Low prealbumin predicts early recurrence after pancreatic cancer surgery: a retrospective cohort study

Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with modest survival gains despite advances in systemic therapy (1). Even after curative-intent resection, more than half of patients experience disease recurrence, and the 5-year overall survival rate after pancreatectomy is reported to be approximately 20–25% (2-4). Although the adjuvant combination of modified oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil (FOLFIRINOX) has been associated with improved outcomes in selected patients, its effectiveness in routine practice remains debated, as a substantial proportion of patients are unable to initiate or complete intensive chemotherapy and early relapse is still common. Among recurrence patterns, early recurrence, which typically occurs within 6–12 months after surgery, is of particular clinical relevance because it is strongly associated with poor long-term survival (2,3). Accordingly, identifying reliable predictors of early recurrence is essential for optimizing perioperative decision-making and ultimately improving patient outcomes.

In parallel, increasing attention has been directed toward host-related determinants, particularly nutritional status and systemic inflammation, that may influence tumor progression, treatment tolerance, and cancer survival (5-7). However, their relationship with early recurrence following PDAC resection has not been clearly established (3). In our previous work, low prealbumin was significantly associated with more advanced disease in hepatobiliary and pancreatic malignancies (8), providing the rationale for investigating its prognostic value, specifically in PDAC. Therefore, the present study aimed to identify factors associated with early recurrence after curative resection for PDAC and to compare the clinical characteristics between the early and non-early recurrence groups to determine independent predictors. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0156/rc).

Methods

Patients

We retrospectively identified 57 consecutive patients who underwent curative-intent resection for PDAC at Pusan National University Hospital between March 2021 and December 2023. Surgical procedures included pancreaticoduodenectomy and radical antegrade modular pancreatosplenectomy. Curative-intent resection was defined as R0/R1 resection without macroscopic residual disease. Patients with non-PDAC pancreatic malignancies, including PDAC arising from intraductal papillary mucinous neoplasms, neuroendocrine tumors, mucinous adenocarcinomas, adenosquamous carcinomas, signet-ring cell carcinomas, or other rare histologies, were excluded.

Early recurrence was defined as recurrence within 1 year after surgery. Patients with recurrence after 1 year and those without recurrence during follow-up were classified as the non-early recurrence group for group comparisons. Recurrence was determined radiologically [computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)-CT], with or without concordant elevation of tumor markers, and was confirmed through multidisciplinary review. The median follow-up duration was 22.6 months.

Data collection and definitions

Baseline hematological and biochemical variables were obtained from laboratory tests performed during the initial visit for PDAC evaluation at Pusan National University Hospital. The pathological assessments were performed by a board-certified pathologist with expertise in hepatobiliary and pancreatic diseases. Resection margin status was classified as R1 when the tumor was within 1 mm of any resection margin (<1 mm).

The reference ranges were as follows: prealbumin, <20 mg/dL; vitamin D, <20 ng/mL; carcinoembryonic antigen (CEA), <5 ng/mL; and carbohydrate antigen 19-9 (CA19-9), <39 U/mL. A statistically derived cut-off value for prealbumin was close to the commonly used lower limit of the clinical reference range; therefore, <20 mg/dL was used as the final cut-off because of its clinical interpretability and consistency with the data-derived threshold.

Preoperative resectability was independently assessed by a multidisciplinary team comprising three radiologists, three gastroenterologists, and two hepatobiliary-pancreatic surgeons and based on chest CT, contrast-enhanced abdominal CT, MRI, endoscopic ultrasonography, and PET-CT.

Follow-up and treatment

Postoperative surveillance consisted of abdominal and chest CT scans with serum tumor marker measurement (CA19-9 and CEA) every 3–4 months to detect recurrence. Neoadjuvant chemotherapy was administered to 15 patients. Adjuvant chemotherapy, including FOLFIRINOX (n=26) and gemcitabine (n=7), was administered to 33 patients. Neoadjuvant chemotherapy was administered to 15 patients. Adjuvant chemotherapy was administered to 33 patients, including FOLFIRINOX in 26 patients and gemcitabine-based chemotherapy in 7 patients. Detailed information on treatment timing, dose intensity, and completion status was not uniformly available and was therefore not included in the adjusted models.

Ethical consideration

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Pusan National University Hospital (IRB No. 2509-051-155), and written informed consent was obtained from the participants.

Statistical analysis

Categorical variables were summarized as numbers and percentages and compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous variables were summarized as mean with standard deviation or median with interquartile range according to distribution.

