Abstract
Background:
Adjuvant therapy prolongs survival in patients with pancreatic ductal adenocarcinoma. However, no clear guidelines are available regarding the oncologic effects of adjuvant therapy (AT) in resected invasive intraductal papillary mucinous neoplasms (IPMN). The aim was to investigate the potential role of AT in patients with resected invasive IPMN.
Materials and methods:
From 2001 to 2020, 332 patients with invasive pancreatic IPMN were retrospectively reviewed in 15 centres in eight countries. Propensity score-matched and stage-matched survival analyses were conducted.
Results:
A total of 289 patients were enroled in the study after exclusion (neoadjuvant therapy, unresectable disease, uncertain AT status, and stage IV). A total of 170 patients were enroled in a 1:1 propensity score-matched analysis according to the covariates. In the overall cohort, disease-free survival was significantly better in the surgery alone group than in the AT group (P=0.003), but overall survival (OS) was not (P=0.579). There were no significant differences in OS in the stage-matched analysis between the surgery alone and AT groups (stage I, P=0.402; stage II, P=0.179). AT did not show a survival benefit in the subgroup analysis according to nodal metastasis (N0, P=0.481; N+, P=0.705). In multivariate analysis, node metastasis (hazard ratio, 4.083; 95% CI, 2.408−6.772, P<0.001), and cancer antigen 19-9 greater than or equal to 100 (hazard ratio, 2.058; 95% CI, 1.247−3.395, P=0.005) were identified as adverse prognostic factors in resected invasive IPMN.
Conclusion:
The current AT strategy may not be recommended to be performed with resected invasive IPMN in stage I and II groups, unlike pancreatic ductal adenocarcinoma. Further investigations of the potential role of AT in invasive IPMN are recommended.
Keyword: adjuvant therapy, invasive IPMN, multicenter study, pancreas cancer, pancreatic IPMN
Introduction
Highlights
The role of adjuvant therapy in resected invasive intraductal papillary mucinous neoplasm remains unclear.
The adjuvant therapy did not show a survival advantage in the stage I and II group.
It’s time to reassess the postoperative adjuvant therapy strategy for invasive intraductal papillary mucinous neoplasm.
The prevalence of intraductal papillary mucinous neoplasm (IPMN) of the pancreas is continuously increasing due to advances in cross-sectional imaging1,2. IPMN of the pancreas is a mucin-producing neoplasm derived from the ductal system of the pancreatic gland and has a broad spectrum from low-grade dysplasia to invasive carcinoma. Among them, high-grade dysplasia and invasive IPMN are considered malignant diseases, and surgical resection with a clear margin is the best treatment option.
The International Association of Pancreatology Sendai guidelines in 20063, Fukuoka guidelines in 20124, and revised Fukuoka guidelines in 20175 have continuously evolved and attempted to define the appropriate indications for surgical resection. In particular, the prediction of IPMN with malignant potential and the development of risk prediction models in patients with branch duct–IPMN (BD-IPMN) are actively being conducted6,7.
The incidence of invasive IPMN is ~23%, according to American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) data, and is associated with a poor prognosis compared to other types of IPMN8. For invasive IPMN, surgical treatment, and adjuvant therapy (AT) are offered and are treated similarly to pancreatic ductal adenocarcinoma (PDAC). Although the molecular alterations specific to invasive IPMN are poorly understood, evidence has shown that the genetic backgrounds of IPMN and PDAC are different9,10. When comparing survival between invasive IPMN and PDAC, the course of invasive IPMN is more indolent than PDAC, based on an optimized stage-to-stage comparison11. AT has been shown to be beneficial in prolonging survival for PDAC12. However, data on the utility of invasive IPMN are limited. Several smaller clinical studies have attempted to address this question, but it is challenging to secure a sufficient number of patients considering the lower prevalence of the disease13–18. Therefore, this study aimed to investigate the potential role of AT in improving overall survival (OS) in patients with resected invasive IPMN through an international multicenter study.
