Borderline Resectable
Pancreatic Cancer:
Charles M. Vollmer, Jr., MD
Director of Pancreatic Surgery
University of Pennsylvania
St. John Providence GI Symposium
Troy, MI
February 28, 2015
I Have No Disclosures
Except appreciation
Borderline Resectable
Pancreatic Cancer:
We’ve Got Issues!
Charles M. Vollmer, Jr., MD
Director of Pancreatic Surgery
University of Pennsylvania
Society of Surgical Oncology
Washington, DC
March 7, 2013
A Cautionary Tale
Just Last Week…
Healthy 70 y.o. presents with vomiting and weight loss
Inappropriate Care
Over 2 weeks time…
• CT, MRI, EUS with Biopsy
• Definition of “Borderline Resectable PDAC
• PICC with TPN
• Staging Laparoscopy with US
• PTC for Biliary Drainage
• Port-a-Cath Placement
• Plan for “Neoadjuvant” therapy ASAP.
The Final Analysis
• Whipple
• Uncomplicated 7 day stay
• Ampullary CA (Intestinal type)
• Moderate Differentiation
• Margin Negative
• 0/27 Nodes
Next Week…
Healthy 73 y.o. presents with jaundice
Today’s Journey
• Conceptual framework.
• The problems with definitions.
• Is neoadjuvant therapy the breakthrough?
• The state of the literature.
• Quandarys
Three Classes of Tumors
Clearly Resectable
Aaaah!
Three Classes of Tumors
Clearly Unresectable
UGGH!
Three Classes of Tumors
Borderline Resectable
Or is it Borderline Unresectable???
Hmmh???
The Essence of “Borderlines”
“Borderline tumors are best conceptualized as:
Those that involve the mesenteric
vasculature to a limited extent.
Those for which resection, while possible,
would likely be compromised by positive
surgical margins … in the absence of
preoperative therapy.”
Katz MHG et al, Ann Surg Oncol ; E-pub Feb 23, 2013
Borderline Resectability
A True Original
There’s nothing like it!
So What Are Those Issues?
Consider This
Where are the borders???
What are the lines???
The Lexicon of Borderline
Resectable PDAC
First things first…
Is it Borderline Resectable?
Or
Borderline Unresectable?
The Lexicon of Borderline
Resectable PDAC
Next Things Next…
What does Locally Advanced mean?
The Parlance
“Touching”
“Involvement”
“Irregularity”
“Pinching”
“Narrowed”
“Flattening”
“Shifted”
“Invested”
“Thrombosed”
“Extension to”
“Impingement”
“Approach”
“Infiltration”
“Occluded”
“Abutment”
“Teardroped”
“Engulfed”
“Obstructing”
“Invasion”
“Interface”
“Displacement”
The Parlance
“Touching”
“Involvement”
“Irregularity”
“Pinching”
“Narrowed”
“Flattening”
“Shifted”
“Invested”
“Thrombosed”
“Extension to”
“Impingement”
“Approach”
“Infiltration”
“Occluded”
“Abutment”
“Teardroped”
“Obstructing”
“Invasion”
“Engulfed”
“Interface”
“Displacement”
Are these nouns or verbs?
The Qualifiers
“Normal ___”
“Minimal ___”
“Bi- vs. Uni-lateral ___”
“Short vs. Long segment ___”
“Outright ___”
“Limited extent ___”
“Marginally ___”
“Partial ___”
< 180○
> 180○
The Lexicon of Borderline
Resectable PDAC
The Distinctions
Are Arteries Different than Veins?
Borderline Resectable Patients
MD Anderson Classification
Three Categories:
A.natomy - Borderline Tumors (1/2 cases)
B.iology - Equivocal Staging
C.ondition - Marginal Performance Status
Katz MGH et al, JACS, 2008
Does this remind you
of the story with
Pancreatic Fistula?
Does this remind you
of the story with
Pancreatic Fistula?
Consensus anyone?
Borderline Resectable
The Evolution
• Mauer/Buchler (1999)
• NCCN (circa 2003, with updates)
• MDACC (2006) – Ann Surg Onc
• MDACC Modification (2008) – JACS
• AHPBA/SSO/SSAT Consensus (2009) Ann Surg Onc
 More inclusive criteria
Borderline Resectable
Lesions--Criteria
MDA
2006
(Type A)
AHPBA/SSAT/
SSO
2009
NCCN
2012
Arterial Involvement:
Abutment Celiac axis
√
Abutment SMA
√
√
√
√
√
√
√
√
√
√
Abutment or encasement of short
segment CHA, typically at GDA
Venous Involvement:
Abutment SMV/PV with/without
impingement
Short segment occlusion of SMV,
PV, or SMV/PV confluence if
reconstructable
‘Abutment’ <180°
‘Encasement’ >180°
√
Varadhachary, Ann Surg Onc, 2006
www.nccn.org, 2012 guidelines
Callery, Ann Surg Onc 2009
More Ambiguity
Radiographic Descriptions
Ishikawa Classification
Circa 1992
There are others…
Tumor Grading
Raptopolous CT Scale (BIDMC - Boston)
Describes tumor relationships with vasculature
0 - 4 scale
 0 - No involvement
 1 – Touches, no deformity
 2 – Deformity of one side of vessel
 3 – Around up to 2/3 of perimeter
 4 – Complete encasement
Kent TS et al HPB 2010
Raptopolous Grade 0
SMV
TUMOR
P
SMA
IVC
Ao
No involvement of critical vasculature (PV, SMV, SMA/Celiac)
Fat plane or normal pancreas between tumor and vessel
Raptopolous Grade 1
P
TUMOR SMV
SMA
IVC
Ao
Loss of fat plane between tumor and vessel with,
or without, smooth displacement of vessel
Raptopolous Grade 2
SMV
P
TUMOR
SMA
IVC
Ao
Flattening or slight irregularity of one side of the vessel
Raptopolous Grade 3
P
SMV
TUMOR
SMA
IVC
Ao
Tumor extending around at least 2/3 vessel perimeter,
altering its contour and narrowing the lumen
Raptopolous Grade 4
PV
TUMOR
SMV
P
GE
Occluded / obliterated vessel
Why Is This Important?
