Mark H. Einstein, MD, MS

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Cervical cancer was the most common cancer killer of persons with a cervix in the early 1900s in the United States. Widespread adoption of the Pap test in the mid-20th century followed by large-scale outreach through programs such as the National Breast and Cervical Cancer Early Detection Program have dramatically reduced deaths from cervical cancer. The development of a highly effective vaccine that targets human papillomavirus (HPV), the virus implicated in all cervical cancers, has made prevention even more accessible and attainable. Primary prevention with HPV vaccination in conjunction with regular screening as recommended by current guidelines is the most effective way we can prevent cervical cancer.

Despite these advances, the incidence and death rates from cervical cancer have plateaued over the last decade.¹ Additionally, many fear that due to the poor attendance at screening visits since the beginning of the COVID-19 pandemic, the incidence might further rise in the United States.² Among those in the United States diagnosed with cervical cancer, more than 50% have not been screened in over 5 years or had their abnormal results not managed as recommended by current guidelines, suggesting that operational and access issues are contributors to incident cervical cancer. In addition, HPV vaccination rates have increased only slightly from year to year. According to the most recent data from the Centers for Disease Control and Prevention (CDC), coverage with 1 or more doses of HPV vaccine in 2021 increased only by 1.8% and has stagnated, with administration to about 75% of those for whom it is recommended.³ The plateauing will limit our ability to eradicate cervical cancer in the United States, permitting death from a largely preventable disease.

Establishing the framework for the eradication of cervical cancer

The World Health Organization (WHO) adopted a global strategy called the Cervical Cancer Elimination Initiative in August 2020. This initiative is a multipronged effort that focuses on vaccination (90% of girls fully vaccinated by age 15), screening (70% of women screened by age 35 with an effective test and again at age 45), and treatment (90% treatment of precancer and 90% management of women with invasive cancer).⁴

These are the numbers we need to achieve if all countries are to reach a cervical cancer incidence of less than 4 per 100,000 persons with a cervix. The WHO further suggests that each country should meet the “90-70-90” targets by 2030 if we are to achieve the low incidence by the turn of the century.⁴ To date, few regions of the world have achieved these goals, and sadly the United States is not among them.

In response to this call to action, many medical and policymaking organizations are taking inventory and implementing strategies to achieve the WHO 2030 targets for cervical cancer eradication. In the United States, the Society of Gynecologic Oncology (SGO; www.sgo.org), the American Society for Colposcopy and Cervical Pathology (ASCCP; www.ASCCP.org), the American College of Obstetricians and Gynecologists (ACOG; www.acog.org), the American Cancer Society (ACS; www.cancer.org), and many others have initiated programs in a collaborative esprit de corps with the aim of eradicating this deadly disease.

In this Update, we review several studies with evidence of screening and management strategies that show promise of accelerating the eradication of cervical cancer.

Continue to: Transitioning to primary HPV screening in the United States...

Downs LS Jr, Nayar R, Gerndt J, et al; American Cancer Society Primary HPV Screening Initiative Steering Committee. Implementation in action: collaborating on the transition to primary HPV screening for cervical cancer in the United States. CA Cancer J Clin. 2023;73:458-460.

The American Cancer Society released an updated cervical cancer screening guideline in July 2020 that recommended testing for HPV as the preferred strategy. Reasons behind the change, moving away from a Pap test as part of the initial screen, are:

• increased sensitivity of primary HPV testing when compared with conventional cervical cytology (Pap test)
• improved risk stratification to identify who is at risk for cervical cancer now and in the future
• improved efficiency in identifying those who need colposcopy, thus limiting unnecessary procedures without increasing the risk of false-negative tests, thereby missing cervical precancer or invasive cancer.

Some countries with organized screening programs have already made the switch. Self-sampling for HPV is currently being considered for an approved use in the United States, further improving access to screening for cervical cancer when the initial step can be completed by the patient at home or simplified in nontraditional health care settings.²

ACS initiative created to address barriers to primary HPV testing

Challenges to primary HPV testing remain, including laboratory implementation, payment, and operationalizing clinical workflow (for example, HPV testing with reflex cytology instead of cytology with reflex HPV testing).⁵ There are undoubtedly other unforeseen barriers in the current US health care environment.

In a recent commentary, Downs and colleagues described how the ACS has convened the Primary HPV Screening Initiative (PHSI), nested under the ACS National Roundtable on Cervical Cancer, which is charged with identifying critical barriers to, and opportunities for, transitioning to primary HPV screening.⁵ The deliverable will be a roadmap with tools and recommendations to support health systems, laboratories, providers, patients, and payers as they make this evolution.

Work groups will develop resources

Patients, particularly those who have had routine cervical cancer screening over their lifetime, also will be curious about the changes in recommendations. The Provider Needs Workgroup within the PHSI structure will develop tools and patient education materials regarding the data, workflow, benefits, and safety of this new paradigm for cervical cancer screening.

Laboratories that process and interpret tests likely will bear the heaviest load of changes. For example, not all commercially available HPV tests in the United States are approved by the US Food and Drug Administration (FDA) for primary HPV testing. Some sites will need to adapt their equipment to ensure adherence to FDA-approved tests. Laboratory workflows will need to be altered for aliquots to be tested for HPV first, and the remainder for cytology. Quality assurance and accreditation requirements for testing will need modifications, and further efforts will be needed to ensure sufficient numbers of trained cytopathologists, whose workforce is rapidly declining, for processing and reading cervical cytology.

In addition, payment for HPV testing alone, without the need for a Pap test, might not be supported by payers that support safety-net providers and sites, who arguably serve the most vulnerable patients and those most at risk for cervical cancer. Collaboration across medical professionals, societies, payers, and policymakers will provide a critical infrastructure to make the change in the most seamless fashion and limit the harm from missed opportunities for screening.

Continue to: The quest for a “molecular Pap”: Dual-stain testing as a predictor of high-grade CIN...

Magkana M, Mentzelopoulou P, Magkana E, et al. p16/Ki-67 Dual staining is a reliable biomarker for risk stratification for patients with borderline/mild cytology in cervical cancer screening. Anticancer Res. 2022;42:2599-2606.

Stanczuk G, Currie H, Forson W, et al. Clinical performance of triage strategies for Hr-HPV-positive women; a longitudinal evaluation of cytology, p16/K-67 dual stain cytology, and HPV16/18 genotyping. Cancer Epidemiol Biomarkers Prev. 2022;31:1492-1498.
 

