Post on 16-Jul-2015
Presented by:
V. Raman Muthusamy, M.D., FACG, FASGE
Director of Interventional Endoscopy
Associate Clinical Professor of Medicine
University of California, Los Angeles
UCLA Medical Center
Suspect Pancreatic Cancer
Non-invasive CT or MRI
“Pancreatic Protocol”
Evaluate Resectability
EUS
Mass Present No Mass Seen
Algorithm for Tumor Detection
Patient with suspected pancreatic cancer.
CT/MRI/ERCP negative. EUS reveals 13 x 13mm hypoechoic mass in pancreas.
Pancreatic adenocarcinoma found at surgery.
1. Does the mass appear surgically resectable?
• Potential cure for appropriate patients
• Avoid unnecessary surgical exploration
2. What is the predicted TNM stage?
• Neoadjuvant tx for locally advanced tumors or regional LN involvement?
Main Questions After Detection
of Pancreatic Cancer
Resectable: No extension to celiac, CHA, SMA Patent SMV-PV confluence Stage I, II (T1-3, Nx, M0)
Borderline: Tumor Abutment of Superior
Mesenteric Artery (SMA) Stage III (minimal T4) Severe unilateral (< 180º) SMV / PV
impingement
Locally Advanced: Celiac, SMA encasement (> 180º) Stage III (T4, Nx, M0)
Metastatic: Distant LNs (Celiac for HOP lesions,
Mediastinal) Stage IV (Tx, Nx, M1) – involves
liver, lungs, carcinomatosis, etc.
Patient presented with jaundice, wt loss
EUS: 3cm hypoechoic mass in head of pancreas extends into duod wall (tumor stage by EUS T3)
Resectable tumor at surgery
Resectable
EUS: Resectable Pancreatic Cancer
Patient presented with wtloss and pain
EUS: 4 cm hypoechoic mass in body/tail of pancreas invading the SMA (tumor stage by EUS T4)
Not resectable at surgery
Locally Advanced
EUS: Unresectable Pancreatic Cancer
Mass
SMA
Invasion into SMA
Borderline Resectable
EUS: Borderline Resectable
Pancreatic Cancer
Lowy, Journal of Gastrointes Surg 2008
Stage Treatment
• BorderlineResectable ERCP w/ stent
Chemo + XRTSurgery
• Locally Advanced
Obtain tissue diagnosis in metastatic cancer
Confirm diagnosis in high risk prior to surgery
Questionable lesion on imaging: tissue dx to confirm
Questionable tumor type: example – lymphoma vs. adenocarcinoma; Knowledge of tumor type might impact treatment
Indicated: tissue biopsy results will affect treatment plan
Indications for Tissue Diagnosis in
Suspected Pancreatic Cancer
NOT indicated: tissue bx will not impact treatment plan
• Example: 50 year-old male with wt loss, painless jaundice, visible mass on CT/EUS that appears surgically resectable
Positive bx: surgery
Negative bx: surgery (assume bx is false negative)
Treatment related: surgery complications, delayed recovery
Disease related: disease progression
Patient related: age, preoperative PS, medical co-morbidities, patient refusal
35% did not receive adjuvant therapy: MDACC
Katz MH, et al. Survival and Quality of Life of Patients with Resected Pancreatic Adenocarcinoma Treated with Adjuvant Interferon-Based Chemoradiation: A Phase II
Trial. Ann Surg Oncol. 2011 Jun 24. [Epub ahead of print].Aloia, Pisters, et al.: J Amer Col Surg 2007;204(3):347-55
Clinical Article Percentage
Corsini, JCO 2008;26:3511-3516-3502 (Mayo) 60%
Herman JCO 2008;26:3503-3510 (Hopkins) 44%
Simons Cancer 2010;116:1681-90 (SEER) 48%
Merchant J Am Coll Surg 2009:208:829-841 50%
Author and Study No. Patients Median Survival P-Value
GITSG (1985): 5-FU/XRT
Surgery alone
2122
2011
.03
EORTC (1999/2007): 5-FU/XRT
Surgery alone
6054
1612
.099
.165
ESPAC-1 (2001): 5-FU/LV No chemo
146139
2016
.011
CONKO (2008 ASCO): Gem
Surgery alone
179175
2320
.05
RTOG (2008): 5-FU/XRTGem vs 5-FU
187201
2117
.05
WE NEED A BETTER ALGORITHM TO TREAT
THIS DISEASE
Provides early treatment of micrometastatic disease (80-90% of “resectable” patients)
Patients with rapidly progressive disease will not be subjected to surgery
A logical strategy for the high incidence of positive margins
Delayed recovery not an issue
Journal of Oncology and Hematology 2011
Recurrent pancreas CA is thought to arise from micro-metastic disease that cannot be detected using current staging procedures.
