Prognosis Of Advanced Pancreatic Cancer Research Articles

Impact of time from diagnosis to chemotherapy on prognosis in advanced pancreatic cancer.

Due to the aggressive nature and poor prognosis of advanced pancreatic cancer, prompt initiation of treatment is critical. We investigated the effect of the interval between cancer diagnosis and initiation of chemotherapy on survival in patients with advanced pancreatic cancer. In this retrospective, single-centre study, consecutive patients with advanced pancreatic cancer between April 2013 and March 2022 were analyzed. Data were extracted from the electronic medical records of patients who received chemotherapy for metastatic, locally advanced or resectable pancreatic cancer or who received chemotherapy due to either being intolerant of or declining surgery. We compared overall survival between two groups: the early waiting time group (waiting time≤30days from diagnosis to chemotherapy initiation) and the elective waiting time group (waiting time≥31days). Prognostic factors, including biliary drainage, were considered. The impact of waiting time on survival was assessed by univariate and multivariate analyses with Cox proportional hazard models. A 1:1 propensity score matching approach was used to balance bias, accounting for significant poor prognosis factors, age and sex. The study involved 137 patients. Overall survival exhibited no statistically significant difference between the early and elective waiting time groups (207 and 261days, P=0.2518). Univariate and multivariate analyses identified poor performance status and metastasis presence as predictors of worse prognosis. This finding persisted post propensity score matching (275 and 222days, P=0.8223). Our study revealed that initiating chemotherapy ˃30days later does not significantly affect treatment efficacy compared to within 30days of diagnosis.

Impact of Initial Body Weight Loss on Prognosis in Advanced Pancreatic Cancer: Insights From a Single-Center Retrospective Study.

Pancreatic cancer (PC) has a poor prognosis, with body weight loss commonly observed at diagnosis. However, the impact on PC prognosis of weight loss at the time of diagnosis on PC prognosis is unknown. This retrospective, single-center study enrolled consecutively patients diagnosed with metastatic or locally advanced PC or resectable PC who were intolerant of or refused surgery. Patients who had lost more than 5% of their body weight or more than 2% and had a body mass index (BMI) of less than 20kg/m2 at diagnosis were classified as experiencing body weight loss. Patients were subclassified into 2 groups: patients with and without weight loss. The study evaluated patient-related and PC-related factors affecting prognosis. Cox proportional hazards models were used to assess factors affecting prognosis. The primary endpoint was overall survival. Additionally, 1:1 propensity score matching was performed to reduce bias. In total, 220 patients were included in the study. The median age of the patients was 74years, and 49.1% were male. Weight loss at diagnosis was observed in 43.2% of patients. There were no significant differences in clinical factors, except for anthropometric parameters, between the groups. The median survival time did not differ between the weight loss and no weight loss groups (149 and 173days, respectively, P = .669). After matching, no significant differences in survival times were observed between the 2 groups. This study found no association between weight loss at diagnosis and prognosis in patients with advanced PC treated with best supportive care or chemotherapy.

The Differential Clinical Impacts of Cachexia and Sarcopenia on the Prognosis of Advanced Pancreatic Cancer.

