Cancer Prevention: Perspectives and Implications
"He is a better physician that keeps diseases off us, than he that cures them
being on us; prevention is so much better than healing because it saves the labour of
being sick."
Thomas Adams,1618
Thomas Adams' statement in 1618 regarding prevention as saving "the labour of
being sick" is timeless. While dramatic strides in therapeutic modalities for the
treatment of cancer have been realized, overall cancer incidence and mortality still show
upward trends, particularly for some common types of cancer. Given these trends, the real
hope for the control of cancer lies with prevention. This issue of Cancer Control
describes the progress in chemoprevention of cancer.
Cancer prevention is commonly divided into three categories of prevention: primary,
secondary, and tertiary. Primary prevention involves the avoidance of cancer causing
exposures and behaviors. While the identification of tobacco as a principal carcinogen in
cancers of the lung, head and neck, and bladder has enabled preventive efforts to be
targeted at the prevention of individuals from initiating smoking, most malignancies do
not have a clearly identified etiologic agent. Secondary prevention involves efforts
directed at the cessation of exposure to carcinogenic agents as well as to screening
individuals to detect malignancy at an earlier stage. This area includes efforts directed
at smoking cessation as well as screening programs designed to detect cancer at an earlier
stage when treatment may be more likely to result in cure. Screening programs have been
very successful in certain areas and were reviewed in the November/December 1995 issue of Cancer
Control. Tertiary prevention includes chemoprevention — the administration of
agents intended to prevent the development of cancer. This issue of Cancer Control
describes some of the recent progress that has been made in chemoprevention in several key
areas.
Dr Eva Szabo and I review the status of biomarkers, particularly as identified in lung
carcinogenesis. Numerous molecular markers may be able to serve as targets to interrupt
the process of carcinogenesis. If these targets can be validated and rational
interventions can be defined to interfere specifically with these steps in the
carcinogenic process, then there is hope for real prevention of lung cancer development.
The challenge remains to identify molecular targets associated with eventual cancer
development in order to substitute such intermediate markers for the final endpoint of
cancer development in clinical studies.
Drs Peter Greenwald and Sharon McDonald discuss the roles of diet and chemoprevention
in cancer development. Many dietary agents have been investigated as possible
chemopreventive agents. While most of the data regarding diet and cancer are based on
epidemiologic studies, the intervention trials have used either supplements or synthetic
analogues of dietary agents. As demonstrated with the betacarotene studies, such
interventions are not always beneficial and may induce harm. Further integration of
understanding of the mechanisms of carcinogenesis and the actions of nutritional
substances on this process is needed before real progress can be made in this area.
Dr Scott Lippman reviews recent advances in head and neck chemoprevention. He describes
multistep carcinogenesis and the biology of retinoids that have demonstrated activity in
head and neck cancers, and he also reviews the oral premaligancy trials that demonstrated
regression of leukoplakia in individuals treated with 13cisretinoic acid. In addition,
Dr Lippman describes the exciting finding of reduction in the risk of developing second
primary tumors following definitive treatment of early stage head and neck squamous cell
cancers in individuals treated with 13cisretinoic acid. Exposure of the aerodigestive
tract to tobacco carcinogens subjects head and neck cancers, lung cancers, and other
aerodigestive cancers to this field cancerization process. In addition, a similar process
may be involved in exposing the bladder urothelium to carcinogens (eg, tobaccorelated
carcinogens). The success in preventing second primary tumors in survivors of a first head
and neck malignancy will determine the direction for future work in head and neck cancer
prevention and hopefully will translate to prevention of first malignancies.
Drs Jean Joseph and Edward Messing provide an overview of the progress of
chemoprevention in genitourinary cancers with specific attention to bladder and prostate
cancer. Bladder cancer is an excellent model for chemoprevention, not only because
superficial bladder cancer has a high rate of local recurrence, but also because it is a
disease that is easily visualized by cystoscopy, is easily resected transurethrally, and
should shed cells containing relevant intermediate markers in the urine. While prostate
cancer is somewhat more difficult to study for chemoprevention, its high incidence makes
it an important disease to target. The large Prostate Cancer Prevention Trial initiated in
1993 should provide important information regarding the ability of finasteride to prevent
prostate cancer.
Finally, Drs Victor Vogel and Lisa Parker discuss the ethics of chemoprevention
clinical trials. Complex issues are raised because, generally, the participants do not
have cancer or may have only specified risk factors for cancer. The definition of risk,
confidentiality and recruitment, randomization, informed consent, and trial monitoring are
all critical issues associated with these trials. The use of placebos in these studies
creates conflict for some investigators as well as for potential participants. Some
studies required to monitor these treatments may be invasive and thus raise further issues
on the ethics of conducting these studies in "healthy" individuals.
Nevertheless, the success of identifying effective chemopreventive agents will rely on
clinical chemoprevention trials. It is only through the education of investigators and
potential study participants that these trials will be able to be conducted in a timely
fashion with meaningful results.
In the previous issue of Cancer Control, Drs Bernard Fisher and Joseph
Costantino reported the history of the National Surgical Adjuvant Breast and Bowel Program
Breast Cancer Prevention Trial. They described the initial scientific basis for the
hypothesis that tamoxifen could prevent or interfere with the progression of breast cancer
in women, as well as the initial steps to conduct the breast cancer prevention trial, the
justification, the objectives and major aspects of the trial, some of the difficulties
that have arisen during the conduct of the trial, and some final comments regarding the
anticipated completion of the trial with preliminary descriptions of the enrolled
population. This trial represents a sentinel trial in the United States in administering
an agent such as tamoxifen to women who have never had breast cancer but who meet criteria
that identify them as being at high risk for its development. The final results of this
trial will determine the risktobenefit ratio of such a chemopreventive agent in a very
high risk population. With the rising incidence of breast cancer — largely related to
increased screening efforts — more information about the prevention of this
malignancy would be important progress.
As more molecular markers are validated to the gold standard endpoint of cancer
incidence, chemoprevention trials may be able to be shortened and conducted with smaller
sample sizes. The booming knowledge gained from the expanding field of molecular biology
has opened real possibilities for this progress. Another direction for chemoprevention
lies along local delivery systems for chemopreventive agents in order to minimize
potential toxicities. The development of such locally directed interventions should enable
the broader application of chemopreventive agents with less toxicity for the population at
risk.
Chemoprevention should not be viewed as subjecting "healthy" individuals to
potentially toxic treatments. We all have cells that, with the process of aging, will
develop multiple molecular genetic defects that have the potential to transform and become
neoplastic. In the same way that antihypertensive agents are directed at lowering blood
pressure to prevent the subsequent development of stroke, heart failure, or myocardial
infarction, chemopreventive agents may arrest the progression of genetic defects in cells
undergoing transformation to prevent invasive cancer. This concept is key to the
development of successful chemoprevention strategies.
Gail L. Shaw, MD, FACP
Associate Professor of Medicine
University of South Florida, Tampa, Fla
Program Leader, Cancer Prevention and Lifetime Cancer Screening Programs
H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla
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