FOLFIRINOX Chemotherapy in Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis of Retrospective and Phase II Studies

Yang

et al. 2019

Cancers

Both gemcitabine and fluoropyrimidine are recommended backbones in the first-line treatment of pancreatic ductal adenocarcinoma (PDAC). To compare the efficacy and safety of these two therapeutic backbones, and to investigate the optimal therapies, we conducted a network meta-analysis. By retrospective analysis of randomized controlled trials (RCT), the most preferred therapeutic regimen may be predicted. The eligible RCTs of the gemcitabine-based therapies and fluoropyrimidine-based therapies were searched up to 31 August 2019. In a frequentist network meta-analysis, treatments were compared and ranked according to overall survival (OS) and progression-free survival (PFS). Thirty-two trials with 10,729 patients were included. The network meta-analyses results for overall survival and progression-free survival showed that fluoropyrimidine-based therapy seems to be the most effective treatment choice. Compared to gemcitabine combined with taxanes or immunotherapy, fluoropyrimidine-based therapy had comparable treatment effects (PFS: 0.67, p-Value = 0.11; 0.76, p-Value = 0.32; OS: 0.80, p-Value = 0.16; 0.77, p-Value = 0.21). Moreover, the combination of immunotherapy and gemcitabine had tolerable toxicities. Based on current evidence, fluoropyrimidine-based therapies and the combination of gemcitabine and taxanes were the most effective therapies in the advanced pancreatic cancer, and the combination of immunotherapy and gemcitabine can be developed into a new form of therapy.

Section: Discussionsupporting

confidence: 89%

Network Meta-Analysis of Efficacy and Safety of Chemotherapy and Target Therapy in the First-Line Setting of Advanced Pancreatic Cancer

Yang

et al. 2019

Cancers

“…In addition, nearly 100% of Austrians have a health assurance, chemotherapy is fully covered and socioeconomic biases may be lower than in other countries and our analysis is likely to be less biased regarding insurance status or other socioeconomic factors than one might assume in international randomized clinical trials. Thus our study is one of the largest single center retrospective analyses of a real world and relatively unselected patient collective with regards to comorbidities, age and performance status [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Novel models for prediction of benefit and toxicity with FOLFIRINOX treatment of pancreatic cancer using clinically available parameters

et al. 2018

BackgroundDespite modern chemotherapy regimens, survival of pancreatic cancer patients remains dismal. Toxicity is a major concern and it is a challenge to upfront identify patients with the highest benefit from aggressive polychemotherapy. We aimed to evaluate ORR and side effects of the FOLFIRINOX regimen, highlighting dose modification and to explore possible prognostic response factors as a clinical tool.MethodsThis retrospective study includes 123 patients with metastatic PC that were treated with FOLFIRINOX between the years 2007 to 2016 in a single academic institution. Survival rates were analysed using the Kaplan-Meier method. Prognostic models including laboratory and clinical parameters were calculated using Cox proportional models in univariate and multivariate analyses.ResultsMedian age at diagnosis was 64 years (47–78 years), 71 (57, 7%) were male and the majority had an ECOG performance status of 0 or 1 (63 patients; 83.7%). After a median follow up of 17.8 months, median progression free survival (PFS) and overall survival (OS) were 5.7 (4.55–6.84; 95%CI) and 11.8 months (9.35–14.24; 95%CI) respectively. Overall response rate with FOLFIRINOX was 34.9% and stable disease rate was 21.9%. Regarding Grade 3/4 side effects, 62 events, were reported in 37 patients. Looking at risk factors e.g. patient characteristics, tumor marker, inflammatory markers and body composition multivariate analyses proved CEA >4 elevation and BMI > 25 at the time point before palliative chemotherapy to be independent negative prognostic factors for OS. Grouping patients with no risk factor, one or two of these risk factors we analyzed a median OS of 17.4 moths, 9.6 months and 6.7 months (p<0.001) respectively. In addition we identified thrombocytosis and low BMI as predictors of early toxicity.ConclusionThis study identifies two easily available factors influencing overall survival with FOLFIRINOX therapy. By combining these two factors to create a score for OS, we propose a prognostic tool for physicians to identify patients, who are unlikely to benefit more from FOLFIRINOX or likely to experience toxicity.

Cancer Biology & Therapy

“…5,6 Although recent study shows that newer combination chemotherapy regimen, FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin) is a superior option for patients with advanced pancreatic cancer, the disease still rapidly develops resistance to the drug and no apparent improvement in OS rate was achieved. 7 Another regimen, consisting of nabpaclitaxel plus gemcitabine, was introduced to increase the available options for the refractory advanced pancreatic adenocarcinoma, the OS or progression-free survival (PFS) was still comparatively low. 8 Taken together, the failure of conventional chemotherapeutic regimens highlights a desperate need for novel treatment strategy.…”

Section: Introductionmentioning

confidence: 99%

Dasatinib can enhance paclitaxel and gemcitabine inhibitory activity in human pancreatic cancer cells

Wei

et al. 2019

SRC and its activated form, phospho-SRC (pSRC), are aberrantly activated in pancreatic cancer and SRC represents a potential target for pancreatic cancer therapy. In this paper, we examined the inhibitory effect of dasatinib, a potent SRC inhibitor in combination with paclitaxel or gemcitabine on human and murine pancreatic cancer cell lines. The results showed that p-SRC can be highly expressed in most human and mouse pancreatic cancer cell lines compared with normal human cell lines and can be induced by paclitaxel or gemcitabine in HPAC cells. Dasatinib can enhance the efficacy of paclitaxel or gemcitabine by reducing the cell viability and inhibiting the cell proliferation. Dasatinib with paclitaxel combination exhibits statistically greater inhibition of the cell migration ability than single agent alone, paclitaxel with gemcitabine or FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin) in HAPC, PANC-1, and BXPC-3 human pancreatic cancer cell lines as well as 8-285 APR and 8-365 APR mouse pancreatic cancer cell lines. In addition, dasatinib with gemcitabine combination also showed statistically greater inhibition of cell migration than single agent alone, paclitaxel with gemcitabine, or FOLFIRINOX in HAPC, PANC-1 and 8-285 APR cells. The combination of dasatinib with paclitaxel or gemcitabine also showed greater inhibition of the colony formation ability of pancreatic cancer cells compared with single-agent monotherapy or FOLFIRINOX. Dasatinib with paclitaxel or gemcitabine combination also inhibits p-SRC, p-STAT3, p-AKT, and/or pERK in these pancreatic cancer cells. Therefore, our results support that combined dasatinib and paclitaxel or gemcitabine therapy may be a viable therapeutic approach for human pancreatic cancer.