text:
Abeloff's Clinical Oncology, 4th Edition
Part I – Science of Clinical Oncology
Section D – Preventing and Treating Cancer
Chapter 26 – Cancer Prevention, Screening, and Early Detection
Chapter 26 – Cancer Prevention, Screening, and Early Detection
Jason A. Zell,Frank L. Meyskens
The guiding principles of this chapter and oncology should be that the best treatment of malignant disease is its prevention, and that the disease to be prevented is carcinogenesis, not cancer ( Fig. 26-1 ).[1]
Figure 26-1 Integration of the biology of carcinogenesis and prevention. *Hereditary alteration(s) or baseline polygenic representation provides the constitutive "set point" on which postzygote changes occur. † Precancer, premalignant lesion in general clinical parlance.
By the time a cancer is diagnosed, even with the advanced techniques now available, more than 90% of the biologic life of the tumor is over, and the best chance to control the malignant process has been missed. The extensive advances in our understanding of carcinogenesis at the molecular level in the past decade, the rediscovery of intraepithelial neoplasia as an early, recognizable precursor of many solid tumors that can be managed simply, and the well-defined successes of screening and early detection in reducing the morbidity and mortality from several major cancers, need to be brought to bear on the problem of malignancy in a concerted and widespread fashion, with clinical oncologists working closely with primary care physicians and subspecialists. Because fewer than 50% of cancers are cured, once established, and because gains in treatment effectiveness have been increasingly incremental and expensive, early detection and prevention of cancer should be pursued aggressively as a means to reduce morbidity and mortality.
Many major diseases of humankind have been controlled by the systematic application of prevention strategies, including morbidity and mortality from nutritional and infectious diseases and vehicular trauma.[1] Among chronic diseases, the incidence of cardiovascular disease has decreased markedly as smoking has declined, cholesterol and blood pressure lowered, and exercise encouraged. It is likely that these simple approaches have led to a greater overall benefit to health for the population than the effect of all intensive care units, but such direct comparisons are difficult to make. In general, appreciation of the role of prevention strategies in the overall management of cancer has been neglected by clinical oncologists, although health care planners and society as a whole are intensely interested in this topic.[2] Cancer prevention strategies can be considered at three different major levels: primary, secondary, and tertiary. This chapter will deal primarily with primary and secondary prevention and with tertiary prevention as represented by chemoprevention of second malignancies.
Normal, asymptomatic individuals are the population at which primary prevention is addressed. Major strategies for risk reduction include changes in diet, increased physical activity, tobacco awareness, decreased exposure to the sun, and reduced intake of alcohol. With the increasing identification of constitutive genetic alterations that predispose individuals to cancer, this group has been targeted for primary interventions such as prophylactic surgery.[3] Annual screening mammography in women older than 50 years of age and smoking cessation or chemoprevention in a group of asymptomatic smoking individuals are also examples of targeted primary prevention.
Secondary prevention is directed toward individuals with evidence of preneoplastic, clinically identifiable progression, but without frank malignancy. The phenomenon of intraepithelial neoplasia, also called preneoplasia or precancer, has become of widespread interest, and management of these lesions has the potential to abrogate the disease process early. Many organ sites have preneoplastic counterparts that should be amenable to early intervention ( Table 26-1 ). Representative examples of this type of secondary prevention include suppression or reversal of oral leukoplakia, cervical intraepithelial neoplasia (CIN) or Barrett's esophagus and inhibition of polyp formation or progression ( Fig. 26-2 ).
Table 26-1 -- Common Clinical Precursors (Intraepithelial Neoplasia) of Cancer
Organ Site
Method of Detection[*]
Actinic keratoses/moles
Barrett's esophagus
Adenoma (polyp)
Sigmoidoscopy, colonoscopy
Mammography, ultrasound, MRI
Intraepithelial neoplasia
Cytology and/or biopsy is required in almost all cases before definitive therapy can be initiated.
Elegant in situ optical spectroscopic methods are being developed to detect early preneoplastic changes, including enhancing the signals with fluorescent molecules.
Lobular and ductal carcinoma in situ.
Figure 26-2 Examples of premalignant lesions. A, Leukoplakia. Whitish lesion on side of tongue. B, Erythroplakia. Reddish (dark area) lesion in otherwise normal-looking buccal cavity. C, Barrett's esophagus (pale area) with high-grade lesion (dark portion). D,Adenomatous polyp in proximal sigmoid colon. (Courtesy of Bill Armstrong and Ken Chang.)
Tertiary prevention involves decreasing the morbidity of established disease. Chemoprevention of second malignancies is a good example of tertiary prevention. The distinction between primary, secondary, and tertiary prevention can sometimes become blurred. Further, tertiary prevention and adjuvant therapies can share many of the same goals. From the viewpoint of the clinical oncologist, probably the best way to look at prevention is as one more therapeutic modality for the management of cancer, directed at its control in the earliest stages. The observation that the addition of a retinoid after bone marrow transplantation markedly enhances the survival of children with refractory neuroblastoma represents an informative synthesis of a quaternary treatment approach and a tertiary prevention modality.[4]
Avoidable Causes
An extensive analysis of the topic of avoidable causes of cancer was performed over 2 decades ago by Doll and Peto[5]; these investigators concluded that 50% to 70% of all human cancers were preventable. No new data have emerged that would alter that overall estimate, although some of the specifics have changed.[6] The major avoidable risk factors can be broadly separated into four areas: tobacco, infectious, chemical (including hormonal), and diet.
Tobacco smoke is far and away the most important carcinogen to which humans are exposed on a routine basis. The morbidity and mortality from tobacco smoke is huge and represents the major preventable cause of all diseases, not just cancer, in modern and many undeveloped societies. It is estimated that more than 500 million smokers now living will die of tobacco-related illnesses. [7] [8] What is generally not appreciated is the wide carcinogenic range of molecular damage and the numerous organ sites affected by cigarette smoke. [9] [10] In addition to the lungs, cigarette smoking contributes significant attributable risk to the development of cancers of the oropharynx (75%), bladder (50%), esophagus (50%), pancreas (25%), cervix (20%), kidney (15%), and bone marrow (10%). Cigarette smoke facilitates chromosomal instability and enhances transformation at all levels of cancer formation (initiation, promotion, progression), including adversely affecting the natural history of successfully resected early-stage lung cancer.[11] Although the incidence of cigarette smoking has fallen among males, in 1994 lung cancer surpassed breast cancer as the most common cause of death from cancer in females. Lung cancer incidence among females has increased from 1975 through 2003, although the rate of increase has declined since 1991.[12] Well-tested modules have been developed to assist health care workers, including physicians, in applying smoking prevention and cessation strategies.[7] Various forms of nicotine (gum, patch, inhalers, nasal sprays) and behavioral modulators (bupropion) have been effective in increasing the quit rate significantly at very low cost.[8]
The evidence for infectious involvement in human cancer has increased dramatically in the last 15 years ( Table 26-2 ). Hepatitis and human papillomavirus (HPV) clearly play major roles in the development and evolution of hepatocellular and cervical carcinoma, respectively. Vaccines using various viral components as the target have recently been tested; results from these trials strongly suggest that liver cancer and cervical cancer are preventable. [13] [14] In addition to the classical and long-recognized associations of the parasites C. sinensis to cholangiocarcinoma and S. haematobium to squamous cell carcinoma of the bladder, the bacterium H. pylori has now been accepted as an etiologic agent associated with gastric dysplasia, stomach cancer, and a rare type of lymphoma.[15] Early on, these diseases can be treated with antibiotics and the process reversed. Finally, it seems that viruses have a role in the evolution of some lymphomas (human T-lymphotropic virus-1, Epstein-Barr virus [EBV]). These findings all offer new approaches for primary and secondary prevention using standard and new microbiologic and immunologic approaches.
Table 26-2 -- Cancers with an Infectious Etiology
Major Mode of Transmission
Hepatocellular carcinoma
Hepatitis virus
Maternal, oral
Helicobacter pylori
Several major cancers are of infectious etiology and can be eradicated by preventive intervention.
A number of chemicals are known to play a role in cancer causation, perhaps the most widespread being aniline dyes (bladder cancer), asbestos (lung, mesothelioma), and hormones (breast, prostate). The role of endogenous and exogenous hormones in cancer causation is complex and is considered in detail in the sections on breast, prostate, and gynecologic organ sites.[16] Some of the most intensely debated issues in medicine relate to this area. For example, is the overall health benefit of hormone replacement therapy (HRT) worthwhile? Results from the Women's Health Initiative (WHI) trial suggest not,[17] and long-term use of HRT is not recommended.
The question of the specific role of dietary components in cancer prevention remains largely unanswered. Many comprehensive reviews on the topic are available, and the overall recommendation to eat an abundant amount of fruits and vegetables has not changed in 20 years.[18] Ambitious campaigns such as the well-known "5-a-day for better health" campaign to encourage large-scale dietary changes continue.[19] The specific components responsible for the protective effects against cardiovascular disease and cancer remain unclear. The roles of macronutrients, fat, and fiber in prevention have been topics of much discussion. The general recommendation to reduce total calories and fat consumption and to increase fiber is a good one with regard to cardiovascular disease prophylaxis, but whether such a strategy affects cancer outcome remains unproven. Increasing epidemiologic data suggests that physical activity and basal metabolic index play critical roles, and several trials are underway to address these issues.[20]
There is growing evidence that changes in the insulin-like growth factor pathways play an important role in many aspects of lifestyle changes represented by a high basal metabolic index and its control.[20]With increasingly positive protective effects of physical exercise on cardiovascular disease being shown, there has been a renewed interest in the influence of physical exercise on malignant transformation and progression.[21] There has been a great deal of interest in micronutrients as preventive agents, but the results emanating from supplementation in well-done randomized clinical trials thus far have been disappointing.[22] Notable exceptions have included the report that supplementation with a modest dose of vitamin A (25,000 IU per day) can decrease the appearance of cutaneous squamous cell cancer of the skin in individuals with prior actinic keratoses and several trials showing that supplementation with a modest dose of calcium can decrease the subsequent prevalence of cancer polyps by 20%. [23] [24] [25]
Probably the most exciting diet-related development has been the identification of a wide range of potentially new and active chemoprevention compounds in food, such as protease inhibitors (soybeans), monoterpenes (citrus fruit oils), polyphenols (nuts), dithiolethiones (cruciferous vegetables), alliums (onion/garlic family), and many others.[26] The opportunity to genetically engineer foods to reduce the risk of heart disease and cancer is a topic of much scientific interest and commercial activity.[27] Nature created these molecules to deal with a hostile toxic environment, and figuring out how to use them for the prevention of cancer should be both scientifically interesting and clinically rewarding.
Screening and Early Detection
Strictly speaking, screening is limited to normal individuals. The science of screening identifies many pitfalls in the design, analysis, and interpretation of such trials, including length and lead-time biases and many others. [28] [29] Beyond the technical issues involved in study design, three other requirements addressing implementation, analysis, and interpretation, must be met to demonstrate that a screening test is useful:
A test must be available that will detect cancer earlier than routine methods (e.g., clinical or self-examination).
There must be evidence that treatment at an earlier stage of disease will result in an improved outcome (decreased cause-specific morbidity or mortality).
There must be evidence of a total health benefit. For example, the benefits of early detection via screening that meets the aforementioned criteria must also outweigh the adverse risks of subsequent diagnostic and therapeutic interventions. In current screening trials, disease-specific vs. all-cause mortality, and risk-benefit have become increasingly important issues—particularly among older individuals. [30] [31]
Fulfilling these requirements is difficult, and the issues specifically related to screening of different organ sites for precancers or cancers are discussed in those sections. Some generic comments are worthwhile. Enough evidence exists for a specific test for some organ sites that has been proven effective to recommend the routine adoption of screening ( Table 26-3 ). Although the availability of cancer screening is generally increasing, usage is relatively low for some organ sites (e.g., colon) and among groups that lack health insurance or a usual source of care.[32] Many screening tests, however, are ineffective (e.g., routine chest roentgenograms in smokers being the most notable).
Table 26-3 -- Effectiveness of Major Screening Approaches for Cancer[*]
Organ Site
Positive Level of Evidence[†]
Over age 50
Age 40–50
Fairly strong
Over age 50
Occult fecal blood
Fairly strong
Chest roentgenogram
Skin examination
Prostate-specific antigen
Listed here are organ sites for which sufficient data exist to make a judgment. Although no specific trial evidence exists, routine physical examination of the skin, oral cavity, testicles, and ovary/uterus is worthwhile, because treatment success is closely related to stage at diagnosis and effective treatment is available in most cases.
The concept of level of evidence is a valuable approach—a quantitative approach that is presented in detail in the PDQ section of the NCI Web site (http://cancernet.nci:nih.gov/clinpolq/screening). A randomized trial with survival as an endpoint is at the top of the hierarchy, whereas anecdotal evidence by experts is at the lowest.
Screening should begin with the onset of sexual activity.
Evidence also exists that colonoscopy with excisional biopsy is an effective therapeutic maneuver, but the cost of the procedure has precluded its general usage.
Several randomized trials of screening chest roentgenograms showed no effect on outcome. Spiral CT is currently being tested in a large national trial.
With careful follow-up and appropriate testing.
Also, a positive screening test may lead to aggressive intervention that could allow "cure" of the organ site disease but result in an overall increased morbidity or mortality that is not efficacious for a person's general health (e.g., radical prostatectomy for older individuals with a minimally increased PSA). Finally, screening for currently incurable malignancies (e.g., pancreatic cancer) offers new ethical dilemmas. If we have little to offer therapeutically, do we want to know the risk? Maybe, maybe not. Perhaps earlier prophylactic surgery might be able to affect the outcome in a few patients—for example, in families with early-onset pancreatic cancer.
Over the past few years, there have been rapid developments applying new imaging modalities for the purpose of cancer screenings. The United States Preventive Services Task Force now recommends screening with imaging techniques for breast cancer (mammography for women aged 40 to 70 years) and colorectal cancer (barium enema, fecal occult blood, endoscopy).[33] Cancer screening trials are ongoing for breast cancer (ultrasound, magnetic resonance imaging [MRI]), colorectal cancer (computed tomography [CT] colonography), liver cancer (ultrasound, CT), and pancreas (endoscopic ultrasound, CT, endoscopic retrograde cholangiopancreatography).[34] Major trials have completed accrual, including the Prostate, Lung, Colorectal and Ovarian (PLCO) trial and the National Lung Screening Trial. Mortality results from the PLCO are expected in 2015 and will assess the role of chest radiography (i.e., x-ray) in lung cancer screening, and transvaginal ultrasound for ovarian cancer screening. Mortality data from the National Lung Screening Trial are expected in 2009, to evaluate low-dose CT for lung cancer screening among high-risk adults.
The age of molecular diagnosis in screening is upon us and holds both promise and peril.[35] Novel functional and molecular imaging techniques for cancer diagnosis currently include measurements of tumor angiogenesis via dynamic contrast-enhanced (DCE)-MRI, DCE-CT with ultrasound, positron emission tomography (PET), and combinations of these techniques.[36] Diffuse optical imaging is another functional imaging technique that has emerged as an adjunct for cancer diagnosis. This noninvasive imaging method uses near-infrared light intensity to address tissue-specific changes between normal and tumor tissue (i.e., tissue hemoglobin concentration, tissue oxygen saturation) in vivo.[37] DCE-MRI, DCE-CT with ultrasound, and PET imaging have varying capabilities to profile microvessel density—a hallmark of angiogenesis—which is essential for tumor growth and invasion. However, even in the setting of cancer diagnosis, these methods are not yet standardized.[36] Appropriate methods for incorporating these functional and molecular imaging techniques into screening trials must be considered, particularly in light of their associated high costs. Thus, the potential impact of such molecular and functional imaging techniques on cancer screening is great, though not yet realized.
Although early detection is, formally speaking, the evaluation of a symptomatic individual for cancer and is therefore different from screening, many of the caveats regarding evaluation of this approach are the same. The increasing ability to identify high-risk populations, either by phenotypic criteria or by genetic analysis, also tends to lead to a blurring of the classic division between screening and early detection. With the rapid advances in molecular diagnostics, routine genetic typing of individuals at risk for major tumor types should not be too distant in the future, and quantitation of that risk (a concept we proposed quite some time ago)[38] and its evaluation at the time of detection leads to real-world angst. Identification and referral of families at high risk for cancer susceptibility should be an increasing emphasis of clinical oncologists, but thus far, participation by oncologists has been low. [2] [39] At the very least, the ability to downshift the stage of a disease at the time of detection should eventually lead to improved survival, because new treatment approaches emanate from causative understanding of a particular cancer. Proving this point, though, has been difficult for cancers of many organ sites.
The effectiveness of screening for the major types of cancer is summarized in Table 26-3 and is discussed in detail in the individual sections of this chapter. There are effective screening modalities for breast cancer, colorectal cancers, melanoma, and cervical cancers, whereas no compelling evidence exists for the value of screening for lung cancer. The effectiveness of PSA in screening for prostate cancer has been a subject of intense debate; we feel that the tide of evidence has turned and that the evidence supports the routine use of PSA screening over age 50 with thoughtful management and appropriate follow-up of abnormal values.
Carcinogenesis and Chemoprevention
Advances in our understanding of the biology of carcinogenesis (cancer formation) have sharpened our thoughts about screening and early detection and provided a guide to thinking about risk assessment and chemoprevention.[40] Figure 26-1 serves as a useful general roadmap to reflect on these issues for all tumor types (see Shureiqi and colleagues).[41] The classical model of carcinogenesis divides cancer evolution into three major epochs: initiation, promotion, and progression. This classification has served as a useful heuristic model for which considerable experimental evidence has been developed. In the past 15 years, the genetic paradigm for the development of cancer has been elegantly articulated and experimentally confirmed for some organ sites. A series of steps in response to separate molecular events at the genetic level is a useful platform from which to understand carcinogenesis in human epithelial tumors. Almost all human cancers examined in any detail have shown evidence of several acquired molecular abnormalities. Although the "pathway" is different for each cancer, the tumor suppressor genes p53 and p16 seem to play a central role in many malignancies. [42] [43] The expression of these abnormalities has allowed the development of markers that could serve as indicators of cancer risk or disease progression or possibly as surrogate endpoints for chemoprevention agent testing.[44]
Use of markers of carcinogenesis to assess the status of the disease relative to diagnosis and treatment and for assessment of chemoprevention effect is an important and complex issue.[45] The continued development and validation of markers will be critical to the intelligent management of early-stage cancer.[46] What also has become clear is that environmental phenomena (e.g., hormones, diet, carcinogens) can influence the expression of genetic changes. At one extreme of the paradigm is retinoblastoma, in which loss of a single gene inevitably results in an ocular tumor at a young age; however, most common solid tumors in adults seem to have underlying polygenic contributions, which can be affected by a large range of exogenous factors, even when a deleterious mutation such as BRCA1 orBRCA2 is present.
