What links these 4 together?

Michael Landon Pavarotti Patrick Swayze Joan Crawford

Pancreatic Cancer: Advances in Treatment

Hisham Rana, MD

Anatomy

Epidemiology

4th commonest cause of cancer death in US, 2nd only to colorectal cancer in GI cancers

37,680 pts diagnosed annually – almost all die

Rare before the age of 45. Incidence rises sharply thereafter.

Males > females (ratio 1.3:1) African Americans (14.8 per 100,000 v 8.8

gen pop) 40-45%: present with metastatic disease 40%: present with locally advanced

disease 5-25%: present with tumors amenable to

resection

Risk Factors: Genetic

5-10% pts have 1st degree relative with disease. Presents at an earlier age.

BRCA1 & BRCA2Peutz-Jeghers syndrome: risk >36%Ataxia-telangiectasia: risk increasedFamilial adenomatous polyposis &

Lynch Syndrome II (HNPCC)Above factors account for only <

20% of cases

Risk Factors: Environmental

Cigarette smoking: RR 1.5. Quitting reduces risk by 48% by 2 years.

Obesity & Lack of physical activityWestern DietCoffee & Alcohol consumption:

conflicting evidence.Aspirin & NSAIDsPartial gastrectomy &

cholecystectomyH. pylori

Clinical Features: H&P

History Pain Weight Loss Jaundice: Painful vs. Painless Initial presentation: Body or tail vs. Head Other factors

Physical findings Mass or ascites Virchow’s Node Other

Diagnosis & Staging

Labs: bilirubin, alkaline phosphatase, Hb/Hct

Radiographic Ultrasound, CT & CT Angio, ERCP, EUS, MRI and

MRCP, PET ScanningSerum Tumor MarkersFNA Biospy: Percutaneous & EUS-

guidedStaging Laparoscopy

Pathology: Cell Types

3 different epithelial cell types Acinar cells (80% by gland volume) Ductal cells (10-15%) Endocrine (islet) cells (1-2%)

95% of malignant pancreatic neoplasms arise from acinar and ductal cells

Pathology: Ductal & Acinar Cell Ductal Carcinoma – 85-90%

60-70% tumors in head of gland, 5-10% in body, and 10-15% in tail

Masses with ill-defined margins or diffusely infiltrating

Varying degrees of differentiation in the same tumor

Acinar Cell Carcinoma – 1% Elderly Large & metastatic at time of diagnosis Resembles endocrine cells – needs EM or IHC

studies

Prognosis

Timing of disease-associated symptoms Median survival: 8-12 months for locally

advanced unresectable disease, and 3-6 months for those who present with metastases

TreatmentWhat do we do now?

Approach to the Patient

Mass lesion not seen on CT or Ultrasound

Mass lesion in a candidate for major pancreatic resection Criteria for resectability

Mass lesion in a patient who is unfit for a major pancreatic resection

Surgery: Major Pancreatic Resection

Tumors in the head of the pancreas Biliary Drainage Pancreaticoduodenectomy (“Whipple Procedure”) Modifications

Tumors in the body or tail of the pancreas Distal subtotal pancreatectomy

Results / Prognosis Stage IA — 41 and 31 percent Stage IB — 35 and 27 percent Stage IIA — 24 and 16 percent Stage IIB — 14 and 8 percent Stage III — 11 and 7 percent Stage IV — 5 and 3 percent

Criteria for Unresectability

Extrapancreatic involvementEncasement or occlusion of the

superior mesenteric vein or the SMV-portal vein confluence.

Direct involvement of the superior mesenteric artery (SMA), inferior vena cava, aorta, or celiac axis

Management of Locally Advanced Pancreatic Cancer

Conventional external beam radiation therapy

Concomitant Chemoradiotherapy 5-FU Gemcitabine Paclitaxel

Management of Metastatic Pancreatic Cancer

Pain Control Long-acting narcotics Neurolytic celiac plexus block (NCPB)

PERT PPI Bacterial overgrowth

Endoscopic Stenting of Biliary and Pancreatic Obstruction

Chemotherapy for Metastatic Pancreatic Cancer

5-FUGemcitabine

Median survival times versus 5-FU Survival rate at 12-months Toxicities Optimizing efficiency

Combination Chemotherapy Trials

Why combine Gemcitabine with another agent?

Results Gemcitabine + capecitabine (GEMCAP) Gemcitabine + platinum analogue

(GEMOX) Everything else

Molecular Targeted Therapies

Growth Factors are expressed at higher levels in pancreatic cancer

Erlotinib: small molecule tyrosine kinase inhibitor of the EGF receptor In combination with gemcitabine Side Effects Cost / Cost in Years of Life Gained (YLG) Single agent

Cetuximab: EGFR monoclonal antibody

Molecular Targeted TherapiesBevacizumab: anti-VEGF (Vascular

endothelial growth factor) monoclonal antibody Bevacizumab + Gemcitabine (CALGB

Trial) Bevacizumab + Gemcitabine + Erlotinib

(AVITA)Sorafenib: inhibitor of Raf-1 and

VEGF receptor 2Future direction: VEGF Trap &

Sunitinib

Immunotherapy

Gemcitabine + Gastrin Vaccine (G17DT)

Future Immunogenic telomerase peptides

(TeloVac) Hopkins: Lethally irradiated allogenic

pancreatic tumor cells transfected with GM-CSF gene

Listeria carrying mesothelin peptide

Second-Line Therapy

Disease progression with standard gemcitabine

OFF Regimen Basic supportive care with or without

oxaliplatin, plus 5-FU and folinic acidMultidrug Regimes

Conclusions

Since 1996, 20 randomized phase III trials have failed to produce improvement in survival outcomes.

Metastatic pancreatic cancer is one of the most frustrating malignancies to treat.

For now, gemcitabine, gemcitabine + erlotinib, and second-line treatment with OFF has shown benefit.

Supportive care strategies should be emphasized.

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Tarceva (erlotinib) Tablets, NDA 21-743: Supplemental NDA Briefing document – 13 September 2005. ODAC Meeting