Introduction to Cancer Prevention

David S. Alberts and Lisa M. Hess

College of Medicine, University of Arizona, Tucson AZ 85724

The goals of cancer prevention are to reduce the incidence, morbidity and
mortality due to cancer through the identification and elimination of precancerous lesions (termed intraepithelial neoplasias or IENs) and/or the early detection of minimally invasive cancers. Cancer is a global term for a variety of
diseases that are characterized by uncontrolled cellular growth. The site of origin of the disease is used to define general categories of cancer (e.g. breast
cancer, skin cancer). Worldwide, the incidence and mortality from cancer has
been increasing, despite recent advances in the understanding and treatment
of many diseases. This emphasizes the need to define the etiology and molecular basis of cancer and to prevent that cancer from developing. The concept of
cancer prevention is changing gradually as we gain a greater understanding of
the genetic and molecular basis of carcinogenesis. Certainly, it is understood
that the cancer patient is not well one day and the next day diagnosed with
cancer. It is estimated that there is an average lag of at least 20 years between
the development of the first cancer cell and the onset of metastatic disease for
a broad range of solid tumors. In that there were an estimated 563,700 cancer
deaths in the U.S. in 2004, and given the 20+ year lag time, more than ten million healthy Americans harbor ultimately deadly cancers.
It is increasingly apparent that virtually all cancers proceed from the first initiated tumor cell (e.g. mutated DNA) to mild, moderate and severe dysplasia,
invasive carcinoma (invasion of cells through the basement membrane) and
metastatic disease (Fig. 1). Dysplasias are represented by small, intermediate
and advanced adenomatous polyps in the colon, atypical hyperplasia and ductile carcinoma in situ in the breast and simple hyperplasia, atypical hyperplasia
and carcinoma in situ in the endometrium. These precancerous lesions IENs
can be identified both histologically and by molecular signatures, using a variety of anlytical methods (e.g. cDNA microarray) (O'Shaughnessy, Kelloff et al.
2002).
Many researchers worldwide have focused their life's work to identify ways
to prevent cancer. This book provides an overview on the science and practice
of cancer prevention for primary caregivers and the research community. The
first section of this book (Chapters 1 through 8) provides information on economic issues in cancer prevention, dietary and environmental risk, cultural considerations in cancer prevention and issues related to drug development. The
second section of the book (Chapters 9 through 16) focuses on the prevention
of specific disease sites and provides the reader with a discussion of the epide-

D. S. Alberts and L. M. Hess

Fig. 1. Progression of precancer to cancer in humans is a multi-year process, adapted from

O'Shaughnessy et al. (O'Shaughnessy, Kelloff et al. 2002)

miology, screening, and prevention of each disease, including both practice

guidelines as well as theories and future research directions.

Overview of Cancer Prevention

It is estimated that there are over 8.1 million cases of cancer diagnosed per year
worldwide (Parkin, Pisani et al. 1999). The five most common worldwide cancers, excluding non-melanoma skin cancer, include lung, stomach, breast, colorectal and liver
cancer (Table 1). There are gender and regional differences in worldwide cancer diagnoses. Most lung cancers (about 58%) occur in developed countries. China accounts
for 38% of all stomach cancers and 53.9% of all liver cancers diagnosed worldwide.
Liver cancer is primarily diagnosed (81% of all cancers worldwide) in developing nations (e.g., Sub-Saharan Africa, Asia). Thirty-four percent of all colorectal cancer cases
are diagnosed in developed nations. Among women, breast cancer accounts for 21%
of all cancers and is the most common cancer in developed countries. Cervical cancer
is the third most common cancer among women; 30% of all cases are diagnosed in
south-central Asia. Prostate cancer is the fourth most common cancer among men
worldwide, but is the most common cancer diagosed among men in North America.
Prostate cancer incidence in North America is more than 80-fold the incidence rate in
China.
In the United States (U.S.), there were 1,368,030 cancers diagnosed in 2004, excluding non-melanoma skin cancer, and cancer accounted for 563,700 deaths (Jemal, Tiwari et al. 2004). Cancer is a major health burden in the U.S., accounting for one of
every four deaths. The most common cancers diagnosed in the U.S. are presented in
Table 2. The three most common cancers account for a similar number of diagnoses
among men and women. Among men, prostate, lung and colorectal cancer account for
396,840 diagnoses in 2004. Among women, breast, lung and colorectal cancer together
accounted for 369,970 diagnoses.

