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

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

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

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

• 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

• 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)

Extent of Disease at Diagnosis

Shaib et al, Aliment Pharmacol Ther 24, 87-94, 2006

Improvements in diagnostic imaging?

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

No Librarian=Confusion

Sener et al, J Am Coll Surg 1999; 189: 1-7.

National Cancer Database Statistics on 100,313 Patients 1985-1995

“Why do you need to go to medical school when you have the Internet?”

• 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

His Expectation

Regionalized Care for Pancreatic Cancer?

Sener et al, J Am Coll Surg 1999; 189: 1-7.

BIDMC Pancreatic Cancer CenterVision

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– 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

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

BIDMC Pancreatic CancerSpecialty Care Center

617-667-PANC (7262)

• Multidisciplinary Clinical Care – Specialized expertise

• Pancreatic surgery• Gastroenterology• Medical oncology• Radiation oncology• Chronic pain• Cancer genetics • Nutrition/ Alternative

Medicine Social Work

• Clinical Research – Pancreatic Cancer Registry

• Database– Clinical Trials

• New drugs• Immunotherapy• Cyberknife• New stents• Molecular diagnosis

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

Allaying Fear of Chemotherapy

• Stage 4; Gemzar/Xeloda• How will chemo make me feel?

• Less burden with time• Reduced coping effort

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:

• response rate• disease control (63%-79% of patients)• Better quality of life at 6 months

– 75% improvement in overall survival

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

Whipple’s Operation:Localized Pancreatic Cancer

Leave No Cancer Behind

Portal vein NOT involved Portal vein involved

No Substitute for Experience

Makary 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 confirms mass• Biopsy revealed adenocarcinoma• ERCP showed obstruction of bile duct• Surgery first vs. clinical trial

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 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

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 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

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

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?

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

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, ?surgery

– Stage IV: systemic therapy

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

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

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

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

Molecular Profiling

• Rational target selection for chemotherapy– Gene expression profiling and immunohistochemistry

Bilimoria K, National Failure to Operate on Early Stage Pancreatic Cancer, Ann Surg 2007 Aug

Perception Trumps Reality

!

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

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)

This is the Future…But Not Yet

Fancy molecular stuff

Minimally-Invasive Pancreatic Oncology

1. Recreate open techniques

2. Maximize margin negative outcomes

3. Minimize conversions

4. Eliminate selection bias

Validated prediction ruleBao et al, HPB 2009

Bilimoria K, National Failure to Operate on Early Stage Pancreatic Cancer, Ann Surg 2007 Aug

Perception Trumps Reality

!

This is the Future…But Not Yet

Fancy molecular stuff

Minimally-Invasive Pancreatic Oncology

1. Recreate open techniques

2. Maximize margin negative outcomes

3. Minimize conversions

4. Eliminate selection bias

Validated prediction ruleBao et al, HPB 2009

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)

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

Data presented as either mean ± SD, median (IQR), or n (%)

• 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

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

Robotic Dissection and Suturing

split_screen.wmv

Technical Feasibility

Outcomes of 100 Robotic-Assisted PD

Characteristic Mean/ Frequency

Age, year, mean ± SD 67.7±12.7Female sex, n (%) 47 (47%)Body mass index, mean ± SD 27.3± 5.7CCI 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

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%)

100 Robot-Assisted Pancreatoduodenectomies

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