• 5-Fluorouracil
• Chemoresistance
• Cholesterol metabolism
• Cyclodextrins
• Gemcitabine
• KRAS
• Pancreatic cancer

• Humans
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/pathology
• Cholesterol/metabolism
• Animals
• Drug Resistance, Neoplasm
• Lipid Metabolism

• Humans
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/surgery
• Pancreatic Neoplasms/therapy
• Pancreatic Neoplasms/pathology
• Biliary Tract Neoplasms/mortality
• Biliary Tract Neoplasms/surgery
• Biliary Tract Neoplasms/pathology
• Liver Neoplasms/mortality
• Liver Neoplasms/surgery
• Liver Neoplasms/secondary
• Liver Neoplasms/therapy
• Retrospective Studies
• Disease-Free Survival
• Chemotherapy, Adjuvant
• Neoplasm Recurrence, Local
• Carcinoma, Pancreatic Ductal/mortality
• Carcinoma, Pancreatic Ductal/surgery
• Carcinoma, Pancreatic Ductal/therapy
• Carcinoma, Pancreatic Ductal/drug therapy
• Survival Rate
• Female
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/surgery
• Carcinoma, Hepatocellular/therapy
• Neoadjuvant Therapy
• Male
• Randomized Controlled Trials as Topic

• Local therapy
• Pancreatic ductal adenocarcinoma
• Recurrence

• Adenocarcinoma/pathology
• Carcinoma, Pancreatic Ductal/pathology
• Feasibility Studies
• Humans
• Neoplasm Recurrence, Local/pathology
• Pancreatectomy/methods
• Pancreatic Neoplasms/pathology
• Prognosis
• Recurrence
• Retrospective Studies
• Pancreatic Neoplasms

• Delphi Technique
• Humans
• Neoadjuvant Therapy
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/surgery

• 11883 Cancer Research UK
• 16186 Cancer Research UK
• 16812 Cancer Research UK
• 17680 Cancer Research UK
• 15957 Cancer Research UK
• 8968 Cancer Research UK

• chemotherapy
• pancreatic cancer
• survival

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Capecitabine/therapeutic use
• Carcinoma, Pancreatic Ductal
• Chemotherapy, Adjuvant
• Deoxycytidine/analogs & derivatives
• Humans
• Pancreatic Neoplasms/pathology
• Gemcitabine
• Pancreatic Neoplasms

• KWF Kankerbestrijding
• ZonMw

Significant advances in surgical techniques and perioperative care, together with adjuvant chemotherapy, have contributed to the increasing number of patients with pancreatic cancer undergoing surgery. However, the results of some studies suggest that the postoperative complications and mortality might be higher in elderly patients undergoing pancreatectomy. We aimed to identify the utility of S-1 adjuvant chemotherapy in elderly patients with resected pancreatic cancer. In our cohort of 80 patients, including 16 octogenarians, univariate and multivariate analyses revealed that S-1 adjuvant chemotherapy was associated with improved prognosis in patients with pancreatic cancer. However, we also observed that skeletal muscle loss and age of 80 years or older predicted the failure to complete adjuvant chemotherapy with S-1. We propose that evaluation of skeletal muscle mass should be considered as a useful preoperative assessment approach for determining feasibility of adjuvant chemotherapy in elderly patients.

The efficacy and prognosis of adjuvant chemotherapy for resected pancreatic cancer remain unclear. We investigated the utility and risk factors of S-1 adjuvant chemotherapy in patients with pancreatic cancer undergoing pancreatectomy. This study comprised 80 patients, including 58 patients who received S-1 adjuvant chemotherapy. Skeletal muscle loss was defined using cutoff values of skeletal muscle mass index. In total, 16 (20%) octogenarian patients underwent pancreatectomy. Skeletal muscle loss was present in 56 (70%) patients. The entire course of S-1 adjuvant chemotherapy for 6 months was completed in 33 patients (41%). S-1 adjuvant chemotherapy <6 months was an independent prognostic indicator of poor overall survival. Patients who completed S-1 adjuvant chemotherapy exhibited significantly longer overall and relapse-free survival rates than those did not complete the chemotherapy (p < 0.0001 and p = 0.0003, respectively). Being an octogenarian and skeletal muscle loss were independent variables associated with the discontinuation of S-1 adjuvant chemotherapy. Finally, the S-1 adjuvant chemotherapy rates were 6.3% (1/16) and 28.6% (16/56) in octogenarian patients and those with skeletal muscle loss, respectively. S-1 adjuvant chemotherapy completion was associated with improved prognosis in patients with pancreatic cancer. Skeletal muscle loss and octogenarian status predicted the failure of S-1 adjuvant chemotherapy completion.

