Borderline Resectable Pancreatic Cancer: Charles M. Vollmer, Jr., MD Director of Pancreatic Surgery University of Pennsylvania St. John Providence GI Symposium

Borderline Resectable Borderline Resectable Pancreatic Cancer: Pancreatic Cancer:

Charles M. Vollmer, Jr., MDCharles M. Vollmer, Jr., MDDirector of Pancreatic SurgeryDirector of Pancreatic Surgery

University of PennsylvaniaUniversity of Pennsylvania

St. John Providence GI SymposiumTroy, MI

February 28, 2015

I Have No Disclosures

Except appreciation


We’ve Got Issues!We’ve Got Issues!



Society of Surgical OncologyWashington, DCMarch 7, 2013

A Cautionary Tale

Just Last Week…Just Last Week…

Healthy 70 y.o. presents with vomiting and weight loss

Inappropriate CareInappropriate CareOver 2 weeks time…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 AnalysisThe Final Analysis

• Whipple • Uncomplicated 7 day stay

• Ampullary CA (Intestinal type)• Moderate Differentiation• Margin Negative• 0/27 Nodes

Next Week…Next Week…

Healthy 73 y.o. presents with jaundice

Today’s JourneyToday’s Journey• Conceptual framework.

• The problems with definitions.

• Is neoadjuvant therapy the breakthrough?

• The state of the literature.

• Quandarys

Three Classes of TumorsThree Classes of Tumors Clearly Resectable

Aaaah!

Three Classes of TumorsThree Classes of Tumors Clearly Unresectable

UGGH!

Three Classes of TumorsThree Classes of Tumors Borderline Resectable Or is it Borderline Unresectable???

Hmmh???

The Essence of “Borderlines”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 ResectabilityBorderline ResectabilityA True Original

There’s nothing like it!

So What Are Those Issues?

Consider ThisConsider This

Where are the borders??? What are the lines???

The Lexicon of Borderline The Lexicon of Borderline Resectable PDACResectable PDAC

First things first…First things first…

Is it Borderline Resectable?

Or

Borderline Unresectable?


Next Things Next…Next Things Next…

What does Locally Advanced mean?

The ParlanceThe Parlance

“Abutment”

“Impingement”

“Pinching”

“Teardroped”

“Engulfed”

“Obstructing”

“Involvement”“Extension to”

“Thrombosed”

“Occluded”

“Interface”

“Touching”

“Approach”

“Infiltration”

“Narrowed”

“Shifted” “Invasion”

“Invested”

“Irregularity”

“Flattening”

“Displacement”

The ParlanceThe Parlance

“Abutment”

“Impingement”

“Pinching”

“Teardroped”

“Engulfed”

“Obstructing”

“Involvement”“Extension to”

“Thrombosed”

“Occluded”

“Interface”

“Touching”

“Approach”

“Infiltration”

“Narrowed”

“Shifted” “Invasion”

Are these nouns or verbs?“Invested”

“Irregularity”

“Flattening”

“Displacement”

The QualifiersThe Qualifiers

“Short vs. Long segment ___”

“Partial ___”

> 180○

< 180○

“Limited extent ___”“Outright ___”

“Bi- vs. Uni-lateral ___”“Minimal ___”“Normal ___”

“Marginally ___”


The DistinctionsThe Distinctions

Are Arteries Different than Veins?

Borderline Resectable Borderline Resectable PatientsPatientsMD 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 ResectableBorderline ResectableThe 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, 2006www.nccn.org, 2012 guidelinesCallery, Ann Surg Onc 2009

More Ambiguity

Radiographic Descriptions

Ishikawa ClassificationIshikawa ClassificationCirca 1992

There are others…

Tumor GradingTumor GradingRaptopolous 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 0Raptopolous Grade 0

No involvement of critical vasculature (PV, SMV, SMA/Celiac)Fat plane or normal pancreas between tumor and vessel

IVCIVCAoAo

SMASMA

SMVSMV

PTUMORTUMOR


Loss of fat plane between tumor and vessel with,

or without, smooth displacement of vessel

IVCIVC AoAo

P TUMORTUMOR

SMASMA

SMVSMV


Flattening or slight irregularity of one side of the vessel

SMVSMV

TUMORTUMORP

IVCIVC

SMASMA

AoAo


Tumor extending around at least 2/3 vessel perimeter, altering its contour and narrowing the lumen

AoAoIVCIVC

SMASMA

SMVSMVTUMORTUMOR

P


Occluded / obliterated vessel

PVPV

P

TUMORTUMOR

GEGESMVSMV

Why Is This Important?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?

