OBG Management

A minimally invasive approach for gynecologic surgery increasingly has become the surgical modality of choice (vs open surgery) due to decreased perioperative and postoperative morbidity for many gynecologic cancers.^1-3 This has included radical hysterectomy for cervical cancers. Until recently, retrospective evidence supported its use, suggesting decreased perioperative and postoperative complications with similar survival outcomes between patients undergoing minimally invasive and open radical hysterectomy.^4,5 In November 2018, two new studies were published in the New England Journal of Medicine, and another study was presented at the American Society of Clinical Oncology (ASCO) annual meeting challenging this practice paradigm. These studies reveal a higher risk of disease recurrence and decreased overall survival with minimally invasive surgery (MIS) compared with open surgery for Stages IA–IB1 cervical cancer. These findings have resulted in a change in practice nationwide.

RCT findings astonish specialty

The first study, the Laparoscopic Approach to Cervical Cancer (LACC) trial, authored by Ramirez and colleagues was a noninferiority randomized controlled trial evaluating MIS versus open radical hysterectomy for patients with cervical cancer (Stage 1A–1B1) conducted from 2008–2017.⁶ The primary outcome was disease-free survival at 4.5 years. Secondary outcomes included recurrence and overall survival rates. Power analysis suggested a sample size of 740 patients to provide greater than 80% power with a noninferiority margin of -7.2% between disease-free rates of the two groups. However, the study was closed prematurely at enrollment of 631 patients (85% recruitment) by the Data Safety Monitoring Committee due to the astounding differences in survival between the two groups.

The rate of disease-free survival at 4.5 years was 86.0% with MIS and 96% with open surgery. There were 27 recurrences (8.5%) in the MIS group and only 7 (2.2%) in the open-surgery group, accounting for a hazard ratio (HR) for disease recurrence or death from cervical cancer of 3.74 (95% confidence interval [CI], 1.63–8.58). This difference remained after adjusting for confounding variables. There were 22 deaths—19 (5.9%) in the MIS group and 3 (0.1%) in the open-surgery group (HR, 6.56). Although patient characteristics between groups appeared to be similar, more than one-third of patients in each group had missing data regarding histology at the time of surgery, grade, tumor size, lymphovascular space invasion, and depth of invasion. Interestingly, intraoperative, perioperative, and postoperative complications between the two groups were similar (with rates of 11%, about 40%, and about 25%, respectively).

Surprising findings continue in NEJM

The second study, by Melamed and colleagues, was a retrospective cohort study using data from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database evaluating women with stage IA2 or IB1 cervical cancer who underwent either minimally invasive or open radical hysterectomy between 2010 and 2013.⁷ The primary outcome was time to death.

Participant characteristics. A total of 2,461 women were included: 49.8% underwent MIS and 50.2% underwent open surgery. According to the raw data, patients undergoing MIS were more likely to be white, privately insured, reside in an area associated with higher income, undergo surgery at a nonacademic institution, have adenocarcinoma, and have smaller, lower-grade tumors. After propensity-score weighting, demographic and clinical characteristics were similar between groups. Median follow-up was 45 months.

Results. A total of 164 deaths occurred: 94 in the MIS and 70 in the open-surgery group. The risk of death during study follow-up was 9.1% in the MIS group versus 5.3% in the open-surgery group, and women who underwent MIS had shorter overall survival (P = .002; HR, 1.65; 95% CI, 1.22–2.22). Mortality rates remained higher in the MIS group after adjusting for adjuvant therapy (HR, 1.62; 95% CI, 1.2–2.19). However, the HR for death with MIS was not statistically significant in a subgroup analysis evaluating tumors 2 cm in size or less (HR, 1.46; 95% CI, 0.70–3.02). The authors demonstrated that the adoption of MIS for radical hysterectomy corresponded to a drop in the 4-year survival rate of 0.8% per year (P = .01).

Continue to: ASCO meeting data emphasize lower...

ASCO meeting data emphasize lower mortality and survival rates for MIS

A third important, but less publicized study, is a retrospective cohort study by Marguland and colleagues that was presented at the ASCO annual meeting and is pending publication. This study evaluated the 5-year survival of women with stage IB1 cervical cancer after MIS or open radical hysterectomy from 2010 to 2013.⁸ The findings demonstrated similar results to the above studies with decreased 5-year survival rates in patients with a tumor size of 2 cm or greater in the MIS group (81.3% vs 90.8; HR, 2.14; 95% CI, 1.36–3.38; P<.001). These results hold true when controlling for confounding clinical variables. Interestingly, in a subset analysis evaluating patients with tumors less than 2 cm, survival rates were similar between groups. This study confirms decreased morbidity and cost associated with MIS radical hysterectomy.

A consistent message emerges from 3 independent studies

We must take the study findings seriously and evaluate the quality of the evidence. There are many strengths to the above studies. First and most importantly, the LACC study is the only prospective randomized controlled trial (RCT) to evaluate this very important clinical question. RCTs are the gold standard for understanding the effectiveness and safety of an intervention compared with an established treatment. The study was well designed in that the study population was clearly defined with detailed inclusion and exclusion criteria. The intention to treat analysis was similar to the per-protocol analysis, and the study followed Consolidated Standards of Reporting Trials (CONSORT) guidelines. While the study was stopped early, there was still 84% power for the primary outcome. Therefore, when it comes to MIS for cervical cancer, this study provides the soundest data we have available. It is also extremely noteworthy that two additional large retrospective studies evaluating this question separately found similar results.

Criticisms remain, but older research has drawbacks

A main concern with these studies is that the findings challenge previously published research, which overall suggest similar survival outcomes between MIS and open surgical approaches. However, in evaluating the previously published retrospective data it is clear that the studies have considerable limitations.

Long-term survival not always evaluated in research. First, the majority of studies comparing MIS and open treatment modalities specifically evaluated perioperative complications and did not consider long-term survival.^4,9,10 Of those studies that did consider survival outcomes, the groups often were not balanced and were skewed toward the open surgery patients having larger tumors and higher-stage disease.⁵

Difficult to compare “apples to apples.” These findings are complicated by the fact that open radical hysterectomies were essentially replaced by MIS radical hysterectomies, and therefore, the comparisons are not equivalent since they are comparing different treatment times. For instance, throughout the time period many of these studies were conducted, the treatment paradigm for early-stage cervical cancer changed regarding who received adjuvant therapy and imaging techniques. Therefore, these studies are not comparing apples to apples.^11,12

Are we going to increase morbidity? Another common concern when considering abandoning MIS for cervical cancer is the increase in morbidity that our patients may incur immediately postoperatively due to open surgery. Multiple studies have associated minimally invasive radical hysterectomies with decreased blood loss, shorter hospital stay, lower transfusion rates, and decreased time until return of bowel function.^4,10,13

Continue to: While we recognize that...

While we recognize that open surgery is associated with increased morbidity, we do argue that, with the almost-universal implementation of Enhanced Recovery Pathways (ERP) in gynecologic oncology, the disparities between the two groups will be minimized and likely are much smaller than that reported in historical literature.¹⁴ Notably, there were no differences in peri-, intra-, or postoperative complications between the two groups in the LACC study, indicating that MIS may not be saving our patients as much morbidity as we think.

Surgical ability differences. Despite the vast strengths associated with the studies we have discussed they certainly embody limitations as well. First, surgical aptitude is difficult to evaluate and tease out. This is extremely pertinent given perioperative, and postoperative, outcomes in cervical cancer, as well as survival outcomes, in multiple surgically managed cancers, which are directly associated with the volume and proficiency of the surgeon.^15-19 Additionally, the mode of minimally invasive surgery that was most commonly utilized was different from practice in the United States. Eighty four percent of the patients in the MIS group of the LACC study underwent laparoscopic and 13.6% underwent robot-assisted radical hysterectomy. This is starkly different from US practice, where 75% of gynecologic oncologists report performing radical hysterectomies only robotically.²⁰

Take-home points

Consider this latest evidence in your surgical planning. Most importantly, the evidence is the evidence. In other words, we can attempt to explain away the findings, but despite arguments against these studies, these data are the most reliable evidence we have to date regarding outcomes for cervical cancer with MIS versus open approaches. These data demonstrate that MIS may be harming our patients and so we must take this into careful consideration during surgical planning.

For small cancers, MIS may be the best option. MIS radical hysterectomy may still be the best approach for patients with tumors less than 2 cm in size. The LACC study is not powered to evaluate oncologic outcomes in this subset of patients and the two retrospective studies suggest no difference in survival in this cohort.

We must work to understand the driving force between the disparate outcomes. Are the increased rates due to the open surgical approach, the uterine manipulator, circulating CO2 gas, or tumor exposure to the intraperitoneal cavity as the authors suggest? Or is it due to surgical expertise, tumor biology, tumor size, or mode of MIS? At this point the impelling cause is unknown.

New NCCN guidelines are to come. Up to this point the National Comprehensive Cancer Network (NCCN) guidelines stated that “radical hysterectomy procedure may be performed either via laparotomy or laparoscopy.” Given these recent studies, however, new NCCN guidelines will be released cautioning the use of the MIS approach. In short, these data have transformed the standard of care.

At our institution, the majority of radical hysterectomies will be performed open. Continued discussion remains regarding small lesions, but even in these cases most surgeons will proceed with open surgery in an attempt to maximize survival.

As providers, it is our duty to honestly reflect on published data and comprehensively counsel patients about the risks and benefits associated with each approach, including the fact that recurrence may be higher with a minimally invasive approach. Patients and providers must then collectively decide what is best for each individual case.

A minimally invasive approach for gynecologic surgery increasingly has become the surgical modality of choice (vs open surgery) due to decreased perioperative and postoperative morbidity for many gynecologic cancers.^1-3 This has included radical hysterectomy for cervical cancers. Until recently, retrospective evidence supported its use, suggesting decreased perioperative and postoperative complications with similar survival outcomes between patients undergoing minimally invasive and open radical hysterectomy.^4,5 In November 2018, two new studies were published in the New England Journal of Medicine, and another study was presented at the American Society of Clinical Oncology (ASCO) annual meeting challenging this practice paradigm. These studies reveal a higher risk of disease recurrence and decreased overall survival with minimally invasive surgery (MIS) compared with open surgery for Stages IA–IB1 cervical cancer. These findings have resulted in a change in practice nationwide.

RCT findings astonish specialty

The first study, the Laparoscopic Approach to Cervical Cancer (LACC) trial, authored by Ramirez and colleagues was a noninferiority randomized controlled trial evaluating MIS versus open radical hysterectomy for patients with cervical cancer (Stage 1A–1B1) conducted from 2008–2017.⁶ The primary outcome was disease-free survival at 4.5 years. Secondary outcomes included recurrence and overall survival rates. Power analysis suggested a sample size of 740 patients to provide greater than 80% power with a noninferiority margin of -7.2% between disease-free rates of the two groups. However, the study was closed prematurely at enrollment of 631 patients (85% recruitment) by the Data Safety Monitoring Committee due to the astounding differences in survival between the two groups.

The rate of disease-free survival at 4.5 years was 86.0% with MIS and 96% with open surgery. There were 27 recurrences (8.5%) in the MIS group and only 7 (2.2%) in the open-surgery group, accounting for a hazard ratio (HR) for disease recurrence or death from cervical cancer of 3.74 (95% confidence interval [CI], 1.63–8.58). This difference remained after adjusting for confounding variables. There were 22 deaths—19 (5.9%) in the MIS group and 3 (0.1%) in the open-surgery group (HR, 6.56). Although patient characteristics between groups appeared to be similar, more than one-third of patients in each group had missing data regarding histology at the time of surgery, grade, tumor size, lymphovascular space invasion, and depth of invasion. Interestingly, intraoperative, perioperative, and postoperative complications between the two groups were similar (with rates of 11%, about 40%, and about 25%, respectively).

Surprising findings continue in NEJM

The second study, by Melamed and colleagues, was a retrospective cohort study using data from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database evaluating women with stage IA2 or IB1 cervical cancer who underwent either minimally invasive or open radical hysterectomy between 2010 and 2013.⁷ The primary outcome was time to death.

Participant characteristics. A total of 2,461 women were included: 49.8% underwent MIS and 50.2% underwent open surgery. According to the raw data, patients undergoing MIS were more likely to be white, privately insured, reside in an area associated with higher income, undergo surgery at a nonacademic institution, have adenocarcinoma, and have smaller, lower-grade tumors. After propensity-score weighting, demographic and clinical characteristics were similar between groups. Median follow-up was 45 months.

Results. A total of 164 deaths occurred: 94 in the MIS and 70 in the open-surgery group. The risk of death during study follow-up was 9.1% in the MIS group versus 5.3% in the open-surgery group, and women who underwent MIS had shorter overall survival (P = .002; HR, 1.65; 95% CI, 1.22–2.22). Mortality rates remained higher in the MIS group after adjusting for adjuvant therapy (HR, 1.62; 95% CI, 1.2–2.19). However, the HR for death with MIS was not statistically significant in a subgroup analysis evaluating tumors 2 cm in size or less (HR, 1.46; 95% CI, 0.70–3.02). The authors demonstrated that the adoption of MIS for radical hysterectomy corresponded to a drop in the 4-year survival rate of 0.8% per year (P = .01).

Continue to: ASCO meeting data emphasize lower...

ASCO meeting data emphasize lower mortality and survival rates for MIS

A third important, but less publicized study, is a retrospective cohort study by Marguland and colleagues that was presented at the ASCO annual meeting and is pending publication. This study evaluated the 5-year survival of women with stage IB1 cervical cancer after MIS or open radical hysterectomy from 2010 to 2013.⁸ The findings demonstrated similar results to the above studies with decreased 5-year survival rates in patients with a tumor size of 2 cm or greater in the MIS group (81.3% vs 90.8; HR, 2.14; 95% CI, 1.36–3.38; P<.001). These results hold true when controlling for confounding clinical variables. Interestingly, in a subset analysis evaluating patients with tumors less than 2 cm, survival rates were similar between groups. This study confirms decreased morbidity and cost associated with MIS radical hysterectomy.

A consistent message emerges from 3 independent studies

We must take the study findings seriously and evaluate the quality of the evidence. There are many strengths to the above studies. First and most importantly, the LACC study is the only prospective randomized controlled trial (RCT) to evaluate this very important clinical question. RCTs are the gold standard for understanding the effectiveness and safety of an intervention compared with an established treatment. The study was well designed in that the study population was clearly defined with detailed inclusion and exclusion criteria. The intention to treat analysis was similar to the per-protocol analysis, and the study followed Consolidated Standards of Reporting Trials (CONSORT) guidelines. While the study was stopped early, there was still 84% power for the primary outcome. Therefore, when it comes to MIS for cervical cancer, this study provides the soundest data we have available. It is also extremely noteworthy that two additional large retrospective studies evaluating this question separately found similar results.

Criticisms remain, but older research has drawbacks

A main concern with these studies is that the findings challenge previously published research, which overall suggest similar survival outcomes between MIS and open surgical approaches. However, in evaluating the previously published retrospective data it is clear that the studies have considerable limitations.

Long-term survival not always evaluated in research. First, the majority of studies comparing MIS and open treatment modalities specifically evaluated perioperative complications and did not consider long-term survival.^4,9,10 Of those studies that did consider survival outcomes, the groups often were not balanced and were skewed toward the open surgery patients having larger tumors and higher-stage disease.⁵

Difficult to compare “apples to apples.” These findings are complicated by the fact that open radical hysterectomies were essentially replaced by MIS radical hysterectomies, and therefore, the comparisons are not equivalent since they are comparing different treatment times. For instance, throughout the time period many of these studies were conducted, the treatment paradigm for early-stage cervical cancer changed regarding who received adjuvant therapy and imaging techniques. Therefore, these studies are not comparing apples to apples.^11,12

Are we going to increase morbidity? Another common concern when considering abandoning MIS for cervical cancer is the increase in morbidity that our patients may incur immediately postoperatively due to open surgery. Multiple studies have associated minimally invasive radical hysterectomies with decreased blood loss, shorter hospital stay, lower transfusion rates, and decreased time until return of bowel function.^4,10,13

Continue to: While we recognize that...