The idea of the chemoprevention of human cancer has been with us for nearly 3 decades, but only in the recent years have positive clinical trials validated the results of preclinical data and their potential for use in human beings. [47] [48] [49] [50] Retinoids are a major group of compounds that have provided convincing "proof of principle" of chemoprevention in humans, but in general they have been too toxic for widespread use and have not been adopted widely.[51] The overall results of some of the key randomized chemoprevention trials are summarized in Table 26-4 and are discussed in more detail in the individual organ site sections. Major problems in developing chemoprevention as a modality for cancer management have been the length and size of the trials required to show changes in a definitive endpoint. [52] [53] Consequently, only the National Cancer Institute and a few large research groups have been able to marshal the resources to develop broad-based chemoprevention efforts. Another significant issue in the design of early trials was that many large studies evolved primarily from epidemiologic observations, with little experimental data available. Because the implementation of large phase III or IV chemoprevention trials is a 10- to 100-million-dollar exercise, political influences on the funding process have also been substantial.
Table 26-4 -- Current Overall Status of Chemoprevention in Preventing Human Cancers[*]
Organ Site
Pretrial Level of Evidence
Status of Chemoprevention
One large trial, very positive; two smaller trials showed no effect. Overall long-term health benefits must be determined.
Ineffective to marginal
Numerous phase III trials of several compounds have not substantiated phase II trials except for topical all-trans-retinoic acid.
Slight decrease (25%) in colon polyp recurrence by calcium or aspirin
Head and neck (secondary)
Moderately strong
13-cis retinoic acid
Effective but toxic
Follow-up trial at lower dose ineffective
Moderately strong
Single randomized trial needs confirmation.
13-cis-retinoic acid
Effective but toxic
Follow-up studies at lower doses in progress
More lung cancers and increased higher overall mortality
Secondary (metaplasia)
Impressively negative
Moderately strong
Accrual complete
Results indicate positive effects but are preliminary.
Results in 2010
Effective in some cases
Seems to depend on stage of cancer development and strength of agent
Causes regression of actinic keratoses
Details are discussed in individual sections.
Cervix, effects on regression of cervical intraepithelial neoplasia.
Selenium and vitamin E. Epidemiologic data from secondary analysis; experimental data moderate.
An attempt to develop chemoprevention agents logically has been outlined, and systematic preclinical testing and evolution of sequential clinical trials are likely to avoid some of the mistakes of the past.[53] [54] Several key elements are featured in this decision analysis process:
Preclinical in vitro and in vivo testing against a battery of molecular targets and cellular and animal models
Accurate identification of side effects and assessment of their importance
Evidence of modulation of anticipated biochemical or molecular markers in the relevant tissue in short-term human trials
A randomized 6- to 12-month study of multiple low doses of the candidate agent in a relevant patient/participant population, with careful identification of side effects and assessment of their importance, and evaluation of their biochemical, molecular, and/or histologic effects
In this regard we have performed a particularly informative series of studies in assessing topical all-trans-retinoic acid in cervical cancer prevention and difluoromethylornithine (DFMO) in colon cancer prevention, [55] [56] [57] whereas the M.D. Anderson group[58] has performed a series of important trials in aerodigestive cancers and the Arizona group has done the same for skin cancers.[59] Following this logical pathway of chemoprevention agent development assures that the probability of conducting a definitive phase III or IV study will be high and maximizes the chance for a successful outcome. Although the term "chemoprevention" has been widely used to describe chemical or dietary intervention to prevent or reverse cancer, it is a misnomer that is out of sync with the nosology used in other areas of medicine. Therapeutic prevention might be a better term—for example, cholesterol-lowering agents and antihypertensives to prevent cardiovascular diseases, prophylactic antibiotics to prevent infections, and many more. Risk-benefit of a drug in a prevention setting has always been a key issue, particularly of individuals at low risk. The unexpected increase of lung cancers and adverse cardiovascular events in two large trials in which β-carotene was administered called this issue into sharp focus in the mid-1990s. [60] [61] Recently, a different level of risk has been appreciated, designated risk-risk. In several large trials, selective/specific COX-2 inhibitors markedly reduced the incidence of colonic polyps but at the price of increased serious cardiovascular events. [62] [63] A careful analysis indicated that overall morbidity would be increased by using selective COX-2 inhibitors to reduce adenomatous colon polyps in individuals at low risk.[64] These important observations do not necessarily preclude using other nonsteroidal anti-inflammatory drugs (NSAIDs) that have more complex effects on the prostaglandin pathways (e.g., aspirin, sulindac); the results of other trials will help in this decision making, but the unexpected outcomes in the COX-2 inhibitor trials has clouded the field of chemoprevention for reduction of cancer incidence, particularly in individuals at low risk. It is important to recall that the development of cardiovascular risk reduction trials met similar problems in the early days until effective and nontoxic agents were developed, and 20 to 30 years ago the regulatory burdens and the ethical bars were considerably lower.[65]
Although thus far most agents have been developed based on epidemiologic observations or carcinogen models in animals, increasing knowledge about the molecular basis of cancer progression in human tumors should result in the discovery and synthesis of highly specific drugs based on altered biochemical and signaling pathways. [66] [67] The number of specific tumors for which prevention strategies could be reviewed is large. In this chapter we review the major organ sites (aerodigestive, colon, breast, prostate) and those sites (skin, ovary, cervix) in which sufficient evidence exists to suggest that preventive strategies currently have a role in clinical oncology. We also offer a few comments on less studied cancers (stomach, liver) that are extremely common outside the United States and Europe. With the rapidly increasing scientific understanding of the biologic basis for many tumor types and the recognition that screening, early detection, and chemoprevention should play a large role in the management of the carcinogenic process, we can anticipate that the list of therapeutic prevention strategies for intraepithelial neoplasia and possibly earlier manifestations of cancer will grow rapidly over the next few years.
Risk Reduction
Aerodigestive malignancies encompass a subset of cancers including those that arise from the oral cavity, pharynx, esophagus, and lung.[58] These organ sites have been grouped together, because they share a mucosal epithelial field that is directly subject to malignant transformation by the common toxin (tobacco), the major underlying etiologic agent for these malignancies. In addition to cigarette smoke, smokeless tobacco has also played an increasing contributory role in oral carcinogenesis, and oral cancer in the young adult has become increasingly common.[68] Alcohol also clearly plays a synergistic role with tobacco carcinogens in the development of oral and esophageal cancers, including second cancers. [69] [70] Polymorphisms in the alcohol dehydrogenase gene involved with tobacco carcinogen metabolism may also play an important role in determining risk for head and neck and tobacco-related malignancies.[71] The identification of HPV in more than 50% of oropharyngeal and nearly 100% of laryngeal tumors has led to acceptance of the role of HPV in head and neck squamous cell carcinomas (HNSCCs) pathogenesis. [72] [73] Compared with HPV-negative HNSCC tumors, which harbor tobacco-induced p53 mutations, HPV-positive HNSCC tumors have wild-type p53, which is inactivated by the viral oncoprotein. [73] [74] Interestingly, HPV-positive HNSCC patients have a different clinical profile compared with HPV-negative patients: they are younger, less likely to ingest alcohol or use tobacco, and show equal gender distribution; the tumors show poorly differentiated and basaloid histology, but such patients have improved survival characteristics. [73] [75] Progress in understanding the biology of tobacco-associated carcinogenesis in the past few years has been rapid, and molecular models of head and neck and lung cancers have been characterized to a substantial degree.[76] What is clear from cytogenetic genomic hybridization and other studies is that, although aerodigestive cancers share many similar changes early on (e.g., loss and gain of 3p and cyclin alterations), discrete subsets exist.[77] Because different genes are involved, this information should have a practical effect on the development of chemoprevention and other interventions.
In 2006 more than 230,000 cancers are expected to develop in aerodigestive sites, and 188,000 related deaths are anticipated in the United States.[78] Because it is estimated that the etiology of more than 80% of aerodigestive cancers is tobacco related, the cost to society of this legal carcinogen is extraordinarily high. The application of prevention strategies should have a favorable impact on decreasing morbidity and mortality from aerodigestive cancers; particularly important for the medical profession should be the adoption of proven, physician-facilitated smoking cessation methods. [7] [8]
Screening and Early Detection
Oropharyngeal cancer occurs in a region of the body that is easily accessible to examination by a health care worker. The morbidity and mortality from oropharyngeal cancer is directly related to the stage at diagnosis, so effective screening and early detection should be worthwhile.[79] However, no definitive trial has demonstrated that an early detection program can downshift stage at diagnosis of oropharyngeal cancer or reduce mortality in a screened population. Nevertheless, an inspection of the oral cavity should be part of every examination in high-risk patients (smokers) and can be made efficacious by careful inspection of the soft palate, tongue, and floor of the mouth, where 90% of all squamous cell cancers occur.[80] The preneoplastic lesions, leukoplakia and particularly erythroplakia, should be identified and biopsy specimens obtained if necessary, because they represent early observable signs of squamous cell carcinomas with different prognoses (see Fig. 26-2A and B ). In appropriately screened populations of high-risk smokers and drinkers over age 40, a detection rate of oral cancers as high as 1 cancer in every 200 individuals examined has been achieved.[81] A successful screening program can be mounted using health caseworkers; for example, in Sri Lanka, where oral cancer is a common malignancy, a sensitivity of 58% was obtained for 660 patients with suspected cancers.[82]
Recent advances in optical biology also suggest that screening using autofluorescent techniques may allow detection of premalignant changes before the clinical appearance of disease.[83] The strong association of HPV with oral cancers in young, nonsmoking individuals[72] and the success of screening techniques in detecting cervical intraepithelial neoplasia (see the discussion that follows) suggest that oral screening for HPV should be adopted for those who are sexually active. Established risk factors for HNSCC related to sexual behavior (i.e., history of genital warts, young age at onset of sexual activity, and a high number of sexual partners) indicate that this group is the same population at risk for genital HPV.
Routine screening of esophageal cancer in the United States has not been attempted to a significant degree, because it is relatively uncommon and therapeutic options are poor. In China and other Asian countries, however, the disease is much more common and found at high frequency in certain geographic locales. In these areas, screening and early detection using esophageal cytology are widely used, although the efficacy of these approaches has yet to be firmly established.[84]
Although lung cancer incidence among men has declined since the 1980s, the incidence for females has increased from 1975 through 2003 in the United States.[12] This trend may be changing, in that recent data indicate that the rate of increase among women has declined since 1991.[12] The issue of screening for lung cancer has been a long and complicated one, without a strong supporting evidence base. In the Mayo Lung Project (a large controlled trial designed to assess lung cancer screening with chest roentgenograms and sputum cytology among high-risk adults conducted in the 1970s and 1980s), chest x-ray imaging was noted to detect early-stage lung cancers, without leading to any difference in lung cancer mortality. [85] [86] Furthermore, excess cases were noted in the intervention arm, leading to "overdiagnosis."[87] Four large randomized trials of screening chest x-rays in smokers have demonstrated no difference in survival between the randomized groups.[88] In subsequent chest CT screening trials at The Mayo Clinic, CT was shown to detect early-stage tumors, but with a high rate of false-positives (i.e., benign nodule detection). Recent support for lung cancer CT screening among high-risk individuals comes from the singular outcome analysis of a large trial in which 85% of the screen-detected lung tumors were stage I at diagnosis, and 10-year overall survival was 88% for these stage I patients.[89] Although these observational findings are impressive, we must await the results of confirmatory randomized controlled prospective screening trials before making broad screening recommendations for lung cancer. Thus, the National Lung Screening Trial (CT imaging) and PLCO (chest x-ray) trials for lung cancer screening will serve as important validation studies to evaluate the efficacy of lung cancer screening among high-risk individuals.
Epithelial cancers of the upper aerodigestive tract and lungs are the most extensively studied system for chemoprevention in humans, and the results are the most negative. The natural history of the disease process has been studied extensively and provides a rich platform from which to conduct chemoprevention trials. Field carcinogenesis by tobacco carcinogens with its associated epidemiologic risk and characterized molecular changes is a straightforward concept that has guided the development of chemoprevention studies in this area.[46] The recent identification of molecular (e.g., DNA repair, telomerase), metabolic (e.g., cytochrome P450, alcohol dehydrogenase), and mutagen sensitivity profiles that predispose to aerodigestive cancers, acquired chromosomal abnormalities in the field and in the cancers, and alterations of several molecular parameters that predict responsiveness and unresponsiveness, have recently provided useful detail from which to consider the next generation of rational chemoprevention trials.[90] The identification of a variety of molecular changes during head and neck cancer progression, in addition to readily identifiable histologic precursors, has provided a biologic base for understanding the interaction of carcinogenesis and chemoprevention of this disease. Recent studies of the molecular changes that accompany the progression of lung cancer also provide a useful paradigm and platform from which to develop well-considered chemoprevention approaches.
Thus far, however, the results of primary, secondary, and tertiary chemoprevention trials of the lung have been disappointing (see Goodman[91]). Two large placebo-controlled, multiagent randomized trials in heavy smokers (more than 47,000 participants) have been negative and showed no beneficial effect of retinol (vitamin A) or α-tocopherol (vitamin E). [60] [61] More disturbingly, these two large, randomized trials indicate that current smokers supplemented with oral β-carotene developed lung cancers at a rate 25% greater than the placebo group and also showed an increased overall mortality. Although these findings remain unexplained, possibilities that might help explain the adverse effect of β-carotene in these studies include the following:
The formation of cyclic epoxides in the setting of tobacco carcinogens, inflammation, and high β-carotene concentrations
The suppression of RAR-b, a major transcription factor important for differentiation in epithelial tissues
Lowering of the concentration of other micronutrients that might be protective
Stimulation of preneoplastic clones by enhancement of growth factor production
Complex genetic polymorphisms that lead to alteration of tobacco carcinogen metabolism
Definitive secondary (metaplasia, atypia) and tertiary (second malignancy) chemoprevention trials that use a number of different retinoids and other compounds (folic acid, N-acetylcysteine) have also yielded negative results. [91] [92] Treatment with anethole dithiolethione (an organo-sulfur compound) was shown in a randomized trial to reduce development of new bronchial dysplasia lesions and to slow progression of pre-existing disease in current or former smokers.[93] However, a randomized trial of inhaled budesonide in smokers with bronchial dysplasia indicated no effect of the active agent in the regression of bronchial dysplastic lesions or prevention of new lesions.[94] A modest decrease in p53 and BCL-2 protein expression in bronchial biopsy specimens was seen, as was a slightly higher rate of resolution of CT-detected lung nodules. Whether budesonide or anethole dithiolthione will be useful in managing preneoplastic lesions of the lung will require assessment in larger and longer trials.
Studies of secondary and tertiary chemoprevention of head and neck cancers have led to somewhat more encouraging results. Randomized trials have shown that isotretinoin causes regression of oral leukoplakia, though accompanied by substantial side effects.[95] Two randomized trials confirmed activity of β-carotene, although results from the later study were less convincing. [96] [97] Several other, less toxic agents (retinol, 4-[hydroxyphenyl]-retinamide, and α-tocopherol) and selenium have also produced responses of premalignant lesions in phase II trials.[98] A randomized trial of the cyclooxygenase inhibitor ketorolac as an oral rinse was negative in patients with oropharyngeal leukoplakia.[99] A recently reported phase II trial of the complex retinoid fenretinide suggested activity for this compound in patients with retinoic acid–resistant oral leukoplakia.[100] We have demonstrated substantial potential activity of Bowman-Birk inhibitor (a soybean-derived compound) against oral leukoplakia.[101] The results of randomized studies for these latter two compounds have not yet been reported.
In a randomized phase III adjuvant trial of patients treated for head and neck cancer by local therapy, the synthetic retinoid 13-cis-retinoic acid (isotretinoin, Accutane) at a high daily oral dose (50 to 100 mg/m2) led to a reduction in the incidence of second primary tumors, a difference that was maintained for more than 5 years.[102] The rate of second primary tumors was affected greatly by tobacco smoking status, with the efficacy of chemoprevention decreasing sequentially in current and former smokers as compared with nonsmokers.[103] The side effects in the 13-cis-retinoic acid trial were substantial at this dosage level, however. These results with 13-cis-retinoic acid were particularly significant in that a similarly designed randomized trial using another retinoid (etretinate) at a high dose showed no reduction of second primary tumors.[104] Therefore, the efficacy of low-dose isotretinoin (30 mg/day) to prevent second primary tumors after treatment of early-stage (I and II) head and neck cancer was tested in a randomized trial, with the hope that side effects could be decreased without losing efficacy. This strategy was unsuccessful, and no difference in the appearance of second malignancies in the placebo and treatment groups could be demonstrated; it is noteworthy that patients who continued to smoke had an increased rate of second primary tumors and death.[105]
The incidence of adenocarcinoma of the esophagus has been increasing over the past 2 decades. Gastroesophageal reflux has been identified as a risk factor leading to the development of a columnar-lined esophagus, called Barrett's esophagus, which progresses to adenocarcinoma via a metaplasia-dysplasia sequence ( Fig. 26-2C ). Both endoscopic resection and thermal or photodynamic ablation have been used to treat this condition,[106] but long-term benefit is unknown. Epidemiologic and clinical observations also suggest that NSAIDs and aspirin, by inhibiting COX enzymes, and proton pump inhibitors by decreasing gastric reflux[107] should be effective as chemopreventive agents, but randomized controlled trials proving this supposition have not yet been reported. Attempts to reverse or suppress these lesions with 13-cis-retinoic acid have been unsuccessful.[108]
Overall, these trials suggest that oral leukoplakia, but not bronchial metaplasia, can be reversed or suppressed by currently available chemopreventive agents. Thus far, "proof of principle" of chemoprevention in head and neck cancers has been achieved. However, large-scale phase III trials will have to show efficacy with a favorable risk-benefit profile before the strategy of chemoprevention can be adopted into standard medical practice for the management of aerodigestive cancers.
