Abstract
Background:
Metastatic pancreatic cancer is an aggressive malignancy with limited survival despite intensive chemotherapy. While modified FOLFIRINOX (mFOLFIRINOX) has illustrated efficacy, its real-world data are limited in low-resource healthcare systems. This study evaluated efficacy and toxicity and identified prognostic factors of mFOLFIRINOX as a first-line therapy for Vietnamese patients with metastatic pancreatic cancer.
Methods:
We conducted a retrospective cohort study of 36 patients receiving mFOLFIRINOX as first-line therapy. All patients received peg-filgrastim as the primary prophylaxis. An application of flexible treatment approach—interruption was permitted between cycles under physician guidance. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events were assessed. Prognostic factors were analyzed using log-rank tests and Cox regression models.
Results:
The median follow-up was 15.6 months (95% confidence interval [CI] 3.8-27.3). The overall response rate (ORR) was 30.6 %, and the disease control rate (DCR) was 66.6%. The median progression-free survival was 6.7 (95% CI 5.4-8) months, and the median overall survival was 12.5 (95% CI 9.5-15.4) months. Grade 3 or 4 toxicities were mainly hematologic, including neutropenia in 33.4%, and anemia in 5.6% of patients. No cases of febrile neutropenia were observed. Univariate analyses identified performance status (PS) and age under 60 years as associated with improved outcomes. In multivariate Cox regression, PS remained an independent prognostic factor for overall survival.
Conclusion:
mFOLFIRINOX regimen demonstrated efficacy and manageable toxicity in Vietnamese patients with metastatic pancreatic cancer. An individualized approach involving treatment interruptions was observed in patients with relatively favorable outcomes. These findings support the feasibility of the regimen in real-world settings.
Keywords
Introduction
Pancreatic cancer is an aggressive malignancy, ranked sixth among causes of cancer deaths worldwide. 1 In the United State, pancreatic cancer is currently the third most common cause of death, with incidence and mortality rate of approximately 13.8 and 11.3 per 100 000 persons per year, respectively. 2 In Vietnam, pancreatic cancer is relatively uncommon, with an estimated 1251 new cases and 1266 death cases of pancreatic cancer reported in 2020. Pancreatic cancer, while less common, has shown a steadily rising trend and contributes significantly to this burden. 3
A major clinical challenge is that most patients are diagnosed at an advanced stage, limiting opportunities for curative intervention. A hospital-based series from Vietnam reported that up to 85% of cases were identified at late stages. 4 Systemic chemotherapy is the primary treatment method for metastatic pancreatic cancer.5-7 Even with high-intensity systemic chemotherapy, outcomes remain dismal in the context of metastasis. The median overall survival time typically ranges from 5 to 6 months and rarely exceeds 11 months in well-selected patient groups. 8
According to PRODIGE 4/ACCORD 11 randomized trials, FOLFIRINOX has significantly improved progression -free survival, overall survival, and quality of life compared with gemcitabine and has become the first-line standard for metastatic pancreatic cancer (MPC). 9 However, the rate of neutropenia and febrile neutropenia was high and reported as 45.3% and 5.4%, respectively. Therefore, FOLFIRINOX was only used in patients with very good performance status. The reduction of irinotecan and fluorouracil bolus dosage has been shown to decrease the side effects of the regimen while maintaining its efficacy according to a phase II trials of modified FOLFIRINOX for untreated pancreatic cancer patients by Ozaka et al. 10 Although various studies have explored alternative treatment strategies to improve tolerability, high rates of treatment-related toxicities remain a major concern.11-14 Thus, it is necessary to add further treatment approach strategies to improve tolerance and maintain the effectiveness of the regimen.
In this context, real-world data can provide critical insights to guide treatment optimization strategies, especially in regions with distinct patient demographics and limited healthcare resources. However, real-world evaluations of modified FOLFIRINOX in metastatic pancreatic cancer remain scarce across Southeast Asia, and to date, no such data have been reported from Vietnam. Given that treatment outcomes may vary according to differences in clinical practices, drug accessibility, and baseline patient characteristics, our study helps to fill an important knowledge gap by offering one of the first Vietnamese real-world analyses of mFOLFIRINOX in this setting. In this retrospective cohort, we examined the efficacy, toxicity and identify prognostic factors of mFOLFIRINOX as a first-line therapy for Vietnamese patients with MPC. To improve tolerability, a clinical strategy permitting temporary interruption between cycles was employed.
