1. Borderline Resectable Pancreatic Cancer:
Charles M. Vollmer, Jr., MD
Director of Pancreatic Surgery
University of Pennsylvania
St. John Providence GI Symposium
Troy, MI
February 28, 2015

2. I Have No Disclosures
Except appreciation

3. Borderline Resectable Pancreatic Cancer:
We’ve Got Issues!
Charles M. Vollmer, Jr., MD
Director of Pancreatic Surgery
University of Pennsylvania
Society of Surgical Oncology
Washington, DC
March 7, 2013

4. A Cautionary Tale

5. Just Last Week…
Healthy 70 y.o. presents with vomiting and weight loss

6. Inappropriate Care 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.

7. The Final Analysis Whipple Uncomplicated 7 day stay
Ampullary CA (Intestinal type)
Moderate Differentiation
Margin Negative
0/27 Nodes

8. Next Week…
Healthy 73 y.o. presents with jaundice

9. Today’s Journey Conceptual framework. The problems with definitions.
Is neoadjuvant therapy the breakthrough?
The state of the literature.
Quandarys

10. Three Classes of Tumors
Clearly Resectable Aaaah!

11. Three Classes of Tumors
Clearly Unresectable UGGH!

12. Three Classes of Tumors
Borderline Resectable
Or is it Borderline Unresectable???
Hmmh???

13. 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

14. Borderline Resectability A True Original
There’s nothing like it!

15. So What Are Those Issues?

16. Consider This
Where are the borders???
What are the lines???

17. The Lexicon of Borderline Resectable PDAC First things first…
Is it Borderline Resectable? Or
Borderline Unresectable?

18. The Lexicon of Borderline Resectable PDAC Next Things Next…
What does Locally Advanced mean?

19. The Parlance “Occluded” “Shifted” “Pinching” “Extension to” “Touching”
“Irregularity”
“Abutment”
“Impingement”
“Pinching”
“Teardroped”
“Engulfed”
“Obstructing”
“Involvement”
“Extension to”
“Thrombosed”
“Occluded”
“Interface”
“Touching”
“Approach”
“Infiltration”
“Narrowed”
“Shifted”
“Invasion”
“Flattening”
“Displacement”
“Invested”

20. The Parlance “Occluded” “Shifted” “Pinching” “Extension to” “Touching”
“Irregularity”
“Abutment”
“Impingement”
“Pinching”
“Teardroped”
“Engulfed”
“Obstructing”
“Involvement”
“Extension to”
“Thrombosed”
“Occluded”
“Interface”
“Touching”
“Approach”
“Infiltration”
“Narrowed”
“Shifted”
“Invasion”
“Flattening”
“Displacement”
“Invested”
Are these nouns or verbs?

21. “Bi- vs. Uni-lateral ___”
The Qualifiers
“Partial ___”
> 180○
< 180○
“Limited extent ___”
“Outright ___”
“Bi- vs. Uni-lateral ___”
“Minimal ___”
“Normal ___”
“Marginally ___”
“Short vs. Long segment ___”

22. The Lexicon of Borderline Resectable PDAC The Distinctions
Are Arteries Different than Veins?

23. Borderline Resectable Patients MD Anderson Classification
Three Categories:
natomy - Borderline Tumors (1/2 cases)
iology - Equivocal Staging
ondition - Marginal Performance Status
Katz MGH et al, JACS, 2008

24. Does this remind you of the story with Pancreatic Fistula?

25. Does this remind you of the story with Pancreatic Fistula?
Consensus anyone?

26. Borderline Resectable The 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

27. 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
Previous 2007 nccn guidelines confusing—now adopted consensus guidelines—nccn says smv impingement WITH impingement and narrowing of vein
Different defn’s make it difficult to interpret—makes understanding results after neoadj difficult
Major diff—does abutment or encasement of smv = resectable or borderline?
AJCC
T3tumor extends beyond pancreas but not to celiac or sma. T3=Stage II
T4 invovles celiac or sma (unresectable) but T4 any n=stage III
Varadhachary, Ann Surg Onc, 2006
guidelines
Callery, Ann Surg Onc 2009
‘Abutment’ <180°
‘Encasement’ >180°

28. Radiographic Descriptions
More Ambiguity
Radiographic Descriptions

29. Ishikawa Classification Circa 1992
There are others…

30. Tumor Grading Raptopolous 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

31. Raptopolous Grade 0
SMV
TUMOR P
SMA
IVC Ao
G0 lack involvement of critical vasculature, often demonstrate a normal interface b/w tumor and vessel.
And should be entirely resectable
No involvement of critical vasculature (PV, SMV, SMA/Celiac)
Fat plane or normal pancreas between tumor and vessel

