ARTICLE CONSULTANTS
CAROLYN M. KAELIN, MD, MPH, Director, Comprehensive Breast Health Center and Associate Surgeon, Brigham and omen's Hospital; Assistant Professor, Harvard
Medical School, Boston, Mass. Dr Kaelin is the author of Living Through Breast Cancer, McGraw-Hill, 2005, and has collaborated with Reebok on a fitness DVD, "The Breast Cancer Survivor's Guide To Fitness."
ALFRED I. NEUGUT, MD, PhD, Professor, Department of Medicine, College of Physicians and Surgeons; Professor, Department of Epidemiology, Mailman School
of Public Health, Columbia University. Co-Director, Cancer Prevention Program, New York Presbyterian Hospital, New York, NY.
Cancer is now the leading cause of death among Americans younger than 65 years. That statement is less alarming than it first
appears, because deaths attributable to heart disease dropped dramatically in recent years. In fact, the number of cancer
deaths has also fallen during the same period, but less rapidly than heart disease deaths.
Several factors account for the discrepancy in death rates between the 2 diseases. Age is the single most important risk factor
for cancer, and as Americans age, the absolute number of cancer cases might be expected to increase. Americans in general
smoke less than they did several decades ago, and smoking cessation reduces the risk of heart disease almost immediately.
In contrast, the reduction in lung cancer risk occurs more slowly. Drugs such as statins and antihypertensive medications
and procedures such as coronary artery bypass grafting and angioplasty prevent or slow the progression of heart disease in
millions of Americans. Similar drugs and procedures to prevent or slow cancer to such a large degree in so many people have
been difficult to identify and develop.
Table 1: A sampling of carcinogenic exposures and corresponding cancer types
|
More than 168,000 Americans will die of tobacco-related malignancies this year, according to the ACS.2 About one third of cancer deaths are attributable to lifestyle factors, including physical inactivity, obesity, overweight,
and poor nutrition.1-3 The ACS states in its most recent cancer prevention report that if we applied what we know about the causes of cancer, about
half of all cancer deaths could be avoided. Table 1 lists a sampling of carcinogenic exposures and corresponding cancers.
The means of preventing cancer often involve difficult changes in lifelong habits, such as eating and exercise patterns. In
patients' minds, this contrasts sharply with the relative ease of swallowing a pill such as a statin or a beta-blocker, even
though lifestyle habits are essential in preventing heart disease, as well. In fact, in June 2004 the ACS, the American Diabetes
Association, and the American Heart Association initiated a collaborative program called Everyday Choices for a Healthier
Life to address the common risk factors for cancer, diabetes, and heart disease: tobacco use, obesity, physical inactivity,
and poor nutrition. The program allows the 3 organizations to be more efficient in their preventive efforts and underscores
their common focus on these risk factors. For patients, this is good news: Many of the steps that they take to prevent heart
disease may also lower cancer risk.
ESTABLISHED MEANS OF PREVENTING CANCER
Tried and true means of preventing cancer range from tobacco avoidance to colonoscopy. Patients need to understand that there
are areas in cancer evaluation and prevention in which they have considerable control and that these areas should be the focus
of their efforts.
Tobacco avoidance
Lung cancer is the single most preventable malignancy. According to the ACS, 87% of lung cancer deaths are attributable to
tobacco use. Lung cancer remains the leading cause of cancer deaths in men and women in the United States, causing 29% of
all cancer deaths nationwide and 13% of all new cancer cases each year.4 Lung cancer rates have been declining by nearly 2% per year among men since 1991 and have reached a plateau among women.1 Among Americans, one quarter of men and one fifth of women smoke cigarettes, usually on a daily basis. Among the other cancers
that have been associated with tobacco use are those of the oral and nasal cavities, larynx, pharynx, esophagus, stomach,
liver, pancreas, kidney, bladder, and uterine cervix.
Although former smokers apparently always have a higher risk of lung cancer than lifelong nonsmokers, those who quit live
an average of 10 years longer than smokers who don't quit. Stopping smoking at age 60, 50, 40, and 30 years, respectively,
gains 3, 6, 9, and 10 years of life.5 Within 10 years of smoking cessation, a patient's risk of dying of lung cancer is decreased by 30% to 50%.4 The risk of lung cancer death begins to decline when a patient quits but never reaches the level of a lifetime nonsmoker.
Accumulated DNA damage in the exposed surfaces of the lung epithelium never completely disappears.6,7
At the molecular level, all smokers are probably partially along the path to cancer, and it is crucial to stop exposure to
tobacco carcinogens. This is the key message for patients: It is always worth quitting, and it's never too late to quit. It
is always preferable to be a former smoker than a current one, and the longer a patient is a former smoker, the lower the
risk.
