Expert Commentary

Objective

To evaluate the safety of hormone therapy (HT) compared to nonhormone therapy (NHT) in women with previously diagnosed breast cancer who are experiencing menopausal symptoms.

Results

Researchers found an increased risk of breast cancer recurrence among women taking HT, with 14% developing recurrence/contralateral breast cancer compared with 4% of nonusers, and terminated the trial early.

Methods

Women were eligible for the HABITS prospective randomized trial if they had a history of in situ, stage I or II breast cancer with up to 4 positive lymph nodes and climacteric symptoms. Both premenopausal and postmenopausal women were accepted into the study, which began accruing participants in May 1997. The trial assigned 434 previous breast cancer patients with menopausal symptoms to either HT or NHT.

The main endpoint was any new breast cancer event (recurrence/contralateral breast cancer), with all analyses done according to intention to treat. Secondary aims were to examine quality of life and risk of death from breast cancer.

After a median follow-up of 2.1 years, 26 women in the HT group and 7 nonusers had a new breast cancer event. All women in the HTgroup and 2 women in the NHT group were exposed to HT; most experienced their event while on treatment.

Outcome

Researchers determined that HT posed an unacceptable risk and ended the trial on Dec 17, 2003.

Expert Commentary

Imperfect study design. Although it was a prospective randomized trial, HABITS leaves much to be desired. It was an open study that was neither placebo-controlled nor blinded.

Treatment was not described in either arm of the study. For example, HT was suggested to be estrogen with or without progestin of “median potency” (undefined), similar to that “commonly given in the environment where the patient lives and the clinician works.” In the NHT arm, therapy was the “best symptomatic treatment without hormones” and could include clonidine, beta blockers, psychological support, physical exercise, and acupuncture. Local estrogen could be used but “natural products” could not. In 2002, because of poor accrual, the “Stockholm” study was folded into the HABITS trial.

The HABITS study was an equivalency trial designed to stop if the hazard ratio (HR) surpassed 1.36. The investigators state that the HR for HT was 3.5 (14% of women had a recurrence/contralateral cancer, compared with 4% in the nonhormonal group). The investigators note that the Stockholm trial had an HR of 0.82 and was not included in the research letter published in Lancet. Since most HABITS participants were from Sweden, one wonders why there are such different results from the same apparent population base.

Unanswered questions. Analyzing the HABITS trial is problematic on several fronts. For instance, mammograms and follow-up are suggested but apparently not required (more than 20% of randomized women were not included in the analysis because they had not had at least 1 follow-up visit). Were these items equal in both groups? Did the HT group have better mammography compliance than the nonhormonal group? Compliance to therapy was not detailed.

Roughly 20% of women in the HT group who developed a recurrence were not on HT at the time of recurrence. With such a short follow-up (2.1 years), details on the length of HT and relationship to time of randomization and recurrence are important. Since breast cancer can reside in the breast for 10 years or more before diagnosis, it is reasonable to assume that the recurrences and contralateral breast cancers were present at the time of randomization.

Two of the most important risk factors in breast cancer are stage and lymphnode status. These 2 items were not stratified at the time of randomization. Were they equal in the 2 groups? What was the receptor status in each group? Were the groups equal in this regard?

Tamoxifen was allowed and stratified at randomization. Since tamoxifen can have an impact on menopausal symptoms, was compliance the same in the 2 groups?

Although the authors noted that a Cox proportional hazard model would be used in their analysis, no such data was given. The results could change once such a model is used.

Bottom Line

We appreciate that a study like this is difficult, as the Women’s Health Initiative amply proves. This one involved low accrual and lenient guidelines regarding treatment, prognostic variables, and compliance. Still, this preliminary research letter is just that: preliminary. We should await thorough evaluation before giving the findings much credence. Certainly the statement in the commentary accompanying this letter, that this study “can now reasonably guide clinical practice for women with breast cancer,” appears premature and without merit.

Objective

To evaluate the safety of hormone therapy (HT) compared to nonhormone therapy (NHT) in women with previously diagnosed breast cancer who are experiencing menopausal symptoms.

Results

Researchers found an increased risk of breast cancer recurrence among women taking HT, with 14% developing recurrence/contralateral breast cancer compared with 4% of nonusers, and terminated the trial early.

Methods

Women were eligible for the HABITS prospective randomized trial if they had a history of in situ, stage I or II breast cancer with up to 4 positive lymph nodes and climacteric symptoms. Both premenopausal and postmenopausal women were accepted into the study, which began accruing participants in May 1997. The trial assigned 434 previous breast cancer patients with menopausal symptoms to either HT or NHT.

The main endpoint was any new breast cancer event (recurrence/contralateral breast cancer), with all analyses done according to intention to treat. Secondary aims were to examine quality of life and risk of death from breast cancer.

After a median follow-up of 2.1 years, 26 women in the HT group and 7 nonusers had a new breast cancer event. All women in the HTgroup and 2 women in the NHT group were exposed to HT; most experienced their event while on treatment.

Outcome

Researchers determined that HT posed an unacceptable risk and ended the trial on Dec 17, 2003.

Expert Commentary

Imperfect study design. Although it was a prospective randomized trial, HABITS leaves much to be desired. It was an open study that was neither placebo-controlled nor blinded.

Treatment was not described in either arm of the study. For example, HT was suggested to be estrogen with or without progestin of “median potency” (undefined), similar to that “commonly given in the environment where the patient lives and the clinician works.” In the NHT arm, therapy was the “best symptomatic treatment without hormones” and could include clonidine, beta blockers, psychological support, physical exercise, and acupuncture. Local estrogen could be used but “natural products” could not. In 2002, because of poor accrual, the “Stockholm” study was folded into the HABITS trial.

The HABITS study was an equivalency trial designed to stop if the hazard ratio (HR) surpassed 1.36. The investigators state that the HR for HT was 3.5 (14% of women had a recurrence/contralateral cancer, compared with 4% in the nonhormonal group). The investigators note that the Stockholm trial had an HR of 0.82 and was not included in the research letter published in Lancet. Since most HABITS participants were from Sweden, one wonders why there are such different results from the same apparent population base.

Unanswered questions. Analyzing the HABITS trial is problematic on several fronts. For instance, mammograms and follow-up are suggested but apparently not required (more than 20% of randomized women were not included in the analysis because they had not had at least 1 follow-up visit). Were these items equal in both groups? Did the HT group have better mammography compliance than the nonhormonal group? Compliance to therapy was not detailed.

Roughly 20% of women in the HT group who developed a recurrence were not on HT at the time of recurrence. With such a short follow-up (2.1 years), details on the length of HT and relationship to time of randomization and recurrence are important. Since breast cancer can reside in the breast for 10 years or more before diagnosis, it is reasonable to assume that the recurrences and contralateral breast cancers were present at the time of randomization.

Two of the most important risk factors in breast cancer are stage and lymphnode status. These 2 items were not stratified at the time of randomization. Were they equal in the 2 groups? What was the receptor status in each group? Were the groups equal in this regard?

Tamoxifen was allowed and stratified at randomization. Since tamoxifen can have an impact on menopausal symptoms, was compliance the same in the 2 groups?

Although the authors noted that a Cox proportional hazard model would be used in their analysis, no such data was given. The results could change once such a model is used.

Bottom Line

We appreciate that a study like this is difficult, as the Women’s Health Initiative amply proves. This one involved low accrual and lenient guidelines regarding treatment, prognostic variables, and compliance. Still, this preliminary research letter is just that: preliminary. We should await thorough evaluation before giving the findings much credence. Certainly the statement in the commentary accompanying this letter, that this study “can now reasonably guide clinical practice for women with breast cancer,” appears premature and without merit.

Objective

To evaluate the safety of hormone therapy (HT) compared to nonhormone therapy (NHT) in women with previously diagnosed breast cancer who are experiencing menopausal symptoms.

Results

Researchers found an increased risk of breast cancer recurrence among women taking HT, with 14% developing recurrence/contralateral breast cancer compared with 4% of nonusers, and terminated the trial early.

Methods

Women were eligible for the HABITS prospective randomized trial if they had a history of in situ, stage I or II breast cancer with up to 4 positive lymph nodes and climacteric symptoms. Both premenopausal and postmenopausal women were accepted into the study, which began accruing participants in May 1997. The trial assigned 434 previous breast cancer patients with menopausal symptoms to either HT or NHT.

The main endpoint was any new breast cancer event (recurrence/contralateral breast cancer), with all analyses done according to intention to treat. Secondary aims were to examine quality of life and risk of death from breast cancer.

After a median follow-up of 2.1 years, 26 women in the HT group and 7 nonusers had a new breast cancer event. All women in the HTgroup and 2 women in the NHT group were exposed to HT; most experienced their event while on treatment.

Outcome

Researchers determined that HT posed an unacceptable risk and ended the trial on Dec 17, 2003.

Expert Commentary

Imperfect study design. Although it was a prospective randomized trial, HABITS leaves much to be desired. It was an open study that was neither placebo-controlled nor blinded.

Treatment was not described in either arm of the study. For example, HT was suggested to be estrogen with or without progestin of “median potency” (undefined), similar to that “commonly given in the environment where the patient lives and the clinician works.” In the NHT arm, therapy was the “best symptomatic treatment without hormones” and could include clonidine, beta blockers, psychological support, physical exercise, and acupuncture. Local estrogen could be used but “natural products” could not. In 2002, because of poor accrual, the “Stockholm” study was folded into the HABITS trial.

The HABITS study was an equivalency trial designed to stop if the hazard ratio (HR) surpassed 1.36. The investigators state that the HR for HT was 3.5 (14% of women had a recurrence/contralateral cancer, compared with 4% in the nonhormonal group). The investigators note that the Stockholm trial had an HR of 0.82 and was not included in the research letter published in Lancet. Since most HABITS participants were from Sweden, one wonders why there are such different results from the same apparent population base.

Unanswered questions. Analyzing the HABITS trial is problematic on several fronts. For instance, mammograms and follow-up are suggested but apparently not required (more than 20% of randomized women were not included in the analysis because they had not had at least 1 follow-up visit). Were these items equal in both groups? Did the HT group have better mammography compliance than the nonhormonal group? Compliance to therapy was not detailed.

Roughly 20% of women in the HT group who developed a recurrence were not on HT at the time of recurrence. With such a short follow-up (2.1 years), details on the length of HT and relationship to time of randomization and recurrence are important. Since breast cancer can reside in the breast for 10 years or more before diagnosis, it is reasonable to assume that the recurrences and contralateral breast cancers were present at the time of randomization.

Two of the most important risk factors in breast cancer are stage and lymphnode status. These 2 items were not stratified at the time of randomization. Were they equal in the 2 groups? What was the receptor status in each group? Were the groups equal in this regard?

Tamoxifen was allowed and stratified at randomization. Since tamoxifen can have an impact on menopausal symptoms, was compliance the same in the 2 groups?

Although the authors noted that a Cox proportional hazard model would be used in their analysis, no such data was given. The results could change once such a model is used.

Bottom Line

We appreciate that a study like this is difficult, as the Women’s Health Initiative amply proves. This one involved low accrual and lenient guidelines regarding treatment, prognostic variables, and compliance. Still, this preliminary research letter is just that: preliminary. We should await thorough evaluation before giving the findings much credence. Certainly the statement in the commentary accompanying this letter, that this study “can now reasonably guide clinical practice for women with breast cancer,” appears premature and without merit.

Context

When labor does not begin spontaneously and delivery is indicated, the question of risk with labor induction becomes a critical issue—especially for women with a previous lower-segment cesarean delivery, most of whom are candidates for a trial of labor with their next pregnancy.

Objective

To compare maternal and neonatal outcomes of spontaneous and induced labor following 1 previous cesarean delivery.

Method

A population-based study of 3,746 women (2,943 spontaneous and 803 induced labors) with 1 previous cesarean delivery who underwent a trial of labor between January 1992 and January 2000.

Outcome

Researchers noted a trend toward higher uterine rupture rates in women who had induced labor by any method compared to spontaneous labor (0.7% versus 0.3%, P = .128), as well as in women who underwent dinoprostone (prostaglandin E₂ [PGE₂]) versus other induction methods, (1.1% versus 0.6%, P = .62), though neither outcome was statistically significant.

The induced-labor group had more frequent:

• early postpartum hemorrhage (7.3% versus 5%; odds ratio [OR] 1.66; 95% confidence interval [CI] 1.18, 2.32)
  
• cesarean delivery (37.5% versus 24.2%; OR 1.84; 95% CI 1.51, 2.25)
  
• neonatal intensive care unit admission (13.3% versus 9.4%; OR 1.69; 95% CI 1.25, 2.29)
  

Expert Commentary

The proportion of women undergoing a trial of labor after cesarean delivery has been decreasing since the mid-1990s, and optimal management of these women is controversial. What’s more, for over a decade we have been increasing labor induction rates for all women in all gestational age ranges.¹

An association between PGE₂ and rupture of a uterine scar was reported more than 20 years ago.² Unfortunately, since that time, only a handful of studies with more than 100 patients have explored this association. Even fewer studies have evaluated the risk of induction with oxytocin for women undergoing a trial of labor after prior cesarean.

