Despite advances in treatment for colon cancer, the five year survival has not significantly altered over the past decade. Survival could improve in several key areas:
* Preventive measures--such as diet and chemoprevention with agents such as non-steroidal anti-inflammatory drugs
* Screening strategies--such as faecal occult blood testing and flexible sigmoidoscopy
* Optimisation of current chemotherapy and radiotherapy regimens and the development of more effective antineoplastic agents
* New therapeutic approaches--such as immunotherapy and gene therapy.
This article will focus on prevention with non-steroidal anti-inflammatory drugs and on new strategies for treating colon cancer.
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. Gene knockout studies in mice suggest that inhibition of the cyclo-oxygenase type 2 pathway by non-steroidal anti-inflammatory drugs may be important in the mechanism of action.
The only randomised controlled trial examining the effect of aspirin in primary prevention of colon cancer did not show any benefit after five years of aspirin use. A recent prospective cohort study suggested, however, that five years may be insufficient to show any benefit and that 10-20 years is needed to show an effect.
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 maximise 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 tumours, but this approach has yet to be tested in a large randomised controlled trial.
Immunotherapy
Many cancers can be destroyed by a tumour specific, cell mediated immune response, usually by CD8 (cytotoxic) lymphocytes. However, colorectal tumours are poorly immunogenic and may evade immune destruction by various mechanisms, such as tumour "tolerance." To overcome these problems, several immunostimulatory approaches have been advocated to augment the innate immune response against tumours.
Vaccination with autologous tumour cells
This approach uses cells derived from the patient's tumour to elicit a cell mediated immune response against the tumour. To increase the efficacy of this response, tumour cells are coadministered with an immunomodulatory adjuvant, such as BCG. This approach has been tested in three randomised, controlled trials in an adjuvant setting in colorectal cancer, after resection of the tumour. No serious side effects were encountered in any of the studies.
Vaccination against tumour associated antigens
An alternative approach is vaccination against a tumour associated antigen, such as the carcinoembryonic antigen, which is overexpressed in 90% of colon cancers. A phase I immunisation study of a recombinant vaccinia virus, encoding the gene for carcinoembryonic antigen, in patients with advanced colorectal cancer, showed HLA specific, cytolytic T cell responses to carcinoembryonic antigen epitopes in vitro. This study did not show any clinical benefit, but several trials are under way, using optimal vaccination approaches in patients with minimal residual disease where clinical responses may be observed.
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Monoclonal antibodies directed against tumour antigens
Monoclonal antibodies against tumour antigens have been shown to elicit immune responses against the tumour, 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 tumours.
In a study among patients with Dukes's stage C colon cancer the patients were randomised 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.
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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 Immunostimulatory approaches for augmenting the innate immune response against tumours
* Vaccination with autologous tumour cells
* Vaccination against tumour associated antigens, such as carcinoembryonic antigen
* Use of monoclonal antibodies directed against tumour antigens
Vaccination with autologous turnout cells Hoover et al, 1993
* 98 patients with colon or rectal cancer were randomised to surgery alone or to surgery plus vaccination with autologous tumour cells
* No significant improvement in the recurrence or the survival rate
* Subgroup analysis of patients with colon cancer showed a significant improvement in survival and disease-free survival in those who received vaccination (P = 0.02, P = 0.039 respectively)
Harris et al, 1994
* 412 patients with Dukes's stage B and C colon cancer were postoperatively randomised to vaccination with autologous tumour cells or to no further treatment
* No significant differences between treated and untreated groups
Vermorken et al, 1999
* 254 postoperative patients with stage H or III colon cancer were randomised to vaccination with autologous tumour cells or to no further treatment. Those randomised to receive vaccination received a 4th booster vaccine after six months (in contrast with the patients in the two previous studies, who received only three doses)
* In the those receiving vaccination, there was a significant reduction in recurrence (44%, 95% confidence interval 7% to 66%) and a reduction in overall survival, although this did not reach significance
* The main benefit was in stage II disease, with a non-significant reduction in recurrence in stage III disease; this was thought to be due to the increased tumour burden in more advanced stages
Further reading
* Langman M, Boyle P. Chemoprevention of colorectal cancer. Gut 1998;45:578-85.
* Gann PH, Manson JE, Glynn RI, Buring JE, Hennekens CH. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Institute 1993;85:1220-4.
