Real-world retrospective cohort study of three conversion therapy regimens for unresectable locally advanced pancreatic cancer: a single-center 5-year analysis focused on conversion resection rate and survival outcomes

Introduction

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and biologically aggressive gastrointestinal malignancies, commonly known as the “king of cancers”, characterized by insidious onset, rapid disease progression, high invasive and metastatic potential, and extremely dismal long-term prognosis (1). Currently, the overall 5-year survival rate of PDAC patients remains as low as 8%, and epidemiological data predict that PDAC will rank as the second leading cause of cancer-related mortality worldwide by 2030, imposing a substantial global oncological and socioeconomic burden (2). Clinically, approximately 30–40% of newly diagnosed PDAC patients present with locally advanced pancreatic cancer (LAPC), wherein extensive peripancreatic vascular invasion and local tumor infiltration render primary radical surgical resection infeasible at initial diagnosis (3,4). For decades, unresectable LAPC was uniformly managed with palliative chemotherapy or best supportive care, with the primary therapeutic goal of alleviating symptoms and prolonging short-term survival, resulting in a median overall survival (OS) of merely 6–12 months and almost no chance of curative treatment (5,6).

In recent years, the rapid development of systemic antitumor therapy has fundamentally transformed the treatment paradigm for unresectable LAPC. Conversion therapy, which refers to standardized systemic or combined locoregional therapy that downsizes and downstages advanced tumors to achieve surgical resectability, has become a breakthrough therapeutic strategy for LAPC (4,7,8). Accumulating clinical evidence has confirmed the remarkable survival benefits of successful conversion therapy. Previous studies have demonstrated that LAPC patients who achieve successful tumor conversion and subsequent radical resection can obtain a median OS of 21.8–40.0 months, with a 5-year survival rate reaching 23.3%, which is significantly superior to that of patients receiving simple palliative treatment and close to the prognostic level of patients with initially resectable PDAC (5,7). These remarkable therapeutic advances have completely changed the passive treatment status of LAPC and highlighted the urgent need for in-depth exploration of optimal conversion regimens and accurate prognostic evaluation systems.

Rationale, research gaps and study objectives

Despite the widespread clinical application of LAPC conversion therapy and continuous emerging relevant research, multiple core clinical controversies and critical knowledge gaps remain to be resolved in current clinical practice. Existing clinical evidence guiding conversion therapy decision-making is predominantly derived from prospective randomized controlled trials (RCTs), which are recognized as the gold standard for clinical research (9,10). However, strictly designed RCTs adopt highly stringent inclusion and exclusion criteria, usually excluding elderly patients, patients with multiple comorbidities, abnormal baseline nutritional status, or heterogeneous underlying diseases. The highly selective enrolled populations in RCTs are far from representing the complex, heterogeneous real-world LAPC patient population, which includes patients with variable physical status, diverse comorbidities, and inconsistent baseline clinical conditions. This inherent limitation leads to poor external validity of RCT-derived evidence, and the optimal conversion regimen screened by controlled trials cannot be fully generalized and applied to real-world clinical scenarios.

Furthermore, current studies lack unified conclusions regarding the comparative efficacy of mainstream conversion regimens, standardized treatment cycles, and unified efficacy evaluation criteria (11). Intensive regimens such as modified FOLFIRINOX and gemcitabine plus nab-paclitaxel (AG) have been verified to have favorable conversion potential in different cohorts, while the clinical value of sequential chemoradiotherapy (CRT) after systemic chemotherapy remains controversial (12). In addition, although emerging biomarkers including dynamic carbohydrate antigen 19-9 (CA19-9) changes, nutritional status indicators, and circulating tumor DNA (ctDNA) have shown potential prognostic predictive value in tumor treatment response and survival prognosis, most existing studies are single-index analyses with insufficient real-world verification, and no stable and effective multi-dimensional prognostic evaluation system has been established for LAPC conversion therapy (13-15). Collectively, the lack of high-quality real-world evidence targeting heterogeneous LAPC cohorts severely restricts the individualized, precise and standardized development of LAPC conversion therapy.

Given the above unresolved clinical controversies and critical research gaps, this single-center real-world retrospective cohort study was designed to compensate for the limitations of traditional RCTs. By analyzing real clinical data of 172 unresectable LAPC patients receiving different mainstream conversion regimens in our center, this study primarily aims to: (I) comprehensively compare the clinical efficacy and practical safety of AG, mFOLFIRINOX, and AG combined with sequential CRT in real-world LAPC populations; (II) screen and verify independent clinical and biomarker prognostic factors affecting conversion success and long-term survival outcomes; (III) summarize real-world clinical experience to provide targeted, evidence-based references for individualized regimen selection, prognostic stratification management, and clinical strategy optimization for LAPC conversion therapy, thereby improving the curative resection rate and long-term survival prognosis of unresectable LAPC patients. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0265/rc).