Materials and Methods
Study design and participants
This single-center, retrospective cohort study was conducted at Vietnam National Cancer Hospital. The institutional medical records were systematically reviewed and all consecutive MPC patients received mFOLFIRINOX as first-line chemotherapy between January 2019 and June 2025 were included. The final follow-up and study cut-off date was August 1, 2025. This study adheres to the STROBE reporting guideline.
Eligible patients were required to meet all the following criteria: (1) Pathological or cytological verification of pancreatic adenocarcinoma with evidence of distant metastasis. (2) Performance status of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG). (3) Aged ⩾ 18 years at the time of diagnosis. (4) Presence of at least one lesion measurable on imaging. (5) Sufficient organ function, defined as: hemoglobin ⩾ 9.0 g/dL; white blood cell count ⩽10 000/mm3; absolute neutrophil count ⩾ 2000/mm3; platelet count ⩾ 100 000/mm3; total bilirubin within the upper limit of normal (ULN); AST and ALT ⩽ 2.5 × ULN; and serum creatinine ⩽ 1.2 mg/dL.
Exclusion criteria include having received chemotherapy or radiation therapy prior; peripheral neuropathy of sensory level 2 or higher; a history of another major cancer; other serious concomitant diseases.
Treatment regimen
The mFOLFIRINOX regimen was delivered every two weeks. Each treatment cycle consisted of oxaliplatin at 85 mg/m2 administered as a 2-hour intravenous infusion, immediately followed by leucovorin 200 mg/m2 given over 2 hours. After this, patients received irinotecan 150 mg/m2 as a 90-minute infusion, and finally fluorouracil at 2400 mg/m2 through a continuous intravenous infusion lasting 46 hours. The treatment continued until disease progression, unacceptable toxicity or patient refusal. All patients received peg-filgrastim as primary prophylaxis.
Treatment cycles were delayed in cases where laboratory or clinical conditions did not meet safety criteria, including neutrophil count below 1500/mm3, platelets under 75 000/mm3, bilirubin exceeding 1.5 mg/dL, peripheral neuropathy of grade 3 or higher, or diarrhea grade ⩾ 2. The dosage reduction was reduced by 25% that depended on the assessment of the treating physician. Patients could be given at least 7 days beyond the standard treatment cycle if any of the following criteria were met: (1) Any adverse event reaching grade 3 or higher; (2) Grade 2 toxicity that persisted across two consecutive evaluations despite supportive measures; (3) The first occurrence of a grade 2 toxicity in patients aged 70 years or older.
Assessment method
Data were extracted from medical records, including demographics (age, sex, performance status, pancreatic tumor location, intervention for biliary obstruction, metastatic sites), laboratory values (Carbohydrate antigen 19-9 [CA19-9] levels), treatment-related information (dose reductions, number of cycles, treatment discontinuation and treatment interruption). Chest and abdominal computed tomography were performed every 4 cycles. Tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 using imaging data from the institutional picture archiving and communication system. 15 The primary endpoints were overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), treatment interruption rate, dose-reduction rate and adverse events (AEs). PFS was measured from the date of treatment initiation until either radiological/clinical evidence of disease progression or death, whichever occurred first. OS was calculated from the start of therapy to death due to any cause. Patients were evaluated for toxicity each cycle. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. 16 Treatment interruption was defined as a temporary discontinuation of therapy for more than 7 days between two cycles due to tolerance ability.
Data analysis
Categorical data were summarized as counts and proportions, whereas continuous variables were reported as medians together with their minimum and maximum values. OS and PFS were estimated using the Kaplan-Meier method and with differences compared by log-rank test. Cox regression identified prognostic factors. Hazard ratio (HRs) and 95% confidence intervals (CIs) were reported. Statistical significance was defined as a two—sided P-value of <.05. Multivariate analysis included variables with a P-value < .1 in univariate analysis variables of clinical importance, regardless of their significance in univariate analysis. All statistical analyses were performed using SPSS version 26.
Results
Patient characteristics
Between January 2019 and June 2025, 36 patients were enrolled (Figure 1). Median age was 57 (range 27-74). 69% of the patients had a PS 0. The tumor was primarily located in the head of the pancreas, accounting for 58.3% of cases. The major sites of metastasis were the liver. 33.3% of the patients had CA19-9 over 1000U/ml. The patient characteristic and baseline are shown in Table 1.
Flowchart.
Demographic and baseline characteristics of patients.
ECOG, Eastern Cooperative Oncology Group; CA19-9, Carbohydrate antigen 19-9.