Introduction to Cancer Prevention

Number (in thousands)
Both sexes
Lung
Stomach
Breast
Colon/rectum
Liver
Prostate
Cervix
Males
Lung
Stomach
Colon/rectum
Prostate
Liver
Esophagus
Bladder
Females
Breast
Colon/rectum
Cervix
Stomach
Lung
Ovary
Endometrium

1036.9
798.3
795.6
782.8
437.4
396.1
371.2

Table 1. Worldwide annual

cancer incidence of the
most common cancers (Parkin, Pisani et al. 1999)

771.8
511.0
401.9
396.1
316.3
212.6
202.5
795.6
381.0
371.2
287.2
265.1
165.5
142.4

Number
Both sexes
Prostate
Breast
Lung/bronchus
Colon/rectum
Melanoma
Males
Prostate
Lung/bronchus
Colon/rectum
Bladder
Melanoma
Females
Breast
Lung/bronchus
Colon/rectum
Endometrium
Ovary

230,110
217,440
173,770
146,940
55,100
230,110
93,110
73,620
60,240
29,900
215,990
80,660
73,320
40,320
25,580

Table 2. Annual cancer incidence of the most common

cancers in the U.S. (Jemal,
Tiwari et al. 2004)

D. S. Alberts and L. M. Hess

Table 3. Factors associated with Cancer Risk, adapted from Giovannucci (Giovannucci 1999)
Factor

Association to Cancer Risk

Height
Obesity

Increases prostate, colon and breast cancer risk

Increases colon, breast, kidney, endometrial and gallbladder cancer
risk; may increase ovarian cancer risk
Increases colon cancer risk; may increase breast and prostate cancer
risk

Physical inactivity

The goal of cancer prevention is to reduce the morbidity and mortality from cancer
by reducing the incidence of cancer. The development of effective cancer prevention
strategies has the potential to impact more than eight million cancer diagnoses and to
prevent more than 5.2 million cancer-related deaths each year worldwide (Parkin, Pisani et al. 1999; Pisani, Parkin et al. 1999). More than half of all cancer incidence and
2.8 million deaths occur in developed countries. Even with the current knowledge
available, it is estimated that 60,000 cancer deaths could be prevented each year in the
U.S. alone (Curry 2003). According to the Director of the National Cancer Institute,
Andrew C. Von Eschenbach, M.D., one of the primary reasons why current knowledge
and information about cancer and its prevention is not applied to the general public
is due to an overload of complicated information. The dissemination of complicated
information is problematic, but is essential to reduce the burden of cancer.
There are many factors known to reduce overall cancer incidence, such as minimizing exposure to carcinogens (e.g. avoiding tobacco), dietary modification, reducing
body weight, increasing physical activity, or through medical intervention (surgery
and/or chemoprevention). Current data, primarily obtained from epidemiologic research, suggests that there are a combination of factors involved in the development of
cancer. As shown in Table 3, there is a critically important interaction of body height,
presence of obesity, physical inactivity and cancer risk (Giovannucci 1999). Thus, it is
important for primary caregivers as well as the research community to take a multidisciplinary approach to investigating and understanding cancer prevention.
There are three basic approaches to prevent cancer: primary, secondary and tertiary prevention. Primary prevention involves a reduction of the impact of carcinogens, such as through administration of a chemopreventive agent or the removal of
environmental carcinogens. The goal of primary prevention is to prevent a cancer
from beginning to develop by reducing individual risk. Current primary prevention
methods include lifestyle modification or interventions that modify risk. Primary prevention methods are best suited for those cancers in which the causes are known.
Worldwide, more than 1.3 million cancer cases are attributed to tobacco exposure
(Parkin, Pisani et al. 1999). Modification of tobacco or other carcinogen exposure and
other factors (i.e. dietary or environmental) could have a significant impact on worldwide health through primary prevention efforts. Many cancers are now known to be
directly attributable to viral infections (e.g. human papillomavirus infection is a necessary factor in the development of cervical cancer; Helicobacter pylori is an initiator
and promotor for gastric cancer). A number of primary prevention efforts are now
being developed (e.g. cervical cancer vaccines; antibiotics and vaccines to eradicate