While we recognize that open surgery is associated with increased morbidity, we do argue that, with the almost-universal implementation of Enhanced Recovery Pathways (ERP) in gynecologic oncology, the disparities between the two groups will be minimized and likely are much smaller than that reported in historical literature.¹⁴ Notably, there were no differences in peri-, intra-, or postoperative complications between the two groups in the LACC study, indicating that MIS may not be saving our patients as much morbidity as we think.

Surgical ability differences. Despite the vast strengths associated with the studies we have discussed they certainly embody limitations as well. First, surgical aptitude is difficult to evaluate and tease out. This is extremely pertinent given perioperative, and postoperative, outcomes in cervical cancer, as well as survival outcomes, in multiple surgically managed cancers, which are directly associated with the volume and proficiency of the surgeon.^15-19 Additionally, the mode of minimally invasive surgery that was most commonly utilized was different from practice in the United States. Eighty four percent of the patients in the MIS group of the LACC study underwent laparoscopic and 13.6% underwent robot-assisted radical hysterectomy. This is starkly different from US practice, where 75% of gynecologic oncologists report performing radical hysterectomies only robotically.²⁰

Take-home points

Consider this latest evidence in your surgical planning. Most importantly, the evidence is the evidence. In other words, we can attempt to explain away the findings, but despite arguments against these studies, these data are the most reliable evidence we have to date regarding outcomes for cervical cancer with MIS versus open approaches. These data demonstrate that MIS may be harming our patients and so we must take this into careful consideration during surgical planning.

For small cancers, MIS may be the best option. MIS radical hysterectomy may still be the best approach for patients with tumors less than 2 cm in size. The LACC study is not powered to evaluate oncologic outcomes in this subset of patients and the two retrospective studies suggest no difference in survival in this cohort.

We must work to understand the driving force between the disparate outcomes. Are the increased rates due to the open surgical approach, the uterine manipulator, circulating CO2 gas, or tumor exposure to the intraperitoneal cavity as the authors suggest? Or is it due to surgical expertise, tumor biology, tumor size, or mode of MIS? At this point the impelling cause is unknown.

New NCCN guidelines are to come. Up to this point the National Comprehensive Cancer Network (NCCN) guidelines stated that “radical hysterectomy procedure may be performed either via laparotomy or laparoscopy.” Given these recent studies, however, new NCCN guidelines will be released cautioning the use of the MIS approach. In short, these data have transformed the standard of care.

At our institution, the majority of radical hysterectomies will be performed open. Continued discussion remains regarding small lesions, but even in these cases most surgeons will proceed with open surgery in an attempt to maximize survival.

As providers, it is our duty to honestly reflect on published data and comprehensively counsel patients about the risks and benefits associated with each approach, including the fact that recurrence may be higher with a minimally invasive approach. Patients and providers must then collectively decide what is best for each individual case.

A minimally invasive approach for gynecologic surgery increasingly has become the surgical modality of choice (vs open surgery) due to decreased perioperative and postoperative morbidity for many gynecologic cancers.^1-3 This has included radical hysterectomy for cervical cancers. Until recently, retrospective evidence supported its use, suggesting decreased perioperative and postoperative complications with similar survival outcomes between patients undergoing minimally invasive and open radical hysterectomy.^4,5 In November 2018, two new studies were published in the New England Journal of Medicine, and another study was presented at the American Society of Clinical Oncology (ASCO) annual meeting challenging this practice paradigm. These studies reveal a higher risk of disease recurrence and decreased overall survival with minimally invasive surgery (MIS) compared with open surgery for Stages IA–IB1 cervical cancer. These findings have resulted in a change in practice nationwide.

RCT findings astonish specialty

The first study, the Laparoscopic Approach to Cervical Cancer (LACC) trial, authored by Ramirez and colleagues was a noninferiority randomized controlled trial evaluating MIS versus open radical hysterectomy for patients with cervical cancer (Stage 1A–1B1) conducted from 2008–2017.⁶ The primary outcome was disease-free survival at 4.5 years. Secondary outcomes included recurrence and overall survival rates. Power analysis suggested a sample size of 740 patients to provide greater than 80% power with a noninferiority margin of -7.2% between disease-free rates of the two groups. However, the study was closed prematurely at enrollment of 631 patients (85% recruitment) by the Data Safety Monitoring Committee due to the astounding differences in survival between the two groups.

The rate of disease-free survival at 4.5 years was 86.0% with MIS and 96% with open surgery. There were 27 recurrences (8.5%) in the MIS group and only 7 (2.2%) in the open-surgery group, accounting for a hazard ratio (HR) for disease recurrence or death from cervical cancer of 3.74 (95% confidence interval [CI], 1.63–8.58). This difference remained after adjusting for confounding variables. There were 22 deaths—19 (5.9%) in the MIS group and 3 (0.1%) in the open-surgery group (HR, 6.56). Although patient characteristics between groups appeared to be similar, more than one-third of patients in each group had missing data regarding histology at the time of surgery, grade, tumor size, lymphovascular space invasion, and depth of invasion. Interestingly, intraoperative, perioperative, and postoperative complications between the two groups were similar (with rates of 11%, about 40%, and about 25%, respectively).

Surprising findings continue in NEJM

The second study, by Melamed and colleagues, was a retrospective cohort study using data from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database evaluating women with stage IA2 or IB1 cervical cancer who underwent either minimally invasive or open radical hysterectomy between 2010 and 2013.⁷ The primary outcome was time to death.

Participant characteristics. A total of 2,461 women were included: 49.8% underwent MIS and 50.2% underwent open surgery. According to the raw data, patients undergoing MIS were more likely to be white, privately insured, reside in an area associated with higher income, undergo surgery at a nonacademic institution, have adenocarcinoma, and have smaller, lower-grade tumors. After propensity-score weighting, demographic and clinical characteristics were similar between groups. Median follow-up was 45 months.

Results. A total of 164 deaths occurred: 94 in the MIS and 70 in the open-surgery group. The risk of death during study follow-up was 9.1% in the MIS group versus 5.3% in the open-surgery group, and women who underwent MIS had shorter overall survival (P = .002; HR, 1.65; 95% CI, 1.22–2.22). Mortality rates remained higher in the MIS group after adjusting for adjuvant therapy (HR, 1.62; 95% CI, 1.2–2.19). However, the HR for death with MIS was not statistically significant in a subgroup analysis evaluating tumors 2 cm in size or less (HR, 1.46; 95% CI, 0.70–3.02). The authors demonstrated that the adoption of MIS for radical hysterectomy corresponded to a drop in the 4-year survival rate of 0.8% per year (P = .01).

Continue to: ASCO meeting data emphasize lower...

ASCO meeting data emphasize lower mortality and survival rates for MIS

A third important, but less publicized study, is a retrospective cohort study by Marguland and colleagues that was presented at the ASCO annual meeting and is pending publication. This study evaluated the 5-year survival of women with stage IB1 cervical cancer after MIS or open radical hysterectomy from 2010 to 2013.⁸ The findings demonstrated similar results to the above studies with decreased 5-year survival rates in patients with a tumor size of 2 cm or greater in the MIS group (81.3% vs 90.8; HR, 2.14; 95% CI, 1.36–3.38; P<.001). These results hold true when controlling for confounding clinical variables. Interestingly, in a subset analysis evaluating patients with tumors less than 2 cm, survival rates were similar between groups. This study confirms decreased morbidity and cost associated with MIS radical hysterectomy.

A consistent message emerges from 3 independent studies

We must take the study findings seriously and evaluate the quality of the evidence. There are many strengths to the above studies. First and most importantly, the LACC study is the only prospective randomized controlled trial (RCT) to evaluate this very important clinical question. RCTs are the gold standard for understanding the effectiveness and safety of an intervention compared with an established treatment. The study was well designed in that the study population was clearly defined with detailed inclusion and exclusion criteria. The intention to treat analysis was similar to the per-protocol analysis, and the study followed Consolidated Standards of Reporting Trials (CONSORT) guidelines. While the study was stopped early, there was still 84% power for the primary outcome. Therefore, when it comes to MIS for cervical cancer, this study provides the soundest data we have available. It is also extremely noteworthy that two additional large retrospective studies evaluating this question separately found similar results.

Criticisms remain, but older research has drawbacks

A main concern with these studies is that the findings challenge previously published research, which overall suggest similar survival outcomes between MIS and open surgical approaches. However, in evaluating the previously published retrospective data it is clear that the studies have considerable limitations.

Long-term survival not always evaluated in research. First, the majority of studies comparing MIS and open treatment modalities specifically evaluated perioperative complications and did not consider long-term survival.^4,9,10 Of those studies that did consider survival outcomes, the groups often were not balanced and were skewed toward the open surgery patients having larger tumors and higher-stage disease.⁵

Difficult to compare “apples to apples.” These findings are complicated by the fact that open radical hysterectomies were essentially replaced by MIS radical hysterectomies, and therefore, the comparisons are not equivalent since they are comparing different treatment times. For instance, throughout the time period many of these studies were conducted, the treatment paradigm for early-stage cervical cancer changed regarding who received adjuvant therapy and imaging techniques. Therefore, these studies are not comparing apples to apples.^11,12

Are we going to increase morbidity? Another common concern when considering abandoning MIS for cervical cancer is the increase in morbidity that our patients may incur immediately postoperatively due to open surgery. Multiple studies have associated minimally invasive radical hysterectomies with decreased blood loss, shorter hospital stay, lower transfusion rates, and decreased time until return of bowel function.^4,10,13

Continue to: While we recognize that...

While we recognize that open surgery is associated with increased morbidity, we do argue that, with the almost-universal implementation of Enhanced Recovery Pathways (ERP) in gynecologic oncology, the disparities between the two groups will be minimized and likely are much smaller than that reported in historical literature.¹⁴ Notably, there were no differences in peri-, intra-, or postoperative complications between the two groups in the LACC study, indicating that MIS may not be saving our patients as much morbidity as we think.

Surgical ability differences. Despite the vast strengths associated with the studies we have discussed they certainly embody limitations as well. First, surgical aptitude is difficult to evaluate and tease out. This is extremely pertinent given perioperative, and postoperative, outcomes in cervical cancer, as well as survival outcomes, in multiple surgically managed cancers, which are directly associated with the volume and proficiency of the surgeon.^15-19 Additionally, the mode of minimally invasive surgery that was most commonly utilized was different from practice in the United States. Eighty four percent of the patients in the MIS group of the LACC study underwent laparoscopic and 13.6% underwent robot-assisted radical hysterectomy. This is starkly different from US practice, where 75% of gynecologic oncologists report performing radical hysterectomies only robotically.²⁰

Take-home points

Consider this latest evidence in your surgical planning. Most importantly, the evidence is the evidence. In other words, we can attempt to explain away the findings, but despite arguments against these studies, these data are the most reliable evidence we have to date regarding outcomes for cervical cancer with MIS versus open approaches. These data demonstrate that MIS may be harming our patients and so we must take this into careful consideration during surgical planning.

For small cancers, MIS may be the best option. MIS radical hysterectomy may still be the best approach for patients with tumors less than 2 cm in size. The LACC study is not powered to evaluate oncologic outcomes in this subset of patients and the two retrospective studies suggest no difference in survival in this cohort.

We must work to understand the driving force between the disparate outcomes. Are the increased rates due to the open surgical approach, the uterine manipulator, circulating CO2 gas, or tumor exposure to the intraperitoneal cavity as the authors suggest? Or is it due to surgical expertise, tumor biology, tumor size, or mode of MIS? At this point the impelling cause is unknown.

New NCCN guidelines are to come. Up to this point the National Comprehensive Cancer Network (NCCN) guidelines stated that “radical hysterectomy procedure may be performed either via laparotomy or laparoscopy.” Given these recent studies, however, new NCCN guidelines will be released cautioning the use of the MIS approach. In short, these data have transformed the standard of care.

At our institution, the majority of radical hysterectomies will be performed open. Continued discussion remains regarding small lesions, but even in these cases most surgeons will proceed with open surgery in an attempt to maximize survival.

As providers, it is our duty to honestly reflect on published data and comprehensively counsel patients about the risks and benefits associated with each approach, including the fact that recurrence may be higher with a minimally invasive approach. Patients and providers must then collectively decide what is best for each individual case.

CASE 1 Huge out-of-pocket cost makes patient forego treatment

Ms. M. is a 28-year-old patient who recently posted this on her Facebook page: “I went to the drugstore this morning to pick up a prescription, and as the pharmacist handed it to me she said, ‘That will be $180.00.’ And that’s after insurance coverage! Wow! I think I’ll pass!”

Our patients probably experience this type of situation more commonly than we know.

CASE 2 Catastrophic medical costs bankrupt family

A middle-class couple who had college degrees and full-time jobs with health insurance had twins at 24 weeks’ gestation. They accrued $450,000 in medical debt after exceeding the $2 million cap of their insurance policy. Having premature twins cost them everything. They liquidated their retirement and savings accounts, sold everything they had, and still ended up filing for bankruptcy.¹

Costs indeed matter to patients, and we have a professional responsibility to help our patients navigate the murky waters of health care so that they can maintain financial as well as physical health.

Rising costs, lower yield,and opportunities for change

Rising health care costs are unsustainable for both our patients and our society. Although the United States spends more on health care than any other developed country, our health outcomes are actually worse—ranking at or near the bottom in both prevalence and mortality for multiple diseases, risk factors, and injuries.²

Of the 171 countries included in a study by the United Nations Maternal Mortality Estimation Inter-Agency Group, the United States was 1 of 13 countries that had an increasing maternal mortality and the only developed nation with an increasing maternal mortality rate.³ This tells us that, as our country spends more on health care, our patients’ health is not improving. For individuals, medical bills are now the leading cause of personal bankruptcy in the United States, even for those who are insured.⁴

ObGyns play an important leadership role in the practice of cost-conscious health care, as 25% of hospitalizations in the United States are pregnancy related.^5,6 In addition, the wide scope of ObGyn practice reaches beyond pregnancy-related conditions and provides multiple opportunities to decrease the use of unnecessary tests and treatments.

The good news is that approximately 30% of health care costs are wasted on unnecessary care that could be eliminated without decreasing the quality of care.⁷

High-value change #1: Eliminate use of expensive products

Embarking on a high-value care improvement project, experts at Greenville Health System examined the cost of different topical pain medications for perineal pain after a vaginal delivery. They found that Epifoam (hydrocortisone acetate/pramoxine hydrochloride) was ordered 2,287 times over the course of a year.

The study intervention consisted of an educational grand rounds and discussion of a Cochrane review, which concluded there was no difference in pain relief with topical anesthetics compared with placebo.⁸ Less expensive options for pain relief were discussed, and the department agreed to remove Epifoam as a standing order.

After the intervention, Epifoam was ordered 228 times, a 90% reduction. Over the period of a year, this translated to a cost savings of $92,655 for the hospital, with reduced charges passed on to patients.⁹ Thus, a seemingly small individual cost ($45.00 per can of Epifoam) can add up to a substantial sum in a large health care system.

Continue to: High-value change #2: Stop ordering unnecessary lab work...

High-value change #2: Stop ordering unnecessary lab work

Another high-value change to consider: Examine each laboratory test order to understand if the test results will really alter the care of a patient. Providers vary, and ordering lab tests to “make sure” can add up as financial expense.

