
==== Front
Ann Gastroenterol Surg
Ann Gastroenterol Surg
10.1002/(ISSN)2475-0328
AGS3
Annals of Gastroenterological Surgery
2475-0328
John Wiley and Sons Inc. Hoboken

10.1002/ags3.12790
AGS312790
AGS-2023-0420.R1
Original Article
Original Article
Is multidisciplinary treatment effective for invasive intraductal papillary mucinous carcinoma?
Hirono et al.
Hirono Seiko https://orcid.org/0000-0003-3054-1038
1 2 se-hirono@hyo-med.ac.jp

Higuchi Ryota 3
Honda Goro 3
Nara Satoshi 4
Esaki Minoru 4
Gotohda Naoto https://orcid.org/0000-0002-4468-5844
5
Takami Hideki 6
Unno Michiaki 7
Sugiura Teiichi https://orcid.org/0000-0001-7163-4084
8
Ohtsuka Masayuki 9
Shimizu Yasuhiro 10
Matsumoto Ippei https://orcid.org/0000-0003-3965-3693
11
Kin Toshifumi 12
Isayama Hiroyuki 13
Hashimoto Daisuke 14
Seyama Yasuji 15
Nagano Hiroaki https://orcid.org/0000-0002-7074-3315
16
Hakamada Kenichi https://orcid.org/0000-0001-6513-1202
17
Hirano Satoshi 18
Nagakawa Yuichi https://orcid.org/0000-0003-1169-8160
19
Mizuno Shugo https://orcid.org/0000-0002-2253-544X
20
Takahashi Hidenori https://orcid.org/0000-0003-4801-3540
21
Shibuya Kazuto 22
Sasanuma Hideki 23
Aoki Taku https://orcid.org/0000-0002-2868-5246
24
Kohara Yuichiro 25
Rikiyama Toshiki 26
Nakamura Masafumi 27
Endo Itaru https://orcid.org/0000-0001-5520-8114
28
Sakamoto Yoshihiro https://orcid.org/0000-0001-7279-9702
29
Horiguchi Akihiko https://orcid.org/0000-0002-2187-1396
30
Hatori Takashi 31
Akita Hirofumi https://orcid.org/0000-0002-3115-9466
32
Ueki Toshiharu 33
Idichi Tetsuya https://orcid.org/0000-0001-8048-2203
34
Hanada Keiji https://orcid.org/0000-0003-3196-8551
35
Suzuki Shuji https://orcid.org/0000-0002-3201-9908
36
Okano Keiichi 37
Maehira Hiromitsu 38
Motoi Fuyuhiko https://orcid.org/0000-0001-7601-8395
39
Fujino Yasuhiro 40
Tanno Satoshi 41
Yanagisawa Akio 42
Takeyama Yoshifumi 11
Okazaki Kazuichi 43
Satoi Sohei https://orcid.org/0000-0001-6527-5409
14
Yamaue Hiroki https://orcid.org/0000-0002-6982-3457
1
1 Second Department of Surgery Wakayama Medical University, School of Medicine Wakayama Japan
2 Division of Hepato‐Biliary‐Pancreatic Surgery, Department of Gastroenterological Surgery Hyogo Medical University Nishinomiya Japan
3 Department of Surgery, Institute of Gastroenterology Tokyo Women's Medical University Tokyo Japan
4 Department of Hepatobiliary and Pancreatic Surgery National Cancer Center Hospital Tokyo Japan
5 Department of Hepatobiliary and Pancreatic Surgery National Cancer Center Hospital East Kashiwa Japan
6 Department of Gastroenterological Surgery Nagoya University Graduate School of Medicine Nagoya Japan
7 Department of Surgery Tohoku University Graduate School of Medicine Sendai Japan
8 Division of Hepato‐Biliary‐Pancreatic Surgery Shizuoka Cancer Center Shizuoka Japan
9 Department of General Surgery Chiba University, Graduate School of Medicine Chiba Japan
10 Department of Gastroenterological Surgery Aichi Cancer Center Hospital Nagoya Japan
11 Division of Hepato‐Biliary‐Pancreatic Surgery, Department of Surgery Kindai University Faculty of Medicine Osakasayama Japan
12 Teine Keijinkai Hospital Sapporo Japan
13 Department of Gastroenterology, Graduate School of Medicine Juntendo University Tokyo Japan
14 Department of Surgery Kansai Medical University Hirakata Japan
15 Department of Hepato‐Biliary‐Pancreatic Surgery Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Tokyo Japan
16 Department of Gastroenterological Breast and Endocrine Surgery Yamaguchi University Graduate Medicine Ube Japan
17 Department of Gastroenterological Surgery Hirosaki University Graduate School of Medicine Hirosaki Japan
18 Department of Gastroenterological Surgery II Hokkaido University Faculty of Medicine Sapporo Japan
19 Department of Gastrointestinal and Pediatric Surgery Tokyo Medical University Tokyo Japan
20 Department of Hepatobiliary Pancreatic & Transplant Surgery Mie University Tsu Japan
21 Department of Gastroenterological Surgery, Graduate School of Medicine Osaka University Suita Japan
22 Department of Surgery and Science, Faculty of Medicine, Academic Assembly University of Toyama Toyama Japan
23 Department of Surgery Jichi Medical University Shimotsuke Japan
24 Department of Hepato‐Biliary‐Pancreatic Surgery Dokkyo Medical University Mibu Japan
25 Department of Surgery Nara Medical University Kashiwara Japan
26 Department of Surgery, Saitama Medical Center Jichi Medical University Saitama Japan
27 Department of Surgery and Oncology, Graduate School of Medical Sciences Kyushu University Fukuoka Japan
28 Department of Gastroenterological Surgery Yokohama City University School of Medicine Yokohama Japan
29 Department of Hepato‐Biliary‐Pancreatic Surgery Kyorin University Hospital Mitaka Japan
30 Department of Gastroenterological Surgery Fujita Health University School of Medicine, Bantane Hospital Nagoya Japan
31 Digestive Disease Center, International University of Health and Welfare Mita Hospital Tokyo Japan
32 Osaka International Cancer Institute Department of Gasteroenterological Sugery Osaka Japan
33 Department of Gastroenterology Fukuoka University Chikushi Hospital Fukuoka Japan
34 Department of Digestive Surgery Kagoshima University Kagoshima Japan
35 Department of Gastroenterology Onomichi General Hospital Onomichi Japan
36 Department of Gastroenterological Surgery, Ibaraki Medical Center Tokyo Medical University Ineshiki Japan
37 Department of Gastroenterological Surgery Kagawa University Kida Japan
38 Department of Surgery Shiga University of Medical Science Otsu Japan
39 Department of Surgery I Yamagata University Yamagata Japan
40 Department of Gastroenterological Surgery Hyogo Cancer Center Akashi Japan
41 Department of Gastroenterology IMS Sapporo Digestive Disease Central General Hospital Sapporo Japan
42 Department of Pathology Japanese Red Cross Kyoto Daiichi Hospital Kamigyo‐ku Japan
43 Kansai Medical University Kouri Hospital Neyagawa Japan
* Correspondence
Seiko Hirono, Division of Hepato‐Biliary‐Pancreatic Surgery, Department of Gastroenterological Surgery, Hyogo Medical University, 1‐1Mukogawa, Nishinomiya 663–8501, Japan.
Email: se-hirono@hyo-med.ac.jp

17 3 2024
9 2024
8 5 10.1002/ags3.v8.5 845859
03 2 2024
06 12 2023
24 2 2024
© 2024 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Abstract

Background

Surgical resection is standard treatment for invasive intraductal papillary mucinous carcinoma (IPMC); however, impact of multidisciplinary treatment on survival including postoperative adjuvant therapy (AT), neoadjuvant therapy (NAT), and treatment for recurrent lesions is unclear. We investigated the effectiveness of multidisciplinary treatment in prolonging survival of patients with invasive IPMC.

