Hubbry Logo
FOLFIRINOXFOLFIRINOXMain
Open search
FOLFIRINOX
Community hub
FOLFIRINOX
logo
7 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
FOLFIRINOX
FOLFIRINOX
FOLFIRINOX
View on Wikipedia
from Wikipedia

FOLFIRINOX is a chemotherapy regimen for treatment of advanced pancreatic cancer. It is made up of the following four drugs:

The regimen emerged in 2010 as a new treatment for patients with metastatic pancreatic cancer.[3][4][5] A 2011 study published in the New England Journal of Medicine found that FOLFIRINOX produced the longest improvement in survival ever seen in a phase III clinical trial of patients with advanced pancreatic cancer, with patients on the FOLFIRINOX treatment living approximately four months longer than patients receiving the standard gemcitabine treatment (11.1 months compared with 6.8 months).[6][7] However, FOLFIRINOX is a potentially highly toxic combination of drugs with serious side effects, and only patients with good performance status are candidates for the regimen.[6][8] Currently FOLFIRINOX is being used as a neoadjuvant therapy, meaning to downstage patients with "borderline and locally advanced" disease with the hope of rendering their tumors amenable to surgical resection.[9]

In 2013, the U.S. Food and Drug Administration approved protein-bound paclitaxel (also known as nab-paclitaxel, sold as Abraxane) used with gemcitabine. This regimen may be less toxic though perhaps a less effective alternative to FOLFIRINOX for treating late-stage pancreatic cancer. Differences in the trials, and the lack of a direct trial comparing the two regimens, preclude a final conclusion.[8] In the United Kingdom, the National Institute for Health and Care Excellence (NICE), in a draft guidance issued in 2014, rejected the use of Abraxane in treatment due to concerns of side effects, efficacy, and cost relative to Gemzar (gemcitabine).[10] However, on 18 May 2017 NICE issued a reappraisal for the use of Abraxane in the UK. This was in response to Celgene putting forward a Patient Access Scheme (PAS) proposal, which would bring down the cost of the drug.[11]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

FOLFIRINOX

View on Grokipedia
from Grokipedia
FOLFIRINOX is a combination comprising (leucovorin), (5-FU), , and , primarily administered to treat advanced in patients with good . The regimen is delivered intravenously over approximately 6 hours every two weeks, with and infused concurrently followed by and a continuous 5-FU . Introduced into clinical practice following a landmark phase III trial published in 2011, FOLFIRINOX demonstrated significantly improved median overall survival of 11.1 months compared to 6.8 months with monotherapy in patients with metastatic pancreatic , establishing it as a superior first-line option alongside alternatives like NALIRIFOX (FDA-approved in 2024), despite higher toxicity. This trial, known as PRODIGE 4/ACCORD 11, involved 342 patients and highlighted benefits in and response rates, though with increased rates of grade 3 or 4 adverse events such as (45.7%) and (12.7%). Beyond metastatic disease, modified versions of FOLFIRINOX have been explored in neoadjuvant and adjuvant settings for resectable or borderline resectable , with promising results in phase II studies for event-free survival and response rates, though a 2025 phase III trial (PREOPANC-2) showed comparable overall survival to gemcitabine-based chemoradiotherapy. While primarily indicated for , the regimen has also been investigated for advanced colorectal and cancers, underscoring its role in multidrug approaches for gastrointestinal malignancies. Patient selection remains critical, favoring those without significant comorbidities due to the regimen's intensive and potential for dose adjustments to manage toxicities like and .

Medical Uses

Indications

FOLFIRINOX is primarily indicated for the treatment of metastatic pancreatic adenocarcinoma in patients with good , defined as Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. This regimen emerged as a standard first-line option following demonstration of superior survival outcomes compared to in the PRODIGE 4/ACCORD 11 trial. The (NCCN) guidelines recommend FOLFIRINOX as a preferred category 1 regimen for fit patients with advanced . Secondary indications include neoadjuvant therapy for borderline resectable pancreatic cancer, where it is used to downstage tumors and improve resectability rates prior to surgery. NCCN guidelines endorse FOLFIRINOX or modified FOLFIRINOX as a preferred neoadjuvant regimen in this setting for patients with adequate performance status. Additionally, modified FOLFIRINOX is indicated as adjuvant therapy following surgical resection of pancreatic ductal adenocarcinoma in patients with good performance status. This adjuvant use is supported by the PRODIGE 24/CCTG PA.6 trial, which established its role in improving disease-free survival post-resection. Off-label applications of FOLFIRINOX are explored in other gastrointestinal malignancies with limited evidence, such as advanced cancers, where phase II trials have shown modest activity as salvage or first-line therapy but it is not considered standard care. Similarly, there is preliminary evidence for its use in liver metastases, though regimens like FOLFOXIRI are more commonly employed in that context, and FOLFIRINOX remains non-standard.

