Gynecologic Cancer

In an open-label, phase 1/2, randomized clinical trial (VICTORIA) performed at 12 cancer centers in France, the combination of the mammalian target of rapamycin inhibitor vistusertib with anastrozole led to reduced progression in hormone receptor–positive (HR+) endometrial cancer with good tolerability.

The study was published in JAMA Oncology.

Treatment of endometrial cancer involves a combination of surgery, radiation, and chemotherapy, but about 20% of patients relapse, usually within 5 years. HR+ endometrial cancer represents about 65% of endometrial cancers. It is usually endometrioid, and about 80% have phosphatase and tensin homologue (PTEN) mutations, while 36-52% have a mutation in the phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway.

Endocrine therapy alone elicits a response rate of 15%-30% in HR+ endometrial cancer, generally in low-grade endometrioid subtypes. Most responses are short in duration. Aromatase inhibitors like anastrozole are used for more often than progestogens because they are better tolerated and they have a lower thromboembolic risk in this patient population. Previously, the phase 2 PARAGON trial showed a response rate of just 7% with anastrozole monotherapy, but 44% in women with recurrent HR+ endometrial cancer gained a clinical benefit.

Deregulation in the PI3K/AKT/mTOR pathway can also lead to hormone resistance, suggesting that combination of an mTOR inhibitor with endocrine therapy might have a synergistic effect.

mTOR inhibition alone or in combination with endocrine treatment has been investigated in some single-arm studies, with some encouraging progression-free survival results, but no clear objective response rate or overall survival benefit.

The new study included just 73 patients with a median age of 69.5 years: 49 received 125 mg vistusertib 2 days per week and 1 mg anastrozole daily and 24 received anastrozole only. The 8-week progression-free rate was 67.3% (unilateral 95% confidence interval, 54.7%) in the combination arm versus 39.1% (unilateral 95% CI, 22.2%) in the anastrozole-only arm.

Among 6 patients in the safety run-in period of the combination arm, there were no serious adverse events. Overall response rate was 24.5% (95% CI, 13.3-38.9%) in the combination arm and 17.4% (95% CI, 5.0-38.8%) in the anastrozole-only arm.

Over a median follow-up of 27.7 months, progression-free survival was 5.2 months in the combination arm (95% CI, 3.4-8.9 months) and 1.9 months (95% CI, 1.6-8.9) In the anastrozole-only arm. Common grade 2 or higher side effects linked to vistusertib included fatigue, lymphopenia, hyperglycemia, and diarrhea.

Although low tumor grade, endometrioid subtype, and HR+ status are associated with response to endocrine therapy, the low overall response and progression-free survival in the anastrozole arm suggest that better patient selection is needed. “The choice of treatment according to the histologic characteristics is not sufficient, and highly selected molecular criteria are necessary,” the authors wrote.

The study is limited by its small size and a lack of data on expression level of hormone receptors.

The study was funded by the National Cancer Institute of France.

In an open-label, phase 1/2, randomized clinical trial (VICTORIA) performed at 12 cancer centers in France, the combination of the mammalian target of rapamycin inhibitor vistusertib with anastrozole led to reduced progression in hormone receptor–positive (HR+) endometrial cancer with good tolerability.

The study was published in JAMA Oncology.

Treatment of endometrial cancer involves a combination of surgery, radiation, and chemotherapy, but about 20% of patients relapse, usually within 5 years. HR+ endometrial cancer represents about 65% of endometrial cancers. It is usually endometrioid, and about 80% have phosphatase and tensin homologue (PTEN) mutations, while 36-52% have a mutation in the phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway.

Endocrine therapy alone elicits a response rate of 15%-30% in HR+ endometrial cancer, generally in low-grade endometrioid subtypes. Most responses are short in duration. Aromatase inhibitors like anastrozole are used for more often than progestogens because they are better tolerated and they have a lower thromboembolic risk in this patient population. Previously, the phase 2 PARAGON trial showed a response rate of just 7% with anastrozole monotherapy, but 44% in women with recurrent HR+ endometrial cancer gained a clinical benefit.

Deregulation in the PI3K/AKT/mTOR pathway can also lead to hormone resistance, suggesting that combination of an mTOR inhibitor with endocrine therapy might have a synergistic effect.

mTOR inhibition alone or in combination with endocrine treatment has been investigated in some single-arm studies, with some encouraging progression-free survival results, but no clear objective response rate or overall survival benefit.

The new study included just 73 patients with a median age of 69.5 years: 49 received 125 mg vistusertib 2 days per week and 1 mg anastrozole daily and 24 received anastrozole only. The 8-week progression-free rate was 67.3% (unilateral 95% confidence interval, 54.7%) in the combination arm versus 39.1% (unilateral 95% CI, 22.2%) in the anastrozole-only arm.

Among 6 patients in the safety run-in period of the combination arm, there were no serious adverse events. Overall response rate was 24.5% (95% CI, 13.3-38.9%) in the combination arm and 17.4% (95% CI, 5.0-38.8%) in the anastrozole-only arm.

Over a median follow-up of 27.7 months, progression-free survival was 5.2 months in the combination arm (95% CI, 3.4-8.9 months) and 1.9 months (95% CI, 1.6-8.9) In the anastrozole-only arm. Common grade 2 or higher side effects linked to vistusertib included fatigue, lymphopenia, hyperglycemia, and diarrhea.

Although low tumor grade, endometrioid subtype, and HR+ status are associated with response to endocrine therapy, the low overall response and progression-free survival in the anastrozole arm suggest that better patient selection is needed. “The choice of treatment according to the histologic characteristics is not sufficient, and highly selected molecular criteria are necessary,” the authors wrote.

The study is limited by its small size and a lack of data on expression level of hormone receptors.

The study was funded by the National Cancer Institute of France.

In an open-label, phase 1/2, randomized clinical trial (VICTORIA) performed at 12 cancer centers in France, the combination of the mammalian target of rapamycin inhibitor vistusertib with anastrozole led to reduced progression in hormone receptor–positive (HR+) endometrial cancer with good tolerability.

The study was published in JAMA Oncology.

Treatment of endometrial cancer involves a combination of surgery, radiation, and chemotherapy, but about 20% of patients relapse, usually within 5 years. HR+ endometrial cancer represents about 65% of endometrial cancers. It is usually endometrioid, and about 80% have phosphatase and tensin homologue (PTEN) mutations, while 36-52% have a mutation in the phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway.

Endocrine therapy alone elicits a response rate of 15%-30% in HR+ endometrial cancer, generally in low-grade endometrioid subtypes. Most responses are short in duration. Aromatase inhibitors like anastrozole are used for more often than progestogens because they are better tolerated and they have a lower thromboembolic risk in this patient population. Previously, the phase 2 PARAGON trial showed a response rate of just 7% with anastrozole monotherapy, but 44% in women with recurrent HR+ endometrial cancer gained a clinical benefit.

Deregulation in the PI3K/AKT/mTOR pathway can also lead to hormone resistance, suggesting that combination of an mTOR inhibitor with endocrine therapy might have a synergistic effect.

mTOR inhibition alone or in combination with endocrine treatment has been investigated in some single-arm studies, with some encouraging progression-free survival results, but no clear objective response rate or overall survival benefit.

The new study included just 73 patients with a median age of 69.5 years: 49 received 125 mg vistusertib 2 days per week and 1 mg anastrozole daily and 24 received anastrozole only. The 8-week progression-free rate was 67.3% (unilateral 95% confidence interval, 54.7%) in the combination arm versus 39.1% (unilateral 95% CI, 22.2%) in the anastrozole-only arm.

Among 6 patients in the safety run-in period of the combination arm, there were no serious adverse events. Overall response rate was 24.5% (95% CI, 13.3-38.9%) in the combination arm and 17.4% (95% CI, 5.0-38.8%) in the anastrozole-only arm.

Over a median follow-up of 27.7 months, progression-free survival was 5.2 months in the combination arm (95% CI, 3.4-8.9 months) and 1.9 months (95% CI, 1.6-8.9) In the anastrozole-only arm. Common grade 2 or higher side effects linked to vistusertib included fatigue, lymphopenia, hyperglycemia, and diarrhea.

Although low tumor grade, endometrioid subtype, and HR+ status are associated with response to endocrine therapy, the low overall response and progression-free survival in the anastrozole arm suggest that better patient selection is needed. “The choice of treatment according to the histologic characteristics is not sufficient, and highly selected molecular criteria are necessary,” the authors wrote.

The study is limited by its small size and a lack of data on expression level of hormone receptors.

The study was funded by the National Cancer Institute of France.

A 5-year cervical screening interval is as safe and effective for women who test negative for human papillomavirus (HPV) as are 3-year intervals, according to a new ‘real life’ study led by King’s College London (KCL) with researchers from the University of Manchester, and the NHS, on behalf of the HPV pilot steering group.

The study, published in The BMJ, used data from the HPV screening pilot to assess rates of detection of high-grade cervical intraepithelial neoplasia (CIN3+) and of cervical cancer following a negative HPV test. It confirmed that 5-yearly screening prevents as many cancers as screening at 3-year intervals, even in women who are not vaccinated against HPV.
 

Change to primary HPV testing since 2019 

Before 2019, the NHS cervical screening program conducted cytology testing first, testing for HPV only if abnormalities were found. In 2019, following reporting of early results of the HPV pilot by the same researchers, the program in England switched to testing for HPV first, on the grounds that since having HPV infection comes before having abnormal cells, HPV testing would detect more women at risk of cervical cancer.

Following the switch to primary HPV testing, the same screening intervals were retained, meaning 3-yearly screening for those aged 24-49 years and testing every 5 years for women aged 50-64 years, or 3 years if they tested positive. However, the National Screening Committee had recommended that invites should be changed from 3 to 5 years for those in the under-50 age group found not to have high-risk HPV at their routine screening test.

For the latest study, funded by Cancer Research UK, the steering group researchers analyzed details for more than 1.3 million women who had attended screening for two rounds of the HPV screening pilot, the first from 2013 to 2016, with a follow-up to the end of 2019. By this time, the data set had doubled in size from the pilot study, and results had been linked with the national cancer registry.

They confirmed that HPV testing was more accurate than a cytology test, irrespective of whether the HPV test assay was DNA- or mRNA-based. With HPV testing, the risk of subsequent cytological changes more than halved overall. Eligible women under 50 who had a negative HPV screen in the first round had a much lower risk of detection of CIN3+ in the second round, with a rate of 1.21 in 1,000, compared with 4.52 in 1,000 after a negative cytology test.
 

Data support extension of the testing interval

“The study confirms that women in this age group are much less likely to develop clinically relevant cervical lesions and cervical cancer, 3 years after a negative HPV screen, compared with a negative smear test,” the researchers said.

They suggested that most women do not need to be screened as frequently as the current program allows, and that the data support an extension of the screening intervals, regardless of the test assay used, to 5 years after a negative HPV test in women aged 25-49 years, and even longer for women aged 50 years and older.

However, the screening interval for HPV-positive women who have negative HPV tests at early recall should be kept at 3 years, they said.

“These results are very reassuring,” said lead author Matejka Rebolj, PhD, senior epidemiologist at KCL. “They build on previous research that shows that following the introduction of HPV testing for cervical screening, a 5-year interval is at least as safe as the previous 3-year interval. Changing to 5-yearly screening will mean we can prevent just as many cancers as before, while allowing for fewer screens.”

Michelle Mitchell, Cancer Research UK’s chief executive, said: “This large study shows that offering cervical screening using HPV testing effectively prevents cervical cancer, without having to be screened as often. This builds on findings from years of research showing HPV testing is more accurate at predicting who is at risk of developing cervical cancer compared to the previous way of testing. As changes to the screening [programs] are made, they will be monitored to help ensure that cervical screening is as effective as possible for all who take part.”
 

If HPV is present, testing interval should remain every 3 years

Responding to the study, Theresa Freeman-Wang, MBChB, consultant gynecologist, president of the British Society for Colposcopy and Cervical Pathology, and spokesperson for the Royal College of Obstetricians and Gynaecologists, told this news organization: “England, Scotland, and Wales and many other countries now use HPV primary screening, which is much better at assessing risk than previous methods. HPV testing is more sensitive and accurate, so changes are picked up earlier.

“Studies have confirmed that if someone is HPV negative (i.e., HPV is not present in the screen test), intervals between tests can very safely be increased from 3 to 5 years. 

“If HPV is present, then the program will automatically look for any abnormal cells. If there are no abnormalities, the woman will be advised to have a repeat screen test in a year. If the HPV remains present over 3 successive years or if abnormal cells are detected at any stage, she will be referred for a more detailed screening examination called a colposcopy.

“It’s important that with any change like this, there is clear information available to explain what these changes mean.

“We have an effective cervical screening program in the UK that has significantly reduced the number of cases and deaths from this preventable cancer. 

“HPV screening every 5 years is safe and to be fully effective it is vital that women take up the invitation for cervical screening when called.”

A version of this article first appeared on Medscape UK.

A 5-year cervical screening interval is as safe and effective for women who test negative for human papillomavirus (HPV) as are 3-year intervals, according to a new ‘real life’ study led by King’s College London (KCL) with researchers from the University of Manchester, and the NHS, on behalf of the HPV pilot steering group.

The study, published in The BMJ, used data from the HPV screening pilot to assess rates of detection of high-grade cervical intraepithelial neoplasia (CIN3+) and of cervical cancer following a negative HPV test. It confirmed that 5-yearly screening prevents as many cancers as screening at 3-year intervals, even in women who are not vaccinated against HPV.
 

Change to primary HPV testing since 2019 

Before 2019, the NHS cervical screening program conducted cytology testing first, testing for HPV only if abnormalities were found. In 2019, following reporting of early results of the HPV pilot by the same researchers, the program in England switched to testing for HPV first, on the grounds that since having HPV infection comes before having abnormal cells, HPV testing would detect more women at risk of cervical cancer.

Following the switch to primary HPV testing, the same screening intervals were retained, meaning 3-yearly screening for those aged 24-49 years and testing every 5 years for women aged 50-64 years, or 3 years if they tested positive. However, the National Screening Committee had recommended that invites should be changed from 3 to 5 years for those in the under-50 age group found not to have high-risk HPV at their routine screening test.

For the latest study, funded by Cancer Research UK, the steering group researchers analyzed details for more than 1.3 million women who had attended screening for two rounds of the HPV screening pilot, the first from 2013 to 2016, with a follow-up to the end of 2019. By this time, the data set had doubled in size from the pilot study, and results had been linked with the national cancer registry.

They confirmed that HPV testing was more accurate than a cytology test, irrespective of whether the HPV test assay was DNA- or mRNA-based. With HPV testing, the risk of subsequent cytological changes more than halved overall. Eligible women under 50 who had a negative HPV screen in the first round had a much lower risk of detection of CIN3+ in the second round, with a rate of 1.21 in 1,000, compared with 4.52 in 1,000 after a negative cytology test.
 

Data support extension of the testing interval

“The study confirms that women in this age group are much less likely to develop clinically relevant cervical lesions and cervical cancer, 3 years after a negative HPV screen, compared with a negative smear test,” the researchers said.

They suggested that most women do not need to be screened as frequently as the current program allows, and that the data support an extension of the screening intervals, regardless of the test assay used, to 5 years after a negative HPV test in women aged 25-49 years, and even longer for women aged 50 years and older.

However, the screening interval for HPV-positive women who have negative HPV tests at early recall should be kept at 3 years, they said.

“These results are very reassuring,” said lead author Matejka Rebolj, PhD, senior epidemiologist at KCL. “They build on previous research that shows that following the introduction of HPV testing for cervical screening, a 5-year interval is at least as safe as the previous 3-year interval. Changing to 5-yearly screening will mean we can prevent just as many cancers as before, while allowing for fewer screens.”

Michelle Mitchell, Cancer Research UK’s chief executive, said: “This large study shows that offering cervical screening using HPV testing effectively prevents cervical cancer, without having to be screened as often. This builds on findings from years of research showing HPV testing is more accurate at predicting who is at risk of developing cervical cancer compared to the previous way of testing. As changes to the screening [programs] are made, they will be monitored to help ensure that cervical screening is as effective as possible for all who take part.”
 

If HPV is present, testing interval should remain every 3 years

Responding to the study, Theresa Freeman-Wang, MBChB, consultant gynecologist, president of the British Society for Colposcopy and Cervical Pathology, and spokesperson for the Royal College of Obstetricians and Gynaecologists, told this news organization: “England, Scotland, and Wales and many other countries now use HPV primary screening, which is much better at assessing risk than previous methods. HPV testing is more sensitive and accurate, so changes are picked up earlier.

“Studies have confirmed that if someone is HPV negative (i.e., HPV is not present in the screen test), intervals between tests can very safely be increased from 3 to 5 years. 

“If HPV is present, then the program will automatically look for any abnormal cells. If there are no abnormalities, the woman will be advised to have a repeat screen test in a year. If the HPV remains present over 3 successive years or if abnormal cells are detected at any stage, she will be referred for a more detailed screening examination called a colposcopy.

“It’s important that with any change like this, there is clear information available to explain what these changes mean.

“We have an effective cervical screening program in the UK that has significantly reduced the number of cases and deaths from this preventable cancer. 

“HPV screening every 5 years is safe and to be fully effective it is vital that women take up the invitation for cervical screening when called.”

A version of this article first appeared on Medscape UK.

A 5-year cervical screening interval is as safe and effective for women who test negative for human papillomavirus (HPV) as are 3-year intervals, according to a new ‘real life’ study led by King’s College London (KCL) with researchers from the University of Manchester, and the NHS, on behalf of the HPV pilot steering group.

