Chemotherapy In Pancreatic Cancer Patients Research Articles

Promising biomarker panel to monitor therapeutic efficacy of neoadjuvant chemotherapy in pancreatic cancer patients.

Neoadjuvant chemotherapy (NAC) can provide improved survival outcomes in pancreatic ductal adenocarcinoma (PDAC) patients who respond to treatment, but currently available biomarkers cannot reliably predict NAC response. This study aimed to determine the potential of a previously identified diagnostic and prognostic biomarker panel (i.e. Ca-125, S100A2, S100A4, Mesothelin and Ca19-9) for the monitoring of NAC-response in PDAC patients. This single-centre, retrospective study, utilised serum from NAC treated PDAC patients to determine the levels of biomarkers by Enzyme-Linked Immunosorbent Assay (ELISA). The percentage of the tumour bed occupied by viable carcinoma (PVC) was used to divide patients into good (PVC < 50%) and poor (PVC ≥ 50%) NAC-responders. Statistical analysis was performed to measure the ability of individual biomarkers and a biomarker panel in NAC treatment response and patient survival. Serum specimens from a total of 108 PDAC patients were assessed. Ca-125, Ca19-9 and S100A2 showed a significant positive correlation with PVC. Ca-125 demonstrated a superior ability to monitor NAC treatment response (Area under receiver operating curve (AUC): .6954) compared to the more widely used clinical biomarker, Ca19-9 (AUC: .6291). A panel of Ca-125 and Ca19-9 showed good ability to monitor NAC response in PDAC patients (AUC: .7349). Patients with high levels of both Ca-125 and Ca19-9 were shown to have the poorest overall survival (median overall survival: 17 vs. 30 months). A serum biomarker panel of Ca-125 and Ca19-9 could be used for effective clinical management of PDAC patients undergoing NAC treatment.

Impact of proton pump inhibitors on pathologic response rates following fluoropyrimidine-based neoadjuvant chemotherapy in pancreatic cancer patients.

Proton pump inhibitors (PPIs) negatively impact fluoropyrimidine-based chemotherapy efficacy in colorectal cancer. This study assessed PPI impact on major pathologic response (mPR) rates of pancreatic adenocarcinoma (PDAC) patients receiving fluoropyrimidine-based chemotherapy. An institutional retrospective review of resected PDAC patients receiving neoadjuvant fluoropyrimidine-based chemotherapy (98% FOLFIRINOX) from 2011 to 2021 was conducted. Outcomes were stratified by use or nonuse of PPIs within 6 months of neoadjuvant chemotherapy initiation. Primary outcome was mPR defined as complete or near complete response. Among 540 patients included, the median age was 64 (IQR: 60-70) years, 297 (55%) were male, and 202 (37%) were PPI users. 170 (31%) patients had mPR with similar rates among PPI users and nonusers (29% vs. 33%, p = 0.38). No difference in mPR was seen between PPI users and nonusers receiving chemoradiation (35% vs. 36%, p = 0.89) or ≥8 cycles of NAC (33% vs. 36%, p = 0.55). Median OS for PPI users was 30.9 versus 31.7 months for nonusers (p = 0.62). On multivariable analysis, PPI therapy was not associated with decreased survival. PPI usage did not significantly influence mPR or OS following neoadjuvant fluoropyrimidine-based chemotherapy in resected PDAC patients. Further analysis of all patients, not just those who underwent resection, is required.

382P Gut microbiome profiles as a novel predictor of tumor response to chemotherapy in pancreatic cancer patients

382P Gut microbiome profiles as a novel predictor of tumor response to chemotherapy in pancreatic cancer patients

Effect of surgery versus chemotherapy in pancreatic cancer patients: a target trial emulation.