Efficacy and Comparisons

FOLFIRINOX demonstrated superior efficacy compared to monotherapy in the phase III PRODIGE 4/ACCORD 11 trial, a landmark randomized study involving 342 patients with metastatic pancreatic and good (ECOG 0 or 1). In this trial, the median overall survival was 11.1 months (95% CI, 9.0-13.1) with FOLFIRINOX versus 6.8 months (95% CI, 5.5-7.6) with , representing a of 0.57 (95% CI, 0.45-0.73; P<0.001). was also significantly longer at 6.4 months (95% CI, 5.5-7.2) versus 3.3 months (95% CI, 2.2-3.6), with a of 0.47 (95% CI, 0.37-0.59; P<0.001), and the objective response rate reached 31.6% (95% CI, 24.7-39.1) compared to 9.4% (95% CI, 5.4-14.7; P<0.001). Subgroup analyses from the PRODIGE 4/ACCORD 11 highlighted consistent benefits of FOLFIRINOX across most patient groups, with particularly pronounced advantages in those under 65 years of age, where age greater than 65 was identified as an independent adverse prognostic factor for overall . The primarily enrolled patients with normal or near-normal levels (excluding those with levels exceeding 1.5 times the upper limit of normal due to irinotecan-related toxicity risks), and was most evident in this , underscoring the regimen's suitability for fitter patients without significant hepatic impairment. In comparisons with gemcitabine alone, FOLFIRINOX offers clear superiority in outcomes but at the cost of increased , as evidenced by higher rates of grade 3 or 4 adverse events such as and in the PRODIGE 4/ACCORD 11 . When contrasted with plus nab-paclitaxel (from the MPACT , which reported a overall of 8.5 months), FOLFIRINOX shows similar overall in real-world and meta-analytic data, with survivals often within 1-2 months, though it is associated with a distinct profile featuring more gastrointestinal and neuropathic effects rather than the myelosuppression predominant in the nab-paclitaxel combination.

Composition and Mechanism of Action

Drug Components

FOLFIRINOX is a combination comprising four distinct drugs: (also known as leucovorin), (5-FU), , and . These components are administered intravenously in a specific sequence every two weeks, with standard doses calibrated to to target advanced effectively. Folinic acid, or leucovorin (calcium folinate), is administered at a dose of 400 mg/m² as a 2-hour IV infusion. It serves as a folate analog that enhances the activity of 5-FU by stabilizing the thymidylate synthase complex, thereby potentiating the antimetabolite's cytotoxic effects. Fluorouracil (5-FU), a pyrimidine analog antimetabolite, is given as 400 mg/m² IV bolus followed by 2400 mg/m² continuous infusion over 46 hours. This drug interferes with DNA and RNA synthesis in rapidly dividing cancer cells. Irinotecan hydrochloride, a converted to its , is dosed at 180 mg/m² IV over 90 minutes. It functions as a I inhibitor, preventing and repair in tumor cells. , a platinum-based alkylating agent, is administered at 85 mg/m² IV over 2 hours. It cross-links DNA strands, leading to arrest and in malignant cells. The acronym FOLFIRINOX derives from the initial letters of its components: (FOL), (F), (IRI), and (OX, stylized as NOX in the full name).

Individual Mechanisms

Leucovorin, also known as , functions as a folate analog that enhances the efficacy of 5-fluorouracil (5-FU) by increasing intracellular levels of reduced folates, such as 5,10-methylenetetrahydrofolate. This cofactor stabilizes the ternary complex formed between 5-FU's active metabolite, fluorodeoxyuridine monophosphate (FdUMP), and (TS), thereby potentiating the inhibition of TS and disrupting in rapidly proliferating cancer cells. Without leucovorin, the binding affinity of FdUMP to TS is reduced, limiting 5-FU's effects; the combination ensures prolonged enzyme inhibition, leading to thymine depletion and subsequent DNA strand breaks. 5-Fluorouracil exerts its cytotoxic effects primarily through two mechanisms: inhibition of thymidylate synthase and incorporation of its metabolites into nucleic acids. As an , 5-FU is converted to FdUMP, which binds to TS in the presence of the cofactor, forming a covalent ternary complex that irreversibly inhibits the responsible for converting deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), essential for . This blockade causes an imbalance in nucleotide pools, particularly depleting dTTP while accumulating dUTP, resulting in futile attempts, uracil misincorporation, and double-strand breaks during replication. Additionally, 5-FU metabolites such as fluorouridine triphosphate (FUTP) are incorporated into , acting as fraudulent that disrupt ribosomal RNA maturation, mRNA processing, and protein synthesis, further impairing cellular function in cancer cells. Irinotecan, a prodrug, is metabolized by carboxylesterases to its active form, SN-38, which is approximately 100- to 1,000-fold more potent. SN-38 targets topoisomerase I (Topo I), an enzyme that relieves torsional stress in DNA during replication and transcription by creating transient single-strand breaks. By stabilizing the covalent Topo I-DNA cleavage complex, SN-38 prevents religation of the DNA strand, leading to collisions with advancing replication forks that generate irreversible double-strand breaks and trigger apoptosis in proliferating tumor cells. This mechanism is particularly effective against S-phase-dependent cytotoxicity, exploiting the high replication rates in cancer cells while sparing quiescent normal tissues to a greater extent. Oxaliplatin, a third-generation platinum analog, induces DNA damage by forming both intra- and interstrand crosslinks after aquation of its oxalate ligand, primarily at the N7 position of guanine residues. These adducts, including 1,2-GG and 1,2-AG intrastrand crosslinks as well as longer-range GNG lesions, distort the DNA helix, inhibiting replication and transcription by blocking polymerases and helicases. The unique diaminocyclohexane (DACH) carrier ligand in oxaliplatin confers resistance to nucleotide excision repair pathways that effectively remove cisplatin adducts, enhancing its persistence and apoptotic signaling through p53 activation and cell cycle arrest. Compared to cisplatin, oxaliplatin exhibits reduced nephrotoxicity due to its bidentate oxalate ligand, which undergoes slower aquation and limits renal accumulation, allowing safer administration in regimens targeting gastrointestinal malignancies. The synergy in FOLFIRINOX arises from the complementary mechanisms of its components, which collectively target multiple DNA damage response pathways, including nucleotide synthesis (5-FU/leucovorin), replication fork progression (), and structural integrity (), thereby overcoming heterogeneous resistance in pancreatic ductal characterized by dense stromal barriers and altered tumor microenvironments. This multi-target strategy enhances tumor cell kill while minimizing escape through single-pathway adaptations.