My colleagues and I were able to document a rate of uterine rupture of 2.3% for women undergoing induction with oxytocin, compared with 0.7% for those who had spontaneous labor.³ More recently, an increased rate of uterine rupture was reported in women induced without prostaglandins compared to women undergoing repeat cesarean, with a relative risk of 4.9 (95% CI 2.4, 9.7).⁴

Oxytocin, PGE₂ were assessed, but not mechanical induction or artificial rupture. Delaney and Young endeavor to put these risks into perspective. They were able to specifically assess the effects of oxytocin and PGE₂ among the 803 women who had labor induced.

Unfortunately, the number of women who experienced artificial rupture of membranes and mechanical methods of induction was inadequate to draw conclusions.

Did a statistical error occur? The difference in the rate of uterine rupture for women with spontaneous labor was not statistically significant compared to those receiving oxytocin (n = 600) or PGE₂ (n = 179), yet the risk of uterine rupture in the oxytocin group more than doubled, and almost quadrupled among those receiving PGE₂. Thus, the possibility of a type II statistical error must be strongly considered.

Rupture risk is almost 3 times greater for women receiving PGE₂ but less than twofold higher for women given oxytocin compared to those in spontaneous labor.

Combined data suggest heightened risk of rupture. When this study is combined with previous studies,^3,4,6 the rate of rupture is 1.7% with PGE₂ and 0.62% with spontaneous labor (P .0001 similarly using data from the same studies women whose labor was induced with oxytocin had a rupture rate of versus in spontaneous>P = .005).

(The rates of uterine rupture for those in spontaneous labor vary slightly due to the inclusion of different sets of studies evaluating these 2 questions in the review by Sanchez-Ramos et al.⁶)

Clinical difference. Although both differences are statistically significant, the clinical differences vary. Those receiving PGE₂ have a risk of rupture almost 3 times greater than women in spontaneous labor, and those receiving oxytocin have less than a twofold increased risk.

All conclusions are based on studies that are not randomized, which limits the strength of any recommendations.

Other risks linked to induction: cesarean, neonatal intensive care unit admission, hemorrhage. Uterine rupture is not the only complication of labor induction in women with a prior cesarean. Delaney and Young also document an increased risk of cesarean delivery, admission to a neonatal intensive care unit, and early postpartum hemorrhage.

Their findings confirm those reported among gravidas undergoing labor induction without a prior cesarean.^7,8 The presence of a uterine scar is associated with uterine rupture, and induction itself remains a significant risk factor for these other adverse outcomes.

Bottom line

The risk of rupture with PGE₂ induction. This study, when combined with current literature, suggests a greater risk of uterine rupture when PGE₂ is used to induce labor in women with a prior cesarean. This risk is likely higher than many women would find acceptable.

 

The risk of rupture with oxytocin induction also is higher compared with spontaneous labor. If induction with oxytocin is attempted among women with a prior cesarean, judicious use is imperative.

Context

When labor does not begin spontaneously and delivery is indicated, the question of risk with labor induction becomes a critical issue—especially for women with a previous lower-segment cesarean delivery, most of whom are candidates for a trial of labor with their next pregnancy.

Objective

To compare maternal and neonatal outcomes of spontaneous and induced labor following 1 previous cesarean delivery.

Method

A population-based study of 3,746 women (2,943 spontaneous and 803 induced labors) with 1 previous cesarean delivery who underwent a trial of labor between January 1992 and January 2000.

Outcome

Researchers noted a trend toward higher uterine rupture rates in women who had induced labor by any method compared to spontaneous labor (0.7% versus 0.3%, P = .128), as well as in women who underwent dinoprostone (prostaglandin E₂ [PGE₂]) versus other induction methods, (1.1% versus 0.6%, P = .62), though neither outcome was statistically significant.

The induced-labor group had more frequent:

• early postpartum hemorrhage (7.3% versus 5%; odds ratio [OR] 1.66; 95% confidence interval [CI] 1.18, 2.32)
  
• cesarean delivery (37.5% versus 24.2%; OR 1.84; 95% CI 1.51, 2.25)
  
• neonatal intensive care unit admission (13.3% versus 9.4%; OR 1.69; 95% CI 1.25, 2.29)
  

Expert Commentary

The proportion of women undergoing a trial of labor after cesarean delivery has been decreasing since the mid-1990s, and optimal management of these women is controversial. What’s more, for over a decade we have been increasing labor induction rates for all women in all gestational age ranges.¹

An association between PGE₂ and rupture of a uterine scar was reported more than 20 years ago.² Unfortunately, since that time, only a handful of studies with more than 100 patients have explored this association. Even fewer studies have evaluated the risk of induction with oxytocin for women undergoing a trial of labor after prior cesarean.

My colleagues and I were able to document a rate of uterine rupture of 2.3% for women undergoing induction with oxytocin, compared with 0.7% for those who had spontaneous labor.³ More recently, an increased rate of uterine rupture was reported in women induced without prostaglandins compared to women undergoing repeat cesarean, with a relative risk of 4.9 (95% CI 2.4, 9.7).⁴

Oxytocin, PGE₂ were assessed, but not mechanical induction or artificial rupture. Delaney and Young endeavor to put these risks into perspective. They were able to specifically assess the effects of oxytocin and PGE₂ among the 803 women who had labor induced.

Unfortunately, the number of women who experienced artificial rupture of membranes and mechanical methods of induction was inadequate to draw conclusions.

Did a statistical error occur? The difference in the rate of uterine rupture for women with spontaneous labor was not statistically significant compared to those receiving oxytocin (n = 600) or PGE₂ (n = 179), yet the risk of uterine rupture in the oxytocin group more than doubled, and almost quadrupled among those receiving PGE₂. Thus, the possibility of a type II statistical error must be strongly considered.

Rupture risk is almost 3 times greater for women receiving PGE₂ but less than twofold higher for women given oxytocin compared to those in spontaneous labor.

Combined data suggest heightened risk of rupture. When this study is combined with previous studies,^3,4,6 the rate of rupture is 1.7% with PGE₂ and 0.62% with spontaneous labor (P .0001 similarly using data from the same studies women whose labor was induced with oxytocin had a rupture rate of versus in spontaneous>P = .005).

(The rates of uterine rupture for those in spontaneous labor vary slightly due to the inclusion of different sets of studies evaluating these 2 questions in the review by Sanchez-Ramos et al.⁶)

Clinical difference. Although both differences are statistically significant, the clinical differences vary. Those receiving PGE₂ have a risk of rupture almost 3 times greater than women in spontaneous labor, and those receiving oxytocin have less than a twofold increased risk.

All conclusions are based on studies that are not randomized, which limits the strength of any recommendations.

Other risks linked to induction: cesarean, neonatal intensive care unit admission, hemorrhage. Uterine rupture is not the only complication of labor induction in women with a prior cesarean. Delaney and Young also document an increased risk of cesarean delivery, admission to a neonatal intensive care unit, and early postpartum hemorrhage.

Their findings confirm those reported among gravidas undergoing labor induction without a prior cesarean.^7,8 The presence of a uterine scar is associated with uterine rupture, and induction itself remains a significant risk factor for these other adverse outcomes.

Bottom line

The risk of rupture with PGE₂ induction. This study, when combined with current literature, suggests a greater risk of uterine rupture when PGE₂ is used to induce labor in women with a prior cesarean. This risk is likely higher than many women would find acceptable.

 

The risk of rupture with oxytocin induction also is higher compared with spontaneous labor. If induction with oxytocin is attempted among women with a prior cesarean, judicious use is imperative.

Context

When labor does not begin spontaneously and delivery is indicated, the question of risk with labor induction becomes a critical issue—especially for women with a previous lower-segment cesarean delivery, most of whom are candidates for a trial of labor with their next pregnancy.

Objective

To compare maternal and neonatal outcomes of spontaneous and induced labor following 1 previous cesarean delivery.

Method

A population-based study of 3,746 women (2,943 spontaneous and 803 induced labors) with 1 previous cesarean delivery who underwent a trial of labor between January 1992 and January 2000.

Outcome

Researchers noted a trend toward higher uterine rupture rates in women who had induced labor by any method compared to spontaneous labor (0.7% versus 0.3%, P = .128), as well as in women who underwent dinoprostone (prostaglandin E₂ [PGE₂]) versus other induction methods, (1.1% versus 0.6%, P = .62), though neither outcome was statistically significant.

The induced-labor group had more frequent:

• early postpartum hemorrhage (7.3% versus 5%; odds ratio [OR] 1.66; 95% confidence interval [CI] 1.18, 2.32)
  
• cesarean delivery (37.5% versus 24.2%; OR 1.84; 95% CI 1.51, 2.25)
  
• neonatal intensive care unit admission (13.3% versus 9.4%; OR 1.69; 95% CI 1.25, 2.29)
  

Expert Commentary

The proportion of women undergoing a trial of labor after cesarean delivery has been decreasing since the mid-1990s, and optimal management of these women is controversial. What’s more, for over a decade we have been increasing labor induction rates for all women in all gestational age ranges.¹

An association between PGE₂ and rupture of a uterine scar was reported more than 20 years ago.² Unfortunately, since that time, only a handful of studies with more than 100 patients have explored this association. Even fewer studies have evaluated the risk of induction with oxytocin for women undergoing a trial of labor after prior cesarean.

My colleagues and I were able to document a rate of uterine rupture of 2.3% for women undergoing induction with oxytocin, compared with 0.7% for those who had spontaneous labor.³ More recently, an increased rate of uterine rupture was reported in women induced without prostaglandins compared to women undergoing repeat cesarean, with a relative risk of 4.9 (95% CI 2.4, 9.7).⁴

Oxytocin, PGE₂ were assessed, but not mechanical induction or artificial rupture. Delaney and Young endeavor to put these risks into perspective. They were able to specifically assess the effects of oxytocin and PGE₂ among the 803 women who had labor induced.

Unfortunately, the number of women who experienced artificial rupture of membranes and mechanical methods of induction was inadequate to draw conclusions.

Did a statistical error occur? The difference in the rate of uterine rupture for women with spontaneous labor was not statistically significant compared to those receiving oxytocin (n = 600) or PGE₂ (n = 179), yet the risk of uterine rupture in the oxytocin group more than doubled, and almost quadrupled among those receiving PGE₂. Thus, the possibility of a type II statistical error must be strongly considered.

Rupture risk is almost 3 times greater for women receiving PGE₂ but less than twofold higher for women given oxytocin compared to those in spontaneous labor.

Combined data suggest heightened risk of rupture. When this study is combined with previous studies,^3,4,6 the rate of rupture is 1.7% with PGE₂ and 0.62% with spontaneous labor (P .0001 similarly using data from the same studies women whose labor was induced with oxytocin had a rupture rate of versus in spontaneous>P = .005).

(The rates of uterine rupture for those in spontaneous labor vary slightly due to the inclusion of different sets of studies evaluating these 2 questions in the review by Sanchez-Ramos et al.⁶)

Clinical difference. Although both differences are statistically significant, the clinical differences vary. Those receiving PGE₂ have a risk of rupture almost 3 times greater than women in spontaneous labor, and those receiving oxytocin have less than a twofold increased risk.

All conclusions are based on studies that are not randomized, which limits the strength of any recommendations.

Other risks linked to induction: cesarean, neonatal intensive care unit admission, hemorrhage. Uterine rupture is not the only complication of labor induction in women with a prior cesarean. Delaney and Young also document an increased risk of cesarean delivery, admission to a neonatal intensive care unit, and early postpartum hemorrhage.

Their findings confirm those reported among gravidas undergoing labor induction without a prior cesarean.^7,8 The presence of a uterine scar is associated with uterine rupture, and induction itself remains a significant risk factor for these other adverse outcomes.

Bottom line

The risk of rupture with PGE₂ induction. This study, when combined with current literature, suggests a greater risk of uterine rupture when PGE₂ is used to induce labor in women with a prior cesarean. This risk is likely higher than many women would find acceptable.

 

The risk of rupture with oxytocin induction also is higher compared with spontaneous labor. If induction with oxytocin is attempted among women with a prior cesarean, judicious use is imperative.

Objective

To determine whether pelvic floor electrical stimulation (PFES) improves outcomes of multicomponent behavioral training for stress incontinence.

Conclusion

Electrical stimulation did not significantly improve outcomes.

Method

Two hundred community-dwelling women with stress incontinence were randomized to 1 of 3 groups for an 8-week period: 1) biofeedback-assisted pelvic floor muscle training (PFMT), home exercises, bladder control strategies, and self-monitoring with bladder diaries; 2) the same program plus home PFES (15 minutes every other day, alternating with home exercises); or 3) self-administered behavioral training consisting of a self-help booklet and bladder diaries.

Results

Intention-to-treat analysis revealed that frequency of incontinent episodes was reduced by 68.6% in group 1, 71.9% in group 2, and 52.5% in group 3. Attrition rates for the 3 groups were 18.2%, 11.9%, and 37.3%, respectively. Efficacy analysis, which examined only those completing treatment (n = 155), showed no significant differences among the groups on reduction of incontinence episodes. Patients in the PFES group reported more satisfaction with their progress, suggesting some placebo effect.