* 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 randomised trial. Lancet 1999;353:345-50.
* 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.
* 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.
* Chung-Faye GA, Kerr DJ, Young LS, Searle PE Gene therapy strategies for colon cancer. Molecular Medicine Today 2000;6:82-7.
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 tumour 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 tumours. Restoration of wild-type p53 in p53 mutated tumours 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 tumours, 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 localise the toxic drug effects to tumour cells. This involves gene transfer of an enzyme into tumour cells, which converts an inactive prodrug into a toxic metabolite, leading to cell death. An important feature of enzyme-prodrug systems is the "bystander effect," whereby surrounding cells (not expressing the enzyme) are also killed by active metabolites. Gene transfer is achieved by viral vectors, such as retroviruses or adenoviruses. 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-tumour effect was seen with the maximally tolerated dose of fluorouracil.
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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 remodeling processes, such as wound healing and angiogenesis. Matrix metalloproteinases are overexpressed, however, in various tumours, including colorectal cancers, and have been implicated in facilitating tumour invasion and metastasis. The matrix metalloproteinase inhibitor, marimastat, has shown reductions in levels of tumour markers in phase I studies, and its clinical efficacy is currently being tested in phase III trials.
Conclusions
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 randomised 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.
Dietary modifications to reduce the incidence of colon cancer may be difficult to implement (dietary interventional studies have shown this to be the case for cardiovascular disease); the roles of screening, chemotherapy, and radiotherapy have been covered earlier in this series
The p53 gene mutation is present in most colon cancers
Two current phase I trials are using a virus directed enzyme-prodrugs approach for treating colorectal liver metastases by direct injection into the tumour of an adenovirus encoding a therapeutic enzyme. One study is using nitroreductase plus the intravenous prodrug CB1954; the other is using cytosine deaminase plus fluorocytosine
Immunostimulatory approaches for augmenting the innate immune response against tumours
* Vaccination with autologous tumour cells
* Vaccination against tumour associated antigens, such as carcinoembryonic antigen
* Use of monoclonal antibodies directed against tumour antigens
Vaccination with autologous turnout cells Hoover et al, 1993
* 98 patients with colon or rectal cancer were randomised to surgery alone or to surgery plus vaccination with autologous tumour cells
* No significant improvement in the recurrence or the survival rate
* Subgroup analysis of patients with colon cancer showed a significant improvement in survival and disease-free survival in those who received vaccination (P = 0.02, P = 0.039 respectively)
Harris et al, 1994
* 412 patients with Dukes's stage B and C colon cancer were postoperatively randomised to vaccination with autologous tumour cells or to no further treatment
* No significant differences between treated and untreated groups
Vermorken et al, 1999
* 254 postoperative patients with stage H or III colon cancer were randomised to vaccination with autologous tumour cells or to no further treatment. Those randomised to receive vaccination received a 4th booster vaccine after six months (in contrast with the patients in the two previous studies, who received only three doses)
* In the those receiving vaccination, there was a significant reduction in recurrence (44%, 95% confidence interval 7% to 66%) and a reduction in overall survival, although this did not reach significance
* The main benefit was in stage II disease, with a non-significant reduction in recurrence in stage III disease; this was thought to be due to the increased tumour burden in more advanced stages
Further reading
* Langman M, Boyle P. Chemoprevention of colorectal cancer. Gut 1998;45:578-85.
* Gann PH, Manson JE, Glynn RI, Buring JE, Hennekens CH. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Institute 1993;85:1220-4.
* 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 randomised trial. Lancet 1999;353:345-50.
* 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.
* 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.
* Chung-Faye GA, Kerr DJ, Young LS, Searle PE Gene therapy strategies for colon cancer. Molecular Medicine Today 2000;6:82-7.
G A Chung-Faye is a clinical research fellow at the Institute for Cancer Studies, University of Birmingham.
The ABC of colorectal cancer is edited by DJ Kerr, professor at the Institute for Cancer Studies, University of Birmingham; Annie Young, research fellow at the School of Health Sciences, University of Birmingham; and F D Richard Hobbs, professor in the department of primary care and general practice, University of Birmingham. The series will be published as a book by the end of 2000.
COPYRIGHT 2000 British Medical Association
COPYRIGHT 2001 Gale Group
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