Colorectal cancer, also called
colon
cancer or
large bowel cancer, includes
cancerous growths in the
colon,
rectum and
appendix.
With 655,000 deaths
worldwide per year, it is the fourth most common form of cancer in
the United
States
and the third leading cause of cancer-related death
in the Western world. Many colorectal cancers are thought to
arise from
adenomatous polyps in the colon. These mushroom-shaped
growths are usually
benign, but some may
develop into cancer over time. The majority of the time, the
diagnosis of localized colon cancer is through
colonoscopy. Therapy is usually through surgery,
which in many cases is followed by
chemotherapy.
Signs and symptoms
The symptoms of colorectal cancer depend on the location of tumor
in bowel and whether it has spread to elsewhere in the body
(
metastasis). Most of the symptoms may
occur in other diseases as well, and hence none of the symptoms
mentioned here is diagnostic of colorectal cancer. Symptoms and
signs are divided into local, constitutional (affecting the whole
body) and metastatic (caused by spread to other organs).
Local
Local symptoms are more likely if the tumor is located closer to
the anus. There may be a change in bowel habit (new-onset
constipation or
diarrhea in the absence of another cause), and a
feeling of incomplete defecation (
tenesmus)
and reduction in diameter of stool; tenesmus and change in stool
shape are both characteristic of rectal cancer.
Lower gastrointestinal
bleeding, including the passage of bright red blood in the
stool, may indicate colorectal cancer, as may the increased
presence of
mucus.
Melena, black stool with a tarry appearance, normally
occurs in
upper
gastrointestinal bleeding (such as from a
duodenal ulcer) but is sometimes encountered
in colorectal cancer when the disease is located in the beginning
of the large bowel.
A tumor that is large enough to fill the entire lumen of the bowel
may cause
bowel obstruction. This
situation is characterized by
constipation,
abdominal pain,
abdominal distension and
vomiting. This occasionally leads to the obstructed
and distended bowel
perforating and causing
peritonitis.
Certain local effects of colorectal cancer occur when the disease
has become more advanced. A large tumor is more likely to be
noticed on feeling the abdomen, and it may be noticed by a doctor
on
physical examination. The
disease may invade other organs, and may cause
blood or
air in the
urine (invasion of the
bladder) or
vaginal discharge (invasion of the
female reproductive
tract).
Constitutional
If a tumor has caused chronic occult bleeding,
iron deficiency anemia may occur;
this may be experienced as
fatigue,
palpitations and noticed as
pallor (pale appearance of the skin). Colorectal
cancer may also lead to
weight loss, generally
due to
a decreased
appetite.
More unusual constitutational symptoms are an unexplained
fever and one of several
paraneoplastic syndrome. The most
common paraneoplastic syndrome is
thrombosis, usually
deep vein thrombosis.
Metastatic
Colorectal cancer most commonly spreads to the
liver. This may go unnoticed, but large deposits in
the liver may cause
jaundice and
abdominal pain (due to stretching of the
capsule). If the tumor
deposit obstructs the
bile duct, the
jaundice may be accompanied by other features of
biliary obstruction, such as
pale stools.
Causes
The lifetime risk of developing colon cancer in the United States
is about 7%. Certain factors increase a person's risk of developing
the disease. These include:
- Age. The risk of developing colorectal cancer increases with
age. Most cases occur in the 60s and 70s, while cases before age 50
are uncommon unless a family history of early colon cancer is
present.
- Polyps of the colon,
particularly adenomatous polyps, are a risk factor for colon
cancer. The removal of colon polyps at the time of colonoscopy
reduces the subsequent risk of colon cancer.
- History of cancer. Individuals who have previously been
diagnosed and treated for colon cancer are at risk for developing
colon cancer in the future. Women who have had cancer of the ovary,
uterus, or breast are at higher risk of developing colorectal
cancer.
- Heredity:
- Smoking. Smokers are more likely to die of colorectal cancer
than non-smokers. An American
Cancer Society study found that "Women who smoked were more
than 40% more likely to die from colorectal cancer than women who
never had smoked. Male smokers had more than a 30% increase in risk
of dying from the disease compared to men who never had
smoked."