Screening for and early detection of colorectal cancers results in 5-year survival rates of 90% for colon cancer and 80% for rectal cancer, providing that diagnosis and treatment occur before the lesions have spread beyond the bowel to regional lymph nodes or distant metastatic sites. Unfortunately, more than 60% of patients still present with higher staged disease, leading to a lower overall 5-year survival rate of 65%.[78] In the United States, colorectal cancer affects 148,000 individuals annually and is responsible for more than 55,000 deaths per year, which is surpassed only by cancer deaths secondary to lung cancer.[78] These statistics highlight the critical importance of identifying individuals at risk for the development of colorectal cancer and of screening and early detection in its management. This section will discuss various risk factors, both modifiable (i.e., extrinsic risk factors) and not modifiable (i.e., intrinsic risk factors), that increase susceptibility for the development of colorectal cancer and will review current screening guidelines. This information can be used to design more effective preventive strategies, which could make use of genetic testing for individuals at risk and apply behavioral modification and chemoprevention.
Numerous epidemiologic, international, and experimental studies have evaluated various hereditary and environmental factors that lead directly or indirectly to the development of colorectal cancers. It is believed that colon cancer is the result of a complex series of genetic and epigenetic events that occur when environmental factors interact with an individual's inherited or acquired susceptibility. [42] [109]This interaction produces somatic mutations that accumulate over time and lead to neoplastic transformation of normal colonic epithelium into premalignant adenomatous polyps (see Fig. 26-2D ) and ultimately into invasive disease. The natural history preceding the development of cancer can progress through several decades. Adenomatous polyps, especially the villous subtype, are the premalignant lesions in more than 90% of colorectal cancers. The risk of malignant degeneration depends on the size of the polyp (increasing greatly in those greater than 1 to 2 cm in size), duration of its presence, number present at the time of the initial examination, and the histologic type.[110] Only adenomatous polyps seem to carry a premalignant risk; however, hyperplastic polyps are diagnosed more commonly in individuals with a smoking or drinking history, two predisposing factors for adenomatous polyp development.[111] The presence of hyperplastic polyps may warrant increased screening and prevention counseling, although further study of this issue is needed before definitive conclusions can be made.
Our understanding of the genetic and molecular alterations that precede the development of colorectal cancers has broadened and deepened over the past 10 to 15 years ( Fig. 26-3 ).[112] This information has facilitated the identification of individuals who might benefit from early interventions with more vigilant screening, chemoprevention, or treatment. Based on studies of family histories, it is estimated that 20% to 30% of colorectal cancers have a significant hereditary component.[112] Thus far, however, genes associated with only two major syndromes—familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC)—have been identified clearly. Allelic deletions have been identified in patients diagnosed with these two autosomal dominant syndromes, FAP and HNPCC.[113] [114] [115] FAP accounts for only 1% of colon cancer cases per year and is associated with a deletion of the APC gene on chromosome 5 (band q21). These patients develop thousands of adenomatous polyps that tend to be evenly distributed throughout the colon and rectum by the second or third decades of life. If surgical treatment by complete colectomy is not done, affected individuals are at high risk to develop colon cancer by the age of 40. A highly specific mutation (T to A at nucleotide 3920) has been found in 6% of Ashkenazi Jews, and about 28% of Ashkenazim have a family history of colorectal cancer.[116] This mutation created a small hypermutable region of the gene, thereby indirectly causing predisposition.
Figure 26-3 Colorectal cancer results from inherited genetic predisposition and acquired molecular alterations interacting with environmental and endogenous toxins that are themselves modified by gene products. TSG, tumor suppressor gene; ONC, oncogene; ROS/RNS, reactive oxygen and reactive nitrogen species form from normal metabolic processes (endogenous) and from exposure to carcinogens and toxins (external).
The incidence of HNPCC was determined to be less than 1% of annual colon cancer cases in a large population-based study, although estimates of 5% are typically reported from nonpopulation-based studies.[117] Diagnosis requires that three or more relatives be diagnosed with colorectal cancer, representing at least two successive generations, and at least one relative must have been diagnosed before the age of 50.[115] One relative must be a first-degree relative of the proband patient. Patients tend to have cancers that arise in the proximal colon, and they also develop ovarian and endometrial cancers at a higher rate than the population at large. This syndrome is associated with defective DNA repair mechanisms, which lead to aberrant cell growth and tumor formation. These mutations occur on chromosomes 3 (hMLH1, 3p21) and 2 (hMSH2, 2p). [118] [119] Based on extensive experimental and clinical data, Vogelstein and colleagues [42] [113] proposed that it is the progressive accumulation of mutations that ultimately lead to invasive disease. This proposal has been substantiated extensively, and mutations associated with colorectal cancers have been identified involving proto-oncogenes, tumor suppressor genes, and certain key regulatory enzymes, such as cytochrome P450 and acetyltransferase. [120] [121] [122] It has been suggested that colorectal cancers in adults develop through one of three different pathways (chromosomal instability, microsatellite instability, and CpG island methylator phenotype) and have different biologic behaviors.[109] The role of polymorphisms in metabolizing key molecules (including those present in the diet) is being examined closely and should provide a platform from which to understand gene-environment interactions. For example, polymorphisms in hepatic cytochrome P450 and acetyltransferase enzymes lead to rapid oxidation and acetylation of genotoxic compounds such as heterocyclic amines, which are present in processed foods.[122] Accelerated metabolism of these compounds increases an individual's risk of developing colorectal cancers threefold.
Although diet seems to play a significant role in colon carcinogenesis, the degree to which individual macronutrients and micronutrients contribute to the development of colorectal cancer has been elusive. In part, this difficulty stems from differences in design and methodology in studies that have been performed to evaluate this subject, including the type of dietary questionnaire administered, differences in cohorts such as age and ethnicity, confounding effects of other dietary components, selection and recall biases, sample size, and length of follow-up.
The majority of past evidence has demonstrated an increase in incidence and mortality rates from colorectal cancers in groups of people who consume a more "westernized" diet that is high in animal fat, total calories, and red meat but low in fiber and fruit and vegetable intake.[123] International and migrant studies have supported this observation. Recent studies, however, have indicated that the older evidence should be reconsidered. Large prospective cohort studies and several large randomized trials indicate that fiber does not seem to be protective nor fat contributory to colon cancer development.[124] [125] [126] In contrast, mechanistic considerations, metabolic studies, and epidemiologic studies suggest a strong protective effect of folate and an important role of insulin and insulin-like growth factors in colon cancer pathogenesis. Potter[109] and other researchers have done a particularly nice job in attempting to relate genetic changes, risk factors (including diet), and downstream molecules and pathogenesis.
Other Factors (Alcohol, Smoking, Exercise, Body Mass Index)
Primary prevention of colorectal cancer also requires that we understand factors other than diet that increase risk for colorectal carcinoma by initiating or promoting carcinogenesis. These include use of alcohol and tobacco, sedentary lifestyle, and the metabolic changes that proceed from these. [18] [127]
Many studies have demonstrated a relationship between alcohol use and colorectal cancer and adenoma formation. [128] [129] It is still uncertain whether alcohol directly initiates DNA damage or acts as a promoter on cells that already have undergone preneoplastic changes. A low-methionine or low-folate diet might contribute to a situation leading to adenomas and colorectal cancer, in that both methionine and folate are cofactors for DNA synthesis; lowered concentrations of these compounds leads to hypomethylation of DNA, which is a precursor to aneuploidy and loss of heterozygosity.[130] Various forms of a key enzyme, 5,10-methylenetetrahydrofolate reductase, which catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, have also been identified.[131] Some mutations of this enzyme increase its activity, whereas others decrease it. Low activity leads to decreased methionine synthesis and antagonizes methyl group metabolism in DNA synthesis.[131] This theory gained some support in the U.S. Male Health Professionals Study.[111] An association was found between high alcohol intake and methionine-deficient diets, after controlling for intakes of fat, red meat, fiber, level of physical activity, body mass index (BMI), and multivitamin and aspirin supplementation. Alcohol might be particularly important for progression of large adenomas to tumors.[128] Avoiding excess alcohol, while increasing dietary folate and methionine, seems like a reasonable approach to decreasing risk for colon cancer. Several large studies are underway to test whether supplementation with folate can reduce adenomata development.
Cigarette smoking has been consistently associated with adenoma formation but less so with colon tumors, an observation that could be explained by the molecular nature of a subset of colon tumors in which microsatellite instability and/or p53-negative status is a prominent feature.[132] The Health Professionals Follow-up Cohort Study and the Nurse's Health Study observed more adenomas in individuals with a history of smoking than in those who did not smoke.[133] Analysis of the very large American Cancer Society Cancer Prevention II study indicates that 20% of colorectal cancers and 12% of deaths are associated with long-term cigarette smoking[134] ( Fig. 26-4 ).
Figure 26-4 The potential effect of diet on risk of colon cancer. NEFA, nonesterified fatty acids; ROS, reactive oxygen species.
Physical inactivity and high BMI also increase one's risk for colorectal cancers. A prospective study found a significant inverse association between leisure-time physical activity and incidence of colon cancer in participants of the Nurse's Health Study.[135] An inverse association was also observed between physical activity and the development of large (>1 cm) adenomas in the distal colon. In this same study, more adenomas were observed in individuals with a high BMI. Obesity, and in particular abdominal adiposity, has also been associated with an elevated risk for adenomatous polyps and colon cancer.[136] Recently, two separate cohort studies have demonstrated that physical activity is associated with improved outcomes among resected colon cancer patients. [137] [138] Increasing physical activity and maintaining lean body weight for the prevention of colorectal cancer probably has considerable merit for decreasing the incidence of polyps and colon cancer, as well as of other chronic diseases.
The mechanisms underlying these proposed effects are not clear, but a unifying hypothesis has been proposed recently and involves the sequential steps of consumption of excess dietary energy, development of insulin resistance, and increased circulating levels of insulin, triglycerides, and nonesterified fatty acids, which results in secondary colonic epithelial damage.[139] Thus, the beneficial effects of physical activity on colon cancer risk and outcomes represents the sum total of numerous cellular and molecular events. A goal of prevention research is to determine which molecular pathways are being affected by physical activity and to evaluate potential biomarkers in this process. However, validated mechanisms have been lacking. Epidemiologic evidence associating insulin, insulin-like growth factor-1, and insulin-like growth factor–binding protein levels with colorectal cancer incidence provides considerable support for the proposal that changes in diet and physical activity may affect key molecular events.[140]
Screening and Early Detection
Population-Based Data
A definitive amount of data has accumulated indicating that colorectal cancer screening for persons at average risk is effective and reduces colorectal morbidity; agreement on the best screening modality remains unsettled, however.[141] Cost-saving analysis even supports the use of universal colonoscopy over the long term, notwithstanding the considerable practical challenges and total cost in achieving this goal. Probably everyone over 50 years of age should be screened. Yet surprisingly, fewer than 50% of individuals who should be screened are evaluated by fecal occult blood tests (FOBT), digital rectal exams (DRE), and/or sigmoidoscopy.[32]
Conflicting recommendations from government and private agencies contribute to the confusion. In general, all groups advocate screening in men and women beginning at the age of 50, because the incidence of colon cancer rises sharply between the ages of 50 and 55 and continues to double with each succeeding decade, reaching a peak by the age of 75. The American Cancer Society and the American College of Obstetricians and Gynecologists support yearly DREs beginning at age 40 and FOBTs performed yearly, once a person reaches 50 years of age. Sigmoidoscopy should occur every 3 to 5 years beginning at 50 years of age. Flexible sigmoidoscopy is superior to rigid sigmoidoscopy, because it allows the examiner to visualize up to 60 cm of bowel mucosa and is easier on the patient.
There are numerous studies validating the use of DRE, FOBT, and sigmoidoscopy as effective screening tools, providing regular screening is performed (to detect lesions in this disease with a long preinvasive phase). [142] [143] [144] This is particularly important with the FOBT, because reported sensitivities are low and range between 22% and 92%. Sensitivity is higher when at least three tests are performed on different days and the samples are rehydrated with hydrogen peroxide. To decrease false-negative results, which also increases the sensitivity of the test, patients should be instructed to avoid vitamin C and to eat a high-residue diet for several days before the test. The incidence of false positives is lowered when gastrointestinal irritants (e.g., aspirin, oral iron, and meat products) are not consumed a few days before the FOBT. In general, screened, asymptomatic patients have a positive test 4% to 6% of the time. Only 5% to 10% of these individuals have colorectal cancers, and an additional 30% have benign polyps. [145] [146] The positive predictive value is only about 20%, so a positive test can be costly, because follow-up requires evaluation by sigmoidoscopy or colonoscopy. Randomized clinical trials have demonstrated a decrease in mortality by 15% to 33% with the regular use of serial FOBT, however.[143] Patients who received FOBT in conjunction with sigmoidoscopy in a Memorial Sloan-Kettering colon cancer trial had a significantly higher survival probability when compared with those who received sigmoidoscopy alone (70% vs. 48%, respectively).[143] This is an impressive result.
Regular screening with sigmoidoscopy among patients over 50 years of age both reduces mortality from colorectal cancer and prolongs survival. [147] [148] Studies must be performed to clarify the optimal interval between screening and to develop recommendations for individuals at higher risk for adenomas or colorectal cancers. The early results of a "once-only" sigmoidoscopy at age 60, in which a high yield of adenomas was obtained, suggests that a less intense approach to screening could be a cost-effective strategy to prevent colon cancers.[149] Follow-up colonoscopy suggested that a significant number of proximal adenomas were present. The efficacy of screening colonoscopy for adenoma detection was directly related to prolonged endoscope withdrawal time in a recent study, a finding that may influence patient management in the near future.[150] There is little doubt that screening colonoscopy is effective at identifying silent, large adenomas and colon cancers, but its cost effectiveness must be demonstrated; so must the optimal usage of fecal occult blood, sigmoidoscopy, and colonoscopy with regard to efficacy and cost. A particularly exciting approach is the identification of colon cancer-specific mutations in fecal DNA.[151] A study of the adenomatous polyposis coli (APC) gene, the initiating abnormality in most sporadic colon cancers, in the fecal DNA of normal individuals and patients with polyps shows considerable promise.[152] Although the specificity of this test was high (100%), the sensitivity was only 57%. However, integration of the test into the screening paradigm (perhaps with FOBT) as a low-cost, general screen is an important goal. The DRE should be included in all examinations, because it permits evaluation of the distal rectum and prostate. Its sensitivity has decreased, however, with the temporal shift to more proximal lesions in the colon.[149] Other tests, including double-contrast barium enema, have not been evaluated completely as screening tests and are more expensive than DRE, FOBT, and sigmoidoscopy. We feel that these modalities should be reserved for those patients with positive screening tests.
High-Risk Individuals
More frequent screening is recommended for certain postpoly-pectomy individuals and other individuals at increased risk for the development of adenomatous polyps or colorectal cancers.[153] One particularly important group includes those who have had previous treatment for a primary colorectal cancer. Recent analysis indicates that evaluation of this high-risk group has been inadequate. Proctosigmoidoscopy or colonoscopy should begin at age 10 for first-degree relatives of individuals with FAP and at age 25 for individuals with a strong family history suggestive of HNPCC. [154] [155]Genetic testing for the mutated APC gene in peripheral mononuclear cells of patients with early onset of adenomatous polyps or in first-degree relatives of FAP-affected individuals will help to determine who needs closer surveillance.[156] Counseling about diet, chemoprevention, and lifestyle issues can be provided for individuals who test positive for the mutated APC gene. In addition, a colectomy should be considered if polyps are found.
Genetic testing for mutations in DNA repair genes should be performed on anyone whose family history is suggestive of HNPCC; counseling can then be provided for individuals who test positive.[157] A positive family history of colorectal cancer that does not meet criteria for FAP or HNPCC probably also warrants earlier screening, but definitive guidelines have not been established. A prospective study of approximately 120,000 men and women who underwent colonoscopy or sigmoidoscopy surveillance concluded that the age-adjusted relative risk for cancer was 1.72 with one first-degree relative with the disease, 2.75 with two first-degree relatives, and 5.37 with one first-degree relative who was under age 45 at the time of diagnosis.[158] It is estimated that as many as 25% of individuals with colon cancer have positive family histories. Baseline colonoscopy before age 50 seems to be a reasonable consideration among this group of patients with a positive family history.
Other high-risk conditions requiring close surveillance include individuals with a long-standing history of inflammatory bowel disease, a prior history of polypectomy or ureterosigmoidostomy, a personal history of ovarian, endometrial, or colon cancer, and finally anyone who has been treated for Streptococcus bovis bacteremia. [154] [159] [160] [161]
Other Health Factors
In considering health care resources, other issues that affect the development of colon cancer should be considered. The role of estrogen replacement in the development of colon cancer and in other health parameters in postmenopausal women is of great importance. The results of the Nurse's Health Study suggested that current estrogen replacement in postmenopausal women can reduce the risk of colon cancer (relative risk = 0.65); this effect disappeared 5 years after discontinuation of estrogen replacement.[162] However, a detailed analysis of the group of postmenopausal women in the WHI trial who received estrogen plus progestin indicated that the colorectal cancers were diagnosed in a more advanced stage even though the number of colorectal cancers was reduced by 45%.[163] When reproductive factors were examined among women who were diagnosed with colon cancer in this study, oral contraceptive pill use and later age of menarche were also associated with a decreased risk. In another study, women who delivered more than five children, especially if they had a positive family history of adenomas, were at increased risk for the development of adenomas.[164] In this study, however, no association was found with age at menarche, menopause, first birth, or oral contraceptive pill use. Although estrogen plus progestin lowered the risk for colorectal cancer in the WHI trial,[163] these favorable results will have to be balanced against the increased risk for breast cancer and cardiovascular disease (see later discussion).
Despite the enormous amount of epidemiologic observations and experimental data that support a protective role of many dietary constituents against the development of adenomatous polyps and colorectal polyps, the results from definitive randomized trials have been modest, at best. Many micronutrients and dietary constituents have been studied. Trials using vitamins C, D, and E, and β-carotene as well as supplementation with fiber or lowering of dietary fat have been uniformly negative. Trials in which calcium has been supplemented have been modestly positive with a 25% to 35% reduction of adenomatous polyps demonstrated. [24] [25] However, daily supplementation of calcium with vitamin D for 7 years had no effect on the incidence of colorectal cancer among postmenopausal women in the WHI.[165] These results suggest that calcium inhibits colon carcinogenesis at early but not late stages.