One new technology that was recently FDA approved and recommended for management of abnormal cervical cancer screening testing is dual-stain (DS) testing. Dual-stain testing is a cytology-based test that evaluates the concurrent expression of p16, a tumor suppressor protein upregulated in HPV oncogenesis, and Ki-67, a cell proliferation marker.^6,7 Two recent studies have showcased the outstanding clinical performance of DS testing and triage strategies that incorporate DS testing.

Higher specificity, fewer colposcopies needed with DS testing

Magkana and colleagues prospectively evaluated patients with atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or negative for intraepithelial lesion or malignancy (NILM) cytology referred for colposcopy, and they compared p16/Ki-67 DS testing with high-risk HPV (HR-HPV) testing for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+); comparable sensitivities for CIN 2+ detection were seen (97.3% and 98.7%, respectively).⁸

Dual-stain testing exhibited higher specificity at 99.3% compared with HR-HPV testing at 52.2%. Incorporating DS testing into triage strategies also led to fewer colposcopies needed to detect CIN 2+ compared with current ASCCP guidelines that use traditional cervical cancer screening algorithms.

DS cytology strategy had the highest sensitivity for CIN 2+ detection

An additional study by Stanczuk and colleagues evaluated triage strategies in a cohort of HR-HPV positive patients who participated in the Scottish Papillomavirus Dumfries and Galloway study with HPV 16/18 genotyping (HPV 16/18), liquid-based cytology (LBC), and p16/Ki-67 DS cytology.⁹ Of these 3 triage strategies, DS cytology had the highest sensitivity for the detection of CIN 2+, at 77.7% (with a specificity of 74.2%), performance that is arguably better than cytology.

When evaluated in sequence as part of a triage strategy after HPV primary screening, HPV 16/18–positive patients reflexed to DS testing showed a similar sensitivity as those who would be triaged with LBC (TABLE).⁹

DS testing’s potential

These studies add to the growing body of literature that supports the use of DS testing in cervical cancer screening management guidelines and that are being incorporated into currently existing workflows. Furthermore, with advancements in digital imaging and machine learning, DS testing holds the potential for a high throughput, reproducible, and accurate risk stratification that can replace the current reliance on cytology, furthering the potential for a fully molecular Pap test.^10,11

Continue to: Cervical cancer screening in women older than age 65: Is there benefit?...

Firtina Tuncer S, Tuncer HA. Cervical cancer screening in women aged older than 65 years. J Low Genit Tract Dis. 2023;27:207-211.

Booth BB, Tranberg M, Gustafson LW, et al. Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged  ≥ 69 referred to colposcopy due to an HPV-positive screening test. BMC Cancer. 2023;23:405.
 

Current guidelines in the United States recommend that cervical cancer screening for all persons with a cervix end at age 65. These age restrictions were a change in guidelines updated in 2012 and endorsed by the US Preventive Services Task Force.^12,13 Evidence suggests that because of high likelihood of regression and slow progression of disease, risks of screening prior to age 21 outweigh its benefits. With primary HPV testing, the age at screening debut is 25 for the same reasons.¹⁴ In people with a history of CIN 2+, active surveillance should continue for at least 25 years with HPV-based screening regardless of age. In the absence of a history of CIN 2+, however, the data to support discontinuation of screening after age 65 are less clear.

HPV positivity found to be most substantial risk for CIN 2+

In a study published this year in the Journal of Lower Genital Tract Disease, Firtina Tuncer and colleagues described their experience extending “routine screening” in patients older than 65 years.¹⁵ Data including cervical cytology, HPV test results, biopsy findings, and endocervical curettage results were collected, and abnormal findings were managed according to the 2012 and 2019 ASCCP guidelines.

When compared with negative HPV testing and normal cytology, the authors found that HPV positivity and abnormal cytology increased the risk of CIN 2+(odds ratio [OR], 136.1 and 13.1, respectively). Patients whose screening prior to age 65 had been insufficient or demonstrated CIN 2+ in the preceding 10 years were similarly more likely to have findings of CIN 2+ (OR, 9.7 when compared with HPV-negative controls).

The authors concluded that, among persons with a cervix older than age 65, previous screening and abnormal cytology were important in risk stratifications for CIN 2+; however, HPV positivity conferred the most substantial risk.

Study finds cervical dysplasia is prevalent in older populations

It has been suggested that screening for cervical cancer should continue beyond age 65 as cytology-based screening may have decreased sensitivity in older patients, which may contribute to the higher rates of advanced-stage diagnoses and cancer-related death in this population.^16,17

Authors of an observational study conducted in Denmark invited persons with a cervix aged 69 and older to have one additional HPV-based screening test, and they referred them for colposcopy if HPV positive or in the presence of ASCUS or greater cytology.¹⁸ Among the 191 patients with HPV-positive results, 20% were found to have a diagnosis of CIN 2+, and 24.4% had CIN 2+ detected at another point in the study period. Notably, most patients diagnosed with CIN 2+ had no abnormalities visualized on colposcopy, and the majority of biopsies taken (65.8%) did not contain the transitional zone.

Biopsies underestimated CIN 2+ in 17.9% of cases compared with loop electrosurgical excision procedure (LEEP). These findings suggest both that high-grade cervical dysplasia is prevalent in an older population and that older populations may be susceptible to false-negative results. They also further support the use of HPV-based screening.

Harnessing the immune system to improve survival rates in recurrent cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Unfortunately, most clinical trials for recurrent or metastatic cervical cancer are negative trials or have results that show limited impact on disease outcomes. Currently, cervical cancer is treated with multiple agents, including platinum-based chemotherapy and bevacizumab, a medication that targets vascular growth. Despite these usually very effective drugs given in combination to cervical cancer patients, long-term survival remains low. Over the past few decades, many trials have been designed to help patients with this terrible disease, but few have shown significant promise.

Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized care for many cancers. Checkpoint inhibitors block the proteins that cause a tumor to remain undetected by the immune system’s army of T cells. By blocking these proteins, the cancer cells can then be recognized by the immune system as foreign. Several studies have concluded that including immune checkpoint inhibitors in the comprehensive regimen for recurrent cervical cancer improves survival.

