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Cancer chemopreventionhttp://bmj.com/cgi/content/full/324/7339/714
Clinical reviewScience, medicine, and the future Cancer chemopreventionPeter Greenwald Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, 6130 Executive Boulevard, Suite 2040, Bethesda, Maryland 20892-7309, USA Chemopreventive agents show promise for preventing and reversing cancer development Chemoprevention of cancer aims to prevent, arrest, or reverse either the
initiation phase of carcinogenesis or the progression of neoplastic
cells to cancer. It has been an active area of research for several
decades; the use of retinoids to prevent cancer of the head and neck
is a notable example.1 Chemoprevention is
widely used and readily accepted by doctors and patients in the
form of drugs that lower cholesterol concentrations and blood
pressure to reduce the risk of cardiovascular disease. It can also be
used in some apparently healthy people at risk of cancer to prevent
or reduce their risk of developing invasive disease. The biomedical
community needs to recognise and advocate approaches to prevent
cancer with the same enthusiasm that it currently directs towards
treating it.
I searched the databases PubMed and CANCERLIT for the period from 1 January
1996 to 31 July 2001 using the key words "chemoprevention" and "neoplasms."
I used recent reviews identified by these searches, plus several
archived journal articles and textbooks on chemoprevention available
at the US National Library of Medicine, to develop an overview of
cancer chemoprevention.
Research into chemoprevention uses a systematic strategy that begins by surveying the results of epidemiological, laboratory, and clinical research for compounds, both naturally occurring and synthetic, that seem to inhibit carcinogenesis. Many compounds, belonging to diverse structural and functional chemical classes, have been identified as potential chemopreventive agents. These include vitamins and minerals (such as folate, vitamin E, vitamin D, calcium, and selenium); naturally occurring phytochemicals (such as curcumin, genistein, indole-3-carbinol, and L-perillyl alcohol); and synthetic compounds (such as retinoids, selective oestrogen receptor modulators, and cyclo-oxygenase-2 inhibitors) (see table A on bmj.com). Several of these potential agents have been investigated in studies of chemoprevention of colorectal cancer.2 Chemopreventive agents might reduce the cancer risk through various mechanisms and different stages of carcinogenesis (fig 1). 3 4 Evidence from epidemiological and laboratory studies Plant derived foods contain thousands of chemically dissimilar phytochemicals, many of which have been investigated in studies in vitro and in vivo to determine their effects on cancer risk and their related mechanisms of action.7-9 In one study, for example, diallyl sulphide (found in allium vegetables such as garlic and onion) seemed to suppress cell division in human colon tumour cells by interfering with the cell cycle; cells remained in the inactive G phase instead of moving to the M phase, where mitosis occurs (fig 2).10 In another example, soybean phytochemicals (such as genistein) may inhibit the growth of prostate tumours through reduced cell proliferation and angiogenesis and increased apoptosis. 11 12
Evidence from systematic evaluation of agent classes
Evidence from cancer treatment A breast cancer prevention trial was initiated in 1992 in response to data from trials in women with early breast cancer that indicated that treatment with tamoxifen resulted in a significant decrease (40-50%) of contralateral breast cancer.15 The trial, conducted with more than 13 000 women at increased risk of breast cancer because of age or other risk factors, was unblinded in 1998 when it was found that women who took tamoxifen daily for five years had a 49% reduced risk of breast cancer compared with those taking placebo.16 An ongoing study of tamoxifen and raloxifene aims to determine whether raloxifene, also a selective oestrogen receptor modulator, is as effective as tamoxifen in reducing the risk of breast cancer in postmenopausal women at high risk.17 The effects of agents such as tamoxifen underscore the sometimes vague boundary between prevention and treatment of cancer, an issue complicated by new findings in molecular biology that blur the distinctions between premalignant and malignant lesions.17
The preclinical development of chemopreventive agents includes an initial
assessment of their efficacy using in vitro and cell based
mechanistic assays and in vivo screens in animal models of
carcinogenesis that are representative of human cancers and exhibit
precancerous lesions (see table B on bmj.com). The most promising
agents are characterised more fully in the animal models to evaluate,
for example, dose-response curves, dosing regimens, and combinations
with other agents tested.13 Compounds that
show high efficacy and low toxicity in animal studies are considered
for testing in humans. Potential chemopreventive agents selected
for testing in people at high risk of developing cancer must have
low toxicities compared with the drugs used to treat existing
cancer.
Phase I clinical trials are generally conducted in a limited number of healthy subjects. They determine the dose related safety and efficacy of an agent and its pharmacokinetic variables, including absorption, distribution, metabolism, and excretion. Phase II clinical trials evaluate the efficacy of an agent in a larger group of subjects at high risk of certain cancers. Important objectives include identifying biochemical, genetic, molecular, cellular, or histological biomarkers of cancer that can be used to estimate possible neoplastic progression and determining whether the chemopreventive agent can affect the modulation of the identified biomarker(s). Phase III clinical trials, conducted either in populations at high risk of specific cancers or in subjects from the general population, are usually randomised, controlled, large scale trials conducted primarily to determine the efficacy of the intervention.18 The selenium and vitamin E clinical trial, for example, is a phase III trial to test vitamin E and selenium, individually and in combination, in 32 000 middle aged men with normal prostate specific antigen concentrations. The primary end point will be prostate cancer diagnosed by community practices, and the trial is projected to last 12 years, including seven years of intervention and five years of follow up.19 The Division of Cancer Prevention of the US National Cancer Institute is currently sponsoring more than 65 phase I, II, and III chemoprevention trials (table 1).
