MD

Everyone in community oncology practice has a role to play in the delivery of quality care. If you are looking to implement a quality program, each member of the practice, patients included, should be involved in the planning, implementing, reporting, and revising processes. Once those processes are in place, the practice can set up partnerships with payers based on standardized measures, costs, and outcomes, with appropriate payments.

Click on the PDF icon at the top of this introduction to read the full article.

Everyone in community oncology practice has a role to play in the delivery of quality care. If you are looking to implement a quality program, each member of the practice, patients included, should be involved in the planning, implementing, reporting, and revising processes. Once those processes are in place, the practice can set up partnerships with payers based on standardized measures, costs, and outcomes, with appropriate payments.

Click on the PDF icon at the top of this introduction to read the full article.

Everyone in community oncology practice has a role to play in the delivery of quality care. If you are looking to implement a quality program, each member of the practice, patients included, should be involved in the planning, implementing, reporting, and revising processes. Once those processes are in place, the practice can set up partnerships with payers based on standardized measures, costs, and outcomes, with appropriate payments.

Click on the PDF icon at the top of this introduction to read the full article.

Review

Walter F. Baile MD

^,

  [Author vitae]

Correspondence to: Walter F. Baile, MD, Program in Interpersonal Communication and Relationship Enhancement, University of Texas MD Anderson Cancer Center, Houston, TX 77030; telephone: (713) 745-4116; fax: (713) 794-4236

Review

Walter F. Baile MD

^,

  [Author vitae]

Correspondence to: Walter F. Baile, MD, Program in Interpersonal Communication and Relationship Enhancement, University of Texas MD Anderson Cancer Center, Houston, TX 77030; telephone: (713) 745-4116; fax: (713) 794-4236

Review

Walter F. Baile MD

^,

  [Author vitae]

Correspondence to: Walter F. Baile, MD, Program in Interpersonal Communication and Relationship Enhancement, University of Texas MD Anderson Cancer Center, Houston, TX 77030; telephone: (713) 745-4116; fax: (713) 794-4236

If they wish, women can have more control over when and if they menstruate. By using hormonal contraceptives in extended or continuous regimens, they can have their period less often, a practice called menstrual manipulation or menstrual suppression.

Actually, with the help of their clinicians, women have been doing this for years. But now that several products have been approved by the US Food and Drug Administration (FDA) specifically for use in extended or continuous regimens, the practice has become more widely accepted.

Reasons for suppressing menstrual flow range from avoiding bleeding during a particular event (eg, a wedding, graduation, or sports competition) to finding relief from dysmenorrhea or reducing or eliminating menstruation in the treatment of endometriosis, migraine, and other medical conditions exacerbated by hormonal changes around the time of menses.¹ Alternatively, some women may practice menstrual manipulation for no other reason than to simply avoid menstruation.

MENSTRUAL DISORDERS ARE TROUBLESOME, COMMON

Each year in the United States, menstrual disorders such as dysmenorrhea (painful menstruation), menorrhagia (excessive or frequent menstruation), metrorrhagia (irregular menstruation), menometrorrhagia (excessive and irregular menstruation), and premenstrual syndrome affect nearly 2.5 million women age 18 to 50 years.² Menstrual disorders are the leading cause of gynecologic morbidity in the United States, outnumbering adnexal masses (the second most common cause) by a factor of three.² In addition, these disorders extend into the workplace, costing US industry about 8% of its total wage bill.³

A BRIEF HISTORY OF CONTRACEPTIVE DEVELOPMENT

The idea of using progestins for birth control was first advanced in the 1950s by Dr. Gregory Pincus, who proposed a regimen of 21 days of active drug followed by 7 drug-free days to allow withdrawal bleeding, mimicking the natural cycle.⁴ This “21/7” regimen was designed to follow the lunar cycle in the hope it would be, in the words of Dr. John Rock, “a morally permissible variant of the rhythm method,”⁵ thereby making it acceptable to women, clinicians, and the Catholic Church.

In 1977, Loudon et al⁶ reported the results of a study in which women took active pills for 84 days instead of 21 days, which reduced the frequency of menstruation to every 3 months. Since then, extending the active pills beyond 21 days to avoid menses and other hormone-withdrawal symptoms has become popular in clinical practice, and many studies have investigated the extended or continuous use of oral and other forms of contraception to delay menses.^7–18

CURRENT METHODS OF MENSTRUAL MANIPULATION

A variety of available products prevent conception by altering the menstrual cycle:

• Oral estrogen-progestin contraceptive pills
• A drug-releasing intrauterine device
• Depot medroxyprogesterone acetate injections
• 
  A transdermal contraceptive patch
• A contraceptive vaginal ring
• An implantable etonogestrel contraceptive.

Their use in menstrual manipulation is summarized in Table 1.

Oral contraceptive pills

The most common way to manipulate the menstrual cycle is to extend the time between hormone-free weeks in an oral contraceptive regimen.

If the patient is young, you can prescribe a monophasic 21/7 oral contraceptive and tell her to take one active pill every day for 21 days and then start a new pack and keep taking active pills for up to 84 consecutive days, skipping the placebo pills until she wants to have her menstrual period. She can choose which week to have it: if the scheduled 12th week of an extended-cycle oral contraceptive regimen is inconvenient, she can plan it for week 10, or week 9, or whichever week is convenient.

The rationale for using an 84-day (12-week) cycle is that it still provides four periods per year, alleviating fears of hypertrophic endometrium.¹⁹

In this scenario, unscheduled or breakthrough bleeding can be managed by taking a “double-up pill” from a spare pack on any day breakthrough bleeding occurs and until it resolves. Menstrual periods should not be planned for intervals shorter than 21 days, owing to the risk of ovulation. Missed days of pills or use of placebo pills should also not exceed 7 days to prevent escape ovulation. ²⁰

In some women with endometriosis and other medical reasons, continuous oral contraception with no placebo week can be prescribed.

Unfortunately, the downside to suppressing withdrawal bleeding is unscheduled or “breakthrough” bleeding. The best way to treat this unscheduled bleeding is not known. Patients who are not sexually active can be reassured that the goal of an atrophic endometrium can still be achieved, with resultant pill amenorrhea (particularly useful for those with severe dysmenorrhea or other reasons to want to avoid flow). Patients could also try to manage flow by periodically taking a 3- to 5-day break from hormone-containing pills to allow flow. They can also try switching to another oral contraceptive that has a different progestin that would spiral the arterioles of the endometrium more tightly and thus more aggressively induce atrophy.^13,17,21 For instance, levonorgestrel is 10 to 20 times more potent than norethindrone. Choosing a pill with a higher monophasic dosing of levonorgestrel or a similar progestin may minimize unscheduled bleeding.

Currently, several oral contraceptives are approved for use in an extended regimen.

Seasonale was the first oral contraceptive marketed in the United States with an extended active regimen.²² It comes in a pack of 84 pills containing ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg, plus 7 placebo pills.

Seasonique is similar to Seasonale, but instead of placebo pills it has seven pills that contain ethinyl estradiol 0.010 mg.

Lybrel is a low-dose combination containing ethinyl estradiol 0.02 mg and levonorgestrel 0.09 mg. Packaged as an entire year’s worth of active pills to be taken continuously for 365 days without a placebo phase or pillfree interval,²³ it is the only FDA-approved continuous oral contraceptive available in the United States.

Intrauterine devices were originally developed as contraceptives. The addition of a progestin to these devices has been shown to reduce heavy menstrual bleeding by up to 90%.^24,25

Mirena IUS, a levonorgestrel-releasing device, is the only medicated intrauterine device that is currently available in the United States. (“IUS” stands for “intrauterine system.”) It was recently approved by the FDA to treat heavy menstrual bleeding in women who use intrauterine contraception as their method of pregnancy prevention.²⁶ About 50% of women who use this device develop amenorrhea within 6 months of insertion, while 25% report oligomenorrhea.²⁷

The Mirena device can be left in the uterus for up to 5 years. It may be a good choice for inducing amenorrhea in women with hemostatic disorders or in whom estrogen either is contraindicated or causes health concerns.¹⁸ The copper intrauterine device (Paragard; Duramed Pharmaceuticals Inc., Pomona, NY) remains a viable option for those who cannot or do not tolerate hormonal therapy. However, Mirena may provide less unscheduled bleeding than the copper intrauterine device.

Depot medroxyprogesterone acetate injections

Depo-Provera (depot medroxyprogesterone acetate) injections are given at 90-day intervals. ²⁸ This contraceptive method inhibits ovulation and decidualizes the endometrium, thereby reducing or eliminating uterine bleeding. ²⁹

While new users may initially experience excessive prolonged bleeding (10 or more days) while shedding their existing lining, the rate of amenorrhea has been shown to increase over time as the lining atrophies.³⁰ Thus, prolonged use of this agent reduces the frequency of menstruation as well as menstruation-related symptoms.

Depot medroxyprogesterone acetate is ideal for patients whose menstrual periods pose a significant hygiene problem (eg, developmentally challenged girls). In our experience, the injections can be given at shorter intervals to induce atrophy of the endometrium quickly. In this scenario, the clinician might give an injection every 4 to 6 weeks for two or three doses to induce amenorrhea and then return to every-12-week dosing.

The main risk when using medroxyprogesterone injections to induce amenorrhea is the potential for bone loss. Users of this method have been shown to have lower mean bone mineral density^31–33 and significantly higher levels of biomarkers of bone formation and resorption^32,34 than nonusers. However, these changes are similar to those seen in breastfeeding women,³⁵ are reversible with cessation, ³⁶ and are not associated with increased fracture risk.³⁷ In adolescent girls, pregnancy poses similar risks to the bones, with longerterm consequences.

Medroxyprogesterone can also stimulate appetite, causing 10 to 20 kg of weight gain in adolescents and women who are already obese and have trouble with appetite regulation.³⁸ Slender users tend not to gain weight, however.

Given this information, depot medroxyprogesterone acetate appears to be a cost-effective contraceptive option that should be considered in the context of the clinical situation and preference of each patient.

Transdermal contraceptive patch

Ortho Evra, a transdermal patch, is designed to deliver ethinyl estradiol 0.02 mg and norelgestromin 0.150 mg daily.³⁹ It is usually applied weekly for 3 weeks, followed by a patch-free week to induce regular monthly withdrawal bleeding.

