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Stage IV Colon Cancer
Overview
Colon cancer is classified as stage IV (D) if the final evaluation
following surgical removal of the cancer shows that the cancer has
spread to distant locations in the body, which may include the
liver, lungs, bones, or other sites. The common perception is that
patients diagnosed with stage IV colon cancer have few treatment
options. However, certain patients can still be cured of their
cancer, and others derive significant benefit from additional
treatment.

Patients with stage IV colon cancer can be broadly divided into two
groups:

Those with cancer that has metastasized to a single site , and
Those with unresectable cancer , or cancer that cannot be treated
with surgery.
When the site of metastasis is a single organ, such as the liver,
and the cancer is confined to a single defined area within the
organ, patients may benefit from local treatment directed at that
single metastasis.

The majority of patients have unresectable or widespread disease.
Historically, these patients have been considered incurable and were
offered treatment with chemotherapy for the purpose of prolonging
their survival and alleviating symptoms from progressive cancer. New
chemotherapy combinations have lead to increased survival.
Combinations approved in early 2004 include:

Eloxatin®/5-FU/LV
AvastinT/5FU/LV
Treatments that are currently being evaluated include the oral
chemotherapy drug Xeloda® (capecitabine), vaccines, and the
monoclonal antibody ErbituxT (cetuximab), which was approved in
early 2004 for recurrent colon cancer and may be available to
patients with stage IV disease through a clinical trial.

The following is a general overview of treatment for stage IV colon
cancer. Treatment may consist of surgery, radiation, chemotherapy,
biological therapy, or a combination of these treatment techniques.
Multi-modality treatment, which is treatment using two or more
techniques, is increasingly recognized as an important approach for
increasing a patient's chance of cure or prolonging survival. In
some cases, participation in a clinical trial utilizing new,
innovative therapies may provide the most promising treatment.
Circumstances unique to each patient's situation may influence how
these general treatment principles are applied. The potential
benefits of multi-modality care, participation in a clinical trial,
or standard treatment must be carefully balanced with the potential
risks. The information on this website is intended to help educate
patients about their treatment options and to facilitate a mutual or
shared decision-making process with their treating cancer physician.

Treatment of Unresectable Stage IV Colon Cancer
For over 30 years, single-agent fluorouracil (5-FU) chemotherapy
with or without leucovorin (LV) was the standard treatment for non-
localized stage IV colon cancer. In 2001, Camptosar®/5-FU/LV was
found to significantly improve patient outcomes and became the new
standard treatment.[1]Significant advances have been made in the
treatment for non-localized stage IV colon cancer over the last few
years, including the following (see data in table 1):

In 2002, patients treated with Eloxatin®/5-FU/LV (FOLFOX) were shown
to be cancer-free longer and live longer than those treated with
Camptosar®/5FU/LV. Importantly, patients reported fewer severe side
effects when treated with Eloxatin®/5-FU/LV than with Camptosar®/5-
FU/LV.[2]Eloxatin® was approved for first-line treatment of advanced
colon cancer in January 2004.
The most recent advance is the combination AvastinT/5FU/LV , which
was approved for initial treatment of advanced colon cancer in
February 2004.[3]Patients who received Avastin® were cancer-free for
longer and lived longer than patients treated with only 5FU/LV.
Additionally, patients treated with AvastinT/Camptosar®/5-FU/LV have
been shown to live longer and be cancer-free longer than those
treated with Camptosar®/5FU/LV.[4]
Table 1 Advances in chemotherapy regimens for advanced colorectal
cancer


Response rate
Progression free survival (months)
Overall survival (months)

Camptosar®/5FU/LV
33%
6.9 (time to progression)
14.6

Eloxatin®/5FU/LV
45%
8.8 (time to progression)
19.4






5FU/LV
24%
5.2
13.6

Avastin®/5FU/LV
40%
9.0
17.6






Camptosar®/5FU/LV
35%
7.1
15.6

Avastin®/
Camptosar®/5-FU/LV
45%
10.4
20.3


While results from different studies cannot be definitively
compared, these findings suggest that the recent developments in
treatment for advanced colon cancer have resulted in better
treatment options and that AvastinT plus chemotherapy may hold the
most promise.

Bevacizumab (AvastinT): AvastinT is a new class of drug known as an
angiogenesis inhibitor. Angiogenesis is the process of developing
new blood vessels. Cancer cells require food, oxygen, and proteins
in order to grow and spread. New blood vessels are necessary to
deliver these essential components of cellular growth.