Methods

Study design and patients

This study was conducted as a single-center, real-world retrospective observational study at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, and the requirement for informed consent was waived due to the retrospective and anonymized nature of the clinical data analysis.

Sample size rationale: The final enrolled cohort comprised 172 patients with unresectable LAPC. This sample size was determined based on single-center clinical recruitment capacity over a 5-year continuous enrollment period (January 2019–December 2023) and previous similar real-world pancreatic cancer cohort studies. Relative to existing single-center retrospective studies focusing on LAPC conversion therapy, a sample size exceeding 150 cases provides sufficient statistical power for inter-group comparison of conversion rates and survival outcomes, and adequately supports stable screening of independent prognostic factors via multivariable regression models, effectively avoiding statistical bias caused by insufficient sample capacity.

All participants were strictly screened from consecutive patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 2019 and December 2023. Uniform resectability judgment was implemented based on the NCCN Guidelines for Pancreatic Adenocarcinoma (2019–2023 edition). Detailed inclusion criteria were as follows: (I) histopathologically confirmed PDAC; (II) radiologically defined unresectable LAPC, defined as tumor contact with the superior mesenteric artery or celiac artery exceeding 180°, or unreconstructible portal vein/superior mesenteric vein invasion on contrast-enhanced computed tomography (CE-CT); (III) no distant metastasis confirmed by baseline systematic imaging evaluation, including CE-CT, positron emission tomography-computed tomography (PET-CT), and bone scan when necessary; (IV) Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 with tolerance for systemic chemotherapy; (V) receipt of no fewer than 2 complete cycles of standardized first-line conversion therapy; (VI) complete baseline and follow-up clinical, imaging, and laboratory data available for analysis.

Standardized exclusion criteria were applied to eliminate confounding interference: (I) occurrence of distant metastatic progression within the first 2 cycles of conversion therapy; (II) prior anti-tumor treatment for PDAC before enrollment; (III) concurrent or historical active malignant tumors other than PDAC; (IV) severe cardiac, hepatic, or renal organ dysfunction that contraindicated standardized systemic treatment.

Baseline data collection and quality control: All baseline demographic, clinical, laboratory, imaging, and pathological variables were systematically extracted from the hospital’s electronic medical record (EMR) system by two independent researchers. Collected baseline indicators included age, gender, body mass index (BMI), ECOG status, tumor location, vascular invasion status, baseline CA19-9 level, nutritional indicators (albumin, prealbumin), and comorbidities. All data were cross-checked and verified to ensure accuracy. For missing baseline data, multivariate multiple imputation was performed for random missing variables, while cases with key missing data (unverifiable tumor staging, incomplete treatment records, missing core laboratory indicators) were directly excluded to guarantee data integrity and research reliability.

Conversion therapy regimens and treatment management

All enrolled patients were evaluated and managed by a fixed pancreatic cancer multidisciplinary team (MDT), consisting of pancreatic surgeons, medical oncologists, radiation oncologists, diagnostic radiologists, and pathologists. The selection of conversion regimens was comprehensively determined based on patients’ physical status, tumor characteristics, and MDT consensus, adhering to institutional standardized treatment protocols. Three mainstream first-line conversion regimens were administered as follows:

The AG regimen: gemcitabine (1,000 mg/m²) combined with nab-paclitaxel (125 mg/m²), administered on days 1, 8, and 15 of a 28-day treatment cycle. The mFOLFIRINOX regimen: oxaliplatin (85 mg/m²), irinotecan (180 mg/m²), and leucovorin (400 mg/m²) were infused on day 1, followed by a 5-fluorouracil (5-FU) 400 mg/m² bolus injection and 46-hour continuous infusion of 2,400 mg/m² 5-FU, with a 14-day cycle. The AG sequential CRT regimen: patients received 4–6 cycles of standard AG systemic chemotherapy first, followed by localized concurrent CRT (total radiation dose of 50.4 Gy in 28 fractions, combined with oral S-1 40 mg twice daily during radiotherapy).

Treatment adverse events were dynamically monitored per cycle. Dose reduction or treatment delay was strictly implemented for grade ≥3 treatment-related adverse events (TRAEs) in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 to ensure treatment safety and standardization.

