The Role of the FOLFIRINOX Regimen for Advanced Pancreatic Cancer

Conroy, Thierry; Gavoille, Céline; Samalin, Emmanuelle; Ychou, Marc; Ducreux, Michel

doi:10.1007/s11912-012-0290-4

Cited by 84 publications

(57 citation statements)

References 35 publications

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“…Borderline Resectable Disease: With response rates exceeding 30% in FOLFIRINOX [103] and gemcitabine/nab-paclitaxel, the utilization of chemotherapy in the neoadjuvant setting has become an area of increased interest. Several small studies, including our institution, have examined the role of neoadjuvant chemotherapy, in combination with concurrent chemoradiation (if necessary).…”

Section: Neoadjuvant Therapy (Preoperative)mentioning

confidence: 99%

The Pathogenesis, Diagnosis, and Management of Pancreatic Cancer

Malhotra¹,

Ahn²,

Bloomston

2015

J Gastrointest Dig Syst

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Pancreatic cancer is an aggressive and devastating disease accounting for 44,000 new cases per year in US. It is characterized by invasiveness, rapid progression and profound resistance to treatment. The majority of cases are diagnosed above age 65 with about 60% of cases at an advanced stage and 5 year survival less than 10%. Advances in molecular biology have greatly improved our understanding of pathogenesis of pancreatic cancer. Many patients have mutations of K-ras oncogene and various tumor suppressor genes are also investigated. Radical surgery remains the only curative treatment option for pancreatic cancer in early stages. For locally advanced, unresectable and metastatic disease, treatment is palliative, in form of adjuvant or neoadjuvant chemotherapy with or without radiotherapy. Gemcitabine based combinations have essentially failed to provide a substantial prolongation of survival and constitute treatment option only in patients with a good performance status. This article provides an overview of epidemiology; risks factors, molecular genetics, biomarkers, diagnostic modality and evidence based therapeutic options for resectable and palliative options for unresectable disease. Keywords: Pancreatic cancer; Diagnosis EpidemiologyPancreatic cancer is one of the most lethal human cancers and is the fourth leading cause of cancer-related deaths in the United States [1,2]. It is estimated that 38,460 of 45,220 people diagnosed with pancreatic cancer in the United States in 2013 will die of their disease, representing approximately 6% of total U.S. cancer deaths [1]. Typically a cancer of the elderly, only 13% of cases occur in patients younger than 55 years, whereas 69% of cases occur in those older than 65. There is a slight predilection for men over women in most countries. Furthermore the incidence of pancreatic cancer in the United States increased from 1999 to 2008, possibly because of the increasing prevalence of obesity and other unknown factors [1,[3][4][5]. Mortality rates have remained largely unchanged [6].The etiology of pancreatic cancer remains unclear, thus making specific risk factors allusive. Still, accepted associated risk factors include smoking, family history of chronic pancreatitis, advancing age, male gender, diabetes mellitus, obesity, non-O blood group, occupational exposures (to chlorinated hydrocarbon solvents and nickel), African American ethnic origin, a high-fat diet, diets high in meat and low in vegetables and folate, and possibly Helicobacter pylori infection and periodontal disease [7]. Findings of preliminary studies suggest that metformin could protect against development of pancreatic cancer [8,9]. A retrospective analysis of 302 patients with pancreatic cancer and diabetes found that metformin use was associated with increased survival at 2 years (30.1% vs. 15.4%; P=0.004) and increased overall survival (OS) (15.2 months vs. 11.1; P=0.009). The OS difference was significant only in patients without distant metastases and remained significant when insulin user...

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Section: Neoadjuvant Therapy (Preoperative)mentioning

confidence: 99%

The Pathogenesis, Diagnosis, and Management of Pancreatic Cancer

Malhotra¹,

Ahn²,

Bloomston

2015

J Gastrointest Dig Syst

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“…Moreover, FOLFIR-INOX has not been readily adopted by oncologists practice due to general safety concerns about the risk of cholangitis in stented patients [65]. Currently, a modified FOLFIRINOX regimen with expected reduced toxicity due to omission of the 5-FU bolus (FOLFOXIRI) is being investigated [66].…”