The study, published in The BMJ, used data from the HPV screening pilot to assess rates of detection of high-grade cervical intraepithelial neoplasia (CIN3+) and of cervical cancer following a negative HPV test. It confirmed that 5-yearly screening prevents as many cancers as screening at 3-year intervals, even in women who are not vaccinated against HPV.
 

Change to primary HPV testing since 2019 

Before 2019, the NHS cervical screening program conducted cytology testing first, testing for HPV only if abnormalities were found. In 2019, following reporting of early results of the HPV pilot by the same researchers, the program in England switched to testing for HPV first, on the grounds that since having HPV infection comes before having abnormal cells, HPV testing would detect more women at risk of cervical cancer.

Following the switch to primary HPV testing, the same screening intervals were retained, meaning 3-yearly screening for those aged 24-49 years and testing every 5 years for women aged 50-64 years, or 3 years if they tested positive. However, the National Screening Committee had recommended that invites should be changed from 3 to 5 years for those in the under-50 age group found not to have high-risk HPV at their routine screening test.

For the latest study, funded by Cancer Research UK, the steering group researchers analyzed details for more than 1.3 million women who had attended screening for two rounds of the HPV screening pilot, the first from 2013 to 2016, with a follow-up to the end of 2019. By this time, the data set had doubled in size from the pilot study, and results had been linked with the national cancer registry.

They confirmed that HPV testing was more accurate than a cytology test, irrespective of whether the HPV test assay was DNA- or mRNA-based. With HPV testing, the risk of subsequent cytological changes more than halved overall. Eligible women under 50 who had a negative HPV screen in the first round had a much lower risk of detection of CIN3+ in the second round, with a rate of 1.21 in 1,000, compared with 4.52 in 1,000 after a negative cytology test.
 

Data support extension of the testing interval

“The study confirms that women in this age group are much less likely to develop clinically relevant cervical lesions and cervical cancer, 3 years after a negative HPV screen, compared with a negative smear test,” the researchers said.

They suggested that most women do not need to be screened as frequently as the current program allows, and that the data support an extension of the screening intervals, regardless of the test assay used, to 5 years after a negative HPV test in women aged 25-49 years, and even longer for women aged 50 years and older.

However, the screening interval for HPV-positive women who have negative HPV tests at early recall should be kept at 3 years, they said.

“These results are very reassuring,” said lead author Matejka Rebolj, PhD, senior epidemiologist at KCL. “They build on previous research that shows that following the introduction of HPV testing for cervical screening, a 5-year interval is at least as safe as the previous 3-year interval. Changing to 5-yearly screening will mean we can prevent just as many cancers as before, while allowing for fewer screens.”

Michelle Mitchell, Cancer Research UK’s chief executive, said: “This large study shows that offering cervical screening using HPV testing effectively prevents cervical cancer, without having to be screened as often. This builds on findings from years of research showing HPV testing is more accurate at predicting who is at risk of developing cervical cancer compared to the previous way of testing. As changes to the screening [programs] are made, they will be monitored to help ensure that cervical screening is as effective as possible for all who take part.”
 

If HPV is present, testing interval should remain every 3 years

Responding to the study, Theresa Freeman-Wang, MBChB, consultant gynecologist, president of the British Society for Colposcopy and Cervical Pathology, and spokesperson for the Royal College of Obstetricians and Gynaecologists, told this news organization: “England, Scotland, and Wales and many other countries now use HPV primary screening, which is much better at assessing risk than previous methods. HPV testing is more sensitive and accurate, so changes are picked up earlier.

“Studies have confirmed that if someone is HPV negative (i.e., HPV is not present in the screen test), intervals between tests can very safely be increased from 3 to 5 years. 

“If HPV is present, then the program will automatically look for any abnormal cells. If there are no abnormalities, the woman will be advised to have a repeat screen test in a year. If the HPV remains present over 3 successive years or if abnormal cells are detected at any stage, she will be referred for a more detailed screening examination called a colposcopy.

“It’s important that with any change like this, there is clear information available to explain what these changes mean.

“We have an effective cervical screening program in the UK that has significantly reduced the number of cases and deaths from this preventable cancer. 

“HPV screening every 5 years is safe and to be fully effective it is vital that women take up the invitation for cervical screening when called.”

A version of this article first appeared on Medscape UK.

A cohort study has found increases in mortality rates among women with non-endometrioid uterine carcinoma, despite incident rates that have stabilized. After correction with hysterectomy, mortality risk was about doubled for Black women, compared with White women, and these results could not be explained by differences in cancer subtype or cancer stage at diagnosis. Non-endometroid uterine carcinoma represents 15%-20% of uterine cancers diagnosed and carries a worse prognosis.

“We do not know why non-endometrioid subtypes are disproportionately increasing among all women, nor do we understand why they are so much more common among non-Hispanic Black women. We need more research to identify risk factors and exposures more specifically associated with non-endometrioid cancers to better understand the strong increases in this subtype among all women and the particularly high rates and recent increases in non-Hispanic black women,” said lead author Megan Clarke, PhD, MHS, the study’s lead author and a cancer epidemiologist with the National Cancer Institute.

The study was published online in JAMA Oncology.

“Physicians should be aware that both incidence and mortality rates of non-endometrioid cancers are on the rise. Because these subtypes are rarer than endometrioid uterine cancers, physicians may be less familiar with diagnosing and treating these aggressive types of cancers. Increasing awareness among clinicians and patients regarding the signs and symptoms of uterine cancer (such as postmenopausal bleeding) and the differences in histologic subtypes among racial and ethnic groups may promote earlier diagnosis and timely referral to appropriate treatment,” Dr. Clarke said.

Previous studies based on death certificates found increased mortality, especially in Black women, but they were limited by an inability to link mortality to tumor characteristics. To address this, the researchers linked mortality data to records of 208,587 women diagnosed with uterine cancer between 2000 and 2017, drawn from the U.S. Surveillance, Epidemiology, and End Results (SEER) Program.

Black women represented 9.7% of cases, but they suffered 17.7% of uterine cancer deaths. Overall, mortality from uterine corpus cancer increased by 1.8% per year (95% confidence interval, 1.5%-2.9%). Non-endometroid cancers increased at 2.7% per year (95% CI, 1.8%-3.6%), and this was higher in Asian (3.4%; 95% CI, 0.3%-6.6%), Black (3.5%; 95% CI, 2.2%-4.9%), Hispanic (6.7%; 95% CI, 1.9%-11.8%), and White women (1.5%; 95% CI, 0.6%-2.4%).

Mortality increased 1.8% per year overall for uterine cancer and 2.7% per year for non-endometrioid uterine cancer. There was no increase in mortality seen in endometrioid cancers.

“The concerning rise in deaths from non-endometrioid cancers warrants clinical attention. Our findings suggest that there may be several factors contributing to racial disparities in uterine cancer mortality. Higher mortality rates among non-Hispanic Black women are partly attributable to higher incidence of tumors with aggressive subtypes and advanced stages. However, non-Hispanic Black women in our study who were diagnosed with less aggressive subtypes and early-stage disease also had the highest mortality rates,” said Dr. Clarke.

That suggests that inequities of treatment and high-quality care may be at least partly to blame, since those factors are known to contribute to differences in uterine cancer outcomes. “Other factors including comorbidities, health care facility characteristics, treatment preferences and adherence, patient and provider communication, provider bias, discrimination and structural racism, and potential biologic differences in response to treatment need to be better understood in terms of how they influence racial disparities,” Dr. Clarke said.

Dr. Clarke reported no relevant disclosures.

A cohort study has found increases in mortality rates among women with non-endometrioid uterine carcinoma, despite incident rates that have stabilized. After correction with hysterectomy, mortality risk was about doubled for Black women, compared with White women, and these results could not be explained by differences in cancer subtype or cancer stage at diagnosis. Non-endometroid uterine carcinoma represents 15%-20% of uterine cancers diagnosed and carries a worse prognosis.

“We do not know why non-endometrioid subtypes are disproportionately increasing among all women, nor do we understand why they are so much more common among non-Hispanic Black women. We need more research to identify risk factors and exposures more specifically associated with non-endometrioid cancers to better understand the strong increases in this subtype among all women and the particularly high rates and recent increases in non-Hispanic black women,” said lead author Megan Clarke, PhD, MHS, the study’s lead author and a cancer epidemiologist with the National Cancer Institute.

The study was published online in JAMA Oncology.

“Physicians should be aware that both incidence and mortality rates of non-endometrioid cancers are on the rise. Because these subtypes are rarer than endometrioid uterine cancers, physicians may be less familiar with diagnosing and treating these aggressive types of cancers. Increasing awareness among clinicians and patients regarding the signs and symptoms of uterine cancer (such as postmenopausal bleeding) and the differences in histologic subtypes among racial and ethnic groups may promote earlier diagnosis and timely referral to appropriate treatment,” Dr. Clarke said.

Previous studies based on death certificates found increased mortality, especially in Black women, but they were limited by an inability to link mortality to tumor characteristics. To address this, the researchers linked mortality data to records of 208,587 women diagnosed with uterine cancer between 2000 and 2017, drawn from the U.S. Surveillance, Epidemiology, and End Results (SEER) Program.

Black women represented 9.7% of cases, but they suffered 17.7% of uterine cancer deaths. Overall, mortality from uterine corpus cancer increased by 1.8% per year (95% confidence interval, 1.5%-2.9%). Non-endometroid cancers increased at 2.7% per year (95% CI, 1.8%-3.6%), and this was higher in Asian (3.4%; 95% CI, 0.3%-6.6%), Black (3.5%; 95% CI, 2.2%-4.9%), Hispanic (6.7%; 95% CI, 1.9%-11.8%), and White women (1.5%; 95% CI, 0.6%-2.4%).

Mortality increased 1.8% per year overall for uterine cancer and 2.7% per year for non-endometrioid uterine cancer. There was no increase in mortality seen in endometrioid cancers.

“The concerning rise in deaths from non-endometrioid cancers warrants clinical attention. Our findings suggest that there may be several factors contributing to racial disparities in uterine cancer mortality. Higher mortality rates among non-Hispanic Black women are partly attributable to higher incidence of tumors with aggressive subtypes and advanced stages. However, non-Hispanic Black women in our study who were diagnosed with less aggressive subtypes and early-stage disease also had the highest mortality rates,” said Dr. Clarke.

That suggests that inequities of treatment and high-quality care may be at least partly to blame, since those factors are known to contribute to differences in uterine cancer outcomes. “Other factors including comorbidities, health care facility characteristics, treatment preferences and adherence, patient and provider communication, provider bias, discrimination and structural racism, and potential biologic differences in response to treatment need to be better understood in terms of how they influence racial disparities,” Dr. Clarke said.

Dr. Clarke reported no relevant disclosures.

A cohort study has found increases in mortality rates among women with non-endometrioid uterine carcinoma, despite incident rates that have stabilized. After correction with hysterectomy, mortality risk was about doubled for Black women, compared with White women, and these results could not be explained by differences in cancer subtype or cancer stage at diagnosis. Non-endometroid uterine carcinoma represents 15%-20% of uterine cancers diagnosed and carries a worse prognosis.

“We do not know why non-endometrioid subtypes are disproportionately increasing among all women, nor do we understand why they are so much more common among non-Hispanic Black women. We need more research to identify risk factors and exposures more specifically associated with non-endometrioid cancers to better understand the strong increases in this subtype among all women and the particularly high rates and recent increases in non-Hispanic black women,” said lead author Megan Clarke, PhD, MHS, the study’s lead author and a cancer epidemiologist with the National Cancer Institute.

The study was published online in JAMA Oncology.

“Physicians should be aware that both incidence and mortality rates of non-endometrioid cancers are on the rise. Because these subtypes are rarer than endometrioid uterine cancers, physicians may be less familiar with diagnosing and treating these aggressive types of cancers. Increasing awareness among clinicians and patients regarding the signs and symptoms of uterine cancer (such as postmenopausal bleeding) and the differences in histologic subtypes among racial and ethnic groups may promote earlier diagnosis and timely referral to appropriate treatment,” Dr. Clarke said.

Previous studies based on death certificates found increased mortality, especially in Black women, but they were limited by an inability to link mortality to tumor characteristics. To address this, the researchers linked mortality data to records of 208,587 women diagnosed with uterine cancer between 2000 and 2017, drawn from the U.S. Surveillance, Epidemiology, and End Results (SEER) Program.

Black women represented 9.7% of cases, but they suffered 17.7% of uterine cancer deaths. Overall, mortality from uterine corpus cancer increased by 1.8% per year (95% confidence interval, 1.5%-2.9%). Non-endometroid cancers increased at 2.7% per year (95% CI, 1.8%-3.6%), and this was higher in Asian (3.4%; 95% CI, 0.3%-6.6%), Black (3.5%; 95% CI, 2.2%-4.9%), Hispanic (6.7%; 95% CI, 1.9%-11.8%), and White women (1.5%; 95% CI, 0.6%-2.4%).

Mortality increased 1.8% per year overall for uterine cancer and 2.7% per year for non-endometrioid uterine cancer. There was no increase in mortality seen in endometrioid cancers.

“The concerning rise in deaths from non-endometrioid cancers warrants clinical attention. Our findings suggest that there may be several factors contributing to racial disparities in uterine cancer mortality. Higher mortality rates among non-Hispanic Black women are partly attributable to higher incidence of tumors with aggressive subtypes and advanced stages. However, non-Hispanic Black women in our study who were diagnosed with less aggressive subtypes and early-stage disease also had the highest mortality rates,” said Dr. Clarke.

That suggests that inequities of treatment and high-quality care may be at least partly to blame, since those factors are known to contribute to differences in uterine cancer outcomes. “Other factors including comorbidities, health care facility characteristics, treatment preferences and adherence, patient and provider communication, provider bias, discrimination and structural racism, and potential biologic differences in response to treatment need to be better understood in terms of how they influence racial disparities,” Dr. Clarke said.

Dr. Clarke reported no relevant disclosures.

CA-125, or cancer antigen 125, is an epitope (antigen) on the transmembrane glycoprotein MUC16, or mucin 16. This protein is expressed on the surface of tissue derived from embryonic coelomic and Müllerian epithelium including the reproductive tract. CA-125 is also expressed in other tissue such as the pleura, lungs, pericardium, intestines, and kidneys. MUC16 plays an important role in tumor proliferation, invasiveness, and cell motility.¹ In patients with epithelial ovarian cancer (EOC), CA-125 may be found on the surface of ovarian cancer cells. It is shed in the bloodstream and can be quantified using a serum test.

There are a number of CA-125 assays in commercial use, and although none have been deemed to be clinically superior, there can be some differences between assays. It is important, if possible, to use the same assay when following serial CA-125 values. Most frequently, this will mean getting the test through the same laboratory.

CA-125 has Food and Drug Administration approval for use in patients with a current or prior diagnosis of ovarian cancer to monitor treatment response, progression of disease, or disease recurrence.

It is frequently used off label in the workup of adnexal masses, while not FDA approved. CA-125 and other serum biomarkers may help determine the etiology of an adnexal mass; however, they are not diagnostic and should be used thoughtfully. It is important to have conversations with patients before ordering a CA-125 (or other serum biomarkers) about potential results and their effect on diagnosis and treatment. This will lessen some patient anxiety when tests results become available, especially in the setting of autoreleasing results under the Cures Act.

One of the reasons that CA-125 can be difficult to interpret when used as a diagnostic tool is the number of nonmalignant disease processes that can result in CA-125 elevations. CA-125 can be elevated in inflammatory and infectious disease states, including but not limited to, chronic obstructive pulmonary disease, pelvic inflammatory disease, diverticulitis, and pneumonia. Severe/critical COVID-19 infection has recently been found to be associated with increased levels of CA-125.² It is important to obtain a complete medical history and to take specific note of any current or recent flares in inflammatory or infectious processes that could contribute to CA-125 elevations.

Special caution should be taken in premenopausal patients. The sensitivity and specificity of CA-125 are lower in this cohort of patients compared to postmenopausal women. This is multifactorial but in part due to gynecologic conditions that can increase CA-125, such as uterine fibroids and endometriosis, and the higher incidence of nonepithelial ovarian cancers (which frequently have different serum biomarkers) in younger patients. A patient’s gynecologic history, her age, and ultrasound or other imaging findings should help determine what, if any, serum biomarkers are appropriate for workup of an adnexal mass rather than the default ordering of CA-125 to determine need for referral to gynecologic oncology. If the decision has been made to take the patient to the operating room, CA-125 is not approved as a triage tool to guide who best to perform the surgery. In this case, one of two serum tumor marker panel tests that has received FDA approval for triage after the decision for surgery has been made (the multivariate index assay or the risk of ovarian malignancy algorithm) should be used.

When considering its ability to serve as a diagnostic test for ovarian cancer, the sensitivity of CA-125 is affected by the number of patients with epithelial ovarian cancer who have a test result that falls within the normal range (up to 50% of patients with stage I disease).³ The specificity of CA-125 is affected by the large number of nonmalignant conditions that can cause its elevation. Depending on the age of the patient, her menopausal status, comorbid conditions, and reason for obtaining serum biomarkers (e.g., decision for surgery has already been made), CA-125 (or CA-125 alone) may not be the best tool to use in the workup of an adnexal mass and can cause significant patient anxiety. In the setting of acute disease, such as COVID-19 infection, it may be better to delay obtaining serum biomarkers for the work-up of an adnexal mass. If delay is not feasible, then repeat serum biomarkers once the acute phase of illness has passed.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Thériault C et al. Gynecol Oncol. 2011 Jun 1;121(3):434-43.

