Prevention and Early Detection
Cancer Progress Report 2013: Contents
In this section you will learn:
More than half of cancer deaths in the United States are a result of preventable causes.
Obesity and type 2 diabetes mellitus significantly increase the incidence and worsen outcomes of some forms of cancer.
Sufficient levels of physical activity reduce the incidence of certain cancers and improve their outcomes.
Tobacco use is responsible for almost 30 percent of cancer deaths in the United States.
Disparities in colorectal cancer incidence and mortality can be reduced by making colonoscopy available to all who are eligible.
Identifying individuals at hightest risk for developing certain cancers can make screening more effective.
Many of the greatest reductions in the morbidity and mortality of cancer have come from advances in cancer prevention and early detection. These remarkable effects were achieved by translating advances in our understanding of the causes and progressive nature of cancer into effective new clinical practices, and public education and policy initiatives.
Changes in the clinic include improved screening practices (e.g., colonoscopy to detect and remove precancerous adenomatous polyps) and the introduction of targeted interventions (e.g., administering vaccines to prevent infection with pathogens associated with cancer risk, such as hepatitis B virus or human papilloma viruses). Likewise, public education regarding common factors that increase cancer risk (such as physical inactivity and unhealthy diets) have also played a role, as has the implementation of policies aimed at promoting healthier lifestyles and minimizing exposure to cancer-causing agents (such as tobacco smoke and asbestos).
Healthy Living Can Prevent Cancer
Decades of research have led to the identification of numerous factors that affect a person’s risk of developing cancer (see
Figure 9). Through this work, scientists have come to the conclusion that more than 50 percent of the 580,350 cancer deaths expected to occur in the United States in 2013 will be related to preventable causes such as tobacco use, obesity, poor diet, and lack of physical activity (10). Modifying personal behaviors (see
Figure 10) to eliminate or reduce these risks, where possible, could, therefore, have a tremendous impact on our nation’s burden of cancer. However, a great deal more research and resources are needed to understand how to best help individuals to change their lifestyle.
Eliminating High-Risk Activities
Everyone could dramatically reduce their risk of certain cancers by making two changes to the ways they live: cutting out tobacco products and avoiding excessive exposure to ultraviolet (UV) light, a form of damaging radiation emitted by the sun, sunlamps, and tanning beds. Making these changes not only reduces the chances of developing certain cancers, but can also reduce cancer recurrence or improve outcomes following a cancer diagnosis.
Tobacco Use and Cancer
The scientifically established causal relationship between cigarette smoking and lung cancer was first brought to the public’s attention in 1964, when the “U.S. Surgeon General’s Report on Smoking and Health” was published (15). This report set in motion major policy changes, media campaigns, and other measures to combat cigarette smoking in the United States. As a result of these efforts, the prevalence of smoking decreased from 42 percent of Americans in 1965 to 18 percent in 2012 (16). This decrease has been credited with saving millions of lives that would otherwise have been lost not only to lung cancer, but also to 17 other types of cancer directly related to tobacco use (9) (see
Even armed with this information, 70 million Americans, including some who have been diagnosed with and/or are actively being treated for cancer, regularly use tobacco products. Further, every day in 2010, 6,500 Americans aged 12 years and older smoked their first cigarette and approximately 40 percent of this group, or 2,600 individuals per day, became regular smokers (17). This is why tobacco use will be responsible for an estimated 30 percent of all cancer deaths that occur in the United States in 2013 (1).
It is not only the lives of those who use tobacco products that are at risk; scientific evidence has shown that exposure to secondhand tobacco smoke also causes cancer. This prompted the surgeon general to declare that there is no safe level of exposure to tobacco smoke (19). Although this has led to some important public health policies restricting smoking in public places, smoking remains a huge threat to the public’s health (20, 21). Countless lives could be saved through continued development and implementation of effective tobacco prevention, cessation, and control strategies.
Outdoor and Indoor Tanning and Cancer
Exposure to UV light is the predominant cause of all three of the main types of skin cancer — basal cell carcinoma, squamous cell carcinoma, and melanoma. In fact, the International Agency for Research on Cancer (IARC), an affiliate of the World Health Organization, includes UV tanning devices and UV radiation from the sun in its highest cancer-risk category, “carcinogenic to humans” (22), alongside agents such as plutonium and cigarettes. Adopting sun-safe habits and avoiding the use of indoor UV tanning devices would dramatically decrease the incidence of skin cancer; for example, daily sunscreen use can cut the incidence of melanoma in half (23).