The primary analysis was performed using Cox proportional hazards models because exact dates of recurrence were available, allowing incorporation of the timing of recurrence after surgery. The time-to-event endpoint was defined as the interval from surgery to radiologically confirmed recurrence within the first postoperative year. Patients who did not develop recurrence within 1 year, including those with late recurrence after
1 year and those without recurrence during follow-up, were censored at 12 months. Patients with follow-up shorter than 12 months without documented recurrence were censored at the last available disease assessment.

Variables with clinical relevance or a univariable P value <0.10 were considered for multivariable analysis. Given the limited number of early recurrence events, multivariable models were kept parsimonious to reduce the risk of overfitting. The proportional hazards assumption was assessed using Schoenfeld residuals. Missing data were handled by complete-case analysis for each model.

Because early recurrence was also defined as a binary 1-year outcome, logistic regression was additionally performed as a sensitivity analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. A parsimonious adjusted logistic model was constructed using prealbumin, margin status, and nodal status, which were selected based on clinical relevance and the findings of the univariable analyses. All statistical tests were two-sided, and P values <0.05 were considered statistically significant.

Results

Risk factors for early recurrence

Table 1 lists the results of the uni- and multivariable analyses of risk factors for early recurrence. During a median follow-up of 22.6 months, early recurrence within 1 year was observed in 20 patients (35.1%). Univariable Cox proportional hazards analysis showed that several clinicopathological variables were associated with early recurrence after curative-intent resection. Specifically, N2 disease was associated with an increased hazard of early recurrence [hazard ratio (HR) 3.43, 95% CI: 1.10–10.68; P=0.03]. A close resection margin (<1 mm) was also associated with early recurrence (HR 2.78, 95% CI: 1.15–6.74; P=0.02). Likewise, low preoperative prealbumin (<20 mg/dL) was significantly associated with early recurrence (HR 3.31, 95% CI: 1.25–8.75; P=0.02).

In contrast, sex, lymphovascular invasion (LVI), perineural invasion (PNI), CEA, CA19-9, vitamin D, receipt of neoadjuvant chemotherapy, transfusion, body mass index (BMI), postoperative complications, and T stage grouping were not significantly associated with early recurrence in univariable analyses.

In the multivariable Cox model, prealbumin <20 mg/dL remained independently associated with early recurrence (HR 4.82, 95% CI: 1.62–14.32; P=0.005). Neither N2 stage (HR 1.70, 95% CI: 0.04–82.12; P=0.79) nor a margin of <1 mm (HR 2.52, 95% CI: 0.88–7.28; P=0.09) reached statistical significance after adjustment. However, the very wide CI for N2 disease suggested substantial imprecision and potential model instability, and therefore these findings should be interpreted cautiously.

As a sensitivity analysis for the binary 1-year endpoint, logistic regression was additionally performed. In univariable logistic regression, prealbumin <20 mg/dL was associated with early recurrence (OR 4.77, 95% CI: 1.40–16.19; P=0.01). In a parsimonious adjusted logistic model including prealbumin, margin status, and node-positive disease, low prealbumin remained associated with early recurrence (adjusted OR 7.50, 95% CI: 1.73–32.48; P=0.007). The direction of association was consistent with the Cox proportional hazards analysis, although the wide CIs should be interpreted cautiously because of the limited sample size and event count.

Comparison between early recurrence and non-early-recurrence groups

The clinicopathological characteristics between the early and non-early recurrence groups differed significantly (Table 2). The non-early recurrence group included patients without recurrence within 1 year, including both those with late recurrence (>1 year) and those who remained recurrence-free during follow-up. A close resection margin (<1 mm) was more common in the early recurrence group (55.0% vs. 21.6%; P=0.01). Similarly, low prealbumin levels (<20 mg/dL) were more frequently observed in patients with early recurrence (68.4% vs. 31.3%, P=0.01).

No significant between-group differences were observed for sex, T stage, N stage, LVI, PNI, CEA, CA19-9, albumin, vitamin D, Glasgow Prognostic Score, neoadjuvant chemotherapy, transfusion, BMI, or postoperative complications. Receipt of neoadjuvant chemotherapy did not differ significantly between the early recurrence and non-early recurrence groups. However, because of the limited sample size, the effects of treatment regimen, timing, and completion status on recurrence could not be fully evaluated.

Nodal burden and elevated CA19-9 levels showed numerical differences between the groups, although these differences did not reach statistical significance. N2 disease was more frequent in the early recurrence group than in the non-early recurrence group (30.0% vs. 13.5%; P=0.16), and CA19-9 ≥39 U/mL was also more common in the early recurrence group (65.0% vs. 40.5%; P=0.08).

