Highlights
Efficacy of Prophylaxis
Primary prophylaxis with pegylated granulocyte colony-stimulating factor (peg-GCSF) drastically reduced the incidence of grade 3-4 neutropenia from 38.5% in the control group to just 2.6% in the treatment group.
Prevention of Febrile Neutropenia
While 12.8% of patients in the control group experienced febrile neutropenia, zero cases were reported in the group receiving primary peg-GCSF prophylaxis.
Patient-Reported Outcomes
Patients receiving primary prophylaxis reported significantly higher global health status and quality of life (QOL) scores compared to the control group, without a corresponding increase in bone pain.
Background: The Challenge of mFOLFIRINOX in Pancreatic Cancer
Pancreatic cancer remains one of the most lethal malignancies, characterized by aggressive biology and a high rate of metastatic presentation at diagnosis. For patients with unresectable, locally advanced, or metastatic disease, the modified-FOLFIRINOX (mFOLFIRINOX) regimen—consisting of oxaliplatin, irinotecan, leucovorin, and fluorouracil—has become a cornerstone of first-line therapy. While mFOLFIRINOX offers superior survival outcomes compared to gemcitabine monotherapy, its clinical utility is often limited by its significant hematologic toxicity profile.
Chemotherapy-induced neutropenia (CIN) is a frequent and severe complication of this regimen. Severe neutropenia (grade 3-4) and febrile neutropenia (FN) often lead to emergency hospitalizations, dose reductions, and treatment delays. These interruptions can compromise the relative dose intensity (RDI), potentially diminishing the overall survival benefit of the treatment. Despite the known risks, the use of primary prophylaxis with peg-GCSF in pancreatic cancer patients remains a subject of clinical debate. Current international guidelines generally recommend primary prophylaxis when the risk of FN is approximately 20% or higher. For regimens with an intermediate risk (10-20%), such as mFOLFIRINOX, the decision is often left to clinical judgment based on patient-specific risk factors. This phase 2 trial was designed to provide high-level evidence to clarify the role of peg-GCSF in this specific patient population.
Study Design and Methodology
This investigator-initiated, open-label, multi-institutional, randomized phase 2 trial (KCT0006536 / NCT06353581) was conducted across several academic centers. The study enrolled 77 treatment-naïve patients aged 19 years or older with locally advanced or metastatic pancreatic cancer. Participants were randomized in a 1:1 ratio to receive either primary prophylaxis with peg-GCSF (pegteograstim 6 mg) or no prophylaxis (control group).
Treatment Regimen
All patients received mFOLFIRINOX: oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, and a continuous infusion of fluorouracil 2400 mg/m2 every two weeks. In the prophylaxis group, peg-GCSF was administered subcutaneously on day 4 of each cycle for the initial eight cycles. The control group received no G-CSF unless they developed grade 3-4 neutropenia, at which point crossover to peg-GCSF was permitted.
Endpoints
The co-primary endpoints were the incidence of grade 3-4 neutropenia and the incidence of febrile neutropenia during the first eight cycles of chemotherapy. Secondary endpoints included overall survival (OS), progression-free survival (PFS), relative dose intensity (RDI), patient-reported quality of life (measured via EORTC QLQ-C30), and the incidence of bone pain, a common side effect of G-CSF therapy.
Key Findings: A Paradigm Shift in Prophylaxis
Primary Efficacy Results
The study results revealed a stark contrast between the two cohorts. In the intention-to-treat analysis, the incidence of grade 3-4 neutropenia was 2.6% (1/38) in the peg-GCSF group compared to 38.5% (15/39) in the control group (P = 0.0001). Furthermore, febrile neutropenia, a potentially life-threatening complication, occurred in 12.8% (5/39) of the control group patients, whereas no patients in the peg-GCSF group experienced FN.
Fig. Primary outcomes and hospitalization or chemotherapy dose delays. (A) Grade 3–4 or febrile neutropenia events for patients with pancreatic cancer with or without prophylactic peg-GCSF, during the initial eight cycles of mFOLFIRINOX. Mean hospitalization days per patient (B) and chemotherapy dose delays (C) within the eight cycles of mFOLFIRINOX with or without prophylactic peg-GCSF. Peg-GCSF, pegylated granulocyte colony-stimulating factor.
Survival and Dose Intensity
With a median follow-up of 19.7 months, the study observed numerical improvements in survival for the prophylaxis group. While the study was not powered to detect a statistically significant difference in OS or PFS at this stage, the trend favored early intervention with peg-GCSF. Crucially, the maintenance of relative dose intensity was more achievable in the prophylaxis group, as fewer dose reductions were required due to hematologic toxicity.
