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. Author manuscript; available in PMC: 2026 Mar 5.
Published in final edited form as: Ann Surg Oncol. 2024 Dec 12;32(3):1879–1886. doi: 10.1245/s10434-024-16649-z

Defining and Predicting Early Recurrence for Optimal Treatment Strategies in Intraductal Papillary Mucinous Neoplasm-derived Pancreatic Cancer: An International Multicenter Study

Joseph R Habib 1,2, Ammar A Javed 1, Ingmar F Rompen 1,3,4, Camila Hidalgo Salinas 1, Anthony Sorrentino 1, Brady A Campbell 5, Paul CM Andel 2, Vincent P Groot 2, Kelly J Lafaro 5, Greg D Sacks 1, Adrian T Billeter 6, I Quintus Molenaar 2, Beat P Müller-Stich 6, Marc G Besselink 3,4, Jin He 5, Christopher L Wolfgang 1, Lois A Daamen 2,7
PMCID: PMC12958335  NIHMSID: NIHMS2137255  PMID: 39666193

Abstract

Background:

Early recurrence is poorly defined in intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC). Predictors are lacking and needed for patient counselling, risk stratification, and postoperative management. We aimed to define and predict early recurrence in patients in resected IPMN-derived PDAC and guide management.

Study Design:

A lowest p-value for survival after recurrence (SAR) was used to define early recurrence in resected IPMN-derived PDAC from five international centers. SAR and overall survival (OS) were compared by log-rank tests. A multivariable logistic regression identified odds ratios (ORs) with 95% confidence intervals (CIs) for early recurrence. Rounded ORs were used to stratify patients into low-, intermediate-, and high-risk groups using upper and lower quartile score distributions. Adjuvant chemotherapy was assessed by Cox-regression and log-rank tests for OS in risk groups.

Results:

In 381 patients, 160 patients (42%) developed recurrence. Early recurrence was defined at 10.5 months and observed in 61 patients (38% of recurrences). The median SAR for patients with early recurrence was 8.3 months (95%CI:3.1-16.1) compared to 12.9 months (95%CI:5.2-27.5) in patients with late recurrence. Elevated CA19-9 [OR:3.80 (95%CI:1.54-9.41] and N2 disease [OR:7.29 (95%CI:3.22-16.49)] were independent predictors of early recurrence. Early recurrence rates in low-, intermediate-, and high-risk groups were 1%, 14%, and 32%, respectively. Adjuvant chemotherapy was only associated with improved OS in high-risk patients [HR:0.50 (95%CI: 0.32-0.79)].

Conclusion:

In IPMN-derived PDAC, the optimal cut-off for early recurrence is 10.5 months. CA19-9 and N-stage predict early recurrence. Adjuvant chemotherapy is only associated with survival benefit in high-risk patients.

Keywords: Intraductal Papillary Mucinous Neoplasm, Pancreatic Neoplasms, Pancreatic Cancer, Invasive IPMN, Recurrence, Early Recurrence

INTRODUCTION

Intraductal papillary mucinous neoplasms (IPMN) are the most common type of pancreatic cystic neoplasms.1 It is estimated that invasive progression of these premalignant lesions accounts for approximately 20% of resected pancreatic ductal adenocarcinomas (PDAC).2–4 Although pancreatic intra-epithelial neoplasm (PanIN)- and IPMN-derived pancreatic carcinomas both have a propensity for local and systemic disease recurrence, recent literature has supported that they are molecularly distinct, with IPMN-derived pancreatic cancer demonstrating superior oncologic outcomes.5–10

In PanIN-derived PDAC, early recurrence, defined anywhere from 6 to 12 months11, 12, is associated with a poorer post-recurrence survival than late recurrence, suggesting that early recurrence after surgery can be used as a measure of aggressiveness and unfavorable biology.12 Furthermore, various factors have been identified that can predict patients at risk of early recurrence after resection of PanIN-derived PDAC.11–13 However, an evidence-based threshold and predictors of early recurrence in IPMN-derived PDAC are not as well developed. Identifying these factors in IPMN-derived PDAC can assist in risk stratification and may be able to help guide adjuvant therapy management in high-risk patients, which remains controversial.14–21