Simple SummaryPancreatic cancer (PC) is one of the most lethal malignancies across the world. More than 80% patients are diagnosed at an advanced stage with limited treatment options. PC has the highest frequency of developing cancer cachexia (CC)–sarcopenia (SC) syndrome, but there is no optimal efficient intervention for CC or SC targeting their complicated biological and irreversible processes. As a result, identifying the clinicopathological features and patient characteristics in each advanced PC patient with CC and/or SC is urgently needed to distinguish different wasting phenotypes or body composition and thus support precision medicine and achieve optimal outcomes. We performed a retrospective cohort study of 232 advanced PC patients to determine the differential clinical characteristics of CC and SC and the overlap of CC- or SC-related factors in each patient. The impacts of CC, SC, and their relevant factors on the outcomes of PC patients were also evaluated.Pancreatic cancer (PC) has the highest frequency of developing cancer cachexia (CC)–sarcopenia (SC) syndrome, which negatively influences patients’ outcome, quality of life, and tolerance/response to treatments. However, the clinical impacts of CC, SC, and their associated factors on outcomes for advanced PC has yet to be fully investigated. A total of 232 patients were enrolled in this study for the retrospective review of their clinical information and the measurement of skeletal muscle areas at the third lumber vertebra by computed tomography scan to identify CC or SC. The association and concurrent occurrence of clinicopathological features in each patient, prevalence rates, and prognosis with the CC or SC were calculated. CC and SC were observed in 83.6% (n = 194) and 49.1% (n = 114) of PC patients, respectively. Low hemoglobin levels more often occurred in CC patients than in non-CC patients (p = 0.014). Older age (p = 0.000), female gender (p = 0.024), low body mass index (BMI) values (p = 0.004), low hemoglobin levels (p = 0.036), and low albumin levels (p = 0.001) were more often found in SC patients than in non-SC patients. Univariate and multivariate analyses showed that CC was an independent poor prognostic factor of overall survival (OS) and progression-free survival for all patients, the chemotherapy (C/T) subgroup, and the high BMI subgroup. Meanwhile, SC was an independent predictor of poor OS for the subgroups of C/T or high BMI but not for all patients. These findings reveal the clinical differences for CC and SC and provide useful information for predicting the prognosis of advanced PC patients and conducting personalized medicine.

Biomarker-oriented study of pembrolizumab in combination with chemotherapy in chemotherapy-naïve advanced pancreatic cancer: A phase 2 trial-in-progress.

TPS639 Background: Pancreatic cancer (PC) is well-known as a strongly immunosuppressive tumor. The tumor microenvironment of PC play a fundamental part in maintaining a non-immunogenic and immuno-suppressive environment through the production of inhibitory cytokines and complex interaction between tumor cells, regulatory T cells, and myeloid-derived suppressor cells (Li KY et al. 2020). However, through integrated genomics and immunophenotyping, the immune-rich type had a relatively good prognosis in advanced PC (Wartenberg M et al. 2018). Based on this, various attempts have been made to apply immune checkpoint inhibitor (ICI) to PC. Disappointingly, ICI monotherapy is ineffective in most advanced PCs, and a strategy of combining ICI with ICI, chemotherapy or targeted therapy has been recently tried. However, the mechanism of immune modulation induced by ICI in combination with chemotherapy in PC is still not well-known, so biomarker studies are needed to understand the role of immunotherapy in advanced PC. Also based on this, it is expected to develop an effective ICI treatment strategy in PC. This study is a non-randomized, parallel assignment phase 2 trial aimed to explore dynamic modulation of the immune system caused by co-administration of pembrolizumab and cytotoxic chemotherapy in patients with advanced PC. Methods: Eligible patients have recurred or metastatic pancreatic cancer. Patients who have received chemotherapy for advanced PC are excluded, except for previous adjuvant chemotherapy. Patients who have received ICI are excluded. There are 2 chemotherapy cohorts (FOLFIRINOX, n=41; Gemcitabine/Nab-paclitaxel, n=36). Patients enrolled in the FOLFIRINOX cohort will receive pembrolizumab 200mg intravenously once every 3 weeks, plus FOLFIRINOX chemotherapy every 2 weeks. In Gemcitabine/Nab-paclitaxel cohort, patients will receive gemcitabine 1000mg/m2 plus nab-paclitaxel 125mg/m2 day 1, 8, 15 of a 4-week cycle, plus pembrolizumab 200mg intravenously once every 3 weeks. The primary endpoint is objective response rate, with key secondary endpoints including progression-free survival, duration of response, disease control rate, overall survival, safety, and patient-reported outcome. For evaluating metabolic response, 18F-FDG PET-CT scan will be conducted before treatment and at the first response evaluation. Tumor tissue biopsies are performed three times in total: screening, the first response evaluation, and disease progression. Blood samples are being collected every cycles for translational biomarker studies. Clinical trial information: NCT04447092.

Gemcitabine in combination with epibrassinolide enhanced the apoptotic response in an ER stress-dependent manner and reduced the epithelial-mesenchymal transition in pancreatic cancer cells.