Extended use of the patch to manipulate menstruation is an off-label use. In the only trial evaluating extended use of the patch, amenorrhea occurred in 12% of users, but unscheduled bleeding and spotting were common. ¹⁶

Although there is some evidence that the long-term use of the patch may increase the risk of venous thromboembolism,^40,41 the risk in women who use the patch has been found to be similar to that in women using an oral contraceptive.⁴² However, serum ethinyl estradiol levels have been found to be higher with the use of the weekly patch than with oral contraceptives or the contraceptive vaginal ring³⁹; as a result, many physicians are hesitant to recommend its continuous use.

Pending further data about the safety profile of this contraceptive, the World Health Organization Medical Eligibility Criteria for Contraceptive Use suggest that the same guidelines for the prescription of combination oral contraceptives should also apply to the patch.⁴³

Contraceptive vaginal ring

NuvaRing, a contraceptive vaginal ring, releases a daily dose of ethinyl estradiol 0.015 mg and etonogestrel 0.12 mg.¹⁰ It is inserted, left in for 21 days, and then removed and left out for 7 days, during which withdrawal bleeding occurs.¹⁰

Vaginal administration has been shown to allow low, continuous dosing, which results in more stable serum concentrations than with the patch or oral contraceptives.³⁹ In the only trial comparing an extended vaginal ring regimen and the traditional 28-day regimen, extended use resulted in fewer overall days of bleeding than monthly use, but with more unscheduled spotting.¹⁵

The most common side effects include headache, vaginitis, and leukorrhea,⁴⁴ but there is no evidence of bacteriologic or cytologic changes in the cervicovaginal epithelium, even with extended use.^45,46

Etonogestrel implantable contraceptive

Implanon, a single-rod progestin implant, is available in the United States and elsewhere. It is placed subdermally in the inner upper arm and provides contraception for as long as 3 years.

Implanon contains 68 mg of the progestin etonogestrel, which it slowly releases over time, initially at 0.06 to 0.07 mg/day, decreasing to 0.035 to 0.045 mg/day at the end of the first year, to 0.03 to 0.04 mg/day at the end of the second year, and then to 0.025 to 0.03 mg/day at the end of the third year.⁴⁷

The amount of vaginal bleeding associated with the use of the implant is generally modest, but the pattern tends to be unpredictable. ⁴⁸ In addition, because amenorrhea is reported as a side effect in only 22% of women during the first 2 years of its use,⁴⁸ the progestin implant is a less satisfactory means of menstrual suppression than the other methods discussed above.

BENEFITS OF MENSTRUAL MANIPULATION

Menstrual manipulation has a number of benefits in terms of both overall health and lifestyle.

For most women, using a long-acting hormonal contraceptive carries low risks and substantial health benefits. Women who take oral contraceptives are less likely to develop osteoporosis, ovarian or endometrial cancer, benign breast changes, or pelvic inflammatory disease. ⁴⁹ Long-term use of an oral contraceptive can also preserve fertility by reducing and delaying the incidence of endometriosis,⁵⁰ and is effective at treating acne vulgaris, which tends to be common among patients with polycystic ovary syndrome.^51,52 In addition, this practice can be used to reduce overall blood loss, an application that is particularly important in women with a bleeding diathesis such as von Willebrand disease, who frequently suffer from menorrhagia.⁵³

Reduced menstruation may also prove more convenient during particular occasions, such as vacations and athletic activities. Specifically, it may be useful to women serving in the military. In a study by Schneider et al,⁵⁴ a cohort of 83 female cadets reported a significant perceived impact of premenstrual and menstrual-related symptoms on academic, physical, and military activities, as well as difficulties in obtaining, changing, and disposing of menstrual materials in a military setting. Likewise, reduced menstrual frequency or amenorrhea may play an important role in female athletes, who reportedly use oral contraceptives to control premenstrual symptoms, to protect bone health, and to manipulate the menstrual cycle in order to maximize performance.⁵⁵

Adolescent girls are another group who may benefit from reduced or absent menses, once they have reached near-final height. By practicing menstrual suppression, girls can avoid dysmenorrhea and the inconvenience of menstruation during the school day, when their access to painkillers, sanitary pads or tampons, and a change of clothes may be limited. ⁵⁶ Clinicians who discuss with teenage patients the benefits of innovative hormonal contraceptive schedules that reduce menstrual frequency may be able to improve the quality of life for these young women.

In a very short girl just after menarche, care must be taken not to start a hormonal method too early so as not to prematurely close epiphyses and stunt final height; after menarche, most girls still have 1 to 4 inches of potential growth. For a young lady 4 feet 11 inches tall, that extra inch may be important.

Finally, menstrual manipulation may also find a niche among the developmentally challenged. Women with cognitive impairment and physical disabilities may have difficulty with hygienic practice around menses. For a number of years, contraceptives have been used to manage menstrual hygiene in patients with catamenial (ie, menstrual) epilepsy, and to address caregiver concerns in women with severe mental retardation, with improved behavior noted in some patients.^57–59 In this setting, an agent that suppresses menses and also provides contraception, especially for those girls and women at risk of abuse, may offer substantial benefits.

DISADVANTAGES OF MENSTRUAL MANIPULATION

Rates of adverse events and of discontinuation of extended and continuous oral contraceptive regimens are comparable with those reported for cyclic regimens, except for higher rates of breakthrough bleeding.

In a trial of continuous oral contraceptive use in more than 2,000 patients, 396 (18.5%) withdrew from the study as a result of bothersome uterine bleeding.⁶⁰ However, while breakthrough bleeding often occurs during the first few months of extended oral contraceptive use, it usually decreases with each successive cycle of therapy and is comparable to that reported by patients on the conventional oral contraceptive regimen by the fourth extended cycle.¹²

CONTRACEPTIVE EFFICACY

The efficacy of extended and continuous oral contraceptive regimens is comparable with that of cyclic regimens.^12,60,61 One reason for this may be better adherence to continuous regimens: women using this regimen have been shown to miss fewer pills than those on a cyclic regimen, especially during the critical first week of the pill pack.²¹

Several studies have shown that some women ovulate during the standard 21/7 oral contraceptive regimen even if they do not miss any pills or take pills off-schedule, putting them at greater risk of pregnancy.⁶² Large studies evaluating the efficacy of an extendedcycle regimen have shown a pregnancy rate during the 1-year study period that was either comparable with⁶¹ or lower than^12,60 rates with standard regimens.

Heterosexual couples need to be advised to use condoms to further reduce the already low failure rate and to prevent sexually transmitted diseases.

ACCEPTABILITY OF MENSTRUAL MANIPULATION

Ever since the earliest trial of an extended oral contraceptive regimen, participants have expressed a favorable response to the resulting decrease in menstrual frequency; in the 1977 study by Loudon et al,⁶ patients on the extended regimen cited infrequent periods (82%), fewer menstrual problems (20%), and easier pill-taking (19%) as favorable features.

In 1999, den Tonkelaar and Oddens⁶³ surveyed 1,300 Dutch women about their preferred frequency of menstruation and found that about 70% between the ages of 15 and 49 preferred a frequency of between every 3 months and never. A similar survey in the United States indicated that 58% preferred a bleeding frequency of either every 3 months or never to more frequent periods.⁶⁴

While patients find menstrual manipulation generally acceptable, clinician approval has been more varied. Loudon et al reported that “the doctors and nurses on the clinic staff were less enthusiastic about this regimen than the volunteers themselves.”⁶ In a survey of 222 clinicians,⁶⁵ 90% of responders reported ever having prescribed extended or continuous dosing regimens to adolescents, and 33% reported that extended cycles made up more than 10% of their total oral contraceptive prescriptions.

Myths and misperceptions about menstrual manipulation abound. Many clinicians believe that routine use of an extended or continuous oral contraceptive regimen is inadvisable, despite the lack of evidence to support this notion.⁶⁶ Therefore, many care providers need more education about the practice and benefits of menstrual manipulation.

THE RIGHT METHOD FOR THE RIGHT PATIENT

Manipulation and suppression of menstruation through continuous or extended use of oral contraceptives or by other means may have a number of advantages to women, including fewer menstrual-related syndromes, reduced absenteeism from work or school, and greater overall satisfaction.

For women whose goal is to reduce but not necessarily to eliminate monthly bleeding, the cyclic use of estrogen-progestin contraception (rather than progestins alone or continuous use of combined hormonal preparations) is suggested.

Clinicians should not overestimate the risks of oral contraceptives and other hormonal methods, but rather educate themselves so that they can utilize menstrual manipulation safely to match the individual patient’s needs.

If they wish, women can have more control over when and if they menstruate. By using hormonal contraceptives in extended or continuous regimens, they can have their period less often, a practice called menstrual manipulation or menstrual suppression.

Actually, with the help of their clinicians, women have been doing this for years. But now that several products have been approved by the US Food and Drug Administration (FDA) specifically for use in extended or continuous regimens, the practice has become more widely accepted.

Reasons for suppressing menstrual flow range from avoiding bleeding during a particular event (eg, a wedding, graduation, or sports competition) to finding relief from dysmenorrhea or reducing or eliminating menstruation in the treatment of endometriosis, migraine, and other medical conditions exacerbated by hormonal changes around the time of menses.¹ Alternatively, some women may practice menstrual manipulation for no other reason than to simply avoid menstruation.

MENSTRUAL DISORDERS ARE TROUBLESOME, COMMON

Each year in the United States, menstrual disorders such as dysmenorrhea (painful menstruation), menorrhagia (excessive or frequent menstruation), metrorrhagia (irregular menstruation), menometrorrhagia (excessive and irregular menstruation), and premenstrual syndrome affect nearly 2.5 million women age 18 to 50 years.² Menstrual disorders are the leading cause of gynecologic morbidity in the United States, outnumbering adnexal masses (the second most common cause) by a factor of three.² In addition, these disorders extend into the workplace, costing US industry about 8% of its total wage bill.³

A BRIEF HISTORY OF CONTRACEPTIVE DEVELOPMENT

The idea of using progestins for birth control was first advanced in the 1950s by Dr. Gregory Pincus, who proposed a regimen of 21 days of active drug followed by 7 drug-free days to allow withdrawal bleeding, mimicking the natural cycle.⁴ This “21/7” regimen was designed to follow the lunar cycle in the hope it would be, in the words of Dr. John Rock, “a morally permissible variant of the rhythm method,”⁵ thereby making it acceptable to women, clinicians, and the Catholic Church.