Additionally, in a double-blind, randomized, placebo-controlled trial of selenium supplementation for skin cancer prevention, a secondary analysis showed that the numbers of colon, prostate, and lung cancers were found to be reduced by 50% in the treatment arm.[166] The results of additional randomized trials are pending and should become available in the next 3 to 5 years.
Study of the effects of micronutrient supplementation on the formation of polyps and colorectal cancers is difficult, given the inherent complexity of carcinogenesis. Understanding how various dietary components inhibit carcinogenesis will be instrumental to the development of novel dietary-derived chemopreventive agents in the future. Factors such as type of micronutrient, dose, and duration of treatment, as well as cohort demographics (age and geographic location), and endpoints (polyp formation, or changes in the incidence and mortality of invasive cancer) are all important variables that will affect trial results. However, despite these difficulties in study design, analysis, and interpretation, we should not dismiss the large amount of epidemiologic evidence and supportive experimental data demonstrating that the consumption of diets rich in fruits and vegetables, but low in fat, have a lower incidence of bowel cancer and cancer in general.[167] Observational and animal studies suggest that reduction of caloric intake and moderate physical exercise should also decrease the risk of colorectal cancer.[168] Meat consumption—particularly red meat that has been processed, has been associated with increased risk of colorectal cancer in numerous epidemiologic studies. Substances in meat that have been implicated in colon carcinogenesis include the known carcinogens: heterocyclic amines (formed in meat during cooking), polycyclic aromatic hydrocarbons and N-nitroso compounds (both found in processed meats), and the amino acid arginine (i.e., a key substrate of the polyamine synthetic pathway).[169] [170] [171] [172] Research from clinical trials should provide us with invaluable data on which to base dietary and lifestyle recommendations for the prevention of colorectal cancer.
There are also abundant scientific opportunities to explore the role of nondietary chemoprevention compounds in controlling colorectal cancer based on substantial studies of colon carcinogenesis (see review[173]). Some of the more active nondietary compounds being studied include NSAIDs and DFMO. Mechanistic studies indicate that epithelial regeneration and focal inflammation may be important early changes in the pathogenic process, [139] [173] so that the use of nontoxic antiproliferative and anti-inflammatory agents as chemoprevention agents has a strong rationale. These biologic features of colon carcinogenesis are also used to support a role for probiotics and prebiotics for the prevention of colorectal cancer.[174]
A considerable amount of experimental and epidemiologic evidence exists to support the use of NSAIDs to decrease the risk of colon cancer.[173] These compounds exert their antiproliferative effects on colonic cells through inhibiting prostaglandin synthesis by reversibly binding to cyclooxgenase as well as through several other newly discovered mechanisms. Laboratory studies have consistently demonstrated that NSAIDs can inhibit chemically induced and transplanted tumors in rodents. The interpretation of epidemiologic trials involving NSAIDs is challenging because of differences in design and methodology, including the particular agent chosen, the dose, frequency, and duration of use, and variable follow-up periods. Nevertheless, most case-control and cohort studies have demonstrated an association of a reduced risk of colon cancer with increased consumption of NSAIDs.
Analyses of subgroups of patients who routinely take these drugs—such as patients with rheumatoid arthritis (aspirin), inflammatory bowel disease (sulfasalazine), and FAP (sulindac)—have reported a decrease in either adenomatous polyp formation or the development of colorectal cancer. A particularly important study was the Nurse's Health Study, which used three consecutive questionnaires to determine the rate of colorectal cancer among women who consumed aspirin and compared these rates to women who reported no aspirin use.[175] After at least a decade of regular aspirin use, at doses similar to those recommended for the prevention of cardiovascular disease, aspirin consumption was found to reduce the risk of colorectal cancer substantially. Both celecoxib and sulindac have been shown to cause regression of polyps in patients with FAP. [176] [177] Sulindac was not effective in preventing the development of new polyps in these patients, however.[178]
The results of several large randomized trials using NSAIDs have been reported. [168] [179] [180] Aspirin has uniformly reduced the recurrence of adenomatous polyps by 25% to 35% in patients at moderate risk with acceptable toxicity. Studies with COX-2 selective inhibitors have produced an unusual conundrum. Several randomized trials have demonstrated substantial benefit with a 40% to 50% reduction in recurrence of adenomas; however, cardiovascular events were markedly increased in the treatment arm. [62] [63] These results have put a significant damper on the development of chemoprevention agents for cancer. Whether similar adverse results will be seen with less selective NSAIDs (e.g., sulindac) is unknown and awaits the results of ongoing trials.
DFMO has been found to be a potent inhibitor of carcinogenesis in experimental animal models by reducing the number and size of adenomas and carcinomas. This drug exerts its effects by irreversibly inhibiting ornithine decarboxylase, the first enzyme in the polyamine synthesis pathway. Suppressing intracellular pools of polyamines decreases cell growth and interferes with the process of carcinogenesis in essentially all animal models. We have reported the results of a long-term clinical trial, which serially measured the effects of different doses of DMFO on rectal mucosal polyamines over a 12-month time period and demonstrated consistent suppression without side effects.[57] Demonstration of a dose of a chemopreventive agent that has a substantial biochemical effect without producing clinical side effects is an important goal. Currently, we are studying the prevention of adenomas in patients that have undergone polypectomies for adenomatous polyps. DMFO will be given in conjunction with sulindac over a 3-year period, and its effect in reducing polyp recurrence is being studied in a randomized, placebo-controlled trial.
The role of tertiary prevention in colorectal cancer has been little explored. As effective chemoprevention agents are developed, the group of patients who have been "cured" by standard therapy should become a focus of investigation, because the incidence of second primary colon cancers is high (about 25%).[181]
Integration of Prevention Activities
Several approaches exist to prevent the development of colorectal cancers. Successful primary prevention depends on public education and counseling about behavioral and dietary modifications that can be made to decrease an individual's risk, including increased physical activity and reduction of total calorie intake. In patients with adenomatous polyps, polypectomy is a useful preventive measure. Patients with FAP or HNPCC might require colectomies at a younger age to prevent development of cancer. New advances in genetic testing will help to select people who not only need closer surveillance but also might benefit from surgical treatment before cancer or premalignant polyps develop.
More vigilant screening in individuals at increased risk for the development of colorectal cancer is reasonable, but the appropriate screening tests, and the optimal interval between tests, require further clarification. More important, given that the majority of cancers occur in patients without a family history, everyone probably should be screened beginning at 50 years of age. Clinical applications of chemoprevention with DFMO, NSAIDs, and various micronutrients are still under development but may offer important alternatives for the future or as part of an overall approach to prevention ( Fig. 26-5).
Figure 26-5 Routine screening and early detection for colorectal cancer and its prevention. *There is a growing consensus that a colonoscopy should be performed at age 50 and all polyps removed. If negative, repeat about every 5 years. If positive, repeat in 3 years. If there is a familial tendency, start 5 years before age of youngest family member with disease.
The morbidity and mortality from breast cancer remains high despite significant advances in our understanding and management over the last several decades. Therefore, prevention and early detection have become important challenges for the medical community. In addition to an enormous health benefit, several billion dollars would be saved annually if breast cancer were prevented and/or the disease were detected at an earlier stage. The widespread use of screening mammography, the increasing recognition that breast density is a major risk factor, the identification of high-risk individuals based on family history, the detection of deleterious mutations, and the "proof of principle" that tamoxifen and raloxifene can reduce the risk for breast cancer all anticipate more effective early management of this disease.
Primary prevention depends on our ability to identify individuals who are at increased risk for the development of breast cancer.[182] Although many risk factors cannot be changed, knowledge of their presence can be used to identify high-risk individuals. Age, socioeconomic class, geographic location, race, and ages of menopause, menarche, and first birth are examples of risk factors that are difficult to change but important to recognize. The incidence of breast cancer, like that of most cancers, increases with age. The majority of cases are diagnosed in women older than 40 years of age, with only 10% to 15% occurring in women younger than 40 years old and fewer than 5% occurring among women younger than 35 years of age. Affluent women and individuals born in colder climates or in the Western hemisphere also tend to have a higher incidence of breast cancer. White women have more breast cancers than black, Asian, Hispanic, or Native American women. It is of considerable interest that Hispanic and Native American women have many of the same demographic variables (obesity, high fat, and low vegetable diet) that are associated with a high incidence of breast cancer in whites, yet their incidence of breast cancer is less than half that of whites.[183] Determining whether this difference is genetically based or if it reflects some other protective dietary or environmental factor is an important issue to address. By identifying who is at higher risk for breast cancer, health professionals can then counsel this subgroup of women and their families about the risks for breast disease and various ways to modify these risks, and they can encourage enrollment into clinical trials aimed at studying novel approaches for breast cancer risk reduction.
The most important step in trying to discern who is at risk is to take a detailed personal and family history extending back at least three generations.[184] Nearly 25% of women diagnosed with breast cancer have a family history of the disease.[184] Recent advances in our understanding of the molecular biology of breast cancer have led to the identification of specific mutations that might help identify women with a hereditary predisposition to developing breast cancer and might help predict who will respond to adjuvant therapy. Medical records, including pathology reports, should be obtained whenever possible to help complete an accurate pedigree. Recall bias is a significant problem when constructing pedigrees and can profoundly influence how we counsel patients; therefore, it is important to collect documentation whenever possible. Family histories must be gathered from the maternal and paternal sides of the family. This latter step is often neglected and makes it impossible to counsel anyone in a meaningful way.
Although most cases of breast cancer are sporadic and a product of many genetic insults, approximately 5% are due to specific inherited germline mutations in the BRCA1 and BRCA2 tumor suppressor genes.[185] The estimated lifetime risk for breast cancer in BRCA1 and BRCA2 mutation carriers ranges from 55% to 85%, in comparison with the 13% lifetime risk for the general population. [185] [186] [187]Women with these mutations are also at increased risk for the development of a second breast cancer; BRCA1 mutation carriers carry up to a 65% lifetime risk, and BRCA2 carriers might share a similar risk.[187] Therefore, carriers of mutations in the BRCA genes and women with a personal or family history might benefit from prevention strategies and genetic counseling.
Genetic testing should be offered to individuals with a strong family history (breast or ovarian cancer in two or more generations), a history of multiple primaries (ovarian or breast, colon, endometrial), early age of onset of breast cancer (<35 years), or individuals of Ashkenazi Jewish descent, who carry a frequency of mutations in the BRCA genes estimated to be 2.2%. [185] [186] Approximately one out of every 300 to 800 American women carries a BRCA1 mutation; however, not every one of these women will develop breast cancer. This variable penetrance seen in BRCA mutation carriers highlights one of the dilemmas of genetic testing for BRCA gene abnormalities. Furthermore, a negative test might offer false reassurance, because it could represent a false negative. In addition, although a number of mutations in the BRCA genes have been sequenced, there are probably many more that we have not identified and for which we therefore cannot test. Practitioners should be aware of the uncertainty inherent in genetic testing for BRCA mutations and be prepared to counsel their patients accordingly.
Family history without a clearly defined genetic syndrome is also important in counseling women about their risks for developing breast cancer. [188] [189] A woman with a first-degree relative with premenopausal breast cancer carries anywhere between a 1.8- and an 8.8-fold increased risk of developing a breast cancer in the future and is at high risk for harboring a deleterious mutation. This risk decreases to 1.2- to 4.0-fold in a woman who has a first-degree relative who developed breast cancer after menopause. Having a second-degree relative with breast cancer increases a woman's risk by approximately 1.5-fold.
Hormonal Factors
Women with a long lifetime exposure to estrogen are also more likely to develop breast cancer. The risk for breast cancer increases by 20% if menarche occurs before the age of 12.[190] Furthermore, women who experience a late menopause, are nulliparous, or deliver their first child after 30 are also at increased risk. An induced abortion does not result in an increased risk of breast cancer ( Box 26-1 ).[191]
Box 26-1
* The indications for genetic testing in breast cancer and in other cancers are in rapid evolution as the true risks become better defi ned and as prevention (e.g., tamoxifen) and early detection (e.g., mammography, MRI) strategies mature.
The subject of HRT and its role in the etiology and progression of breast cancer has been among the most intensely studied in medicine. Studies evaluating the role of hormone replacement in postmenopausal women have reported contradictory results—not surprising given that many of the studies evaluated different doses, preparations, follow-up times, and different age cohorts. [192] [193] [194]Results from the WHI study (i.e., the largest prospective randomized clinical trial to address the issue of HRT on breast cancer development), however, conclusively demonstrated an increased risk of invasive breast cancer (relative risk = 1.26) among those women taking estrogen plus progestin compared with placebo control subjects.[17] Additionally, the supplementation of postmenopausal women with estrogen plus progestin in the WHI trial led to increased mammographic density and breast cancer, [195] [196] These findings have sparked an intense debate, with proponents of HRT advocating no change in prescribing habits and opponents vociferously advocating the opposite.
Compelling data in support of the aforementioned WHI results have emerged from recent epidemiologic reports indicating a sharp decrease in breast cancer incidence in 2003, particularly in estrogen receptor (ER)–positive tumors. [197] [198] This time period represents the first year after results of the WHI trial were released, with a resultant immediate 50% decrease in HRT use. The rapidity of this observed decreased breast cancer incidence supports an effect of hormone therapy on progression of subclinical lesions. These reports from the California Cancer Registry and in the national U.S. Surveillance, Epidemiology, and End Results (SEER) registry have sparked a renewed debate about the role of HRT in early breast cancer development, because it represents the first significant decrease in breast cancer incidence in the United States in more than half a century.
In contrast, the preponderance of evidence suggests that the risk for breast cancer from oral contraceptive use is very low or nonexistent. An overview of 54 epidemiologic studies evaluating the role of oral contraceptives and breast cancer found the RR of current users to be 1.24 vs. no risk for women who had not taken them for 10 or more years.[199] Thomas[200] summarized the results of five cohort studies and found that the overall risk for ever-users to be 1.06. On the other hand, in a large, matched case-control study of BRCA mutation carriers use of oral contraceptives was associated with increased risk of breast cancer in BRCA1 (overall risk = 1.20) but not in BRCA2.[201]
Oral contraceptives are used by more than 150 million women worldwide and offer a number of health benefits, including reduction in dysmenorrhea, fibrocystic breast changes, iron deficiency anemia, pelvic pain secondary to endometriosis, ectopic pregnancy, pelvic inflammatory disease, functional ovarian cyst formation, and the incidence of endometrial and ovarian cancers.[189] Women should be counseled that there could be a slightly increased risk of developing breast cancer, although some believe that the apparent increase is due to surveillance bias, because physicians examine women taking oral contraceptive pills more frequently. Supporting this viewpoint is the observation that women with breast cancer who have taken oral contraceptives in the past do not experience lower survival rates when compared with women who have not taken them. Based on these data, current prescribing practices for oral contraceptives should not be changed, although the special case of BCRA mutation carriers must be assessed carefully on an individual basis.[201]
Other risk factors associated with breast cancer, such as proliferative fibrocystic changes in the breast, sedentary lifestyle, and diet, may be used to design preventive strategies for the high-risk woman. Overall, typical or atypical proliferative fibrocystic changes of the breast are associated with a two- to fourfold increased risk for the development of breast cancer.[202] Because the clinical significance varies depending upon the degree of hyperplasia and atypia present, the Cancer Committee of the College of American Pathologists has replaced the term fibrocystic disease with fibrocystic changes.Possible treatment options for relieving symptoms related to fibrocystic changes include decreasing the consumption of foods rich in methylxanthines (e.g., chocolate, coffee, tea, and cola) or taking a supplement such as vitamin E, or medications such as danocrine, bromocriptine, or tamoxifen. Although consumption of these drugs has been shown to decrease fibrocystic changes in the breast, studies have not been done to evaluate whether these changes actually decrease the increased risk of breast cancer.
Numerous observational studies have reported on the role of diet in breast cancer development with disparate findings, whereas experimental studies are more definitive. [203] [204] [205] Many public health agencies advocate a low-fat, high-fiber diet to prevent breast cancer. Data linking diet to breast cancer come largely from international and migration studies. First-generation Japanese-American women and women who have recently migrated from Japan have risks for the development of breast cancer that approach those of Native American women.[206] Differences are seen among women from various countries as well; for example, women in Great Britain have age-standardized mortality rates of approximately 28 per 100,000 versus those of Japanese women of 6 per 100,000.[207]
The WHI study is the only randomized prospective study performed to address the role of diet in the development of breast cancer, in which women were randomized to low-fat diets or no dietary intervention.[208] In this randomized trial of a low-fat dietary intervention among postmenopausal women aged 50 through 79 years, the low-fat diet resulted in a nonsignificant 8% reduction in breast cancer incidence over an 8-year study period. However, secondary analysis revealed a benefit from the dietary intervention among women with baseline high-fat diets, and women who were strictly adherent to the intervention. Therefore, we consider these results to be promising, if not definitive data related to dietary modification of breast cancer risk. Initial data from the WHI study related to calcium–vitamin D supplementation compared to placebo among postmenopausal women revealed no reduction in breast cancer risk, although the incident breast cancers in the intervention group were smaller in size.[209]
Women of tall stature or who have high body fat and mass have higher rates of breast cancer than other women. [203] [204] [205] An increase in estrone and estradiol as BMI increases has also been documented.[210] The recognition that a hormone (leptin) produced by fat cells vigorously stimulates the growth of normal and malignant breast cells may provide an important biologic link to the phenomenologic observation.[211] Some animal studies, however, have shown that caloric restriction in general, rather than a low-fat diet per se, decreases risk of breast cancer. This effect of caloric restriction could underlie the observation that women who exercise have a lower risk of breast cancer. Another consideration is that women who exercise ovulate less frequently and therefore are not exposed to the higher levels of estrogen that normally occur in women who ovulate regularly.