Administration and Dosage

Standard Regimen

The FOLFIRINOX regimen is administered in cycles every 14 days, typically for up to 12 cycles or until disease progression or unacceptable occurs. This biweekly allows for recovery between treatments while maintaining therapeutic intensity. The infusion sequence begins with (85 mg/m²) administered over 2 hours, followed by leucovorin (400 mg/m²) and (180 mg/m²) infused concurrently (leucovorin over 2 hours and irinotecan over 90 minutes). Subsequently, 5-fluorouracil (400 mg/m² bolus followed by 2400 mg/m² continuous infusion over 46 hours) is given using a portable . This structured delivery minimizes drug interactions and optimizes . Premedications include antiemetics such as dexamethasone and 5-HT3 antagonists to prevent and , administered prior to . Atropine is provided as needed to manage irinotecan-induced effects. Supportive measures during administration encompass hydration to maintain fluid balance and availability of anti-diarrheals like for potential gastrointestinal effects. The total treatment time per cycle approximates 48 hours, enabling outpatient administration after initial setup in a clinical facility. Dose adjustments for toxicity are considered as detailed in subsequent guidelines.

Dose Modifications

Dose modifications for FOLFIRINOX are essential to enhance tolerability while preserving efficacy, particularly in patients with advanced who may experience significant toxicity. Initial dose reductions of 25% for and are commonly recommended for patients over 75 years of age, those with an Eastern Cooperative Oncology Group (ECOG) of 1, or elevated levels (e.g., greater than 1.5 times the upper limit of normal), to mitigate risks of severe and gastrointestinal toxicity associated with irinotecan.04664-6/fulltext) These adjustments are based on patient-specific factors and are supported by real-world data showing improved safety without compromising overall survival. Toxicity-based modifications follow a stepwise approach to manage adverse events. For grade 3 or , and doses are typically reduced by 25%, with further reductions or omission if events recur; for grade 3 , 5-fluorouracil (5-FU) infusion is held until resolution, often accompanied by dose reduction upon resumption. These protocols prioritize rapid intervention, such as delaying cycles for unresolved grade 2 or higher non-hematologic toxicities, to prevent escalation to life-threatening complications. In frail patients, modified FOLFIRINOX (mFOLFIRINOX) regimens employ upfront dose reductions, such as at 150 mg/m² and at 85 mg/m² (with 5-FU at 2400 mg/m² over 46 hours and leucovorin at 400 mg/m²), often omitting the 5-FU bolus to reduce while maintaining comparable efficacy to standard FOLFIRINOX, as demonstrated in phase III trials for adjuvant and metastatic settings. Clinical studies confirm that these adaptations yield similar and overall response rates in vulnerable populations, with lower rates of grade 3/4 adverse events. Discontinuation is warranted for persistent grade 3 (typically after omission fails to resolve symptoms) or life-threatening events such as grade 4 non-hematologic toxicity, unresponsive to supportive care, or irreversible organ damage. Pharmacokinetic considerations include UGT1A1 prior to initiating , as poor metabolizers (*28/*28 ) face a higher risk of severe ; dose reductions of 25-50% (e.g., to 135 mg/m² for heterozygous or 90 mg/m² for homozygous variants) are advised to avoid accumulation and toxicity. This -guided approach has been validated in prospective studies of FOLFIRINOX-treated patients, significantly lowering the incidence of grade 3/4 .