Efficacy, safety, biomarker and surgical evaluation with precise timeframes

Tumor response evaluation: imaging re-evaluation with abdominal pelvic contrast-enhanced CT was performed every 2 treatment cycles to dynamically assess tumor changes. Tumor response was uniformly evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Conversion success was strictly defined as post-treatment tumor downstaging to resectable status, specifically referring to tumor-vessel contact reduced to less than 180° or reconstructible vascular invasion confirmed by imaging.

Surgical re-evaluation and intervention timeframe: after 4–8 cycles of standardized conversion therapy, all patients underwent a second MDT re-evaluation of tumor resectability. For patients judged as potentially resectable, laparoscopic exploration was selectively performed to exclude occult peritoneal metastasis. Radical resection was conducted immediately once resectable conditions were confirmed. R0 resection was defined as no microscopic tumor residue at the incised surgical margin on postoperative pathological examination.

Post-treatment biomarker evaluation timeframe: peripheral blood CA19-9 and nutritional status indicators were detected before each treatment cycle during conversion therapy. Postoperative biomarker re-examination was conducted within 1 month after surgery to evaluate pathological treatment response.

Pathological evaluation: postoperative resected specimens were independently assessed by specialized gastrointestinal pathologists. Tumor regression grade (TRG) was classified according to the Evans classification system. Major pathological response (MPR) was defined as residual viable tumor cells ≤10%, and pathological complete response (pCR) was defined as no detectable viable tumor cells in specimens.

Safety evaluation: all TRAEs occurring during systemic treatment were recorded and graded per CTCAE v5.0. Postoperative complications within 30 days after surgery were classified based on the Clavien-Dindo grading system for comprehensive safety assessment.

Standardized follow-up protocol and quality control

A standardized long-term follow-up system was strictly implemented for all enrolled patients, with unified follow-up time nodes and content to minimize follow-up bias and loss to follow-up. The detailed follow-up schedule was as follows: clinical follow-up, serum CA19-9 detection, and abdominal contrast-enhanced CT examination were performed every 3 months within the first 2 years after treatment initiation, every 6 months from the 3rd to 5th year, and annual follow-up after the 5th year until the follow-up cutoff date (December 2025).

Follow-up quality control measures: follow-up work was undertaken by two dedicated researchers, combining outpatient on-site follow-up and standardized telephone follow-up for patients unable to return to the hospital. All follow-up information was recorded in a unified electronic follow-up database in real time. For patients with lost follow-up risk, repeated telephone and WeChat verification were conducted to reduce the loss rate. No patients were lost to follow-up in the final enrolled cohort, ensuring the integrity of survival outcome data.

The primary survival endpoints were clearly defined: OS was calculated from the date of initial PDAC diagnosis to the date of death from any cause or the last valid follow-up time; disease-free survival (DFS) was calculated from the date of radical surgical resection to tumor recurrence or the last follow-up time. All outcome measurements were uniformly defined and assessed throughout the cohort to ensure the internal validity and consistency of the study results.

Statistical analysis

All statistical analyses were performed using IBM SPSS Statistics 26.0, and all statistical tests conducted in this study were two-tailed, with a P value less than 0.05 defined as the threshold of statistical significance. Given the inherent selection bias and confounding bias of real-world retrospective observational studies, strict statistical adjustment strategies were adopted to optimize data robustness and eliminate indication bias caused by unbalanced baseline characteristics among different treatment groups.

Baseline characteristic comparisons were performed as follows: categorical variables were compared using the Chi-squared test or Fisher’s exact test for small-sample subgroups; continuous variables were first tested for normal distribution, with independent sample t-tests applied for normally distributed data and Mann-Whitney U non-parametric tests for non-normally distributed data. Survival curves for OS and DFS were generated via the Kaplan-Meier method, and inter-group survival differences were compared using the log-rank test.

Detailed specification of Cox proportional hazards regression model: univariate Cox regression analysis was first performed to screen potential prognostic variables associated with conversion success and survival outcomes. All variables with P<0.1 in univariate analysis were included in the multivariate Cox proportional hazards regression model. Before modeling, the proportional hazards assumption was verified for all candidate variables using Schoenfeld residual tests to ensure model applicability. To address the core limitation of unbalanced baseline confounding factors in real-world treatment groups and mitigate indication bias, advanced confounding adjustment strategies were implemented in this study. Rigorous multivariable adjustment was conducted in the multivariate Cox model. A full set of clinically significant baseline confounding variables were comprehensively incorporated for adjustment, including age, gender, ECOG performance status, baseline CA19-9 level, nutritional indicators, tumor vascular invasion status, and comorbidities, to eliminate the interference of baseline heterogeneity on survival and efficacy outcomes. The optimal cutoff value of prognostic nutritional index (PNI) was determined via receiver operating characteristic (ROC) curve analysis based on our enrolled cohort data. The cut-off point corresponding to the maximum Youden index was calculated as 41.7, which is consistent with the optimal PNI range of 40–45 reported in previous published literature, supporting the rationality of this threshold (16).

