Abstract
Background/Aim: In this study we aimed to determine if advanced age represents a risk factor for negative perioperative and long-term outcome in patients undergoing curative surgery ductal pancreatic adenocarcinoma surgery. Patients and Methods: Two-hundred-twenty-one consecutive patients, twelve (6%) patients ≥80 years were included in the study. We assessed perioperative and long-term outcome and independent predictors for in-hospital mortality with Cox regression analysis. Results: Advanced age was not a predictor for in-hospital mortality (6.3% in non-octogenarian versus 8.3% in octogenarians; p=0.55) nor for morbidity (31% vs. 32%; p=0.69). An ASA score >II was the only predictor for in-hospital mortality (odds ratio (OR)=10.10, 95%CI=1.28-79.60; Hosmer-Lemeshow: p=0.86). No significant difference was observed in one- and five-year survival rates (68 and 58% vs. 16 and 14%; log-rank p=0.61). Conclusion: Advanced age is not a risk factor for negative outcome in curative pancreatic cancer surgery. Therefore, this single curative option should be considered in octogenarians at risk.
- Pancreatic ductal adenocarcinoma
- pancreatic resection
- perioperative risk
- octogenarians vs. non-octogenarians
- short-term outcome
- long-term outcome
Although significant improvements in chemotherapeutical regimens have been carried-out during the last years, complete surgical resection remains the only curative treatment for patients with non-metastasized pancreatic ductal adenocarcinoma (PDAC) (1). Due to ongoing changes in demographics with older patients and consecutively numerous comorbidities increasing the perioperative risk, the mean age of patients undergoing pancreatic resection for PDAC is increasing over the years. Despite being the only viable option for survival, there is still controversy, whether surgery benefits or harms octogenarians (2-19). The aim of this study was to determine if patients ≥80 years are at higher risk for unfavorable perioperative and long-term outcome.
Patients and Methods
General. We performed a single-center audit at a University surgical Unit from the year 2000 to 2013; the study cohort compromised of 221 consecutive patients [112 females; median age=67 years (interquartile range, IQR=60-72 years)] who underwent pancreatic resection for PDAC; twelve patients (6%) were older than eighty years. Perioperative risk factors were recorded prospectively in our Institutional database; the ASA (American Association of Anesthesiologist's) score was applied to estimate the perioperative risk (definitions are provided in Table I). In most cases, the initial diagnosis of a pancreatic mass was carried out via multi-detector row computed tomography (MDCT). All patients scheduled for pancreatic resection underwent a standardized preoperative screening program including detailed physical examination, analysis of tumor markers CEA, CA19-9 and liver function tests; preoperative oncological staging comprised of PET (positron emission tomography) scan, ERCP (endoscopic retrograde cholangio-pancreaticography) and/or MRCP (magnetic resonance cholangio-pancreaticography) and esophagogastroduodenoscopy; if not performed at initial diagnosis, a preoperative MDCT scan was conducted in all patients. All patients eligible for surgery were admitted to the Institutional tumor board including surgeons, oncologists, histopathologists and radiologists. The Institutional review board approved of the study and waived the need for patient consent.
Surgical technique. Depending on the primary tumor localization, either a standard- or pylorus-preserving pancreatico-duodenectomy, distal pancreatectomy with splenectomy or total pancreatectomy was performed. The bilio-digestive anastomoses were connected with a 5-0 double-layer single suture; the pancreatico-jejunostomy and the hepaticojejunostomy were protected routinely by means of drainage placement in the biliodigestive anastomoses; in case of involvement of porto-mesenteric venous branches, the affected vein segment was resected, and the portal axis was reconstructed or with direct anastomoses, with patch reconstruction or interposition of a vascular tube graft, depending on the degree of involvement of the venous wall. Before closure of the abdominal wall, all patients received intra-abdominal drainage. Intravenous octreotide was applied in all patients and continued for five days postoperatively.
Follow-up. Postoperative morbidity was classified according to Clavien and Dindo (CDC) (20) classification. All patients routinely underwent a drainage cholangiography to exclude anastomotic leakage before discharge. Clinical, laboratory and radiological follow-up was carried out routinely at 3, 6 and 12 months postoperatively. Long-term mortality data were obtained from the Austrian National Cancer registry (21).