Despite the overwhelming scientific evidence that tanning bed use increases an individual’s risk for developing cancer, particularly at a younger age (24, 25), tens of millions of Americans visit tanning salons each year (25). According to a 2011 report from the Centers for Disease Control and Prevention (CDC), this number includes more than 13 percent of all high school students and 21 percent of high school girls (27, 28). Responding to the clear cancer risk posed by tanning beds, the FDA has proposed reclassifying tanning beds into a more stringent category of medical products that would require warning labels to advertise their role in increasing skin cancer risk.
Preventing skin cancer by protecting skin from UV light exposure would not only limit the morbidity and mortality caused by these conditions, but would also save enormous amounts of money. It has been estimated that the total direct cost associated with the treatment of melanoma in 2010 was $2.36 billion in the United States (28). Given that melanoma incidence rates continue to increase (1), patients, researchers, and politicians seeking to balance their budgets need to come together to develop and implement more effective policy changes and public education campaigns to help reduce the health and economic burdens of skin cancer.
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Cancer-associated Infectious Agents
Persistent infection with one of several pathogens is an important cause of about 20 percent of cancers worldwide (29, 30). This knowledge has enabled the development of new cancer prevention strategies that use medicines and vaccines to eliminate or prevent infection with these agents. One of the best examples of this relates to human papillomavirus (HPV), which is estimated to have been responsible for almost 39,000 new cases of cancer in the United States in 2010 and more than 9,500 deaths (31).
Several decades of research have established that persistent infection with certain strains of HPV causes most, it not all, cervical cancers, a majority of anogenital cancers, and many cancers arising in the upper part of the neck (32). This information enabled the development of a clinical test for detecting the cancer-causing types of HPV. This test, when combined with a standard Pap test for cervical cancer, more effectively identifies women at high risk for cervical cancer than a standard Pap test alone. As a result, this test safely extends cervical cancer screening intervals (33), providing a less-burdensome cervical cancer screening option and potentially reducing health care costs.
Determining which strains of HPV can cause cervical cancer also led to the development of two vaccines that the FDA has approved for the prevention of cervical cancer (31, 34). In addition, the FDA approved one of the vaccines, Gardasil, for the prevention of vulvar and vaginal precancerous lesions as well as for the prevention of HPV-associated anal cancer. Future studies will determine whether the vaccines also reduce the risk for head and neck cancers caused by HPV. Early signs are promising, as a recent study found that vaccination dramatically reduced oral infection with HPV (34).
Even though two highly effective vaccines are available, the CDC estimates that in 2012 only 33 percent of girls in the United States aged 13 to 17 years had received the recommended three doses of HPV vaccine (35) (see sidebar on
HPV Vaccine Usage). Moreover, coverage has been reported to be significantly lower among the uninsured and in several states in which cervical cancer rates are highest and recent Pap testing prevalence is the lowest (33). However, recent data indicate that despite the low vaccine uptake, there has been a dramatic reduction in cervical infection with HPV among girls aged 14 to 19 years since the introduction of the vaccines (36). Thus, research has provided the tools for dramatic reductions in the burden of HPV-related cancers, but their use must be fully implemented if they are to have maximum impact.
Energy Balance: Weighing in on Cancer
“Energy balance” refers to the difference between the number of calories consumed and the number burned. Tipping of this balance so that a person accumulates excess energy reserves plays a crucial role in promoting the diseases responsible for the majority of deaths in the United States: heart disease and cancer.
While calories are consumed only through eating and drinking, they are burned in many ways. Simply existing, breathing, digesting food, and pumping blood around the body use some calories. Added to these expenditures are the calories burned through a person’s daily routine; the more physical activity in a routine, the more calories are burned.
Although this may seem straightforward, research has shown that energy balance is, in fact, a complex dynamic (see
Figure 12). It is not only influenced by calorie consumption and physical activity, but also by numerous other factors including genetics, diet composition, body weight or body composition, and sleep (see sidebar on
Sleep Disturbances and Cancer).
Obesity and Cancer
Obesity increases risk for a growing number of cancers, most prominently the adenocarcinoma subtype of esophageal cancer, and colorectal, endometrial, kidney, pancreatic, and postmenopausal breast cancers (8). It also negatively impacts tumor recurrence, metastasis, and patient survival for several types of cancers (51, 53, 54).
How, then, does obesity promote and adversely affect survival for certain cancers? Several recent scientific discoveries have identified just some of the interrelated factors through which obesity influences cancer (46, 51, 52) (see
Figure 12). Among these factors are hormones such as estrogen and insulin, which directly influence cell survival and division; and chemicals released by the fat itself, which influence the function of many organs of the body. In addition, obesity leads to inflammation, which is clearly linked to cancer development and progression (14, 55) (see
The Immune System).