Treatment
The median number of chemotherapy cycles administered was 9 (range 4-34). Of the 36 patients, 33 received ⩽ 12 cycles. Only one patient received up to 34 cycles. Treatment interruption due to tolerance ability and dose reduction occurred in 14 patients (38.9%) and 5 patients (13.9%), respectively. The median number of treatment interruption was 3 (range 1-3). Seven patients were switched permanently to a 3 week cycle after experiencing three consecutive episodes of grade 2 toxicity. 2 patients (5.6%) were terminated treatment due to intolerance. Neutropenia represented the leading reason for treatment modification, including treatment interruption, dose reduction and even early discontinuation. 25 patients (86.2%) out of 29 patients who progressed with the first-line treatment received a second-line therapy. Among second-line treatments, gemcitabine-based regimen was the most common, administered to 27 patients.
Efficacy
The objective response rate and disease control rate in all patients were 30.6% (95% CI 16.8-47.2) and 66.7% (95%CI 52.8-80.6), respectively (Table 2)
Objective response of patients by RECIST criteria.
ORR = CR + PR; DCR = CR + PR + SD.
The median follow-up was 15.6 (95%CI 3.8-27.3) months. The overall survival was conducted after 22 out of 36 patients (61.1%) had died. The median OS was 12.5 months (95%CI 9.5-15.4). Progression -free survival was estimated after 29 of the 36 patients (80.6%) had experienced progression or death. The median PFS was 6.7 months (95%CI 5.4-8.0). Figure 2 shows the results for OS and PFS, respectively. In subgroup analysis, median PFS and OS tended to be longer in the treatment interruption group compared with the non- treatment interruption group, with median values of 8 (95%CI 5.0-11.2) vs 5.4 (95%CI 2.1-9.4) months for PFS and 14.1 (95%CI 8.5-21.1) vs 11.1 (95%CI 9.9-12.3) months for OS, respectively. These differences did not reach statistical significance (P > 0.05).
Kaplan–Meier curves for (A) median progression-free survival and (B) median overall survival.
Adverse events
Grade 3 or 4 toxicity occurred in 18 patients (50%). The major grade 3 and 4 toxicity are summarized in Table 3. The most frequent grade ⩾ 3 adverse events (AEs) were hematologic toxicity, including neutropenia (33.4%), anemia (5.6%). Grade ⩾ 3 non-hematologic AEs were relatively uncommon: vomiting (8.3%), sensory neuropathy (5.6%), diarrhea (5.6%). No febrile neutropenia or treatment -related deaths were recorded.
Treatment -related adverse events.
Factors associated with survival
Univariate analysis using the long-rank test and Cox regression both indicated that an age under 60 and an ECOG PS 0 associated with longer PFS (P < .05). There was a general consistency between the log-rank test and univariate Cox models. The overall multivariate Cox regression model was statistically significant (Likelihood Ratio Test, P = .016), indicating the combined prognostic value of the variables. Multivariate Cox regression analysis demonstrated that none of the individual variables reached statistical significance, age under 60 years showed trends toward association with longer PFS (P = .058). (Table 4)
Univariate and multivariate analyses of factors associated with progression-free survival (PFS) (N = 36).
ECOG PS, Eastern Cooperative Oncology Group Performance Status; CA19-9, carbohydrate antigen; TI, Treatment interruption; HR, Hazard ratio; CI, Confidence interval. Subgroup sizes: <60 (n = 22), ⩾60 (n = 14); Male (n = 22), Female (n = 14); ECOG 0 (n = 25), ECOG 1 (n = 11); CA19-9 < 1000 U/mL (n = 24), ⩾1000 U/mL (n = 12); TI yes (n = 14), TI no (n = 22).
Age under 60 years, ECOG PS 0 showed a correlation with longer OS by Log-rank test. These trends were confirmed in univariate Cox analysis. In multivariate Cox regression, only ECOG PS 0 was an important independent factor in predicting OS (HR 0.036, 95%CI 0.13-0.98, P < .047). The overall Cox regression model was statistically significant (Likelihood Ratio Test, P = .015), indicating potential value in combined risk. (Table 5)
Univariate and multivariate analyses of factors associated with overall survival (OS) (N = 36).
ECOG PS, Eastern Cooperative Oncology Group Performance Status; CA19-9, carbohydrate antigen; TI, Treatment interruption; HR, Hazard ratio; CI, Confidence interval. Subgroup sizes: < 60 (n = 22), ⩾60 (n = 14); male (n = 22), female (n = 14); ECOG 0 (n = 25), ECOG 1 (n = 11); CA19-9 < 1000 U/mL (n = 24), ⩾1000 U/mL (n = 12); TI yes (n = 14), TI no (n = 22).