32. Raptopolous Grade 1 Loss of fat plane between tumor and vessel with,
SMV P
SMA
IVC Ao
Abutment
No caliber change
Although a G1 tumor may lose the fat plan and even displace a vessel, it does not distort the vessel.
Loss of fat plane between tumor and vessel with,
or without, smooth displacement of vessel

33. Raptopolous Grade 2
SMV P
TUMOR
SMA Ao
IVC
G2 lesions are distinguished by a …..
Flattening or slight irregularity of one side of the vessel

34. Raptopolous Grade 3 P
SMV
TUMOR
SMA
G3 tumors are more extensive, …
Here you can see a nice demonstration of the so-called teardrop sign.
IVC Ao
Tumor extending around at least 2/3 vessel perimeter, altering its contour and narrowing the lumen

35. Raptopolous Grade 4 Occluded / obliterated vessel PV P TUMOR SMV GE
The highest grade in the system, g4, denotes
Occluded or obliterated vessel, without technical options for reconstruction GE
Occluded / obliterated vessel

36. Why Is This Important?

37. 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?
We’ve all faced scenarios like this, with a tumor encroaching on the SMV, and presenting as well with biliary obstruction.
We ask ourselves these questions:……
And if it does come out, what are the implications on survival?

38. Unresectability by CT Grade
P<.0001
100%
82%
From this you can see the escalating unresectability by grade. Note that a signif proportion of g0 tumors are still found to be unresectable intraoperatively, and that all grade 4 lesions were predictably unresectable.
60%
29%
16%
Kent TS et al HPB 2010

39. + Margin Status P=.04 83% 43% 25% 21% Kent TS et al HPB 2010
Similarly, positive margins, both R1 and R2 combined, occurred more frequently at higher grades, and was routine for g3 lesions.
25%
21%
Kent TS et al HPB 2010

40. Overall Survival by Grade
Median survival (Overall 21 mos)
Grade m
Grade m
Grade m
Grade m
Grade m
Moving on to the longer term,
All 401 patients were stratified by grade for survival over x month median f/u period.
As you can see, there was an incremental decline in median survival by grade for all comers. Keep in mind, however, the increasing unresectability rate as grade increases. Accordingly,
P<.0001

41. Is Neoadjuvant The Answer?

42. Neoadjuvant Treatment
Potential Advantages
Realizing it works in other solid malignancies…

43. Consensus Statement
Preoperative “Neoadjuvant” Therapy for Localized Operable Pancreas Cancer
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

44. Neoadjuvant Treatment
Contrary Opinions
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…

45. BIDMC Experience Cyberknife Radiotherapy Salvage of + Margins Cohort N
Median Survival
(Months)
2-Year Survival
(Actuarial)
5-Year Survival
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
ChemoRT+CK Boost 25
30.5
66%

46. Neoadjuvant Treatment
Other Disadvantages
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

47. Which Is Better?
Here’s the data directly comparing the preoperative vs. postoperative adjuvant process in a rigorous manner…

48. The Evidence Phase III-studies for Neoadjuvant therapy
Borderline Resectable Tumors
Group-Study
year
Patients (n)
Inclusion criteria Resection-Status
Treatment arms
Median overall survival (Months)
p-value
Preoperative Imaging

49. Approaches to Borderline Resectable Pancreas Cancer
Consensus Statement
Approaches to Borderline Resectable Pancreas Cancer
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.
Abrams RA et al. Ann Surg Oncol 2009

50. Borderline Resectable

51. What to do about these? Benefit to Neoadjuvant?
Can they be down-staged radiographically? Can they be down-staged pathologically? Is it more (or less) cost effective than surgery-first?

52. Will it be worth it in terms of survival?
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?

53. The Literature on BRPC Is limited. Is dominated by NA reports.
Is not pure….
polluted by data from locally- advanced, unresectable cases.

54. 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.

55. NA Studies 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, 2011
Andriulli A, Ann Surg Onc, 2012

56. Are we really altering Biology?
Or is this just improved selection?

57. Tumor Markers
What happens with CA 19.9 with neoadjuvant therapy of borderline tumors?

58. CA 19-9 Change and Resection Status
This pie graph represents all patients. The shades of green are the resected pts – 59%
41% in red shades were not resected after NT.
You can see in this big picture view that 25% of patients had CA 19-9 decrease (presumably a good thing) yet were unable to be resected.
In the two pie pieces which are out of the circle represent pts in whom CA 19-9 increased, which is presumably a bad thing on NT. And in those people, only a small proportion in light green were resected.