48 patients with ductal adenocarcinoma of the pancreas with histologically tumor-free resection margins (R0)
Of the 17 patients with pN0 disease, micrometastases were detected in 29% of patients
Routine histopathological examinations of resected lymph nodes revealed lymph nodes metastasis in 31 patients (65%)
Brian Kadera, R Muthusamy, R Watson, W Isacoff, O. Joe Hines, J Tomlinson, D Dawson, H Reber, Timothy Donahue
Locally Advanced Pancreatic Cancer: Prolonged
Preoperative Treatment is Associated with Lymph Node
Negativity and Excellent Overall Survival
Figure Adapted from Morreale, ASCO 2004.
All patients with LA/BR PDAC
Retrospective Review from 1992 - 2011
Received downstaging therapy (chemotherapy/radiation)
Successful surgical resection, with biopsy or surgical
pathology confirmed PDAC
Treatment
Continued local tumor growth, evidence of systemic
disease, unresectable at surgical exploration
n = 49
CT/MRI evidence of shrinkage or change in signs of vascular involvement
CA 19.9 decrease
Good functional status
Number (%) of patients
Age, y (Median, IQR) 60 (56-69)
SexMale 17/49 (34.7%)
Female 32/49 (65.3%)
Tumor Location in PancreasHead 45/49 (91.8%)
Body/Tail 4/49 (8.2%)
Reason for Unresectability
Vascular 49/49 (100%)
SMV/PV Involvement 30/46 (65.2%)
SMA Involvement 13/46 (28.3%)
Hepatic Artery Involvement 13/46 (28.3%)
Celiac Artery Involvement 4/46 (8.7%)
IVC Involvement 2/46 (4.3%)
Number (%) of patients
Median Follow-up of Survivors,
Months (median, IQR)48.9 (22.8 - 97.8)
Recurrence at Last Follow-up
No 25/49 (51.0%)
Yes 24/49 (49.0%)
Local Recurrence 3/24 (12.5%)
Distant Recurrence 13/24 (54.2%)
Unknown 8/24 (33.3%)
Disease-Free Survival Months
(median, IQR)23.2 (18.2 - 47.0)
Overall Survival Months (median, IQR) 40.1 (22.7 - 65.9)
5-year Survival 15 of 35 patients (42.9%)
Tissue diagnosis required (EUS-FNA)
Durable biliary decompression required (ERCP)
Physicians must work together
Pre-op drainage
SEMS better than plastic?
Covered or uncovered?
Cost-Effective?
Role in Chemotherapy
Weber A et al, Pancreas 2009
Plastic Metal p
Median Patency (days) 57 126 n.s.
Total Time in Hospital After Initial Tx (days)
16.5 7 0.001
Median Survival (months)
4.4 5.9 n.s.
Adams et al, Journal of GI Oncology, Dec 2012; 3(4): 309-313
N = 52 pts
N= 113 stents placed70 plastic43 metal
Ge et al, Pending Acceptance at GIE
Ge et al, Pending Acceptance at GIE
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
3 Weeks 6 Weeks 9 Weeks 12 Weeks
80%
61%
45%
34%
80%
57%
43%
29%
Num
ber
of
Ste
nts
(%
)
Stent Patency
All Stents
Premature Stent
Exchanges
Ge et al, Pending Acceptance at GIE
SEMS better than plastic?
Covered or Uncovered?
Cost effective?
Role in chemotherapy?
Covered Self-Expandable Metal Stents With an Anti-Migration System Improves Patency Duration Without Increased Complications Compared With Uncovered
Stents for Distal Biliary Obstruction Caused by Pancreatic Carcinoma: A Randomized Multicenter Trial
2013 by the American College of Gastroenterology, Masayuki Kitano, et al.
2013 by the American College of Gastroenterology, Masayuki Kitano, et al.
2013 by the American College of Gastroenterology, Masayuki Kitano, et al.
JH Lee et al, GIE(78:3), 2013◦ Retrospective study
◦ 11 yrs, 749 pts (171 CSEMS/578 USEMS)
◦ No difference in overall survival or stent time to reocclusion
◦ Similar adverse event rates (about 27%)
CSEMS: < tumor ingrowth (9% vs 76%), but more migration (36% vs 2%)/pancreatitis (6% vs 1%)
Telford et al, GIE (72), 2010◦ Prospective multicenter (4) RCT
◦ 5.5 yrs; 129 pts
◦ Recurrent obstruction: 18% UCSEMS vs 29% CSEMS
◦ More adverse events with CSEMS, esp. stent migration
Saleem et al GIE 72:4, 2011
Saleem et al GIE 72:4, 2011
• Median f/u = 212 days• CSEMS: Improved stent patency (WMD -61 d)• CSEMS: Improved stent survival (WMD -69 d)
• CSEMS associated with more:• Stent migration (RR – 8.11)• Tumor overgrowth (RR – 2.02)• Sludge formation (RR – 2.89)
Saleem et al GIE 72:4, 2011
Gastroenterology Research and Practice Volume 2013, Article ID 642428, 7 pages
Palliation
SEMS better than plastic?