Numerous epidemiologic studies suggest that alcohol has an effect on the development of invasive breast cancer. An extensive and detailed meta-analysis of the six largest prospective cohort studies addressing this issue showed that alcohol consumption was associated with a linear increase in breast cancer incidence for intakes less than 60 g/day (about two to five drinks).[212] The association was not modified by other factors, and higher alcoholic intakes (>60 g/day) were not associated with additional increased risk. Low dietary levels of selenium and antioxidants such as vitamins C and E, and β-carotene have been associated with breast cancer development and differences in survival.[213] β-carotene is the major provitamin A carotenoid and has differentiating and antiproliferative effects on a variety of cells, including mammary carcinomas. Levels of β-carotene have been analyzed in numerous studies and are lower in women with higher staged breast cancer and breast cancer in general. A case-control study from Europe, however, observed no differences in vitamin A or β-carotene levels between cases and control subjects.[214] Studies of soy intake in Singapore Chinese women are of great interest. [210] [215] Soy intake was significantly associated with lowered plasma estrone and with more favorable mammographic patterns. Recently, there has been a great interest in gene-environment interactions and studies of micronutrients in relationship to metabolic pathways, and genetic polymorphisms are likely to be informative. Among women at high risk for breast cancer for other reasons (e.g., heredity), reducing alcohol consumption should be a straightforward way to reduce breast cancer risk.
Screening and Early Detection
Secondary prevention is aimed at detecting preinvasive lesions such as ductal carcinoma in situ, lobular carcinoma in situ, or early-staged breast cancers that have the potential to be cured with limited treatment. Screening tests include the breast self-examination, the clinical breast examination administered by health care professionals, and mammography. Successful implementation of wide-scale screening programs that incorporate these techniques, followed by treatment of detected lesions, is probably responsible for most of the decline in the overall death rate from breast cancer that occurred among American women from 1989 through 1993.[216] This decline continues and probably represents both the increased use of mammography and the effectiveness of systemic adjuvant therapy. Currently, 5-year survival rates for localized breast cancers have increased to more than 98%.[78]
Although we encourage women to perform monthly breast examinations, a randomized trial indicated that this practice does not decrease overall mortality rates.[217] The most effective combination for decreasing the incidence of invasive disease is the clinical breast examination and mammography. The Breast Cancer Detection Demonstration Project showed that the sensitivity of the clinical breast examination and mammogram together was 70% to 80%, with sensitivity increased for older patients.[218] Although it is standard practice for a clinical breast examination to be performed annually, there has been a great deal of controversy surrounding the appropriate time to begin routine screening with mammograms. Randomized controlled trials of a large number of women on trials from several countries have unequivocally demonstrated a 40% decrease in mortality from breast cancer in women who have annual mammograms beginning at the age of 50.[219] Throughout the years, controversies have erupted regarding the magnitude of benefit from screening mammography. We continue to recommend the practice to women beginning at the age of 50 but encourage discussion of the risks and benefits associated with this procedure.
The opinion on routine screening in women between the ages of 40 and 49, however, is mixed.[220] Eight randomized controlled trials performed between 1963 and 1982 do not demonstrate a statistically significant difference in breast cancer mortality within 7 years after screening was initiated in women randomized to receive or not receive screening mammograms. A majority in a recent consensus panel used this information to state that there currently was not sufficient evidence to advocate routine screening mammography in women ages 40 to 49. Five of these trials, however, demonstrated a 16% decrease in mortality if follow-up continued for 10 years, prompting release of a minority report advocating routine screening in the 40 to 49 age group.[220] As the minority report highlighted, the goal of mammography is to detect preinvasive lesions, and 15% to 20% of breast cancers are now diagnosed as ductal carcinoma in situ or lobular carcinoma in situ in younger women. The minority report correctly pointed out that the risk from radiation during mammography screening was overemphasized. The U.S. Preventive Task Force has considered the issues carefully and recommends a screening mammography every 1 or 2 years for women aged 40 and older,[221] a position we favor. An important recent observation is that mammographic density is strongly associated with risk and is heritable.[222]This information should further target the premenopausal woman at higher risk for breast cancer; determination of the underlying genetic basis for breast density has now become of great interest, particularly in that the use of a postmenopausal hormone therapy was strongly associated with an increase in mammographic density in the Postmenopausal Estrogen/Progestin Interventions and WHI trials.[195] [196]
New areas that are currently being evaluated for the enhancement of primary and secondary prevention strategies include digital mammography, DCE-MRI, DCE-CT with ultrasound, PET, optical scanning, ductal lavage for cytologies and molecular testing, nipple aspirates, and blood and urine assays for growth factors and autoantibodies to oncoproteins and to tumor DNA. Validated biologic markers of breast cancer risk and/or more sophisticated screening modalities might well increase our ability to detect lesions earlier in high-risk populations.
Successful therapeutic prevention for breast cancer has progressed faster than for any other malignancy.[223] Two compounds, tamoxifen and raloxifene, which are estrogen receptor antagonists, have been shown to reduce the incidence of primary breast cancer in women at high risk. [224] [225] In a head-to-head randomized trial of tamoxifen and raloxifene, efficacy was comparable with a 50% reduction of breast cancers; the toxicity of raloxifene was considerably less than that of tamoxifen.[226] Based on the positive activity of anastrozole (an inhibitor of estrogen synthesis) in the adjuvant setting and its minimal toxicity,[227] a randomized trial of this compound versus raloxifene in women at high risk for breast cancer is now underway. Preclinical studies at our institution using a transgenic mouse model suggest that antiprogestational agents may be of particular benefit in BCRA1-positive breast cancers.[228] The pros and cons of chemoprevention for breast cancer were recently reviewed, and the overall conclusion was that it cannot yet be recommended for general usage but should be useful for reduction of risk among high-risk individuals.[229]
There are several other options for a woman who is at very high risk for breast cancer, including bilateral mastectomy or oophorectomy and lifestyle modification. Prophylactic bilateral mastectomies have been performed on some mutation carriers, but cases of breast cancer developing in the remaining breast tissue after subcutaneous and total mastectomies have been reported. In addition, such surgeries are dramatic procedures for a woman who has only a "probability" of developing breast cancer, and a decision analysis paradigm for these interventions is available.[230] No long-term data exist on the effect of these surgeries in increasing the life expectancy of mutation carriers, yet one meta-analysis reveals considerable global variation in the utility of prophylactic surgery among unaffected BRCA1 and BRCA2mutation carriers.[231] Bilateral oophorectomy has been proposed as another option for premenopausal women who have completed their childbearing. Although castration has been shown to decrease the risk of breast cancer in young, nulliparous women, especially when it is performed before the age of 35, this remains a very controversial area in the management of breast disease. Secondary prevention can be accomplished by instructing these high-risk women about the importance of clinical breast examinations by a physician and screening mammograms, which should begin at a younger age, preferably at least 5 years earlier than the age at which the relative developed breast cancer. Observational studies and initial clinical trials suggest that moderate physical exercise and control of obesity may decrease the risk for breast cancer, [232] [233] [234] as has been suggested for colorectal cancer. Recently, several randomized interventional trials have been initiated to definitively address these issues.
The age-adjusted incidence of prostate cancer rose slowly from 1965 to 1985 for unclear reasons. Parallel with aging of the baby-boomer population, the prevalence has also markedly increased since the general recommendation in the late 1980s by the American Cancer Society and the American Urological Association of yearly screening for PSA after age 50. This recommendation led to widespread screening and a rapid increase in the incidence of prostate cancer that peaked in the early 1990s.[235] In the most recent national estimates using SEER data from 1999 through 2003, the age-adjusted incidence of prostate cancer was 165 cases per 100,000 individuals—the highest rate of any cancer type among men.[12] Major differences in the incidence of prostate cancer are observed across the major U.S. ethnic groups, with blacks having the highest incidence rates (243 per 100,000) and Asian-Pacific Islanders having the lowest incidence rates (104 per 100,000). Overall, 234,460 cases of prostate cancer are expected in the United States in 2006, along with 27,350 deaths—making prostate cancer the third deadliest cancer in men after cancer of the lung and colorectal cancer.[78]
Several factors—age, familial/genetic, environmental, and hormonal—seem to contribute to the development of prostate cancer.[236] Prostate cancer shows a familial tendency that is currently not well defined, but at least one study suggests that 10% to 15% of cases could have a strong genetic component.[237] The loss of heterozygosity in certain chromosomes in prostate cancer suggests that a gene related to some prostate cancers will be found.[238] The existence of a locus in chromosome 1 (band q 24) that predisposes men to develop early-onset prostate cancer has been verified, but a gene has not yet been isolated.[239]
The androgen dependence of prostate cancer led to the interesting hypothesis that variations in transcriptional activity by the androgen receptor regulated by CAG repeats could determine risk. Subsequent findings, however, argue against such an association, although there may be specific underlying situations in which other genotype influences lead to such an effect.[240] Because these studies concentrate on identifying prostate cancer risk and most prostate cancers are not clinically significant, others have argued for identifying genotypes that are associated with clinically aggressive cancers that predict outcome (mortality). In this regard, a report documenting extensive mitochondrial mutations in primary prostate cancers might provide new insights into progression.[241]
Both epidemiologic and experimental data suggest that hormones, particularly testosterone, play a definitive role in the development of prostate cancer. In the rat model, testosterone induces prostate cancer, and in humans prostate cancer rarely occurs in castrated men. [242] [243] Also, black men have a higher incidence of prostate cancer at all ages than white men, and Japanese men have the lowest incidence.[244] [245] Whether this racial-ethnic variation in prostate cancer risk has a hormonal basis is still unclear, but a substantive amount of data supports this viewpoint.[245]
A high-fat diet and obesity may be associated with an increased risk of prostate cancer, but the studies to date have yielded inconsistent results.[246] One investigation suggests that the preadult hormonal milieu, as reflected in attained height and childhood obesity, could have a strong influence on prostate carcinogenesis.[247] Epidemiologic, animal model, and in vitro studies indicate that n-3 polyunsaturated fatty acids, lycopene, and selenium might also be important in the pathogenesis of prostate cancer.[248] Additionally, GSTP1 has been proposed as a caretaker gene that serves to detoxify carcinogens associated with various lifestyle habits.[249]
Screening and Early Detection
The relative benefits and costs of screening for prostate cancer are currently among the most contentious issues in the medical community. [250] [251] [252] There are several major reasons why this controversy continues:
All available first-line techniques (DRE and serum PSA) have high rates of false-positive results. This leads to a relatively low positive predictive value and the unnecessary workup of many normal individuals.
The natural history of prostatic intraepithelial neoplasia (PIN), the probable precursor of prostate cancer, is highly variable, and the natural history of the disease cannot currently be predicted reliably in any one particular case or by any specific biologic or pathologic marker.
The workup of abnormal screening tests is invasive, requiring several biopsies of the prostate.
The treatment of prostate cancer produces significant morbidity and measurable mortality.
The rate of false-negative results is also high, which can produce a false level of assurance about the reliability of the screening tests ( Fig. 26-6 ).
Figure 26-6 Screening and early detection for prostate cancer.
These same five concerns regarding the use of PSA and DRE for screening also exist for their use for early detection purposes, but the consequences are mitigated somewhat, because individuals are by definition symptomatic on presentation.
The two most commonly used screening tests for prostate cancer are PSA and DRE, with transrectal ultrasound (TRUSP) reserved for patients with a positive PSA and/or DRE. Before the 1990s, yearly DRE after age 50 was the standard test used both for detection of prostate cancer and for screening. Although many primary care physicians use the DRE as part of a routine physical examination, assessment of its routine use indicates that DRE is performed in less than 50% of primary care encounters in which one would expect it to be done.[253]
A summary of the data indicates that the positive predictive value of DRE is relatively low (11% to 26%), whereas the negative predictive value (85% to 96%) is relatively high.[254] The most complete assessment thus far evaluated 811 unselected serial patients from 50 to 80 years of age who underwent DREs; 43 patients had a palpable nodule, and the positive predictive value of the 38 patients who underwent biopsy was 25%.[254] It is of great interest that 68% of the detected tumors were clinically localized, but only 30% were pathologically localized after radical prostatectomy. These data and other studies suggest that only about 20% to 25% of cases are localized at the time of a positive DRE; on the other hand, more than 25% of cases of prostate cancer are metastatic by the time a detectable palpable lump is detected on DRE. [254] [255] Although the effectiveness of DRE is probably also significantly influenced by the skill of the examiner, the proper technique can easily be taught to health workers, is inexpensive, and is relatively noninvasive. Its usage as a primary screening tool, however, has not been widely adopted, probably because of its inconvenience. Whether routine screening by DRE alone can reduce mortality from prostate cancer is unknown. With the emergence of serum PSA as the screening test of choice, it is unlikely that the specific value of DRE in reducing prostate cancer morbidity and mortality per se will ever be demonstrated conclusively.
Annual measurement of serum PSA as a screening test for prostate cancer has been adopted widely following the initial 1993 recommendation of the American Cancer Society. At the current time, the professional community remains split over the question whether serum PSA should be recommended for routine screening in men older than age 50. The issues have been presented and analyzed extensively, and the same arguments that are used to discourage routine screening are used by others to recommend its widespread use. Estimates of overdiagnosis of clinically insignificant lesions have ranged from 15% to 84% in well-done investigations. [251] [252]
Several studies have demonstrated that PSA screening results in a stage downshift and increases the detection rate of early-stage cancers. [256] [257] The false-positive rate (25% to 50%) is high, however, resulting in a positive predictive value of PSA in screening studies of about 30%. Because most of the studies have been done on symptomatic men, the positive predictive values in a true screening effort are likely to be lower (i.e., due to an expected lower prevalence of disease). In practical terms, this observation means that less than one-third of men with an elevated PSA will have biopsy-proven prostate cancer, and two-thirds will have a biopsy result that is negative for prostate cancer. Even if biologically aggressive tumors (and this is unlikely in most cases) were being identified (see the discussion later in this chapter), a large number of men would undergo unnecessary prostate biopsies with the attendant fiscal cost and morbidity.
Because the value of a "normal" level of PSA (<4 ng/mL) is influenced by several physiologic parameters, there has been a great interest in enhancing the specificity of the test. Techniques to improve the positive predictive value of PSA have included using age-adjusted reference ranges, PSA density (PSA level/size of prostate as measured by ultrasound), PSA velocity (change in PSA per unit of time), and ratio of bound to free PSA. [258] [259] Although the validity of these strategies is currently unconfirmed, modeling has been important in determining the most effective use of tumor markers in other diseases, and it is likely that with enough time and information, the rate of false-positive results with PSA screening can be reduced. One way to reduce the false-positive rate is to combine PSA screening with DRE, and when appropriate, with TRUSP. A positive DRE increases the likelihood that a positive (i.e., abnormal) determination PSA is a true positive and therefore enhances the positive predictive value of the test. Additional evaluations with TRUSP should further increase the positive predictive value. The prostate component of the large, multicenter, randomized, controlled PLCO Cancer Screening Trial is expected to contribute significantly to our understanding of the value of PSA and DRE screening on mortality among men aged 55 to 74 years. In this study, the intervention arm receives screening examinations at scheduled intervals, but clinical management of these results are left to the individual study clinicians. However, such mortality data are not expected until the year 2015.
Initial reports addressing the rate of diagnostic procedures performed from the PLCO have emerged. At baseline through the year 2000, 4801 men with positive PSA (i.e., >4 ng/mL) or DRE were identified.[260] Among the 2717 men with elevated PSA, 64% received biopsy within 3 years, and among men with positive DRE and negative PSA only 27% underwent biopsy within 3 years. As might be expected, higher biopsy rates were noted for those with PSA above 7 ng/mL as compared with those whose PSA level was 4 to 7 ng/mL. Follow-up data regarding mortality, and also the positive predictive value for PSA, DRE, or both among different demographic strata are not yet available but are expected to assist greatly in our understanding of the utility of these commonly used screening tests.
The second major obstacle to the successful use of any screening modality for prostate cancer is that the biologic aggressiveness of PIN and early prostate cancer is not identified with high reliability by serum PSA. Progressive prostate cancer is a serious disease with high morbidity and mortality; however, not all prostate cancers are serious, and indolent behavior is more common than not. For example, about 30% of men over age 50 have histologic evidence of prostate cancer at routine autopsy, suggesting a prevalence of prostate cancer of about 9 million.[261] About 1.2 to 1.5 million of these 9 million men, or about 15%, will eventually die of their disease. Thus, most prostate cancers in the population are latent and do not progress to clinical adversity; therefore, an aggressive workup of an elevated PSA should not be a reflex action.
A third major consideration in evaluating PSA as a useful screening test is that the subsequent workup and treatment have a significant complication rate. Follow-up testing of an elevated PSA requires a repeat PSA, DRE, TRUSP, and biopsy. These are relatively safe procedures, but about 0.1% to 0.4% of the 20% of screened men who undergo biopsy experience infection or bleeding, and almost all experience considerable anxiety while waiting for the results. [262] [263] The potential complications of treatment can be quite serious and include impotence, incontinence, and death from radical prostatectomy. Adverse outcomes of radical prostatectomy have been compared with watchful waiting in a randomized clinical trial. In this study, erectile dysfunction (80% vs. 45%) and urinary leakage (49% vs. 21%) were more common among patients who underwent radical prostatectomy; however, symptoms of urinary obstruction were improved (28% vs. 44%).[264] Radiation therapy is no less benign, but it carries a lower incidence of incontinence, a higher incidence of acute gastrointestinal complications, and a similar incidence of impotence.
