R A C H N A S H R O F F , M D , M SA S S I S TA N T P R O F E S S O R ,

D E P T O F G I M E D I C A L O N C O L O G YM . D . A N D E R S O N C A N C E R C E N T E R

R S H R O F F @ M D A N D E R S O N . O R G

A U B H O 2 0 1 4

PREOPERATIVE THERAPY FOR RESECTABLE

PANCREATIC CANCER

PANCREATIC CANCER SURVIVAL BY STAGE/TREATMENT

n 5-yr OS (%) Median OS (Mos.)

Adjusted HR(95% CI)

Resectable -> OR 2736 24.6 19.3

Resectable -> No OR 3644 2.9 8.4 2.24 (2.07 – 2.43)

Stage III or IV 68521 0.8 4.2 4.16 (3.86 – 4.48)

Billimoria, Ann Surg 2007

LOCAL DISEASE STAGINGPotentially Resectable

BorderlineResectable*

LocallyAdvanced

SMV-PV T-V-I < 180ºT-V-I ≥ 180º and / or

reconstructable occlusionUnreconstructable

Occlusion

SMA No T-V-I T-V-I < 180º T-V-I ≥ 180º

CHA No T-V-IReconstructable short-segment

T-V-I of any degreeUnreconstructable

CeliacTrunk

No T-V-I T-V-I < 180º T-V-I ≥ 180

*, Intergroup Definition; T-V-I: tumor-vessel interface

CONKO-001

Oettle, JAMA 2007

DFS with surgery alone: DISMALDFS with postoperative gemcitabine: BETTER

EVIDENCE IN SUPPORT OF ADJUVANT THERAPY

Systemic gemcitabine +/- CXRT is standard postoperative therapy

Trial Year n Treatment arm Control armMedian OS (mos)

(treatment v. control)p

             

GITSG 1985 435-FU-based

chemoradiation followed by maintenance 5-FU

Observation 21.0 v. 10.9 0.03

             

EORTC 1999 1145-FU-based

chemoradiationObservation 17.1 v. 12.6 NS

             ESPAC-1 2001 541 Chemotherapy No chemotherapy 19.7 v. 14.0 < 0.01      Chemoradiation No chemoradiation 15.5 v. 16.1 NS             ESPAC-1 2004 289 Chemotherapy No chemotherapy 20.1 v. 15.5 < 0.01      Chemoradiation No chemoradiation 15.9 v. 17.9 0.05             CONKO 2008 368 Gemcitabine Observation 22.8 v. 20.2 0.005             

RTOG97-04

2008 388Gemcitabine, 5-FU-

based chemoradiation, Gemcitabine

5-FU, 5-FU-based chemoradiation, 5-FU

20.5 v. 16.9 NS

Oettle, JAMA 2007

DFS with adjuvant therapy for the “best of the best”Let’s face it: also pretty dismal.

3-year DFS: 24%

Median age: 61

Median PS: 80

Postop CA 19-9: < 2.5 ULN

Median time to randomization: 3 weeks

Most rec in year 1-2

CONKO-001

RATIONALE FOR NEOADJUVANT THERAPY

• Provides immediate therapy for subclinical mets

• All resected patients get multimodality therapy

• Patient selection for surgery• Oncologic issues• Performance status

• Enhancement of R0 resection

OCCULT MICROSCOPIC METASTASES

Van den Broeck, E J Surg Onc 2009

Rapid recurrence common following “radical” resection +/- postop therapy due to existing disease that is not dealt with surgically

ADJUVANT VS. NEOADJUVANT THERAPY

CTX +/- CXRT (~6 months)S

Presentation w

ith PD

AC

SORRecovery4-8 weeks

S CTX +/- CXRT on/off protocol (2 – 6 months) S OR

The goal is eradication of microscopic disease – local and distant

Dropout

Series (Year) N Margin Status % Median OS(Mos.) p

Johns Hopkins (2006) 1175

R1/R2 42 14 < 0.0001R0 58 20

University of Leeds - UK (2006) 26

R1 85 110.01

R0 15 37

ESPAC -1 (2001) 541R1 19 11

0.006R0 81 17

University of Naples - Italy (2000)

75R1/R2 20 9

0.001R0 80 26

Rush-Presbyterian- St. Luke's (1999)

75R1 29 8

0.01R0 71 17

MGH (1993) 72R1/R2 51 12

0.05R0 49 20

At least macroscopically complete resection is critical to OS

WHAT IS RESECTABLE PANCREATIC CANCER?

• Absence of extrapancreatic disease

• Tissue plane between tumor and SMA/CA

• Patent SMV-PV confluence

2

3

1

Criteria yield high rates of microscopically complete (R0) resection

T

VA

SMA distance (mm) by pathology

SM

A d

ista

nce

(mm

) by

rad

iolo

gy

0 2 4 6 8

01

02

03

0

The SMA margin distance is routinely overestimated by preoperative CT

Concordance Coefficient 0.07 (95% CI: 0.02 – 0.13)

Overestim

atedU

nderestimated

RADIOLOGY:PATHOLOGY

SMA MarginDistance

N

(n = 194)

Preop CXRT

(n = 147)

Initial Surgery

(n = 47)p*

Positive 8 3 (2) 5 (11)

0.01

≤1mm 40 28 (19) 12 (26)

>1mm < 1cm 72 53 (36) 19 (40)

≥1cm 66 57 (39) 9 (19)

SMA margin distance measured histopathologically following pancreaticoduodenectomy

Preop CXRT associated with longer SMA margin distance even though include all patients with borderline resectable disease

* Not recorded in 8 patients

Local recurrence from dartmouth

Greer, JACS 2008

P = 0.03

Neodjuvant

Adjuvant

Preoperative CXRT prolongs time to LR

TIME TO LOCAL RECURRENCE

Neoadjuvant

DISEASE-FREE SURVIVAL

26 (95% CI: 15 - 38) mos

P = 0.003

Katz, JOGS 2011Margin length and preop CXRT prolong DFS