Inhibition of angiogenesis is a growing area of cancer research. Two
key proteins that are necessary for the process of angiogenesis are
called vascular endothelial growth factor (VEGF) and matrix
metalloproteinases (MMPs). VEGF causes endothelial cells (cells
comprising the innermost layer of blood vessels) to replicate and
migrate from existing blood vessels to the cancer. Endothelial cells
secrete MMPs, which create an opening in existing tissues
surrounding the cancer, allowing the endothelial cells to move near
the cancer and form new blood vessels to "feed" the cancer.
Researchers have been evaluating targeted treatment approaches which
hinder or reduce the effects of VEGF and thus, slow cancer
progression.

AvastinT produces its anti-angiogenic effects by binding to VEGF and
inhibiting or reducing the growth of new blood vessels that are
necessary for cancer cell growth. Two studies have demonstrated that
the addition of AvastinT to standard chemotherapy treatment improves
survival in patients with metastatic colorectal cancer.

Researchers from the United States recently conducted a multi-
institutional clinical trial to evaluate the addition of AvastinT to
a standard chemotherapy combination in patients with metastatic
colorectal cancer. This trial involved over 100 patients who were
treated with one of the following regimens: fluorouracil (FU) and
leucovorin (LV), FU/LV and low-dose AvastinT or FU/LV and high-dose
AvastinT. The patients that received AvastinT showed a greater anti-
cancer response, longer time before their cancer progressed, and
higher overall survival rate. Low-dose AvastinT appears to be more
effective than high-dose (see Table 2). Side effects for patients
treated with AvastinT included blood clots, high blood pressure,
protein in the urine, and bloody nose.[5]

Table 2 Effect of AvastinT in patients with metastatic colorectal
cancer



FU/LV
FU/LV plus
low-dose AvastinT
FU/LV plus
high-dose AvastinT

Anti-cancer response
17%
40%
24%

Time to cancer progression (months)

5.2

9.0

7.2

Overall survival (months)
13.8
21.5
23


According to results of a large trial published in mid-2004, the
addition of AvastinT to chemotherapy showed that patients treated
with AvastinT lived longer and were more likely to experience
shrinkage of their cancer, a delay in cancer progression than
patients not treated with AvastinT (see table 3). Side effects were
similar between the two groups of patients; however, high blood
pressure was more prevalent in the group treated with AvastinT.[6]

Table 3 Results of a large trial demonstrating the effect of
AvastinT in patients with metastatic colorectal cancer


Camptosar®/5FU/LV plus AvastinT
Camptosar®/5FU/LV plus placebo

Response rate
44.8%
34.8%

Complete response rate
3.7%
2.2%

Time to cancer progression (months)
10.4
7.1

One-year survival
74.3%
63.4%

Median survival (months)
20.3
15.6


Oral chemotherapy: Several new chemotherapy agents are being
developed that can be taken orally. The most common are the
fluoropyramidines, which may provide the same or greater benefit as
intravenous (IV) fluorouracil (5-FU) without requiring intravenous
administration. Results from recent clinical trials have
demonstrated that the oral chemotherapy agent Xeloda® (capecitabine)
provides similar treatment outcomes to 5-FU/LV and allows patients
to be treated at home with fewer side effects.

Three trials have been completed in the last several years comparing
oral Xeloda® to IV 5-FU/LV in the treatment of patients with
advanced colon cancer. Two trials published in 2001 demonstrated no
difference in response to treatment, the length of time before the
cancer progressed, and duration of survival between the oral and IV
treatments.[7][8]A trial presented at the 2004 meeting of the
American Society of Clinical Oncology showed that more patients
treated with oral Xeloda® were free of cancer for 3 years or more
compared to patients treated with IV 5FU/LV (65.5% vs. 61.1%,
p=0.0407). All of these trials reported significantly fewer side
effects with Xeloda®, including low white blood cell count,
diarrhea, and nausea/vomiting. The only side effect that was more
prevalent with Xeloda® was hand/foot syndrome, which is a thickening
of the skin on the hands and feet.[9]

Treatment of Colon Cancer that has Metastasized to a Single Site
Stage IV colon cancer commonly spreads to the liver or the lungs.
Treatment for patients with colon cancer that has spread to one of
these locations may include surgery or specialized delivery of
chemotherapy that targets the cancer. Surgical removal of the cancer
metastasis has been shown to provide benefit, or even cure for some
patients. For patients with liver metastases, chemotherapy treatment
delivered into the blood vessel that supplies the liver (hepatic
artery infusion) has been shown to provide some benefit. Patients
with colon cancer that has spread to the liver or lungs should be
evaluated by doctors in a medical center that has significant
experience treating patients with these circumstances.

