Patients and clinicopathological data collection
This was a retrospective observational study. Patients who were either enrolled in the JASPAC 05 trial or received NACRT with S-1 for BRPC at the National Cancer Center Hospital East (NCCHE) between 2008 and 2017 were examined. The patients were included in the present study if a laparotomy was conducted for curative-intent after NACRT. Patients who were found to have distant metastasis at the time of laparotomy were excluded. Among the 14 institutions that enrolled patients in JASPAC 05, 8 institutions agreed to collaborate with the present study. As a result, 24 patients with BRPC who had participated in the JASPAC 05 trial and 5 patients with BRPC who had received NACRT at the NCCHE were included. All 29 patients had a cytologically or histologically confirmed diagnosis of pancreatic ductal adenocarcinoma prior to undergoing NACRT.
Clinicopathological data were retrieved from the JASPAC 05 data and the medical records of the patients who were treated at the NCCHE. Patient characteristics including age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, tumor location, clinical staging as per the Union for International Cancer Control (UICC) classification (7th edition),12 and type of tumor-vessel contact before NACRT were noted. Tumor size on CT imaging, the carcinoembryonic antigen (CEA) level, and the carbohydrate antigen 19 − 9 (CA 19 − 9) level were analyzed before and after NACRT. The tumor response was evaluated according to the response evaluation criteria in solid tumors classification (RECIST) v1.1.13 Intraoperative variables including the type of surgical procedure, portal vein resection, partial resection of the superior mesenteric artery (SMA) plexus, the number of retrieved lymph nodes, and blood loss were also examined.
Pathological findings including the tumor size, lymph node metastasis, portal vein invasion, plexus invasion, pathological staging as per the UICC classification (7th edition), resection margin, and pathological response were noted. R0 resection was defined as the absence of tumor cells present at the resection margin. The pathological response for NACRT was evaluated using the Evans classification14. The pathological response was classified as follows: grade I < 10% or no tumor cell destruction; grade IIa, destruction of 10–50% of tumor cells; grade IIb, destruction of 51–90% of tumor cells; grade III, < 10% viable-appearing tumor cells; and grade IV, no viable cells. A pathologist at each institution evaluated the histological examination results.
Neoadjuvant Chemoradiotherapy
The NACRT regimen consisted of S-1 with concurrent radiotherapy, as reported previously.15 Briefly, a total dose of 50.4 Gy was delivered in 28 fractions over 5.5 weeks. S-1 was administered orally at 40 mg/m2 twice daily for 28 consecutive days, followed by a 14-day rest period per course on the day of irradiation.
Surgical Indication After Nacrt
Patients who met the surgery-entry criteria, consisting of the absence of distant metastasis, no local progression precluding an R0 or R1 resection, a good performance status (PS 0/1), no massive ascites, no massive pleural effusion, no serious infection, no serious adverse NACRT events, and adequate organ system function, underwent surgery 15 to 56 days after the end of NACRT.
When diagnosing local progression precluding R0 or R1 resection, the occurrence of progressive disease (PD) according to the RECIST was basically used as our consensus-based standards for the criteria, while 1 patient with PD who conducted laparotomy at the NCCHE because of patient’s strong preference was included in the study. The perivascular findings obtained using MDCT after NACRT were not taken into consideration when determining the surgical indications unless the tumor response was PD.
Diagnosis And Classification Of Ct Imaging Findings
BRPC was diagnosed via a 16- or 64-slice MDCT with a pancreas protocol including triphasic cross-sectional imaging with a 2-mm slice thickness. BRPC was defined as bilateral impingement on the superior mesenteric vein or portal vein (BR-PV) or tumor contact ≤ 180° with the superior mesenteric artery (BR-SMA), the common hepatic artery (BR-CHA), or the celiac artery (BR-CeA) based on the NCCN 2009 guidelines.6
Two radiologists (T.K. and H.K.) who were blinded to the patients’ clinical histories retrospectively analyzed the CT images before and after NACRT. The radiological response of the perivascular component of the tumor was evaluated and graded as peripancreatic major vessel invasion. The response of the peripancreatic major vessel invasion was graded according to the change in the longitudinal length of tumor-vessel contact. The progression or the shrinkage of peripancreatic major vessel invasion was defined as an increase or decrease in the length of tumor-vessel contact ≥ 2 mm. Otherwise, the peripancreatic major vessel invasion was graded as stable. Patients were classified into 2 groups: progression of vascular invasion (PVI, progression) or non-progression of vascular invasion (NVI, shrinkage or stable).
The R0 resection rates according to the various combinations of peripancreatic major vessel invasion response and tumor response were analyzed. The relationships between the peripancreatic major vessel invasion response and other evaluation items such as the rates of reduction in CEA and CA 19 − 9 after NACRT, the tumor response according to the RECIST, and the pathological response according to the Evans classification were evaluated. Factors associated with a pathological response of Evans grade ≥ IIb were also analyzed.
Statistical analysis
Categorical variables were analyzed using the Fisher exact test and are shown as numbers with percentages. Continuous variables were analyzed using the Mann-Whitney U test and are shown as the median and range. All P values were based on two-sided statistical tests, and the significance level was set at 0.05. All the statistical analyzes were performed using JMP12.0.1 (SAS Institute, Cary, NC, USA).
This study was approved by the National Cancer Center Institutional Review Board (IRB) and by the IRBs of the other 7 participating institutions.