Expert Commentary

The strength of this timely study is its design: a prospective randomized controlled trial with a large sample size and adequate power. It suffers, however, due to its short-term follow-up and a significantly greater attrition rate in the control group.

Only 2 prior studies have evaluated the effect of electrical stimulation as an adjunct to PFMT for stress incontinence. A study of 14 patients showed that the addition of electrical stimulation improved outcome of physiotherapy.¹ Another study found the addition of both biofeedback and electrical stimulation improved symptoms and muscle strength, but the study did not isolate the effects of PFES as a single adjunct.²

Bottom Line

Patient compliance is vital to the success of behavioral therapy. The motivated patient with adequate neuromuscular function will improve with PFMT, with or without adjunctive therapy, and thus may forego surgical intervention. Less motivated patients, those who lack awareness of pelvic floor muscles, or those with decreased pelvic floor function may achieve greater success with adjunctive therapy, be it biofeedback or PFES. Still, long-term efficacy of such therapies is not known.

Objective

To determine whether pelvic floor electrical stimulation (PFES) improves outcomes of multicomponent behavioral training for stress incontinence.

Conclusion

Electrical stimulation did not significantly improve outcomes.

Method

Two hundred community-dwelling women with stress incontinence were randomized to 1 of 3 groups for an 8-week period: 1) biofeedback-assisted pelvic floor muscle training (PFMT), home exercises, bladder control strategies, and self-monitoring with bladder diaries; 2) the same program plus home PFES (15 minutes every other day, alternating with home exercises); or 3) self-administered behavioral training consisting of a self-help booklet and bladder diaries.

Results

Intention-to-treat analysis revealed that frequency of incontinent episodes was reduced by 68.6% in group 1, 71.9% in group 2, and 52.5% in group 3. Attrition rates for the 3 groups were 18.2%, 11.9%, and 37.3%, respectively. Efficacy analysis, which examined only those completing treatment (n = 155), showed no significant differences among the groups on reduction of incontinence episodes. Patients in the PFES group reported more satisfaction with their progress, suggesting some placebo effect.

Expert Commentary

The strength of this timely study is its design: a prospective randomized controlled trial with a large sample size and adequate power. It suffers, however, due to its short-term follow-up and a significantly greater attrition rate in the control group.

Only 2 prior studies have evaluated the effect of electrical stimulation as an adjunct to PFMT for stress incontinence. A study of 14 patients showed that the addition of electrical stimulation improved outcome of physiotherapy.¹ Another study found the addition of both biofeedback and electrical stimulation improved symptoms and muscle strength, but the study did not isolate the effects of PFES as a single adjunct.²

Bottom Line

Patient compliance is vital to the success of behavioral therapy. The motivated patient with adequate neuromuscular function will improve with PFMT, with or without adjunctive therapy, and thus may forego surgical intervention. Less motivated patients, those who lack awareness of pelvic floor muscles, or those with decreased pelvic floor function may achieve greater success with adjunctive therapy, be it biofeedback or PFES. Still, long-term efficacy of such therapies is not known.

Objective

To determine whether pelvic floor electrical stimulation (PFES) improves outcomes of multicomponent behavioral training for stress incontinence.

Conclusion

Electrical stimulation did not significantly improve outcomes.

Method

Two hundred community-dwelling women with stress incontinence were randomized to 1 of 3 groups for an 8-week period: 1) biofeedback-assisted pelvic floor muscle training (PFMT), home exercises, bladder control strategies, and self-monitoring with bladder diaries; 2) the same program plus home PFES (15 minutes every other day, alternating with home exercises); or 3) self-administered behavioral training consisting of a self-help booklet and bladder diaries.

Results

Intention-to-treat analysis revealed that frequency of incontinent episodes was reduced by 68.6% in group 1, 71.9% in group 2, and 52.5% in group 3. Attrition rates for the 3 groups were 18.2%, 11.9%, and 37.3%, respectively. Efficacy analysis, which examined only those completing treatment (n = 155), showed no significant differences among the groups on reduction of incontinence episodes. Patients in the PFES group reported more satisfaction with their progress, suggesting some placebo effect.

Expert Commentary

The strength of this timely study is its design: a prospective randomized controlled trial with a large sample size and adequate power. It suffers, however, due to its short-term follow-up and a significantly greater attrition rate in the control group.

Only 2 prior studies have evaluated the effect of electrical stimulation as an adjunct to PFMT for stress incontinence. A study of 14 patients showed that the addition of electrical stimulation improved outcome of physiotherapy.¹ Another study found the addition of both biofeedback and electrical stimulation improved symptoms and muscle strength, but the study did not isolate the effects of PFES as a single adjunct.²

Bottom Line

Patient compliance is vital to the success of behavioral therapy. The motivated patient with adequate neuromuscular function will improve with PFMT, with or without adjunctive therapy, and thus may forego surgical intervention. Less motivated patients, those who lack awareness of pelvic floor muscles, or those with decreased pelvic floor function may achieve greater success with adjunctive therapy, be it biofeedback or PFES. Still, long-term efficacy of such therapies is not known.

Objective

To compare 3 management strategies for a diagnosis of atypical squamous cells of undetermined significance (ASCUS).

Conclusion

Human papillomavirus (HPV) testing is at least as sensitive as immediate colposcopy for detecting cervical intraepithelial neoplasia (CIN) grade 3—and refers about half as many women to colposcopy. Follow-up using repeat cytology is sensitive at an ASCUS referral threshold, but requires 2 follow-up visits and ultimately more colposcopic examinations than HPV triage.

Method

A total of 3,488 women with community-acquired conventional cervical cytology interpreted as ASCUS were randomized to immediate colposcopy; triage based on enrollment HPV testing and liquid-based cytology, with referral to colposcopy for a finding of high-grade squamous intraepithelial lesion (HSIL); or repeat cytology at a referral threshold of HSIL (ie, conservative management).

Results

After 2 years, the cumulative diagnosis of CIN grade 3 was 8% to 9% in all 3 study arms. The immediate colposcopy group had a 53.6% sensitivity for CIN grade 3, versus 72.3% for HPV triage and 54.6% for conservative management. The HPV triage strategy referred 55.6% of women for colposcopy, while the conservative strategy referred 12.3%.

Expert commentary

Since the 1991 introduction of the Bethesda System for cervical cytology classification, there has been disagreement on the best method to further evaluate womenwith a diagnosis of ASCUS. Commonly proposed triage strategies are immediate colposcopy, repeat cytology, or HPV testing. The importance of determining the best method is clear, since 5 million women per year have an ASCUS finding on cervical cytology.

This study’s great strength is its design and low dropout rate: a randomized prospective evaluation of a large group of women, few of whom did not complete the protocol.

This trial demonstrates that each of the 3 strategies is equally effective in detecting CIN grades 2 and 3 after 2 years. The investigators estimated that, of the women in the trial who were ultimately found to have CIN 3, HPV testing would have properly triaged 92.4% and referred 53.1% for colposcopy. Repeating cytology twice would have provided the same threshold for detecting CIN 3, but would have resulted in colposcopy for 67.1% of women.

Study findings indicate that HPV testing is an effective method to triage women with ASCUS cytology. Only 1.4% of patients who were HPV-negative at enrollment were found to have CIN 3 during the 2 years of study.

Cost considerations. Unfortunately, in this report, the ALTS group did not present any data concerning cost-effectiveness. It seems reasonable, however, that because fewer colposcopies were performed in the HPVtesting arm, this strategy would be the most efficient. Since all the triage methods were equally effective at diagnosing CIN 3, the least costly should be preferred.

High- versus low-grade lesions. It is important to note that in the repeat cytology arm (which required a high-grade cytology for triage to colposcopy), one third of women with CIN 3 were diagnosed at the time of exit from the study by colposcopy or loop electrosurgical excision procedure that was performed due to persistent low-grade lesions. This finding calls into question the sensitivity of using highgrade histology to trigger colposcopy when following patients with ASCUS cytology.

Bottom line

For women with ASCUS cervical cytology, reflex HPV testing is as efficient as immediate colposcopy or repeat cytology and is most likely less costly. Thus, it is the preferred strategy for women with ASCUS cytology.

Objective

To compare 3 management strategies for a diagnosis of atypical squamous cells of undetermined significance (ASCUS).

Conclusion

Human papillomavirus (HPV) testing is at least as sensitive as immediate colposcopy for detecting cervical intraepithelial neoplasia (CIN) grade 3—and refers about half as many women to colposcopy. Follow-up using repeat cytology is sensitive at an ASCUS referral threshold, but requires 2 follow-up visits and ultimately more colposcopic examinations than HPV triage.

Method

A total of 3,488 women with community-acquired conventional cervical cytology interpreted as ASCUS were randomized to immediate colposcopy; triage based on enrollment HPV testing and liquid-based cytology, with referral to colposcopy for a finding of high-grade squamous intraepithelial lesion (HSIL); or repeat cytology at a referral threshold of HSIL (ie, conservative management).

Results

After 2 years, the cumulative diagnosis of CIN grade 3 was 8% to 9% in all 3 study arms. The immediate colposcopy group had a 53.6% sensitivity for CIN grade 3, versus 72.3% for HPV triage and 54.6% for conservative management. The HPV triage strategy referred 55.6% of women for colposcopy, while the conservative strategy referred 12.3%.

Expert commentary

Since the 1991 introduction of the Bethesda System for cervical cytology classification, there has been disagreement on the best method to further evaluate womenwith a diagnosis of ASCUS. Commonly proposed triage strategies are immediate colposcopy, repeat cytology, or HPV testing. The importance of determining the best method is clear, since 5 million women per year have an ASCUS finding on cervical cytology.

This study’s great strength is its design and low dropout rate: a randomized prospective evaluation of a large group of women, few of whom did not complete the protocol.

This trial demonstrates that each of the 3 strategies is equally effective in detecting CIN grades 2 and 3 after 2 years. The investigators estimated that, of the women in the trial who were ultimately found to have CIN 3, HPV testing would have properly triaged 92.4% and referred 53.1% for colposcopy. Repeating cytology twice would have provided the same threshold for detecting CIN 3, but would have resulted in colposcopy for 67.1% of women.

Study findings indicate that HPV testing is an effective method to triage women with ASCUS cytology. Only 1.4% of patients who were HPV-negative at enrollment were found to have CIN 3 during the 2 years of study.

Cost considerations. Unfortunately, in this report, the ALTS group did not present any data concerning cost-effectiveness. It seems reasonable, however, that because fewer colposcopies were performed in the HPVtesting arm, this strategy would be the most efficient. Since all the triage methods were equally effective at diagnosing CIN 3, the least costly should be preferred.

High- versus low-grade lesions. It is important to note that in the repeat cytology arm (which required a high-grade cytology for triage to colposcopy), one third of women with CIN 3 were diagnosed at the time of exit from the study by colposcopy or loop electrosurgical excision procedure that was performed due to persistent low-grade lesions. This finding calls into question the sensitivity of using highgrade histology to trigger colposcopy when following patients with ASCUS cytology.

Bottom line

For women with ASCUS cervical cytology, reflex HPV testing is as efficient as immediate colposcopy or repeat cytology and is most likely less costly. Thus, it is the preferred strategy for women with ASCUS cytology.

Objective

To compare 3 management strategies for a diagnosis of atypical squamous cells of undetermined significance (ASCUS).

Conclusion

Human papillomavirus (HPV) testing is at least as sensitive as immediate colposcopy for detecting cervical intraepithelial neoplasia (CIN) grade 3—and refers about half as many women to colposcopy. Follow-up using repeat cytology is sensitive at an ASCUS referral threshold, but requires 2 follow-up visits and ultimately more colposcopic examinations than HPV triage.

Method

A total of 3,488 women with community-acquired conventional cervical cytology interpreted as ASCUS were randomized to immediate colposcopy; triage based on enrollment HPV testing and liquid-based cytology, with referral to colposcopy for a finding of high-grade squamous intraepithelial lesion (HSIL); or repeat cytology at a referral threshold of HSIL (ie, conservative management).

Results

After 2 years, the cumulative diagnosis of CIN grade 3 was 8% to 9% in all 3 study arms. The immediate colposcopy group had a 53.6% sensitivity for CIN grade 3, versus 72.3% for HPV triage and 54.6% for conservative management. The HPV triage strategy referred 55.6% of women for colposcopy, while the conservative strategy referred 12.3%.

Expert commentary

Since the 1991 introduction of the Bethesda System for cervical cytology classification, there has been disagreement on the best method to further evaluate womenwith a diagnosis of ASCUS. Commonly proposed triage strategies are immediate colposcopy, repeat cytology, or HPV testing. The importance of determining the best method is clear, since 5 million women per year have an ASCUS finding on cervical cytology.

This study’s great strength is its design and low dropout rate: a randomized prospective evaluation of a large group of women, few of whom did not complete the protocol.

This trial demonstrates that each of the 3 strategies is equally effective in detecting CIN grades 2 and 3 after 2 years. The investigators estimated that, of the women in the trial who were ultimately found to have CIN 3, HPV testing would have properly triaged 92.4% and referred 53.1% for colposcopy. Repeating cytology twice would have provided the same threshold for detecting CIN 3, but would have resulted in colposcopy for 67.1% of women.

