Eshuis , van der Gaag , Rauws et al November 2010 Annals of Surgery;252(5):840-849
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Transcript of 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 alNovember 2010
Annals of Surgery;252(5):840-849
Journal Club 15th 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 authors1 concluded ▫Patients undergoing PBD had more overall
treatment complications than patients who had surgery without PBD
1. NEJM, 2010; 32(2):129-137
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 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
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
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 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
Patient Characteristics
PBD (n=95) ES (n=90) P
Males, n (%) 63 (70) 51 (54) 0.02
Body mass index 24.0 ± 3.1 25.2 ± 3.9 0.04
• 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:10.1-15.3 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 0.84-0.99)
Survival after Resection
ES PBD
Resection 60 (67%) 53 (58%) P=0.20
RO resection 44 (73%) 33 (62%) P=0.21
2 year mortality 47 (78%) 35 (66%)
Median survival 17.8 months 21.6 months P=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 0.75-0.96)
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