Surgery for liver and lung metastases: Physicians from the Mayo
Clinic have determined that select patients with colon cancer that
has metastasized to the liver and lungs may have an increased chance
for long-term survival with surgical removal of these metastases.
This trial involved 58 patients with colon cancer who had metastases
to both the liver and lungs, but no relapse of their cancer at the
original site. All patients underwent the surgical removal of their
metastases at the Mayo Institution between 1980 and 1988. There were
no deaths during surgery. Five years following surgery, 55% of
patients remained cancer-free. The patients that responded best to
treatment did not have thoracic lymph node involvement and did not
have an elevated carcinoembryonic antigen, which is a type of
protein found on the surface of cancer cells.[10]

Hepatic artery infusion: The infusion of chemotherapy directly into
the vessel that delivers blood to the liver is called hepatic artery
infusion. This technique is used to treat patients with colon cancer
that has metastasized to the liver. The pooled results of several
small studies indicate that hepatic artery infusion produced more
anti-cancer responses and caused patients to live longer than those
treated with traditional systemic chemotherapy[11](see table 4).

Table 4 Outcomes with hepatic artery infusion or systemic
chemotherapy


Hepatic artery infusion
Systemic chemotherapy

Response rate
41%
14%

Average duration of survival
16 months
12 months


Also, treatment with hepatic artery infusion plus traditional
chemotherapy has been shown to increase duration of survival and
reduce recurrences compared to treatment with systemic chemotherapy
only (see table 5).[12]


Hepatic artery infusion plus systemic chemotherapy
Systemic chemotherapy

Average duration of survival
72 months
59 months

Cancer recurrence rate
10%
60%


Liver-directed treatment approaches, such as hepatic artery
infusion, are highly specialized procedures and are best performed
by experienced individuals. Furthermore, this approach is only
appropriate for select patients. The benefit of the procedure must
outweigh the risk, and these must be carefully compared to the
benefit and risk of undergoing standard surgical removal and
systemic chemotherapy.

Treatment of the Elderly
A large percentage of patients with advanced colorectal cancer are
65 years or older. Because elderly patients commonly have concurrent
illnesses or other medical difficulties that are perceived to
exacerbate the side effects of chemotherapy, elderly patients are
often treated with reduced doses of chemotherapy. Clinical studies
have shown however, that elderly patients get the same benefit from
chemotherapy treatment as younger patients. While a dose reduction
or delay may sometimes be necessary, it may also compromise the
optimal treatment of some patients. All patients over 65 should be
closely monitored for toxic side effects of chemotherapy, especially
during their initial chemotherapy administration cycle. Moreover,
The NCCTG trial demonstrated that Eloxatin® when combined with 5-
FU/LV had fewer side effects than Camptosar® and may represent a
better treatment option for elderly patients.

Strategies to Improve Treatment of Stage IV Colon Cancer
The development of more effective cancer treatments requires that
new and innovative therapies be evaluated with cancer patients.
Clinical trials are studies that evaluate the effectiveness of new
drugs or treatment strategies. Future progress in the treatment of
stage IV colon cancer will result from the continued evaluation of
new treatments in clinical trials. Participation in a clinical trial
may offer patients access to better treatments and advance the
existing knowledge about treatment of this cancer. Patients who are
interested in participating in a clinical trial should discuss the
risks and benefits of clinical trials with their physician. Areas of
active exploration to improve the treatment of stage IV colon cancer
include the following:

Epidermal Growth Factor Receptor (EGFR) Inhibitors
ErbituxT(IMC-225)
COX-2 inhibitors
Celocoxib (Celebrex®)
Other treatments
Managing side effects
Liver-directed therapies
Biological therapy
Vaccines
Phase I clinical trials
Epidermal Growth Factor Receptor (EGFR) Inhibitors
Epidermal growth factor receptors (EGFR) are small proteins that are
found on the surface of all cells. EGFR binds exclusively to small
proteins circulating in the blood called growth factors. The binding
action between EGFR and growth factors stimulates biological
processes within the cell to promote growth of a cell in a strictly
controlled manner. However, in many cancer cells, EGFR is either
abundantly overexpressed or the EGFR biological processes that
normally stimulate cell growth are constantly active, leading to the
uncontrolled and excessive growth of the cancer cell. It is
estimated that approximately 70% of patients with colon cancer are
positive for EGFR.

