The Ribbon Newsletter

Life is not simple, especially when it comes to health choices. The educated consumer is continually bombarded with an ever-changing list of exposures from diet, other health behaviors, and the environment that increase the risk of developing diseases, including cancer. Making it all the more overwhelming, in a number of cases the beneficial and risky exposures can overlap to varying degrees, placing one in a position where a balance between these two effects must be reached. This discussion will examine the basic characteristics of this balance between risk and benefit. Postmenopausal hormone therapy, also called hormone replacement therapy, will be used as an example throughout this discussion (See BCERF Fact Sheet No. 40, Hormone Treatments and the Risk of Breast Cancer). Scientific understanding of the balance of risk and benefit for postmenopausal hormone therapy has changed rapidly in the last year and provides a good example for this discussion. Although the focus will be breast cancer risk, these risk/benefit characteristics should be applicable to other health areas.

It is commonly known that risk refers to increases in injury or harm, while benefit refers to decreases in injury or harm. But these terms, as used in epidemiology, are frequently misunderstood. The misunderstanding arises from two of their characteristics.

First, both terms represent the probability (or in other words, the possibility or likelihood) of the occurrence of harm or benefit. Risk is linked to increased possibility of injury or harm and benefit is linked to decreased possibility of injury or harm. In epidemiological studies, risk and benefit are given numerical values. A lack of an effect on risk or benefit -- no risk or benefit -- has a value of one. Benefits (implying decreased risk) have a risk value less than one, and a risk (implying increased risk) has a value greater than one.

Second, most epidemiological studies evaluate risk or benefit relatively. This means that the risk or benefit of an exposed group is determined in relation or comparison to that of a similar but unexposed group. As an example, a study can examine the relative risk of breast cancer for women using postmenopausal hormone therapy. Such a study would compare the risk of breast cancer among women using postmenopausal hormone therapy with the breast cancer risk of a similar group of women who were not using this treatment. Studies of this type have found that women using postmenopausal hormone therapy had a probability of getting breast cancer that was greater than that of women not using this treatment. The size of the difference in these two probabilities is expressed as the relative risk. The relative risk is the number by which the non-user's breast cancer probability would have to be multiplied to equal the user's breast cancer probability.

Women currently using postmenopausal hormone treatment containing estrogen alone for five years or more had a relative breast cancer risk of 1.35, or a 35% increase in breast cancer risk (Collaborative Group, 1997). It is important to realize that this finding only pertains to women in these two groups. Further, the risk value is accurate across the whole group of women with these characteristics (currently using estrogen-only hormone replacement treatment for five years or more years) but is not accurate for a single individual within the group. Thus, looking at two individual women, "Jane" who is currently using estrogen-only postmenopausal hormone treatment and "Mary" who is not, Jane's risk of breast cancer is not 35% greater that of Mary's. The individual breast cancer risk for each of these women is not known. The epidemiological studies only define the breast cancer risk of the groups to which these two women belong.

We are all aware that anything, even something good, taken to an extreme is likely to be harmful. This suggests that dose -- or level of exposure -- may play a key role in the risk/benefit balance. In most cases, the dose or level of exposure does indeed determine the balance between risk and benefit. Yet this is not always the case, and there can be overlaps in risks and benefits for some exposures. Postmenopausal hormone treatment provides a good example. Postmenopausal hormone treatment was very successfully marketed in the 1960s for the control of symptoms associated with menopause, protection against osteoporosis, reduction of breast and genital cancers, as well as for the unsubstantiated claims of reducing wrinkles, aiding mental clarity and increasing sexual libido. The early preparations contained only estrogens (estrogen-only treatment). In the mid 1970s two groups of investigators reported that there was a delicate risk/benefit balance for estrogen-only postmenopausal hormone treatment (Smith et al., 1975; Ziel and Finkle, 1975). Estrogen-only treatment was found to greatly increase the risk of uterine cancer. One of these studies found that use for seven or more years increased the relative risk of uterine cancer among women in the group of users to a very large extent (the relative risk was 14). Subsequent to these studies, estrogen-only postmenopausal hormone treatment was recommended for use only in women who had had a hysterectomy and did not have a uterus. Later studies indicated that the addition of another reproductive hormone, progesterone, to the estrogen-only treatment would greatly decrease the risk of ovarian cancer and apparently restore the risk-benefit balance to an acceptable level. This type of treatment, called combination postmenopausal hormone treatment (estrogen combined with progesterone), was substituted for the estrogen-only treatment and became commonly used.

