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.
References
Ahmad NA, Lewis JD, Siegelman ES. Et al. Role of endoscopic ultrasound and magnetic resonance imaging in the preoperative staging of pancreatic adenocarcinoma. Am J Gastroenterol 2000; 95: 1926
Barish MA, Yucel EK, Ferrucci JT. Magnetic resonance cholangiopancreatography. N Engl J Med 1999; 341:258
Burris III H. and Rocha-Lima C. New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways. The Oncologist 2008; 13: 289-298
Escalante-Glorsky S, Angulo P, Blonis PAL, Raijman I. 2008. Endoscopic methods for the diagnosis of pancreaticobiliary neoplasms. (Updated April 2008). Available at: http://www.uptodate.com/online/content/topic.do?topicKey =biliaryt/15416&selectedTitle=21~117&source=search_result [Accessed 15 Sept 2008]
Fernandez-del Castillo C, Tanabe KK, Jimenez RE. Et al. 2008. Surgery in the treatment of pancreatic exocrine cancer. [Online] (Updated May 2008). Available at: http://www. uptodate.com/online/content/ topic.do? topicKey = gicancer / 14548&selectedTitle=16~117&source = search_result#13 . [Accessed 15 Sept 2008]
Fernandez-del Castillo C, Tanabe KK, Jimenez RE. Et al. 2008. Risk factors for and molecular pathogenesis of pancreatic cancer.[Online] (Updated October 2007).Availableat:http://www.uptodate.com/online/content/topic.do?topicKey=gicancer/14030&selectedTitle=3~117&source=search_result# [Accessed 15 Sept 2008]
References
Fujino Y, Sakai T, Kuroda Y. Palliative pancreatectomy with postoperative gemcitabine for patients with advanced pancreatic cancer. Journal of Gastroenterology 2008; 43(3): 233-238
Gress FG, Howell DA, Bonis PAL. 2008. The role of endoscopic ultrasound in the staging of pancreatic adenocarcinoma. [Online] (Updated April 2007). Available at: http://www.uptodate.com/online/content/topic.do?topicKey=pancdis/2512&selectedTitle=18~117&source=search_result [Accessed 14 Sept 2008]
Gunaratnam NT, Howell DA, Bonis PAL. Et al. 2008. Endosonography-guided celiac plexus neurolysis. [Online] (Updated Sept 2006). Available at: http:// www.uptodate.com /online /content /topic.do?topicKey=pancdis/9683&selectedTitle=7~117&source=search_result. [Accessed 13 Sept 2008]
Jemal A, Siegel R, Ward E. et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56:106 Johns Hopkins - Surgical Treatment of Pancreatic Cancer [Online] Available at:
http: //pathology .jhu.edu/pancreas/TreatmentSurgery.php [Accessed 15 Sept 2008] Karnam US, Kruskal JB, Reddy KR. 2008. Magnetic resonance cholangiopancreatography.
[Online] (Updated 8 May 2008) Available at: http://www.uptodate.com /online/content / topic.do? Topic Key=biliaryt/6181&selectedTitle=12~117&source=search_result [Accessed 14 Sept 2008]
Laurent-Puig P, Talieb J. Lessons from Tarceva in pancreatic cancer: where are we now, and how should future trials be designed in pancreatic cancer? Current Opinion in Oncology 2008; 20(4): 454-458
Lee CJ, Dosch J, Simeone DM. Pancreatic cancer stem cells. Journal of Clinical Oncology 2008; 26(17): 2806-2812
McWilliams RR, Rabe KG, Olswold C, et al. Risk of malignancy in first-degree relatives of patients with pancreatic carcinoma. Cancer 2005; 104:388
References
Neoptolemos JP, Stocken DD, Friess H et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350:1200-10
Nieto J, Grossbard ML, Kozuch P. Metastatic pancreatic cancer 2008: Is the glass less empty? The Oncologist 2008; 13: 562-576
Pancreatic Cancer 2007. [Online] Available at: http://en.wikipedia.org /wiki / Pancreatic cancer [Accessed 16 Sept 2008]
Ryan DP, Mamon H, Goldberg RM. Et al. 2008. Adjuvant and neoadjuvant therapy for pancreatic and ampullary adenocarcinoma (Updated 2008) Available at: http: //www. uptodate.com/online/content/topic.do?topicKey=gicancer/12842&selectedTitle=8~117&source=search_result. [Accessed 12 Sept 2008]
Ryan DP, Goldberg RM, Savarese DMF. Et al. 2008. Management of locally advanced pancreatic exocrine cancer. [Online] (Updated May 2007). Available at: http: //www. uptodate.com/online/content/topic.do?topicKey=gicancer/13604&selectedTitle=4~117&source=search_result#20 [Accessed 14 Sept 2008]
Steer ML, Whitcomb DC, Bonis PAL, et al. 2007. Pathology of exocrine pancreatic cancer. [Online]. Available at: http: //www.uptodate.com /online/content / topic. Do ? topicKey=pancdis/8602&selectedTitle=2~117&source=search_result#3 [Accessed 16 Sept 2008].
Steer ML, Tanabe KK, Howell DA et al. 2008. Clinical manifestations, diagnosis, and surgical staging of exocrine pancreatic cancer.[Online] (Updated May 2008) Available at: http://www.uptodate.com/online/content/topic.do?topicKey=gicancer/23938#15 [Accessed 14 Sept 2008]
Tarceva (erlotinib) Tablets, NDA 21-743: Supplemental NDA Briefing document – 13 September 2005. ODAC Meeting
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