Best practices from the American College of Obstetricians and Gynecologists (ACOG) and other professional societies can help guide decision-making as we order lab tests. Think twice, for example, about whether every evaluation for preeclampsia requires a uric acid test, since ACOG does not endorse that as part of the diagnostic criteria. While a single uric acid test costs only $8.00 to $38.00 (according to Healthcare Bluebook), testing uric acid in many patients over the course of a year can add up to significant dollars.¹¹

High-value change #3: Consider care redesign

In addition to seeking opportunities to use more cost-effective products and reduce the use of unnecessary tests, “care redesign” is an innovative way to provide high-quality care (and increased patient satisfaction) at a lower cost for both the health care system and the patient. A prime example of care redesign is using telehealth to enhance prenatal care.

Several health systems around the country are piloting and implementing remote blood pressure monitoring, app-based prenatal education, and telehealth visits to enhance prenatal care.^12,13 Use of a home blood pressure monitor can reduce in-person visits for low-risk prenatal care and open up access for other patients. Additionally, allowing the patient to participate in her own care at home or work can eliminate drives to and waits in the office and reduce absence from work because of a doctor visit.

A systematic review of more than 60,000 women showed that low-risk women who attend 5 to 9 prenatal visits have the same outcomes as women who attend the standard schedule of 13 to 15 visits.¹⁴ Although patient satisfaction was higher with more visits, when a bidirectional app or a telehealth visit is offered as an option, then patient satisfaction is equivalent to that in the standard schedule group.¹² So why not expand the choice for patients?

The challenge of teaching high-value care: Medical education responds

In a 2010 article in the New England Journal of Medicine, Dr. Molly Cooke commented on medical education’s responsibility regarding cost consciousness in patient care, and she highlighted the importance of teaching medical students and residents about considering cost in treating patients.¹⁵ Similarly, the Accreditation Council for Graduate Medical Education asks residents to consider cost and stewardship of medical resources as one of its system-based practice competencies.¹⁶ In 2012, the Choosing Wisely campaign, initiated by the American Board of Internal Medicine Foundation, asked specialty society members to identify tests or procedures commonly used in their field whose necessity should be questioned and discussed.¹⁷ ACOG and other women’s health specialty societies participate in this campaign.

From an educational standpoint, ACOG’s Council on Resident Education in Obstetrics and Gynecology has developed a curriculum resource, “Cases in High Value Care,” that can be used by any women’s health department to start the conversation on high-value care.¹⁸ The web program encourages medical students and residents to submit clinical vignettes that demonstrate examples of low- and high-value care. These cases can be used for discussion and debate and can serve as high-value care performance improvement projects in your own department.

Other useful publications are available outside the ObGyn specialty. Consider the Society of Hospital Medicine’s article series in the Journal of Hospital Medicine, “Choosing Wisely: Things We Do for No Reason”and “Choosing Wisely: Next Steps in Improving Healthcare Value.”¹⁹ The former focuses on discussing practices (tests, procedures, supplies, and prescriptions) that may be poorly supported by evidence or are part of standard practice even though other less expensive, higher-value alternatives may be available. The latter highlights perspective pieces that describe health care value initiatives relating to the practice of hospital medicine.

Continue to: The bottom line...

The bottom line

ObGyns and other health care providers are concerned about providing high-value care to patients and are working toward improving performance in this area. We really do care about the health care–related financial burdens that confront Ms. M., the premature twins’ parents, and all our patients.

CASE 1 Huge out-of-pocket cost makes patient forego treatment

Ms. M. is a 28-year-old patient who recently posted this on her Facebook page: “I went to the drugstore this morning to pick up a prescription, and as the pharmacist handed it to me she said, ‘That will be $180.00.’ And that’s after insurance coverage! Wow! I think I’ll pass!”

Our patients probably experience this type of situation more commonly than we know.

CASE 2 Catastrophic medical costs bankrupt family

A middle-class couple who had college degrees and full-time jobs with health insurance had twins at 24 weeks’ gestation. They accrued $450,000 in medical debt after exceeding the $2 million cap of their insurance policy. Having premature twins cost them everything. They liquidated their retirement and savings accounts, sold everything they had, and still ended up filing for bankruptcy.¹

Costs indeed matter to patients, and we have a professional responsibility to help our patients navigate the murky waters of health care so that they can maintain financial as well as physical health.

Rising costs, lower yield,and opportunities for change

Rising health care costs are unsustainable for both our patients and our society. Although the United States spends more on health care than any other developed country, our health outcomes are actually worse—ranking at or near the bottom in both prevalence and mortality for multiple diseases, risk factors, and injuries.²

Of the 171 countries included in a study by the United Nations Maternal Mortality Estimation Inter-Agency Group, the United States was 1 of 13 countries that had an increasing maternal mortality and the only developed nation with an increasing maternal mortality rate.³ This tells us that, as our country spends more on health care, our patients’ health is not improving. For individuals, medical bills are now the leading cause of personal bankruptcy in the United States, even for those who are insured.⁴

ObGyns play an important leadership role in the practice of cost-conscious health care, as 25% of hospitalizations in the United States are pregnancy related.^5,6 In addition, the wide scope of ObGyn practice reaches beyond pregnancy-related conditions and provides multiple opportunities to decrease the use of unnecessary tests and treatments.

The good news is that approximately 30% of health care costs are wasted on unnecessary care that could be eliminated without decreasing the quality of care.⁷

High-value change #1: Eliminate use of expensive products

Embarking on a high-value care improvement project, experts at Greenville Health System examined the cost of different topical pain medications for perineal pain after a vaginal delivery. They found that Epifoam (hydrocortisone acetate/pramoxine hydrochloride) was ordered 2,287 times over the course of a year.

The study intervention consisted of an educational grand rounds and discussion of a Cochrane review, which concluded there was no difference in pain relief with topical anesthetics compared with placebo.⁸ Less expensive options for pain relief were discussed, and the department agreed to remove Epifoam as a standing order.

After the intervention, Epifoam was ordered 228 times, a 90% reduction. Over the period of a year, this translated to a cost savings of $92,655 for the hospital, with reduced charges passed on to patients.⁹ Thus, a seemingly small individual cost ($45.00 per can of Epifoam) can add up to a substantial sum in a large health care system.

Continue to: High-value change #2: Stop ordering unnecessary lab work...

High-value change #2: Stop ordering unnecessary lab work

Another high-value change to consider: Examine each laboratory test order to understand if the test results will really alter the care of a patient. Providers vary, and ordering lab tests to “make sure” can add up as financial expense.

Best practices from the American College of Obstetricians and Gynecologists (ACOG) and other professional societies can help guide decision-making as we order lab tests. Think twice, for example, about whether every evaluation for preeclampsia requires a uric acid test, since ACOG does not endorse that as part of the diagnostic criteria. While a single uric acid test costs only $8.00 to $38.00 (according to Healthcare Bluebook), testing uric acid in many patients over the course of a year can add up to significant dollars.¹¹

High-value change #3: Consider care redesign

In addition to seeking opportunities to use more cost-effective products and reduce the use of unnecessary tests, “care redesign” is an innovative way to provide high-quality care (and increased patient satisfaction) at a lower cost for both the health care system and the patient. A prime example of care redesign is using telehealth to enhance prenatal care.

Several health systems around the country are piloting and implementing remote blood pressure monitoring, app-based prenatal education, and telehealth visits to enhance prenatal care.^12,13 Use of a home blood pressure monitor can reduce in-person visits for low-risk prenatal care and open up access for other patients. Additionally, allowing the patient to participate in her own care at home or work can eliminate drives to and waits in the office and reduce absence from work because of a doctor visit.

A systematic review of more than 60,000 women showed that low-risk women who attend 5 to 9 prenatal visits have the same outcomes as women who attend the standard schedule of 13 to 15 visits.¹⁴ Although patient satisfaction was higher with more visits, when a bidirectional app or a telehealth visit is offered as an option, then patient satisfaction is equivalent to that in the standard schedule group.¹² So why not expand the choice for patients?

The challenge of teaching high-value care: Medical education responds

In a 2010 article in the New England Journal of Medicine, Dr. Molly Cooke commented on medical education’s responsibility regarding cost consciousness in patient care, and she highlighted the importance of teaching medical students and residents about considering cost in treating patients.¹⁵ Similarly, the Accreditation Council for Graduate Medical Education asks residents to consider cost and stewardship of medical resources as one of its system-based practice competencies.¹⁶ In 2012, the Choosing Wisely campaign, initiated by the American Board of Internal Medicine Foundation, asked specialty society members to identify tests or procedures commonly used in their field whose necessity should be questioned and discussed.¹⁷ ACOG and other women’s health specialty societies participate in this campaign.

From an educational standpoint, ACOG’s Council on Resident Education in Obstetrics and Gynecology has developed a curriculum resource, “Cases in High Value Care,” that can be used by any women’s health department to start the conversation on high-value care.¹⁸ The web program encourages medical students and residents to submit clinical vignettes that demonstrate examples of low- and high-value care. These cases can be used for discussion and debate and can serve as high-value care performance improvement projects in your own department.

Other useful publications are available outside the ObGyn specialty. Consider the Society of Hospital Medicine’s article series in the Journal of Hospital Medicine, “Choosing Wisely: Things We Do for No Reason”and “Choosing Wisely: Next Steps in Improving Healthcare Value.”¹⁹ The former focuses on discussing practices (tests, procedures, supplies, and prescriptions) that may be poorly supported by evidence or are part of standard practice even though other less expensive, higher-value alternatives may be available. The latter highlights perspective pieces that describe health care value initiatives relating to the practice of hospital medicine.

Continue to: The bottom line...

The bottom line

ObGyns and other health care providers are concerned about providing high-value care to patients and are working toward improving performance in this area. We really do care about the health care–related financial burdens that confront Ms. M., the premature twins’ parents, and all our patients.

CASE 1 Huge out-of-pocket cost makes patient forego treatment

Ms. M. is a 28-year-old patient who recently posted this on her Facebook page: “I went to the drugstore this morning to pick up a prescription, and as the pharmacist handed it to me she said, ‘That will be $180.00.’ And that’s after insurance coverage! Wow! I think I’ll pass!”

Our patients probably experience this type of situation more commonly than we know.

CASE 2 Catastrophic medical costs bankrupt family

A middle-class couple who had college degrees and full-time jobs with health insurance had twins at 24 weeks’ gestation. They accrued $450,000 in medical debt after exceeding the $2 million cap of their insurance policy. Having premature twins cost them everything. They liquidated their retirement and savings accounts, sold everything they had, and still ended up filing for bankruptcy.¹

Costs indeed matter to patients, and we have a professional responsibility to help our patients navigate the murky waters of health care so that they can maintain financial as well as physical health.

Rising costs, lower yield,and opportunities for change

Rising health care costs are unsustainable for both our patients and our society. Although the United States spends more on health care than any other developed country, our health outcomes are actually worse—ranking at or near the bottom in both prevalence and mortality for multiple diseases, risk factors, and injuries.²

Of the 171 countries included in a study by the United Nations Maternal Mortality Estimation Inter-Agency Group, the United States was 1 of 13 countries that had an increasing maternal mortality and the only developed nation with an increasing maternal mortality rate.³ This tells us that, as our country spends more on health care, our patients’ health is not improving. For individuals, medical bills are now the leading cause of personal bankruptcy in the United States, even for those who are insured.⁴

ObGyns play an important leadership role in the practice of cost-conscious health care, as 25% of hospitalizations in the United States are pregnancy related.^5,6 In addition, the wide scope of ObGyn practice reaches beyond pregnancy-related conditions and provides multiple opportunities to decrease the use of unnecessary tests and treatments.

The good news is that approximately 30% of health care costs are wasted on unnecessary care that could be eliminated without decreasing the quality of care.⁷

High-value change #1: Eliminate use of expensive products

Embarking on a high-value care improvement project, experts at Greenville Health System examined the cost of different topical pain medications for perineal pain after a vaginal delivery. They found that Epifoam (hydrocortisone acetate/pramoxine hydrochloride) was ordered 2,287 times over the course of a year.

The study intervention consisted of an educational grand rounds and discussion of a Cochrane review, which concluded there was no difference in pain relief with topical anesthetics compared with placebo.⁸ Less expensive options for pain relief were discussed, and the department agreed to remove Epifoam as a standing order.

After the intervention, Epifoam was ordered 228 times, a 90% reduction. Over the period of a year, this translated to a cost savings of $92,655 for the hospital, with reduced charges passed on to patients.⁹ Thus, a seemingly small individual cost ($45.00 per can of Epifoam) can add up to a substantial sum in a large health care system.

Continue to: High-value change #2: Stop ordering unnecessary lab work...

High-value change #2: Stop ordering unnecessary lab work

Another high-value change to consider: Examine each laboratory test order to understand if the test results will really alter the care of a patient. Providers vary, and ordering lab tests to “make sure” can add up as financial expense.

Best practices from the American College of Obstetricians and Gynecologists (ACOG) and other professional societies can help guide decision-making as we order lab tests. Think twice, for example, about whether every evaluation for preeclampsia requires a uric acid test, since ACOG does not endorse that as part of the diagnostic criteria. While a single uric acid test costs only $8.00 to $38.00 (according to Healthcare Bluebook), testing uric acid in many patients over the course of a year can add up to significant dollars.¹¹

High-value change #3: Consider care redesign

In addition to seeking opportunities to use more cost-effective products and reduce the use of unnecessary tests, “care redesign” is an innovative way to provide high-quality care (and increased patient satisfaction) at a lower cost for both the health care system and the patient. A prime example of care redesign is using telehealth to enhance prenatal care.

Several health systems around the country are piloting and implementing remote blood pressure monitoring, app-based prenatal education, and telehealth visits to enhance prenatal care.^12,13 Use of a home blood pressure monitor can reduce in-person visits for low-risk prenatal care and open up access for other patients. Additionally, allowing the patient to participate in her own care at home or work can eliminate drives to and waits in the office and reduce absence from work because of a doctor visit.

A systematic review of more than 60,000 women showed that low-risk women who attend 5 to 9 prenatal visits have the same outcomes as women who attend the standard schedule of 13 to 15 visits.¹⁴ Although patient satisfaction was higher with more visits, when a bidirectional app or a telehealth visit is offered as an option, then patient satisfaction is equivalent to that in the standard schedule group.¹² So why not expand the choice for patients?

The challenge of teaching high-value care: Medical education responds

In a 2010 article in the New England Journal of Medicine, Dr. Molly Cooke commented on medical education’s responsibility regarding cost consciousness in patient care, and she highlighted the importance of teaching medical students and residents about considering cost in treating patients.¹⁵ Similarly, the Accreditation Council for Graduate Medical Education asks residents to consider cost and stewardship of medical resources as one of its system-based practice competencies.¹⁶ In 2012, the Choosing Wisely campaign, initiated by the American Board of Internal Medicine Foundation, asked specialty society members to identify tests or procedures commonly used in their field whose necessity should be questioned and discussed.¹⁷ ACOG and other women’s health specialty societies participate in this campaign.

From an educational standpoint, ACOG’s Council on Resident Education in Obstetrics and Gynecology has developed a curriculum resource, “Cases in High Value Care,” that can be used by any women’s health department to start the conversation on high-value care.¹⁸ The web program encourages medical students and residents to submit clinical vignettes that demonstrate examples of low- and high-value care. These cases can be used for discussion and debate and can serve as high-value care performance improvement projects in your own department.

Other useful publications are available outside the ObGyn specialty. Consider the Society of Hospital Medicine’s article series in the Journal of Hospital Medicine, “Choosing Wisely: Things We Do for No Reason”and “Choosing Wisely: Next Steps in Improving Healthcare Value.”¹⁹ The former focuses on discussing practices (tests, procedures, supplies, and prescriptions) that may be poorly supported by evidence or are part of standard practice even though other less expensive, higher-value alternatives may be available. The latter highlights perspective pieces that describe health care value initiatives relating to the practice of hospital medicine.

Continue to: The bottom line...

