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Lalan S. Wilfong
GI malignancies
September 26, 2005
Colon Cancer
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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
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Age, Western countries, high-fat diets
Obesity, Genetics, Inflammatory Bowel
Disease
Genetic Causes
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Familial Adenomatous
Polyposis
Hereditary
Nonpolyposis
Colorectal Cancer
Hamartomatous
Polyposis Syndromes
Familial Colorectal
Cancer
Familial Adenomatous
Polyposis
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1% of all colorectal cancer
Hallmark is hundreds to
thousands of colon polyps
100% develop colon
cancer
Extracolonic features:
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Hypertrophy of retinal
epithelium
Mandibular osteomas
Epidermal cysts
Desmoid tumors
Adrenal cortical adenomas
Gene is APC on 5q21
HNPCC
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3% of colorectal
cancer
Usually occurs in right
colon
Accelerated
progression of polyps
to cancer
Can have extracolonic
tumors
Risk:
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80% for colon cancer
40% for endometrial
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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?
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Mismatch Repair genetic defect
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Encode enzymes that repair errors during
DNA replication
Main genes MLH1, MSH2, MSH6 and PMS2
Microsatellite instability
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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
Putative Role of Mutations in Mismatch-Repair Genes
Lynch, H. T. et al. N Engl J Med 2003;348:919-932
Strategy for Risk Reduction
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Colonoscopy every 1-3 years beginning age 2025 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
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Slow progression
from adenoma to
cancer make
screening appropriate
Best approach is
unknown
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DRE
Fecal occult blood
Sigmoidoscopy
Barium enema
Colonoscopy
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Average Risk
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FOBT
Flex sig every 5 yrs
Colon every 10 yrs
Increased Risk
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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
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Colon Carcinogenesis and the Effects of Chemopreventive Agents
Janne, P. A. et al. N Engl J Med 2000;342:1960-1968
Stage
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I
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II
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N
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III
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IV
1: invades submucosa
2: invades muscularis
propria
3: through muscularis
propria
4: invades other organs
0: no lymph nodes
1: 1-3 lymph nodes
2: 4 or more lymph
nodes
M:
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0: no mets
1: with mets
100
90
80
70
60
50
40
30
20
10
0
5 year
survival
II
II
I
IV
T
I
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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
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Disease-free survival after adjuvant chemotherapy for colorectal
cancer using Fluorouracil and Leucovorin (FL) or FL +
Oxaliplatin
Andre, T. et al. NEJM 2004; 350:2343-2351
Trends in the Median Survival of Patients with
Advanced Colorectal Cancer
Meyerhardt, J. A. et al. NEJM 2005; 352:476-487
Adapted from Grothey et al
Targeted Therapies
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Avastin
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VEGF inhibitor
Blocks blood vessel formation
All cells need O2 and therefore blood
Erbitux
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EGFR inhibitor
Overexpression in many cancer cell lines
Important ligand for growth factors
Angiogenesis
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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
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Fig 1. Mechanisms of receptor activation
Mendelsohn, J. J Clin Oncol; 20:1s-13s 2002
Copyright © American Society of Clinical Oncology
Esophageal Cancer
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12,000 cases in US per year
More common in Asia, blacks, males, age
>50
Two Cell Types
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Squamous –
• associated with smoking, etoh, nitrities, pickled
vegetaqble, lye, achalasia, esophageal web, diet
• Incidence decreasing
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Adenocarcinoma –
• associated with reflux, Barrett’s, obesity
• Incidence increasing esp in white males
Clinical Features
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Location
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15% upper 1/3
40% middle 1/3
45% lower third
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Symptoms
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Dysphagia
Weight loss
Pain
vomiting
Spread
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Adjacent lymph
nodes
Lung
Liver
Pleura
Diagnosis
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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
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Gastric Cancer
Incidence decreasing
 21,500 new cases per year
 More common in Asia
 85% adenocarcinomas
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Diffuse – infiltrate and thicken the
stomach wall causing linitis plastica
 Intestinal type – glandlike structures
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Features
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Etiology
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Ingestion of nitrates
H pylori
Loss of gastric acidity
Presentation
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Upper abdominal pain
Anorexia +/- nausea
Weight loss
dysphagia
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Spread
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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
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Resection for early stage
Lymph node dissection
 20% 5 year survival
 Palliative even in advanced disease
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Chemotherapy for advanced disease
Palliative benefit
 ? Prolongs survival
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Radiation only for palliation
Pancreatic Cancer
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Incidence increasing – 28,299 cases in
2000
Risk factors
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Smoking
Age
Male
Blacks
Chronic pancreatitis
Diabetes
obesity
Treatment
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Resection
Only 15% have resectable lesions
 5 year survival 10%
 Maybe improved with chemoradiation
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Unresectable or metastatic
Survival 6 months
 Chemo offers palliation
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Clincal Features
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90% adenocarcinomas
70% in head, 30% in body and tail
Onset insidious
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Jaundice
Pain
Weight loss
Diagnosis
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Ct scan
MRI
EGD, ERCP, EUS
Ca 19-9