The Benefit of Advanced Age on Survival in Patients Undergoing Laparoscopic Pancreaticodoudenectomy, A Multi-Center, Comparative study-Cohort Study


 Background: Management of malignant diseases in elderly patients has become a global clinical issue because of the increased life expectancy worldwide. The advancements in surgical techniques and perioperative management have reduced age-related contraindications for LPD. Past papers have reported that elderly patients undergoing laproscopic pancreatoduodenectomy (LPD) are at an increased risk compared to non-elderly patients. The aim of this paper is to compare a single centre risk of LPD in elderly and non-elderly patients.Methods: Retrospective review (n = 237) of perisurgical outcomes in patients undergoing LPD during the months of September 2012–December 2017. Outcomes in elderly patients (aged ≥75 years) were compared with those in non-elderly patients.Results: In elderly patients, transfer to ICU was more frequent (odds ratio [OR] 6.49, P = 0.001) and mean hospital stay was lengthier (21.4 days compared with 16.6 days, （P = 0.0033) than for non-elderly patients. There was no statistically significant difference in operation time (P=0.494), estimated blood loss (P=0.0519), blood transfusion (P=0.863), decreased gastric emptying (DGE) (P=0.397), abdominal pain (P=0.454), food intake (P=0.241), time to self ambulation (P=1), reoperation (P=0.543), postoperative pancreatic fistula (POPF) grade A (P=0.454), POPF grade B (P=0.736), POPF grade C (P=0.164), hemorrhage (P=0.319), bile leakage (P=0.428), infection (P=0.259), GI bleeding (P=0.286), morbidity (P=0.272) or mortality (P=0.449) between the two groups.Conclusions: Elderly patients who underwent LPD in this study had significantly good overall survival after LPD and similar to young patients . The perioperative and long term outcomes of LPD are not worse .The Both rate of ICU admission and hospital stay increased in elderly patients undergoing LPD when compared with non-elderly ones. LPD can be performed on elderly patients with similar outcomes as younger patients; therefore Age it self should not be a contraindication to LPD for pancreatic cancer, but it suggests that elderly patients with comorbidities should be more stringently selected for surgery.

Introduction the increased life expectancy in many countries. (26)(27)Laparoscopic pancreatoduodenectomy (LPD) was introduced in 1994( 24) In recent years, this approach has been shown to be safe and feasible when performed by experienced surgeons in high volume centers. (25)Laparoscopic surgery is now a widely utilized technique for the treatment of a variety of both benign and malignant diseases, because it is associated with a lower degree of invasion, less pain and shortened postoperative hospital stay than open surgery. Laparoscopic surgery bestows several advantages when compared to open surgery in elderly patients undergoing pancreatoduodenectomy (PD) 1,2,3,4 .In addition,the two have similar oncological results 1,4,5 . Laparoscopic surgery has, in a number of studies, been shown to result in less postoperative pain, fewer wound complications, shorter hospital stays, decreased pancreatic fistula rates and decreased surgical morbidity and mortality 1,6,7,8 . However, those selected for laparoscopic PD are predominantly otherwise healthy patients under the age of 75, with good performance status; thus, the extrapolation of results from such trials to daily practice necessitates careful consideration. Longer operation times and higher incidences of organ injury 9,10,11,12 , are of particular concern when considering LPD surgery for elderly patients 13 . One retrospective analysis of Robot-assisted PDs concluded that the procedure can be performed safely in elderly patients with mortality, morbidity, and outcomes comparable to those in younger patients 14 . Sperti et al. showed that outcomes after pancreatectomy were not markedly different in octogenarians than in younger patients 15 and Maehara et al. found no statistically significant difference in the mortality rate or overall morbidity rate in patients undergoing PD for periampullary tumors above and below the age of 75 16 .
In our department centre, 237 patients underwent LPD in a relatively short period 5 years to be exact. Patients aged 75 years and above comprised nearly 26 percent of the analysis, which is comparable to the age distribution of the world's population and the increasing age at which pancreatic cancer is now being diagnosed. Following this, a retrospective review (n = 237) of perisurgical outcomes for elderly (aged ≥75 years) and non-elderly LPD patients was carried out.
Our centre favours a laparoscopic approach for pancreatic cancer resection, regardless of patient age.
However, a huge body mass is a contraindication for the procedure. Consequently, approximately 80% of our pancreatic cancer patients underwent laparoscopic surgery, minimizing surgical approach selection bias in this study Aim: This study aimed to evaluate the safety of LPD for elderly patients with pancreatic disease by retrospectively analyzing the medical records of elderly patients aged ≥75 years that underwent surgery between September 2012 and December 2016 in our centre

