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Ramesh K. Ramanathan MDGI Medical Oncology

Mayo Clinic, AZ

Clinical Professor, TGEN

TN: 480-301-8000

New Developments for Pancreatic Cancer

The Big Picture

• Worldwide incidence and diagnosis of PC is

increasing

• Early diagnosis if uncommon, no screening test yet

• Treatment is complex and a multi-disciplinary team

(surgeons, GI, oncologists, radiation, pain specialists

etc) are needed

• Research is needed in understanding the molecular

biology to develop targeted strategies for prevention

and treatment

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Worldwide Statistics

•About 45,000 in the US and 250,000 cases worldwide

•Rapidly increasing in China and India

Koorstra et al. Pancreatology 8:110, 2008

Pancreas- behind other structures

That is why it usually presents late and advanced-Only 10-20% are operable

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Epidemiology of Pancreatic Cancer

1. The risk of pancreatic cancer is low in the first 3-4 decades of life

• Increases sharply after age 50

• Most patients are between 60-80 years of age at diagnosis

2. Pancreatic cancer can occur in younger patients

• < 30 years.

• Frequently familial

3. In past, pancreatic cancer was more common in men than women

• Now reverse it true

• Probably because of increasing use of tobacco by women*

Etiology of Pancreatic Cancer

1. Diabetes

2. Pancreatitis

3. Cigarette smoking

• Strongest association, stopping decreases risk

4. Diet

• High intake of fat or meat increases the risk

• High intake of fruit and vegetables reduces the risk

• Sugary, fizzy drinks, Coffee, Alcohol – no

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Inherited Cancer Syndromes

1. BRCA1, BRCA2, Lynch syndrome etc

• Suspect if a parent sibling has cancer at age < 60

• BRACA genes. Most common inherited predisposition to pancreatic cancer

• Generalized mutations found in 5-10% of patients with familial pancreatic cancer and in 1-2 % of patients with sporadic pancreatic cancer

• These findings have serious therapeutic implications: New agent FDA approved for ovarian cancer called PARP inhibitor

Inherited Cancer Syndromes

New York times 2007, Tersuette et al. Clin. Cancer Res. 7: 738-744, 2001

• Familial pancreatic kindred:

• 2 first degree relatives with pancreatic cancer

• * 57 fold increase in chance of getting pancreatic

cancer

*

“We started out a long time ago with

my father dying of pancreatic cancer.

One by one, both my sisters and

brother died of pancreatic cancer.”

For a time, Mr. Carter said, he had CT

scans twice a year to look for lesions

on his pancreas.

New York Times, 2007

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Symptoms and Signs

1. 50% of patients with pancreatic cancer have jaundice at diagnosis (can be something good if small tumor in a critical place)

2. Pain

• Dull fairly constant visceral pain localized to middle and upper back (invasion of celiac/mesenteric plexus)

• Intermittent epigastric pain

• Weight loss

• Anorexia

• Malabsorption (floating stools)

• Diarrhea

• hyperglycemia

3. Physical exam

4. No specifc findings

Staging of Pancreatic Cancer

A pancreatic protocol CT is mandatory!

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Whipple’s Operation: First Performed in 1935

• Dr Allan Whipple (1881-1963). Columbia University (Also Known for Whipple’s Triad and mentor of Virginia Apgar MD)

• Whipple AO. Observations on radical surgery for lesions of the pancreas. Surg Gyn Obst1946;82:62

The Whipple Operation

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Von Hoff, Mahadevan and Bearss. Clinical Oncology Updates 4:1-15, 2001.

Summary of Therapies for

1. Localized• Surgery with follow up

treatment2. Locally advanced

• XRT + chemo or chemo alone

3. Metastatic• chemotherapy

Issues for the Pancreatic Cancer Patient

• Fatigue/ loss of appetite

• Proper diet and regular exercise are critical

• Bile duct (Jaundice) and Gastric outlet obstruction (Nausea/vomiting)

• “No one to watch over me”

– Physician specialization

• Regionalization of care

• The Internet has no librarian-Need reputable information: ACS, Pancreatic Cancer Action Network

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Spiritual Functional

Social

Pain is Multidimensional

Emotional

PAIN

Relief of Symptoms

• Relief of jaundice (biliary obstruction)

– Endoscopic stents (Wallstent)

– Outpatient procedure

• Gastric outlet obstruction

– Laparoscopic surgery (Band-Aid surgery) Short hospital

stay

– Endoscopic stent

• Pain control

– Permanent nerve blocks

– Long-acting pain medicines

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May 1998 May 2001 March 2013

Are We Making Progress?

What Has Happened in The Last 50

years?

• Pancreatic surgery is done routinely and

a safe operation

• No screening test yet, but early

diagnosis is increasing

• Interventional GI-ERCP, EUS, stents

• Symptom control

• New agents and clinical trials

• Understanding the molecular biology

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New Drugs for Pancreatic

Cancer• Gemcitabine is a standard agent

• Most patients with minimal symptoms will receive a combination of agents– Gemcitabine and nab-paclitaxel

– 5FU, oxaliplatin and irinotecan(FOLFIRINOX)

• Active area of research, more than 20 new drugs in clinical trials

Clinical Trials

• Studies designed to evaluate new

treatments

• Goal is to help find better ways of

treating cancer

• Most advances in cancer have occurred

due to clinical trials

• <5% of patients are treated in trials

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Why Take Part?

• New drugs and treatments are often

available only in trials

• May be more effective than “standard

therapy”

• Patients receive close and intensive

monitoring

• May help scientists and other patients

with cancer

How Do Clinical Trials Work?

• Initial testing occurs in the laboratory

and animal research

• Promising drugs enter clinical trials

• Clinical protocol: A detailed

standardized plan is followed

• All studies are evaluated by a review

board

• Placebo trials are rare in cancer

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Why Take Part?

• Every new drug that is approved comes

through clinical trials

• Nationwide less than 5% of pancreatic

cancer patients enter clinical trials

• 80% of Pediatric patients are treated in

clinical trials: Outcome is much better

Types of Trials

• Phase I: Initial trials of a new drug to

evaluate the safety and toxicity of the

compound

• Phase II: Will test the effectiveness of a

new drug in certain cancers

• Phase III: Large studies. The new

treatment is compared to a standard

treatment

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Visualization Of Complete Genome By Circos Map

Coverage- Germline and Tumor

All De Novo changesCyan tics

Somatic nonsynonymousRed tics

Somatic copy number

Somatic synonymousOrange tics

Circos map legend:

Deletion

Bioinformatics is CriticalThe TGen /ASU Saquaro II Supercomputer System

The supercomputer handles 50,000,000,000,000 calculations per second and stores 1.5 quadrillion

bytes of data.

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Signaling Pathways

Jones S. Science. 321:1801-6; 2008

•PC has average of

63 genetic alterations.

•Most are point

mutations.

•Alterations define a

core set of 12 cellular

signaling pathways

• Agents can be

developed to inhibit 1

or more of these

pathways

Albumin Lipids

Protein Lipid

New Studies: Degrade the Stroma and Attack the Fuel Supply (albumin and lipids)

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Immunology-The Next FrontierProgrammed Death Receptor

The Future: Personalized Therapy

MacConaill L E , Garraway L A JCO 2010;28:5219-5228

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Q & A