Methods

This retrospective multi‐institutional study included 1183 patients with invasive IPMC undergoing surgery at 40 academic institutions. We analyzed the effects of AT, NAT, and treatment for recurrence on survival of patients with invasive IPMC.

Results

Completion of the planned postoperative AT for 6 months improved the overall survival (OS), disease‐specific survival (DSS), and recurrence‐free survival (RFS) of patients with stage IIB and stage III resected invasive IPMC, elevated preoperative carbohydrate antigen 19–9 level, lymphovascular invasion, perineural invasion, serosal invasion, and lymph node metastasis on un‐matched and matched analyses. Of the patients with borderline resectable (BR) invasive IPMC, the OS (p = 0.001), DSS (p = 0.001), and RFS (p = 0.001) of patients undergoing NAT was longer than that of those without on the matched analysis. Of the 484 invasive IPMC patients (40.9%) who developed recurrence after surgery, the OS of 365 patients who received any treatment for recurrence was longer than that of those without treatment (40.6 vs. 22.4 months, p < 0.001).

Conclusion

Postoperative AT might benefit selected patients with invasive IPMC, especially those at high risk of poor survival. NAT might improve the survivability of BR invasive IPMC. Any treatment for recurrence after surgery for invasive IPMC might improve survival.

Completion of postoperative adjuvant therapy for 6 months might be beneficial for patients with invasive intraductal papillary mucinous carcinoma (IPMC) at high risk of poor survival. Neoadjuvant therapy might prolong survival for patients with borderline resectable invasive IPMC. Any treatment for recurrence, especially surgical resection for remnant pancreatic recurrence, improved survival for patients who underwent surgery for invasive IPMC.

invasive IPMC
multidisciplinary treatment
neoadjuvant therapy
postoperative adjuvant therapy
recurrence
Japan Pancreas Society source-schema-version-number2.0
cover-dateSeptember 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:02.09.2024
Hirono S , Higuchi R , Honda G , Nara S , Esaki M , Gotohda N , et al. Is multidisciplinary treatment effective for invasive intraductal papillary mucinous carcinoma? Ann Gastroenterol Surg. 2024;8 :845–859. 10.1002/ags3.12790
==== Body
pmc1 INTRODUCTION

Intraductal papillary mucinous neoplasms (IPMNs) are pathologically categorized as low‐grade dysplasia, high‐grade dysplasia (HGD), and invasive intraductal papillary mucinous carcinoma (IPMC) based on the degree of cellular atypia and the growth pattern of the lining epithelium. 1 Invasive IPMC has high malignant potential, which can lead to metastasis and recurrence even after curative resection, similar to conventional pancreatic ductal adenocarcinoma (PDAC). 2 , 3 Many biological features of invasive IPMC are similar to those of conventional PDAC; however, some features are different such as pathological subtype, recurrence pattern, and survival. 4 , 5 , 6

Although surgical resection is the standard treatment for invasive IPMC, 1 , 7 the impact of multidisciplinary treatment on survival including postoperative adjuvant therapy (AT), neoadjuvant therapy (NAT), and treatment for recurrent lesions is not clear. The CONKO‐001 randomized trial clearly showed that AT after surgery is useful for prolonging survival and preventing the recurrence of conventional PDAC 8 ; however, the effectiveness of AT has not been established for invasive IPMC. Several studies have shown no impact of AT on the survival of patients with resected invasive IPMC, whereas others have shown the usefulness of AT in improving survival, especially in patients with advanced resected invasive IPMC. 5 , 9 , 10 , 11 , 12 , 13 , 14 However, these studies had the following limitations: small sample size; unclear definition of tumor size, which T stage is based on, whether invasive component with or without noninvasive IPMN lesions; and no information on regimen or duration of AT. To evaluate the impact of postoperative AT on the survival of patients with invasive IPMC as accurately as possible, the Japan Pancreas Society (JPS) collected data from all of Japan, defined tumor size used to T stage as maximum invasive length without noninvasive IPMN region, and evaluated the correlation between AT regimen and survival. We defined the completion of postoperative AT as patients who received the planned AT for 6 months and evaluated the impact of AT completion on survival.

European guidelines on pancreatic cystic neoplasms do not recommend NAT even for locally advanced invasive IPMC because of insufficient data and suggest palliative chemotherapy for recurrent lesions after surgery for invasive IPMC although there is no supporting evidence available. 7 In this study, we assessed the impact of NAT on survival, especially for patients with borderline resectable (BR) invasive IPMC, as well as the impact of treatment for recurrent lesions.

To identify an effective treatment strategy to prolong the survival of patients with invasive IPMC, we analyzed the effects of AT, NAT, and treatment for recurrence after surgery on the survival of patients with invasive IPMC. This was a large cohort study of patients with invasive IPMC who underwent surgery in a project study by the JPS.

2 METHODS

2.1 Study population

A retrospective multi‐institutional, observational study by the JPS evaluated patients undergoing surgical resection for invasive IPMC between January 1996 and December 2018. This study was based at 40 academic institutions. The inclusion criteria were as follows: histologically proven invasive component of carcinoma arising from IPMN, and no local residual tumor (R0) or microscopic residual tumor (R1) based on pathological findings. Patients with conventional PDAC concomitant with IPMN were excluded. A total of 1183 patients were included in this study. This study was approved by the institutional review board of each participating institution prior to initiation of the study and conducted in accordance with the Declaration of Helsinki.

2.2 Clinical data collection

Age, sex, preoperative symptom, comorbidities, and preoperative serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA19‐9) were evaluated. Furthermore, we also evaluated radiographic morphological type including branch duct type, mixed type, and main duct type based on preoperative cross‐sectional imaging, 1 as well as the resectability, including resectable or BR invasive IPMC according to the resectability criteria established by the National Comprehensive Cancer Network. 15 Surgical procedure and peri‐operative outcomes, histopathological features, AT, NAT, site of initial recurrence, and survival were also assessed.

The regimen of postoperative AT included oral S‐1 monotherapy, intravenous gemcitabine monotherapy (GEM), and combination therapy with GEM and S‐1 (GS), depending on the physician's instructions. The completion of postoperative AT was defined as receiving: (1) four cycles of S‐1 for the first 28 consecutive days followed by a 14‐day rest; (2) six cycles of 4 weeks of GEM on days 1, 8, and 15; and (3) eight cycles of 3 weeks of GEM on days 1 and 8 plus S‐1 for first 14 consecutive days followed by a 7‐day rest.