• adjuvant chemotherapy
• elderly patients
• outcome
• pancreatic cancer
• sarcopenia

Multiple guidelines for pancreatic ductal adenocarcinoma (PDAC) suggest that all stages of patients need to receive postoperative adjuvant chemotherapy. S-1 is a recently emerged oral antitumour agent recommended by the guidelines. However, which population would benefit from S-1 needs to be determined, and predictors of chemotherapy response are needed for personalized precision medicine. This pilot study aimed to initially identify whether whole-tumour evaluation with MRI and radiomics features could be used for predicting the efficacy of S-1 and to find potential predictors of the efficacy of S-1 as evidence to assist personalized precision treatment.

Forty-six patients with PDAC (31 in the primary cohort and 15 in the validation cohort) who underwent curative resection and subsequently adjuvant chemotherapy with S-1 were included. Pre-operative abdominal contrast-enhanced MRI was performed, and radiomics features of the whole PDAC were extracted from the primary cohort. After univariable analysis and radiomics features selection, a multivariable Cox regression model for survival analysis was subsequently used to select statistically significant factors associated with postoperative disease-free survival (DFS). Predictive capacities of the factors were tested on the validation cohort by using Kaplan–Meier method.

Multivariable Cox regression analysis identified the probability of T₁WI_NGTDM_Strength and tumour location as independent predictors of the efficacy of S-1 for adjuvant chemotherapy of PDAC (p = 0.005 and 0.013) in the primary cohort, with hazard ratios (HRs) of 0.289 and 0.293, respectively. Further survival analysis showed that patients in the low-T₁WI_NGTDM_Strength group had shorter DFS (median = 5.1 m) than those in the high-T₁WI_NGTDM_Strength group (median = 13.0 m) (p = 0.006), and patients with PDAC on the pancreatic head exhibited shorter DFS (median = 7.0 m) than patients with tumours in other locations (median = 20.0 m) (p = 0.016). In the validation cohort, the difference in DFS between patients with low-T₁WI_NGTDM_Strength and high-T₁WI_NGTDM_Strength and the difference between patients with PDAC on the pancreatic head and that in other locations were approved, with marginally significant (p = 0.073 and 0.050), respectively.

Whole-tumour radiomics feature of T₁WI_NGTDM_Strength and tumour location were potential predictors of the efficacy of S-1 and for the precision selection of S-1 as adjuvant chemotherapy regimen for PDAC.

• Carcinoma, Pancreatic Ductal
• Drug therapy
• Magnetic resonance imaging
• Personalized medicine
• Radiomics
• Survival analysis

• ABO blood group
• biliary tract cancer
• pancreatoduodenectomy
• prognosis

• apoptosis
• cell cycle
• crocin
• hepatic injury
• pancreatic cancer
• radiation

• Animals
• Antineoplastic Agents, Phytogenic
• Apoptosis/drug effects
• Carotenoids/therapeutic use
• Cell Cycle Proteins/metabolism
• Cell Line, Tumor
• Cell Survival/drug effects
• Crocus/chemistry
• Cytochromes c/metabolism
• Female
• Humans
• Lipid Peroxidation/drug effects
• Liver Diseases/etiology
• Liver Diseases/prevention & control
• Mice
• Mice, Nude
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/radiotherapy
• Radiation Injuries/prevention & control
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Transcriptome
• Xenograft Model Antitumor Assays

• MPCST/YSFA/27/2012 M.P. Council of Science and Technology
• 295 Dowager Countess Eleanor Peel Trust

We aimed to assess whether disease-free survival (DFS) could serve as a reliable surrogate endpoint for overall survival (OS) in adjuvant trials of pancreatic cancer.

We systematically reviewed adjuvant randomized trials for non-metastatic pancreatic cancer after curative resection that reported a hazard ratio (HR) for DFS and OS. We assessed the correlation between treatment effect (HR) on DFS and OS, weighted by sample size or precision of hazard ratio estimate, assuming fixed and random effects, and calculated the surrogate threshold effect (STE). We also performed sensitivity analyses and a leave-one-out cross validation approach to evaluate the robustness of our findings.

After screening 450 relevant articles, we identified a total of 20 qualifying trails comprising 5170 patients for quantitative analysis. We noted a strong correlation between the treatment effects for DFS and OS, with coefficient of determination of 0.82 in the random effect model, 0.82 in the fixed effect model, and 0.80 in the sample size weighting; the robustness of this finding was further verified by the leave-one-out cross-validation approach. Sensitivity analyses with restriction to phase 3 trials, large trials, trials with mature follow-up periods, and trials with adjuvant therapy versus adjuvant therapy strengthened the correlation (0.75 to 0.88) between DFS and OS. The STE was 0.96 for DFS.