The bottom line

ObGyns and other health care providers are concerned about providing high-value care to patients and are working toward improving performance in this area. We really do care about the health care–related financial burdens that confront Ms. M., the premature twins’ parents, and all our patients.

Breast cancer survivors entering menopause face the risk of several menopausal symptoms:

• Hot flashes, the most common symptom, occur in more than 75% of women during menopause and have the potential to persist for as long as 15 years.¹ That lengthy interval becomes a major issue for patients, especially when hot flashes are associated with other menopausal symptoms, including sleep disruption, difficulty concentrating, and emotional instability (crying, irritability).

• Painful intercourse and loss of interest in sexual activity often develop as a result of vaginal atrophy and dryness.

• Urinary tract symptoms include urgency and, compared to the patient’s history, more frequent infections.
• Bone loss is a concern for many women after breast cancer, especially if they are, or have been, on aromatase inhibitor therapy.

• Depression might be related to hormonal changes due to menopause or hormonal therapies, a consequence of merely having a diagnosis of cancer, or an adverse effect of chemotherapy.

In this brief review, I’ll examine options for treating symptoms of menopause by strategy—lifestyle modifications, over-the-counter treatments, and prescription drugs. Separately, I’ll look at options for managing genitourinary syndrome of menopause (GSM).

CASE 1

Rose is a 56-year-old woman who presents to clinic with a new breast mass, felt on breast self exam. The mass is about 1 cm, mobile, and firm. Diagnostic mammogram and ultrasound confirm a worrisome mass; biopsy returns positive with a 9-mm invasive, estrogen-receptor positive, ductal carcinoma with negative sentinel nodes at the time of lumpectomy. Radiation therapy was completed. She then met with oncology and decided against chemotherapy. Instead, she began an aromatase inhibitor 3 months ago. Bone density showed osteopenia. She presents to your office reporting frequent bothersome hot flashes and disrupted sleep.

Strategy #1: Lifestyle adaptations

First-line interventions for menopausal women who have had breast cancer usually involve taking a critical look at lifestyle and undertaking modifications that can alleviate discomfort. Because overall health is important for women who have had breast cancer, you should, across the spectrum of patients, encourage them to:

• increase physical activity
• reduce body weight by approximately 10% (if overweight or obese)
• reduce alcohol consumption
• stop smoking
• ensure adequate intake of calcium (1,200 mg, preferably by diet)
• optimize the level of vitamin D, including by increasing intake of fresh fish, eggs, and numerous other fortified foods.

The value of nondrug therapy for hot flashes is difficult to prove. Certain lifestyle changes are sensible, even if not evidence-based, and will help some women (but not others). We suggest that patients try lowering the temperature in the home (65–68˚ at night); running a fan; wearing clothing that can be removed in layers; and avoiding triggers such as spicy food, alcohol, cigarettes, and hot drinks. Hypnosis and cognitive behavioral therapy (CBT) have been shown to help in clinical trials. Measures with benefit and minimal risks, but effectiveness not established, include acupuncture (sham worked as well as traditional), exercise, yoga, paced respiration, relaxation training, and mindfulness-based stress reduction.

Continue to: Strategy #2: OTC compounds...

Strategy #2: OTC compounds

Over-the-counter products—from soy products to black cohosh to flax seed, and including dong quai, evening primrose oil, maca, omegas, pollen extract, ginseng, and red clover,² or several compounds formulated in combination—have not been proven to be of more benefit for relieving symptoms of menopause than placebo in randomized trials, and thus might or might not be effective in a given patient. S-equol, a metabolite of a soy isoflavone taken by women who are non-equol producers, is available under the trade name Equelle and has shown some benefit. Note: There is concern that supplements that contain estrogen-like compounds, like soy products, might actually increase the risk of breast cancer. Dietary soy is not felt to be a concern.

Ask questions about the severity of a patient’s hot flashes. When a patient reports hot flashes, and is requesting help to relieve her discomfort, inquire 1) how often she has hot flashes, 2) how severe they are, and 3) how bothered she is by them (not all women are equally troubled, of course). The patient’s answers to these questions will help you decide which treatment option to offer, based on evidence and your experience.

CASE 1 Continued

Rose tried black cohosh OTC without improvement. She was interested in hypnosis but did not find it effective for her. She returned 3 months later stating that she is miserable, exhausted, not getting enough sleep, and her hot flashes and night sweats are affecting both her work and her relationship.

Strategy #3: Prescription medication

When addressing hot flashes, consider whether they occur more at night or during the day, or do not follow a day–night pattern. For women whose hot flashes occur mostly at night, and might therefore make sleeping difficult and cause fatigue and irritability, gabapentin, taken approximately 1 hour before bed, can be helpful. If tolerated without excessive somnolence the next day, the dose can be increased at night or additional doses provided during the day depending on hot flash response. For women who have hot flashes day and night, we often prescribe a low-dose antidepressant from the selective serotonin-reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) class.

When prescribing an antidepressant, we make a distinction between breast cancer patients who are taking tamoxifen and those who are not, to avoid cytochrome P450 2D6 inhibitors in women taking tamoxifen.³ Better choices for women taking tamoxifen include desvenlafaxine, venlafaxine, escitalopram, or gabapentin or pregabalin.

For women with breast cancer who are taking an aromatase inhibitor, and who are also experiencing mood changes with their hot flashes, we often choose a trial of a low-dose antidepressant, either an SSRI or SNRI. One drug is approved by the US Food and Drug Administration (FDA) for the treatment of hot flashes (but not for mood disorder). This is low-dose salt of paroxetine, 7.5 mg/d, which has the advantage of exerting no adverse effect on libido or weight (but is sometimes difficult to obtain because it is a branded product that might not be covered, or not covered fully, by a given patient’s insurance plan). Other antidepressants can be used in doses lower than needed for depression, with more rapid onset of effect on hot flashes, often within 2 weeks.

Last, transdermal clonidine, an antihypertensive, also has been found to relieve hot flashes.

Continue to: Not a recommended strategy: Systemic hormone therapy

Not a recommended strategy: Systemic hormone therapy

Although hormone therapy is, in general, the gold standard for alleviating hot flashes, it is contraindicated in most women with breast cancer.⁴ At our institution, we avoid systemic hormone therapy for hot flashes in almost all breast cancer patients.

CASE 2

Sarah first presented with hot flashes that improved while taking escitalopram 10 mg. Her night sweats persisted, however. Gabapentin 300 mg was added to take nightly. With this regimen, she finally felt that she was coping better. Six months later, she reported that she and her long-term partner had not been able to resume vaginal intercourse post–breast cancer treatment because of pain.

The challenge of managing GSM

What if your patient says, “Doctor, I’m really doing OK with my hot flashes, but sex has become painful. I don’t have any interest. I have vaginal dryness, and it’s affecting my quality of life”?

Studies have shown that GSM affects up to 50% of women, and even more than that among women who have had breast cancer.⁵ The condition interferes with sexual intimacy, disrupts quality of life, and can sour a partnership—significant quality-of-life concerns for breast cancer survivors.

For mild symptoms, encourage patients to apply a lubricant just before intercourse or a vaginal moisturizer twice weekly; moisturizers improve vaginal pH, too. These treatments do not fix the problem of a lack of superficial cells due to estrogen loss, however; to accomplish that, consider prescribing low-dose vaginal estrogen therapy or intravaginal dehydroepiandrosterone (DHEA). This strategy is felt to be safe for many breast cancer survivors, as systemic absorption of estrogen is minimal if dosed low, keeping levels in the postmenopausal range.

The American College of Obstetricians and Gynecologists (ACOG), the North American Menopause Society (NAMS), and the Endocrine Society agree that vaginal estrogen therapy may be a good option for many women with breast cancer for whom moisturizers and lubricants are inadequate.⁶ Delivery options include vaginal creams, tablets, suppositories used 2 or 3 times per week, or the low-dose vaginal estrogen ring, replaced every 3 months. We are concerned about using vaginal estrogen in women who have had aromatase inhibitor (AI) therapy; their estrogen levels are so low that absorbing even a small amount might make a difference in terms of effectiveness of AI. For women who need more than lubricants or vaginal moisturizers, particularly those taking anti-estrogen therapy (aromatase therapy), the use of low-dose vaginal hormones may be considered on an individual basis, but should include the oncologist in decision making.^1,3

Beyond low-dose vaginal estrogen therapies, there are additional options that can be considered but with less supporting data for treating GSM in women with breast cancer.

Oral ospemifene, a selective estrogen-receptor modulator (SERM; Osphena), might be neutral or even protective in its effect on the breast, as demonstrated in preclinical trials.⁷ In human trials, the drug is approved only for painful intercourse, not for loss of libido, and has not been tested in breast cancer patients.

Intravaginal DHEA (Prasterone), has been on the market for almost 1 year. The drug is approved for treating painful intercourse, but it also reverses vaginal atrophy and alleviates urinary symptoms. Because DHEA is a prohormone, it is converted to estrogen and androgen in the vagina. Again, absorption appears minimal. Intravaginal DHEA does not have the US Food and Drug Administration (FDA) black-box warning that vaginal estrogen products do, but it is accompanied by a warning that it has not been tested in women with breast cancer.

Tissue selective estrogen receptor modulator is a conjugated estrogen combined with a third-generation SERM bazedoxifene, which treats hot flashes and reverses vaginal atrophy. This new systemic agent is probably neutral on the breast (at least that is the finding in clinical trials at 2 years⁸); again, however, it has not been tested in patients with breast cancer.

Continue to: Nonhormone therapies...

Nonhormone therapies

Topical lidocaine for insertional dyspareunia has been studied in postmenopausal women with breast cancer with severe GSM, dyspareunia, increased sexual distress scores, or abnormal sexual function with improvement seen using 4% aqueous lidocaine versus saline applied with a cotton ball to the vestibule for 3 minutes before vaginal penetration.⁹

Vaginal laser therapy has the potential to ameliorate distressing GSM without the need for local hormone intervention; however, placebo or active-controlled trials and long-term safety follow-up are needed.⁵

Treatment begins with a conversation

Most importantly, we need to listen to our patients in discomfort because of their menopausal symptoms. Consider proceeding along these lines: “You’ve been treated for breast cancer; now, let’s look at the medical issues that are affecting your quality of life. Are you depressed? Are you having hot flashes? Are you getting enough sleep? Have you stopped having sex or not restarted after your breast cancer treatment? Are you having painful sex or avoiding sex due to fear of pain? Let’s discuss options and work with your oncologist to try to relieve your symptoms and make your life better.”

First-line therapy for the treatment of menopausal symptoms in women with a history of breast cancer should start with lifestyle changes and nonhormone therapies. For GSM, lubricants and vaginal moisturizers should be tried first and may be effective. Reassure patients that there are many treatment options, even though not all of them have been well-tested in breast cancer patients, and that new modalities are under investigation and review (see “Newly arrived and on the horizon,”). Become familiar with published data on the safety and effectiveness of the range of available treatments; guide patients through the process of finding what works best for them; and invite their oncologist into the therapeutic partnership. If you do not feel comfortable with these issues in women who are breast cancer survivors, find a menopause specialist to help, available by zip code at Find a Provider, http://www.menopause.org.

Breast cancer survivors entering menopause face the risk of several menopausal symptoms:

• Hot flashes, the most common symptom, occur in more than 75% of women during menopause and have the potential to persist for as long as 15 years.¹ That lengthy interval becomes a major issue for patients, especially when hot flashes are associated with other menopausal symptoms, including sleep disruption, difficulty concentrating, and emotional instability (crying, irritability).

• Painful intercourse and loss of interest in sexual activity often develop as a result of vaginal atrophy and dryness.

• Urinary tract symptoms include urgency and, compared to the patient’s history, more frequent infections.
• Bone loss is a concern for many women after breast cancer, especially if they are, or have been, on aromatase inhibitor therapy.

• Depression might be related to hormonal changes due to menopause or hormonal therapies, a consequence of merely having a diagnosis of cancer, or an adverse effect of chemotherapy.

In this brief review, I’ll examine options for treating symptoms of menopause by strategy—lifestyle modifications, over-the-counter treatments, and prescription drugs. Separately, I’ll look at options for managing genitourinary syndrome of menopause (GSM).

CASE 1

Rose is a 56-year-old woman who presents to clinic with a new breast mass, felt on breast self exam. The mass is about 1 cm, mobile, and firm. Diagnostic mammogram and ultrasound confirm a worrisome mass; biopsy returns positive with a 9-mm invasive, estrogen-receptor positive, ductal carcinoma with negative sentinel nodes at the time of lumpectomy. Radiation therapy was completed. She then met with oncology and decided against chemotherapy. Instead, she began an aromatase inhibitor 3 months ago. Bone density showed osteopenia. She presents to your office reporting frequent bothersome hot flashes and disrupted sleep.

Strategy #1: Lifestyle adaptations

First-line interventions for menopausal women who have had breast cancer usually involve taking a critical look at lifestyle and undertaking modifications that can alleviate discomfort. Because overall health is important for women who have had breast cancer, you should, across the spectrum of patients, encourage them to:

• increase physical activity
• reduce body weight by approximately 10% (if overweight or obese)
• reduce alcohol consumption
• stop smoking
• ensure adequate intake of calcium (1,200 mg, preferably by diet)
• optimize the level of vitamin D, including by increasing intake of fresh fish, eggs, and numerous other fortified foods.

The value of nondrug therapy for hot flashes is difficult to prove. Certain lifestyle changes are sensible, even if not evidence-based, and will help some women (but not others). We suggest that patients try lowering the temperature in the home (65–68˚ at night); running a fan; wearing clothing that can be removed in layers; and avoiding triggers such as spicy food, alcohol, cigarettes, and hot drinks. Hypnosis and cognitive behavioral therapy (CBT) have been shown to help in clinical trials. Measures with benefit and minimal risks, but effectiveness not established, include acupuncture (sham worked as well as traditional), exercise, yoga, paced respiration, relaxation training, and mindfulness-based stress reduction.

Continue to: Strategy #2: OTC compounds...

Strategy #2: OTC compounds

Over-the-counter products—from soy products to black cohosh to flax seed, and including dong quai, evening primrose oil, maca, omegas, pollen extract, ginseng, and red clover,² or several compounds formulated in combination—have not been proven to be of more benefit for relieving symptoms of menopause than placebo in randomized trials, and thus might or might not be effective in a given patient. S-equol, a metabolite of a soy isoflavone taken by women who are non-equol producers, is available under the trade name Equelle and has shown some benefit. Note: There is concern that supplements that contain estrogen-like compounds, like soy products, might actually increase the risk of breast cancer. Dietary soy is not felt to be a concern.

Ask questions about the severity of a patient’s hot flashes. When a patient reports hot flashes, and is requesting help to relieve her discomfort, inquire 1) how often she has hot flashes, 2) how severe they are, and 3) how bothered she is by them (not all women are equally troubled, of course). The patient’s answers to these questions will help you decide which treatment option to offer, based on evidence and your experience.

CASE 1 Continued

Rose tried black cohosh OTC without improvement. She was interested in hypnosis but did not find it effective for her. She returned 3 months later stating that she is miserable, exhausted, not getting enough sleep, and her hot flashes and night sweats are affecting both her work and her relationship.

Strategy #3: Prescription medication

When addressing hot flashes, consider whether they occur more at night or during the day, or do not follow a day–night pattern. For women whose hot flashes occur mostly at night, and might therefore make sleeping difficult and cause fatigue and irritability, gabapentin, taken approximately 1 hour before bed, can be helpful. If tolerated without excessive somnolence the next day, the dose can be increased at night or additional doses provided during the day depending on hot flash response. For women who have hot flashes day and night, we often prescribe a low-dose antidepressant from the selective serotonin-reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) class.

When prescribing an antidepressant, we make a distinction between breast cancer patients who are taking tamoxifen and those who are not, to avoid cytochrome P450 2D6 inhibitors in women taking tamoxifen.³ Better choices for women taking tamoxifen include desvenlafaxine, venlafaxine, escitalopram, or gabapentin or pregabalin.

