Instructor: Hi everyone.
In this lecture, we'll be continuing our discussion
of the epidemiology of colon cancer.
Here we'll focus on risk factors and prevention.
The goals of this lecture are to discuss the risk factors
for colorectal cancer,
to characterize trends in colorectal cancer rates,
to discuss the chemoprevention of colorectal cancer
and to discuss the impact of screening by colonoscopy.
So to begin with, chronic alcohol abuse is strongly linked
to colorectal carcinogenesis.
Analysis of data from the US National Health
and Nutrition Examination survey showed a 70% increase
in colorectal cancer among individuals
who consumed one or more drinks
of alcoholic beverages daily.
In a pooled analysis of eight prospective cohort studies
performed in five countries,
it was found that the risk increased by 40%
at the highest level of alcohol consumption,
greater than 45 grams of alcohol daily.
Pooled results from five Japanese studies
suggest that one quarter of all colorectal cancers
in Japan are attributable
to alcohol consumption above 23 grams daily.
Chronic tobacco addiction
has also been linked to colorectal cancer development.
The epidemiologic evidence shows
that chronic smokers of a two to threefold
increased incidence of pre-malignant adenomas of the colon
compared to non-smokers.
In a meta-analysis of 106 studies,
it was found that smoking significantly
increases both the incidence
and mortality of colorectal cancer.
The existing evidence therefore supports the addition
of colorectal cancer to the list
of tobacco associated malignancies.
Various mechanisms may be responsible for the effects
of alcohol and tobacco on colorectal carcinogenesis.
One mechanism involves the combination
of chronic alcohol consumption and folate deficiency.
As ethanol enters the large bowel, it's metabolized into
acetaldehyde by anaerobic microbes.
Acetaldehyde in terms rapidly degrades folates.
Since folate is essential
for normal DNA synthesis and repair,
the fact that it's being degraded rapidly
could readily lead to DNA instability
and carcinogenesis in the colorectal mucosa.
Alcohol consumption may also delay peristalsis
in the large bowel and increase transit time
and exposure to carcinogens and other toxic substances.
Carcinogens from tobacco can reach the colorectal mucosa
through the gastrointestinal tract
or the circulatory system and may accentuate
neurogenesis, inflammation and carcinogenesis,
particularly in the distal colon.
There's also speculation that tobacco and alcohol
may synergistically heighten the risk
of colorectal cancer.
High levels of circulating insulin
and insulin like growth factors
have also been found to increase the risk
of developing colorectal cancer.
Individuals who manifest clinical conditions
associated with high levels of insulin
like type two diabetes,
the metabolic syndrome and acromegaly,
are at increased risk
for the development of colorectal cancer.
Phenotypic and lifestyle factors
associated with hyperinsulinemia
and high IGF one levels increase the risk.
Components of the IGF axis,
IGF1, IGF2, IGF cell membrane receptors
and binding molecules
constitute an important molecular interface
with exposures that initiate
and promote colorectal carcinogenesis.
Chronic inflammation conditions of the intestinal tract
also predispose to the development of colorectal cancer.
Ulcerative colitis is characterized by chronic inflammation
and ulceration of the epithelial lining of the colon
plus other extra colonic lesions.
The primary site of attack is usually
in the descending or left colon,
and approximately 1% of colorectal cancer patients
have a history of chronic ulcerative colitis.
Approximately 40 to 50% of individuals
with long-standing ulcerative colitis develop colon cancer.
Crohn's disease also increases the risk
of colorectal cancer development.
Both ulcerative colitis and Crohn's disease
appear to have an autoimmune basis
and are characterized by similar alterations
in the IGF axis.
The investigation of a large multi-generational family
in the early 1900s
identified a hereditary form of colorectal cancer.
33 relatives with colorectal cancer were diagnosed
among 70 members of the family.
Hereditary nonpolyposis colorectal cancer, or HNPCC,
was later named the Lynch syndrome,
after Dr. Henry T. Lynch,
who documented two large families
with this autosomal dominant syndrome.
Lynch and his colleagues initially designated HNPCC
as the cancer family syndrome.
The cause of HNPCC is an inherited germline mutation
in at least one of a set of genes that normally repair DNA,
the mismatch repair genes.
In 1993, the first of these genes was discovered
on chromosome two,
and in 1994 the second gene was discovered
on chromosome three.
Mutations in these two genes
account for 90% of the known HNPCC families.
Carriers of either gene
have a lifetime colon cancer risk
approaching a hundred percent.