Therefore, DFS could be regarded as a surrogate endpoint for OS in adjuvant trials of pancreatic cancer. In future similar adjuvant trials, a hazard ratio for DFS of 0.96 or less would predict a treatment impact on OS.

• Disease-free survival
• Overall survival
• Pancreatic cancer
• Surrogate

• chemoradiation
• chemotherapy
• immunotherapy
• molecular mechanism
• pancreatic cancer
• surgery
• therapeutic targets
• treatment options

• Chemoradiotherapy, Adjuvant
• Chemotherapy, Adjuvant
• Clinical Trials as Topic
• Gene Expression Regulation, Neoplastic
• Humans
• Neoadjuvant Therapy/methods
• Palliative Care
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/therapy
• Treatment Outcome

Pancreatic cancer is one of the most common and lethal malignancies worldwide. The common treatment options for resectable pancreatic cancer include surgery alone, neoadjuvant chemotherapy (CT), neoadjuvant chemoradiotherapy (CRT), adjuvant CT, and adjuvant CRT. However, the optimal treatment is still controversial.

To identify the most effective approach for pancreatic cancer using network meta-analysis.

Eligible studies were searched from PubMed, MEDLINE, EMBASE, Cochrane database, and Google scholar. We searched and included randomized controlled trials reporting on neoadjuvant and adjuvant therapies. For direct comparisons, standard pairwise meta-analysis was performed using the inverse variance DerSimonian-Laird random-effects model. For indirect comparisons, Bayesian network meta-analysis was used to combine direct and indirect evidence. We used relative hazard ratios (HRs) to estimate death difference of different treatments, and relative odds ratios (ORs) for toxic effects. Treatment effects were ranked based on their efficacy for improving survival or reducing toxicity using rankogram. The quality of evidence of estimates from direct comparison and network meta-analysis was evaluated following the GRADE approach.

We included 13 high quality trials with 1591 participants in this network meta-analysis. Compared with surgery alone [pooled HR = 0.7, 95% confidence interval (CI): 0.62-0.79] and surgery with adjuvant CRT (pooled HR = 0.6, 95%CI: 0.54-0.72), surgery with adjuvant CT had a higher rate of overall survival. In contrast, standard pairwise meta-analysis showed a statistically significant survival advantage of surgery with adjuvant CT compared with surgery alone (pooled HR = 0.75, 95%CI: 0.63-0.89; P < 0.001). Rankogram showed that surgery with adjuvant CT was most likely to rank the best in terms of overall survival (probability: 94.2%), followed by surgery alone (probability: 5.8%). No significant differences in overall toxicity or haematological toxicity were found between all the therapies. High quality evidence supported surgery with adjuvant CT over surgery alone for increasing overall survival. Moderate quality evidence supported surgery with adjuvant CT over surgery with adjuvant CRT for increasing overall survival.

Surgery with adjuvant CT prolongs overall survival compared with surgery alone and surgery with adjuvant CRT, suggesting surgery with adjuvant CT is the optimal treatment for resectable pancreatic cancer.

• Pancreatic cancer
• Surgery
• Network meta-analysis
• Adjuvant therapy
• Neoadjuvant therapy

Neoadjuvant therapy has emerged as an alternative treatment strategy for potentially resectable pancreatic cancer. In the absence of large randomized controlled trials offering a direct comparison, this study aims to use Markov decision analysis to compare efficacy of traditional surgery first (SF) and neoadjuvant treatment (NAT) pathways for potentially resectable pancreatic cancer.

An advanced Markov decision analysis model was constructed to compare SF and NAT pathways for potentially resectable pancreatic cancer. Transition probabilities were calculated from randomized control and Phase II/III trials after comprehensive literature search. Utility outcomes were measured in overall and quality-adjusted life months (QALMs) on an intention-to-treat basis as the primary outcome. Markov cohort analysis of treatment received was the secondary outcome. Model uncertainties were tested with one and two-way deterministic and probabilistic Monte Carlo sensitivity analysis.

SF gave 23.72 months (18.51 QALMs) versus 20.22 months (16.26 QALMs). Markov Cohort Analysis showed that where all treatment modalities were received NAT gave 35.05 months (29.87 QALMs) versus 30.96 months (24.86QALMs) for R0 resection and 34.08 months (29.87 QALMs) versus 25.85 months (20.72 QALMs) for R1 resection. One-way deterministic sensitivity analysis showed that NAT was superior if the resection rate was greater than 51.04% or below 75.68% in SF pathway. Two-way sensitivity analysis showed that pathway superiority depended on obtaining multimodal treatment in either pathway.