Due to a lack of large evidence-based studies, most of our postoperative therapeutic and surveillance strategies for IPMN-derived PDAC are extrapolated from our more developed understanding of how PanIN-derived PDAC biologically behaves.22, 23 Given the molecular differences and more indolent biology observed in IPMN-derived PDAC, we hypothesize that the cut-off for early recurrence may be different than in PanIN-derived PDAC. Thus, to optimally inform patient prognostication and postoperative management in patients with resected IPMN-derived PDAC, we must improve our limited understanding of how this disease behaves. Herein, we aimed to define early recurrence, predict which patients are at risk of early recurrence, and evaluate the role of adjuvant chemotherapy in patients at low- or high-risk of early recurrence.

METHODS

Local institutional review board approval was obtained by all participating centers. The strengthening and reporting of observational studies in epidemiology (STROBE) guidelines24 were abided by, and this study complied with the 1964 Helsinki Declaration and its later amendments.

Study Design

An international multicenter retrospective cohort study was performed, involving five high-volume pancreatic surgery centers (2000-2022), including, Amsterdam University Medical Center, University of Basel Clarunis University Digestive Health Care Center, the Johns Hopkins Hospital, New York University Langone Health, and the Regional Academic Cancer Center Utrecht. Diagnosis of IPMN-derived PDAC was confirmed on postoperative assessment of the pathologic specimen. Exclusion criteria included concomitant PanIN-derived PDAC arising separately from an adjacent IPMN, intraductal oncocytic papillary neoplasms, gross positive resection margin, missing recurrence-focused follow-up data, metastatic disease at diagnosis, and 90-day postoperative mortality unrelated to disease recurrence.

Definitions

IPMN-derived PDAC was confirmed by pancreas specialized local pathologists to confirm that the invasive component was arising from an IPMN and not concomitant. The AJCC-TNM system 8th edition was evaluated for staging.25 T3 and T4 tumors were combined into one T3/4 group. Microscopic evidence of invasive cancer at or within 1 millimeter of the resection margin was defined as R1. Carbohydrate antigen 19-9 (CA19-9) was defined as non-secreter (<5 U/ml), normal (≥5 and ≤37 U/ml), or elevated (> 37 U/ml). Recurrence was defined based on postoperative imaging or biopsy. Location of invasive carcinoma recurrence was defined as local (pancreatic remnant, surrounding vasculature, surgical bed, or peripancreatic lymph nodes), liver, lung, peritoneum/multiple sites, or other distant sites.

Data Collection and Outcomes

Demographic and clinicopathologic details including age, sex, preoperative CA19-9, receipt of neoadjuvant chemotherapy, T-stage, N-stage, margin status, grade of tumor differentiation, perineural invasion, lymphovascular invasion, histologic subtype (tubular versus colloid), and receipt of adjuvant radiation or chemotherapy were collected. Overall survival (OS) was defined from the date of surgery to the date of death or censorship at last follow-up. Time to recurrence was defined from the date of surgery to date of recurrence. Survival after recurrence (SAR) was defined as the time between the date of first recurrence to the date of death or censorship at last follow-up.

Statistical Analysis

Descriptive statistics were used to describe baseline characteristics in all patients and stratified by presence or absence of disease recurrence. Non-parametric continuous variables were summarized as a median with interquartile range (IQR). Categorical variables were summarized as counts and percentages and compared using a χ2 or Fisher’s exact test, when appropriate.

To define early recurrence, a minimum p-value approach using log-rank statistics was performed to evaluate various SAR cut-offs and determine the optimal (lowest p-value) cut-off.13 Patients with recurrence were then stratified into early vs late recurrence based on the calculated cut-off. Kaplan-Meier curves and log-rank tests were performed to evaluate time to recurrence in patients with early versus late recurrence. Median OS (mOS) was calculated with 95% confidence intervals (CI). Location of first recurrence in patients with early recurrence was compared to those with late recurrence using a χ2 or Fisher’s exact test, when appropriate.