In 1977, Loudon et al⁶ reported the results of a study in which women took active pills for 84 days instead of 21 days, which reduced the frequency of menstruation to every 3 months. Since then, extending the active pills beyond 21 days to avoid menses and other hormone-withdrawal symptoms has become popular in clinical practice, and many studies have investigated the extended or continuous use of oral and other forms of contraception to delay menses.^7–18

CURRENT METHODS OF MENSTRUAL MANIPULATION

A variety of available products prevent conception by altering the menstrual cycle:

• Oral estrogen-progestin contraceptive pills
• A drug-releasing intrauterine device
• Depot medroxyprogesterone acetate injections
• 
  A transdermal contraceptive patch
• A contraceptive vaginal ring
• An implantable etonogestrel contraceptive.

Their use in menstrual manipulation is summarized in Table 1.

Oral contraceptive pills

The most common way to manipulate the menstrual cycle is to extend the time between hormone-free weeks in an oral contraceptive regimen.

If the patient is young, you can prescribe a monophasic 21/7 oral contraceptive and tell her to take one active pill every day for 21 days and then start a new pack and keep taking active pills for up to 84 consecutive days, skipping the placebo pills until she wants to have her menstrual period. She can choose which week to have it: if the scheduled 12th week of an extended-cycle oral contraceptive regimen is inconvenient, she can plan it for week 10, or week 9, or whichever week is convenient.

The rationale for using an 84-day (12-week) cycle is that it still provides four periods per year, alleviating fears of hypertrophic endometrium.¹⁹

In this scenario, unscheduled or breakthrough bleeding can be managed by taking a “double-up pill” from a spare pack on any day breakthrough bleeding occurs and until it resolves. Menstrual periods should not be planned for intervals shorter than 21 days, owing to the risk of ovulation. Missed days of pills or use of placebo pills should also not exceed 7 days to prevent escape ovulation. ²⁰

In some women with endometriosis and other medical reasons, continuous oral contraception with no placebo week can be prescribed.

Unfortunately, the downside to suppressing withdrawal bleeding is unscheduled or “breakthrough” bleeding. The best way to treat this unscheduled bleeding is not known. Patients who are not sexually active can be reassured that the goal of an atrophic endometrium can still be achieved, with resultant pill amenorrhea (particularly useful for those with severe dysmenorrhea or other reasons to want to avoid flow). Patients could also try to manage flow by periodically taking a 3- to 5-day break from hormone-containing pills to allow flow. They can also try switching to another oral contraceptive that has a different progestin that would spiral the arterioles of the endometrium more tightly and thus more aggressively induce atrophy.^13,17,21 For instance, levonorgestrel is 10 to 20 times more potent than norethindrone. Choosing a pill with a higher monophasic dosing of levonorgestrel or a similar progestin may minimize unscheduled bleeding.

Currently, several oral contraceptives are approved for use in an extended regimen.

Seasonale was the first oral contraceptive marketed in the United States with an extended active regimen.²² It comes in a pack of 84 pills containing ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg, plus 7 placebo pills.

Seasonique is similar to Seasonale, but instead of placebo pills it has seven pills that contain ethinyl estradiol 0.010 mg.

Lybrel is a low-dose combination containing ethinyl estradiol 0.02 mg and levonorgestrel 0.09 mg. Packaged as an entire year’s worth of active pills to be taken continuously for 365 days without a placebo phase or pillfree interval,²³ it is the only FDA-approved continuous oral contraceptive available in the United States.

Intrauterine devices were originally developed as contraceptives. The addition of a progestin to these devices has been shown to reduce heavy menstrual bleeding by up to 90%.^24,25

Mirena IUS, a levonorgestrel-releasing device, is the only medicated intrauterine device that is currently available in the United States. (“IUS” stands for “intrauterine system.”) It was recently approved by the FDA to treat heavy menstrual bleeding in women who use intrauterine contraception as their method of pregnancy prevention.²⁶ About 50% of women who use this device develop amenorrhea within 6 months of insertion, while 25% report oligomenorrhea.²⁷

The Mirena device can be left in the uterus for up to 5 years. It may be a good choice for inducing amenorrhea in women with hemostatic disorders or in whom estrogen either is contraindicated or causes health concerns.¹⁸ The copper intrauterine device (Paragard; Duramed Pharmaceuticals Inc., Pomona, NY) remains a viable option for those who cannot or do not tolerate hormonal therapy. However, Mirena may provide less unscheduled bleeding than the copper intrauterine device.

Depot medroxyprogesterone acetate injections

Depo-Provera (depot medroxyprogesterone acetate) injections are given at 90-day intervals. ²⁸ This contraceptive method inhibits ovulation and decidualizes the endometrium, thereby reducing or eliminating uterine bleeding. ²⁹

While new users may initially experience excessive prolonged bleeding (10 or more days) while shedding their existing lining, the rate of amenorrhea has been shown to increase over time as the lining atrophies.³⁰ Thus, prolonged use of this agent reduces the frequency of menstruation as well as menstruation-related symptoms.

Depot medroxyprogesterone acetate is ideal for patients whose menstrual periods pose a significant hygiene problem (eg, developmentally challenged girls). In our experience, the injections can be given at shorter intervals to induce atrophy of the endometrium quickly. In this scenario, the clinician might give an injection every 4 to 6 weeks for two or three doses to induce amenorrhea and then return to every-12-week dosing.

The main risk when using medroxyprogesterone injections to induce amenorrhea is the potential for bone loss. Users of this method have been shown to have lower mean bone mineral density^31–33 and significantly higher levels of biomarkers of bone formation and resorption^32,34 than nonusers. However, these changes are similar to those seen in breastfeeding women,³⁵ are reversible with cessation, ³⁶ and are not associated with increased fracture risk.³⁷ In adolescent girls, pregnancy poses similar risks to the bones, with longerterm consequences.

Medroxyprogesterone can also stimulate appetite, causing 10 to 20 kg of weight gain in adolescents and women who are already obese and have trouble with appetite regulation.³⁸ Slender users tend not to gain weight, however.

Given this information, depot medroxyprogesterone acetate appears to be a cost-effective contraceptive option that should be considered in the context of the clinical situation and preference of each patient.

Transdermal contraceptive patch

Ortho Evra, a transdermal patch, is designed to deliver ethinyl estradiol 0.02 mg and norelgestromin 0.150 mg daily.³⁹ It is usually applied weekly for 3 weeks, followed by a patch-free week to induce regular monthly withdrawal bleeding.

Extended use of the patch to manipulate menstruation is an off-label use. In the only trial evaluating extended use of the patch, amenorrhea occurred in 12% of users, but unscheduled bleeding and spotting were common. ¹⁶

Although there is some evidence that the long-term use of the patch may increase the risk of venous thromboembolism,^40,41 the risk in women who use the patch has been found to be similar to that in women using an oral contraceptive.⁴² However, serum ethinyl estradiol levels have been found to be higher with the use of the weekly patch than with oral contraceptives or the contraceptive vaginal ring³⁹; as a result, many physicians are hesitant to recommend its continuous use.

Pending further data about the safety profile of this contraceptive, the World Health Organization Medical Eligibility Criteria for Contraceptive Use suggest that the same guidelines for the prescription of combination oral contraceptives should also apply to the patch.⁴³

Contraceptive vaginal ring

NuvaRing, a contraceptive vaginal ring, releases a daily dose of ethinyl estradiol 0.015 mg and etonogestrel 0.12 mg.¹⁰ It is inserted, left in for 21 days, and then removed and left out for 7 days, during which withdrawal bleeding occurs.¹⁰

Vaginal administration has been shown to allow low, continuous dosing, which results in more stable serum concentrations than with the patch or oral contraceptives.³⁹ In the only trial comparing an extended vaginal ring regimen and the traditional 28-day regimen, extended use resulted in fewer overall days of bleeding than monthly use, but with more unscheduled spotting.¹⁵

The most common side effects include headache, vaginitis, and leukorrhea,⁴⁴ but there is no evidence of bacteriologic or cytologic changes in the cervicovaginal epithelium, even with extended use.^45,46

Etonogestrel implantable contraceptive

Implanon, a single-rod progestin implant, is available in the United States and elsewhere. It is placed subdermally in the inner upper arm and provides contraception for as long as 3 years.

Implanon contains 68 mg of the progestin etonogestrel, which it slowly releases over time, initially at 0.06 to 0.07 mg/day, decreasing to 0.035 to 0.045 mg/day at the end of the first year, to 0.03 to 0.04 mg/day at the end of the second year, and then to 0.025 to 0.03 mg/day at the end of the third year.⁴⁷

The amount of vaginal bleeding associated with the use of the implant is generally modest, but the pattern tends to be unpredictable. ⁴⁸ In addition, because amenorrhea is reported as a side effect in only 22% of women during the first 2 years of its use,⁴⁸ the progestin implant is a less satisfactory means of menstrual suppression than the other methods discussed above.

BENEFITS OF MENSTRUAL MANIPULATION

Menstrual manipulation has a number of benefits in terms of both overall health and lifestyle.

For most women, using a long-acting hormonal contraceptive carries low risks and substantial health benefits. Women who take oral contraceptives are less likely to develop osteoporosis, ovarian or endometrial cancer, benign breast changes, or pelvic inflammatory disease. ⁴⁹ Long-term use of an oral contraceptive can also preserve fertility by reducing and delaying the incidence of endometriosis,⁵⁰ and is effective at treating acne vulgaris, which tends to be common among patients with polycystic ovary syndrome.^51,52 In addition, this practice can be used to reduce overall blood loss, an application that is particularly important in women with a bleeding diathesis such as von Willebrand disease, who frequently suffer from menorrhagia.⁵³

Reduced menstruation may also prove more convenient during particular occasions, such as vacations and athletic activities. Specifically, it may be useful to women serving in the military. In a study by Schneider et al,⁵⁴ a cohort of 83 female cadets reported a significant perceived impact of premenstrual and menstrual-related symptoms on academic, physical, and military activities, as well as difficulties in obtaining, changing, and disposing of menstrual materials in a military setting. Likewise, reduced menstrual frequency or amenorrhea may play an important role in female athletes, who reportedly use oral contraceptives to control premenstrual symptoms, to protect bone health, and to manipulate the menstrual cycle in order to maximize performance.⁵⁵

Adolescent girls are another group who may benefit from reduced or absent menses, once they have reached near-final height. By practicing menstrual suppression, girls can avoid dysmenorrhea and the inconvenience of menstruation during the school day, when their access to painkillers, sanitary pads or tampons, and a change of clothes may be limited. ⁵⁶ Clinicians who discuss with teenage patients the benefits of innovative hormonal contraceptive schedules that reduce menstrual frequency may be able to improve the quality of life for these young women.

