Pancreatic Cancer. Dr Matt Katz

1. Multimodality
management of
pancreatic cancer
Matthew HG Katz, MD
Department of Surgical Oncology
UT MD Anderson Cancer Center
AUBHO 2015
Bangkok, Thailand
August 29, 2015

2. • 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
V
A
Resectable pancreatic cancer

3. Trial Year n Treatment arm Control arm
Median OS (mos)
(treatment v. control)
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
CONKO 2008 368 Gemcitabine Observation 22.8 v. 20.2 0.005
Postoperative (adjuvant) therapy helps

4. Median age: 61
Median PS: 80
Postop CA 19-9:
< 2.5 ULN
Time to
randomize: 3 wks
3-year DFS: 24%
Oettle, JAMA 2007
…but is not the answer

5. Problem with surgery first:
Ignores known biology of the tumor
and physiology of the host

6. TUMOR BIOLOGY
25% of patients
≥ 5yrs
n = 328 resected
patients
Median OS = 20.4
months
Katz, Annals Surg Onc 2008
25% of patients
≤ 12 months

7. Metastasis occurs early and often
Problem 1

8. Occult Microscopic Disease
Van den Broeck, E J Surg Onc 2009
Rapid recurrence common following “radical” resection

9. Glant, Surgery 2011
Frequency of unanticipated metastases identified

10. Rhim Cell 2012
We’re behind the 8 ball
Preop chemotherapy is a more rational approach
Hematogenous spread and liver seeding precede tumor formation

11. The CT scanner is not a microscope
Problem 2

12. 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
Influence of margin status on survival
At least macroscopically complete resection is critical to OS

13. Katz JOGS 2010
Occult extension even in resectable cases

14. SMA distance (mm) by pathology
SMAdistance(mm)byradiology
0 2 4 6 8
0102030
Distance between cancer and margin is routinely overestimated by CT
Concordance Coefficient 0.07 (95% CI: 0.02 – 0.13)
OverestimatedUnderestimated
Katz JOGS 2010

15. Yamada, Pancreas 2013
Worse with increasing TVI
n OS (mo)
Resectable 137 24
PV 91 15
CHA 21 14
SMA 30 13
Cohort- Preoperative
Imaging
Any radiographic interface between tumor and vessel
None
(n = 137)
PV
(n = 91)
CHA
(n = 21)
SMA
(n = 30)
P
R0 rate 77% 70% 48% 37% 0.0001

16. Problem 3
Postoperative therapy is not guaranteed

17. Merkow, Ann Surg 2013
2047 patients in NSQIP-NCDB, pancreatectomy 2006-2009
Adverse events prevent postoperative tx

18. • United States
– SEER-Medicare 1992-2002
– 1383 resected patients >65 years
– Only 49% received adjuvant therapy
– Pts ≥ 75 half as likely to receive (OR 0.43, HR 0.34-0.54)
• Australia
– Data from 12 hospitals 1990-2011
– 439 resected patients
– Only 47% received adjuvant therapy
– Pts ≥ 70 less likely to receive (30% v. 52%, p < 0.0001)
Davila, Pancreas 2009
Nagrial, BJC 2014
Elders do not receive adjuvant therapy

19. 66 y/o
Vein + splenorenal shunt
73 y/o
Vein + hepatic artery
66 y/o
Vein + celiac trunk
AEs occur after big operations

20. Surgery first sequencing is an
INappropriate strategy for BLR PDAC
• Surgery does not address known systemic
disease
• Surgery is suboptimal local therapy
• Niether postop chemo nor cXRT do much…
• …and only 50% receive it

21. CTXS OR
Neoadjuvant therapy for PDAC
Three primary components
Varadhachary, Ann Surg Onc 2006
Katz, JACS 2008
Abrams, Ann Surg Onc 2009
XRTS S R
NR
• CTX: Cytotoxic effect on systemic cancer cells
• XRT: Sterilization of surgical margins and local cytotoxicity
• Time: Selection of tumor biology and patient physiology for surgery