2.3 Pathologic assessment

Invasive IPMC was defined as the presence of a continuous invasive component from HGD in pathological findings to distinguish it from conventional PDAC concomitant with IPMN. 16 , 17 In case of difficulty differentiating between invasive IPMC and conventional PDAC concomitant with IPMN, a central review was undertaken by a specialized pathologist (AY) who was blinded to the clinical outcomes.

The type of invasive component was classified as tubular or colloid based on differentiations in the invasive components. Invasive IPMC tumors were staged according to the Tumor, Node, and Metastasis Classification of Malignant Tumors, 8th edition, published by the American Joint Committee on Cancer and the Union for International Cancer Control (AJCC/UICC TNM staging system). 18 , 19 The tumor size was determined as the maximum length of invasive component without noninvasive IPMN, according to a previously reported method. 20 , 21 Resection margin status involvement (R1) was defined as the presence of the tumor at the resection margin under the microscope.

2.4 Statistical analysis

Continuous variables are expressed as the median and range. Categorical variables are described as percentages (%). Recurrence was defined as convincing radiographic evidence of the disease initially during follow‐up after surgery and was histologically confirmed when possible. The sites of recurrence were classified as the remnant pancreas and extra‐pancreas. Recurrence in the remnant pancreas was defined as new development or progression of IPMN meeting the surgical indication in each institution, which meant suspected HGD or invasive IPMC, or metachronous development of conventional PDAC. Extra‐pancreatic recurrence was defined as the appearance of tumors outside the pancreas including the local area (retroperitoneal or surgical bed), lungs, liver, peritoneal cavity, or bone.

Overall survival (OS) was defined by death events or censoring as of the last follow‐up. Disease‐specific survival (DSS) was defined as the time interval from surgery to death by disease or the last follow‐up. Disease‐free survival (DFS) was defined as the time interval from the date of surgical resection to diagnosis of recurrence on follow‐up. The Kaplan–Meier method was used to estimate the incidence curves, which were compared by univariate analysis using the log‐rank test.

Of the 1183 patients included in this study, 1143 who underwent surgical resection for invasive IPMC without NAT were analyzed for impact of postoperative AT on survival and risk factors of poor survival after surgery. To identify the risk factors associated with poor OS, DSS, and RFS, multivariate analysis was performed using the Cox proportional hazards regression model, which included variables found to be significant in univariate analysis (p < 0.05). Furthermore, the propensity score was generated by binary logistic regression, and patients with similar propensity scores were selected from patients with and without completion of AT to reduce bias in patient distribution [covariate: age, residual tumor status, lymphovascular invasion, perineural invasion, and lymph node metastasis]. We analyzed the impact of NAT on the survival of patients with invasive IPMC by comparing the survival between patients undergoing surgery with and without NAT, and we also performed propensity score matched analysis (PSM) with covariate of age, resectability, and operation to reduce bias between the patients with and without NAT. The recurrence pattern and impact of treatment for recurrent diseases on the survival were analyzed in 1183 patients with invasive IPMC who underwent surgery. All statistical analyses were performed with SPSS software (version 26; IBM Corp, Somers, NY, USA). Statistical significance was set at p < 0.05.

3 RESULTS

3.1 Demographics and clinicopathologic characteristics of patients undergoing surgery without NAT

The demographics of 1143 patients who underwent surgical resection for histologically confirmed invasive IPMC without NAT between 1996 and 2018 are summarized in Table 1. The median age was 71 years (range: 35–91) and 671 (58.7%) patients were male. Of the 1143 patients, 486 (42.5%) received AT after surgery and 333 (29.1%) completed the planned AT for 6 months. The median follow‐up duration after surgery was 46.8 months (range: 4.9–236.2 months).

TABLE 1 Clinicopathological characteristics of 1143 patients with resected invasive IPMC without NAT.

Parameter	Total	Frequency of postoperative AT (n=486)	p	Frequency of completion of postoperative AT (n=333)	p	
Age, ≥70/<70, n (%)	647(56.6)/496(43.4)	254(39.3)/232(46.8)	0.011	165(25.5)/168(33.9)	0.002	
Sex, Male/female, n (%)	671(58.7)/472(41.3)	277(41.3)/209(44.3)	0.313	192(28.6)/141(29.9)	0.645	
Symptom, yes/no, n (%)	417(36.5)/726(63.5)	187(44.8)/299(41.2)	0.228	129(30.9)/204(28.1)	0.310	
Jaundice, yes/no, n (%)	132(11.5)/1,011(88.5)	66(50.0)/420(41.5)	0.065	42(31.8)/291(28.8)	0.470	
Diabetes mellitus, yes/no, n (%)	449(39.3)/694(60.7)	197(43.9)/289(41.6)	0.456	132(29.4)/201(29.0)	0.874	
Serum CEA level, elevated/normal, n (%)	265(23.5)/865(76.5)	164(61.9)/481(55.6)	0.071	67(25.3)/265(30.6)	0.094	
Missing	n=13					
Serum CA19‐9, elevated/normal, n (%)	459(40.5)/673(59.5)	228(49.7)/257(38.2)	<0.001	141(30.7)/191(28.4)	0.396	
Missing	n=11					
Morphological type, branch/mixed/main, n (%)	227(19.9)/651(57.0)/265(23.2)	106(46.7)/284(43.6)/96(36.2)	0.044	65(28.6)/200(30.7)/68(25.7)	0.306	
Resectability, Resectable/BR, n (%)	1,097(96.0)/46(4.0)	460(41.9)/26(56.6)	0.050	322(29.4)/11(23.9)	0.426	
Type of surgery, PD/DP/TP/CP, n (%)	655(57.3)/300(26.2)/172(15.0)/16(1.4)	279(42.6)/137(45.7)/70(40.7)/0(0)	0.004	186(28.4)/96(32.0)/51(29.7)/0(0)	0.047	
Transfusion, yes/no, n (%)	184(16.1)/959(83.9)	70(38.0)/416(43.4)	0.180	36(19.6)/297(31.0)	0.090	
Pathological findings, n (%)	
Invasive component, tubular/colloid	697(66.1)/357(33.9)	349(50.1)/236(66.1)	<0.001	232(33.3)/93(26.1)	0.016	
Missing	n=89					
Lymphovascular invasion, yes/no	511(44.7)/632(55.3)	314(61.4)/172(27.2)	<0.001	202(39.5)/131(20.7)	<0.001	
Perineural invasion, yes/no	436(38.1)/707(61.9)	267(61.2)/219(31.0)	<0.001	170(39.0)/163(23.1)	<0.001	
Bile duct invasion, yes/no	156(13.6)/987(86.4)	81(51.9)/405(41.0)	0.011	51(32.7)/282(28.6)	0.293	
Duodenal invasion, yes/no	210(18.4)/933(81.6)	113(53.8)/373(40.0)	<0.001	66(31.4)/267(28.6)	0.418	
Serosal invasion, yes/no	269(23.5)/874(76.5)	172(63.9)/314(35.9)	<0.001	102(37.9)/231(26.4)	<0.001	
Retropancreatic tissue invasion, yes/no	401(35.1)/742(64.9)	239(59.6)/247(33.3)	<0.001	149(37.2)/184(24.8)	<0.001	
Portal vein invasion, yes/no	77(6.7)/1,066(93.3)	47(61.0)/439(41.2)	0.001	27(35.1)/306(28.7)	0.236	
Arterial invasion, yes/no	21(1.8)/1,122(98.2)	13(61.9)/473(42.2)	0.070	5(23.8)/328(29.2)	0.588	
Extra‐pancreatic nerve plexus invasion, yes/no	79(6.9)/1,064(93.1)	50(63.3)/436(41.0)	<0.001	29(36.7)/304(28.6)	0.125	
Other organ invasion, yes/no	30(2.6)/1,113(97.4)	16(53.3)/470(42.2)	0.225	8(26.7)/325(29.2)	0.763	
Residual tumor status, R0/R1	1,049(91.8)/94(8.2)	428(40.8)/58(61.7)	<0.001	301(28.7)/32(34.0)	0.274	
AJCC/UICC stage (8th)	
T stage, T1a/T1b/T1c/T2/T3/T4, n (%)	376(33.9)/32(11.0)/188(17.0)/297(26.8)/123(11.1)/2(0.4)	60(16.0)/57(46.7)/114(60.6)/181(60.9)/70(56.9)/2(100)	<0.001	48(12.8)/43(35.2)/87(46.3)/111(37.4)/42(34.1)/1(50.0)	<0.001	
Missing	n=35					
N stage, N0/N1/N2, n (%)	807(70.6)/212(18.5)/124(10.8)	257(31.8)/144(67.9)/85(68.5)	<0.001	86(23.0)/102(48.1)/45(36.3)	<0.001	
Stage, IA/IB/IIA/IIB/III/IV, n (%)	573(51.2)/149(13.3)/60(5.4)/205(18.3)/105(9.4)/27(2.4)	149(26.0)/77(51.7)/29(48.3)/140(68.3)/70(66.7)/20(74.1)	<0.001	120(20.9)/49(32.9)/17(28.3)/99(48.3)/40(38.1)/8(29.6)	<0.001	
Missing	n=24					
Abbreviations: AJCC/UICC, American Joint Committee on Cancer and the Union for International Cancer Control; AT, adjuvant therapy; BR, borderline resectable; CA, carbohydrate antigen; CEA, carcinoembryonic antigen; CP, central pancreatectomy; DP, distal pancreatectomy; IPMC, intraductal papillary mucinous carcinoma; NAT, neoadjuvant therapy; PD, pancreatoduodenectomy; TP, total pancreatectomy.

