ntc dr muthusamy bridge to surgery talk final 6 18

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