Treatment Of Metastatic Pancreatic Cancer Research Articles

Efficacy and treatment-related adverse events of gemcitabine plus nab-paclitaxel for treatment of metastatic pancreatic cancer “in a Korean” population: A single-center cohort study

Pancreatic cancer has poor prognosis because of its rapid progression and treatment resistance. Based on the results of the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), a combination regimen of gemcitabine with nab-paclitaxel is currently used as standard therapy for the treatment of metastatic pancreatic cancer. However, because studies in Asian populations are lacking, we investigated the treatment efficacy and safety of this combination therapy in Korean population. Patients with metastatic pancreatic cancer (n=81) treated with gemcitabine and nab-paclitaxel (1,000 and 125 mg/m2, respectively) as the first-line chemotherapy from January 2016 were identified using the Severance Hospital Pancreatic Cancer Cohort Registry. Treatment efficacy and treatment-related adverse events (AEs) were analyzed. The median follow-up period was 10.7 months (range, 1.5–23.3 months). Median overall survival, progression-free survival, and objective response rates were 12.1 months (95% confidence interval [CI], 10.7–not estimable), 8.4 months (95% CI, 5.0–11.8), and 46.9%, respectively. The incidence of grade ≥3 neurotoxicity and neutropenia were 18.5% and 46.9%, respectively. Febrile neutropenia and grade ≥3 gastrointestinal AEs occurred in 13 (16.0%) and 16 (19.8%) patients, respectively. Dose reductions because of AEs were required in 60.5% of patients. The combination of gemcitabine with nab-paclitaxel is an effective anti-cancer regimen in Korean population of patients with metastatic pancreatic adenocarcinoma. However, careful monitoring and management are required because of occurrence of treatment-related AEs.

Nab-paclitaxel plus gemcitabine in the treatment of metastatic pancreatic cancer: our experience

Background: Pancreatic cancer (PA) is the fourth most fatal cancer for both man and women. Many of patients(pts) with metastatic disease are often not included in clinical trials due to comorbidity such as diabetes, jaundice, etc.and poor performance status at diagnosis. These patients are the most treat in our clinical practice and they have few opportunities for cure. Von Hoff D. et all. (2013) published the data of the phase III MPACT study showing a statistically significant benefit of the nab-paclitaxel plus gemcitabine vs gemcitabine alone in terms of OS (8,5 vs 6,7 months) and PFS(5,5 vs 3,7months) as first line treatment for metastatic disease with acceptable toxicity. Materials and methods: From September 2015 to May 2017 we collected the data of 26 unselected metastatic pancreatic cancer pts treated with nab-paclitaxel 125mg/mq and gemcitabine 1g/mq on days 1,8,15 q 28 days cycle, as first line treatment. Median age was 64 year (range 46-78); 9pts (34%) were over 70 years old. 9pts(34%) were male and 17(65%) female. PS 0: 10pts(38%), PS1:10pts(38%), PS2:6pts(23%). NLR was > 5 in 6pts(23%). They received a median of 15 drug administrations (range 1-32). Results: The treatment was well tolerated. No toxic death or grade 4toxicity were recordedHematologic G3 toxicity included: Neutropenia 4pts (15%), Thrombocytopenia 4pts(15%). Non Hematologic G3 toxicity included: Neuropathy 1pts (3%), Asthenia 2pts (7%). ORR was 38%(10/26), DCR(PR+SD) was 53%(14/26), median PFS was 6 months (range 1-12), median OS was 9 months (range 2-18). 38%(10/26) of pts received a second line treatment. Conclusion: We believe that nab–paclitaxel plus gemcitabine is an active and discreetly tolerated schedule and that the literature data can be reproduced in clinical practice in unselected pts with metastatic disease.