Materials and methods
Database and patient selection
This study included 332 patients who underwent surgical resection for invasive IPMN in 15 institutions in eight countries: South Korea (four centres), Japan (four centres), England (one centre), Taiwan (two centres), the United States (one centre), Singapore (one centre), Germany (one centre), and Mongolia (one centre) between January 2001 and December 2020. After excluding patients with unresectable stage IV disease, neoadjuvant therapy, and uncertain AT status, propensity score-matched (PSM) analysis was adopted in the remaining 289 patients to reduce the bias from several confounding factors (Fig. 1). This study included data on demographic, clinicopathological, and oncologic information such as age, sex, levels of cancer antigen 19-9 (CA 19-9), and stage based on the American Joint Committee on Cancer (AJCC) staging guidelines, 8th edition. All data were collected and analyzed at the Department of Surgery, Yonsei University College of Medicine, Korea. This study was approved by the Institutional Review Board of the Yonsei University College of Medicine (registration date: December 20, 2020; registration number:4-2020-1243). In addition, this study was registered at Clinical Research information Service (UIN: KCT0008256) in accordance with the World Medical Association’s Declaration of Helsinki, 2013. This retrospective study has been reported in line with the STROCSS criteria19. Supplemental Digital Content 1, http://links.lww.com/JS9/A688.
Figure 1.
Study flow diagram. IPMNS, intraductal papillary mucinous neoplasm.
Statistical analysis
All statistical analyses were performed using SPSS software (version 25.0; SPSS Inc.). Continuous variables are expressed as mean±SD or range, and categorical variables are expressed as frequencies and percentages. Student’s t-test was performed to compare continuous variables, and the χ2 test and Fisher’s exact test were performed to compare categorical data. The Kaplan–Meier method was used for disease-free survival (DFS) and OS analyses. Cox proportional hazards analysis was performed to estimate prognostic factors for OS throughout the population. The propensity score was generated by binary logistic regression, and patients with similar propensity scores were selected from the surgery alone (SA) and AT groups (1:1 matching) to reduce bias in patient distribution [covariate: R status, stage, lymphovascular invasion (LVI), and perineural invasion (PNI)]. Statistical significance was set at P less than 0.05.
Results
Clinicopathological characteristics
The demographic and tumour characteristics of 289 patients with invasive IPMN are presented in Table 1. Among them, 157 (54.3%) were in the AT group. Patients who received AT were significantly younger, with a mean age at diagnosis of 67.2 years vs. 70.3 years in the SA group. There were no differences in tumour location between the two groups, but for the morphological type, the type of the main duct showed a much higher incidence in the AT group (P<0.001). Other differences were found between the two groups in terms of type of surgery (P=0.018), N stage (P<0.001), AJCC 8th stage (P<0.001), LVI (P=0.008), PNI (P<0.001), and R status (P=0.01). After the PSM analysis, there were no differences between the two groups, except for age and body mass index. The mean duration of follow-up was 36.34 months (SD=33.47).
Table 1.
Characteristics of patients who received adjuvant therapy vs. those who underwent surgery alone in the overall cohort after the PSM analysis.
| Total population | PSM | |||||
|---|---|---|---|---|---|---|
| Surgery alone (n=132) | Adjuvant chemotherapy (n=157) | P value | Surgery alone (n=85) | Adjuvant chemotherapy (n=85) | P | |
| Age | 70.3±9.9 | 67.2±9.8 | 0.008 | 72.8±9.0 | 66.6±10.2 | <0.001 |