2. Wei X et al. J Med Virol. 2020;92(10):2036-41.

3. Zurawski VR Jr et al. Int J Cancer. 1988;42:677-80.

CA-125, or cancer antigen 125, is an epitope (antigen) on the transmembrane glycoprotein MUC16, or mucin 16. This protein is expressed on the surface of tissue derived from embryonic coelomic and Müllerian epithelium including the reproductive tract. CA-125 is also expressed in other tissue such as the pleura, lungs, pericardium, intestines, and kidneys. MUC16 plays an important role in tumor proliferation, invasiveness, and cell motility.¹ In patients with epithelial ovarian cancer (EOC), CA-125 may be found on the surface of ovarian cancer cells. It is shed in the bloodstream and can be quantified using a serum test.

There are a number of CA-125 assays in commercial use, and although none have been deemed to be clinically superior, there can be some differences between assays. It is important, if possible, to use the same assay when following serial CA-125 values. Most frequently, this will mean getting the test through the same laboratory.

CA-125 has Food and Drug Administration approval for use in patients with a current or prior diagnosis of ovarian cancer to monitor treatment response, progression of disease, or disease recurrence.

It is frequently used off label in the workup of adnexal masses, while not FDA approved. CA-125 and other serum biomarkers may help determine the etiology of an adnexal mass; however, they are not diagnostic and should be used thoughtfully. It is important to have conversations with patients before ordering a CA-125 (or other serum biomarkers) about potential results and their effect on diagnosis and treatment. This will lessen some patient anxiety when tests results become available, especially in the setting of autoreleasing results under the Cures Act.

One of the reasons that CA-125 can be difficult to interpret when used as a diagnostic tool is the number of nonmalignant disease processes that can result in CA-125 elevations. CA-125 can be elevated in inflammatory and infectious disease states, including but not limited to, chronic obstructive pulmonary disease, pelvic inflammatory disease, diverticulitis, and pneumonia. Severe/critical COVID-19 infection has recently been found to be associated with increased levels of CA-125.² It is important to obtain a complete medical history and to take specific note of any current or recent flares in inflammatory or infectious processes that could contribute to CA-125 elevations.

Special caution should be taken in premenopausal patients. The sensitivity and specificity of CA-125 are lower in this cohort of patients compared to postmenopausal women. This is multifactorial but in part due to gynecologic conditions that can increase CA-125, such as uterine fibroids and endometriosis, and the higher incidence of nonepithelial ovarian cancers (which frequently have different serum biomarkers) in younger patients. A patient’s gynecologic history, her age, and ultrasound or other imaging findings should help determine what, if any, serum biomarkers are appropriate for workup of an adnexal mass rather than the default ordering of CA-125 to determine need for referral to gynecologic oncology. If the decision has been made to take the patient to the operating room, CA-125 is not approved as a triage tool to guide who best to perform the surgery. In this case, one of two serum tumor marker panel tests that has received FDA approval for triage after the decision for surgery has been made (the multivariate index assay or the risk of ovarian malignancy algorithm) should be used.

When considering its ability to serve as a diagnostic test for ovarian cancer, the sensitivity of CA-125 is affected by the number of patients with epithelial ovarian cancer who have a test result that falls within the normal range (up to 50% of patients with stage I disease).³ The specificity of CA-125 is affected by the large number of nonmalignant conditions that can cause its elevation. Depending on the age of the patient, her menopausal status, comorbid conditions, and reason for obtaining serum biomarkers (e.g., decision for surgery has already been made), CA-125 (or CA-125 alone) may not be the best tool to use in the workup of an adnexal mass and can cause significant patient anxiety. In the setting of acute disease, such as COVID-19 infection, it may be better to delay obtaining serum biomarkers for the work-up of an adnexal mass. If delay is not feasible, then repeat serum biomarkers once the acute phase of illness has passed.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Thériault C et al. Gynecol Oncol. 2011 Jun 1;121(3):434-43.

2. Wei X et al. J Med Virol. 2020;92(10):2036-41.

3. Zurawski VR Jr et al. Int J Cancer. 1988;42:677-80.

CA-125, or cancer antigen 125, is an epitope (antigen) on the transmembrane glycoprotein MUC16, or mucin 16. This protein is expressed on the surface of tissue derived from embryonic coelomic and Müllerian epithelium including the reproductive tract. CA-125 is also expressed in other tissue such as the pleura, lungs, pericardium, intestines, and kidneys. MUC16 plays an important role in tumor proliferation, invasiveness, and cell motility.¹ In patients with epithelial ovarian cancer (EOC), CA-125 may be found on the surface of ovarian cancer cells. It is shed in the bloodstream and can be quantified using a serum test.

There are a number of CA-125 assays in commercial use, and although none have been deemed to be clinically superior, there can be some differences between assays. It is important, if possible, to use the same assay when following serial CA-125 values. Most frequently, this will mean getting the test through the same laboratory.

CA-125 has Food and Drug Administration approval for use in patients with a current or prior diagnosis of ovarian cancer to monitor treatment response, progression of disease, or disease recurrence.

It is frequently used off label in the workup of adnexal masses, while not FDA approved. CA-125 and other serum biomarkers may help determine the etiology of an adnexal mass; however, they are not diagnostic and should be used thoughtfully. It is important to have conversations with patients before ordering a CA-125 (or other serum biomarkers) about potential results and their effect on diagnosis and treatment. This will lessen some patient anxiety when tests results become available, especially in the setting of autoreleasing results under the Cures Act.

One of the reasons that CA-125 can be difficult to interpret when used as a diagnostic tool is the number of nonmalignant disease processes that can result in CA-125 elevations. CA-125 can be elevated in inflammatory and infectious disease states, including but not limited to, chronic obstructive pulmonary disease, pelvic inflammatory disease, diverticulitis, and pneumonia. Severe/critical COVID-19 infection has recently been found to be associated with increased levels of CA-125.² It is important to obtain a complete medical history and to take specific note of any current or recent flares in inflammatory or infectious processes that could contribute to CA-125 elevations.

Special caution should be taken in premenopausal patients. The sensitivity and specificity of CA-125 are lower in this cohort of patients compared to postmenopausal women. This is multifactorial but in part due to gynecologic conditions that can increase CA-125, such as uterine fibroids and endometriosis, and the higher incidence of nonepithelial ovarian cancers (which frequently have different serum biomarkers) in younger patients. A patient’s gynecologic history, her age, and ultrasound or other imaging findings should help determine what, if any, serum biomarkers are appropriate for workup of an adnexal mass rather than the default ordering of CA-125 to determine need for referral to gynecologic oncology. If the decision has been made to take the patient to the operating room, CA-125 is not approved as a triage tool to guide who best to perform the surgery. In this case, one of two serum tumor marker panel tests that has received FDA approval for triage after the decision for surgery has been made (the multivariate index assay or the risk of ovarian malignancy algorithm) should be used.

When considering its ability to serve as a diagnostic test for ovarian cancer, the sensitivity of CA-125 is affected by the number of patients with epithelial ovarian cancer who have a test result that falls within the normal range (up to 50% of patients with stage I disease).³ The specificity of CA-125 is affected by the large number of nonmalignant conditions that can cause its elevation. Depending on the age of the patient, her menopausal status, comorbid conditions, and reason for obtaining serum biomarkers (e.g., decision for surgery has already been made), CA-125 (or CA-125 alone) may not be the best tool to use in the workup of an adnexal mass and can cause significant patient anxiety. In the setting of acute disease, such as COVID-19 infection, it may be better to delay obtaining serum biomarkers for the work-up of an adnexal mass. If delay is not feasible, then repeat serum biomarkers once the acute phase of illness has passed.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Thériault C et al. Gynecol Oncol. 2011 Jun 1;121(3):434-43.

2. Wei X et al. J Med Virol. 2020;92(10):2036-41.

3. Zurawski VR Jr et al. Int J Cancer. 1988;42:677-80.

Imiquimod cream is a safe, effective, first-line alternative to surgery for the treatment of vulvar high-grade squamous intraepithelial lesions (vHSILs), suggest the results from the first randomized trial to compare the two approaches directly.

The findings provide women with human papillomavirus (HPV)–related precancerous lesions with a new treatment option that can circumvent drawbacks of surgery, according to first author Gerda Trutnovsky, MD, deputy head of the Division of Gynecology at the Medical University of Graz, Austria.

“Surgical removal of [vulvar intraepithelial neoplasia] can cause wound healing disorders, scarring, and even sexual complaints later on,” she explained in a press statement. Further, recurrences are common, and repeat surgeries are often necessary, she said.

The results from the trial show that “imiquimod cream was effective and well tolerated, and the rate of success of this treatment equaled that of surgery,” Dr. Trutnovsky said.

The study was published online in The Lancet.

The findings are of note because HPV vaccination rates remain low, and the incidence of both cervical and vulvar intraepithelial neoplasia has increased in recent years, particularly among younger women, the authors comment.
 

First head-to-head trial

For the trial, Dr. Trutnovsky and her colleagues randomly assigned 110 women with vHSIL to receive either imiquimod treatment or surgery between June 2013 and January 2020. Of these patients, 78% had unifocal lesions, and 22% had multifocal lesions.

The participants (aged 18-90 years) were recruited from six hospitals in Austria. All had histologically confirmed vHSIL with visible unifocal or multifocal lesions. Those with suspected invasive disease, a history of vulvar cancer or severe inflammatory dermatosis of the vulva, or who had undergone active treatment for vHSIL in the prior 3 months were excluded.

Imiquimod treatment was self-administered. The dose was slowly escalated to no more than three times per week for 4-6 months. Surgery involved either excision or ablation.

The team reports that 98 patients (of the 110 who were randomly assigned) completed the study: 46 in the imiquinod arm and 52 in the surgery arm.

Complete clinical response rates at 6 months were 80% with imiquimod versus 79% with surgery. No significant difference was observed between the groups with respect to HPV clearance, adverse events, and treatment satisfaction, the authors report.

“Long-term follow-up ... is ongoing and will assess the effect of treatment modality on recurrence rates,” the team comments.

Dr. Trutnovsky and colleagues recommend that patients with vHSIL be counseled regarding the potential benefits and risks of treatment options. “On the basis of our results, the oncological safety of imiquimod treatment can be assumed as long as regular clinical check-ups are carried out,” they write.

They also note that good patient compliance is important for treatment with imiquimod to be successful and that surgery might remain the treatment of choice for patients who may not be adherent to treatment.

“In all other women with vHSIL, imiquimod can be considered a first-line treatment option,” the authors conclude.

The study was funded by the Austrian Science Fund and Austrian Gynaecological Oncology group. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Imiquimod cream is a safe, effective, first-line alternative to surgery for the treatment of vulvar high-grade squamous intraepithelial lesions (vHSILs), suggest the results from the first randomized trial to compare the two approaches directly.

The findings provide women with human papillomavirus (HPV)–related precancerous lesions with a new treatment option that can circumvent drawbacks of surgery, according to first author Gerda Trutnovsky, MD, deputy head of the Division of Gynecology at the Medical University of Graz, Austria.

“Surgical removal of [vulvar intraepithelial neoplasia] can cause wound healing disorders, scarring, and even sexual complaints later on,” she explained in a press statement. Further, recurrences are common, and repeat surgeries are often necessary, she said.

The results from the trial show that “imiquimod cream was effective and well tolerated, and the rate of success of this treatment equaled that of surgery,” Dr. Trutnovsky said.

The study was published online in The Lancet.

The findings are of note because HPV vaccination rates remain low, and the incidence of both cervical and vulvar intraepithelial neoplasia has increased in recent years, particularly among younger women, the authors comment.
 

First head-to-head trial

For the trial, Dr. Trutnovsky and her colleagues randomly assigned 110 women with vHSIL to receive either imiquimod treatment or surgery between June 2013 and January 2020. Of these patients, 78% had unifocal lesions, and 22% had multifocal lesions.

The participants (aged 18-90 years) were recruited from six hospitals in Austria. All had histologically confirmed vHSIL with visible unifocal or multifocal lesions. Those with suspected invasive disease, a history of vulvar cancer or severe inflammatory dermatosis of the vulva, or who had undergone active treatment for vHSIL in the prior 3 months were excluded.

Imiquimod treatment was self-administered. The dose was slowly escalated to no more than three times per week for 4-6 months. Surgery involved either excision or ablation.

The team reports that 98 patients (of the 110 who were randomly assigned) completed the study: 46 in the imiquinod arm and 52 in the surgery arm.

Complete clinical response rates at 6 months were 80% with imiquimod versus 79% with surgery. No significant difference was observed between the groups with respect to HPV clearance, adverse events, and treatment satisfaction, the authors report.

“Long-term follow-up ... is ongoing and will assess the effect of treatment modality on recurrence rates,” the team comments.

Dr. Trutnovsky and colleagues recommend that patients with vHSIL be counseled regarding the potential benefits and risks of treatment options. “On the basis of our results, the oncological safety of imiquimod treatment can be assumed as long as regular clinical check-ups are carried out,” they write.

They also note that good patient compliance is important for treatment with imiquimod to be successful and that surgery might remain the treatment of choice for patients who may not be adherent to treatment.

“In all other women with vHSIL, imiquimod can be considered a first-line treatment option,” the authors conclude.

The study was funded by the Austrian Science Fund and Austrian Gynaecological Oncology group. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Imiquimod cream is a safe, effective, first-line alternative to surgery for the treatment of vulvar high-grade squamous intraepithelial lesions (vHSILs), suggest the results from the first randomized trial to compare the two approaches directly.

The findings provide women with human papillomavirus (HPV)–related precancerous lesions with a new treatment option that can circumvent drawbacks of surgery, according to first author Gerda Trutnovsky, MD, deputy head of the Division of Gynecology at the Medical University of Graz, Austria.

“Surgical removal of [vulvar intraepithelial neoplasia] can cause wound healing disorders, scarring, and even sexual complaints later on,” she explained in a press statement. Further, recurrences are common, and repeat surgeries are often necessary, she said.

The results from the trial show that “imiquimod cream was effective and well tolerated, and the rate of success of this treatment equaled that of surgery,” Dr. Trutnovsky said.

The study was published online in The Lancet.

The findings are of note because HPV vaccination rates remain low, and the incidence of both cervical and vulvar intraepithelial neoplasia has increased in recent years, particularly among younger women, the authors comment.
 

First head-to-head trial

For the trial, Dr. Trutnovsky and her colleagues randomly assigned 110 women with vHSIL to receive either imiquimod treatment or surgery between June 2013 and January 2020. Of these patients, 78% had unifocal lesions, and 22% had multifocal lesions.

The participants (aged 18-90 years) were recruited from six hospitals in Austria. All had histologically confirmed vHSIL with visible unifocal or multifocal lesions. Those with suspected invasive disease, a history of vulvar cancer or severe inflammatory dermatosis of the vulva, or who had undergone active treatment for vHSIL in the prior 3 months were excluded.

Imiquimod treatment was self-administered. The dose was slowly escalated to no more than three times per week for 4-6 months. Surgery involved either excision or ablation.

The team reports that 98 patients (of the 110 who were randomly assigned) completed the study: 46 in the imiquinod arm and 52 in the surgery arm.

Complete clinical response rates at 6 months were 80% with imiquimod versus 79% with surgery. No significant difference was observed between the groups with respect to HPV clearance, adverse events, and treatment satisfaction, the authors report.

“Long-term follow-up ... is ongoing and will assess the effect of treatment modality on recurrence rates,” the team comments.

Dr. Trutnovsky and colleagues recommend that patients with vHSIL be counseled regarding the potential benefits and risks of treatment options. “On the basis of our results, the oncological safety of imiquimod treatment can be assumed as long as regular clinical check-ups are carried out,” they write.

They also note that good patient compliance is important for treatment with imiquimod to be successful and that surgery might remain the treatment of choice for patients who may not be adherent to treatment.

“In all other women with vHSIL, imiquimod can be considered a first-line treatment option,” the authors conclude.

The study was funded by the Austrian Science Fund and Austrian Gynaecological Oncology group. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Cervical cancer is an important global health problem with an estimated 604,127 new cases and 341,831 deaths in 2020.¹ Nearly 85% of the disease burden affects individuals from low and middle-income countries. The World Health Organization (WHO) set forth the goal for all countries to reach and maintain an incidence rate of below 4 per 100,000 women by 2030 as part of the Global Strategy to Accelerate the Elimination of Cervical Cancer.

Although traditional Pap cytology has been the cornerstone of screening programs, its poor sensitivity of approximately 50% and limitations in accessibility require new strategies to achieve the elimination of cervical cancer.² The discovery that persistent infection with oncogenic human papillomavirus (HPV) is an essential step in the development of cervical cancer led to the development of diagnostic HPV tests, which have higher sensitivity than cytology (96.1% vs 53.0%) but somewhat lower specificity (90.7% vs 96.3%) for the detection of cervical intraepithelial neoplasia (CIN) 2 or worse lesions.² Initially, HPV testing was incorporated as a method to triage atypical squamous cells of undetermined significance (ASCUS) cytology results.³ Later, the concept of cotesting with cytology emerged,^4,5 and since then, several clinical trials have demonstrated the effectiveness of primary HPV screening.^6-9

In 2020, the WHO recommended HPV DNA testing as the primary screening method starting at the age of 30 years, with regular testing every 5 to 10 years, for the general population.¹⁰ Currently, primary HPV has been adopted in multiple countries, including Australia, the Netherlands, Turkey, England, and Argentina.