Discussion of confounding control challenges in real-world research: Unlike strictly controlled randomized controlled trials with balanced baseline grouping, real-world retrospective cohorts inevitably exhibit inherent baseline heterogeneity in patient physical status, tumor burden, and clinical comorbidities. Treatment regimen selection in clinical practice is determined by patient condition and physician judgment, which leads to inherent indication confounding and cannot be completely eliminated by conventional simple statistical comparison. Given this methodological challenge, multi-dimensional multivariate Cox adjustment in this study maximally minimized residual confounding effects. This comprehensive statistical strategy overcomes the technical defects of unadjusted inter-group comparison in traditional retrospective studies, ensuring that the survival analysis results are scientifically reliable, clinically credible, and suitable for guiding individualized clinical conversion therapy decision-making.

Results

Patient baseline characteristics

A total of 172 patients were enrolled (Table 1). The median age was 61.3 years (range, 38–78 years), with 57.0% (98/172) male patients. Tumors were predominantly located in the pancreatic head (68.6%, 118/172). Baseline CA19-9 median level was 387.5 U/mL (range, 12.3–2,156.8 U/mL). ECOG 0–1 accounted for 89.5% (154/172) of patients. The AG regimen was most commonly used (51.7%), followed by mFOLFIRINOX (30.8%) and AG sequential CRT (17.4%).

Conversion efficacy and surgical outcomes

The median treatment duration was 7.2 months (range, 4.5–10.8 months). Overall conversion rate was 38.4% (66/172). The mFOLFIRINOX regimen achieved the highest conversion rate (52.8%), significantly higher than AG (32.6%, P=0.008) but not significantly different from AG+CRT (33.3%, P=0.06). Of 66 converted patients, 64 (97.0%) underwent surgical resection, with R0 resection rate of 87.9% (58/66). MPR was observed in 34.8% (23/66) of resected patients, including 6 (9.1%) with pCR. The mFOLFIRINOX group had the highest MPR rate (47.2% vs. 27.3% for AG vs. 26.7% for AG + CRT, P=0.04).

Survival outcomes

Median follow-up was 35.6 months (range, 6.2–58.4 months). The median OS for the entire cohort was 16.8 months (95% CI: 14.5–19.1). Converted patients had significantly longer median OS (32.5 months, 95% CI: 28.6–36.4) than non-converted patients (12.3 months, 95% CI: 10.8–13.8, P<0.001) (Figure 1). The 3-year OS rate was 57.6% for converted patients and 8.2% for non-converted patients. For resected patients, median DFS was 18.2 months (95% CI: 15.3–21.1), with 3-year DFS rate of 41.2%. Patients achieving CA19-9 normalization had significantly longer OS (median 38.7 vs. 22.3 months, P<0.001) and DFS (median 24.5 vs. 12.1 months, P<0.001).

Figure 1 OS comparison between converted and non-converted patients with locally advanced pancreatic cancer. OS, overall survival.

Prognostic factors

Univariate analysis identified CA19-9 normalization (HR 0.22, P<0.001), PNI ≥41.7 (HR 0.05, P<0.001), mFOLFIRINOX regimen (HR 0.58, P=0.02), MPR (HR 0.36, P=0.003), and R0 resection (HR 0.28, P<0.001) as favorable prognostic factors. Multivariate analysis confirmed CA19-9 normalization (HR 0.24, 95% CI: 0.11–0.52, P<0.001) and PNI ≥41.7 (HR 0.06, 95% CI: 0.01–0.28, P<0.001) as independent prognostic factors (Table 2).

Safety profile

Grade 3-4 TRAEs occurred in 42.4% (73/172) of patients. The mFOLFIRINOX group had the highest incidence of grade 3-4 TRAEs (56.6% vs. 36.0% for AG vs. 33.3% for AG + CRT, P=0.007), predominantly neutropenia (32.1% vs. 18.0% vs. 16.7%, P=0.02) and diarrhea (13.2% vs. 3.4% vs. 3.3%, P=0.02). No treatment-related mortality occurred. Postoperative major complications (Clavien-Dindo ≥IIIa) developed in 37.9% (24/63) of resected patients. The most common complications were pancreatic fistula (16.7%), delayed gastric emptying (12.1%), and postoperative bleeding (6.3%). The 90-day postoperative mortality rate was 1.6% (1/63).

