Is remnant pancreatic cancer after pancreatic resection more frequent in early‐stage pancreatic cancer than in advanced‐stage cancer?

Abstract Aim As the prognosis of patients who undergo resection for pancreatic cancer has improved, reports of remnant pancreatic cancer after pancreatic cancer resection have been increasing. Previous studies regarding early‐stage pancreatic cancer showed a high incidence of remnant pancreatic cancer in these patients. The aim of this study was to investigate the incidence of remnant pancreatic cancer according to the degree of progression of the initial pancreatic cancer. Methods Patients who underwent partial pancreatic resection for primary pancreatic cancer were retrospectively reviewed and divided into an early‐stage group and an advanced‐stage group according to the stage of the initial cancer. Patient characteristics and long‐term outcomes, including development of remnant pancreatic cancer, were compared between the two groups. Results This study included 321 patients who underwent partial pancreatectomy for pancreatic cancer; 32 patients in the early‐stage group and 289 patients in the advanced‐stage group. Remnant pancreatic cancer developed in 19 patients (5.9%); seven patients (21.9%) in the early‐stage group and 12 patients (4.5%) in the advanced‐stage group. The cumulative incidence of remnant pancreatic cancer according to the Kaplan–Meier method was comparable between the two groups (5‐year cumulative incidence: 20.6% vs 9.9%, early‐stage group vs advanced‐stage group; P = .1827). Conclusion Our results suggested that the potential for developing remnant pancreatic cancer was comparable between the early‐stage and the advanced‐stage groups. Therefore, the incidence of remnant pancreatic cancer may increase along with improved pancreatic cancer treatment.


| INTRODUC TI ON
Pancreatic cancer is the most lethal malignancy of the digestive system, with a 5-year relative survival rate of only 9%. 1 Currently, the only way to cure pancreatic cancer is complete surgical resection of a primary lesion, if the lesion is resectable. Because of early detection and improved multidisciplinary treatments, the prognosis of patients who undergo resection for pancreatic cancer has improved. 2,3 While the number of long-term survivors after surgery for pancreatic cancer has been increasing, reports of patients who develop metachronous cancer in the remnant pancreas have also increased. 4 The proportion of patients who develop remnant pancreatic cancer after resection of pancreatic cancer has been reported to range from 0.7% to 26.7%. 4 Notably, some studies focusing on early-stage pancreatic cancer (stage 0-I) patients showed a high incidence of remnant pancreatic cancer. 5,6 However, no study has compared the incidence of remnant pancreatic cancer after resection of early-stage pancreatic cancer with that of advanced-stage pancreatic cancer.
In this study, to investigate the incidence of remnant pancreatic cancer according to the degree of progression of the initial pancreatic cancer, we compared the long-term outcomes of patients who underwent partial pancreatic resection for early-stage pancreatic cancer to outcomes of patients who had surgery for advanced-stage pancreatic cancer.

| Study design
This study was approved by the Ethics Committee of Kyushu University and conducted according to the Helsinki Declaration.
Patients who underwent pancreatic resection for primary pancreatic cancer at the Department of Surgery and Oncology, Kyushu University, between 1992 and 2013 were retrospectively reviewed.
Patients who underwent neoadjuvant therapy for pancreatic cancer and those who underwent total pancreatectomy were excluded. (c) more than a 12-month interval between the initial pancreatic resection and the secondary lesion; and (d) pathological or cytological diagnosis of carcinoma or radiological findings strongly suggesting malignancy, such as invasion to the surrounding tissue or distant metastasis. Patients with initial pancreatic cancer at stage 0, IA, and IB were designated as the early-stage group, while patients with stage IIA-IV pancreatic cancer were designated as the advancedstage group. The patient characteristics and long-term outcomes of the early-stage group were analyzed and compared with those of the advanced-stage group. The disease-free interval was defined as the duration between the date of the initial operation and the date of diagnosis of extrapancreatic recurrence or remnant pancreatic cancer. Overall survival (OS) was defined as the duration between the date of initial surgery and the date of death or last follow-up. The Kaplan-Meier method was used to estimate OS and the cumulative incidence of extrapancreatic recurrence or remnant pancreatic cancer, and the log-rank test was used for comparisons. A two-sided P-value of <.05 was considered statistically significant.

| RE SULTS
Among the 422 patients who underwent pancreatic resection for pancreatic cancer, 321 were included in this study ( Figure 1). Among the 321 patients, 32 were classified as the early-stage group, and 289 patients were classified as the advanced-stage group. The characteristics of the patients in the two groups are shown in Table 1.
Age and the male-female ratio were comparable between the two groups. Cancer in the pancreatic body-tail was more frequent in the early-stage group. Concomitant IPMN was also recognized more seven patients in the early-stage group and 12 patients in the advanced-stage group ( Figure 1). We did not include one patient who developed a remnant pancreatic lesion that was pathologically diagnosed as adenocarcinoma that appeared 8 months after the initial pancreatic resection. The cumulative incidence of remnant pancreatic cancer was comparable between the two groups (5-year cumulative incidence: 20.6% vs 9.9%, early-stage group vs advanced-stage group; P = .1827; Figure 4). The characteristics of the patients who developed remnant pancreatic cancer are shown in Table 2 and were comparable between the two groups except for stage. Although two patients with remnant pancreatic cancer in the advanced-stage group underwent R1 resection in the initial operation, pancreatic cut margins were negative. The interval between the initial pancreatic resection and the diagnosis of remnant pancreatic cancer was also comparable between the two groups (51 months vs 54 months, early-stage group vs advanced-stage group; P = .9053). Thirteen of the 19 patients underwent total pancreatectomy for remnant pancreatic cancer. In all 13 patients, the pathological diagnosis of the remnant pancreatic cancer was conventional PDAC. Our indication for surgical resection of remnant pancreatic cancer was the same as for primary pancreatic cancer, and the reasons for non-surgical treatment were metastatic disease TA B L E 1 Characteristics of patients who underwent partial pancreatectomy for pancreatic cancer   Figure 6).  Generally, pancreatic cancer occurs more frequently in the pancreatic head, 3 suggesting that the pancreatic head is more susceptible to carcinogenesis. It is suspected that remnant pancreatic cancer develops more frequently after resection of cancer in the pancreatic body-tail. In this study, indeed, remnant pancreatic cancer developed more frequently after resection of cancer in the pancreatic body-tail (14/19) 18 In their study, patients whose initial cancer was UICC stage IA-IB had a tendency for lower OS than those whose In conclusion, this was the first study to analyze the incidence of remnant pancreatic cancer according to the degree of progression of the initial cancer. The potential for developing remnant pancreatic cancer was comparable between the early-stage and the advanced-stage groups. The lower incidence of remnant pancreatic cancer in the advanced-stage group may be attributable to shorter observation periods secondary to the poor prognosis of this group.

F I G U R E 3
Therefore, we expect that the incidence of remnant pancreatic cancer will increase if long-term outcomes of patients who undergo surgery for pancreatic cancer are improved owing to progress in multidisciplinary treatment. In the near future, long-term surveillance after pancreatic resection for pancreatic cancer will be more important to detect remnant pancreatic cancer in a resectable state.

ACK N OWLED G EM ENTS
We thank James P. Mahaffey, PhD, and Jane Charbonneau, DVM, from Edanz Group (https://en-autho r-servi ces.edanz group.com/) for editing a draft of this manuscript.