| Sex, n (%) | 0.043 | 0.539 | ||||
| Male | 73 (55.3) | 67 (42.7) | 43 (50.6) | 38 (44.7) | ||
| Female | 59 (44.7) | 90 (57.3) | 42 (49.4) | 47 (55.3) | ||
| BMI | 23.2±4.1 | 24.3±4.6 | 0.038 | 23.2±4.1 | 24.7±5.0 | 0.035 |
| Tumour location, n (%) | 0.238 | 0.154 | ||||
| Head | 92 (70.2) | 92 (59.0) | 58 (68.2) | 42 (50.0) | ||
| Head + body | 0 | 3 (1.9) | 0 | 3 (3.6) | ||
| Body | 14 (10.7) | 28 (17.9) | 11 (12.9) | 18 (21.4) | ||
| Tail | 13 (9.9) | 17 (10.9) | 7 (8.2) | 8 (9.5) | ||
| Body + tail | 9 (6.9) | 11 (7.1) | 7 (8.2) | 10 (11.9) | ||
| Entire pancreas | 3 (2.3) | 5 (3.2) | 2 (2.4) | 3 (3.6) | ||
| Operative method, n (%) | 0.260 | 0.097 | ||||
| PD/PPPD | 87 (65.9) | 89 (56.7) | 53 (62.4) | 39 (45.9) | ||
| Distal pancreatectomy | 30 (22.7) | 43 (27.4) | 20 (23.5) | 28 (32.9) | ||
| Total pancreatectomy | 15 (11.4) | 25 (15.9) | 12 (14.1) | 18 (21.2) | ||
| Type of surgery, n (%) | 0.018 | 0.091 | ||||
| Open | 80 (60.6) | 107 (68.2) | 57 (67.1) | 56 (65.9) | ||
| Laparoscopic | 35 (26.5) | 44 (28.0) | 17 (20.0) | 25 (29.4) | ||
| Robotic | 17 (12.9) | 6 (3.8) | 11 (12.9) | 4 (4.7) | ||
| Morphologic type, n (%) | 0.001 | 0.181 | ||||
| Branch | 34 (26.4) | 28 (18.8) | 16 (19.5) | 13 (16.0) | ||
| Main | 51 (39.5) | 93 (62.4) | 38 (46.3) | 49 (60.5) | ||
| Mixed | 44 (34.1) | 28 (18.8) | 28 (34.1) | 19 (23.5) | ||
| Tumour size | 5.4±7.9 | 6.0±13.1 | 0.633 | 5.4±8.0 | 6.3±15.3 | 0.639 |
| N stage, n (%) | <0.001 | 0.589 | ||||
| N0 | 108 (81.8) | 75 (47.8) | 61 (71.8) | 55 (64.7) | ||
| N1 | 21 (15.9) | 75 (47.8) | 21 (24.7) | 27 (31.8) | ||
| N2 | 3 (2.3) | 7 (4.5) | 3 (3.5) | 3 (3.5) | ||
| Stage, n (%) | <0.001 | 0.758 | ||||
| IA | 61 (46.2) | 23 (14.6) | 22 (25.9) | 22 (25.9) | ||
| IB | 21 (15.9) | 24 (15.3) | 13 (15.3) | 12 (14.1) | ||
| IIA | 23 (17.4) | 27 (17.2) | 23 (27.1) | 21 (24.7) | ||
| IIB | 21 (15.9) | 74 (47.1) | 21 (24.7) | 27 (31.8) | ||
| III | 6 (4.5) | 9 (5.7) | 6 (7.1) | 3 (3.5) | ||
| CA 19-9 | 1492.4±11655.7 | 473.8±1804.7 | 0.356 | 2327.0±14600.3 | 276.0±1244.7 | 0.236 |
| LVI, n (%) | 27 (21.8) | 57 (37.3) | 0.008 | 26 (32.1) | 15 (18.5) | 0.071 |
| PNI, n (%) | 37 (30.1) | 98 (64.1) | <0.001 | 37 (45.7) | 34 (42.0) | 0.751 |
| LNR | 0.0±0.1 | 0.2±0.3 | <0.001 | 0.1±0.1 | 0.2±0.4 | 0.036 |
| R status, n (%) | 0.01 | 0.095 | ||||
| R0 | 116 (87.9) | 125 (79.6) | 74 (87.1) | 71 (83.5) | ||
| R1 | 13 (9.8) | 32 (20.4) | 8 (9.4) | 14 (16.5) | ||
| R2 | 3 (2.3) | 0 | 3 (3.5) | 0 | ||
| Recurrence, n (%) | 21 (16.4) | 87 (56.5) | <0.001 | 17 (20.5) | 44 (53.0) | <0.001 |
CA 19-9, cancer antigen 19-9; LNR, lymph node ratio; LVI, lymphovascular invasion; PD, pancreaticoduodenectomy; PNI, perineural invasion; PPPD, pylorus-preserving pancreaticoduodenectomy; PSM, propensity score-matched.
Patients were included in the AT group if they had received adjuvant chemotherapy. Gemcitabine-based (n=70), 5-fluorouracil based (n=5), titanium silicate (TS)-1 (n=8), capecitabine (n=1), and pembrolizumab (n=1) were administered postoperatively as AT to those in the invasive IPMN group. Of these, three patients underwent radiation therapy for recurrence as a palliative aim. (Table 2).
Table 2.
Distribution of regimen of adjuvant chemotherapy.
| Regimen | Total, n=85, n (%) |
|---|---|
| Gemcitabine-based | 70 (82.35) |
| Fluorouracil based | 5 (5.88) |
| TS-1 | 8 (9.41) |
| Capecitabine | 1 (1.17) |
| Pembrolizumab | 1 (1.17) |
TS-1, titanium silicate-1.
Comparison of survival in the overall cohort
After adjusting for major confounders, we found no significant benefit of AT for OS but not in DFS. Patients who received AT had a 5-year OS rate of 56.5% compared with 60.3% in patients who underwent SA (P=0.579, Fig. 2B). The 5-year DFS rate in patients who received AT was 43.8% compared with 72.6% in patients who underwent SA (P=0.003, Fig. 2A).
