Therapeutic Delay and Survival after Surgery for Cancer of the Pancreatic Head with or without Preoperative Biliary Drainage Eshuis, van der Gaag, Rauws et al November 2010 Annals of Surgery;252(5): Journal Club 15 th November 2010

Background Periampullary/pancreatic head tumours often present with obstructive jaundice In the absence of radiological signs of unresectable disease surgical exploration is the treatment of choice

Background Preoperative biliary drainage (PBD) ▫ Often performed due to a perceived risk of increased postoperative complications in jaundiced patients A recent trial by these authors 1 concluded ▫ Patients undergoing PBD had more overall treatment complications than patients who had surgery without PBD 1. NEJM, 2010; 32(2):

Background PBD may still be warranted in: ▫ Severe jaundice ▫ Cholangitis ▫ Neoadjuvant chemoradiotherapy (in the future) ▫ Cases where early surgery is not possible for logistic reasons ▫ Cases to be transferred to a high volume centre for surgery

Objective of Study To investigate the effect ▫ On survival ▫ Of the therapeutic delay ▫ Of PBD followed by surgery versus surgery alone ▫ In patients with pancreatic head malignancy

Methods A randomised controlled multicentre trial ▫ 5 university medical centres & 8 teaching hospitals Inclusion criteria: ▫ Age ▫ Serum total bilirubin umol/L ▫ No evidence of unresectable disease on CT Exclusion criteria: (NEJM;32(2): ) ▫ Ongoing cholangitis ▫ Pre-existing biliary stenting ▫ Severe gastric outlet obstruction ▫ A contraindication to major surgery

Methods Within 4 days of CT patients were randomised to ▫ PBD for a period of 4-6 weeks or ▫ Surgery within 1 week (early surgery) ▫ Stratified according to study centre ▫ Randomisation performed by a computer program at the coordinating trial centre (NEJM;36(2): ) PBD: ERCP & placement of a plastic stent ▫ Rescue percutaneous transhepatic cholangiography in 2 cases

Methods Surgery : Pylorus preserving pancreatoduodenectomy with removal of lymph nodes at right side of portal vein With tumour ingrowth into the pylorus or duodenum a classic Whipple’s was performed In cases of metastasis or local tumour ingrowth biopsies were taken for histology Data was collected on all patients with histologically proven malignancy

Methods Regular follow up data was collected until 12 weeks post randomisation Additional survival data was collected through contacting physicians, hospitals where patients died or registry databases The main endpoint of the study was overall survival from the time of randomisation Cancer-specific survival was also evaluated

Statistical Analysis Kaplan-Meier estimates of survival Survival was compared between groups using log- rank tests The effect of delay in surgery on survival was examined using multivariable Cox proportional hazards modelling P<0.05 was considered statistically significant

Results Between November 2003 and June patients were recruited 6 were excluded due to withdrawal of consent (n=2) or bilirubin outside required values (n=4) 185 patients had a histologically proven malignancy and were included in final analysis

Patient Characteristics PBD (n=95)ES (n=90)P Males, n (%)63 (70)51 (54)0.02 Body mass index24.0 ± ± Demographic and clinical characteristics were comparable except for sex and BMI: 5 ES patients underwent PBD due to: ▫ Surgery could not be scheduled (n=3) ▫ Cholangitis (n=1) or severe hyperglycaemia (n=1) There were 3 technical failures in the PBD group: ▫ Failed ERCP and PTC, bile duct perforation at ERCP, haemorrhage at sphincterotomy halting the procedure

Results – Time to Surgery Mean difference in time to surgery was 4 weeks Mean time to surgery 1.2 weeks for ES vs 5.2 weeks for PBD

Results – Operative Procedure p=0.20

Results - Survival Two year follow up was complete in 177 (96%) 32 patients were still alive Causes of death (n=153): ▫ Disease related = 148 ▫ Cardiac = 2 ▫ Colonic cancer with metastases = 1 ▫ Metastasised amelanotic melanoma = 1 ▫ Unknown = 1

Results – Overall Survival Median overall survival time was 12.7 months (95% CI: months )

Results – Survival for study groups Median survival: 12.7 months for PBD vs 12.2 months for ES (p=0.91)

Prognostic Factors for Survival Patients with a longer delay to surgery had a slightly lower mortality (HR = 0.91, 96% CI )

Survival after Resection ESPBD Resection60 (67%)53 (58%)P=0.20 RO resection44 (73%)33 (62%)P= year mortality47 (78%)35 (66%) Median survival17.8 months21.6 monthsP=0.25

Survival after Resection The following characteristics were significantly associated with worse overall survival after surgery: ▫ High bilirubin ▫ Pancreatic adenocarcinoma ▫ Tumour positive lymph nodes ▫ Microscopically residual disease Multivariable analysis showed patients with a longer delay to surgery had a slightly lower mortality (HR = 0.85, 95% CI )

Survival after Palliative Surgery 1 patient (2%) with unresectable disease was still alive 27.6 months post randomisation Median survival time was 7.5 months in the PBD group vs 9.4 months in the ES group

Conclusions PBD followed by surgery does not impair long term overall survival in patients with obstructive jaundice due to cancer in the pancreatic head region, as compared with surgery alone PBD does not offer a survival benefit either In view of the risk of procedural complications ES remains the treatment of choice

Critique of Study: Positives Multicentre randomised controlled trial Well defined inclusion criteria Descriptions of dropouts and protocol deviations Appropriate statistical tests used Intention to treat analysis Similar study population characteristics

Critique of Study: Negatives Study was powered for outcome of procedure related complications not survival ▫ May not be adequately powered to show statistical survival difference Not blinded Patients were not routinely followed up until survival requiring ad hoc survival data collection No mention of adjuvant chemotherapy in survival analysis No analysis performed per centre/per surgeon

What this study adds.... Previous analysis by these authors has recommended ES over PBD due to higher complication rate of PBD However this is not always feasible, especially when a patient presents to a non-specialist centre This study shows that PBD does not affect overall survival in jaundiced patients who require pancreatic resection but cannot achieve ES