Covered or Uncovered?
Cost effective?
Role in chemotherapy?
To determine which strategy is less expensive:
• Placement of a plastic stent initially, with elective exchange every 10 weeks
• Metal stent initially, with replacement in the event of occlusion
Agarwal N et al, DDW 2013
Patient with borderline resectable pancreatic cancer
Downstaging chemotherapy
Biliary obstruction requiring endoscopic decompression
Agarwal N et al, DDW 2013
Outcomes of pancreatic cancer
• Death
• Surgery
• Tumor progression
Outcomes of stent placement (metal/plastic)
• Migration rates
• Occlusion rates
• Cholangitis rates
Agarwal N et al, DDW 2013
Medicare for procedure costs/ hospitalizations
Manufacturers for stent costs
Agarwal N et al, DDW 2013
Decision tree using TreeAge software
• Placement of a plastic stent initially, with elective exchange every 10 weeks
• Metal stent initially, with replacement in the event of occlusion
Endpoints:
• One year
• Surgery
• Tumor progression
• Death
Agarwal N et al, DDW 2013
One year costs of each strategy
Two way sensitivity analyses
Agarwal N et al, DDW 2013
Agarwal N et al, DDW 2013
Variable Base Case Range
Rate of occlusion (plastic) 0.15 0 – 0.60
Rate of migration (plastic) 0.05 0 – 0.10
Rate of occlusion (SEMS) 0.15 0 – 0.70
Rate of migration (SEMS) 0.02 0 – 0.05
Cholangitis 0.05 0 – 0.30
Pancreatitis 0.05 0 – 0.15
Initial ERCP cost 2044 0 – 2044
F/u ERCP stent exchange cost 1179 0 – 2044
Plastic stent cost 83 0 – 83
SEMS cost 995 0 – 995
Pancreatitis hospitalization 4255 1063 - 10000
0 10,000 20,000
Plastic Stent
SEMS
Cost
Agarwal N et al, DDW 2013
$6,571
$17,709
Agarwal N et al, DDW 2013
Least Costly Strategy Threshold
Plastic Stents
• Stent patency > 190 days
• ERCP cost < $380
SEMS
• Duration of stenting period > 136 days
• Cost of metal stent < $12,000
Palliation
SEMS better than plastic?
Covered or Uncovered?
Cost effective?
Role in chemotherapy?
• Metal stents reduce the risk of chemotherapy postponement due to stent occlusion (more frequent with plastic stents)
• Adams et al. published in the Journal of Gastrointestinal Oncology, keeping in line with prior studies, the complications were 7 times higher among patients with plastic stents than with metal stents.
• In addition, the study showed a 3x higher rate of hospitalization in patients with plastic stent group.
World J Gastroenterol 2006Osamu Takasawa, Naotaka Fujita, Go Kobayashi, Yutaka Noda, Kei Ito, Jun Horaguchi
J Gastrointest Oncol 2012, 309-313.Adams MA, Anderson MA, Myles JD, Khalatbari S, Scheiman JM
SEMS better than plastic
Covered better than uncovered
Cost-effective: SEMS
Role in chemotherapy: SEMS
Is necessary? Not always!
Increasingly, nearly all patients will receive preoperative “downstaging” therapy
This is done to treat micrometastases that are not visible on any currently available imaging modality
The use of neoadjuvant therapy will require pre-treatment EUS -FNA for tissue diagnosis
Given the fact that many of these patients will require > 3 months of treatment, durable biliary stenting is needed.
Many patients receiving neoadjuvant therapy will progress/fail to regress and will never become operative candidates -> they will benefit from durable stenting
Plastic stents have reduced patency in patients receiving neoadjuvant therapy
The use of short (4-6cm) covered metal biliary stents is preferred given their prolonged patency
• Much wider diameter
• Covering aims to reduce tumor ingrowth
• Short stents avoid complicating surgical resection by avoiding the hilum and reduce the chance of covering the cystic duct in patients with intact GBs
Reported rates of cholecystitis and stent migration with fully covered stents are low
• Stent migration may predict tumor response to treatment and a reduced need for biliary stenting
• Patients with suspected cholecystitis can easily have their stent removed