Missed Opportunities to Prevent Cervical Cancer: Use of HPV Vaccine Still Low

Photo: Flickr/Melissa Wiese 

To work in the field of cancer prevention one has to be an optimist at heart.  In the science, in the statistics, and in the news, you see not only the broad burden of cancer but also the vast opportunities that exist to lower risk and prevent the disease.

At the same time, we understand that shifting environments, attitudes, and behaviors in positive directions can take years, and most likely decades.  We didn't overnight become a nation where two-thirds of us are overweight/obese and half of us get little or no activity.  So it follows that shifting the pendulum in the other direction won't happen overnight either.  Such issues take daily efforts year after year to address both on a personal level and on a societal level.  There are no magic bullets.

Yet, however optimistic, there are two issues that leave many in the public health and medical professions scratching their heads over: the underuse of two relatively simple medical strategies that have vast potential for preventing cancer.

We've written at length about both of these strategies here in CNiC: the use of medications to prevent breast cancer in those at high risk of the disease (posts), and the use of the HPV vaccine to prevent cervical cancer (posts).

Of these two, the low use of the medications tamoxifen and raloxifene is perhaps the hardest to understand, given the large demonstrated benefits they have in preventing breast cancer in high risk women and the yawning gap between the number of women who likely stand to benefit from taking them (well over 2 million) and the number who actually do take them (just 117,000).

While new data on the HPV vaccine show there's been some progress in its use, the numbers also fall well short of what should be possible based on the use of other standard childhood vaccines. The vaccine is recommended for all girls and boys ages 11 or 12, given in a three dose course.  Its safety has been well-documented. Yet, only 57% of girls and 35% of boys get one or more doses of the vaccine.  Count only those who've received the full three doses, and the numbers fall to 38% for girls and 14% for boys.  Based on the number of children in this age-group cohort who receive other vaccines at their standard health care visits, and these percentages could realistically be as high as 91%.

The primary reasons parents give for not vaccinating their children were similar for both girls and boys, including the vaccine not being recommended by the health care provider, concerns about safety, and lack of knowledge of the vaccine or feeling it wasn't needed.

Both of these cases -  low use of the HPV vaccine and of tamoxifen/raloxifene - demonstrate just how important broad-based efforts at education are. It is not enough to demonstrate cancer prevention benefits - even benefits from activities as relatively simple as getting a vaccine or taking a pill.  Concerns of patients, parents, and health care providers must be appropriately addressed while we also move ahead fostering knowledge of, and demand for, the benefits the vaccine and preventive medications provide.

The trend in HPV vaccination show's we're making some progress on that front.  We have to be happy with that, but as usually, we'll keep striving for more.

More potential for breast cancer prevention

In the Journal of the National Cancer Institute a new study shows promise for reducing risk for beats cancer through another osteoporosis drug (Lacroix, Powles et al. 2010). Risk of breast cancer is reduced but the small number of women in the trial does not rule out side effects similar to tamoxifen. 

The potential for prevention of breast cancer through drug therapies is supported by results from randomized trials of SERMs (Fisher, Costantino et al. 1998; Cummings, Duong et al. 2002; Martino, Cauley et al. 2004; Vogel 2010; Vogel, Costantino et al. 2010). Both tamoxifen and raloxifene have been shown to reduce the incidence of invasive breast cancer by approximately 50%, with the benefit largely limited to ER+ tumors, where risk is reduced by as much as 80%. Adverse effects of tamoxifen suggest that the potential use for chemoprevention will be limited to a subset of women at increased risk and younger in age, in large part because of increasing incidence of adverse effects with age (Gail, Costantino et al. 1999). The adverse effects experienced in the 8 year randomized trial of raloxifene (Continuing Outcomes Relevant to Evista (CORE)), on the other hand, are somewhat fewer than those observed for tamoxifen (Chen, Rosner et al. 2007). Of note, there was no statistically significant difference in overall mortality or uterine cancer among women randomized to Raloxifene compared to placebo. While Raloxifene is approved in the United States for use to prevent osteoporosis in postmenopausal women (Physicians' Desk Reference 2005), and a number of cost effectiveness studies support this use in conjunction with screening for osteoporosis (Kanis, Borgstrom et al. 2005; Stevenson, Lloyd Jones et al. 2005; Mobley, Hoerger et al. 2006).

We calculated some numbers to help women decided (Chen, Rosner et al. 2007). Among women in the top 10 percent of breast cancer risk in each 5-year age group we estimated how many women would need to take a SERM for 5 years to prevent one case of breast cancer. Thee numbers are summarized in the table below from Chen, et al., Cancer 2007. Physicians will need to play a key role in advising women in this rapidly evolving field.

Age group	Incidence of breast cancer per 100,000	Number treated for 5 years to prevent 1 case
50-54	504	79
55-59	668	60
60-64	756	53
65-69	921	43

A number of explanations have been proposed for the low use of tamoxifen for preventing breast cancer (Waters, Cronin et al. 2010)(see story) . These include the need for drug (hormone therapy), conerns regarding the adverse effect (increased risk fo endometrial cancer), and other side effects (Waters, Weinstein et al. 2007; Waters, Weinstein et al. 2009)

Related CNiC post

Reduce risk of breast cancer through action today

Literature cited

Chen, W. Y., B. Rosner, et al. (2007). "Moving forward with breast cancer prevention." Cancer 109(12): 2387-2391.

Cummings, S. R., T. Duong, et al. (2002). "Serum estradiol level and risk of breast cancer during treatment with raloxifene." JAMA 287(2): 216-220.

Fisher, B., J. 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: 1371-1388.