- Diet. Studies show that a diet high in red meat and low in
fresh fruit, vegetables, poultry and fish increases the risk of
colorectal cancer. In June 2005, a study by the European
Prospective Investigation into Cancer and Nutrition suggested
that diets high in red and processed meat, as well as those low in
fiber, are associated with an increased risk of colorectal cancer.
Individuals who frequently eat fish showed a decreased risk.
However, other studies have cast doubt on the claim that diets high
in fiber decrease the risk of colorectal cancer; rather, low-fiber
diet was associated with other risk factors, leading to
confounding. The nature of the relationship between dietary fiber
and risk of colorectal cancer remains controversial.
- Physical inactivity. People who are physically active are at
lower risk of developing colorectal cancer.
- Virus. Exposure to some viruses (such as particular strains of
human papilloma virus) may be
associated with colorectal cancer.
- Primary sclerosing
cholangitis offers a risk independent to ulcerative colitis
- Low levels of selenium.
- Inflammatory bowel disease. About one percent of colorectal
cancer patients have a history of chronic ulcerative colitis. The
risk of developing colorectal cancer varies inversely with the age
of onset of the colitis and directly with the extent of colonic
involvement and the duration of active disease. Patients with
colorectal Crohn's disease have a
more than average risk of colorectal cancer, but less than that of
patients with ulcerative colitis.
- Environmental factors. Industrialized countries are at a
relatively increased risk compared to less developed countries that
traditionally had high-fiber/low-fat diets. Studies of migrant
populations have revealed a role for environmental factors,
particularly dietary, in the etiology of colorectal cancers.
- Exogenous hormones. The differences in the time trends in
colorectal cancer in males and females could be explained by cohort
effects in exposure to some sex-specific risk factor; one
possibility that has been suggested is exposure to estrogens. There
is, however, little evidence of an influence of endogenous hormones
on the risk of colorectal cancer. In contrast, there is evidence
that exogenous estrogens such as hormone replacement therapy (HRT),
tamoxifen, or oral contraceptives might be associated with
colorectal tumors.
- Alcohol. Drinking, especially heavily, may be a risk
factor.
Alcohol
The
WCRF panel report
Food, Nutrition, Physical Activity and the Prevention of Cancer: a
Global Perspective finds the evidence "convincing" that
alcoholic drinks increase the risk of colorectal cancer in
men.
The NIAAA reports that: "Epidemiologic studies have found a small
but consistent dose-dependent association between alcohol
consumption and colorectal cancer even when controlling for fiber
and other dietary factors. Despite the large number of studies,
however, causality cannot be determined from the available
data."
"Heavy alcohol use may also increase the risk of colorectal cancer"
(NCI). One study found that "People who drink more than 30 grams of
alcohol per day (and especially those who drink more than 45 grams
per day) appear to have a slightly higher risk for colorectal
cancer." Another found that "The consumption of one or more
alcoholic beverages a day at baseline was associated with
approximately a 70% greater risk of colon cancer."
One study found that "While there was a more than twofold increased
risk of significant colorectal neoplasia in people who drink
spirits and beer, people who drank wine had a lower risk. In our
sample, people who drank more than eight servings of beer or
spirits per week had at least a one in five chance of having
significant colorectal neoplasia detected by screening
colonoscopy.".
Other research suggests that "to minimize your risk of developing
colorectal cancer, it's best to drink in moderation."
On its colorectal cancer page, the
National Cancer Institute does not
list alcohol as a risk factor: however, on another page it states,
"Heavy alcohol use may also increase the risk of colorectal
cancer"
Drinking may be a cause of earlier onset of colorectal
cancer.
Pathogenesis
Colorectal cancer is a disease originating from the
epithelial cells lining the
gastrointestinal tract.
Hereditary or
somatic mutations in
specific
DNA sequences, among which are included
DNA replication or
DNA repair genes, and also
the
APC,
K-Ras,
NOD2 and
p53 genes, lead to unrestricted cell division. The exact
reason why (and whether) a diet high in fiber might prevent
colorectal cancer remains uncertain. Chronic inflammation, as in
inflammatory bowel
disease, may predispose patients to malignancy.
