Innovations in Pancreatic Cancer:        Reason to Hope            A. James Moser, M.D. FACS.Director, Institute for Hepat...
We Share Your Mission• Imagine a Future without Pancreatic Cancer!   – Raise Awareness Today      • Early diagnosis and pr...
Focus on the Imminent:    Modern Total Pancreatectomy•   62 yo man; recurring abdominal pain•   chronic pancreatitis; PRSS...
Rising Incidence of Pancreatic Cancer• Geographic risk of  pancreatic cancer     – Rising in Cape Cod and       New Englan...
• By 2030:   – 2nd cause of cancer death   – 1.4-1.8% incr. per year• Possible Factors   – Obesity   – Caucasian
Pancreatic Cancer Statistics• 4th most common cause of cancer death   – 34,000 new cases every year   – “Silent” disease  ...
Extent of Disease at Diagnosis  Improvements in diagnostic imaging?    Shaib et al, Aliment Pharmacol Ther 24, 87-94, 2006
Issues for the Pancreatic Cancer Patient     • Can you treat my cancer?     • Can you relieve my symptoms?        –   Nutr...
No Librarian=ConfusionNational Cancer Database Statistics on 100,313 Patients 1985-1995                 Sener et al, J Am ...
“Why do you need to go to medical      school when you have the Internet?”                                            His ...
Regionalized Care for Pancreatic Cancer?            Sener et al, J Am Coll Surg 1999; 189: 1-7.
BIDMC Pancreatic Cancer Center           Vision  The state of the art for   pancreatic cancer is a      clinical trial.
Internet Resources
Evolution of Personalized Medicine• 19th century   – “The practice of medicine is an art…” William Osler• 20th century   –...
The Future of Pancreatic Cancer  • Combine new treatments to     – Kill cancer cells around the main tumor       and in th...
BIDMC Pancreatic Cancer                Specialty Care Center                      617-667-PANC (7262)• Multidisciplinary C...
Staging, Diagnosis, and Treatment• Stage the disease   – Stage I/II: surgery is possible   – Stage III: too advanced for s...
Allaying Fear of Chemotherapy• Stage 4; Gemzar/Xeloda• How will chemo make me feel?   • Less burden with time   • Reduced ...
Better Quality of Life• Stage 4 pancreatic cancer• Gemzar/Xeloda   – Reduced pain   – Improved mood
Chemotherapy That Works• FOLFIRINOX vs. Gemcitabine (2011)  – Stage 4 pancreatic cancer  – Significantly improved:     • r...
Stereotactic Radiosurgery (Cyberknife)• Highly-conformal XRT  with real-time imaging• Gold fiducials for targeting• Breath...
Whipple’s Operation:Localized Pancreatic Cancer
Leave No Cancer BehindPortal vein NOT involved   Portal vein involved
No Substitute for ExperienceMakary et al, Pancreaticoduodenectomy in the very elderly, JOGS 2006.
Case Presentation:• 70 y/o woman with painless jaundice• CT showed 2x3 cm ill defined mass in head  of pancreas• EUS confi...
Endoscopic Ultrasound• Hypoechoic lesion  in pancreatic head• Intact hyperechoic  interface between  tumor and PV
Case Presentation• Robot-assisted minimally-invasive  pancreaticoduodenectomy (Whipple operation)• Uneventful recovery dis...
Advanced Pancreatic Cancer
Worse Cancer = Even Bigger        Operation      Portal vein involved
Preoperative Therapy for PAC• Goals of neoadjuvant multimodality therapy:   – reduce risk of positive margin   – Sterilize...
BIDMC Pancreatic Cancer Center          Mission• Combine new treatments to:   – Improve survival   – Optimize patient sele...
Does Radical Surgery Improve Outcome?• “Regional” pancreatectomy to clear SMA margin   – increased morbidity and mortality...
What We Do• Multidisciplinary evaluation by expert team  • BIDMC Pancreatic Cancer Specialty Care Center    – Multidiscipl...
Staging, Diagnosis, and          Treatment• Stage the disease   – Stage I/II: surgery is possible (resectable)      • Tumo...
Lessons from Radical Surgery• Locally and regionally aggressive disease at diagnosis• Resection improves survival in a sub...
Evolution of Personalized Medicine• 19th century   – “The practice of medicine is an art…” William Osler• 20th century   –...
Personalized Medicine for PAC• Continuous quality improvement   – Minimizing perioperative morbidity   – Maximize adjuvant...
Neoadjuvant Design Elements• Analysis of treated tumor   – Science leads the way• Potential clinical benefits   – reduce r...
Molecular Profiling• Rational target selection for chemotherapy   – Gene expression profiling and immunohistochemistry
Perception Trumps Reality                                                                           !Bilimoria K, National...
Why Minimally-Invasive Surgery? • Potential benefits    –   Improved quality of life    –   Increased patient acceptance  ...
Minimally-Invasive Pancreatic Surgery• World‟s largest experience: 250 cases to date• Tumors in the pancreatic neck, body,...
This is the Future…               But Not YetFancymolecularstuff
Minimally-Invasive Pancreatic Oncology1. Recreate open techniques2. Maximize margin negative   outcomes3. Minimize convers...
Perception Trumps Reality                                                                           !Bilimoria K, National...
This is the Future…               But Not YetFancymolecularstuff
Minimally-Invasive Pancreatic Oncology1. Recreate open techniques2. Maximize margin negative   outcomes3. Minimize convers...
Minimally-Invasive Surgery for PDC• Retrospective, 9 centers, 2000-2008   – 212 distal panc for PDC, 23 laparoscopic   – 3...
Minimally-Invasive vs. Open• Retrospective, UPMC, 2002-2010  – 62 distal pancreatectomies for PDC (34 open, 28 MIS)  – Int...
• Robotic procedure superior   – Greater risk of PDC in robot group (43% vs. 19%)   – No robotic conversions to open surge...
Robotic Pancreatoduodenectomy• Two experienced surgeons• Surgeon console   – Stereoscopic vision   – Fine motor and foot c...
Robotic Dissection and Suturing                      split_screen.w mv
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 of 100 Robotic-Assisted PD  Characteristic                            Mean/ Frequency  Age, year, mean ± SD      ...
IndicationsLesion                                          n, (%)Pancreatic ductal adenocarcinoma (PDA)          36 (36%)P...
100 Robot-Assisted Pancreatoduodenectomies          600          500          400   7 hoursMinutes          300          200
Innovations in Pancreatic Cancer: A Reason to Hope
Innovations in Pancreatic Cancer: A Reason to Hope
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Innovations in Pancreatic Cancer: A Reason to Hope