A fourth major issue in PSA screening is the high rate of false-negative results. Numerous studies have demonstrated that many individuals (25%) with a normal PSA level have disease beyond the prostate.[265] Such results can lead to false reassurances and decreased follow-up when other factors suggest that a more aggressive workup might be reasonable. Several studies suggest that a rising PSA, even in the normal range, is a cause for concern and reason enough to biopsy. [266] [267]
Although serum measurement of PSA has been widely adopted in men over age 50 as a primary screening tool for prostate cancer, its value in improving the overall health of men has not been shown to date. The equally important issue of whether screening does more harm than good also remains unanswered, because the natural history of prostate cancer is so variable.[265] Decision analysis has been used to determine the benefits and risks of age- and quality-adjusted survival, but the results remain inconclusive. [268] [269] Other studies suggest that screening might have the potential to decrease survival, particularly in the older individual.[269] There is, of course, no lack of critics of this viewpoint.[270] What information is needed to resolve this difficult and important issue? Perhaps only a series of randomized trials can lay this question to rest, and to this aim, the prostate component of the PLCO Cancer Screening Trial may provide answers to these important questions. The results of a randomized trial involving more than 40,000 men in the city of Quebec have been reported, and those subjects with a regular PSA screening had a 60% decrease in mortality from prostate cancer after 7 years.[271] The conduct and interpretation of this type of trial is complex, and the results of several other large screening studies will have to be available before definitive recommendations about the value of routine screening PSA can be made.[272] These targeted trials, however, will provide only a general guide regarding population-based screening using serum PSA in men over age 50 as an approach to identify potential prostate cancers. The current consensus by the U.S. Preventive Services Task Force is that the evidence is insufficient to recommend for or against routine screening for prostate cancer using PSA.[272]
An equally important issue is this: How do we identify and distinguish a biologically aggressive tumor in any one individual from those that will remain latent for the life of the individual? This is a very difficult problem to study. Although the earliest features of prostate cancer pathogenesis remain obscure, recent studies of the biologic features of intraepithelial hyperplasia of the prostate and of the "normal" prostate in individuals with a strong family history could shed some light on this issue. [272] [273] [274] Recent studies of the cytogenetic and molecular alterations in high-grade PIN have indicated that loss of heterozygosity is prominent and that certain oncogenes are expressed.[274] Defining the biologic features of the preclinical phase of prostate cancer is critical to answer for innumerable reasons, not the least of which is to increase the effectiveness of PSA screening. In this regard, a large, randomized trial of men with T1b, T1c, or T2 prostate cancer demonstrated that radical prostatectomy was superior to "watchful waiting" in terms of disease-free survival but not in terms of overall survival.[275]
Although the development of rat prostate tumors has been studied for some time, this model system has been regarded as a poor one for carcinogenesis of the human prostate. The development of transgenic models that simulate the human disease represents an improvement in this regard.[276] Epithelial changes, including PIN, were identified in the human prostate long ago, although only recently have the biologic (and clinical) implications of these changes been recognized. The importance of these alterations, the recognition of the analogous evolution of the process to other epithelial cancers (e.g., cervical, oral), and its association with a wide spectrum of biologic abnormalities has moved PIN into the forefront as the probable, but clinically uncommon, preneoplastic precursor of prostate cancer.[276] An impressive array of studies measuring various biologic and molecular parameters in PIN have been done, and various biologic changes associated with the progression of prostate cancer have been identified.[277] What should be done now is to relate these biologic findings to the clinical aggressiveness of PIN and/or the eventual outcome of clinically relevant (nonindolent) prostate cancer. To be able to do so will help guide the difficult decisions after detection of an elevated serum PSA in biopsy samples during the screening and/or identification of PIN and during the early detection process. Three major categories of chemoprevention agents are being currently considered: inhibitors of proliferation, hormonal modulators, and stimulators of differentiation.
Thus far, two definitive randomized trials have been launched. The results of a phase III study using the 5a-reductase inhibitor finasteride (thereby lowering levels of dihydrotestosterone, the active metabolite of testosterone) in a high-risk population has been reported. The incidence of prostate cancer was decreased about 25%, and the side effects were minimal.[278] However, conclusions about the overall benefit were compromised by the finding that the risk for higher grade tumors was increased in the treatment arm. Although a large number of explanations have been offered for these contradictory findings, the future of finasteride as a therapeutic agent for prostate prevention is uncertain.
A second trial uses selenium, vitamin E, or both. The rationale for the study was based on secondary analyses of several large intervention trials in which prostate cancer was not the target, although recently some supportive experimental data also have become available. [279] [280] Accrual to this 2 × 2 factorial randomized trial (vitamin E, selenium) is ongoing, and results are anticipated in 2013. A large number of compounds are being investigated at the preclinical level, and a few have advanced to the phase I/II clinical level. Studies of fenretinide failed to show an effect on relevant surrogate markers, whereas DFMO was more successful. [273] [281]
Two other relatively unexplored areas of chemoprevention research in prostate cancer should also be mentioned: PIN and familial risk. Just as understanding the biology of PIN will affect our screening and early detection decisions, PIN should also serve as a useful marker in chemoprevention studies. Although the heterogeneity of lesions will make interpretation of effect of an intervention a challenge, PIN represents an important parameter for advancing our knowledge of early prostate cancer carcinogenesis and its modulation by candidate chemoprevention agents. Several studies are in progress to use PIN as a screening tool for new chemoprevention agents including studies of biologic markers to determine risk.[282] The roles of family studies and genetics in identifying individuals at high risk for prostate cancer are in their infancy, but epidemiologic studies support the notion that genetic risk plays a role, and clinical studies support the observation that early prostate cancer in some individuals is highly aggressive, whereas in others it is indolent. Linking these two parameters should identify a population of individuals in whom screening, early detection, and chemoprevention agents should be intensively directed.
Advances in the systemic therapy of advanced prostate cancer have been slow in coming. In a real sense, advances in the management of prostate cancer have been minimal since the introduction of hormonal therapy more than 50 years ago. It is likely that the widespread use of screening and early detection with an appropriate follow-up will reduce the morbidity and mortality from prostate cancer in a substantial way and that effective chemoprevention will be developed, because the major biologic enhancer (androgens) of prostate cancer carcinogenesis is known.
Each year, more than $2 billion is spent to treat patients diagnosed with skin cancers, the majority of which are malignant melanoma and basal and squamous cell carcinomas. These figures underestimate the true cost, because many of these cancers are treated in physicians' offices, and nonmelanoma skin cancers are not routinely reported to tumor registries. An aging population, depletion of the stratospheric ozone layer, and increased recreational exposure to ultraviolet radiation (UVR) represent some of the factors that contribute to the development of over 1 million cases of nonmelanoma (basal and squamous cell carcinomas), 49,000 cases of melanoma in situ, and 62,000 cases of invasive melanoma diagnosed annually in the United States.[78] Understanding how these and other risk factors lead to alterations in key cellular processes like DNA synthesis and repair, oncogene activation, cell-cycle control, and apoptosis is the focus of intense research efforts aimed at designing novel preventive, diagnostic, and treatment strategies.[59] This section details the various primary, secondary, and tertiary preventive approaches for melanoma and nonmelanoma skin cancers. Incorporating these strategies into medical practice should decrease the incidence and mortality from skin cancer and should also decrease health care costs.
Etiology and Primary Prevention
Successful primary prevention depends on the ability to identify individuals at risk for skin cancer and to use this information to educate both high-risk groups and the general population about various ways to reduce risk ( Table 26-5 ). Many factors have been identified that increase an individual's risk for the development of melanoma and nonmelanoma skin cancers. Exposure to UVR is a major risk factor.[283] Not only is cumulative UVR exposure important in the development of skin cancers, but it is apparent that acute, intermittent exposure to UVR is carcinogenic.
Table 26-5 -- Predisposition and Risk Factors for Skin Cancer
The electromagnetic spectrum is composed of infrared, visible, and UV light; the latter is responsible for causing the cellular and architectural changes in the epidermis and dermis that lead to photoaging and skin cancer.[283] Although the UVR spectrum is broad, UVR-β (290–320 nm) and UVR-A (320–400 nm) are the only wavelengths that routinely reach the earth's surface, in that shorter wavelengths (UVR-C) are absorbed by the ozone layer. UVR-β is more potent than UVR-A in inducing neoplastic transformation in epidermal keratinocytes and melanocytes, which give rise to basal and squamous cell cancers, and melanoma, respectively. UVR-A, however, has been found to penetrate the skin more deeply and is the predominant wavelength emitted from artificial lamps found in tanning salons.[283] More than a million adolescent and young women frequent these facilities daily and expose themselves to up to five times the amount of UVR that is emitted from the sun at any given time. The role of UVR-A radiation in the development of skin cancer will increase as this industry continues to grow.
The mechanism of action of UVR on the skin has been studied extensively. Once photons penetrate through the stratum corneum, they are absorbed by cellular DNA and produce base substitutions in pyrimidines.[284] The substitution of thymidine for cytosine is pathognomonic for UVB-induced skin damage and is found in the tumor suppressor gene p53 in more than 90% of squamous cell skin cancers. [285] [286] Basal cell cancers also contain p53 mutations.[287] Although UVR is regarded as contributing to the pathogenesis of melanoma, these types of mutations are uncommon, therefore raising the likelihood that the role of UVR is associative or complementary to the process. Normally, p53 acts to protect damaged cells by either inducing cell-cycle arrest (so that mutated DNA can be repaired or excised) or by inducing apoptosis.[288] UVR-induced p53 mutations disturb the cell cycle by inhibiting cyclin-dependent kinases, leading to uncontrolled cell proliferation. Cells with one mutated p53 allele can undergo clonal expansion, and, if the other p53 allele is mutated, neoplastic transformation occurs. Therefore, UVR could both initiate and promote carcinogenesis.[288] UV light might also have immunosuppressive effects by interfering with the ability of Langerhans cells to process antigens.[289]
Other risk factors that increase susceptibility for the development of skin cancers include skin complexion and response to sunlight, degree of freckling, ethnicity, gender, age, geographic location, presence of premalignant skin lesions, medical history of exposure to ionizing radiation or psoralen and UV therapy, chronic skin irritation (ulcers, inflammation, or trauma), or a personal history of a germatodermatoses (xeroderma pigmentosum, nevoid basal cell carcinoma syndrome, and familial dysplastic nevus syndrome), lymphoreticular malignancy, granulomatous diseases, or other immunosuppressed states such as organ transplantation in which development of multiple cutaneous squamous cell carcinomas is a major problem.
Health care providers should be aware of several premalignant dermatoses for the purpose of identifying individuals who are at increased risk for the development of skin cancers. The most common lesion, actinic keratoses (solar keratoses), has been reported to undergo malignant transformation to squamous cell cancer in 12% of patients.[290] Histologic evaluation of white patches occurring on mucous membranes, known as leukoplakia, is also important, because up to 20% could be dysplastic, with 3% to 6% becoming invasive cancers. Atypical and dysplastic nevi, large congenital nevi (>9 cm), and an increased number of moles are common precursor lesions of melanoma.[291] Chronic skin irritation from radiation (radiation dermatitis), chemicals (tar and arsenical keratoses), infrared light (thermal keratoses), and scars (scar keratoses) might also lead to malignant transformation. Any patient who is immunosuppressed (human immunodeficiency virus [HIV] diagnosis or transplant recipient) or who has a history of epidermodysplasia veruciformis or Bowen's disease (an intradermal carcinoma that often occurs on sun-exposed areas) should be considered for prevention protocols. Anyone who has a prior history of skin cancer is also at risk for a second primary cutaneous malignancy. [292] [293] Patients diagnosed with thin melanomas (<75 mm in thickness; Breslow staging) were found to have a 4% chance of developing a second primary melanoma.[294] First-degree relatives of skin cancer patients also carry an increased risk.[292]
Recently, a risk model for melanoma risk has been proposed using data from a case-control study, based on similar methodologies developed by Gail for the breast cancer risk model developed nearly 2 decades ago. [295] [296] This melanoma risk model incorporates subject responses to simple questions about complexion, history of blistering sunburn, and ability to tan, with findings on examination of the back describing the number of small and large nevi. This risk model captures attributable risk for melanoma development of 86% for men and 89% for women. Though promising, further risk models are still needed for individuals with a history of melanoma or nonmelanoma skin cancer, or persons with a first-degree relative with melanoma. Such models could identify high-risk individuals who could be referred for chemoprevention trials.[297]
Several molecular abnormalities have been identified that could be responsible for the genetic instability preceding the development of invasive nonmelanoma skin cancers ( Table 26-6 ). Defects in DNA repair genes, oncogenes, and tumor suppressor genes, as well as allelic losses in a number of chromosomes, have been described.[287] Mutations in the Ras oncogene have been shown to initiate epidermal skin cancers.[298] Mutations in DNA repair genes (xeroderma pigmentosum, for example) bring about an inability to repair UVR damage to DNA efficiently, leading to the development of melanoma and epidermal skin cancers.[299] DNA repair capacity might be particularly important for individuals with other strong risk factors, such as low tanning ability and the presence of dysplastic nevi.[300] There are numerous examples of specific chromosomal abnormalities in nonmelanoma skin cancers. Allelic losses have been found in 9p, 13q, 17p, 17q, and 3p in squamous cell cancers and in 9q in basal cell cancers.[298] Studies of keratinocyte transformation have also focused on the UVR-mediated phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase pathways.[301]
Table 26-6 -- Molecular Determinants of Carcinogenesis in Skin Cancer
The genes and genetics of melanoma have been summarized.[302] One autosomal dominant syndrome that markedly increases an individual's lifetime risk for melanoma is familial dysplastic nevus syndrome. Melanoma in one or more first-degree relatives and the presence of a large number of moles (between 10 and 100) are required to diagnose this syndrome.[303] Rearrangements or deletions of genes have been found to occur in chromosomes 9 and 10 in patients with familial melanoma, atypical nevi, or early melanoma lesions. Two cyclin-dependent, kinase, tumor suppressor genes have been isolated on chromosome 9 (p15, p16). Mutations in this region lead to uncontrolled cell proliferation, because the transition from G1 to S of the cell cycle is no longer inhibited.[304] The finding that the penetrance of one of these genes to frank melanoma is dependent on geographic variation emphasizes the role of environment in genetic expression[305] and the potential interaction of UVR and sunburn genotype.[306] Certain polymorphisms in the melanocortin-1 receptor gene have been shown to correlate with a reduced response to melanotrophin, the major natural hormone that regulates cutaneous pigmentation.[307] Other studies suggest that loss-of-function mutations in the MCIR gene sensitize human melanocytes to the DNA-damaging effects of UVR, which could increase melanoma cancer risk.[308]
The identification of frequent RafB mutations in both melanomas and benign moles is also of great interest and suggests that this alteration may be the initial molecular change leading to immortalization.[309] Once the significance of the genetic abnormalities in causing nonmelanoma and melanoma skin cancers is understood, we might be able to incorporate this information into new risk models to identify high-risk individuals who would benefit from prevention protocols and increased surveillance.
Preventive Measures
Numerous examples of primary preventive strategies exist. Protective clothing (hats, long sleeves, special fabrics approved by the U.S. Food and Drug Administration), behavioral modification (avoidance of peak sun from 10:00 am to 3:00 pm, avoidance of sun tanning salons, and use of appropriate shading), and liberal application of sunscreens are three such examples.[310] There are two types of sunscreens: blockers and reflectors. Blockers such as paraminobenzoic acid absorb UVR-β only. Nonparaminobenzoic acid blocker sunscreens absorb both UVR-A and UVR-B. Reflectors such as zinc oxide completely reflect UVR light. The SPF, or sun protective factor, is a measure of the comparison of the minimal erythema dose with and without sunscreen and should be at least 15. Finally, sunscreens should not wash off easily when bathing or sweating.
The current role of sunscreens in preventing skin cancer is the subject of considerable controversy.[311] Randomized trials have demonstrated that sunscreen use encourages prolonged sun exposure.[312]Another randomized study, however, has shown a protective effect of sunscreen use against the development of squamous cell cancer and nevi.[313] Based on these findings, we probably can conclude that regular sunscreen application should be combined with protective clothing to reduce the long-term risk for the development of melanoma and nonmelanoma skin cancers.[283]
In Australia, which has the highest incidence of skin cancers, other approaches have been adopted, including the passage of laws for employers to provide sun protection for employees, distribution of free sunscreens, tree planting campaigns, and public shade structures. In the United States, the Federal Trade Commission requires that protective eyewear be worn in tanning salons. In addition, signed informed consents and signs about health risks of UVR exposure in tanning salons are required. Furthermore, in Texas an adult must accompany children attending tanning salons, and parental permission is mandatory for all minors. Attitude and behavioral modification of children (and their parents) informed by education and knowledge about sun exposure and skin damage/cancer is a reasonable goal and is most effective when started at a young age ( Box 26-2 ). [314] [315]
Box 26-2
* A wet T-shirt has an SPF of 0; several companies now make clothes that are specifically treated to give a high SPF.
Screening and Early Detection
The following are essential for effective screening:
An understanding of the four characteristics of skin lesions that are suggestive of premalignant or malignant changes (i.e., the ABCDs): asymmetry, border irregularity, color variegation, and diameter (6 mm or greater)
Knowledge of important prognostic factors that should be recorded: anatomic location, ulceration, number of atypical lesions, presence of lymph nodes
Familiarity with the types and indications for the particular type of biopsy: shave biopsy, incisional biopsy, excisional biopsy, punch biopsy
Access to skilled pathologists who can comment on key histologic criteria such as thickness (Breslow staging), margins, ulceration, regression, satellitosis, angiolymphatic invasion, mitotic activity, precursor lesions, host response, and growth phase (radial vs. horizontal)
Screening for skin cancer, and in particular for melanoma, is supported by several criteria. Skin cancer is the most common cancer worldwide and is an important public health problem. Melanoma is second only to leukemia in terms of years of potential life lost, because it often affects younger people during the most productive periods of their lives.[315] Although basal and squamous cell cancers have a much better prognosis than melanoma, they cause considerable local disfigurement if not diagnosed and treated early. In addition, screening skin examinations are acceptable to both patients and health care providers. Premalignant cutaneous lesions tend to have a long latent phase, making early diagnosis and treatment possible with evidence that supports subsequent decreases in both incidence and mortality rates.[290]
Although no randomized, prospective studies evaluating the efficacy of screening for skin cancer have been conducted, nonrandomized studies support its practice. Thinner melanoma lesions (stages I and II) are diagnosed more frequently with routine screening and intensive education programs. The Sydney, Australia Melanoma Project demonstrated that widespread screening and education led to a decrease in the thickness of lesions from 2.5 mm to 0.8 mm, a decrease in the number of ulcerated lesions, an increase in the number of melanomas diagnosed in the radial rather than the vertical growth phase, and an increase in the 5-year survival rate to 94%.[316] A decrease in lesion thickness and an increase in the number of melanomas diagnosed were also confirmed in studies in Scotland and the United States.[316] [317] Interestingly, a large skin cancer education and screening demonstration project found that 80% of study participants did not have a regular dermatologist, 50% saw their physician only because of the free skin examination, and 80% were receiving their first skin examination. Another interesting population-based, case-control study investigated whether skin self-examination would reduce the incidence of melanoma.[318] Although only 15% of participants in the study cohort practiced skin self-examination, they found that skin self-examination was associated with a reduced risk of melanoma in general and a reduced incidence of more advanced disease in melanoma patients. The authors concluded that mortality from melanoma might be reduced by as much as 63% if regular skin self-examinations were performed.