In the United States, there are 3 currently acceptable screening strategies: cytology, cytology plus HPV (cotesting), and primary HPV testing (TABLE). The American Cancer Society (ACS) specifically states that HPV testing alone every 5 years is preferred starting at age 25 years; cotesting every 5 years or cytology alone every 3 years are also acceptable.¹¹ The US Preventive Services Task Force (USPSTF) states that cytology alone every 3 years starting at 21 years and then HPV testing alone or cotesting every 5 years or cytology every 3 years starting at age 30 are all acceptable strategies.¹²

When applying these guidelines, it is important to note that they are intended for the screening of patients with all prior normal results with no symptoms. These routine screening guidelines do not apply to special populations, such as those with a history of abnormal results or treatment, a history of immunosuppression,¹³ a history of HPV-related vulvar or vaginal dysplasia,^14-16 or a history of hysterectomy with removal of the cervix and no prior history of cervical dysplasia.^17,18 By contrast, surveillance is interval testing for those who have either an abnormal prior test result or treatment; these may be managed per risk-based estimates provided by the American Society for Colposcopy and Cervical Pathology (ASCCP).^18,19 Finally, diagnosis is evaluation (which may include diagnostic cytology) of a patient with abnormal signs and/or symptoms (such as bleeding, pain, discharge, or cervical mass).

In this Update, we present the evidence for primary HPV testing, the management options for a positive result in the United States, and research that will improve uptake of primary HPV testing as well as accessibility.

Change in screening paradigm: Evidence for primary HPV testing

HPV DNA tests are multiplex assays that detect the DNA of targeted high-risk HPV types, using multiple probes, either by direct genomic detection or by amplification of a viral DNA fragment using polymerase chain reaction (PCR).^20,21 Alternatively, HPV mRNA-based tests detect the expression of E6 and E7 oncoproteins, a marker of viral integration.²⁰ In examining the data from well-conducted clinical trials, 2 important observations are that different HPV assays were used and that direct comparison may not be valid. In addition, not all tests used in the studies are approved by the US Food and Drug Administration (FDA) for primary HPV testing.

Continue to: FDA-approved HPV tests...

Currently, 2 tests are FDA approved for primary HPV screening. The Cobas HPV test (Roche Molecular Diagnostics) was the first FDA-approved test for primary HPV screening in women aged 25 years and older.⁶ This test reports pooled results from 12 high-risk (hr) HPV types (31/33/35/39/45/51/52/56/58/59/66/68) with reflex genotyping for HPV 16/18, and thus it provides an immediate triage option for HPV-positive women. Of note, it is also approved for cotesting. The second FDA-approved test is the BD Onclarity HPV assay (Becton, Dickinson and Company) for primary HPV screening.²² It detects 14 hrHPV types, types 16/18/45 specifically as well as types 31/33/35/39/51/52/56/58/59/66/68.

Other HPV tests are FDA approved for cotesting and reflex testing but not for primary HPV testing. The Hybrid Capture test, or HC2 (Qiagen Inc), was the first HPV test to be approved by the FDA in 1997 for reflex testing of women with ASCUS cytology. In 2003, it was approved for cotesting along with cytology in women aged 30 years and older.^20,21 In 2009, the Cervista HPV HR test (Hologic Inc) was approved for cotesting. The Aptima HPV assay (Hologic Inc), which is also approved for cotesting, is an RNA-based assay that allows detection of E6/E7 mRNA transcripts of 14 HPV types.²³

Comparing HPV testing with cytology

Ronco and colleagues pooled data from 4 European randomized controlled trials (RCTs)—Swedescreen, POBASCAM, NTCC, ARTISTIC—with a total of 176,464 participants randomly assigned to HPV or cytology screening.²⁴ Swedescreen and POBASCAM used GP5/GP6 PCR, while ARTISTIC and NTCC used HC2 for primary HPV screening. The screening interval was 3 years in all except 5 years in POBASCAM. The pooled detection rate of invasive disease was similar in the 2 arms, with pooled rate ratio for cancer detection being 0.79 (95% confidence interval [CI], 0.46–1.36) in the first 2.5 years, but was 0.45 (95% CI, 0.25–0.81), favoring the HPV arm, after 2.5 years. HPV testing was more effective in preventing cases of adenocarcinoma than squamous cell carcinoma (0.31 [95% CI, 0.14–0.69] vs 0.78 [95% CI, 0.49–1.25]). The authors concluded that HPV-based screening from age 30 years provided 60% to 70% better protection than cytology.

The result of the above meta-analysis was confirmed by the HPV FOCAL RCT that investigated the efficacy of HPV testing (HC2) in comparison with cytology.²⁵ The detection rates for CIN 3 lesions supported primary HPV screening, with an absolute difference in incidence rate of 2.67/1,000 (95% CI, 0.53–4.88) at study randomization and 3.22/1,000 (95% CI, 5.12–1.48) at study exit 4 years later.

Cotesting using HPV and cytology: Marginal benefit

Dillner and colleagues were one of the first groups to report on the risk of CIN 3 based on both HPV and cytology status.²⁶ Using pooled analysis of data from multiple countries, these investigators reported that the cumulative incidence rates (CIR) of CIN 3 after 6 years of follow-up increased consistently in HPV-positive subjects, and an HPV-positive result more accurately predicted CIN 3+ at 5 years than cytology alone. Furthermore, HPV negativity provided greater reassurance than cytology alone. At 5 years of follow-up, the rates of CIN 3+ were 0.25% (0.12%–0.41%) for women negative for HPV compared with 0.83% (0.50%–1.13%) for women with negative cytology results. There was little difference in rates for CIN 3+ between women with negative results on both tests and women who were negative for HPV.

The important question is then the marginal benefit of cotesting, which is the most costly screening option. A study of 331,818 women enrolled for cotesting at Kaiser Permanente found that the risk of CIN 3+ predicted by HPV testing alone when compared with cytology was significantly higher at both 3 years (5.0% vs 3.8%; P = .046) and 5 years (7.6% vs 4.7%; P = .001).²⁷ A negative cytology result did not decrease the risk of CIN 3 further for HPV-negative patients (3 years: 0.047% vs 0.063%, P = .6; 5 years: 0.16% vs 0.17%, P = .8). They concluded that a negative HPV test was enough reassurance for low risk of CIN 3+ and that an additional negative cytology result does not provide extra reassurance.

Furthermore, a systematic meta-analysis of 48 studies, including 8 RCTs, found that the addition of cytology to HPV testing raised the sensitivity by 2% for CIN 3 compared with HPV testing alone. This improvement in sensitivity was at the expense of considerable loss of specificity, with a ratio of 0.93 (95% CI, 0.92–0.95) for CIN 3.²⁸ Schiffman and colleagues also assessed the relative contribution of HPV testing and cytology in detection of CIN 3 and cancer.²⁹ The HPV component alone identified a significantly higher proportion of preinvasive and invasive disease than cytology. Only 3.5% of precancers and 5.9% of cancers were preceded by HPV-negative, cytology-positive results. Thus, cytology contributed only 5 cases per million women per year to the sensitivity of the combined test, at the cost of significantly more colposcopies. Hence, the evidence suggests that there is limited benefit of adding cytology to HPV testing.³⁰

Continue to: Triage of a positive HPV result...

An important limitation of HPV testing is its inability to discriminate between transient and persistent infections. Referral of all HPV-positive cases to colposcopy would overburden the system with associated unnecessary procedures. Hence, a triage strategy is essential to identify clinically important infections that truly require colposcopic evaluation. The FIGURE illustrates the management of a primary HPV test result performed for screening.

HPV genotyping

One strategy for triaging a positive HPV test result is genotyping. HPV 16 and 18 have the highest risk of persistence and progression and merit immediate referral to colposcopy. In the ATHENA trial, CIN 3 was identified in 17.8% (95% CI, 14.8–20.7%) of HPV 16 positive women at baseline, and the CIR increased to 25.2% (95% CI, 21.7–28.7%) after 3 years. The 3-year CIR of CIN 3 was only 5.4% (95% CI, 4.5–6.3%) in women with HPV genotypes other than 16/18. HPV 18–positive women had a 3-year CIR that was intermediate between women with HPV 16 and women with the 12 other genotypes.⁶ Hence, HPV 16/18–positive cases should be referred for immediate colposcopy, and negative cases should be followed up with cytology and referred for colposcopy if the cytology is ASCUS or worse.³¹

In July 2020, extended genotyping was approved by the FDA with individual detection of HPV 31, 51, 52 (in addition to 16, 18, and 45) and pooled detection of 33/58, 35/39/68, and 56/59/66. One study found that individual genotypes HPV 16 and 31 carry baseline risk values for CIN 3+ (8.1% and 7.5%, respectively) that are above the 5-year risk threshold for referral to colposcopy following the ASCCP risk-based management guideline.³²

Cytology

The higher specificity of cytology makes it an option for triaging HPV-positive cases, and current management guidelines recommend triage to both genotyping and cytology for all patients who are HPV positive, and especially if they are HPV positive but HPV 16/18 negative. Of note, cytology results remain more subjective than those of primary HPV testing, but the combination of initial HPV testing with reflex to cytology is a reasonable and cost effective next step.¹⁸ The VASCAR trial found higher colposcopy referrals in the HPV screening and cytology triage group compared with the cytology alone group (19.36 vs 14.54 per 1,000 women).³³ The ATHENA trial investigated various triage strategies for HPV-positive cases and its impact on colposcopy referrals.⁶ Using HPV genotyping and reflex cytology, if HPV 16/18 was positive, colposcopy was advised, but if any of the other 12 HPV types were positive, reflex cytology was done. If reported as ASCUS or worse, colposcopy was performed; conversely, if it was normal, women were rescreened with cotesting after 1 year. Although this strategy led to a reduction in the number of colposcopies, referrals were still higher in the primary HPV arm (3,769 colposcopies per 294 cases) compared with cytology (1,934 colposcopies per 179 cases) or cotesting (3,097 colposcopies per 240 cases) in women aged 25 years.¹⁴

p16/Ki-67 Dual-Stain

Diffused p16 immunohistochemical staining, as opposed to focal staining, is associated with active HPV infection but can be present in low-grade as well as high-grade lesions.³⁴ Ki-67 is a marker of cellular proliferation. Coexpression of p16 and Ki-67 indicates a loss of cell cycle regulation and is a hallmark of neoplastic transformation. When positive, these tests are supportive of active HPV infection and of a high-grade lesion. Incorporation of these stains to cytology alone provides additional objective reassurance to cytology, where there is much inter- and intra-observer variability. These stains can be done by laboratories using the stains alone or they can use the FDA-approved p16/Ki-67 Dual-Stain immunohistochemistry (DS), CINtec PLUS Cytology (Roche Diagnostics). However, DS is not yet formally incorporated into triage algorithms by national guidelines.

The IMPACT trial assessed the performance of DS compared with cytology in the triage of HPV-positive results, with or without HPV 16/18 genotyping.³⁵ This was a prospective observational screening study of 35,263 women aged 25 to 65 years across 32 sites in the United States. Of the 4,927 HPV-positive patients with DS results, the sensitivity of DS for CIN 3+ was 91.9% (95% CI, 86.1%–95.4%) and 86.0% (95% CI, 77.5%–91.6%) in HPV 16/18–positive and in the 12 other genotypes, respectively. Using DS alone to triage HPV-positive results showed significantly higher sensitivity and specificity than HPV 16/18 genotyping with cytology triage of 12 “other” genotypes, and substantially higher sensitivity but lower specificity than using cytology alone. Of note, triage with DS alone would have referred significantly fewer women to colposcopy than HPV 16/18 genotyping with cytology triage for the 12 other genotypes (48.6% vs 56.0%; P< .0001).

Similarly, a retrospective analysis of the ATHENA trial cohort of HPV-positive results of 7,727 patients aged 25 years or older also demonstrated increased sensitivity of DS compared with cytology (74.9% vs 51.9%; P<.0001) and similar specificities (74.1% vs 75%; P = .3198).³⁶ The European PALMS study, which included 27,349 women aged 18 years or older across 5 countries who underwent routine screening with HPV testing, cytology, and DS, confirmed these findings.³⁷ The sensitivity of DS was higher than that of cytology (86.7% vs 68.5%; P<.001) for CIN 3+ with comparable specificities (95.2% vs 95.4%; P = .15).

Challenges and opportunities to improve access to primary HPV screening

The historical success of the Pap test in reducing the incidence of cervical cancer relied on individuals having access to the test. This remains true as screening transitions to primary HPV testing. Limitations of HPV-based screening include provider and patient knowledge; access to tests; cost; need for new laboratory infrastructure; need to leverage the electronic health record to record results, calculate a patient’s risk and determine next steps; and the need to re-educate patients and providers about this new model of care. The American Cancer Society and the Centers for Disease Control and Prevention are currently leading initiatives to help adopt primary HPV screening in the United States and to facilitate new care approaches.

Self-collection and independence from subjective cytology would further improve access. Multiple effectiveness studies and patient acceptability studies have shown that primary HPV screening via self-collection is effective, cost effective, and acceptable to women, especially among underscreened populations.³⁸ Sensitivity is comparable to clinician-obtained samples with polymerase chain reaction–based HPV tests. Furthermore, newer molecular tests that detect methylated target host genes or methylated viral genome can be used to triage HPV-positive cases. Several host methylation markers that identify the specific host genes (for example, CADM1, MAL, and miR-124-2) have been shown to be more specific, reproducible, and can be used in self-collected samples as they are based on molecular methylation analysis.³⁹ The ASCCP monitors these new developments and will incorporate promising tests and approaches once validated and FDA approved into the risk-based management guidelines. An erratum was recently published, and the risk-calculator is also available on the ASCCP website free of charge (https://app.asccp.org).⁴⁰

In conclusion, transition to primary HPV testing from Pap cytology in cervical cancer screening has many challenges but also opportunities. Learning from the experience of countries that have already adopted primary HPV testing is crucial to successful implementation of this new screening paradigm.⁴¹ The evidence supporting primary HPV screening with its improved sensitivity is clear, and the existing triage options and innovations will continue to improve triage of patients with clinically important lesions as well as accessibility. With strong advocacy and sound implementation, the WHO goal of cervical cancer elimination and 70% of women being screened with a high-performance test by age 35 and again by age 45 is achievable. ●

Cervical cancer is an important global health problem with an estimated 604,127 new cases and 341,831 deaths in 2020.¹ Nearly 85% of the disease burden affects individuals from low and middle-income countries. The World Health Organization (WHO) set forth the goal for all countries to reach and maintain an incidence rate of below 4 per 100,000 women by 2030 as part of the Global Strategy to Accelerate the Elimination of Cervical Cancer.

Although traditional Pap cytology has been the cornerstone of screening programs, its poor sensitivity of approximately 50% and limitations in accessibility require new strategies to achieve the elimination of cervical cancer.² The discovery that persistent infection with oncogenic human papillomavirus (HPV) is an essential step in the development of cervical cancer led to the development of diagnostic HPV tests, which have higher sensitivity than cytology (96.1% vs 53.0%) but somewhat lower specificity (90.7% vs 96.3%) for the detection of cervical intraepithelial neoplasia (CIN) 2 or worse lesions.² Initially, HPV testing was incorporated as a method to triage atypical squamous cells of undetermined significance (ASCUS) cytology results.³ Later, the concept of cotesting with cytology emerged,^4,5 and since then, several clinical trials have demonstrated the effectiveness of primary HPV screening.^6-9

In 2020, the WHO recommended HPV DNA testing as the primary screening method starting at the age of 30 years, with regular testing every 5 to 10 years, for the general population.¹⁰ Currently, primary HPV has been adopted in multiple countries, including Australia, the Netherlands, Turkey, England, and Argentina.

In the United States, there are 3 currently acceptable screening strategies: cytology, cytology plus HPV (cotesting), and primary HPV testing (TABLE). The American Cancer Society (ACS) specifically states that HPV testing alone every 5 years is preferred starting at age 25 years; cotesting every 5 years or cytology alone every 3 years are also acceptable.¹¹ The US Preventive Services Task Force (USPSTF) states that cytology alone every 3 years starting at 21 years and then HPV testing alone or cotesting every 5 years or cytology every 3 years starting at age 30 are all acceptable strategies.¹²

When applying these guidelines, it is important to note that they are intended for the screening of patients with all prior normal results with no symptoms. These routine screening guidelines do not apply to special populations, such as those with a history of abnormal results or treatment, a history of immunosuppression,¹³ a history of HPV-related vulvar or vaginal dysplasia,^14-16 or a history of hysterectomy with removal of the cervix and no prior history of cervical dysplasia.^17,18 By contrast, surveillance is interval testing for those who have either an abnormal prior test result or treatment; these may be managed per risk-based estimates provided by the American Society for Colposcopy and Cervical Pathology (ASCCP).^18,19 Finally, diagnosis is evaluation (which may include diagnostic cytology) of a patient with abnormal signs and/or symptoms (such as bleeding, pain, discharge, or cervical mass).

In this Update, we present the evidence for primary HPV testing, the management options for a positive result in the United States, and research that will improve uptake of primary HPV testing as well as accessibility.

Change in screening paradigm: Evidence for primary HPV testing

HPV DNA tests are multiplex assays that detect the DNA of targeted high-risk HPV types, using multiple probes, either by direct genomic detection or by amplification of a viral DNA fragment using polymerase chain reaction (PCR).^20,21 Alternatively, HPV mRNA-based tests detect the expression of E6 and E7 oncoproteins, a marker of viral integration.²⁰ In examining the data from well-conducted clinical trials, 2 important observations are that different HPV assays were used and that direct comparison may not be valid. In addition, not all tests used in the studies are approved by the US Food and Drug Administration (FDA) for primary HPV testing.

Continue to: FDA-approved HPV tests...