To estimate the causal effect of surgery vs chemotherapy on survival in patients with T1-3NxM0 pancreatic cancer in a rigorous framework addressing selection bias and immortal time bias. We used population-based Danish health-care registries to conduct a cohort study emulating a hypothetical randomized trial to estimate the absolute difference in survival, comparing surgery with chemotherapy. We included pancreatic cancer patients diagnosed during 2008-2021. Exposure was surgery or chemotherapy initiated within a 16-week grace period after diagnosis. At the time of diagnosis, data of each patient were duplicated; one copy was assigned to the surgery protocol, and one copy to the chemotherapy protocol of the hypothetical trial. Copies were censored when the assigned treatment deviated from the observed treatment. To account for informative censoring, uncensored patients were weighted according to confounders. For comparison, we also applied a more conventional analysis using propensity score-based inverse probability weighting. We included 1744 patients with a median age of 68 years: 73.6% underwent surgery, and 18.6% had chemotherapy without surgery; 7.8% received no treatment. The 3-year survival was 39.7% (95% confidence interval [CI] = 36.7% to 42.6%) after surgery and 22.7% (95% CI = 17.7% to 28.4%) after chemotherapy, corresponding to an absolute difference of 17.0% (95% CI = 10.8% to 23.1%). In the conventional survival analysis, this difference was 23.0% (95% CI = 17.0% to 29.0%). Surgery was superior to chemotherapy in achieving long-term survival for pancreatic cancer. The difference comparing surgery and chemotherapy was substantially smaller when using the clone-censor-weight approach than conventional survival analysis.

Effect of surgery versus chemotherapy in pancreatic cancer patients: a cohort study emulating a target trial

Effect of surgery versus chemotherapy in pancreatic cancer patients: a cohort study emulating a target trial

Clinical outcomes and response to chemotherapy in a cohort of pancreatic cancer patients with germline variants of unknown significance (VUS) in BRCA1 and BRCA2 genes.

The clinical outcome and the efficacy of chemotherapy in pancreatic cancer patients with BRCA1/2 Variants of Unknown Significance (VUS) is unknown. We explored the effects of chemotherapy with or without Platinum in non metastatic and metastatic pancreatic cancer patients with BRCA1/2 VUS. A retrospective analysis of non-metastatic or metastatic pancreatic cancer patients with gBRCA1/2 VUS treated in 13 Italian centers between November 2015 and December 2020 was performed. All patients were assessed for toxicity and RECIST 1.1 response. Metastatic patients were evaluated for survival outcome. 30 pancreatic cancer patients with gBRCA1/2 VUS were considered: 20 were M+ and 10 were non-M+. Pl-CT was recommended to 16 patients: 10 M+ (6 FOLFIRINOX and 4 PAXG) and 6 non-M+ (3 FOLFIRINOX and 3 PAXG); 11 patients received Nabpaclitaxel-Gemcitabine (AG; 8 M+) and 3 patients (2 M+) were treated with Gemcitabine (G). The RECIST 1.1 response rate was 27% for AG and 44% for Pl-CT (22% for (m) FOLFIRINOX and 71% PAXG). 1year Progression-Free Survival was 37.5% for patients treated with AG and 33% in the Pl-CT subgroup. Median Overall Survival (OS) was 23.5months for patients treated with AG and 14months for the Pl-CT subgroup. 1Year and 2Year OS were numerically better for AG (1Year OS: 75% vs 60% and 2Year OS: 50% and 20% in AG and Pl-CT subgroups, respectively) as well. Pl-CT does not seem to be associated with a better outcome compared to AG chemotherapy in PDAC patients with BRCA 1/2 VUS.