Adverse Effects

Common Toxicities

FOLFIRINOX therapy is associated with a substantial incidence of grade 3 or 4 toxicities, occurring in 75.9% of patients compared to 52.9% with in the adjuvant PRODIGE 24 trial. In the seminal metastatic setting from the PRODIGE 4/ACCORD 11 trial, the regimen demonstrated manageable but frequent adverse effects across multiple systems. Gastrointestinal toxicities are prevalent, with grade 3 or 4 reported in 12.7% of patients in the PRODIGE 4 trial, though rates up to 18.6% have been observed in adjuvant use. and each occurred at grade 3 or 4 levels in approximately 5-8% of cases, contributing to treatment interruptions in some patients. , often manifesting as , affects about 1-5% at grade 3 severity. Hematologic toxicities represent the most common severe effects, particularly at grade 3 or 4 in 45-50% of patients from the metastatic PRODIGE 4 , necessitating support in many instances. occurs at grade 3 levels in 3-5% of recipients, with rates of 3.4-7.8% documented across trials. Neurologic toxicities primarily involve peripheral sensory neuropathy due to , with grade 3 events in 9-12% of patients; this cumulative effect often leads to dose reductions after several cycles. Fatigue is widely reported, affecting 60-70% of patients overall, predominantly at grade 1 or 2, though grade 3 or 4 instances reach 11-24% in clinical evaluations.

Severe Complications

FOLFIRINOX administration carries risks of severe complications, particularly in patients with metastatic , where the regimen's intensity can exacerbate underlying frailty. , defined as neutropenia with fever in the absence of , occurs in approximately 5.4% of patients receiving FOLFIRINOX, based on from the pivotal PRODIGE 4/ACCORD 11 trial comparing it to . This incidence rises to 5-10% across broader real-world cohorts, with higher rates observed in certain populations such as Japanese patients, where it can reach up to 22%. In specifically, poses an elevated mortality risk due to patients' often compromised and comorbidities. Severe diarrhea and associated dehydration represent another critical toxicity, primarily driven by irinotecan and fluorouracil components. Grade 3 or 4 affects about 12-13% of patients, frequently leading to imbalances, , and hospitalization. This late-onset form, peaking 5-11 days post-infusion, results from mucosal damage in the and can necessitate dose interruptions or reductions to prevent life-threatening . Oxaliplatin contributes to severe , manifesting initially as acute cold-induced dysesthesias—such as jaw pain, muscle cramps, or perioral paresthesias—occurring in up to 90% of patients during or shortly after infusion. These symptoms can progress to chronic sensory neuropathy, with grade 3 or 4 events in approximately 9% of FOLFIRINOX recipients, characterized by persistent numbness, tingling, or pain in the extremities that impairs daily function. Fortunately, chronic neuropathy resolves in about 70-80% of cases within 6-8 months after treatment discontinuation, though a subset experiences lasting deficits. Irinotecan-specific acute toxicities include syndrome, affecting 20-30% of patients and presenting as abdominal cramping, diaphoresis, salivation, and early-onset within hours of due to muscarinic receptor inhibition. The more insidious late-onset , mediated by the active metabolite SN-38's accumulation in the gut mucosa, can escalate to severe grades requiring hospitalization and is exacerbated by UGT1A1 polymorphisms that impair . Additional severe complications encompass and infusion reactions. Venous thromboembolism, including deep vein thrombosis or , arises in 5-10% of advanced patients on FOLFIRINOX, linked to the malignancy's prothrombotic state and chemotherapy-induced endothelial damage, often warranting anticoagulation. Infusion reactions, such as or , are uncommon, occurring in less than 1% of cycles, but can manifest as , bronchospasm, or , typically during or delivery.

Contraindications and Clinical Considerations

Patient Selection Criteria

Patient selection for FOLFIRINOX therapy in advanced prioritizes individuals with favorable prognostic factors to maximize efficacy while minimizing toxicity risks. Ideal candidates typically include those under 76 years of age, with an Eastern Cooperative Oncology Group (ECOG) of 0 or 1, indicating good functional capacity. Adequate organ function is essential, such as serum levels not exceeding 1.5 times the upper limit of normal (ULN) and creatinine clearance greater than 60 mL/min, ensuring the body can tolerate the regimen's demands. Prior to initiating therapy, for dihydropyrimidine (DPYD) variants is recommended, as severe DPYD deficiency contraindicates full-dose or requires substantial dose reduction to prevent life-threatening . Contraindications focus on conditions that heighten the risk of severe adverse events from individual components. A history of uncontrolled precludes use due to 's potential to exacerbate gastrointestinal . Pre-existing severe , often from prior therapies, contraindicates to avoid cumulative nerve damage. , which impairs metabolism via UGT1A1 deficiency, requires dose reduction of , as it increases the risk of severe and ; UGT1A1 may guide dosing. Comorbidities must be carefully evaluated, as certain conditions amplify regimen-specific risks. Patients with significant cardiac disease, including a history of or arrhythmias, should avoid FOLFIRINOX owing to 5-fluorouracil's association with and ischemia. Renal impairment, defined as creatinine clearance below 30-50 mL/min depending on the component, warrants caution or exclusion, particularly for , which relies on renal . For geriatric patients, age alone does not determine eligibility; a comprehensive geriatric assessment is recommended to evaluate frailty, nutritional status, and comorbidities beyond chronological age. This holistic approach helps identify fit older adults (e.g., aged 70-85) who may tolerate modified FOLFIRINOX similarly to younger patients with good . While not direct selection criteria, baseline levels and tumor burden provide predictive insights into treatment response and survival expectations, guiding informed discussions on potential benefits. Elevated often correlates with higher tumor burden and poorer outcomes, though early declines during therapy signal better prognosis.