Diagnosis
Colorectal cancer can take many years to develop and early
detection of colorectal cancer greatly improves the chances of a
cure. The National Cancer Policy Board of the
Institute of Medicine estimated in
2003 that even modest efforts to implement colorectal cancer
screening methods would result in a 29 percent drop in cancer
deaths in 20 years. Despite this, colorectal cancer screening rates
remain low. Therefore, screening for the disease is recommended in
individuals who are at increased risk. There are several different
tests available for this purpose.
- Digital rectal exam (DRE):
The doctor inserts a lubricated, gloved finger into the rectum to
feel for abnormal areas. It only detects tumors large enough to be
felt in the distal part of the rectum but is useful as an initial
screening test.
- Fecal occult blood test
(FOBT): a test for blood in the stool. Two types of tests can be
used for detecting occult blood in stools i.e. guaiac based
(chemical test) and immunochemical. The sensitivity of
immunochemical testing is superior to that of chemical testing
without an unacceptable reduction in specifity.
- Endoscopy:
- Sigmoidoscopy: A lighted probe
(sigmoidoscope) is inserted into the rectum and lower colon to
check for polyps and other abnormalities.
- Colonoscopy: A lighted probe called
a colonoscope is inserted into the rectum and the entire colon to
look for polyp and other
abnormalities that may be caused by cancer. A colonoscopy has the
advantage that if polyp are found
during the procedure they can be immediately removed. Tissue can
also be taken for biopsy.
In the United States, colonoscopy or FOBT plus sigmoidoscopy are
the preferred screening options.
Other screening methods
- Double contrast barium
enema (DCBE): First, an overnight preparation is taken to
cleanse the colon. An enema containing
barium sulfate is administered, then
air is insufflated into the colon, distending it. The result is a
thin layer of barium over the inner lining of the colon which is
visible on X-ray films. A cancer or a precancerous polyp can be
detected this way. This technique can miss the (less common) flat
polyp.
- Virtual colonoscopy replaces
X-ray films in the double contrast barium enema (above) with a
special computed tomography scan
and requires special workstation software in order for the radiologist to interpret. This technique is
approaching colonoscopy in sensitivity
for polyps. However, any polyps found must still be removed by
standard colonoscopy.
- Standard computed axial
tomography is an x-ray method that can be used to determine the
degree of spread of cancer, but is not sensitive enough to use for
screening. Some cancers are found in CAT scans performed for other
reasons.
- Blood tests: Measurement of the
patient's blood for elevated levels of certain proteins can give an indication of tumor load. In
particular, high levels of carcinoembryonic antigen (CEA) in
the blood can indicate metastasis of
adenocarcinoma. These tests are
frequently false positive
or false negative, and are
not recommended for screening, it can be useful to assess disease
recurrence.
- Genetic counseling and
genetic testing for families who may
have a hereditary form of colon cancer, such as hereditary
nonpolyposis colorectal cancer (HNPCC) or familial adenomatous
polyposis (FAP).
- Positron emission
tomography (PET) is a 3-dimensional scanning technology where a
radioactive sugar is injected into the patient, the sugar collects
in tissues with high metabolic activity, and an image is formed by
measuring the emission of radiation from the sugar. Because cancer
cells often have very high metabolic rate, this can be used to
differentiate benign and malignant tumors. PET is not used for
screening and does not (yet) have a place in routine workup of
colorectal cancer cases.
- Whole-Body PET imaging is the most accurate diagnostic test for
detection of recurrent colorectal cancer, and is a cost-effective
way to differentiate resectable from non-resectable disease. A PET
scan is indicated whenever a major management decision depends upon
accurate evaluation of tumour presence and extent.
- Stool DNA testing is an emerging technology in screening for
colorectal cancer. Pre-malignant adenomas and cancers shed DNA
markers from their cells which are not degraded during the
digestive process and remain stable in the stool. Capture, followed
by PCR amplifies the DNA
to detectable levels for assay. Clinical studies have shown a
cancer detection sensitivity of 71%-91%.
Monitoring Colorectal Cancer
Carcinoembryonic antigen
(CEA) is a protein found on virtually all colorectal tumors. CEA
may be used to monitor and assess response to treatment in patients
with metastatic disease. CEA can also be used to monitor recurrence
in patients post-operatively.