Exercise intervention during chemotherapy for pancreatic cancer: Changes in body composition and function

AbstractBackgroundPatients with pancreatic cancer often lose weight during chemotherapy with associated changes in body composition. The goal of the present analysis was to describe changes in body composition in pancreatic cancer patients on an exercise regimen. The long‐term goal is to determine whether an exercise intervention may attenuate changes in body composition and function.MethodsTwenty‐two pancreatic cancer patients of all stages who were to receive chemotherapy were recruited into a pre‐post exercise intervention study. A standard exercise prescription was individualized to include aerobic, resistance, stretch, and balance exercises. Pre‐ and post‐intervention computed tomography‐derived measures of body composition [skeletal muscle index (SMI), skeletal muscle density, visceral fat area, and subcutaneous fat area] and physical function measures (grip strength, timed up and go, 30‐s chair stand, and tandem balance stand) were evaluated using paired t‐tests, χ2 tests, and Pearson correlation coefficients.ResultsThe subjects were, on average, 62 years of age, 55% were female, 95% non‐Hispanic White, and 45% were Stage IV. Body composition changes included a median 4.6% decrease in SMI (P = 0.04), 7.91% increase in skeletal muscle density (P = 0.05), 25.07% decrease in visceral fat area (P = 0.0001), and 22.08% decrease in subcutaneous fat area (P = 0.001). Adherence to aerobic and strength exercise was 65% and 57%, respectively. Some physical function measures improved, though not significantly: chair stands increased from a mean of 11.5 to 13.0 (P = 0.59) and timed up and go improved from a mean of 11.7 to 10.3 (P = 0.26). Change in right hand grip strength was marginally positively associated with changes in SMI (r = 0.53, P = 0.06). Improvements in skeletal muscle density were seen in 63% of patients, including Stage IV patients but did not correlate with change in function.ConclusionsExercise is feasible during neoadjuvant chemotherapy for pancreatic cancer patients of all stages and may assist with maintaining physical function and improving body composition. Further research is needed.

Calcium channel blockers potentiate gemcitabine chemotherapy in pancreatic cancer.

There is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC). While palliative chemotherapy offers a survival benefit to most patients, nearly all will eventually progress on treatment and long-term survivability remains poor. Given the lack of subsequent line treatment options, in this study, we sought to identify novel strategies to prevent, delay, or overcome resistance to gemcitabine, one of the most widely used medications in PDAC. Using a combination of single-cell RNA sequencing and high-throughput proteomic analysis, we identified a subset of gemcitabine-resistant tumor cells enriched for calcium/calmodulin signaling. Pharmacologic inhibition of calcium-dependent calmodulin activation led to the rapid loss of drug-resistant phenotypes in vitro, which additional single-cell RNA sequencing identified was due to impaired activation of the RAS/ERK signaling pathway. Consistent with these observations, calcium chelation or depletion of calcium in the culture media also impaired ERK activation in gemcitabine-resistant cells, and restored therapeutic responses to gemcitabine in vitro. We observed similar results using calcium channel blockers (CCBs) such as amlodipine, which inhibited prosurvival ERK signaling in vitro and markedly enhanced therapeutic responses to gemcitabine in both orthotopic xenografts and transgenic models of PDAC. Combined, these results offer insight into a potential means of gemcitabine resistance and suggest that select CCBs may provide a clinical benefit to PDAC patients receiving gemcitabine-based chemotherapy.

Role of Chemoradiation in the Adjuvant Treatment of Radically Resected Pancreatic Cancer Patients: A Mono-Institutional Retrospective Analysis.

Pancreatic cancer (PC) represents an unfavorable prognosis condition, even in patients with resectable disease. The aim of this series was to investigate the role of treatment intensification with adjuvant chemoradiation (CRT) in radically resected PC patients. Data from PC patients who underwent radical surgery, adjuvant chemotherapy (CT), and CRT throughout a 20-year period were retrospectively collected. Actuarial local control (LC) and the overall survival (OS) were the primary endpoints, with disease-free survival and metastasis-free survival (MFS) representing secondary endpoints. The analysis included 108 PC patients treated with adjuvant CRT and CT from January 2000 to August 2019. Median age was 66 years (range: 40-83), and all patients underwent radical surgical resection with adjuvant CT (88, 81.5%) plus concomitant CRT (101, 93.5%) or radiotherapy alone (7, 6.5%). The median dose delivered to the tumor bed was 50.4 Gy (range: 45-50.6 Gy), while median dose to regional lymphatic drainage stations was 39.6 Gy (range 39.6-45 Gy). Concomitant CT was a gemcitabine-based regimen in the vast majority of patients (87, 80.6%). Median follow-up time was 21 months; the 2- and 5-year LC rates were 75.8% and 59.1%, respectively. Perineural invasion at pathological assessment was found significantly associated with LC (p = 0.028). Median OS was 40 months with 2- and 5-year OS rates of 73.9% and 41.6%, respectively. The outcomes of this series suggest to investigate the possible impact of adding adjuvant CRT to CT in PC patients. Timing and combination of modern CRT with new systemic therapies need to be further investigated to personalize therapy and optimize clinical advantages.

