Download New Developments for Pancreatic Cancer The Big Picture

New Developments for
Pancreatic Cancer
Ramesh K. Ramanathan MD
GI Medical Oncology
Mayo Clinic, AZ
Clinical Professor, TGEN
TN: 480-301-8000
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
1
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 advancedOnly 10-20% are operable
2
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
3
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
•
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
New York times 2007, Tersuette et al. Clin. Cancer Res. 7: 738-744, 2001
4
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!
5
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 Obst
1946;82:62
The Whipple Operation
6
Summary of Therapies for
1. Localized
• Surgery with follow up
treatment
2. Locally advanced
• XRT + chemo or chemo
alone
3. Metastatic
• chemotherapy
Von Hoff, Mahadevan and Bearss. Clinical Oncology Updates 4:1-15, 2001.
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
7
Pain is Multidimensional
Social
Emotional
PAIN
Spiritual
Functional
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
8
Are We Making Progress?
May 1998
May 2001
March 2013
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
9
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
10
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
11
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
12
Visualization Of Complete
Genome By Circos Map
Circos map
legend:
Coverage
- Germline and Tumor
All De Novo changes
Cyan tics
Somatic synonymous
Orange tics
Somatic nonsynonymous
Red tics
Somatic copy number
Deletion
Bioinformatics is Critical
The 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.
13
Signaling Pathways
•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
Jones S. Science. 321:1801-6; 2008
New Studies: Degrade the Stroma and Attack the
Fuel Supply (albumin and lipids)
Albumin
Protein
Lipids
Lipid
14
Immunology-The Next Frontier
Programmed Death Receptor
The Future: Personalized Therapy
MacConaill L E , Garraway L A JCO 2010;28:5219-5228
15
Q&A
16