Efficacy and safety of Nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer

Background: Nab-paclitaxel is a solvent-free, taxane-based antiblastic drug approved for the treatment of metastatic pancreatic cancer, as first line therapy in association with gemcitabine.* This retrospective analysis examines clinical benefit and toxicities in a group of consecutive MPC. Patients and methods: Until Jan. 2017 we analyzed 18 consecutive patients affected by metastatic pancreatic cancer. Nab-paclitaxel was given intravenously at dose of 125 mg/mq in association with gemcitabine 1000 mg/mq on day 1-8-15 q.28 for 3 cycles, and until progression for responders. Clinical benefit was defined as disease control rate (DCR), classified by radiologic evaluation every 3 months. We also evaluated mTTP for responders and overall survival.Toxicity was recorded every cycle. Results: We recorded 18 pts (1 F + 17M) on average 57 years old (41-76). All patients were caucasian, with adenocarcinoma, 3 stage III + 15 stage IV, PS 0-1, Metastatic lesions were 6 in liver, 4 in lung and 5 in peritoneum. Biliar duct stents were performed in 7 pts. The median number of CT cycles was 5 (range: 1-9). At first clinical/radiological evaluation after three cycles the DCR was 56% (7 pts RP; 5 pts NC). The responders continued CT until progression disease, with 3 pts that underwent local RT also and five pts underwent to second line treatment with 5FU or Oxaliplatin. Peripheral neuropathy G3 was the major toxicity in 20% of cases. We observed only 4 cases of neutropenia (grade 3-4) that required G-CSF treatment, and 3 cases of anemia G3 that required blood trasfusions. Fatigue G 1-2 was 20% e Thrombocytopenia G 2 was 10% The median time to progression in 7 responders pts was 5 months (range 2-8 months). Median OS was 12 months with 50% pts live at 1 year, 25% at 18 months and 11% at 2 y. Conclusion: This retrospective study shows the efficacy, clinical benefit and tolerability of nab-paclitaxel associated with gemcitabine in MPC with only mild neurological and ematological toxicity. *Von Hoff DD et al. Gemcitabine plus nab-paclitaxel is an activeregimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011; 29:4548-54.

Comparative effects of Folfirinox and Gemcitabine/nab-paclitaxel as first and second line chemotherapy for metastatic pancreatic cancer: single choice or sequence

Background: Gemcitabine/nab-paclitaxel and Folfirinox are standard of care of treatment of metastatic pancreatic cancer as first and second line in patients with good performance status or “fit”. Progression-free survival shows similar data in both chemotherapy regimens. No data on the better treatment sequence is available. Methods: We have retrospectively analyzed 43 patients with histological diagnosis of metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. 23 (53,5%) and 20 (46,5%) of 43 patients received Folfirinox and Gemcitabine/Nab-paclitaxel as first line chemotherapy respectively. Only 19 (44,1%) patients, after progression disease, started second line chemotherapy. 8 patients received Folfirinox, whereas 11 patients were treated with Gemcitabine Nab-paclitaxel as second line regardless of prior chemotherapy. The sequence of chemotherapy Folfirinoxàgemcitabine/Nab-paclitaxel versus Gemcitabine/Nab-paclitaxelà Folfirinox was administered to 10 patients 5 for both, respectively. Results: Median Progression-Free Survival was 5 months in the Folfirinox group as compared with 6 months in gemcitabine Nab-paclitaxel group (hazard ratio for disease progression, 0.83; 95% CI, 0.34 to 1.32; P value = 0.95). No difference between the two groups were identified in first line. The median of progression-free survival in second line was 2.5 months in the Folfirinox group and 4 months in the Gemcitabine/nab-paclitaxel. Hazard ratio for second disease progression was 0.62; 95% CI, 0.24 to 1.00; P value = 0.03. The median overall survival in patients with the sequence of chemotherapy Folfirinoxàgemcitabine/Nab-paclitaxel versus Gemcitabine/Nab-paclitaxelà Folfirinox was retrospectively 8 months and 11 months. Conclusion: In this retrospective study, similar progression-free survival we observed between Folfirinox group and Gemcitabine/Nab-paclitaxel group in first line metastatic pancreatic cancer. These data need to be confirm in prospective randomized trial.

MicroRNA-452 suppresses pancreatic cancer migration and invasion by directly targeting B-cell-specific Moloney murine leukemia virus insertion site 1.