Some cancer specialists view lung cancer as a pediatric disease in the sense that the die is cast when a teenager makes the
decision to smoke. If he or she starts and becomes addicted, the lung cancer risk may never return to baseline. Smoking prevention
efforts aimed at teenagers remain a crucial avenue for cancer prevention.
Establishing a relationship between second-hand exposure to cigarette smoke and lung cancer risk took years because the risk
posed by second-hand smoke is so much lower than that posed by smoking itself. Compared to an active smoker, a passive smoker
is exposed to much lower concentrations of tobacco carcinogens. The risk of lung cancer is small but real, however, and your
nonsmoking patients should be encouraged to reduce their passive exposure to cigarette smoke.
Restriction of UV exposure
Skin cancer, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, is the most common form of cancer
among Americans and is responsible for 2% of all cancer deaths. Although most of the cancers are basal cell or squamous cell
carcinomas, most of the skin cancer deaths are caused by melanoma. Nearly 60,000 Americans will receive a diagnosis of melanoma
this year, and this cancer will take the lives of almost 8000 people. Melanoma rates among men have been stable since 1990
and have decreased among women since 1988.1
For nonmelanoma skin cancers, a strong, dose-response correlation exists between sun exposure and cancer risk.8,9 Regular use of sunscreen and protective clothing reduces the incidence of premalignant lesions such as solar keratoses and
has been observed to induce remissions in existing solar keratoses.10
The relationship between melanoma and sun exposure is more complex. Data collected among the fair-skinned descendants of European
immigrants to Australia have long suggested that genetics and UV exposure interact to increase melanoma risk. Other host factors
that increase melanoma risk include a patient's tendency to burn and the presence of benign melanocytic nevi and atypical
nevi.
It is unclear whether sunscreen use protects against melanoma. Some studies have reported an association between a greater
risk of melanoma and the use of sunscreens. But in a recent meta-analysis of 18 studies of the relationships among UV exposure,
sunscreen use, and melanoma, the authors concluded that many of these studies had not properly accounted for the fact that
people who are most likely to use sunscreen may be the ones who are at highest risk for melanoma. In addition, some evidence
suggests that people who use high-SPF (sun protection factor) products spend more time in the sun, further confounding the
interpretation of data on sunscreen use and melanoma.11
Melanoma may also appear on areas of the body that are not exposed to sunlight, including the perineum, mucosal surfaces,
and between the toes. Melanoma that develops at these sites also tends to have a more severe prognosis. The 10-fold difference
in melanoma incidence between whites and African Americans nearly disappears when melanoma occurring only at these body sites
is considered.
Some data suggest that the UV exposure experienced during childhood and adolescence is a powerful determinant of melanoma
risk later in life.12 In contrast, sun exposure during adulthood is more closely tied to an increased incidence of basal and squamous cell carcinomas.
Patients should be made aware in the strongest possible terms that the lights used in tanning salons are just as damaging
as the sun, regardless of what salon operators may say about "safe" tans.
Colon cancer screening and prevention
Approximately 105,000 new cases of colon cancer and more than 40,000 cases of rectal cancer will be diagnosed in Americans
this year.1 Between 1998 and 2001, the incidence of colorectal cancer decreased by nearly 2%, a decline that experts attribute to an increase
in screening rates, which permits the removal of precancerous polyps.
Patients may be aware of many possible ways to reduce colon cancer risk. In particular, the roles of fruits, vegetables, and
fiber have been debated recently. But the bottom line is that colon cancer screening has the strongest potential to reduce
colon cancer deaths.13 Fecal occult blood tests (FOBT), fecal immunochemical tests, flexible sigmoidoscopy, and colonoscopy each has advantages and
disadvantages (see "Updates in colon, cervical, breast, and prostate cancer screening,").
The approach to preventing colon cancer—involving a cancer prevention breakthrough that occurred decades ago—is in some ways
analogous to that of cervical cancer and Pap smears. For neither test is the target lesion a malignancy. In fact, if cancer
is detected, it represents a screening failure.
Prophylactic mastectomy and/or oophorectomy
Five to 10% of women with breast cancer harbor a familial genetic mutation. Factors that suggest that a family is at increased
risk of having such a mutation include breast cancer in multiple family members, diagnosis at a young age (premenopausal),
bilateral disease, breast cancer in males, and ovarian cancer in female family members. The majority of genetic mutations
associated with an increased risk of breast cancer are located within the BRCA1 gene on chromosome 17 or within the BRCA2 gene on chromosome 13. Depending on the mutation involved, the increased risk ranges from 40 to 85% for breast cancer and
15% to 40% for ovarian cancer. One mutation may confer a lifetime breast cancer risk of 50%, for example, while another might
be associated with an 80% lifetime risk.