New imaging technologies may play increasingly important roles in screening and early detection for skin cancers in the future. To this aim, diffuse optical spectroscopy represents an exciting new technology that is emerging. Recently, diffuse optical spectroscopy technology has been used via a hand-held probe with direct skin contact to define the optical properties of skin in vivo, including quantification of melanin, hemoglobin, and water concentrations.[319] Thus, the potential for noninvasive identification of malignant versus benign skin lesions is an anticipated application for this technology. However, the utility in accurately identifying malignant cutaneous lesions has not been described analytically, and the appropriate validation studies on melanoma and nonmelanoma skin cancers must be performed before widespread usage of this novel screening device can be recommended.
Challenges to effective screening examinations include the following:
Lack of standardization of the examination and training that health care providers receive
Lack of accurate reporting to tumor registries (for melanoma; nonmelanoma skin cancers are not reported at all)
Inability to motivate certain high-risk groups (e.g., white males) to come in for examination
An inability to screen adequately for the 1% to 2% of amelanotic cases of melanoma
One step toward overcoming these challenges has been to designate the months of May and June as free skin cancer screening months in the United States in an attempt to attract more people for evaluation.
Nonmelanoma Skin Cancers
Clinical trials investigating the use of β-carotene, 13-cis-retinoic acid, selenium, and NSAIDs have been performed on individuals with a history of nonmelanoma skin cancers. Results using vitamin A derivatives have been mixed, which most likely reflects the complex biochemical and molecular mechanisms underlying the prodifferentiation or promaturation changes that these compounds produce. Three randomized clinical trials did not find a decrease in the recurrence rates of basal or squamous cell cancers in individuals at high risk for new skin cancers. Levine and coworkers[320] found no beneficial effect when using isotretinoin or retinol in high-risk subjects with at least four prior basal cell or squamous cell cancers. The Isotretinoin–Basal Cell Carcinoma Study Group also demonstrated that isotretinoin did not prevent the recurrence of basal cell cancer in patients previously treated for basal cell cancer.[321] Finally β-carotene was not shown to prevent nonmelanoma cancers.[322] In contrast, in 2297 moderate-risk subjects with a history of actinic keratoses and at most two squamous or basal cell carcinomas, supplementation with a moderate dose of retinol (25,000 IU daily) reduced the incidence of squamous cell (but not basal cell) cancers by 25%.[23] In addition, patients with xeroderma pigmentosum develop fewer new skin cancers after receiving high-dose isotretinoin.[323] However, interest in the retinoids as preventive agents has waned, and it is unlikely that their usage will be adopted unless a new generation of nontoxic compounds can be developed.
Negative results have been produced in a large multicenter study involving selenium supplementation.[166] In this double-blind, randomized, placebo-controlled study, 200 mg of selenium daily did nor seem to prevent the development of future nonmelanoma skin cancers in patients with a history of basal or squamous cell skin cancer. A secondary analysis of the effect of NSAIDs in this trial on nonmelanoma skin cancer also suggested no effect for this class of agents.[324] Finally, NSAIDs have been found to prevent the erythema that occurs 6 to 12 hours after acute sun exposure. In a large, randomized trial, topical application of the COX-1 inhibitor diclofenac was superior to placebo in clearing actinic keratosis lesions, and this formulation has now been approved for clinical use, although recent concern about the cardiovascular toxicity of selective COX inhibitors leave its usage uncertain.[325] A small placebo-controlled study of 2-DFMO suggests that this compound might have comparable activity.[326] A comprehensive strategy for the development of chemoprevention drugs for nonmelanoma skin cancers has recently been described.[59]
Melanoma and Dysplastic Nevi
Topical β-all-trans-retinoic acid has been demonstrated to cause regression of dysplastic nevi [327] [328]; however, the inconvenience of topical application has limited its usage.
The development of chemoprevention agents for melanoma has progressed slowly, although the development of a risk model for melanoma is an important first step, as is the development of an in vitro model for assessing the potential value of chemoprevention agents. [297] [324] A great deal of new preclinical work has advanced our understanding of melanoma pathogenesis as well,[329] including a unique redox-based paradigm.[330] The recent development of a transgenic model that simulates the human disease is also an important advance and should lead to a more systematic development of chemoprevention drugs.[331]
Tertiary Prevention
Lifetime surveillance of patients who have been diagnosed and treated for skin cancer is an important component of prevention. Many studies have shown that laboratory and radiologic surveillance do not detect second primaries or recurrences beyond what is found on skin examination in patients with a history of melanoma. Patients with a history of melanoma should be evaluated every 6 months with skin and regional lymph node examinations. Particular attention should be paid to the scar of the previous excision site during these examinations. After 2 years of normal examinations, the interval between visits can be extended to 1 year. If an individual has any atypical moles, a positive family history for melanoma, or other poor prognostic factors, an evaluation (including cutaneous photography) every 3 to 6 months for the first 2 years (lengthening the interval between examinations only if the atypical moles are stable) is recommended. No recent findings have affected these general recommendations. Newer biomarkers are being explored to detect melanoma earlier, but thus far no validated successes have been reported.
Prevention of skin cancer depends on increasing the awareness of health care professionals and the public about the importance of early diagnosis and skin self-examinations. More research needs to be devoted to ways of motivating high-risk individuals to receive screening examinations. Public policy measures should be expanded and consideration given to other approaches, such as mandatory use of sunscreen and adequate clothing in daycare centers and public schools. The true measure of the various prevention strategies will come from studies of their ability to decrease both the incidence of and the mortality from skin cancers. Recent evaluations of the value of screening and early detection for cutaneous melanoma suggest that survival has been increased from 50% 30 years ago to over 85% today.
Ovarian cancer will affect an estimated 20,180 women in the United States during 2006 and is the fifth leading cause of cancer mortality among women, after cancer of the lung, breast, colorectum, and pancreas.[78] Approximately 10% of ovarian cancers are associated with a BRCA mutation, whereas the remainder are sporadic.[332] The lifetime risk of developing ovarian cancer for the general population is approximately 1.5%.[333] Advanced-stage disease (spread beyond the pelvis or FIGO stage III/IV) is present in 70% of these women; this has led to a 40% overall 5-year survival rate with low 5-year survival rates for advanced-stage disease (stage III 5-year survival, 25.1%; stage IV 5-year survival, 11.1%).[334] Hence, most women who present with advanced disease die from their disease. Therefore, prevention of ovarian cancer is an important goal. Given that 90% of all ovarian cancers arise from the epithelial lining of the ovary rather than from the germ cells or sex-cord derivatives, preventive strategies outlined in the following paragraphs pertain to the prevention of epithelial cancers.
Primary Prevention and Risk Reduction
Epigenetic Factors
Several reproductive, environmental, and genetic factors could influence an individual's risk of developing ovarian cancer ( Table 26-7 ). Advancing age is an important risk factor, in that data from SEER and the National Center for Health Statistics reveal that more than 48% of all cases of ovarian cancer occurred among women older than 65 years of age.[335]
Table 26-7 -- Risk Factors for the Development of Ovarian Cancer
Important protective reproductive factors include increased number of pregnancies, oral contraceptive use, and breastfeeding. Reanalysis of six large case-control studies involving 2768 incident cases demonstrated an overall risk of 0.66 in oral contraceptive users that continued to fall with duration of use; the effect was projected to persist for a lifetime after stopping.[336] Only a limited number of studies have examined the effect of HRT on ovarian cancer development. In the largest investigation reported thus far, a cohort study of 44,241 participants in the Breast Cancer Detection and Demonstration Project (329 cases of ovarian cancer), estrogen-only use (but not combined estrogen-progesterone) was associated with a modest increased relative risk of ovarian cancer.[337] No relationship between ovarian cancer risk and age of menarche, age of menopause, or duration of HRT has been observed in one large meta-analysis.[338] Conversely, increased risk was observed in nulliparous women who had a history of infertility. Critical analysis suggests that women with a history of infertility alone are at increased risk, and fertility drugs might not alter this risk further.[339] Tubal ligation, and to a lesser degree hysterectomy, are associated with decreased risk of ovarian cancer.[340]
A large prospective cohort study of 300,537 women (1511 deaths from ovarian cancer) showed that mortality rates from ovarian cancer were significantly increased in overweight and obese women who had never used HRT.[341] Other dietary factors, such as consumption of milk and selenium, might also modify an individual's risk for ovarian cancer, but the data are not convincing.
Finally, talc has been suggested as a possible factor leading to the development of ovarian cancer, in that epithelial ovarian malignancy shares similarities with mesotheliomas, and talc is structurally similar to asbestos, a proven cause of mesotheliomas. Cramer and associates[342] first reported this association in 1982 when they assessed genital exposure to talc in 215 white females with epithelial ovarian cancer and 215 matched controls. They reported that 92 of the patients (48%) regularly used talc, either as a dusting powder on the perineum or on sanitary napkins, compared with 61 controls (28.4%). A relative risk of 1.92 was associated with these practices in the women with ovarian cancer. In a follow-up study, researchers determined that the risk for ovarian cancer was highest in women who applied talc directly to the perineum or undergarments on a daily basis for more than 10 years.[343]
Genetic Factors
Approximately 10% of all epithelial ovarian cancers are related to genetic mutations (hereditary, familial, other rare syndromes). Women considered to have a hereditary ovarian cancer syndrome must have at least two first-degree relatives with histologically confirmed ovarian cancer. These individuals carry an overall lifetime probability of developing ovarian cancer of approximately 50%. There are three "hereditary" autosomal dominant syndromes, which include the site-specific ovarian cancer syndrome, hereditary breast and ovarian cancer syndrome, and HNPCC, Lynch II.[344] Together, these cancer syndromes account for 1% to 5% of the ovarian cancers that are diagnosed and generally occur 1 to 2 decades earlier than nonhereditary ovarian cancer.[345] The genetic linkage for the majority of the hereditary breast and ovarian cancer and the site-specific ovarian cancer syndromes has been found on the BRCA1 and BRCA2 loci on chromosome 17 (band q21). Specifically, the lifetime risk of developing ovarian cancers among BRCA1 and BRCA2 carriers is 15% to 60% and 15% to 28%, respectively.[346]
Women who report a family history of either a single first-degree relative and/or one or more non-first-degree relatives with ovarian cancer meet the definition of familial ovarian cancer syndrome. About 5% of diagnosed ovarian cancers fall into this category. Ovarian cancers can also occur as part of other rare, inherited, genetic syndromes such as Cowden's disease or Li-Fraumeni syndrome. Once individuals are identified with a familial or hereditary ovarian cancer syndrome, or a germline BRCA mutation carrier, primary preventive strategies can be implemented, including oral contraceptive pill use, risk-reducing salpingo-oophorectomy, and possibly dietary modification.
Prophylactic oophorectomy is a subject of substantial controversy. It has been estimated that 700 prophylactic oophorectomies might need to be performed to prevent one case of ovarian cancer.[347] A person's age, medical history, reproductive plans, and proximity to menopause must be considered when trying to make an informed decision. In general, postmenopausal women or women older than 50 years are encouraged to undergo this procedure, because the risk of ovarian cancer increases with age. Women who are younger than 50 but older than 40 years of age should be counseled on the risks and benefits associated with surgical menopause and subsequent HRT, and on the risks of developing ovarian cancer based on their pedigree. There are two exceptions to these rules. One is the performance of prophylactic oophorectomies on women who are being operated on for a bowel cancer, because metastases are found in 25% of cases when the ovaries are carefully examined.[347] In addition, women with one of the three hereditary ovarian cancer syndromes, and also BRCA1 or BRCA2 carriers should strongly consider risk-reducing salpingo-oophorectomy at age 35 or at the completion of childbearing. [348] [349] These women, however, should be counseled that they are still at increased risk for the development of intra-abdominal carcinomatosis, which is histologically similar to epithelial ovarian cancer but arises from the peritoneal lining. As mentioned, carriers of germline mutations in BRCA1 and BRCA2 genes should be counseled about the option of prophylactic risk-reducing salpingo-oophorectomy.[350]The recommendation is problematic, however, because there is heterogeneity in the type and number of mutations at the BRCA loci, which thus far has made it difficult to quantify an individual's risk of developing ovarian cancer. An interesting decision analysis study has been performed[351] to determine the effect of prophylactic oophorectomy on life expectancy in women with BRCA1 and BRCA2mutations. On average, a 30-year-old woman would increase her life expectancy from 0.3 to 1.7 years after undergoing bilateral oophorectomies. The analysis suggested that a woman could delay oophorectomy until she was 40 years of age with minimal loss of life expectancy.
Screening and Early Diagnosis
Early detection of ovarian cancer has not contributed to an overall improvement in survival of gynecologic malignancies.[352] Effective screening for a disease requires that the disease of interest has a premalignant phase, a long preclinical phase, stage-dependent outcome, curative treatments that are acceptable and readily available, and a cost-effective screening test that demonstrates good sensitivity, specificity, and positive predictive values. Unfortunately, the premalignant condition that progresses to invasive ovarian cancer has not been well defined. In addition, once invasive ovarian cancers develop, the preclinical phase is asymptomatic, with the result that most women present with advanced disease. Survival is not only stage dependent but also grade dependent. Primary treatment is surgical and in general is curative only if disease is confined to the ovaries. The available screening tests (pelvic ultrasound, serum cancer antigen [CA-125] levels, and pelvic examinations) are acceptable to patients and physicians but suffer from decreased specificity secondary to unacceptably high false-positive rates. Furthermore, the likelihood that an individual has ovarian cancer after a positive test (positive predictive value) is too low for available tests to be used for mass screening. In addition, screening might actually increase morbidity and mortality, because surgical exploration is the only way to diagnose ovarian cancer definitively. A decrease in mortality from ovarian cancer will occur only if we can detect early-stage disease reliably, which is not possible given available screening tests. Currently, there is insufficient evidence to support routine screening with transvaginal ultrasound and serial CA-125 serum measurements.
Specific screening tests have been evaluated both individually and together in a variety of populations. Although the pelvic examination should be included in every annual physical examination, studies have shown that it is not extremely effective in diagnosing adnexal masses.[353] CA-125 is an antigenic determinant on a high-molecular-weight glycoprotein that is recognized by a monoclonal antibody (OC125).[354] It is expressed by 82% of ovarian carcinomas and in a percentage of other normal or pathologic conditions including pelvic infections, endometriosis, pregnancy, menstruation, pancreatitis, renal failure, hepatitis, peritonitis, and congestive heart failure. Even in early-stage disease, however, CA-125 can detect only 50% of stage I disease and 60% of stage II disease.[354] Therefore, a normal CA-125 in the setting of an abnormal examination should not keep the physician from performing other diagnostic studies or surgical exploration. The real value of this tumor marker is in a premenopausal or postmenopausal woman who has a pelvic mass, particularly in the postoperative period, to measure response to treatment and progression of disease ( Box 26-3 ).
Box 26-3
Ultrasonography by itself is easy to perform, but like CA-125 measurements, it is not an acceptable enough screening test to warrant its general use. Currently, color flow imaging and measurements of pulsatility indexes are being coupled to transvaginal ultrasound to try to decrease the rate of false-positive results. Improvements in the ability to visualize both ovaries during a given examination might improve the accuracy of transvaginal ultrasound as a screening test. So might more accurate measurements of the morphologic variations that exist between ovaries, among patients, and during different periods of the reproductive life cycle of a woman.[354] Numerous studies have combined pelvic examinations, CA-125 serum measurements, and transvaginal ultrasound. Results from an ongoing National Cancer Institute–supported multicenter trial evaluating the utility of transvaginal ultrasound and serial CA-125 measurements in 74,000 women who have been randomized to either annual pelvic examinations with CA-125 measurements and pelvic ultrasonography or annual pelvic examinations without CA-125 or ultrasound evaluation will help direct future screening practices. Until improvements in test characteristics of the various screening techniques can be accomplished, multimodality screening for ovarian cancer is recommended only for women with a hereditary ovarian cancer syndrome orBRCA1 or BRCA2 mutation, although no specific studies are available to support this practice. Individuals with a strong family history that does not demonstrate an autosomal dominant inheritance pattern should be evaluated on a case-by-case basis.
Chemoprevention studies for epithelial ovarian cancer have not been performed, although the data for oral contraceptive pills suggest strongly that these agents would be effective. In addition, DePalo and colleagues[355] completed a preliminary analysis of women with T1-T2 breast cancer who were randomized to oral 4-hydroxy-fenretinamide or placebo. Six cases of ovarian cancer were diagnosed in the placebo group vs. none in the treated group (P = 0.02).[355] Long-term follow-up after the intervention phase has shown that no significant difference between the two groups was maintained once the intervention was stopped. Fenretinide and its derivatives continue to have considerable appeal, however, and further studies should clarify the role that this vitamin A derivative might play in the chemoprevention of ovarian cancer.[356] Studies in primates suggest a strong synergistic effect of oral contraceptives plus fenretinide on markers that should be associated with a reduction in ovarian cancer[357]; however, proving via a classical randomized trial whether ovarian cancer can be prevented will be difficult.
In conclusion, a great deal of work remains to be done both in establishing the etiology of ovarian cancer and in developing strategies to prevent its occurrence and reoccurrence, but the opportunities seem great.
Prevention of cervical cancer is one of medicine's greatest accomplishments. The recent demonstration of an effective vaccine against HPV, the major etiologic agent of cervical cancer, suggests that this disease eventually could become a concern of the past.[358] The U.S. annual mortality rate for cervical cancer has decreased from 26,000 deaths in 1941 to an estimated 3700 deaths in 2006, which is impressive given the twofold increase in population in the United States during the second half of the 20th century.[78] Widespread usage of Papanicolaou smear screening is largely responsible for reduction of cervical cancer from the leading cause of cancer death in American women to an uncommon one. In fact, the incidence of cervical cancer has decreased by 70% since widespread screening began in the early 1940s.