Discussion

In this study, N2 stage, close resection margins (<1 mm), and low preoperative prealbumin levels were associated with early recurrence in the univariable analyses. After multivariable adjustment, a prealbumin level <20 mg/dL remained consistently associated with early recurrence. However, because of the limited sample size and the modest number of early recurrence events, this finding should be interpreted as an exploratory association requiring external validation rather than definitive evidence of an independent causal effect. Consistent with these findings, the early recurrence group more frequently exhibited a margin of
<1 mm and low prealbumin levels, supporting the potential clinical utility of these parameters for perioperative risk stratification. Prealbumin (transthyretin), a sensitive marker of short-term nutritional changes and inflammatory burden, may reflect reduced protein reserves, impaired immune competence, and underlying metabolic stress (9). However, evidence supporting prealbumin as a predictor of early recurrence of PDAC remains limited because relatively few studies examined preoperative prealbumin- or prealbumin-based indices in this context (10-12).

Across complementary analyses, prealbumin level emerged as the most consistent predictor of early recurrence. This finding is consistent with accumulating evidence regarding the prognostic relevance of prealbumin in PDAC (10,12). As a negative acute-phase reactant with a short half-life, low prealbumin levels may indicate concurrent nutritional depletion and systemic inflammatory stress (9). One possible explanation is that host vulnerability reflected by low prealbumin may be associated with a more permissive inflammatory and metabolic environment, which could facilitate tumor cell persistence and occult micrometastatic progression; however, this mechanism remains hypothetical and was not directly evaluated in the present study (13-16). Taken together, the persistence of prealbumin after multivariable adjustment suggests that host nutritional vulnerability may be one of several factors associated with early recurrence risk, alongside conventional tumor-related factors. However, because prealbumin was analyzed as a dichotomized variable, some information from the original continuous measurement may have been lost, potentially affecting model stability in this small cohort; therefore, this finding requires validation in larger prospective cohorts (5-7,14-16).

Historically, prognostic assessments have emphasized tumor-related pathological features, including lymph node metastasis, close or positive margins, and lymphovascular or PNI, which are consistently associated with postoperative recurrence (3,17,18). However, these factors are determined after resection and, therefore, have limited value in guiding preoperative decision-making, including the selection of neoadjuvant therapy (3,19). To enable earlier risk stratification, molecular biomarkers such as KRAS-mutated circulating tumor DNA, exosome-derived markers, and tumor/stromal mRNA expression signatures have been explored as predictors of recurrence and surrogates of biological aggressiveness beyond traditional clinicopathologic variables (19-22). Nonetheless, their implementation in routine practice remains limited by cost, restricted availability, insufficient assay standardization, and turnaround-time requirements (20,23). Moreover, tumor-intrinsic factors alone do not fully explain the marked heterogeneity in recurrence timing and patterns observed after curative-intent surgery (19).

Although a margin of <1 mm was associated with early recurrence in the univariable analysis and was more prevalent in the early recurrence group, it did not remain independently significant after multivariable adjustment. Margin involvement is commonly regarded as a surrogate for aggressive tumor behavior and/or technical constraints that limit the achievement of complete oncological clearance. Accordingly, the between-group difference in margin status is biologically plausible and clinically informative, even if the margin distance does not retain its independent prognostic value after accounting for other covariables (24,25).

Similarly, the N2 stage was significant in the univariable analysis but did not remain significant in the multivariable model. The higher proportion of advanced nodal disease (N1–2) in the early recurrence group is consistent with previous reports, indicating that nodal burden contributes to recurrence risk (26,27). The absence of an independent association after adjustment may reflect shared biological features with other tumor-related variables and potential host vulnerability, highlighting the multifactorial nature of postoperative recurrence. Although nodal burden and elevated CA19-9 levels did not reach statistical significance, both showed directional differences between the early recurrence and non-early recurrence groups. Given the small sample size, these non-significant findings should not be interpreted as evidence of no association. Rather, they suggest that conventional tumor-related factors may still be clinically relevant and should be evaluated further in larger cohorts.

Overall, these results underscore the importance of integrating host-related factors, particularly nutritional status, into the prognostic frameworks for pancreatic cancer. Although tumor biology remains a major determinant of recurrence, the consistent prognostic signal of prealbumin suggests that potentially modifiable preoperative vulnerability may also shape outcomes (28). Identifying patients with low prealbumin may improve early risk stratification, support more intensive postoperative surveillance in high-risk subsets, facilitate timely initiation and completion of adjuvant therapy, and enable preoperative or perioperative nutritional optimization (“prehabilitation”) (29,30). Collectively, our findings suggest that enhancing nutritional and metabolic resilience may be an actionable target for future interventional studies.

