1. Innovations in Pancreatic Cancer:
Reason to Hope
A. James Moser, M.D. FACS.
Director, Institute for Hepatobiliary and Pancreatic Surgery
Beth Israel Deaconess Medical Center
Visiting Associate Professor of Surgery
Harvard Medical School

2. We Share Your Mission
• Imagine a Future without Pancreatic Cancer!
– Raise Awareness Today
• Early diagnosis and prevention
– Hope for Tomorrow
• Dedicated team of cancer specialists
• “Living” with pancreatic cancer
– Change in the FUTURE
• Clinical trials
• Outreach and Fundraising for a “cure”
• Laboratory research

3. Focus on the Imminent:
Modern Total Pancreatectomy
• 62 yo man; recurring abdominal pain
• chronic pancreatitis; PRSS1 gene mutation
• Predicted 25% lifetime risk of PDA
• PanIN3; Back at work three weeks postop

4. Rising Incidence of Pancreatic Cancer
• Geographic risk of
pancreatic cancer
– Rising in Cape Cod and
New England
– Falling in Western PA and
West Virginia
• Aging population
• Obesity
• Genetic risk factors
• Smoking

5. • By 2030:
– 2nd cause of cancer death
– 1.4-1.8% incr. per year
• Possible Factors
– Obesity
– Caucasian

6. Pancreatic Cancer Statistics
• 4th most common cause of cancer death
– 34,000 new cases every year
– “Silent” disease
• Vague abdominal pain or unexplained weight loss
• New-onset diabetes (one in 332 new patients)
• Smoking (two-fold increased risk)
• Family history of cancer (two-fold in 1st degree relatives)
• When the tumor is found:
– 15% of patients have operable cancer (stage 1/2)
– 25-30% have advanced pancreatic cancer (stage 3)
– 55% cancer has spread (metastatic, stage 4)

7. Extent of Disease at Diagnosis
Improvements in diagnostic imaging?
Shaib et al, Aliment Pharmacol Ther 24, 87-94, 2006

8. Issues for the Pancreatic Cancer Patient
• Can you treat my cancer?
• Can you relieve my symptoms?
– Nutrition: Fatigue/ loss of appetite
– Pain
– Jaundice: Bile duct blocked
– Nausea and vomiting
• Narrowing of outlet from stomach
• “No one to watch over me”
– Physician specialization
– Regionalization of care
• The Internet has no librarian

9. No Librarian=Confusion
National Cancer Database Statistics on 100,313 Patients 1985-1995
Sener et al, J Am Coll Surg 1999; 189: 1-7.

10. “Why do you need to go to medical
school when you have the Internet?”
His Expectation
• PubMed citations for pancreatic cancer:
– 2592 clinical trial reports
• 1530 chemotherapy trials
• 1134 surgery citations
• 165 chemoradiation trials
• “Don‟t be afraid to see what you see.”
Ronald Reagan

11. Regionalized Care for Pancreatic Cancer?
Sener et al, J Am Coll Surg 1999; 189: 1-7.

12. BIDMC Pancreatic Cancer Center
Vision
The state of the art for
pancreatic cancer is a
clinical trial.

13. Internet Resources

14. Evolution of Personalized Medicine
• 19th century
– “The practice of medicine is an art…” William Osler
• 20th century
– RCTs to delineate outcome variables
• NSABP „s triumph over radical mastectomy
• 21st century: art replaced by science
– The tumor target: the 6th vital sign
– Oncotype DX
• Stage I/II node negative ER(+) breast cancer
• Recurrence risk based on gene expression profiling

15. The Future of Pancreatic Cancer
• Combine new treatments to
– Kill cancer cells around the main tumor
and in the liver
– Optimize patient selection for surgery
– Maximize survival
• Maximize quality of life after surgery
• Immunotherapy
• Novel Chemotherapy after surgery

16. BIDMC Pancreatic Cancer
Specialty Care Center
617-667-PANC (7262)
• Multidisciplinary Clinical Care • Clinical Research
– Specialized expertise – Pancreatic Cancer Registry
• Pancreatic surgery • Database
• Gastroenterology – Clinical Trials
• Medical oncology • New drugs
• Radiation oncology • Immunotherapy
• Chronic pain • Cyberknife
• Cancer genetics • New stents
• Nutrition/ Alternative Medicine • Molecular diagnosis
Social Work