Gender-specific side effects of chemotherapy in pancreatic cancer patients.

Pancreatic carcinoma incidence showed a significant increase in men over the last few years and the prognosis remains poor. Patients are treated with different pharmacological plans with no evidence about gender-specific adverse effects. We aimed to investigate differences in the incidence of chemotherapy side effects in the treatment of pancreatic cancer, to provide insights toward a personalized assistance based in individual needs. The sample population is composed of 207 patients. Regression model highlighted the predictive role of female gender for alopecia, constipation, hand-foot syndrome, and epigastric pain. Also, considering single therapeutic schemes, gender differences have been reported. Moreover, evaluating the effect of age, a general reduced risk of toxicity has been reported in younger patients. To personalize chemotherapy and increase patient survival rate and life quality during the therapy, gender medicine and pharmacology studies are recommended.

PRELIMINARY EVALUATION OF THE EFFECTIVENESS OF HIFU-THERAPY IN PATIENTS WITH PANCREATIC CANCER

Purpose: to conduct a preliminary analysis of the safety and effectiveness of hifu-therapy with a lowenergy hifu-2001 device (shenzhen Huikang Medical apparatus Co., ltd) performed concurrently with chemotherapy in pancreatic cancer patients who are not suitable for surgery or chemoradiotherapy.Material and Method. The study included 24 pancreatic cancer patients who were treated at the Hertsen Moscow Oncology Research institute in the period from 2016 to 2019. There were 17 (71 %) women and 7 (29 %) men. The percentage of patients in the elderly group was 79 %. Stage iia pancreatic cancer was diagnosed in 3 (12.5 %) patients, stage ii in 5 (21 %) patients, stage iii in 9 (37.5 %) patients, and stage iv in 7 (29 %) patients. All patients received combination therapy, including systemic chemotherapy and hifu-therapy. Results. The most frequent adverse events of treatment were skin burns (n=6), with third-degree burns occurring in 2 (8.3 %) patients. Local sclerosis of subcutaneous adipose tissue was observed in 4 (17 %) patients; development of asymptomatic pancreatic pseudocysts in the area of hifu exposure was observed in 1 (4 %) patient. Pain control was achieved in 17 (85 %) patients, and local tumor control was achieved in 19 (79.2 %) patients. The follow-up time ranged from 5 to 30 months with a median time of 14.5 months. The median total life expectancy of patients was 16 months, and the median time to progression was 9 months. The overall 6-month survival rate was 100 %. The 1- and 1.5-year survival rates were 75.0 % and 41.7 %, respectively. The 2-year survival rate was 17.2 %. The 6-month and 1-year disease-free survival rates were 62.5 % and 12.5 %, respectively. Conclusion. The short- and long-term outcomes were consistent with those described in other studies, which indicated that a combination of systemic drug therapy and hifu-therapy is an appropriate approach for the treatment of patients with pancreatic cancer.