Section: Recent Developments and Current Issues In The Treatment Of Pmentioning

confidence: 99%

Recent Developments and Current Issues in the Treatment of Pancreatic Cancer

Oettle¹

2013

JCT

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Presently, many questions exist about what the optimal regimen comprises for all stages and treatment settings for pancreatic cancer. Since the CONKO-001 trial, adjuvant therapy following resection has become standard of care; however, outcomes are poor, with most patients experiencing disease recurrence, and new therapies have yet to be validated. Furthermore, the value of adjuvant radiotherapy has still not been clearly defined. Targeted treatment in combination with chemotherapy has been mostly disappointing so far in the adjuvant setting but immunotherapy holds potential for improving survival outcomes. Neoadjuvant treatment does not appear to provide much benefit in resectable patients but in the small subgroup of patients with borderline resectable/unresectable locally advanced disease it may increase the possibility of an R0 resection and, consequently, a substantial increase in survival duration. Use of capecitabine-based radiotherapy in patients with unresectable locally advanced disease appears to be more efficacious and better tolerated than gemcitabine-based chemoradiotherapy, with respect to survival outcomes. However, as with adjuvant treatment, the benefit of adding radiotherapy has not yet been definitively demonstrated. In patients with metastatic pancreatic cancer, targeting the stroma with nab-paclitaxel has shown promising results in a phase III trial setting when administered in combination with gemcitabine and, furthermore, this regimen is suitable for a broad range of patients due to its generally good tolerability profile. Because of its high toxicity, FOLFIRINOX is more suitable for younger patients with an excellent performance status who can withstand aggressive treatment and in patients with a worse performance status, gemcitabine monotherapy is considered to be a more appropriate treatment. Alternatively, gemcitabine in combination with erlotinib, the only targeted compound that has resulted in significant albeit small improvements in survival in patients with advanced disease, could be selected. However, the benefit-risk profile of this regimen is only favorable in a strictly defined, small patient subgroup who develop a treatment-related rash. Finally, with the elucidation of prognostic and predictive markers, treatment is expected to become ever more individualized, leading to improved efficacy outcomes and less unnecessary toxicity.

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“…The prodrug utilized for validation was the glucuronide of SN-38 (SN-38G), a topoisomerase I inhibitor. SN-38 has shown efficacy in a PEGylated form against triplenegative, previously-treated breast cancer in a Phase II clinical trial (Osborne et al, 2012) and promise for pancreatic cancer based on outcomes of FOLFIRINOX regimen trials (Conroy et al, 2013). All aims were achieved in this study: A chemically defined, suspension culture-based production method for βG fusion proteins was developed.…”

Section: Introductionmentioning

confidence: 99%

Annexin-directed β-glucuronidase for the targeted treatment of solid tumors

Guillen

Ruben

Virani

et al. 2016

Protein Engineering, Design and Selection

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Enzyme prodrug therapy has the potential to remedy the lack of selectivity associated with the systemic administration of chemotherapy. However, most current systems are immunogenic and constrained to a monotherapeutic approach. We developed a new class of fusion proteins centered about the human enzyme β-glucuronidase (βG), capable of converting several innocuous prodrugs into chemotherapeutics. We targeted βG to phosphatidylserine on tumor cells, tumor vasculature and metastases via annexin A1/A5. Phosphatidylserine shows promise as a universal marker for solid tumors and allows for tumor type-independent targeting. To create fusion proteins, human annexin A1/A5 was genetically fused to the activity-enhancing 16a3 mutant of human βG, expressed in chemically defined, fed-batch suspension culture, and chromatographically purified. All fusion constructs achieved >95% purity with yields up to 740 μg/l. Fusion proteins displayed cancer selective cell-surface binding with cell line-dependent binding stability. One fusion protein in combination with the prodrug SN-38 glucuronide was as effective as the drug SN-38 on Panc-1 pancreatic cancer cells and HAAE-1 endothelial cells, and demonstrated efficacy against MCF-7 breast cancer cells. βG fusion proteins effectively enable localized combination therapy that can be tailored to each patient via prodrug selection, with promising clinical potential based on their near fully human design.

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The Role of the FOLFIRINOX Regimen for Advanced Pancreatic Cancer

Cited by 84 publications

References 35 publications

The Pathogenesis, Diagnosis, and Management of Pancreatic Cancer

The Pathogenesis, Diagnosis, and Management of Pancreatic Cancer

Recent Developments and Current Issues in the Treatment of Pancreatic Cancer

Annexin-directed β-glucuronidase for the targeted treatment of solid tumors

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