Abstract
Background/Aim: The prognosis of pancreatic cancer remains poor with a high incidence of recurrence even after curative resection. The aim of this study was to investigate prognostic factors in patients with recurrent pancreatic cancer using the multicenter database. Patients and Methods: The subjects were 196 patients with recurrent pancreatic cancer who underwent resection between 2008 and 2015. We retrospectively investigated the relation between clinicopathological characteristics of the patients and overall survival from recurrence using univariate and multivariate analyses. Results: In univariate analysis, the positive lymphatic invasion (p=0.0240), time to recurrence from resection <1 year (p<0.0001), sites of recurrence except for local or lymph node (p=0.0273), liver recurrence (p=0.0389) and peritoneal recurrence (p<0.0001) were significantly associated with poor overall survival from recurrence. In multivariate analysis, time to recurrence from resection <1 year (p<0.0001) and peritoneal recurrence (p<0.0001) were independently associated with poor overall survival from recurrence. Conclusion: Time to recurrence from resection <1 year and peritoneal recurrence were significant independent predictors of poor overall survival from recurrence in patients with recurrent pancreatic cancer.
Pancreatic cancer is currently the fourth leading cause of cancer death worldwide (1). Despite improvements in surgical techniques, chemotherapy and follow-up methodology, pancreatic cancer remains a fatal disease, with a global 5-year survival rate of less than 10% (1). The majority of patients with pancreatic cancer present with locally advanced or metastatic disease, and less than 20% of patients are fit for resection at the time of diagnosis (2). Surgical resection is still considered the only potentially curative treatment for pancreatic cancer, but approximately 80% of surgically resected pancreatic cancer recur within 5 years, and over 60% of patients develop recurrences within 2 years (3). Therefore, identifying poor prognostic factors that may predict the tumor recurrence and prognosis of patients is important for selecting appropriate treatment.
There have been reports identifying prognostic factors for pancreatic cancer (4), but most previous studies were based on surgically resected or heterogeneous unresectable including metastatic and recurrent pancreatic cancer. It is therefore worthy to identify prognostic factors in patients who developed recurrent pancreatic cancer.
Here, we retrospectively performed a prognostic factor analysis using a multicenter database in patients with recurrence after surgical resection for pancreatic cancer.
Patients and Methods
Between 2008 and 2015, a total of 332 patients with pancreatic cancer underwent pancreatic resection at four university hospitals (The Jikei University Hospital, Katsushika Medical Center, Daisan Hospital and Kashiwa Hospital) and an associated facility (The Kawaguchi Municipal Medical Center). Of these, recurrence was observed in 236 patients. We excluded 40 patients from the analysis for the following reasons: 2 with anaplastic cancer and 38 due to lack of data. Finally, 196 patients were included in the final analysis.
Tumor-nodes-metastasis (TNM) staging was based on the eighth edition of the Union for International Cancer Control (UICC) (5). Postoperatively, the patients received adjuvant chemotherapy using gemcitabine, S-1 or gemcitabine and intra-arterial transfusion of nafamostat mesylate (6), excluding the patients with poor performance status or those who refused treatment. Tumor recurrence was defined as newly detected local or distant metastatic tumors based on the findings of ultrasonography, computed tomography, or magnetic resonance imaging with or without increased serum carcinoembryonic antigen or carbohydrate antigen 19-9 (CA19-9) levels. When multiple sites of recurrence were detected simultaneously, each site was counted. For recurrence, chemotherapy or conversion to another chemotherapy were chosen based on performance status.
At first, we retrospectively investigated the relation between patient characteristics and overall survival from recurrence in patients with recurrent pancreatic cancer by univariate and multivariate analyses. The factors included age, gender, operative time, intraoperative blood loss, tumor position, tumor differentiation, lymphatic invasion, venous invasion, TNM classification, curability, time to recurrence from resection and sites of recurrence.
Next, we compared time to recurrence from resection ≥1 year and <1 year using the following factors: age, gender, operative time, intraoperative blood loss, tumor location, tumor differentiation, lymphatic invasion, venous invasion, neural invasion, TNM classification, curability and sites of recurrence. We then analyzed patient characteristics in relation to peritoneal recurrence using the following factors: age, gender, operative time, intraoperative blood loss, tumor location, tumor differentiation, lymphatic invasion, venous invasion, neural invasion, TNM classification, curability and time to recurrence from resection.
This study was approved by the Ethics Committee of the Jikei University School of Medicine (30-322).
Statistical analysis. The data were expressed as a mean±standard deviation (SD). Univariate analyses were performed using the log-rank test, non-paired t-test and Chi-square test. Multivariate analysis was performed using the Cox proportional regression model. Survival rates were calculated by the Kaplan-Meier method. All p-values were considered statistically significant when the associated probability was less than 0.05.
Results
Patient characteristics and overall survival from recurrence by univariate and multivariate analyses. Characteristics of the patients are summarized in Table I. Tables II and III list the relationship between patient characteristics and overall survival from recurrence in patients that underwent resection for pancreatic cancer. In univariate analysis, the positive lymphatic invasion (p=0.0240), time to recurrence from resection <1 year (p<0.0001, Figure 1A), sites of recurrence except for local or lymph node (p=0.0273), liver recurrence (p=0.0389) and peritoneal recurrence (p<0.0001, Figure 1B) were significantly associated with poor overall survival from recurrence. In multivariate analysis, time to recurrence from resection <1 year (p<0.0001) and peritoneal recurrence (p<0.0001) were independently associated with poor overall survival from recurrence.
