Clinicopathologic characteristics, laboratory parameters, treatment protocols, and outcomes of pancreatic cancer: a retrospective cohort study of 1433 patients in China

Medical ethics

This retrospective cohort study was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki (sixth revision, 2008) and was approved by the Ethical Committee of China National Cancer Center (no. NCC2017SF-72).

Inclusion and exclusion criteria

Patients who were diagnosed with pancreatic cancer and hospitalized at the China National Cancer Center/Cancer Hospital between April 1, 2006 and May 31, 2016 were identified and included. The diagnoses for all patients had been confirmed by pathological or cytological examinations. For the review, all patients must have been first treated at our center and should have complete medical records.

We excluded patients with pancreatic neuroendocrine tumor, solid pseudopapillary tumor of pancreas, all kinds of pancreatitis and other benign pancreatic diseases, and so on.

Data collection

Data on basic patient characteristics (sex, age, region of residency, race, payment method, job, marital status, lifestyle factors, comorbidities, year of diagnosis, and initial diagnostic department); clinicopathologic features (symptoms, tumor location, tumor diameter, and tumor stage); laboratory parameters (blood cell count, blood biochemical parameters, and tumor markers); and treatment information were collected from the medical records by trained investigators.

Vital status was collected using several methods. The primary methods included a telephone interview of patients or their next of kin and via Short Message Service. For patients who could not be reached, data were obtained from population registries from local health units, municipal registration offices, and local authorities. The outpatient records system was also queried for obtaining follow-up information and treatment records. All data were anonymized and de-identified.

Tumor stages were confirmed in accordance with the American Joint Committee on Cancer (AJCC) staging manual, 8th edition (Amin et al., 2017).

Statistical analysis

Continuous variables were expressed as means ± standard deviation or medians with range, and categorical variables were expressed as frequencies and ratios. Student’s t test, one-way analysis of variance, the Mann–Whitney U test, and Kruskal–Wallis H test were used for comparing continuous variables among different groups. The chi-square or Fisher’s exact tests were used for comparing categorical variables among different groups. Ranked data among different groups was compared using the Mann–Whitney U or Kruskal–Wallis H tests.

Overall survival was defined as the time from the date of definite diagnosis until the death or end of follow-up. The Kaplan–Meier method and the log-rank test were used for calculating median OS rates with 95% confidence intervals (CIs), comparing OS rates among different groups, and generating survival curves. The results of univariate and multivariate analyses of OS in patients with pancreatic cancer were expressed as hazard ratios (HRs) with 95% CIs. Because some variables were repeated, the following three different models were used when we performed the Cox multivariate analyses: (1) Model 1: adjusted for gender, age, diagnosis year, and variables with P < 0.05 in the univariate analysis. We excluded tumor diameter because this data partly overlapped with T stage data. We also excluded total AJCC stage because this data overlapped with T stage, N stage, and M stage data. (2) Model 2: adjusted for gender, age, diagnosis year, and variables with P < 0.1 in the Cox multivariate analysis of Model 1. Variables included were gender, age, diagnosis year, total bilirubin (TBil), carbohydrate antigen 19-9 (CA19-9), tumor location, N stage, M stage, surgical resection, and systemic chemotherapy. We excluded T stage because this data partly overlapped with tumor diameter. (3) Model 3: adjusted for gender, age, diagnosis year, and variables with P < 0.1 in the Cox multivariate analysis of Model 1. Variables included were gender, age, diagnosis year, TBil, CA19-9, tumor location, surgical resection, and systemic chemotherapy. We excluded T stage, N stage, and M stage because this data overlapped with total AJCC stage data.

Statistical analyses were performed using IBM SPSS software, version 20.0 (SPSS, Chicago, IL, USA). All tests were two-sided, with a P value of <0.05 considered as statistically significant. And in some conditions, we set the test level at 0.1.

Overall cohort characteristics

This retrospective cohort consisted of 1,433 pancreatic cancer patients with median follow up period of 6.3 (0–132.0) months. Overall demographic included 125 (9.0%) stage I, 157 (11.3%) stage II, 584 (42.0%) stage III, and 524 (37.7%) stage IV pancreatic cancer, respectively.