In a very short girl just after menarche, care must be taken not to start a hormonal method too early so as not to prematurely close epiphyses and stunt final height; after menarche, most girls still have 1 to 4 inches of potential growth. For a young lady 4 feet 11 inches tall, that extra inch may be important.

Finally, menstrual manipulation may also find a niche among the developmentally challenged. Women with cognitive impairment and physical disabilities may have difficulty with hygienic practice around menses. For a number of years, contraceptives have been used to manage menstrual hygiene in patients with catamenial (ie, menstrual) epilepsy, and to address caregiver concerns in women with severe mental retardation, with improved behavior noted in some patients.^57–59 In this setting, an agent that suppresses menses and also provides contraception, especially for those girls and women at risk of abuse, may offer substantial benefits.

DISADVANTAGES OF MENSTRUAL MANIPULATION

Rates of adverse events and of discontinuation of extended and continuous oral contraceptive regimens are comparable with those reported for cyclic regimens, except for higher rates of breakthrough bleeding.

In a trial of continuous oral contraceptive use in more than 2,000 patients, 396 (18.5%) withdrew from the study as a result of bothersome uterine bleeding.⁶⁰ However, while breakthrough bleeding often occurs during the first few months of extended oral contraceptive use, it usually decreases with each successive cycle of therapy and is comparable to that reported by patients on the conventional oral contraceptive regimen by the fourth extended cycle.¹²

CONTRACEPTIVE EFFICACY

The efficacy of extended and continuous oral contraceptive regimens is comparable with that of cyclic regimens.^12,60,61 One reason for this may be better adherence to continuous regimens: women using this regimen have been shown to miss fewer pills than those on a cyclic regimen, especially during the critical first week of the pill pack.²¹

Several studies have shown that some women ovulate during the standard 21/7 oral contraceptive regimen even if they do not miss any pills or take pills off-schedule, putting them at greater risk of pregnancy.⁶² Large studies evaluating the efficacy of an extendedcycle regimen have shown a pregnancy rate during the 1-year study period that was either comparable with⁶¹ or lower than^12,60 rates with standard regimens.

Heterosexual couples need to be advised to use condoms to further reduce the already low failure rate and to prevent sexually transmitted diseases.

ACCEPTABILITY OF MENSTRUAL MANIPULATION

Ever since the earliest trial of an extended oral contraceptive regimen, participants have expressed a favorable response to the resulting decrease in menstrual frequency; in the 1977 study by Loudon et al,⁶ patients on the extended regimen cited infrequent periods (82%), fewer menstrual problems (20%), and easier pill-taking (19%) as favorable features.

In 1999, den Tonkelaar and Oddens⁶³ surveyed 1,300 Dutch women about their preferred frequency of menstruation and found that about 70% between the ages of 15 and 49 preferred a frequency of between every 3 months and never. A similar survey in the United States indicated that 58% preferred a bleeding frequency of either every 3 months or never to more frequent periods.⁶⁴

While patients find menstrual manipulation generally acceptable, clinician approval has been more varied. Loudon et al reported that “the doctors and nurses on the clinic staff were less enthusiastic about this regimen than the volunteers themselves.”⁶ In a survey of 222 clinicians,⁶⁵ 90% of responders reported ever having prescribed extended or continuous dosing regimens to adolescents, and 33% reported that extended cycles made up more than 10% of their total oral contraceptive prescriptions.

Myths and misperceptions about menstrual manipulation abound. Many clinicians believe that routine use of an extended or continuous oral contraceptive regimen is inadvisable, despite the lack of evidence to support this notion.⁶⁶ Therefore, many care providers need more education about the practice and benefits of menstrual manipulation.

THE RIGHT METHOD FOR THE RIGHT PATIENT

Manipulation and suppression of menstruation through continuous or extended use of oral contraceptives or by other means may have a number of advantages to women, including fewer menstrual-related syndromes, reduced absenteeism from work or school, and greater overall satisfaction.

For women whose goal is to reduce but not necessarily to eliminate monthly bleeding, the cyclic use of estrogen-progestin contraception (rather than progestins alone or continuous use of combined hormonal preparations) is suggested.

Clinicians should not overestimate the risks of oral contraceptives and other hormonal methods, but rather educate themselves so that they can utilize menstrual manipulation safely to match the individual patient’s needs.

If they wish, women can have more control over when and if they menstruate. By using hormonal contraceptives in extended or continuous regimens, they can have their period less often, a practice called menstrual manipulation or menstrual suppression.

Actually, with the help of their clinicians, women have been doing this for years. But now that several products have been approved by the US Food and Drug Administration (FDA) specifically for use in extended or continuous regimens, the practice has become more widely accepted.

Reasons for suppressing menstrual flow range from avoiding bleeding during a particular event (eg, a wedding, graduation, or sports competition) to finding relief from dysmenorrhea or reducing or eliminating menstruation in the treatment of endometriosis, migraine, and other medical conditions exacerbated by hormonal changes around the time of menses.¹ Alternatively, some women may practice menstrual manipulation for no other reason than to simply avoid menstruation.

MENSTRUAL DISORDERS ARE TROUBLESOME, COMMON

Each year in the United States, menstrual disorders such as dysmenorrhea (painful menstruation), menorrhagia (excessive or frequent menstruation), metrorrhagia (irregular menstruation), menometrorrhagia (excessive and irregular menstruation), and premenstrual syndrome affect nearly 2.5 million women age 18 to 50 years.² Menstrual disorders are the leading cause of gynecologic morbidity in the United States, outnumbering adnexal masses (the second most common cause) by a factor of three.² In addition, these disorders extend into the workplace, costing US industry about 8% of its total wage bill.³

A BRIEF HISTORY OF CONTRACEPTIVE DEVELOPMENT

The idea of using progestins for birth control was first advanced in the 1950s by Dr. Gregory Pincus, who proposed a regimen of 21 days of active drug followed by 7 drug-free days to allow withdrawal bleeding, mimicking the natural cycle.⁴ This “21/7” regimen was designed to follow the lunar cycle in the hope it would be, in the words of Dr. John Rock, “a morally permissible variant of the rhythm method,”⁵ thereby making it acceptable to women, clinicians, and the Catholic Church.

In 1977, Loudon et al⁶ reported the results of a study in which women took active pills for 84 days instead of 21 days, which reduced the frequency of menstruation to every 3 months. Since then, extending the active pills beyond 21 days to avoid menses and other hormone-withdrawal symptoms has become popular in clinical practice, and many studies have investigated the extended or continuous use of oral and other forms of contraception to delay menses.^7–18

CURRENT METHODS OF MENSTRUAL MANIPULATION

A variety of available products prevent conception by altering the menstrual cycle:

• Oral estrogen-progestin contraceptive pills
• A drug-releasing intrauterine device
• Depot medroxyprogesterone acetate injections
• 
  A transdermal contraceptive patch
• A contraceptive vaginal ring
• An implantable etonogestrel contraceptive.

Their use in menstrual manipulation is summarized in Table 1.

Oral contraceptive pills

The most common way to manipulate the menstrual cycle is to extend the time between hormone-free weeks in an oral contraceptive regimen.

If the patient is young, you can prescribe a monophasic 21/7 oral contraceptive and tell her to take one active pill every day for 21 days and then start a new pack and keep taking active pills for up to 84 consecutive days, skipping the placebo pills until she wants to have her menstrual period. She can choose which week to have it: if the scheduled 12th week of an extended-cycle oral contraceptive regimen is inconvenient, she can plan it for week 10, or week 9, or whichever week is convenient.

The rationale for using an 84-day (12-week) cycle is that it still provides four periods per year, alleviating fears of hypertrophic endometrium.¹⁹

In this scenario, unscheduled or breakthrough bleeding can be managed by taking a “double-up pill” from a spare pack on any day breakthrough bleeding occurs and until it resolves. Menstrual periods should not be planned for intervals shorter than 21 days, owing to the risk of ovulation. Missed days of pills or use of placebo pills should also not exceed 7 days to prevent escape ovulation. ²⁰

In some women with endometriosis and other medical reasons, continuous oral contraception with no placebo week can be prescribed.

Unfortunately, the downside to suppressing withdrawal bleeding is unscheduled or “breakthrough” bleeding. The best way to treat this unscheduled bleeding is not known. Patients who are not sexually active can be reassured that the goal of an atrophic endometrium can still be achieved, with resultant pill amenorrhea (particularly useful for those with severe dysmenorrhea or other reasons to want to avoid flow). Patients could also try to manage flow by periodically taking a 3- to 5-day break from hormone-containing pills to allow flow. They can also try switching to another oral contraceptive that has a different progestin that would spiral the arterioles of the endometrium more tightly and thus more aggressively induce atrophy.^13,17,21 For instance, levonorgestrel is 10 to 20 times more potent than norethindrone. Choosing a pill with a higher monophasic dosing of levonorgestrel or a similar progestin may minimize unscheduled bleeding.

Currently, several oral contraceptives are approved for use in an extended regimen.

Seasonale was the first oral contraceptive marketed in the United States with an extended active regimen.²² It comes in a pack of 84 pills containing ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg, plus 7 placebo pills.

Seasonique is similar to Seasonale, but instead of placebo pills it has seven pills that contain ethinyl estradiol 0.010 mg.

Lybrel is a low-dose combination containing ethinyl estradiol 0.02 mg and levonorgestrel 0.09 mg. Packaged as an entire year’s worth of active pills to be taken continuously for 365 days without a placebo phase or pillfree interval,²³ it is the only FDA-approved continuous oral contraceptive available in the United States.