Figure 2.
(A) Overall survival, overall cohort, after PSM analysis; surgery alone group vs. adjuvant therapy group, P=0.579. (B) Disease-free survival, overall cohort, after PSM analysis; surgery alone group vs. adjuvant therapy group, P=0.003. AT, adjuvant therapy; PSM, propensity score-matched; SA, surgery alone.
Subgroup analysis
In the staged matched analysis of OS, no significant survival differences were found between the AT and SA groups according to the stage (stage I group, P=0.402, Fig. 3A; stage II group, P=0.179, Fig. 3B). In the comparison of OS according to lymph node (LN) metastasis, there were no differences in OS according to AT in the N0 and N+ groups (N0 group, P=0.481, Fig. 4A; N+group, P=0.705, Fig. 4B). A comparison of the clinicopathological characteristics between the SA and AT groups according to the nodal status is described in the Supplementary Table, Supplemental Digital Content 2, http://links.lww.com/JS9/A689.
Figure 3.
(A) Overall survival, stage I group, after PSM analysis; surgery alone group vs. adjuvant therapy group, P=0.402. (B) Overall survival, stage II group, after PSM analysis; surgery alone group vs. adjuvant therapy group, P=0.179. AT, adjuvant therapy; PSM, propensity score-matched; SA, surgery alone.
Figure 4.
(A) Overall survival, N0 group, after PSM analysis; surgery alone group vs. adjuvant therapy group, P=0.481. (B) Overall survival, N+ group, after PSM analysis; surgery alone group vs. adjuvant therapy group, P=0.705. AT, adjuvant therapy; PSM, propensity score-matched; SA, surgery alone.
Univariable and multivariable survival analysis for resected inv-IPMN
The association of OS with patient, tumour, and treatment variables was evaluated using univariate and multivariate analyses. Multiple factors, such as CA 19-9 greater than or equal to 100, AJCC stage, R status, LVI, PNI, and adjuvant chemotherapy, were associated with OS after the resection of invasive IPMN (Table 3). On multivariable analysis, CA 19-9 greater than or equal to 100 and LN metastasis were independently associated with an unfavourable prognosis. Based on the hazard ratio, LN metastasis was identified as the strongest predictor of survival in patients with resected invasive IPMN.
Table 3.
Multivariate analysis of clinicopathological factors influencing overall survival in invasive IPMN (before PSM).
| Univariable analysis | Multivariable analysis | |||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Age | 1.022 (0.999−1.045) | 0.057 | ||
| CA 19-9≥100 | 2.764 (1.727−4.424) | <0.001 | 2.058 (1.247−3.395) | 0.005 |
| AJCC stage | ||||
| I | 1.000 | |||
| II | 4.395 (2.613−7.391) | <0.001 | ||
| III | 3.816 (1.509−9.648) | 0.005 | ||
| N stage I/II | 4.697 (3.049−7.236) | <0.001 | 4.038 (2.408−6.772) | <0.001 |
| R1 or R2 | 1.836 (1.154−2.921) | 0.010 | 1.630 (0.940−2.825) | 0.082 |
| LVI | 1.612 (1.058−2.456) | 0.026 | ||
| PNI | 2.802 (1.804−4.352) | <0.001 | ||
| Adjuvant therapy | 1.573 (1.025−2.412) | 0.038 | ||
AJCC, American Joint Committee on Cancer; CA19-9, cancer antigen 19-9; HR, hazard ratio; IPMN, intraductal papillary mucinous neoplasm; LVI, lymphovascular invasion; PNI, perineural invasion; PSM, propensity score-matched.
Discussion
This study aimed to investigate the potential role of AT in improving OS in patients with invasive IPMN through an international multicenter study. To this end, we collated a large retrospective cohort of patients who underwent pancreatic resection for invasive IPMN. In the PSM analysis, especially in stage I and II groups, we found that AT did not have a significant survival benefit in OS and DFS. Additionally, there were no significant survival benefits of AT in patients with node metastasis, regardless of stage. When the multivariable analysis was performed on the entire cohort without PSM analysis, the independent prognostic factors related to OS were CA 19-9 greater than or equal to 100 and LN metastasis.