Gemcitabine is a broad-spectrum antimetabolite and a deoxycytidine analog recognized as a standard therapy alone or in combination with other antineoplastic agents in the therapy of pancreas cancer. Drug resistance following gemcitabine treatment is a common phenomenon; therefore, combinational therapy models are usually preferred. Pancreatic ductal adenocarcinoma, or pancreas cancer, is the fourth leading cause of cancer-related deaths worldwide. With the increasing incidence of pancreatic cancer every year, the mortality rate is also rising significantly because of late diagnosis, and limited chemotherapy options. Adjuvant chemotherapy after surgical resection is the typical option for the treatment of early pancreatic cancer. Mostly, 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel is used for the prognosis of advanced pancreatic cancer; however, chemoresistance usually occurs limiting the effectiveness of the chemotherapy. Therefore, most of the studies are focused on gemcitabine combination with other drugs to overcome the situation. As an apoptotic agent and a member of brassinosteroids, epibrassinolide (EBR) induces endoplasmic reticulum (ER) stress-dependent cell death in different cancer cells, as shown by our group. In this study, we aimed to enhance the gemcitabine apoptotic effect by EBR combined treatment in pancreatic cancer cells. EBR treatment reduced cell viability and inhibited cell proliferation in PANC-1, MIA PaCa-2, and AsPC-1 cells. Each pancreatic cancer cell gave different responses to the EBR treatment because of different aggressiveness. However, EBR induced apoptosis through increasing ROS generation, which was associated with ER stress in PANC-1 and MIA PaCa-2 cells. Gemcitabine alone reduced the cell viability of each pancreatic cancer cell line; however, combination with EBR led to further induction of apoptotic cell death in each pancreatic cancer cell line. In addition, combined treatment of gemcitabine and EBR further decreased N-cadherin and vimentin expressions, suggesting that epithelial-mesenchymal transition of pancreatic cells is reduced. In conclusion, EBR had therapeutic potential to avoid the gemcitabine-induced side effects during the treatment of pancreatic cancer.

Number of nonsynonymous genomic variants may correlate with prognosis in advanced pancreatic cancer.

432 Background: Pancreatic cancer is associated with poor outcomes at any stage. A very small number of patients - approximately 3% of those with metastatic disease - experience long-term survival through 5 years but the biologic mechanisms underlying the benefit observed with these “exceptional responders” are incompletely understood. We explored potential genomic differences between exceptional responders and typical responders to treatment for advanced pancreatic cancer that could confer a more favorable biology. Methods: We included consecutive exceptional responders and matched controls (MCs) with advanced pancreatic cancer in a 1:3 ratio from the Cleveland Clinic from April, 2013 – August, 2017. ERs were defined as patients with overall survival (OS) > 18 months for metastatic disease and > 24 months for locally advanced disease. Controls were matched by age, gender, stage and type of chemotherapy given and experienced OS at or below median survival for their stages. Clinical variables including demographics, comorbidities, stage, histology and treatment history were collected. Next generation sequencing (NGS) was performed for DNA sequencing of 648 genes and tumor mutation burden (TMB) on available tissue. The study population initially comprised of 14 exceptional responders and 42 MCs. However, only 4 exceptional responders and 6 MCs were included for analysis due to insufficient tissue for NGS for the remaining patients. Descriptive statistics were used for statistical analysis. Differences in survival outcomes were assessed using the Kaplan-Meier method and log-rank test. Results: The median ages for the exceptional responders and MCs were 69 and 67.5 years, respectively. Both groups were at least 75% male and white. Of the exceptional responders, 50% had pancreatic tail primaries compared to 0% of the MCs. There were no differences between groups in first-line chemotherapy used. Exceptional responders had significantly fewer non-synonymous mutations compared to MCs (2.25 vs. 5.17, p = 0.014). Mutation count < 3 was associated with significantly better progression-free survival (PFS) and OS as shown in the Table. TMB did not differ between exceptional responders and MCs (4.88 vs. 5.70 Muts/Mb, p = 0.39). Of the exceptional responders, 50% had alterations in BAGE2 versus 0% of MCs. Conversely, 50% of MCs had alterations in LRP1B, CUL4B or APC vs. 0% of exceptional responders. Conclusions: Having a lower number of non-synonymous mutations may correlate with exceptional response to systemic therapy and therefore with improved survival in pancreatic cancer. Pancreatic tail primary may also be associated with improved outcomes. These findings, though limited by small sample size, should encourage future study into genomic signatures of exceptional response. [Table: see text]