For women with breast cancer who are taking an aromatase inhibitor, and who are also experiencing mood changes with their hot flashes, we often choose a trial of a low-dose antidepressant, either an SSRI or SNRI. One drug is approved by the US Food and Drug Administration (FDA) for the treatment of hot flashes (but not for mood disorder). This is low-dose salt of paroxetine, 7.5 mg/d, which has the advantage of exerting no adverse effect on libido or weight (but is sometimes difficult to obtain because it is a branded product that might not be covered, or not covered fully, by a given patient’s insurance plan). Other antidepressants can be used in doses lower than needed for depression, with more rapid onset of effect on hot flashes, often within 2 weeks.

Last, transdermal clonidine, an antihypertensive, also has been found to relieve hot flashes.

Continue to: Not a recommended strategy: Systemic hormone therapy

Not a recommended strategy: Systemic hormone therapy

Although hormone therapy is, in general, the gold standard for alleviating hot flashes, it is contraindicated in most women with breast cancer.⁴ At our institution, we avoid systemic hormone therapy for hot flashes in almost all breast cancer patients.

CASE 2

Sarah first presented with hot flashes that improved while taking escitalopram 10 mg. Her night sweats persisted, however. Gabapentin 300 mg was added to take nightly. With this regimen, she finally felt that she was coping better. Six months later, she reported that she and her long-term partner had not been able to resume vaginal intercourse post–breast cancer treatment because of pain.

The challenge of managing GSM

What if your patient says, “Doctor, I’m really doing OK with my hot flashes, but sex has become painful. I don’t have any interest. I have vaginal dryness, and it’s affecting my quality of life”?

Studies have shown that GSM affects up to 50% of women, and even more than that among women who have had breast cancer.⁵ The condition interferes with sexual intimacy, disrupts quality of life, and can sour a partnership—significant quality-of-life concerns for breast cancer survivors.

For mild symptoms, encourage patients to apply a lubricant just before intercourse or a vaginal moisturizer twice weekly; moisturizers improve vaginal pH, too. These treatments do not fix the problem of a lack of superficial cells due to estrogen loss, however; to accomplish that, consider prescribing low-dose vaginal estrogen therapy or intravaginal dehydroepiandrosterone (DHEA). This strategy is felt to be safe for many breast cancer survivors, as systemic absorption of estrogen is minimal if dosed low, keeping levels in the postmenopausal range.

The American College of Obstetricians and Gynecologists (ACOG), the North American Menopause Society (NAMS), and the Endocrine Society agree that vaginal estrogen therapy may be a good option for many women with breast cancer for whom moisturizers and lubricants are inadequate.⁶ Delivery options include vaginal creams, tablets, suppositories used 2 or 3 times per week, or the low-dose vaginal estrogen ring, replaced every 3 months. We are concerned about using vaginal estrogen in women who have had aromatase inhibitor (AI) therapy; their estrogen levels are so low that absorbing even a small amount might make a difference in terms of effectiveness of AI. For women who need more than lubricants or vaginal moisturizers, particularly those taking anti-estrogen therapy (aromatase therapy), the use of low-dose vaginal hormones may be considered on an individual basis, but should include the oncologist in decision making.^1,3

Beyond low-dose vaginal estrogen therapies, there are additional options that can be considered but with less supporting data for treating GSM in women with breast cancer.

Oral ospemifene, a selective estrogen-receptor modulator (SERM; Osphena), might be neutral or even protective in its effect on the breast, as demonstrated in preclinical trials.⁷ In human trials, the drug is approved only for painful intercourse, not for loss of libido, and has not been tested in breast cancer patients.

Intravaginal DHEA (Prasterone), has been on the market for almost 1 year. The drug is approved for treating painful intercourse, but it also reverses vaginal atrophy and alleviates urinary symptoms. Because DHEA is a prohormone, it is converted to estrogen and androgen in the vagina. Again, absorption appears minimal. Intravaginal DHEA does not have the US Food and Drug Administration (FDA) black-box warning that vaginal estrogen products do, but it is accompanied by a warning that it has not been tested in women with breast cancer.

Tissue selective estrogen receptor modulator is a conjugated estrogen combined with a third-generation SERM bazedoxifene, which treats hot flashes and reverses vaginal atrophy. This new systemic agent is probably neutral on the breast (at least that is the finding in clinical trials at 2 years⁸); again, however, it has not been tested in patients with breast cancer.

Continue to: Nonhormone therapies...

Nonhormone therapies

Topical lidocaine for insertional dyspareunia has been studied in postmenopausal women with breast cancer with severe GSM, dyspareunia, increased sexual distress scores, or abnormal sexual function with improvement seen using 4% aqueous lidocaine versus saline applied with a cotton ball to the vestibule for 3 minutes before vaginal penetration.⁹

Vaginal laser therapy has the potential to ameliorate distressing GSM without the need for local hormone intervention; however, placebo or active-controlled trials and long-term safety follow-up are needed.⁵

Treatment begins with a conversation

Most importantly, we need to listen to our patients in discomfort because of their menopausal symptoms. Consider proceeding along these lines: “You’ve been treated for breast cancer; now, let’s look at the medical issues that are affecting your quality of life. Are you depressed? Are you having hot flashes? Are you getting enough sleep? Have you stopped having sex or not restarted after your breast cancer treatment? Are you having painful sex or avoiding sex due to fear of pain? Let’s discuss options and work with your oncologist to try to relieve your symptoms and make your life better.”

First-line therapy for the treatment of menopausal symptoms in women with a history of breast cancer should start with lifestyle changes and nonhormone therapies. For GSM, lubricants and vaginal moisturizers should be tried first and may be effective. Reassure patients that there are many treatment options, even though not all of them have been well-tested in breast cancer patients, and that new modalities are under investigation and review (see “Newly arrived and on the horizon,”). Become familiar with published data on the safety and effectiveness of the range of available treatments; guide patients through the process of finding what works best for them; and invite their oncologist into the therapeutic partnership. If you do not feel comfortable with these issues in women who are breast cancer survivors, find a menopause specialist to help, available by zip code at Find a Provider, http://www.menopause.org.

Breast cancer survivors entering menopause face the risk of several menopausal symptoms:

• Hot flashes, the most common symptom, occur in more than 75% of women during menopause and have the potential to persist for as long as 15 years.¹ That lengthy interval becomes a major issue for patients, especially when hot flashes are associated with other menopausal symptoms, including sleep disruption, difficulty concentrating, and emotional instability (crying, irritability).

• Painful intercourse and loss of interest in sexual activity often develop as a result of vaginal atrophy and dryness.

• Urinary tract symptoms include urgency and, compared to the patient’s history, more frequent infections.
• Bone loss is a concern for many women after breast cancer, especially if they are, or have been, on aromatase inhibitor therapy.

• Depression might be related to hormonal changes due to menopause or hormonal therapies, a consequence of merely having a diagnosis of cancer, or an adverse effect of chemotherapy.

In this brief review, I’ll examine options for treating symptoms of menopause by strategy—lifestyle modifications, over-the-counter treatments, and prescription drugs. Separately, I’ll look at options for managing genitourinary syndrome of menopause (GSM).

CASE 1

Rose is a 56-year-old woman who presents to clinic with a new breast mass, felt on breast self exam. The mass is about 1 cm, mobile, and firm. Diagnostic mammogram and ultrasound confirm a worrisome mass; biopsy returns positive with a 9-mm invasive, estrogen-receptor positive, ductal carcinoma with negative sentinel nodes at the time of lumpectomy. Radiation therapy was completed. She then met with oncology and decided against chemotherapy. Instead, she began an aromatase inhibitor 3 months ago. Bone density showed osteopenia. She presents to your office reporting frequent bothersome hot flashes and disrupted sleep.

Strategy #1: Lifestyle adaptations

First-line interventions for menopausal women who have had breast cancer usually involve taking a critical look at lifestyle and undertaking modifications that can alleviate discomfort. Because overall health is important for women who have had breast cancer, you should, across the spectrum of patients, encourage them to:

• increase physical activity
• reduce body weight by approximately 10% (if overweight or obese)
• reduce alcohol consumption
• stop smoking
• ensure adequate intake of calcium (1,200 mg, preferably by diet)
• optimize the level of vitamin D, including by increasing intake of fresh fish, eggs, and numerous other fortified foods.

The value of nondrug therapy for hot flashes is difficult to prove. Certain lifestyle changes are sensible, even if not evidence-based, and will help some women (but not others). We suggest that patients try lowering the temperature in the home (65–68˚ at night); running a fan; wearing clothing that can be removed in layers; and avoiding triggers such as spicy food, alcohol, cigarettes, and hot drinks. Hypnosis and cognitive behavioral therapy (CBT) have been shown to help in clinical trials. Measures with benefit and minimal risks, but effectiveness not established, include acupuncture (sham worked as well as traditional), exercise, yoga, paced respiration, relaxation training, and mindfulness-based stress reduction.

Continue to: Strategy #2: OTC compounds...

Strategy #2: OTC compounds

Over-the-counter products—from soy products to black cohosh to flax seed, and including dong quai, evening primrose oil, maca, omegas, pollen extract, ginseng, and red clover,² or several compounds formulated in combination—have not been proven to be of more benefit for relieving symptoms of menopause than placebo in randomized trials, and thus might or might not be effective in a given patient. S-equol, a metabolite of a soy isoflavone taken by women who are non-equol producers, is available under the trade name Equelle and has shown some benefit. Note: There is concern that supplements that contain estrogen-like compounds, like soy products, might actually increase the risk of breast cancer. Dietary soy is not felt to be a concern.

Ask questions about the severity of a patient’s hot flashes. When a patient reports hot flashes, and is requesting help to relieve her discomfort, inquire 1) how often she has hot flashes, 2) how severe they are, and 3) how bothered she is by them (not all women are equally troubled, of course). The patient’s answers to these questions will help you decide which treatment option to offer, based on evidence and your experience.

CASE 1 Continued

Rose tried black cohosh OTC without improvement. She was interested in hypnosis but did not find it effective for her. She returned 3 months later stating that she is miserable, exhausted, not getting enough sleep, and her hot flashes and night sweats are affecting both her work and her relationship.

Strategy #3: Prescription medication

When addressing hot flashes, consider whether they occur more at night or during the day, or do not follow a day–night pattern. For women whose hot flashes occur mostly at night, and might therefore make sleeping difficult and cause fatigue and irritability, gabapentin, taken approximately 1 hour before bed, can be helpful. If tolerated without excessive somnolence the next day, the dose can be increased at night or additional doses provided during the day depending on hot flash response. For women who have hot flashes day and night, we often prescribe a low-dose antidepressant from the selective serotonin-reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) class.

When prescribing an antidepressant, we make a distinction between breast cancer patients who are taking tamoxifen and those who are not, to avoid cytochrome P450 2D6 inhibitors in women taking tamoxifen.³ Better choices for women taking tamoxifen include desvenlafaxine, venlafaxine, escitalopram, or gabapentin or pregabalin.

For women with breast cancer who are taking an aromatase inhibitor, and who are also experiencing mood changes with their hot flashes, we often choose a trial of a low-dose antidepressant, either an SSRI or SNRI. One drug is approved by the US Food and Drug Administration (FDA) for the treatment of hot flashes (but not for mood disorder). This is low-dose salt of paroxetine, 7.5 mg/d, which has the advantage of exerting no adverse effect on libido or weight (but is sometimes difficult to obtain because it is a branded product that might not be covered, or not covered fully, by a given patient’s insurance plan). Other antidepressants can be used in doses lower than needed for depression, with more rapid onset of effect on hot flashes, often within 2 weeks.

Last, transdermal clonidine, an antihypertensive, also has been found to relieve hot flashes.

Continue to: Not a recommended strategy: Systemic hormone therapy

Not a recommended strategy: Systemic hormone therapy

Although hormone therapy is, in general, the gold standard for alleviating hot flashes, it is contraindicated in most women with breast cancer.⁴ At our institution, we avoid systemic hormone therapy for hot flashes in almost all breast cancer patients.

CASE 2

Sarah first presented with hot flashes that improved while taking escitalopram 10 mg. Her night sweats persisted, however. Gabapentin 300 mg was added to take nightly. With this regimen, she finally felt that she was coping better. Six months later, she reported that she and her long-term partner had not been able to resume vaginal intercourse post–breast cancer treatment because of pain.

The challenge of managing GSM

What if your patient says, “Doctor, I’m really doing OK with my hot flashes, but sex has become painful. I don’t have any interest. I have vaginal dryness, and it’s affecting my quality of life”?

Studies have shown that GSM affects up to 50% of women, and even more than that among women who have had breast cancer.⁵ The condition interferes with sexual intimacy, disrupts quality of life, and can sour a partnership—significant quality-of-life concerns for breast cancer survivors.

For mild symptoms, encourage patients to apply a lubricant just before intercourse or a vaginal moisturizer twice weekly; moisturizers improve vaginal pH, too. These treatments do not fix the problem of a lack of superficial cells due to estrogen loss, however; to accomplish that, consider prescribing low-dose vaginal estrogen therapy or intravaginal dehydroepiandrosterone (DHEA). This strategy is felt to be safe for many breast cancer survivors, as systemic absorption of estrogen is minimal if dosed low, keeping levels in the postmenopausal range.

The American College of Obstetricians and Gynecologists (ACOG), the North American Menopause Society (NAMS), and the Endocrine Society agree that vaginal estrogen therapy may be a good option for many women with breast cancer for whom moisturizers and lubricants are inadequate.⁶ Delivery options include vaginal creams, tablets, suppositories used 2 or 3 times per week, or the low-dose vaginal estrogen ring, replaced every 3 months. We are concerned about using vaginal estrogen in women who have had aromatase inhibitor (AI) therapy; their estrogen levels are so low that absorbing even a small amount might make a difference in terms of effectiveness of AI. For women who need more than lubricants or vaginal moisturizers, particularly those taking anti-estrogen therapy (aromatase therapy), the use of low-dose vaginal hormones may be considered on an individual basis, but should include the oncologist in decision making.^1,3

Beyond low-dose vaginal estrogen therapies, there are additional options that can be considered but with less supporting data for treating GSM in women with breast cancer.

Oral ospemifene, a selective estrogen-receptor modulator (SERM; Osphena), might be neutral or even protective in its effect on the breast, as demonstrated in preclinical trials.⁷ In human trials, the drug is approved only for painful intercourse, not for loss of libido, and has not been tested in breast cancer patients.

Intravaginal DHEA (Prasterone), has been on the market for almost 1 year. The drug is approved for treating painful intercourse, but it also reverses vaginal atrophy and alleviates urinary symptoms. Because DHEA is a prohormone, it is converted to estrogen and androgen in the vagina. Again, absorption appears minimal. Intravaginal DHEA does not have the US Food and Drug Administration (FDA) black-box warning that vaginal estrogen products do, but it is accompanied by a warning that it has not been tested in women with breast cancer.

Tissue selective estrogen receptor modulator is a conjugated estrogen combined with a third-generation SERM bazedoxifene, which treats hot flashes and reverses vaginal atrophy. This new systemic agent is probably neutral on the breast (at least that is the finding in clinical trials at 2 years⁸); again, however, it has not been tested in patients with breast cancer.

Continue to: Nonhormone therapies...

Nonhormone therapies

Topical lidocaine for insertional dyspareunia has been studied in postmenopausal women with breast cancer with severe GSM, dyspareunia, increased sexual distress scores, or abnormal sexual function with improvement seen using 4% aqueous lidocaine versus saline applied with a cotton ball to the vestibule for 3 minutes before vaginal penetration.⁹

Vaginal laser therapy has the potential to ameliorate distressing GSM without the need for local hormone intervention; however, placebo or active-controlled trials and long-term safety follow-up are needed.⁵

Treatment begins with a conversation

Most importantly, we need to listen to our patients in discomfort because of their menopausal symptoms. Consider proceeding along these lines: “You’ve been treated for breast cancer; now, let’s look at the medical issues that are affecting your quality of life. Are you depressed? Are you having hot flashes? Are you getting enough sleep? Have you stopped having sex or not restarted after your breast cancer treatment? Are you having painful sex or avoiding sex due to fear of pain? Let’s discuss options and work with your oncologist to try to relieve your symptoms and make your life better.”