Addition of pembrolizumab increased survival

Investigators in the phase 3 double-blinded KEYNOTE-826 trial evaluated whether or not the addition of pembrolizumab to standard of care improved progression-free and overall survival in advanced, recurrent, or persistent cervical cancer.¹⁹ As part of the evaluation, the investigators measured the protein that turns off the immune system’s ability to recognize tumors, anti-programmed cell death protein-1 (PD-1).

Compared with placebo, the investigators found that, regardless of PD-1 status, the addition of pembrolizumab immunotherapy to the standard regimen increased progression-free survival and overall survival without any significantly increased adverse effects or safety concerns (FIGURE).¹⁹ At 1 year after treatment, more patients who received pembrolizumab were still alive regardless of PD-1 status, and their responses lasted longer. The most profound improvements were seen in patients whose tumors exhibited high expression of PD-L1, the target of pembrolizumab and many other immune checkpoint inhibitors.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Cervical cancer was the most common cancer killer of persons with a cervix in the early 1900s in the United States. Widespread adoption of the Pap test in the mid-20th century followed by large-scale outreach through programs such as the National Breast and Cervical Cancer Early Detection Program have dramatically reduced deaths from cervical cancer. The development of a highly effective vaccine that targets human papillomavirus (HPV), the virus implicated in all cervical cancers, has made prevention even more accessible and attainable. Primary prevention with HPV vaccination in conjunction with regular screening as recommended by current guidelines is the most effective way we can prevent cervical cancer.

Despite these advances, the incidence and death rates from cervical cancer have plateaued over the last decade.¹ Additionally, many fear that due to the poor attendance at screening visits since the beginning of the COVID-19 pandemic, the incidence might further rise in the United States.² Among those in the United States diagnosed with cervical cancer, more than 50% have not been screened in over 5 years or had their abnormal results not managed as recommended by current guidelines, suggesting that operational and access issues are contributors to incident cervical cancer. In addition, HPV vaccination rates have increased only slightly from year to year. According to the most recent data from the Centers for Disease Control and Prevention (CDC), coverage with 1 or more doses of HPV vaccine in 2021 increased only by 1.8% and has stagnated, with administration to about 75% of those for whom it is recommended.³ The plateauing will limit our ability to eradicate cervical cancer in the United States, permitting death from a largely preventable disease.

Establishing the framework for the eradication of cervical cancer

The World Health Organization (WHO) adopted a global strategy called the Cervical Cancer Elimination Initiative in August 2020. This initiative is a multipronged effort that focuses on vaccination (90% of girls fully vaccinated by age 15), screening (70% of women screened by age 35 with an effective test and again at age 45), and treatment (90% treatment of precancer and 90% management of women with invasive cancer).⁴

These are the numbers we need to achieve if all countries are to reach a cervical cancer incidence of less than 4 per 100,000 persons with a cervix. The WHO further suggests that each country should meet the “90-70-90” targets by 2030 if we are to achieve the low incidence by the turn of the century.⁴ To date, few regions of the world have achieved these goals, and sadly the United States is not among them.

In response to this call to action, many medical and policymaking organizations are taking inventory and implementing strategies to achieve the WHO 2030 targets for cervical cancer eradication. In the United States, the Society of Gynecologic Oncology (SGO; www.sgo.org), the American Society for Colposcopy and Cervical Pathology (ASCCP; www.ASCCP.org), the American College of Obstetricians and Gynecologists (ACOG; www.acog.org), the American Cancer Society (ACS; www.cancer.org), and many others have initiated programs in a collaborative esprit de corps with the aim of eradicating this deadly disease.

In this Update, we review several studies with evidence of screening and management strategies that show promise of accelerating the eradication of cervical cancer.

Continue to: Transitioning to primary HPV screening in the United States...

Downs LS Jr, Nayar R, Gerndt J, et al; American Cancer Society Primary HPV Screening Initiative Steering Committee. Implementation in action: collaborating on the transition to primary HPV screening for cervical cancer in the United States. CA Cancer J Clin. 2023;73:458-460.

The American Cancer Society released an updated cervical cancer screening guideline in July 2020 that recommended testing for HPV as the preferred strategy. Reasons behind the change, moving away from a Pap test as part of the initial screen, are:

• increased sensitivity of primary HPV testing when compared with conventional cervical cytology (Pap test)
• improved risk stratification to identify who is at risk for cervical cancer now and in the future
• improved efficiency in identifying those who need colposcopy, thus limiting unnecessary procedures without increasing the risk of false-negative tests, thereby missing cervical precancer or invasive cancer.

Some countries with organized screening programs have already made the switch. Self-sampling for HPV is currently being considered for an approved use in the United States, further improving access to screening for cervical cancer when the initial step can be completed by the patient at home or simplified in nontraditional health care settings.²

ACS initiative created to address barriers to primary HPV testing

Challenges to primary HPV testing remain, including laboratory implementation, payment, and operationalizing clinical workflow (for example, HPV testing with reflex cytology instead of cytology with reflex HPV testing).⁵ There are undoubtedly other unforeseen barriers in the current US health care environment.

In a recent commentary, Downs and colleagues described how the ACS has convened the Primary HPV Screening Initiative (PHSI), nested under the ACS National Roundtable on Cervical Cancer, which is charged with identifying critical barriers to, and opportunities for, transitioning to primary HPV screening.⁵ The deliverable will be a roadmap with tools and recommendations to support health systems, laboratories, providers, patients, and payers as they make this evolution.

Work groups will develop resources

Patients, particularly those who have had routine cervical cancer screening over their lifetime, also will be curious about the changes in recommendations. The Provider Needs Workgroup within the PHSI structure will develop tools and patient education materials regarding the data, workflow, benefits, and safety of this new paradigm for cervical cancer screening.

Laboratories that process and interpret tests likely will bear the heaviest load of changes. For example, not all commercially available HPV tests in the United States are approved by the US Food and Drug Administration (FDA) for primary HPV testing. Some sites will need to adapt their equipment to ensure adherence to FDA-approved tests. Laboratory workflows will need to be altered for aliquots to be tested for HPV first, and the remainder for cytology. Quality assurance and accreditation requirements for testing will need modifications, and further efforts will be needed to ensure sufficient numbers of trained cytopathologists, whose workforce is rapidly declining, for processing and reading cervical cytology.