Association between patient characteristics and time to recurrence from resection. Table IV lists the association between patient characteristics and time to recurrence from resection. In time to recurrence from resection <1-year group, lymphatic invasion and liver recurrence were significantly more frequent than in those in time to recurrence from resection ≥1-year group (p=0.0038 and 0.0085, respectively).
Patient characteristics.
Association between patient characteristics and peritoneal recurrence. Table V lists the association between patient characteristics and peritoneal recurrence. In the peritoneal recurrence present group, intraoperative blood loss, well differentiated tumor and venous invasion were significantly more frequent than in those in the peritoneal recurrence absent group (p=0.0408, 0.0033 and 0.0211, respectively).
Univariate analysis of overall survival from recurrence for pancreatic cancer.
Multivariate analysis of overall survival from recurrence for pancreatic cancer.
Discussion
We herein demonstrated that time to recurrence from resection <1 year and peritoneal recurrence were independently significant predictors of poor prognosis in patients with recurrence after resection for pancreatic cancer using a multicenter database. To the best of our knowledge, there were only two reports on prognostic factors in patients with recurrent pancreatic cancer. Sakamoto, et al. reported that the combination of neutrophil-to-lymphocyte ration (NLR) and serum CA19-9 level were independent prognostic factors in 66 patients with recurrent pancreatic cancer (7). Yamada, et al. reported that the performance status, invasion of lymph vessels, kind of treatment for recurrence and initial recurrence were independent significant risk factors for the survival time after recurrence in 85 patients who developed recurrence after curative surgery for pancreatic cancer (8).
Recurrence can develop at various sites including the locoregional area, liver, peritoneum and lung. The prognosis differs according to the site of recurrence because each type of recurrence is caused by different mechanisms and has its own specific characteristics (9). Kim, et al. reported that patients with peritoneal recurrence had the shortest survival and patients with lung recurrence had the longest survival (10). In the current study, patients with peritoneal recurrence had the shortest survival after recurrence.
Peritoneal recurrence is the most dismal type of recurrence in terms of symptoms and prognosis due to ascites and intestinal obstruction leading to abdominal distension (11, 12). Ariake, et al. reported that excessive blood loss, artery invasion, pancreatic nerve plexus invasion and histological grade 3 were risk factors for peritoneal recurrence (12). On the other hand, the current study interestingly showed that a well differentiated tumor was a risk factor for peritoneal recurrence, and an independent predictor for poor overall survival from recurrence. Our previous study reported that well tumor differentiation was an independent predictor for good disease-free and overall survival in patients who underwent pancreaticoduodenectomy for pancreatic cancer (13), which could indicate that the prevention of the peritoneal recurrence in patients with a well differentiated tumor is important for better prognosis. Our multicenter database showed that overall survival rates at 1, 3 and 5-year were 85.3%, 60.0% and 47.1% in 77 patients with well differentiated pancreatic cancer without peritoneal recurrence.
Association between patient characteristics and time to recurrence from resection.
Kaplan-Meier curves of overall survival from recurrence in patients with time to recurrence from resection ≥1 and <1 year (A), and those with and without peritoneal recurrence (B).
Nab-paclitaxel plus gemcitabine is one of the standard first-line systemic chemotherapy regimens for patients with metastatic pancreatic cancer (14). Paclitaxel has been shown to have a promising efficacy for gastric cancer with peritoneal metastasis (15), and nab-paclitaxel was more effective for peritoneal metastasis than paclitaxel in patients with advanced gastric cancer (16). Therefore, nab-paclitaxel plus gemcitabine as adjuvant chemotherapy may prevent peritoneal recurrence in patients with resected pancreatic cancer, resulting in better prognosis. A randomized controlled study of adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer is now ongoing (17).
Association between patient characteristics and peritoneal recurrence.
The current study had a retrospective and observational design. Furthermore, the detailed treatment for recurrence was not described due to lack of data. However, a unique strong point was that this was the first report analyzing prognostic factors for recurrent pancreatic cancer using a multicenter database.
In conclusion, time to recurrence from resection <1 year and peritoneal recurrence were the significant independent predictors of poor overall survival from recurrence in patients with recurrence after resection for pancreatic cancer.
Footnotes
Authors' Contributions
Kenei Furukawa: Design of the study, collection and analysis of data and drafting of the article; Hiroaki Shiba: Revision of the article; Ryoga Hamura: Collection of data; Koichiro Haruki: Collection of data; Yuki Fujiwara: Collection of data; Teruyuki Usuba: Collection of data; Yukio Nakabayashi: Collection of data; Takeyuki Misawa: Collection of data; Tomoyoshi Okamoto: Collection of data; Katsuhiko Yanaga: Revision of the article and final approval of the article.
Conflicts of Interest
The Authors have no conflicts of interest to declare regarding this study.
- Received November 20, 2019.
- Revision received November 26, 2019.
- Accepted November 27, 2019.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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