Tuesday, March 30, 2010

Oral contraceptives reduce cancer deaths

A recent study in the British Medical Journal adds further evidence that use of oral contraceptives reduces cancer mortality (full study). In the long term study of over 46,000 women who were followed for up to 39 years, Hannaford and colleagues reported that women who used oral contraceptives (OCs)  had lower mortality from cancers of the ovary, uterine body and colon (Hannaford, Iversen et al. 2010). OC use was not related to breast cancer mortality.

Approximately half of the women who had used OCs had used them for more than 4 years, and the risk of cancer death decreased the longer women had used OCs. These data extend previous work from the Nurses’ Health Study, which showed no overall adverse effect from use of OCs (Colditz and for the NHS research group 1994).

Oral contraceptives are one of the most widely used medications. Use of oral contraceptives (OCs) for 5 years halves a woman’s risk of developing ovarian cancer (see figure) and substantially reduces the risk of endometrial cancer  (Collaborative Group on Epidemiological Studies of Ovarian, Beral et al. 2008).

Data source: Beral et al, 2008 (click figure to enlarge)

The protection is long lasting and in high income countries rates of use approach 80 per cent. Adverse effects are largely limited to an increased risk of breast cancer and stroke while women are currently using OCs, a risk which seems to disappear within about ten years of stopping. These side-effects are strongly age-dependent - being more common the older a woman is. Thus use of OCs during late teens and early 20s could be expanded for greater reduction in ovarian and endometrial cancers and overall net public health benefit (Kawachi, Colditz et al. 1994).

Strong scientific evidence supports several other medications as either causing cancer  (e.g. postmenopausal hormone therapy with estrogen plus progestin) (Colditz 2007), or reducing cancer (e.g aspirin and colon cancer) (Chan, Giovannucci et al. 2005).

Postmenopausal hormones
For combination oestrogen plus progestin, the International Agency for Research on Cancer (IARC) has now classified this combination hormone therapy as carcinogenic in humans (2007), and estimates indicate that the reduction in use of hormones after the widespread publicity of the results of the Women’s Health Initiative (stopped early due to excess breast cancer) accounts for approximately a 10 per cent decline in breast cancer incidence among women 40 to 70 years of age (Colditz 2007). Thus for this combination therapy evidence shows that risk rises with duration of use and that acting as a late promoter, removal of the drug leads to a rapid decline in incidence (Colditz 2007), though among women with longer durations of use risk may not return to that of women who have never used combination therapy (Colditz and Rosner 2000).

Other less widespread drugs may also contribute to cancer risk (e.g., DES), but the population impact will be substantially smaller than the examples based on much more widespread use described above.

For some medications that reduce cancer risk, the benefits have been limited to date to those who have had the specific indications to use the medication. Broader population strategies may be developed for more widespread protection, such as could be achieved if all women took oral contraceptives as a chemopreventive for a minimum of 5-years.

Aspirin has been extensively studied in observational studies that address duration of use, dose, and magnitude of risk reduction. This evidence is consistent with evidence from randomized primary prevention trials showing that the use of 300 mg or more of aspirin a day for 5 years or more is effective in preventing colon cancer; reducing risk by approximately 25 per cent (Flossmann and Rothwell 2007). A latency of about 10 years is observed between onset of use of aspirin and the reduction in cancer. Like all chemoprevention strategies, risks and benefits must be balanced (Glasziou and Irwig 1995). To date, the risk-benefit considerations of cardiovascular disease, bleeding complications, stomach pain and heart burn caused by aspirin have precluded recommendations for aspirin use as a widespread prevention strategy (Gralow, Ozols et al. 2008).

Selective estrogen receptor modulators (SERMs)
Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, have been shown in randomized controlled prevention trials to reduce incidence of pre-invasive and invasive breast cancer (Fisher, Costantino et al. 1998; Martino, Cauley et al. 2004). While tamoxifen increases risk of uterine cancer, this is not so for raloxifene and the risk profile for raloxifene looks considerably safer (Chen, Rosner et al. 2007).