A multivariable logistic regression using backwards selection (including all clinically relevant variables) was utilized to create a simple and clinically useful tool using pre- and post-operative factors (age, sex, preoperative CA19-9, neoadjuvant chemotherapy, T-stage, N-stage, margin status, grade of differentiation, perineural invasion, lymphovascular invasion, and histologic subtype) to predict early recurrence versus late or no recurrence. Results were presented as odds ratios (OR) and corresponding 95% CIs. The area under the curve (AUC) with 95% CI was reported to assess performance of the final model. A scoring system based on the rounded off ORs obtained in the logistic regression model was developed as previously described.26 Three risk groups were created based on the scoring system, which were defined as low, intermediate, or high-risk cut-offs for the probability of early recurrence. A sub-analysis using Kaplan Meier curves, log-rank tests, and a univariable Cox-regression was performed to investigate the role of adjuvant therapy in these risk groups.

A p-value <0.05 was used to define statistical significance. Statistical analysis was completed using the “R” statistical software (version 4.2.3) using the “MaxStat” package and STATA v.17.0 (StataCorp LLC, TX).

RESULTS

Study Population

Overall, 381 patients with IPMN-derived PDAC were included with a median follow-up for surviving patients of 40.3 months (IQR:19.8-64.5 months). Of the overall study population, 97 (25%) were less than 65 years old and over half were male (n=203, 53%). Neoadjuvant and adjuvant chemotherapy were administered in 16 (4%) and 196 (53%) patients, respectively. Preoperative CA19-9 was available in 264 (69%) patients and was elevated in 145 (55%) of these patients. T1 tumors were present in 141 (37%) patients and 213 (56%) had node negative disease. Baseline characteristics and clinicopathologic data are further summarized in Table 1.

Table 1.

Baseline clinicopathologic characteristics of study population stratified by no recurrence or recurrence.

Variable All N = 381 No Recurrence N = 221 Recurrence N = 160 p-value
Age <65 years, n (%) 97 (25) 58 (26) 39 (24) 0.679
Male, n (%) 203 (53) 119 (54) 84 (52) 0.795
Preoperative CA19-9, n (%) <0.001
Normal (5-37, U/ml) 101 (38) 73 (50) 28 (24)
Elevated (>37 U/ml) 145 (55) 69 (47) 76 (65)
Non-secretor (<5 U/ml) 18 (7) 5 (3) 13 (11)
Neoadjuvant Chemotherapy, n (%) 16 (4) 9 (4) 7 (4) 0.884
Operation, n (%) 0.688
Pancreatoduodenectomy 239 (63) 137 (62) 102 (64)
Distal Pancreatectomy 85 (22) 48 (22) 37 (23)
Total Pancreatectomy 57 (15) 36 (16) 21 (13)
Year of Operation, n (%) 0.177
2000-2011 141 (38) 88 (40) 53 (34)
2011-2022 235 (63) 130 (60) 105 (66)
T-stage, n (%) <0.001
T1 141 (37) 107 (49) 34 (21)
T2 147 (39) 59 (27) 88 (55)
T3-4 90 (24) 53 (24) 37 (23)
N-stage, n (%) <0.001
N0 213 (56) 150 (68) 63 (39)
N1 89 (23) 49 (22) 40 (25)
N2 78 (21) 21 (10) 57 (36)
Grade of Differentiation, n (%) 0.001
Well 69 (19) 53 (26) 16 (10)
Moderate 166 (46) 90 (44) 76 (50)
Poor 123 (34) 62 (30) 61 (40)
Tubular, n (%) 279 (80) 146 (73) 133 (90) <0.001
Perineural Invasion, n (%) 218 (59) 108 (50) 110 (71) <0.001
Lymphovascular Invasion, n (%) 134 (36) 55 (26) 79 (51) <0.001
R1 Margin, n (%) 61 (16) 20 (9) 41 (26) <0.001
Adjuvant Chemotherapy, n (%) 196 (53) 95 (44) 101 (66) <0.001
Adjuvant Radiation, n (%) 53 (18) 22 (13) 31 (24) 0.008
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Recurrence