Statistical analysis. All statistical analyses were performed with SPSS 22.0 for Windows (IBM Inc., Somers, NY, USA). Continuous variables were reported as median and interquartile range; categorical data were reported as count and percentages; if not otherwise indicated. Categorical variables were compared with Fisher's exact or the Chi-square test, where appropriate; numeric variables were compared with the Wilcoxon test. A two-sided p-value <0.05 was considered statistically significant. A logistic regression model was used to assess the strongest independent predictor for in-hospital mortality. Results of the regression model are given as the odds ratio (OR) and 95% confidence interval (CI), the calibration of the regression model was assessed via the Hosmer-Lemeshow test. Overall survival was calculated according to the method of Kaplan and Meier. A Cox regression model was used for analysis to identify independent predictors for mortality during follow-up. Both logistic and Cox regression model were confirmed via boot-strap analysis with 1,000 replications.
Results
Between the year 2000 to 2013, 221 consecutive patients (112 females; median age=67 years, IQR=60-72 years) were subjected to pancreatic resection for PDAC at our Institution, with 12 patients (6%) aged 80 years or older. In 47 (21%) patients, resection of porto-mesenteric branches and subsequent vascular reconstructions had to be performed due to radiological and/or intraoperative tumor affection of porto-mesenteric branches.
Detailed demographics of the overall cohort are shown in Table II; cohort comparisons are given in Table III. Baseline and perioperative characteristics did not significantly differ between the cohorts, as an exception, in the non-octogenarian cohort, a pylorus-preserving pancreaticoduodenectomy was performed more frequently (31% vs. 8%; p<0.001).
Postoperative complication rates according to CDC were 31% vs. 34% (p=0.69), and 14 patients (13 vs. 1; p=0.77) died in-hospital. An ASA-Score >2 was the only independent predictor for in-hospital mortality in logistic regression analysis (OR=10.10, 95%CI=1.28-79.60; H/L=0.86, p=0.028), age ≥80 years was not a predictor for in-hospital mortality (OR=1.91, 95%CI=0.20-17.97, p=0.57). The strong influence of an ASA score >2 on in-hospital mortality could be confirmed in bootstrap-analysis (p=0.014) (Table IV).
Follow-up was completed in 99.5%, and comprised of 4,393 patients-months of follow-up; one patient was lost to follow-up because he moved abroad: one-; two- and five-year overall survival were 68% vs. 58%; 42% vs. 29% and 16% vs. 14% for non-octogenarians vs. octogenarians (log-rank: p=0.61) (Figure 1). Median overall survival was 20 months for non-octogenarians vs. 15 months for octogenarians.
For survival during follow-up, lymphovascular invasion (OR=1.79, 95%CI=1.26-2.56) was the only independent predictor but not an age ≥80 years (OR=1.21, 95%CI=0.55-2.68) (Table V).
Discussion
Due to changes in patient's demographics, patients scheduled for curative pancreatic resection in the diagnosis of PDAC become older and older at initial presentation (4, 22-24). Despite being the only viable option for survival, there is still controversy, whether surgery benefits or harms octogenarians (2-19). We aimed to determine if advanced age represents a risk factor for perioperative and long-term morbidity and mortality. As to our single-center long-term university results, an age of eighty years or older alone does not represent a risk factor for negative outcome in patients undergoing curative pancreatic resection for PDAC as preoperative health conditions are prevailing.
However, as in nowadays practice, doctors and surgeons can be too quick to decide against offering surgery because of “outdated assumptions of age and fitness”; some years ago, most patients aged 80 years or older were not even referred and thus not eligible for curative surgery for PDAC. Changing demographics and healthcare guidelines has led to an increasing number of octogenarians presenting to the surgeon (22-24). At this moment, no strong evidence is available if advanced age alone is associated with elevated perioperative morbidity and mortality or not (2-19, 24, 25). Doctors and surgeons should, therefore, stop using chronological age to assess suitability for a procedure and instead use their “biological age”, or overall health, because growing life expectancy and the increasingly good health of senior citizens make birth date alone redundant as the only deciding factor.