Importantly, identifying some of the factors that link obesity and cancer is providing potential targets for treating obesity-related cancers. For example, the knowledge that several of the factors discovered act directly on cancer cells to drive their survival and division via a signaling network called the PI3K/AKT/mTOR (46, 51, 52), suggests that drugs targeting this pathway might be effective in this context.
Any new therapeutic approaches developed in the future will need to be used together with approaches to balancing energy intake and output. For many people, modifying behaviors to reduce calorie consumption and increase physical activity may be sufficient, but other people may require surgical or therapeutic interventions to help them lose weight. The urgent need for an effective and comprehensive strategy is highlighted by the fact that the number of Americans classified as obese is at an all-time high. Currently, more than 35 percent of adults and 17 percent of children and adolescents are obese (56).
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Type 2 Diabetes Mellitus and Cancer
Type 2 diabetes mellitus is a complex medical condition caused by a combination of factors, including obesity. Independent of obesity, type 2 diabetes increases an individual’s risk of developing cancer (57, 58). Those with type 2 diabetes are most at risk for developing liver, pancreatic, and endometrial cancers, but also have an increased risk for developing biliary tract, bladder, breast, colorectal, esophageal, and kidney cancers, as well as certain forms of lymphoma (58, 59).
Type 2 diabetes not only increases cancer risk, but also reduces short- and long-term cancer survival rates through both direct and indirect mechanisms (58). For example, type 2 diabetes has been reported to have a direct negative effect on tumor recurrence and survival in patients with colon cancer (60). In general, survival for cancer patients with type 2 diabetes is worse than for their nondiabetic counterparts because of indirect factors associated with diabetes. For example, they are more likely to suffer from other potentially fatal diseases, like heart disease, and to be poor candidates for surgery and the highest doses of chemotherapy (58).
Despite the fact that type 2 diabetes affects about 7.5 percent of the U.S. population (61), it is not well established how type 2 diabetes increases cancer risk. Research suggests that it likely influences cancer development in several ways, many of which are similar to the ways in which obesity affects cancer (58, 59). For example, similar to obesity, type 2 diabetes increases levels of insulin and causes persistent inflammation.
Importantly, recent evidence suggests that treatments directed at reducing the hallmark of type 2 diabetes may influence cancer risk. Metformin, which is one of the most commonly used drugs for treating patients with type 2 diabetes, appears to reduce a type 2 diabetic’s risk of developing colon and pancreatic cancers (62, 63). In contrast, sulfonylureas, a different class of drugs commonly used to treat type 2 diabetes, may increase risk of cancer development (58). However, further studies are needed to clarify these issues (58). Given what we have learned about the anticancer effects of metformin in patients with type 2 diabetes, numerous clinical studies are underway to assess whether it has the potential to benefit nondiabetic patients with cancer (64).
In light of the large number of Americans living with type 2 diabetes (61), it is critical for physicians managing these patients to be keenly aware of their patients’ increased cancer risks if we are to reduce the burden of cancer in this portion of the population. Moreover, it is vital that we undertake more research so that we better understand the biological pathways linking the disease to cancer. Armed with this knowledge, we can investigate potential new therapeutic approaches. However, our best approach to reducing individuals’ risks for type 2 diabetes and for certain forms of cancer, as well as improving outcomes, is to combine any new therapeutic approaches with behavior modifications, like eating a healthier diet, increasing physical activity, and reducing calorie consumption.
Physical Activity and Cancer
A lack of regular physical activity (see sidebar on
Physical Activity Guidelines) is strongly associated with an increased risk for colon, endometrial, and postmenopausal breast cancers, independent of weight (8). Mounting evidence suggests that it may also be associated with lung, pancreatic, and premenopausal breast cancers (8).
In addition, several recent studies indicate that sedentary behavior may increase risk for developing certain cancers and for mortality in cancer survivors independent of physical activity and weight.
For example, one study showed that individuals who spent 10 or more years in sedentary work had almost twice the risk of cancers arising in their rectum or in a specific part of their colon compared with individuals who did not spend any time in sedentary work (67). In a second study, patients with colorectal cancer who spent six or more hours a day sitting after their diagnosis had a dramatically increased risk of death from their cancer compared with patients who spent fewer than three hours a day sitting (68). Likewise, a large-scale study also showed that the more time a person spent sitting, the greater their risk of death from any cause, regardless of their level of physical activity (69).