The median OS of this cohort was 115.5 months and the estimated OS at 5 and 10 years was 63.7% and 49.2%, respectively. The median DSS was not reached and the estimated 5‐ and 10‐year DSS rates were 71.5% and 61.8%, respectively. The median RFS was 154.9 months, and the estimated 5‐ and 10‐year RFS rates were 57.8% and 52.1%, respectively. The OS, DSS, and RFS were significantly shortened as the AJCC/UICC stage advanced (p < 0.001; Table 2 and Figure 1).

TABLE 2 Overall survival, disease‐specific survival, and recurrence‐free survival based on AJCC/UICC stage (8th) in 1143 patients with invasive IPMC who underwent surgery without NAT.

Stage	Number (%)	Median OS (m)	p	Median DSS (m)	p	Median RFS (m)	p	
T stage	
T1a	376 (33.9)	NR	<0.001	NR	<0.001	153.4	<0.001	
T1b	122 (11.0)	NR	NR	128.1	
T1c	188 (17.0)	87.5	NR	91.9	
T2	297 (26.8)	57.9	83.5	25.6	
T3	123 (11.1)	29.3	34.7	15.4	
T4	2 (46.3)	25.2	25.2	20.7	
N stage	
N0	807 (70.6)	156.0	<0.001	NR	<0.001	198.3	<0.001	
N1	212 (18.5)	46.0	64.6	20.1	
N2	124 (10.8)	21.0	23.3	9.7	
Stage	
IA	573 (51.2)	NR	<0.001	NR	<0.001	198.3	<0.001	
IB	149 (13.3)	123.8	NR	NR	
IIA	60 (5.4)	61.0	126.6	31.5	
IIB	205 (18.3)	46.1	25.1	20.7	
III	105 (9.4)	22.1	25.1	10.3	
IV	27 (2.4)	17.3	17.3	5.7	
All stage	n=1,143	
AT, yes/no	486 (42.5)/657 (57.5)	72.7/151.9	0.102	88.4/NR	<0.001	38.2/198.3	<0.001	
Completion of AT, yes/no	333 (29.1)/810 (70.9)	87.5/140.6	0.555	108.1/NR	0.105	61.6/198.3	0.054	
Stage IA	n=573	
AT, yes/no	149 (26.0)/424 (74.0)	108.1/NR	0.102	NR/NR	0.007	NR/198.3	0.064	
Completion of AT, yes/no	120 (20.9)/453 (79.1)	108.1/NR	0.198	NR/NR	0.064	NR/198.3	0.397	
Stage IB	n=149	
AT, yes/no	77 (51.7)/72 (48.3)	119.7/123.8	0.695	NR/NR	0.571	106.1/NR	0.220	
Completion of AT, yes/no	49 (32.9)/100 (67.1)	119.7/123.8	0.284	NR/NR	0.681	106.1/NR	0.896	
Stage IIA	n=60	
AT, yes/no	29 (48.3)/31 (51.7)	68.7/61.0	0.696	126.6/NR	0.695	25.2/NR	0.477	
Completion of AT, yes/no	17 (28.3)/43 (71.7)	71.0/43.2	0.547	126.6/NR	0.627	31.5/27.7	0.778	
Stage IIB	n=205	
AT, yes/no	140 (68.3)/65 (31.7)	46.1/38.0	0.253	65.9/55.8	0.917	19.3/22.4	0.902	
Completion of AT, yes/no	99 (48.3)/106 (51.7)	71.5/28.1	0.002	83.5/51.1	0.016	25.7/15.3	0.006	
Stage III	n=105	
AT, yes/no	70 (66.7)/35 (33.3)	28.0/13.8	<0.001	30.2/13.9	0.001	14.6/6.8	0.001	
Completion of AT, yes/no	40 (38.1)/65 (61.9)	36.7/15.8	<0.001	39.0/16.6	<0.001	18.2/6.8	<0.001	
Stage IV	n=27	
AT, yes/no	20 (74.1)/7 (25.9)	18.3/9.1	0.115	18.3/9.1	0.230	5.7/5.7	0.874	
Completion of AT, yes/no	8 (29.6)/19 (70.4)	23.3/5.3	0.072	23.3/15.3	0.089	7.2/5.7	0.441	
In propensity score matched analysis	
All stage	n=666	
AT, yes/no	249 (37.4)/417 (62.6)	81.3/134.3	0.169	100.3/NR	0.003	45.1/NR	0.016	
Completion of AT, yes/no	333 (50.0)/333 (50.0)	87.5/85.7	0.109	108.1/NR	0.430	61.6/57.3	0.199	
Stage IA	n=266	
AT, yes/no	129 (48.5)/145 (54.5)	122.7/NR	0.426	NR/NR	0.221	NR/NR	0.994	
Completion of AT, yes/no	120 (45.1)/146 (54.9)	108.1/NR	0.187	NR/NR	0.100	NR/NR	0.839	
Stage IB	n=97	
AT, yes/no	65 (67.0)/32 (33.0)	119.7/143.5	0.312	NR/NR	0.954	106.1/NR	0.889	
Completion of AT, yes/no	49 (50.5)/48 (49.5)	119.7/143.5	0.368	NR/NR	0.654	106.1/NR	0.910	
Stage IIA	n=33	
AT, yes/no	22 (66.7)/11 (33.3)	71.0/22.3	0.009	126.6/29.3	0.175	31.5/8.7	0.112	
Completion of AT, yes/no	17 (51.5)/16 (48.5)	71.0/32.0	0.215	126.6/43.2	0.460	31.5/19.6	0.154	
Stage IIB	n=164	
AT, yes/no	126 (76.8)/38 (23.2)	56.5/34.3	0.071	71.5/51.7	0.383	20.8/18.5	0.128	
Completion of AT, yes/no	99 (60.4)/65 (39.6)	71.5/25.3	<0.001	83.5/34.3	0.005	25.7/12.3	0.003	
Stage III	n=76	
AT, yes/no	58 (76.3)/18 (23.7)	28.8/14.6	0.001	31.1/14.6	0.007	15.4/5.0	0.007	
Completion of AT, yes/no	40 (52.6)/36 (47.4)	36.7/16.6	<0.001	39.0/19.8	<0.001	18.2/5.6	<0.001	
Stage IV	n=22	
AT, yes/no	17 (77.3)/5 (22.7)	18.3/9.1	0.145	18.3/9.1	0.324	5.7/3.0	0.724	
Completion of AT, yes/no	8 (36.4)/14 (63.6)	23.3/14.7	0.021	23.3/14.7	0.029	7.2/5.5	0.353	
Abbreviations: AJCC/UICC, American Joint Committee on Cancer and the Union for International Cancer Control; IPMC, intraductal papillary mucinous carcinoma; NAT, neoadjuvant therapy; AT, postoperative adjuvant therapy; NR, not reached.