The incidence of IPMN has increased with the development of cross-sectional imaging, and the rate of high-grade dysplasia or invasive IPMN has reached 23%2,8. As the prevalence increases, there have been developments in treatment strategies and guidelines, most predominantly focused on identifying patients before developing the malignant disease. Currently, there are no established guidelines for administering AT to patients who have undergone pancreatic resection for invasive IPMN. Therefore, most oncologists still adhere to the guidelines for PDAC treatment. Although the genetic background of invasive IPMN has not been clearly identified, it shows a more indolent pattern than that of PDAC20,21. Koh and colleagues compared the pathological characteristics of invasive IPMN and PDAC in a meta-analysis. The invasive IPMN group showed a lower rate of T3 or T4 tumours and a substantially lower rate of lymph node metastasis. In addition, they found that infiltration of surrounding tissues, such as LVI or PNI, is relatively infrequent and is related to R status22. A recent meta-analysis also reported that invasive IPMN was associated with better tumour differentiation23. According to a recent study, in a stage-matched analysis of OS and DFS between invasive IPMN and PDAC, the invasive IPMN group showed a better survival rate in stage I and II groups11. Therefore, a different AT strategy from PDAC in invasive IPMN after pancreatic resection is urgently needed.
Looking at the results of previous studies, some groups claim survival benefits when AT is administered to the LN+ group, while others point out that the effects of AT are unclear (Table 4). Therefore, it can be explained that it is not appropriate to perform AT unconditionally in patients with resected invasive IPMN according to the PDAC guidelines. Invasive IPMN has a more indolent pattern than PDAC, and the evidence for its anticancer effect in the LN+ group is unclear. Moreover, the problem with recent studies is that there is no clear standard for selecting a therapeutic agent and implementing additional radiotherapy due to the absence of clear guidelines. In most cases, these studies were based on small-scale data. However, McMillan et al.16 found a survival benefit of AT in stage II or higher, LN+ group, or poorly differentiated group in a study based on the National Cancer Database (NCDB). However, detailed information on AT was not provided. Furthermore, Mungo et al.24 also reported a survival benefit in the LN+ group for 492 patients using NCDB, but there is also no detailed information about AT. This study attempted to derive convincing results by performing PSM analysis on 289 patients by recruiting the most significant number of cases among studies excluding NCDB data.
Table 4.
Literature review reporting the effects of AT on resected invasive IPMN.
| Type of study | No. patients | Regimen of adjuvant therapy | Benefit from AT | |
|---|---|---|---|---|
| Swartz et al. 13 | Retrospective | 70 (SA vs. AT, 30 vs. 40) | 5-FU, n=40 Additional radiotherapy, n=40 |
<OS> LN+ group (RR=0.43, P=0.047) |
| Caponi et al. 15 | Retrospective | 64 (SA vs. AT, 31 vs. 33) | Gemcitabine, n=23 Additional radiotherapy, n=10 |
<DFS, OS> LN+ group (7.5 vs. 16.5 months; P=0.04) |
| McMillan et al. 16 | Retrospective | 1220 (SA vs. AT, 679 vs. 541) | No details | <OS> Stage II (30.42 vs. 22.83 months; P=0.039) Stage III/IV (17.41 vs. 11.40 months; P<.0001) LN+ group (19.38 vs. 12.19 months, P<0.001) Poorly differentiated (15.51 vs. 9.56 months, P=0.002) |
| Marchegiani et al. 17 | Retrospective | 102 (SA vs. AT, 83 vs. 19) | Gemcitabine, n=15 Gemcitabine + oxaliplatin, n=2 5-FU + oxaliplatin, n=2 Additional radiotherapy, n=5 |
<DSS> LN+ group (5-years-DSS 76 vs. 35.8%, P=0.01) Tubular carcinoma (5-years-DSS 88.9 vs. 53%, P=0.03) |
| Mungo et al. 24 | Retrospective | 492 (SA vs. AT, 267 vs. 225) | NS | LN+ group (HR, 0.05; 95% CI 0.32−0.79) |
| Turrini et al. 14 | Retrospective | 98 (SA vs. AT, 61 vs. 37) | 5-FU and/or Gemcitabine, n=7 Chemoradiation 45 Gy over 5 weeks, n=30 |
No benefit from adjuvant therapy |
| Rodrigues et al. 18 | Retrospective | 103 (SA vs. AT, 69 vs. 34) | Gemcitabine, n=34 Gemcitabine-capecitabine, n=2 5-FU, n=2 Additional radiotherapy, n=19 |
No benefit from adjuvant therapy |
| Choi et al. 11 | Retrospective | 67 (SA vs. AT, 38 vs. 25) External validation 34 (SA vs. AT, 24 vs. 10) |
Gemcitabine, n=16 Gemcitabine-capecitabine n=10 5-FU, n=2 Additional radiotherapy, n=3 |
No benefit from adjuvant therapy |
AT, adjuvant therapy; DFS, disease-free survival; DSS, disease-specific survival; HR, hazard ratio; IPMN, intraductal papillary mucinous neoplasm; OS, overall survival; RR, relative risk; SA, surgery alone.
