The goals of cancer prevention are to reduce the incidence, morbidity and mortality due to cancer through the identification and elimination of precan- cerous lesions (termed intraepithelial neoplasias or IENs) and/or the early de- tection of minimally invasive cancers. Cancer is a global term for a variety of diseases that are characterized by uncontrolled cellular growth. The site of ori- gin 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 molecu- lar 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 mil- lion ªhealthyº Americans harbor ultimately deadly cancers.
It is increasingly apparent that virtually all cancers proceed from the first in- itiated 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 duc- tile 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 vari- ety 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 eco- nomic issues in cancer prevention, dietary and environmental risk, cultural con- siderations 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- David S. Alberts and Lisa M. Hess
College of Medicine, University of Arizona, Tucson AZ 85724
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, ex- cluding non-melanoma skin cancer, include lung, stomach, breast, colorectal and liver cancer (Table 1). There are gender and regional differences in worldwide cancer diag- noses. 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 na- tions (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, exclud- ing non-melanoma skin cancer, and cancer accounted for 563,700 deaths (Jemal, Ti- wari 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.
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)
Number (in thousands) Both sexes
Lung 1036.9
Stomach 798.3
Breast 795.6
Colon/rectum 782.8
Liver 437.4
Prostate 396.1
Cervix 371.2
Males
Lung 771.8
Stomach 511.0
Colon/rectum 401.9
Prostate 396.1
Liver 316.3
Esophagus 212.6
Bladder 202.5
Females
Breast 795.6
Colon/rectum 381.0
Cervix 371.2
Stomach 287.2
Lung 265.1
Ovary 165.5
Endometrium 142.4
Table 1. Worldwide annual cancer incidence of the most common cancers (Par- kin, Pisani et al. 1999)
Number Both sexes
Prostate 230,110
Breast 217,440
Lung/bronchus 173,770
Colon/rectum 146,940
Melanoma 55,100
Males
Prostate 230,110
Lung/bronchus 93,110
Colon/rectum 73,620
Bladder 60,240
Melanoma 29,900
Females
Breast 215,990
Lung/bronchus 80,660
Colon/rectum 73,320
Endometrium 40,320
Ovary 25,580
Table 2. Annual cancer inci- dence of the most common cancers in the U.S. (Jemal, Tiwari et al. 2004)
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, Pi- sani 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 minimiz- ing 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 re- search, 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 multi- disciplinary approach to investigating and understanding cancer prevention.
There are three basic approaches to prevent cancer: primary, secondary and ter- tiary prevention. Primary prevention involves a reduction of the impact of carcino- gens, 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 pre- vention 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 world- wide health through primary prevention efforts. Many cancers are now known to be directly attributable to viral infections (e.g. human papillomavirus infection is a neces- sary 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 Table 3. Factors associated with Cancer Risk, adapted from Giovannucci (Giovannucci 1999)
Factor Association to Cancer Risk
Height Increases prostate, colon and breast cancer risk
Obesity Increases colon, breast, kidney, endometrial and gallbladder cancer risk; may increase ovarian cancer risk
Physical inactivity Increases colon cancer risk; may increase breast and prostate cancer risk
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 pre- venting 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, ad- juvant 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 neo- plasia (IEN), before they can become cancerous. As shown earlier in Figure 1, the pro- cess 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 pro- gresses over as many as 40 to 50 years from mild to moderate, then severe intraepithe- lial 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 vir- tually every solid tumor type, lifestyle changes, simple surgical procedures and che-
Fig. 2. Multi-step carcinogenesis pathway, adapted from Alberts, et al. (Alberts 1999)
mopreventive agents can be used to impede the development of these potentially dan- gerous precancerous lesions (Fig. 2). For example, multiple lifestyle changes, taken to- gether, 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 cessa- tion 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 ad- dition of an effective chemoprevention agent, such as tamoxifen for moderately or se- verely 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 nu- merous 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 under- stated. 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 al- terations. For many individuals, these initiating factors are the early steps to the de- velopment 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 ef- fectiveness of new methods of cancer prevention or screening. They are key to under- standing 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 chemopreven- tion research differs from treatment research in several important ways as shown in Table 4. Cancer chemoprevention trials generally are performed in relatively healthy Fig. 3. Chemoprevention of intraepithelial neoplasia (IEN)
