Author Affiliations: Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China (Lin H, Ma Y, Wang JZ, Pan HY, Liu LX, Qiao HQ, Sun B and Jiang HC)

Corresponding Author: Hong-Chi Jiang, MD, PhD, FACS, Key Laboratory of Hepatosplenic Surgery, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China (Tel: +86-451-85552358; Fax: +86-451-53622672; Email: jianghongchi2014@163.com)

 

© 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(16)60066-8

Published online January 19, 2016.

 

 

Acknowledgements: The authors thank Mr. Shang-Ha Pan and Mr. Jian-Qi Wang for their assistance in study design and writing the manuscript.

Contributors: LH, SB and JHC proposed the study. LH, MY and WJZ performed the research and wrote the first draft. LH, PHY, LLX and QHQ collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. JHC is the guarantor.

Funding: This study was supported in part by grants from the National Natural Scientific Foundation of China (81270527), the Health Industry Special Projects of Research (201202007), and the Scientific Foundation of the First Affiliated Hospital of Harbin Medical University (2014B15).

Ethical approval: This study was approved by the Ethics Committee of the First Affiliated Hospital of Harbin Medical University (200928).

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Most of the reports on the prognostic indicators of patients with pancreatic adenocarcinoma are from developed countries. The present study focused on the prognostic indicators of Chinese patients with pancreatic adenocarcinoma.

 

METHODS: A total of 300 patients with pancreatic adenocarcinoma who had undergone curative resection were included. The resection and R0/R1 resection rates for adenocarcinomas from different parts of the pancreas were calculated and clinical characteristics were analyzed.

 

RESULTS: In 3427 patients diagnosed with pancreatic adenocarcinomas, only 300 (8.8%) were eligible for radical resection. The total median survival of these patients was 19 months, and their 1-, 3-, and 5-year survival rates were 72.5%, 28.0% and 23.4%, respectively. The prognostic factors included socioeconomic status, smoking history, symptoms, high blood glucose, and various tumor characteristics, including perineural and vascular invasion, lymph node metastases, and CA19-9 levels before and after operation. Operation-associated prognostic indicators included operation time, blood loss and transfusions, pancreatic fistula, and complications. Independent predictors of mortality included poor socioeconomic status, smoking history, symptoms, CA19-9, perineural invasion and lymph node metastasis, grade of fistula and complications. Patient survival was not correlated with either resection margin or adjuvant chemotherapy in multivariate analysis.

 

CONCLUSIONS: The survival rates of patients with curative resection for pancreatic adenocarcinoma in China are close to those in developed countries, but curative resection rate is far below. Socioeconomic status, symptoms, and CA19-9 are the three most prominent prognostic factors, which are helpful in patient selection and perioperative care.

 

(Hepatobiliary Pancreat Dis Int 2016;15:189-197)

KEY WORDS: pancreatic adenocarcinoma; prognostic factor; curative resection; developing countries

Pancreatic adenocarcinoma is a devastating disease because the latent clinical feature and lack of effective treatment, especially in developing countries. In 2014, the incidence and mortality rates of pancreatic adenocarcinoma were identical, and there were 46 420 deaths, making pancreatic cancer the fourth leading cause of cancer death for both men and women in the USA.^[1] Based on the nationwide statistics in the USA, less than 6% of patients with pancreatic adenocarcinoma can survive for more than 5 years,^[1] and the survival rate is even lower in China.^[2] Unfortunately, due to the insidious onset of pancreatic adenocarcinoma, only 10%-20% of these patients are candidates for surgical treatment, which is still the only feasible curative treatment for this highly malignant and lethal disease.^[3-9] In addition to the slim probability of a curative resection of pancreatic adenocarcinoma, the long-term survival after surgery is also unlikely. Previous studies^{[3, 9-12]} have indicated that the 5-year survival rate of patients who have received curative resection for pancreatic adenocarcinoma is only 5%-20%.In addition, recent studies^{[13, 14]} demonstrated that the 5-year survival rate after resection is only less than 20%, even in the most advanced and high-volume medical centers.

 

Currently, there is an improvement in the curative resection of pancreatic adenocarcinoma. Some scholars have attributed the success to the increased experience, advances in perioperative care, and increased use of adjuvant therapy. The determinants of survival can be sorted into the following categories: (i) patient demographics, such as gender, socioeconomic status (SES),^{[15, 16]} and body mass index (BMI);^[17] (ii) tumor factors, such as tumor stage^{[2, 4, 6, 7]} and size;^{[6, 13, 15, 18]} (iii) surgical technique and operative details, such as resection margin;^{[6, 13, 14, 18]} and (iv) perioperative managements including adjuvant therapy^{[15, 18, 19]} and packed red blood cell transfusion.^[18]

 

Most of the studies on pancreatic adenocarcinoma are from developed countries, such as the USA, France, Netherlands, Japan and Korea,^{[6, 15, 20-23]} and a few are from developing countries. Because of the differences in socioeconomic, cultural, and medical environments, the data harvested from developed countries may not be applicable to the developing countries. The present study was to analyze the prognosis of the patients with pancreatic adenocarcinoma who had undergone curative resection at a single, high-volume institution.