Pathology
The
pathology of the
tumor is usually reported from the analysis of tissue
taken from a biopsy or surgery. A pathology report will usually
contain a description of
cell type and
grade. The most common colon cancer cell type is
adenocarcinoma which accounts for 95% of
cases. Other, rarer types include
lymphoma
and
squamous cell
carcinoma.
Cancers on the right side (ascending colon and
cecum) tend to be exophytic, that is, the tumour grows
outwards from one location in the bowel wall. This very rarely
causes obstruction of
feces, and presents with
symptoms such as
anemia. Left-sided tumours
tend to be circumferential, and can obstruct the bowel much like a
napkin ring.
Adenocarcinoma is a malignant epithelial tumor, originating from
glandular epithelium of the colorectal mucosa. It invades the wall,
infiltrating the
muscularis
mucosae, the
submucosa and thence the
muscularis propria. Tumor cells describe irregular tubular
structures, harboring pluristratification, multiple lumens, reduced
stroma ("back to back" aspect). Sometimes, tumor cells are
discohesive and secrete mucus, which invades the interstitium
producing large pools of mucus/colloid (optically "empty" spaces) -
mucinous (colloid) adenocarcinoma, poorly differentiated.
If the mucus remains inside the tumor cell, it pushes the nucleus
at the periphery - "signet-ring cell." Depending on glandular
architecture, cellular pleomorphism, and mucosecretion of the
predominant pattern, adenocarcinoma may present three degrees of
differentiation: well, moderately, and poorly differentiated.
Most colorectal cancer tumors are thought to be
cyclooxygenase-2 (COX-2) positive. This
enzyme is generally not found in healthy colon tissue, but is
thought to fuel abnormal cell growth.
Staging
Colon
cancer staging is an estimate
of the amount of penetration of a particular cancer. It is
performed for diagnostic and research purposes, and to determine
the best method of treatment. The systems for staging colorectal
cancers depend on the extent of local invasion, the degree of lymph
node involvement and whether there is distant
metastasis.
Definitive staging can only be done after
surgery has been performed and pathology reports
reviewed. An exception to this principle would be after a
colonoscopic polypectomy of a malignant pedunculated polyp with
minimal invasion. Preoperative staging of rectal cancers may be
done with
endoscopic
ultrasound. Adjunct staging of metastasis include
Abdominal Ultrasound,
CT,
PET Scanning, and other imaging
studies.
The most common staging system is the
TNM (for tumors/nodes/metastases) system,
from the
American
Joint Committee on Cancer (AJCC). The
TNM
system assigns a number based on three categories. "T" denotes the
degree of invasion of the intestinal wall, "N" the degree of
lymphatic node involvement, and "M" the
degree of
metastasis. The broader stage
of a cancer is usually quoted as a number I, II, III, IV derived
from the TNM value grouped by prognosis; a higher number indicates
a more advanced cancer and likely a worse outcome. Details of this
system are in the graph below:
| AJCC
stage |
TNM
stage |
TNM stage criteria for colorectal
cancer |
| Stage 0 |
Tis N0 M0 |
Tis: Tumor confined to mucosa;
cancer-in-situ |
| Stage I |
T1 N0 M0 |
T1: Tumor invades submucosa |
| Stage I |
T2 N0 M0 |
T2: Tumor invades muscularis
propria |
| Stage II-A |
T3 N0 M0 |
T3: Tumor invades subserosa or beyond (without other organs
involved) |
| Stage II-B |
T4 N0 M0 |
T4: Tumor invades adjacent organs or perforates the visceral
peritoneum |
| Stage III-A |
T1-2 N1 M0 |
N1: Metastasis to 1 to 3 regional lymph
nodes. T1 or T2. |
| Stage III-B |
T3-4 N1 M0 |
N1: Metastasis to 1 to 3 regional lymph nodes. T3 or T4. |
| Stage III-C |
any T, N2 M0 |
N2: Metastasis to 4 or more regional lymph nodes. Any T. |
| Stage IV |
any T, any N, M1 |
M1: Distant metastases present. Any T, any N. |
- Dukes system
Dukes classification is an
older and less complicated staging system, that predates the TMN
system, and was first proposed by Dr.