Study findings indicate that HPV testing is an effective method to triage women with ASCUS cytology. Only 1.4% of patients who were HPV-negative at enrollment were found to have CIN 3 during the 2 years of study.

Cost considerations. Unfortunately, in this report, the ALTS group did not present any data concerning cost-effectiveness. It seems reasonable, however, that because fewer colposcopies were performed in the HPVtesting arm, this strategy would be the most efficient. Since all the triage methods were equally effective at diagnosing CIN 3, the least costly should be preferred.

High- versus low-grade lesions. It is important to note that in the repeat cytology arm (which required a high-grade cytology for triage to colposcopy), one third of women with CIN 3 were diagnosed at the time of exit from the study by colposcopy or loop electrosurgical excision procedure that was performed due to persistent low-grade lesions. This finding calls into question the sensitivity of using highgrade histology to trigger colposcopy when following patients with ASCUS cytology.

Bottom line

For women with ASCUS cervical cytology, reflex HPV testing is as efficient as immediate colposcopy or repeat cytology and is most likely less costly. Thus, it is the preferred strategy for women with ASCUS cytology.

Objective

To test the effectiveness of 5 years of letrozole therapy in postmenopausal women with estrogen-receptor–positive forms of early breast cancer who have completed 5 years of tamoxifen therapy.

Conclusion

The primary endpoint, disease-free survival, significantly improved with letrozole therapy compared with placebo.

The study was halted and patients were informed of the results even before this initial report was published, less than halfway into the trial period.

Women who match the study group criteria should be considered for letrozole treatment, although the trial’s early termination leaves optimal duration of treatment undefined and the question of long-term toxicity unanswered, the investigators stated in their report.

Who May Be Affected

Postmenopausal women with primary breast cancer.

Background

In women with hormone-dependent breast cancer, tamoxifen therapy prolongs postoperative disease-free and overall survival for 5 years, but has not been found beneficial beyond the 5-year mark. This Canadian-led international clinical trial analyzed the effects of treatment with letrozole in years 5 through 10 after diagnosis. The research question was whether the aromatase inhibitor letrozole, by suppressing estrogen production, would improve the outcome after the initial 5-year course of tamoxifen. Estrogen is thought to stimulate development and growth of breast cancer.

Methods And Results

This double-blind, placebo-controlled trial enrolled 5,157 post-menopausal women with primary breast cancer who had completed 4.5 to 6 years of adjuvant tamoxifen therapy less than 3 months before study enrollment. Of this group, 2,575 were randomized to receive 2.5 mg oral letrozole daily for 5 years; the remaining 2,582 received placebo. The study included women in the United States, Canada, and Europe. All patients were to undergo clinical evaluation twice in the first year and annually thereafter.

At the first interim analysis, after a median follow-up of 2.4 years, results in the letrozole group were significantly more favorable in these respects:

• Greater disease-free survival: 93% versus 87%.
  
• Lower primary cancer recurrence rate: 2.4% versus 4.1%.
  
• Lower rate of new contralateral breast cancers: 0.5% versus 1%.
  

Expert Commentary

In the United States, more than 200,000 women are diagnosed with invasive breast cancer each year. The vast majority have disease that is confined to the breast or regional lymph nodes, and more than two thirds have disease that is hormone-receptor positive. Many of these patients are being placed on tamoxifen. All told, as many as 1 million women may be taking tamoxifen as adjuvant therapy for resected breast cancer.

Although a 5-year course of tamoxifen substantially lowers the risk of disease recurrence and death in women with invasive breast cancer, the quest for additional therapies that may extend the disease-free window continues. In recent years, there has been considerable focus on third-generation aromatase inhibitors as possible adjuvant treatment.

‘Postmenopausal women with hormone-receptor–positive tumors who have completed about 5 years of adjuvant tamoxifen therapy should be considered for letrozole treatment.’ (Goss et al, N Engl J Med)

Anastrozole paves the way. The ATAC trial compared a 5-year course of tamoxifen with a 5-year course of anastrozole in postmenopausal women.¹ Researchers found that anastrozole results in a statistically significant decrease in recurrences compared to tamoxifen; however, there has been no reported difference in survival, and followup remains relatively limited.

This study led the US Food and Drug Administration to approve anastrozole in the adjuvant setting, but many physicians continue to recommend tamoxifen for most postmenopausal women and all premenopausal women with receptor-positive breast cancer.²

Letrozole: 4 caveats. The current study, led by Goss on behalf of the National Cancer Institute of Canada and the North American Intergroup, randomized women who completed a 5-year course of tamoxifen to either letrozole or placebo. With a median follow-up of just under 2.5 years, the data safety monitoring board stopped and unblinded the trial due to a statistically significant difference in recurrences favoring the letrozole arm.

Physicians and patients alike have celebrated these results, heartened that a treatment has been identified for use after 5 years of tamoxifen therapy. However, we must bear several issues in mind:

1. No patient from the trial has completed the full 5-year course.
   
2. The absolute benefits associated with treatment are modest (just over 2% for recurrences and approximately 1% in distant disease-free survival).
   
3. The long-term toxicity is uncertain.
   
4. There is concern that aromatase inhibitors may result in bone loss, and it is not fully established to what extent any bone loss can be ameliorated with bisphosphonates or other therapies.
   

Further follow-up is needed to establish a clear picture of the risk-benefit relationship, though the unblinding of the trial will complicate future interpretation of the findings.

 

Nevertheless, the results are clinically meaningful. Many women remain at moderate risk of disease recurrence even after a 5-year course of tamoxifen, and letrozole can decrease this risk. In the next few years, multiple trials will provide additional information about aromatase inhibitors as adjuvant therapy. The landscape may well change in the not-so-distant future.

Bottom Line

Physicians should discuss the pros and cons of letrozole therapy with postmenopausal women completing a 5-year course of tamoxifen. However, both doctor and patient must carefully weigh the treatment’s known benefits against potential risks.

Objective

To test the effectiveness of 5 years of letrozole therapy in postmenopausal women with estrogen-receptor–positive forms of early breast cancer who have completed 5 years of tamoxifen therapy.

Conclusion

The primary endpoint, disease-free survival, significantly improved with letrozole therapy compared with placebo.

The study was halted and patients were informed of the results even before this initial report was published, less than halfway into the trial period.

Women who match the study group criteria should be considered for letrozole treatment, although the trial’s early termination leaves optimal duration of treatment undefined and the question of long-term toxicity unanswered, the investigators stated in their report.

Who May Be Affected

Postmenopausal women with primary breast cancer.

Background

In women with hormone-dependent breast cancer, tamoxifen therapy prolongs postoperative disease-free and overall survival for 5 years, but has not been found beneficial beyond the 5-year mark. This Canadian-led international clinical trial analyzed the effects of treatment with letrozole in years 5 through 10 after diagnosis. The research question was whether the aromatase inhibitor letrozole, by suppressing estrogen production, would improve the outcome after the initial 5-year course of tamoxifen. Estrogen is thought to stimulate development and growth of breast cancer.

Methods And Results

This double-blind, placebo-controlled trial enrolled 5,157 post-menopausal women with primary breast cancer who had completed 4.5 to 6 years of adjuvant tamoxifen therapy less than 3 months before study enrollment. Of this group, 2,575 were randomized to receive 2.5 mg oral letrozole daily for 5 years; the remaining 2,582 received placebo. The study included women in the United States, Canada, and Europe. All patients were to undergo clinical evaluation twice in the first year and annually thereafter.

At the first interim analysis, after a median follow-up of 2.4 years, results in the letrozole group were significantly more favorable in these respects:

• Greater disease-free survival: 93% versus 87%.
  
• Lower primary cancer recurrence rate: 2.4% versus 4.1%.
  
• Lower rate of new contralateral breast cancers: 0.5% versus 1%.
  

Expert Commentary

In the United States, more than 200,000 women are diagnosed with invasive breast cancer each year. The vast majority have disease that is confined to the breast or regional lymph nodes, and more than two thirds have disease that is hormone-receptor positive. Many of these patients are being placed on tamoxifen. All told, as many as 1 million women may be taking tamoxifen as adjuvant therapy for resected breast cancer.

Although a 5-year course of tamoxifen substantially lowers the risk of disease recurrence and death in women with invasive breast cancer, the quest for additional therapies that may extend the disease-free window continues. In recent years, there has been considerable focus on third-generation aromatase inhibitors as possible adjuvant treatment.

‘Postmenopausal women with hormone-receptor–positive tumors who have completed about 5 years of adjuvant tamoxifen therapy should be considered for letrozole treatment.’ (Goss et al, N Engl J Med)

Anastrozole paves the way. The ATAC trial compared a 5-year course of tamoxifen with a 5-year course of anastrozole in postmenopausal women.¹ Researchers found that anastrozole results in a statistically significant decrease in recurrences compared to tamoxifen; however, there has been no reported difference in survival, and followup remains relatively limited.

This study led the US Food and Drug Administration to approve anastrozole in the adjuvant setting, but many physicians continue to recommend tamoxifen for most postmenopausal women and all premenopausal women with receptor-positive breast cancer.²

Letrozole: 4 caveats. The current study, led by Goss on behalf of the National Cancer Institute of Canada and the North American Intergroup, randomized women who completed a 5-year course of tamoxifen to either letrozole or placebo. With a median follow-up of just under 2.5 years, the data safety monitoring board stopped and unblinded the trial due to a statistically significant difference in recurrences favoring the letrozole arm.

Physicians and patients alike have celebrated these results, heartened that a treatment has been identified for use after 5 years of tamoxifen therapy. However, we must bear several issues in mind:

1. No patient from the trial has completed the full 5-year course.
   
2. The absolute benefits associated with treatment are modest (just over 2% for recurrences and approximately 1% in distant disease-free survival).
   
3. The long-term toxicity is uncertain.
   
4. There is concern that aromatase inhibitors may result in bone loss, and it is not fully established to what extent any bone loss can be ameliorated with bisphosphonates or other therapies.
   

Further follow-up is needed to establish a clear picture of the risk-benefit relationship, though the unblinding of the trial will complicate future interpretation of the findings.

 

Nevertheless, the results are clinically meaningful. Many women remain at moderate risk of disease recurrence even after a 5-year course of tamoxifen, and letrozole can decrease this risk. In the next few years, multiple trials will provide additional information about aromatase inhibitors as adjuvant therapy. The landscape may well change in the not-so-distant future.

Bottom Line

Physicians should discuss the pros and cons of letrozole therapy with postmenopausal women completing a 5-year course of tamoxifen. However, both doctor and patient must carefully weigh the treatment’s known benefits against potential risks.

Objective

To test the effectiveness of 5 years of letrozole therapy in postmenopausal women with estrogen-receptor–positive forms of early breast cancer who have completed 5 years of tamoxifen therapy.

Conclusion

The primary endpoint, disease-free survival, significantly improved with letrozole therapy compared with placebo.

The study was halted and patients were informed of the results even before this initial report was published, less than halfway into the trial period.

Women who match the study group criteria should be considered for letrozole treatment, although the trial’s early termination leaves optimal duration of treatment undefined and the question of long-term toxicity unanswered, the investigators stated in their report.

Who May Be Affected

Postmenopausal women with primary breast cancer.

Background

In women with hormone-dependent breast cancer, tamoxifen therapy prolongs postoperative disease-free and overall survival for 5 years, but has not been found beneficial beyond the 5-year mark. This Canadian-led international clinical trial analyzed the effects of treatment with letrozole in years 5 through 10 after diagnosis. The research question was whether the aromatase inhibitor letrozole, by suppressing estrogen production, would improve the outcome after the initial 5-year course of tamoxifen. Estrogen is thought to stimulate development and growth of breast cancer.

Methods And Results

This double-blind, placebo-controlled trial enrolled 5,157 post-menopausal women with primary breast cancer who had completed 4.5 to 6 years of adjuvant tamoxifen therapy less than 3 months before study enrollment. Of this group, 2,575 were randomized to receive 2.5 mg oral letrozole daily for 5 years; the remaining 2,582 received placebo. The study included women in the United States, Canada, and Europe. All patients were to undergo clinical evaluation twice in the first year and annually thereafter.

At the first interim analysis, after a median follow-up of 2.4 years, results in the letrozole group were significantly more favorable in these respects:

• Greater disease-free survival: 93% versus 87%.
  
• Lower primary cancer recurrence rate: 2.4% versus 4.1%.
  
• Lower rate of new contralateral breast cancers: 0.5% versus 1%.
  

Expert Commentary

In the United States, more than 200,000 women are diagnosed with invasive breast cancer each year. The vast majority have disease that is confined to the breast or regional lymph nodes, and more than two thirds have disease that is hormone-receptor positive. Many of these patients are being placed on tamoxifen. All told, as many as 1 million women may be taking tamoxifen as adjuvant therapy for resected breast cancer.

Although a 5-year course of tamoxifen substantially lowers the risk of disease recurrence and death in women with invasive breast cancer, the quest for additional therapies that may extend the disease-free window continues. In recent years, there has been considerable focus on third-generation aromatase inhibitors as possible adjuvant treatment.