17. Staging, Diagnosis, and Treatment
• Stage the disease
– Stage I/II: surgery is possible
– Stage III: too advanced for surgery
– Stage IV: metastatic
• Stage-specific therapy
– Stage I/II: surgery, systemic therapy, radiation
– Stage III: systemic therapy, radiation, ?surgery
– Stage IV: systemic therapy

18. Allaying Fear of Chemotherapy
• Stage 4; Gemzar/Xeloda
• How will chemo make me feel?
• Less burden with time
• Reduced coping effort

19. Better Quality of Life
• Stage 4 pancreatic cancer
• Gemzar/Xeloda
– Reduced pain
– Improved mood

20. Chemotherapy That Works
• FOLFIRINOX vs. Gemcitabine (2011)
– Stage 4 pancreatic cancer
– Significantly improved:
• response rate
• disease control (63%-79% of patients)
• Better quality of life at 6 months
– 75% improvement in overall survival

21. Stereotactic Radiosurgery (Cyberknife)
• Highly-conformal XRT
with real-time imaging
• Gold fiducials for targeting
• Breath-tracker software
• 36 Gy, 3 fractions
• Multiple studies
– All pts had local control
– Distant mets as first site of
progression

22. Whipple’s Operation:
Localized Pancreatic Cancer

23. Leave No Cancer Behind
Portal vein NOT involved Portal vein involved

25. No Substitute for Experience
Makary et al, Pancreaticoduodenectomy in the very elderly, JOGS 2006.

26. Case Presentation:
• 70 y/o woman with painless jaundice
• CT showed 2x3 cm ill defined mass in head
of pancreas
• EUS confirms mass
• Biopsy revealed adenocarcinoma
• ERCP showed obstruction of bile duct
• Surgery first vs. clinical trial

28. Endoscopic Ultrasound
• Hypoechoic lesion
in pancreatic head
• Intact hyperechoic
interface between
tumor and PV

29. Case Presentation
• Robot-assisted minimally-invasive
pancreaticoduodenectomy (Whipple operation)
• Uneventful recovery discharged home on POD 10
eating a regular diet.
• Final pathology revealed 2 cm adenocarcinoma,
negative margins and no lymph node involvement
• Received adjuvant chemotherapy on a clinical trial

30. Advanced Pancreatic Cancer

31. Worse Cancer = Even Bigger
Operation
Portal vein involved

32. Preoperative Therapy for PAC
• Goals of neoadjuvant multimodality therapy:
– reduce risk of positive margin
– Sterilize regional lymph nodes
– Treat systemic disease
• Candidates for neoadjuvant therapy
– Resectable (new indication)
– Locally-advanced disease
• invasion of SM-PV confluence, mesenteric arteries
• local lymphadenopathy
• Published: 5-FU, gemcitabine, paclitaxel, + XRT

33. BIDMC Pancreatic Cancer Center
Mission
• Combine new treatments to:
– Improve survival
– Optimize patient selection for surgery
• Chemotherapy and radiation before surgery
– Surgical patients with “resectable” pancreatic cancer
– Reduce recurrences in the liver
– Chemotherapy/Cyberknife for advanced cancers
• Novel radiotherapy: Stereotactic radiosurgery
• Immunotherapy and new agents for metastatic disease

34. Does Radical Surgery Improve Outcome?
• “Regional” pancreatectomy to clear SMA margin
– increased morbidity and mortality (Fortner)
– No patients with positive margins survive 5 years
• Extended lymphadenectomy does NOT improve
survival
• EQUIVALENT results after portal vein resection
• tumor interface with PV/SMV
• Location, not biology?