 

 

With the approval from the ethics committee of the hospital, we reviewed our prospectively maintained pancreas database to identify patients with pancreatic adenocarcinoma who had undergone curative resection between 1995 and 2013 in the First Affiliated Hospital of Harbin Medical University. The patients were eligible for study inclusion if they had had a pancreatic adenocarcinoma and had undergone tumor resection with a curative intent.

 

The curative resection procedure was determined according to the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM). The ICD-9 codes were related to pancreatic resection operations with curative intent, such as the Whipple procedure (52.7), radical pancreaticoduodenectomy (52.7), distal pancreatectomy (52.52), and total pancreatectomy (52.6). The primary tumor origin was mainly determined by pathological diagnosis; however, gross findings and image characteristics were also taken into consideration, especially when the pathological evidence was unclear. After curative resection, patients were followed-up at 6-month intervals until death or loss of follow-up.

 

Most of the patient demographic data were prospectively collected, including age, gender, smoking or drinking history, SES, BMI, symptoms, blood type, glucose, alanine aminotransferase (ALT), asparate aminotransferase (AST), total or direct bilirubin, albumin, lactate dehydrogenase (LDH), triglycerides, total cholesterol, serum or urinary amylase, hepatitis, and Charlson comorbidity score (CCS). The SES was divided as low or high based on the median household income. The census-level of SES is similar to that of the medical record.^[24] The BMI was calculated according to patient’s height and weight before operation. We identified pre-existing comorbidities from the patients’ medical records and graded them by CCS.^[25]

 

The greatest tumor diameter, encapsulation, lymph node status, peripheral nerve invasion, and vascular invasion were obtained from pathology reports. The tumor location and number in the pancreas were verified by preoperative imaging findings. Additionally, the TNM stage was categorized based on the TNM Classification of Malignant Tumors, 7th edition.^[26] Preoperative and postoperative (on the 7th day after resection) CA19-9 or CEA data were collected from the medical records.

 

The operative procedure, technical approach, and operative details such as operation or anesthetic time, blood loss, drain numbers, surgeon experience, and wound protector were collected. Moreover, the resection margin was assessed using the previously validated Leeds Pathology Protocol (LEEPP).^{[27, 28]} And R1 was defined as tumor within one millimeter of the margin.^[29] We calculated the rates of resection and R0/R1 resection for adenocarcinomas arising from different parts of the pancreas (when we found that the tumor was unresectable or had metastasis during operation, we closed the abdomen directly without any other medical intervention. This procedure was called O-C, short for open and closure).

 

The length of stay or postoperative stay, adjuvant chemotherapy, perioperative blood transfusion and wound infection data were collected. Complications defined as any deviation from the normal postoperative course during the hospital stay were recorded and divided into Grades I-V according to a validated classification.^[30]

 

Grade I: any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, and radiological interventions. Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics, electrolytes, and physiotherapy. This grade also includes wound infections opened at the bedside. Grade II: requiring pharmacological therapies and invasive procedure. Grade III: requiring surgical, endoscopic or radiological intervention. Grade IV: life-threatening complication (including central nervous system complications) requiring IC/ICU management. Grade V: death of a patient.

 

Pancreatic fistulas were defined as drained fluid on or after postoperative day 3 containing amylase that was greater than 3 times of the upper normal serum value, and they were divided into grades A, B and C according to the International Study Group on Pancreatic Fistula Classification.^[31] The principal outcome variable in this study was the survival time after curative resection. Additionally, we compared the independent prognostic factors among the patient groups in different SES.

 

The Chi-square test and Wilcoxon’s rank-sum test were used to compare the data between groups for categorical and continuous variables. The survival rates of the patients were compared using the Kaplan-Meier method and log-rank test for the demographic, histopathological, operative, and perioperative variables.^[32] All factors that were found to be univariately significant at P<0.05 were entered into the Cox proportional hazards model, and multivariate analysis was performed to determine the independent prognostic factors associated with long-term survival after surgery.^[33] A P value less than 0.05 was considered statistically significant. All statistical analyses were performed with the Statistical Analysis Software (SAS) version 9.13 for Windows XP (SAS Institute Inc., Cary, NC, USA).