Introduction to Cancer Prevention

Helicobacter pylori) to prevent the development of these cancers via the prevention of
viral infection.
Secondary prevention involves the concept of a precancerous lesion, or abnormal
changes that precede the development of malignancy. Secondary prevention involves
screening and early detection methods (e.g. mammogram, prostate-specific antigen
test) that can identify abnormal changes before they become cancerous, thereby preventing the cancer before it fully develops. In some cases, secondary prevention can
involve the treatment of precancerous lesions in an attempt to reverse carcinogenesis
(e.g. cause the lesion to regress).
Tertiary prevention involves the care of established disease and the prevention of
disease-related complications and often encompasses the treatment of patients at high
risk of developing a second primary cancer. Tertiary prevention, often referred to as
cancer control, involves a variety of aspects of patient care, such as quality of life, adjuvant therapies, surgical intervention and palliative care.

Multi-step Carcinogenesis Pathway

Prevention of cancer requires an understanding of the process of cancer initiation and
the steps to progression of disease. This process is referred to as carcinogenesis, a
process of genetic alterations that cause a normal cell to become malignant. Cancer
prevention involves the identification and classification, as well as interventions for
the regression or removal of precursor lesions, often referred to as intraepithelial neoplasia (IEN), before they can become cancerous. As shown earlier in Figure 1, the process of carcinogenesis may take many years. In the case of colorectal cancer, it may
take up to 35 years from the first initiated colonic mucosal cell to an adenomatous
polyp to develop invasive cancer. The same is true for prostate cancer, which progresses over as many as 40 to 50 years from mild to moderate, then severe intraepithelial neoplasia, to latent cancer (see Chapter 13).
The vast majority of current treatment modalities are used to treat far advanced
and/or metastatic cancers; however, now that it is possible to identify IENs for virtually every solid tumor type, lifestyle changes, simple surgical procedures and che-

Fig. 2. Multi-step carcinogenesis pathway, adapted from Alberts, et al. (Alberts 1999)

D. S. Alberts and L. M. Hess

Fig. 3. Chemoprevention of intraepithelial neoplasia (IEN)

mopreventive agents can be used to impede the development of these potentially dangerous precancerous lesions (Fig. 2). For example, multiple lifestyle changes, taken together, could profoundly reduce the risk of the first initiated cell progressing to mild
dysplasia. This would include reducing dietary fat intake, increasing the number of
servings of fruits and vegetables, minimizing alcohol intake, tobacco exposure cessation and markedly increasing physical activity. These changes may potentially reduce
risk for several cancers by up to 60 to 80% (Doll and Peto 1981). Furthermore, the addition of an effective chemoprevention agent, such as tamoxifen for moderately or severely dysplastic intraepithelial neoplasia such as ductile carcinoma in situ, can reduce
cancer risk by as much as 50% (Fisher, Costantino et al. 1998). Thus, the concept of
cancer prevention is now evolving into the mainstream of cancer therapeutics.
The process of carcinogenesis involves multiple molecular events over many years
to evolve to the earliest dysplastic lesion or IEN. This multi-year process provides numerous opportunities to intervene with screening, early detection, surgical procedures,
and chemoprevention (i.e. the use of specific nutrients and/or chemicals to treat IENs
and/or delay their development) (Sporn 1976). Figure 3 presents the concept that an
effective chemopreventive agent could prevent IEN growth, progression or, ultimately,
invasion through the tissue basement membrane.