Discussion
This retrospective cohort study aimed to evaluate the efficacy and toxicity of modified FOLFIRINOX in Vietnamese naïve chemotherapy patients with MPC. The results demonstrated a median progression-free survival (PFS) of 6.7 months (95% CI 5.4-8.0) and an overall survival (OS) of 12.5 months (95% CI 9.5-15.4) (Figure 2), with objective response rate (ORR) of 30.6% and disease control rate (DCR) of 66.7% (Table 2), which appeared to show a trend toward more favorable outcomes relative to previous reports.
The median PFS in the present analysis was consistent with the results of the landmark phase III PRODIGE 4/ACCORD 11 trial in pancreatic cancer patients treated with FOLFIRINOX, where the median PFS 6.4 (95% CI, 5.5-7.2) months while the median OS appeared longer (11.1 months, 95% CI, 9.0-13.1). 9 Furthermore, both median PFS and OS in our study showed a trend toward longer survival than those observed in a phase II study by Ozaka et al, 10 which evaluated the efficacy mFOLFIRINOX in 69 chemotherapy-naïve Japanese patients (5.5 (95% CI, 4.1-6.7) and 11.2 (95% CI, 9.0-not reached) months, respectively). These differences, although quite modest, may carry clinical significance in the context of pancreatic cancer with limited survival. Several factors may have contributed to the observed outcomes in our cohort. In our study, all patients were proactively used peg-filgrastim as a primary prophylaxis, which was not observed in two studies above. Primary prophylaxis with peg-filgrastim has been shown to improve outcomes compared with the non-prophylaxis group in patients with MPC treated with the FOLFIRINOX regimen, as demonstrated by the study conducted by the author Jung et al, 17 along with Angelo Borsarelli Carvalho de Brito et al. 18 In Ozaka’s study, the rate of dose reduction and delayed treatment were both notably high, with dose reduction occurring in 79.7% of patients and delayed occurring in 20%. The flexible treatment approach included delaying treatment in the event of toxicity or treatment could be interrupted at least 7 days beyond the standard treatment cycle if the physician assesses that the patients were unable to tolerate the next chemotherapy dose, which has not been described in other cohorts, with treatment interruption of 38.9%. Therefore, our dose-reduction rate was 13.9% and two patients (5.6%) discontinued treatment due to chemotherapy-related toxicity. This approach has enhanced the treatment tolerance and extended the duration of patients receiving intensive chemotherapy. In subgroup analysis, median OS in the non-interruption group appeared to be consistent with previous reports (11.1 (95% CI, 9.9-12.3) months). In contrast, the interruption group showed a trend toward longer median OS (14.1 (95% CI, 8.5-21.1) months). No statistical significance was observed, possibly owing to the relatively small cohort, but it suggests the potential benefit of a flexible treatment approach in improving patient outcomes.
A prospective study on metastatic pancreatic cancer in the Chinese population implemented a dose-reduction strategy, reducing oxaliplatin and irinotecan to 85% and 75% of the full dose of the FOLFIRINOX regimen, and eliminating the intravenous bolus of fluorouracil. Hence, the cumulative dose achieved was lower relative to ours. 19 The adverse events observed was consistent with our study and lower than those reported in previous studies. Notably, in Chinese study, although the median PFS was comparable to that observed in our cohort (7.0 months), median OS appeared to be lower (10.3 vs. 12.5 (95% CI, 9.5-15.4) months). This discrepancy can be partially explained by the differences in treatment approaches. The flexible treatment approach maintained a longer duration of intensive treatment, with a higher median number of treatment cycles (5 vs 9) and cumulative dose. Thus, this approach may have preserved efficacy while enhancing tolerability, which could partly explain the outcomes observed in our cohort.
Flexible treatment approach was associated with observed survival outcomes and appeared to reduce treatment-related toxicity. The rate of neutropenia of grade 3 or higher was 33.4% and no cases of febrile neutropenia were observed. Our study showed a trend toward lower hematologic toxicity compared with previous reports. In PRODIGE 4/ACCORD 11 trial, the rate of neutropenia and febrile neutropenia were 45.7% and 5.4%, respectively, while in Ozaka’s study, the corresponding rates were 48.7% and 8.7%.9,10 The data from prospective and retrospective studies has also shown high rate of grade 3 or 4 neutropenia, ranging from 12.2% to 74.4% (Table 6).9,10,13,19-23
The incidence of Grade 3 or 4 neutropenia and febrile neutropenia in previous reports.