Conversely, research has shown that for patients with certain forms of cancer, including breast, colorectal, and prostate cancers, physical activity improves outcomes by reducing recurrence and increasing survival (8, 70-73).
Clear guidelines for physical activity for cancer survivors have been published (8, 65, 66). However, it appears that these have mostly been applied in clinical settings and research interventions, and that they have not yet become general standards of practice in the United States.
There are many barriers to increasing physical activity among cancer survivors and the general public. More research and resources at all levels are needed if this lifestyle modification is to be widely adopted.
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Looking For Cancer: Who, When, and Where
We know that most cancers arise from genetic mutations that have accumulated during the patient’s lifetime (see
Developing Cancer). Our knowledge of the causes, timing, sequence, and frequency of these pivotal changes is increasing, as is our insight into the specific implications of the changes. This knowledge provides us with unique opportunities for developing the means to prevent cancer onset or to detect it and intervene earlier in its progression.
Unfortunately, we have also learned that it is not always easy to identify at-risk patients or those with early-stage disease. However, researchers and clinicians are looking to pair our molecular understanding of cancer development with indicators of cancer risk to create personalized prevention and early-stage intervention programs. For example, some patients may be able to reduce their risk by simply modifying their behaviors. Others might need to increase their participation in screening or early detection programs or even consider taking a preventive medicine or having precautionary surgery.
Prevention and Early Detection of Primary Tumors
About 5 percent of all new cases of cancer diagnosed in the United States each year are caused by an inherited mutation (1) (see sidebar on
How do I Know if I am at High Risk for Developing an Inherited Cancer?). In most of these cases the inherited mutation is unknown. However, research has identified 17 mutations that put people, like
Congresswoman Wasserman Schultz, at very high risk of developing cancer. If a patient’s cancer is suspected to be caused by one of these mutations, genetic testing can be performed to verify this and identify relatives who carry the familial mutation. These family members can then consider taking risk-reducing measures, while those without the mutation can avoid unnecessary and costly medical procedures.
Beyond inherited cancers, a number of medical conditions place an even smaller group of individuals at high risk for developing certain types of cancer. Among these medical conditions are ulcerative colitis and Crohn’s disease, which are chronic inflammatory diseases of the intestines that increase an individual’s risk for colorectal cancer sixfold (74). Moreover, medical conditions and interventions that suppress the normal function of the immune system, such as HIV/AIDS and the treatment of solid organ transplantation with immunosuppressive drugs, also increase risk for certain types of cancer (75).
However, high-risk individuals are the minority, so what is to be done for the broader population? One approach to identifying at-risk patients, as well as those with early-stage disease, is to test generally healthy individuals for potential disease through population-based screening programs (see sidebar on
USPSTF Cancer Screening Guidelines). These programs largely function by using age and gender to grade, or stratify, a person’s risk, with those identified as most at risk being those who are most likely to benefit from the screening.
This approach to risk stratification has been extremely successful for cervical cancer screening, as the program has greatly reduced the incidence and mortality of cervical cancer in the United States (76, 77). Further inroads against cervical cancer incidence are likely given the dramatic reduction in cervical infection with the cervical cancer–causing infectious agent HPV among girls aged 14 to 19 years since the introduction of the HPV vaccines (36).
Stratifying risk based on age has also worked for colonoscopy, which has contributed significantly to dramatic declines in colorectal cancer incidence and mortality (38). However, only about 59 percent of all Americans aged 50 years and older, the group for whom colorectal cancer screening is currently recommended, get screened (78). Among the more than one-third of Americans who do not follow colorectal cancer screening guidelines is a disproportionately high number of African-Americans (78, 80), a group that shoulders an overly high colorectal cancer burden (see sidebar on
Cancer Health Disparities in America). Evidently, innovative ways to increase the number of individuals, in particular racial and ethnic minorities, following colorectal cancer screening guidelines are needed.
Since 2003, a spectacularly successful initiative at eliminating colorectal cancer disparities has been running in Delaware (81). The cancer control program, as it is known, increased colorectal cancer screening among all Delawareans age 50 or older from 57 percent in 2002 to 74 percent in 2009. Moreover, screening rates for African-Americans rose from 48 percent to 74 percent, matching the screening rate among non-Hispanic whites for the same period of time. Perhaps most importantly, disparities in colorectal cancer incidence and mortality rates between non-Hispanic whites and African-Americans were also equalized as a result of the equivalent screening rates between the two groups. The researchers who conducted this study predict that if similar programs could be implemented in all states, racial disparities in colorectal cancer incidence and mortality could be greatly reduced (81).
