in AG and AS group) and sensory neuropathy (21.4% and 24%, all grade; 3.6% and 4%, grade 3 or 4, in AG and AS group) were the most common hematologic and non-hematologic toxicity. Thus, we believed that AS is a reasonable and convenient alternative for patients treated with AG as first-line chemotherapy for metastatic pancreatic cancer.

Impact of New Chemotherapy Regimens on the Treatment Landscape and Survival of Locally Advanced and Metastatic Pancreatic Cancer Patients.

Background: New chemotherapy regimens for the treatment of metastatic pancreatic cancer have changed the therapy paradigm. We aimed to assess their impact on the treatment landscape and clinical outcome at our academic institution. Methods: In this single institutional posthoc registry analysis, we assessed characteristics and survival rates from all patients with locally advanced and metastatic pancreatic cancer who started a systemic treatment between 01/2011 and 12/2017. Survival analyses were performed by Kaplan-Meier and Cox proportional hazards model. Results: A total of 301 patients started a systemic treatment in the observation period. In the first line treatment, we observed a shift from the four different main regimens (gemcitabine/nab-paclitaxel, modified FOLFIRINOX, gemcitabine/oxaliplatin +/− erlotinib or gemcitabine alone) to gemcitabine/nab-paclitaxel and modified FOLFIRINOX that add up to more than 80% of administered first line treatments in each of the time cohorts (2011–2013 vs. 2014–2017). The rate for first line modified FOLFIRINOX treatment was balanced between the two groups (19% and 15%). Median overall survival differed significantly between the two time cohorts (8.89 versus 11.9 months, p = 0.035). Survival rates for different first to second line treatment sequences (modified FOLFIRINOX to gemcitabine/nab-paclitaxel, gemcitabine/nab-paclitaxel to fluoropyrimidines plus nanoliposomal irinotecan, or gemcitabine/nab-paclitaxel to fluoropyrimidines plus oxaliplatin) were not significantly different and median overall survival ranged from 14.27 to 15.64 months. Conclusion: Our study provides real-world evidence for the effectiveness of the new chemotherapy regimens and underscores the importance of the choice of the front-line regimen when considering different sequencing strategies.

FOLFIRINOX vs gemcitabine/nab-paclitaxel for treatment of metastatic pancreatic cancer: Single-center cohort study.

BACKGROUNDFOLFIRINOX and gemcitabine plus nab-paclitaxel (Gem + nabPTX) were recently introduced for metastatic pancreatic cancer treatment. However, studies that compared these two regimens and studies in Asian populations are lacking.AIMTo compare the treatment outcomes of FOLFIRINOX and Gem + nabPTX regimen for metastatic pancreatic cancer treatment in Korean population.METHODSPatients with metastatic or recurrent pancreatic cancer treated with FOLFIRINOX (n = 86) or Gem + nabPTX (n = 81) as the first-line since January 2015 were identified using the Severance Hospital Pancreatic Cancer Cohort Registry. Treatment efficacy, treatment-related adverse events and economic aspects were compared.RESULTSPatients in the FOLFIRINOX group were significantly younger (54 vs 65 years; P < 0.001) and had better performance statuses at diagnosis. The median overall survival (10.7 vs 12.1 mo; P = 0.157), progression-free survival (8.0 vs 8.4 mo; P = 0.134), and objective response rates (33.7% vs 46.9%; P = 0.067) were not significantly different when compared with Gem + nabPTX group. Grade ≥ 3 neutropenia and gastrointestinal adverse events were more common in the FOLFIRINOX group. The drug costs of both regimens were similar.CONCLUSIONTreatment efficacy and economic burdens were comparable between the two regimens. But, the details of adverse event were different. Gem + nabPTX regimen might be considered preferentially in certain conditions.

Timing and location of palliative care consultation in metastatic pancreatic cancer: A retrospective, single-center observational study.

770 Background: Patients (pts) receiving treatment for metastatic pancreatic cancer (MPC) experience significant symptoms, treatment related side effects and psychosocial burdens. The ASCO guidelines recommend early palliative care consultation (PCC) to improve quality of life and survival. However, limited real-world data is available regarding the timing of PCC, hospice enrollment and location of death (LOD) in pts with MPC. Methods: We conducted a retrospective observational analysis of pts treated with chemotherapy for MPC at the Yale Smilow Cancer Hospital and affiliated community care centers (CCC) from January 2011 to April 2019. Patient demographics, treatment dates, initial PCC, enrollment of hospice at the time of death and LOD were manually abstracted from the electronic medical record. Univariate and multivariable logistic regression analyses were conducted to predict for PCC and death outside the hospital. Results: Of 363 pts identified with MPC who received chemotherapy, 38% (138) had a PCC. 67% (93) of patients’ initial PCC was in the hospital versus 33% (45) in the outpatient setting. The median time from the start of first-line chemotherapy to the first PCC was 5.2 months (interquartile range [IQR] 1.2 – 12.9). The median time from the first PCC to death was 1.5 months (IQR 0.5 – 4.42). At the time of our analysis, 300 pts had died and of those 76% (229) were enrolled on hospice at the time of death while 24% (71) were not. With respect to LOD, 47% (139) of pts died at home with hospice, 31% (94) at an inpatient hospice facility and 22% (67) died in the hospital. Female gender was associated with an increased likelihood of a PCC (HR 1.78, 95% CI 1.07-2.94, P = 0.026). Pts treated at a CCC were less likely to have a PCC (HR 0.21, 95% CI 0.12-0.36, P &lt; 0.001). A PCC was not associated with a higher likelihood of death outside the hospital (HR 1.31, 95% CI 0.75-2.29, P = 0.346). Conclusions: Although most pts with MPC enroll in hospice, PCC is generally underutilized. In fact, many pts receive PCC near the end of life and in the hospital. Further studies are warranted to determine how best to incorporate early PCC to maximize supportive care for pts with MPC.

Stromal Modulation and Treatment of Metastatic Pancreatic Cancer with Local Intraperitoneal Triple miRNA/siRNA Nanotherapy.

Nanomedicines achieve tumor-targeted delivery mainly through enhanced permeability and retention (EPR) effect following intravenous (IV) administration. Unfortunately, the EPR effect is severely compromised in pancreatic cancer due to hypovascularity and dense desmoplastic stroma. Intraperitoneal (IP) administration may be an effective EPR-independent local delivery approach to target peritoneal tumors. Besides improved delivery, effective combination delivery strategies are needed to improve pancreatic cancer therapy by targeting both cancer cells and cellular interactions within the tumor stroma. Here, we described simple cholesterol-modified polymeric CXCR4 antagonist (PCX) nanoparticles (to block cancer-stroma interactions) for codelivery of anti-miR-210 (to inactivate stroma-producing pancreatic stellate cells (PSCs)) and siKRASG12D (to kill pancreatic cancer cells). IP administration delivered the nanoparticles to an orthotopic syngeneic pancreatic tumors as a result of preferential localization to the tumors and metastases with disrupted mesothelium and effective tumor penetration. The local IP delivery resulted in nearly 15-fold higher tumor accumulation than delivery by IV injection. Through antagonism of CXCR4 and downregulation of miR-210/KRASG12D, the triple-action nanoparticles favorably modulated desmoplastic tumor microenvironment via inactivating PSCs and promoting the infiltration of cytotoxic T cells. The combined therapy displayed improved therapeutic effect when compared with individual therapies as documented by the delayed tumor growth, depletion of stroma, reduction of immunosuppression, inhibition of metastasis, and prolonged survival. Overall, we present data that a local IP delivery of a miRNA/siRNA combination holds the potential to improve pancreatic cancer therapy.