1D. Alberts, L.M. Hess (eds.), Fundamentals of Cancer Prevention,DOI 10.1007/978-3-642-38983-2_1, © Springer-Verlag Berlin Heidelberg 2014

1.1 Introduction

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 fi rst cancer cell and the onset of end-stage metastatic disease for a broad range of solid tumors. In that there were an estimated 1,660,290 new cancer cases and 580,350 cancer deaths in the USA in 2013 (Siegel et al. 2013 ) and given the 20+-year lag time, more than 11 million “healthy” Americans currently harbor ultimately deadly cancers, many of which may be fully preventable.

Given the average 20-year lag time from the point of the fi rst altered cell to carcinoma, secondary and tertiary prevention strategies represent effective and cost- effective opportunities to dramatically reduce cancer mortality in the next decades. Cancer costs exceeded US$201.5 billion in 2008 alone (ACS 2013 ). These represent both direct and indirect economic costs (not considering the psychosocial costs to patients and families) that could be avoided. Chapter 2 discusses the human and economic benefi ts of cancer prevention in more detail.

D. S. Alberts , MD (*) College of Medicine, University of Arizona Cancer Center , Tucson , AZ 85724 , USA e-mail: dalberts@azcc.arizona.edu

L. M. Hess , PhD Department of Obstetrics and Gynecology , Indiana University School of Medicine and School of Public Health , Indianapolis , IN 46202 , USA

Eli Lilly and Company , Indianapolis , IN 46225 , USA e-mail: lmhess@iupui.edu

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1.2 Summary of Changes to Third Edition

In 2009, the Union of International Cancer Control Annual Report stated that our current knowledge shows that “40 % of cancers can be prevented” and 25–33 % can be avoided by eating a healthy diet, maintaining a healthy body weight, and remain-ing physically active; however, the tragedy is that we are not using this knowledge to reduce the global burden of cancer (UICC 2010 ). Many researchers worldwide have focused their life’s work to identify ways to prevent cancer. One reason why current knowledge and information about cancer and its prevention is not fully applied to the general public is due to an overload of complicated, contradictory, and even inaccurate information through various Internet and printed sources (Cline and Hayes 2001 ). The dissemination of complicated information is problematic, but comprehensive information is essential to reduce the burden of cancer. The third edition of this book is designed to provide this information in the form of a compre-hensive overview on the science and practice of cancer prevention for primary care-givers and the research community.

Because of the rapid advancement in cancer prevention research, several impor-tant changes have been made to the third edition of this book. The fi rst section of this book (Chaps. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , and 11 ) provides information on economic issues in cancer prevention, dietary and environmental risk, immune response, drug development, the role of telemedicine technology, and cultural considerations in cancer prevention. New chapters included in this section address topical drug deliv-ery systems, the global issues in cancer prevention, reaching underserved popula-tions, and regulatory considerations in cancer prevention. The second section of the book (Chaps. 12 , 13 , 14 , 15 , 16 , 17 , 18 , and 19 ) focuses on the prevention of specifi c cancers by site of origin and provides the reader with a discussion of the epidemiol-ogy, screening, and prevention of each disease, including practice guidelines as well as theories and future research directions. The book concludes with Chap. 20 , dis-cussing issues related to cancer survivorship.

The fi eld of cancer prevention is constantly changing as research progresses and our knowledge about cancer expands. Each chapter has been revised in the third edition. Important new chapters in this revised edition include Chap. 6 , which addresses the important issue of inequity in health care and proposes solutions to reduce inequalities. Additionally, a second new chapter has been added (Chap. 10 ), which focuses on cancer as a global issue that our world is facing.