Prolonged time to treatment initiation in advanced pancreatic cancer patients has no major effect on treatment outcome: a retrospective cohort study controlled for lead time bias and waiting time paradox.

A prolonged time to treatment initiation (TTI) correlates with an adverse prognosis in different cancer types including resectable pancreatic cancer (PC). Only limited evidence on the correlation between TTI and prognosis in advanced PC exists. Consecutive PC patients (n = 368) who were diagnosed or treated at our high-volume comprehensive cancer center were included in a prospectively maintained database. We retrospectively analyzed time from first imaging showing advanced PC to initiation of palliative first-line chemotherapy. Lead time bias and waiting time paradox were addressed by landmark analysis and correlation of tumor burden with TTI. Two hundred and ninety-seven patients met the pre-specified in- and exclusion criteria of our study. Median TTI was 29days (range: 1-124days). Most common reasons for prolonged TTI (> 21days) were referral from an external treatment center (39%) and a second biopsy (31%). A TTI above the median-, 75th or 90th percentile (43 or 60days, respectively) had no impact on overall survival. Furthermore, no correlation between levels of carbohydrate antigen 19-9 (CA 19-9) at time of treatment initiation and TTI was observed. While a timely work-up of advanced PC patients remains important, delays in treatment initiation due to repeated biopsies, inclusion in a clinical study or transfer to a specialized cancer center appear to be justified in light of the absence of a strong adverse effect of prolonged TTI on prognosis in advanced PC patients.

Chemoresistance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance.

The CRP/Albumin Ratio Predicts Survival And Monitors Chemotherapeutic Effectiveness In Patients With Advanced Pancreatic Cancer.

PurposeThe CRP/albumin (Alb) ratio, a recently reported predictor, has shown value for prognosis in various human cancers. This study aimed to determine the prognostic value of baseline CRP/Alb and to explore the relevance between postchemotherapy CRP/Alb and the efficacy of chemotherapy in advanced pancreatic cancer patients.Patients and methodsFive hundred and ninety-five patients diagnosed with locally advanced or metastatic adenocarcinoma of the pancreas were enrolled. Cut-off Finder was used to calculate the best cut‑off value for baseline CRP/Alb. The primary endpoint was overall survival, which was analyzed by Kaplan-Meier survival curves with 95% confidence intervals. The log rank test and Cox proportional hazard model were used to evaluate the univariate and multivariate analyses.ResultsThe optimal cut-off value for baseline CRP/Alb was determined to be 0.18. Both the baseline CRP/Alb (CRP/Alb≥0.18 vs. CRP/Alb<0.18, hazard ratio [HR] = 2.506; p<0.001) and postchemotherapy CRP/Alb (CRP/Alb≥0.18 vs. CRP/Alb<0.18, HR = 1.854; p =0.002) were significant predictors of overall survival according to multivariate analysis and were independent of other factors. Patients with a baseline and postchemotherapy CRP/Alb ≥0.18 had the worst prognosis.ConclusionCRP/Alb is a strong and useful indicator of prognosis for advanced pancreatic cancer. Both baseline and postchemotherapy CRP/Alb can be used in predicting the survival of patients and monitoring the effectiveness of chemotherapy in clinical practice.

Predicting mortality and adverse events in patients with advanced pancreatic cancer treated with palliative gemcitabine-based chemotherapy in a multicentre phase III randomized clinical trial: the APC-SAKK risk scores.