Cuthbert Dukes in 1932; it identifies the
stages as:
- A - Tumour confined to the intestinal wall
- B - Tumour invading through the intestinal wall
- C - With lymph node(s) involvement (this is further subdivided
into C1 lymph node involvement where the apical node is not
involved and C2 where the apical lymph node is involved)
- D - With distant metastasis
A few cancer centers still use this staging system.
Prevention
Most colorectal cancers should be preventable, through increased
surveillance, improved lifestyle, and, probably, the use of dietary
chemopreventative agents.
Surveillance
Most colorectal cancer arise from adenomatous polyps. These lesions
can be detected and removed during colonoscopy. Studies show this
procedure would decrease by > 80% the risk of cancer death,
provided it is started by the age of 50, and repeated every 5 or 10
years.
As per current guidelines under
National Comprehensive
Cancer Network, in average risk individuals with negative
family history of colon cancer and personal history negative for
adenomas or
Inflammatory Bowel diseases,
flexible sigmoidoscopy every 5 years with fecal occult blood
testing annually or double contrast barium enema are other options
acceptable for screening rather than colonoscopy every 10 years
(which is currently the Gold-Standard of care).
Lifestyle and nutrition
The comparison of colorectal cancer incidence in various countries
strongly suggests that sedentarity, overeating (i.e., high caloric
intake), and perhaps a diet high in meat (red or processed) could
increase the risk of colorectal cancer. In contrast, a healthy body
weight, physical fitness, and good nutrition decreases cancer risk
in general. Accordingly, lifestyle changes could decrease the risk
of colorectal cancer as much as 60-80%.
A high intake of dietary fiber (from eating fruits, vegetables,
cereals, and other high fiber food products) has, until recently,
been thought to reduce the risk of colorectal cancer and adenoma.
In the largest study ever to examine this theory (88,757 subjects
tracked over 16 years), it has been found that a fiber rich diet
does not reduce the risk of colon cancer. A 2005 meta-analysis
study further supports these findings.
The Harvard School of Public Health states:"Health Effects of
Eating Fiber: Long heralded as part of a healthy diet, fiber
appears to reduce the risk of developing various conditions,
including heart disease, diabetes, diverticular disease, and
constipation. Despite what many people may think, however, fiber
probably has little, if any effect on colon cancer risk."
Chemoprevention
More than 200 agents, including the above cited phytochemicals, and
other food components like calcium or folic acid (a B vitamin), and
NSAIDs like aspirin, are able to decrease
carcinogenesis in
pre-clinical
development models: Some studies show full inhibition of
carcinogen-induced tumours in the colon of rats. Other studies show
strong inhibition of spontaneous intestinal polyps in mutated mice
(Min mice). Chemoprevention clinical trials in human volunteers
have shown smaller prevention, but few intervention studies have
been completed today. The "chemoprevention database" shows the
results of all published scientific studies of chemopreventive
agents, in people and in animals.
Aspirin chemoprophylaxis
Aspirin should not be taken routinely to prevent colorectal cancer,
even in people with a family history of the disease, because the
risk of bleeding and kidney failure from high dose aspirin
(300 mg or more) outweigh the possible benefits.
A
clinical practice
guideline of the
U.S.
Preventive Services Task Force (USPSTF) recommended
against taking
aspirin (
grade D recommendation). The Task Force acknowledged
that aspirin may reduce the incidence of colorectal cancer, but
"concluded that harms outweigh the benefits of aspirin and NSAID
use for the prevention of colorectal cancer". A subsequent
meta-analysis concluded "300 mg or more of
aspirin a day for about 5 years is effective in primary prevention
of colorectal cancer in randomised controlled trials, with a
latency of about 10 years". However, long-term doses over
81 mg per day may increase bleeding events.
Calcium
The
meta-analysis by the
Cochrane Collaboration of
randomized controlled trials
published through 2002 concluded "Although the evidence from two
RCTs suggests that calcium supplementation might contribute to a
moderate degree to the prevention of colorectal adenomatous polyps,
this does not constitute sufficient evidence to recommend the
general use of calcium supplements to prevent colorectal cancer.".