‘Postmenopausal women with hormone-receptor–positive tumors who have completed about 5 years of adjuvant tamoxifen therapy should be considered for letrozole treatment.’ (Goss et al, N Engl J Med)

Anastrozole paves the way. The ATAC trial compared a 5-year course of tamoxifen with a 5-year course of anastrozole in postmenopausal women.¹ Researchers found that anastrozole results in a statistically significant decrease in recurrences compared to tamoxifen; however, there has been no reported difference in survival, and followup remains relatively limited.

This study led the US Food and Drug Administration to approve anastrozole in the adjuvant setting, but many physicians continue to recommend tamoxifen for most postmenopausal women and all premenopausal women with receptor-positive breast cancer.²

Letrozole: 4 caveats. The current study, led by Goss on behalf of the National Cancer Institute of Canada and the North American Intergroup, randomized women who completed a 5-year course of tamoxifen to either letrozole or placebo. With a median follow-up of just under 2.5 years, the data safety monitoring board stopped and unblinded the trial due to a statistically significant difference in recurrences favoring the letrozole arm.

Physicians and patients alike have celebrated these results, heartened that a treatment has been identified for use after 5 years of tamoxifen therapy. However, we must bear several issues in mind:

1. No patient from the trial has completed the full 5-year course.
   
2. The absolute benefits associated with treatment are modest (just over 2% for recurrences and approximately 1% in distant disease-free survival).
   
3. The long-term toxicity is uncertain.
   
4. There is concern that aromatase inhibitors may result in bone loss, and it is not fully established to what extent any bone loss can be ameliorated with bisphosphonates or other therapies.
   

Further follow-up is needed to establish a clear picture of the risk-benefit relationship, though the unblinding of the trial will complicate future interpretation of the findings.

 

Nevertheless, the results are clinically meaningful. Many women remain at moderate risk of disease recurrence even after a 5-year course of tamoxifen, and letrozole can decrease this risk. In the next few years, multiple trials will provide additional information about aromatase inhibitors as adjuvant therapy. The landscape may well change in the not-so-distant future.

Bottom Line

Physicians should discuss the pros and cons of letrozole therapy with postmenopausal women completing a 5-year course of tamoxifen. However, both doctor and patient must carefully weigh the treatment’s known benefits against potential risks.

Objective

To determine the true cost differences between vaginal delivery and elective cesarean and to assess the economic impact of a “cesarean on demand” policy.

Methods and Results

Using data on direct costs (those that can be directly attributed to the care of mother and neonate) from a community-based hospital over a 12-month period, the author calculated the average perpatient costs of both vaginal delivery and elective cesarean.

He found that, compared with elective cesarean delivery ($918), multiparous vaginal delivery costs 7.1% less ($853) but nulliparous vaginal delivery costs 5.9% more ($972), on average.

Who may be affected by these findings?

Women who would prefer cesarean delivery, payers of health-care costs (including patients), health plans, and society.

Expert commentary

For 2 decades the merits and drawbacks of elective cesarean delivery have been debated in the medical literature.¹ This practice is seen in Brazil, Chile, and Taiwan, among other countries, where physicians seem to encourage delivery by cesarean section.² In the United States, no formal guidelines exist. However, with approximately 4 million births per year, this country needs a clear policy concerning elective cesarean that considers

• risks and benefits,
  
• effects on the provision of care, and
  
• costs to patients and society.
  

It is this last item that the current study examines.

Other costs must be considered. Dr. Bost’s analysis of the short-term direct costs of attempted vaginal and elective cesarean delivery finds little difference between the 2 modes of delivery. The strength of this study is its use of estimated costs from supplies, labor, and amortization of equipment. However, the author does not consider any of the indirect costs, the expenditures related to rare but expensive complications, and, notably, future costs these patients might incur in later pregnancies or subsequent medical care.

Health-care expenditures accounted for 13% of the gross domestic product in the United States for 2002 ($1.3 trillion),³ and are projected to outstrip the economy’s growth at even higher rates during the next few decades.⁴ Thus, when considering a new policy regarding clinical care, cost is clearly a crucial factor—but it is not the only issue for us to weigh.

Evidence sparse on clinical outcomes. In a recent commentary, Minkoff and Chervenak⁵ support “a physician’s decision to accede to an informed patient’s request for [elective cesarean] delivery.” The authors discuss the risks and benefits of elective cesarean to both mother and fetus. These include protecting the pelvic floor, a slightly reduced rate of neonatal complications at term, and increased risks to the mother from surgery and anesthesia. They advise that these data should be used to counsel patients considering elective cesarean, but concede that there is no overwhelming evidence on either side to guide a clear decision.

The issue of consent. There also is the concern of how well women can be counseled regarding complications. It is unclear whether patients are able to truly understand⁶ and incorporate⁷ small risks of rare complications into the decision-making process. Certainly, psychologists, economists, and sociologists have found that there are many ways in which individuals are unable to make well-informed decisions based on the proper use of probabilities; these limitations have been designated as “bounded rationality.”⁸ This observation raises the issue of patient autonomy versus paternalism.

While we as clinicians endeavor to consistently achieve informed consent by educating patients about the range of possible outcomes, bounded rationality may prevent us from always reaching this goal. Further, many clinical situations call for shared decision-making between patients, families, and physicians. Thus, we must exercise at least some paternalism in order to optimize the medical care we provide to our patients. This balance is particularly relevant when establishing practice standards, guidelines, and other such policies.

Bottom line

This investigation found a slightly increasing trend in the short-term direct costs of successful vaginal delivery (least costly), cesarean delivery, and unsuccessful attempted vaginal delivery (most costly). However, indirect, long-term costs may have larger variation, and clinical outcomes also must be considered. Both require further examination in prospective studies.

Objective

To determine the true cost differences between vaginal delivery and elective cesarean and to assess the economic impact of a “cesarean on demand” policy.

Methods and Results

Using data on direct costs (those that can be directly attributed to the care of mother and neonate) from a community-based hospital over a 12-month period, the author calculated the average perpatient costs of both vaginal delivery and elective cesarean.

He found that, compared with elective cesarean delivery ($918), multiparous vaginal delivery costs 7.1% less ($853) but nulliparous vaginal delivery costs 5.9% more ($972), on average.

Who may be affected by these findings?

Women who would prefer cesarean delivery, payers of health-care costs (including patients), health plans, and society.

Expert commentary

For 2 decades the merits and drawbacks of elective cesarean delivery have been debated in the medical literature.¹ This practice is seen in Brazil, Chile, and Taiwan, among other countries, where physicians seem to encourage delivery by cesarean section.² In the United States, no formal guidelines exist. However, with approximately 4 million births per year, this country needs a clear policy concerning elective cesarean that considers

• risks and benefits,
  
• effects on the provision of care, and
  
• costs to patients and society.
  

It is this last item that the current study examines.

Other costs must be considered. Dr. Bost’s analysis of the short-term direct costs of attempted vaginal and elective cesarean delivery finds little difference between the 2 modes of delivery. The strength of this study is its use of estimated costs from supplies, labor, and amortization of equipment. However, the author does not consider any of the indirect costs, the expenditures related to rare but expensive complications, and, notably, future costs these patients might incur in later pregnancies or subsequent medical care.

Health-care expenditures accounted for 13% of the gross domestic product in the United States for 2002 ($1.3 trillion),³ and are projected to outstrip the economy’s growth at even higher rates during the next few decades.⁴ Thus, when considering a new policy regarding clinical care, cost is clearly a crucial factor—but it is not the only issue for us to weigh.

Evidence sparse on clinical outcomes. In a recent commentary, Minkoff and Chervenak⁵ support “a physician’s decision to accede to an informed patient’s request for [elective cesarean] delivery.” The authors discuss the risks and benefits of elective cesarean to both mother and fetus. These include protecting the pelvic floor, a slightly reduced rate of neonatal complications at term, and increased risks to the mother from surgery and anesthesia. They advise that these data should be used to counsel patients considering elective cesarean, but concede that there is no overwhelming evidence on either side to guide a clear decision.

The issue of consent. There also is the concern of how well women can be counseled regarding complications. It is unclear whether patients are able to truly understand⁶ and incorporate⁷ small risks of rare complications into the decision-making process. Certainly, psychologists, economists, and sociologists have found that there are many ways in which individuals are unable to make well-informed decisions based on the proper use of probabilities; these limitations have been designated as “bounded rationality.”⁸ This observation raises the issue of patient autonomy versus paternalism.

While we as clinicians endeavor to consistently achieve informed consent by educating patients about the range of possible outcomes, bounded rationality may prevent us from always reaching this goal. Further, many clinical situations call for shared decision-making between patients, families, and physicians. Thus, we must exercise at least some paternalism in order to optimize the medical care we provide to our patients. This balance is particularly relevant when establishing practice standards, guidelines, and other such policies.

Bottom line

This investigation found a slightly increasing trend in the short-term direct costs of successful vaginal delivery (least costly), cesarean delivery, and unsuccessful attempted vaginal delivery (most costly). However, indirect, long-term costs may have larger variation, and clinical outcomes also must be considered. Both require further examination in prospective studies.

Objective

To determine the true cost differences between vaginal delivery and elective cesarean and to assess the economic impact of a “cesarean on demand” policy.

Methods and Results

Using data on direct costs (those that can be directly attributed to the care of mother and neonate) from a community-based hospital over a 12-month period, the author calculated the average perpatient costs of both vaginal delivery and elective cesarean.

He found that, compared with elective cesarean delivery ($918), multiparous vaginal delivery costs 7.1% less ($853) but nulliparous vaginal delivery costs 5.9% more ($972), on average.

Who may be affected by these findings?

Women who would prefer cesarean delivery, payers of health-care costs (including patients), health plans, and society.

Expert commentary

For 2 decades the merits and drawbacks of elective cesarean delivery have been debated in the medical literature.¹ This practice is seen in Brazil, Chile, and Taiwan, among other countries, where physicians seem to encourage delivery by cesarean section.² In the United States, no formal guidelines exist. However, with approximately 4 million births per year, this country needs a clear policy concerning elective cesarean that considers

• risks and benefits,
  
• effects on the provision of care, and
  
• costs to patients and society.
  

It is this last item that the current study examines.

Other costs must be considered. Dr. Bost’s analysis of the short-term direct costs of attempted vaginal and elective cesarean delivery finds little difference between the 2 modes of delivery. The strength of this study is its use of estimated costs from supplies, labor, and amortization of equipment. However, the author does not consider any of the indirect costs, the expenditures related to rare but expensive complications, and, notably, future costs these patients might incur in later pregnancies or subsequent medical care.

Health-care expenditures accounted for 13% of the gross domestic product in the United States for 2002 ($1.3 trillion),³ and are projected to outstrip the economy’s growth at even higher rates during the next few decades.⁴ Thus, when considering a new policy regarding clinical care, cost is clearly a crucial factor—but it is not the only issue for us to weigh.

Evidence sparse on clinical outcomes. In a recent commentary, Minkoff and Chervenak⁵ support “a physician’s decision to accede to an informed patient’s request for [elective cesarean] delivery.” The authors discuss the risks and benefits of elective cesarean to both mother and fetus. These include protecting the pelvic floor, a slightly reduced rate of neonatal complications at term, and increased risks to the mother from surgery and anesthesia. They advise that these data should be used to counsel patients considering elective cesarean, but concede that there is no overwhelming evidence on either side to guide a clear decision.

The issue of consent. There also is the concern of how well women can be counseled regarding complications. It is unclear whether patients are able to truly understand⁶ and incorporate⁷ small risks of rare complications into the decision-making process. Certainly, psychologists, economists, and sociologists have found that there are many ways in which individuals are unable to make well-informed decisions based on the proper use of probabilities; these limitations have been designated as “bounded rationality.”⁸ This observation raises the issue of patient autonomy versus paternalism.

While we as clinicians endeavor to consistently achieve informed consent by educating patients about the range of possible outcomes, bounded rationality may prevent us from always reaching this goal. Further, many clinical situations call for shared decision-making between patients, families, and physicians. Thus, we must exercise at least some paternalism in order to optimize the medical care we provide to our patients. This balance is particularly relevant when establishing practice standards, guidelines, and other such policies.

Bottom line

This investigation found a slightly increasing trend in the short-term direct costs of successful vaginal delivery (least costly), cesarean delivery, and unsuccessful attempted vaginal delivery (most costly). However, indirect, long-term costs may have larger variation, and clinical outcomes also must be considered. Both require further examination in prospective studies.

Objective

To determine whether a strength index that accounts for both bone density and bone size might better predict the risk of fracture than bone mineral density (BMD) alone.

Methods and Results

For this prospective investigation, researchers recruited 241 white women, all 48 years of age. Analysis was based on the 108 women who were followed through age 67, the study’s endpoint.

For the duration of the trial, participants’ right and left forearms were regularly evaluated via single photon absorptiometry for bone mineral content and BMD. From these scans, investigators calculated periosteal diameter, medullary diameter, and cortical thickness of the distal radius. Serum estradiol levels were also regularly assessed.