Intrauterine devices were originally developed as contraceptives. The addition of a progestin to these devices has been shown to reduce heavy menstrual bleeding by up to 90%.^24,25

Mirena IUS, a levonorgestrel-releasing device, is the only medicated intrauterine device that is currently available in the United States. (“IUS” stands for “intrauterine system.”) It was recently approved by the FDA to treat heavy menstrual bleeding in women who use intrauterine contraception as their method of pregnancy prevention.²⁶ About 50% of women who use this device develop amenorrhea within 6 months of insertion, while 25% report oligomenorrhea.²⁷

The Mirena device can be left in the uterus for up to 5 years. It may be a good choice for inducing amenorrhea in women with hemostatic disorders or in whom estrogen either is contraindicated or causes health concerns.¹⁸ The copper intrauterine device (Paragard; Duramed Pharmaceuticals Inc., Pomona, NY) remains a viable option for those who cannot or do not tolerate hormonal therapy. However, Mirena may provide less unscheduled bleeding than the copper intrauterine device.

Depot medroxyprogesterone acetate injections

Depo-Provera (depot medroxyprogesterone acetate) injections are given at 90-day intervals. ²⁸ This contraceptive method inhibits ovulation and decidualizes the endometrium, thereby reducing or eliminating uterine bleeding. ²⁹

While new users may initially experience excessive prolonged bleeding (10 or more days) while shedding their existing lining, the rate of amenorrhea has been shown to increase over time as the lining atrophies.³⁰ Thus, prolonged use of this agent reduces the frequency of menstruation as well as menstruation-related symptoms.

Depot medroxyprogesterone acetate is ideal for patients whose menstrual periods pose a significant hygiene problem (eg, developmentally challenged girls). In our experience, the injections can be given at shorter intervals to induce atrophy of the endometrium quickly. In this scenario, the clinician might give an injection every 4 to 6 weeks for two or three doses to induce amenorrhea and then return to every-12-week dosing.

The main risk when using medroxyprogesterone injections to induce amenorrhea is the potential for bone loss. Users of this method have been shown to have lower mean bone mineral density^31–33 and significantly higher levels of biomarkers of bone formation and resorption^32,34 than nonusers. However, these changes are similar to those seen in breastfeeding women,³⁵ are reversible with cessation, ³⁶ and are not associated with increased fracture risk.³⁷ In adolescent girls, pregnancy poses similar risks to the bones, with longerterm consequences.

Medroxyprogesterone can also stimulate appetite, causing 10 to 20 kg of weight gain in adolescents and women who are already obese and have trouble with appetite regulation.³⁸ Slender users tend not to gain weight, however.

Given this information, depot medroxyprogesterone acetate appears to be a cost-effective contraceptive option that should be considered in the context of the clinical situation and preference of each patient.

Transdermal contraceptive patch

Ortho Evra, a transdermal patch, is designed to deliver ethinyl estradiol 0.02 mg and norelgestromin 0.150 mg daily.³⁹ It is usually applied weekly for 3 weeks, followed by a patch-free week to induce regular monthly withdrawal bleeding.

Extended use of the patch to manipulate menstruation is an off-label use. In the only trial evaluating extended use of the patch, amenorrhea occurred in 12% of users, but unscheduled bleeding and spotting were common. ¹⁶

Although there is some evidence that the long-term use of the patch may increase the risk of venous thromboembolism,^40,41 the risk in women who use the patch has been found to be similar to that in women using an oral contraceptive.⁴² However, serum ethinyl estradiol levels have been found to be higher with the use of the weekly patch than with oral contraceptives or the contraceptive vaginal ring³⁹; as a result, many physicians are hesitant to recommend its continuous use.

Pending further data about the safety profile of this contraceptive, the World Health Organization Medical Eligibility Criteria for Contraceptive Use suggest that the same guidelines for the prescription of combination oral contraceptives should also apply to the patch.⁴³

Contraceptive vaginal ring

NuvaRing, a contraceptive vaginal ring, releases a daily dose of ethinyl estradiol 0.015 mg and etonogestrel 0.12 mg.¹⁰ It is inserted, left in for 21 days, and then removed and left out for 7 days, during which withdrawal bleeding occurs.¹⁰

Vaginal administration has been shown to allow low, continuous dosing, which results in more stable serum concentrations than with the patch or oral contraceptives.³⁹ In the only trial comparing an extended vaginal ring regimen and the traditional 28-day regimen, extended use resulted in fewer overall days of bleeding than monthly use, but with more unscheduled spotting.¹⁵

The most common side effects include headache, vaginitis, and leukorrhea,⁴⁴ but there is no evidence of bacteriologic or cytologic changes in the cervicovaginal epithelium, even with extended use.^45,46

Etonogestrel implantable contraceptive

Implanon, a single-rod progestin implant, is available in the United States and elsewhere. It is placed subdermally in the inner upper arm and provides contraception for as long as 3 years.

Implanon contains 68 mg of the progestin etonogestrel, which it slowly releases over time, initially at 0.06 to 0.07 mg/day, decreasing to 0.035 to 0.045 mg/day at the end of the first year, to 0.03 to 0.04 mg/day at the end of the second year, and then to 0.025 to 0.03 mg/day at the end of the third year.⁴⁷

The amount of vaginal bleeding associated with the use of the implant is generally modest, but the pattern tends to be unpredictable. ⁴⁸ In addition, because amenorrhea is reported as a side effect in only 22% of women during the first 2 years of its use,⁴⁸ the progestin implant is a less satisfactory means of menstrual suppression than the other methods discussed above.

BENEFITS OF MENSTRUAL MANIPULATION

Menstrual manipulation has a number of benefits in terms of both overall health and lifestyle.

For most women, using a long-acting hormonal contraceptive carries low risks and substantial health benefits. Women who take oral contraceptives are less likely to develop osteoporosis, ovarian or endometrial cancer, benign breast changes, or pelvic inflammatory disease. ⁴⁹ Long-term use of an oral contraceptive can also preserve fertility by reducing and delaying the incidence of endometriosis,⁵⁰ and is effective at treating acne vulgaris, which tends to be common among patients with polycystic ovary syndrome.^51,52 In addition, this practice can be used to reduce overall blood loss, an application that is particularly important in women with a bleeding diathesis such as von Willebrand disease, who frequently suffer from menorrhagia.⁵³

Reduced menstruation may also prove more convenient during particular occasions, such as vacations and athletic activities. Specifically, it may be useful to women serving in the military. In a study by Schneider et al,⁵⁴ a cohort of 83 female cadets reported a significant perceived impact of premenstrual and menstrual-related symptoms on academic, physical, and military activities, as well as difficulties in obtaining, changing, and disposing of menstrual materials in a military setting. Likewise, reduced menstrual frequency or amenorrhea may play an important role in female athletes, who reportedly use oral contraceptives to control premenstrual symptoms, to protect bone health, and to manipulate the menstrual cycle in order to maximize performance.⁵⁵

Adolescent girls are another group who may benefit from reduced or absent menses, once they have reached near-final height. By practicing menstrual suppression, girls can avoid dysmenorrhea and the inconvenience of menstruation during the school day, when their access to painkillers, sanitary pads or tampons, and a change of clothes may be limited. ⁵⁶ Clinicians who discuss with teenage patients the benefits of innovative hormonal contraceptive schedules that reduce menstrual frequency may be able to improve the quality of life for these young women.

In a very short girl just after menarche, care must be taken not to start a hormonal method too early so as not to prematurely close epiphyses and stunt final height; after menarche, most girls still have 1 to 4 inches of potential growth. For a young lady 4 feet 11 inches tall, that extra inch may be important.

Finally, menstrual manipulation may also find a niche among the developmentally challenged. Women with cognitive impairment and physical disabilities may have difficulty with hygienic practice around menses. For a number of years, contraceptives have been used to manage menstrual hygiene in patients with catamenial (ie, menstrual) epilepsy, and to address caregiver concerns in women with severe mental retardation, with improved behavior noted in some patients.^57–59 In this setting, an agent that suppresses menses and also provides contraception, especially for those girls and women at risk of abuse, may offer substantial benefits.

DISADVANTAGES OF MENSTRUAL MANIPULATION

Rates of adverse events and of discontinuation of extended and continuous oral contraceptive regimens are comparable with those reported for cyclic regimens, except for higher rates of breakthrough bleeding.

In a trial of continuous oral contraceptive use in more than 2,000 patients, 396 (18.5%) withdrew from the study as a result of bothersome uterine bleeding.⁶⁰ However, while breakthrough bleeding often occurs during the first few months of extended oral contraceptive use, it usually decreases with each successive cycle of therapy and is comparable to that reported by patients on the conventional oral contraceptive regimen by the fourth extended cycle.¹²

CONTRACEPTIVE EFFICACY

The efficacy of extended and continuous oral contraceptive regimens is comparable with that of cyclic regimens.^12,60,61 One reason for this may be better adherence to continuous regimens: women using this regimen have been shown to miss fewer pills than those on a cyclic regimen, especially during the critical first week of the pill pack.²¹

Several studies have shown that some women ovulate during the standard 21/7 oral contraceptive regimen even if they do not miss any pills or take pills off-schedule, putting them at greater risk of pregnancy.⁶² Large studies evaluating the efficacy of an extendedcycle regimen have shown a pregnancy rate during the 1-year study period that was either comparable with⁶¹ or lower than^12,60 rates with standard regimens.

Heterosexual couples need to be advised to use condoms to further reduce the already low failure rate and to prevent sexually transmitted diseases.

ACCEPTABILITY OF MENSTRUAL MANIPULATION

Ever since the earliest trial of an extended oral contraceptive regimen, participants have expressed a favorable response to the resulting decrease in menstrual frequency; in the 1977 study by Loudon et al,⁶ patients on the extended regimen cited infrequent periods (82%), fewer menstrual problems (20%), and easier pill-taking (19%) as favorable features.

In 1999, den Tonkelaar and Oddens⁶³ surveyed 1,300 Dutch women about their preferred frequency of menstruation and found that about 70% between the ages of 15 and 49 preferred a frequency of between every 3 months and never. A similar survey in the United States indicated that 58% preferred a bleeding frequency of either every 3 months or never to more frequent periods.⁶⁴

While patients find menstrual manipulation generally acceptable, clinician approval has been more varied. Loudon et al reported that “the doctors and nurses on the clinic staff were less enthusiastic about this regimen than the volunteers themselves.”⁶ In a survey of 222 clinicians,⁶⁵ 90% of responders reported ever having prescribed extended or continuous dosing regimens to adolescents, and 33% reported that extended cycles made up more than 10% of their total oral contraceptive prescriptions.

Myths and misperceptions about menstrual manipulation abound. Many clinicians believe that routine use of an extended or continuous oral contraceptive regimen is inadvisable, despite the lack of evidence to support this notion.⁶⁶ Therefore, many care providers need more education about the practice and benefits of menstrual manipulation.

THE RIGHT METHOD FOR THE RIGHT PATIENT

Manipulation and suppression of menstruation through continuous or extended use of oral contraceptives or by other means may have a number of advantages to women, including fewer menstrual-related syndromes, reduced absenteeism from work or school, and greater overall satisfaction.

For women whose goal is to reduce but not necessarily to eliminate monthly bleeding, the cyclic use of estrogen-progestin contraception (rather than progestins alone or continuous use of combined hormonal preparations) is suggested.

Clinicians should not overestimate the risks of oral contraceptives and other hormonal methods, but rather educate themselves so that they can utilize menstrual manipulation safely to match the individual patient’s needs.

Editor’s Note: This commentary, written by members of the Cleveland Clinic Breast Cancer Screening Task Force, was not independently peer-reviewed.

In November 2009, the US Preventive Services Task Force (USPSTF) announced its new guidelines for breast cancer screening—and created an instant controversy by suggesting that fewer screening tests be done.¹

The November 2009 update recommended that most women wait until age 50 to get their first screening mammogram instead of getting it at age 40, that they get a mammogram every other year instead of every year, and that physicians not teach their patients breast self-examination anymore. However, on December 4, 2009, the USPSTF members voted to modify the recommendation for women under age 50, stating that the decision to start screening mammography every 2 years should be individualized, taking into account the patient’s preferences after being apprised of the possible benefits and harms.²

Various professional and advocacy groups have reacted differently to the new guidelines, and as a result, women are unsure about the optimal screening for breast cancer.

NEW GUIDELINES ARE BASED ON TWO STUDIES

The USPSTF commissioned two studies, which it used to formulate the new recommendations.^3,4 Its goal was to evaluate the current evidence for the efficacy of several screening tests and schedules in reducing breast cancer mortality rates.

An updated systematic review

Nelson et al³ performed a systematic review of studies of the benefit and harm of screening with mammography, clinical breast examination, and breast self-examination.

Screening mammography continued to demonstrate a reduction in deaths due to breast cancer. The risk reduction ranged from 14% to 32% in women age 50 to 69. Similarly, it was calculated to reduce the incidence of deaths due to breast cancer by 15% in women age 39 to 49. However, this younger age group has a relatively low incidence of breast cancer, and therefore, according to this analysis, 556 women need to undergo one round of screening to detect one case of invasive breast cancer, and 1,904 women need to be offered screening (over several rounds, which varied by trial) to prevent one breast cancer death.³

Most of the harm of screening in the 39-to-49-year age category was due to false-positive results, which were more common in this group than in older women. The authors calculated that after every round of screening mammography, about 84 of every 1,000 women in the younger age category need additional imaging and about 9 need a biopsy. The issue of overdiagnosis (detection of cancers that would have never been a problem in one’s lifetime) was not specifically addressed for this age category, and in different studies, estimates of overdiagnosis rates for all age groups varied widely, from less than 1% to 30%.

Beyond age 70, the authors reported the data insufficient for evaluating the benefit and harm of screening mammography.

Breast self-examination was found to offer no benefit, based largely on two randomized studies, one in St. Petersburg, Russia,⁵ and the other in Shanghai, China,⁶ both places where screening mammography was not routinely offered. These studies and one observational study in the United States⁷ failed to show a reduction in breast cancer mortality rates with breast self-examination.

Clinical breast examination (ie, by a health care provider) lacked sufficient data to draw conclusions.

A study based on statistical models of mammography

Mandelblatt et al⁴ used statistical modeling to estimate the effect of mammographic screening at various ages and at different intervals.

The authors used six statistical models previously shown to give similar qualitative estimates of the contribution of screening in reducing breast cancer mortality rates. They estimated the number of mammograms required relative to the number of cancers detected, the number of breast cancer deaths prevented, and the harms (false-positive mammograms, unnecessary biopsies, and overdiagnosis) incurred with 20 different screening strategies, ie, screening with different starting and stopping ages and at intervals of either 1 or 2 years.

They estimated that screening every other year would achieve most of the benefit of screening every year, with less harm. Looking at the different strategies and models, on average, biennial screening would, by their calculations, achieve about 81% of the mortality reduction achieved with annual screening. Compared with screening women ages 50 to 69 only, extending screening to women age 40 to 49 would reduce the cancer mortality rate by 3% more, while extending it up to age 79 would reduce it by another 7% to 8%.

In terms of harm, the models predicted more false-positive studies if screening were started before age 50 and if it were done annually rather than biennially. They also predicted that more unnecessary biopsies would be done with annual screening than with screening every 2 years. The models suggested that the risk for overdiagnosis was higher in older age groups because of higher rates of death from causes other than breast cancer, and that the overdiagnosis rate was also somewhat higher with annual than with 2-year screening.

WHAT WOULD LESS SCREENING MEAN?

Our practice has been to initiate annual screening with mammography at age 40 and to continue as long as the patient’s life expectancy is at least 10 years.

According to the models used by Mandelblatt et al,⁴ screening 1,000 women every year, starting at age 40 and continuing until age 84, would result in 177 to 227 life-years gained compared with no screening. In contrast, screening only women age 50 to 74 and only every other year (as advocated in the new guidelines) would entail about one-third the number of mammograms but would result in fewer life-years gained per 1,000 women screened: between 96 and 128. If we take the mean of the estimates from the six models, adherence to the new screening guidelines would be estimated to result in about 79 fewer life-years gained for every 1,000 women screened. On the other hand, each woman screened would need to undergo about 25 fewer screening mammograms in her lifetime.⁴

KEY POINTS ABOUT BREAST CANCER SCREENING

Together, these studies demonstrate several points about breast cancer screening.

Importantly, randomized controlled trials and model analyses continue to show that screening mammography reduces the breast cancer mortality rate.

The studies and models also reinforce the concept that those at greatest risk get the most benefit from screening. Because the incidence of breast cancer rises with age, the probability of a true-positive result is higher in women over age 50 than it is in younger women, and, therefore, the screening test performs better.

On the other hand, women at high risk of dying of other causes, such as those over age 75, achieve less benefit from screening, as some of the cancers detected in this manner may not contribute to their death even if they are not detected early.

Screening is therefore best targeted at people who are healthy but who are at sufficient risk for the disease in question to justify the screening.

CLEVELAND CLINIC’S POSITION

In December 2009, the Cleveland Clinic Breast Cancer Screening Task Force, a multidisciplinary panel of breast cancer experts, breast radiologists, and primary care providers, convened to review the literature and set forth institutional recommendations for breast cancer screening for healthy women. The authors of this paper are members of this task force. Our consensus recommendations:

• We continue to recommend annual mammography for most healthy women over age 40.
• Screening every other year is an option for older postmenopausal women, as they are likely to achieve most of the benefit of annual screening with this schedule.
• We agree with the USPSTF finding that there are insufficient data to provide evidenced-based recommendations regarding the benefits and harms of clinical breast examination. However, breast examination was done as part of the screening in many of the randomized trials of mammography and cannot easily be separated from mammography. Therefore, we believe that careful examination of the breasts remains an important consideration in the general physical examination.
• The USPSTF recommendation not to teach breast self-examination was based on studies that probably do not apply to the US population. Therefore, we continue to recommend that women be familiar with their breasts and report any changes to their physicians.

How we reached these conclusions

The task force discussions focused heavily on at what age mammography should be started and how often it should be done. In addition to an in-depth review of the studies on which the USPSTF recommendations were based, we considered a review posted on the Society of Breast Imaging (SBI) Web site.⁸

A key point from the SBI’s review is that although breast cancer occurs less often in women under age 50, approximately 1 in 69 women are diagnosed with invasive cancer when in their 40s. Some—probably a minority— have a family history of breast cancer and thus warrant earlier screening on that basis.

Breast cancer is, therefore, an important public health concern for women ages 40 to 49. While mammography is an imperfect test, it has a demonstrated ability to find cancers at an earlier stage in this age group. The SBI statement also summarized data suggesting that the 40-to-49-year age group would experience significantly fewer lives saved by screening if the mammography interval were increased from once a year to every other year (ie, by approximately one-half—from 36% of deaths prevented with annual screening to 18% deaths prevented with screening every other year).

Screening every other year is also expected to result in fewer lives saved in women ages 50 to 69 (39% of deaths prevented by biennial screening instead of 44% to 46% with annual screening). However, this proportion of deaths prevented with more frequent (ie, annual) screening is smaller than in the younger age group. Breast cancers that arise before menopause are considered biologically more aggressive, so the longer the interval between screening tests, the lower the likelihood of detecting some of these potentially more lethal cancers.

We believe, for several reasons, that the randomized trials may have underestimated the benefit of mammography. The trials included in the USPSTF studies did not use modern mammographic techniques such as digital mammography. Some of the trials used single-view mammography, which may be less sensitive. Also, the rate of compliance with screening in these randomized trials was only about 70%, which would lead to an underestimation of the number of lives saved with mammography screening. Yet in spite of these limitations, the data continue to show a reduction in breast cancer deaths in all age categories studied.

Other issues the task force considered

Harms of screening are acceptable. We agree that the need for additional imaging or possibly breast biopsy is an acceptable consequence of screening for most women, especially when weighed against the potential benefit of improving survival. Nelson et al³ briefly discussed the risk of inducing other cancers through radiation exposure, and any such risk appears to be low enough that it is overshadowed by the reduction in the breast cancer mortality rate achieved from screening.

The USPSTF studies did not address the issue of cost, which is another potential harm of screening. However, screening mammography is relatively inexpensive compared with other potentially life-saving screening tests.

Our position differs from that of the American College of Physicians (ACP), which has endorsed the USPSTF recommendation for reduced breast cancer screening. The USPSTF has been a leading group in providing practice recommendations based on high-level evidence predominantly from randomized controlled clinical trials, and its recommendations have been consistently followed by the ACP and many of its members, including Cleveland Clinic physicians. It is, therefore, not without considerable discussion that we have come to our consensus.

Evidence for less screening was not compelling. One of our concerns about the new USPSTF recommendations is that the changes are based largely on a model analysis of the efficiency of different screening strategies rather than on randomized controlled trials comparing different strategies. We did not find this level of present evidence to be sufficiently compelling to make a change in our practice that may result in loss of lives from breast cancer.

Screening guidelines will continue to change over time as technology improves and new data are introduced. In the future, risk-assessment strategies such as incorporating genetic profiles may allow us to use factors more predictive than age to target our screening population.

While we continue to strive for better means of early detection and cancer prevention, the Cleveland Clinic task force is currently recommending yearly screening with mammography and breast examination for most women, starting at age 40.

Editor’s Note: This commentary, written by members of the Cleveland Clinic Breast Cancer Screening Task Force, was not independently peer-reviewed.

In November 2009, the US Preventive Services Task Force (USPSTF) announced its new guidelines for breast cancer screening—and created an instant controversy by suggesting that fewer screening tests be done.¹

The November 2009 update recommended that most women wait until age 50 to get their first screening mammogram instead of getting it at age 40, that they get a mammogram every other year instead of every year, and that physicians not teach their patients breast self-examination anymore. However, on December 4, 2009, the USPSTF members voted to modify the recommendation for women under age 50, stating that the decision to start screening mammography every 2 years should be individualized, taking into account the patient’s preferences after being apprised of the possible benefits and harms.²

Various professional and advocacy groups have reacted differently to the new guidelines, and as a result, women are unsure about the optimal screening for breast cancer.

NEW GUIDELINES ARE BASED ON TWO STUDIES

The USPSTF commissioned two studies, which it used to formulate the new recommendations.^3,4 Its goal was to evaluate the current evidence for the efficacy of several screening tests and schedules in reducing breast cancer mortality rates.

An updated systematic review

Nelson et al³ performed a systematic review of studies of the benefit and harm of screening with mammography, clinical breast examination, and breast self-examination.

Screening mammography continued to demonstrate a reduction in deaths due to breast cancer. The risk reduction ranged from 14% to 32% in women age 50 to 69. Similarly, it was calculated to reduce the incidence of deaths due to breast cancer by 15% in women age 39 to 49. However, this younger age group has a relatively low incidence of breast cancer, and therefore, according to this analysis, 556 women need to undergo one round of screening to detect one case of invasive breast cancer, and 1,904 women need to be offered screening (over several rounds, which varied by trial) to prevent one breast cancer death.³

Most of the harm of screening in the 39-to-49-year age category was due to false-positive results, which were more common in this group than in older women. The authors calculated that after every round of screening mammography, about 84 of every 1,000 women in the younger age category need additional imaging and about 9 need a biopsy. The issue of overdiagnosis (detection of cancers that would have never been a problem in one’s lifetime) was not specifically addressed for this age category, and in different studies, estimates of overdiagnosis rates for all age groups varied widely, from less than 1% to 30%.

Beyond age 70, the authors reported the data insufficient for evaluating the benefit and harm of screening mammography.

Breast self-examination was found to offer no benefit, based largely on two randomized studies, one in St. Petersburg, Russia,⁵ and the other in Shanghai, China,⁶ both places where screening mammography was not routinely offered. These studies and one observational study in the United States⁷ failed to show a reduction in breast cancer mortality rates with breast self-examination.

Clinical breast examination (ie, by a health care provider) lacked sufficient data to draw conclusions.

A study based on statistical models of mammography

Mandelblatt et al⁴ used statistical modeling to estimate the effect of mammographic screening at various ages and at different intervals.

The authors used six statistical models previously shown to give similar qualitative estimates of the contribution of screening in reducing breast cancer mortality rates. They estimated the number of mammograms required relative to the number of cancers detected, the number of breast cancer deaths prevented, and the harms (false-positive mammograms, unnecessary biopsies, and overdiagnosis) incurred with 20 different screening strategies, ie, screening with different starting and stopping ages and at intervals of either 1 or 2 years.

They estimated that screening every other year would achieve most of the benefit of screening every year, with less harm. Looking at the different strategies and models, on average, biennial screening would, by their calculations, achieve about 81% of the mortality reduction achieved with annual screening. Compared with screening women ages 50 to 69 only, extending screening to women age 40 to 49 would reduce the cancer mortality rate by 3% more, while extending it up to age 79 would reduce it by another 7% to 8%.

In terms of harm, the models predicted more false-positive studies if screening were started before age 50 and if it were done annually rather than biennially. They also predicted that more unnecessary biopsies would be done with annual screening than with screening every 2 years. The models suggested that the risk for overdiagnosis was higher in older age groups because of higher rates of death from causes other than breast cancer, and that the overdiagnosis rate was also somewhat higher with annual than with 2-year screening.

WHAT WOULD LESS SCREENING MEAN?

Our practice has been to initiate annual screening with mammography at age 40 and to continue as long as the patient’s life expectancy is at least 10 years.

According to the models used by Mandelblatt et al,⁴ screening 1,000 women every year, starting at age 40 and continuing until age 84, would result in 177 to 227 life-years gained compared with no screening. In contrast, screening only women age 50 to 74 and only every other year (as advocated in the new guidelines) would entail about one-third the number of mammograms but would result in fewer life-years gained per 1,000 women screened: between 96 and 128. If we take the mean of the estimates from the six models, adherence to the new screening guidelines would be estimated to result in about 79 fewer life-years gained for every 1,000 women screened. On the other hand, each woman screened would need to undergo about 25 fewer screening mammograms in her lifetime.⁴

KEY POINTS ABOUT BREAST CANCER SCREENING

Together, these studies demonstrate several points about breast cancer screening.

Importantly, randomized controlled trials and model analyses continue to show that screening mammography reduces the breast cancer mortality rate.

The studies and models also reinforce the concept that those at greatest risk get the most benefit from screening. Because the incidence of breast cancer rises with age, the probability of a true-positive result is higher in women over age 50 than it is in younger women, and, therefore, the screening test performs better.

On the other hand, women at high risk of dying of other causes, such as those over age 75, achieve less benefit from screening, as some of the cancers detected in this manner may not contribute to their death even if they are not detected early.

Screening is therefore best targeted at people who are healthy but who are at sufficient risk for the disease in question to justify the screening.

CLEVELAND CLINIC’S POSITION

In December 2009, the Cleveland Clinic Breast Cancer Screening Task Force, a multidisciplinary panel of breast cancer experts, breast radiologists, and primary care providers, convened to review the literature and set forth institutional recommendations for breast cancer screening for healthy women. The authors of this paper are members of this task force. Our consensus recommendations:

• We continue to recommend annual mammography for most healthy women over age 40.
• Screening every other year is an option for older postmenopausal women, as they are likely to achieve most of the benefit of annual screening with this schedule.
• We agree with the USPSTF finding that there are insufficient data to provide evidenced-based recommendations regarding the benefits and harms of clinical breast examination. However, breast examination was done as part of the screening in many of the randomized trials of mammography and cannot easily be separated from mammography. Therefore, we believe that careful examination of the breasts remains an important consideration in the general physical examination.
• The USPSTF recommendation not to teach breast self-examination was based on studies that probably do not apply to the US population. Therefore, we continue to recommend that women be familiar with their breasts and report any changes to their physicians.

How we reached these conclusions

The task force discussions focused heavily on at what age mammography should be started and how often it should be done. In addition to an in-depth review of the studies on which the USPSTF recommendations were based, we considered a review posted on the Society of Breast Imaging (SBI) Web site.⁸

A key point from the SBI’s review is that although breast cancer occurs less often in women under age 50, approximately 1 in 69 women are diagnosed with invasive cancer when in their 40s. Some—probably a minority— have a family history of breast cancer and thus warrant earlier screening on that basis.

Breast cancer is, therefore, an important public health concern for women ages 40 to 49. While mammography is an imperfect test, it has a demonstrated ability to find cancers at an earlier stage in this age group. The SBI statement also summarized data suggesting that the 40-to-49-year age group would experience significantly fewer lives saved by screening if the mammography interval were increased from once a year to every other year (ie, by approximately one-half—from 36% of deaths prevented with annual screening to 18% deaths prevented with screening every other year).

Screening every other year is also expected to result in fewer lives saved in women ages 50 to 69 (39% of deaths prevented by biennial screening instead of 44% to 46% with annual screening). However, this proportion of deaths prevented with more frequent (ie, annual) screening is smaller than in the younger age group. Breast cancers that arise before menopause are considered biologically more aggressive, so the longer the interval between screening tests, the lower the likelihood of detecting some of these potentially more lethal cancers.

We believe, for several reasons, that the randomized trials may have underestimated the benefit of mammography. The trials included in the USPSTF studies did not use modern mammographic techniques such as digital mammography. Some of the trials used single-view mammography, which may be less sensitive. Also, the rate of compliance with screening in these randomized trials was only about 70%, which would lead to an underestimation of the number of lives saved with mammography screening. Yet in spite of these limitations, the data continue to show a reduction in breast cancer deaths in all age categories studied.

Other issues the task force considered

Harms of screening are acceptable. We agree that the need for additional imaging or possibly breast biopsy is an acceptable consequence of screening for most women, especially when weighed against the potential benefit of improving survival. Nelson et al³ briefly discussed the risk of inducing other cancers through radiation exposure, and any such risk appears to be low enough that it is overshadowed by the reduction in the breast cancer mortality rate achieved from screening.

The USPSTF studies did not address the issue of cost, which is another potential harm of screening. However, screening mammography is relatively inexpensive compared with other potentially life-saving screening tests.

Our position differs from that of the American College of Physicians (ACP), which has endorsed the USPSTF recommendation for reduced breast cancer screening. The USPSTF has been a leading group in providing practice recommendations based on high-level evidence predominantly from randomized controlled clinical trials, and its recommendations have been consistently followed by the ACP and many of its members, including Cleveland Clinic physicians. It is, therefore, not without considerable discussion that we have come to our consensus.

Evidence for less screening was not compelling. One of our concerns about the new USPSTF recommendations is that the changes are based largely on a model analysis of the efficiency of different screening strategies rather than on randomized controlled trials comparing different strategies. We did not find this level of present evidence to be sufficiently compelling to make a change in our practice that may result in loss of lives from breast cancer.