This study has several limitations. Its retrospective, single-center design and modest sample size may limit its generalizability and leave room for residual confounding. In particular, only 20 patients experienced early recurrence, raising the possibility of overfitting in multivariable models. The extremely wide CI observed for N2 disease in the adjusted Cox model further suggests model instability and imprecision. Although we attempted to address this issue by using a parsimonious sensitivity analysis, the adjusted estimates should be interpreted cautiously. Treatment heterogeneity may have affected recurrence timing. In particular, low prealbumin may reflect not only nutritional or inflammatory vulnerability but also reduced ability to tolerate, initiate, or complete systemic therapy. Because detailed treatment-related factors were not uniformly available, residual confounding related to perioperative treatment could not be excluded. Therefore, the association between low prealbumin and early recurrence should be regarded as hypothesis-generating and requires validation in larger prospective multicenter cohorts.

Collectively, these findings support the potential relevance of preoperative nutritional status in recurrence risk assessment after curative-intent resection for PDAC, while emphasizing the need for cautious interpretation and external validation.

Conclusions

Low preoperative prealbumin level was consistently associated with early recurrence after curative-intent resection for PDAC in this retrospective cohort. Although close resection margin and nodal burden were also associated with early recurrence in univariable analyses, their independent effects were less certain after adjustment. These findings suggest that preoperative prealbumin may serve as a simple and clinically accessible marker for recurrence risk stratification. Further prospective multicenter studies are needed to validate its prognostic value.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0156/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0156/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0156/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0156/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 Institutional Review Board of Pusan National University Hospital (IRB No. 2509-051-155), and written informed consent was obtained from the participants.

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/.

