Post on 02-Nov-2014
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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