A woman who is a known mutation carrier may be a candidate for prophylactic mastectomy. This surgery reduces the risk of breast
cancer by 90%. Thus, a woman whose estimated lifetime risk for breast cancer is 50% has her risk reduced to a 5% lifetime
risk after surgery, which is less than that in the general female population.
Ideally, it is best to perform an evaluation for a breast cancer genetic mutation on a high-risk family member who herself
has been affected by breast or ovarian cancer. If a known mutation can not be identified in a patient who has been affected
by cancer, it will not be found in unaffected relatives. If, however, a mutation is identified, blood relatives can be tested
for that same mutation.
Refer candidates for the test to a center with expertise in evaluating and counseling high-risk women. These facilities have
physicians, geneticists, and nurse/geneticists who engage patients in detailed, thorough discussions. Where testing is appropriate,
the blood work should be sent for analysis only to a laboratory whose evaluations for this type of test have been well-validated.
Surgical techniques are improving, yet clearly still have limitations considering that risk reduction is 90% rather than 100%.
Breast glandular tissue that remains after surgery may adhere to the skin or pectoralis muscle. Studies of prophylactic mastectomy
efficacy were initiated before electrical cautery and modern surgical techniques were widely available; thus, contemporary
prevention rates may exceed 90%.
When a woman with a known mutation chooses a mastectomy for a newly diagnosed cancer in one breast, prophylactic mastectomy
may be considered for her unaffected breast to reduce the risk of an occurrence of a second breast cancer primary.
Prophylactic oophorectomy can be considered for a woman with a known BRCA mutation whose childbearing is complete. This procedure will reduce the risks of breast and ovarian cancer by approximately
50% and 90%, respectively. For women with an apparently average risk of ovarian cancer, prophylactic removal of the ovaries
during appendectomy, for example, is not recommended.
VACCINE-PREVENTABLE CANCERS
Viruses are known to cause several kinds of cancer, including some cases of liver cancer and nearly all cases of cervical
cancer and Kaposi's sarcoma. The means by which viral infection leads to cancer are not well-defined but may include
- Chronic inflammation
- Virally induced immune suppression
- Chronic stimulation
- Direct stimulation of cell replication.1
The development of vaccines against these viruses represents a major—and sometimes underutilized—advance against cancer. Some
of these vaccines are available, and others are expected on the market soon. Bacterial infections have also been associated
with some malignancies such as stomach cancers. Progress in this area has been slower.
Liver cancer
More than 17,000 Americans will receive a diagnosis of liver cancer this year. According to the newest data from the ACS,
more than 6% of liver cancer cases in North America are attributable to chronic infection with hepatitis B virus (HBV) and
23% to infection with hepatitis C virus (HCV). Hepatitis A virus causes neither chronic infection nor liver cancer.
Among Americans, acquisition of HBV often occurs in adolescence or early adulthood. HBV infection rates have been rising among
young men and women since 1999. A highly effective vaccine has been available for more than 20 years and is recommended for
infants, children not vaccinated as infants, and adults in high-risk groups. The latter includes health care workers, those
who engage in high-risk sexual activity, and who use injectable drugs. A study completed in Taiwan has confirmed that vaccination
against HBV is associated with a reduced risk of hepatocellular carcinoma, making liver cancer the first vaccine-preventable
malignancy.14 Although several antiviral drugs are available to treat acute HBV infection, it is unclear whether they prevent hepatocellular
carcinoma. They have been associated with reductions in levels of HBV DNA levels, however, suggesting that they may have anticarcinogenic
effects.15
No vaccine is available for HCV infection. Primary prevention is limited to avoiding use of injectable drugs, having health
care workers use universal precautions, and screening the blood supply, as well as donors of organs, tissue, and semen. Although
the use of antiviral drugs has been linked to decreased levels of HCV RNA, it is unclear whether antiviral treatment reduces
cancer risk.