Monitoring and Supportive Care

During FOLFIRINOX therapy, laboratory monitoring is essential to detect hematologic and organ toxicities early. Complete blood counts (CBC) are typically performed baseline and before each cycle to identify and other cytopenias, given the regimen's high risk of grade 3-4 (up to 45% without prophylaxis). (LFTs) and s, including magnesium and , are assessed at the beginning of each cycle to monitor for and electrolyte imbalances associated with and . Clinical assessments focus on common toxicities to guide dose adjustments and interventions. , primarily from , is graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), with cumulative incidence reaching grade 2 or higher in over 30% of patients; regular neurologic exams are conducted before each cycle. Diarrhea, often irinotecan-induced, is tracked using the to quantify severity, as grade 3-4 events occur in approximately 13% of cases. Supportive interventions mitigate these toxicities and improve tolerability. Primary prophylaxis with (G-CSF), such as , is recommended from the first cycle for patients at high risk of , reducing incidence from 18.5% to 1.8%. For , is initiated at 4 mg orally followed by 2 mg after each loose stool (maximum 16 mg/day) for grade 1-2; (100-150 μg subcutaneously three times daily) is used for refractory grade 3-4 cases. Oral during infusion helps prevent by inducing , though this toxicity is less frequent with continuous infusion. Treatment response is evaluated every 2-3 months using contrast-enhanced CT or MRI to assess tumor burden per RECIST criteria, alongside serial measurements (every 8 weeks) as a surrogate marker, with declines correlating to improved . A multidisciplinary approach is crucial, particularly for support in , which affects up to 80% of patients; this includes referral to dietitians for high-calorie supplementation, pancreatic replacement , and resistance exercise to preserve mass during .

History and Development

Early Development

FOLFIRINOX, a combination comprising (leucovorin), fluorouracil (5-FU), , and , emerged from earlier multi-agent protocols developed primarily for . The regimen built upon the backbone, which integrated with 5-FU and leucovorin in the early 2000s to enhance efficacy against metastatic colorectal tumors by targeting mechanisms and synthesis. Similarly, incorporated into the 5-FU/leucovorin framework in the early 2000s, leveraging I inhibition to address resistance in gastrointestinal malignancies. These precursors provided a foundation for quadruple therapy in , where single-agent treatments often failed due to the disease's inherent resistance and aggressive biology. In the early 2000s, French collaborative groups, such as GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie), began conceptualizing intensified multi-drug combinations for pancreatic , motivated by the limited response rates of monotherapy options. , approved by the FDA in 1996 as the standard first-line therapy, offered only modest survival benefits, with median overall survival around 5-6 months in advanced cases, underscoring the need for regimens that could synergistically disrupt multiple pathways in this chemoresistant tumor type. GERCOR's explorations were driven by preclinical evidence of pancreatic cancer's rapid proliferation and , prompting trials to test the tolerability of combining platinum agents, topoisomerase inhibitors, and antimetabolites. Pre-2010 phase I and II studies laid the groundwork for FOLFIRINOX's application in advanced gastrointestinal cancers, including pancreatic. A pivotal open-label phase I conducted between 1998 and 2000 enrolled 41 patients with advanced solid tumors to assess the feasibility of biweekly , , 5-FU, and leucovorin. The study established a recommended dose of 85 mg/m² and 180 mg/m², demonstrating feasibility with manageable toxicities primarily limited to and ; objective responses occurred in 11 of 34 evaluable patients, yielding rates of approximately 32%, predominantly in digestive tract cancers. Subsequent early-phase evaluations in pancreatic cohorts confirmed response rates of 20-30%, supporting the regimen's potential to overcome resistance through non-overlapping toxicities and mechanisms.