Background:The prognosis of advanced pancreatic cancer (APC) is poor and differs considerably among patients. Therefore, it is clinically relevant to identify patients with APC who are more likely to benefit from palliative chemotherapy with reduced risk of toxicity. To date, there is no prognostic score universally recommended to help clinicians in planning the therapeutic management.Methods:Using individual patient data from 319 cases of APC treated with gemcitabine-based chemotherapy and enrolled in the SAKK 44/00-CECOG/PAN.1.3.001 randomized trial, several baseline variables, including inflammatory markers, were analysed post hoc as predictors of mortality and/or grade 3 or 4 chemotherapy-related toxicity and separate risk scores were developed.Results:Median survival of the study patients was 7.9 months (interquartile range 3.7–13.3 months). Independent predictors of mortality included increased Aspartate transaminase (ASAT), low performance status, increased derived neutrophil to lymphocyte ratio, increased Carbohydrate Antigen 19-9 (CA 19-9), low haemoglobin, presence of pain, presence of metastasis and increased alkaline phosphatase (ALP). During the study, 117 patients experienced at least one grade 3 or 4 adverse event. Independent predictors of toxicity included white blood cells, ALP, renal function and bilirubin levels at baseline. Both models displayed moderate levels of discrimination (C-statistic 0.68 and 0.64 for mortality and toxicity, respectively) and adequate calibration.Conclusions:We developed simple-to-use prognostic scores for mortality and severe toxicity for patients with APC. These scores can be useful in daily practice to identify patients with increased risk of death or toxicity and to plan the most appropriate therapeutic strategy to improve survival and quality of life. Further prospective studies to validate such scores are needed.

Pretreatment values of bilirubin and albumin are not prognostic predictors in patients with advanced pancreatic cancer.

PurposeTo identify the pretreatment values of bilirubin and albumin and other serum biomarkers in predicting the prognosis for advanced pancreatic cancer.MethodsA total of 201 consecutive patients pathologically diagnosed as advanced pancreatic cancer were retrospectively reviewed. Tumor location, TNM classification, the level of baseline total bilirubin (TBIT), direct bilirubin (DBIT), albumin (ALB), globulin (GLOB), total protein (TP), ALB to GLOB ratio (AGR), CA19‐9, CA242, and CA50 were collected. The values of CA19‐9, CA242, and CA50 were divided into two groups according to the upper limit value which were 1000 U/mL, 150 IU/mL, and 500 IU/mL, respectively. The values of TBIL, DBIL, IBIL, ALB, GLOB, TP, ALB, and GLOB were divided into low and high groups according to the median. To investigate if the median was an effective discriminator in dividing these markers, the patients were divided into a test set (n = 100) and a validation set (n = 101). Kaplan‐Meier (K‐M) survival analysis and Cox regression analysis were performed to explore the potential relationship between them and overall survival (OS).ResultsA K‐M survival analysis revealed that the investigated markers in test set, including TBIL, DBIL, IBIL, ALB, GLOB, TP, ALB, and GLOB, were not associated with the OS. The findings from the validation set were consistent with those in the test set. Factors with P value smaller than 0.1 in the univariate analysis along with the tumor location, CA19‐9, CA242, CA50, were entered into the multivariate analysis. A Cox regression analysis suggested that the cancerization at head of pancreas (P = 0.01) and a high level of CA19‐9 (P = 0.02) were independent prognostic indicators for poor OS of pancreatic cancer.ConclusionsBaseline bilirubin and serum proteins were not associated with the prognosis of advanced pancreatic cancer. Tumor location and level of CA19‐9 may serve as significant indicators for poor prognosis in those patients.

Second-line chemotherapy for advanced pancreatic cancer: Which is the best option?