Pancreatic cancer, one of the most common cancers globally, is the fourth most common cause of cancer-associated mortality in the USA. The 5-year relative survival rate for patients with pancreatic cancer is ~5% and the median survival time is only 6 months. The poor prognosis is mainly due to early and aggressive local invasion and metastasis, as well as dissemination of the pancreatic cancer cells. The present study demonstrated that microRNA-452 (miR-452) was markedly downregulated in pancreatic cancer tissues, particularly in metastatic tumors and pancreatic cancer cell lines. Overexpression of miR-452 significantly inhibited migration and invasion in pancreatic cancer cells. In addition, the molecular mechanism underlying the inhibitory functions of miR-452 in pancreatic cancer was also investigated. The results indicated that B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) was a direct target gene of miR-452 in pancreatic cancer. Overexpression of miR-452 inhibited the migration and invasion of pancreatic cancer, at least partially by knockdown of BMI1 expression. The results provided novel insight with potential therapeutic applications for the treatment of metastatic pancreatic cancer.

Immunotherapy for pancreatic cancer: present and future.

Despite the identification of some efficient drugs for the treatment of metastatic pancreatic cancer, this tumor remains one of the most lethal cancers and is characterized by a strong resistance to therapies. Pancreatic cancer has some unique features including the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma, which is both a physical barrier to drug penetration and a dynamic entity involved in immune system control. Therefore, the immune system has been hypothesized to play an important role in pancreatic cancer. Thus, therapies acting on innate or adaptive immunity are being investigated. Here, we review the literature, report the most interesting results and hypothesize future treatment directions.

Postmarketing surveillance study of erlotinib plus gemcitabine for pancreatic cancer in Japan: POLARIS final analysis.

Erlotinib plus gemcitabine is approved in Japan for the treatment of metastatic pancreatic cancer. The POLARIS surveillance study investigated safety (focusing on interstitial lung disease [ILD]) and efficacy of erlotinib plus gemcitabine in Japanese pancreatic cancer patients. Patients receiving erlotinib plus gemcitabine for pancreatic cancer in Japan between July 2011 and August 2012 were enrolled. ILD-like events were independently confirmed by a review committee. Overall survival (OS) and progression-free survival (PFS) were assessed, and risk factors for ILD occurrence were analyzed by multivariate Cox regression analysis. Safety data were available for 843 patients and efficacy data for 841. Adverse drug reactions were reported in 83.5% of patients, no new safety signals were identified. ILD events were confirmed by the review committee in 52 patients (6.2%), with two fatal cases (0.2%). Median time from initial erlotinib treatment to ILD events was 70.5 days. Of the 52 patients with ILD events, 86.5% improved or fully recovered from ILD (median time 24 days). Multivariate analysis identified previous or concurrent lung disease (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.0-4.5; P = 0.0365) and ≥3 organs with metastases (HR, 4.2; 95% CI, 2.2-8.2; P < 0.0001) as potential ILD risk factors. Accumulated OS rate at 28 weeks was 68.2%, and median PFS was 92 days (95% CI, 86-101). Erlotinib plus gemcitabine has an acceptable safety and efficacy profile in pancreatic cancer; however, patients should be assessed for previous/concurrent lung disease and metastatic burden, before and during treatment.

SMK/SM88 toxicity, efficacy, and patient reported outcomes in metastatic pancreas cancer.