In addition, payment for HPV testing alone, without the need for a Pap test, might not be supported by payers that support safety-net providers and sites, who arguably serve the most vulnerable patients and those most at risk for cervical cancer. Collaboration across medical professionals, societies, payers, and policymakers will provide a critical infrastructure to make the change in the most seamless fashion and limit the harm from missed opportunities for screening.

Continue to: The quest for a “molecular Pap”: Dual-stain testing as a predictor of high-grade CIN...

Magkana M, Mentzelopoulou P, Magkana E, et al. p16/Ki-67 Dual staining is a reliable biomarker for risk stratification for patients with borderline/mild cytology in cervical cancer screening. Anticancer Res. 2022;42:2599-2606.

Stanczuk G, Currie H, Forson W, et al. Clinical performance of triage strategies for Hr-HPV-positive women; a longitudinal evaluation of cytology, p16/K-67 dual stain cytology, and HPV16/18 genotyping. Cancer Epidemiol Biomarkers Prev. 2022;31:1492-1498.
 

One new technology that was recently FDA approved and recommended for management of abnormal cervical cancer screening testing is dual-stain (DS) testing. Dual-stain testing is a cytology-based test that evaluates the concurrent expression of p16, a tumor suppressor protein upregulated in HPV oncogenesis, and Ki-67, a cell proliferation marker.^6,7 Two recent studies have showcased the outstanding clinical performance of DS testing and triage strategies that incorporate DS testing.

Higher specificity, fewer colposcopies needed with DS testing

Magkana and colleagues prospectively evaluated patients with atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or negative for intraepithelial lesion or malignancy (NILM) cytology referred for colposcopy, and they compared p16/Ki-67 DS testing with high-risk HPV (HR-HPV) testing for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+); comparable sensitivities for CIN 2+ detection were seen (97.3% and 98.7%, respectively).⁸

Dual-stain testing exhibited higher specificity at 99.3% compared with HR-HPV testing at 52.2%. Incorporating DS testing into triage strategies also led to fewer colposcopies needed to detect CIN 2+ compared with current ASCCP guidelines that use traditional cervical cancer screening algorithms.

DS cytology strategy had the highest sensitivity for CIN 2+ detection

An additional study by Stanczuk and colleagues evaluated triage strategies in a cohort of HR-HPV positive patients who participated in the Scottish Papillomavirus Dumfries and Galloway study with HPV 16/18 genotyping (HPV 16/18), liquid-based cytology (LBC), and p16/Ki-67 DS cytology.⁹ Of these 3 triage strategies, DS cytology had the highest sensitivity for the detection of CIN 2+, at 77.7% (with a specificity of 74.2%), performance that is arguably better than cytology.

When evaluated in sequence as part of a triage strategy after HPV primary screening, HPV 16/18–positive patients reflexed to DS testing showed a similar sensitivity as those who would be triaged with LBC (TABLE).⁹

DS testing’s potential

These studies add to the growing body of literature that supports the use of DS testing in cervical cancer screening management guidelines and that are being incorporated into currently existing workflows. Furthermore, with advancements in digital imaging and machine learning, DS testing holds the potential for a high throughput, reproducible, and accurate risk stratification that can replace the current reliance on cytology, furthering the potential for a fully molecular Pap test.^10,11

Continue to: Cervical cancer screening in women older than age 65: Is there benefit?...

Firtina Tuncer S, Tuncer HA. Cervical cancer screening in women aged older than 65 years. J Low Genit Tract Dis. 2023;27:207-211.

Booth BB, Tranberg M, Gustafson LW, et al. Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged  ≥ 69 referred to colposcopy due to an HPV-positive screening test. BMC Cancer. 2023;23:405.
 

Current guidelines in the United States recommend that cervical cancer screening for all persons with a cervix end at age 65. These age restrictions were a change in guidelines updated in 2012 and endorsed by the US Preventive Services Task Force.^12,13 Evidence suggests that because of high likelihood of regression and slow progression of disease, risks of screening prior to age 21 outweigh its benefits. With primary HPV testing, the age at screening debut is 25 for the same reasons.¹⁴ In people with a history of CIN 2+, active surveillance should continue for at least 25 years with HPV-based screening regardless of age. In the absence of a history of CIN 2+, however, the data to support discontinuation of screening after age 65 are less clear.

HPV positivity found to be most substantial risk for CIN 2+

In a study published this year in the Journal of Lower Genital Tract Disease, Firtina Tuncer and colleagues described their experience extending “routine screening” in patients older than 65 years.¹⁵ Data including cervical cytology, HPV test results, biopsy findings, and endocervical curettage results were collected, and abnormal findings were managed according to the 2012 and 2019 ASCCP guidelines.

When compared with negative HPV testing and normal cytology, the authors found that HPV positivity and abnormal cytology increased the risk of CIN 2+(odds ratio [OR], 136.1 and 13.1, respectively). Patients whose screening prior to age 65 had been insufficient or demonstrated CIN 2+ in the preceding 10 years were similarly more likely to have findings of CIN 2+ (OR, 9.7 when compared with HPV-negative controls).

The authors concluded that, among persons with a cervix older than age 65, previous screening and abnormal cytology were important in risk stratifications for CIN 2+; however, HPV positivity conferred the most substantial risk.

Study finds cervical dysplasia is prevalent in older populations

It has been suggested that screening for cervical cancer should continue beyond age 65 as cytology-based screening may have decreased sensitivity in older patients, which may contribute to the higher rates of advanced-stage diagnoses and cancer-related death in this population.^16,17

Authors of an observational study conducted in Denmark invited persons with a cervix aged 69 and older to have one additional HPV-based screening test, and they referred them for colposcopy if HPV positive or in the presence of ASCUS or greater cytology.¹⁸ Among the 191 patients with HPV-positive results, 20% were found to have a diagnosis of CIN 2+, and 24.4% had CIN 2+ detected at another point in the study period. Notably, most patients diagnosed with CIN 2+ had no abnormalities visualized on colposcopy, and the majority of biopsies taken (65.8%) did not contain the transitional zone.

Biopsies underestimated CIN 2+ in 17.9% of cases compared with loop electrosurgical excision procedure (LEEP). These findings suggest both that high-grade cervical dysplasia is prevalent in an older population and that older populations may be susceptible to false-negative results. They also further support the use of HPV-based screening.