Cancer Prevention Research

The importance of conducting and participating in clinical trials cannot be understated. Every person is at risk of genetic mutations that may lead to cancer. Due to
both endogenous or exogenous factors, every human body has undergone genetic alterations. For many individuals, these initiating factors are the early steps to the development of IEN or cancer. The time period from the first initiated cell to the time of
cancer is estimated to be approximately 20 years. In 2004, there were an estimated
563,700 deaths due to cancer in the U.S. This would translate to more than 11,000,000
individuals in the U.S. alone who are currently in some phase of cancer progression
that will ultimately result in death (Wattenberg 1993).
Cancer prevention trials are research studies designed to evaluate the safety and effectiveness of new methods of cancer prevention or screening. They are key to understanding the appropriate use of chemoprevention agents or screening tools. The focus
of cancer prevention research can involve chemoprevention (including vaccination),
screening, genetics, and/or lifestyle changes (e.g. diet, exercise). Cancer chemoprevention research differs from treatment research in several important ways as shown in
Table 4. Cancer chemoprevention trials generally are performed in relatively healthy

Introduction to Cancer Prevention

Table 4. Cancer chemoprevention versus cancer treatment phase III trials, adapted from
Alberts, et al. (Alberts 2004)
Characteristic Cancer Chemoprevention Trials
Participants

Cancer Treatment Trials

Relatively healthy volunteers with

IENs or at moderate/high risk
Commonly double-blind, placebo
controlled
Minimize dose, emphasize safety
Dosage changes with any toxicity,
concern for long-term use of agent

Patients diagnosed with invasive

cancer
Trial design
Unblinded to both patient and investigator
Dosage
Maximize dose, emphasize efficacy
Toxicity
Moderate toxicity acceptable, less
concern with toxicity due to severity
of disease
Adherence
Concern for drop ins due to media Concern for drop outs due to toxor hype
icity
End point
Surrogate biomarkers; cancer inciMortality
dence
Sample size
A few thousand to several thousand A few hundred to a thousand
participants
participants
Trial duration Often 510 years
Several months to several years

volunteers who have well-documented IENs (e.g. colorectal adenomas, bladder papillomas, ductal carcinoma in situ, actinic keratosis in the skin) or at increased risk due to
genetic or other factors. These trials are usually double-blind (i.e. both physician and
participant do not know the assigned treatment), placebo-controlled and involve a few
thousand to several thousand randomized participants. As opposed to cancer treatment phase III trials, that rarely extend beyond five years in duration, cancer chemoprevention trials often take 5 to 10 years to complete.
The phases of investigation in cancer prevention research trials (phase I through
IV trials) are described in more detail in Chapter 7. Briefly, phase I trials take place
after an agent has demonstrated activity with low toxicity in preclinical models.
Phase I trials are brief (several weeks), preliminary research studies in humans to determine safety of an agent. Phase II trials are longer in duration (several weeks to
months) to determine the activity of an agent and to further evaluate safety. Phase III
trials are large, randomized trials to evaluate the effectiveness and safety of an agent
in a sample of the target population. For a chemopreventive agent to be used in a
phase III research setting, it must meet several criteria. The agent must have strong
data supporting its mechanistic activity and there must be preclinical efficacy data
from appropriate models. If the chemopreventive agent is a nutritient, there must be
strong epidemiologic data supporting its potential effectiveness and it must have demonstrated safety and activity in phase II trials. Finally, phase III trials of a novel chemopreventive agent should not be performed in the absence of a fundamental understanding of its mechanism of action.
When the mechanism of activity of a putative chemoprevention agent has not been
explored in the setting of broad populations, the results of phase III trials can be
alarming. Two examples of this include the results of the Finnish Alpha-Tocopherol,
Beta-Carotene (ATCB) Trial and the University of Washington Carotene and Efficacy