References

1. Roth S, Apte M, Balachandran VP, et al. Pancreatic cancer. Nat Rev Dis Primers 2026;12:23. [Crossref] [PubMed]
2. Brunner M, Flessa M, Jacobsen A, et al. Recurrence pattern and its risk factors in patients with resected pancreatic ductal adenocarcinoma - A retrospective analysis of 272 patients. Pancreatology 2024;24:930-7. [Crossref] [PubMed]
3. Leonhardt CS, Gustorff C, Klaiber U, et al. Prognostic Factors for Early Recurrence After Resection of Pancreatic Cancer: A Systematic Review and Meta-Analysis. Gastroenterology 2024;167:977-92. [Crossref] [PubMed]
4. Malleo G, Maggino L, Lionetto G, et al. A dynamic analysis of empirical survival outcomes after pancreatectomy for pancreatic ductal adenocarcinoma. Surgery 2023;173:1030-8. [Crossref] [PubMed]
5. Muscaritoli M, Arends J, Bachmann P, et al. ESPEN practical guideline: Clinical Nutrition in cancer. Clin Nutr 2021;40:2898-913. [Crossref] [PubMed]
6. Arends J, Strasser F, Gonella S, et al. Cancer cachexia in adult patients: ESMO Clinical Practice Guidelines☆. ESMO Open 2021;6:100092. Erratum in: ESMO Open 2022;7:100614.
7. McGovern J, Dolan RD, Skipworth RJ, et al. Cancer cachexia: a nutritional or a systemic inflammatory syndrome? Br J Cancer 2022;127:379-82. [Crossref] [PubMed]
8. Kwon CH, Seo HI, Kim DU, et al. Clinical significance of C-reactive protein-to-prealbumin ratio in predicting early recurrence in resectable pancreatic cancer. Korean J Clin Oncol 2023;19:11-7. [Crossref] [PubMed]
9. Ingenbleek Y. Plasma transthyretin is a nutritional biomarker in human morbidities. Front Med 2022;16:540-50. [Crossref] [PubMed]
10. Guo Y, Dou Y, Ma X, et al. Prognostic Significance of C-Reactive Protein or Prealbumin in Pancreatic Ductal Adenocarcinoma. J Surg Res 2025;306:543-53. [Crossref] [PubMed]
11. Nanno Y, Toyama H, Mizumoto T, et al. Preoperative level of serum transthyretin as a novel biomarker predicting survival in resected pancreatic ductal adenocarcinoma with neoadjuvant therapy. Pancreatology 2024;24:917-24. [Crossref] [PubMed]
12. Chang S, Zou Y, Huang J, et al. Fibrinogen to pre-albumin ratio is an independent prognostic index for patients with pancreatic ductal adenocarcinoma after radical resection. World J Surg Oncol 2024;22:284. [Crossref] [PubMed]
13. Ma X, Pei B, Wu N, et al. Current research and future prospects of immunonutrition in gastrointestinal malignancies. Front Immunol 2024;15:1420415. [Crossref] [PubMed]
14. Denk D, Greten FR. Inflammation: the incubator of the tumor microenvironment. Trends Cancer 2022;8:901-14. [Crossref] [PubMed]
15. Gong R, Chen Y, Li C, et al. Targeting myeloid cells in pancreatic ductal adenocarcinoma: from primary tumors to liver metastasis. Front Immunol 2025;16:1555036. [Crossref] [PubMed]
16. Lambert AW, Zhang Y, Weinberg RA. Cell-intrinsic and microenvironmental determinants of metastatic colonization. Nat Cell Biol 2024;26:687-97. [Crossref] [PubMed]
17. Gümüş T, Özkılıç A, Temel R, et al. Perineural and Lymphovascular Invasion in Resected Pancreatic Ductal Adenocarcinoma: A High-Risk Subgroup That Could Benefit from Adjuvant Radiotherapy. J Clin Med 2025;14:7763. [Crossref] [PubMed]
18. Obonyo D, Uslar VN, Münding J, et al. The impact of resection margin distance on survival and recurrence in pancreatic ductal adenocarcinoma in a retrospective cohort analysis. PLoS One 2023;18:e0281921. [Crossref] [PubMed]
19. Hilmi M, Cros J, Puleo F, et al. Tumour and stroma RNA signatures predict more accurately distant recurrence than clinicopathological factors in resected pancreatic adenocarcinoma. Eur J Cancer 2021;148:171-80. [Crossref] [PubMed]
20. Alqahtani A, Alloghbi A, Coffin P, et al. Prognostic utility of preoperative and postoperative KRAS-mutated circulating tumor DNA (ctDNA) in resected pancreatic ductal adenocarcinoma: A systematic review and meta-analysis. Surg Oncol 2023;51:102007. [Crossref] [PubMed]
21. Bunduc S, Gede N, Váncsa S, et al. Exosomes as prognostic biomarkers in pancreatic ductal adenocarcinoma-a systematic review and meta-analysis. Transl Res 2022;244:126-36. [Crossref] [PubMed]
22. Halder K, Borazanci EH, Jameson GS, et al. Exosomal ALPPL2 and THBS2 as biomarkers for early detection and disease monitoring of pancreatic ductal adenocarcinoma. Br J Cancer 2025;133:1335-43. [Crossref] [PubMed]
23. Sheriff S, Saba M, Patel R, et al. A scoping review of factors influencing the implementation of liquid biopsy for cancer care. J Exp Clin Cancer Res 2025;44:50. [Crossref] [PubMed]
24. Leonhardt CS, Pils D, Qadan M, et al. The Revised R Status is an Independent Predictor of Postresection Survival in Pancreatic Cancer After Neoadjuvant Treatment. Ann Surg 2024;279:314-22. [Crossref] [PubMed]
25. Augustinus S, Schafrat PJM, Janssen BV, et al. Nationwide Impact of Centralization, Neoadjuvant Therapy, Minimally Invasive Surgery, and Standardized Pathology Reporting on R0 Resection and Overall Survival in Pancreatoduodenectomy for Pancreatic Cancer. Ann Surg Oncol 2023;30:5051-60. [Crossref] [PubMed]
26. Leonhardt CS, Narbekovas K, Qadan M, et al. Prognostic factors for very early recurrence after neoadjuvant treatment and curative resection in pancreatic ductal adenocarcinoma. Surgery 2025;187:109647. [Crossref] [PubMed]
27. Shi H, Qin C, Zhao Y, et al. Lymphatic metastasis in pancreatic cancer: from bedside to bench and back. Cancer Metastasis Rev 2025;44:79. [Crossref] [PubMed]
28. Argilés JM, López-Soriano FJ, Stemmler B, et al. Cancer-associated cachexia - understanding the tumour macroenvironment and microenvironment to improve management. Nat Rev Clin Oncol 2023;20:250-64. [Crossref] [PubMed]
29. Skořepa P, Ford KL, Alsuwaylihi A, et al. The impact of prehabilitation on outcomes in frail and high-risk patients undergoing major abdominal surgery: A systematic review and meta-analysis. Clin Nutr 2024;43:629-48. [Crossref] [PubMed]
30. Wijma AG, Hoogwater FJH, Nijkamp MW, et al. Personalized multimodal prehabilitation reduces cardiopulmonary complications after pancreatoduodenectomy: results of a propensity score matching analysis. HPB (Oxford) 2023;25:1429-37. [Crossref] [PubMed]