Our results foster this changing general opinion, that advanced age has no impact upon immediate survival; only an ASA score >2 was the only independent predictor for in-hospital mortality in logistic regression analysis (OR=10.66, 95%CI=1.24-91.30; H/L=0.73, c-statistics: p=0.79), as confirmed via bootstrap modeling. It is our opinion, that this well-established and validated anesthesiologic score gives an excellent picture of patient's preoperative general health conditions not only predicting the anesthesiologic risk alone but also the perioperative risk for pancreatic resections (26, 27). We are aware that more sophisticated and more precise classification systems such as the Charlson comorbidity index (28) as well as frailty indexes (29) have been introduced; however compared to those, the ASA scoring system allows bed-side computation, thus real-life application is feasible.
Despite growing evidence in literature showing that curative surgery for pancreas adenocarcinoma can be offered safely even to octogenarians (2, 5, 8-16, 18), total evidence is fair as clinical studies are limited to small case series (2-5, 7-18); recent evidence according to a recent systematic review by Beltrame et al. comprises of a total of 15 studies, reporting results of a total of 3,693 patients at risk (Table VI): pooled perioperative mortality rate is given median at 14%, ranging from 0% to 15.5% (18). This heterogeneity of results can be explained by the retrospective and single center of most studies, reflecting also different ways of patient's selection for curative surgery for PDAC. Our results are, therefore, comparable to others even our sample size is limited by our single-center design and the limited patient number because only few patients with the diagnosis of PDAC at an age of 80 years or older present with potentially resectable disease and/or fit enough to be eligible for potential curative pancreatic surgery. Another recent multicenter series from the Netherlands reported a postoperative mortality that decreased over the eight years of study duration from 10% to 5%, with the best outcome for elderly patients aged >75 years in high-volume centers (that is defined >28 resections/year); they also reported an increasing rate of elderly patients from 15 -20 % (24).
Perioperative morbidity according to Clavien and Dindo (CDC) has been reported in recent literature from 27% to 68% (4-5, 8-16, 18), thus some authors propose to limit the extent of surgical procedures in the elderly (6, 7).
Hepatobiliary surgeons undergo a dedicated training program for pancreatic surgery, focusing in vascular surgical techniques that are needed for portal vein resections. This particular fact might explain our acceptable postoperative complication rates according to CDC-criteria of 31% vs. 33% in the non-octogenarian versus octogenarian group.
As a direct consequence of our radical approach, no difference in long-term outcome between octogenarians and non-octogenarians could be observed in our series with acceptable and comparable one- and five-year overall survival rates that is in line with most published reports (2-5, 8, 14-18, 24). In our cohort, we were able to demonstrate that lympho-vascular invasion, representing a surrogate for the aggressive tumorous behavior, was the only independent predictor for mortality during follow-up, thus further supporting a more radical surgical approach even in the elderly. Recent surveys also reported lower long-term survival for octogenarians who underwent pancreatic resection for PDAC because of less frequent use of (neo)adujuvant chemotherapy (25, 30). In our series, we did not assess the effect of chemotherapy separately.
Limitations of the Study
Some limitations of the present study have to be acknowledged: due to the retrospective nature of the study design, it comprises of all potential drawbacks and confounders; we tried to limit confounding and limitations given by the very small sample size via advanced regression techniques as boot-strap analysis which clearly confirmed our findings. The percentage of patients aged over 80 years in our series was comparable to large multi-center surveys (4.7% in the series from van der Geest and coworkers (31) vs. 5.4% in the present series). In the distribution of demographic, pre-, intra- and postoperative data did not differ significantly between the two sub-groups in our dataset; in contrast to other clinical studies (3-8, 18), we did not include patients with other pancreatic pathologies than PDAC to gain a nearly perfect, homogenous study population. Residual confounding by patient-management at the operating theater and intensive care unit, however, may be still present. Such confounders are impossible to control in an observational retrospective study design. But considering overall death, our main end-point, this bias appears to be negligible as patient-related data were retrieved from a validated nationwide Austrian Cancer Database.
Conclusion
The perioperative and long-term outcome in octogenarians undergoing curative surgery for PDAC is not influenced by age, but by comorbidities. Thus, this single curative option should be considered in octogenarians at-risk.
- Received January 29, 2016.
- Revision received March 9, 2016.
- Accepted March 2, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved