Hello jimmy,
Thanks for asking this question. As you requested in the
clarification (see above), I will only be answering part B of the
question you posed.
As you have mentioned, NSAIDs and COX-2 inhibitors play an emerging
role in the chemoprophylaxis of colorectal cancer.
This is the current medical recommendation on the role of NSAIDs in
colorectal cancer.
From UptoDate:
“Despite the relative uncertainty regarding the mechanism of action, a
number of epidemiologic and experimental observations support a role
for NSAIDs in the prevention of colorectal cancer. The optimal age to
start NSAIDs, the effective dose, and the best NSAID are unknown. In
addition, the risks of NSAIDs and cost-effectiveness of a
chemoprevention program must be considered. Until further data are
available, NSAIDs cannot presently be recommended solely for the
prevention of colon cancer; the results of clinical trials on this
subject are awaited. In addition, investigation into the use of NSAIDs
to promote tumor regression or as adjuncts to chemotherapy regimens is
needed.” (1)
I can give you the specific studies in another question if you desire.
Here is your question:
What would be another (relatively non-toxic) approach for the non-
responding patient (in the treatment of colorectal cancer)?
I assume you are asking about novel and emerging treatment for
colorectal cancer. First, I will briefly discuss what is current
standard of care.
1) Current standard of care
Surgery: Regardless of the extent of the cancer, surgery has the most
important role in treating colon cancer for the following reasons. In
patients with cancer limited to the colon, the type of surgery depends
upon the location and stage of the tumor. As a general rule, the tumor
is usually removed along with a portion of the adjacent healthy colon.
The colon is then reconnected allowing for normal bowel function. In
some cases, a temporary colostomy (an opening between the colon and
the skin made to collect waste from the intestine) may be necessary to
allow healing of the intestine before the reconnection can be
accomplished safely.
Chemotherapy: Adjuvant chemotherapy is usually recommended for
patients in whom it is suspected that residual cancer remains in the
body after the primary tumor has been removed. Even if the tumor has
been completely removed, tiny cancer cells may remain in the body and
grow, causing relapse after surgery. This is most likely in patients
who have positive lymph nodes (stage III disease). In such patients,
chemotherapy can prevent relapse and prolong survival. The best
treatment for patients who are at high risk for relapse following
surgery is an area of intense ongoing research. At the present time,
the best approach appears to involve chemotherapy. Standard
chemotherapy includes two medications: 5-fluorouracil (5-FU) and
leucovorin, given in cycles over a period of six to eight months. An
alternative drug, levamisole, is also effective when combined with 5-
FU for adjuvant treatment. Although this regimen may be slightly less
effective than combinations of 5-FU and leucovorin, it is generally
associated with fewer side effects. (2)
2) Novel and emerging treatments
Non-steroidal anti-inflammatory drugs:
Evidence strongly suggests a protective effect of non-steroidal anti-
inflammatory drugs in colon cancer. Several cohort and case-control
studies have consistently shown dose related reductions of colorectal
cancer in regular users of these drugs. Furthermore, patients with
familial adenomatous polyposis who took the non-steroidal anti-
inflammatory sulindac had reductions in the number and size of their
polyps.
The predominant side effect from using non-steroidal anti-inflammatory
drugs is the increased incidence of gastrointestinal bleeds. On the
current evidence, the mortality risk from such bleeding would be
outweighed by the reduction in mortality from colon cancer. To
maximize the benefit to risk ratio, however, targeting individuals at
high risk of colon cancer may prove more fruitful.
Non-steroidal anti-inflammatory drugs could be used as secondary
prevention after surgical resection of colonic tumors, but this
approach has yet to be tested in a large randomized controlled trial.
Immunotherapy:
Many cancers can be destroyed by a tumor specific, cell mediated
immune response, usually by CD8 (cytotoxic) lymphocytes. However,
colorectal tumors are poorly immunogenic and may evade immune
destruction by various mechanisms, such as tumor "tolerance." To
overcome these problems, several immunostimulatory approaches have
been advocated to augment the innate immune response against tumors.
Vaccination with autologous tumor cells:
This approach uses cells derived from the patient's tumor to elicit a
cell mediated immune response against the tumor. To increase the
efficacy of this response, tumor cells are coadministered with an
immunomodulatory adjuvant, such as BCG. This approach has been tested
in three randomized, controlled trials in an adjuvant setting in
colorectal cancer, after resection of the tumor. No serious side
effects were encountered in any of the studies.
Vaccination against tumor associated antigens:
An alternative approach is vaccination against a tumor associated
antigen, such as the carcinoembryonic antigen, which is overexpressed
in 90% of colon cancers. Several trials are under way, using optimal
vaccination approaches in patients with minimal residual disease where
clinical responses may be observed.
Monoclonal antibodies directed against tumor antigens:
Monoclonal antibodies against tumor antigens have been shown to elicit
immune responses against the tumor, which may previously have induced
immunogenic tolerance. The 17-1A antigen is a surface glycoprotein
with a putative role in cell adhesion and is present in over 90% of
colorectal tumors. In a study among patients with Dukes's stage C
colon cancer the patients were randomized to receive either surgery
alone or surgery plus repeat administrations of a monoclonal antibody
against the 17-1A antigen. Side effects of the treatment were
infrequent, consisting mainly of mild constitutional and
gastrointestinal symptoms. Four patients experienced an anaphylactic
reaction, which required intravenous steroids but no hospital
admission.
