Stage 4 colon cancer

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