 

 

A total of 300 out of 3427 (8.8%) patients with pancreatic adenocarcinoma were eligible for radical resection. This rate was gradually improved from 3.6% in 1995 to 15.9% in 2013 (Fig. 1B). Among them, 7.6% (2.6%-11.2%) of tumors were from the head and neck, 26.2% (0-40.0%) from the pancreatic body and tail, and fluctuated for tumors from the whole pancreas (Fig. 1D, 1F and 1H). In addition, the R0 resection rates for patients who underwent pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy were 80.0%, 76.8% and 100% respectively, and the overall R0 resection rate was 80.0%.

 

From 2001 to 2013, the palliative resection rate decreased yearly while the nonsurgical treatment rate increased gradually (Fig. 1D). The radical resection rate of distal pancreatectomy rose from 20% to 40% in the last decade, while the O-C and nonsurgical rates dropped significantly (Fig. 1F). The O-C rate was significantly decreased and nonsurgical rate was significantly increased in recent years for patients with pancreatic adenocarcinoma from the whole pancreas (Fig. 1H).

 

The postoperative mortality rate of this cohort was 4.7% (14 patients), and the median survival time was 19 months. The 1-, 3-, and 5-year survival rates were 72.5%, 28.0%, and 23.4%, respectively (Table 1). The details of the prognostic indicators for each of the four prognostic categories are described in the following text.

 

As shown in Table 1, 193 patients were 60 years old or younger and 107 were older than 60 years; there were 162 males and 138 females. The study population consisted of 78 smokers and 222 non-smokers. There were significant differences in survival according to the age and gender (P<0.05). Smokers had a worse prognosis than non-smoking patients (Fig. 2A).

 

Patients in high-SES had significantly higher survival rate compared with those in low-SES (Fig. 2B). We did not find the relationship between BMI and patient survival. A total of 110 patients had no symptoms and were diagnosed via routine medical examination; 90 had jaundice; 62 had abdominal pain; and 38 had weight loss. The presenting symptom was significantly associated with worse survival (Fig. 2C). A total of 68% of the patients had comorbid disease; 190 (63%) had a CCS of 1 to 2, and 15 (5%) had a CCS of 3 or greater. One hundred and forty-five patients had a high level of blood glucose which was significantly related to poor prognosis.

 

Patients with tumors in the distal region of the pancreas had higher 1-, 3-, and 5-year survival rates than those in the head and neck, and those with total pancreas involvement had the worst prognosis. Univariate analyses showed that tumor size was not significantly related to survival. Peripheral nerve invasion, vascular invasion and lymph node metastasis significantly shortened patients’ survival time (Table 2, Fig. 2D and 2E). Earlier TNM stage and lower level of CA19-9 was significantly associated with higher survival rate (Table 2 and Fig. 2F). Serum levels of CA19-9 at day 7 after resection were significantly related to the survival rate.

 

The median survival time and 1-, 3-, and 5-year survival rates for patients who underwent total pancreatectomy were significantly different from those who underwent pancreaticoduodenectomy and distal pancreatectomy (Table 3). Long operative time significantly shortened the survival and decreased the 1-, 3-, and 5-year survival rates. Patients with blood loss of ≥750 mL had worse survival outcomes than those with <750 mL. Furthermore, the median survival time and survival rates of patients who underwent R0 resection were significantly different from those who underwent R1 resection.

 

Univariate analysis revealed that the length of postoperative stay was not significant. Patients who needed blood transfusion exhibited lower 1-, 3-, and 5-year survival rates. The median survival time was significantly shorter in patients with pancreatic fistula and even shorter in those with higher grade (Fig. 2G). The classification of surgical complications was a highly significant survival determinant (Fig. 2H). Moreover, patients undergoing adjuvant chemotherapy had a better survival outcome with higher 1-, 3-, and 5-year survival rates (86.0%, 46.1%, and 38.6%, respectively).

 

The independent survival predictors determined by the multivariate survival analysis are shown in Table 4. Eight factors (3 demographic, 3 tumor, and 2 perioperative factors) were significantly negative prognostic variables. The presenting symptom, especially preoperative weight loss, was the most significant negative predictor of survival (HR=30.06). Grade C pancreatic fistula (HR=2.92), lymph node metastasis, low SES, smoking history, a high level of CA19-9, peripheral nerve invasion, and surgical complication classification were also highly associated with prognosis.