22. Guarantees administration of non-operative
therapy to all patients who undergo
pancreatectomy
Advantage 1

23. NA: no severe AEs
NA: severe AEs
SF: no severe AEs
SF: severe AEs
NA: not resected
SF: no adjuvant
Ameliorates long-term adverse effects of
severe postoperative complications

24. High risk populations
patients ≥ 70 who presented with res/BL PDAC
179 (76%) treated curatively
26 (15%)
resected
153 (85%)
CTX +/- CXRT
79 (52%)
Unresected
74 (48%)
Resected
11 (42%)
CTX +/- CXRT
Cooper, JACS 2014
All patients who underwent surgery received essential nonoperative therapy

25. Selection for meaningful operations
Advantage 2

26. Evans, JCO 2008
Katz, JACS 2008
Neoadjuvant therapy selects for
surgery
Resectable Borderline Resectable

27. Tzeng, Ann Surg Onc 2012
“Failure” of preoperative therapy
Most fail due to progression of pre-existing micrometastases

28. Early local and systemic cytotoxic effects
Advantage 3

29. Wang, Cancer 2012
IV
Pathologic response is associated
with survival
For some patients: therapy is active! – may improve with better regimens

30. SMA margin
SMA margin R1/R2 10 – 85% and 80% die with LR
Good surgery is not good enough!
Iacobuzio-Donahue, JCO 2009

31. SMA Margin
Distance
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
* Not recorded in 8 patients
Preop CXRT increases SMA margin
clearance
Katz, JOGS 2011

32. 0 12 24 36 48 60 72 84 96
0
20
40
60
80
100
CXRT, > 1mm
Initial Surgery, > 1mm
CXRT, <= 1mm
Initial Surgery, <= 1mm
Months
Percentsurvival
DFSTime to LR
Greer, JACS 2008; Katz, JOGS 2011
Preop CXRT prolongs TTR
Cytotoxic activity at the margin translates to a survival advantage (not OS)

33. “Downstaging” to resectability
Advantage 4

34. Preoperative/Neoadjuvant Therapy in Pancreatic Cancer:
A Systematic Review and Meta-analysis of Response and
Resection Percentages
Sonja Gillen1
, Tibor Schuster2
, Christian Meyer zum Bu¨schenfelde3
, Helmut Friess1
, Jo¨ rg Kleeff 1 , 4
*
1 Department of Surgery, Technische Universita¨t Mu¨nchen, Munich, Germany, 2 Institute of Medical Statistics and Epidemiology, Technische Universita¨t Mu¨nchen,
Munich, Germany, 3 Department of Hematology and Oncology, Technische Universita¨t Mu¨nchen, Munich, Germany, 4 Center of Cancer Systems Biology, Department of
Medicine, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Massachusetts, United States of America
Abst ract
Background: Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with
macroscopic tumor clearance. There is a strong rationale for a neoadjuvant approach, since a relevant percentage of
pancreatic cancer patients present with non-metastatic but locally advanced disease and microscopic incomplete resections
are common. The objective of the present analysis was to systematically review studies concerning the effects of
neoadjuvant therapy on tumor response, toxicity, resection, and survival percentages in pancreatic cancer.
Methods and Findings: Trials were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of
Controlled Trials from 1966 to December 2009 as well as through reference lists of articles and proceedings of major
meetings. Retrospective and prospective studies analyzing neoadjuvant radiochemotherapy, radiotherapy, or chemother-
apy of pancreatic cancer patients, followed by re-staging, and surgical exploration/resection were included. Two reviewers
independently extracted data and assessed study quality. Pooled relative risks and 95% confidence intervals were calculated
using random-effects models. Primary outcome measures were proportions of tumor response categories and percentages
of exploration and resection. A total of 111 studies (n = 4,394) including 56 phase I–II trials were analyzed. A median of 31
(interquartile range [IQR] 19–46) patients per study were included. Studies were subdivided into surveys considering initially
resectable tumors (group 1) and initially non-resectable (borderline resectable/unresectable) tumors (group 2). Neoadjuvant
chemotherapy was given in 96.4% of the studies with the main agents gemcitabine, 5-FU (and oral analogues), mitomycin
C, and platinum compounds. Neoadjuvant radiotherapy was applied in 93.7% of the studies with doses ranging from 24 to
63 Gy. Averaged complete/partial response probabilities were 3.6% (95% CI 2%–5.5%)/30.6% (95% CI 20.7%–41.4%) and
4.8% (95% CI 3.5%–6.4%)/30.2% (95% CI 24.5%–36.3%) for groups 1 and 2, respectively; whereas progressive disease
fraction was estimated to 20.9% (95% CI 16.9%–25.3%) and 20.8% (95% CI 14.5%–27.8%). In group 1, resectability was
35% with unresectable cancers had partial or complete response
33% of patients underwent resection
“One-third of initially staged non-resectable tumor patients would be
expected to have resectable tumors following neoadjuvant therapy”