ErbituxT(IMC-225): ErbituxT is a monoclonal antibody that blocks the
binding action between EGFR and growth factors. Monoclonal
antibodies are proteins that have been manufactured in a laboratory
to bind to specific sites on designated cells. ErbituxT binds to
EGFR so that growth factors are unable to bind to EGFR. This
ultimately slows or stops the growth process of EGFR-positive cancer
cells. In addition, ErbituxT appears to augment anti-cancer activity
of chemotherapy agents through biological processes not yet
elucidated.

In February 2004, the Food and Drug Administration (FDA) approved
ErbituxT for the treatment of recurrent colorectal cancer that
expresses the epidermal growth factor receptor (EGFR). The FDA
indication specifies that ErbituxT be used in combination with the
chemotherapy agent Camptosar® in patients who stopped responding to
previous therapy with Camptosar®, or as a single agent in patients
who are not able to tolerate Camptosar®-based chemotherapy. ErbituxT
may be available to patients with stage IV disease through a
clinical trial.

Cox-2 Inhibitors
Clinical trials evaluating Cox-2 inhibitors in combination with
Camptosar® are ongoing in an attempt to improve the treatment of
colon cancer. Clinical studies have suggested that the regular use
of non-steroidal anti-inflammatory drugs reduces the risk for
developing colorectal cancer.

Celocoxib (Celebrex®): Non-cancerous tumors, called adenomatous
polyps, may grow in the colon or rectum. In some individuals, these
polyps eventually become cancerous and develop into colorectal
cancer. Familial adenomatous polyposis (FAP) is a genetic disease
that most often affects adolescents and young adults, causing
hundreds of adenomatous polyps to form in the colon and rectum.
Because of the presence of these polyps, many of these people
develop colorectal cancer at an early age. In 2000, the Food and
Drug Administration approved Celebrex®, previously approved for the
treatment of individuals with arthritis, to be used in conjunction
with the usual therapy for individuals with FAP. Celebrex® has been
reported to reduce the number of colon polyps that develop in
individuals with FAP, thus significantly reducing their risk for
developing colorectal cancer.

Other Treatments
Managing side effects (supportive care): Treatment designed to
prevent or control the side effects of cancer and cancer therapies
are called supportive care. Side effects not only cause patients
discomfort, but also may prevent the delivery of therapy at its
planned dose and schedule. In order to achieve optimal outcomes from
treatment and improve quality of life, it is imperative that
treatment is delivered as planned and that side effects resulting
from cancer and its treatment are appropriately managed. For more
information, visit Managing Side Effects .

Liver-directed therapies: Continued development and refinement of
hepatic artery infusion, chemoembolization, and other liver-directed
therapies is ongoing. For patients with liver dominant disease,
these strategies are being utilized to shrink the cancer and
increase the number of patients eligible for surgical removal of
their cancer.

Biological therapy: Biologic therapy consists of naturally occurring
or synthesized substances that direct, facilitate, or enhance the
body's normal immune defenses. Examples of compounds used for
biological therapy include interferons, interleukins, vaccines and
monoclonal antibodies. In an attempt to improve survival rates,
these and other agents are being tested alone or in combination with
chemotherapy in clinical trials.

Vaccines: The purpose of a vaccine is to help the patient's immune
system destroy the cancer by activating the patient's immune cells
against the cancer. Vaccines have already been shown to improve the
survival of certain patients with colorectal cancer and continue to
be evaluated in clinical trials. The majority of colorectal cancer
cells display a protein on their surface called the carcinoembryonic
antigen (CEA). Through mechanisms not clearly elucidated, CEAs are
not recognized by the patient's immune system when they are
presented on cancer cells in the body. Researchers have recently
been investigating novel strategies to stimulate the immune system
to recognize CEA as foreign which would cause an attack on cancer
cells presenting this antigen.