Cervical cancer
Consider these statistics: Worldwide, cervical cancer is the second most common cancer among women, and about 80% of all cervical
cancer cases occur in developing countries. In most of these, Pap tests are either unavailable or unaffordable. In the United
States, where Pap smears have provided a standard of care for decades, cervical cancer is the 14th leading cause of cancer
in women. The advantages provided by the Pap smear screening may soon be augmented by vaccines against the viral agent that
is believed to cause nearly 100% of cervical cancer cases, the human papillomavirus (HPV).1
Very few women who are infected with the HPV types that are most closely linked to cervical cancer actually develop this malignancy,
apparently because the infection usually resolves spontaneously. Nonetheless, most sexually active women eventually acquire
at least one type of HPV, an observation that has been the rationale for vaccine development. The major targets of the vaccines
now in development are HPV-16 and HPV-18, which account for about 70% of all cervical cancers according to the National Cancer
Institute.
Phase III trials are now under way for a quadrivalent HPV vaccine. In addition to HPV types 16 and 18, this vaccine also targets
types 6 and 11. In a phase II trial, this vaccine reduced the incidence of HPV infection by 90% in women who received the
vaccine compared to those who received a sham vaccine.16 Approval of this vaccine may occur within a year or 2.
Stomach cancer
About 20,000 Americans will receive a diagnosis of stomach cancer this year, making that malignancy the 15th most common one
in the United States. Its incidence has been declining here since 1975.
Infection with the bacterium Helicobacter pylori is considered the most likely cause of gastritis and peptic ulcers, and infection also increases the risk of gastric cancer,
except that of the gastric cardia, by a factor of at least 2 to 5 times.1 Overall, more than 60% of stomach cancer among Americans is probably attributable to H pylori infection.
Although regimens containing proton pump inhibitors and antibiotics effectively treat H pylori-induced ulcers, it remains unclear whether these regimens also prevent stomach cancer. It is interesting to note that some
investigators speculate that H pylori infection may reduce the risk of adenocarcinoma of the esophagus and gastric cardia by reducing gastric acid production and
stemming the progress of Barrett's esophagus (see "Latest thinking in Barrett's esophagus: Heading off esophageal cancer,").
Efforts to manufacture a vaccine against H pylori have been unsuccessful to date.
PHYSICAL ACTIVITY, WEIGHT REDUCTION, AND CANCER RISK
In its most recent document on cancer prevention, the ACS stated that among nonusers of tobacco, "improving diet, increasing
physical activity, and maintaining a healthy weight are the most important approaches to reducing the risk of developing cancer."2 The interactions of physical activity, overweight and obesity, weight reduction, and dietary factors are highly complex,
but some clarity is emerging from recent research. Most recently, data on exercise in the prevention of breast cancer recurrence
have been highly encouraging.
According to research compiled by the ACS, the risk of breast cancer is reduced by vigorous physical activity, probably because
exercise helps maintain a healthy body weight. In addition, it reduces levels of circulating estrogen. Exercise is associated
with lower cancer rates at other sites, including endometrial and prostate cancer. Physical activity is known to reduce the
risk of diabetes, which, as discussed, is linked to a higher probability of cancers of the colon, pancreas, and other organs.
The evidence supporting a link between increased physical activity and reduced cancer risk is now considered strong, and exercise
is a staple of any cancer prevention program. As one expert explains, even if the role of exercise in cancer prevention is
incompletely understood, exercise rarely has a down side. It helps keep body weight down, and it helps prevent heart disease,
osteoporosis, and diabetes and helps manage stress and depression.1 The same expert adds, however, that many patients would rather take a pill than exercise, and that physicians should be prepared
to spend time explaining the many-faceted importance of exercise in primary and secondary cancer prevention.
Drs Kaelin and Neugut disclose that they have no financial relationship with any manufacturer in this area of medicine.
This article was written by Mary Desmond Pinkowish, MPH, based on individual interviews with Drs Kaelin and Neugut. Barnett
Kramer, MD, Associate Director of Disease Prevention at the National Institutes of Health, also contributed to this article.
REFERENCES
1. American Cancer Society. Cancer Facts and Figures 2005. Atlanta: American Cancer Society, 2005. Available at: http://www.cancer.org/downloads/STT/CAFF2005f4PWSecured.pdf. Accessed August 29, 2005.
2. American Cancer Society. Cancer Prevention and Early Detection Facts and Figures 2005. Atlanta: American Cancer Society,
2005. Available at: http://www.cancer.org/downloads/STT/CPED2005v5PWSecured.pdf. Accessed August 29, 2005.
3. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001.
JAMA. 2003;289:76-79.
4. National Cancer Institute. Lung Cancer (PDQ): Prevention. Available at: http://www.nci.nih.gov/cancertopics/pdq/prevention/lung/healthprofessional. Accessed July 28, 2005.