FIGURE 1 The overall survival (OS) (p < 0.001), disease‐specific survival (DSS) (p < 0.001), and recurrence‐free survival (RFS) (p < 0.001) of invasive intraductal papillary mucinous carcinoma (IPMC) were significantly shortened as the AJCC/UICC stage advanced.

3.2 Risk factors of poor OS, DSS, and RFS in patients undergoing surgery without NAT

The results of univariate and multivariate Cox regression analyses for OS, DSS, and RFS are shown in Table 3. Multivariate analysis showed that the independent risk factors of poor OS were age ≥ 70 years (hazard ratio [HR] 1.42; p = 0.001), diabetes mellitus (HR 1.30; p = 0.013), elevated serum CEA level (HR 1.45; p < 0.001), elevated serum CA19‐9 level (HR 1.25; p = 0.049), BR (HR 1.86; p = 0.003), transfusion (HR 1.71; p < 0.001), tubular type of invasive component (HR 1.78; p < 0.001), perineural invasion (HR 1.57; p < 0.001), serosal invasion (HR 1.78; p < 0.001), R1 (HR 1.71; p = 0.001), and lymph node metastasis (HR 1.97; p < 0.001). The following independent risk factors of poor DSS were found by multivariate analysis: age ≥ 70 years (HR 1.32; p = 0.031), BR (HR 1.80; p = 0.013), transfusion (HR 1.56; p = 0.002), tubular type of invasive component (HR 1.96; p < 0.001), lymphovascular invasion (HR 1.46; p = 0.041), perineural invasion (HR 1.89; p < 0.001), serosal invasion (HR 1.80; p < 0.001), R1 (HR 1.81; p < 0.001), and lymph node metastasis (HR 2.38; p < 0.001). The independent risk factors of poor RFS on multivariate analysis were elevated serum CEA level (HR 1.27; p = 0.037), BR (HR 1.59; p = 0.030), transfusion (HR 1.39; p = 0.010), tubular type of invasive component (HR 1.56; p < 0.001), lymphovascular invasion (HR 1.53; p = 0.004), perineural invasion (HR 1.50; p = 0.002), serosal invasion (HR 1.82; p < 0.001), portal vein invasion (HR 1.43; p = 0.034), R1 (HR 1.86; p < 0.001), and lymph node metastasis (HR 2.29; p < 0.001) (Table 3).

TABLE 3 Univariate and multivariate analyses of clinicopathological parameters for poor overall, disease‐specific, and recurrence‐free survival in 1143 patients with invasive IPMC without NAT.

Variable	Overall survival Univariate analysis p	Multivariate analysis p	HR (95% CI)	Disease‐specific survival Univariate analysis p	Multivariate analysis p	HR (95% CI)	Recurrence‐free survival Univariate analysis p	Multivariate analysis p	HR (95% CI)	
Age, ≥70 years	0.001	0.001	1.42 (1.15‐1.76)	0.002	0.031	1.32 (1.03‐1.71)	0.025	0.491		
Sex, male	0.778			0.402			0.113			
Preoperative symptom	0.031	0.503		0.001	0.103		0.002	0.511		
Preoperative jaundice	<0.001	0.982		<0.001	0.722		<0.001	0.117		
Diabetes mellites	<0.001	0.013	1.30 (1.06‐1.59)	0.010	0.083		0.024	0.167		
Morphological type	
Branch	0.005	0.553		0.002	0.253		0.006	0.593		
Mixed	
Main	
Serum CEA, elevated	<0.001	<0.001	1.45 (1.16‐1.82)	0.001	0.057		<0.001	0.037	1.27 (1.01‐1.60)	
Serum CA19‐9, elevated	<0.001	0.049	1.25 (1.00‐1.56)	<0.001	0.199		<0.001	0.126		
Resectability, BR	<0.001	0.003	1.86 (1.23‐2.82)	<0.001	0.013	1.80 (1.13‐2.87)	<0.001	0.030	1.59 (1.05‐2.41)	
Operation	
TP	0.297			0.369			0.212			
PD	
DP	
CP	
Transfusion	<0.001	<0.001	1.71 (1.35‐2.16)	<0.001	0.002	1.56 (1.18‐2.08)	<0.001	0.010	1.39 (1.08‐1.78)	
Pathological findings	
Invasive component, tubular	<0.001	<0.001	1.78 (1.38‐2.29)	<0.001	<0.001	1.96 (1.43‐2.70)	<0.001	<0.001	1.56 (1.23‐1.98)	
Lymphovascular invasion	<0.001	0.187		<0.001	0.041	1.46 (1.02‐2.10)	<0.001	0.004	1.53 (1.15‐2.04)	
Perineural invasion	<0.001	<0.001	1.57 (1.22‐2.02)	<0.001	<0.001	1.89 (1.40‐2.51)	<0.001	0.002	1.50 (1.16‐1.92)	
Bile duct invasion	<0.001	0.088		<0.001	0.821		<0.001	0.968		
Duodenal invasion	<0.001	0.764		<0.001	0.796		<0.001	0.415		
Serosal invasion	<0.001	<0.001	1.78 (1.40‐2.28)	<0.001	<0.001	1.80 (1.37‐2.37)	<0.001	<0.001	1.82 (1.45‐2.28)	
Retropancreatic tissue invasion	<0.001	0.856		<0.001	0.238		<0.001	0.381		
Portal vein invasion	<0.001	0.173		<0.001	0.182		<0.001	0.034	1.43 (1.03‐2.00)	
Arterial invasion	0.022	0.265		0.017	0.127		0.005	0.100		
Extra‐pancreatic nerve plexus invasion	<0.001	0.296		<0.001	0.145		<0.001	0.407		
Other organ invasion	<0.001	0.425		<0.001	0.659		0.002	0.973		
Residual tumor status, R1	<0.001	0.001	1.71 (1.26‐2.32)	<0.001	<0.001	1.81 (1.29‐2.53)	<0.001	<0.001	1.86 (1.38‐2.49)	
Lymph node metastasis	<0.001	<0.001	1.97 (1.56‐2.46)	<0.001	<0.001	2.38 (1.80‐3.16)	<0.001	<0.001	2.29 (1.82‐2.90)	
Era of surgery, 1996‐2008	0.016	0.234		0.034	0.439		0.299			
Introduction of AT	0.102		<0.001	0.892	<0.001	0.837	
Completion of AT	0.555		0.105		0.054		
Abbreviations: AT, adjuvant therapy; BR, borderline rese; CA, carbohydrate antigen; CEA, carcinoembryonic antigen; CI, confidence interval; HR, hazard ratio; IPMC, intraductal papillary mucinous carcinoma; NAT, neoadjuvant therapy.