1.3 Overview of Cancer Prevention

Cancer is a global term for a variety of diseases that share some similar character-istics, such as uncontrolled cellular growth, enhanced angiogenesis, and/or reduced programmed cell death. The site of origin of the disease is used to defi ne general categories of disease (e.g., breast cancer, skin cancer). It is increasingly apparent that despite the variation across cancer types, the majority of cancers proceed from the fi rst initiated tumor cell (e.g., mutated DNA) to mild, moderate, and severe

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dysplasia, invasive carcinoma (invasion of cells through the basement membrane), and metastatic disease (Fig. 1.1 ). A single mutated cell can begin to divide incor-rectly and produce additional abnormal cells. Cancer prevention research is working to identify these changes as early as possible to intervene to prevent their progres-sion to cancer. If abnormal cells continue to divide and expand, they can develop into precancerous lesions. These lesions (IENs) can be identifi ed both histologically and by molecular signatures, using a variety of analytical methods (e.g., cDNA microarray) (O’Shaughnessy et al. 2002 ). They are represented by small, intermedi-ate, and advanced adenomatous polyps in the colon; atypical hyperplasia and ductal carcinoma in situ in the breast; and simple hyperplasia, atypical hyperplasia, and carcinoma in situ in the endometrium. As atypia increases, these dysplasias are believed to develop into cancer and if left unchecked have the great potential to metastasize to adjacent and distant organs.

It is estimated that there are over 12.7 million cases of cancer diagnosed and 7.6 million deaths each year worldwide (Jemal et al. 2011 ). The fi ve most common worldwide cancers, excluding nonmelanoma skin cancer, include lung, stomach, breast, colorectal, and liver cancer (Table 1.1 ). There are gender and regional differ-ences in worldwide cancer diagnoses. Although less than 20 % of the world’s popu-lation lives in developed nations, close to half (44 %) of all cancer cases and 36 % of cancer deaths occur in these countries (Jemal et al. 2011 ). Eighty-two percent (82 %) of all cervical cancer cases and 70 % of all stomach cancers occur in devel-oping nations, whereas 71 % of all prostate cancers, 50 % of breast cancers, and 58.9 % of all colorectal cancers are diagnosed in developed nations (Jemal et al. 2011 ). The highest rates of esophageal cancer are found in Eastern Asia and East Africa, and half of all liver cancers are diagnosed in China.

Similar to the rest of the developed world, cancer is a major health burden in the USA, responsible for approximately 580,350 deaths in 2013. Cancer is the leading

Normal Initiated Mild Moderate SevereCarcinoma

in situ Cancer

Precancer = IEN

Colon Adenoma

Breast DCISAtypical hyperplasia

5–15 years5–20 years

6–10 years14–18 years

Fig. 1.1 Progression of precancer to cancer in humans is a multiyear process (Adapted from O’Shaughnessy et al. ( 2002 ))

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cause of death among those under the age of 80 years in the USA (Siegel et al. 2013 ). The leading modifi able causes of increased cancer risk include tobacco use, infection, alcohol abuse, physical inactivity, and obesity. Obesity and body weight alone account for 20 % of all cancers in the USA (Wolin et al. 2010 ). In the USA, 68.8 % of the population is overweight or obese and 35.7 % are obese, and the num-bers are increasing rapidly (Flegal et al. 2012 ). Globally, obesity rates doubled from 1980 to 2008 and are increasing (Stevens et al. 2012 ). As this trend continues, global cancer incidence rates will also continue to rise.

Unfortunately, another pervasive problem in the USA and many other nations is poor access to health care because of a lack of health insurance (USA) and/or lack of services (rural or remote regions and many developing nations). Access to screen-ing programs and improved health-care programs are essential to prevent cancer. For example, among nations with organized cervical cancer screening programs, the risk of cervical cancer morbidity and mortality has been continuously declining (e.g., Sweden, Finland, and France have all seen cervical cancer decrease by greater than 4 % per year since the initiation of cervical cancer screening programs), whereas among nations that lack these programs, cervical cancer remains a major health risk for all women (e.g., Slovakia and Slovenia have seen annual increases in cervical cancer without these programs) (Mackay et al. 2006 ). Similarly, nations that have organized tobacco control policies have shown decreases in youth tobacco use. However, even among nations that have established public health policies, indi-viduals must have access to these programs for them to be effective. The USA has the greatest health-care expenditures in the world and substantial per capita medical expenses at approximately US$8,000 per person per year, which is substantially higher than many other nations (e.g., in Norway, spending is $5,352; Canada $4,363; France $3,978; the UK $3,487; Australia $3,445; and Japan $2,878 per person per year) (Martin et al. 2012 ; Squires 2012 ). Despite this investment, 50 million