UnUnresectability by CT Graderesectability by CT Grade

0

10

2030

40

5060

7080

90

100

G0 G1 G2 G3 G4

P<.0001P<.0001

16%16%29%29%

60%60%

82%82%

100%100%


+ Margin Status+ Margin Status

0

10

20

30

40

50

60

70

80

90

G0 G1 G2 G3

P=.04P=.04

21%

43%

25%

83%


Overall Survival by GradeOverall Survival by GradeMedian survival Median survival (Overall 21 mos)(Overall 21 mos)

Grade 0 27mGrade 0 27m





P<.0001

Is Neoadjuvant The Answer?Is Neoadjuvant The Answer?

Neoadjuvant TreatmentNeoadjuvant TreatmentPotential Advantages

Realizing it works in other solid malignancies…

Consensus StatementConsensus Statement

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

Preoperative “Neoadjuvant” Therapy for Localized Operable Pancreas Cancer

Neoadjuvant TreatmentNeoadjuvant Treatment

• 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…

Contrary Opinions

BIDMC Experience

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%

Cyberknife Radiotherapy Salvage of + Margins

Neoadjuvant TreatmentNeoadjuvant Treatment

• 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

Other Disadvantages

Which Is Better?

Here’s the data directly comparing the preoperative vs. postoperative adjuvant

process in a rigorous manner…

Group-Study year

Patients (n)

Inclusion criteria

Resection-Status

Treatment arms

Median overall

survival (Months)

p-value Preoperative Imaging

The EvidenceThe Evidence

Phase III-studies for Neoadjuvant therapyBorderline Resectable Tumors

Consensus StatementConsensus Statement

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.

Approaches to Borderline Resectable Pancreas Cancer

Abrams RA et al. Ann Surg Oncol 2009

Borderline ResectableBorderline Resectable

What to do about these?What to do about these?

Can they be down-staged radiographically?

Can they be down-staged pathologically?

Is it more (or less) cost effective than surgery-first?

Benefit to Neoadjuvant?

The Big Questions?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 BRPCThe Literature on BRPC

Is limited.

Is dominated by NA reports.

Is not pure…. polluted by data from locally-

advanced, 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 StudiesNA StudiesWhat’s Out There?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, 2011Andriulli 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

PPV=70%

NPV=88% (Increase = No Resection)

Pre- vs. Post-NT CA 19-9: Association with Metastases

AUC=0.67

AUC=0.80

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 SituationOriginal Situation

You decide not to operate

6 Months Later6 Months LaterYou Get What You GetYou Get What You Get

<1% of these pictures will change with NA

Katz MH, Cancer, 2012

If you didn’t like it then, If you didn’t like it then, why do you like it now?why do you like it now?

It’s a CrapshootIt’s a Crapshoot

Axial Imaging

Sensitivity = 60%

Specificity =77%

PPV = 49%

NPV = 84%

Porembka M, HPB, 2011

The LiteratureThe Literature

Vein Involvement During Pancreaticoduodenectomy:Is There a Need for Redefinition of “BorderlineResectable 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 ProgressionEarly 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 stagingActually rarely done in NA protocols

This Stuff is ConfusingThis 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?Patients want clarity?

They fear Chemo…

It Is… But It Isn’tIt 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 021101Alliance 021101Borderline Resectable PDAC (Head)

Adjuvant Tx(1

cycle=28days)Gem d 1,8,15 for 2 cycles

Submit image

for Central Review

Induction Therapy(1 cycle=14

days)mFOLFIRIN

OX for 4 cycles

Combined ChemoRTCapecitabine w/ RT every day for 28

days

Surgery

Parting ThoughtParting Thought

CounterpointCounterpoint

How would the numbers look if we took all borderline resectable patients, went to surgery, resected those which can, and

palliated unresectable patents surgically?

Intent to treat?

Survival From DiagnosisSurvival From Diagnosis

Surgery First

Preoperative CRT





We’ve got our work cut out for us.


Definitions and ApproachesDefinitions and Approaches



St. John Providence GI SymposiumTroy, MI

February 28, 2015

AHPBA/SSAT/SSO DefinitionAHPBA/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.

Documents

Borderline Resectable Pancreatic Cancer: Charles M. Vollmer, Jr., MD Director of Pancreatic Surgery University of Pennsylvania St. John Providence GI Symposium