Despite recent biological insight and therapeutic advances, the prognosis of advanced pancreatic cancer still remains poor. For more than 15 years, gemcitabine monotherapy has been the cornerstone of first-line treatment. Recently, prospective randomized trials have shown that novel upfront combination regimens tested in prospective randomized trials have resulted in improved patients' outcome increasing the proportion of putative candidate to second-line therapy. There is no definite standard of care after disease progression. A novel formulation in which irinotecan is encapsulated into liposomal-based nanoparticles may increase the efficacy of the drug without incrementing its toxicity. NAPOLI-1 was the first randomized trial to compare nanoliposomal irinotecan and fluorouracil-leucovorin (5-FU/LV) to 5-FU/LV alone after a gemcitabine-based chemotherapy. This review focuses on the current data for the management of second-line treatment for metastatic pancreatic adenocarcinoma, presents the most interesting ongoing clinical trials and illustrates the biologically-driven future options beyond disease progression.

Combination therapy of portal vein resection and adjuvant gemcitabine improved prognosis of advanced pancreatic cancer.

Although adjuvant chemotherapy (AC) using gemcitabine improves the prognosis of patients with resectable pancreatic cancer, the effect of gemcitabine AC on the prognosis of patients with borderline resectable pancreatic cancer is not clear. We analyzed the prognosis of patients with pancreatic cancer who underwent curative pancreatoduodenectomy or total pancreatectomy in combination with portal/superior mesenteric vein resection (PVR) [PVR (+) group] or without PVR [PVR(-) group]. MST of the PVR (+) group was significantly shorter than that of the PVR(-) group (p=0.017). In contrast, when we focused on the patients with gemcitabine AC, there was no significant difference in MST between the PVR (+) and the PVR (-) groups (p=0.247). Furthermore, we compared MST of two subgroups in the PVR (+) group depending on gemcitabine AC status. In the PVR (+) group, MST of the patients with gemcitabine AC was significantly longer than that without gemcitabine AC (p=0.003). This was also true for the patients with pancreatic cancer which had histologically proven invasion to portal/superior mesenteric vein (PV/SMV) (p=0.001). The prognosis of patients with pancreatic cancer invading PV/SMV can be improved by combination therapy with PVR and gemcitabine adjuvant chemotherapy.

Abstract LB-257: The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma

Abstract Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer1-4. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2−ve tumors correlating with poor prognosis5. However, there is no evidence so far of a functional contribution of AT1R to breast tumorigenesis. We explored the potential benefit of ARB use in breast cancer patients and clarified the mechanisms associated with its success. Compared to normal breast, high AT1R expression occurs in 73% of tumors, with &amp;gt;10-fold higher AT1R levels observed in 30% of tumors. We show that therapeutic inhibition of AT1R, with Losartan, results in a significant reduction in tumor burden and no mammary tumor incidence in 20% of animals. We observe a significant reduction in tumor progression from DCIS to invasive cancer with Losartan treatment. This is associated with reduced tumor IL-6, pSTAT3 and TNF levels, reduced tumor cell proliferation and de-differentiation. Our data demonstrate that the AT1R is a potential therapeutic target, with the availability of a range of well-tolerated inhibitors currently used in clinics. We describe a novel signalling pathway critical in breast tumorigenesis, that may provide new therapeutic avenues to complement current treatments.

1612 Early venous thromboembolism is associated with worse prognosis in advanced pancreatic cancer

1612 Early venous thromboembolism is associated with worse prognosis in advanced pancreatic cancer

Hyperfibrinogen Is Associated With the Systemic Inflammatory Response and Predicts Poor Prognosis in Advanced Pancreatic Cancer.

The aim of this study was to examine the prognostic prediction value of plasma fibrinogen level for overall survival (OS) in patients with advanced pancreatic cancer. A total of 321 patients with locally advanced or metastatic pancreatic adenocarcinoma were retrospectively recruited. The association between plasma fibrinogen level and OS was analyzed. We also evaluated the relationship between plasma fibrinogen level and the systemic inflammatory response markers: the neutrophil-lymphocyte ratio, platelets/lymphocyte ratio, and lymphocyte/monocyte ratio. High plasma fibrinogen levels were significantly correlated with shorter OS in patients with advanced pancreatic cancer (175 days for patients with high fibrinogen levels vs 357 days for patients with low fibrinogen levels; log rank, 22.949; P < 0.001). Multivariate analyses confirmed that plasma fibrinogen level was an independent prognostic predictor for OS (hazard ratio, 2.184; 95% confidence interval, 1.574-3.032; P < 0.001). Receiver operating characteristic analyses showed that including plasma fibrinogen level alongside traditional factors (tumor stage and CA 19-9) significantly improved prognostic prediction capability (traditional model area under the curve of 0.62 versus combined model area under the curve of 0.708; P = 0.016). In addition, plasma fibrinogen level was positively correlated with neutrophil-lymphocyte ratio and platelets/lymphocyte ratio and negatively correlated with lymphocyte/monocyte ratio. Hyperfibrinogen is associated with the systemic inflammatory response and predicts poor prognosis for advanced pancreatic cancer.