Hyperthermic intra-operative intraperitoneal chemotherapy as an adjuvant to pancreatic cancer resection

Even after potentially curative resection the long-term survival of pancreatic cancer is poor. The local-regional failures are frequent. Previous studies have shown that adjuvant treatment with hyperthermic intra-operative intraperitoneal chemotherapy (HIPEC) may effectively control local disease. The objective of the study is to update the results of the prior publications by integrating data from recently accrued cases. Also, to revisit the clinical and pharmacological rationale for the intraperitoneal administration of chemotherapy in pancreatic cancer patients undergoing potentially curative resection. This is a prospective study of pancreatic cancer patients that underwent R0 resection in combination with HIPEC-gemcitabine. Morbidity and mortality were recorded. Survival was calculated and the sites for recurrent disease were recorded. The updated results for 33 patients that underwent treatment until 2016 and for 6 more patients that were included until 2018 were presented. The hospital mortality and morbidity rate were 5.1% (2 patients), and 28.2% (11 patients) respectively. The median and 5-year survival rate was 17 months and 24% respectively. With a median follow-up time of 13 months 23 patients (59%) were recorded with recurrence. Local regional failures were recorded in 4 patients (10.3%). HIPEC following R0 resection is a feasible and safe adjuvant treatment for pancreatic cancer. The local-regional failures appear to be significantly decreased and to result in an increased overall survival. Further studies with combined intraperitoneal and systemic perioperative chemotherapy may serve to supplement our data with an increased benefit for patients having pancreas cancer resection.

Circulating cytokine levels as biomarkers for response to FOLFIRINOX chemotherapy in pancreatic cancer patients

Introduction: FOLFIRINOX chemotherapy is currently standard treatment in patients with advanced pancreatic cancer (PDAC) and is being investigated as neoadjuvant treatment in resectable disease. However, patient stratification is essential, because of the low response to FOLFIRINOX and severe side effects. The balance of tumor-promoting and tumor-suppressing components of the immune system plays a crucial role in cancer progression and treatment response. Cytokines are key players in immune cell signaling. The aim of this study was to identify circulating cytokines as potential biomarkers for FOLFIRINOX response. Methods: Serum samples of 88 PDAC patients were prospectively collected before and after one cycle of FOLFIRINOX chemotherapy. Patients were categorized as disease control patients (DC) or progressive disease patients (PD), based on the RECIST criteria. Cytokine detection rates and concentrations were measured using a 34-plex Luminex immunoassay (Procarta). Results: Before start of treatment, the detection rate of IL-2 was higher in DC compared to PD (21.1% vs 0%, p=0.031), but not after chemotherapy. Only after chemotherapy, the detection rate of IL-1RA was higher in DC compared to PD (50.9% vs 21.1%, p=0.032). The IL-1RA detection rate increased during chemotherapy in DC patients only (1.8% before, 50.9% after, p< 0.001). Moreover, absolute IL-1RA concentrations increased in DC patients (0.00 pg/mL before, 16.85 pg/mL after, p< 0.001), but not in PD patients. Conclusions: IL-2 and IL-1RA are differentially expressed in serum of PDAC patients with DC and patients with PD after FOLFIRINOX chemotherapy. Cytokines are promising biomarkers to aid chemotherapy decision making in PDAC patients.

Laparoscopic Pancreaticoduodenectomy with Superior Mesenteric Vein Resection and Artificial Vascular Graft Reconstruction for Borderline Resectable Pancreatic Cancer