Researchers found that, annually, medullary diameter increased by 1.1% and periosteal diameter rose by 0.7%. BMD, however, decreased an average of 1.9% each year. The net result was a 0.7% annual decrease in the strength index, which accounted for both bone mass and skeletal structure.

Postmenopausal serum estradiol was related inversely to periosteal diameter and directly to BMD.

Who may be affected by these findings?

Women at risk for osteoporosis.

Expert commentary

We know that BMD correlates well with fracture risk. However, bone architecture—not assessed by BMD studies—also plays a role in bone strength.

Indeed, a recent trial on risedronate use noted a probable relationship between early changes in bone resorption and reduced fracture risk.¹ Risedronate reduces the risk of vertebral fracture within the first year of therapy, but some believe this effect occurs too rapidly to be solely attributable to BMD changes, which are maximum by the third year. The implication is that bone-strength factors beyond BMD are at work.

Clinical relevance of bone size. Few would argue the need to treat all patients with documented osteoporosis (World Health Organization definition: a T-score of -2.5 or less); however, from a public health perspective it is not cost-effective to treat all women with low bone mass/osteopenia—even though there is an increased incidence of fractures among these patients. Thus, a strength index such as that described in this article would—if effective—help further stratify postmenopausal women with low bone mass into low, medium, and high risk for future fractures.

Flaws in study’s bone size measurements. In this timely study by Ahlborg et al, the authors theorize that the observed postmenopausal increase in periosteal apposition and size partially preserves bone strength—but this hypothesis has not been proven. With the crude images rendered by large pixels, it is impossible to note true bone size; furthermore, no evidence exists to confirm that we can actually measure bone size with single photon densitometry. In addition, the authors here evaluated the distal third of the forearm; ultradistal forearm measurements would have yielded a more accurate assessment since these correlate better with Colle’s fractures of the wrist/forearm.

It is anticipated that, in the future, quantitative computed tomography scanning with ultrathin slices will allow clinicians to assess bone architecture in a way that will allow for more accurate bone-strength measurements.

The authors theorize that the observed postmenopausal increase in periosteal apposition and size preserves bone strength—but this has not been proven.

Bottom line

Correctly classifying women into the appropriate bone-risk category is even more critical in this post-Women’s Health Initiative era. Many women who are stopping hormone therapy may still be at risk for losing bone mass; others who already have low bone mass may not have been offered other bone therapies. The current study is important only for raising the issue of the relationship of bone strength to future fracture risk.

Dual-energy bone densitometry—a valuable tool for diagnosing osteoporosis, assessing a patient’s fracture risk, and following the effects of bone treatments—remains the standard of care.

Objective

To determine whether a strength index that accounts for both bone density and bone size might better predict the risk of fracture than bone mineral density (BMD) alone.

Methods and Results

For this prospective investigation, researchers recruited 241 white women, all 48 years of age. Analysis was based on the 108 women who were followed through age 67, the study’s endpoint.

For the duration of the trial, participants’ right and left forearms were regularly evaluated via single photon absorptiometry for bone mineral content and BMD. From these scans, investigators calculated periosteal diameter, medullary diameter, and cortical thickness of the distal radius. Serum estradiol levels were also regularly assessed.

Researchers found that, annually, medullary diameter increased by 1.1% and periosteal diameter rose by 0.7%. BMD, however, decreased an average of 1.9% each year. The net result was a 0.7% annual decrease in the strength index, which accounted for both bone mass and skeletal structure.

Postmenopausal serum estradiol was related inversely to periosteal diameter and directly to BMD.

Who may be affected by these findings?

Women at risk for osteoporosis.

Expert commentary

We know that BMD correlates well with fracture risk. However, bone architecture—not assessed by BMD studies—also plays a role in bone strength.

Indeed, a recent trial on risedronate use noted a probable relationship between early changes in bone resorption and reduced fracture risk.¹ Risedronate reduces the risk of vertebral fracture within the first year of therapy, but some believe this effect occurs too rapidly to be solely attributable to BMD changes, which are maximum by the third year. The implication is that bone-strength factors beyond BMD are at work.

Clinical relevance of bone size. Few would argue the need to treat all patients with documented osteoporosis (World Health Organization definition: a T-score of -2.5 or less); however, from a public health perspective it is not cost-effective to treat all women with low bone mass/osteopenia—even though there is an increased incidence of fractures among these patients. Thus, a strength index such as that described in this article would—if effective—help further stratify postmenopausal women with low bone mass into low, medium, and high risk for future fractures.

Flaws in study’s bone size measurements. In this timely study by Ahlborg et al, the authors theorize that the observed postmenopausal increase in periosteal apposition and size partially preserves bone strength—but this hypothesis has not been proven. With the crude images rendered by large pixels, it is impossible to note true bone size; furthermore, no evidence exists to confirm that we can actually measure bone size with single photon densitometry. In addition, the authors here evaluated the distal third of the forearm; ultradistal forearm measurements would have yielded a more accurate assessment since these correlate better with Colle’s fractures of the wrist/forearm.

It is anticipated that, in the future, quantitative computed tomography scanning with ultrathin slices will allow clinicians to assess bone architecture in a way that will allow for more accurate bone-strength measurements.

The authors theorize that the observed postmenopausal increase in periosteal apposition and size preserves bone strength—but this has not been proven.

Bottom line

Correctly classifying women into the appropriate bone-risk category is even more critical in this post-Women’s Health Initiative era. Many women who are stopping hormone therapy may still be at risk for losing bone mass; others who already have low bone mass may not have been offered other bone therapies. The current study is important only for raising the issue of the relationship of bone strength to future fracture risk.

Dual-energy bone densitometry—a valuable tool for diagnosing osteoporosis, assessing a patient’s fracture risk, and following the effects of bone treatments—remains the standard of care.

Objective

To determine whether a strength index that accounts for both bone density and bone size might better predict the risk of fracture than bone mineral density (BMD) alone.

Methods and Results

For this prospective investigation, researchers recruited 241 white women, all 48 years of age. Analysis was based on the 108 women who were followed through age 67, the study’s endpoint.

For the duration of the trial, participants’ right and left forearms were regularly evaluated via single photon absorptiometry for bone mineral content and BMD. From these scans, investigators calculated periosteal diameter, medullary diameter, and cortical thickness of the distal radius. Serum estradiol levels were also regularly assessed.

Researchers found that, annually, medullary diameter increased by 1.1% and periosteal diameter rose by 0.7%. BMD, however, decreased an average of 1.9% each year. The net result was a 0.7% annual decrease in the strength index, which accounted for both bone mass and skeletal structure.

Postmenopausal serum estradiol was related inversely to periosteal diameter and directly to BMD.

Who may be affected by these findings?

Women at risk for osteoporosis.

Expert commentary

We know that BMD correlates well with fracture risk. However, bone architecture—not assessed by BMD studies—also plays a role in bone strength.

Indeed, a recent trial on risedronate use noted a probable relationship between early changes in bone resorption and reduced fracture risk.¹ Risedronate reduces the risk of vertebral fracture within the first year of therapy, but some believe this effect occurs too rapidly to be solely attributable to BMD changes, which are maximum by the third year. The implication is that bone-strength factors beyond BMD are at work.

Clinical relevance of bone size. Few would argue the need to treat all patients with documented osteoporosis (World Health Organization definition: a T-score of -2.5 or less); however, from a public health perspective it is not cost-effective to treat all women with low bone mass/osteopenia—even though there is an increased incidence of fractures among these patients. Thus, a strength index such as that described in this article would—if effective—help further stratify postmenopausal women with low bone mass into low, medium, and high risk for future fractures.

Flaws in study’s bone size measurements. In this timely study by Ahlborg et al, the authors theorize that the observed postmenopausal increase in periosteal apposition and size partially preserves bone strength—but this hypothesis has not been proven. With the crude images rendered by large pixels, it is impossible to note true bone size; furthermore, no evidence exists to confirm that we can actually measure bone size with single photon densitometry. In addition, the authors here evaluated the distal third of the forearm; ultradistal forearm measurements would have yielded a more accurate assessment since these correlate better with Colle’s fractures of the wrist/forearm.

It is anticipated that, in the future, quantitative computed tomography scanning with ultrathin slices will allow clinicians to assess bone architecture in a way that will allow for more accurate bone-strength measurements.

The authors theorize that the observed postmenopausal increase in periosteal apposition and size preserves bone strength—but this has not been proven.

Bottom line

Correctly classifying women into the appropriate bone-risk category is even more critical in this post-Women’s Health Initiative era. Many women who are stopping hormone therapy may still be at risk for losing bone mass; others who already have low bone mass may not have been offered other bone therapies. The current study is important only for raising the issue of the relationship of bone strength to future fracture risk.

Dual-energy bone densitometry—a valuable tool for diagnosing osteoporosis, assessing a patient’s fracture risk, and following the effects of bone treatments—remains the standard of care.

Objective

To determine whether weekly injections of 17 alpha-hydroxyprogesterone caproate (17P) reduce the risk of preterm delivery in women with a documented history of spontaneous preterm delivery.

Methods And Results

In this double-blind, placebo-controlled trial, researchers randomly assigned 463 patients at high risk for preterm delivery to receive weekly intramuscular injections of 17P (250 mg) or placebo from 16 to 20 weeks of gestation through 36 weeks. Outcome data were available for 459 women (99.1%).

Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks’ gestation: Incidence was 36.3% in the progesterone group versus 54.9% in the placebo group (relative risk, 0.66; 95% confidence interval, 0.54 to 0.81). It also reduced the risk of delivery at less than 35 weeks and less than 32 weeks. Infants of women treated with the compound had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen. There was no significant difference in miscarriage or stillbirth rates.

Who May Be Affected By These Findings?

Gravidas at high risk for preterm delivery.

Expert Commentary

Although we have improved our ability to identify women at risk, we have not been successful at preventing preterm birth—indeed, its incidence is actually rising, due primarily to increased use of assisted reproductive technology. Preterm birth complicates approximately 12% of deliveries, but accounts for more than 85% of perinatal morbidity and mortality.^1,2

The study by Meis and colleagues is a well-designed and well-executed randomized, double-blind, placebo-controlled, multicenter trial. Compliance with designated therapy was reported as 91.5%. The preterm delivery rate of 54.9% in the control group confirms that this cohort is indeed at high risk of preterm birth (see “Why progesterone?”).

I have only 1 minor criticism: The authors chose to deliver the drug via weekly intramuscular injections, which may not be a desirable route of administration for many women. Half of the women (231 of 463) reported at least 1 adverse effect, though most of these were minor local reactions at the injection site.

The authors found no evidence of teratogenicity—of note, no virilization of female offspring, which was a theoretic concern.

Findings apply only to high-risk gravidas. More study is required to determine whether progesterone supplementation can reduce preterm birth in low-risk women. This is important because most preterm births occur in patients with no identifiable risk factors.

The results of this study are consistent with prior publications.^8,9 In a similar recent trial carried out in Brazil, 142 women at high risk for preterm birth were randomized to receive daily supplementation with progesterone vaginal suppositories (100 mg) or placebo from 24 through 34 weeks of gestation.⁹ The preterm delivery rate was significantly lower in the progesterone group, as was the rate of delivery before 34 weeks. By monitoring patients with an external tocodynamometer once a week for 60 minutes, researchers also were able to demonstrate a significant difference in spontaneous uterine contractions between the groups, suggesting that progesterone supplementation may exert its effect by maintaining uterine quiescence in the latter half of pregnancy.

 

Bottom Line

Progesterone supplementation to prevent preterm birth remains investigational. Further studies are needed to evaluate its effectiveness in decreasing preterm delivery rates in high- and low-risk populations and to better understand its mechanism of action.

Given the absence of proven alternatives, however, it may be appropriate to offer such treatment to patients at highest risk for early preterm birth, such as those with higher-order multifetal pregnancies or a history of recurrent preterm deliveries. Evidence is insufficient to recommend progesterone treatment for women presenting in acute preterm labor.

Objective

To determine whether weekly injections of 17 alpha-hydroxyprogesterone caproate (17P) reduce the risk of preterm delivery in women with a documented history of spontaneous preterm delivery.

Methods And Results

In this double-blind, placebo-controlled trial, researchers randomly assigned 463 patients at high risk for preterm delivery to receive weekly intramuscular injections of 17P (250 mg) or placebo from 16 to 20 weeks of gestation through 36 weeks. Outcome data were available for 459 women (99.1%).

Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks’ gestation: Incidence was 36.3% in the progesterone group versus 54.9% in the placebo group (relative risk, 0.66; 95% confidence interval, 0.54 to 0.81). It also reduced the risk of delivery at less than 35 weeks and less than 32 weeks. Infants of women treated with the compound had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen. There was no significant difference in miscarriage or stillbirth rates.

Who May Be Affected By These Findings?

Gravidas at high risk for preterm delivery.

Expert Commentary

Although we have improved our ability to identify women at risk, we have not been successful at preventing preterm birth—indeed, its incidence is actually rising, due primarily to increased use of assisted reproductive technology. Preterm birth complicates approximately 12% of deliveries, but accounts for more than 85% of perinatal morbidity and mortality.^1,2

The study by Meis and colleagues is a well-designed and well-executed randomized, double-blind, placebo-controlled, multicenter trial. Compliance with designated therapy was reported as 91.5%. The preterm delivery rate of 54.9% in the control group confirms that this cohort is indeed at high risk of preterm birth (see “Why progesterone?”).