Discussion

Efficacy of conversion therapy regimens

This study confirms the substantial survival benefit of conversion therapy in unresectable LAPC, with converted patients achieving a 3-year OS rate of 57.6%, consistent with recent dual-center data reporting 5-year OS of 58.6% (7). Notably, mFOLFIRINOX demonstrated superior conversion efficacy (52.8%) compared to AG (32.6%), aligning with reported findings that FOLFIRINOX yields better OS than AG in LAPC patients.

The role of radiotherapy in conversion therapy remains debated. In our cohort, AG sequential CRT did not improve conversion rates compared to AG alone, echoing the LAP07 trial which failed to show survival benefit with CRT (13). However, stereotactic body radiation therapy (SBRT) has shown promise in local control, with recent studies reporting local control rates >80%, warranting further investigation in prospective trials.

The NALIRIFOX regimen (irinotecan liposome + oxaliplatin + 5-FU/LV) emerged as a breakthrough in advanced PDAC, with NAPOLI-3 showing superior OS to AG (11.1 vs. 9.2 months) (14). Post-hoc analyses demonstrated that dose adjustments do not compromise efficacy, making it suitable for elderly or frail patients. While not employed in our cohort, NALIRIFOX represents a promising future conversion strategy, particularly for patients intolerant of FOLFIRINOX.

Prognostic factors and response assessment

CA19-9 normalization emerged as a critical independent prognostic factor, consistent with multiple studies linking CA19-9 dynamics to survival (12,17-19). A dual-center study of 41 converted patients found CA19-9 normalization (HR 0.23) to predict favorable prognosis, supporting its role in treatment monitoring. For the 5–10% of patients lacking Lewis antigen expression (CA19-9-negative), Dupan-2 has shown promise as an alternative marker (12,18).

Nutritional status, quantified by PNI ≥41.7, was the strongest prognostic factor (HR 0.06), highlighting the importance of supportive care during prolonged conversion therapy. Malnutrition is common in PDAC due to pancreatic exocrine insufficiency and systemic inflammation, and proactive nutritional intervention may improve treatment tolerance and outcomes (10,20).

Imaging assessment remains challenging due to treatment-induced fibrosis obscuring tumor boundaries. Novel techniques such as FAPI PET-CT demonstrate superior sensitivity in detecting micro-metastases and assessing treatment response compared to conventional CT (21,22). Laparoscopic exploration is also valuable, identifying radiologically occult metastases in 19%-58% of LAPC patients (23).

Surgical considerations

Advances in surgical technique have expanded resectability after conversion therapy. Vascular reconstruction is now standard, with portal vein/superior mesenteric vein resection achieving acceptable morbidity rates (24). Our 87.9% R0 resection rate reflects improved surgical expertise, though it remains lower than the 95% rate in initially resectable disease.

The “immortal time bias” remains a concern in conversion therapy studies, as surgical patients must survive the preoperative treatment period. Propensity score matching analyses have addressed this, confirming that conversion surgery independently improves survival when balancing prognostic factors.

Limitations and future directions

This study has inherent limitations of retrospective design and single-center bias. Selection bias may have favored younger patients for mFOLFIRINOX, as reflected by the lower median age in this group. Additionally, we did not evaluate emerging targeted therapies, such as KRAS G12D inhibitors (e.g., RMC-9805) or Claudin 18.2-targeted antibodies (e.g., FG-M108), which show preliminary activity in advanced PDAC.

Future research should focus on: (I) prospective comparison of NALIRIFOX vs. FOLFIRINOX in conversion therapy; (II) integrating liquid biopsies and proteomic markers (e.g., LIF, S-PM proteins) for personalized patient selection; (III) exploring immunotherapy combinations in patients with HRD or MSI-H tumors.

Conclusions

Conversion therapy is a cornerstone of unresectable LAPC management, with mFOLFIRINOX offering the highest conversion efficacy despite increased toxicity. CA19-9 normalization and maintained nutritional status are strong prognostic indicators. MDT-driven individualized treatment, combining effective systemic therapy with advanced surgical techniques, maximizes survival benefits. Future advances in targeted therapies and imaging will further refine conversion strategies for this lethal disease.

Acknowledgments

We acknowledge all patients who contributed to this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0265/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0265/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0265/prf

Funding: This work was supported by the Key Project of Tongji Hospital Foundation (No. 2025 to X.J.G.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0265/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, and the requirement for informed consent was waived due to the retrospective and anonymized nature of the clinical data analysis.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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