Understanding risk/benefit balance is dependent on current scientific knowledge

The apparent balance between risk and benefit in postmenopausal hormone therapy is totally dependent on the current understanding of the process or form of treatment being evaluated. In addition, some types of scientific evaluations have greater certainty and are less likely to change to a great extent. Studies that examine the health effects of practices and treatments can be divided into two classes. First are the observational studies that examine the health of people under treatment and compare them to similar people not being treated. These types of studies continue to provide a great deal of scientific understanding, but they are less reliable than the second type of studies, the clinical trial. Clinical trials gather together a group of people, randomly assign them to a treatment or placebo (no treatment) group and assure that neither the scientists nor the subjects know to which group they belong. Such clinical trials are considered the 'gold standard' for determining the effectiveness and safety of treatments.

A recent large clinical trial, the Women's Health Initiative, organized by the Center for Disease Control and prevention, the National Center for Chronic Disease Prevention and Health Promotion and the National Institutes of Health, examined the health effects of both combination and estrogen-only postmenopausal hormone treatment (Rossouw et al., 2002). Even though these treatments had been in use for many years, this was the first clinical trial to examine postmenopausal hormone therapy in healthy women. The results were very surprising. Prior to this study use of postmenopausal hormone treatment was based largely on observational studies. Many but not all of these observational studies supported the idea that postmenopausal hormone treatment had a favorable risk/benefit balance. It appeared to decrease the risk of cardiovascular disease, prevent osteoporosis and decrease colorectal cancer, which would apparently outweigh a increased risk of breast cancer (2% for each year of use for estrogen-only treatment and 6% to 8% per year for combination treatment) and ovarian cancer. After an average follow-up of five years, the combination therapy part of the Women's Health Initiative trial was stopped due to an excess number of breast cancer cases; breast cancer risk was increased 26%. (The portion of the study examining estrogen-only postmenopausal hormone therapy will be completed in March 2005.) Analysis of other health effects raised further concern. Cardiovascular benefits were not seen: the risk of coronary heart disease was increased 29%, the risk of stroke was increased 41% and the risk of blood clots in the lungs was increased 113%. Some benefits were seen but not to the extent that they outweighed these risks. The risk of colorectal cancer decreased by 37% and the risk of hip fractures was decreased by 34%. It should be kept in mind that these values represent those seen when the trial was terminated for subject safety reasons. A longer period of treatment is typical for postmenopausal hormone treatment and excess risk would be expected to be higher.

Risks and benefits are different for different parts of the body; overall balance is critical

The balance of risk and benefit must be seen from a holistic point of view. Treatments and practices may be harmful to one aspect of health while helpful to another. The recent findings of the Women's Health Initiative trial described above illustrate this characteristic well. Combination postmenopausal hormone therapy decreased the risk of colorectal cancer and hip fractures, but these benefits were outweighed by increased risks of breast cancer, heart disease, stroke and blood clots in the lungs.

Responses to different treatments and exposures can be different depending on a person's age and the development of the organs in question. This characteristic has special relevance for the breast. Women's breasts change throughout life and can be characterized as having multiple periods of development. Studies in animals and humans have suggested that the breast is affected by estrogen differently during these periods. During some periods, estrogen exposure is considered beneficial, such as during adolescence when estrogen plays a role in normal development of the breast. However, during other periods estrogen exposure can be harmful, as the Women's Health Initiative trial of postmenopausal hormone therapy has shown for the period after menopause (postmenopause).