First-line therapy for the treatment of menopausal symptoms in women with a history of breast cancer should start with lifestyle changes and nonhormone therapies. For GSM, lubricants and vaginal moisturizers should be tried first and may be effective. Reassure patients that there are many treatment options, even though not all of them have been well-tested in breast cancer patients, and that new modalities are under investigation and review (see “Newly arrived and on the horizon,”). Become familiar with published data on the safety and effectiveness of the range of available treatments; guide patients through the process of finding what works best for them; and invite their oncologist into the therapeutic partnership. If you do not feel comfortable with these issues in women who are breast cancer survivors, find a menopause specialist to help, available by zip code at Find a Provider, http://www.menopause.org.

The US Food and Drug Administration (FDA) recently extended the approval for Gardasil 9 (to prevent HPV-associated cancers, cancer precursors, and genital lesions) to men and women aged 27 to 45.¹ In this editorial, we discuss the evolution of the HPV vaccine since its initial approval more than 10 years ago, the benefits of primary prevention with the HPV vaccine, and the case for the FDA’s recent extension of coverage to older men and women.

The evolution of the HPV vaccine

Since recognition in the 1980s and 90s that high-risk strains of HPV, notably HPV types 16 and 18, were linked to cervical cancer, there have been exciting advances in detection and prevention of high-risk HPV infection. About 70% of cervical cancers are attributable to these 2 oncogenic types.² The first vaccine licensed, Gardasil (Merck), was approved in 2006 for girls and women aged 9 through 26 to prevent HPV-related diseases caused by types 6, 11, 16, and 18.³ The vaccine was effective for prevention of cervical cancer; genital warts; and grades 2 and 3 of cervical, vulvar, and vaginal intraepithelial neoplasia. In 2008, prevention of vulvar and vaginal cancers was added to the indication. By 2009, prevention of genital warts was added, and use in males aged 9 to 15 was approved. By 2010 sufficient data were accumulated to document prevention of anal cancer and anal intraepithelial neoplasia in men and women, and this indication was added.

In 2014 Gardasil 9 was approved to extend coverage to an additional 5 oncogenic HPV types (31, 33, 45, 52, and 58), now covering an additional 20% of cervical cancers, and in 2015 Gardasil 9 indications were expanded to include boys and men 9 to 26 years of age. Immunogenicity studies were performed to infer effectiveness of a 2-dose regimen in boys and girls aged 9 to 14 years, which was recommended by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) in late 2016.⁴

Until October 2018, Gardasil 9 was indicated for prevention of genital warts, cervical, vaginal, vulvar and anal cancers and cancer precursors for males and females aged 9 to 26 years. In October the FDA extended approval of the 3-dose vaccine regimen to men and women up to age 45.

HPV vaccine uptake

HPV vaccination has been underutilized in the United States. In 2017, a disappointing 49% of adolescents were up to date on vaccination, and 66% had received at least one dose.⁵ In rural areas the vaccination rates are 11 points lower than in urban regions.⁶ The CDC notes an increasing number of HPV-associated cancers—from 30,000 per year in 1999 to 43,000 per year in 2015—due mostly to increases in oral and anal carcinomas. Vaccination with Gardasil 9 could prevent 90% of those cases.⁷

Non-US successes. HPV vaccine uptake in Australia provides an excellent opportunity to study the impact of universally available, school-based vaccinations. In 2007 Australia implemented a program of free HPV vaccination distributed through schools. Boys and girls aged 12 and 13 were targeted that year, with catch-up vaccinations for those aged 13 to 18 in 2007-2009 in schools and for those aged 18 to 26 reached in the community.⁸ 

Continue to: Ali and colleagues studied the... 

Ali and colleagues studied the preprogram and postprogram incidence of genital warts.⁹ About 83% received at least 1 dose of vaccine, and 73% of the eligible population completed the 3-dose regimen. There was a significant reduction in warts in both men and women younger than age 21 from 2007 to 2011 (12.1% to 2.2% in men and 11.5% to 0.85% in women). In the 21 to 30 age group there were similar reductions. This study demonstrates that with universal access and public implementation, the rates of HPV-associated disease can be reduced dramatically.

Data informing expanded vaccination ages

Will vaccination of an older population, with presumably many of whom sexually active and at risk for prior exposure to multiple HPV types, have a reasonable impact on lowering HPV-associated cancers? Are HPV-detected lesions in 27- to 45-year-old women the result of reactivation of latent HPV infection, or are they related to new-onset exposure? The FDA reviewed data from 3 studies of HPV vaccination in women aged 27 to 45. The first enrolled women who were naïve to oncogenic HPV types and provided all 3 doses of quadrivalent vaccine were followed for 4 years, along with a comparison group of nonvaccinated women. The second study allowed the nonvaccinated group to receive vaccine in year 4. Both groups were followed up to 10 years with the relevant outcome defined as cumulative incidence of HPV 6/11/16/18-related CIN and condyloma. The third study looked at the same outcomes in a set of all women—whether HPV high-risk naïve or not—after receiving vaccine and followed more than 10 years.⁷ This last study is most relevant to ObGyns, as it is closest to how we would consider vaccinating our patients.

The study findings are reassuring: A large proportion of HPV infections in women between 27 and 45 are the result of new exposure/infection. A study of 420 online daters aged 25 to 65 showed an annual incidence of high-risk HPV types in vaginal swabs of 25.4%, of which 64% were likely new acquisitions.¹⁰ The 2013-2014 National Health and Nutrition Examination Survey of 1,757 men aged 18 to 59 estimated approximately 45% had genital HPV infection. There was a bimodal distribution of disease with peaks at 28 to 32 and a larger second peak at 58 to 59 years of age.¹¹ Bottom line: Men and women older than age 26 who are sexually active likely acquire new HPV infections with oncogenic types. Exposure to high-risk HPV types prior to vaccination—as we would expect in the real-world setting—did not eliminate the substantial benefit of immunization.

Based on these study results, and extrapolation to the 9-valent vaccine, the FDA extended the approval of Gardasil 9 to men and women from age 9 to 45. The indications and usage will remain the same: for prevention of cervical, vulvar, vaginal, and anal cancer and genital warts as well as precancerous or dysplastic lesions of the cervix, vulva, vagina, and anus related to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

Continue to: Impact of the new... 

Impact of the new indication on HPV-related disease

As described above, widespread vaccination of young girls and boys is going to have major impact on HPV-related disease, including precancer and cancer. Because there is evidence that older women and men are at risk for new HPV infection,¹⁰ there likely will be some benefit from vaccination of adults. It is difficult, however, to extrapolate the degree to which adult vaccination will impact HPV-related disease. This is because we do not fully understand the rates at which new HPV infection in the cervices of older women will progress to high-grade dysplasia or cancer. Further, the pathophysiology of HPV-related cancers at other anogenital sites and new oral-pharyngeal infection is poorly understood in comparison with our knowledge of the natural history of high-risk HPV infection in younger women. That said, because of the outstanding efficacy of HPV vaccination and the low-risk profile, even if the actual impact on prevention of cancer or morbidity from dysplasia is relatively low, adult vaccination benefits outweigh the limited risks.

It may be that increased vaccination and awareness of vaccination for adults may enhance the adherence and acceptance of widespread vaccination of boys and girls. Adult vaccination could create a cultural shift toward HPV vaccination acceptance when adult parents and loved ones of vaccine-age boys and girls have been vaccinated themselves.

Current and future insurance coverage

The Affordable Care Act, otherwise known as Obamacare, mandates coverage for all immunizations recommended by the ACIP. HPV vaccination up to age 26 is fully covered, without copay or deductible. The ACIP did consider extension of the indications for HPV vaccination to men and women up to age 45 at their October 2018 meeting. They are tasked with considering not only safety and efficacy but also the cost effectiveness of implementing vaccination. They continue to study the costs and potential benefits of extending HPV vaccination to age 45. Their recommendations may be determined at the February 2019 meeting—or even later in 2019. The American College of Obstetricians and Gynecologists (ACOG) relies upon ACIP for practice guidance. Once the ACIP has made a determination, and if new guidelines are published in the Morbidity and Mortality Weekly Report, insurance coverage and ACOG guidance will be updated.

How should we react and change practice based on this new indication?

Given the information reviewed by the FDA, ObGyns will want to discuss the availability of Gardasil 9 with our patients between ages 27 and 45 who have not been previously immunized.

Especially for our patients with exposure to multiple or new sexual partners, immunization against oncogenic HPV viral types is effective in providing protection from cancer precursors and cancers of the cervix, vulva, vagina, and anus—and of course from genital warts. They should understand that, until formal recommendations are published by the ACIP, they are likely to be responsible for the cost of the vaccination series. These conversations will also remind our patients to immunize their teens against HPV. The more conversation we have regarding the benefits of vaccination against high-risk HPV types, the more likely we are to be able to achieve the impressive results seen in Australia.

The US Food and Drug Administration (FDA) recently extended the approval for Gardasil 9 (to prevent HPV-associated cancers, cancer precursors, and genital lesions) to men and women aged 27 to 45.¹ In this editorial, we discuss the evolution of the HPV vaccine since its initial approval more than 10 years ago, the benefits of primary prevention with the HPV vaccine, and the case for the FDA’s recent extension of coverage to older men and women.

The evolution of the HPV vaccine

Since recognition in the 1980s and 90s that high-risk strains of HPV, notably HPV types 16 and 18, were linked to cervical cancer, there have been exciting advances in detection and prevention of high-risk HPV infection. About 70% of cervical cancers are attributable to these 2 oncogenic types.² The first vaccine licensed, Gardasil (Merck), was approved in 2006 for girls and women aged 9 through 26 to prevent HPV-related diseases caused by types 6, 11, 16, and 18.³ The vaccine was effective for prevention of cervical cancer; genital warts; and grades 2 and 3 of cervical, vulvar, and vaginal intraepithelial neoplasia. In 2008, prevention of vulvar and vaginal cancers was added to the indication. By 2009, prevention of genital warts was added, and use in males aged 9 to 15 was approved. By 2010 sufficient data were accumulated to document prevention of anal cancer and anal intraepithelial neoplasia in men and women, and this indication was added.

In 2014 Gardasil 9 was approved to extend coverage to an additional 5 oncogenic HPV types (31, 33, 45, 52, and 58), now covering an additional 20% of cervical cancers, and in 2015 Gardasil 9 indications were expanded to include boys and men 9 to 26 years of age. Immunogenicity studies were performed to infer effectiveness of a 2-dose regimen in boys and girls aged 9 to 14 years, which was recommended by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) in late 2016.⁴

Until October 2018, Gardasil 9 was indicated for prevention of genital warts, cervical, vaginal, vulvar and anal cancers and cancer precursors for males and females aged 9 to 26 years. In October the FDA extended approval of the 3-dose vaccine regimen to men and women up to age 45.

HPV vaccine uptake

HPV vaccination has been underutilized in the United States. In 2017, a disappointing 49% of adolescents were up to date on vaccination, and 66% had received at least one dose.⁵ In rural areas the vaccination rates are 11 points lower than in urban regions.⁶ The CDC notes an increasing number of HPV-associated cancers—from 30,000 per year in 1999 to 43,000 per year in 2015—due mostly to increases in oral and anal carcinomas. Vaccination with Gardasil 9 could prevent 90% of those cases.⁷

Non-US successes. HPV vaccine uptake in Australia provides an excellent opportunity to study the impact of universally available, school-based vaccinations. In 2007 Australia implemented a program of free HPV vaccination distributed through schools. Boys and girls aged 12 and 13 were targeted that year, with catch-up vaccinations for those aged 13 to 18 in 2007-2009 in schools and for those aged 18 to 26 reached in the community.⁸ 

Continue to: Ali and colleagues studied the... 

Ali and colleagues studied the preprogram and postprogram incidence of genital warts.⁹ About 83% received at least 1 dose of vaccine, and 73% of the eligible population completed the 3-dose regimen. There was a significant reduction in warts in both men and women younger than age 21 from 2007 to 2011 (12.1% to 2.2% in men and 11.5% to 0.85% in women). In the 21 to 30 age group there were similar reductions. This study demonstrates that with universal access and public implementation, the rates of HPV-associated disease can be reduced dramatically.

Data informing expanded vaccination ages

Will vaccination of an older population, with presumably many of whom sexually active and at risk for prior exposure to multiple HPV types, have a reasonable impact on lowering HPV-associated cancers? Are HPV-detected lesions in 27- to 45-year-old women the result of reactivation of latent HPV infection, or are they related to new-onset exposure? The FDA reviewed data from 3 studies of HPV vaccination in women aged 27 to 45. The first enrolled women who were naïve to oncogenic HPV types and provided all 3 doses of quadrivalent vaccine were followed for 4 years, along with a comparison group of nonvaccinated women. The second study allowed the nonvaccinated group to receive vaccine in year 4. Both groups were followed up to 10 years with the relevant outcome defined as cumulative incidence of HPV 6/11/16/18-related CIN and condyloma. The third study looked at the same outcomes in a set of all women—whether HPV high-risk naïve or not—after receiving vaccine and followed more than 10 years.⁷ This last study is most relevant to ObGyns, as it is closest to how we would consider vaccinating our patients.

The study findings are reassuring: A large proportion of HPV infections in women between 27 and 45 are the result of new exposure/infection. A study of 420 online daters aged 25 to 65 showed an annual incidence of high-risk HPV types in vaginal swabs of 25.4%, of which 64% were likely new acquisitions.¹⁰ The 2013-2014 National Health and Nutrition Examination Survey of 1,757 men aged 18 to 59 estimated approximately 45% had genital HPV infection. There was a bimodal distribution of disease with peaks at 28 to 32 and a larger second peak at 58 to 59 years of age.¹¹ Bottom line: Men and women older than age 26 who are sexually active likely acquire new HPV infections with oncogenic types. Exposure to high-risk HPV types prior to vaccination—as we would expect in the real-world setting—did not eliminate the substantial benefit of immunization.

Based on these study results, and extrapolation to the 9-valent vaccine, the FDA extended the approval of Gardasil 9 to men and women from age 9 to 45. The indications and usage will remain the same: for prevention of cervical, vulvar, vaginal, and anal cancer and genital warts as well as precancerous or dysplastic lesions of the cervix, vulva, vagina, and anus related to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

Continue to: Impact of the new... 

Impact of the new indication on HPV-related disease

As described above, widespread vaccination of young girls and boys is going to have major impact on HPV-related disease, including precancer and cancer. Because there is evidence that older women and men are at risk for new HPV infection,¹⁰ there likely will be some benefit from vaccination of adults. It is difficult, however, to extrapolate the degree to which adult vaccination will impact HPV-related disease. This is because we do not fully understand the rates at which new HPV infection in the cervices of older women will progress to high-grade dysplasia or cancer. Further, the pathophysiology of HPV-related cancers at other anogenital sites and new oral-pharyngeal infection is poorly understood in comparison with our knowledge of the natural history of high-risk HPV infection in younger women. That said, because of the outstanding efficacy of HPV vaccination and the low-risk profile, even if the actual impact on prevention of cancer or morbidity from dysplasia is relatively low, adult vaccination benefits outweigh the limited risks.

It may be that increased vaccination and awareness of vaccination for adults may enhance the adherence and acceptance of widespread vaccination of boys and girls. Adult vaccination could create a cultural shift toward HPV vaccination acceptance when adult parents and loved ones of vaccine-age boys and girls have been vaccinated themselves.