Currently, 2 tests are FDA approved for primary HPV screening. The Cobas HPV test (Roche Molecular Diagnostics) was the first FDA-approved test for primary HPV screening in women aged 25 years and older.⁶ This test reports pooled results from 12 high-risk (hr) HPV types (31/33/35/39/45/51/52/56/58/59/66/68) with reflex genotyping for HPV 16/18, and thus it provides an immediate triage option for HPV-positive women. Of note, it is also approved for cotesting. The second FDA-approved test is the BD Onclarity HPV assay (Becton, Dickinson and Company) for primary HPV screening.²² It detects 14 hrHPV types, types 16/18/45 specifically as well as types 31/33/35/39/51/52/56/58/59/66/68.

Other HPV tests are FDA approved for cotesting and reflex testing but not for primary HPV testing. The Hybrid Capture test, or HC2 (Qiagen Inc), was the first HPV test to be approved by the FDA in 1997 for reflex testing of women with ASCUS cytology. In 2003, it was approved for cotesting along with cytology in women aged 30 years and older.^20,21 In 2009, the Cervista HPV HR test (Hologic Inc) was approved for cotesting. The Aptima HPV assay (Hologic Inc), which is also approved for cotesting, is an RNA-based assay that allows detection of E6/E7 mRNA transcripts of 14 HPV types.²³

Comparing HPV testing with cytology

Ronco and colleagues pooled data from 4 European randomized controlled trials (RCTs)—Swedescreen, POBASCAM, NTCC, ARTISTIC—with a total of 176,464 participants randomly assigned to HPV or cytology screening.²⁴ Swedescreen and POBASCAM used GP5/GP6 PCR, while ARTISTIC and NTCC used HC2 for primary HPV screening. The screening interval was 3 years in all except 5 years in POBASCAM. The pooled detection rate of invasive disease was similar in the 2 arms, with pooled rate ratio for cancer detection being 0.79 (95% confidence interval [CI], 0.46–1.36) in the first 2.5 years, but was 0.45 (95% CI, 0.25–0.81), favoring the HPV arm, after 2.5 years. HPV testing was more effective in preventing cases of adenocarcinoma than squamous cell carcinoma (0.31 [95% CI, 0.14–0.69] vs 0.78 [95% CI, 0.49–1.25]). The authors concluded that HPV-based screening from age 30 years provided 60% to 70% better protection than cytology.

The result of the above meta-analysis was confirmed by the HPV FOCAL RCT that investigated the efficacy of HPV testing (HC2) in comparison with cytology.²⁵ The detection rates for CIN 3 lesions supported primary HPV screening, with an absolute difference in incidence rate of 2.67/1,000 (95% CI, 0.53–4.88) at study randomization and 3.22/1,000 (95% CI, 5.12–1.48) at study exit 4 years later.

Cotesting using HPV and cytology: Marginal benefit

Dillner and colleagues were one of the first groups to report on the risk of CIN 3 based on both HPV and cytology status.²⁶ Using pooled analysis of data from multiple countries, these investigators reported that the cumulative incidence rates (CIR) of CIN 3 after 6 years of follow-up increased consistently in HPV-positive subjects, and an HPV-positive result more accurately predicted CIN 3+ at 5 years than cytology alone. Furthermore, HPV negativity provided greater reassurance than cytology alone. At 5 years of follow-up, the rates of CIN 3+ were 0.25% (0.12%–0.41%) for women negative for HPV compared with 0.83% (0.50%–1.13%) for women with negative cytology results. There was little difference in rates for CIN 3+ between women with negative results on both tests and women who were negative for HPV.

The important question is then the marginal benefit of cotesting, which is the most costly screening option. A study of 331,818 women enrolled for cotesting at Kaiser Permanente found that the risk of CIN 3+ predicted by HPV testing alone when compared with cytology was significantly higher at both 3 years (5.0% vs 3.8%; P = .046) and 5 years (7.6% vs 4.7%; P = .001).²⁷ A negative cytology result did not decrease the risk of CIN 3 further for HPV-negative patients (3 years: 0.047% vs 0.063%, P = .6; 5 years: 0.16% vs 0.17%, P = .8). They concluded that a negative HPV test was enough reassurance for low risk of CIN 3+ and that an additional negative cytology result does not provide extra reassurance.

Furthermore, a systematic meta-analysis of 48 studies, including 8 RCTs, found that the addition of cytology to HPV testing raised the sensitivity by 2% for CIN 3 compared with HPV testing alone. This improvement in sensitivity was at the expense of considerable loss of specificity, with a ratio of 0.93 (95% CI, 0.92–0.95) for CIN 3.²⁸ Schiffman and colleagues also assessed the relative contribution of HPV testing and cytology in detection of CIN 3 and cancer.²⁹ The HPV component alone identified a significantly higher proportion of preinvasive and invasive disease than cytology. Only 3.5% of precancers and 5.9% of cancers were preceded by HPV-negative, cytology-positive results. Thus, cytology contributed only 5 cases per million women per year to the sensitivity of the combined test, at the cost of significantly more colposcopies. Hence, the evidence suggests that there is limited benefit of adding cytology to HPV testing.³⁰

Continue to: Triage of a positive HPV result...

An important limitation of HPV testing is its inability to discriminate between transient and persistent infections. Referral of all HPV-positive cases to colposcopy would overburden the system with associated unnecessary procedures. Hence, a triage strategy is essential to identify clinically important infections that truly require colposcopic evaluation. The FIGURE illustrates the management of a primary HPV test result performed for screening.

HPV genotyping

One strategy for triaging a positive HPV test result is genotyping. HPV 16 and 18 have the highest risk of persistence and progression and merit immediate referral to colposcopy. In the ATHENA trial, CIN 3 was identified in 17.8% (95% CI, 14.8–20.7%) of HPV 16 positive women at baseline, and the CIR increased to 25.2% (95% CI, 21.7–28.7%) after 3 years. The 3-year CIR of CIN 3 was only 5.4% (95% CI, 4.5–6.3%) in women with HPV genotypes other than 16/18. HPV 18–positive women had a 3-year CIR that was intermediate between women with HPV 16 and women with the 12 other genotypes.⁶ Hence, HPV 16/18–positive cases should be referred for immediate colposcopy, and negative cases should be followed up with cytology and referred for colposcopy if the cytology is ASCUS or worse.³¹

In July 2020, extended genotyping was approved by the FDA with individual detection of HPV 31, 51, 52 (in addition to 16, 18, and 45) and pooled detection of 33/58, 35/39/68, and 56/59/66. One study found that individual genotypes HPV 16 and 31 carry baseline risk values for CIN 3+ (8.1% and 7.5%, respectively) that are above the 5-year risk threshold for referral to colposcopy following the ASCCP risk-based management guideline.³²

Cytology

The higher specificity of cytology makes it an option for triaging HPV-positive cases, and current management guidelines recommend triage to both genotyping and cytology for all patients who are HPV positive, and especially if they are HPV positive but HPV 16/18 negative. Of note, cytology results remain more subjective than those of primary HPV testing, but the combination of initial HPV testing with reflex to cytology is a reasonable and cost effective next step.¹⁸ The VASCAR trial found higher colposcopy referrals in the HPV screening and cytology triage group compared with the cytology alone group (19.36 vs 14.54 per 1,000 women).³³ The ATHENA trial investigated various triage strategies for HPV-positive cases and its impact on colposcopy referrals.⁶ Using HPV genotyping and reflex cytology, if HPV 16/18 was positive, colposcopy was advised, but if any of the other 12 HPV types were positive, reflex cytology was done. If reported as ASCUS or worse, colposcopy was performed; conversely, if it was normal, women were rescreened with cotesting after 1 year. Although this strategy led to a reduction in the number of colposcopies, referrals were still higher in the primary HPV arm (3,769 colposcopies per 294 cases) compared with cytology (1,934 colposcopies per 179 cases) or cotesting (3,097 colposcopies per 240 cases) in women aged 25 years.¹⁴

p16/Ki-67 Dual-Stain

Diffused p16 immunohistochemical staining, as opposed to focal staining, is associated with active HPV infection but can be present in low-grade as well as high-grade lesions.³⁴ Ki-67 is a marker of cellular proliferation. Coexpression of p16 and Ki-67 indicates a loss of cell cycle regulation and is a hallmark of neoplastic transformation. When positive, these tests are supportive of active HPV infection and of a high-grade lesion. Incorporation of these stains to cytology alone provides additional objective reassurance to cytology, where there is much inter- and intra-observer variability. These stains can be done by laboratories using the stains alone or they can use the FDA-approved p16/Ki-67 Dual-Stain immunohistochemistry (DS), CINtec PLUS Cytology (Roche Diagnostics). However, DS is not yet formally incorporated into triage algorithms by national guidelines.

The IMPACT trial assessed the performance of DS compared with cytology in the triage of HPV-positive results, with or without HPV 16/18 genotyping.³⁵ This was a prospective observational screening study of 35,263 women aged 25 to 65 years across 32 sites in the United States. Of the 4,927 HPV-positive patients with DS results, the sensitivity of DS for CIN 3+ was 91.9% (95% CI, 86.1%–95.4%) and 86.0% (95% CI, 77.5%–91.6%) in HPV 16/18–positive and in the 12 other genotypes, respectively. Using DS alone to triage HPV-positive results showed significantly higher sensitivity and specificity than HPV 16/18 genotyping with cytology triage of 12 “other” genotypes, and substantially higher sensitivity but lower specificity than using cytology alone. Of note, triage with DS alone would have referred significantly fewer women to colposcopy than HPV 16/18 genotyping with cytology triage for the 12 other genotypes (48.6% vs 56.0%; P< .0001).

Similarly, a retrospective analysis of the ATHENA trial cohort of HPV-positive results of 7,727 patients aged 25 years or older also demonstrated increased sensitivity of DS compared with cytology (74.9% vs 51.9%; P<.0001) and similar specificities (74.1% vs 75%; P = .3198).³⁶ The European PALMS study, which included 27,349 women aged 18 years or older across 5 countries who underwent routine screening with HPV testing, cytology, and DS, confirmed these findings.³⁷ The sensitivity of DS was higher than that of cytology (86.7% vs 68.5%; P<.001) for CIN 3+ with comparable specificities (95.2% vs 95.4%; P = .15).

Challenges and opportunities to improve access to primary HPV screening

The historical success of the Pap test in reducing the incidence of cervical cancer relied on individuals having access to the test. This remains true as screening transitions to primary HPV testing. Limitations of HPV-based screening include provider and patient knowledge; access to tests; cost; need for new laboratory infrastructure; need to leverage the electronic health record to record results, calculate a patient’s risk and determine next steps; and the need to re-educate patients and providers about this new model of care. The American Cancer Society and the Centers for Disease Control and Prevention are currently leading initiatives to help adopt primary HPV screening in the United States and to facilitate new care approaches.

Self-collection and independence from subjective cytology would further improve access. Multiple effectiveness studies and patient acceptability studies have shown that primary HPV screening via self-collection is effective, cost effective, and acceptable to women, especially among underscreened populations.³⁸ Sensitivity is comparable to clinician-obtained samples with polymerase chain reaction–based HPV tests. Furthermore, newer molecular tests that detect methylated target host genes or methylated viral genome can be used to triage HPV-positive cases. Several host methylation markers that identify the specific host genes (for example, CADM1, MAL, and miR-124-2) have been shown to be more specific, reproducible, and can be used in self-collected samples as they are based on molecular methylation analysis.³⁹ The ASCCP monitors these new developments and will incorporate promising tests and approaches once validated and FDA approved into the risk-based management guidelines. An erratum was recently published, and the risk-calculator is also available on the ASCCP website free of charge (https://app.asccp.org).⁴⁰

In conclusion, transition to primary HPV testing from Pap cytology in cervical cancer screening has many challenges but also opportunities. Learning from the experience of countries that have already adopted primary HPV testing is crucial to successful implementation of this new screening paradigm.⁴¹ The evidence supporting primary HPV screening with its improved sensitivity is clear, and the existing triage options and innovations will continue to improve triage of patients with clinically important lesions as well as accessibility. With strong advocacy and sound implementation, the WHO goal of cervical cancer elimination and 70% of women being screened with a high-performance test by age 35 and again by age 45 is achievable. ●

Cervical cancer is an important global health problem with an estimated 604,127 new cases and 341,831 deaths in 2020.¹ Nearly 85% of the disease burden affects individuals from low and middle-income countries. The World Health Organization (WHO) set forth the goal for all countries to reach and maintain an incidence rate of below 4 per 100,000 women by 2030 as part of the Global Strategy to Accelerate the Elimination of Cervical Cancer.

Although traditional Pap cytology has been the cornerstone of screening programs, its poor sensitivity of approximately 50% and limitations in accessibility require new strategies to achieve the elimination of cervical cancer.² The discovery that persistent infection with oncogenic human papillomavirus (HPV) is an essential step in the development of cervical cancer led to the development of diagnostic HPV tests, which have higher sensitivity than cytology (96.1% vs 53.0%) but somewhat lower specificity (90.7% vs 96.3%) for the detection of cervical intraepithelial neoplasia (CIN) 2 or worse lesions.² Initially, HPV testing was incorporated as a method to triage atypical squamous cells of undetermined significance (ASCUS) cytology results.³ Later, the concept of cotesting with cytology emerged,^4,5 and since then, several clinical trials have demonstrated the effectiveness of primary HPV screening.^6-9

In 2020, the WHO recommended HPV DNA testing as the primary screening method starting at the age of 30 years, with regular testing every 5 to 10 years, for the general population.¹⁰ Currently, primary HPV has been adopted in multiple countries, including Australia, the Netherlands, Turkey, England, and Argentina.

In the United States, there are 3 currently acceptable screening strategies: cytology, cytology plus HPV (cotesting), and primary HPV testing (TABLE). The American Cancer Society (ACS) specifically states that HPV testing alone every 5 years is preferred starting at age 25 years; cotesting every 5 years or cytology alone every 3 years are also acceptable.¹¹ The US Preventive Services Task Force (USPSTF) states that cytology alone every 3 years starting at 21 years and then HPV testing alone or cotesting every 5 years or cytology every 3 years starting at age 30 are all acceptable strategies.¹²

When applying these guidelines, it is important to note that they are intended for the screening of patients with all prior normal results with no symptoms. These routine screening guidelines do not apply to special populations, such as those with a history of abnormal results or treatment, a history of immunosuppression,¹³ a history of HPV-related vulvar or vaginal dysplasia,^14-16 or a history of hysterectomy with removal of the cervix and no prior history of cervical dysplasia.^17,18 By contrast, surveillance is interval testing for those who have either an abnormal prior test result or treatment; these may be managed per risk-based estimates provided by the American Society for Colposcopy and Cervical Pathology (ASCCP).^18,19 Finally, diagnosis is evaluation (which may include diagnostic cytology) of a patient with abnormal signs and/or symptoms (such as bleeding, pain, discharge, or cervical mass).

In this Update, we present the evidence for primary HPV testing, the management options for a positive result in the United States, and research that will improve uptake of primary HPV testing as well as accessibility.

Change in screening paradigm: Evidence for primary HPV testing

HPV DNA tests are multiplex assays that detect the DNA of targeted high-risk HPV types, using multiple probes, either by direct genomic detection or by amplification of a viral DNA fragment using polymerase chain reaction (PCR).^20,21 Alternatively, HPV mRNA-based tests detect the expression of E6 and E7 oncoproteins, a marker of viral integration.²⁰ In examining the data from well-conducted clinical trials, 2 important observations are that different HPV assays were used and that direct comparison may not be valid. In addition, not all tests used in the studies are approved by the US Food and Drug Administration (FDA) for primary HPV testing.

Continue to: FDA-approved HPV tests...

Currently, 2 tests are FDA approved for primary HPV screening. The Cobas HPV test (Roche Molecular Diagnostics) was the first FDA-approved test for primary HPV screening in women aged 25 years and older.⁶ This test reports pooled results from 12 high-risk (hr) HPV types (31/33/35/39/45/51/52/56/58/59/66/68) with reflex genotyping for HPV 16/18, and thus it provides an immediate triage option for HPV-positive women. Of note, it is also approved for cotesting. The second FDA-approved test is the BD Onclarity HPV assay (Becton, Dickinson and Company) for primary HPV screening.²² It detects 14 hrHPV types, types 16/18/45 specifically as well as types 31/33/35/39/51/52/56/58/59/66/68.

Other HPV tests are FDA approved for cotesting and reflex testing but not for primary HPV testing. The Hybrid Capture test, or HC2 (Qiagen Inc), was the first HPV test to be approved by the FDA in 1997 for reflex testing of women with ASCUS cytology. In 2003, it was approved for cotesting along with cytology in women aged 30 years and older.^20,21 In 2009, the Cervista HPV HR test (Hologic Inc) was approved for cotesting. The Aptima HPV assay (Hologic Inc), which is also approved for cotesting, is an RNA-based assay that allows detection of E6/E7 mRNA transcripts of 14 HPV types.²³

Comparing HPV testing with cytology

Ronco and colleagues pooled data from 4 European randomized controlled trials (RCTs)—Swedescreen, POBASCAM, NTCC, ARTISTIC—with a total of 176,464 participants randomly assigned to HPV or cytology screening.²⁴ Swedescreen and POBASCAM used GP5/GP6 PCR, while ARTISTIC and NTCC used HC2 for primary HPV screening. The screening interval was 3 years in all except 5 years in POBASCAM. The pooled detection rate of invasive disease was similar in the 2 arms, with pooled rate ratio for cancer detection being 0.79 (95% confidence interval [CI], 0.46–1.36) in the first 2.5 years, but was 0.45 (95% CI, 0.25–0.81), favoring the HPV arm, after 2.5 years. HPV testing was more effective in preventing cases of adenocarcinoma than squamous cell carcinoma (0.31 [95% CI, 0.14–0.69] vs 0.78 [95% CI, 0.49–1.25]). The authors concluded that HPV-based screening from age 30 years provided 60% to 70% better protection than cytology.

