Abstract
Background: We investigated the impact of the surgical Apgar score (SAS) on survival in patients with pancreatic cancer and recurrence after curative surgery followed by adjuvant chemotherapy. Patients and Methods: This study included 103 patients who underwent curative surgery for pancreatic cancer between 2005 and 2014. Patients with a SAS of 0-4 were classified into the low SAS group, while those with a SAS of 5-10 were classified into the high SAS group. The risk factors for overall (OS) and recurrence-free (RFS) survival were identified. Results: The OS rates at 3 and 5 years after surgery were 23.0% and 14.4%, respectively, in the low-SAS group and 32.3% and 21.4%, respectively, in the high-SAS group, which was a statistically significant difference (p=0.039). The RFS rates at 3 and 5 years after surgery were 13.1% and 13.1%, respectively, in the low-SAS group and 21.4% and 19.2%, respectively, in the high-SAS group, which was a marginally significant difference (p=0.100). Multivariate analysis demonstrated that the SAS was a significant independent risk factor for OS and a marginally significant risk factor for RFS. Conclusion: The SAS was a risk factor for OS in patients who underwent curative surgery followed by adjuvant chemotherapy for pancreatic cancer. The surgical procedure, perioperative care and surgical strategy should be carefully planned to improve survival.
Pancreatic cancer, which has a 5-year survival rate of less than 5%, is a major cause of cancer-related death worldwide (1, 2). Complete resection is essential for obtaining a cure in patients with pancreatic cancer. However, such patients suffer recurrence, even after complete curative resection followed by adjuvant chemotherapy. It is, therefore, important to identify the prognostic factors for pancreatic cancer in order to select candidates for more aggressive treatment. Various clinicopathological factors, including tumor size, lymph node metastasis, preoperative performance status, and preoperative nutritional status, have been reported to be significant prognostic factors that could be used to predict survival in patients with pancreatic cancer (3-7). However, these reports only analyzed the preoperative or postoperative elements and did not include the perioperative elements.
Recently, the quality of surgery and anesthesia, and the patient's condition before and during surgery have been shown to affect the systemic inflammatory response (SIR) during and after surgery (8). Moreover, the presence of an ongoing SIR has been recognized in oncological patients to be associated with a poor prognosis, and it has been suggested that markers of SIR may serve as valuable prognostic or predictive biomarkers in these patients (9, 10). Thus, the perioperative elements might affect the outcome in patients with pancreatic cancer.
The surgical Apgar score (SAS) was first proposed by Gawande et al. in 2007 (11). This surgical score reflects intraoperative hemodynamic stability, and is influenced by various factors, such as the quality of surgery and anesthesia, and the patient's condition before and during surgery. Similarly to the widely used obstetrical Apgar score that was developed by Virginia Apgar in 1953, the SAS was intended to be used to predict patient outcomes immediately after surgery. Thus, the SAS might have some clinical impact on the outcome of patients with pancreatic cancer.
Evaluation for the original surgical Apgar score.
In the present study, we investigated whether overall (OS) and recurrence-free (RFS) survival were affected by the SAS of patients with pancreatic cancer patients who underwent pancreatoduodenectomy followed by adjuvant chemotherapy.
Patients and Methods
Patients. The study participants were selected from the medical records of consecutive patients who underwent surgery for pancreatic cancer at the Kanagawa Cancer Center from 2005 to 2014. The inclusion criteria were as follows: (i) patients with a common pathological type of pancreatic cancer [according to the International Union Against Cancer (UICC) TNM seventh edition] (12); (ii) patients in whom curative resection was successful as the initial treatment for pancreatic cancer and who received gemcitabine or S-1 adjuvant chemotherapy; and (iii) the absence of synchronous or metachronous malignancies. The resected specimens were examined histopathologically and were staged according to the UICC TNM seventh edition. Patients with other pancreatic and periampullary neoplasms, such as intraductal papillary mucinous neoplasms, cystadenocarcinoma and endocrine tumors, were excluded from the present study.
Surgical procedure. All of the operations were performed by four surgeons from the Pancreatic Unit. All pancreatic surgeries were performed in accordance with standardized procedures that have been described elsewhere (13-16). Briefly, in cases of pancreaticoduodenectomy, we performed subtotal stomach-preserving pancreaticoduodenectomy as the standard procedure. The lymph node groups that were resected en bloc included the anterior pancreatic duodenal lymph nodes, the posterior pancreatic duodenal lymph nodes, nodes in the lower hepatoduodenal ligament, and nodes along the right lateral aspect of the superior mesenteric artery and vein. In our institution, we cut the pancreas using an energy device. Our method of reconstruction is a modification of Child's method that includes end-to-side pancreaticojejunostomy and end-to-side hepaticojejunostomy. In end-to-side pancreaticojejunostomy, duct-to-mucosa anastomosis is performed with a 5-F lost stent tube with eight 5-0 absorbable monofilament sutures. The pancreatic stump and jejunal wall are approximated with four 3-0 absorbable monofilament interrupted sutures (17, 18). End-to-side hepaticojejunostomy is performed without a stent. The jejunum and stomach are anastomosed with retro-colic reconstruction. Multiple intraperitoneal drains are placed: the first is placed posterior to the hepaticojejunostomy; the second is placed on the anterior surface of the pancreaticojejunostomy. To prevent hypothermia, a blanket warming system and a warming set for intravenous infusions are used.