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Innovations in Pancreatic Cancer: A Reason to Hope

  1. 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. 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. 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. 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. 5. • By 2030: – 2nd cause of cancer death – 1.4-1.8% incr. per year• Possible Factors – Obesity – Caucasian
  6. 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. 7. Extent of Disease at Diagnosis Improvements in diagnostic imaging? Shaib et al, Aliment Pharmacol Ther 24, 87-94, 2006
  8. 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. 9. No Librarian=ConfusionNational Cancer Database Statistics on 100,313 Patients 1985-1995 Sener et al, J Am Coll Surg 1999; 189: 1-7.
  10. 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. 11. Regionalized Care for Pancreatic Cancer? Sener et al, J Am Coll Surg 1999; 189: 1-7.
  12. 12. BIDMC Pancreatic Cancer Center Vision The state of the art for pancreatic cancer is a clinical trial.
  13. 13. Internet Resources
  14. 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. 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. 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. 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. 18. Allaying Fear of Chemotherapy• Stage 4; Gemzar/Xeloda• How will chemo make me feel? • Less burden with time • Reduced coping effort
  19. 19. Better Quality of Life• Stage 4 pancreatic cancer• Gemzar/Xeloda – Reduced pain – Improved mood
  20. 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. 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. 22. Whipple’s Operation:Localized Pancreatic Cancer
  23. 23. Leave No Cancer BehindPortal vein NOT involved Portal vein involved
  24. 24. No Substitute for ExperienceMakary et al, Pancreaticoduodenectomy in the very elderly, JOGS 2006.
  25. 25. 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
  26. 26. Endoscopic Ultrasound• Hypoechoic lesion in pancreatic head• Intact hyperechoic interface between tumor and PV
  27. 27. 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
  28. 28. Advanced Pancreatic Cancer
  29. 29. Worse Cancer = Even Bigger Operation Portal vein involved
  30. 30. 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
  31. 31. 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
  32. 32. 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?
  33. 33. 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
  34. 34. 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,
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. Molecular Profiling• Rational target selection for chemotherapy – Gene expression profiling and immunohistochemistry
  40. 40. Perception Trumps Reality !Bilimoria K, National Failure to Operate on Early Stage Pancreatic Cancer, Ann Surg 2007 Aug
  41. 41. 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
  42. 42. 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)
  43. 43. This is the Future… But Not YetFancymolecularstuff
  44. 44. Minimally-Invasive Pancreatic Oncology1. Recreate open techniques2. Maximize margin negative outcomes3. Minimize conversions4. Eliminate selection bias Validated prediction rule Bao et al, HPB 2009
  45. 45. Perception Trumps Reality !Bilimoria K, National Failure to Operate on Early Stage Pancreatic Cancer, Ann Surg 2007 Aug
  46. 46. This is the Future… But Not YetFancymolecularstuff
  47. 47. Minimally-Invasive Pancreatic Oncology1. Recreate open techniques2. Maximize margin negative outcomes3. Minimize conversions4. Eliminate selection bias Validated prediction rule Bao et al, HPB 2009
  48. 48. 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)
  49. 49. 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
  50. 50. • 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 (%)
  51. 51. 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
  52. 52. Robotic Dissection and Suturing split_screen.w mv
  53. 53. 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, PAAnn Surg OncolDOI 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
  54. 54. 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
  55. 55. IndicationsLesion 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%)
  56. 56. 100 Robot-Assisted Pancreatoduodenectomies 600 500 400 7 hoursMinutes 300 200

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