Fig. Kaplan–Meier estimates of progression-free and overall survival. (A) Progression-free survival (PFS) by group, (B) overall survival (OS) by group. Hazard ratios (HRs) for the peg-GCSF primary prophylaxis group versus the control group are shown. Median survival by months and 95% confidence intervals (CIs) are shown for each group. Multivariable analyses of PFS (C) or OS (D) with variables including age (≥65 vs. <65), ECOG performance status (PS) (1–2 vs. 0), disease status (initially metastatic vs. locally advanced), CA19-9 (≥37 vs. <37 U/mL), prior biliary stenting, and peg-GCSF primary prophylaxis (peg-GCSF vs. control). Peg-GCSF, pegylated granulocyte colony-stimulating factor; NR, not reached.
Quality of Life and Safety
One of the most significant findings was the impact on patient well-being. The adjusted mean change in Global Health Status and QOL scores was significantly higher in the peg-GCSF group (P = 0.0264). This suggests that preventing the physiological stress of severe neutropenia and the psychological burden of treatment delays directly translates to better patient experiences. Interestingly, despite concerns that G-CSF might increase treatment-related discomfort, there was no significant increase in reported bone pain between the two groups.
Fig. Adjusted mean changes from baseline scores for global health status or QOL and functioning (A) and symptoms (B) assessed with the QLQ-C30, and bone pain development (C, D) assessed with patient-reported outcomes. Functioning (A) and symptoms (B) assessed with the QLQ-C30, and bone pain development (C, D) assessed with patient-reported outcomes. Dotted lines represent the predefined threshold of absolute change of ≥10 points. Only P-value <0.05 is labeled. Patients with bone pain development throughout the treatment cycles are shown in whole (C) or per cycle (D). Error bars indicate standard deviation. Peg-GCSF, pegylated granulocyte colony-stimulating factor; QOL, quality of life; QLQ-C30, 30-item Quality of Life of Cancer Patients questionnaire.
Expert Commentary: Clinical Implications
The results of this phase 2 trial provide compelling evidence for the routine use of peg-GCSF primary prophylaxis in pancreatic cancer patients receiving mFOLFIRINOX. From a clinical perspective, the reduction of grade 3-4 neutropenia from nearly 40% to less than 3% is transformative. It allows clinicians to deliver the full dose of chemotherapy more reliably, which is particularly vital in pancreatic cancer where the window for effective treatment can be narrow.
Mechanistic Insights
Pegteograstim, a pegylated form of recombinant human G-CSF, works by stimulating the survival, proliferation, and differentiation of neutrophil precursors. The pegylation extends the half-life of the drug, allowing for once-per-cycle dosing. By administering this on day 4 (approximately 24-72 hours after chemotherapy), the study optimized the timing to rescue the bone marrow from the cytotoxic nadir expected with mFOLFIRINOX.
Addressing Guideline Gaps
Traditionally, primary prophylaxis has been reserved for regimens with a >20% risk of FN. However, this study underscores that even if the FN risk is lower, the risk of grade 3-4 neutropenia remains high enough to warrant intervention. The improvement in QOL scores is a powerful argument for patient-centered care, suggesting that prophylaxis should be viewed not just as a safety measure, but as a supportive care standard to maintain the patient’s functional status during intensive chemotherapy.
Study Limitations and Considerations
While the findings are robust, certain limitations must be acknowledged. This was an open-label phase 2 trial with a relatively small sample size (n=77). While the primary endpoints were met with high statistical significance, larger phase 3 trials would be necessary to confirm the survival benefits. Additionally, the study focused on the first eight cycles; the long-term economic impact of continuous peg-GCSF use versus the cost of treating FN-related hospitalizations in this specific population deserves further pharmacoeconomic analysis.
Conclusion
This randomized trial provides a strong rationale for the integration of peg-GCSF primary prophylaxis into the standard of care for patients with unresectable pancreatic cancer treated with mFOLFIRINOX. By nearly eliminating severe neutropenia and significantly enhancing the quality of life, primary prophylaxis addresses a major barrier to effective treatment. Clinicians should consider these findings when planning chemotherapy for pancreatic cancer to ensure both the safety and the well-being of their patients.
Funding and Trial Registration
This study was supported by GC Biopharma Corp., the Severance Hospital Research Fund for Clinical Excellence, and a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT). The trial is registered with the Clinical Research Information Service (CRIS, KCT0006536) and ClinicalTrials.gov (NCT06353581).
References
- Lee CK, Kim I, Seo DH, et al. Pegylated granulocyte colony-stimulating factor primary prophylaxis versus no prophylaxis in patients with unresectable pancreatic cancer treated with modified-FOLFIRINOX: a randomized, open-label, multicenter, phase 2 trial. EClinicalMedicine. 2025;90:103646.
- Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.
- Klastersky J, de Naurois J, Rolston K, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016;27(suppl 5):v111-v118.