BackgroundLaparoscopic pancreaticoduodenectomy (LPD) technique with artificial vascular graft reconstruction for patients with borderline resectable pancreatic cancer has been rarely reported since it is a very challenging technique. However, preliminary experience for the technique has been reported at the Department of Pancreatic Surgery, West China Hospital, Sichuan University.1,2 The rising popularity of neoadjuvant chemotherapy for pancreatic cancer patients may result in the increase of operative difficulty due to tissue edema and many other factors caused by the chemotherapy. The main aim of this study was to demonstrate the feasibility, safety, and key surgical procedure for LPD using video evidence. MethodsA three-dimensional upper abdominal computed tomography angiography (CTA) scan done to a 51-year-old man brought to the center with upper abdominal pain showed a mass in the uncinate process of the pancreas, with over 180-degree involvement of the superior mesenteric vein. Percutaneous transhepatic cholangial drainage (PTCD) was performed to reduce jaundice while endoscopic ultrasound and fine-needle aspiration (EUS-FNA) were done to confirm the diagnosis of adenocarcinoma. The patient underwent two cycles of neoadjuvant chemotherapy using albumin-bound paclitaxel gemcitabine + program. The chemotherapy helped in significantly relieving the symptoms where CA 199 reduced from 586.7 IU/ml to 36.73 IU/ml, and the tumor maximum diameter was reduced from 4.3 cm to 2.2 cm. The violated superior mesenteric vein (SMV) and the tumor were en bloc resected, and a 4.0-cm artificial vascular graft was placed for reconstruction. Bing’s anastomosis was performed using pancreaticojejunostomy3 while cholangiojejunostomy was performed using continuous stitching. The gastroduodenal artery (GDA) stump was wrapped with ligamentum teres hepatis after the completion of gastrointestinal anastomosis. The specimen was then removed through the extended umbilical incision (4 cm) and the operation was completed after the drainage tube was placed. ResultsThe length of intraoperative excisional SMV, duration of artificial vascular graft reconstruction, operation time, and volume of intraoperative blood loss were 4.0 cm, 30 min, 520 min, and 800 mL, respectively. Histopathological examination of ypT2N1 indicated that 1 of the 27 lymph nodes was positive. Pathological results showed a moderately differentiated adenocarcinoma with all margins being negative. ConclusionsThis study demonstrated the feasibility of total laparoscopic pancreaticoduodenectomy combined with vascular resection and artificial vascular graft reconstruction in properly selected cases of pancreatic cancer with vein involvement after neoadjuvant chemotherapy. It is worth noting that skilled laparoscopic technicians and effective teamwork are necessities for safe completion of the procedure.

Real-world survival outcomes of using neoadjuvant chemotherapy in pancreatic cancer patients: Findings from the PURPLE clinical registry.

e16755 Background: Only a minority of pancreatic cancer patients (pts) are surgical candidates at presentation. Neoadjuvant chemotherapy (NAT) is proposed to increase the proportion of surgical candidates. This study investigates the impact of NAT in routine care of pancreatic cancer. Three cohorts were analysed, patients with early-stage resectable (ER), borderline resectable (BR) and locally advanced (LA) pancreatic cancer. Within these groups, survival outcomes of those undergoing immediate resection (IR) was compared to those receiving NAT with nab-paclitaxel and Gemcitabine (nabPGem) and NAT with FOLFIRINOX. Methods: The PURPLE registry consists of 1492 pancreatic cancer pts from 27 hospitals in Australia, New-Zealand and Singapore, collated between 2016-2019. After exclusion of LA unresectable and metastatic pts (n = 809), 683 pts were included. Kaplan-Meir curves estimated survival between groups with 95% confidence intervals. Multivariable cox proportional hazards models adjusted for age, gender and ECOG performance status. Results: Of 683 pts, 107 received NAT and 576 underwent IR. Those in the NAT group had favourable characteristics, including younger age (mean 63 vs. 66 yrs, p &lt; 0.01) and higher proportion of ECOG 0 vs. ≥1 (64% vs 46%) than those undergoing IR. Of those that received NAT, 64 received FOLFIRINOX and 35 nabPGem. Those receiving FOLFIRINOX were younger (mean: 60 vs. 67 yrs, p &lt; 0.01) and were more likely ECOG 0 compared to those receiving nabPGem (72% vs. 46%, p = 0.02). Resection rates for pts undergoing IR vs. NAT were 88% vs. 50% in ER and 16% vs. 43% in BR. Rates of R0 resection margins in pts undergoing IR vs. NAT were 54% vs. 25% in ER and 6% vs. 21% in BT. Comparing ER to BR, mOS was 29.9 vs. 20.3 mths (HR: 0.54, p &lt; 0.01). Within BR, mOS was 20.3 vs. 17.2 mths for NAT vs. IR (HR: 1.11, p = 0.74). Comparing those receiving FOLFIRINOX vs. nabPGem over all groups, mOS was 22 mths vs. 12 mths (HR: 0.31, p &lt; 0.01). Conclusions: Real-world data confirms the use of NAT remains infrequent in this Asia-Pacific population. The use of FOLFIRINOX was associated with better survival than nabPGem based on this observational study. Improved methods for treatment selection are required. Potential biomarkers including circulating tumor DNA are being explored in the DYNAMIC-Pancreas clinical trial.