Key Clinical Trials

The PRODIGE 4/ACCORD 11 trial, a multicenter phase III randomized controlled study conducted from 2005 to 2009, established FOLFIRINOX as a standard first-line therapy for metastatic pancreatic in patients with good . Involving 342 patients with ECOG 0 or 1, the trial randomized participants to FOLFIRINOX ( 85 mg/m², 180 mg/m², leucovorin 400 mg/m², and 400 mg/m² bolus followed by 2400 mg/m² over 46 hours, every 2 weeks) or monotherapy (1000 mg/m² weekly for 7 weeks, then weekly for 3 out of 4 weeks). The primary endpoint was overall survival (OS), with FOLFIRINOX yielding a OS of 11.1 months compared to 6.8 months with ( [HR] 0.57; 95% CI, 0.45-0.73; p<0.001). Secondary endpoints, including (6.4 months vs. 3.3 months; HR 0.47; p<0.001) and objective response rate (31.6% vs. 9.4%; p<0.001), further supported FOLFIRINOX's efficacy, despite higher rates of grade 3 or 4 adverse events (75.9% vs. 52.9%). This landmark study shifted the treatment paradigm for fit patients with metastatic disease, demonstrating a clinically meaningful survival benefit over single-agent , the prior standard. Extending FOLFIRINOX's role to the adjuvant setting, the PRODIGE 24 trial (also known as CCTG PA.6), a phase III randomized study reported in 2018, compared modified FOLFIRINOX (mFOLFIRINOX; omitting the bolus and reducing to 150 mg/m² and to 85 mg/m²) with in patients with resected pancreatic ductal . Enrolling 493 patients ( age 65 years, ECOG 0-1) within 3 months post-surgery, the trial administered 12 cycles of mFOLFIRINOX every 2 weeks or (1000 mg/m² weekly for 3 weeks every 4 weeks) for 6 months. The primary endpoint was disease-free survival (DFS), revealing a DFS of 21.6 months with mFOLFIRINOX versus 12.8 months with (HR 0.58; 95% CI, 0.46-0.73; p<0.001), with 3-year DFS rates of 39.7% versus 21.4%. Overall survival also favored mFOLFIRINOX ( 54.4 months vs. 35.0 months; HR 0.64; 95% CI, 0.48-0.86; p=0.003), with 3-year OS rates of 63.4% versus 48.6%, though at the cost of increased grade 3 or 4 (21.6% vs. 3.8%) and (12.7% vs. 4.1%). These findings positioned mFOLFIRINOX as a preferred adjuvant option for eligible patients post-resection, improving outcomes over alone. In the neoadjuvant context, several phase II trials between 2012 and 2015 investigated FOLFIRINOX for borderline resectable , aiming to increase resectability and R0 margins through tumor downstaging. A and patient-level meta-analysis of 24 such studies (n=313 patients, primarily borderline resectable disease) reported an overall resection rate of 67.8% (95% CI, 60.1-74.6%) following FOLFIRINOX-based therapy, with R0 resection rates of 83.9% (95% CI, 76.8-89.1%) among those resected. Representative examples included single-arm phase II evaluations where neoadjuvant FOLFIRINOX enabled surgical exploration in 61-68% of cases, achieving R0 resections in approximately 50-60% overall, often after restaging with to confirm vascular improvement. These trials highlighted FOLFIRINOX's tolerability in this setting (grade 3/4 toxicity in ~50-60%) and its potential to convert borderline cases to operable status, though without randomized controls, long-term benefits remained inferential. The cumulative evidence from these trials drove of FOLFIRINOX, influencing updates to ESMO and ASCO guidelines between 2011 and to recommend it as first-line therapy for metastatic in patients with ECOG 0-1 and favorable risk profiles. By , ASCO endorsed FOLFIRINOX for fit patients based on PRODIGE 4's survival gains, while ESMO similarly integrated it into metastatic treatment algorithms. For adjuvant use, PRODIGE 24's results further solidified its guideline position by 2019. Despite these advances, key trials shared limitations, notably the underrepresentation of elderly and frail patients, which restricts applicability to broader populations. In PRODIGE 4, only 11% of participants were aged 70 or older, with strict eligibility excluding those with ECOG ≥2 or significant comorbidities. Similarly, PRODIGE 24 enrolled patients up to age 80 but primarily those with ECOG 0-1 post-recovery from , comprising just 20.5% aged ≥70. Neoadjuvant phase II studies echoed this, focusing on younger cohorts (median age ~60), potentially overestimating benefits in vulnerable groups where toxicity could outweigh gains.