Harnessing the immune system to improve survival rates in recurrent cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Unfortunately, most clinical trials for recurrent or metastatic cervical cancer are negative trials or have results that show limited impact on disease outcomes. Currently, cervical cancer is treated with multiple agents, including platinum-based chemotherapy and bevacizumab, a medication that targets vascular growth. Despite these usually very effective drugs given in combination to cervical cancer patients, long-term survival remains low. Over the past few decades, many trials have been designed to help patients with this terrible disease, but few have shown significant promise.

Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized care for many cancers. Checkpoint inhibitors block the proteins that cause a tumor to remain undetected by the immune system’s army of T cells. By blocking these proteins, the cancer cells can then be recognized by the immune system as foreign. Several studies have concluded that including immune checkpoint inhibitors in the comprehensive regimen for recurrent cervical cancer improves survival.

Addition of pembrolizumab increased survival

Investigators in the phase 3 double-blinded KEYNOTE-826 trial evaluated whether or not the addition of pembrolizumab to standard of care improved progression-free and overall survival in advanced, recurrent, or persistent cervical cancer.¹⁹ As part of the evaluation, the investigators measured the protein that turns off the immune system’s ability to recognize tumors, anti-programmed cell death protein-1 (PD-1).

Compared with placebo, the investigators found that, regardless of PD-1 status, the addition of pembrolizumab immunotherapy to the standard regimen increased progression-free survival and overall survival without any significantly increased adverse effects or safety concerns (FIGURE).¹⁹ At 1 year after treatment, more patients who received pembrolizumab were still alive regardless of PD-1 status, and their responses lasted longer. The most profound improvements were seen in patients whose tumors exhibited high expression of PD-L1, the target of pembrolizumab and many other immune checkpoint inhibitors.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Cervical cancer was the most common cancer killer of persons with a cervix in the early 1900s in the United States. Widespread adoption of the Pap test in the mid-20th century followed by large-scale outreach through programs such as the National Breast and Cervical Cancer Early Detection Program have dramatically reduced deaths from cervical cancer. The development of a highly effective vaccine that targets human papillomavirus (HPV), the virus implicated in all cervical cancers, has made prevention even more accessible and attainable. Primary prevention with HPV vaccination in conjunction with regular screening as recommended by current guidelines is the most effective way we can prevent cervical cancer.

Despite these advances, the incidence and death rates from cervical cancer have plateaued over the last decade.¹ Additionally, many fear that due to the poor attendance at screening visits since the beginning of the COVID-19 pandemic, the incidence might further rise in the United States.² Among those in the United States diagnosed with cervical cancer, more than 50% have not been screened in over 5 years or had their abnormal results not managed as recommended by current guidelines, suggesting that operational and access issues are contributors to incident cervical cancer. In addition, HPV vaccination rates have increased only slightly from year to year. According to the most recent data from the Centers for Disease Control and Prevention (CDC), coverage with 1 or more doses of HPV vaccine in 2021 increased only by 1.8% and has stagnated, with administration to about 75% of those for whom it is recommended.³ The plateauing will limit our ability to eradicate cervical cancer in the United States, permitting death from a largely preventable disease.

Establishing the framework for the eradication of cervical cancer

The World Health Organization (WHO) adopted a global strategy called the Cervical Cancer Elimination Initiative in August 2020. This initiative is a multipronged effort that focuses on vaccination (90% of girls fully vaccinated by age 15), screening (70% of women screened by age 35 with an effective test and again at age 45), and treatment (90% treatment of precancer and 90% management of women with invasive cancer).⁴

These are the numbers we need to achieve if all countries are to reach a cervical cancer incidence of less than 4 per 100,000 persons with a cervix. The WHO further suggests that each country should meet the “90-70-90” targets by 2030 if we are to achieve the low incidence by the turn of the century.⁴ To date, few regions of the world have achieved these goals, and sadly the United States is not among them.

In response to this call to action, many medical and policymaking organizations are taking inventory and implementing strategies to achieve the WHO 2030 targets for cervical cancer eradication. In the United States, the Society of Gynecologic Oncology (SGO; www.sgo.org), the American Society for Colposcopy and Cervical Pathology (ASCCP; www.ASCCP.org), the American College of Obstetricians and Gynecologists (ACOG; www.acog.org), the American Cancer Society (ACS; www.cancer.org), and many others have initiated programs in a collaborative esprit de corps with the aim of eradicating this deadly disease.

In this Update, we review several studies with evidence of screening and management strategies that show promise of accelerating the eradication of cervical cancer.

Continue to: Transitioning to primary HPV screening in the United States...

Downs LS Jr, Nayar R, Gerndt J, et al; American Cancer Society Primary HPV Screening Initiative Steering Committee. Implementation in action: collaborating on the transition to primary HPV screening for cervical cancer in the United States. CA Cancer J Clin. 2023;73:458-460.

The American Cancer Society released an updated cervical cancer screening guideline in July 2020 that recommended testing for HPV as the preferred strategy. Reasons behind the change, moving away from a Pap test as part of the initial screen, are:

• increased sensitivity of primary HPV testing when compared with conventional cervical cytology (Pap test)
• improved risk stratification to identify who is at risk for cervical cancer now and in the future
• improved efficiency in identifying those who need colposcopy, thus limiting unnecessary procedures without increasing the risk of false-negative tests, thereby missing cervical precancer or invasive cancer.

Some countries with organized screening programs have already made the switch. Self-sampling for HPV is currently being considered for an approved use in the United States, further improving access to screening for cervical cancer when the initial step can be completed by the patient at home or simplified in nontraditional health care settings.²

ACS initiative created to address barriers to primary HPV testing

Challenges to primary HPV testing remain, including laboratory implementation, payment, and operationalizing clinical workflow (for example, HPV testing with reflex cytology instead of cytology with reflex HPV testing).⁵ There are undoubtedly other unforeseen barriers in the current US health care environment.

In a recent commentary, Downs and colleagues described how the ACS has convened the Primary HPV Screening Initiative (PHSI), nested under the ACS National Roundtable on Cervical Cancer, which is charged with identifying critical barriers to, and opportunities for, transitioning to primary HPV screening.⁵ The deliverable will be a roadmap with tools and recommendations to support health systems, laboratories, providers, patients, and payers as they make this evolution.

Work groups will develop resources

Patients, particularly those who have had routine cervical cancer screening over their lifetime, also will be curious about the changes in recommendations. The Provider Needs Workgroup within the PHSI structure will develop tools and patient education materials regarding the data, workflow, benefits, and safety of this new paradigm for cervical cancer screening.