Of the 381 patients, 160 patients (42%) had disease recurrence. Compared to those without disease recurrence, patients with recurrence were more likely to have an elevated preoperative CA19-9 (p<0.001), more T2 staged tumors compared to T1 (p<0.001), advanced N-stage (p<0.001), poorer grade of differentiation (p=0.001), tubular histology (p<0.001), presence of perineural (p<0.001) and lymphovascular invasion (p<0.001), an R1 resection margin (p<0.001), and were more likely to receive adjuvant chemo (p<0.001) or radiation therapy (p=0.008, Table 1). Year of surgery (p=0.117) and American Society Anesthesiologist (ASA) score (p=0.468) were similar between the two groups. The median OS of patients without recurrence [92.3 months (95%CI:29.3-134.8)] was superior to those with recurrence [26.2 months (95%CI:16.2-52.4), p<0.001, Figure S1].

Defining Cut-off and Outcomes of Early Recurrence

The optimal length of time to distinguish early recurrence from late using SAR was 10.5 months (p=0.022, Figure 1). This corresponded to a median SAR of 8.3 months (95%CI: 3.1-16.1) and 12.9 months (95%CI: 5.2-27.5) in patients with early and late recurrence, respectively. Using this cut-off, 61 patients (38%) with recurrence had early recurrence, while the remaining 99 patients (62%) had late recurrence. Early recurrence was thus present in 16% of all resected patients. The median time to recurrence in the early recurrence cohort was 6.2 months (95%CI: 3.7-8.3) compared to 17.9 months (95%CI: 13.2-33.1) in the late recurrence cohort (p<0.001). The mOS of patients with early recurrence was 14.5 months (95%CI:9.0-22.0) and 63.2 months (95%CI:25.9-122.0, p<0.001) for patients with late or no recurrence (Figure 2).

Figure 1.

Figure 1.

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Derivation of early recurrence cut-off based on survival after recurrence using a minimum p-value.

Figure 2.

Figure 2.

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Kaplan-Meier curves displaying survival after recurrence stratified by early versus late recurrence.

Comparing early versus late recurrence based on location identified, local (44% versus 40%, p=0.569), lung (17% vs. 22%, p=0.397), peritoneum/multiple sites (15% vs. 20%, p=0.410), and other sites (10% vs. 7%, p=0.513) were all similar in the two groups. However, liver recurrence was significantly more prevalent in the early recurrence group (45%) compared to the late recurrence group (27%, p=0.022).

Predicting Early Recurrence

CA19-9 [elevated: OR:3.80 (95%CI:1.54-9.41), p=0.004), non-secretor: OR:2.82 (95%CI:0.67-11.88, p=0.158)] and N-stage [N1: OR:1.80 (95%CI:0.72-4.52), p=0.209) and N2: OR:7.29 (95%CI:3.22-16.49), p<0.001)] emerged as predictors of early recurrence. The AUC for this model was 0.78 (95%CI: 0.71-0.85).

Based on rounded ORs, the early recurrence scores given for CA19-9 values were normal=0, non-secretor=3, and elevated=4, while for N-stage the scores were N0=0, N1=2, and N2=7. The maximum score was 11 (elevated CA19-9 and N2 disease), while the minimum score was 0 (normal CA19-9 and N0 disease). The lower quartile for the scores generated on the study population was 0 while the upper quartile for the score was 6. Based on these, the three risk groups for early recurrence were low-risk (score 0), intermediate-risk (score 1-5), and high-risk (6-11).