I have only 1 minor criticism: The authors chose to deliver the drug via weekly intramuscular injections, which may not be a desirable route of administration for many women. Half of the women (231 of 463) reported at least 1 adverse effect, though most of these were minor local reactions at the injection site.

The authors found no evidence of teratogenicity—of note, no virilization of female offspring, which was a theoretic concern.

Findings apply only to high-risk gravidas. More study is required to determine whether progesterone supplementation can reduce preterm birth in low-risk women. This is important because most preterm births occur in patients with no identifiable risk factors.

The results of this study are consistent with prior publications.^8,9 In a similar recent trial carried out in Brazil, 142 women at high risk for preterm birth were randomized to receive daily supplementation with progesterone vaginal suppositories (100 mg) or placebo from 24 through 34 weeks of gestation.⁹ The preterm delivery rate was significantly lower in the progesterone group, as was the rate of delivery before 34 weeks. By monitoring patients with an external tocodynamometer once a week for 60 minutes, researchers also were able to demonstrate a significant difference in spontaneous uterine contractions between the groups, suggesting that progesterone supplementation may exert its effect by maintaining uterine quiescence in the latter half of pregnancy.

 

Bottom Line

Progesterone supplementation to prevent preterm birth remains investigational. Further studies are needed to evaluate its effectiveness in decreasing preterm delivery rates in high- and low-risk populations and to better understand its mechanism of action.

Given the absence of proven alternatives, however, it may be appropriate to offer such treatment to patients at highest risk for early preterm birth, such as those with higher-order multifetal pregnancies or a history of recurrent preterm deliveries. Evidence is insufficient to recommend progesterone treatment for women presenting in acute preterm labor.

Objective

To determine whether weekly injections of 17 alpha-hydroxyprogesterone caproate (17P) reduce the risk of preterm delivery in women with a documented history of spontaneous preterm delivery.

Methods And Results

In this double-blind, placebo-controlled trial, researchers randomly assigned 463 patients at high risk for preterm delivery to receive weekly intramuscular injections of 17P (250 mg) or placebo from 16 to 20 weeks of gestation through 36 weeks. Outcome data were available for 459 women (99.1%).

Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks’ gestation: Incidence was 36.3% in the progesterone group versus 54.9% in the placebo group (relative risk, 0.66; 95% confidence interval, 0.54 to 0.81). It also reduced the risk of delivery at less than 35 weeks and less than 32 weeks. Infants of women treated with the compound had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen. There was no significant difference in miscarriage or stillbirth rates.

Who May Be Affected By These Findings?

Gravidas at high risk for preterm delivery.

Expert Commentary

Although we have improved our ability to identify women at risk, we have not been successful at preventing preterm birth—indeed, its incidence is actually rising, due primarily to increased use of assisted reproductive technology. Preterm birth complicates approximately 12% of deliveries, but accounts for more than 85% of perinatal morbidity and mortality.^1,2

The study by Meis and colleagues is a well-designed and well-executed randomized, double-blind, placebo-controlled, multicenter trial. Compliance with designated therapy was reported as 91.5%. The preterm delivery rate of 54.9% in the control group confirms that this cohort is indeed at high risk of preterm birth (see “Why progesterone?”).

I have only 1 minor criticism: The authors chose to deliver the drug via weekly intramuscular injections, which may not be a desirable route of administration for many women. Half of the women (231 of 463) reported at least 1 adverse effect, though most of these were minor local reactions at the injection site.

The authors found no evidence of teratogenicity—of note, no virilization of female offspring, which was a theoretic concern.

Findings apply only to high-risk gravidas. More study is required to determine whether progesterone supplementation can reduce preterm birth in low-risk women. This is important because most preterm births occur in patients with no identifiable risk factors.

The results of this study are consistent with prior publications.^8,9 In a similar recent trial carried out in Brazil, 142 women at high risk for preterm birth were randomized to receive daily supplementation with progesterone vaginal suppositories (100 mg) or placebo from 24 through 34 weeks of gestation.⁹ The preterm delivery rate was significantly lower in the progesterone group, as was the rate of delivery before 34 weeks. By monitoring patients with an external tocodynamometer once a week for 60 minutes, researchers also were able to demonstrate a significant difference in spontaneous uterine contractions between the groups, suggesting that progesterone supplementation may exert its effect by maintaining uterine quiescence in the latter half of pregnancy.

 

Bottom Line

Progesterone supplementation to prevent preterm birth remains investigational. Further studies are needed to evaluate its effectiveness in decreasing preterm delivery rates in high- and low-risk populations and to better understand its mechanism of action.

Given the absence of proven alternatives, however, it may be appropriate to offer such treatment to patients at highest risk for early preterm birth, such as those with higher-order multifetal pregnancies or a history of recurrent preterm deliveries. Evidence is insufficient to recommend progesterone treatment for women presenting in acute preterm labor.

Objective

To assess the efficacy, reliability, patient recovery, and patient satisfaction associated with a tubal-occlusion microinsert (Essure; Conceptus, San Carlos, Calif) for permanent contraception.

Methods and Results

A cohort of 518 fertile women participated in this phase III, international, multicenter trial. Microinsert placement was attempted in 507 of these women, with 464 (92%) ultimately undergoing successful bilateral insertion.

The average time to discharge was 80 minutes; 60% of women resumed normal function in 1 day or less. More than half of the women reported either mild or no pain with the procedure, and 88% described tolerance of the procedure as good to excellent. Three months after placement, correct bilateral placement and tubal occlusion were confirmed in 96% and 92% of cases, respectively. Ultimately, 449 of 518 women (87%) were able to rely on the device for permanent contraception.

Who May be Affected by These Findings?

Women who desire sterilization.

Expert Commentary

This pivotal trial demonstrates that permanent sterilization for women can now be accomplished without incisions, general anesthesia, use of an operating room, or a prolonged recovery period.

In the trial, all sterilization procedures were performed hysteroscopically, either in an office setting or ambulatory treatment center, and patient satisfaction was over 98%. Fifty-two percent of women required only paracervical block anesthesia, and just 12% of patients required postplacement narcotic analgesics. Ninety-two percent of women missed 1 day of work or less.

In contrast to conventional incisional sterilization (laparoscopic, abdominal, and vaginal), there were no serious procedurerelated complications associated with microinsert placement. Further, as of January 3, 2003, no pregnancies were reported in 449 women and 9,620 woman-months, with a mean follow-up of 21.4 months.

Easy to learn and perform. Among the 20 clinical investigators in this study, hysteroscopic skill levels ranged from average to excellent, yet high device-placement rates were noted for all physicians. For the typical gynecologist who performs only diagnostic hysteroscopy, a short learning curve is required for efficient placement. Physicians also must take a half-day course sponsored by the manufacturer prior to beginning microinsert placement.

I have placed these devices in more than 30 women using only paracervical block anesthesia and found visualization and placement to be easy to moderate.

Steps to proficiency. For the clinician with average hysteroscopic skills, a number of steps can help simplify the first few cases of microinsert placement:

• Perform hysteroscopic procedures only during the first 10 days of the patient’s cycle.
  
• Practice by inserting scissors or biopsy forceps through the small operating channel of the hysteroscope.
  
• Identify the proximal tubal ostia during hysteroscopy, and observe the ostia for peristaltic closing. Increase intrauterine fluid pressure and note improved visualization.
  
• Experiment with both 12° and 30° hystero-scopes. The latter are more difficult to learn, but provide better visualization for hysteroscopic sterilization procedures.
  
• Observe as an experienced hysteroscopist performs the procedure, then seek proctoring for the first 1 to 3 cases.
  

Sterilization is likely irreversible. What about the feasibility of pregnancy at a future date in women who have undergone this sterilization method? In contrast to conventional incisional sterilization, microsurgical tubal reversal is not an option because of the fibrous occlusion of the proximal and interstitial tubal segments. As for whether in vitro fertilization would be possible, it is unclear if the portion of the device that projects into the endometrial cavity has any impact on embryo implantation or creates an increased risk of first-trimester abortion. Further, no method has been developed for hysteroscopic resection of the metal “tail”that projects into the uterus.

Bottom Line

This hysteroscopic microinsert sterilization method is not only safe and reliable, but also offers a high level of patient satisfaction. In addition, cost savings should be realized since neither general anesthesia nor an operating or recovery room is necessary.

Dr. Galen reports no financial relationship with any companies whose products are mentioned in this article.

Objective

To assess the efficacy, reliability, patient recovery, and patient satisfaction associated with a tubal-occlusion microinsert (Essure; Conceptus, San Carlos, Calif) for permanent contraception.

Methods and Results

A cohort of 518 fertile women participated in this phase III, international, multicenter trial. Microinsert placement was attempted in 507 of these women, with 464 (92%) ultimately undergoing successful bilateral insertion.

The average time to discharge was 80 minutes; 60% of women resumed normal function in 1 day or less. More than half of the women reported either mild or no pain with the procedure, and 88% described tolerance of the procedure as good to excellent. Three months after placement, correct bilateral placement and tubal occlusion were confirmed in 96% and 92% of cases, respectively. Ultimately, 449 of 518 women (87%) were able to rely on the device for permanent contraception.

Who May be Affected by These Findings?

Women who desire sterilization.

Expert Commentary

This pivotal trial demonstrates that permanent sterilization for women can now be accomplished without incisions, general anesthesia, use of an operating room, or a prolonged recovery period.

In the trial, all sterilization procedures were performed hysteroscopically, either in an office setting or ambulatory treatment center, and patient satisfaction was over 98%. Fifty-two percent of women required only paracervical block anesthesia, and just 12% of patients required postplacement narcotic analgesics. Ninety-two percent of women missed 1 day of work or less.

In contrast to conventional incisional sterilization (laparoscopic, abdominal, and vaginal), there were no serious procedurerelated complications associated with microinsert placement. Further, as of January 3, 2003, no pregnancies were reported in 449 women and 9,620 woman-months, with a mean follow-up of 21.4 months.

Easy to learn and perform. Among the 20 clinical investigators in this study, hysteroscopic skill levels ranged from average to excellent, yet high device-placement rates were noted for all physicians. For the typical gynecologist who performs only diagnostic hysteroscopy, a short learning curve is required for efficient placement. Physicians also must take a half-day course sponsored by the manufacturer prior to beginning microinsert placement.

I have placed these devices in more than 30 women using only paracervical block anesthesia and found visualization and placement to be easy to moderate.

Steps to proficiency. For the clinician with average hysteroscopic skills, a number of steps can help simplify the first few cases of microinsert placement:

• Perform hysteroscopic procedures only during the first 10 days of the patient’s cycle.
  
• Practice by inserting scissors or biopsy forceps through the small operating channel of the hysteroscope.
  
• Identify the proximal tubal ostia during hysteroscopy, and observe the ostia for peristaltic closing. Increase intrauterine fluid pressure and note improved visualization.
  
• Experiment with both 12° and 30° hystero-scopes. The latter are more difficult to learn, but provide better visualization for hysteroscopic sterilization procedures.
  
• Observe as an experienced hysteroscopist performs the procedure, then seek proctoring for the first 1 to 3 cases.
  

Sterilization is likely irreversible. What about the feasibility of pregnancy at a future date in women who have undergone this sterilization method? In contrast to conventional incisional sterilization, microsurgical tubal reversal is not an option because of the fibrous occlusion of the proximal and interstitial tubal segments. As for whether in vitro fertilization would be possible, it is unclear if the portion of the device that projects into the endometrial cavity has any impact on embryo implantation or creates an increased risk of first-trimester abortion. Further, no method has been developed for hysteroscopic resection of the metal “tail”that projects into the uterus.

Bottom Line

This hysteroscopic microinsert sterilization method is not only safe and reliable, but also offers a high level of patient satisfaction. In addition, cost savings should be realized since neither general anesthesia nor an operating or recovery room is necessary.

Dr. Galen reports no financial relationship with any companies whose products are mentioned in this article.

Objective

To assess the efficacy, reliability, patient recovery, and patient satisfaction associated with a tubal-occlusion microinsert (Essure; Conceptus, San Carlos, Calif) for permanent contraception.

Methods and Results

A cohort of 518 fertile women participated in this phase III, international, multicenter trial. Microinsert placement was attempted in 507 of these women, with 464 (92%) ultimately undergoing successful bilateral insertion.

The average time to discharge was 80 minutes; 60% of women resumed normal function in 1 day or less. More than half of the women reported either mild or no pain with the procedure, and 88% described tolerance of the procedure as good to excellent. Three months after placement, correct bilateral placement and tubal occlusion were confirmed in 96% and 92% of cases, respectively. Ultimately, 449 of 518 women (87%) were able to rely on the device for permanent contraception.

Who May be Affected by These Findings?

Women who desire sterilization.

Expert Commentary

This pivotal trial demonstrates that permanent sterilization for women can now be accomplished without incisions, general anesthesia, use of an operating room, or a prolonged recovery period.