35. What We Do
• Multidisciplinary evaluation by expert team
• BIDMC Pancreatic Cancer Specialty Care Center
– Multidisciplinary Pancreatic Cancer Conference
• Helical pancreas mass protocol CT
• Endoscopic Ultrasound (EUS)
• Encourage neoadjuvant therapy on protocol
• Staging laparoscopy
– Inspect peritoneal surfaces; UTZ for suspicious hepatic lesions
• Portal vein resection: Yes
• En bloc resection of adjacent organs: Probably
• Adjuvant chemotherapy: Yes

36. Staging, Diagnosis, and
Treatment
• Stage the disease
– Stage I/II: surgery is possible (resectable)
• Tumor diameter
• Presence of lymph nodes
– Stage III: too advanced for surgery
• Mesenteric vascular involvement
• “Borderline” resectable vs. locally-advanced
– Stage IV: metastatic
• Stage-specific therapy
– Stage I/II: surgery, systemic therapy,
?radiation
– Stage III: systemic therapy, radiation,

37. Lessons from Radical Surgery
• Locally and regionally aggressive disease at diagnosis
• Resection improves survival in a subset of patients
– No validated models to determine who will/will
not benefit
– nodal, retroperitoneal margin status and PV
invasion difficult to evaluate with certainty
• Time to focus on tumor biology, not location
– sterilize locoregional nodes and peripancreatic
tissue

38. Evolution of Personalized Medicine
• 19th century
– “The practice of medicine is an art…” William Osler
• 20th century
– RCTs to delineate outcome variables
• NSABP „s triumph over radical mastectomy
• 21st century: art replaced by science
– The tumor target: the 6th vital sign
– Oncotype DX
• Stage I/II node negative ER(+) breast cancer
• Recurrence risk based on gene expression profiling

39. Personalized Medicine for PAC
• Continuous quality improvement
– Minimizing perioperative morbidity
– Maximize adjuvant therapy
• Individualize surgical decision-making
– Beyond the “one-size-fits-all” approach
– Genetic predictors of aggressive biology
• Tumor genetics accessible preoperatively
– Identifying responders prior to surgery
• Rational target selection for chemotherapy
– Tailor the treatment to the tumor

40. Neoadjuvant Design Elements
• Analysis of treated tumor
– Science leads the way
• Potential clinical benefits
– reduce risk of positive margin
– Sterilize regional lymph nodes
– Early treatment of systemic disease
• Candidates for neoadjuvant therapy
– Resectable (new indication)
– Locally-advanced disease
• invasion of SM-PV confluence, mesenteric arteries
• local lymphadenopathy (Stage 2B)
• Published: gemcitabine, cisplation, paclitaxel, etc

41. Molecular Profiling
• Rational target selection for chemotherapy
– Gene expression profiling and immunohistochemistry

42. Perception Trumps Reality
!
Bilimoria K, National Failure to Operate on Early Stage Pancreatic Cancer, Ann Surg 2007 Aug

43. Why Minimally-Invasive Surgery?
• Potential benefits
– Improved quality of life
– Increased patient acceptance
– Earlier/more frequent adjuvant chemotherapy
– Better cancer outcomes?
• Foreseeable risks
– Oncologic compromises
• Margin negative rate/ nodal harvest
– Preventable technical harm
• Conversion events
• Fear of Cost differential

44. Minimally-Invasive Pancreatic Surgery
• World‟s largest experience: 250 cases to date
• Tumors in the pancreatic neck, body, tail
– Benign and malignant lesions
– Distal and extended distal pancreatectomy
• With/without splenectomy
– Enucleation for islet cell tumors
• Pancreatic head lesions
– Enucleation
– Robotic pancreatoduodenectomy (Whipple)

45. This is the Future…
But Not Yet
Fancy
molecular
stuff

46. Minimally-Invasive Pancreatic Oncology
1. Recreate open techniques
2. Maximize margin negative
outcomes
3. Minimize conversions
4. Eliminate selection bias
Validated prediction rule
Bao et al, HPB 2009

47. Perception Trumps Reality
!
Bilimoria K, National Failure to Operate on Early Stage Pancreatic Cancer, Ann Surg 2007 Aug

48. This is the Future…
But Not Yet
Fancy
molecular
stuff

49. Minimally-Invasive Pancreatic Oncology
1. Recreate open techniques
2. Maximize margin negative
outcomes
3. Minimize conversions
4. Eliminate selection bias
Validated prediction rule
Bao et al, HPB 2009

