new developments for pancreatic cancer · ovarian cancer called parp inhibitor inherited cancer...
TRANSCRIPT
1
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
2
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
3
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
4
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
5
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!
6
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
7
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
8
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
9
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
10
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
11
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
12
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
13
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.
14
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)
15
Immunology-The Next FrontierProgrammed Death Receptor
The Future: Personalized Therapy
MacConaill L E , Garraway L A JCO 2010;28:5219-5228
16
Q & A