e14060 Background: SMK/SM-88 is a combination of novel tyrosine isomer ( TI) and 3 low dose repurposed agents that are generally recognized as safe for typical use. Its mechanism of action is based on the Warburg effect. It has previously been reported to have clinical benefit with little toxicity in a variety of cancers (J. Clin. Oncol. 2013 31: e22095). We now report on a subset of subjects with pancreas cancer. Methods: Retrospective chart review. Results: Subjects received all four SMK/SM-88 components orally and subcutaneously, consisting of a proprietary altered TI, CYP3a4 inducer, mTOR inhibitor and mitochondrial oxidative stress catalyst, five days per week for a period of six weeks (1 cycle). A total of 11 pancreatic cancers cases were identified. The average age was 63.2 (44-81), 36.4% (4/11) were female. Prior treatment included surgery only (n = 3); chemo only (n = 4); multi-modality therapy (n = 2) and unknown or none (n = 2). Duration on study regimen was 3-57 weeks (mean = 28.5). Clinical benefits documented for all subjects included: 1-3 points improvement in ECOG performance status; 1-5 point mean improvement on EORTC questionnaire (scale 1-7); weight gain (1-5 lbs.); and reduction in pain levels (1-9 points/10 scale) with cessation of all analgesics by the end of cycle 1 in 36% (4/11). Overall reduction in tumor size was seen in 27.3% (3/11) including one CR with PFS of at least 6 months duration, and 2 PRs with one known PFS of 15wks. 72.7% (8/11) had stable disease for 6-61wks. One patient had an overall survival of 23.3 months with no further treatment, and one had an overall survival of 43.2 months. All subjects developed hyperpigmentation. Overall, all subjects tolerated the SMK/SM-88 compounds well. No serious or unexpected adverse events related to the agent have been reported. Conclusions: SMK/SM-88 is a promising treatment for metastatic pancreatic cancer with no significant toxicity. Additional studies are on going in other cancers and confirmatory pancreas investigations are planned.

A systematic review examining the relationship between progression-free survival and overall survival in adults with untreated metastatic pancreatic cancer.

e15724 Background: The majority of pancreatic cancers are diagnosed in advanced stages with a median survival of 3 to 5 months. From 2005 to 2012, the US Food and Drug Administration approved 41 oncology drugs; surrogate endpoints were used in 84% of the trials providing the basis of approval. The aim of this systematic review was to evaluate the relationship between PFS/TTP and OS in metastatic pancreatic cancer. Methods: A systematic literature review used the Centre for Reviews and Dissemination principles to identify studies that reported median PFS or TTP and OS. We searched Medline, Medline In-Process, and Embase, with the following additional limits: English language and published 1/1990 to 7/ 2016. Selection criteria, defined a priori, included chemo, immuno or targeted therapy, randomized controlled studies (Phase 2 or 3) in patients with metastatic pancreatic cancer. Studies were assessed for quality using the Cochrane Risk of Bias tool and the Jadad scale. Studies were excluded if full-text articles were not available, and if patients received chemotherapy plus radiotherapy or surgery. Correlation analyses and weighted linear regression were used to assess the association between median PFS/TTP and median OS. The distributions of median PFS/TTP and OS were examined using scatterplots. Results: 1,691 studies were identified. After screening by title and abstract, 212 full articles were assessed, of which 28 studies (evaluating 6,734 patients) met the selection criteria. The mean median PFS/TTP and OS were, respectively, 3.82 months (range 1.2 to 6.8 months), and 7.06 months (range 2.5 to 11.9 months). The correlation coefficient was 0.837; 95% CI (0.734-0.903) indicating a very strong positive correlation between median OS and median PFS/TTP. Regression analysis indicated that median PFS/TTP was a highly significant predictor of median OS = 2.177 + 1.247 * median PFS/TTP (p &lt; 0.001). Conclusions: The analysis demonstrates a very strong positive correlation of median PFS/TTP with median OS for the treatment of metastatic pancreatic cancer, which reinforces the hypothesis that PFS or TTP is a useful surrogate endpoint for OS in this cancer setting.

Patterns of Chemotherapy Use in a U.S.-Based Cohort of Patients with Metastatic Pancreatic Cancer.