What is Borderline Resectability?
 Can this tumor come out?
 Will it be a harder operation?
 Will it come out completely?
 If it does….What survival can
we expect?
Unresectability by CT Grade
100
90
80
70
60
50
40
30
20
10
0
P<.0001
100%
82%
60%
29%
16%
G0
G1
G2
G3
G4
Kent TS et al HPB 2010
+ Margin Status
90
80
P=.04
83%
70
60
50
40
43%
30
20
25%
21%
10
0
G0
G1
G2
G3
Kent TS et al HPB 2010
Overall Survival by Grade
Median survival
(Overall 21 mos)
 Grade 0
 Grade 1
 Grade 2
 Grade 3
 Grade 4
P<.0001
27m
22m
17m
16m
9m
Is Neoadjuvant The Answer?
Neoadjuvant Treatment
Potential Advantages
Realizing it works in other solid malignancies…
Consensus Statement
Preoperative “Neoadjuvant” Therapy for
Localized Operable Pancreas Cancer
 Provides a rational alternative to a “surgery-first”
approach to resectable pancreas cancer
 Can be initiated for all eligible patients and successfully
identifies a subset of patients for whom resection will not
offer a survival benefit
 May improve negative-margin resection rates and
decrease local failure rates
 Should be considered investigational but merits broader
studies with multidisciplinary expertise
 Will be better defined with more standardized definitions,
techniques, and grading systems
Neoadjuvant Treatment
Contrary Opinions
• Biology of pancreatic cancer precludes any
therapeutic effect (Stroma/Cell paucity)
• Local/regional metastatic disease can be staged
preoperatively in most cases without “waiting it out”
(Laparoscopy)
• Early declaration of metastatic disease is exceedingly
rare (<10%)
• Can’t be cured without the primary therapy (resection)
• Positive margins may not matter as much…
BIDMC Experience
Cyberknife Radiotherapy Salvage of + Margins
Cohort
N
Median
Survival
(Months)
2-Year
Survival
(Actuarial)
5-Year Survival
(Actuarial)
Overall
184
21
43%
23%
Negative Margins (R0)
118
24
49%
25%
Positive Margins (R1)
66
19
35%
22%
Untreated
13
8.5
0%
ChemoRT
28
19
49%
ChemoRT+CK Boost
25
30.5
66%
Neoadjuvant Treatment
Other Disadvantages
• Requires full multidisciplinary approach
• Need for acquisition of a secure diagnosis
• Chronic management of biliary obstruction
• Initial staging of the tumor is unknown
• Dropout of initially good surgical candidates
• Patients want clarity…immediately
Which Is Better?
Here’s the data directly comparing the
preoperative vs. postoperative adjuvant
process in a rigorous manner…
The Evidence
Phase III-studies for Neoadjuvant therapy
Borderline Resectable Tumors
GroupStudy
year
Patients
(n)
Inclusion
criteria
Resection
-Status
Treatment
arms
Median
overall
survival
(Months)
p-value
Preoperative
Imaging
Consensus Statement
Approaches to Borderline Resectable
Pancreas Cancer
 To facilitate comparison of future clinical trials, a
standardized definition of borderline resectable
pancreas cancer that uses objective CT criteria should
be adopted.
 Patients in this category should be studied differently
from those whose tumors meet such objective criteria
for either resectability or unresectability.
 Patients in this category should be treated with
neoadjuvant therapy, ideally in the context of a clinical
trial.
Abrams RA et al. Ann Surg Oncol 2009
Borderline Resectable
What to do about these?
Benefit to Neoadjuvant?
Can they be down-staged radiographically?
Can they be down-staged pathologically?
Is it more (or less) cost effective than surgeryfirst?
The Big Questions?
Will Neoadjuvant therapy make some of
these resectable when once they were not?
Will it be worth it in terms of survival?
The Literature on BRPC
Is limited.
Is dominated by NA reports.
Is not pure….
polluted by data from locallyadvanced, unresectable cases.