3.3 Frequency of introduction and completion of AT after surgery for invasive IPMC without NAT

Of the 1143 patients with invasive IPMC, 657 (57.5%) did not receive AT after surgery because of the early stage of invasive IPMC (n = 288), poor condition of the patients including old age (n = 129), patients' refusal (n = 122), and physician's policy that invasive IPMC is not an indication for AT (n = 118). AT after surgery was more often introduced to patients with invasive IPMC aged <70 years (p = 0.011), elevated serum CA19‐9 level (p < 0.001), branch or mixed type (p = 0.044), colloid type of invasive component (p < 0.001), lymphovascular invasion (p < 0.001), perineural invasion (p < 0.001), bile duct invasion (p = 0.001), duodenal invasion (p < 0.001), serosal invasion (p < 0.001), retropancreatic tissue invasion (p < 0.001), portal vein invasion (p = 0.001), extra‐pancreatic nerve plexus invasion (p < 0.001), R1 (p < 0.001), advanced T stage (p < 0.001), advanced n stage (p < 0.001), and advanced stage (p < 0.001) (Table 1).

A total of 303 patients (29.1%) completed the planned postoperative AT for 6 months, whereas 108 patients could not complete it due to adverse events, and 45 patients due to recurrence.

3.4 Comparison of OS, DSS, and RFS between invasive IPMC patients with and without AT after surgery

In the 1143 patients with invasive IPMC without NAT, the DSS (p < 0.001) and RFS (p < 0.001) in patients receiving postoperative AT were worse than those in patients who did not receive this therapy, although the OS was not different (Table 2). The OS, DSS, and RFS were not different between patients undergoing surgery with and without completion of postoperative AT (Table 2). In the 666 patients with invasive IPMC on the PSM analysis, we found similar results to those on un‐matched 1143 patients (Table 2).

Based on the AJCC/UICC stage, completion of postoperative AT could improve the OS, DSS, and RFS in patients with stage IIB and III invasive IPMC, although the introduction of postoperative AT could improve the OS, DSS, and RFS for patients with stage III invasive IPMC (Table 2). The PSM analysis also showed similar results (Table 2).

The completion of postoperative AT could improve the OS, DSS, and RFS for patients with invasive IPMC with elevated preoperative serum CA19‐9 level (MST before PSM; OS: 69.0 vs. 45.7 months, p = 0.011; DSS: 93.0 vs. 85.7 months, p = 0.027; RFS: 46.9 vs. 25.2 months, p = 0.028, MST after PSM; OS: 69.0 vs. 24.7 months, p < 0.001; DSS: 93.0 vs. 41.9 months, p < 0.001; RFS: 46.9 vs. 18.4 months, p < 0.001; Figure 2A–C), lymphovascular invasion (MST before PSM; OS: 64.6 vs. 30.2 months, p < 0.001; DSS: 71.5 vs. 41.3 months, p = 0.001; RFS: 29.3 vs. 15.8 months, p < 0.001, MST after PSM; OS: 64.6 vs. 27.2 months, p < 0.001; DSS: 71.5 vs. 41.3 months, p = 0.001; RFS: 29.3 vs. 14.5 months, p < 0.001; Figure 2D–F), perineural invasion (MST before PSM; OS: 52.9 vs. 29.3 months, p < 0.001; DSS: 64.8 vs. 34.3 months, p = 0.002; RFS: 28.6 vs. 15.4 months, p = 0.001, MST after PSM; OS: 52.9 vs. 25.5 months, p < 0.001; DSS: 64.8 vs. 30.7 months, p = 0.001; RFS: 28.6 vs. 11.3 months, p < 0.001; Figure 2G–I), serosal invasion (MST before PSM; OS: 64.6 vs. 22.5 months, p < 0.001; DSS: 64.6 vs. 22.5 months, p < 0.001; RFS: 21.8 vs. 10.7 months, p = 0.001, MST after PSM; OS: 64.6 vs. 18.3 months, p < 0.001; DSS: 93.0 vs. 22.4 months, p < 0.001; RFS: 21.8 vs. 7.2 months, p < 0.001; Figure 2J–L), and lymph node metastasis (MST before PSM; OS: 46.1 vs. 20.5 months, p < 0.001; DSS: 67.5 vs. 24.4 months, p < 0.001; RFS: 21.7 vs. 9.4 months, p < 0.001, MST after PSM; OS: 46.1 vs. 20.5 months, p < 0.001; DSS: 67.5 vs. 23.0 months, p < 0.001; RFS: 21.7 vs. 8.0 months, p < 0.001; Figure 2M–O).

FIGURE 2 Completion of the planned postoperative adjuvant therapy (AT) for 6 months could prolong the OS, DSS, and RFS for patients with invasive IPMC with high preoperative carbohydrate antigen 19–9 level (A–C), lymphovascular invasion (D–F), perineural invasion (G–I), serosal invasion (J–L), and lymph node metastasis (M‐O).

Regarding the postoperative AT regimen, of the 333 patients who completed postoperative AT, the OS, DSS, and RFS of those whose regimen was S‐1 (n = 226) were significantly better than those whose regimen was GEM (n = 97) or GS (n = 10) (MST of S‐1, GEM, and GS; OS: 126.6, 64.8, and 43.3 months, respectively, p = 0.001; DSS: 127.6, 83.5, and 43.4 months, respectively, p = 0.001; RFS: not reached, 33.8, and 16.3 months, respectively, p = 0.001; Figure 3).

FIGURE 3 Of the 333 patients who completed the postoperative AT, the OS (p = 0.001), DSS (p = 0.001), and RFS (p = 0.001) of those whose regimen was S‐1 monotherapy (n = 226) were significantly better than those whose regimen was gemcitabine (GEM) monotherapy (n = 97) or combination therapy with GEM and S‐1 (GS) (n = 10).