Screening guidelines will continue to change over time as technology improves and new data are introduced. In the future, risk-assessment strategies such as incorporating genetic profiles may allow us to use factors more predictive than age to target our screening population.

While we continue to strive for better means of early detection and cancer prevention, the Cleveland Clinic task force is currently recommending yearly screening with mammography and breast examination for most women, starting at age 40.

Editor’s Note: This commentary, written by members of the Cleveland Clinic Breast Cancer Screening Task Force, was not independently peer-reviewed.

In November 2009, the US Preventive Services Task Force (USPSTF) announced its new guidelines for breast cancer screening—and created an instant controversy by suggesting that fewer screening tests be done.¹

The November 2009 update recommended that most women wait until age 50 to get their first screening mammogram instead of getting it at age 40, that they get a mammogram every other year instead of every year, and that physicians not teach their patients breast self-examination anymore. However, on December 4, 2009, the USPSTF members voted to modify the recommendation for women under age 50, stating that the decision to start screening mammography every 2 years should be individualized, taking into account the patient’s preferences after being apprised of the possible benefits and harms.²

Various professional and advocacy groups have reacted differently to the new guidelines, and as a result, women are unsure about the optimal screening for breast cancer.

NEW GUIDELINES ARE BASED ON TWO STUDIES

The USPSTF commissioned two studies, which it used to formulate the new recommendations.^3,4 Its goal was to evaluate the current evidence for the efficacy of several screening tests and schedules in reducing breast cancer mortality rates.

An updated systematic review

Nelson et al³ performed a systematic review of studies of the benefit and harm of screening with mammography, clinical breast examination, and breast self-examination.

Screening mammography continued to demonstrate a reduction in deaths due to breast cancer. The risk reduction ranged from 14% to 32% in women age 50 to 69. Similarly, it was calculated to reduce the incidence of deaths due to breast cancer by 15% in women age 39 to 49. However, this younger age group has a relatively low incidence of breast cancer, and therefore, according to this analysis, 556 women need to undergo one round of screening to detect one case of invasive breast cancer, and 1,904 women need to be offered screening (over several rounds, which varied by trial) to prevent one breast cancer death.³

Most of the harm of screening in the 39-to-49-year age category was due to false-positive results, which were more common in this group than in older women. The authors calculated that after every round of screening mammography, about 84 of every 1,000 women in the younger age category need additional imaging and about 9 need a biopsy. The issue of overdiagnosis (detection of cancers that would have never been a problem in one’s lifetime) was not specifically addressed for this age category, and in different studies, estimates of overdiagnosis rates for all age groups varied widely, from less than 1% to 30%.

Beyond age 70, the authors reported the data insufficient for evaluating the benefit and harm of screening mammography.

Breast self-examination was found to offer no benefit, based largely on two randomized studies, one in St. Petersburg, Russia,⁵ and the other in Shanghai, China,⁶ both places where screening mammography was not routinely offered. These studies and one observational study in the United States⁷ failed to show a reduction in breast cancer mortality rates with breast self-examination.

Clinical breast examination (ie, by a health care provider) lacked sufficient data to draw conclusions.

A study based on statistical models of mammography

Mandelblatt et al⁴ used statistical modeling to estimate the effect of mammographic screening at various ages and at different intervals.

The authors used six statistical models previously shown to give similar qualitative estimates of the contribution of screening in reducing breast cancer mortality rates. They estimated the number of mammograms required relative to the number of cancers detected, the number of breast cancer deaths prevented, and the harms (false-positive mammograms, unnecessary biopsies, and overdiagnosis) incurred with 20 different screening strategies, ie, screening with different starting and stopping ages and at intervals of either 1 or 2 years.

They estimated that screening every other year would achieve most of the benefit of screening every year, with less harm. Looking at the different strategies and models, on average, biennial screening would, by their calculations, achieve about 81% of the mortality reduction achieved with annual screening. Compared with screening women ages 50 to 69 only, extending screening to women age 40 to 49 would reduce the cancer mortality rate by 3% more, while extending it up to age 79 would reduce it by another 7% to 8%.

In terms of harm, the models predicted more false-positive studies if screening were started before age 50 and if it were done annually rather than biennially. They also predicted that more unnecessary biopsies would be done with annual screening than with screening every 2 years. The models suggested that the risk for overdiagnosis was higher in older age groups because of higher rates of death from causes other than breast cancer, and that the overdiagnosis rate was also somewhat higher with annual than with 2-year screening.

WHAT WOULD LESS SCREENING MEAN?

Our practice has been to initiate annual screening with mammography at age 40 and to continue as long as the patient’s life expectancy is at least 10 years.

According to the models used by Mandelblatt et al,⁴ screening 1,000 women every year, starting at age 40 and continuing until age 84, would result in 177 to 227 life-years gained compared with no screening. In contrast, screening only women age 50 to 74 and only every other year (as advocated in the new guidelines) would entail about one-third the number of mammograms but would result in fewer life-years gained per 1,000 women screened: between 96 and 128. If we take the mean of the estimates from the six models, adherence to the new screening guidelines would be estimated to result in about 79 fewer life-years gained for every 1,000 women screened. On the other hand, each woman screened would need to undergo about 25 fewer screening mammograms in her lifetime.⁴

KEY POINTS ABOUT BREAST CANCER SCREENING

Together, these studies demonstrate several points about breast cancer screening.

Importantly, randomized controlled trials and model analyses continue to show that screening mammography reduces the breast cancer mortality rate.

The studies and models also reinforce the concept that those at greatest risk get the most benefit from screening. Because the incidence of breast cancer rises with age, the probability of a true-positive result is higher in women over age 50 than it is in younger women, and, therefore, the screening test performs better.

On the other hand, women at high risk of dying of other causes, such as those over age 75, achieve less benefit from screening, as some of the cancers detected in this manner may not contribute to their death even if they are not detected early.

Screening is therefore best targeted at people who are healthy but who are at sufficient risk for the disease in question to justify the screening.

CLEVELAND CLINIC’S POSITION

In December 2009, the Cleveland Clinic Breast Cancer Screening Task Force, a multidisciplinary panel of breast cancer experts, breast radiologists, and primary care providers, convened to review the literature and set forth institutional recommendations for breast cancer screening for healthy women. The authors of this paper are members of this task force. Our consensus recommendations:

• We continue to recommend annual mammography for most healthy women over age 40.
• Screening every other year is an option for older postmenopausal women, as they are likely to achieve most of the benefit of annual screening with this schedule.
• We agree with the USPSTF finding that there are insufficient data to provide evidenced-based recommendations regarding the benefits and harms of clinical breast examination. However, breast examination was done as part of the screening in many of the randomized trials of mammography and cannot easily be separated from mammography. Therefore, we believe that careful examination of the breasts remains an important consideration in the general physical examination.
• The USPSTF recommendation not to teach breast self-examination was based on studies that probably do not apply to the US population. Therefore, we continue to recommend that women be familiar with their breasts and report any changes to their physicians.

How we reached these conclusions

The task force discussions focused heavily on at what age mammography should be started and how often it should be done. In addition to an in-depth review of the studies on which the USPSTF recommendations were based, we considered a review posted on the Society of Breast Imaging (SBI) Web site.⁸

A key point from the SBI’s review is that although breast cancer occurs less often in women under age 50, approximately 1 in 69 women are diagnosed with invasive cancer when in their 40s. Some—probably a minority— have a family history of breast cancer and thus warrant earlier screening on that basis.

Breast cancer is, therefore, an important public health concern for women ages 40 to 49. While mammography is an imperfect test, it has a demonstrated ability to find cancers at an earlier stage in this age group. The SBI statement also summarized data suggesting that the 40-to-49-year age group would experience significantly fewer lives saved by screening if the mammography interval were increased from once a year to every other year (ie, by approximately one-half—from 36% of deaths prevented with annual screening to 18% deaths prevented with screening every other year).

Screening every other year is also expected to result in fewer lives saved in women ages 50 to 69 (39% of deaths prevented by biennial screening instead of 44% to 46% with annual screening). However, this proportion of deaths prevented with more frequent (ie, annual) screening is smaller than in the younger age group. Breast cancers that arise before menopause are considered biologically more aggressive, so the longer the interval between screening tests, the lower the likelihood of detecting some of these potentially more lethal cancers.

We believe, for several reasons, that the randomized trials may have underestimated the benefit of mammography. The trials included in the USPSTF studies did not use modern mammographic techniques such as digital mammography. Some of the trials used single-view mammography, which may be less sensitive. Also, the rate of compliance with screening in these randomized trials was only about 70%, which would lead to an underestimation of the number of lives saved with mammography screening. Yet in spite of these limitations, the data continue to show a reduction in breast cancer deaths in all age categories studied.

Other issues the task force considered

Harms of screening are acceptable. We agree that the need for additional imaging or possibly breast biopsy is an acceptable consequence of screening for most women, especially when weighed against the potential benefit of improving survival. Nelson et al³ briefly discussed the risk of inducing other cancers through radiation exposure, and any such risk appears to be low enough that it is overshadowed by the reduction in the breast cancer mortality rate achieved from screening.

The USPSTF studies did not address the issue of cost, which is another potential harm of screening. However, screening mammography is relatively inexpensive compared with other potentially life-saving screening tests.

Our position differs from that of the American College of Physicians (ACP), which has endorsed the USPSTF recommendation for reduced breast cancer screening. The USPSTF has been a leading group in providing practice recommendations based on high-level evidence predominantly from randomized controlled clinical trials, and its recommendations have been consistently followed by the ACP and many of its members, including Cleveland Clinic physicians. It is, therefore, not without considerable discussion that we have come to our consensus.

Evidence for less screening was not compelling. One of our concerns about the new USPSTF recommendations is that the changes are based largely on a model analysis of the efficiency of different screening strategies rather than on randomized controlled trials comparing different strategies. We did not find this level of present evidence to be sufficiently compelling to make a change in our practice that may result in loss of lives from breast cancer.

Screening guidelines will continue to change over time as technology improves and new data are introduced. In the future, risk-assessment strategies such as incorporating genetic profiles may allow us to use factors more predictive than age to target our screening population.

While we continue to strive for better means of early detection and cancer prevention, the Cleveland Clinic task force is currently recommending yearly screening with mammography and breast examination for most women, starting at age 40.