Subsequently, one
randomized
controlled trial by the
Women's Health Initiative (WHI)
reported negative results. A second
randomized controlled trial
reported reduction in all cancers, but had insufficient colorectal
cancers for analysis.
Vitamin D
A scientific review undertaken by the
National Cancer Institute found
that vitamin D was beneficial in preventing colorectal cancer,
which showed an inverse relationship with blood levels of 80 nmol/L
or higher associated with a 72% risk reduction compared with lower
than 50 nmol/L.
Management
The treatment depends on the staging of the cancer. When colorectal
cancer is caught at early stages (with little spread) it can be
curable. However, when it is detected at later stages (when distant
metastases are present) it is less likely
to be curable.
Surgery remains the primary treatment while chemotherapy and/or
radiotherapy may be recommended depending on the individual
patient's staging and other medical factors.
Because colon cancer primarily affects the elderly, it can be a
challenge to determine how aggressively to treat a particular
patient, especially after surgery. Clinical trials suggest that
"otherwise fit" elderly patients fare well if they have adjuvant
chemotherapy after surgery, so chronological age alone should not
be a contraindication to aggressive management.
Surgery
Surgeries can be categorised into curative, palliative, bypass,
fecal diversion, or open-and-close.
Curative Surgical treatment
can be offered if the tumor is localized.
- Very early cancer that develops within a polyp can often be cured by removing the polyp (i.e.,
polypectomy) at the time of colonoscopy.
- In colon cancer, a more advanced tumor typically requires
surgical removal of the section of colon containing the tumor with
sufficient margins, and radical en-bloc resection of mesentery and lymph
nodes to reduce local recurrence (i.e., colectomy). If
possible, the remaining parts of colon are anastomosed together to create a functioning
colon. In cases when anastomosis is not possible, a stoma (artificial orifice) is created.
- Curative surgery on rectal cancer includes total mesorectal excision
(lower anterior resection)
or abdominoperineal
excision.
In case of multiple metastases,
palliative (non
curative)
resection of the primary tumor
is still offered in order to reduce further
morbidity caused by tumor bleeding, invasion, and
its catabolic effect. Surgical removal of isolated liver metastases
is, however, common and may be curative in selected patients;
improved
chemotherapy has increased the
number of patients who are offered surgical removal of isolated
liver metastases.
If the tumor invaded into adjacent vital structures which makes
excision technically difficult, the
surgeons may prefer to
bypass the tumor
(ileotransverse bypass) or to do a proximal
fecal
diversion through a
stoma.
The worst case would be an
open-and-close surgery,
when surgeons find the tumor unresectable and the small bowel
involved; any more procedures would do more harm than good to the
patient. This is uncommon with the advent of laparoscopy and better
radiological imaging. Most of these cases formerly subjected to
"open and close" procedures are now diagnosed in advance and
surgery avoided.
Laparoscopic-assisted
colectomy is a
minimally-invasive technique
that can reduce the size of the incision and may reduce
post-operative pain.
As with any surgical procedure, colorectal surgery may result in
complications including
- wound infection, Dehiscence (bursting
of wound) or hernia
- anastomosis breakdown, leading to abscess or fistula formation,
and/or peritonitis
- bleeding with or without hematoma
formation
- adhesions resulting in
bowel obstruction. A 5-year study
of patients who had surgery in 1997 found the risk of hospital
readmission to be 15% after panproctocolectomy, 9% after total
colectomy, and 11% after ileostomy
- adjacent organ injury; most commonly to the small intestine,
ureters, spleen, or bladder
- Cardiorespiratory complications such as myocardial infarction, pneumonia, arrythmia,
pulmonary embolism etc
Chemotherapy
Chemotherapy is used to reduce the
likelihood of metastasis developing, shrink tumor size, or slow
tumor growth. Chemotherapy is often applied after surgery
(adjuvant), before surgery (neo-adjuvant), or as the primary
therapy (palliative). The treatments listed here have been shown in
clinical trials to improve survival
and/or reduce mortality rate and have been approved for use by the
US Food and Drug
Administration. In colon cancer, chemotherapy after surgery is
usually only given if the cancer has spread to the lymph nodes
(Stage III).At the 2008 annual meeting of the American Society of
Clinical Oncology, researchers announced that colorectal cancer
patients that have a mutation in the KRAS gene do not respond to
certain therapies, those that inhibit the epidermal growth factor
receptor (EGFR)--namely Erbitux (cetuximab) and Vectibix
(panitumumab). Following recommendations by ASCO, patients should
now be tested for the KRAS gene mutation before being offered these
EGFR-inhibiting drugs. In July 2009, the US Food and Drug
Administration (FDA) updated the labels of two anti-EGFR monoclonal
antibody drugs (
panitumumab (Vectibix)
and
cetuximab (Erbitux)) indicated for
treatment of metastatic colorectal cancer to include information
about KRAS mutations.