volunteers who have well-documented IENs (e.g. colorectal adenomas, bladder papillo- mas, 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 treat- ment phase III trials, that rarely extend beyond five years in duration, cancer chemo- prevention 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 de- termine 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 dem- onstrated safety and activity in phase II trials. Finally, phase III trials of a novel che- mopreventive agent should not be performed in the absence of a fundamental under- standing 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 Table 4. Cancer chemoprevention versus cancer treatment phase III trials, adapted from Alberts, et al. (Alberts 2004)
Characteristic Cancer Chemoprevention Trials Cancer Treatment Trials Participants Relatively healthy volunteers with
IENs or at moderate/high risk Patients diagnosed with invasive cancer
Trial design Commonly double-blind, placebo
controlled Unblinded to both patient and in-
vestigator
Dosage Minimize dose, emphasize safety Maximize dose, emphasize efficacy Toxicity Dosage changes with any toxicity,
concern for long-term use of agent Moderate toxicity acceptable, less concern with toxicity due to severity of disease
Adherence Concern for ªdrop insº due to media
or hype Concern for ªdrop outsº due to tox-
icity End point Surrogate biomarkers; cancer inci-
dence Mortality
Sample size A few thousand to several thousand
participants A few hundred to a thousand
participants
Trial duration Often 5±10 years Several months to several years
Trial (CARET). Both of these phase III trials used relatively high doses of beta-caro- tene as compared to placebo in heavy smokers to reduce the incidence of and mortal- ity 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 ci- garette 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. can- cer) 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 ta- moxifen (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 es- trogen 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 can- cer. After 69 months of follow up, tamoxifen was found to be associated with an over- all 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
greater than two-fold increase in early stage endometrial cancer and an increased inci- dence of deep vein thrombosis and pulmonary embolism (Fig. 4). Since the publica- tion 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 in- creased 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 reduc- tion 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 pre- vention 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 ac- ceptable treatment regimen, and would be inexpensive. Similarly, screening or early detection modalities should be minimally invasive, have high sensitivity and specifici- ty, and be acceptable to the target population. Interventions that fail to maintain ade- quate adherence or that have high attrition rates during phase III trials will likely also not be acceptable to the patient in clinical practice.
References
Alberts, D.S., R.R. Barakat, et al. (1994). ªThe effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group.º N Engl J Med 330(15): 1029±1035.
Alberts, D.S., R.R. Barakat, et al. (2004). Prevention of gynecologic malignancies. Gynecologic Cancer: Controversies in Management. D.M. Gershenson, W.P. McGuire, M. Gore, M.A.
Quinn, G. Thomas (Eds.), Philadelphia, El Sevier Ltd.
Burton, G.W. and K.U. Ingold (1984). ªBeta-Carotene: an unusual type of lipid antioxidant.º Science 224(4649): 569±573.
Curry, S. J., T. Byers, M. Hewitt (2003). Fulfilling the Potential for Cancer Prevention and Early Detection. Washington DC, National Academies Press, National Cancer Policy Board, Insti- tute of Medicine.
Doll, R. and R. Peto (1981). ªThe causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today.º J Natl Cancer Inst 66(6): 1191±1308.
Fisher, B., J.P. Costantino, et al. (1998). ªTamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.º J Natl Cancer Inst 90(18): 1371±1388.
Giovannucci, E. (1999). The epidemiologic basis for nutritional influences on the cancer cell.
Nutritional Oncology. D. Heber, Blackburn, G. L., Go, V.L.W. San Diego, Academic Press.
Jemal, A., R.C. Tiwari, et al. (2004). ªCancer statistics, 2004.º CACancer J Clin 54(1): 8±29.
Omenn, G.S., G.E. Goodman, et al. (1996). ªRisk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.º J Natl Cancer Inst 88(21):
1550±1559.
O'Shaughnessy, J.A., G.J. Kelloff, et al. (2002). ªTreatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development.º Clin Cancer Res 8(2): 314±346.
Parkin, D.M., P. Pisani, et al. (1999). ªEstimates of the worldwide incidence of 25 major can- cers in 1990.º Int J Cancer 80(6): 827±841.
Pisani, P., D.M. Parkin, et al. (1999). ªEstimates of the worldwide mortality from 25 cancers in 1990.º Int J Cancer 83(1): 18±29.
Sporn, M.B. (1976). ªApproaches to prevention of epithelial cancer during the preneoplastic period.º Cancer Res 36(7 PT 2):2699±2702.
Wattenberg, L.W. (1993). ªPrevention±therapy±basic science and the resolution of the can- cer problem.º Cancer Res 53(24): 5890±5896.