35. RECIST of 122 patients restaged following neoadjuvant therapy
RECIST Example N (%)
Resected
n (%)
Stable
Disease
84 (69) 70 (83)
Partial
Response
15 (12) 15 (100)
Progressive
Disease
(Local)
2 (2) 0 (0)
21 (17%) progressive disease due to metastases, 0 resected
v
v
+6%
v
v
-38%
v
+22%
Katz, Cancer 2012

36. Change in stage of 122 patients restaged following neoadjuvant therapy
21 (17%) upstaged due to metastases, 0 resected
Stage
Change
Example N (%)
Resected
n (%)
No change 98 (80) 82 (84)
Downstaged 1 (1) 1 (100)
Upstaged
(Local)
2 (2) 2 (100)
H
A A
V
V
C
C
Katz, Cancer 2012

37. T AV
Successful downstaging
Or inaccurate interpretation of pretreatment stage?
• 73 yo woman, mass in HOP
• Attempted resection but mass
“surgically unresectable”
• Biliary-enteric bypass performed
• FOLFIRINOX
• 5-FU based CXRT
• Referred: R0 resection
Pretreatment scan
Poor staging leads to overestimation of the effects of preoperative therapy

38. • 68 year old man with mass in HOP
• Clinician: “it’s borderline… let’s see
what happens with some
‘preoperative therapy’”
• FOLFIRINOX
• 5-FU-based CXRT
• Remained unresectable
• (+/- “exploration with attempt at
resection”)
“But I was told it would shrink!”
Rational treatment relies on precise staging
T
A
V
Pretreatment scan
Should this patient have received chemoradiation? – LAP-07

39. Treatment phase Break
~ 6 wks
CTX
Staging CT
Restaging
Treatment Program
Restaging
CXRT
OR
Clinical
Assessment
• Assessment of “tumor biology”
• Assessment of patient physiologic state
• Local control concerns
• Likelihood of surgery
• Psychosocial concerns and logistics
• Modulate agents based upon PS, etc.

40. •How can treatment sequencing best be individualized?
•What treatment modalities should be used and when?
•How long is “long enough” (and “too long”)?
•How can response to preoperative therapy be measured?
•When is postoperative therapy also indicated?
Unanswered Questions

41. • Advantages:
– Gaurantees receipt of nonoperative therapy
– Selects patients for effective operations
– Allows for early cytotoxic effects
• Treatment decisions: on the basis of an analysis of anatomy,
biology and host physiology
• Treatment sequence must be optimized and individualized
• Neoadjuvant therapy is an appropriate treatment strategy for
patients with anatomically resectable and borderline
resectable disease
Conclusions

42. Thank you
Matthew Katz
mhgkatz@mdanderson.org