Current and future insurance coverage

The Affordable Care Act, otherwise known as Obamacare, mandates coverage for all immunizations recommended by the ACIP. HPV vaccination up to age 26 is fully covered, without copay or deductible. The ACIP did consider extension of the indications for HPV vaccination to men and women up to age 45 at their October 2018 meeting. They are tasked with considering not only safety and efficacy but also the cost effectiveness of implementing vaccination. They continue to study the costs and potential benefits of extending HPV vaccination to age 45. Their recommendations may be determined at the February 2019 meeting—or even later in 2019. The American College of Obstetricians and Gynecologists (ACOG) relies upon ACIP for practice guidance. Once the ACIP has made a determination, and if new guidelines are published in the Morbidity and Mortality Weekly Report, insurance coverage and ACOG guidance will be updated.

How should we react and change practice based on this new indication?

Given the information reviewed by the FDA, ObGyns will want to discuss the availability of Gardasil 9 with our patients between ages 27 and 45 who have not been previously immunized.

Especially for our patients with exposure to multiple or new sexual partners, immunization against oncogenic HPV viral types is effective in providing protection from cancer precursors and cancers of the cervix, vulva, vagina, and anus—and of course from genital warts. They should understand that, until formal recommendations are published by the ACIP, they are likely to be responsible for the cost of the vaccination series. These conversations will also remind our patients to immunize their teens against HPV. The more conversation we have regarding the benefits of vaccination against high-risk HPV types, the more likely we are to be able to achieve the impressive results seen in Australia.

The US Food and Drug Administration (FDA) recently extended the approval for Gardasil 9 (to prevent HPV-associated cancers, cancer precursors, and genital lesions) to men and women aged 27 to 45.¹ In this editorial, we discuss the evolution of the HPV vaccine since its initial approval more than 10 years ago, the benefits of primary prevention with the HPV vaccine, and the case for the FDA’s recent extension of coverage to older men and women.

The evolution of the HPV vaccine

Since recognition in the 1980s and 90s that high-risk strains of HPV, notably HPV types 16 and 18, were linked to cervical cancer, there have been exciting advances in detection and prevention of high-risk HPV infection. About 70% of cervical cancers are attributable to these 2 oncogenic types.² The first vaccine licensed, Gardasil (Merck), was approved in 2006 for girls and women aged 9 through 26 to prevent HPV-related diseases caused by types 6, 11, 16, and 18.³ The vaccine was effective for prevention of cervical cancer; genital warts; and grades 2 and 3 of cervical, vulvar, and vaginal intraepithelial neoplasia. In 2008, prevention of vulvar and vaginal cancers was added to the indication. By 2009, prevention of genital warts was added, and use in males aged 9 to 15 was approved. By 2010 sufficient data were accumulated to document prevention of anal cancer and anal intraepithelial neoplasia in men and women, and this indication was added.

In 2014 Gardasil 9 was approved to extend coverage to an additional 5 oncogenic HPV types (31, 33, 45, 52, and 58), now covering an additional 20% of cervical cancers, and in 2015 Gardasil 9 indications were expanded to include boys and men 9 to 26 years of age. Immunogenicity studies were performed to infer effectiveness of a 2-dose regimen in boys and girls aged 9 to 14 years, which was recommended by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) in late 2016.⁴

Until October 2018, Gardasil 9 was indicated for prevention of genital warts, cervical, vaginal, vulvar and anal cancers and cancer precursors for males and females aged 9 to 26 years. In October the FDA extended approval of the 3-dose vaccine regimen to men and women up to age 45.

HPV vaccine uptake

HPV vaccination has been underutilized in the United States. In 2017, a disappointing 49% of adolescents were up to date on vaccination, and 66% had received at least one dose.⁵ In rural areas the vaccination rates are 11 points lower than in urban regions.⁶ The CDC notes an increasing number of HPV-associated cancers—from 30,000 per year in 1999 to 43,000 per year in 2015—due mostly to increases in oral and anal carcinomas. Vaccination with Gardasil 9 could prevent 90% of those cases.⁷

Non-US successes. HPV vaccine uptake in Australia provides an excellent opportunity to study the impact of universally available, school-based vaccinations. In 2007 Australia implemented a program of free HPV vaccination distributed through schools. Boys and girls aged 12 and 13 were targeted that year, with catch-up vaccinations for those aged 13 to 18 in 2007-2009 in schools and for those aged 18 to 26 reached in the community.⁸ 

Continue to: Ali and colleagues studied the... 

Ali and colleagues studied the preprogram and postprogram incidence of genital warts.⁹ About 83% received at least 1 dose of vaccine, and 73% of the eligible population completed the 3-dose regimen. There was a significant reduction in warts in both men and women younger than age 21 from 2007 to 2011 (12.1% to 2.2% in men and 11.5% to 0.85% in women). In the 21 to 30 age group there were similar reductions. This study demonstrates that with universal access and public implementation, the rates of HPV-associated disease can be reduced dramatically.

Data informing expanded vaccination ages

Will vaccination of an older population, with presumably many of whom sexually active and at risk for prior exposure to multiple HPV types, have a reasonable impact on lowering HPV-associated cancers? Are HPV-detected lesions in 27- to 45-year-old women the result of reactivation of latent HPV infection, or are they related to new-onset exposure? The FDA reviewed data from 3 studies of HPV vaccination in women aged 27 to 45. The first enrolled women who were naïve to oncogenic HPV types and provided all 3 doses of quadrivalent vaccine were followed for 4 years, along with a comparison group of nonvaccinated women. The second study allowed the nonvaccinated group to receive vaccine in year 4. Both groups were followed up to 10 years with the relevant outcome defined as cumulative incidence of HPV 6/11/16/18-related CIN and condyloma. The third study looked at the same outcomes in a set of all women—whether HPV high-risk naïve or not—after receiving vaccine and followed more than 10 years.⁷ This last study is most relevant to ObGyns, as it is closest to how we would consider vaccinating our patients.

The study findings are reassuring: A large proportion of HPV infections in women between 27 and 45 are the result of new exposure/infection. A study of 420 online daters aged 25 to 65 showed an annual incidence of high-risk HPV types in vaginal swabs of 25.4%, of which 64% were likely new acquisitions.¹⁰ The 2013-2014 National Health and Nutrition Examination Survey of 1,757 men aged 18 to 59 estimated approximately 45% had genital HPV infection. There was a bimodal distribution of disease with peaks at 28 to 32 and a larger second peak at 58 to 59 years of age.¹¹ Bottom line: Men and women older than age 26 who are sexually active likely acquire new HPV infections with oncogenic types. Exposure to high-risk HPV types prior to vaccination—as we would expect in the real-world setting—did not eliminate the substantial benefit of immunization.

Based on these study results, and extrapolation to the 9-valent vaccine, the FDA extended the approval of Gardasil 9 to men and women from age 9 to 45. The indications and usage will remain the same: for prevention of cervical, vulvar, vaginal, and anal cancer and genital warts as well as precancerous or dysplastic lesions of the cervix, vulva, vagina, and anus related to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

Continue to: Impact of the new... 

Impact of the new indication on HPV-related disease

As described above, widespread vaccination of young girls and boys is going to have major impact on HPV-related disease, including precancer and cancer. Because there is evidence that older women and men are at risk for new HPV infection,¹⁰ there likely will be some benefit from vaccination of adults. It is difficult, however, to extrapolate the degree to which adult vaccination will impact HPV-related disease. This is because we do not fully understand the rates at which new HPV infection in the cervices of older women will progress to high-grade dysplasia or cancer. Further, the pathophysiology of HPV-related cancers at other anogenital sites and new oral-pharyngeal infection is poorly understood in comparison with our knowledge of the natural history of high-risk HPV infection in younger women. That said, because of the outstanding efficacy of HPV vaccination and the low-risk profile, even if the actual impact on prevention of cancer or morbidity from dysplasia is relatively low, adult vaccination benefits outweigh the limited risks.

It may be that increased vaccination and awareness of vaccination for adults may enhance the adherence and acceptance of widespread vaccination of boys and girls. Adult vaccination could create a cultural shift toward HPV vaccination acceptance when adult parents and loved ones of vaccine-age boys and girls have been vaccinated themselves.

Current and future insurance coverage

The Affordable Care Act, otherwise known as Obamacare, mandates coverage for all immunizations recommended by the ACIP. HPV vaccination up to age 26 is fully covered, without copay or deductible. The ACIP did consider extension of the indications for HPV vaccination to men and women up to age 45 at their October 2018 meeting. They are tasked with considering not only safety and efficacy but also the cost effectiveness of implementing vaccination. They continue to study the costs and potential benefits of extending HPV vaccination to age 45. Their recommendations may be determined at the February 2019 meeting—or even later in 2019. The American College of Obstetricians and Gynecologists (ACOG) relies upon ACIP for practice guidance. Once the ACIP has made a determination, and if new guidelines are published in the Morbidity and Mortality Weekly Report, insurance coverage and ACOG guidance will be updated.

How should we react and change practice based on this new indication?

Given the information reviewed by the FDA, ObGyns will want to discuss the availability of Gardasil 9 with our patients between ages 27 and 45 who have not been previously immunized.

Especially for our patients with exposure to multiple or new sexual partners, immunization against oncogenic HPV viral types is effective in providing protection from cancer precursors and cancers of the cervix, vulva, vagina, and anus—and of course from genital warts. They should understand that, until formal recommendations are published by the ACIP, they are likely to be responsible for the cost of the vaccination series. These conversations will also remind our patients to immunize their teens against HPV. The more conversation we have regarding the benefits of vaccination against high-risk HPV types, the more likely we are to be able to achieve the impressive results seen in Australia.

Expert Commentary

Data demonstrate efficacy and safety of the IUD in adolescents. In addition, IUDs (particularly the levonorgestrel-containing IUD) have many noncontraceptive benefits. There is still reluctance, however, among clinicians to use IUDs in adolescents. In a sample of fellows of the American College of Obstetricians and Gynecologists, only 43% considered adolescents appropriate candidates for use of an IUD.¹

Study details

In this retrospective chart review, Kebodeaux and Schwartz sought to compare successful IUD insertion rates on first attempt in 120 sexually active (SA) and 82 never sexually active (NSA) adolescents. The IUD type used for all women was the 52-mg levonorgestrel IUD (Mirena), except for 3 copper IUDs (Paragard) used in the SA group. The primary indications for IUD use were contraception (85.2%) in the SA group and abnormal uterine bleeding (43.9%) and menstrual suppression (24.4%) in the NSA group.

In the NSA group, 82.9% of adolescents had had some type of prior treatment affecting the menstrual cycle, compared with 60.9% in the SA group (P = .001).

Non–office insertion. Either a sedation unit or operating room was utilized in 5.5% of the IUD insertions in the SA group and 47.6% of the NSA group. Among the 39 adolescents in the NSA group undergoing non–office insertion, 19 (48.7%) had special needs (learning or intellectual disabilities, autism/autism spectrum, or physical disabilities, such as cerebral palsy). Only 1 adolescent with special needs in the NSA group had an office insertion compared with 5 out of 6 in the SA group.

The performance of another procedure other than the IUD insertion (including diagnostic laparoscopy and hymenectomy) was common among adolescents undergoing procedures in the sedation unit or operating room who did not have special needs. It is also important to note that adolescents with special needs were routinely offered insertion under anesthesia while SA adolescents were offered insertion under anesthesia only if they were undergoing another procedure as well.

Study strengths and weaknesses

The study’s strengths include IUD insertions performed at a children’s hospital by providers with experience working with adolescent populations. This likely accounts for the high rates of “tolerance of the procedure well” (93.8% in the SA group vs 81.7% in the NSA group; P = .006). The study also included a patient population—adolescents with special needs—that has not been studied relative to IUD use previously.

A significant weakness of the study, however, is that there are no long-term follow-up data, particularly related to continuation rates.

Expert Commentary

Data demonstrate efficacy and safety of the IUD in adolescents. In addition, IUDs (particularly the levonorgestrel-containing IUD) have many noncontraceptive benefits. There is still reluctance, however, among clinicians to use IUDs in adolescents. In a sample of fellows of the American College of Obstetricians and Gynecologists, only 43% considered adolescents appropriate candidates for use of an IUD.¹

Study details

In this retrospective chart review, Kebodeaux and Schwartz sought to compare successful IUD insertion rates on first attempt in 120 sexually active (SA) and 82 never sexually active (NSA) adolescents. The IUD type used for all women was the 52-mg levonorgestrel IUD (Mirena), except for 3 copper IUDs (Paragard) used in the SA group. The primary indications for IUD use were contraception (85.2%) in the SA group and abnormal uterine bleeding (43.9%) and menstrual suppression (24.4%) in the NSA group.

In the NSA group, 82.9% of adolescents had had some type of prior treatment affecting the menstrual cycle, compared with 60.9% in the SA group (P = .001).

Non–office insertion. Either a sedation unit or operating room was utilized in 5.5% of the IUD insertions in the SA group and 47.6% of the NSA group. Among the 39 adolescents in the NSA group undergoing non–office insertion, 19 (48.7%) had special needs (learning or intellectual disabilities, autism/autism spectrum, or physical disabilities, such as cerebral palsy). Only 1 adolescent with special needs in the NSA group had an office insertion compared with 5 out of 6 in the SA group.

The performance of another procedure other than the IUD insertion (including diagnostic laparoscopy and hymenectomy) was common among adolescents undergoing procedures in the sedation unit or operating room who did not have special needs. It is also important to note that adolescents with special needs were routinely offered insertion under anesthesia while SA adolescents were offered insertion under anesthesia only if they were undergoing another procedure as well.

Study strengths and weaknesses

The study’s strengths include IUD insertions performed at a children’s hospital by providers with experience working with adolescent populations. This likely accounts for the high rates of “tolerance of the procedure well” (93.8% in the SA group vs 81.7% in the NSA group; P = .006). The study also included a patient population—adolescents with special needs—that has not been studied relative to IUD use previously.

A significant weakness of the study, however, is that there are no long-term follow-up data, particularly related to continuation rates.

Expert Commentary

Data demonstrate efficacy and safety of the IUD in adolescents. In addition, IUDs (particularly the levonorgestrel-containing IUD) have many noncontraceptive benefits. There is still reluctance, however, among clinicians to use IUDs in adolescents. In a sample of fellows of the American College of Obstetricians and Gynecologists, only 43% considered adolescents appropriate candidates for use of an IUD.¹

Study details

In this retrospective chart review, Kebodeaux and Schwartz sought to compare successful IUD insertion rates on first attempt in 120 sexually active (SA) and 82 never sexually active (NSA) adolescents. The IUD type used for all women was the 52-mg levonorgestrel IUD (Mirena), except for 3 copper IUDs (Paragard) used in the SA group. The primary indications for IUD use were contraception (85.2%) in the SA group and abnormal uterine bleeding (43.9%) and menstrual suppression (24.4%) in the NSA group.

In the NSA group, 82.9% of adolescents had had some type of prior treatment affecting the menstrual cycle, compared with 60.9% in the SA group (P = .001).

Non–office insertion. Either a sedation unit or operating room was utilized in 5.5% of the IUD insertions in the SA group and 47.6% of the NSA group. Among the 39 adolescents in the NSA group undergoing non–office insertion, 19 (48.7%) had special needs (learning or intellectual disabilities, autism/autism spectrum, or physical disabilities, such as cerebral palsy). Only 1 adolescent with special needs in the NSA group had an office insertion compared with 5 out of 6 in the SA group.

The performance of another procedure other than the IUD insertion (including diagnostic laparoscopy and hymenectomy) was common among adolescents undergoing procedures in the sedation unit or operating room who did not have special needs. It is also important to note that adolescents with special needs were routinely offered insertion under anesthesia while SA adolescents were offered insertion under anesthesia only if they were undergoing another procedure as well.