Pharmacometabolomics Identifies 3-Hydroxyadipic Acid, d-Galactose, Lysophosphatidylcholine (P-16:0), and Tetradecenoyl-l-Carnitine as Potential Predictive Indicators of Gemcitabine Efficacy in Pancreatic Cancer Patients.

Gemcitabine (GEM)-based chemotherapy is the standard regimen for the treatment of pancreatic cancer (PC). However, chemoresistance is a major challenge in PC treatment. Reliable biomarkers are urgently needed to predict the response to GEM-based therapies. GEM-sensitive (GEM-S) and GEM-resistant (GEM-R) pancreatic carcinoma xenograft models were established, and GEM monotherapy and GEM plus nanoparticle albumin-bound paclitaxel (nab-PTX) doublet therapy were administered to GEM-S/R tumor-bearing mice. Metabolomic mass spectrometry (MS) analysis of serum, liver, and tumor samples was performed using an ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometer. The results showed that both GEM monotherapy and combination therapy significantly inhibited the tumor growth in GEM-S subgroup. However, in the GEM-R subgroup, tumor growth was not significantly inhibited by GEM monotherapy, but was significantly suppressed by GEM combination therapy. Metabolic profiling analysis by hierarchical cluster analysis and partial least squares discriminant analysis showed that the differences in metabolites were most significant in serum of three types of samples in the GEM-S/R subgroups, regardless of the administration of GEM monotherapy or combination therapy. The differential metabolite analysis of serum samples revealed 38 and 26 differential metabolites between the GEM-R and GEM-S subgroups treated with GEM monotherapy or combination therapy, and four common discriminating metabolites were investigated: 3-hydroxyadipic acid, d-galactose, lysophosphatidylcholine (LysoPC) (P-16:0), and tetradecenoyl-l-carnitine. The relative amounts of the four metabolites changed significantly and consistently after GEM monotherapy or combination therapy. The levels of these four metabolites were significantly different in the GEM-S and GEM-R pancreatic carcinoma xenograft models; thus, these metabolites could be effective predictive indicators of the efficacy of chemotherapy in PC patients, regardless of the administration of GEM alone or GEM plus nab-PTX.

MiRNA Predictors of Pancreatic Cancer Chemotherapeutic Response: A Systematic Review and Meta-Analysis.

Background: pancreatic cancer (PC) has increasing incidence and mortality in developing countries, and drug resistance is a significant hindrance to the efficacy of successful treatment. The objective of this systematic review and meta-analysis was to evaluate the association between miRNAs and response to chemotherapy in pancreatic cancer patients. Methods: the systematic review and meta-analysis was based on articles collected from a thorough search of PubMed and Science Direct databases for publications spanning from January 2008 to December 2018. The articles were screened via a set of inclusion and exclusion criteria based on the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. Data was extracted, collated and tabulated in MS Excel for further synthesis. Hazard ratio (HR) was selected as the effect size metric to be pooled across studies for the meta-analysis, with the random effects model being applied. Subgroup analysis was also conducted, and the presence of publication bias in the selected studies was assessed. Publication bias of the included studies was quantified. Findings: of the 169 articles screened, 43 studies were included in our systematic review and 13 articles were included in the meta-analysis. Gemcitabine was observed to be the principal drug used in a majority of the studies. A total of 48 miRNAs have been studied, and 18 were observed to have possible contributions to chemoresistance, while 15 were observed to have possible contributions to chemosensitivity. 41 drug-related genetic pathways have been identified, through which the highlighted miRNA may be affecting chemosensitivity/resistance. The pooled HR value for overall survival was 1.603; (95% Confidence Interval (CI) 1.2–2.143; p-value: 0.01), with the subgroup analysis for miR-21 showing HR for resistance of 2.061; 95% CI 1.195–3.556; p-value: 0.09. Interpretation: our results highlight multiple miRNAs that have possible associations with modulation of chemotherapy response in pancreatic cancer patients. Further studies are needed to discover the molecular mechanisms underlying these associations before they can be suggested for use as biomarkers of response to chemotherapeutic interventions in pancreatic cancer.