Gene therapy:
Gene therapy represents a new treatment approach for colon cancer. It
is at a developmental stage, and preclinical studies are only just
being translated into clinical trials. Two gene therapy strategies are
currently used, gene correction and enzyme-prodrug systems.
Gene correction:
The most logical approach to gene therapy is the correction of a
single gene defect, which causes the disease phenotype. In colon
cancer, as in many other cancers, this goal is elusive as malignant
transformation is usually accompanied by a series of genetic mutations.
However, some of these mutations, such as the p53 gene mutation, are
important for the propagation of the malignant phenotype, and the
corollary is that correcting these mutations may inhibit the growth of
tumor cells.
P53 gene:
The p53 gene regulates the cell cycle and can cause growth arrest or
apoptosis in response to DNA damage. Loss of p53 control leads to
uncontrolled growth and is associated with more aggressive tumors.
Restoration of wild-type p53 in p53 mutated tumors inhibits growth. In
a phase I trial an adenovirus encoding wild-type p53 was delivered by
hepatic artery infusion to 16 patients with p53 mutated colorectal
liver metastases. This procedure was well tolerated, with the side
effects of fever and transiently damaged liver function. Although gene
expression was detected in subsequently resected tumors, no
radiographic responses were seen at 28 days. This study has now
proceeded to a phase II trial, in combination with intrahepatic
floxuridine based chemotherapy, in which 11 out of 12 patients have
had partial responses.
Virus directed enzyme-prodrug treatment:
Enzyme-prodrug systems are used to localize the toxic drug effects to
tumor cells. This involves gene transfer of an enzyme into tumor cells,
which converts an inactive prodrug into a toxic metabolite, leading
to cell death. One such enzyme-prodrug combination is the bacterial
enzyme cytosine deaminase, which converts the antifungal agent
fluorocytosine into the antineoplastic agent fluorouracil.
Fluorouracil induces apoptosis by inhibition of the enzyme thymidylate
synthase during DNA replication. In murine models with colon cancer
xenografts expressing cytosine deaminase, 75% of mice were cured by
administration of fluorocytosine, whereas no anti-tumor effect was
seen with the maximally tolerated dose of fluorouracil.
New therapeutic agents:
The matrix metalloproteinases are a group of enzymes involved in the
physiological maintenance of the extracellular matrix. They degrade
the extracellular matrix and promote the formation of new blood
vessels and are involved in tissue remodelling processes, such as
wound healing and angiogenesis. Matrix metalloproteinases are
overexpressed, however, in various tumors, including colorectal
cancers, and have been implicated in facilitating tumor invasion and
metastasis. The matrix metalloproteinase inhibitor, marimastat, has
shown reductions in levels of tumor markers in phase I studies, and
its clinical efficacy is currently being tested in phase III trials.
Summary
Non-steroidal anti-inflammatory drugs seem to be the most promising
drug for prevention of colon cancer; case-control and prospective
cohort studies strongly suggest they reduce the risk of colon cancer.
This is further supported by studies in familial cancer patients and
animal data. However, this effect of non-steroidal anti-inflammatory
drugs is unproved in randomized controlled trials, and the issue
remains to be addressed.
Immunotherapy seems to be well tolerated and effective in an adjuvant
setting in colon cancer with limited residual disease. Its effect in
stage II disease is comparable to that of adjuvant chemotherapy in
Dukes's C colon cancer. In more advanced disease it may have a role in
combination with chemotherapy, and this approach is being explored in
ongoing trials.
Gene therapy for colon cancer is still at an early stage of
development. Preclinical studies have prompted several phase I trials.
However, significant problems remain, such as low efficiency in gene
transfer and the inhibitory effect of the host immunity, which may be
addressed by developments in vector technology. As our understanding
of the molecular biology of cancer increases, gene therapy is likely
to have an increasingly important role in the expanding array of
treatment options for colon cancer.
Please use the answer clarification to ask any questions before rating
this answer. I will be happy to explain any issue.
Thanks,
Kevin, M.D.
Search strategy:
No internet search engine was used in this answer. All sources are
from objective, physician-written, peer-reviewed resources.
Bibliography:
1)Simon, L. Role of NSAIDS in the prevention of colorectal cancer.
UptoDate, 2002.
2)Ott. Patient information: Treatment of colon cancer. UptoDate,
2002.
3)Vermorken JB, Claessen AME, van Tintern H, Gall HE, Ezinga R, Meijer
S, et al. Active specific immunotherapy for stage II and stage III
human colon cancer: a randomized trial. Lancet 1999;353:345-50.
4)Riethmuller G, Holz E, Schlimok G, Schmiegel W, Raab R, Hoffken K,
et al. Monoclonal antibody therapy for resected Dukes' C colorectal
cancer: seven-year outcome of a multicenter randomized trial. J Clin
Oncol 1998;16:1788-94.
5)Roth JA, Cristiano RJ. Gene therapy for cancer: what have we done
and where are we going? J Natl Cancer Institute 1997;89:21-39.
6)Chung-Faye GA, Kerr DJ, Young LS, Searle PF. Gene therapy strategies
for colon cancer. Molecular Medicine Today 2000;6:82-7.
7)Chung-Faye et al. Innovative treatment for colon cancer. BMJ 2000:
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