Current Research

Ongoing Trials

As of November 2025, several phase II and III clinical trials are actively investigating combinations of FOLFIRINOX with immunotherapies, particularly for patients with instability-high (MSI-high) or mismatch repair-deficient (dMMR) pancreatic ductal (PDAC), aiming to enhance response rates in this immunogenic subset. For instance, a phase II (NCT06896188, recruiting) is evaluating the combination of modified FOLFIRINOX (mFOLFIRINOX) with the PD-1 inhibitor retifanlimab and the GSK-3β inhibitor 9-ING-41 in treatment-naïve patients with metastatic PDAC, focusing on safety, tolerability, and preliminary efficacy in altering the to boost . Similarly, another phase II study (NCT06941857, recruiting) is assessing NC410, a bifunctional , combined with FOLFIRINOX and nivolumab (with or without ) in advanced PDAC, with exploratory analyses in MSI-high cases to identify novel toxicities and response patterns. These efforts build on prior phase II data showing tolerable integration of PD-1 inhibitors like nivolumab with mFOLFIRINOX in metastatic PDAC, where objective response rates reached 32% without exceeding grade 3 toxicities beyond historical benchmarks. Biomarker-driven trials are extending FOLFIRINOX's role in BRCA-mutated PDAC through combinations with , targeting maintenance therapy post-induction. The ongoing phase II/III trial (NCT06115499, recruiting) optimizes second-line for metastatic PDAC with germline /2 or mutations, comparing nab-paclitaxel// (NABPLAGEM) versus nab-paclitaxel/ after first-line -based regimens like FOLFIRINOX, with maintenance eligibility for responders to assess improvements. This follows extensions from the completed trial, where maintenance after (including FOLFIRINOX) yielded a median of 7.4 months in BRCA-mutated cases, prompting investigations into sequential or concurrent strategies to overcome resistance. Additionally, the APOLLO trial (EA2192, recruiting) is exploring adjuvant versus in resected PDAC with BRCA/ alterations following standard adjuvant , which may include FOLFIRINOX, aiming to confirm disease-free survival benefits in this genetically defined subgroup. Innovations in dose and delivery are addressing FOLFIRINOX's toxicity profile through hypofractionated modifications and integration with stereotactic body radiotherapy (SBRT). A phase II trial (NCT04986930, recruiting) is randomizing patients with locally advanced PDAC to mFOLFIRINOX alone versus mFOLFIRINOX plus SBRT, evaluating local control and overall survival while monitoring for reduced systemic exposure via dose adjustments like omitting bolus 5-FU and lowering irinotecan by 25%. This approach stems from follow-up data to earlier studies like NCT01926197, which demonstrated feasible SBRT addition without prohibitive toxicity. Toxicity reduction strategies in recent trials (2022-2025) emphasize relative dose intensity ≥70% with mFOLFIRINOX, correlating with CA 19-9 normalization and improved survival, as seen in real-world analyses where such modifications maintained efficacy while limiting grade 3/4 adverse events to under 40%. Limited ongoing trials explore FOLFIRINOX in rare applications, such as . The phase III PRODIGE 98 (NCT06813976, recruiting) is recruiting to compare adjuvant mFOLFIRINOX versus or in resected , assessing 3-year disease-free survival across histological subtypes with a focus on tolerability in this heterogeneous group. Exploratory studies in metastatic PDAC, such as NCT07026279 (recruiting), incorporate mFOLFIRINOX with narmafotinib, with analyses on . Recent data from 2022-2025 analyses of adjuvant FOLFIRINOX in resected PDAC confirm sustained benefits, with 5-year overall survival reaching 43.2% versus 31.4% for in the PRODIGE 24 trial update, alongside disease-free survival improvements to 21.4 months, underscoring its role despite initial toxicity concerns. These outcomes support ongoing efforts to refine supportive care, such as prophylactic G-CSF and dose capping, to broaden applicability.

Emerging Applications

FOLFIRINOX has shown promising activity in phase II trials for advanced cancers, including , with objective response rates ranging from 20% to 31% in first-line settings, though these regimens are not yet endorsed by major clinical guidelines. In gastroesophageal junction adenocarcinomas, phase II studies have reported objective response rates of approximately 60% in HER2-negative patients and up to 85% in HER2-positive cases treated with FOLFIRINOX plus , demonstrating improved compared to historical standards, but without guideline recommendation for routine use. Investigational combinations of FOLFIRINOX with targeted therapies, such as the EGFR inhibitor or the anti-angiogenic agent , have been evaluated in small phase I/II studies for metastatic , yielding modest gains of 1-2 months over FOLFIRINOX alone, primarily through enhanced vascular normalization and reduced tumor perfusion. These approaches aim to overcome limitations of monotherapy but require larger confirmatory trials due to increased profiles. To address the logistical burden of continuous 5-fluorouracil infusion, modified regimens incorporating oral 5-FU analogs like —such as plus and —have been tested in phase II settings for advanced pancreatic and biliary cancers, maintaining comparable efficacy to standard FOLFIRINOX while improving patient convenience and reducing hospital visits. into resistance mechanisms highlights the role of the in limiting FOLFIRINOX efficacy, with studies showing that dense stromal fibrosis and immunosuppressive macrophages contribute to chemoresistance; modulation strategies, including ATR inhibitors, have demonstrated potential to remodel the microenvironment and enhance cytotoxic effects in preclinical models. Looking ahead, FOLFIRINOX's integration into is advancing through genomic profiling, particularly in RAS wild-type subsets of , where patients exhibit differential responses and may benefit from tailored combinations based on actionable mutations in alternative pathways like MAPK or EGFR.