5. Doll R, Peto R, Boreham J, et al. Mortality in relation to smoking: 50 years' observations on male British doctors. BMJ. 2004;328:1519. Epub 2004 Jun 22.
6. Mao L, Lee JS, Kurie JM, et al. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst. 1997;89:857-862.
7. Wistuba II, Lam S, Behrens C, et al. Molecular damage in the bronchial epithelium of current and former smokers. J Natl Cancer Inst. 1997;89: 1366-1373.
8. Preston DS, Stern RS: Nonmelanoma cancers of the skin. N Engl J Med. 1992;327:1649-1662.
9. English DR, Armstrong BK, Kricker A, et al. Case-control study of sun exposure and squamous cell carcinoma of the skin.
Int J Cancer. 1998; 77:347-353.
10. Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med. 1993;329:1147-1151.
11. Dennis LK, Beane Freeman LE, VanBeek MJ. Sunscreen use and the risk for melanoma: a quantitative review. Ann Intern Med. 2003;39:966-978.
12. Koh HK. Cutaneous melanoma. N Engl J Med. 1991;325:171-182.
13. Winawer S, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study
Workgroup. N Engl J Med. 1993;329:1977-1981.
14. Chang MH. Decreasing incidence of hepatocellular carcinoma among children following universal hepatitis B immunization.
Liver Int. 2003; 23:309-314.
15. Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857-861.
16. Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like
particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005;6:271-278.
And what about diet?
Cancer experts readily admit that the evidence favoring a plant-based diet is stronger for heart disease prevention than
for any other chronic disease, including cancer. The relationship between diet and cancer is notoriously difficult to study.
Foods with beta carotene have been associated with lower cancer rates, but trials of beta carotene supplementation have been
disappointing. Two studies, the Alpha-Tocopherol Beta Carotene (ATBC) trial and the Beta-Carotene and Retinol Efficacy Trial
(CARET), demonstrated that dietary supplementation with beta carotene in men who were heavy smokers actually increased rather
than decreased the risk of lung cancer. A prospective, randomized, controlled trial that could answer the most crucial questions
regarding diet and cancer would take years to complete and have many logistical and ethical challenges.
A 2004 prospective study of 72,000 women and nearly 38,000 men who were queried over a 14-year period about their dietary
choices showed a 12% decreased risk for heart disease among people who ate at least 5 servings of fruits and vegetables each
day. Plant consumption had no apparent effect on cancer incidence, however.1 In the European Prospective Investigation into Cancer and Nutrition, a 2005 study that included more than 285,000 women, no
association was found between breast cancer risk and plant consumption. The mean follow-up for this study was less than 6
years, however, leaving the door open to the possibility that an effect might have been observed if the participants had been
studied for a longer period.2
Several theories have been advanced to explain why more recent studies of diet and cancer risk have had different findings
than older studies, which tended to show that cancer risk was reduced when people ate high-fiber, high-plant diets. In general,
the older studies were retrospective. Prospective studies like the newer ones are considered more accurate. Others have suggested
that diet during childhood is more important than diet during adulthood. Finally, perhaps findings from population-based studies
obscure the possibility that diet makes a difference only in a minority of people who may be genetically predisposed to experience
a benefit from a plant-rich diet.
One new study supports an older relationship: Consumption of red meat is associated with an increased risk of colon cancer.3 The relationship is strongest for processed meats. This study also showed that long-term consumption of poultry and fish
was inversely correlated with colon cancer risk.
Alcohol increases the risk of cancers of the mouth, pharynx, larynx, esophagus, liver, and breast. The ACS cites a 2 drink
per day threshold for these malignancies. The effect is particularly damaging when combined with cigarette smoking. The effect
on breast cancer may be mediated by an alcohol-induced increase in estrogen levels. As a rule of thumb, women are encouraged
to restrict their intake to 1 standard drink per day, men to 2 drinks.
What should you tell patients about the association between diet and cancer? No magic bullets exist. It is prudent to eat
a plant-rich diet, but the benefits may tend toward cardiovascular risk rather than cancer risk. Eating a diet rich in vegetables
and fruits has no known drawbacks. Because cancer risk probably evolves over years, parents should make sure that children
and teens eat plenty of fruits and vegetables.
1. Hung HC, Joshipura KJ, Jiang R, et al. Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst. 2004;96:1577-1584.
2. Chao A, Thun MJ, Connell CJ, et al. Meat consumption and risk of colorectal cancer. JAMA. 2005;293:172-182.
3. van Gils CH, Peeters PHM, Bueno-de-Mesquita HB, et al. Consumption of vegetables and fruits and risk of breast cancer.
JAMA. 2005;293:183-193.
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