However, having the normal KRAS version does not guarantee that
these drugs will benefit the patient.
“The trouble with the KRAS mutation is that it’s
downstream of EGFR,” says Richard Goldberg, MD, director of
oncology at the Lineberger Comprehensive Cancer Center at the
University of North Carolina.
“It doesn’t matter if you plug the socket if there’s a
short downstream of the plug.
The mutation turns [EGFR] into a switch that’s always
on.” But this doesn’t mean that having normal, or wild-type, KRAS
is a fail-safe.
“It isn’t foolproof,” cautions Goldberg.
“If you have wild-type KRAS, you’re more likely to
respond, but it’s not a guarantee.” Tumors shrink in response to
these drugs in up to 40 percent of patients with wild-type KRAS,
and progression-free and overall survival is
increased.
The cost benefit of testing patients for the KRAS gene could
potentially save about $740 million a year by not providing
EGFR-inhibiting drugs to patients who would not benefit from the
drugs. "With the assumption that patients with mutated Kras (35.6%
of all patients) would not receive cetuximab (other studies have
found Kras mutation in up to 46% of patients), theoretical drug
cost savings would be $753 million; considering the cost of Kras
testing, net savings would be $740 million."
- In clinical trials for treated/untreated metastatic disease.
Radiation therapy
Radiotherapy is not used routinely in colon cancer, as it could
lead to
radiation enteritis, and
it is difficult to target specific portions of the colon. It is
more common for radiation to be used in rectal cancer, since the
rectum does not move as much as the colon and is thus easier to
target. Indications include:
- Colon cancer
- pain relief and palliation - targeted at metastatic tumor deposits if they compress vital
structures and/or cause pain
- Rectal cancer
- neoadjuvant - given before surgery in patients with tumors that
extend outside the rectum or have spread to regional lymph nodes,
in order to decrease the risk of recurrence following surgery or to
allow for less invasive surgical approaches (such as a low anterior
resection instead of an abdomino-perineal resection)
- adjuvant - where a tumor perforates the rectum or involves
regional lymph nodes (AJCC T3 or T4 tumors or Duke's B or C
tumors)
- palliative - to decrease the tumor burden in order to relieve
or prevent symptoms
Sometimes chemotherapy agents are used to increase the
effectiveness of radiation by sensitizing tumor cells if
present.
Immunotherapy
Bacillus
Calmette-Guérin (BCG) is being investigated as an adjuvant
mixed with autologous tumor cells in immunotherapy for colorectal
cancer.
Vaccine
In November 2006, it was announced that a
vaccine had been developed and tested with very
promising results. The new vaccine, called
TroVax, works in a totally different way to existing
treatments by harnessing the patient's own immune system to fight
the disease. Experts say this suggests that
gene therapy vaccines could prove an effective
treatment for a whole range of cancers.
Oxford
BioMedica is a British spin-out from Oxford
University
specialising
in the development of gene-based treatments. Phase III
trials are underway for renal cancers and planned for colon
cancers.
Treatment of liver metastases
According to the American Cancer Society statistics in 2006, over
20% of patients present with metastatic (stage IV) colorectal
cancer at the time of diagnosis, and up to 25% of this group will
have isolated liver metastasis that is potentially resectable.
Lesions which undergo curative resection have demonstrated 5-year
survival outcomes now exceeding 50%.
