ReviewRecent advances in cancer chemoprevention, with emphasis on breast and colorectal cancer
Introduction
Chemoprevention is a recently introduced and rapidly growing area of oncology. The number of chemoprevention trials have increased substantially in just a few years, for there is no doubt that the prospect of being able to prevent cancer is universally attractive. The term chemoprevention was used in 1979 by Sporn and Newton who defined it as “the prevention of cancer by the use of pharmacological agents that inhibit or reverse the process of carcinogenesis” [1].
Carcinogenesis is a complex and multistage process involving interactions between genes and environmental insults that ultimately affect cell proliferation and death. Chemoprevention focuses on intervening in the processes in the cascade of carcinogenic events to prevent the final progression to neoplastic disease, unlike chemotherapy, which concentrates on containing or eradicating cells that have already undergone malignant transformation. Whilst chemotherapy is targeted at people with manifest disease, chemoprevention is directed at individuals who are apparently well, although those in high-risk groups could arguably have existing premalignant conditions. These important differences raise several considerations related to the design and execution of clinical trials of chemopreventive agents. Careful thought must be given to defining the sample population, to defining what is an acceptable intervention in a ‘well’ person and what are valid endpoints for measuring outcome, for if the primary aim is to avoid malignancy, a successful intervention would need to be studied for many years.
The rationale behind many chemoprevention studies comes often, but not necessarily, from epidemiological and observational studies that look for an association between environmental factors and tumour occurrence. But environmental factors are hugely complex and dissecting out the primary causative factor within that association can be a long and frustrating task. It is notable that some important chemoprevention trials have contributed to our knowledge through totally negative findings.
This review discusses both the general considerations for chemoprevention trials and reviews intervention trials that have been conducted for specific cancers.
Section snippets
Target populations
Epidemiological and genetic studies have allowed us to define high-risk groups for many malignancies. Risk may be conferred by inheritance of particular genes, such as the adenomatous polyposis coli (APC) gene in colorectal cancer, or by exposure to known carcinogens, such as smoking and lung cancer. However, there are many considerations in deciding whether high-risk groups are the most appropriate cohort for chemoprevention studies. If the sample population is a high-risk group there is an
Surrogate endpoints in chemoprevention trials
Surrogate endpoints are biological markers or events that may be assessed or observed prior to the clinical appearance of the disease, and that bear some relationship to the development of that disease. They are intermediate in the sense that they occur sometime between a given intervention that affected the disease process and the time of the clinical diagnosis of the disease. The use of surrogate endpoint biomarkers (SEBs) in pivotal cancer chemoprevention trials may lead to a rational choice
Histopathological markers
As cancer is a histopathological disease by definition (although driven by germline and somatic genetic alterations), histopathological markers closest to the incidence of invasive cancer both theoretically and demonstrably hold the greatest predictive value amongst the range of intermediate efficacy markers currently available for application in cancer prevention studies. Such markers may be reductions in the number, area, or grade of incident pre-invasive neoplastic lesions (atypia of
Circulating insulin-like growth factor-I (IGF-I)
The IGF system plays a pivotal, permissive role in cell proliferation of both epithelial and mesenchymal tissues in at least three different ways: (1) it is highly mitogenic; (2) it protects normal and tumour cells from apoptosis; and (3) it is required in several types of cells for the establishment and maintenance of the transformed phenotype and for tumorigenesis [11]. Large, well conducted, long-term prospective studies have clearly shown that high circulating levels of IGF-I and low levels
Mammographic density
There is a consistent line of evidence that a higher mammographic density is associated with an increased risk of breast cancer (>50% relative risk (RR)=4–5 compared with women with lucent mammograms). There is a high degree of consistency amongst epidemiological studies that the higher category of breast density (>75%) has an approximately 5-fold increased risk of breast cancer compared with the lower category. This conclusion is mainly based on three prospective nested case–control studies (
Tamoxifen studies
Tamoxifen is a non-steroidal triphenylethylene derivative which can be classified as a first generation selective oestrogen receptor modulator (SERM). Tamoxifen is widely used for palliative endocrine treatment of advanced breast cancer and as adjuvant therapy to control micrometastatic relapse and new primaries in women treated surgically for early breast cancer. It has been investigated in three large cooperative phase III trials for prevention of breast cancer in at-risk women. The results
Future studies
It seems to be a common occurrence that chemoprevention trials that set out to investigate the specific interaction of a putative chemopreventive agent with a particular cancer provide equally useful data concerning other cancer types. Thus, the study evaluating the effect of selenium on the incidence of skin cancer [9] showed positive effects on prostate cancers. Similarly, the ATBC study of lung cancer 14, 84 showed a protective role for vitamin E on the incidence and mortality of prostate
Acknowledgements
This paper is largely based on a chapter prepared for the Oxford Textbook of Oncology, second edition, edited by R. Souhami Oxford University Press 2000, and reproduced here with the permission of the authors and publishers. The authors wish to thank Dr Serena Mora for her technical assistance and Dr Jan Hawthorn for reviewing the English style.
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