This study included patients in a real-world context and broader inclusion criteria, encompassing many elderly patients and those with comorbidities, thus better reflecting routine clinical practice. Despite the difference in race and limited healthcare resources, with primary neutropenia prophylaxis and treatment interruption, the results were comparable to prospective trials indicating that the mFOLFIRINOX regimen is effective and safe for Vietnamese patients with MPC. Nevertheless, the overall burden of toxicity remains substantial. This highlights the need for careful patient selection when offering mFOLFIRINOX in routine practice.
In analyzing the univariate prognostic factors related to PFS and OS (Tables 4 and 5), both log-rank test and univariate Cox regression were largely concordant, identifying age under 60 years, ECOG PS 0 as associated with longer survival outcomes(P < .05). This consistency among the methods enhanced the statistical significance of the findings and showed that these variables reflect true prognostic relevance rather than model—dependent artifacts. CA19-9 is a valuable predictive marker in pancreatic cancer. 24 Although CA199 did not reach statistical significance in univariate Cox regression, this variable was still included in multivariate Cox regression models. This aligned with standard practices in statistical analysis in medical literature, while also enhanced the clinical applicability of model. The results of the multivariate analysis related to PFS and OS, which included the factors of ECOG, age and CA199, indicated that only ECOG PS 0 was an important independent factor in predicting OS. While none of the individual variables demonstrated independent statistical significance in the multivariate Cox model, the overall models remained significant. This suggest that these factors, although modest in their individual effects, may exert a cumulative prognostic influence. Our results were consistent with previous reports, which also demonstrated that PS 0 was an independent prognostic factor in pancreatic cancer.25-28
There were several limitations in this study that need to be acknowledged. As a retrospective analysis from one institution, the study design may have led to selection bias and reduced the extent to which the conclusions can be generalized. Although efforts had been made to gather comprehensive clinical data, there were several variables such as comorbidities and quality of life that were not adequately assessed and thus were not included in the analysis. In addition, enzymatic biomarkers related to fluoropyrimidine or irinotecan metabolism (for example, dihydropyrimidine dehydrogenase and uridine diphosphate glucuronosyltransferase 1A1) were not routinely evaluated at our center due to limited availability and cost constraints, which may have prevented more detailed adjustment for potential pharmacogenomic confounding. The small sample size (n = 36) reduced the statistical power to identify relevant factors in multivariate analysis. In addition, the extended inclusion period may have been associated with temporal heterogeneity related to supportive care, imaging practices, or access to subsequent lines of therapy. The assessment of responses and classification of toxicity based on clinical records may vary among observers and incomplete documentation. Therefore, the results should be interpreted with appropriate caution. Given that all patients had ECOG performance status 0–1 and received routine G-CSF support, the applicability of these findings beyond this clinical context may be limited. Prospective multicenter studies with lager sample size and standardized data collection are necessary to validate and extend the findings of this study.
Conclusion
In this retrospective cohort of patients with metastatic pancreatic cancer, modified FOLFIRINOX demonstrated efficacy and manageable toxicity. Performance status remained an independent prognostic factor for overall survival. The application of our flexible treatment approach—interruption was permitted under the guidance of physician between cycles —may have been associated with better tolerability compared with previous studies. These findings suggest that the regimen may be applicable in selected patients and point to the potential relevance of flexible treatment approaches in routine clinical practice.
Footnotes
Ethics approval
The study was approved by the Institutional Review Board of the Vietnam National Cancer Hospital (IRB ID: 00003642; Approval No.: 1400/BVK-HĐĐĐ; Date of approval: April 28, 2025). All procedures were conducted in accordance with the Declaration of Helsinki and local regulations on clinical research ethics.
Consent to participate
The requirement for individual informed consent was waived by the IRB due to the retrospective design of the study and the use of anonymized patient data.
Consent for publication
Not applicable. This study does not include any individual person’s data in any form
Author contributions
Huy Van Nguyen: Conceptualization, Visualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing-original draft, Writing- review& editing
Phuong Thi Dinh: Conceptualization, Investigation, Formal analysis, Writing-review & editing
Thang Tran: Conceptualization, Methodology, Visualization, Writing-review & editing
Cuc Thi Hoang: Investigation, Writing-review & editing. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data availability statement
The datasets used during the current study are not publicly available due to institutional policy and patient privacy concerns but are available from the corresponding author upon reasonable request.