Table 1.1 Worldwideannual cancer incidenceand mortality of selected common cancers(Jemal et al. 2011 )

Number of new cases each year

Number of deathseach year

Males Lung 1,095,200 951,000 Prostate 903,500 258,400 Colon/rectum 663,600 320,600 Stomach 640,600 464,400 Liver 522,400 478,300 Esophagus 326,600 276,100 Bladder 297,300 112,300 Females Breast 1,383,500 458,400 Colon/rectum 570,100 288,100 Cervix 529,800 275,100 Lung 513,600 427,400 Stomach 349,000 273,600 Liver 225,900 217,680 Ovary 225,500 140,200

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Americans (15.7 % of the total US population) lack even the most basic health insurance coverage and therefore do not have access to general or preventive health care (ACS 2013 ). Lack of access to health care has been demonstrated to result in late cancer diagnosis (e.g., at an advanced stage) when costs are greater and out-comes are poor, more cancer treatment delays, and ultimately higher mortality (ACS 2008 ). Even when patients without insurance are diagnosed at the same stage as patients with insurance, they still have a signifi cantly increased risk of death (e.g., patients without insurance have a 30–50 % higher rate of death from colorectal or breast cancer than patients with insurance) (IOM 2002 ).

The goal of cancer prevention is to reduce the morbidity and mortality from can-cer by reducing the incidence of cancer due to these modifi able factors as well as to reduce the impact of unmodifi able factors contributing to cancer. The development of effective cancer prevention strategies has the potential to impact a signifi cant por-tion of the cancer-related deaths each year worldwide (Jemal et al. 2011 ). Therefore, cancer prevention is the best approach possible to reduce the burden of cancer worldwide. Cancer prevention research takes a three-pronged approach to target different aspects reducing cancer morbidity and mortality: primary, secondary, and tertiary prevention.

1.4 Primary 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 modifi cation or interventions that modify risk. Primary prevention methods are best suited for those cancers in which the causes are known. There are many factors known to reduce overall cancer incidence, such as minimizing exposure to carcinogens (e.g., avoiding tobacco), dietary modifi cation, reducing body weight, increasing physical activity, avoiding infection, or through medical intervention (surgery and/or chemoprevention). Among developed nations, the leading risk fac-tors for cancer include an unhealthy diet, obesity, and tobacco use (together account-ing for 40 % of cases), whereas among developing nations, poor diet/nutrition is the leading risk factor in 20 % of all cancer cases, and infection accounts for another 26 % of all cancer cases.

Tobacco use, which represents the greatest preventable cause of cancer death by far, is the direct cause of more than 20 % of all cancer deaths worldwide each year (primarily lung cancer, but smoking also increases the risk of cancers of the larynx, oral cavity, lip, nasal cavity, esophagus, bladder, kidney, cervix, stomach, liver, and many other sites) (Thun et al. 2010 ). Tobacco use is the leading cause of smoking- related cancer death among both men and women (80 % of all lung cancers among males and 50 % among females are directly attributed to tobacco) (Jemal et al. 2011 ). However, all damage done during smoking is not completely irreversible. Smoking cessation can begin to reverse the risk of cancer. Benefi ts from quitting

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smoking begin within the fi rst year of cessation and continue to increase over time. The risk of lung, oral, and laryngeal cancers can be signifi cantly reduced following smoking cessation, with an estimated overall 9-year gain in life expectancy associ-ated with smoking cessation (Jha et al. 2013 ). The results of tobacco cessation are particularly pronounced if a person quits smoking before the age of 40 (associated with a 90 % reduction in premature death that is associated with smoking in midlife) (Jha et al. 2013 ). Primary tobacco prevention efforts include cessation support pro-grams (behavioral and pharmacologic), public awareness and education, smoke- free public policies, increased tobacco pricing through taxation, and very importantly efforts to reduce the initiation of the use of any form of burnt and smokeless tobacco, all of which are carcinogenic and deadly (Thun et al. 2010 ; Jemal et al. 2011 ).

