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