The Impact of Diabetes Mellitus and Metformin Treatment on Survival of Patients with Advanced Pancreatic Cancer Undergoing Chemotherapy.

PurposeA causal relationship between diabetes mellitus (DM) and pancreatic cancer is well established. However, in patients with advanced pancreatic cancer (APC) who receive palliative chemotherapy, the impact of DM on the prognosis of APC is unclear.Materials and MethodsWe retrospectively enrolled APC patients who received palliative chemotherapy between 2003 and 2010. The patients were stratified according to the status of DM, in accordance with 2010 DM criteria (American Heart Association/American Diabetes Association). DM at least 2 years’ duration prior to diagnosis of APC was defined as remote-onset DM (vs. recent-onset).ResultsOf the 349 APC patients, 183 (52.4%) had DM. Among the patients with DM, 160 patients had DM at the time of diagnosis of APC (remote-onset, 87; recent-onset, 73) and the remaining 23 patients developed DM during treatment of APC. Ultimately, 73.2% of patients (134/183) with DM received antidiabetic medication, including metformin (56 patients, 41.8%), sulfonylurea (62, 45.5%), and insulin (43, 32.1%). In multivariate analysis, cancer extent (hazard ratio [HR], 1.792; 95% confidence interval [CI], 1.313 to 2.445; p < 0.001) showed association with decreased overall survival (OS), whereas a diagnosis of DM (HR, 0.788; 95% CI, 0.615 to 1.009; p=0.059) conferred positive tendency on the OS. Metformin treatment itself conferred better OS in comparison within DM patients (HR 0.693; 95% CI, 0.492 to 0.977; p=0.036) and even in all APC patients (adjusted HR, 0.697; 95% CI, 0.491 to 1.990; p=0.044).ConclusionFor APC patients receiving palliative chemotherapy, metformin treatment is associated with longer OS. Patients with DM tend to survive longer than those without DM.

Sequential gemcitabine and platinum versus first-line combination of gemcitabine and platinum for advanced pancreatic cancer treatment: a retrospective study

The purpose of this study was to investigate the impact of combinational versus sequential gemcitabine and platinum on prognosis of advanced pancreatic cancer. Two hundred and three patients with advanced pancreatic cancer were selected. They were divided into GemP (first-line gemcitabine and platinum), Gem-then-P(sequential gemcitabine and platinum), Gem/other (first-line gemcitabine-based therapy without subsequent platinum),and Gem (first-line gemcitabine-based therapy without subsequent systemic therapy) groups. The Kaplan–Meier method and log-rank test were used for survival analyses. Cox regression model and propensity score matching were used for prognostic analyses. The median survival was 12.5 months [95 %confidence interval (CI), 11.2-13.7] in the GemP group(N = 65), 8.3 months (95 % CI 5.0-11.7) in the Gem-then-P group (N = 35), 11.6 months (95 % CI 4.6–18.5) in the Gem/other group (N = 26), and 4.7 months (95 % C I3.3-6.0) in the Gem group (N = 77) (P<0.001). Considering the GemP and Gem-then-P groups, performance status, serum creatinine, and response to first-line treatment were independent prognostic factors for overall survival in the multivariate analysis. No specific factors were identified for predicting the choice between GemP and Gem-then-P. First-line gemcitabine and platinum-based combinations were not superior to sequential gemcitabine and platinum for overall survival. The best sequence of chemotherapy for advanced pancreatic cancer should be explored in future clinical trials.