AT is performed regardless of stage in patients with PDAC according to current guidelines; however, in this study, it was found that AT was not beneficial in stage I, II, and N+ groups in resected invasive IPMN. In the N+ group in this study, there were no differences in stages between the SA and AT groups, and LVI showed a higher ratio in the AT group, but there were no differences in OS (Fig. 4A). In addition, the recurrence rate was significantly higher in the group that underwent AT in both the N0 and N+ groups; therefore, the adverse effect of AT was also considered (Supplementary Table, Supplemental Digital Content 2, http://links.lww.com/JS9/A689). The initial hypothesis suggests that despite the similarity in conditions between the SA and AT groups, the patients who receive anticancer treatment in clinical practice are often more advanced in their illness, and this may not be adequately reflected in a retrospective study. Second, although there is no definitive evidence, the cause of the high recurrence rate observed in the group that received AT may be related to the increased risk of malignancy associated with both primary and secondary immunosuppression, as compared with the general population. AT exhibits both immunosuppressive and cancer-killing effects, and if it is not effective in destroying invasive IPMN, only the immunosuppressive effect remains, which could be contributing to the high recurrence rate after surgery. In addition, according to Shockley et al.25, genetic and metabolic changes, along with other disruptions to the cellular microenvironment, including immune alterations and inflammation, can contribute to tumorigenesis. Furthermore, Roth et al.26 have demonstrated that alterations in the microenvironment caused by immunosuppression are linked to the advancement of IPMN to an invasive form, which provides important insights for improving the effectiveness of immunotherapies in enhancing the body’s natural antitumor immune response.
This study has several limitations. First, due to the retrospective nature of data collection and the absence of a standardized protocol for AT administration, it was difficult to confirm the exact number of cycles of AT drug administered. As a result, this factor could potentially confound the analysis of survival rates. Moreover, we attempted to obtain a substantial amount of retrospective data, which in turn led to a relatively lengthy observational period. Second, the proportion of patients with stage III or IV disease was low due to the characteristics of invasive IPMN; therefore, a subgroup analysis of the usefulness of AT could not be performed at the corresponding stage. Third, invasive IPMN is a heterogeneous disease with three histological types: colloid, tubular, and oncocytic. Survival analysis could not be performed by dividing into tubular type, which is known to be relatively similar to PDAC and has a poor prognosis, and colloid and oncocytic types, which are known to have a relatively good prognosis, are considered an essential limitation of this study.
In conclusion, AT may not be recommended to be performed in stage I and II groups, unlike PDAC in this retrospective international multicenter study. However, insufficient research on the appropriate therapeutic agents for invasive IPMN is also considered to have contributed to these results. Going forward, it is imperative to conduct a randomized controlled trial of FOLFIRINOX on resected invasive IPMN based on the consensus reached in this study. Alternatively, efforts can be made to identify new target drugs and explore the feasibility of conducting clinical trials for them. Therefore, more studies based on larger study populations, such as well-designed nationwide multicenter collaborative randomized controlled trial, are warranted to validate the present observations and investigate the potential effect of AT on resected invasive IPMN.
Ethical approval
This study was approved by the Institutional Review Board of the Yonsei University College of Medicine (registration date: December 20, 2020; registration number:4-2020-1243).
Source of funding
No funding was received for this study.
Author contribution
Conceptualization, Pejman Radkani and Chang Moo Kang; Investigation, Joon Seong Park, Hyung Sun Kim, Sung Hoon Choi, Jin Ho Lee, Jae Uk Chong, Yuichi Nagakawa, Byoung UK Park, Emily Winslow, Thomas Fishbein, Jason Hawksworth and Keita Wada; Methodology, Yoshiharu Nakamura, Hiroki Sunagawa, Bobby VM Dasari, Cheng-Ming Peng, Lee Lip Seng, Heiner Wolters and Unenbat Gurbadam, Resources, Hyung Sun Kim, Sung Hoon Choi, Yuichi Nagakawa, Keita Wada, Yoshiharu Nakamura, Hiroki Sunagawa, Bobby VM Dasari, Cheng-Ming Peng, Lee Lip Seng, Heiner Wolters, Unenbat Gurbadam, Munseok Choi and Shin-E Wang; Supervision, Pejman Radkani and Chang Moo Kang; Writing – original draft, Munseok Choi and Shin-E Wang; Writing – review & editing, Pejman Radkani and Chang Moo Kang. The author(s) read and approved the final manuscript.