Patients Selection
We analyzed data for 237 consecutive patients who underwent LPD in two centres between September 2012 to December 2017. Zhejiang University Sir Run Run Shaw Hospital and Zhejiang Provincial People's Hospital, of which 61 were elderly (aged≥75 years). The collected data were retrieved from prospectively maintained databases and included baseline patients characteristics.
Results of pathological examinations were used as an indicator of preoperative factors, based on the assumption that preoperative findings would correlate with postoperative staging. This study was approved by the Institutional Review of Zhejiang Provincial People's Hospital and Zhejiang University.
The patients were prospectively followed up at institution . Most of the patients were traditionally observed according to a protocol similar to the Chinese guidelines, (28)(29).The commonly used imaging modalities in suspected pancreatic carcinoma include ultrasonography, Novel imaging modalities including MRI (13.9%), PET/CT (1.8%), and EUS (5.6%) were not widely used in our population. Only 39.7% of cases were histologically verifified (surgery with histologic diagnosis 31.0%, cytological diagnosis 8.7%, surgery without histologic diagnosis 12.1%, and clinical diagnosis 48.2%).
Overall, 30.0% of patients underwent curative-intent operation, and only 9.8% of patients received comprehensive treatment.The prognosis of all registered patients was followed until confirmation of death. All these data were collected and registered with the approval of each institution.

Surgical procedure
rest being carried out by surgeons with sufficient experience of laparoscopic pancreatic surgery under supervision. Our surgical procedures called ( Wu Kong Zi ) have been previously described 17 . The procedures for patients with resectable PD, wereperformed using general anesthesia with the patient in the supine position and legs apart. "Five Trocars'' 17 , were used for the procedure. The trocars were placed as follows; one initial 10mm trocar was placed below the umbilicus for laparoscopy. The other four trocars, one 12mm in diameter and three 5mm in diameter, were inserted into the left upper flank, left flank, right upper flank and right flank quadrants, respectively. The five trocars were arranged in a V formation. However, for patients who had SMV encasement which made creating the retro-pancreatic tunnel difficult (borderline resectable pancreatic cancer), we used the "Easy First" strategy to perform LPD 18 . The definition of mesopancreas used was; the soft connective tissue along the celiac axis, superior mesenteric vessels and the uncinate process of pancreas, especially the lymphatic and nervous structures of retroperitoneal margin, as has been previously reported 19 .After the specimens were removed from the enlarged umbilical port, a frozen section was sent off to confirm the negative margins. Child's reconstruction was then performed in a complete laparoscopic manner following individual construction. Laparoscopic pancreaticojejunostomy (LPJ) was performed using the duct-to-mucosa method. If the diameter of MPD was between 2 and 5 mm, LPJ was carried out using interrupted sutures of 4-6 stitches with stents of the proper diameter. As for MPDs larger than 5 mm, running sutures were uesed without stents, and non-absorbable sutures were used instead of absorbable sutures. Laparoscopic choledochojejunostomy was performed with running sutures if the CBD was larger than 8 mm or with interrupted sutures if CBDs were less than 8 mm. As for the laparoscopic gastrojejunostomy, we used an endoscopic linear stapler to perform a side-toside anastomosis with running sutures to close the opening

Definition of the Difficulty
Difficulty of LPD in both groups was categorized into 2 steps.Resections, and Reconstruction.
Surgeons who frequently perform LPD may handle reconstruction difficulty surgical cases. More experienced surgeons who regularly perform reconstruction difficulty LPD can perform high-difficulty LPD cases. The operative time, total intraoperative blood loss, and Re-operation rate were evaluated to address surgical difficulty with a certain degree of objectivity, because surgical difficulty can be reflected in a combination of these intraoperative factors.