Whilst NAT is a viable alternative to traditional SF approach, superior pathway selection depends on the individual patient’s likelihood of receiving multimodal treatment in either pathway.

• Adult
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Clinical Decision-Making
• Clinical Trials, Phase II as Topic
• Clinical Trials, Phase III as Topic
• Decision Support Techniques
• Disease-Free Survival
• Humans
• Intention to Treat Analysis
• Markov Chains
• Neoadjuvant Therapy/methods
• Pancreatectomy
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/therapy
• Patient Selection
• Quality-Adjusted Life Years
• Randomized Controlled Trials as Topic
• Survival Analysis
• Time Factors

• Chemotherapy
• Gemcitabine
• Meta-analysis
• Pancreatic cancer

• Antimetabolites, Antineoplastic/therapeutic use
• Chemotherapy, Adjuvant
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/therapeutic use
• Disease-Free Survival
• Humans
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/physiopathology
• Progression-Free Survival
• Randomized Controlled Trials as Topic
• Gemcitabine

Background and Aim: Pancreatic cancer is one of the most fatal cancers. Cytotoxic chemotherapy remains the mainstream treatment for unresectable pancreatic cancer. This systematic review evaluated and compared the overall survival (OS) and progression-free survival (PFS) outcomes obtained from recent phase 2 and 3 clinical trials of pancreatic cancer chemotherapy. Materials and methods: Thirty-two studies were included and compared based on chemotherapy agents or combinations used. Additionally, outcomes of first-line versus second-line chemotherapy in pancreatic cancer were compared. Results: In studies that investigated the treatments in adjuvant settings, the highest OS reported was for S-1 in patients, who received prior surgical resection (46.5 months). In neoadjuvant settings, the combination of gemcitabine, docetaxel, and capecitabine prior to the surgical resection had promising outcomes (OS of 32.5 months). In non-adjuvant settings, the highest OS reported was for the combination of temsirolimus plus bevacizumab (34.0 months). Amongst studies that investigated second-line treatment, the highest OS reported was for the combination of gemcitabine plus cisplatin (35.5 months), then temsirolimus plus bevacizumab (34.0 months). Conclusions: There is a need to develop further strategies besides chemotherapy to improve the outcomes in pancreatic cancer treatment. Future studies should consider surgical interventions, combination chemotherapy, and individualized second-line treatment based on the prior chemotherapy.

• chemotherapy
• first-line treatment
• pancreatic cancer
• second-line treatment
• survival

• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Capecitabine/therapeutic use
• Chemotherapy, Adjuvant/mortality
• Deoxycytidine/analogs & derivatives
• Deoxycytidine/therapeutic use
• Disease-Free Survival
• Docetaxel/therapeutic use
• Female
• Humans
• Male
• Neoadjuvant Therapy/mortality
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/mortality
• Survival Analysis
• Treatment Outcome
• Gemcitabine

• cancer
• tumour biomarkers

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor/metabolism
• Carcinoma, Pancreatic Ductal/diagnosis
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/metabolism
• Carcinoma, Pancreatic Ductal/mortality
• Deoxycytidine/administration & dosage
• Deoxycytidine/analogs & derivatives
• Dihydrouracil Dehydrogenase (NADP)/metabolism
• Equilibrative Nucleoside Transporter 1/metabolism
• Female
• Fluorouracil/administration & dosage
• Humans
• Immunohistochemistry
• Leucovorin/administration & dosage
• Male
• Middle Aged
• Pancreatic Neoplasms/diagnosis
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/mortality
• Prognosis
• Randomized Controlled Trials as Topic
• Survival Analysis
• Tissue Array Analysis
• Gemcitabine

• C245/A9855 Cancer Research UK
• C245/A 15957 Cancer Research UK
• 11883 Cancer Research UK
• RIF2014_03_COSTELLO Pancreatic Cancer UK
• 16186 Cancer Research UK
• 16812 Cancer Research UK
• 17680 Cancer Research UK
• 08/29/02 Department of Health
• 15957 Cancer Research UK
• 8968 Cancer Research UK
• 16791 Cancer Research UK
• C245/A82390 Cancer Research UK
• C35628/A11588 Cancer Research UK

