Safety and efficacy of FOLFIRINOX in elderly patients with metastatic or locally advanced pancreatic adenocarcinoma: A retrospective analysis

Baldini, Capucine; Escande, Anne; Bouché, Olivier; Hajbi, Farid El; Volet, Julien; Bourgeois, Vincent; Vantroys, T. Renaut; Ploquin, Anne; Desauw, Christophe; Hebbar, Mohamed

doi:10.1016/j.pan.2016.12.009

Cited by 31 publications

(21 citation statements)

References 8 publications

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“…Although many studies have been performed and the mechanisms underlying chemotherapy resistance in pancreatic cancer have been explored, a low response rate to gemcitabine is common in the clinic, gemcitabine exhibits restricted effects [ 39 ], and less than 20% of patients experience the ideal effects of gemcitabine [ 40 ]. Recently, a combination of oxaliplatin, leucovorin, fluorouracil, and irinotecan, which is called FOLFIRINOX, has been widely used as a clinical therapy for the treatment of metastatic pancreatic cancer patients [ 41 – 43 ]. However, the FOLFIRINOX treatment program is accompanied by seriously adverse reactions and drug resistance, which limits its cytotoxic efficacy.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol‐Induced Downregulation of NAF‐1 Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine via the ROS/Nrf2 Signaling Pathways

Liu

Yan

Chen

et al. 2018

Oxidative Medicine and Cellular Longevity

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NAF-1 (nutrient-deprivation autophagy factor-1), which is an outer mitochondrial membrane protein, is known to play important roles in calcium metabolism, antiapoptosis, and antiautophagy. Resveratrol, a natural polyphenolic compound, is considered as a potent anticancer agent. Nevertheless, the molecular mechanisms underlying the effects of resveratrol and NAF-1 and their mediation of drug resistance in pancreatic cancer remain unclear. Here, we demonstrate that resveratrol suppresses the expression of NAF-1 in pancreatic cancer cells by inducing cellular reactive oxygen species (ROS) accumulation and activating Nrf2 signaling. In addition, the knockdown of NAF-1 activates apoptosis and impedes the proliferation of pancreatic cancer cells. More importantly, the targeting of NAF-1 by resveratrol can improve the sensitivity of pancreatic cancer cells to gemcitabine. These results highlight the significance of strategies that target NAF-1, which may enhance the efficacy of gemcitabine in pancreatic cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Resveratrol‐Induced Downregulation of NAF‐1 Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine via the ROS/Nrf2 Signaling Pathways

Liu

Yan

Chen

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…Despite extensive study and the elucidation of the underlying mechanisms in greater detail, PDAC remains a notoriously malignant tumor characterized by the lack of an effective therapeutic strategy and poor life expectancy. Gemcitabine, the standard chemotherapeutic agent for PDAC, is indispensable but exhibits restricted effects [ 37 ], and combination chemotherapy regimens such as FOLFIRINOX, which is composed of folinic acid, 5-fluorouracil (5-FU), irinotecan, and oxaliplatin, show efficacy but also toxicity [ 38 , 39 ]. Novel chemotherapeutic agents and therapeutic targets are urgently required.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Inhibits ROS‐Promoted Activation and Glycolysis of Pancreatic Stellate Cells via Suppression of miR‐21

Yan

Liu

Jiang

et al. 2018

Oxidative Medicine and Cellular Longevity

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Activation of pancreatic stellate cells (PSCs) initiates pancreatic fibrosis in chronic pancreatitis and furnishes a niche that enhances the malignancy of pancreatic cancer cells (PCCs) in pancreatic ductal adenocarcinoma (PDAC). Resveratrol (RSV), a natural polyphenol, exhibits potent antioxidant and anticancer effects. However, whether and how RSV influences the biological properties of activated PSCs and the effects of these changes on tumor remain unknown. In the present study, we found that RSV impeded hydrogen peroxide-driven reactive oxygen species- (ROS-) induced activation, invasion, migration, and glycolysis of PSCs. In addition, miR-21 expression in activated PSCs was downregulated after RSV treatment, whereas the PTEN protein level increased. miR-21 silencing attenuated ROS-induced activation, invasion, migration, and glycolysis of PSCs, whereas the overexpression of miR-21 rescued the responses of PSCs treated with RSV. Moreover, RSV or N-acetyl-L-cysteine (NAC) administration or miR-21 knockdown in PSCs reduced the invasion and migration of PCCs in coculture, and the effects of RSV were partly reversed by miR-21 upregulation. Collectively, RSV inhibits PCC invasion and migration through suppression of ROS/miR-21-mediated activation and glycolysis in PSCs. Therefore, targeting miR-21-mediated glycolysis by RSV in tumor stroma may serve as a new strategy for clinical PDAC prevention or treatment.