Perioperative care. In principle, the patients received the same perioperative care. In brief, the patients were allowed to eat until midnight on the day before surgery and were required to drink the contents of two 500-ml plastic bottles containing oral rehydration solution until 3 h before surgery. The nasogastric tube was removed on postoperative day (POD) 1. Oral intake, beginning with water and an oral nutritional supplement, was initiated on POD 2. The patients began to eat rice gruel and soft food on POD 3, then solid food on POD 5 and advanced in three steps to regular food intake on POD 10. The patients were discharged when adequate pain relief and soft food intake were achieved, after they returned to their preoperative mobility level and exhibited normal laboratory data.
Adjuvant chemotherapy. Treatment with gemcitabine was initiated within 8 weeks after surgery. The patients received a weekly dose of 1,000 mg/m2 for 3 weeks, followed by one week of rest. S-1 chemotherapy was started within 10 weeks after surgery (18). The patients received 40 mg/m2 of S-1 twice a day for 4 weeks, followed by 2 weeks of rest as one course (6-week schedule) or 2 weeks followed by 1 week of rest as one course (3-week schedule) (19). All of the patients in the present study received either gemcitabine or S-1 treatment for 6 months.
Definition of postoperative complications. The grade 2-5 postoperative complications [according to the Clavien-Dindo classification (20)] that occurred during hospitalization and within 30 days after surgery were retrospectively determined from the patient's records. Grade 1 complications were not evaluated to exclude the possibility of a description bias in the patient's records.
Follow-up. Patients were followed-up at outpatient clinics. Hematological tests and physical examinations were performed at least every 3 months for 5 years. For the patients who received adjuvant chemotherapy, hematological tests and physical examinations were performed at least every 2 weeks during adjuvant chemotherapy, and at least every 3 months for 5 years after the patients finished adjuvant chemotherapy. Carcinoembryonic antigen and carbohydrate antigen 19-9 levels were checked at least every 3 months for 5 years. Patients underwent a computed tomographic examination every 3 months during the first 3 years after surgery, and then every 6 months until 5 years after surgery.
The overall survival curves of the groups with low and high surgical Apgar score (SAS).
Evaluations and statistical analyses. The parameters evaluated in this study included the estimated blood loss the lowest intraoperative mean arterial pressure and the lowest intraoperative heart rate. The SAS was calculated using these three parameters (Table I) (11).The significance of correlations between the SAS and clinicopathological parameters was determined using Fisher's exact test or the χ2 test. OS was defined as the period between surgery and death. RFS was defined as the period between surgery and recurrence or death, whichever came first. The data of the patients who did not experience an event were censored on the date of the final observation. OS and RFS were evaluated by univariate and multivariate analyses. OS and RES curves were calculated using the Kaplan–Meier method, and were compared by the log-rank test. A Cox proportional hazards model was used to perform the univariate and multivariate survival analyses. In order to select a model, we used backward elimination. p-Values of less than 0.05 were considered to indicate statistical significance. The survival data were obtained from hospital records or from the city registry system. The SPSS software program (v11.0 J Win; SPSS, Chicago, IL, USA) was used for all of the statistical analyses. This study was approved by the Kanagawa Cancer Center (IRB number 32-4).
Results
Patients. We evaluated 103 patients in the present study. The patients' ages ranged from 40-81 years (median=66 years); 56 patients were male, and 47 were female. The median follow-up period was 62.6 months (range=23.9-129.8 months). Forty-one patients had a SAS of 0-4 points (low SAS group); 62 patients had a SAS of 5-10 points (high SAS group). Sixty-nine patients received gemcitabine adjuvant chemotherapy and 34 patients received S-1 adjuvant chemotherapy. The median duration of adjuvant gemcitabine administration was 4.6 months (range=0.2-7.2 months). The median duration of adjuvant S-1 administration was 5.3 months (range=0.7-6.8 months).
The recurrence-free survival curves of the groups with low and high surgical Apgar score (SAS).
Survival analysis. The OS rates at 3 and 5 years after surgery were 23.0% and 14.4%, respectively, in the low-SAS group and were 32.3% and 21.4%, respectively, in the high-SAS group. The difference was statistically significant (p=0.039). The OS curves are shown in Figure 1. The univariate analyses for OS demonstrated that the SAS was a significant prognostic factor and that lymph node metastasis was also marginally significant (Table II). The SAS was selected for the final multivariate analysis model.