Conclusions From The Literature
• Objective radiographic response is rare (<12%).
• Borderlines with NA are more often LN and Margin –
• Borderline survival is better when the tumor is
surgically removed.
• BRPC survival is equivalent to otherwise resectable
tumors (if you can get it out!)
• Unknown whether chemo alone or C-XRT is superior.
• Don’t do this if you can’t perform vascular resections
or don’t have suitable multidisciplinary care.
• There are few comparisons of BRPC tumors with
neoadjuvant therapy vs. surgery alone.
NA Studies
What’s Out There?
2 Meta-analyses show no survival benefit of NA for
“Resectable” disease
Single arm, Phase II studies show modest benefit
for “Borderline Resectable” tumors
NCCN: “Based on lower level evidence (Category
2B), there is NCCN consensus that the
intervention is appropriate”
Assifi MM, Surgery, 2011
Andriulli A, Ann Surg Onc, 2012
Are we really altering
Biology?
Or is this just improved selection?
Tumor Markers
What happens with CA 19.9 with neoadjuvant
therapy of borderline tumors?
CA 19-9 Change and Resection Status
Association Between Change in
CA 19-9 and Resection
NPV=88%
(Increase = No Resection)
PPV=70%
Pre- vs. Post-NT CA 19-9:
Association with Metastases
AUC=0.80
AUC=0.67
CA 19-9 Normalization and Survival
Other “Issues”
• What is an operable tumor after therapy?
• The variable use of vascular reconstruction
• Pathologic assessment of the specimen
 What is a positive margin???
• Quality Assurance in med- & rad-onc care
Original Situation
You decide not to operate
6 Months Later
You Get What You Get
<1% of these pictures will change with NA
Katz MH, Cancer, 2012
If you didn’t like it then,
why do you like it now?
It’s a Crapshoot
Axial Imaging
Sensitivity = 60%
Specificity =77%
PPV = 49%
NPV = 84%
Porembka M, HPB, 2011
The Literature
Vein Involvement During Pancreaticoduodenectomy:
Is There a Need for Redefinition of “Borderline
Resectable Disease”?
Kaitlyn J. Kelly, Emily Winslow, David Kooby, Neha L. Lad, Alexander A.
Parikh, Charles R. Scoggins, Syed Ahmad, Robert C. Martin, Shishir K.
Maithel, H. J. Kim, Nipun B. Merchant, Clifford S. Cho, Sharon M. Weber
J Gastrointest Surg (2013) 17:1209–1217
These data suggest that up-front surgical resection is an
appropriate option, and call into question the inclusion of
isolated vein involvement in the definition of “borderline
resectable disease.”
Early Progression
NA therapy as a biologic “incubator”
<5% occurrence within 6 months
How can you rule out “early progression of
disease” with NA when the regimens used are as
short as 2 weeks long?
My solution – Laparoscopic staging
Actually rarely done in NA protocols
This Stuff is Confusing
Folks…Tell me:
 What drugs should I use?
 What modalities should I use?
 How “hot” should they be (XRT)?
 How long does it take?
Patients want clarity?
They fear Chemo…
It Is… But It Isn’t
If the purpose of NA is to guarantee the
“complete” delivery of systemic therapy
early….
Why do so many patients (up to 50%) get
more after their surgery???
Alliance 021101
Borderline Resectable PDAC (Head)
P
R
E
R
E
G
I
S
T
E
R
Submit
image
for
Central
Review
Induction
Therapy
R
E
G
I
S
T
E
R
Combined
R
ChemoRT
E
(1 cycle=14
Capecitabine
S
days)
w/ RT every
T
mFOLFIRIN
R day for 28
A
OX for 4
days
E
G
cycles
S
E
T
A
N
D
R
E
S
T
A
G
E
Surgery
R
E
S
T
A
G
E
A
N
D
A
N
D
R
E
S
T
R
E
S
T
Adjuvant
Tx
(1
cycle=28days)
Gem d 1,8,15
for 2 cycles
Parting Thought
Counterpoint
Intent to treat?
How would the numbers look if we took
all borderline resectable patients, went to
surgery, resected those which can, and
palliated unresectable patents surgically?
Survival From Diagnosis
Preoperative
CRT
Surgery First
Borderline Resectability
A True Original
There’s nothing like it!
Borderline Resectability
A True Original
There’s nothing like it!
We’ve got our work cut out for us.
Borderline Resectable
Pancreatic Cancer:
Definitions and Approaches
Charles M. Vollmer, Jr., MD
Director of Pancreatic Surgery
University of Pennsylvania
St. John Providence GI Symposium
Troy, MI
February 28, 2015
AHPBA/SSAT/SSO Definition
A) Tumor abutment of the SMA not to exceed <180 Degrees
of the circumference of the vessel wall.
B) Segmental tumor involvement of the hepatic artery without
extension into the celiac axis.
C) Venous involvement of the SMV/portal vein demonstrating
tumor abutment with or without impingement and narrowing
of the lumen.
D) Short segment venous occlusion resulting from either
tumor thrombus or encasement but with suitable vessel
proximal and distal to the area of vessel involvement.