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Eshuis , van der Gaag , Rauws et al November 2010 Annals of Surgery;252(5):840-849

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):840-849 Journal Club 15 th November 2010. Background.

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Eshuis , van der Gaag , Rauws et al November 2010 Annals of Surgery;252(5):840-849

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  1. Therapeutic Delay and Survival after Surgery for Cancer of the Pancreatic Head with or without Preoperative Biliary Drainage Eshuis, van derGaag, Rauws et al November 2010 Annals of Surgery;252(5):840-849 Journal Club 15th November 2010

  2. 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

  3. Background • Preoperative biliary drainage (PBD) • Often performed due to a perceived risk of increased postoperative complications in jaundiced patients • A recent trial by these authors1 concluded • Patients undergoing PBD had more overall treatment complications than patients who had surgery without PBD 1. NEJM, 2010; 32(2):129-137

  4. 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

  5. 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

  6. Methods • A randomised controlled multicentre trial • 5 university medical centres & 8 teaching hospitals • Inclusion criteria: • Age 18-85 • Serum total bilirubin 40-150umol/L • No evidence of unresectable disease on CT • Exclusion criteria: (NEJM;32(2):129-137) • Ongoing cholangitis • Pre-existing biliary stenting • Severe gastric outlet obstruction • A contraindication to major surgery

  7. 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):129-137) • PBD: ERCP & placement of a plastic stent • Rescue percutaneous transhepatic cholangiography in 2 cases

  8. 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

  9. 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

  10. 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

  11. Results • Between November 2003 and June 2008 202 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

  12. Patient Characteristics • 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

  13. 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

  14. Results – Operative Procedure p=0.20

  15. 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

  16. Results – Overall Survival • Median overall survival time was 12.7 months • (95% CI:10.1-15.3 months)

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

  18. Prognostic Factors for Survival • Patients with a longer delay to surgery had a slightly lower mortality (HR = 0.91, 96% CI 0.84-0.99)

  19. Survival after Resection

  20. 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 0.75-0.96)

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

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