Few population studies have examined patterns of systemic therapy administration in metastatic pancreatic cancer (MPC) or the predictors associated with specific treatment choices. We assessed 4,011 consecutive MPC patients who received chemotherapy between January 2005 and December 2015 at academic, private, and community-based oncology practices subscribing to a U.S.-wide chemotherapy order entry system capturing disease, patient, provider, and treatment data. Multivariate analyses of these prospectively recorded characteristics identified significant predictors of specific therapeutic choices. Overall, 100 different regimens were used in first-line treatment of MPC. First-line gemcitabine monotherapy usage fell steadily from 72% in 2006 to 16% in 2015. This steep decline mirrored increases in first-line usage of both 5 fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine + nab-paclitaxel. Younger male patients were more likely to receive FOLFIRINOX as first-line treatment, whereas patients treated at community practices and by oncologists with lower MPC patient volume were more likely to receive gemcitabine plus nab-paclitaxel (all p ≤ .05). Among all patients receiving first-line chemotherapy for MPC, 49% went on to receive second-line therapy and 19% received third-line therapy; administration of second- and third-line therapies increased steadily over the time course of follow-up. Younger patients and those treated by oncologists with higher MPC patient volume were more likely to receive second- and third-line therapies. This population-based study provides insight into treatment patterns of MPC in the U.S. Usage patterns varied greatly according to patient and provider characteristics. This study examined real world metastatic pancreatic cancer treatment patterns in the United States with the goals of understanding changes in chemotherapy treatment frequencies over time and determining the individual predictors that underlie the chemotherapy choices oncologists make for their patients. Our data set is unique in that it captured not only patient-level data, but also oncologist-level data. It also captured data from private and community practices as well as academic centers. To our knowledge, this is the only data set that can give this degree of insight into oncologist decision making practices.

Update on the role of nanoliposomal irinotecan in the treatment of metastatic pancreatic cancer

Median survival for patients with metastatic pancreatic cancer (MPC) treated with combination chemotherapeutic agents such as gemcitabine-based regimens and FOLFIRINOX is currently less than 12 months. This highlights the need for more efficacious first-line, as well as second-line therapies. Nanoliposomal irinotecan, in combination with 5-fluorouracil (5-FU)/folinic acid has recently been assessed as second-line therapy after initial gemcitabine-based therapy. It is the first, second-line treatment approved by the US Food and Drug Administration to treat patients with MPC based on results of the NAnoliPOsomaL Irinotecan (NAPOLI-1) study, which showed that this regimen significantly prolonged progression-free survival (3.1 months versus 1.5 months) and overall survival (6.2 months versus 4.1 months) compared with 5-FU/folinic acid alone. In addition, this study also represented an important step forward in improving the efficacy of previously used chemotherapeutic agents by using nanoformulation to extend pharmacokinetic advantages such as slow clearance, low steady-state volume of distribution, and longer half-life. However, certain adverse effects that are seen more frequently with nanoliposomal irinotecan and 5-FU/folinic acid, compared with 5-FU/folinic acid alone, include neutropenia, fatigue, diarrhea, and nausea/vomiting. This merits close monitoring of patients who are on this combination, since these adverse events may necessitate dose reductions and growth factor support. It is imperative to check UGT1A1 gene status in all patients being considered for treatment with nanoliposomal irinotecan. Patients found to be homozygous for the UGT1A1*28 gene need to be started on a lower initial dose. As we gain more data with clinical use, we anticipate further characterization of the aforementioned toxicities in patients with UGT1A1 gene polymorphisms and other genetic variants.

Analysis of ctDNA to predict prognosis and monitor treatment responses in metastatic pancreatic cancer patients

Cell-free circulating tumor DNA (ctDNA) in plasma has been used as a potential noninvasive biomarker for various tumors. Our study was performed to evaluate the clinical implications of ctDNA detection in patients with metastatic pancreatic cancer. First, we attempted to prospectively screen a panel of 60 genes in cell-free DNA (cfDNA) from ten metastatic pancreatic cancer patients via exome sequencing. Second, droplet digital PCR (ddPCR) was used to identify potential mutations in a cohort of 188 patients with metastatic pancreatic cancer. Finally, to preliminary evaluate the potential role of ctDNA in monitoring tumor responses following chemotherapy, we detected the presence of ctDNA in serial plasma samples from 13 metastatic pancreatic cancer patients (Clinical trial: NCT02017015). The analysis revealed five somatic mutations at BRCA2, EGFR, KDR and ERBB2 gene loci. The frequencies of ctDNA mutation at BRCA2, KDR, EGFR, ERBB2 exon17 and ERBB2 exon27 were 11.7%, 13.8%, 13.3%, 13.3% and 6.4% respectively. Univariate and multivariate analyses identified the ERBB2 exon17 mutation (p = 0.035, HR = 1.61) as an independent factor associated with overall survival among metastatic pancreatic cancer patients. Furthermore, the rate of coincident detection of ctDNA and response to treatment as assessed by CT imaging was 76.9% (10 of 13 cases), and the presence of ctDNA provided the earliest measure of treatment in 6 of 10 patients (60%). ctDNA sequencing may have clinical value for determining metastatic pancreatic cancer treatment and monitoring the tumor response.

Nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: a subgroup analysis of the Western European cohort of the MPACT trial.

PurposeThe global Phase III MPACT trial demonstrated superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone as first-line treatment for metastatic pancreatic cancer. Region was a randomization stratification factor in the MPACT trial. This subgroup analysis of MPACT examined efficacy and safety of patients treated in Western Europe.Patients and methodsPatients received nab-paclitaxel plus gemcitabine or gemcitabine alone as first-line treatment for metastatic pancreatic cancer as previously described. A total of 76 patients were included in this analysis (n=38 for each arm).ResultsDifferences between the overall Western European cohort and the intention-to-treat population included lower percentages of male patients (46% and 58%, respectively) and patients with biliary stents (8% and 17%), and higher percentages of patients with Karnofsky performance status of 90–100 (78% and 60%) and primary tumors in the body of the pancreas (48% and 31%). The median overall survival was 10.7 months with nab-paclitaxel plus gemcitabine vs 6.9 months with gemcitabine alone (hazard ratio [HR]: 0.82 [95% confidence interval (CI): 0.48–1.40]; P=0.471). Median progression-free survival was 5.3 vs 3.7 months, respectively (HR: 0.70 [95% CI: 0.37–1.33]; P=0.277). The independently assessed overall response rate was 18% vs 5% (response rate ratio, 3.50 [95% CI: 0.78–15.78]; P=0.076). The most common grade ≥3 adverse events with nab-paclitaxel plus gemcitabine and gemcitabine alone were neutropenia (46% vs 33%, respectively), leukopenia (35% vs 19%), anemia (22% vs 0%), asthenia (21% vs 6%), thrombocytopenia (14% vs 3%), and peripheral neuropathy (13% vs 3%).ConclusionAlthough a statistically significant difference between the treatment arms was not reached for efficacy endpoints, this study does report treatment benefit and a manageable safety profile associated with nab-paclitaxel plus gemcitabine in patients treated in Western Europe with metastatic pancreatic cancer.

Short and long-term survival in metastatic pancreatic adenocarcinoma, 1993-2013.

232 Background: Over the previous two decades several new agents have been approved for the treatment of metastatic pancreatic cancer (mPDAC). Their efficacy was demonstrated amongst highly selected patients that participate in randomized phase III trials, hence it is not clear to what extent these advances are reflected within the broader mPDAC population. We performed a population-based survival analysis of newly diagnosed patients who presented with mPDAC. Methods: Survival statistics were extracted from the Survival, Epidemiology and End Results (SEER) Database for patients diagnosed with mPDAC between 1993-2013. Demographic variables collected included age, gender, race, and marital status. Tumor characteristics collected included location and grade. Survival was analyzed using the Kaplan-Meier method and proportional hazard models as appropriate. Exclusion criteria included diagnosis at autopsy, unknown histology and pancreatic neuroendocrine tumors. Results: The study population consisted of 57,263 patients diagnosed with mPDAC from 1993-2013, 52% male, median age 69 years (range 15-104). Prognosis correlated with age, gender, race, marital status, tumor location, grade and year of diagnosis. Median overall survival (OS) stayed stable at 2 months between 1993 and 2013. Improvements in OS were seen for all patients, but especially for younger patients ( &lt; 50 years of age) and more recent year of diagnosis group (2009-2013). The percentage of patients who died within two months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%, p &lt; 0.0001). The subgroup of patients achieving longer-term survival has increased, with 12-month survival improving from 4.9 % to 12.7% (p &lt; 0.0001) between 1993 and 2013. Conclusions: There has been a continuous but modest improvement in OS of patients diagnosed with mPDAC between 1993 and 2013. The percentage of patients living beyond one year has significantly increased over time; however the percentage of patients dying within 2 months has only slightly decreased.