Unfortunately, these favorable statistics cannot be generalized to other countries or to certain subgroups within the United States. Cervical cancer is still the number one killer of women in underdeveloped nations, with 500,000 cases still being diagnosed worldwide every year. Despite the tremendous resources dedicated to improved screening methodologies and identification of high-risk individuals, simple visual inspection of the cervix after acetic acid application is the most effective approach in underdeveloped countries, in terms of both cost and lives saved.[359]
Primary Prevention and Risk Reduction
Numerous risk factors for preinvasive and invasive cervical disease have been identified, some of which are modifiable and others not ( Table 26-8 ). Age and race are nonmodifiable risk factors, whereas socioeconomic status and degree of immunosuppression (HIV-positive individuals, transplant recipients) are risk factors that are difficult to change. Other factors, such as sexual and behavioral risk factors—including a high number of sexual partners for a woman or her partner; early age at first coitus, pregnancy, or marriage; history of sexually transmitted diseases; HPV infection; contraceptive choice; nutritional status; tobacco smoking; and frequency of Papanicolaou smear screening—are modifiable risk factors, and areas for strategic prevention efforts.
Table 26-8 -- Risk Factors for the Development of Cervical Cancer
Sexual behavior is probably largely a surrogate for the risk of exposure to HPV.
Cervical cancer is a sexually transmitted disease. Many of the epidemiologic and behavioral risk factors are direct and indirect surrogate markers for infection with HPV. Recently the National Institutes of Health has released a consensus statement that cervical cancer is largely preventable if young people modify their sexual behavior and decrease their exposure to HPV, which is the most important risk factor for the development of preinvasive and invasive cervical disease.[360] More than 100 types of this double-stranded DNA virus exist, with approximately 50 types found in the epithelial cells of the genital tract. HPV is further subclassified into high, intermediate, and low-risk types. For example, HPV 16 and 18 are high-risk types and have been found in many high-grade, preneoplastic, and invasive cervical lesions. In contrast, HPV 6 and 11 are low-risk types and are generally found in condylomata accuminata (genital warts) or low-grade cervical lesions. Almost 90% of invasive cervical cancer specimens and more than 75% of high-grade cervical lesions have measurable titers of HPV detected by available molecular biologic techniques (hybridization or the polymerase chain reaction).[361]
The mechanism of action of HPV oncogenesis is related to viral production of the E6 and E7 proteins that bind and inactivate tumor suppressor genes such as p53 and Rb (E7) in cervical cells. [362] [363]This, in turn, could lead to neoplastic transformation. HPV DNA has been found to integrate into host chromosomal DNA in many high-grade dysplastic and invasive cancer cervical specimens but not in the majority of low-grade cervical cancer precursor lesions. In the latter, the HPV DNA tends to exist in an unintegrated, circular form known as an episome. Molecular epidemiologic studies suggesting that different HPV 16 variants have different oncogenic potential could partly explain the wide geographic variation of CIN and cervical cancer in similarly infected populations.[364]
In general, women with cytologic or histologic evidence of HPV DNA should be counseled that they are at increased risk for the development of cervical disease, even though it is difficult to provide definitive risk assessments. In addition, Koutsky and associates[13] performed two large prospective studies of women who had a normal Pap smear and found that those who tested HPV-positive had a 10- to 15-fold chance of developing a cytologic lesion compared with those who were HPV-negative.[13]
Clearly, not everyone with cytologic evidence of HPV will progress to developing a preneoplastic cervical lesion, and even fewer will progress to invasive disease. Investigators have detected HPV DNA in 6% of women of reproductive age with healthy cervixes.[365] The presence of HPV DNA in women with normal Pap smears might be as high as 40%, however, and it is estimated that approximately 10 to 20 million women in the United States have detectable HPV DNA. [366] [367] Although numerous experimental, clinical, and epidemiologic studies have established a definitive role for HPV in the development of cervical cancer, other factors such as age, contraceptive method, smoking history, degree of immunosuppression, and nutritional status probably play a role in the progression and neoplastic transformation of HPV-infected cervical cells.
The grade of the cervical lesion also influences the risk of a cervical lesion progressing to invasive cancer. Many prospective studies have documented the percentage of the different grades of squamous intraepithelial lesions that will progress to higher grade lesions.[368] Estimates indicate that it could take approximately 10 years, on average, for a preinvasive lesion to progress to an invasive cancer. Sixty percent of low-grade lesions spontaneously regress on their own without treatment, in comparison with 30% of high-grade cervical lesions. It is estimated that anywhere from 35% (CIN 2) to 56% (CIN 3) of high-grade lesions will persist.[368] Therefore, the higher the grade of the lesion, the more likely it will either persist or progress. These wide ranges suggest that other factors play a significant role in determining the eventual outcome of premalignant cervical lesions.
Differences in incidence and mortality rates of carcinoma in situ and cervical cancer have been reported across different ethnic groups. Although socioeconomic factors might be substantially responsible for the discrepancies, African Americans and Mexican Americans, especially if they do not speak English, are more commonly diagnosed with cervical cancer and ultimately will die more frequently than white women.[369] The age-adjusted incidence rates for blacks are 14 per 100,000, compared with 7.8 per 100,000 for white Americans.[370] Subsequent data from the National Institutes of Health, however, revealed that the difference in incidence of cervical cancer between blacks and whites is disappearing, which suggests that efforts to target this high-risk group are succeeding.[360] This is not the case for Hispanics, because approximately 1.6 million Hispanic women remained unscreened in the United States.
Different methods of contraception might have different effects on the development of cervical disease. Barrier methods of contraception have been found to significantly decrease an individual's risk of developing cervical cancer (relative risk ≈ 0.4).[371] Conversely, a weakly positive association has been observed between oral contraceptive use and the development of cervical disease.[372] It is difficult to conclude definitively that oral contraceptive use increases a person's risk for cervical disease because of important confounders such as sexual behavior and HPV infection.[373]
Evidence strongly implicates smoking as an independent risk factor in the development of cervical disease.[374] It has been estimated that smokers have a 4.5-fold increased risk of carcinoma in situ as compared with matched controls.[375] In a 10-year prospective study of cervical dysplasia, tobacco smoking was associated with a two- to fourfold increased risk of CIN 3 and invasive cervical cancer in those women also infected with oncogenic HPV.[376] In addition, a significant dose-response relationship has been observed in women who smoked more or for longer periods of time.[374] Elevated levels of nicotine and cotinine have been found in the cervical mucus of smokers, which could alter local defense mechanisms (such as Langerhans cells) and/or be mutagenic themselves, leading to transformation of HPV-infected cervical cells.[377]
The relationship between immunosuppression and neoplasia is strong and has been documented in several ways. Studies of renal allograft patients have demonstrated a 4- to 16-fold increase in cervical dysplasia, a 2- to 9-fold increase in HPV infection, and a marked increase in synchronous cervical, vulvar, vaginal, and anal lesions.[378] The HIV epidemic has created a large population of immunosuppressed patients at risk for the development of cancer in general. In 1993, cervical cancer was added to Kaposi's sarcoma and non-Hodgkin's lymphoma as an acquired immunodeficiency syndrome–defining malignancy based on published reports describing the development of more aggressive cervical cancers in HIV-infected women.[379] It was observed that HIV-infected women, though still asymptomatic from their disease, presented with more advanced cancers, of higher grade, and at a younger age than what was expected in the immunocompetent population.
Screening and Early Detection
The Pap smear is considered to be medicine's most successful screening test. Although it has never been subject to a randomized controlled clinical trial, this diagnostic test has been in widespread use since Drs. Traut and Papanicolaou published their findings in 1941.[380] International and regional surveys have documented decreases in both the incidence and mortality rates from cervical cancer among clinics that have widely adopted Pap smear screening. Scandinavian countries have reported reductions in mortality rates from cervical cancer by 30% to 80%, depending on the country, the duration of the screening program, and frequency of screening (Iceland, 80% reduction; Finland, 50%; Sweden, 34%).[381] Canada and the United States also have experienced similar reductions in both incidence and mortality rates. The Pap smear is an effective screening test because it can detect disease early—at a stage when it can subsequently be managed by available and effective treatments ( Fig. 26-7 ). In addition, the Pap smear is cost effective and acceptable to both physicians and patients. Currently, 50 million Pap smears are performed annually in the United States.
Figure 26-7 Routine screening and early detection for cervical cancer and its prevention.
Despite the profound impact that the Pap test has had on decreasing the incidence of cervical cancer by facilitating early detection of preinvasive lesions, its validity has been questioned periodically. General misperceptions by the media, public regulatory agencies, plaintiffs, physicians, and the community at large exist regarding the role of this screening test.[382]
Several problems have arisen regarding the Pap smear as a screening tool. A great deal of media attention has focused on screening errors that have occurred in "Pap mills," where technicians were paid according to the number of slides they could screen. Studies have reported that the false-negative rate ranges between 5% and 20% in good laboratories, suggesting that the overall sensitivity is approximately 80%. Many of the false-negative results are actually due to sampling errors rather than to screening or interpretation errors. In sampling errors, abnormal cells are either absent or unidentifiable because of inappropriate technique, unsatisfactory equipment, or difficult patient examination, making it hard to obtain a satisfactory sample. Interpretation errors occur when the health care provider fails to fill out the patient history on the cytology requisition or cytotechnologists are supervised inadequately.
New technologies to improve the accuracy of the Pap smear are emerging, but there are some concerns that these tests might be too costly for high-risk patients who need them the most (low-income, minority, or elderly women). If this new technology improves the sensitivity of testing sufficiently, however, there ultimately might be a positive cost-benefit effect through the prevention of cervical cancer. A detailed analysis of the costs and benefits of different strategies to screen for cervical cancer in less-developed countries has been presented.[383] Compared with no well-organized screening, all strategies saved lives, at costs ranging from $121 to $6720 per life year saved, and they reduced mortality by as much as 58%. The simple approach of visual inspection of the cervix after applying acetic acid with appropriate follow-up was highly cost effective ($524 per life year saved and 83% reduction in mortality) and could be a more reasonable approach in less well-developed countries or certain hard-to-reach populations in the United States.
Current screening guidelines of the American College of Gynecologists and the American Cancer Society include annual Pap smear and pelvic examinations for any woman who is sexually active and/or 18 or more years of age. After three consecutive normal Pap smears and examinations, a "low-risk" patient may increase the interval between screenings from 1 year to 3 years. A high-risk individual is anyone who has had two or more sexual partners in her lifetime, intercourse before 20 years of age, a relationship with a male with multiple sexual partners, history of an abnormal Pap smear or gynecologic cancer, or anyone who is immunosuppressed. Most American women should probably be considered to be at high risk and therefore should undergo yearly Pap smear screening until sexually inactive.
Conventional Pap smear screening has proven to be extremely effective. The success of this test and future screening modalities depends on realistic expectations about screening tests, continued quality assurance, improved sampling of cervical tissue, and the incor poration of newer technologies with a view to improving the accuracy of screening and interpretation of Pap smears. Successful implementation, however, must be cost effective and lead to further declines in the incidence of and mortality from cervical cancer. Follow-up rates for abnormal Pap smears, particularly among underserved populations, remain another barrier for successful implementation of this important test. An attempt to improve the follow-up rates for severely abnormal Pap test results in underserved populations has been performed in the setting of a randomized controlled trial.[384] Patients in the single-visit intervention arm were required to wait in the clinic until the Pap smear results were available, and then large-loop electrosurgical excision procedure was performed immediately for severely abnormal results. This single-visit intervention resulted in a higher proportion of patients with abnormal Pap results receiving a full course of therapy within 6 months as compared with those in the usual-care study arm (88% vs. 53%), with a higher rate of follow-up at 1 year (63% vs. 21%). These results demonstrate that a single-visit cervical screening program was feasible among patients in an underserved population. Adoption of such a program could help narrow the gap in cervical cancer rates for underserved and minority populations. The challenge of the next decade will be for cervical cancer screening to optimize the medical outcomes and economic costs in general and in special high-risk populations.[385]
The goal of chemoprevention of cervical disease is to prevent or delay the development of cervical cancer and its precursor lesions by interrupting or preventing the process of carcinogenesis at the cellular level. The cervix is ideally suited for clinical studies that evaluate the process of carcinogenesis, because it is easily accessible for evaluation by Pap smear and colposcopy, and in general, abnormal cervical cells progress from low-grade lesions (HPV-positive cells and CIN 1) to high-grade lesions (CIN 2, CIN 3, carcinoma in situ) over an extended period of time.
Numerous experimental and epidemiologic trials have implicated HPV in the etiology of cervical cancer, and several large randomized trials have demonstrated spectacular efficacy (100% effectiveness) of an HPV vaccine in individuals who are sexually naive and/or HPV unaffected,[13] an effect that has been sustained over the long term.[14] Based on these results, a vaccine effective against a range of common subtypes has been approved for administration to young girls. [386] [387] Epidemiologic studies of diet have suggested that low intake of several nutrients is associated with cervical cancer; however, the results of supplementation trials thus far have been almost uniformly negative, notwithstanding the experiences with topical retinoic acid and positive results from a recent randomized trial of celecoxib in which a favorable effect on high-grade dysplasia was demonstrated. [388] [389] [390] The eventual role of supplementation in late stages of the disease remains unconfirmed; clearly, continuation of smoking has an adverse effect,[391] an observation that remains important for overall cancer control.
Hepatocellular carcinoma (HCC) and stomach cancer are the number one and two causes of death from cancer worldwide.[392] With the increasing influx of Asian immigrants, these diseases have become more common in the United States as well. Over the past several years, important advances related to their control have become evident, and therefore a brief review of these findings is presented. An excellent review recently has become available.[393] The major risk factor for HCC is exposure to hepatitis B or C virus, which is typically transmitted vertically (i.e., mother to child) in Asian countries and horizontally (i.e., intravenous injection, sexual contact, blood transfusion) in the United States. [393] [394] Contributory risk factors include hepatotoxins such as aflatoxin, excess alcohol exposure, and smoking, as well as male gender. [393] [395] Numerous studies have demonstrated that vaccination can prevent the development of HCC caused by hepatitis B. [395] [396] Likewise, interferon treatment seems effective in interrupting or slowing the processes that lead to HCC initiated by hepatitis C.[397] A large phase III randomized controlled trial addressing HCC screening is currently underway to evaluate the optimal screening interval (3 months versus 6 months) for liver ultrasonography or CT among cirrhotic patients.[398]
Chemoprevention agents also seem to be effective in populations at risk for HCC due to hepatitis C infection. A randomized trial of a cyclic retinoid has shown that this compound reduced development of a second primary HCC by one-third, but this study has not been repeated or confirmed.[399] A phase III randomized trial of an anti-hepatitis C vaccine is underway, and a unique trial of supplementation withS-adenosylmethionine to prevent progression has recently been initiated at the University of California, Irvine. Overall, advances in microbial oncology have led to a great deal of progress in understanding the etiologic basis of HCC and in developing strategies for its eradication and prevention.
Our basic understanding of the etiologic origin of stomach cancer has been affected greatly by a paradigm shift, and the recognition that H. pylori infection is central to gastric carcinogenesis in humans has been critical to the development of new prevention strategies.[400] Although individual susceptibility, lifestyle issues, and diet all play a role in the pathogenesis of gastric carcinoma, attributable risks for H. pylori range as high as 73%.[401] There now exists a full-fledged attempt to prevent gastric cancer by appropriate screening in high-risk populations followed by H. pylori eradication. [401] [402]Epidemiologic data are supportive of a protective role for fruit and vegetable consumption. Two large randomized trials suggest that H. pylori treatment interferes with the progression of gastric preneoplasia and gastric cancer [403] [404] although a definitive trial is needed to prove the latter issue. Supplementation with antioxidants in both trials failed to add benefits to eradication of the bacterium.
Rational approaches to the early detection and prevention of the microbial origin of HCC and stomach cancer are now established. Concerted public health efforts should lead to screening and their eradication.
Nasopharyngeal carcinoma (NPC) is uncommon in the United States but has a high incidence in China and Southeast Asia, due to increased susceptibility to EBV.[405] In the endemic regions NPC is typically undifferentiated carcinoma (World Health Organization [WHO] type 3), whereas in the United States the majority of patients have the keratinizing squamous cell carcinoma (WHO type 1) NPC subtype. The WHO type 1 NPC subtype histologically resembles typical HNSCC and is more commonly associated with tobacco exposure and alcohol consumption. Nearly all type III NPC tumors involve latent EBV infection, whereas EBV infection is absent from type I NPC tumors in nonendemic regions; furthermore, survival is improved for type III NPC as compared with type I NPC.[406] Although the majority of type I NPC patients in the United States are Caucasian, Asian ethnicity within type I NPC has been shown to be an independent prognostic factor for improved survival.[407] This may be related to a higher proportion of EBV-positive type I tumors among U.S. Asians, or genotypic differences such as overexpression of epidermal growth factor receptor 1, which has been associated with poor survival in NPC and HNSCCs. [408] [409] [410] Recent advances in molecular targeted therapeutics of HNSCC involving epidermal growth factor receptor small molecule inhibitors and monoclonal antibodies have emerged.[411] Based on the findings and toxicity profile of agents in such therapeutic trials, opportunities may present for a targeted approach to prevention strategies for NPC and HNSCC among selected patients.
For those interested in cancer prevention, particularly useful resources include the Journal of the National Cancer Institute and the Cancer Epidemiology Biomarkers and Prevention journal, and publications from the International Agency for Research on Cancer (http://www.iarc.fr/). This latter entity publishes a continuing series on early detection and prevention that represents an invaluable and critical analysis of current controversies. A particularly important Task Force Report from the American Association for Cancer Research on chemoprevention drug development recently has been published.[412] Useful Internet sites include
The Division of Cancer Prevention, National Cancer Institute, National Institutes of Health (http://www.prevention.cancer.gov).
Chemoprevention—The Answer to Cancer? (http://ohioline.ag.ohio-state.edu/hyg-fact/5000/5051.html).
Harvard Center for Cancer Prevention, Harvard School of Public Health (http://www.hsph.harvard.edu/cancer/).
American Institute of Cancer Research (http://www.aicr.org/index).
International Society of Cancer Chemoprevention (http://www.iscac.org).
Cancer Research Foundation of America (http://www.preventcancer.org).
National Foundation for Cancer Research (http://www.nfcr.org).
ClinicalTrials.gov, search words "Cancer Prevention," "Screening," and "Chemoprevention" (http://www.clinicaltrials.gov).
United States Department of Health and Human Services, Agency for Healthcare Research and Quality, United States Preventive Services Task Force (USPSTF) (http://www.ahrq.gov/clinic/prevenix.htm).
The authors thank Sandy Schroeder for excellent administrative assistance in the preparation of this chapter. We thank Bill Armstrong and Ken Chang for the photographs in Figure 26-2 . This work was supported in part by P30CA62203 from the National Institutes of Health.
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