Study strengths and weaknesses

The study’s strengths include IUD insertions performed at a children’s hospital by providers with experience working with adolescent populations. This likely accounts for the high rates of “tolerance of the procedure well” (93.8% in the SA group vs 81.7% in the NSA group; P = .006). The study also included a patient population—adolescents with special needs—that has not been studied relative to IUD use previously.

A significant weakness of the study, however, is that there are no long-term follow-up data, particularly related to continuation rates.

Norman JE, Heazell AE, Rodriguez A, et al; for the AFFIRM investigators. Awareness of fetal movements and care package to reduce fetal mortality (AFFIRM): a stepped wedge, cluster-randomised trial. Lancet. 2018;392:1629-1638.

Norman JE, Heazell AE, Rodriguez A, et al; for the AFFIRM investigators. Awareness of fetal movements and care package to reduce fetal mortality (AFFIRM): a stepped wedge, cluster-randomised trial. Lancet. 2018;392:1629-1638.

Norman JE, Heazell AE, Rodriguez A, et al; for the AFFIRM investigators. Awareness of fetal movements and care package to reduce fetal mortality (AFFIRM): a stepped wedge, cluster-randomised trial. Lancet. 2018;392:1629-1638.

Medical science’s broad knowledge of endometriosis notwithstanding, “many questions remain unanswered” about the management of a condition that is often refractory to established therapies, observed Sawsan As-Sanie, MD, MPH, at the 2018 Pelvic Anatomy and Gynecologic Surgery Symposium meeting in Las Vegas, Nevada. Dr. As-Sanie is Associate Professor and Director, Minimally Invasive Gynecologic Surgery Fellowship, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor. How, then, should clinicians approach the challenge of caring for women with this enigmatic disease in the larger context of chronic pelvic pain, in which, as Dr. As-Sanie said, “one size never fits all”?

Complex correlation between endometriosis and CPP

Despite high prevalence and negative impact on the health and quality of life of women who suffer from endometriosis, Dr. As-Sanie emphasized, it remains unclear why only some women with endometriosis develop chronic pelvic pain (CPP) and why there is little, if any, correlation between disease severity and the intensity of pain.

The clinical approach to endometriosis and CPP can be frustrating for several reasons: there is minimal relationship between extent or location of disease with pain symptoms; there is no consistent relationship among inflammatory markers, nerve-fiber density, and pain symptoms; and pain can recur after medical and surgical therapy—often without evidence of recurrent endometriosis. Furthermore, the differential diagnosis of CPP is broad, and also includes adenomyosis, adhesions, chronic pelvic inflammatory disease, uterine fibroids, pelvic congestion, ovarian remnant, and residual ovarian syndrome. Chronic overlapping pain conditions are prevalent, too, including interstitial cystitis, irritable bowel syndrome, and vulvodynia, to name a few.¹

_

CPP is not just a pain disorder

Dr. As-Sanie said that understanding of CPP must extend to include fatigue, memory difficulties, poor sleep, and heightened sensitivity to multiple sensory stimuli (e.g., sound and light).² So what, she asked, do we know about endometriosis, chronic pelvic pain, and the brain? We know that CPP, with and without endometriosis, is associated with increased pain sensitivity and altered central nervous system structure and function.^3-5 Central amplification of pain can lead to chronic pain independent of nociceptive signals, including multifocal, widespread pain; higher lifetime history of pain throughout the body; and pain triggered or exacerbated by stressors. And CPP brings with it other, potentially debilitating problems, including elevated distress, decreased activity, isolation, poor sleep, and maladaptive illness behaviors.

Finding, then addressing, the culprit

Identifying the underlying cause(s) of CPP in the individual woman should guide clinical care. This includes the decision to proceed with, or avoid, surgery. Remember: Patients with centralized pain respond differently to therapy; surgery is less likely to help relieve the pain.

Dr. As-Sanie offered several fundamental guidelines for managing CPP:

• Treat early, to prevent transition from acute to chronic pain; treatment delay increases connectivity between pain regulatory regions.
• Hysterectomy is not definitive therapy for all women with endometriosis or CPP.⁶
• Take a multisystem approach, comprising medical, behavioral, and interventional strategies.
• If an organ- or disease-based diagnostic and treatment approach does not work, reconsider the diagnosis; re-evaluate comorbid psychosocial variables; and consider treating centralized pain.
• Choice of treatment should include consideration of cost and adverse-effect profile.
• If one modality is ineffective, try another.

Continue to: What are the levels of evidence for centralized pain treatment?

Available pharmacotherapeutic agents have modest benefit, possibly because the population of pain patients is heterogeneous, with various underlying mechanisms of pain. And, Dr. As-Sanie pointed out, clinical tools do not currently exist to pre-emptively select the right medicine for individual patients.

Evidence is strong, Dr. As-Sanie noted, for dual reuptake-inhibitor antidepressants, such as tricyclic compounds (amitriptyline, cyclobenzaprine) and serotonin–norepinephrine reuptake inhibitors, and for anticonvulsants with analgesic properties (pregabalin, gabapentin). Evidence is “modest,” Dr. As-Sanie said, for tramadol, gamma hydroxybutyrate, and low-dose naltrexone, and “weak” for cannabinoids, human growth hormone, 5-hydroxytryptamine, tropisetron, and S-adenosyl-L-methionine. There is no evidence for using opioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepine and non–benzodiazepine hypnotics, or guaifenesin.⁷

When surgery or pharmacotherapy alone fail to yield the necessary outcome, consider adjunctive nonpharmacotherapy.⁸ For example, there is strong evidence for patient education, aerobic exercise, and cognitive behavior therapy; modest evidence for acupressure, acupuncture, strength training, hypnotherapy, biofeedback, trigger-point injection, and neuromodulation; but only weak evidence for chiropractic, manual and massage therapy, electrotherapy, and ultrasound. ⁷

_

With CPP, “one size never fits all”

Dr. As-Sanie concluded with a reminder that CPP can be the product of any of a range of underlying contributory causes. Pathology might stand foremost as you search for the source of pain and an effective treatment, but keep in mind that genetics, environment, co-existing pain conditions, the patient’s ability to cope, and her resilience and social support might play a role.

Medical science’s broad knowledge of endometriosis notwithstanding, “many questions remain unanswered” about the management of a condition that is often refractory to established therapies, observed Sawsan As-Sanie, MD, MPH, at the 2018 Pelvic Anatomy and Gynecologic Surgery Symposium meeting in Las Vegas, Nevada. Dr. As-Sanie is Associate Professor and Director, Minimally Invasive Gynecologic Surgery Fellowship, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor. How, then, should clinicians approach the challenge of caring for women with this enigmatic disease in the larger context of chronic pelvic pain, in which, as Dr. As-Sanie said, “one size never fits all”?

Complex correlation between endometriosis and CPP

Despite high prevalence and negative impact on the health and quality of life of women who suffer from endometriosis, Dr. As-Sanie emphasized, it remains unclear why only some women with endometriosis develop chronic pelvic pain (CPP) and why there is little, if any, correlation between disease severity and the intensity of pain.

The clinical approach to endometriosis and CPP can be frustrating for several reasons: there is minimal relationship between extent or location of disease with pain symptoms; there is no consistent relationship among inflammatory markers, nerve-fiber density, and pain symptoms; and pain can recur after medical and surgical therapy—often without evidence of recurrent endometriosis. Furthermore, the differential diagnosis of CPP is broad, and also includes adenomyosis, adhesions, chronic pelvic inflammatory disease, uterine fibroids, pelvic congestion, ovarian remnant, and residual ovarian syndrome. Chronic overlapping pain conditions are prevalent, too, including interstitial cystitis, irritable bowel syndrome, and vulvodynia, to name a few.¹

_

CPP is not just a pain disorder

Dr. As-Sanie said that understanding of CPP must extend to include fatigue, memory difficulties, poor sleep, and heightened sensitivity to multiple sensory stimuli (e.g., sound and light).² So what, she asked, do we know about endometriosis, chronic pelvic pain, and the brain? We know that CPP, with and without endometriosis, is associated with increased pain sensitivity and altered central nervous system structure and function.^3-5 Central amplification of pain can lead to chronic pain independent of nociceptive signals, including multifocal, widespread pain; higher lifetime history of pain throughout the body; and pain triggered or exacerbated by stressors. And CPP brings with it other, potentially debilitating problems, including elevated distress, decreased activity, isolation, poor sleep, and maladaptive illness behaviors.

Finding, then addressing, the culprit

Identifying the underlying cause(s) of CPP in the individual woman should guide clinical care. This includes the decision to proceed with, or avoid, surgery. Remember: Patients with centralized pain respond differently to therapy; surgery is less likely to help relieve the pain.

Dr. As-Sanie offered several fundamental guidelines for managing CPP:

• Treat early, to prevent transition from acute to chronic pain; treatment delay increases connectivity between pain regulatory regions.
• Hysterectomy is not definitive therapy for all women with endometriosis or CPP.⁶
• Take a multisystem approach, comprising medical, behavioral, and interventional strategies.
• If an organ- or disease-based diagnostic and treatment approach does not work, reconsider the diagnosis; re-evaluate comorbid psychosocial variables; and consider treating centralized pain.
• Choice of treatment should include consideration of cost and adverse-effect profile.
• If one modality is ineffective, try another.

Continue to: What are the levels of evidence for centralized pain treatment?

Available pharmacotherapeutic agents have modest benefit, possibly because the population of pain patients is heterogeneous, with various underlying mechanisms of pain. And, Dr. As-Sanie pointed out, clinical tools do not currently exist to pre-emptively select the right medicine for individual patients.

Evidence is strong, Dr. As-Sanie noted, for dual reuptake-inhibitor antidepressants, such as tricyclic compounds (amitriptyline, cyclobenzaprine) and serotonin–norepinephrine reuptake inhibitors, and for anticonvulsants with analgesic properties (pregabalin, gabapentin). Evidence is “modest,” Dr. As-Sanie said, for tramadol, gamma hydroxybutyrate, and low-dose naltrexone, and “weak” for cannabinoids, human growth hormone, 5-hydroxytryptamine, tropisetron, and S-adenosyl-L-methionine. There is no evidence for using opioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepine and non–benzodiazepine hypnotics, or guaifenesin.⁷

When surgery or pharmacotherapy alone fail to yield the necessary outcome, consider adjunctive nonpharmacotherapy.⁸ For example, there is strong evidence for patient education, aerobic exercise, and cognitive behavior therapy; modest evidence for acupressure, acupuncture, strength training, hypnotherapy, biofeedback, trigger-point injection, and neuromodulation; but only weak evidence for chiropractic, manual and massage therapy, electrotherapy, and ultrasound. ⁷

_

With CPP, “one size never fits all”

Dr. As-Sanie concluded with a reminder that CPP can be the product of any of a range of underlying contributory causes. Pathology might stand foremost as you search for the source of pain and an effective treatment, but keep in mind that genetics, environment, co-existing pain conditions, the patient’s ability to cope, and her resilience and social support might play a role.

Medical science’s broad knowledge of endometriosis notwithstanding, “many questions remain unanswered” about the management of a condition that is often refractory to established therapies, observed Sawsan As-Sanie, MD, MPH, at the 2018 Pelvic Anatomy and Gynecologic Surgery Symposium meeting in Las Vegas, Nevada. Dr. As-Sanie is Associate Professor and Director, Minimally Invasive Gynecologic Surgery Fellowship, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor. How, then, should clinicians approach the challenge of caring for women with this enigmatic disease in the larger context of chronic pelvic pain, in which, as Dr. As-Sanie said, “one size never fits all”?

Complex correlation between endometriosis and CPP

Despite high prevalence and negative impact on the health and quality of life of women who suffer from endometriosis, Dr. As-Sanie emphasized, it remains unclear why only some women with endometriosis develop chronic pelvic pain (CPP) and why there is little, if any, correlation between disease severity and the intensity of pain.

The clinical approach to endometriosis and CPP can be frustrating for several reasons: there is minimal relationship between extent or location of disease with pain symptoms; there is no consistent relationship among inflammatory markers, nerve-fiber density, and pain symptoms; and pain can recur after medical and surgical therapy—often without evidence of recurrent endometriosis. Furthermore, the differential diagnosis of CPP is broad, and also includes adenomyosis, adhesions, chronic pelvic inflammatory disease, uterine fibroids, pelvic congestion, ovarian remnant, and residual ovarian syndrome. Chronic overlapping pain conditions are prevalent, too, including interstitial cystitis, irritable bowel syndrome, and vulvodynia, to name a few.¹

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CPP is not just a pain disorder

Dr. As-Sanie said that understanding of CPP must extend to include fatigue, memory difficulties, poor sleep, and heightened sensitivity to multiple sensory stimuli (e.g., sound and light).² So what, she asked, do we know about endometriosis, chronic pelvic pain, and the brain? We know that CPP, with and without endometriosis, is associated with increased pain sensitivity and altered central nervous system structure and function.^3-5 Central amplification of pain can lead to chronic pain independent of nociceptive signals, including multifocal, widespread pain; higher lifetime history of pain throughout the body; and pain triggered or exacerbated by stressors. And CPP brings with it other, potentially debilitating problems, including elevated distress, decreased activity, isolation, poor sleep, and maladaptive illness behaviors.

Finding, then addressing, the culprit

Identifying the underlying cause(s) of CPP in the individual woman should guide clinical care. This includes the decision to proceed with, or avoid, surgery. Remember: Patients with centralized pain respond differently to therapy; surgery is less likely to help relieve the pain.

Dr. As-Sanie offered several fundamental guidelines for managing CPP:

• Treat early, to prevent transition from acute to chronic pain; treatment delay increases connectivity between pain regulatory regions.
• Hysterectomy is not definitive therapy for all women with endometriosis or CPP.⁶
• Take a multisystem approach, comprising medical, behavioral, and interventional strategies.
• If an organ- or disease-based diagnostic and treatment approach does not work, reconsider the diagnosis; re-evaluate comorbid psychosocial variables; and consider treating centralized pain.
• Choice of treatment should include consideration of cost and adverse-effect profile.
• If one modality is ineffective, try another.

Continue to: What are the levels of evidence for centralized pain treatment?

Available pharmacotherapeutic agents have modest benefit, possibly because the population of pain patients is heterogeneous, with various underlying mechanisms of pain. And, Dr. As-Sanie pointed out, clinical tools do not currently exist to pre-emptively select the right medicine for individual patients.

Evidence is strong, Dr. As-Sanie noted, for dual reuptake-inhibitor antidepressants, such as tricyclic compounds (amitriptyline, cyclobenzaprine) and serotonin–norepinephrine reuptake inhibitors, and for anticonvulsants with analgesic properties (pregabalin, gabapentin). Evidence is “modest,” Dr. As-Sanie said, for tramadol, gamma hydroxybutyrate, and low-dose naltrexone, and “weak” for cannabinoids, human growth hormone, 5-hydroxytryptamine, tropisetron, and S-adenosyl-L-methionine. There is no evidence for using opioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepine and non–benzodiazepine hypnotics, or guaifenesin.⁷

When surgery or pharmacotherapy alone fail to yield the necessary outcome, consider adjunctive nonpharmacotherapy.⁸ For example, there is strong evidence for patient education, aerobic exercise, and cognitive behavior therapy; modest evidence for acupressure, acupuncture, strength training, hypnotherapy, biofeedback, trigger-point injection, and neuromodulation; but only weak evidence for chiropractic, manual and massage therapy, electrotherapy, and ultrasound. ⁷

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With CPP, “one size never fits all”

Dr. As-Sanie concluded with a reminder that CPP can be the product of any of a range of underlying contributory causes. Pathology might stand foremost as you search for the source of pain and an effective treatment, but keep in mind that genetics, environment, co-existing pain conditions, the patient’s ability to cope, and her resilience and social support might play a role.