Screening programs have successfully reduced the incidence and mortality for cervical and colorectal cancers because they identify the diseases at an early-stage before they become life threatening, thereby providing opportunities for early intervention. However, not all population-based screening programs have been equally effective.
For example, while the prostate-specific antigen (PSA) test is very good at detecting early-stage prostate cancer lesions, it does not distinguish between lesions that will progress to advanced disease and those that will not (88). As a result, many patients undergo unnecessary treatment. Concerns about overdiagnosis and overtreatment have led to the current recommendation by a number of organizations to discontinue routine PSA screening (89) and highlight the need for better ways to stratify PSA-positive patients.
Early detection of breast cancer through regular mammography screening of women older than 40 has been credited with reducing the mortality rate for breast cancer (1). However, there is growing concern that it can detect breast tumors that will never cause symptoms or threaten a woman’s life. Thus, mammography screening, like PSA screening, can potentially lead to overdiagnosis of the disease and subsequent overtreatment, which carries its own risks. In fact, one study estimated that in 2008, breast cancer was overdiagnosed in more than 70,000 women; this accounted for 31 percent of all breast cancers diagnosed (90).
One approach to more precisely identify at-risk patients is to use their history. In a study investigating the usefulness of low-dose computed tomography (CT) screening for early detection of lung cancer, current and former heavy smokers aged 55 to 74 years were classified as having the highest risk for developing disease (91, 92). The researchers found that in this population, low-dose CT screening reduced lung cancer mortality by 20 percent because it identified small and early-stage tumors (91, 92). There are an estimated 94 million current and former smokers in the United States; however, the majority of them are unlikely to benefit from screening because they are or were not heavy smokers (93).
More work is needed to ensure that Americans understand that cancer screening approaches, including low-dose CT screening for early detection of lung cancer, are most clinically effective when targeted at those at highest risk of developing the disease for which they are being screened (94). Targeting those most at risk also has the benefit of decreasing the complications and cost of unnecessary health care interventions for those at low risk of disease. Research to develop new, accurate, and reliable ways to discern an individual’s cancer risk is vital to ensure that the public has confidence in current screening guidelines and any future changes to these guidelines.
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Prevention and Detection of Tumor Recurrence
As for prevention and early detection of primary tumors, our increasing knowledge of the risk factors for cancer occurrence and progression is enabling us to identify those cancer survivors with the highest risk for tumor recurrence (see sidebar on
Cancer Survivorship). This is allowing us to direct risk-reducing medical interventions to only those who will benefit, reducing health care costs associated with treating those who will not benefit and may even be harmed.
Currently, there are few established ways to identify cancer survivors at high risk for disease recurrence. One group known to be at high risk is women who have successfully completed treatment for invasive breast cancer. A subset of patients in this group has breast cancer powered by the hormone estrogen. For these women, drugs that block the effects or production of estrogen have proven very successful at reducing tumor recurrence if taken for five years (96-98). Moreover, recent data from long-term clinical trials indicate that 10 years of therapy with one of these drugs, tamoxifen (Nolvadex), is even more effective at reducing tumor recurrence (99, 100). As all anti-estrogen drugs have serious side effects, our knowledge that these drugs are ineffective for women whose breast cancers are not fueled by estrogen spares these patients from unnecessary and potentially harmful treatments.
Recent research has identified a potential new way to target treatment that reduces tumor recurrence to only those cancer survivors likely to benefit (101). Prior research had indicated that regular aspirin use could lower risk of both primary and recurrent colorectal cancer (102, 103). However, widespread aspirin use was not recommended because of concerns over side effects such as gastrointestinal bleeding. Fortunately, researchers have been able to narrow down the population of colorectal cancer survivors who will benefit from aspirin (101). They found that regular aspirin use by colorectal cancer survivors with tumors harboring mutations in the PIK3CA gene reduced their risk of colorectal cancer death by about 80 percent, but that aspirin showed no benefit for survivors who lacked this mutation in their tumors.
This knowledge promises to reduce colorectal cancer morbidity and mortality for certain colorectal cancer survivors and to eliminate the needless treatment of those who will not benefit. However, additional, large-scale studies are needed before aspirin use can become a standard treatment for patients with PIK3CA-mutated colorectal tumors.
Despite these successes, the use of medical interventions to reduce primary and recurrent tumor risk is not widespread. Therefore, continued research is needed to develop more concrete evidence to identify the most at-risk patients, better screening approaches, and more and better ways to intervene earlier in the progression of cancer.
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Progress Report 2013 Contents