Efficacy of S-1 compared to modified FOLFIRINOX as second-line chemotherapy regimens after gemcitabine plus nab-paclitaxel for patients with metastatic pancreatic cancer.

449 Background: Recently, gemcitabine (GEM) plus nab-paclitaxel (nab-PTX) has been frequently used as a first-line chemotherapy regimen for the treatment of metastatic pancreatic cancer (mPC) in Japan. Nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin (MM-398 plus 5FU/LV) has not yet been approved in Japan. Under these circumstances, a modified FOLFIRINOX (mFFX) regimen or S-1 is commonly used as a second-line chemotherapy regimen for patients with mPC after GEM plus nab-PTX has failed. Methods: Between December 2014 and March 2016, 45 patients with mPC received second-line chemotherapy after the failure of GEM plus nab-PTX (standard dose regimen) at the National Cancer Center Hospital East. Twenty-two patients received mFFX (irinotecan, 150 mg/m2; bolus of 5FU was eliminated), 19 received S-1 (80 mg/m2/d; d1-28, q6w or d1-14, q3w), and 4 received other chemotherapy regimens. The clinical records of the patients were reviewed retrospectively. Results: At baseline, S-1 group had a more severe disease status than the mFFX group (performance status of 0: 21% vs. 68%, P = 0.003; median CA19-9 level: 1832 vs. 577 U/mL, P = 0.30). No significant difference in the response rate (S-1, 5.3% vs. mFFX, 9.1%, P = 0.56) or the disease control rate (S-1, 42% vs. mFFX, 36%, P = 0.71) was seen between the two groups. The progression free survival (PFS) (median: S-1 vs. mFFX: 2.7 vs. 2.4 months (m), P = 0.77), the overall survival (OS) from the second-line treatment (median: 6.1 vs. 6.4m, P = 0.87) and the OS from the first-line treatment (median: 10.9 vs. 12.4m, P = 0.77) were not significantly different between the two groups. These results were similar to those observed for MM-398 plus 5FU/LV (PFS, 3.1m; OS, 6.1m) in a pivotal Phase III study (NAPOLI-1). The incidences of peripheral neuropathy (5.3% vs. 32%, P = 0.04), fatigue (11% vs. 50%, P = 0.007), and neutropenia (11% vs. 64%, P = 0.001) were significantly lower in the S-1 group. Conclusions: S-1 was less toxic than mFFX and exerted a similar anti-tumor effect in the present study. S-1 could be a treatment option for patients with mPC refractory to GEM plus nab-PTX.

Cost Effectiveness of Metal Stents in Relieving Obstructive Jaundice in Patients with Pancreatic Cancer.

ASGE and ESGE guidelines recommend endoscopic metal stent placement for pancreatic carcinoma patients with biliary obstruction, and whose estimated life expectancy is greater than 6months. Because median overall survival (OS) of metastatic pancreatic adenocarcinoma until recently has been less than 6months, plastic biliary stents were preferentially placed rather than metal due to the greater upfront cost of the latter. Recent advances in the treatment of metastatic pancreatic cancer have extended median OS beyond the 6-month range. Given this improvement in OS, we performed a cost-effectiveness analysis of initial metal biliary versus plastic stent placement in metastatic pancreatic cancer patients with biliary obstruction. A Markov model was developed to predict lifetime costs, quality-adjusted life years (QALYs), and cost effectiveness of metal compared with plastic stents. Adult patients entered the model with locally advanced cancer and underwent endoscopic retrograde cholangiopancreatography (ERCP) with placement of metal or plastic stents. A targeted literature search was conducted to identify published sources, which were used to estimate clinical, cost, utility, and event rate inputs to the model. Results were estimated from the third-party payer perspective in 2012 US dollars per QALY. One-way and probabilistic sensitivity analyses were conducted to assess the impact on model outcomes resulting from uncertainty among inputs. Our analysis found that initial placement of metal stents was more cost effective than plastic biliary stents with lower overall costs due to lower restenting rates while at the same time associated with a better quality of life. Based on model projections, placement of metal stents could save approximately $1450 per patient over a lifetime, while simultaneously improving quality of life. These findings were robust in sensitivity analyses. Placement of metal biliary stents at initial onset of obstructive jaundice in adult patients with metastatic pancreatic carcinoma with an expected OS greater than 6months was found to be a more cost-effective strategy than plastic stents. These results reinforce guidelines' suggestions for metal stent placement.