References

  1. https://www.cancer.gov/about-cancer/treatment/drugs/folfirinox
  2. https://www.drugs.com/medical-answers/what-folfirinox-regimen-how-used-3579922/
  3. https://www.cancerresearchuk.org/about-cancer/treatment/drugs/folfirinox
  4. https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/folfirinox
  5. https://www.nejm.org/doi/full/10.1056/NEJMoa1011923
  6. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nalirifox-metastatic-pancreatic-adenocarcinoma
  7. https://pmc.ncbi.nlm.nih.gov/articles/PMC4472208/
  8. https://jamanetwork.com/journals/jamaoncology/fullarticle/2820217
  9. https://www.nature.com/articles/bjc201645
  10. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00363-8/fulltext
  11. https://www.sciencedirect.com/topics/neuroscience/folfirinox
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC4988311/
  13. https://www.asco.org/abstracts-presentations/ABSTRACT134503
  14. https://jnccn.org/view/journals/jnccn/19/4/article-p439.xml
  15. https://ascopost.com/issues/july-10-2021/modified-folfirinox-established-as-preferred-neoadjuvant-treatment-of-borderline-resectable-pancreatic-cancer/
  16. https://www.nccn.org/patients/guidelines/content/PDF/pancreatic-patient.pdf
  17. https://www.nejm.org/doi/full/10.1056/NEJMoa1809775
  18. https://www.nature.com/articles/s41416-019-0698-9
  19. https://pmc.ncbi.nlm.nih.gov/articles/PMC7643190/
  20. https://bmccancer.biomedcentral.com/articles/10.1186/s12885-021-08605-x
  21. https://pubmed.ncbi.nlm.nih.gov/2521810/
  22. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/fluorouracil
  23. https://pmc.ncbi.nlm.nih.gov/articles/PMC10466002/
  24. https://www.cancer.gov/about-cancer/treatment/drugs/oxaliplatin
  25. https://go.drugbank.com/drugs/DB00650
  26. https://pubmed.ncbi.nlm.nih.gov/2195138/
  27. https://www.nature.com/articles/nrc1074
  28. https://go.drugbank.com/drugs/DB05482
  29. https://www.clinpgx.org/pathway/PA2029
  30. https://go.drugbank.com/drugs/DB00526
  31. https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-023-03116-2
  32. https://www.sciencedirect.com/science/article/abs/pii/S0142961223002430
  33. https://www.nejm.org/doi/suppl/10.1056/NEJMoa1011923/suppl_file/nejmoa1011923_protocol.pdf
  34. https://www.cancernetwork.com/view/pancreatic-neuroendocrine-gi-and-adrenal-cancers
  35. https://www.northerncanceralliance.nhs.uk/wp-content/uploads/2018/11/FOLFIRINOX-for-Pancreatic-ca-CRP11-UGI014-v1.2.pdf
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC6494255/
  37. https://www.cancercareontario.ca/en/system/files_force/MFOLFIRINOX_GI_PAN_A.pdf?download=1
  38. https://pubmed.ncbi.nlm.nih.gov/34464782/
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC6247105/
  40. https://pubmed.ncbi.nlm.nih.gov/30645764/
  41. https://www.sciencedirect.com/science/article/pii/S0959804921012648
  42. https://pmc.ncbi.nlm.nih.gov/articles/PMC9481868/
  43. https://ar.iiarjournals.org/content/43/9/4115
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC3126005/
  45. https://pmc.ncbi.nlm.nih.gov/articles/PMC5897924/
  46. https://www.sciencedirect.com/topics/medicine-and-dentistry/oxaliplatin-induced-neuropathy
  47. https://www.mdpi.com/1424-8247/18/3/359
  48. https://pubmed.ncbi.nlm.nih.gov/34255340/
  49. https://www.chemoexperts.com/folfirinox.html
  50. https://www.ncbi.nlm.nih.gov/books/NBK395610/
  51. https://www.eviq.org.au/medical-oncology/upper-gastrointestinal/pancreas-and-biliary/1512-pancreas-metastatic-folfirinox-modified-fl
  52. https://www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols/gastrointestinal/515.pdf
  53. https://pmc.ncbi.nlm.nih.gov/articles/PMC9529638/
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC5107701/
  55. https://link.springer.com/article/10.1007/s12094-024-03386-8
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC9434418/
  57. https://www.annalsofoncology.org/article/S0923-7534%2819%2930731-8/pdf
  58. https://pmc.ncbi.nlm.nih.gov/articles/PMC5762326/
  59. https://www.annalsofoncology.org/article/S0923-7534(23)00824-4/fulltext
  60. https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4145
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC1891194/
  62. https://ascopubs.org/doi/10.1200/JCO.20.01364
  63. https://pubmed.ncbi.nlm.nih.gov/25579803/
  64. https://www.hemonc.org/wiki/Gemcitabine_%28Gemzar%29
  65. https://pubmed.ncbi.nlm.nih.gov/15908661/
  66. https://pubmed.ncbi.nlm.nih.gov/12598357/
  67. https://academic.oup.com/jnci/article/111/8/782/5488951
  68. https://clinicaltrials.gov/study/NCT06896188
  69. https://clinicaltrials.gov/study/NCT06941857
  70. https://pubmed.ncbi.nlm.nih.gov/39516689/
  71. https://clinicaltrials.gov/study/NCT06115499
  72. https://www.nejm.org/doi/full/10.1056/NEJMoa1903387
  73. https://clinicaltrials.gov/study/NCT04858334
  74. https://clinicaltrials.gov/study/NCT04986930
  75. https://clinicaltrials.gov/study/NCT01926197
  76. https://pmc.ncbi.nlm.nih.gov/articles/PMC12455553/
  77. https://clinicaltrials.gov/study/NCT06813976
  78. https://clinicaltrials.gov/study/NCT07026279
  79. https://pubmed.ncbi.nlm.nih.gov/36048453/
  80. https://journals.sagepub.com/doi/10.1177/17588359231175441
  81. https://pmc.ncbi.nlm.nih.gov/articles/PMC9718456/
  82. https://pmc.ncbi.nlm.nih.gov/articles/PMC7260693/
  83. https://pmc.ncbi.nlm.nih.gov/articles/PMC11905668/
  84. https://www.nature.com/articles/s41419-024-07110-w
  85. https://pmc.ncbi.nlm.nih.gov/articles/PMC5968824/
Add your contribution
Related Hubs
User Avatar
No comments yet.