Outcomes of Neoadjuvant Chemotherapy for Invasive Intraductal Papillary Mucinous Neoplasm Compared with de Novo Pancreatic Adenocarcinoma

Background The management of invasive intraductal papillary mucinous cystic neoplasm (I-IPMN) does not differ from de novo pancreatic ductal adenocarcinoma (PDAC); however, I-IPMNs are debated to have better prognosis. Despite being managed similarly to PDAC, no data are available on the response of I-IPMN to neoadjuvant chemotherapy. Methods All patients undergoing pancreatic resection for a pancreatic adenocarcinoma from 2011 to 2022 were included. The PDAC and I-IPMN cohorts were compared to evaluate response to neoadjuvant therapy (NAT) and overall survival (OS). Results This study included 1052 PDAC patients and 105 I-IPMN patients. NAT was performed in 25% of I-IPMN patients and 65% of PDAC patients. I-IPMN showed a similar pattern of pathological response to NAT compared with PDAC (p = 0.231). Furthermore, positron emission tomography (PET) response (71% vs. 61%; p = 0.447), CA19.9 normalization (85% vs. 76%, p = 0.290), and radiological response (32% vs. 37%, p = 0.628) were comparable between I-IPMN and PDAC. A significantly higher OS and disease-free survival (DFS) of I-IPMN was denoted by Kaplan–Meier analysis, with a p-value of < 0.001 in both plots. In a multivariate analysis, I-IPMN histology was independently associated with lower risk of recurrence and death. Conclusions I-IPMN patients have a longer OS and DFS after surgical treatment when compared with PDAC patients. The more favorable oncologic outcome of I-IPMNs does not seem to be related to early detection, as I-IPMN histological subclass is independently associated with a lower risk of disease recurrence. Moreover, neoadjuvant effect on I-IPMN was non-inferior to PDAC in terms of pathological, CA19.9, PET, and radiological response and thus can be considered in selected patients. Supplementary Information The online version contains supplementary material available at 10.1245/s10434-023-14875-5.

4][5] The optimal management of patients affected by an invasive IPMN (I-IPMN) is currently debated.I-IPMNs are a specific type of pancreatic adenocarcinoma arising from an IPMN precursor lesion, and there is controversial evidence of a more favorable oncological outcome of these tumors after surgical resection when compared with de novo pancreatic ductal adenocarcinoma (PDAC). 6,7Nonetheless, National Comprehensive Cancer Network (NCCN) guidelines 8,9 do not acknowledge I-IPMNs as a separate entity from PDAC but limit the mention of IPMNs as precursor lesions for pancreatic cancer.When facing an IPMN with a known invasive component, it is currently recommended that both medical and surgical treatment do not differ from the management of PDACs, but data on the effects of chemotherapy on I-IPMN are scarce.
The aim of this study was to determine the prognosis of resected I-IPMNs compared with de novo PDAC, and to assess the response of I-IPMNs to neoadjuvant chemotherapy compared with de novo PDAC.

METHODS
All consecutive patients with a confirmed pathological diagnosis of PDAC or I-IPMN who underwent pancreatic resection between 1 January 2011 and 30 January 2022 in a high-volume center for pancreatic surgery were included in this study.The differentiation between I-IPMN and de novo PDAC is routinely assessed by the institution pathologists by looking for the presence of an IPMN environment around PDAC. Chart review was performed retrospectively and included demographical characteristics, surgical variables, tumor characteristics, imaging characteristics, and follow-up data.Demographical characteristics included age, sex, tumor histology, Eastern Cooperative Oncology Group (ECOG) and American Society of Anesthesiologists (ASA) score, while surgical variables included type of pancreatic resection, concomitant vascular resection, and Clavien-Dindo grade 10 of postoperative complications assessed within 90 days from surgery.Tumor characteristics included tumor size, staging according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic adenocarcinoma, preoperative CA19.9, number of harvested and positive lymph nodes, resection margins, tumor grading, perineural invasion and lymphovascular invasion, and follow-up data included overall survival (OS) and disease-free survival (DFS).Disease recurrence was defined as 'early recurrence' when occurring in the first 6 months after surgery.
The primary outcome of this study was pathological response to neoadjuvant therapy (NAT), and was defined according to the guidelines of the College of American Pathologists. 11Pathological response score was assigned as follows: complete response (score 0), near complete response (score 1), partial response (score 2), and minimal/ no response (score 3).Subjects with scores of 0 or 1 were grouped together as 'major response', while scores of 2 or 3 were grouped together as 'partial/no response'.Secondary outcomes were radiological response as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 12 CA19.9response defined as normalization of marker level (≤37 UI/mL) after NAT regardless of initial CA19.9level, and positron emission tomography (PET) response.Non-secretor patients were excluded from the CA19.9 response analysis.PET response was defined as 'major response' when tumor fluorodeoxyglucose (FDG) uptake was below hepatic FDG uptake, and similar to the background pancreatic tissue or 'minor response' if tumor FDG uptake was persistent or higher than the background.
Data were collected in a Microsoft Excel (Microsoft Corporation, Redmond, WA, USA) database and then transferred to SPSS statistics.Statistical analysis was performed using SPSS statistics version 28.0 (IBM Corporation, Armonk, NY, USA).Continuous variables were tested for normality using the Shapiro-Wilk test.Normally distributed continuous variables were expressed as the mean ± standard deviation and compared using Student's t-test, and non-normally distributed variables were expressed as the median with interquartile range and compared using the Mann-Whitney U test.Categorical variables were expressed as number of events (%) and were compared using the Chisquare test.A univariate and multivariate logistic regression analysis was performed to assess correlation to tumor recurrence, and a univariate and multivariate Cox regression analysis was performed to assess correlation to OS. Variables with a p-value < 0.05 at univariate analysis were selected for multivariate analysis.The OS and DFS were compared using Kaplan-Meier curves and log-rank test.A p-value of < 0.05 was considered as the cut-off for statistical significance.When data regarding a variable were not available, the patient was excluded from that specific variable analysis.
In the subset of patients who underwent NAT, the PDAC group was composed of 678 patients and the I-IPMN group was composed of 26 patients.In this subgroup of patients, there was only a significant difference in age (64.7 ± 9.6 vs. 69.5 ± 6.3, p = 0.006) between PDAC and I-IPMN patients.No significant differences were observed in the type of NAT regimen (p = 0.187), the number of NAT cycles (7.8 ± 7 vs. 6.1 ± 3.5, p = 0.109), and concomitant vascular resection (46% vs. 31%, p = 0.133).The characteristics of the NAT subgroups are presented in Table 1 of the electronic supplementary material (ESM).

DISCUSSION
The present study involves a large cohort of resected pancreatic cancer patients who were treated in a high-volume tertiary center for pancreatic surgery.I-IPMNs accounted for 9% of surgical resection for PDAC, which is similar to prior reported rates. 13The aim of this study was to compare the OS and the response to NAT of I-IPMN and PDAC.In the observed cohorts we observed a significantly longer OS of I-IPMN, however no differences in pathological, CA19.9, PET, and radiological response to NAT between I-IPMN and PDAC was observed.From the demographical data observed in this study, there are some differences in the average I-IPMN and de novo PDAC populations.I-IPMN patients tend to be older, they undergo a distal and total pancreatectomy slightly more often, they are less likely to need a vascular resection, they receive NAT less often, and they have fewer major postoperative complications.The increased age of I-IPMN patients might be the consequence of a slow process of malignant degeneration. 14The higher proportion of total pancreatectomies is instead probably to be attributed to the nature of these pancreatic cystic neoplasms, as they can present with an involvement of the whole gland.As I-IPMN patients were less often undergoing a pancreaticoduodenectomy and vascular resection, 15 they also had fewer major postoperative complications, but the 90-day mortality after surgery did not differ.The lower use of NAT in I-IPMN patients can be partially explained by the 37% preoperative uncertainty of malignancy and the lower proportion of tumor with vascular involvement, but even by accounting for these patients it appears that in current clinical practice I-IPMNs with a known malignancy are more likely to receive upfront surgery, even though current medical oncology guidelines do not mention a different approach to I-IPMN and PDAC. 8,9he role of NAT in I-IPMN has not been thoroughly investigated and currently available literature on the subject is scarce; however, in a large cohort of 240 resected I-IPMN patients, it was reported that NAT was used in only 2.5% of cases. 16Regarding histological differences between the two cohorts, I-IPMNs had more well-differentiated (G1) tumors, more T1 tumors, and were less likely to invade perineurally.Nonetheless, the nodal involvement was similar and the overall staging distribution of I-IPMN and PDAC did not differ significantly.
The role of adjuvant chemotherapy in I-IPMN has recently been discussed, with several retrospective studies [17][18][19] suggesting that it might not improve OS in the absence of nodal involvement.Unfortunately, as only a minority of patients with an I-IPMN undergo NAT, the I-IPMN cohort was small and no strong recommendations are possible on the basis of this study.Despite the small statistical power of this study, to our knowledge, this is the first study to assess the response of I-IPMN to NAT and to compare it with de novo PDAC.This makes the study a relevant first step in understanding the topic.In light of our observations, the scarce use of NAT in I-IPMN might not be justified.In the case of preoperative confirmation of malignancy with fine needle aspiration, the use of NAT in I-IPMN could provide the same advantages that it provides in PDAC. 20,21][19] A secondary result obtained from this study is the suggestion that I-IPMNs are not the same disease as de novo PDAC.Similar to other observations in the literature, 22 I-IPMNs have been associated with a more favorable outcome than PDAC, with a higher OS and DFS.Another indicator of a less aggressive biology was the lower rate of early recurrence in the first 6 months after surgery.Moreover, at multivariate analysis, the I-IPMN subtype of pancreatic cancer was an independent predictor of both lower risk of recurrence and death.
The retrospective nature of this study and the small cohort of I-IPMNs undergoing NAT make it hard to draw strong conclusions.Selection and time bias may have influenced treatment decisions, including the use of NAT in I-IPMN.The small size of the I-IPMN cohort may have led our analysis to be underpowered to detect clinically significant differences in some comparisons with PDAC.

CONCLUSION
Pancreatic adenocarcinoma arising from an IPMN is independently associated with longer OS and DFS after surgical treatment when compared with de novo PDAC.Patients with I-IPMNs are less likely to receive NAT before surgical resection, but when undergoing NAT, they have a similar response compared with patients affected by de novo PDAC.These data show that the potential efficacy of NAT on I-IPMN is similar to that of PDAC and thus may be considered in selected high-risk patients with I-IPMN similar to PDAC indications.

TABLE 3
an OR of 3.18 (CI 2.03-4.97,p < 0.001).At last, I-IPMN subtype of pancreatic cancer was strongly associated with a reduced chance of disease recurrence, with an OR of 0.35 (CI 0.22-0.57,p < 0.001).

TABLE 4
Multivariate logistic regression analysis for disease recurrence