The RFS rates at 3 and 5 years after surgery were 13.1% and 13.1%, respectively, in the low SAS group and were 21.4% and 19.2%, respectively, in the high SAS group. This was a marginally significant difference (p=0.100). The RFS curves are shown in Figure 2. The univariate and multivariate analyses demonstrated that lymph node metastasis and age were significant independent risk factors that were associated with RFS. Moreover, marginally significant associations were found between gender and RFS and the SAS and RFS (Table III).
Table IV summarizes the demographic and clinical characteristics of patients in the low- and high-SAS groups. There were significant differences in the body mass index (BMI) values and the incidence of postoperative infectious complications in the two groups. In the low-SAS group, the BMI value and the incidence of postoperative infectious complications were higher than in the high-SAS group.
Univariate and multivariate Cox proportional hazards analyses of the clinicopathological factors associated with overall survival.
Univariate and multivariate Cox proportional hazards analyses of the clinicopathological factors associated with recurrence-free survival.
Discussion
The present study examined whether the SAS was associated with poorer OS and RFS in patients with pancreatic cancer who underwent curative surgery followed by adjuvant chemotherapy. Our findings clearly indicate that a low SAS was an independent risk factor for poorer OS. Moreover, a marginally significant association was found between the SAS and the RFS.
There are several possible reasons why the SAS affected the long-term outcomes of patients with pancreatic cancer. One possible reason for this association is that the SAS might be associated with postoperative surgical complications. In fact, the incidence of postoperative infectious complications was higher in the low-SAS group than in the high-SAS group. Recent studies have demonstrated that the development of postoperative complications reduces survival or increases the risk of disease recurrence in various types of malignancies (21-26). We previously investigated the impact of postoperative complications on survival and recurrence after curative surgery for pancreatic cancer (27). This study included 164 patients who underwent curative surgery for pancreatic cancer between 2005 and 2014. The patients with postoperative complications were classified into the C group, while those without postoperative complications were classified into the NC group. The RFS rates at 5 years after surgery in the C and NC groups were 10.6% and 21.0%, respectively. RFS tended to be worse in the C group than in the NC group (p=0.1756). The OS rates at 5 years after surgery in the C and NC groups were 7.4% and 22.8%, respectively, which was statistically significant (p=0.0189). The multivariate analysis demonstrated that postoperative complications were a significant independent risk factor for poorer OS and a marginally significant risk factor for RFS. In addition, Kamphues et al. evaluated 428 patients who underwent resection for cancer of the pancreatic head, and reported a correlation between postoperative complications and poorer survival (28). Another possible reason for this association is that patients who were in the low-SAS group might have had some factors that led to decreased immunity against their tumors. For example, Goldfarb et al. reported that treatment aimed at the perioperative enhancement of cell-mediated immunity with the simultaneous inhibition of excessive catecholamine and prostaglandin responses was successful in limiting postoperative immune suppression and metastatic progression (29). In addition, Dunn et al. suggested that the adaptive immune system could function by identifying and eliminating nascent tumor cells in experimental models (30).
Several scoring models have been reported to be useful in predicting the quality of surgery and anesthesia, and the patient's condition before and during surgery. However, the previously reported scoring models, which include the Physiologic and Operative Severity Score for the Enumeration of Mortality (POSSUM), the National Surgical Quality Improvement Program (NSQIP) and the Estimation of Physiologic Ability and Surgical Stress (E-PASS), require complex calculations using numerous perioperative variables that are not available at the bedside (31-34).
Clinicopathological factors of the high and low surgical Apgar score groups.
The present study is associated with several potential limitations, thus, care should be taken in interpreting its results. Firstly, this study was retrospective in nature, was performed at a single center and had a relatively small sample size. The SAS was calculated from the patients' records. Our findings might therefore have been obtained by chance. Moreover, there might have been a selection bias. Secondly, the degree of immune suppression was not assessed in this study. Previous studies have demonstrated that the prognosis of patients with pancreatic adenocarcinoma is influenced by their general status, their nutritional status, and their immune status (31, 32). However, we were not able to evaluate these factors. Future studies should therefore be performed that focus on this issue. Considering these limitations, the current results should be validated in another series with a larger number of patients.
In conclusion, the SAS was found to be a risk factor for OS and disease recurrence in patients who underwent curative surgery for pancreatic cancer. To improve the survival of patients with pancreatic cancer, it is necessary to carefully plan surgical procedures, perioperative care and select the optimal surgical strategy.
Acknowledgements
This work was supported, in part, by the Uehara Memorial foundation and the Takeda Science Foundation.
Footnotes
↵* These Authors contributed equally to this study.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received February 29, 2016.
- Revision received April 7, 2016.
- Accepted April 11, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