In the trial, all sterilization procedures were performed hysteroscopically, either in an office setting or ambulatory treatment center, and patient satisfaction was over 98%. Fifty-two percent of women required only paracervical block anesthesia, and just 12% of patients required postplacement narcotic analgesics. Ninety-two percent of women missed 1 day of work or less.

In contrast to conventional incisional sterilization (laparoscopic, abdominal, and vaginal), there were no serious procedurerelated complications associated with microinsert placement. Further, as of January 3, 2003, no pregnancies were reported in 449 women and 9,620 woman-months, with a mean follow-up of 21.4 months.

Easy to learn and perform. Among the 20 clinical investigators in this study, hysteroscopic skill levels ranged from average to excellent, yet high device-placement rates were noted for all physicians. For the typical gynecologist who performs only diagnostic hysteroscopy, a short learning curve is required for efficient placement. Physicians also must take a half-day course sponsored by the manufacturer prior to beginning microinsert placement.

I have placed these devices in more than 30 women using only paracervical block anesthesia and found visualization and placement to be easy to moderate.

Steps to proficiency. For the clinician with average hysteroscopic skills, a number of steps can help simplify the first few cases of microinsert placement:

• Perform hysteroscopic procedures only during the first 10 days of the patient’s cycle.
  
• Practice by inserting scissors or biopsy forceps through the small operating channel of the hysteroscope.
  
• Identify the proximal tubal ostia during hysteroscopy, and observe the ostia for peristaltic closing. Increase intrauterine fluid pressure and note improved visualization.
  
• Experiment with both 12° and 30° hystero-scopes. The latter are more difficult to learn, but provide better visualization for hysteroscopic sterilization procedures.
  
• Observe as an experienced hysteroscopist performs the procedure, then seek proctoring for the first 1 to 3 cases.
  

Sterilization is likely irreversible. What about the feasibility of pregnancy at a future date in women who have undergone this sterilization method? In contrast to conventional incisional sterilization, microsurgical tubal reversal is not an option because of the fibrous occlusion of the proximal and interstitial tubal segments. As for whether in vitro fertilization would be possible, it is unclear if the portion of the device that projects into the endometrial cavity has any impact on embryo implantation or creates an increased risk of first-trimester abortion. Further, no method has been developed for hysteroscopic resection of the metal “tail”that projects into the uterus.

Bottom Line

This hysteroscopic microinsert sterilization method is not only safe and reliable, but also offers a high level of patient satisfaction. In addition, cost savings should be realized since neither general anesthesia nor an operating or recovery room is necessary.

Dr. Galen reports no financial relationship with any companies whose products are mentioned in this article.

Objective

To evaluate the efficacy, safety, discontinuation, and acceptability of the cervical cap in comparison with the diaphragm.

Methods and Results

Investigators searched the literature for randomized controlled trials comparing the cervical cap to the diaphragm. Two trials met inclusion criteria; both recruited sexually active women aged 18 to 40 years. The first trial randomized subjects to the Prentif Cavity Rim Cervical Cap (Lamberts Ltd, Oxford, England) or the Ortho diaphragm (Ortho Pharmaceutical, Raritan, NJ). The second compared the FemCap cervical cap (FemCap Inc, Del Mar, Calif) with the All-Flex diaphragm (Ortho). Outcomes were calculated as Peto odds ratios with 95% confidence intervals (CI), using total number of women as the denominator. Life-table and Kaplan-Meier cumulative rate ratios were also calculated for selected measures.

As a contraceptive, the Prentif Cap was comparable in efficacy to the diaphragm, but the FemCap was less effective than its comparison diaphragm.

The Prentif Cap had a higher proportion of class I to class III (older classification of Papanicolaou smears) cervical cytologic conversions at 3 months than the diaphragm, with an odds ratio of 2.3 (95% CI, 1.0-5.1); there were no differences in Pap smear results between groups in the FemCap trial. Prentif Cap users had a lower odds ratio of vaginal ulcerations or lacerations (0.3; 95% CI, 0.1-0.7) than diaphragm users, and FemCap users had a higher odds ratio of blood in the device on removal (2.3; 95% CI, 1.3-4.1). FemCap users also had a lower odds ratio of urinary tract infections than women using the diaphragm (0.6; 95% CI, 0.4-1.0).

Expert commentary

Few women use the cervical cap as their primary contraceptive, although it has been available since the late 1980s. Concerns about efficacy, frequent office visits, and limited sexual spontaneity likely contribute to its relatively low popularity. Further, residency training programs tend to focus on hormonal contraception.

Unfortunately, despite its comprehensive and detailed database review, this metaanalysis is of limited value, since only 2 studies were deemed worthy of inclusion. Other concerns include:

• Unacceptable dropout rates. Only 34% of women assigned to the Prentif Cap completed the study. The FemCap group had a similar but slightly lower rate of discontinuation. These dropout rates contribute negatively to any predetermined significance.
  
• Different follow up durations. For the Prentif Cap, investigators calculated the cumulative life-table rate ratios of pregnancy in comparison with the diaphragm for periods ranging from 6 months to 2 years. (At 6 months, it was 1.3.) In the FemCap trial, the Kaplan-Meier 6-month cumulative pregnancy rate in comparison with the diaphragm was 1.7, but the FemCap’s efficacy beyond that time was not established.
  
• Incomparable groups for cytologic review. As the authors discuss, the cervical cap has been implicated in the progression of cytologic abnormalities on Pap smears. Further, it does not protect women from sexually transmitted infections such as human papil-lomavirus, so the risk of developing subsequent cytologic abnormalities exists.
  
• The difficulty of determining acceptability. Accurate estimates of acceptability are difficult to formulate, although the high dropout rate in both trials suggests limited popularity. Interestingly, 31% of FemCap users experienced dislodgement of the device and a significant number had difficulty with removal, yet there was a lower dropout rate than among Prentif Cap users.
  

Bottom line

Both the diaphragm and cervical cap provide acceptable levels of birth control, but should be recommended primarily to women unable to utilize more effective methods and those who have infrequent intercourse. Frequent office visits may be required to ensure proper use, ascertain rates of discontinuation, and assess for Pap smear abnormalities.

Objective

To evaluate the efficacy, safety, discontinuation, and acceptability of the cervical cap in comparison with the diaphragm.

Methods and Results

Investigators searched the literature for randomized controlled trials comparing the cervical cap to the diaphragm. Two trials met inclusion criteria; both recruited sexually active women aged 18 to 40 years. The first trial randomized subjects to the Prentif Cavity Rim Cervical Cap (Lamberts Ltd, Oxford, England) or the Ortho diaphragm (Ortho Pharmaceutical, Raritan, NJ). The second compared the FemCap cervical cap (FemCap Inc, Del Mar, Calif) with the All-Flex diaphragm (Ortho). Outcomes were calculated as Peto odds ratios with 95% confidence intervals (CI), using total number of women as the denominator. Life-table and Kaplan-Meier cumulative rate ratios were also calculated for selected measures.

As a contraceptive, the Prentif Cap was comparable in efficacy to the diaphragm, but the FemCap was less effective than its comparison diaphragm.

The Prentif Cap had a higher proportion of class I to class III (older classification of Papanicolaou smears) cervical cytologic conversions at 3 months than the diaphragm, with an odds ratio of 2.3 (95% CI, 1.0-5.1); there were no differences in Pap smear results between groups in the FemCap trial. Prentif Cap users had a lower odds ratio of vaginal ulcerations or lacerations (0.3; 95% CI, 0.1-0.7) than diaphragm users, and FemCap users had a higher odds ratio of blood in the device on removal (2.3; 95% CI, 1.3-4.1). FemCap users also had a lower odds ratio of urinary tract infections than women using the diaphragm (0.6; 95% CI, 0.4-1.0).

Expert commentary

Few women use the cervical cap as their primary contraceptive, although it has been available since the late 1980s. Concerns about efficacy, frequent office visits, and limited sexual spontaneity likely contribute to its relatively low popularity. Further, residency training programs tend to focus on hormonal contraception.

Unfortunately, despite its comprehensive and detailed database review, this metaanalysis is of limited value, since only 2 studies were deemed worthy of inclusion. Other concerns include:

• Unacceptable dropout rates. Only 34% of women assigned to the Prentif Cap completed the study. The FemCap group had a similar but slightly lower rate of discontinuation. These dropout rates contribute negatively to any predetermined significance.
  
• Different follow up durations. For the Prentif Cap, investigators calculated the cumulative life-table rate ratios of pregnancy in comparison with the diaphragm for periods ranging from 6 months to 2 years. (At 6 months, it was 1.3.) In the FemCap trial, the Kaplan-Meier 6-month cumulative pregnancy rate in comparison with the diaphragm was 1.7, but the FemCap’s efficacy beyond that time was not established.
  
• Incomparable groups for cytologic review. As the authors discuss, the cervical cap has been implicated in the progression of cytologic abnormalities on Pap smears. Further, it does not protect women from sexually transmitted infections such as human papil-lomavirus, so the risk of developing subsequent cytologic abnormalities exists.
  
• The difficulty of determining acceptability. Accurate estimates of acceptability are difficult to formulate, although the high dropout rate in both trials suggests limited popularity. Interestingly, 31% of FemCap users experienced dislodgement of the device and a significant number had difficulty with removal, yet there was a lower dropout rate than among Prentif Cap users.
  

Bottom line

Both the diaphragm and cervical cap provide acceptable levels of birth control, but should be recommended primarily to women unable to utilize more effective methods and those who have infrequent intercourse. Frequent office visits may be required to ensure proper use, ascertain rates of discontinuation, and assess for Pap smear abnormalities.

Objective

To evaluate the efficacy, safety, discontinuation, and acceptability of the cervical cap in comparison with the diaphragm.

Methods and Results

Investigators searched the literature for randomized controlled trials comparing the cervical cap to the diaphragm. Two trials met inclusion criteria; both recruited sexually active women aged 18 to 40 years. The first trial randomized subjects to the Prentif Cavity Rim Cervical Cap (Lamberts Ltd, Oxford, England) or the Ortho diaphragm (Ortho Pharmaceutical, Raritan, NJ). The second compared the FemCap cervical cap (FemCap Inc, Del Mar, Calif) with the All-Flex diaphragm (Ortho). Outcomes were calculated as Peto odds ratios with 95% confidence intervals (CI), using total number of women as the denominator. Life-table and Kaplan-Meier cumulative rate ratios were also calculated for selected measures.

As a contraceptive, the Prentif Cap was comparable in efficacy to the diaphragm, but the FemCap was less effective than its comparison diaphragm.

The Prentif Cap had a higher proportion of class I to class III (older classification of Papanicolaou smears) cervical cytologic conversions at 3 months than the diaphragm, with an odds ratio of 2.3 (95% CI, 1.0-5.1); there were no differences in Pap smear results between groups in the FemCap trial. Prentif Cap users had a lower odds ratio of vaginal ulcerations or lacerations (0.3; 95% CI, 0.1-0.7) than diaphragm users, and FemCap users had a higher odds ratio of blood in the device on removal (2.3; 95% CI, 1.3-4.1). FemCap users also had a lower odds ratio of urinary tract infections than women using the diaphragm (0.6; 95% CI, 0.4-1.0).

Expert commentary

Few women use the cervical cap as their primary contraceptive, although it has been available since the late 1980s. Concerns about efficacy, frequent office visits, and limited sexual spontaneity likely contribute to its relatively low popularity. Further, residency training programs tend to focus on hormonal contraception.

Unfortunately, despite its comprehensive and detailed database review, this metaanalysis is of limited value, since only 2 studies were deemed worthy of inclusion. Other concerns include:

• Unacceptable dropout rates. Only 34% of women assigned to the Prentif Cap completed the study. The FemCap group had a similar but slightly lower rate of discontinuation. These dropout rates contribute negatively to any predetermined significance.
  
• Different follow up durations. For the Prentif Cap, investigators calculated the cumulative life-table rate ratios of pregnancy in comparison with the diaphragm for periods ranging from 6 months to 2 years. (At 6 months, it was 1.3.) In the FemCap trial, the Kaplan-Meier 6-month cumulative pregnancy rate in comparison with the diaphragm was 1.7, but the FemCap’s efficacy beyond that time was not established.
  
• Incomparable groups for cytologic review. As the authors discuss, the cervical cap has been implicated in the progression of cytologic abnormalities on Pap smears. Further, it does not protect women from sexually transmitted infections such as human papil-lomavirus, so the risk of developing subsequent cytologic abnormalities exists.
  
• The difficulty of determining acceptability. Accurate estimates of acceptability are difficult to formulate, although the high dropout rate in both trials suggests limited popularity. Interestingly, 31% of FemCap users experienced dislodgement of the device and a significant number had difficulty with removal, yet there was a lower dropout rate than among Prentif Cap users.
  

Bottom line

Both the diaphragm and cervical cap provide acceptable levels of birth control, but should be recommended primarily to women unable to utilize more effective methods and those who have infrequent intercourse. Frequent office visits may be required to ensure proper use, ascertain rates of discontinuation, and assess for Pap smear abnormalities.