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“…The lack of additional toxicities in older patients is encouraging and in contrast to other regimens. For example, a retrospective study of FOLFIRINOX (5-FU, LV, irinotecan and oxaliplatin) in older patients (70-79 years) in five centres in France found that, while efficacy was similar to that reported for younger patients in the phase II/III PRODIGE 4/ACCORD 11 trial (which excluded patients aged N75 years) [10], there was an increased incidence of grade 3 neurotoxicity in older patients [24].…”

Section: Discussionmentioning

confidence: 89%

Liposomal irinotecan and 5-fluorouracil/leucovorin in older patients with metastatic pancreatic cancer – A subgroup analysis of the pivotal NAPOLI-1 trial

Macarulla

Blanc

Wang‐Gillam

et al. 2019

Journal of Geriatric Oncology

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Objectives: Pancreatic cancer is a highly lethal disease predominantly affecting older patients. Characterization of outcomes in these patients may help optimise treatment decisions. The global, phase 3 NAPOLI-1 trial (NCT01494506) demonstrated an overall survival (OS) benefit with liposomal irinotecan and 5-flurouracil/ leucovorin (nal-IRI + 5-FU/LV) versus 5-FU/LV. This subgroup analysis explored impact of age on outcomes in NAPOLI-1 patients, and nal-IRI + 5-FU/LV efficacy and safety in older patients. Materials and Methods: This exploratory, post-hoc analysis of the NAPOLI-1 trial included patients aged ≥eighteen years (no upper limit) with metastatic pancreatic adenocarcinoma that had progressed on gemcitabine-based therapy. Patients were stratified by age (cut-offs at 65, 70, and 75 years); OS and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results: Of 417 randomized patients, 192 (46%), 110 (26%) and 43 (10%) were aged ≥65, ≥70 and ≥ 75 years, respectively. Mortality risk and risk of disease progression were similar in older and younger patients independent of treatment (HRs for median [m]OS/mPFS comparisons were 0.88/0.95 [b65 versus ≥65 years], 0.89/0.88 [b70 versus ≥70 years] and 1.04/0.98 [b75 versus ≥75 years]; P N .25). Reduced mortality/morbidity risk with nal-IRI + 5-FU/LV in older subgroups was in line with the wider population. No additional toxicities with nal-IRI + 5-FU/LV were observed in older patients: 86% of patients ≥75 years versus 69% b75 years required a dose delay or reduction due to toxicities (43% versus 32% dose reductions). Discussion: Results suggest that older patients with metastatic pancreatic adenocarcinoma that progressed on prior gemcitabine-based treatment can benefit from second-line therapy, supporting nal-IRI + 5-FU/LV treatment in older patients.

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Safety and efficacy of FOLFIRINOX in elderly patients with metastatic or locally advanced pancreatic adenocarcinoma: A retrospective analysis

Cited by 31 publications

References 8 publications

Resveratrol‐Induced Downregulation of NAF‐1 Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine via the ROS/Nrf2 Signaling Pathways

Resveratrol‐Induced Downregulation of NAF‐1 Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine via the ROS/Nrf2 Signaling Pathways

Resveratrol Inhibits ROS‐Promoted Activation and Glycolysis of Pancreatic Stellate Cells via Suppression of miR‐21

Liposomal irinotecan and 5-fluorouracil/leucovorin in older patients with metastatic pancreatic cancer – A subgroup analysis of the pivotal NAPOLI-1 trial

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