59. Association Between Change in CA 19-9 and Resection
NPV=88%
(Increase = No Resection)
So you could say that the PPV of a good CA 19-9 decrease for predicting resection is poor at just 70%
On the other hand, a negative response of CA 19-9, in other words, an increase, is highly predictive of no resection.
Detection of metastases was the most common reason for failure to undergo pancreatectomy (37/57, 65% of reason for failure)
Rather than use CA 19-9 change to predict resection, which is multifactorial and dependent on anatomy, biology, and condition of the patient, perhaps CA 19-9 is better for predicting objective findings like metastases?
PPV=70%

60. Pre- vs. Post-NT CA 19-9: Association with Metastases
AUC=0.80
AUC=0.67
This is a receiver operating characteristic curve in which all the CA19-9 values for each pt are plotted on a graph against a categorical variable – in this case: mets. The curve shows the balance at each CA 19-9 value between sensitivity and specificity. The farther the AUC is away from 0.5 (the diagonal reference line), the better it is in general.
Comparing pre-NT vs. post-NT absolute CA 19-9 levels, it seems that post-NT levels are better predictors of metastases
Post-NT CA 19-9 was more useful as a predictor of mets compared to pre-NT CA 19-9 (Figure 3). The AUC for pre-NT and post-NT CA 19-9 levels were (95% CI , p=0.002) and (95% CI, , p<0.001) with optimum cutoff values of 257 and 111 U/ml, respectively.
Next I will show you why we think that CA 19-9 is better as a prognostic marker of tumor biology and survival rather than as a predictor of resectability after NT.

61. CA 19-9 Normalization and Survival
Post-NT CA 19-9 offers a view of tumor biology that is far better than the starting value of CA Pts can be low, medium, or high producers at baseline.
Shown graphically, you can see that among resected pts, those who had CA 19-9 normalization, not just a random cutoff and not just an absolute decrease, had better survival than their resected counterparts who never normalized. The difference in median OS is 38 vs. 26 mo. This suggests that CA 19-9 normalization stratifies pts based on their tumor biology and response to cytotoxic therapy.
Interesting this marker of tumor biology is even useful for unresected patients, in which CA 19-9 normalization was associated with a median OS of 15 mo vs. 11 mo. Of note, 15 months median OS for borderline resectable PC is probably as good as or better than surgery alone without multimodality therapy.

62. 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

63. Original Situation
You decide not to operate

64. 6 Months Later You Get What You Get
<1% of these pictures will change with NA
Katz MH, Cancer, 2012

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

66. It’s a Crapshoot
Axial Imaging Sensitivity = 60% Specificity =77% PPV = 49% NPV = 84%
Porembka M, HPB, 2011

67. The Literature Vein Involvement During Pancreaticoduodenectomy:
Is There a Need for Redefinition of “Borderline
Resectable 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.”

68. Early 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 staging
Actually rarely done in NA protocols

69. This 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?

70. Patients want clarity?
They fear Chemo…

71. It 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???

72. Alliance 021101 Borderline Resectable PDAC (Head)
Adjuvant Tx
(1 cycle=28days)
Gem d 1,8,15 for 2 cycles
PRE-REGISTER
Submit image for Central Review
REGISTER
Induction Therapy
(1 cycle=14 days)
mFOLFIRINOX for 4 cycles
Combined ChemoRT
Capecitabine w/ RT every day for 28 days
Surgery
RESTAGE AND REST
Scheduled to open 3/15
Borderline resectable primary tumor, defined by the presence of any one or more of the following on CT/MRI, and confirmed by central radiographic review (see Section 6.4):
- An interface between the primary tumor and the superior mesenteric vein or portal vein (SMV-PV) measuring ≥ 180° of the circumference of the vessel wall
- Short-segment occlusion of the SMV-PV with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction
- Short segment interface (of any degree) between tumor and hepatic artery with normal artery proximal and distal to the interface that is amenable to resection and reconstruction.
- An interface between the tumor and SMA measuring < 180º of the circumference of the vessel wall.

73. Parting Thought

74. Counterpoint Intent to treat?
How would the numbers look if we took all borderline resectable patients, went to surgery, resected those which can, and palliated unresectable patents surgically?

75. Survival From Diagnosis
Preoperative CRT
Surgery First
Here we can see survival from the preoperative CRT cohort and the surgery first cohort. Preop CRT patients had a median survival of 19.9 months, which was signfiicantly better than the surgery first cohort, which had a median survival of 15.3 months. This is a gap of 4.6 months
Keep in mind, however, that this is survival from the point of diagnosis, and not from the point of surgery.

76. Borderline Resectability A True Original
There’s nothing like it!

77. Borderline Resectability A True Original
There’s nothing like it!
We’ve got our work cut out for us.

78. Borderline Resectable Pancreatic Cancer:
Definitions and Approaches
Charles M. Vollmer, Jr., MD
Director of Pancreatic Surgery
University of Pennsylvania
St. John Providence GI Symposium
Troy, MI
February 28, 2015

79. AHPBA/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.
Dr Yeo: Here is what our society has posed as a working definition? Do you contest any of this?
Anyone adhere to the MDACC definition which includes fraility and suspicious metastatic disease?
So, I hope this serves as a good backdrop for the first two cases…..