Human chorionic gonadotropic (hCG) hormone is a hormone that is
normally only produced during pregnancy. However, researchers have
discovered that many cancer cells express hCG and have been
developing a vaccine that specifically targets hCG. Avicine® is a
vaccine that is comprised of parts of the hCG hormone and is linked
to the diphtheria toxin. Once injected, a patient's immune system
recognizes the whole vaccine complex as "foreign" and researchers
speculate that the immune system recognizes the whole vaccine
complex as "foreign" and researchers speculate that the immune
system neutralizes hCG in the body and its possible growth
stimulatory effects on cancer, as well as stops the growth of the
cancer cells expressing hCG.

Results from a recent clinical trial including 12 medical centers in
the United States involved 77 patients with stage IV colorectal
cancer who were treated with Avicine®. Of these patients, 56
patients demonstrated an immune response against hCG. The overall
survival of all patients in the trial was 34 weeks. Patients who
developed an immune response to the vaccine had an average survival
of 45 weeks. Patients who developed an immune response to two
segments of hCG had an average survival of 66 weeks. Avicine® was
very well tolerated.[13]

Vaccines are also being developed which are made from the actual
cancer cells removed from the patient. This is referred to as an
autologous vaccine. The difficulty in preparing vaccines is that the
patient's cancer cells must be processed immediately following
surgery. Therefore, patients and their surgeon must be prepared in
advance to ensure that the removed cancer cells can be handled
properly for vaccine preparation.

Phase I clinical trials: New chemotherapy drugs continue to be
developed and evaluated in patients with recurrent cancers in phase
I clinical trials. The purpose of phase I trials is to evaluate new
drugs in order to determine the best way of administering the drug
and whether the drug has any anti-cancer activity in patients.

References


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[1] Saltz LB, Cox JV, Blanke C, Rosen LS, et al. Irinotecan plus
Fluorouracil and Leucovorin for Metastatic Colorectal Cancer. New
England Journal of Medicine 2000;343(13):905-914.

[2] Sanofi-Synthelabo. EloxatinT (oxaliplatin for injection)
Approved in the United States for the 1st Line Treatment of
Metastatic Colorectal Cancer. Available at: http://www.sanofi-
synthelabous.com/news/2004/20040112.html. Accessed January 2003.

[3] Hurwitz H, et al. Late-Breaking Oral Presentation. Proceedings
of the 39th Meeting of the American Society of Clinical Oncology
2004; Abstract #3646.

[4] Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus
Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal
Cancer. New England Journal of Medicine. 2004;350:2335-2342.

[5] Hurwitz H, et al. Late-Breaking Oral Presentation. Proceedings
of the 39th Meeting of the American Society of Clinical Oncology
2004; Abstract #3646.

[6] Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus
Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal
Cancer. New England Journal of Medicine. 2004;350:2335-2342.

[7] Hoff PM, Ansari R, Batist G, et al. Comparison of oral
capecitabine versus intravenous fluorouracil plus leucovorin as
first-line treatment in 605 patients with metastatic colorectal
cancer: results of a randomized phase III study. J Clin Oncol.
2001;19:2282-2292.

[8] Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine
compared with intravenous 5-fluorouracil plus leucovorin in patients
with metastatic colorectal cancer: results of a large phase III
study. J Clin Oncol. 2001;19:4097-4106.

[9] Cassidy J, Scheithauer W, McKendrick J, Kroning H, et al.
Capecitabine (X) vs bolus 5-FU/leucovorin (LV) as adjuvant therapy
for colon cancer (the X-ACT study): Efficacy results of a phase III
trial. Proceedings from the 40th annual meeting of the American
Society of Clinical Oncology, held in New Orleans LA, June 5-8,
2004; Abstract #3509.

[10] Headrick JR, Miller DL, Nagorney DM, Allen MS, et al. Surgical
treatment of hepatic and pulmonary metastases from colon cancer.
Annals of Thoracic Surgery 2001;71:975-980.

[11] Harmantas A, Rotstein LE, Langer B. Regional versus systemic
chemotherapy in the treatment of colorectal carcinoma metastatic to
the liver: Is there a survival difference?--Meta-analysis of the
published literature. Cancer 1996;78:1639-1645.

[12] Kemeny N, Huang Y, Cohen AM, Shi W, et al. Hepatic Arterial
Infusion of Chemotherapy after Resection of Hepatic Metastases from
Colorectal Cancer. New England Journal of Medicine 1999;342:2039-
2048.

[13] AVI Biopharma. Available at:
http://www.avibio.com/html/NFFrameSet.htm. Accessed August 7, 2002.


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