A score of 0 was found in 71 patients (27%), of which 1 patient (1%) suffered from early recurrence. A score between 1-5 was observed in 95 patients, of which 13 patients (14%) suffered from early recurrence. A score of 6 or more was observed in 98 patients, of which 31 patients (32%) suffered from early recurrence (Table 2). Of note, the single patient with a score of 0 that developed early recurrence had an R1 resection with progression at the cut margin at 8.11 months in the absence of systemic recurrence.

Table 2.

Distribution of early recurrence risk scores and frequency of early recurrence.

Early Recurrence Risk Score Population Early Recurrence, n (%)
Low Risk (0) Normal CA19-9 and N0 1 (1)
Intermediate Risk (1-5) Normal CA19-9 and N1 13 (14)
Non-secretor and N0 or N1
Elevated CA19-9 and N0 or N1
High Risk (6-11) N2 31 (32)
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Adjuvant Chemotherapy in Early Recurrence Risk Groups

Of the 71 patients with a low risk of early recurrence, 34 patients (48%) received adjuvant chemotherapy. Adjuvant chemotherapy was not associated with an improved OS in this cohort [HR:0.99 (95%CI:0.46-2.11), p=0.972, Figure 3A]. Of the 95 patients with an intermediate-risk of early recurrence, 49 patients (52%) received adjuvant chemotherapy. Adjuvant chemotherapy was not associated with an improved OS in this cohort [HR:0.90 (95%CI: 0.51-1.57), p=0.702, Figure 3B]. Of the 98 patients with a high-risk of early recurrence, 61 patients (62%) received adjuvant chemotherapy. Adjuvant chemotherapy was associated with an improved OS in this cohort (HR:0.50 (95%CI:0.32-0.79), p=0.003, Figure 3C).

Figure 3.

Figure 3.

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Kaplan-Meier curves displaying overall survival in low risk (A), intermediate risk (B), and high risk (C) early recurrence groups stratified by adjuvant chemotherapy.

DISCUSSION

This international multicenter study focusing on early recurrence in IPMN-derived PDAC determined that 10.5 months is the optimal threshold for defining early recurrence based on survival after recurrence. Furthermore, elevated CA19-9 and advanced N-stage emerged as robust predictors of early recurrence. A scoring system was developed based on this predictive model and three distinct risk groups were described (low-, intermediate-, and high-risk for early recurrence). Finally, the role of adjuvant chemotherapy was investigated in these risk groups, and there was an observed association with improved survival in the highest risk group only.

Several studies have aimed to define early recurrence in PanIN-derived PDAC.12, 13, 27 Using a similar early recurrence derivation methodology to the present study, Seelen et al. defined early recurrence at 6 months after resection in locally advanced PanIN-derived PDAC13 while Groot et al. defined early recurrence at 12 months in upfront surgery PanIN-derived PDAC.12 The cut-off of 10.5 months observed in IPMN-derived PDAC may be due its more distinct disease biology.28 Despite this, the presence of aggressive markers of biology causing early recurrence implicates IPMN-derived PDAC may, similarly, be systemic at resection. This hypothesis is supported given the predominance of liver recurrence in the early recurrence cohort. Moreover, we observed early recurrence in 16% of all resected patients which is similar to the number reported by Lucocq et al.29 Thus, the incidence of early recurrence in IPMN-derived PDAC appears to be substantially lower than that observed in PanIN-derived PDAC, which has been estimated to range anywhere between 29% and 52%.12, 13, 27, 30