Laboratories that process and interpret tests likely will bear the heaviest load of changes. For example, not all commercially available HPV tests in the United States are approved by the US Food and Drug Administration (FDA) for primary HPV testing. Some sites will need to adapt their equipment to ensure adherence to FDA-approved tests. Laboratory workflows will need to be altered for aliquots to be tested for HPV first, and the remainder for cytology. Quality assurance and accreditation requirements for testing will need modifications, and further efforts will be needed to ensure sufficient numbers of trained cytopathologists, whose workforce is rapidly declining, for processing and reading cervical cytology.

In addition, payment for HPV testing alone, without the need for a Pap test, might not be supported by payers that support safety-net providers and sites, who arguably serve the most vulnerable patients and those most at risk for cervical cancer. Collaboration across medical professionals, societies, payers, and policymakers will provide a critical infrastructure to make the change in the most seamless fashion and limit the harm from missed opportunities for screening.

Continue to: The quest for a “molecular Pap”: Dual-stain testing as a predictor of high-grade CIN...

Magkana M, Mentzelopoulou P, Magkana E, et al. p16/Ki-67 Dual staining is a reliable biomarker for risk stratification for patients with borderline/mild cytology in cervical cancer screening. Anticancer Res. 2022;42:2599-2606.

Stanczuk G, Currie H, Forson W, et al. Clinical performance of triage strategies for Hr-HPV-positive women; a longitudinal evaluation of cytology, p16/K-67 dual stain cytology, and HPV16/18 genotyping. Cancer Epidemiol Biomarkers Prev. 2022;31:1492-1498.
 

One new technology that was recently FDA approved and recommended for management of abnormal cervical cancer screening testing is dual-stain (DS) testing. Dual-stain testing is a cytology-based test that evaluates the concurrent expression of p16, a tumor suppressor protein upregulated in HPV oncogenesis, and Ki-67, a cell proliferation marker.^6,7 Two recent studies have showcased the outstanding clinical performance of DS testing and triage strategies that incorporate DS testing.

Higher specificity, fewer colposcopies needed with DS testing

Magkana and colleagues prospectively evaluated patients with atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or negative for intraepithelial lesion or malignancy (NILM) cytology referred for colposcopy, and they compared p16/Ki-67 DS testing with high-risk HPV (HR-HPV) testing for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+); comparable sensitivities for CIN 2+ detection were seen (97.3% and 98.7%, respectively).⁸

Dual-stain testing exhibited higher specificity at 99.3% compared with HR-HPV testing at 52.2%. Incorporating DS testing into triage strategies also led to fewer colposcopies needed to detect CIN 2+ compared with current ASCCP guidelines that use traditional cervical cancer screening algorithms.

DS cytology strategy had the highest sensitivity for CIN 2+ detection

An additional study by Stanczuk and colleagues evaluated triage strategies in a cohort of HR-HPV positive patients who participated in the Scottish Papillomavirus Dumfries and Galloway study with HPV 16/18 genotyping (HPV 16/18), liquid-based cytology (LBC), and p16/Ki-67 DS cytology.⁹ Of these 3 triage strategies, DS cytology had the highest sensitivity for the detection of CIN 2+, at 77.7% (with a specificity of 74.2%), performance that is arguably better than cytology.

When evaluated in sequence as part of a triage strategy after HPV primary screening, HPV 16/18–positive patients reflexed to DS testing showed a similar sensitivity as those who would be triaged with LBC (TABLE).⁹

DS testing’s potential

These studies add to the growing body of literature that supports the use of DS testing in cervical cancer screening management guidelines and that are being incorporated into currently existing workflows. Furthermore, with advancements in digital imaging and machine learning, DS testing holds the potential for a high throughput, reproducible, and accurate risk stratification that can replace the current reliance on cytology, furthering the potential for a fully molecular Pap test.^10,11

Continue to: Cervical cancer screening in women older than age 65: Is there benefit?...

Firtina Tuncer S, Tuncer HA. Cervical cancer screening in women aged older than 65 years. J Low Genit Tract Dis. 2023;27:207-211.

Booth BB, Tranberg M, Gustafson LW, et al. Risk of cervical intraepithelial neoplasia grade 2 or worse in women aged  ≥ 69 referred to colposcopy due to an HPV-positive screening test. BMC Cancer. 2023;23:405.
 

Current guidelines in the United States recommend that cervical cancer screening for all persons with a cervix end at age 65. These age restrictions were a change in guidelines updated in 2012 and endorsed by the US Preventive Services Task Force.^12,13 Evidence suggests that because of high likelihood of regression and slow progression of disease, risks of screening prior to age 21 outweigh its benefits. With primary HPV testing, the age at screening debut is 25 for the same reasons.¹⁴ In people with a history of CIN 2+, active surveillance should continue for at least 25 years with HPV-based screening regardless of age. In the absence of a history of CIN 2+, however, the data to support discontinuation of screening after age 65 are less clear.

HPV positivity found to be most substantial risk for CIN 2+

In a study published this year in the Journal of Lower Genital Tract Disease, Firtina Tuncer and colleagues described their experience extending “routine screening” in patients older than 65 years.¹⁵ Data including cervical cytology, HPV test results, biopsy findings, and endocervical curettage results were collected, and abnormal findings were managed according to the 2012 and 2019 ASCCP guidelines.

When compared with negative HPV testing and normal cytology, the authors found that HPV positivity and abnormal cytology increased the risk of CIN 2+(odds ratio [OR], 136.1 and 13.1, respectively). Patients whose screening prior to age 65 had been insufficient or demonstrated CIN 2+ in the preceding 10 years were similarly more likely to have findings of CIN 2+ (OR, 9.7 when compared with HPV-negative controls).

The authors concluded that, among persons with a cervix older than age 65, previous screening and abnormal cytology were important in risk stratifications for CIN 2+; however, HPV positivity conferred the most substantial risk.