Resectability of a liver metastasis is determined using
preoperative imaging studies (CT or MRI), intraoperative
ultrasound, and by direct palpation and visualization during
resection. Lesions confined to the right lobe are amenable to en
bloc removal with a right hepatectomy (liver resection) surgery.
Smaller lesions of the central or left liver lobe may sometimes be
resected in anatomic "segments", while large lesions of left
hepatic lobe are resected by a procedure called hepatic
trisegmentectomy. Treatment of lesions by smaller, non-anatomic
"wedge" resections is associated with higher recurrence rates. Some
lesions which are not initially amenable to surgical resection may
become candidates if they have significant responses to
preoperative chemotherapy or immunotherapy regimens. Lesions which
are not amenable to surgical resection for cure can be treated with
modalities including radio-frequency ablation (RFA), cryoablation,
and chemoembolization.
Patients with colon cancer and metastatic disease to the liver may
be treated in either a single surgery or in staged surgeries (with
the colon tumor traditionally removed first) depending upon the
fitness of the patient for prolonged surgery, the difficulty
expected with the procedure with either the colon or liver
resection, and the comfort of the surgery performing potentially
complex hepatic surgery.
Aspirin
A study published in 2009 found that Aspirin reduces risk of
colorectal
neoplasia in randomized trials
and inhibits tumor growth and metastases in animal models. The
influence of aspirin on survival after diagnosis of colorectal
cancer is unknown . Several reports including a prospective cohort
of 1,279 people diagnosed with stages I-III (non-metastatic)
colorectal cancer have suggested a significant improvement in
cancer-specific survival in a subset of patients using
aspirin.
Support therapies
Cancer diagnosis very often results in an enormous change in the
patient's psychological wellbeing. Various support resources are
available from hospitals and other agencies which provide
counseling, social service support,
cancer support groups, and other
services. These services help to mitigate some of the difficulties
of integrating a patient's medical complications into other parts
of their life.
Prognosis
Survival is directly related to detection and the type of cancer
involved. Survival rates for early stage detection is about 5 times
that of late stage cancers. CEA level is also directly related to
the prognosis of disease, since its level correlates with the bulk
of tumor tissue.
Follow-up
The aims of follow-up are to diagnose in the earliest possible
stage any metastasis or tumors that develop later but did not
originate from the original cancer (metachronous lesions).
The U.S.
National
Comprehensive Cancer Network and
American Society of
Clinical Oncology provide guidelines for the follow-up of colon
cancer. A
medical history and
physical examination are
recommended every 3 to 6 months for 2 years, then every 6 months
for 5 years.
Carcinoembryonic
antigen blood level measurements follow the same timing, but
are only advised for patients with T2 or greater lesions who are
candidates for intervention. A
CT-scan of the chest, abdomen and pelvis
can be considered annually for the first 3 years for patients who
are at high risk of recurrence (for example, patients who had
poorly differentiated tumors or venous or lymphatic invasion) and
are candidates for curative surgery (with the aim to cure). A
colonoscopy can be done after 1 year,
except if it could not be done during the initial staging because
of an obstructing mass, in which case it should be performed after
3 to 6 months. If a villous polyp, polyp >1 centimeter or high
grade dysplasia is found, it can be repeated after 3 years, then
every 5 years. For other abnormalities, the colonoscopy can be
repeated after 1 year.
Routine
PET or
ultrasound scanning,
chest X-rays,
complete blood count or
liver function tests are not
recommended. These guidelines are based on recent meta-analyses
showing that intensive surveillance and close follow-up can reduce
the 5-year mortality rate from 37% to 30%.
Epidemiology
[[Image:Colon and rectum cancers world map - Death -
WHO2004.svg|thumb|
Age-standardized
death from colorectal cancer per 100,000 inhabitants in 2004.
]]
Society and culture
Notable people diagnosed with colorectal cancer
Research
Mathematical modeling
Colorectal cancer has been the subject of mathematical modeling for
many years.
See also
References
External links
_Endoscopic_resection.jpg/180px-Colonic_carcinoid_(1)_Endoscopic_resection.jpg)
Wikis
Quiz
Facts
Map
Search