Basic characteristics

Table 1 shows the basic characteristics of the cohort. Median age was 60 (23–90) years, and male/female ratio was 1.61:1. The majority of the patients (61.6%) were from North China, one of the six regions in China, were of Han ethnicity (93.6%), payed the treatment costs by insurance (75.7%), and were married (97.5%). Mean BMI was 23.2 kg/m² and median BMI was 22.9 kg/m². Compared with the other stages, the number of patients with a family history of cancer was lower in stage I or III, and the number of patients with a family history of pancreatic cancer was higher in stage II. More than 70% of patients with stage I to III cancer were admitted to the department of abdominal surgery at their first visit, while more than half of the patients with stage IV cancer were admitted to the department of internal medicine or intervention therapy (Table 1). No significant differences were noted in sex, age, region of origin, race, payment method, job, marital status, lifestyle factors (drinking, smoking, BMI) and comorbidities (hypertension, diabetes mellitus, and biliary or gallbladder disease) among the different stages of pancreatic cancer (P > 0.05, Table 1).

Clinical symptoms

Abdominal or back pain were observed in most patients (74.3%) at the time of diagnosis. Other common symptoms included weight loss (45.0%), jaundice (30.3%), and alimentary symptoms (14.1%). Only 116 patients (8.2%) reported no symptoms at the time of diagnosis. There was a correlation between pain and cancer stage, with pain reported more frequently by patients with advanced stage cancer. The number of patients with jaundice was lowest in stage IV (P < 0.001), and the number of patients with no obvious symptoms was higher in stages I and II (P < 0.001, Table 2).

Laboratory parameters

The number of patients with elevated white cell and neutrophilic granulocyte counts were lowest in stage IV (P < 0.05), whereas the number of patients with elevated lymphocyte counts were highest in stages I and II (P < 0.05). Patients with metastatic pancreatic cancer had lower blood platelet counts. Alanine aminotransferase, TBil, indirect bilirubin (IBil), and alkaline phosphatase (ALP) levels significantly differed across the four stages with the highest being among stage III patients (P < 0.05). The level of prealbumin was the lowest in stage IV, while C-reactive protein was the highest in stage IV (P < 0.001). The levels of tumor markers (carcinoembryonic antigen (CEA), CA19-9, and carbohydrate antigen 242 (CA242)) were significantly higher in patients with stage IV cancer than in those with other stages of cancer (P < 0.05). There were no differences noted in red blood cell count and hemoglobin among the stages (P > 0.05, Table 2).

Tumor features

Most tumors were located in the pancreatic head (61.7%). Median tumor diameter was 4.2 (0.5–15.0) cm. Majority of the tumors were T4 stage (66.8%). Lymph node and distant metastases were noted in 49.5% and 36.8% of patients, respectively, and liver was the most common distant metastatic organ (Table 2).

Treatment protocols

Among the 1,433 patients, 182 (12.7%) who were hospitalized at our center refused any treatment or received supportive treatments alone (not including biliary drainage), and 784 patients (54.7%) had surgeries. Among these 784 patients, 272 (34.7%) underwent surgical resection, 277 (35.3%) received intraoperative radiotherapy, 233 (29.7%) underwent exploratory laparotomy or palliative bypass surgery, and the remaining two patients (0.3%) underwent intraoperative freezing and microwave treatments, respectively. A total of 646 patients (45.1%) received nonsurgical anticancer treatment. The most frequently performed non-surgical treatments included systemic chemotherapy (n = 351, 24.5%); interventional therapy (n = 250, 30.3%); concurrent chemoradiotherapy (n = 98, 6.8%); and extracorporeal radiotherapy (n = 55, 3.8%). Among all patients with pancreatic cancer, 39.2% underwent biliary drainage; of these, 434 underwent bypass surgery and 146 underwent non-surgical drainage (Table 2).