Many cancers are directly attributable to viral or bacterial infections (e.g., human papillomavirus, HPV, infection is a necessary factor in the development of cervical cancer; Helicobacter pylori is an initiator and promoter for gastric cancer). Advances in vaccination research led to the development of HPV vaccines that are available to adolescent males and females (See Chap. 17 ). If these vaccines would be used and available worldwide, nearly all cervical cancers could be prevented. Unfortunately, even in the USA where the vaccine is widely available, less than one third of all eligible young women are vaccinated and remain at risk for cervical cancer (Jemal et al. 2013 ). These rates are lowest in the regions and among populations with the highest rates of cervical cancer (Jemal et al. 2013 ). Primary prevention research and efforts continue to remain underfunded. In the USA and Europe, less than 10 % of all cancer research funding is dedicated to cancer prevention efforts (Mackay et al. 2006 ). This lack of prioritization results in delays in improving and delivering early detection and prevention strategies that have the potential to save millions of lives.

1.5 Secondary Prevention

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, colonoscopy) that can identify abnormal changes before they become cancerous, thereby identifying and removing the precancer before it fully develops or before it becomes malignant. In some cases, secondary prevention can involve the treatment of precancerous lesions in an attempt to reverse carcinogenesis (e.g., causes the lesion to regress). Secondary prevention is described in more detail specifi c to each disease site (Chaps. 12 , 13 , 14 , 15 , 16 , 17 , 18 , and 19 ) in this book.

1.6 Tertiary Prevention

Tertiary prevention involves the care of established disease and the prevention of disease recurrence as well as the prevention of disease-related complications and often encompasses the treatment of patients at high risk of developing a second

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primary cancer. In this setting, emerging evidence suggests that physical activity may have an even greater impact on reducing cancer risk than nutritional interven-tions to reduce the risk of disease recurrence and to prolong survival in early-stage breast cancer. In a prospective study of women with early-stage breast cancer (George et al. 2011 ), women with any physical activity and better quality diets had a lower risk of death from breast cancer than those who had poor nutrition and exer-cise; nutrition alone did not demonstrate any differences between groups (Fig. 1.2 ). These fi ndings are hypothesis generating rather than confi rmatory due to the self- reported diet and activities and non-randomized study design. Additional research is ongoing to explore this hypothesis in breast cancer and a variety of other tumor types. Tertiary prevention is most often referred to as cancer control and involves a variety of aspects of patient care, such as quality of life, maintenance or adjuvant therapies, surgical intervention, palliative care, and control of obesity. These efforts are described in more detail in Chap. 20 .

1.7 Multistep 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 carcinogen-esis, a process of genetic alterations that cause a normal cell to become malig-nant. Cancer prevention involves the identifi cation and classifi cation, as well as

8.10 % 8.20 %

6.20 %

1.60 %

0.00 %

1.00 %

2.00 %

3.00 %

4.00 %

5.00 %

6.00 %

7.00 %

8.00 %

9.00 %

10.00 %

Women with poor nutrition Women with better nutrition

No exercise

Any exercise

n = 37 n = 130 n = 73 n = 430

Fig. 1.2 Percentage of deaths due to breast cancer in patients with early-stage disease according to amount of exercise and nutrition after diagnosis (George et al. 2011 )

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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 Fig. 1.1 , the process of carcinogenesis may take many years. In the case of colorectal cancer, it may take up to 35 years from the fi rst initiated colonic mucosal cell to an adenomatous polyp to develop invasive cancer (see Chap. 13 ). The same is true for prostate cancer, which progresses over as many as 40–50 years from mild to moderate, then severe intraepithelial neoplasia, to latent or invasive cancer (see Chap. 16 ). Other cancers, however, such as ovarian cancer (see Chap. 18 ) is not known to follow the same lengthy carcinogenic process and as a result has many challenges for interventions for early detection and prevention.