The result of the above meta-analysis was confirmed by the HPV FOCAL RCT that investigated the efficacy of HPV testing (HC2) in comparison with cytology.²⁵ The detection rates for CIN 3 lesions supported primary HPV screening, with an absolute difference in incidence rate of 2.67/1,000 (95% CI, 0.53–4.88) at study randomization and 3.22/1,000 (95% CI, 5.12–1.48) at study exit 4 years later.

Cotesting using HPV and cytology: Marginal benefit

Dillner and colleagues were one of the first groups to report on the risk of CIN 3 based on both HPV and cytology status.²⁶ Using pooled analysis of data from multiple countries, these investigators reported that the cumulative incidence rates (CIR) of CIN 3 after 6 years of follow-up increased consistently in HPV-positive subjects, and an HPV-positive result more accurately predicted CIN 3+ at 5 years than cytology alone. Furthermore, HPV negativity provided greater reassurance than cytology alone. At 5 years of follow-up, the rates of CIN 3+ were 0.25% (0.12%–0.41%) for women negative for HPV compared with 0.83% (0.50%–1.13%) for women with negative cytology results. There was little difference in rates for CIN 3+ between women with negative results on both tests and women who were negative for HPV.

The important question is then the marginal benefit of cotesting, which is the most costly screening option. A study of 331,818 women enrolled for cotesting at Kaiser Permanente found that the risk of CIN 3+ predicted by HPV testing alone when compared with cytology was significantly higher at both 3 years (5.0% vs 3.8%; P = .046) and 5 years (7.6% vs 4.7%; P = .001).²⁷ A negative cytology result did not decrease the risk of CIN 3 further for HPV-negative patients (3 years: 0.047% vs 0.063%, P = .6; 5 years: 0.16% vs 0.17%, P = .8). They concluded that a negative HPV test was enough reassurance for low risk of CIN 3+ and that an additional negative cytology result does not provide extra reassurance.

Furthermore, a systematic meta-analysis of 48 studies, including 8 RCTs, found that the addition of cytology to HPV testing raised the sensitivity by 2% for CIN 3 compared with HPV testing alone. This improvement in sensitivity was at the expense of considerable loss of specificity, with a ratio of 0.93 (95% CI, 0.92–0.95) for CIN 3.²⁸ Schiffman and colleagues also assessed the relative contribution of HPV testing and cytology in detection of CIN 3 and cancer.²⁹ The HPV component alone identified a significantly higher proportion of preinvasive and invasive disease than cytology. Only 3.5% of precancers and 5.9% of cancers were preceded by HPV-negative, cytology-positive results. Thus, cytology contributed only 5 cases per million women per year to the sensitivity of the combined test, at the cost of significantly more colposcopies. Hence, the evidence suggests that there is limited benefit of adding cytology to HPV testing.³⁰

Continue to: Triage of a positive HPV result...

An important limitation of HPV testing is its inability to discriminate between transient and persistent infections. Referral of all HPV-positive cases to colposcopy would overburden the system with associated unnecessary procedures. Hence, a triage strategy is essential to identify clinically important infections that truly require colposcopic evaluation. The FIGURE illustrates the management of a primary HPV test result performed for screening.

HPV genotyping

One strategy for triaging a positive HPV test result is genotyping. HPV 16 and 18 have the highest risk of persistence and progression and merit immediate referral to colposcopy. In the ATHENA trial, CIN 3 was identified in 17.8% (95% CI, 14.8–20.7%) of HPV 16 positive women at baseline, and the CIR increased to 25.2% (95% CI, 21.7–28.7%) after 3 years. The 3-year CIR of CIN 3 was only 5.4% (95% CI, 4.5–6.3%) in women with HPV genotypes other than 16/18. HPV 18–positive women had a 3-year CIR that was intermediate between women with HPV 16 and women with the 12 other genotypes.⁶ Hence, HPV 16/18–positive cases should be referred for immediate colposcopy, and negative cases should be followed up with cytology and referred for colposcopy if the cytology is ASCUS or worse.³¹

In July 2020, extended genotyping was approved by the FDA with individual detection of HPV 31, 51, 52 (in addition to 16, 18, and 45) and pooled detection of 33/58, 35/39/68, and 56/59/66. One study found that individual genotypes HPV 16 and 31 carry baseline risk values for CIN 3+ (8.1% and 7.5%, respectively) that are above the 5-year risk threshold for referral to colposcopy following the ASCCP risk-based management guideline.³²

Cytology

The higher specificity of cytology makes it an option for triaging HPV-positive cases, and current management guidelines recommend triage to both genotyping and cytology for all patients who are HPV positive, and especially if they are HPV positive but HPV 16/18 negative. Of note, cytology results remain more subjective than those of primary HPV testing, but the combination of initial HPV testing with reflex to cytology is a reasonable and cost effective next step.¹⁸ The VASCAR trial found higher colposcopy referrals in the HPV screening and cytology triage group compared with the cytology alone group (19.36 vs 14.54 per 1,000 women).³³ The ATHENA trial investigated various triage strategies for HPV-positive cases and its impact on colposcopy referrals.⁶ Using HPV genotyping and reflex cytology, if HPV 16/18 was positive, colposcopy was advised, but if any of the other 12 HPV types were positive, reflex cytology was done. If reported as ASCUS or worse, colposcopy was performed; conversely, if it was normal, women were rescreened with cotesting after 1 year. Although this strategy led to a reduction in the number of colposcopies, referrals were still higher in the primary HPV arm (3,769 colposcopies per 294 cases) compared with cytology (1,934 colposcopies per 179 cases) or cotesting (3,097 colposcopies per 240 cases) in women aged 25 years.¹⁴

p16/Ki-67 Dual-Stain

Diffused p16 immunohistochemical staining, as opposed to focal staining, is associated with active HPV infection but can be present in low-grade as well as high-grade lesions.³⁴ Ki-67 is a marker of cellular proliferation. Coexpression of p16 and Ki-67 indicates a loss of cell cycle regulation and is a hallmark of neoplastic transformation. When positive, these tests are supportive of active HPV infection and of a high-grade lesion. Incorporation of these stains to cytology alone provides additional objective reassurance to cytology, where there is much inter- and intra-observer variability. These stains can be done by laboratories using the stains alone or they can use the FDA-approved p16/Ki-67 Dual-Stain immunohistochemistry (DS), CINtec PLUS Cytology (Roche Diagnostics). However, DS is not yet formally incorporated into triage algorithms by national guidelines.

The IMPACT trial assessed the performance of DS compared with cytology in the triage of HPV-positive results, with or without HPV 16/18 genotyping.³⁵ This was a prospective observational screening study of 35,263 women aged 25 to 65 years across 32 sites in the United States. Of the 4,927 HPV-positive patients with DS results, the sensitivity of DS for CIN 3+ was 91.9% (95% CI, 86.1%–95.4%) and 86.0% (95% CI, 77.5%–91.6%) in HPV 16/18–positive and in the 12 other genotypes, respectively. Using DS alone to triage HPV-positive results showed significantly higher sensitivity and specificity than HPV 16/18 genotyping with cytology triage of 12 “other” genotypes, and substantially higher sensitivity but lower specificity than using cytology alone. Of note, triage with DS alone would have referred significantly fewer women to colposcopy than HPV 16/18 genotyping with cytology triage for the 12 other genotypes (48.6% vs 56.0%; P< .0001).

Similarly, a retrospective analysis of the ATHENA trial cohort of HPV-positive results of 7,727 patients aged 25 years or older also demonstrated increased sensitivity of DS compared with cytology (74.9% vs 51.9%; P<.0001) and similar specificities (74.1% vs 75%; P = .3198).³⁶ The European PALMS study, which included 27,349 women aged 18 years or older across 5 countries who underwent routine screening with HPV testing, cytology, and DS, confirmed these findings.³⁷ The sensitivity of DS was higher than that of cytology (86.7% vs 68.5%; P<.001) for CIN 3+ with comparable specificities (95.2% vs 95.4%; P = .15).

Challenges and opportunities to improve access to primary HPV screening

The historical success of the Pap test in reducing the incidence of cervical cancer relied on individuals having access to the test. This remains true as screening transitions to primary HPV testing. Limitations of HPV-based screening include provider and patient knowledge; access to tests; cost; need for new laboratory infrastructure; need to leverage the electronic health record to record results, calculate a patient’s risk and determine next steps; and the need to re-educate patients and providers about this new model of care. The American Cancer Society and the Centers for Disease Control and Prevention are currently leading initiatives to help adopt primary HPV screening in the United States and to facilitate new care approaches.

Self-collection and independence from subjective cytology would further improve access. Multiple effectiveness studies and patient acceptability studies have shown that primary HPV screening via self-collection is effective, cost effective, and acceptable to women, especially among underscreened populations.³⁸ Sensitivity is comparable to clinician-obtained samples with polymerase chain reaction–based HPV tests. Furthermore, newer molecular tests that detect methylated target host genes or methylated viral genome can be used to triage HPV-positive cases. Several host methylation markers that identify the specific host genes (for example, CADM1, MAL, and miR-124-2) have been shown to be more specific, reproducible, and can be used in self-collected samples as they are based on molecular methylation analysis.³⁹ The ASCCP monitors these new developments and will incorporate promising tests and approaches once validated and FDA approved into the risk-based management guidelines. An erratum was recently published, and the risk-calculator is also available on the ASCCP website free of charge (https://app.asccp.org).⁴⁰

In conclusion, transition to primary HPV testing from Pap cytology in cervical cancer screening has many challenges but also opportunities. Learning from the experience of countries that have already adopted primary HPV testing is crucial to successful implementation of this new screening paradigm.⁴¹ The evidence supporting primary HPV screening with its improved sensitivity is clear, and the existing triage options and innovations will continue to improve triage of patients with clinically important lesions as well as accessibility. With strong advocacy and sound implementation, the WHO goal of cervical cancer elimination and 70% of women being screened with a high-performance test by age 35 and again by age 45 is achievable. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

David G. Mutch, MD: The cervical cancer screening guidelines, using Pap testing, have changed significantly since the times of yearly Paps and exams. Coupled with vaccination and new management guidelines (recommending HPV testing, etc), we actually hope that we are on the way to eradicating cervical cancer from our environment.

Screening: Current recommendations

Dr. Mutch: Warner, the American Society of Colposcopy and Cervical Pathology (ASCCP)¹ endorses the cervical cancer screening guidelines for several professional organizations, including the American Cancer Society (ACS),² the US Preventive Services Task Force (USPSTF),³ and the American College of Obstetricians and Gynecologists (ACOG).⁴ What are the current screening recommendations, as these organizations have disparate views?

Warner Huh, MD: There was a time, around 2012-2013, when for the first time ever, we had significant harmonization of the guidelines between ACOG and the USPSTF and ACS. But in the last 10 years there has been an explosion of data in terms of how to best screen patients.

The move to primary HPV testing. The USPSTF³ initially had recommended looking into primary HPV screening, which is just using HPV testing by itself as the screening modality. But there was a lot of pushback at that time. I think a lot of people thought that we were not prepared to make that leap. Therefore, they endorsed screening with cytology by itself as well as HPV testing by itself, as well as co-testing; but in their recommendations, they made it very clear that they were leaning toward primary HPV screening.

A new patient age to begin screening. In 2020, the ACS put out their new guidelines,² which are a significant departure from what we are used to—they are recommending that we start screening at 25 years of age. Like you said, Dr. Mutch, it doesn’t seem that long ago when we were screening people at age 18, or within 3 years of sexual intercourse. But the reason for it is that the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already do this.

The other major departure in the ACS guidelines is that they really are asking clinicians and screeners to focus on primary HPV screening. Overall, they have sort of doubled down on why they think primary HPV screening is so important.

ACOG sits sort of in the middle of the other recommendations. ACOG understands the value of primary HPV screening, but I don’t think that they are quite ready to recommend screening at age 25. If you look at their updated guidelines from April 2021,⁴ they state that we should continue a screening-starting age of 21 years. So there are some disparate views, but I am confident, Dr. Mutch, that in the next 2 to 3 years, there will be greater harmonization of these guidelines and less confusion for our providers. The greatest barrier is understanding the science and the comfort level of clinicians to go with just an HPV test, since for the last 40 years the Pap test has anchored gynecologic care in this country. And it took at least 10 years to get to what I consider to be widespread adoption to co-testing. The other thing that readers should recognize is that the Task Force is actually revisiting their cervical cancer screening guidance now, so expect another major revision.

Reimbursement and access are barriers. Reimbursement is a further real issue. We are now using one less test, but insurance companies may not reimburse when just the HPV test is used. The other issue is access to labs that can do the HPV testing.

Dr. Mutch: We used to see patients yearly and picked up a lot of adjunctive or additional illnesses. Now they are not being seen yearly it could impact negatively their overall health care. We need to understand that cervical cancer screening is simply a test, which should not eliminate other health care.

Dr. Huh: Yes, I think the extended interval between recommended HPV screenings scares people. I have been involved in these screening guidelines (and I can only speak for myself, not for my colleagues), but even I do think we made a leap to a longer interval way too quickly in this country. Screening changes are slow, and sometimes a glacial process. I think it can worry providers when we make rapid changes.

But this is a test that should not anchor the yearly visit. There are plenty of other reasons—and ACOG actually states this⁴—why patients should come for a wellness exam on a yearly basis. So I think our ObGyns in the United States need to recognize that, but I understand there are underlying concerns that if you extend intervals too long, (a) will patients come back, and (b), as a consequence, is the interval going to miss something in between? Those are real legitimate concerns.

Continue to: Management guidelines...

Dr. Mutch: The ASCCP issued new management guidelines in 2019.⁵ Can you address what you feel are the most important updates?

Dr. Huh: Going back to 2002, we have revised these guidelines every 5 years. For this one, the revision came out a little bit later for various reasons, but the reason we revised it is because we collect new data that we think markedly changes our understanding of the disease process and natural history and the interventions for women that have preinvasive disease of the cervix.

Briefly, I think the biggest changes based on what we were hearing from our providers and users of our apps and algorithms was that our algorithms were becoming way too complicated, and they were. If you look over the last 10 years, the number of branch points on our algorithms basically quadrupled. If we incorporated the new data this time, the algorithms would be unworkable, and you could not use them on your phone because they would be too complicated.

So, we created a system where, in essence, providers have 5 choices for patients:

• treatment
• colposcopy
• follow-up in 1 year
• follow-up in 3 years
• follow-up in 5 years.

Those recommendations are based on what we call “clinically actionable thresholds”—basically, the percent chance of developing immediate CIN3 or worse. That threshold will probably change over time, but what we did is create a system that (a) makes it easier for the provider, (although they have to trust the system—and they can look under the hood and understand how we did this) and (b) allows us to create a foundation where we can add future technologies that use the same rubric or paradigm so that they still wind up getting the same result without having to go to another algorithm.

This new system is probably the most marked change in the history of the ASCCP management guidelines, but we did it to make it ultimately easier for providers going forward for the next 10 to 20 years. There are real opportunities, Dr. Mutch, in terms of how do we integrate this into the electronic medical record (EMR), and how do we pull data so clinicians don’t have to manually enter it.

The other difference is now there is a web-based application. Back in 2012, there were a lot of people that were not using EMRs. Now the majority of the country is, and so they actually are on a browser more than they are on their phone. We actually have an equally robust web platform that allows them to get the information that they need.

Dr. Mutch: I think that is really important—the utility of utilizing a mobile app, if you will, for triaging your patient with a specific test result so that patients are followed up at the proper interval, and that ultimately becomes cost-effective.

Dr. Huh: Yes, the app now is very different than the app that I think people are used to using for the last almost 10 years. You don’t put inputs, pull up the algorithm, and look at the outcome. This is different. You enter the patient’s age. You add their cytology, their HPV results, the clinical scenario that you are in, and then it puts out a recommendation of what to do next. Over time, we want to get away from an algorithm and for our providers to understand what the risk is and how that risk calculation then translates into a clinical recommendation.

Dr. Mutch: I think to utilize an app is almost necessary given the complexity of the triaging process so that it does become, in fact, the most cost-effective way to screen patients.

Dr. Huh: I would agree with that. There is a learning curve for whenever you see new technology. There was a learning curve for even ASCCP leadership as they tried to educate providers. I think people will ultimately see that this is a much better way of managing patients with cervical abnormalities, and I am hoping actually that we will use a similar platform for many other diseases that we manage in women’s health.

Continue to: Chipping away of the yearly exam...

Dr. Mutch: With this moving away from the yearly exam and Pap test, women may not get yearly examinations. Do you feel that this could affect a stage migration to a higher stage at diagnosis, for instance, of a cervical cancer? Or that it might adversely impact other health issues?

Dr. Huh: I think that’s a good question. I am worried about the interval—I think 5 years is a bit long. I am more worried that patients will miss out on visits because they may think that they need to only come back for their Pap, even though they should be re-educated on that.

COVID-19 has made this a little hard for us to analyze because, clearly, we have had access to care issues. But I am a little concerned that we could see an uptick in invasive cancer rates in this country, including an uptick in the stage and more locally advanced cervical cancer because of the changes in the screening paradigms. But we don’t know that to be the case.