Gail, M. H., J. P. Costantino, et al. (1999). "Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer." J Natl Cancer Inst 91(21): 1829-1846.

Kanis, J. A., F. Borgstrom, et al. (2005). "Cost-effectiveness of raloxifene in the UK: an economic evaluation based on the MORE study." Osteoporos Int 16(1): 15-25.

Lacroix, A. Z., T. Powles, et al. (2010). "Breast Cancer Incidence in the Randomized PEARL Trial of Lasofoxifene in Postmenopausal Osteoporotic Women." J Natl Cancer Inst.

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.

Mobley, L. R., T. J. Hoerger, et al. (2006). "Cost-effectiveness of osteoporosis screening and treatment with hormone replacement therapy, raloxifene, or alendronate." Med Decis Making 26(2): 194-206.

Physicians' Desk Reference (2005). Evista. Physicians' Desk Reference. Montvael, NJ, Thompson: 1836-1839.

Stevenson, M., M. Lloyd Jones, et al. (2005). "A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis." Health Technol Assess 9(22): 1-160.

Vogel, V. G. (2010). "Tipping the Balance for the Primary Prevention of Breast Cancer." J Natl Cancer Inst.

Vogel, V. G., J. P. Costantino, et al. (2010). "Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer." Cancer Prev Res (Phila) 3(6): 696-706.

Waters, E. A., K. A. Cronin, et al. (2010). "Prevalence of tamoxifen use for breast cancer chemoprevention among U.S. women." Cancer Epidemiol Biomarkers Prev 19(2): 443-446.

Waters, E. A., N. D. Weinstein, et al. (2009). "Explanations for side effect aversion in preventive medical treatment decisions." Health Psychol 28(2): 201-209.

Waters, E. A., N. D. Weinstein, et al. (2007). "Reducing aversion to side effects in preventive medical treatment decisions." J Exp Psychol Appl 13(1): 11-21.

Breast Cancer Prevention

New data from long term follow-up of women participating in the STAR trial, a study comparing Tamoxifen and Raloxifene (known as SERMS) for prevention of breast cancer, show strong and persisting benefits of reduced breast cancer risk after stopping therapy (see abstract). This is an important addition to our understanding. Based on follow-up of 18,747 women in the STAR trial the updated results highlight the value of extended follow-up of participants in trials to better understand the overall impact of interventions for cancer prevention. We summarized these key questions for cancer prevention in an earlier blog posting and in a recent article.

Moving from the results of the STAR trial to implementing prevention requires that we have an approach to identify women who are at increased risk of breast cancer. While numerous models have been developed to prediction of breast cancer, it is worth remembering that any of these models does not tell us who will get cancer and who will not, but rather we can place women according to their level of risk, much above average, above average, average, etc. This is the approach we use in Your Disease Risk and is based on evidence from communication science about understanding of risk. For decisions regarding use of a drug to prevent cancer, the challenge is balancing the risks of side effects against the known benefits. The higher the risk group taking the preventive agent the stronger the balance of benefits exceeding risks.  This balance, of course, applies throughout medicine whether we talk about drugs, surgery, or other medical interventions.

Take for example the strong genetic predisposition to breast cancer that is present in women who carry the BRCA1 or BRCA2 mutation. Lifetime risk in these women is around 50 to 60% so among those with the mutation we have about a 50/50 chance of knowing who will get breast cancer. On the other hand the combined data from 10 studies now clearly show that for these high risk women bilateral oophorectomy halves their risk of breast cancer (see article).

To bring results from a randomized trial of efficacy to the patient population we must weigh risks of side effects against the expected benefits of therapy for individual patients (Glasziou and Irwig set out an approach for evidence based individualized treatment).  We previously estimated a scenario to weight risks and benefits under the assumption that we wanted to prevent more breast cancers than major medical events that might be caused as side effects from taking drugs, see article. We show that among the 26 million women in the US between ages 50 and 69, 7.8 million have risk above a break even point and that over 22,000 cases of breast cancer can be avoided each year by using a SERM in this group. The new data add a refinement to these estimates as the benefit of taking a SERM persists after stopping and the side effects are reduced after stopping. This tips the ratio of benefits to risks more strongly in favor of taking drug to prevention breast cancer. The overall reduction in risk remains at about 50%, or halving the risk of breast cancer during the years the drug is taken and this benefit continuing after stopping.

What are the side effects? Tamoxifen causes endometrial cancer while Raloxifene does not. Pulmonary embolism and deep-vein thrombosis are now well recognized side effects of Tamoxifen. Raloxifene had significantly lower rates of these events in the STAR trial. Overall 2.47 thromboembolic events were reported per 1000 women per year among those taking Raloxifene. One approach to estimating benefits and risks assumes women have a 4% risk of breast cancer over the next 5 years. See related report.  The benefits and risks are summarized below for 1000 women over 7 years

	Raloxifene	Tamoxifen
Invasive breast cancer prevented	15	20
Noninvasive breast cancer prevented	16	20
Endometrial cancer caused	0	2.25
Thromboembolic events caused	2.47	3.3
Benefit to risk ratio	31 vs. 2.47 or 13:1	40 vs. 5.55 or 7:1

If we rerun these numbers using a lower cut point for the 5-year risk of breast cancer, the benefit to risk ratio will come closer to 1.

Of course the importance placed on side effects from SERMS may differ among women. In our estimate, we assumed a deep vein thrombosis (a side effect of SERMS) was equal to a prevented breast cancer. Other options may apply in individual decision making. Tools to help women and their health care providers balance risks and benefits may soon help lay out these considerations.