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 many solid tumor types. Lifestyle changes, simple surgical procedures, and chemopreven-tive agents can be used to impede the development of these potentially dangerous precancerous lesions (Fig. 1.3 ). For example, multiple lifestyle changes, taken together, could profoundly reduce the risk of the fi rst initiated cell progressing to mild dysplasia or stop the progression of IENs to invasive cancer. This would include reducing dietary fat intake, increasing the number of servings of fruits and vegetables, minimizing alcohol intake, tobacco exposure cessation, and increasing physical activity (Brown et al. 2003 ; Chlebowski et al. 2002 ; Ornish et al. 2005 ; Schmitz et al. 2005 ; Davies et al. 2006 ; Meyerhard et al. 2006 ; Holmes et al. 2005 ; Rock and Deark-Wahnefried 2002 ; Nagle et al. 2003 ). Furthermore, the addition of an effective chemoprevention agent, such as tamoxifen for moderately or severely dysplastic intraepithelial neoplasia such as ductal carcinoma in situ, can reduce can-cer risk by as much as 50 % (Fisher et al. 1998 ). Thus, the concept of cancer preven-tion 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 multiyear process pro-vides numerous opportunities to intervene with screening, early detection, surgical procedures, and chemoprevention (i.e., the use of specifi c nutrients and/or chemi-cals to treat IENs and/or delay their development) (Sporn 1976 ). Figure 1.4 presents

Normalepithelium

ScreeningHealthy diet

Healthy lifestylePhysical excerciseD/C tobacco

D/C tobacco

D/C tobaccoReduce alcoholBehavioral research

Behavioral research

Chemoprevention Chemotherapy/radiation therapyDietaryintervention

Supportive care

SupportivecareQOLDietary intervention

Decrease infection

Milddysplasia

Moderate/severe

dysplasia

Invasivecancer

Metastaticcancer

End oflife

Fig. 1.3 Multistep carcinogenesis pathway (Adapted from Alberts ( 1999 ))

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the concept that an effective chemopreventive agent could prevent IEN growth, progression, or, ultimately, invasion through the tissue basement membrane.

1.8 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 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 fi rst initiated cell to the time of cancer is estimated to be approximately 20 years. As described earlier, the early steps towards cancer occur over time, which means that literally millions of individuals in the USA alone are currently in some phase of undetected cancer pro-gression that will ultimately result in their death (Wattenberg 1993 ).

Cancer prevention trials are research studies designed to evaluate the safety and effectiveness of new methods of cancer prevention or screening. The focus of can-cer prevention research can involve chemoprevention (including vaccination), screening, genetics, and/or lifestyle changes (e.g., diet, exercise, tobacco cessation). Cancer chemoprevention research differs from treatment research in several impor-tant ways as shown in Table 1.2 . Cancer chemoprevention trials generally are per-formed in relatively healthy volunteers who have well-documented IENs (e.g., colorectal adenomas, bladder papillomas, breast 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) and placebo controlled and involve a few thousand to tens of thousands of randomized participants. As opposed to cancer treatment phase III tri-als, that rarely extend beyond 5 years in duration, cancer chemoprevention trials often take many years to complete and are extremely costly. The high cost of cancer prevention trials and the need to develop reliable and meaningful intermediate end points are signifi cant barriers that must be overcome. Cancer prevention clinical trials take between 5 and 10 years (or more) to complete and require thousands of participants. In US dollars, the cost to complete large-scale trials (10,000 partici-pants or more) is in the $100 to $200 million range and, of course, may not always result in the discovery of an effective prevention strategy.