 

 

The aim of this study was to thoroughly evaluate the prognostic factors influencing survival following curative resection at a single, high-volume medical center in China. Curative surgical resection of pancreatic adenocarcinoma decreases perioperative mortality and significantly improved survival.^{[4, 7, 8, 12, 15]} A total of 3 427 patients were diagnosed in our center with pancreatic adenocarcinoma from 1995 to 2013, but only 300 (8.8%) of them were candidates for curative resection. The median survival time was 19 months after curative resection, and their 1-, 3-, and 5-year survival rates were 72.5%, 28.0% and 23.4%, respectively. These data are in accordance with the recent literature.^{[4, 15, 18, 22, 34, 35]} However, the rates of overall and three different operative procedures applied in curative resection were far below those in developed countries.^[5-9] The difference might be explained by economic and financial status. Indeed, patients with high SES had a higher rate of curative resection and better prognosis. Following the improvement of economy and financial status, the rate of curative resection in this population is increasing year by year, especially in this century which drove the 3-year and 5-year survival rate to a high level.

 

The most important predictor of mortality after curative resection in this study was the presenting symptom; in particular, patients with preoperative weight loss, jaundice, and abdominal pain exhibited a high mortality. These findings are consistent with those reported in the literature.^{[4, 7, 15]} The presenting symptom is related to tumor characteristics, such as tumor size, TNM stage, perineural invasion, and lymph node metastasis. In our study, high SES favored survival which is in agreement with a study by Lim et al and Cheung et al.^{[15, 16]} The majority of high SES patients sought medical care routinely and the pancreatic adenocarcinoma was diagnosed earlier. Additionally, more low SES patients were in later TNM stage (II to IV), had a high level of CA19-9 and peripheral nerve invasion, and were less likely to receive adjuvant chemotherapy. Smoking history is another unfavorable factor. This is in line with Pelucchi’s study which showed that smoking history is significant in the prognosis of pancreatic adenocarcinomas.^[17]

 

Most studies^{[4, 6, 7, 13, 15, 18, 21, 34, 35]} have demonstrated that tumor-related biological characteristics are significant in the survival of patients with pancreatic adenocarcinoma who have undergone curative resection. Thus, the tumor size, histological differentiation and lymph node status are all important biological determinants of prognosis. According to our findings, patients with high levels of serum CA19-9,^[36-38] peripheral neutral invasion,^{[4, 22]} and lymph node metastasis^{[6, 7, 13, 18, 21, 22, 34, 35]} are likely to have a worse prognosis.

 

Our data were similar to those presented in the existing literature on surgical techniques and operative details,^{[4, 6, 13, 14, 18]} including operative time, blood loss and resection margin status. However, these factors, although confirmed by the univariate analysis, were not found to be significant in the multivariate analysis.

 

There is evidence that a pancreatic fistula can influence the prognosis of patients after curative resection.^[23] Nagai’s group^[23] observed that patients with no pancreatic fistulas exhibited better survival than those with pancreatic fistulas of grades B and C, especially in the low recurrence rate group. Similarly, we found that patients without a fistula exhibited better survival than those with a fistula. We also observed an improvement trend in which patients with low classes of surgical complications had better outcomes. The use of adjuvant chemotherapy in combination with curative resection has been supported by many publications.^{[15, 18, 19]} However, some studies have demonstrated that adjuvant chemotherapy is not as beneficial as previously reported.^{[4, 13, 23]} Interestingly, adjuvant chemotherapy was only significantly correlated with survival in our univariate analysis. Furthermore, patients with high SES had a lower R0 resection rate, which was acknowledged as a significant prognostic factor of long-term survival.^{[6, 14, 18]}

 

Several limitations exist in our study. The analysis of data at a single, high-volume regional medical center with the same team over the course of the study provides a unique perspective on the status of surgical treatment for pancreatic adenocarcinoma with greater uniformity and accuracy than what can be gleaned from a multicenter study or a study using registry data. However, the results presented are likely not generalizable.

 

Despite the limitation, this study is the first population-based analysis of the prognostic factors for resectable pancreatic adenocarcinomas, which was based on the data from a single, high-volume medical center in China. Our findings demonstrated that the survival rates of patients with curative resection for pancreatic adenocarcinomas in China are close or equal to those in developed countries. However, our curative resection rate is far below that in the developed countries. This situation indicated that some aspects can be improved in health consciousness, medical insurance and early diagnosis of pancreatic adenocarcinomas.

 

We also found eight significant, independent determinants of survival; the strongest of these prognostic factors were the presenting symptom, CA19-9 and SES. Among them, SES influences the survival through direct and indirect mechanisms. These results indicated an important deficiency in medical care received by patients of low SES in developing countries, which directly affects the survival of populations. These findings will facilitate the improvement of patient selection and perioperative care in developing countries. Further larger population-based and multiple-institution studies are needed to confirm these observations and to explore the reasons for these disparities.

 

 

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