lalan s. wilfong gi malignancies september 26, 2005
TRANSCRIPT
Lalan S. Wilfong
GI malignanciesSeptember 26, 2005
Colon Cancer 800,000 new cases per year globably 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
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 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
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