As with all screenings, the bottom line is you have to worry about what the false-negative and false-positive rates of screening are, and that affects everything. I want the readers to know that primary HPV should be used for screenings. It is not perfect, but it is much better than cytology alone. We need to think about how to better adapt screening in the age that we live in.

HPV self-sampling

Dr. Mutch: Could self-sampling for HPV testing, which obviously would be easier for the patient, and certainly useful in terms of screening, address some health care disparities with regard to cervical cancer?

Dr. Huh: The short answer is, yes. Self-sampling is not US Food and Drug Administration-approved in this country. It’s not being widely used without that approval. But there are multiple countries, including the United States, that have done lots of studies on this topic. There are many public health experts and champions for HPV self-sampling. I think we have learned, based on some studies, that the sensitivity is reasonable.⁶

I live in a part of the country that is woefully underserved; where you are there are pockets in Missouri that are woefully underserved as well. So the issue is, can we reduce these disparities and access to care with something like self-sampling? My personal feeling is I think that we can make a dent in that, and it is never going to fully replace screening, but it at least will allow us to reallocate our resources and attention to those women that are at highest risk for developing cervical cancer or precancer based on the self-sampling result.

I don’t think it will ever replace screening per se, but if we have an abnormal self-sampling test, we might say to that patient, “You really do need to come in to get re-tested or to get re-evaluated.” So it could be a better resource and use of our health care dollars and investments in terms of trying to reduce the incidence of cervical cancer. Of course the verdict is out, but I think there are a lot of people who would love to see this scenario.

If we screen and treat perfectly in this country, we would not even need the HPV vaccine when it comes to cervical cancer. That is how effective screening is. But, up to 50% to 60% of women in this country now still are underscreened or unscreened. We were talking about that number almost 25-30 years ago, Dr. Mutch. So access to screening is a big problem, but the other problem is how do you get patients in to be seen if they have an abnormal screening test? It’s not just about screening. It’s about screening, evaluation, and treatment; all 3 components are really important.

Continue to: Where do we stand with HPV vaccination?...

Dr. Mutch: Those are great points.

You brought up vaccination. We have a long way to go with regard to that, certainly in the United States, because of the various factions opposed to vaccination and so on. But do you think that vaccination has allowed us to decrease the incidence of cervical cancer?

Dr. Huh: Yes. There is clear evidence from the Nordic countries.⁷ There is emerging evidence from Australia.⁸ There is emerging evidence from other industrialized nations that clearly demonstrate vaccination’s positive effect in reducing the incidence of cervical cancer. None of this should be a surprise. Every population-based study that has been published with the HPV vaccine in populations that have a low frequency of vaccination have demonstrated substantial reductions in things like genital warts, abnormal Pap tests, precancer, and now evidence that there is a downward trend in terms of the incidence of cervical cancer.⁹

I don’t think that there is any debate anymore that vaccination is the way to go. Our challenge is about implementation and getting the vaccine to people. We still have a long way to go with that. There are parts of the world that are so affected by invasive cervical cancers; we need to get the vaccine to those parts of the world.

Dr. Mutch: What are the barriers to vaccination? How can we overcome those barriers?

Dr. Huh: There is a lot of criticism that we are not vaccinating more in the United States. However, the rates of vaccination are going up every single year. The pandemic may have blunted that rise a bit, but if you look at the vaccination curves, they are going up, not down. We need to continue to educate patients, parents, and pediatricians on the importance of vaccination.

Boys still get vaccinated less frequently than girls, so we have some work to do there. I think globally it is the issue of getting the vaccine to people, making sure that vaccine is available. The thing that I think will be the game-changer going forward is whether or not we will have evidence to indicate that 1 dose is as effective as 2 doses or 3 doses. If we can vaccinate boys and girls with just 1 dose, then in the next generation or two, we seriously might eradicate not just cervical cancer but a lot of HPV-related malignancies worldwide.

Educating patients, clinicians is key

Dr. Mutch: So it seems education, education, education, with regard to screening guidelines, with regard to the need for continued examinations, and that HPV testing is only a test, it does not supplant overall care. Finally, education regarding eradication of cervical cancer through vaccination.

Dr. Huh: That summarizes it well. We are still going to screen for cervical cancer. We are still going to vaccinate, and providers are still going to manage abnormal Pap tests. It is confusing because we are changing it up it seems every year or 2, so this conversation you and I are having is particularly important for clinicians to understand the basis of that. There has been an explosion of data that has come out in this area in the last decade.

Dr. Mutch: Thank you, Dr. Huh. I really appreciate your thoughts on this. As you all know, Dr. Huh has been President of the ASCCP and is instrumental in writing and disseminating these guidelines, so we are very grateful that he has consented to agree to come and talk with us today.

Dr. Huh: My pleasure. Thank you for inviting me. This was fun, and I have really enjoyed talking to you and participating. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

David G. Mutch, MD: The cervical cancer screening guidelines, using Pap testing, have changed significantly since the times of yearly Paps and exams. Coupled with vaccination and new management guidelines (recommending HPV testing, etc), we actually hope that we are on the way to eradicating cervical cancer from our environment.

Screening: Current recommendations

Dr. Mutch: Warner, the American Society of Colposcopy and Cervical Pathology (ASCCP)¹ endorses the cervical cancer screening guidelines for several professional organizations, including the American Cancer Society (ACS),² the US Preventive Services Task Force (USPSTF),³ and the American College of Obstetricians and Gynecologists (ACOG).⁴ What are the current screening recommendations, as these organizations have disparate views?

Warner Huh, MD: There was a time, around 2012-2013, when for the first time ever, we had significant harmonization of the guidelines between ACOG and the USPSTF and ACS. But in the last 10 years there has been an explosion of data in terms of how to best screen patients.

The move to primary HPV testing. The USPSTF³ initially had recommended looking into primary HPV screening, which is just using HPV testing by itself as the screening modality. But there was a lot of pushback at that time. I think a lot of people thought that we were not prepared to make that leap. Therefore, they endorsed screening with cytology by itself as well as HPV testing by itself, as well as co-testing; but in their recommendations, they made it very clear that they were leaning toward primary HPV screening.

A new patient age to begin screening. In 2020, the ACS put out their new guidelines,² which are a significant departure from what we are used to—they are recommending that we start screening at 25 years of age. Like you said, Dr. Mutch, it doesn’t seem that long ago when we were screening people at age 18, or within 3 years of sexual intercourse. But the reason for it is that the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already do this.

The other major departure in the ACS guidelines is that they really are asking clinicians and screeners to focus on primary HPV screening. Overall, they have sort of doubled down on why they think primary HPV screening is so important.

ACOG sits sort of in the middle of the other recommendations. ACOG understands the value of primary HPV screening, but I don’t think that they are quite ready to recommend screening at age 25. If you look at their updated guidelines from April 2021,⁴ they state that we should continue a screening-starting age of 21 years. So there are some disparate views, but I am confident, Dr. Mutch, that in the next 2 to 3 years, there will be greater harmonization of these guidelines and less confusion for our providers. The greatest barrier is understanding the science and the comfort level of clinicians to go with just an HPV test, since for the last 40 years the Pap test has anchored gynecologic care in this country. And it took at least 10 years to get to what I consider to be widespread adoption to co-testing. The other thing that readers should recognize is that the Task Force is actually revisiting their cervical cancer screening guidance now, so expect another major revision.

Reimbursement and access are barriers. Reimbursement is a further real issue. We are now using one less test, but insurance companies may not reimburse when just the HPV test is used. The other issue is access to labs that can do the HPV testing.

Dr. Mutch: We used to see patients yearly and picked up a lot of adjunctive or additional illnesses. Now they are not being seen yearly it could impact negatively their overall health care. We need to understand that cervical cancer screening is simply a test, which should not eliminate other health care.

Dr. Huh: Yes, I think the extended interval between recommended HPV screenings scares people. I have been involved in these screening guidelines (and I can only speak for myself, not for my colleagues), but even I do think we made a leap to a longer interval way too quickly in this country. Screening changes are slow, and sometimes a glacial process. I think it can worry providers when we make rapid changes.

But this is a test that should not anchor the yearly visit. There are plenty of other reasons—and ACOG actually states this⁴—why patients should come for a wellness exam on a yearly basis. So I think our ObGyns in the United States need to recognize that, but I understand there are underlying concerns that if you extend intervals too long, (a) will patients come back, and (b), as a consequence, is the interval going to miss something in between? Those are real legitimate concerns.

Continue to: Management guidelines...

Dr. Mutch: The ASCCP issued new management guidelines in 2019.⁵ Can you address what you feel are the most important updates?

Dr. Huh: Going back to 2002, we have revised these guidelines every 5 years. For this one, the revision came out a little bit later for various reasons, but the reason we revised it is because we collect new data that we think markedly changes our understanding of the disease process and natural history and the interventions for women that have preinvasive disease of the cervix.

Briefly, I think the biggest changes based on what we were hearing from our providers and users of our apps and algorithms was that our algorithms were becoming way too complicated, and they were. If you look over the last 10 years, the number of branch points on our algorithms basically quadrupled. If we incorporated the new data this time, the algorithms would be unworkable, and you could not use them on your phone because they would be too complicated.

So, we created a system where, in essence, providers have 5 choices for patients:

• treatment
• colposcopy
• follow-up in 1 year
• follow-up in 3 years
• follow-up in 5 years.

Those recommendations are based on what we call “clinically actionable thresholds”—basically, the percent chance of developing immediate CIN3 or worse. That threshold will probably change over time, but what we did is create a system that (a) makes it easier for the provider, (although they have to trust the system—and they can look under the hood and understand how we did this) and (b) allows us to create a foundation where we can add future technologies that use the same rubric or paradigm so that they still wind up getting the same result without having to go to another algorithm.

This new system is probably the most marked change in the history of the ASCCP management guidelines, but we did it to make it ultimately easier for providers going forward for the next 10 to 20 years. There are real opportunities, Dr. Mutch, in terms of how do we integrate this into the electronic medical record (EMR), and how do we pull data so clinicians don’t have to manually enter it.

The other difference is now there is a web-based application. Back in 2012, there were a lot of people that were not using EMRs. Now the majority of the country is, and so they actually are on a browser more than they are on their phone. We actually have an equally robust web platform that allows them to get the information that they need.

Dr. Mutch: I think that is really important—the utility of utilizing a mobile app, if you will, for triaging your patient with a specific test result so that patients are followed up at the proper interval, and that ultimately becomes cost-effective.

Dr. Huh: Yes, the app now is very different than the app that I think people are used to using for the last almost 10 years. You don’t put inputs, pull up the algorithm, and look at the outcome. This is different. You enter the patient’s age. You add their cytology, their HPV results, the clinical scenario that you are in, and then it puts out a recommendation of what to do next. Over time, we want to get away from an algorithm and for our providers to understand what the risk is and how that risk calculation then translates into a clinical recommendation.

Dr. Mutch: I think to utilize an app is almost necessary given the complexity of the triaging process so that it does become, in fact, the most cost-effective way to screen patients.

Dr. Huh: I would agree with that. There is a learning curve for whenever you see new technology. There was a learning curve for even ASCCP leadership as they tried to educate providers. I think people will ultimately see that this is a much better way of managing patients with cervical abnormalities, and I am hoping actually that we will use a similar platform for many other diseases that we manage in women’s health.

Continue to: Chipping away of the yearly exam...

Dr. Mutch: With this moving away from the yearly exam and Pap test, women may not get yearly examinations. Do you feel that this could affect a stage migration to a higher stage at diagnosis, for instance, of a cervical cancer? Or that it might adversely impact other health issues?

Dr. Huh: I think that’s a good question. I am worried about the interval—I think 5 years is a bit long. I am more worried that patients will miss out on visits because they may think that they need to only come back for their Pap, even though they should be re-educated on that.

COVID-19 has made this a little hard for us to analyze because, clearly, we have had access to care issues. But I am a little concerned that we could see an uptick in invasive cancer rates in this country, including an uptick in the stage and more locally advanced cervical cancer because of the changes in the screening paradigms. But we don’t know that to be the case.

As with all screenings, the bottom line is you have to worry about what the false-negative and false-positive rates of screening are, and that affects everything. I want the readers to know that primary HPV should be used for screenings. It is not perfect, but it is much better than cytology alone. We need to think about how to better adapt screening in the age that we live in.

HPV self-sampling

Dr. Mutch: Could self-sampling for HPV testing, which obviously would be easier for the patient, and certainly useful in terms of screening, address some health care disparities with regard to cervical cancer?

Dr. Huh: The short answer is, yes. Self-sampling is not US Food and Drug Administration-approved in this country. It’s not being widely used without that approval. But there are multiple countries, including the United States, that have done lots of studies on this topic. There are many public health experts and champions for HPV self-sampling. I think we have learned, based on some studies, that the sensitivity is reasonable.⁶

I live in a part of the country that is woefully underserved; where you are there are pockets in Missouri that are woefully underserved as well. So the issue is, can we reduce these disparities and access to care with something like self-sampling? My personal feeling is I think that we can make a dent in that, and it is never going to fully replace screening, but it at least will allow us to reallocate our resources and attention to those women that are at highest risk for developing cervical cancer or precancer based on the self-sampling result.

I don’t think it will ever replace screening per se, but if we have an abnormal self-sampling test, we might say to that patient, “You really do need to come in to get re-tested or to get re-evaluated.” So it could be a better resource and use of our health care dollars and investments in terms of trying to reduce the incidence of cervical cancer. Of course the verdict is out, but I think there are a lot of people who would love to see this scenario.

If we screen and treat perfectly in this country, we would not even need the HPV vaccine when it comes to cervical cancer. That is how effective screening is. But, up to 50% to 60% of women in this country now still are underscreened or unscreened. We were talking about that number almost 25-30 years ago, Dr. Mutch. So access to screening is a big problem, but the other problem is how do you get patients in to be seen if they have an abnormal screening test? It’s not just about screening. It’s about screening, evaluation, and treatment; all 3 components are really important.

Continue to: Where do we stand with HPV vaccination?...

Dr. Mutch: Those are great points.

You brought up vaccination. We have a long way to go with regard to that, certainly in the United States, because of the various factions opposed to vaccination and so on. But do you think that vaccination has allowed us to decrease the incidence of cervical cancer?

Dr. Huh: Yes. There is clear evidence from the Nordic countries.⁷ There is emerging evidence from Australia.⁸ There is emerging evidence from other industrialized nations that clearly demonstrate vaccination’s positive effect in reducing the incidence of cervical cancer. None of this should be a surprise. Every population-based study that has been published with the HPV vaccine in populations that have a low frequency of vaccination have demonstrated substantial reductions in things like genital warts, abnormal Pap tests, precancer, and now evidence that there is a downward trend in terms of the incidence of cervical cancer.⁹

I don’t think that there is any debate anymore that vaccination is the way to go. Our challenge is about implementation and getting the vaccine to people. We still have a long way to go with that. There are parts of the world that are so affected by invasive cervical cancers; we need to get the vaccine to those parts of the world.

Dr. Mutch: What are the barriers to vaccination? How can we overcome those barriers?

Dr. Huh: There is a lot of criticism that we are not vaccinating more in the United States. However, the rates of vaccination are going up every single year. The pandemic may have blunted that rise a bit, but if you look at the vaccination curves, they are going up, not down. We need to continue to educate patients, parents, and pediatricians on the importance of vaccination.

Boys still get vaccinated less frequently than girls, so we have some work to do there. I think globally it is the issue of getting the vaccine to people, making sure that vaccine is available. The thing that I think will be the game-changer going forward is whether or not we will have evidence to indicate that 1 dose is as effective as 2 doses or 3 doses. If we can vaccinate boys and girls with just 1 dose, then in the next generation or two, we seriously might eradicate not just cervical cancer but a lot of HPV-related malignancies worldwide.

Educating patients, clinicians is key

Dr. Mutch: So it seems education, education, education, with regard to screening guidelines, with regard to the need for continued examinations, and that HPV testing is only a test, it does not supplant overall care. Finally, education regarding eradication of cervical cancer through vaccination.

Dr. Huh: That summarizes it well. We are still going to screen for cervical cancer. We are still going to vaccinate, and providers are still going to manage abnormal Pap tests. It is confusing because we are changing it up it seems every year or 2, so this conversation you and I are having is particularly important for clinicians to understand the basis of that. There has been an explosion of data that has come out in this area in the last decade.

Dr. Mutch: Thank you, Dr. Huh. I really appreciate your thoughts on this. As you all know, Dr. Huh has been President of the ASCCP and is instrumental in writing and disseminating these guidelines, so we are very grateful that he has consented to agree to come and talk with us today.

Dr. Huh: My pleasure. Thank you for inviting me. This was fun, and I have really enjoyed talking to you and participating. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

David G. Mutch, MD: The cervical cancer screening guidelines, using Pap testing, have changed significantly since the times of yearly Paps and exams. Coupled with vaccination and new management guidelines (recommending HPV testing, etc), we actually hope that we are on the way to eradicating cervical cancer from our environment.

Screening: Current recommendations

Dr. Mutch: Warner, the American Society of Colposcopy and Cervical Pathology (ASCCP)¹ endorses the cervical cancer screening guidelines for several professional organizations, including the American Cancer Society (ACS),² the US Preventive Services Task Force (USPSTF),³ and the American College of Obstetricians and Gynecologists (ACOG).⁴ What are the current screening recommendations, as these organizations have disparate views?

Warner Huh, MD: There was a time, around 2012-2013, when for the first time ever, we had significant harmonization of the guidelines between ACOG and the USPSTF and ACS. But in the last 10 years there has been an explosion of data in terms of how to best screen patients.