D. S. Alberts and L. M. Hess

Trial (CARET). Both of these phase III trials used relatively high doses of beta-carotene as compared to placebo in heavy smokers to reduce the incidence of and mortality from lung cancer (1994; Omenn, Goodman et al. 1996). Unfortunately, both trials
found that the beta-carotene intervention was asociated with a 18 to 28% increase in
lung cancer incidence and an associated increase in mortality. Perhaps the reason for
these unexpected and extremely unfortunate results relates to the fact that at high
beta-carotene concentrations in the setting of high partial pressures of oxygen (e.g. as
achieved in the lung) and in the presence of heat (e.g. as achieved in the lung with cigarette smoking), beta-carotene can become an autocatalytic pro-oxidant (versus its
usual role as an anti-oxidant) (Burton and Ingold 1984).
The design of chemoprevention phase III trials must be founded on a hypothesis
that is soundly based on the mechanism of action of the agent, epidemiologic data
and its preclinical efficacy. The population to be enrolled to a phase III prevention
trial must be relatively high risk, to assure that there will be a sufficient number of
events (e.g. precancers or cancers) to compare the treatment to the control. Phase III
prevention trials should include both intermediate (e.g. IEN) and long-term (e.g. cancer) endpoint evaluations. Most importantly, the endpoint analyses should be planned
in advance, including well-defined and well-powered primary and secondary analyses.
One example of a potentially high-impact phase III chemoprevention trial is the
Breast Cancer Prevention Trial with Tamoxifen (BCPT) (Fisher, Costantino et al.
1998). Healthy women at increased risk of breast cancer were randomized to either tamoxifen (20 mg per day) or placebo for up to five years. Tamoxifen was selected for
this trial because of its well-documented mechanism of action (i.e. binding to the estrogen receptor to prevent estrogen's effect on tumor cell proliferation), its strong
safety profile in the setting of adjuvant breast cancer therapy, and its extreme activity
in the prevention of contralateral breast cancer in patients with stage I/II breast cancer. After 69 months of follow up, tamoxifen was found to be associated with an overall 49% reduction in the risk of invasive breast cancer (Fisher, Costantino et al. 1998).
The benefit of breast cancer risk must be balanced with its toxicities, which include a

Fig. 4. Events in the Breast Cancer Prevention Trial

Introduction to Cancer Prevention

greater than two-fold increase in early stage endometrial cancer and an increased incidence of deep vein thrombosis and pulmonary embolism (Fig. 4). Since the publication of these results, much discussion has led to the identification of women who
would most benefit from treatment with tamoxifen. Certainly, women who are at increased breast cancer risk, have already undergone a hysterectomy, and who at lower
risk for thrombophlebitis (e.g. due to higher levels of physical activity, lack of obesity)
would be good candidates for this intervention. Tamoxifen is a relatively expensive
drug, but it is now approved by the U.S. Food and Drug Administration for the reduction of breast cancer risk among women at high risk. Nevertheless, without adequate
health insurance coverage, there is very limited access to this prevention treatment
among underserved populations.
The translation of research findings to the clinic is the ultimate goal of cancer prevention research. Chemoprevention agents or screening modalities must be acceptable
to the target population that would benefit from such interventions. For example, the
ideal chemoprevention agent would have a known mechanism of action and would
have no or minimal toxicity, high efficacy, be available orally or topically, have an acceptable treatment regimen, and would be inexpensive. Similarly, screening or early
detection modalities should be minimally invasive, have high sensitivity and specificity, and be acceptable to the target population. Interventions that fail to maintain adequate adherence or that have high attrition rates during phase III trials will likely also
not be acceptable to the patient in clinical practice.

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D. S. Alberts and L. M. Hess: Introduction to Cancer Prevention

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