Cytokeratin 19-fragments (CYFRA 21-1) as a novel serum biomarker for response and survival in patients with advanced pancreatic cancer

Background:CYFRA 21-1 serves as biomarker in several epithelial malignancies. However, its role in pancreatic cancer (PC) has not yet been investigated.Methods:Within a prospective single-centre study serial blood samples were collected from patients with confirmed advanced PC. Pre-treatment values and weekly measurements of CYFRA 21-1, carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (assessed by Elecsys 2010, Roche Diagnostics) during palliative first-line chemotherapy were obtained. Biomarker data were correlated with objective response (determined by RECIST) as well as time to progression (TTP) and overall survival (OS) using uni- and multivariate analyses.Results:Seventy-eight patients were included, 45% of these received treatment in prospective clinical trials. Median TTP was 3.9 months, median OS 7.7 months. Pre-treatment CYFRA 21-1 levels were significantly associated with performance status (P=0.0399) and stage of disease (P=0.0001). Marker values before chemotherapy and at the 2-month staging of all three markers were considered significant predictors for objective treatment response. Pre-treatment CYFRA 21-1 levels, as well as CA 19-9 values, could be applied to define subgroups (categorised by tertiles) with a different OS outcome (CYFRA: 14.8 vs 7.1 vs 4.8 months, CA 19-9: 14.2 vs 7.1 vs 5.2 months; P<0.0001). CYFRA 21-1 and CA 19-9 (both as categorised and as continuous variables) showed a highly significant correlation with TTP and OS at nearly all-time points assessed in univariate analysis. In multivariate analysis, only CYFRA 21-1 and performance status were independent predictors for OS.Conclusions:CYFRA 21-1 may serve as a valuable tool for monitoring treatment response and assessing prognosis in advanced PC.

O3-005 - Phase 1 and 2 Trials of Combination Therapy with Gemcitabine and Candesartan in Advanced Pancreatic Cancer

ABSTRACT Background Inhibition of renin-angiotensin (RA) system is one of the attractive targets in the treatment of pancreatic cancer (PaC). Our retrospective analysis showed the association of inhibition of RA system with better prognosis in advanced PaC (Br J Cancer. 2010;103: 1644–8). Here we reported the results of phase 1 and 2 trials of gemcitabine and candesartan (GECA) therapy in advanced PaC. Patients In phase 1 trial in normotensive patients, candesartan was administered orally at escalating dose (4, 8, 16 and 32 mg) qd daily and gemcitabine was administered 1000 mg/m2 30 min i.v. day 1, 8, 15, repeated every 4 weeks. DLT was defined as grade 4 hematological toxic effects, Grade 2 hypotension, abnormal creatinine or potassium and grade 3 or 4 other non-hematological toxic effects. In phase 2 trial, candesartan was administered 16 mg in normotensive patients and 8 mg in patients with hypertension, followed by increase up to 16 mg in cases without adverse events. Eligible criteria were unresectable locally advanced or metastatic PaC without any prior treatment, ECOG PS 0-2, normal renal function and without hypotension. Results In phase 1 trial, 14 patients (locally advanced/metastatic 7/7, candesartan 4 mg: 3 patients, 8 mg: 3 patients, 16 mg: 6 patients, 32 mg: 2 patients) were enrolled between July 2009 and October 2010. One of six patients at 16 mg demonstrated DLT of grade 4 neutropenia and two of two patients at 32 mg demonstrated DLT of grade 2 hypotension. The response rate (RR) and the disease control rate (DCR) were 0% and 79%. Progression-free survival and overall survival were 7.6 and 22.9 months. In phase 2 trial, 35 patients (locally advanced/metastatic 9/26) were enrolled between May 2011 and December 2011. Major severe adverse events were neutropenia 24% and thrombocytopenia 18%. Grade 2 hypotension was seen in three patients. RR and DCR were 11% and 63%. Median PFS and OS were 4.3 and 7.7 months. Conclusion GECA in advanced PaC appeared safe and promising, though a phase 2 study failed to meet our primary objective of 5-month median PFS.