Study designs and findings for several phase III trials have been summarised.20
The outcomes of the
Considerable research is currently focused on identifying biomarkers as surrogate end points in place of overt cancer in cancer chemoprevention trials. Cancer is a comparatively infrequent event, and clinically overt cancer usually takes many years to develop. Clinical trials to test the effectiveness of chemopreventive agents therefore require large study populations and a long term commitment of resources. The availability of biomarkers as surrogate end points for clinical disease would allow smaller trials of shorter duration, facilitating clinical research into chemoprevention. Acceptable biomarkers for cancer must be reliable (repeatable), highly sensitive and specific, quantitative, readily obtained by non-invasive methods, part of the causal pathway for disease, capable of being modulated by the chemopreventive agent, and have high predictive value for clinical disease.24 Table 2 shows examples of potential biomarkers that are being evaluated as surrogate end points in phase II and III trials sponsored by the National Cancer Institute's Division of Cancer Prevention. The use of presurgical models, in which a chemopreventive agent is administered for several weeks before surgery, is an innovative approach to identifying possible biomarkers and evaluating the effects of agents on these. For example, phase II trials of finasteride and lycopene have been conducted in patients before they had radical prostatectomies, and patients with early breast cancer are being recruited to a presurgical intervention with tamoxifen and fenretinide.25-27 Finasteride did not exhibit any chemopreventive effect on potential biomarkers in prostate tissue at the dose given.25 Lycopene, however, significantly reduced the extent of diffuse high grade prostatic intraepithelial neoplasia.26
No biomarkers have yet been validated as surrogate end points for cancer.
Research is focusing on intraepithelial neoplasia, a premalignant
condition exemplified by colorectal adenomas, prostatic
intraepithelial neoplasia, and cervical intraepithelial neoplasia.
Intraepithelial neoplasia and its associated genetic and molecular
changes are currently considered to provide the best opportunities
for validating surrogate endpoint biomarkers in epithelial tissues.24
The National Cancer Institute's early detection research network
was established to accelerate the development and validation of
biomarkers for evaluating cancer risk and detecting premalignancy.
The network links centres of expertise from academia and industry and
includes a centre for data management and coordination that will
develop a common database for network research.
The medical community can play an important part in cancer prevention by
recognising the multistage nature of cancer development, making all
patients aware of factors that increase cancer risk and ways to
reduce risk, and identifying patients at high risk of cancer who
might benefit from chemopreventive interventions. Primary care
doctors should evaluate cancer risk even for people who seem healthy.
A woman's risk of invasive breast cancer, for example, can be
calculated by using the breast cancer assessment tool found at
http://bcra.nci.nih.gov/brc/questions.htm Similar assessment
tools are not yet available for other cancers, but risk factors for
various cancers are outlined at www.cancer.org
and provide some basis for assessing a patient's degree of risk
for a particular cancer. Although this approach needs refinement, it
allows doctors to develop an individual risk profile for cancer that
may help guide preventive interventions, such as chemoprevention, and
motivate patients to change their behaviour.
Competing interests: None declared.
ALL INFORMATION, DATA, AND
MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION
PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS
OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR
LEGAL ADVICE. THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND
COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH
YOUR HEALTH CARE PROVIDER.
DISCLAIMER: All information, data, and material contained, presented, or provided here is for general information purposes only and is not to be construed as reflecting the knowledge or opinions of the publisher, and is not to be construed or intended as providing medical or legal advice. The decision whether or not to vaccinate is an important and complex issue and should be made by you, and you alone, in consultation with your health care provider.
Copyright 2012 by Vaccination News, A Non-Profit Corporation. All Rights Reserved. This content may not be copied unless permission in writing from Sandy Gottstein has been obtained. 
|
 "A foolish faith in authority is the worst enemy of truth." -- Albert Einstein, letter to a friend, 1901 "I know of no safe depository of the ultimate powers of the society but the people themselves, and if we think them not enlightened enough to exercise control with a wholesome discretion, the remedy is not to take it from them, but to inform their discretion by education." -- Thomas Jefferson, letter to William C. Jarvis, September 28, 1820 "What's the point of vaccination if it doesn't protect you from the unvaccinated?" -- Sandy Gottstein "Who gets to decide what the greater good is and how many will be sacrificed to it?" -- Sandy Gottstein |
Top
Methods
Identifying
suitable...
for
example, finasteride (a 5-
-reductase
inhibitor used to treat benign prostatic hyperplasia) for prostate
cancer and tamoxifen (a selective oestrogen receptor modulator) for
breast cancer. Finasteride is being tested in a prostate cancer
prevention trial in about 18 000 men aged over 55 whose
concentrations of prostate specific antigen (PSA) are lower than 3 ng/ml
and in whom a digital rectal examination was negative.
carotene cancer
prevention study and the 
Extra tables appear on bmj.com 