What would you recommend as first line therapy for a 68 y/o woman with local pancreatic cancer and no metastatic disease with ECOG-1? Chemoradiation: Rachna Shroff, MD Surgical Resection: Yongyut Sirivatanauksorn, MD

1. PREOPERATIVE THERAPY
FOR RESECTABLE
PANCREATIC CANCER
R AC H N A S H ROF F , MD , MS
A S S I S T A N T P ROF E S SOR ,
D E P T OF GI ME D I CA L ONCOLOGY
M. D . A N D E R SON CA NCE R CE N T E R
R S H ROF F@MD A N D E R SON .ORG
A U B HO 2 0 1 4

2. 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

3. LOCAL DISEASE STAGING
Potentially
Resectable
Borderline
Resectable*
Locally
Advanced
SMV-PV T-V-I < 180º
T-V-I ≥ 180º and / or
reconstructable occlusion
Unreconstructable
Occlusion
SMA No T-V-I T-V-I < 180º T-V-I ≥ 180º
CHA No T-V-I
Reconstructable
short-segment
T-V-I of any degree
Unreconstructable
Celiac
Trunk
No T-V-I T-V-I < 180º T-V-I ≥ 180
*, Intergroup Definition; T-V-I: tumor-vessel interface

4. CONKO-001
Oettle, JAMA 2007
DFS with surgery alone: DISMAL
DFS with postoperative gemcitabine: BETTER

5. EVIDENCE IN SUPPORT OF ADJUVANT
THERAPY
Trial Year n Treatment arm Control arm
Median OS (mos)
(treatment v. control)
Systemic gemcitabine +/- CXRT is standard postoperative therapy
p
GITSG 1985 43
5-FU-based
chemoradiation followed
by maintenance 5-FU
Observation 21.0 v. 10.9 0.03
EORTC 1999 114
5-FU-based
chemoradiation
Observation 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
RTOG
97-04
2008 388
Gemcitabine, 5-FU-based
chemoradiation,
Gemcitabine
5-FU, 5-FU-based
chemoradiation, 5-FU
20.5 v. 16.9 NS

6. Oettle, JAMA 2007
CONKO-001
3-year DFS: 24%
DFS with adjuvant therapy for the “best of the best”
Let’s face it: also pretty dismal.
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

7. 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

8. OCCULT MICROSCOPIC METASTASES
Rapid recurrence common following “radical” resection +/- postop therapy due to
existing disease that is not dealt with surgically
Van den Broeck, E J Surg Onc 2009

9. ADJUVANT VS. NEOADJUVANT
THERAPY
Recovery
4-8 weeks
S CTX +/- CXRT (~6 months)
Presentation with PDAC
OR S
Dropout
S CTX +/- CXRT on/off protocol (2 – 6 months) S OR
The goal is eradication of microscopic disease – local and distant

10. Series (Year) N Margin Status %
Median OS
(Mos.)
p
Johns Hopkins
(2006)
1175
R1/R2 42 14
< 0.0001
R0 58 20
University of Leeds
- UK (2006)
26
R1 85 11
0.01
R0 15 37
ESPAC -1 (2001) 541
R1 19 11
0.006
R0 81 17
University of
Naples - Italy
(2000)
75
R1/R2 20 9
0.001
R0 80 26
Rush-Presbyterian-
St. Luke's (1999)
75
R1 29 8
0.01
R0 71 17
MGH (1993) 72
R1/R2 51 12
0.05
R0 49 20
At least macroscopically complete resection is critical to OS

11. WHAT IS RESECTABLE PANCREATIC
CANCER?
• Absence of
extrapancreatic
disease
• Tissue plane
between tumor and
SMA/CA
• Patent SMV-PV
confluence
2
3
1
T
V
A
Criteria yield high rates of microscopically complete (R0) resection

12. Concordance Coefficient 0.07 (95% CI: 0.02 – 0.13)
The SMA margin distance is routinely overestimated by preoperative CT
Overestimated Underestimated
RADIOLOGY:PATHOLOGY

13. SMA margin distance measured histopathologically following
SMA Margin
Distance
N
pancreaticoduodenectomy
(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)
Preop CXRT associated with longer SMA margin distance even though include all patients
with borderline resectable disease
* Not recorded in 8 patients

14. TIME TO LOCAL RECURRENCE
Neoadjuvant
Local recurrence from dartmouth
Greer, JACS 2008
Neodjuvant
P = 0.03
Adjuvant
Preoperative CXRT prolongs time to LR

15. DISEASE-FREE SURVIVAL
P = 0.003
0 12 24 36 48 60 72 84 96
100
80
60
40
20
0
CXRT, > 1mm
Initial Surgery, > 1mm
CXRT, <= 1mm
Initial Surgery, <= 1mm
Months
Percent survival
26 (95% CI: 15 - 38) mos
Katz, JOGS 2011
Margin length and preop CXRT prolong DFS