The development of early recurrence after a morbid pancreatectomy is often perceived as early treatment failure where the surgeon and patient may question the index decisions leading to surgical intervention. Although it provides the best chance for long-term survival, operative stress has been implicated as tumor promoting.31, 32 Thus, identification of factors that may inform surgeon-patient discussions and that can potentially alter treatment and surveillance algorithms are urgently needed. In PanIN-derived PDAC, CA19-9, nodal disease, grade of differentiation, adjuvant chemoradiotherapy, and postoperative complications amongst other factors have been identified as variables associated with early recurrence.12, 13, 30, 33, 34 In IPMN-derived PDAC, there is very little literature present. A recent multi-center study on IPMN-derived PDAC, using a predetermined 12 month cut-off, looked at factors associated with recurrence and found perineural invasion and tail lesions to be associated with early recurrence.29 However, the present study derived an evidence-based cut-off unique to the biologically distinct IPMN-derived pancreatic cancers and highlights the importance of preoperative CA19-9 while validating AJCC nodal stage as robust predictors of early recurrence.35 In support of our findings, Choi et al., also found CA19-9 and nodal disease to be the only robust predictors of OS in resected IPMN-derived PDAC.16 The ability to partially prognosticate risk of early recurrence before surgery using preoperative CA19-9 is particularly attractive.

Herein, we leveraged the predictive model for early recurrence developed here, to design a simple and clinically useful risk score to inform the probability of early recurrence using CA19-9 and N-stage. Using this model, a patient with a normal CA19-9 and no nodal disease has an almost zero percent chance of developing early recurrence. Alternatively, a high-risk patient has a greater than 30% chance of developing early recurrent disease. The median time to recurrence in the early recurrence cohort was about 6 months, thus underscoring the importance of a 6-month surveillance scan in detecting early recurrence half of these patients. Risk-tailored surveillance strategies may be warranted.

One of the most important, yet controversial, aspects of the management in IPMN-derived PDAC that remains poorly understood is the role of adjuvant therapy with conflicting literature.14–21, 36–40 Given the inconsistent guidance, there likely is a cohort of patients that benefits from adjuvant therapy while another cohort of patients does not. Since we observed an increased likelihood of liver (systemic) recurrence in the early recurrence group, we further investigated the role of adjuvant chemotherapy in the low-, intermediate-, and high-risk cohorts. Accordingly, only the high-risk cohort had an associated OS benefit from the administration of adjuvant chemotherapy. Prospective studies are needed to validate the use of adjuvant chemotherapy in high-risk patients.

Several limitations in the present study should be acknowledged. First, this retrospective study involved five international surgical centers where different surgical and pathologic reporting practices may have impacted results. However, this may also improve the generalizability of these conclusions and recommendations. Mutational profiling of primary tumors was not routinely performed at all centers to confirm IPMN-derived pancreatic cancer. Additionally, a small proportion (4%) of the study population received neoadjuvant chemotherapy, and future studies should investigate if early recurrence and patterns of recurrence differ in these selected patients. Next, most of the recurrences were defined based on postoperative imaging in conjunction with clinical information such as increasing CA19-9, while biopsy and tissue confirmation were rarely performed. Variations in surveillance and post recurrence treatment strategies at different institutions and across the study period may have further impacted results. Finally, the retrospective study design limits the ability to make direct causal relationships and future prospective studies are needed to validate these findings and the role of adjuvant chemotherapy in high-risk patients.

CONCLUSION

In conclusion, this international multicenter study derived an optimal cut-off 10.5 months to define early recurrence after resection of IPMN-derived PDAC. An elevated preoperative CA19-9 and advanced N-stage are robust predictors of early recurrence, and a scoring system was developed to risk-stratify patients into low-, intermediate-, and high-risk early recurrence cohorts. Risk-tailored surveillance strategies may be warranted. Finally, an associated benefit of adjuvant chemotherapy was only observed in patients at high-risk for early recurrence.

Supplementary Material

Supplementary Figure

Supplement Figure 1. Kaplan-Meier curve for OS comparing patients with and without recurrence.

Funding:

This work was also supported by the Ben and Rose Cole Charitable PRIA Foundation. Joseph R. Habib was supported by the NIH T32 grant T32CA193111.

Footnotes

Disclosures: There are no conflicts of interest for any of the authors.

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Associated Data

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Supplementary Materials

Supplementary Figure

Supplement Figure 1. Kaplan-Meier curve for OS comparing patients with and without recurrence.

NIHMS2137255-supplement-Supplementary_Figure.png (149.1KB, png)

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