Normaltissue

EarlyIEN

LateIEN

Invasivecancer

Chemoprevention Chemoprevention Chemoprevention

Fig. 1.4 Chemoprevention of intraepithelial neoplasia (IEN)

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Research on developing and implementing effective cancer prevention and control interventions lags in funding relative to its potential impact on reducing the cancer burden. Despite the known cancer-causing effects of tobacco use, few non- nicotine medications are currently approved by the U.S. Food and Drug Administration (FDA) for smoking cessation, though others are in the pipeline, and these existing medications achieve smoking cessation quit rates that are 25 % at best. Since many health-care organizations do not include smoking cessation medications as a covered benefi t, the incentive for pharmaceutical companies to prioritize the development of smoking cessation medications is not high – thus fostering a negative feedback loop that disincentivizes health-care organizations from covering medications because the effectiveness of those medications is low. Similarly, pharmaceutical companies have traditionally been unwilling to invest in the development of chemopreventive agents because of the required length of time, size, and cost of phase III confi rmatory trials. Furthermore, companies are concerned about the uncovering of unexpected, life-threatening toxicities that may be observed with the long-term exposure required for many cancer preven-tion intervention strategies. This can have an extremely negative impact on safety profi les of approved drugs (e.g., COX-2 inhibitors increased cardiovascular events with twice-daily dosing in prospective randomized trials) (Baron et al. 2008 ).

The stages of investigation in cancer prevention research trials include a series of phases of clinical trials. Phase I trials take place after an agent has demon-strated activity with low toxicity in preclinical models. Phase I chemoprevention trials are relatively brief (i.e., 1–3 months), preliminary research studies in healthy humans to determine dose and safety of an agent. Phase II trials generally are randomized, double blinded, placebo controlled, and of longer duration (i.e., 6–12 months). The goals of phase II chemoprevention trials are to determine the activ-ity of an agent in IEN and to further evaluate safety. Phase III trials generally are

Table 1.2 Cancer chemoprevention versus cancer treatment phase III trials

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 patientand investigator

Dosage Minimize dose, emphasize safety Maximize dose, emphasize effi cacy Toxicity Dosage changes with any toxicity,

concern for long-term use of agent Moderate toxicity acceptable,less concern with toxicitydue to severity of disease

Adherence Concern for “drop-ins” due to media or hype

Concern for “dropouts”due to toxicity

End point Surrogate biomarkers; cancer incidence

Mortality

Sample size A few thousand to severalthousand participants

A few hundred to a thousand participants

Trial duration Often 5–10 years Several months to several years

Adapted from Alberts et al. ( 2004 )

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large, double-blind, multiple-year, placebo-controlled randomized trials to evalu-ate the effi cacy and safety of an agent in a sample of the target population. Often, cancer incidence is the primary end point in phase III prevention studies. 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 activ-ity, and there must be preclinical effi cacy data from appropriate animal models. If the chemopreventive agent is a nutrient, there must be strong epidemiologic data supporting its potential effectiveness, and it must have demonstrated safety and activity in phase II trials. Phase III trials of novel chemopreventive agents should not be performed in the absence of a fundamental understanding of their mecha-nism of action. Finally, phase IV trials are focused on the dissemination of the phase III trial results into the population and the effi cacy of these interventions in a real-world setting. Inadequate funding and insuffi cient attention have been given for these vitally important dissemination studies, leading to underutilization of effective chemoprevention strategies, such as tamoxifen or raloxifene to prevent the development of breast cancer in post-menopausal women (Fisher et al. 1998 ).

When the mechanism of action 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 (ATBC) Trial and the University of Washington Carotene and Retinol Effi cacy 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 (Alberts et al. 1994 ; Omenn et al. 1996 ). Unfortunately, both trials found that the beta-carotene intervention was associated with an 18–28 % 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 antioxidant) producing reactive oxygen species and DNA damage (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 effi cacy. The population to be enrolled to a phase III prevention trial must be relatively high risk, to assure that there will be a suffi cient number of events (e.g., precancers or cancers) to compare the treatment to the control group. Phase III prevention trials should include both intermediate (e.g., IEN) and long- term (e.g., cancer) end point evaluations. Most importantly, the end point analyses should be planned in advance, including well-defi ned 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 et al. 1998 ). Healthy women at increased risk of breast cancer were randomized to either tamoxifen (20 mg/day) or placebo for up to 5 years. Tamoxifen was selected for this trial because of its well-documented mechanism of action (i.e., binding to the