50. Minimally-Invasive Surgery for PDC
• Retrospective, 9 centers, 2000-2008
– 212 distal panc for PDC, 23 laparoscopic
– 3:1 matched comparison to historical controls
– Minimally-invasive patients heavier
• Pathology
– No differences in margin status or nodal harvest
• Minimally-invasive group
– Reduced hospitalization (2 days)
– Reduced blood loss
Kooby et al J Am Coll Surg 2010; 210(5)

51. Minimally-Invasive vs. Open
• Retrospective, UPMC, 2002-2010
– 62 distal pancreatectomies for PDC (34 open, 28 MIS)
– Intention to treat methodology/Propensity score analysis
• Control imbalances between the groups
– No selection bias evident
• Demographics, comorbid conditions, imaging factors
• Short-term outcomes: reduced EBL and LOS
– 5 laparoscopic conversions to ODP
– Complication rates same
– Cancer outcomes identical

52. • Robotic procedure superior
– Greater risk of PDC in robot group (43% vs. 19%)
– No robotic conversions to open surgery
• 0% robotic vs. 16% laparoscopic, p<0.05
– Retrieved more lymph nodes (19 vs. 9, p<0.05)
– Reduced risk of a positive surgical margin
• 0% robotic vs. 36% laparoscopic (p<0.05)
• Effect of conversion on outcome
– Incision; longer hospitalization (2 days); blood loss
Data presented as either mean SD, median (IQR), or n (%)

53. Robotic Pancreatoduodenectomy
• Two experienced surgeons
• Surgeon console
– Stereoscopic vision
– Fine motor and foot control
– Tremor dampening
• Patient console
– Three articulated arms
– Camera
• Seven laparoscopic ports

54. Robotic Dissection and Suturing
split_screen.w mv

55. Technical Feasibility
Ann Surg Oncol
DOI 10.1245/s10434-011-2045-0
ORI GI NA L A RT I CL E – PA N CREA T I C T UM ORS
Outcomes After Robot-Assisted Pancr eaticoduodenectomy
for Per iampullar y L esions
F
Her ber t J. Zeh1,2, Amer H. Zur eikat 1, Aar on Secr est 1, M ustapha Dauoudi 1, David Bar tlett 1, and A. James M oser 1,2
1
Division of Surgical Oncology, Department of Surgery, University of Pittsburgh, Pittsburgh, PA; 2Division of HPB
OO
Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
Ann Surg Oncol
DOI 10.1245/s10434-011-2045-0
ABSTRACT robot-assisted approach holds promise. Larger, more 40
ORI GI NA L A RTI CL E – theoretical advantages that
Backgr ound. There are manyPA NCREA TI C TUM ORS mature multi-institutional cohorts will be needed to explore 41
a minimally invasive approach to the pancreaticoduoden- potential benefits over open and laparoscopic techniques. 42

56. Outcomes of 100 Robotic-Assisted PD
Characteristic Mean/ Frequency
Age, year, mean ± SD 67.7±12.7
Female sex, n (%) 47 (47%)
Body mass index, mean ± SD 27.3± 5.7
CCI Age Unadjusted 1 (1-3) (Median/ IQR)
CCI Age Adjusted 4 (2-5) (Median/ IQR)
Prior abdominal surgery, n (%) 51 (51%)
ASA score, n (%)
I 0(0%)
II 33 (33%)
III 62 (62%)
IV 5 (5%)
Pre-op CA 19-9 40.7 (16-225)
(Median/IQR)
ASA American Society of Anesthesiologists

57. Indications
Lesion n, (%)
Pancreatic ductal adenocarcinoma (PDA) 36 (36%)
Peri -ampullary carcinoma ( AC, DCC,Duodenal) 28(28%)
Pre- malignant ( IPMN, adenoma, SCA,MCN) 23 (22%)
Neuroendocrine tumor (NET) 10 (10%)
PPN (n=2), MRCC (n=1) 3 (4%)

58. 100 Robot-Assisted Pancreatoduodenectomies
600
500
400 7 hours
Minutes
300
200