Based on these risks and benefits of therapy, we have estimated the potential for risk reduction among women over age 50 who are postmenopausal. Our estimates indicate that if the trade-off of excess adverse events versus cases of breast cancer prevented must be less than 1, then approximately 30 per cent of the 27 million women between ages 50 and 69 in the United States have benefits exceeding risks, and would achieve a 50 percent reduction in the burden of breast cancer by taking a SERM. This is a population benefit of 42,900 fewer cases of invasive breast cancer among the more than 7 million women with sufficiently high risk to justify chemoprevention (Chen, Rosner et al. 2007).

The reduction in breast cancer risk observed in the chemoprevention randomized trials is very rapid; within 2 years of beginning SERM therapy, incidence curves have clearly separated. This is consistent with the pharmacologic action of these agents inhibiting estrogen receptors. Importantly these agents show protection against estrogen receptor (ER) positive breast cancers (risk reduction up to 76 per cent) and no protection against receptor negative cancers (Martino, Cauley et al. 2004).

While statistical models to predict and classify risk of breast cancer have been developed and validated, to date, prediction of receptor positive tumors is no more accurate than prediction of risk overall (Colditz, Rosner et al. 2004).  Refining risk stratification and developing tools to aid women in considering trade-offs of risks and benefits of chemoprevention therapy are necessary next steps to informed choices for prevention for women at elevated risk of breast cancer.

While all drugs have risks and benefits, some of the agents described here have the potential to substantially reduce risk of cancer. Balancing risks and benefits remains an important decisions that should be reviewed with a heath care provider.

Literature cited
Chan, A. T., E. L. Giovannucci, et al. (2005). "Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer." JAMA 294(8): 914-923.
Chen, W. Y., B. Rosner, et al. (2007). "Moving forward with breast cancer prevention." Cancer 109(12): 2387-2391.
Colditz, G. and for the NHS research group (1994). "Oral contraceptive use and mortality during twelve years of follow-up." Ann Intern med 120: 821-826.
Colditz, G. A. (2007). "Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin." Breast Cancer Res 9(4): 108.
Colditz, G. A. and B. Rosner (2000). "Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses' Health Study." Am J Epidemiol 152(10): 950-964.
Colditz, G. A., B. A. Rosner, et al. (2004). "Risk factors for breast cancer according to estrogen and progesterone receptor status." J Natl Cancer Inst 96(3): 218-228.
Collaborative Group on Epidemiological Studies of Ovarian, C., V. Beral, et al. (2008). "Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls." Lancet 371(9609): 303-314.
Fisher, B., J. P. Costantino, et al. (1998). "Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study." J Natl Cancer Inst 90(18): 1371-1388.
Flossmann, E. and P. M. Rothwell (2007). "Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies." Lancet 369(9573): 1603-1613.
Glasziou, P. P. and L. M. Irwig (1995). "An evidence based approach to individualising treatment." BMJ 311(7016): 1356-1359.
Gralow, J., R. F. Ozols, et al. (2008). "Clinical cancer advances 2007: major research advances in cancer treatment, prevention, and screening--a report from the American Society of Clinical Oncology." J Clin Oncol 26(2): 313-325.
Hannaford, P. C., L. Iversen, et al. (2010). "Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners' Oral Contraception Study." BMJ 340: c927.
International Agency for Research on Cancer (2007). "Combined estrogen-progestogen contraceptives and combined estrogen-progestogen menopausal therapy." IARC Monogr Eval Carcinog Risks Hum 91: 1-528.
Kawachi, I., G. A. Colditz, et al. (1994). "Long-term benefits and risks of alternative methods of fertility control in the United States." Contraception 50(1): 1-16.
Martino, S., J. A. Cauley, et al. (2004). "Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene." J Natl Cancer Inst 96(23): 1751-1761.

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