Pathological complete response (pCR) with or without the residual intraductal carcinoma component following preoperative treatment for pancreatic cancer: Revisiting the definition of “pCR” from the prognostic standpoint

Abstract Background and Aim There are no previous reports describing the prognostic significance of the residual intraductal carcinoma component (carcinoma in situ [CIS]) following preoperative treatment for pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to investigate the prognostic significance of a minimal residual CIS in cases with complete absence of an invasive component after preoperative treatment for PDAC. Methods Eighty‐one of 594 PDAC patients with preoperative treatment and subsequent surgery in our institute showed remarkable remission in the invasive component, which included 48 patients with the minimal residual invasive component (Min‐inv group) and 33 with absence of an invasive component (No‐inv group). We assessed the survival of these patients in association with the presence or absence of an invasive component and intraductal CIS. Results Five‐year overall survival in the No‐inv group patients was significantly better than that of the Min‐inv group patients (82%/66%, P = .041). Among the 33 patients in the No‐inv group, residual CIS was observed in 16 patients (CIS‐positive group), and the remaining 17 patients had no residual CIS (CIS‐negative group). There was no significant difference in survival between patients in the CIS‐positive and CIS‐negative groups (92%/78%, P = .31). Conclusions Residual CIS in the absence of an invasive component after preoperative treatment does not yield a prognostic impact after receiving perioperative treatment for PDAC. It might be reasonable to define pathological complete response (pCR) from the prognostic standpoint as follows: pCR is the complete absence of an invasive carcinoma component regardless of residual CIS.


| INTRODUC TI ON
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease because tumor cells have a tendency to spread to the surroundings and/or distant organs and become systematic disease from an early stage. [1][2][3] A solely surgical approach for PDAC is able to potentially cure this disease in few patients. 4,5 The surgery-alone strategy provides the minimum survival benefit in the majority of patients with localized PDAC (ie, resectable [R] or borderline resectable [BR] stage); 6 thus, multimodal strategies, including surgery plus pre-/ postoperative therapies, have been attempted to improve surgical outcomes in patients with R/BR-PDAC. [7][8][9][10][11][12][13][14][15][16][17] In our institute, we conducted a multimodal treatment strategy consisting of surgical resection following preoperative treatment and subsequent postoperative treatment for patients with PDAC. 7,8 Preoperative therapies have certain possible clinical benefits, [18][19][20][21][22] including a locoregional effect, early administration of systemic therapy and possible reduction in systemic recurrence after surgery. Histopathological evaluations of resected specimens after preoperative treatment (ie, histopathological response) are one of the indicators to assess the efficacy of preoperative treatment, and the histopathological response has been investigated in association with survival after surgery. Several reports have shown a remarkable response to preoperative therapy for PDAC, indicating a significantly preferable patient prognosis. [11][12][13][14][15][16] Pathological complete response (pCR) is recognized as the ultimate form of histopathological response, and previous reports showed that 1.6%-13% of PDAC patients showed pCR to preoperative therapy (the total number of patients with pCR was 44 cases in those studies), 15,16,[21][22][23] [27][28][29][30] In this context, no report has addressed whether pCR applies to cases of minimal residual CIS in the preoperative treatment strategy for PDAC. The clinical significance of minimal residual CIS remains unclear from the prognostic standpoint, whereas a few reports have indicated that the prognosis of patients with the minimal residual invasive component was significantly worse than that of patients showing complete absence of an invasive component in post-treatment tissues after preoperative treatment for PDAC. 15,16,21 Therefore, we conducted the present study with the aim of investigating the clinical significance of minimal residual CIS in patients with the absence of an invasive component with reference to the prognostic impact of the minimal residual invasive component in a resected specimen after preoperative chemoradiation therapy for R/BR-PDAC. From the prognostic viewpoint, we evaluated whether it is appropriate that patients with residual PDAC cells in the intraductal component only are classified as having pCR status.