Anti-LRP/LR-specific antibody IgG1-iS18 impedes adhesion and invasion of pancreatic cancer and neuroblastoma cells.

BackgroundCancer has become a global burden due to its high incidence and mortality rates, with an estimated 14.1 million cancer cases reported worldwide in 2012 particularly as a result of metastasis. Metastasis involves two crucial steps: adhesion and invasion, and the non-integrin receptor; the 37-kDa/67-kDa laminin receptor precursor/ high affinity laminin receptor (LRP/LR) has been shown to be overexpressed on the surface of tumorigenic cells, thus being implicated in the enhancement of these two crucial steps. The current study investigated the role of LRP/LR on the aggressiveness of pancreatic cancer (AsPC-1) and neuroblastoma (IMR-32) cells with respect to their adhesive and invasive potential.MethodsAsPC-1 and IMR-32 cells were utilized as the experimental cell lines for the study. Cell surface LRP/LR levels were visualised and quantified on the experimental and control (MCF-7) cell lines via confocal microscopy and flow cytometry, respectively. Total LRP/LR levels in the cell lines were assessed by Western blotting and the adhesive and invasive potential of the above-mentioned cell lines was determined before and after supplementation with the anti-LRP/LR specific antibody IgG1-iS18. Statistical significance of the data was confirmed via the use of the two-tailed student’s t-test and Pearson’s correlation coefficient.ResultsFlow cytometry revealed that AsPC-1 and IMR-32 cells displayed significantly higher cell surface LRP/LR levels in comparison to the MCF-7 control cell line. However, Western blotting and subsequent densitometric analysis revealed that all three tumorigenic cell lines displayed no significant difference in total LRP/LR levels. The treatment of AsPC-1 and IMR-32 cells with IgG1-iS18 caused a significant reduction in the adhesive and invasive potential of the cells to laminin-1 and through the ECM-like Matrigel™, respectively. Pearson’s correlation coefficients indicated a high correlation, thus suggesting a directly proportional relationship between cell surface LRP/LR levels and the adhesive and invasive potential of AsPC-1 and IMR-32 cells.ConclusionThese findings suggest that through the interference of the LRP/LR-laminin-1 interaction, the anti-LRP/LR specific antibody IgG1-iS18 may act as an alternative therapeutic tool for the treatment of metastatic pancreatic cancer and neuroblastoma.

O3-16-2 - Gemcitabine and nab-paclitaxel combination therapy for the treatment of metastatic pancreatic cancer

O3-16-2 - Gemcitabine and nab-paclitaxel combination therapy for the treatment of metastatic pancreatic cancer

EE1 - Economic Evaluation for the United Kingdom of Systemic Chemotherapies as First-Line Treatment for Metastatic Pancreatic Cancer

EE1 - Economic Evaluation for the United Kingdom of Systemic Chemotherapies as First-Line Treatment for Metastatic Pancreatic Cancer

Current management and future directions in metastatic pancreatic adenocarcinoma.

Of the anticipated 50,000 individuals expected to be diagnosed with pancreatic cancer in 2016, the majority will have metastatic disease. Given the noncurative nature of advanced pancreatic adenocarcinoma, treatment is aimed at inducing disease regression, controlling symptom, and extending life. The last 5 years have been marked by advances in the treatment of metastatic pancreatic cancer, specifically the approval by the US Food and Drug Administration of 2 combination chemotherapy regimens and the widespread use of a third, which have reproducibly been shown to improve survival. Ongoing studies are building on these regimens along with targeted and immunotherapeutic agents. This article will review the current treatment standards and emerging targets for metastatic pancreatic cancer. Cancer 2016;122:3765-3775. © 2016 American Cancer Society.