Statistical analysis
A comparison of baseline and post treatment levels of each variable was carried out to identify statistically significant differences between elderly and non-elderly patients. Continuous data was expressed as mean (SD) or mean (SEM) or median (interquartile range, IQR), and the means were compared using two independent samples of Student's t test. Categorical data was compared using the Chi-squared test or Fisher's exact probability test. The Mann-Whitney U test was used for abnormally distributed variables. Statistical significance was defined at the level of 0.05. All analyses were performed using statistical software SPSS 19.0 (SPSS Inc, Chicago, IL, USA).

Histopathological analysis
Operative details are shown in Table .Tumour size of >5cm and the rate of R0 resection were similar in the two groups 98.7 % vs 98.8 % ( Table 1). The mean number of lymph nodes removed was similar in the two groups, lymph nodes retrieved in the LPD Non-elderly group and LPD elderly groups were (21.3±10.9 vs 20.3±11.9) respectively (P =1). Median pancreatic duct diameter was >5mm (P =1).The histoPath outcomes can be seen in. performed we can seen it in Figure 1.  Table 1. ASA, American Society of Anesthesiologists; BMI, body mass index;SD, standard deviation;

Operative Outcomes
Operative details are shown in both Table 1 and Table 3 and Table 4.The definition of mortality we used in this paper was either death before being discharged from the hospital or within 30 days of surgery. Surgical morbidity was also measured for 30 days after the operation and was based on    postoperative mortality rates compared with younger patients 23 . In addition elderly patients (when defined as aged >80 years) were found to have an increased risk for postoperative complications compared with non-elderly patients 23 . Elderly patients (aged >75 years) were also found to have increased risk for pulmonary complications compared with non-elderly patients 23 . One possible reason for this disparity could be the higher age of elderly patient definition used in the aforementioned papers. However, another retrospective review, which defined elderly as over 70, found elderly pancreatoduodenectomy patients (n = 860) were more likely to experience postoperative cardiorespiratory complications 1 . This difference could be due to our study cohort being of insufficient size, and hence underpowered, to reveal statistically significant differences for such rare events. Total mortality, for example, in our study was just 0.84%. It is possible that this very low mortality rate may also reflect an increase in skill of laproscopic surgeons in recent years. Our study demonstrated an increased risk of ICU admission and an increased length of hospital stay for elderly patients. However, this could be due to the fact that admission to ICU and hospital discharge decisions are made partly in accordance withthe patient's age, which would make it a confounding factor. Our study supported Buchs et al comparison of elderly patients (defined as those aged >70 years) and non-elderly patients undergoing robotic PD in that it identified no statistically significant differences in operative time, blood loss, postoperative mortality or overall morbidity between the two groups 14 . Limitations of our study and previous ones executed in a similar manner are their retrospective nature, which makes them susceptible to selection bias.

Conclusion
In our conclusion, we report here our experience over 5years with 237 cases included ur experience during the last 461 cases over than 75 years laparoscopic resections. And this is an extremely challenging task to perform such complicated procedures like laparoscopic pancreatoduodenectomy whether young or older patients safely and without compromising outcomes, but our paper suggests that neither morbidity nor mortality increased in elderly LPD patients when compared to non-elderly patients. Elderly LPD patients experienced a higher admittance rate to ICU and a longer hospital stay post operation. No statistically significant differences were found in any other complications assessed in this study.Therefore Age it self should not be a contraindication to LPD for pancreatic cancer, but it suggests that elderly patients with comorbidities should be more stringently selected for surgery. This study was approved by the Ethics Committee of Zhejiang Provincial Peoples Hospital and Zhejiang University. Written consent was obtained from every patient prior to surgery.

Consent for publication
Not applicable

Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available due to data privacy according to the license for the current study, but are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests

Funding
This research was supported by Scientific and Technological Project of Zhejiang Province (Grant No. 2015C03049). The funders had no role in study design, data collection and analysis, interpretation of data and preparation of the manuscript.

Authors' contributions
MH,YPM wrote the manuscript, YPM,XWX,RCZ,YCZ performed the operations, CL,CK,BZ reviewed the medical records and collected data,all authors read and approved the final manuscript.