| Patients
We retrospectively investigated all patients with histologically confirmed PDAC who received an R0 resection following preoperative therapy in our institute from January 2003 to December 2016, and 594 patients were included in this study. Our main strategy for PDAC was not changed during this 14-year period. 7,8 Patients with PDAC growing outside the pancreas but not into nearby major blood vessels (T3 stage of UICC 7th edition including the R/ BR stage of NCCN classification ver. 1, 2019) are usually recommended to undergo preoperative chemoradiation therapy (CRT, chemotherapy and radiation as conventional external-beam radiotherapy) for 2-3 months before surgery.

| Preoperative therapy
All patients included in the present study received preoperative therapy. During the observation period, several preoperative therapies were used according to the relevant clinical studies.
CRT was mainly used, and chemotherapy regimens were selected at our discretion, mainly depending on the national availability of chemo-drugs. In the first stage, patients were treated by single gemcitabine agent plus radiation. 7 After that, gemcitabinebased combination regimens (gemcitabine/nab-paclitaxel or gemcitabine/S-1) concomitant with radiation therapy were often used. 8,10 Patients unsuitable for gemcitabine therapy or for radiation therapy were treated with single S-1 agent plus radiation or with gemcitabine-based combination chemotherapy omitting radiation therapy. All of these patients provided written informed consent for participation.

| Surgery
Computed tomography (CT) or magnetic resonance imaging (MRI) was carried out to judge the resectability of PDAC within the 4 weeks before surgery. Patients who proceeded to surgery underwent pancreaticoduodenectomy, distal pancreatectomy, or total pancreatectomy as determined by the location and extent of the tumor. Vascular resections were done if involvement of the superior mesenteric vein, portal vein, celiac axis, or hepatic artery was substantial. Vascular reconstruction was preferentially carried out by primary repair. Patch venous repair or interposition grafting was used only when primary repair was not feasible.

| Pathological examination
Pathological examinations were carried out as previously described.

| Adjuvant chemotherapy and follow up
We carried out liver perfusion chemotherapy (LPC) through the portal vein followed by surgery, as reported previously. 7 All patients received LPC from the first day after surgery if their condition allowed it, and the perfusion was continued for 4 weeks in the hospital. Follow-up observations were carried out as described previously. 8 To investigate recurrence, three types of examination were carried out every 3-4 months: a routine physical examination; laboratory tests, including the analysis of the serum level of CA19-9 (tumor marker); and radiological imaging, including chest and abdominal CT (or MRI). Date of recurrence was defined as the date on which the investigator detected recurrence on an image or in a biopsy specimen.
The last follow-up date was June 2018, and the median observation time after initial diagnosis of patients was 39.1 months.

| Evaluation of clinicopathological features
We investigated various preoperative variables, including patient characteristics, tumor factors and treatment factors ( Table 1). We collected common patient parameters and all tumor information, including initial findings at the first visit and before surgery (after preoperative therapy), and the pathological diagnoses were estimated using the resected specimens.

| Statistical analysis
Data are expressed as mean ± standard deviation. The chi-squared test and Fisher's exact test were used for comparing categorical variables, as appropriate. A Kaplan-Meier analysis and log-rank test were used to construct survival curves and to evaluate differences in univariate analysis. Logistic regression was carried out for both the multivariate analysis and the partition analysis of the detected factors. All analyses were done using the JMP 13 software program (SAS Institute. P values <.05). 32

| Ethical considerations
This study was carried out at Osaka International Cancer Institute, Japan, and was approved by the ethics committee of our institution (no. 18195).

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Presence More specifically, the 5-year survival rates of the patients who received postoperative LPC and those who did not were 76% and 79%, respectively (P = .36), and those of patients who received systemic adjuvant chemotherapy and those who did not were 68% and 84%, respectively (P = .14).

| CON CLUS ION
The

ACK N OWLED G EM ENT
We thank Dr Shigenori Nagata who is a pathologist in our institute for excellent support. Hiroshi Wada https://orcid.org/0000-0001-8862-7833