Lalan S. Wilfong

GI malignanciesMay 28, 2009

Colon Cancer 800,000 new cases per year globaly 11% of cancer mortality in the US Lifetime risk of 0.5-2.0% of

developing colon cancer Risk factors

Age, Western countries, high-fat diets Obesity, Genetics, Inflammatory Bowel

Disease

Genetic Causes Familial Adenomatous

Polyposis Hereditary

Nonpolyposis Colorectal Cancer

Hamartomatous Polyposis Syndromes

Familial Colorectal Cancer

Familial Adenomatous Polyposis 1% of all colorectal cancer Hallmark is hundreds to

thousands of colon polyps 100% develop colon

cancer Extracolonic features:

Hypertrophy of retinal epithelium

Mandibular osteomas Epidermal cysts Desmoid tumors Adrenal cortical

adenomas Gene is APC on 5q21

HNPCC 3% of colorectal

cancer Usually occurs in right

colon Accelerated

progression of polyps to cancer

Can have extracolonic tumors

Risk: 80% for colon cancer 40% for endometrial

With skin tumors called Muir-Torre syndrome

Autosomal dominant with 80% penetrance

Defect in mismatch repair genes

Can test for Microsatellite instability in tumors

Diagnosis of HNPCC

Diagnosis of HNPCC

What Happens? Mismatch Repair genetic defect

Encode enzymes that repair errors during DNA replication

Main genes MLH1, MSH2, MSH6 and PMS2 Microsatellite instability

Microsatellites are repetitive DNA sequences found throughout the genome

Loss of MMR results in repetitive coding and noncoding regions of genes including genes involved in tumor initiation and progression

Lynch, H. T. et al. N Engl J Med 2003;348:919-932

Putative Role of Mutations in Mismatch-Repair Genes

Strategy for Risk Reduction Colonoscopy every 1-3 years beginning age 20-

25 or 10 years before earliest relative Prophylactic colectomy Chemoprevention? Transvaginal ultrasound or endometrial

aspiration annually Prophylactic hysterectomy If stomach cancer in family, EGD every 1-2 years If urinary tract cancer, sono or urine cytology

every 1-2 years

Screening for Population Slow progression from

adenoma to cancer make screening appropriate

Best approach is unknown DRE Fecal occult blood Sigmoidoscopy Barium enema Colonoscopy

Average Risk FOBT Flex sig every 5 yrs Colon every 10 yrs Stop at age 75-85

Increased Risk Colon starting 10 years

before youngest affected member

3 or more polyps, colon in 3 years

1-2 polyps (<1cm) colon in 5 yrs

Chemoprevention Medications to prevent cancer

before cancer begins Since colon cancer has stepwise

progression from adenoma to invasive disease, if we can block one of the steps we can stop cancer

Janne, P. A. et al. N Engl J Med 2000;342:1960-1968

Colon Carcinogenesis and the Effects of Chemopreventive Agents

Stage T

1: invades submucosa 2: invades muscularis

propria 3: through muscularis

propria 4: invades other organs

N 0: no lymph nodes 1: 1-3 lymph nodes 2: 4 or more lymph nodes

M: 0: no mets 1: with mets

I

II

III

IV

0

10

20

30

40

50

60

70

80

90

100

5 yearsurvival

Treatment Stage I – surgery Stage II – surgery unclear role of

chemotherapy Stage III – surgery followed by

adjuvant chemotherapy Stage IV – palliative chemotherapy Rectal Cancer – surgery, radiation

and chemotherapy

Andre, T. et al. NEJM 2004; 350:2343-2351

Disease-free survival after adjuvant chemotherapy for colorectal cancer using Fluorouracil and Leucovorin (FL) or FL +

Oxaliplatin

Meyerhardt, J. A. et al. NEJM 2005; 352:476-487Adapted from Grothey et al

Trends in the Median Survival of Patients with Advanced Colorectal Cancer

Targeted Therapies Avastin

VEGF inhibitor Blocks blood vessel formation All cells need O2 and therefore blood

Erbitux/Vectibix EGFR inhibitor Overexpression in many cancer cell lines Important ligand for growth factors

Angiogenesis Cells cannot survive if

they lack oxygen and nutrients

Oxygen can diffuse from capillaries to a distance of only 150 to 200 µm

when cells are farther away from a blood supplythey die.

Thus, to become clinically relevant, a tumor requires neovascularization or angiogenesis to survive

Epidermal Growth Factor Receptor Inhibitor EGFR overexpressed on many epithelial

cancers Correlates with poor outcome Acts as a tyrosine kinase Blocking this receptor can lead to cell

cycle arrest and apoptosis EGFR blockade can improve survival in

many cancers Only effective in tumors with wild-type

kras

Copyright © American Society of Clinical Oncology

Mendelsohn, J. J Clin Oncol; 20:1s-13s 2002

Fig 1. Mechanisms of receptor activation

Esophageal Cancer 12,000 cases in US per year More common in Asia, blacks, males, age

>50 Two Cell Types

Squamous – • associated with smoking, etoh, nitrities, pickled

vegetaqble, lye, achalasia, esophageal web, diet• Incidence decreasing

Adenocarcinoma – • associated with reflux, Barrett’s, obesity• Incidence increasing esp in white males

Clinical Features Location

15% upper 1/3 40% middle 1/3 45% lower third

Symptoms Dysphagia Weight loss Pain vomiting

Spread Adjacent lymph

nodes Lung Liver Pleura

Diagnosis Endoscopy CT scans PET

Treatment Most patients present with advanced

disease and prognosis is <5% 5 year survival

Resection for early stage disease Chemoradiation for locally advanced

disease Chemotherapy for advanced disease PEG tube or stents for nutrition

Gastric Cancer Incidence decreasing 21,500 new cases per year More common in Asia 85% adenocarcinomas

Diffuse – infiltrate and thicken the stomach wall causing linitis plastica

Intestinal type – glandlike structures

Features Etiology

Ingestion of nitrates H pylori Loss of gastric acidity

Presentation Upper abdominal pain Anorexia +/- nausea Weight loss dysphagia

Spread Directly to perigasatric

tissues Peritoneal seeding Intra-abdominal and

supraclavicular lymph nodes

Ovary (Krukenberg) Periumbilical (sister

Mary Joseph) Peritoneal cul-de-sac

(Blummers shelf) Liver

Treatment Resection for early stage

Lymph node dissection 20% 5 year survival Palliative even in advanced disease

Chemotherapy for advanced disease Palliative benefit ? Prolongs survival

Radiation only for palliation

Pancreatic Cancer Incidence increasing – 28,299 cases in

2000 Risk factors

Smoking Age Male Blacks Chronic pancreatitis Diabetes obesity

Treatment Resection

Only 15% have resectable lesions 5 year survival 10% Maybe improved with chemoradiation

Unresectable or metastatic Survival 6 months Chemo offers palliation

Clincal Features 90% adenocarcinomas 70% in head, 30% in body and tail Onset insidious

Jaundice Pain Weight loss

Diagnosis Ct scan MRI EGD, ERCP, EUS Ca 19-9

Median Survival: 18.8 months with Gemzaar vs. 16.7 months for 5-FU

Current Research at PHD Colon Cancer

SPIRITT: Folfiri with panitumimab or avastin 2nd line MCRC in kras wild-type

Folfiri +/- AMG479 or AMG 655 or placebo in 2nd line kras mutant colon cancer

Gastric Docetaxel and Oxaliplatin +/- cetuximab for metastatic

gastric adenoca Pancreatic

Gemcitabine +/- amplimexon for met pancreatic cancer Gemcitabine +/- GI-4000 for resected pancreatic cancer