A drug for metastasis prevention is necessary. The orally administered anticancer drug S‐1 contributes to cancer therapy. In a mouse xenograft model of metastatic breast cancer from our previous study, the administration of S‐1 inhibited lung metastasis. However, the mechanism of inhibition remains elusive. S‐1 contains 5‐chloro‐2,4‐dihydroxypyridine (CDHP), which does not have the antigrowth activity, but prevents the degradation of 5‐fluorouracil, an anticancer reagent. In this study, we found that CDHP treatment shrinks cell morphology in metastatic basal‐like breast cancer cell lines. Wound healing assays showed reduced cell migration in CDHP‐treated cells. At the molecular level, CDHP treatment reduced the number of nascent adhesions, whereas the number of mature focal adhesions was not changed. These findings indicate that CDHP impairs focal adhesion formation, which results in a reduction in cell migration. For the in vivo metastasis assay, we used a highly lung‐metastatic cell line. We xenografted them into immunodeficient mice, and administered CDHP. To determine whether CDHP prevents metastasis, we measured the weights of harvested lungs. The results showed that the lung weights of the CDHP‐treated animals were not significantly different compared to the no‐tumor controls, whereas the vehicle group showed a number of metastatic foci and an increase in lung weight. These observations indicate that CDHP administration prevents metastasis. This study reveals a novel effect of CDHP for lung metastasis prevention. Our findings may facilitate the establishment of future metastasis prevention therapies.

• 5-chloro-2,4-dihydroxypyridine
• S-1
• basal-like breast cancer
• gimeracil
• metastasis

• Deoxyribonucleotide triphosphate nucleoside pools balance
• Epithelial to mesenchymal transition
• Metastasis
• Pancreatic ductal adenocarcinoma
• Thymidylate synthase

Adjuvant chemotherapy improves survival in patients with resected pancreatic cancer but the optimal regimen remains unclear. We aim to compare all possible adjuvant chemotherapy in terms of overall survival and toxic effects. Pubmed, Trial registries and Cochrane library databases for randomized controlled trials were searched until November 2016. Thirteen trials were included for network analysis and the hazard ratios (HRs) for survival and odds ratios for toxic effects were assessed via Aggregate Data Drug Information System software. Only S-1 chemotherapy improved 1-year, 3-year and 5-year survival compared with observation (HR (95% CI): 3.94 (1.18–12.34); 4.08 (1.58–8.24) and 5.09 (1.16–29.83) respectively). Although not significant, gemcitabine plus uracil/tegafur was associated with poorer 1-year and 3-year survival compared with observation (HR (95% CI): 0.85 (0.16–4.03) and 0.86 (0.23–2.95)). Adding radiation to chemotherapy has no significant improvement in survival. S-1 and gemcitabine plus capecitabine are currently the most effective adjuvant therapies for pancreatic cancer. While S1 has only been validated in Asian people, higher toxicity is an issue for gemcitabine plus capecitabine.

• adjuvant chemotherapy
• network meta-analysis
• pancreatic cancer
• surgery resection
• toxic effect

The predictive roles of dihydropyrimidine dehydrogenase (DPD) in patients who undergo curative resection and adjuvant chemotherapy with S-1, which is the oral 5-fluorouracil prodrug tegafur combined with oteracil and gimeracil, remain unclear. In the present study, the clinical data from 66 consecutive patients who underwent curative resection and received adjuvant chemotherapy with S-1 for the treatment of pancreatic cancer at Kanagawa Cancer Center (Yokohama City, Japan) from April 2005 to March 2014 were retrospectively analyzed. The association between the DPD status and the survival and clinicopathological features were investigated. Of the 66 patients, 34 patients exhibited positive DPD expression (51.5%). Although a significant increase in DPD expression in male patients was observed, no significant differences were identified for other clinicopathological parameters, including tumor factor or node factor, between the DPD-positive expression group and the DPD-negative expression group. The median follow-up period of the present study was 29.2 months. There was no significant difference in the 3-year overall survival (OS) rates following surgery, which were 12.6 and 14.5% in the DPD-positive and DPD-negative expression groups, respectively (P=0.352). However, in a subgroup analysis, a significant difference in the 3-year OS rates following surgery was noted, which were 58.9 and 14.5% in the DPD-high and DPD-low expression groups, respectively (P=0.019). The intratumoral DPD expression in curatively resected pancreatic cancer patients treated with S-1 adjuvant chemotherapy was identified to not be useful as a predictive marker, whereas the level of DPD expression is a potential predictive marker. The results of the present study require confirmation in another cohort or in a prospective multicenter study.

• S-1
• adjuvant chemotherapy
• dihydropyrimidine dehydrogenase
• pancreatic cancer

• Adjuvant
• Chemotherapy
• Pancreatic ductal adenocarcinoma
• Radiotherapy
• Target therapy

• Chemotherapy
• Imaging
• Pancreatic cancer
• Pathology
• Radiotherapy
• Targeted therapy