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estrogen receptor to prevent estrogen’s effect on tumor cell proliferation), its strong safety profi le 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 et al. 1998 ). The benefi t of breast cancer risk must be balanced with its toxicities, which include a greater than twofold increase in early-stage endome-trial cancer and an increased incidence of deep vein thrombosis and pulmonary embolism. Since the publication of these results, much discussion has led to the identifi cation of women who would most benefi t 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. Furthermore, there has been a relative lack of dissemination of this information to both primary care physicians and the population, resulting in lim-ited tamoxifen usage (Freedman et al. 2003 ). More recently, the results of the phase III Study of Tamoxifen and Raloxifene (STAR) revealed equivalent activity of tamoxifen as compared to raloxifene for the reduction of breast cancer risk among postmenopausal women at moderately increased risk (Vogel et al. 2006 ). Raloxifene was associated with an improved safety profi le (e.g., lower thrombo-embolic events and cataracts), leading to its approval as a chemopreventive agent with the FDA. Only time will tell if these results will lead to increased chemopre-vention utilization. Currently, only a small fraction of eligible women at increased risk of breast cancer are taking advantage of the established effi cacy of these chemopreventive strategies.

The translation of research fi ndings 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 benefi t from such interventions. For example, the ideal chemoprevention agent would have a known mechanism of action and would have no or minimal toxicity, high effi cacy, 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 specifi city, 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.

References

ACS (2008) American Cancer Society Cancer Facts & Figures 2008, Special Section, pp 22–42. Available at: http://www.cancer.org/acs/groups/content/@nho/documents/document/2008cafffinalsecuredpdf.pdf . Accessed 13 Feb 13

ACS (2013) American Cancer Society Facts and Figures, 2013. Available at: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf . Accessed 13 Feb 13

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13

Alberts DS, Barakat RR et al (1994) The 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. N Engl J Med 330(15):1029–1035

Alberts DS (1999) A unifying vision of cancer therapy for the 21st century. J Clin Oncol 17(11 Suppl):13–21

Alberts DS, Barakat RR et al (2004) Prevention of gynecologic malignancies. In: Gershenson DM, McGuire WP, Gore M, Quinn MA, Thomas G (eds) Gynecologic cancer: controversies in man-agement. El Sevier Ltd, Philadelphia

Baron JA, Sandler RS, Bresalier RS, Lanas A, Morton DG, Riddell R, Iverson ER, Demets DL (2008) Cardiovascular events associated with rofecoxib: fi nal analysis of the APPROVe trial. Lancet 372(9651):1756–1764

Brown JK, Byers T, Doyle C et al (2003) Nutrition and physical activity during and after cancer treatment. CA Cancer J Clin 53:268–291

Burton GW, Ingold KU (1984) Beta-carotene: an unusual type of lipid antioxidant. Science 224(4649):569–573

Chlebowski RT, Aiello E, McTiernan A (2002) Weight loss in breast cancer patient management. J Clin Oncol 20:1128–1143

Cline RJW, Hayes KM (2001) Consumer health information seeking on the internet: the state of the art. Health Educ Res 16(6):671–692

Davies AA, Davey Smith G, Harbord R et al (2006) Nutritional intervention and outcome in patients with cancer or preinvasive lesions: a systematic review. J Natl Cancer Inst 98:961–973

Fisher B, Costantino JP et al (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90(18):1371–1388

Flegal KM, Carroll MD, Kit BK, Ogden CL (2012) Prevalence of obesity and trends in the distri-bution of body mass index among US adults, 1999–2010. JAMA 307(5):491–497

Freedman AN, Graubard BI, Rao SR et al (2003) Estimates of the number of US women who could benefi t from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst 95(7):526–532