Study finds cervical dysplasia is prevalent in older populations

It has been suggested that screening for cervical cancer should continue beyond age 65 as cytology-based screening may have decreased sensitivity in older patients, which may contribute to the higher rates of advanced-stage diagnoses and cancer-related death in this population.^16,17

Authors of an observational study conducted in Denmark invited persons with a cervix aged 69 and older to have one additional HPV-based screening test, and they referred them for colposcopy if HPV positive or in the presence of ASCUS or greater cytology.¹⁸ Among the 191 patients with HPV-positive results, 20% were found to have a diagnosis of CIN 2+, and 24.4% had CIN 2+ detected at another point in the study period. Notably, most patients diagnosed with CIN 2+ had no abnormalities visualized on colposcopy, and the majority of biopsies taken (65.8%) did not contain the transitional zone.

Biopsies underestimated CIN 2+ in 17.9% of cases compared with loop electrosurgical excision procedure (LEEP). These findings suggest both that high-grade cervical dysplasia is prevalent in an older population and that older populations may be susceptible to false-negative results. They also further support the use of HPV-based screening.

Harnessing the immune system to improve survival rates in recurrent cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Unfortunately, most clinical trials for recurrent or metastatic cervical cancer are negative trials or have results that show limited impact on disease outcomes. Currently, cervical cancer is treated with multiple agents, including platinum-based chemotherapy and bevacizumab, a medication that targets vascular growth. Despite these usually very effective drugs given in combination to cervical cancer patients, long-term survival remains low. Over the past few decades, many trials have been designed to help patients with this terrible disease, but few have shown significant promise.

Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized care for many cancers. Checkpoint inhibitors block the proteins that cause a tumor to remain undetected by the immune system’s army of T cells. By blocking these proteins, the cancer cells can then be recognized by the immune system as foreign. Several studies have concluded that including immune checkpoint inhibitors in the comprehensive regimen for recurrent cervical cancer improves survival.

Addition of pembrolizumab increased survival

Investigators in the phase 3 double-blinded KEYNOTE-826 trial evaluated whether or not the addition of pembrolizumab to standard of care improved progression-free and overall survival in advanced, recurrent, or persistent cervical cancer.¹⁹ As part of the evaluation, the investigators measured the protein that turns off the immune system’s ability to recognize tumors, anti-programmed cell death protein-1 (PD-1).

Compared with placebo, the investigators found that, regardless of PD-1 status, the addition of pembrolizumab immunotherapy to the standard regimen increased progression-free survival and overall survival without any significantly increased adverse effects or safety concerns (FIGURE).¹⁹ At 1 year after treatment, more patients who received pembrolizumab were still alive regardless of PD-1 status, and their responses lasted longer. The most profound improvements were seen in patients whose tumors exhibited high expression of PD-L1, the target of pembrolizumab and many other immune checkpoint inhibitors.

Cervical cancer rates remain low in the United States, with the incidence having plateaued for decades. And yet, in 2019, more than 13,000 US women will be diagnosed with cervical cancer.¹ Globally, in 2018 almost 600,000 women were diagnosed with cervical cancer²; it is the fourth most frequent cancer in women. This is despite the fact that we have adequate primary and secondary prevention tools available to minimize—and almost eliminate—cervical cancer. We must continue to raise the bar for preventing, screening for, and managing this disease.

Human papillomavirus (HPV) vaccines provide a highly effective primary prevention strategy, but we need to improve our ability to identify and diagnose dysplastic lesions prior to the development of cervical cancer. Highly sensitive HPV testing and cytology is a powerful secondary prevention approach that enables us to assess a woman’s risk of having precancerous cells both now and in the near future. These modalities have been very successful in decreasing the incidence of cervical cancer in the United States and other areas with organized screening programs. In low- and middle-income countries, however, access to, availability of, and performance with these modalities is not optimal. Innovative strategies and new technologies are being evaluated to overcome these limitations.

Advances in radiation and surgical technology have enabled us to vastly improve cervical cancer treatment. Women with early-stage cervical cancer are candidates for surgical management, which frequently includes a radical hysterectomy and lymph node dissection. While these surgeries traditionally have been performed via an exploratory laparotomy, minimally invasive techniques (laparoscopic and robot-assisted surgical techniques) have decreased the morbidity with these surgeries. Notable new studies have shed light on the comparative effectiveness of minimally invasive technologies and have shown us that new is not always better.

The US Preventive Services Task Force (USPSTF) recently released its updated cervical cancer screening guidelines. The suggested approach to screening differs from previous recommendations. HPV testing as a primary test (that is, HPV testing alone or followed by cytology) takes the spotlight now, according to the analysis by the Task Force.

In this Update, we highlight important studies published in the past year that address these issues.

Continue to: New tech's potential to identify high-grade...

New tech's potential to identify high-grade cervical dysplasia may be a boon to low-resource settings 

Hu L, Bell D, Antani S, et al. An observational study of deep learning and automated evaluation of cervical images for cancer screening. J Natl Cancer Inst. 2019;doi:10.1093/jnci/djy225. 

When cervical screening tests like cytology and HPV testing show abnormal results, colposcopy often is recommended. The goal of colposcopy is to identify the areas that might harbor a high-grade precancerous lesion or worse. The gold standard in this case, however, is histology, not colposcopic impression, as many studies have shown that colposcopy without biopsies is limited and that performance is improved with more biopsies.^3,4 

Visual inspection with acetic acid (VIA) is an approach used often in low-resource settings where visual impression is the gold standard. However, as with colposcopy, a visual evaluation without histology does not perform well, and often women are overtreated. Many attempts have been made with new technologies to overcome the limitations of time, cost, and workforce required for cytology and histology services. New disruptive technologies may be able to surmount human limitations and improve on not only VIA but also the need for histology. 

Novel technology uses images to develop algorithm with predictive ability 

In a recent observational study, Hu and colleagues used images that were collected during a large population study in Guanacaste, Costa Rica.⁵ More than 9,000 women were followed for up to 7 years, and cervical photographs (cervigrams) were obtained. Well-annotated histopathology results were obtained for women with abnormal screening, and 279 women had a high-grade dysplastic lesion or cancer. 

Cervigrams from women with high-grade lesions and matched controls were collected, and a deep learning-based algorithm using artificial intelligence technology was developed using 70% of the images. The remaining 30% of images were used as a validation set to test the algorithm's ability to "predict" high-grade dysplasia without knowing the final result. 

Findings. Termed automated visual evaluation (AVE), this new technology demonstrated a very accurate ability to identify high-grade dysplasia or worse, with an area under the curve (AUC) of 0.91 from merely a cervicogram (FIGURE). This outperformed conventional Pap smears (AUC, 0.71), liquid-based cytology (AUC, 0.79) and, surprisingly, highly sensitive HPV testing (AUC, 0.82) in women in the prime of their screening ages (>25 years of age). 