3.5 Impact of NAT on the survival of patients with invasive IPMC

Forty patients with invasive IPMC received NAT before surgery. The rate of BR invasive IPMC was higher in patients with invasive IPMC receiving NAT than in those without NAT (60.0% vs. 4.0%; p < 0.001). Patients with invasive IPMC receiving NAT before surgery more often received transfusion (p = 0.002) and postoperative AT (p = 0.002), and completion of postoperative AT (p = 0.005). Pathologically, the incidences of perineural invasion (p = 0.005), serosal invasion (p = 0.006), and portal vein invasion (p < 0.001) were higher in patients with invasive IPMC with NAT than in those without. When the survival of invasive IPMC patients who underwent surgical resection with and without NAT was compared, OS (p = 0.003) and DSS (p = 0.006) in invasive IPMC patients without NAT were better than those with NAT. The PSM analysis showed no significant differences of OS (p = 0.763), DSS (p = 0.953), and RFS (p = 0.327) between the patients undergoing surgery for invasive IPMC with (n = 40) and without NAT (n = 40).

Of the 70 patients with BR invasive IPMC, 24 (34.3%) received NAT before surgery. There were no significant differences in the OS, DSS, and RFS between patients with invasive IPMC with and without NAT (MST; OS: 51.6 vs. 24.6 months, p = 0.108; DSS: 51.6 vs. 25.2 months, p = 0.146; and RFS: 24.2 vs. 13.9 months, p = 0.183). However, in the 36 patients with BR invasive IPMC on the PSM analysis, we found that NAT could improve the OS (51.6 vs. 14.9 months, p = 0.001; Figure 4A), DSS (51.6 vs. 14.9 months, p = 0.001; Figure 4B), and RFS (24.2 vs. 5.3 months, p = 0.001; Figure 4C).

FIGURE 4 Of the 70 patients with borderline resectable (BR) invasive IPMC, (A) the OS (p = 0.027) and (B) DSS (p = 0.040) of the 14 patients who received neoadjuvant therapy (NAT) followed by surgery and completion of postoperative AT were significantly better than the other 56 patients with BR invasive IPMC, although the difference in (C) RFS between them did not reach statistical significance (p = 0.088).

3.6 Pattern and treatment of postoperative recurrence in patients with invasive IPMC who underwent surgery

Postoperative recurrence was found in 484 patients (40.9%) at a median of 14.2 months, including remnant pancreatic recurrence in 94 patients (7.9%) and extra‐pancreatic recurrence in 390 patients (33.0%). The 5‐ and 10‐year cumulative incidences of remnant pancreatic recurrence were 10.0% and 15.8%, respectively, and those of extra‐pancreatic recurrence were 32.8% and 49.1%, respectively. Of the 94 patients who developed remnant pancreatic recurrence, 27 developed metachronous PDAC and 67 developed recurrent IPMC in the remnant pancreas. A total of 390 patients with initial extra‐pancreatic recurrence after surgery included only local recurrence in 104 patients (26.7%), only liver metastasis in 87 patients (22.3%), only lung metastasis in 71 patients (18.2%), only peritoneal dissemination in 59 patients (15.1%), only bone metastasis in two patients (0.5%), and multiple recurrences in 67 patients (17.2%).

Of the 484 patients who developed any recurrence after surgery for invasive IPMC, 365 received treatment for the recurrence including chemotherapy in 299 patients, surgical resection in 93 patients, and radiation therapy in 21 patients. The OS of patients who received any treatment for recurrence was significantly better than that of those who did not (MST; 40.6 vs. 22.4 months; p < 0.001) (Figure 5A). In the 94 patients who developed remnant pancreatic recurrence, the OS of 63 patients who underwent surgical resection for the remnant pancreatic recurrence was significantly better than that of 31 patients who did not (MST; 153.6 vs. 69.9 months; p < 0.001) (Figure 5B).

FIGURE 5 (A) Of the 484 patients who developed any recurrence after surgery for invasive IPMC, the OS of 365 patients receiving any treatment for the recurrence was significantly better than that of those who did not (p < 0.001). (B) In the 94 patients who developed remnant pancreatic recurrence, the OS of 63 patients who underwent surgical resection for remnant pancreatic recurrence was significantly better than that of the 31 patients who did not (p < 0.001).

4 DISCUSSION

This was one of the largest cohort studies of patients with invasive IPMC who underwent curative resection. First, we assessed the applicability of the 8th edition of the AJCC/UICC TNM staging system for invasive IPMC. In most previous reports investigating the applicability of the staging system for invasive IPMC, it was unclear how to measure the tumor size, which could cause a lack of coherence of T stage on 8th edition of AJCC/UICC staging system, possibly leading to unreliable conclusions. Margonis et al. 22 reported that this TNM staging system was only moderately accurate in predicting OS in 275 patients with invasive IPMC, whereas Kaiser et al. 9 reported that it could classify OS well in 424 patients. In this study, the 8th edition of the AJCC/UICC TNM staging system, from which T stage is determined by invasive length without the noninvasive IPMN region, provided a reliable prognostic classification for 1143 patients with resected invasive IPMC without NAT. Our results indicate that this staging system is useful for the prediction of survival for invasive IPMC, similar to conventional PDAC.

Previous studies assessing the effectiveness of postoperative AT for invasive IPMC based on National Cancer Data Base have demonstrated that patients with invasive IPMC with advanced stage invasive IPMC benefit from postoperative AT. 10 , 11 These databases did not clarify how to determine T stage depending on tumor size, only evaluated the impact of AT introduction on prognosis, and did not focus on the duration of AT. When we defined the completion of postoperative AT as receiving the planned AT for 6 months, completion of postoperative AT improved OS, DSS, and RFS for the invasive IPMC patients with stage IIB and III, elevated preoperative serum CA19‐9 level, lymphovascular invasion, perineural invasion, serosal invasion, and lymph node metastasis. Our results indicate that completion of postoperative AT might benefit selected invasive IPMC patients, including those with high‐risk of poor survival, whereas it will not benefit patients with early‐stage invasive IPMC. However, in this study, the frequency of completion of postoperative AT by patients with early‐stage invasive IPMC and/or poor condition was lower than in those without, which may have caused huge bias. Therefore, a future large‐scale prospective study is required to establish the role of AT after surgery for invasive IPMC.

When we assessed the impact of postoperative AT regimen on survival, we found that S‐1 was superior to GEM or GS for improvement of OS, DSS, and RFS. This result might be similar to that of the JASPAC01 trial, which is a randomized controlled trial (RCT) that compared survival between postoperative AT using S‐1 vs. GEM for conventional PDAC. 23 A possible reason to explain the survival advantage of S‐1 might be good toleration for S‐1 compared to GEM or GS. However, in this study, of 333 patients who received completion of postoperative AT, the rate of reduction of the dose required due to side effects was not different between in the use of S‐1 (19.9%), GEM (19.6%), and GS (50.0%) (p = 0.068). Therefore, the superior toleration for S‐1 to that for GEM or GS was not proved in this study, and the reason to explain the survival advantage of S‐1 is unclear. A prospective study is essential to confirm which regimen, including multi‐agent chemotherapy regimens, is most useful to prolong the survival of patients with invasive IPMC.