Conflicts of interest disclosure
There are no conflicts of interest.
Research registration unique identifying number (UIN)
Name of the registry: Clinical Research information Service.
Unique Identifying number or registration ID: KCT0008256.
Hyperlink to the registration (must be publicly accessible): https://cris.nih.go.kr/cris/search/listDetail.do?searchWord=KCT0008256&search_yn=Y.
Guarantor
Chang Moo Kang.
Data statement
Due to the sensitive nature of the questions asked in this study, survey respondents were assured raw data would remain confidential and would not be shared.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Supplementary Material
Footnotes
M.C. and S.-E.W. contributed equally to this work.
This work was presented at HBP Surgery Week 2022 & 57th Annual Congress of the Korean Association of HBP Surgery.
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.lww.com/international-journal-of-surgery.
Published online 7 June 2023
Contributor Information
Munseok Choi, Email: cms2598@yuhs.ac.
Shin-E Wang, Email: sewang@vghtpe.gov.tw.
Joon Seong Park, Email: JSPARK330@yuhs.ac.
Hyung Sun Kim, Email: MILK8508@yuhs.ac.
Sung Hoon Choi, Email: feel415@cha.ac.kr.
Jin Ho Lee, Email: jhlee75@nhimc.or.kr.
Jae Uk Chong, Email: jaeuk1216@nhimc.or.kr.
Yuichi Nagakawa, Email: ynagakawa@gmail.com.
Keita Wada, Email: k_wada@pg8.so-net.ne.jp.
Yoshiharu Nakamura, Email: keishun@nms.ac.jp.
Hiroki Sunagawa, Email: sunageka0624@yahoo.co.jp.
Bobby VM Dasari, Email: bobby.dasari@yahoo.com.
Cheng-Ming Peng, Email: jimy5989@gmail.com.
Lee Lip Seng, Email: lee.lip.seng@singhealth.com.sg.
Heiner Wolters, Email: H.Wolters@lukas-gesellschaft.de.
Unenbat Gurbadam, Email: gurbadam_unenbat@yahoo.com.
Byoung UK Park, Email: Byoungukpark@gmail.com.
Emily Winslow, Email: Emily.r.winslow@gunet.Georgetown.edu.
Thomas Fishbein, Email: Thomas.m.fishbein@gunet.Georgetown.edu.
Jason Hawksworth, Email: Jshawk@gmail.com.
Pejman Radkani, Email: pradkani@gmail.com.
Chang Moo Kang, Email: cmkang@yuhs.ac.
References
- 1.Fong ZV, Fernandez-Del Castillo C. Intraductal papillary mucinous neoplasm of the pancreas. Surg Clin North Am 2016;96:1431–1445. [DOI] [PubMed] [Google Scholar]
- 2.Klibansky DA, Reid-Lombardo KM, Gordon SR, et al. The clinical relevance of the increasing incidence of intraductal papillary mucinous neoplasm. Clin Gastroenterol Hepatol 2012;10:555–558. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6:17–32. [DOI] [PubMed] [Google Scholar]
- 4.Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183–197. [DOI] [PubMed] [Google Scholar]
- 5.Tanaka M, Fernandez-Del Castillo C, Kamisawa T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology 2017;17:738–753. [DOI] [PubMed] [Google Scholar]
- 6.Jang JY, Park T, Lee S, et al. Proposed nomogram predicting the individual risk of malignancy in the patients with branch duct type intraductal papillary mucinous neoplasms of the pancreas. Ann Surg 2017;266:1062–1068. [DOI] [PubMed] [Google Scholar]
- 7.Kim HS, Song W, Choo W, et al. Development, validation, and comparison of a nomogram based on radiologic findings for predicting malignancy in intraductal papillary mucinous neoplasms of the pancreas: an international multicenter study. J Hepato-Biliary-Pancreatic Sci 2023;30:133–143. [DOI] [PubMed] [Google Scholar]
- 8.Khoury RE, Kabir C, Maker VK, et al. What is the incidence of malignancy in resected intraductal papillary mucinous neoplasms? An analysis of over 100 US institutions in a single year. Ann Surg Oncol 2018;25:1746–1751. [DOI] [PubMed] [Google Scholar]