The move to primary HPV testing. The USPSTF³ initially had recommended looking into primary HPV screening, which is just using HPV testing by itself as the screening modality. But there was a lot of pushback at that time. I think a lot of people thought that we were not prepared to make that leap. Therefore, they endorsed screening with cytology by itself as well as HPV testing by itself, as well as co-testing; but in their recommendations, they made it very clear that they were leaning toward primary HPV screening.

A new patient age to begin screening. In 2020, the ACS put out their new guidelines,² which are a significant departure from what we are used to—they are recommending that we start screening at 25 years of age. Like you said, Dr. Mutch, it doesn’t seem that long ago when we were screening people at age 18, or within 3 years of sexual intercourse. But the reason for it is that the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already do this.

The other major departure in the ACS guidelines is that they really are asking clinicians and screeners to focus on primary HPV screening. Overall, they have sort of doubled down on why they think primary HPV screening is so important.

ACOG sits sort of in the middle of the other recommendations. ACOG understands the value of primary HPV screening, but I don’t think that they are quite ready to recommend screening at age 25. If you look at their updated guidelines from April 2021,⁴ they state that we should continue a screening-starting age of 21 years. So there are some disparate views, but I am confident, Dr. Mutch, that in the next 2 to 3 years, there will be greater harmonization of these guidelines and less confusion for our providers. The greatest barrier is understanding the science and the comfort level of clinicians to go with just an HPV test, since for the last 40 years the Pap test has anchored gynecologic care in this country. And it took at least 10 years to get to what I consider to be widespread adoption to co-testing. The other thing that readers should recognize is that the Task Force is actually revisiting their cervical cancer screening guidance now, so expect another major revision.

Reimbursement and access are barriers. Reimbursement is a further real issue. We are now using one less test, but insurance companies may not reimburse when just the HPV test is used. The other issue is access to labs that can do the HPV testing.

Dr. Mutch: We used to see patients yearly and picked up a lot of adjunctive or additional illnesses. Now they are not being seen yearly it could impact negatively their overall health care. We need to understand that cervical cancer screening is simply a test, which should not eliminate other health care.

Dr. Huh: Yes, I think the extended interval between recommended HPV screenings scares people. I have been involved in these screening guidelines (and I can only speak for myself, not for my colleagues), but even I do think we made a leap to a longer interval way too quickly in this country. Screening changes are slow, and sometimes a glacial process. I think it can worry providers when we make rapid changes.

But this is a test that should not anchor the yearly visit. There are plenty of other reasons—and ACOG actually states this⁴—why patients should come for a wellness exam on a yearly basis. So I think our ObGyns in the United States need to recognize that, but I understand there are underlying concerns that if you extend intervals too long, (a) will patients come back, and (b), as a consequence, is the interval going to miss something in between? Those are real legitimate concerns.

Continue to: Management guidelines...

Dr. Mutch: The ASCCP issued new management guidelines in 2019.⁵ Can you address what you feel are the most important updates?

Dr. Huh: Going back to 2002, we have revised these guidelines every 5 years. For this one, the revision came out a little bit later for various reasons, but the reason we revised it is because we collect new data that we think markedly changes our understanding of the disease process and natural history and the interventions for women that have preinvasive disease of the cervix.

Briefly, I think the biggest changes based on what we were hearing from our providers and users of our apps and algorithms was that our algorithms were becoming way too complicated, and they were. If you look over the last 10 years, the number of branch points on our algorithms basically quadrupled. If we incorporated the new data this time, the algorithms would be unworkable, and you could not use them on your phone because they would be too complicated.

So, we created a system where, in essence, providers have 5 choices for patients:

• treatment
• colposcopy
• follow-up in 1 year
• follow-up in 3 years
• follow-up in 5 years.

Those recommendations are based on what we call “clinically actionable thresholds”—basically, the percent chance of developing immediate CIN3 or worse. That threshold will probably change over time, but what we did is create a system that (a) makes it easier for the provider, (although they have to trust the system—and they can look under the hood and understand how we did this) and (b) allows us to create a foundation where we can add future technologies that use the same rubric or paradigm so that they still wind up getting the same result without having to go to another algorithm.

This new system is probably the most marked change in the history of the ASCCP management guidelines, but we did it to make it ultimately easier for providers going forward for the next 10 to 20 years. There are real opportunities, Dr. Mutch, in terms of how do we integrate this into the electronic medical record (EMR), and how do we pull data so clinicians don’t have to manually enter it.

The other difference is now there is a web-based application. Back in 2012, there were a lot of people that were not using EMRs. Now the majority of the country is, and so they actually are on a browser more than they are on their phone. We actually have an equally robust web platform that allows them to get the information that they need.

Dr. Mutch: I think that is really important—the utility of utilizing a mobile app, if you will, for triaging your patient with a specific test result so that patients are followed up at the proper interval, and that ultimately becomes cost-effective.

Dr. Huh: Yes, the app now is very different than the app that I think people are used to using for the last almost 10 years. You don’t put inputs, pull up the algorithm, and look at the outcome. This is different. You enter the patient’s age. You add their cytology, their HPV results, the clinical scenario that you are in, and then it puts out a recommendation of what to do next. Over time, we want to get away from an algorithm and for our providers to understand what the risk is and how that risk calculation then translates into a clinical recommendation.

Dr. Mutch: I think to utilize an app is almost necessary given the complexity of the triaging process so that it does become, in fact, the most cost-effective way to screen patients.

Dr. Huh: I would agree with that. There is a learning curve for whenever you see new technology. There was a learning curve for even ASCCP leadership as they tried to educate providers. I think people will ultimately see that this is a much better way of managing patients with cervical abnormalities, and I am hoping actually that we will use a similar platform for many other diseases that we manage in women’s health.

Continue to: Chipping away of the yearly exam...

Dr. Mutch: With this moving away from the yearly exam and Pap test, women may not get yearly examinations. Do you feel that this could affect a stage migration to a higher stage at diagnosis, for instance, of a cervical cancer? Or that it might adversely impact other health issues?

Dr. Huh: I think that’s a good question. I am worried about the interval—I think 5 years is a bit long. I am more worried that patients will miss out on visits because they may think that they need to only come back for their Pap, even though they should be re-educated on that.

COVID-19 has made this a little hard for us to analyze because, clearly, we have had access to care issues. But I am a little concerned that we could see an uptick in invasive cancer rates in this country, including an uptick in the stage and more locally advanced cervical cancer because of the changes in the screening paradigms. But we don’t know that to be the case.

As with all screenings, the bottom line is you have to worry about what the false-negative and false-positive rates of screening are, and that affects everything. I want the readers to know that primary HPV should be used for screenings. It is not perfect, but it is much better than cytology alone. We need to think about how to better adapt screening in the age that we live in.

HPV self-sampling

Dr. Mutch: Could self-sampling for HPV testing, which obviously would be easier for the patient, and certainly useful in terms of screening, address some health care disparities with regard to cervical cancer?

Dr. Huh: The short answer is, yes. Self-sampling is not US Food and Drug Administration-approved in this country. It’s not being widely used without that approval. But there are multiple countries, including the United States, that have done lots of studies on this topic. There are many public health experts and champions for HPV self-sampling. I think we have learned, based on some studies, that the sensitivity is reasonable.⁶

I live in a part of the country that is woefully underserved; where you are there are pockets in Missouri that are woefully underserved as well. So the issue is, can we reduce these disparities and access to care with something like self-sampling? My personal feeling is I think that we can make a dent in that, and it is never going to fully replace screening, but it at least will allow us to reallocate our resources and attention to those women that are at highest risk for developing cervical cancer or precancer based on the self-sampling result.

I don’t think it will ever replace screening per se, but if we have an abnormal self-sampling test, we might say to that patient, “You really do need to come in to get re-tested or to get re-evaluated.” So it could be a better resource and use of our health care dollars and investments in terms of trying to reduce the incidence of cervical cancer. Of course the verdict is out, but I think there are a lot of people who would love to see this scenario.

If we screen and treat perfectly in this country, we would not even need the HPV vaccine when it comes to cervical cancer. That is how effective screening is. But, up to 50% to 60% of women in this country now still are underscreened or unscreened. We were talking about that number almost 25-30 years ago, Dr. Mutch. So access to screening is a big problem, but the other problem is how do you get patients in to be seen if they have an abnormal screening test? It’s not just about screening. It’s about screening, evaluation, and treatment; all 3 components are really important.

Continue to: Where do we stand with HPV vaccination?...

Dr. Mutch: Those are great points.

You brought up vaccination. We have a long way to go with regard to that, certainly in the United States, because of the various factions opposed to vaccination and so on. But do you think that vaccination has allowed us to decrease the incidence of cervical cancer?

Dr. Huh: Yes. There is clear evidence from the Nordic countries.⁷ There is emerging evidence from Australia.⁸ There is emerging evidence from other industrialized nations that clearly demonstrate vaccination’s positive effect in reducing the incidence of cervical cancer. None of this should be a surprise. Every population-based study that has been published with the HPV vaccine in populations that have a low frequency of vaccination have demonstrated substantial reductions in things like genital warts, abnormal Pap tests, precancer, and now evidence that there is a downward trend in terms of the incidence of cervical cancer.⁹

I don’t think that there is any debate anymore that vaccination is the way to go. Our challenge is about implementation and getting the vaccine to people. We still have a long way to go with that. There are parts of the world that are so affected by invasive cervical cancers; we need to get the vaccine to those parts of the world.

Dr. Mutch: What are the barriers to vaccination? How can we overcome those barriers?

Dr. Huh: There is a lot of criticism that we are not vaccinating more in the United States. However, the rates of vaccination are going up every single year. The pandemic may have blunted that rise a bit, but if you look at the vaccination curves, they are going up, not down. We need to continue to educate patients, parents, and pediatricians on the importance of vaccination.

Boys still get vaccinated less frequently than girls, so we have some work to do there. I think globally it is the issue of getting the vaccine to people, making sure that vaccine is available. The thing that I think will be the game-changer going forward is whether or not we will have evidence to indicate that 1 dose is as effective as 2 doses or 3 doses. If we can vaccinate boys and girls with just 1 dose, then in the next generation or two, we seriously might eradicate not just cervical cancer but a lot of HPV-related malignancies worldwide.

Educating patients, clinicians is key

Dr. Mutch: So it seems education, education, education, with regard to screening guidelines, with regard to the need for continued examinations, and that HPV testing is only a test, it does not supplant overall care. Finally, education regarding eradication of cervical cancer through vaccination.

Dr. Huh: That summarizes it well. We are still going to screen for cervical cancer. We are still going to vaccinate, and providers are still going to manage abnormal Pap tests. It is confusing because we are changing it up it seems every year or 2, so this conversation you and I are having is particularly important for clinicians to understand the basis of that. There has been an explosion of data that has come out in this area in the last decade.

Dr. Mutch: Thank you, Dr. Huh. I really appreciate your thoughts on this. As you all know, Dr. Huh has been President of the ASCCP and is instrumental in writing and disseminating these guidelines, so we are very grateful that he has consented to agree to come and talk with us today.

Dr. Huh: My pleasure. Thank you for inviting me. This was fun, and I have really enjoyed talking to you and participating. ●

Gupta A, Jha P, Baran TM, et al. Ovarian cancer detection in average-risk women: classic- versus nonclassic-appearing adnexal lesions at US. Radiology. 2022;212338. doi: 10.1148/radiol.212338.

Expert commentary

Gupta and colleagues conducted a multicenter, retrospective review of 970 adnexal lesions among 878 women—75% were premenopausal and 25% were postmenopausal.

Imaging details

The lesions were characterized by pattern recognition as “classic” (simple cysts, endometriomas, hemorrhagic cysts, or dermoids) or “nonclassic.” Out of 673 classic lesions, there were 4 malignancies (0.6%), of which 1 was an endometrioma and 3 were classified as simple cysts. However, out of 297 nonclassic lesions (multilocular, unilocular with solid areas or wall irregularity, or mostly solid), 32% (33/103) were malignant when vascularity was present, while 8% (16/184) were malignant when no intralesional vascularity was appreciated.

The authors pointed out that, especially because their study was retrospective, there was no standardization of scan technique or equipment employed. However, this point adds credibility to the “real world” nature of such imaging.

Other data corroborate findings

Other studies have looked at pattern recognition in efforts to optimize a conservative approach to benign masses and referral to oncology for suspected malignant masses, as described above. This was the main cornerstone of the International Consensus Conference,² which also identified next steps for indeterminate masses, including evidence-based risk assessment algorithms and referral (to an expert imager or gynecologic oncologist). A multicenter trial in Europe³ found that ultrasound experience substantially impacts on diagnostic performance when adnexal masses are classified using pattern recognition. This occurred in a stepwise fashion with increasing accuracy directly related to the level of expertise. Shetty and colleagues⁴ found that pattern recognition performed better than the risk of malignancy index (sensitivities of 95% and 79%, respectively). ●

Gupta A, Jha P, Baran TM, et al. Ovarian cancer detection in average-risk women: classic- versus nonclassic-appearing adnexal lesions at US. Radiology. 2022;212338. doi: 10.1148/radiol.212338.

Expert commentary

Gupta and colleagues conducted a multicenter, retrospective review of 970 adnexal lesions among 878 women—75% were premenopausal and 25% were postmenopausal.

Imaging details

The lesions were characterized by pattern recognition as “classic” (simple cysts, endometriomas, hemorrhagic cysts, or dermoids) or “nonclassic.” Out of 673 classic lesions, there were 4 malignancies (0.6%), of which 1 was an endometrioma and 3 were classified as simple cysts. However, out of 297 nonclassic lesions (multilocular, unilocular with solid areas or wall irregularity, or mostly solid), 32% (33/103) were malignant when vascularity was present, while 8% (16/184) were malignant when no intralesional vascularity was appreciated.

The authors pointed out that, especially because their study was retrospective, there was no standardization of scan technique or equipment employed. However, this point adds credibility to the “real world” nature of such imaging.

Other data corroborate findings

Other studies have looked at pattern recognition in efforts to optimize a conservative approach to benign masses and referral to oncology for suspected malignant masses, as described above. This was the main cornerstone of the International Consensus Conference,² which also identified next steps for indeterminate masses, including evidence-based risk assessment algorithms and referral (to an expert imager or gynecologic oncologist). A multicenter trial in Europe³ found that ultrasound experience substantially impacts on diagnostic performance when adnexal masses are classified using pattern recognition. This occurred in a stepwise fashion with increasing accuracy directly related to the level of expertise. Shetty and colleagues⁴ found that pattern recognition performed better than the risk of malignancy index (sensitivities of 95% and 79%, respectively). ●

Gupta A, Jha P, Baran TM, et al. Ovarian cancer detection in average-risk women: classic- versus nonclassic-appearing adnexal lesions at US. Radiology. 2022;212338. doi: 10.1148/radiol.212338.

Expert commentary

Gupta and colleagues conducted a multicenter, retrospective review of 970 adnexal lesions among 878 women—75% were premenopausal and 25% were postmenopausal.

Imaging details

The lesions were characterized by pattern recognition as “classic” (simple cysts, endometriomas, hemorrhagic cysts, or dermoids) or “nonclassic.” Out of 673 classic lesions, there were 4 malignancies (0.6%), of which 1 was an endometrioma and 3 were classified as simple cysts. However, out of 297 nonclassic lesions (multilocular, unilocular with solid areas or wall irregularity, or mostly solid), 32% (33/103) were malignant when vascularity was present, while 8% (16/184) were malignant when no intralesional vascularity was appreciated.

The authors pointed out that, especially because their study was retrospective, there was no standardization of scan technique or equipment employed. However, this point adds credibility to the “real world” nature of such imaging.

Other data corroborate findings

Other studies have looked at pattern recognition in efforts to optimize a conservative approach to benign masses and referral to oncology for suspected malignant masses, as described above. This was the main cornerstone of the International Consensus Conference,² which also identified next steps for indeterminate masses, including evidence-based risk assessment algorithms and referral (to an expert imager or gynecologic oncologist). A multicenter trial in Europe³ found that ultrasound experience substantially impacts on diagnostic performance when adnexal masses are classified using pattern recognition. This occurred in a stepwise fashion with increasing accuracy directly related to the level of expertise. Shetty and colleagues⁴ found that pattern recognition performed better than the risk of malignancy index (sensitivities of 95% and 79%, respectively). ●

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

Moderate to severe anxiety, depression, and shortness of breath indicate increased risk for nonfatal self-injury (NFSI) among patients newly diagnosed with cancer, according to a Canadian study.

In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.

“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.

Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”

The study was published online in JAMA Oncology.
 

Nine common symptoms

The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).

The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
 

Toward tailored intervention

A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).

“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”

In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.

“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
 

Self-injury vs. suicidality

Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.

“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”

The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.

“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.

The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Moderate to severe anxiety, depression, and shortness of breath indicate increased risk for nonfatal self-injury (NFSI) among patients newly diagnosed with cancer, according to a Canadian study.

In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.

“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.

Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”

The study was published online in JAMA Oncology.
 

Nine common symptoms

The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).

The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
 

Toward tailored intervention

A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).

“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”

In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.

“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
 

Self-injury vs. suicidality

Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.

“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”

The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.

“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.

The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Moderate to severe anxiety, depression, and shortness of breath indicate increased risk for nonfatal self-injury (NFSI) among patients newly diagnosed with cancer, according to a Canadian study.

In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.

“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.

Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”

The study was published online in JAMA Oncology.
 

Nine common symptoms

The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).

The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
 

Toward tailored intervention

A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).

“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”

In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.

“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
 

Self-injury vs. suicidality

Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.

“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”

The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.

“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.

The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.