Overall survival

By the end of the follow-up period, there were 874 deaths, and 342 patients remained alive or died because of non-tumor reasons. The remaining 217 patients were lost to follow-up. Overall, the 1-, 3-, and 5-year survival rates were 43.7%, 14.8%, and 8.8% respectively. Median OS was 10.6 months (95% CI, 9.8–11.3 months, Fig. 1A), and median OS rates of stages I, II, III, and IV were 34.7, 17.6, 11.0, and 6.1 months, respectively (Fig. 1B).

Prognostic factors

We examined the association between tumor stage (Fig. 1B), laboratory parameters (Figs. 1C and 1D), and treatment protocols (Figs. 1E and 1F) and OS using the Kaplan–Meier method and the log-rank test.

Univariate analysis findings revealed that the following factors negatively affecting OS: older age (≥65 years), elevated neutrophilic granulocyte count, elevated TBil, decreased prealbumin, elevated CRP, elevated tumor biomarker levels (CEA and CA19-9), tumor being located in pancreatic body and tail, larger tumor diameter (>4 cm), higher tumor stage (total AJCC stage, T stage, N stage, and M stage), the absence of surgical resection, the absence of systemic chemotherapy, the absence of concurrent chemoradiotherapy, the presence of interventional therapy, and the presence of biliary drainage (Table 3). Using Model 1, Cox multivariate analysis found that the following factors were independent factors for OS: gender (female vs male, HR 0.72, 95% CI [0.54–0.95]), elevated TBil (HR 1.82, 95% CI [1.34–2.47]), elevated CA19-9 (HR 1.72, 95% CI [1.17–2.54]), tumor being located in pancreatic body and tail (HR 1.52, 95% CI [1.10–2.10]), advanced T stage (T3-4 vs T1-2, HR 1.62, 95% CI [1.15–2.27]), lymph node metastasis (HR 1.57, 95% CI [1.20–2.07]), distant metastasis (HR 1.59, 95% CI [1.12–2.27]), the presence of surgical resection (HR 0.53, 95% CI [0.34–0.81]), and the presence of systemic chemotherapy (HR 0.62, 95% CI [0.45–0.82]). When we set the significant level at 0.1, age (≥65 vs <65 years, HR 1.28, 95% CI [0.97–1.69]) and diagnostic time (2014–2016 vs 2006–2013, HR 0.73, 95% CI [0.53–1.001]) were also independent prognostic factors (Table 4). When adjusted using Models 2 and 3, and the significant level was set at 0.1, tumor diameter (>4 vs ≤4 cm, HR 1.17, 95% CI [0.99–1.39]) and AJCC stage (III–IV vs I–II, HR 2.10, 95% CI [1.57–2.80]) were both independent prognostic factors (Table 4).

Comparison between long- and short-term survivors

We also compared probable prognostic factors between long-term (≥3 years) and short-term (<3 years) survivors with pancreatic cancer. Long-term survivors were more likely to be younger and not have hypertension or diabetes mellitus as comorbidities; they also tended to not show specific symptoms of pain and weight loss and had lower levels of liver function tests (TBil, IBil, ALP, and γ-GT) and of tumor markers (CEA, CA19-9, and CA242). These long-term survivors also tended to have lower tumor stage (total AJCC, T, N, and M stages). They were also more likely to receive more antitumor treatments including surgical resection, systemic chemotherapy, and concurrent chemoradiotherapy but were less likely to undergo biliary drainage (Table 5).

For treatment, more than half (51.5%) of the long-term survivors received surgical resection, and approximately 1/3 (35.1%) received systemic chemotherapy. We failed to detect a significant difference between the long- and short-term survivors regarding interventional therapy (P = 0.150).

Limitations and strengths

This study has several pertinent limitations. First, there may be confounding factors that could influence the results because of the retrospective design of the study. Second, this was a single-center study. Third, detailed data on chemotherapy specifics such as single vs multi drugs were not collected, and prognostic analyses of chemotherapy characteristics could not be performed. Fourth, prognostic analyses of subgroups were not performed. Some factors, such as interventional therapy, may be associated with better OS in specific patient subgroups, which we plan to address with future study series. Nonetheless, several notable strengths of this study included the analysis of a relatively large cohort (large diameter) and comprehensive analysis of a wide variety of factors that may have association with OS in pancreatic cancer, which should provide an important reference point for clinicians.