- 9.Furukawa T, Kuboki Y, Tanji E, et al. Whole-exome sequencing uncovers frequent GNAS mutations in intraductal papillary mucinous neoplasms of the pancreas. Sci Rep 2011;1:161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Mas L, Lupinacci RM, Cros J, et al. Intraductal papillary mucinous carcinoma versus conventional pancreatic ductal adenocarcinoma: a comprehensive review of clinical-pathological features, outcomes, and molecular insights. Int J Molecular Sci 2021;22:6756. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Choi M, Chong JU, Hwang HK, et al. Role of postoperative adjuvant therapy in resected invasive intraductal papillary mucinous neoplasm of the pancreas: a multicenter external validation. J Hepatobiliary Pancreat Sci 2021;28:671–679. [DOI] [PubMed] [Google Scholar]
- 12.Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018;379:2395–2406. [DOI] [PubMed] [Google Scholar]
- 13.Swartz MJ, Hsu CC, Pawlik TM, et al. Adjuvant chemoradiotherapy after pancreatic resection for invasive carcinoma associated with intraductal papillary mucinous neoplasm of the pancreas. Int J Radiat Oncol Biol Phys 2010;76:839–844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Turrini O, Waters JA, Schnelldorfer T, et al. Invasive intraductal papillary mucinous neoplasm: predictors of survival and role of adjuvant therapy. HPB (Oxford) 2010;12:447–455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Caponi S, Vasile E, Funel N, et al. Adjuvant chemotherapy seems beneficial for invasive intraductal papillary mucinous neoplasms. Eur J Surg Oncol 2013;39:396–403. [DOI] [PubMed] [Google Scholar]
- 16.McMillan MT, Lewis RS, Drebin JA, et al. The efficacy of adjuvant therapy for pancreatic invasive intraductal papillary mucinous neoplasm (IPMN). Cancer 2016;122:521–533. [DOI] [PubMed] [Google Scholar]
- 17.Marchegiani G, Andrianello S, Dal Borgo C, et al. Adjuvant chemotherapy is associated with improved postoperative survival in specific subtypes of invasive intraductal papillary mucinous neoplasms (IPMN) of the pancreas: it is time for randomized controlled data. HPB (Oxford) 2019;21:596–603. [DOI] [PubMed] [Google Scholar]
- 18.Rodrigues C, Hank T, Qadan M, et al. Impact of adjuvant therapy in patients with invasive intraductal papillary mucinous neoplasms of the pancreas. Pancreatology 2020;20:722–728. [DOI] [PubMed] [Google Scholar]
- 19.Mathew G, Agha R, Albrecht J, et al. STROCSS 2021: Strengthening the reporting of cohort, cross-sectional and case-control studies in surgery. Int J Surg Open 2021;37:100430. [DOI] [PubMed] [Google Scholar]
- 20.Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg 2004;239:788–797; discussion 97-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Wasif N, Bentrem DJ, Farrell JJ, et al. Invasive intraductal papillary mucinous neoplasm versus sporadic pancreatic adenocarcinoma: a stage-matched comparison of outcomes. Cancer 2010;116:3369–3377. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Koh Y-X, Chok A-Y, Zheng H-L, et al. Systematic review and meta-analysis comparing the surgical outcomes of invasive intraductal papillary mucinous neoplasms and conventional pancreatic ductal adenocarcinoma. Ann Surg Oncol 2014;21:2782–2800. [DOI] [PubMed] [Google Scholar]
- 23.Aronsson L, Bengtsson A, Torén W, et al. Intraductal papillary mucinous carcinoma versus pancreatic ductal adenocarcinoma: a systematic review and meta-analysis. Int J Surg 2019;71:91–99. [DOI] [PubMed] [Google Scholar]
- 24.Mungo B, Croce C, Oba A, et al. Controversial role of adjuvant therapy in node-negative invasive intraductal papillary mucinous neoplasm. Ann Surg Oncol 2021;28:1533–1542. [DOI] [PubMed] [Google Scholar]
- 25.Shockley KE, To B, Chen W, et al. The role of genetic, metabolic, inflammatory, and immunologic mediators in the progression of intraductal papillary mucinous neoplasms to pancreatic adenocarcinoma. Cancers (Basel) 2023;15:1722. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Roth S, Zamzow K, Gaida MM, et al. Evolution of the immune landscape during progression of pancreatic intraductal papillary mucinous neoplasms to invasive cancer. EBioMedicine 2020;54:102714. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.