There have been few reports about the impact of NAT on the survival of patients with invasive IPMC. BR‐PDAC defined as radiologic invasion to major vessels has aggressive malignant potential and is associated with a high risk of positive surgical margins even after extended dissection of nerve plexus and lymph nodes and vessel resection, and the presence of occult distant metastasis. 24 NAT might lead to systemic treatment for undetected micrometastasis, R0 resection rate increment, and optimal selection of patients for surgery. Several studies showed that NAT followed by surgery could improve the survival of patients with BR‐PDAC, compared to upfront surgery. 25 , 26 , 27 , 28 In the current study, we found that NAT followed by surgery might improve the survival of patients with BR‐invasive IPMC by the PSM analysis. However, additional studies are essential to confirm our findings.

In this study, the postoperative recurrence in 40.9% of 1183 patients with invasive IPMC, including extra‐pancreatic recurrence in 33.0% and remnant pancreatic recurrence in 7.9%, which were similar to those of previous reports. 10 , 29 Winter et al. 21 showed 24% of postoperative recurrences even in patients with T1 (invasive length ≤ 20 mm) invasive IPMC. Furthermore, we also found that any treatment for recurrent diseases, especially surgical resection for remnant pancreatic recurrence, could improve survival. Our results suggest that the same close surveillance after surgery as that of conventional PDAC might be necessary for invasive IPMC, to detect the recurrence early and offer patients a chance for treatments.

This study had several limitations. As it was a multi‐institutional retrospective study from 40 different academic institutes, our findings are subject to selection bias, particularly with respect to operative variations between surgeons and institutional characteristics, and to surveillance protocol after surgery. Moreover, the cohort who received AT after surgery for invasive IPMC more often had advanced stage disease. Such bias might limit the validity of the study's findings, although we performed the PSM analyses to reduce potential sources of bias.

In conclusion, when we defined tumor size as the length of invasive component separately from noninvasive IPMN region, the 8th edition of AJCC/UICC TNM staging system was applicable as a prognostic predictor for invasive IPMC patients. This study found that completion of postoperative AT for 6 months after surgery might prolong survival of patients with stage IIB and III invasive IPMC, elevated preoperative CA19‐9 level, lymphovascular invasion, perineural invasion, serosal invasion, and lymph node metastasis. In addition, our results indicate that systemic treatment by AT in addition to local treatment by surgical resection are necessary for these aggressive tumors. NAT followed by surgery might improve the survival of patients with BR invasive IPMC. Finally, any treatment for recurrence after surgery for invasive IPMC, especially surgical resection for remnant pancreatic recurrence, might improve survival. However, our study is limited by its retrospective nature; thus, prospective studies are needed to confirm our findings.

AUTHOR CONTRIBUTIONS

Conceptualization, design, and methodology: SH Acquisition of data: SH, RH, GH, SN, ME, NG, HT, MU, TS, MO, YS, IM, TK, HI, DH, YS, HN, KH, SH, YN, SM, HT, KS, HS, TA, YK, TR, MN, IE, YS, AH, TH, HA, TU, TI, KH, SS, KO, HM, FM, YF, and ST. Analysis and interpretation of data: SH, AY, and HY. Writing, review, and/or revision of the manuscript: SH, RH, GH, SN, ME, NG, HT, MU, TS, MO, YS, IM, TK, HI, DH, YS, HN, KH, SH, YN, SM, HT, KS, HS, TA, YK, TR, MN, IE, YS, AH, TH, HA, TU, TI, KH, SS, KO, HM, FM, YF, ST, AY, YT, KO, SS, and HY. Study supervision: SH, AY, and HY.

CONFLICT OF INTEREST STATEMENT

Author SH was supported by grants from the Japan Pancreas Society. Author MU was supported by grants from Taiho Pharma, however, the funding source had no role in the design, practice, or analysis of this study. Author SS was supported by grants from Nihon Servier, Amino‐Up co, however, the funding source had no role in the design, practice, or analysis of this study. Authors HN, KH, and HY are editorial board members of Annals of Gastroenterological Surgery. Authors SH, IE, and AH are associate editors of Annals of Gastroenterological Surgery.

FUNDING INFORMATION

This study was supported by grants from the Japan Pancreas Society.

ETHICS STATEMENTS

Approval of the research protocol: This study was approved by the institutional review board of each participating institution prior to initiation of the study.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.

ACKNOWLEDGMENTS

We appreciate the following members of this study for their valuable support in data collection and drafting of the manuscript: Motokazu Sugimoto, Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan; Masamichi Hayashi, Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan; Masaharu Ishida, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan; katsuhisa Ohgi, Division of Hepato‐Biliary‐Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan; Takashi Mishima, Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan; Kazuo Hara, Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan; Keiko Kamei, Division of Hepato‐Biliary‐Pancreatic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osakasayama, Japan; Akio Katanuma, Teine Keijinkai Hospital, Sapporo, Japan; Ko Tomishima, Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan; So Yamaki, Department of Surgery, Kansai Medical University, Hirakata, Japan; Satoshi Nemoto, Department of Hepato‐Biliary‐Pancreatic Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan; Yoshitaro Shindo, Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate Medicine, Ube, Japan; Keinosuke Ishido, Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Toru Nakamura, Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan; Hiroaki Osakabe, Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan; Masashi Kishiwada, Department of Hepatobiliary Pancreatic & Transplant Surgery, Mie University, Tsu, Japan; Shogo Kobayashi, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan; Tsutomu Fujii, Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan; Naohiro Sata, Department of Surgery, Jichi Medical University, Shimotsuke, Japan; Keiichi Kubota, Department of Hepato‐Biliary‐Pancreatic Surgery, Dokkyo Medical University, Mibu, Japan; Masayuki Sho, Department of Surgery, Nara Medical University Kashiwara, Japan; Fumiaki Watanabe, Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan; Kohei Nakata, Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, Ryusei Matsuyama, Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan; Yutaka Suzuki, Department of Hepato‐Biliary‐Pancreatic Surgery, Kyorin University Hospital, Mitaka, Japan; Yukio Asano, Department of Gastroenterological Surgery, Fujita Health University School of Medicine, Bantane Hospital, Nagoya, Japan; Hiroshi Wada, Osaka International Cancer Institute, Department of Gastroenterological Surgery, Osaka, Japan; Rintaro Nagayama, Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan; Takao Ohtsuka, Department of Digestive Surgery, Kagoshima University, Kagoshima, Japan; Akinori Shimizu, Department of Gastroenterology, Onomichi General Hospital, Onomichi, Japan; Mitsugi Shimoda, Department of Gastroenterological Surgery, Ibaraki Medical Center, Tokyo Medical University, Ineshiki, Japan; Hironobu Suto, Department of Gastroenterological Surgery, Kagawa University, Kida, Japan; Masaji Tani, Department of Surgery, Shiga University of Medical Science, Otsu, Japan; Shuichiro Sugawara, Department of Surgery I, Yamagata University, Yamagata Japan; Taku Matsumoto, Department of Gastroenterological Surgery, Hyogo Cancer Center, Akashi, Japan.
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