Circulating Biomarkers for Prediction of Objective Response to Chemotherapy in Pancreatic Cancer Patients.

Pancreatic cancer is a lethal disease with increasing incidence. Most patients present with advanced disease, for which palliative systemic chemotherapy is the only therapeutic option. Despite improved median survival rates with FOLFIRINOX or gemcitabine chemotherapy compared to the best supportive care, many individual patients may not benefit from chemotherapy. Biomarkers are needed to predict who will benefit from chemotherapy and to monitor a patient’s response to chemotherapy. This review summarizes current research and future perspectives on circulating biomarkers for systemic chemotherapy response.

Positive relationship between subsequent chemotherapy and overall survival in pancreatic cancer: meta-analysis of postprogression survival for first-line chemotherapy.

To gain a better understanding of the impact of postprogression survival (PPS) and post-trial anticancer therapy on overall survival (OS) in first-line pancreatic cancer patients. A literature search identified 54 randomized trials, focusing on gemcitabine monotherapy to eliminate effects of heterogeneity of first-line regimens. We evaluated the relation between OS and either progression-free survival (PFS) or PPS. We also examined whether any association might be affected by the year of completion of trial enrollment. For all 54 trials, PPS was strongly associated with OS (r = 0.844), whereas PFS was moderately associated with OS (r = 0.623). Average OS and PPS were significantly longer in recent trials than in older trials, (7.29 versus 6.15 months, p < 0.001) and (3.64 versus 2.86 months, p < 0.001), respectively. The correlation between OS and PPS in recent trials was much stronger than that in older trials (r = 0.846 versus 0.729). The relation between OS and PFS in recent and older trials did not differ (r = 0.595 versus 0.563). The percentage of patients with post-trial treatment was significantly higher in recent trials than in older trials (52.7 versus 39.7%, p < 0.001). The rate of post-trial anticancer therapy was significantly associated with OS (r = 0.910). We found an increase in median PPS in accordance with an increase in median OS in recent trials compared with older trials and that rate of post-trial anticancer therapy was strongly associated with median OS. It is important that researchers be aware of these findings in designing clinical trials of first-line chemotherapy for pancreatic cancer patients.

The Values of Several Inflammatory Markers, Including the Neutrophil/Lymphocyte Ratio, in Patients With Pancreatic Cancer Treated by Curative Resection Followed by Adjuvant Chemotherapy

The aim of this study was to determine the relationship between the values of several systemic inflammatory markers and the prognosis in pancreatic cancer patients treated by curative resection followed by adjuvant chemotherapy. A total of 110 pancreatic cancer patients treated by curative resection followed by adjuvant chemotherapy were reviewed for this study. Univariate and multivariate analyses were performed to identify the clinicopathologic factors influencing the overall survival, including the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), Glasgow prognostic score (GPS), and the direction of change of the NLR (increase or decrease) after 1 cycle of adjuvant chemotherapy, compared to the value recorded prior to the start of the chemotherapy. A multivariate analysis identified only the direction of change of the NLR after the first cycle of adjuvant chemotherapy as an independent risk factor for the overall survival (NLR decrease versus NLR increase, hazard ratio = 1.925; P = 0.044). The NLR, PLR and GPS were not identified as significant predictors of the overall survival. The direction of change of the NLR after the first cycle of adjuvant chemotherapy may help in predicting the effect of chemotherapy in pancreatic cancer patients treated by curative resection followed by adjuvant chemotherapy.