The Women's Health Initiative has also recently reported another serious effect of combination postmenopausal hormone therapy that was age-specific and affected older postmenopausal women (Shumaker et al., 2003). Women older than 65 using combination postmenopausal hormone therapy were found to have twice the risk of dementia of similar women receiving placebo.

Risk and benefit information is derived from representative populations -- but this information does not apply directly to individuals within those populations

Epidemiological analyses of risk and benefit optimally study large groups of people that are representative of the population in question. The risks and benefits determined from these studies are not accurate for individual people. This is well shown by the risk/benefit analysis from the Women's Health Initiative trial of combination postmenopausal hormone therapy discussed above (Rossouw et al., 2002). The table below converts the changes in risk for heart disease, stroke, etc., to increases (risk) or decreases (benefits) in health-related events each year for every 10,000 women using this treatment.

	Risk Increased in health-related events per year for every 10,000 women	Benefit Decrease in health-related events per year for every 10,000 women
Heart Disease	7
Strokes	8
Blood Clots in Lungs	8
Breast Cancer	8
Colorectal Cancer		6
Hip Fractures		5
TOTAL	31	11

Table 1. Risks and Benefits of Combination Postmenopausal Hormone Treatment
from the Women's Health Initiative trial at the time it was terminated

As the table shows, an increase of 31 health-related risks (heart disease, strokes, lung blood clots and breast cancer) would be predicted for every 10,000 women using this treatment. This is almost three times the predicted decrease in health-related benefits. In addition, these numbers would have been greater if the study had not been ended early. This does not, however, indicate a large individual risk: 0.3 % of the women would be predicted to have harmful health effects. However, acceptance of even this low level of risk has been questioned as other treatments with a more favorable risk/benefit balance are available for most of the menopausal symptoms for which postmenopausal hormonal hormone therapy has been typically used (Grady, 2003). The exceptions would be extreme osteoporosis and extreme hot flashes. In the case of the hot flashes, minimal doses have been recommended. Since this symptom in usually resolved in a few years, it has also been recommended that the need to continue the treatment be checked every six months.

The Women's Health Initiative has also predicted that, although the individual risk for this treatment is low, the impact on society as a whole is large. It is estimated that at least five million women in this country were using combination hormone therapy. From this number it would be predicted that each year more than 15,500 women would suffer serious adverse health effects related to this treatment. In addition, the women who will suffer adverse affects related to this treatment cannot be medically identified.

This article describes some characteristics of the balance between risk and benefit, as they relate to our evaluation of health choices. Knowing what we do that increases our risk for various diseases, as well as which actions decrease our risk, can focus our efforts for change. It is also important to be aware of areas in which the balance of risk and benefit is less well defined scientifically -- and to be aware of changes that take place over time in these scientific understandings.

Collaborative Group on Hormonal Factors in Breast Cancer. "Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer." Lancet 350 (1997): 1047-1059.

Smith, D. C., Prentice, R., Thompson, D. J., and Herrmann, W. L. "Association of exogenous estrogen and endometrial carcinoma." N Engl J Med 293 (1975): 1164-1167.

Ziel, H. K., and Finkle, W. D. "Increased risk of endometrial carcinoma among users of conjugated estrogens." N Engl J Med 293 (1975): 1167-1170.

Rossouw, J. E., Anderson, G. L., Prentice, R. L., LaCroix, A. Z., Kooperberg, C., Stefanick, M. L., Jackson, R. D., Beresford, S. A., Howard, B. V., Johnson, K. C., et al. "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial." Jama 288 (2002): 321-333.

Shumaker, S. A., Legault, C., Thal, L., Wallace, R. B., Ockene, J. K., Hendrix, S. L., Jones, B. N., 3rd, Assaf, A. R., Jackson, R. D., Kotchen, J. M., et al. "Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial." Jama 289 (2003): 2651-2662.

Grady, D. "Postmenopausal hormones--therapy for symptoms only." N Engl J Med 348 (2003): 1835-1837. 6 Risk/Benefit Balance

Balancing Risk and Benefit in an Environment of Emerging and Shifting Understandings The Ribbon

Balancing Risk and Benefit in an Environment of Emerging and Shifting Understandings
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