The Lynch syndrome accounts for a small percentage
of all colorectal cancer cases,
accounting for only about one to 3% of all
colorectal cancer cases.
So the Amsterdam criteria
is related to familial colon cancer
and the criteria apply when three or more family members
have a confirmed diagnosis of colorectal cancer
and one of them is a first degree relative of the other two.
This needs to apply to two successive affected generations
and one or more of the three cases
has to be diagnosed under age 50 years.
In 1951, a report of a large Utah family
containing many relatives with diffuse polyps of the colon
and intestinal tract in multiple relatives
with colorectal cancer was published.
It was called Gardener's Syndrome,
and it's a rare form of familial adenomatous polyposis,
or FAP,
and is characterized by the presence of multiple polyps
in the colon together with tumors outside the colon.
In Gardener's syndrome,
the extra colonic tumors or tumors outside the colon
may include osteomas of the skull,
thyroid cancer, epidermoid cysts,
fibromas, sebaceous cysts, and desmoid tumors.
The countless polyps in the colon of FAP patients
predispose to the development of colon cancer
with a hundred percent probability
unless the colon is removed.
The onset of polyps occurs during the teenage years
and the average age of diagnosis of colon cancer
is 35 to 40 years.
Polyps can also grow in the stomach, duodenum,
spleen, kidneys, liver, mesentery and small bowel.
In a small number of cases
polyps have also occurred in the cerebellum.
Extra colon cancers related to FAP
commonly occur in the thyroid, liver and kidneys.
FAP, or familial adenomatous polyposis,
and Gardener's syndrome are caused by an autosomal dominant
germline mutation in the adenomatous polyposis coli,
or APC gene,
which is located on band Q21 of chromosome five.
The APC gene is a tumor suppressor gene
that regulates cell adhesion, cell migration and apoptosis
in the colorectal epithelium.
It's important to note
that regular intake of aspirin, ibuprofen, or other NSAIDs
reduces the risk of polyp development
by suppressing the formation of adenomatous polyps
and leading to the regression of existing polyps
in patients with FAP.
The results of many epidemiologic studies
provide strong evidence
that regular intake of non-steroidal anti-inflammatory drugs
or NSAIDs like aspirin and ibuprofen
reduces the risk of colorectal cancer development.
In a meta-analysis of published estimate,
significant risk reductions were observed
in 28 of 32 studies and regular use of NSAIDs
produced a 43% reduction in the risk.
It's important to note key epidemiological issues
in chemopreventative trials.
The first consideration is to do no harm to the patient.
The dose also makes the poison.
So some drugs, while non-toxic at a low dose
may quickly become toxic at elevated doses.
So it's important to understand the possible ramifications
before designing a clinical trial
of a certain chemopreventative drug.
Trials also frequently
run into the issue of the placebo effect.
That is, it's important to consider the ways
in which someone blindly receiving a placebo
rather than an actual chemopreventative drug
may be affected by
the thought that they might be receiving
a drug with an active ingredient.
It's also important to consider the ways
and to facilitate compliance as best
as possible in clinical trials
and to think about the ways that risk factors
may or may not be matched among different treatment groups
in chemopreventative trials.
So if we look at the rates of colorectal cancer
over time in the US,
we see that rates have declined in the US
during the past 50 years.
In women rates began to decline in mid-century
and have decreased by more than 50%.
In men, rates began to decline during 1970 to 1980
and have decreased by about 40%.
Contributing factors including increased screening,
more efficacious treatment,
improvement in diet, reduction in risk factors
and greater use of chemo preventative agents like NSAIDs.
These declines have occurred
in the face of concurrent epidemics of obesity
and related conditions like type two diabetes.
The declining pattern of colorectal cancer mortality
in the US is most compatible
with a relatively large contribution from screening
and a smaller impact of risk factor reductions
and improved treatments.
Colonoscopy has gained greater acceptance
in the general population
and is the most reliable method of screening
for the early detection of adenomatous polyps
and cancer of the large bowel.
In addition, visual determination of the exact location
and size of existing tumors
is an invaluable tool in planning and implementing
definitive surgical resection.
Colonoscopic imaging coupled with effective surgery
has produced five year survival rates greater than 90%
for patients whose tumors have not progressed
beyond the bowel wall.
And as I just mentioned, there's a couple different methods
for screening for colon cancer.
There's a blood test,
there's sigmoidoscopy, colonoscopy and biopsy.