George SM, Irwin ML, Smith AW, Neuhouser ML et al (2011) Postdiagnosis diet quality, the combination of diet quality and recreational physical activity, and prognosis after early-stage breast cancer. Cancer Causes Control 22(4):589–598

Giovannucci E (1999) The epidemiologic basis for nutritional infl uences on the cancer cell. In: Heber D, Blackburn GL, Go VLW (eds) Nutritional oncology. Academic, San Diego

Holmes MD, Chen WY, Feskanich D et al (2005) Physical activity and survival after breast cancer. JAMA 293:2479–2486

Howlader N, Noone AM, Krapcho M et al (eds) (2012) SEER cancer statistics review, 1975–2009, National Cancer Institute, Bethesda. http://seer.cancer.gov/csr/1975_2009_pops09/ , based on November 2011 SEER data submission, posted to the SEER web site, Apr 2012

IOM (Institute of Medicine) (2002) Care without coverage: too little, too late. National Academy Press, Washington, DC

Jemal A, Ward E, Thun M (2010) Declining death rates refl ect progress against cancer. PLoS One 15(3):e9584

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

Jemal A, Simard EP, Dorrell C, Noone AM et al (2013) Annual report to the nation on the status of cancer, 1975–2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst 105(3):175–201

Jha P, Ramasundarahettige C, Landsman V, Rostron B, Thun M, Anderson RN, McAfee T, Peto R (2013) 21st century hazards of smoking and benefi ts of cessation in the United States. N Engl J Med 368:341–350

Mackay J, Jemal A, Lee N et al (2006) The cancer atlas. The American Cancer Society, Atlanta Martin AB, Lassman D, Washington B, Catlin A (2012) Growth in US health spending remained

slow in 2010; health share of gross domestic product was unchanged from 2009). Health Aff 31(1):208–219

1 Introduction to Cancer Prevention

14

Meyerhard JA, Giovannucci EL, Holmes MD et al (2006) Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol 24:3527–3534

Nagle CM, Purdie DM, Webb PM et al (2003) Dietary infl uences on survival after ovarian cancer. Int J Cancer 106:264–269

Omenn GS, Goodman GE et al (1996) Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Effi cacy Trial. J Natl Cancer Inst 88(21):1550–1559

O’Shaughnessy JA, Kelloff GJ et al (2002) Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 8(2):314–346

Ornish D, Weidner G, Fair WR et al (2005) Intensive lifestyle changes may affect the progression of prostate cancer. J Urol 174:1065–1069

Rock CL, Deark-Wahnefried W (2002) Nutrition and survival after the diagnosis of breast cancer: a review of the evidence. J Clin Oncol 20:3302–3316

Schmitz KH, Holtzman J, Courneye KS et al (2005) Controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 14:1588–1595

Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30 Sporn MB (1976) Approaches to prevention of epithelial cancer during the preneoplastic period.

Cancer Res 36(7 PT 2):2699–2702 Squires D (2012) Explaining high health care spending in the United States: an international com-

parison of supply, utilization, prices and quality. The Commonwealth Fund. May 2012 Stevens GA, Singh GM, Lu Y et al (2012) National, regional and global trends in adult overweight

and obesity prevalences. Popul Health Metr 10:22. doi: 10.1186/1478-7954-10-22 Thun MJ, DeLancey JO, Center MM, Jemal A, Ward EM (2010) The global burden of cancer:

priorities for prevention. Carcinogenesis 31(1):100–110 UICC (2010) Annual report 2009. Available at http://www.uicc.org/resources/annual-report-2009 .

Accessed 1 Feb 13 Vogel VG, Constantino VP et al (2006). Effects of tamoxifen vs raloxifene on the risk of develop-

ing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA 295(23):2727–2741

Wattenberg LW (1993) Prevention–therapy–basic science and the resolution of the cancer prob-lem. Cancer Res 53(24):5890–5896

Wolin KY, Carson K, Coldiz GA (2010) Obesity and cancer. Oncologist 15(6):556–565

D.S. Alberts and L.M. Hess