Continue to: Data offer persuasive evidence...

Data offer persuasive evidence to abandon minimally invasive surgery in management of early-stage cervical cancer 

Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914. 

Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904. 

Over the past decade, gynecologic cancer surgery has shifted from what routinely were open procedures to the adoption of minimally invasive techniques. Recently, a large, well-designed prospective study and a large retrospective study both demonstrated worse outcomes with minimally invasive radical hysterectomy (MIRH) as compared with traditional open radical abdominal hysterectomy (RAH). These 2 landmark studies, initially presented at the Society of Gynecologic Oncology's 2018 annual meeting and later published in the New England Journal of Medicine, have really affected the gynecologic oncology community. 

Shorter overall survival in women who had MIRH 

Melamed and colleagues conducted a large, retrospective US-based study to evaluate all-cause mortality in women with cervical cancer who underwent MIRH compared with those who had RAH.⁶ The authors also sought to evaluate national trends in 4-year relative survival rates after minimally invasive surgery was adopted. 

The study included 2,461 women who met the inclusion criteria; 49.8% (1,225) underwent MIRH procedures and, of those, 79.8% (978) had robot-assisted laparoscopy. Most women had stage IB1 tumors (88%), and most carcinomas were squamous cell (61%); 40.6% of tumors were less than 2 cm in size. There were no differences between the 2 groups with respect to rates of positive parametria, surgical margins, and lymph node involvement. Administration of adjuvant therapy, in those who qualified, was also similar between groups. 

Results. At a median follow-up of 45 months, 94 deaths occurred in the minimally invasive group and 70 in the open surgery group. The risk of death at 4 years was 9.1% in the minimally invasive group versus 5.3% in the open surgery group, with a 65% higher risk of death from any cause, which was highly statistically significant. 

Prospective trial showed MIRH was associated with lower survival rates 

From 2008 to 2017, Ramirez and colleagues conducted a phase 3, multicenter, randomized controlled trial to prospectively establish the noninferiority of MIRH compared with RAH.⁷ The study included 631 women from 33 centers. The prespecified expected disease-free survival rate was 90% at 4.5 years. 

To be included as a site, centers were required to submit details from 10 minimally invasive cases as well as 2 unedited videos for review by the trial management committee. In contrast to Melamed and colleagues' retrospective study, of the 319 procedures that were classified as minimally invasive, only 15.6% were robotically assisted. Similarly, most women had stage IB1 tumors (91.9%), and most were squamous cell carcinomas (67%). There were also no differences in the postoperative pathology findings or the need for adjuvant therapy administered between groups. The median follow-up was 2.5 years. 

Results. At that time there were 27 recurrences in the MIRH group and 7 in the RAH group; there were also 19 deaths after MIRH and 3 after RAH. Disease-free survival at 4.5 years was 86% with MIRH versus 96.5% with RAH. Reported 3-year disease-free survival and overall survival were also significantily lower in the minimally invasive subgroup (91.2% vs 97.1%, 93.8% vs 99.0%, respectively). 

Study limitations. Criticisms of this trial are that noninferiority could not be declared; in addition, the investigators were unable to complete enrollment secondary to early enrollment termination after the data and safety monitoring board raised survival concerns. 

Many argue that subgroup analyses suggest a lower risk of poor outcomes in patients with smaller tumors (<2 cm); however, it is critical to note that this study was not powered to detect these differences. 

Continue to: USPSTF updated guidance on cervical cancer screening...

USPSTF updated guidance on cervical cancer screening 

Melnikow J, Henderson JT, Burda BU, et al. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;320:687-705. 

US Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686. 

Past guidelines for cervical cancer screening have included testing for high-risk HPV (hrHPV) as a cotest with cytology or for triage of atypical squamous cells of undetermined significance (ASCUS) in women aged 30 to 65 years.⁸ The American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology, with other stakeholder organizations, issued interim guidance for primary HPV testing--that is, HPV test first and, in the case of non-16/18 hrHPV types, cytology as a triage. The most recent evidence report and systematic review by Melnikow and colleagues for the USPSTF offers an in-depth analysis of risks, benefits, harms, and value of cotesting and other management strategies.⁹ 

Focus on screening effectiveness 

Large trials of cotesting were conducted in women aged 25 to 65.^10-13 These studies all consistently showed that primary hrHPV screening led to a statistically significant increased detection of cervical intraepithelial neoplasia (CIN) 3+ in the initial round of screening, with a relative risk of detecting CIN 3+ ranging from 1.61 to 7.46 compared with cytology alone. 

Four additional studies compared cotesting with conventional cytology for the detection of CIN 3+. None of these trials demonstrated a significantly higher detection rate of CIN 3+ with cotesting compared with conventional cytology testing alone. Notably, the studies reviewed were performed in European countries that had organized screening programs in place and a nationalized health care system. Thus, these data may not be as applicable to women in the United States, particularly to women who have limited health care access. 

Risks of screening 

In the same studies reviewed for screening effectiveness, the investigators found that overall, screening with hrHPV primary or cotesting was associated with more false-positive results and higher colposcopy rates. Women screened with hrHPV alone had a 7.9% referral rate to colposcopy, while those screened with cytology had a 2.8% referral rate to colposcopy. Similarly, the rate of biopsy was higher in the hrHPV-only group (3.2% vs 1.3%). 

Overall, while cotesting might have some improvement in performance compared with hrHPV as a single modality, there might be risks of overreferral to colposcopy and overtreatment with additional cytology over hrHPV testing alone. 

This evidence review also included an analysis of more potential harms. Very limited evidence suggests that positive hrHPV test results may be associated with greater psychological harm, including decreased sexual satisfaction, increased anxiety and distress, and worse feelings about sexual partners, than abnormal cytology results. These were assessed, however, 1 to 2 weeks after the test results were provided to the patients, and long-term assessment was not done. 

New recommendations from the USPSTF 

Based on these data, the USPSTF issued new recommendations regarding screening (TABLE).¹⁴ For women aged 21 to 29, cytology alone should be used for screening every 3 years. Women aged 30 to 65 can be screened with cytology alone every 3 years, with hrHPV testing alone every 5 years, or with cotesting every 5 years.   

Cervical cancer rates remain low in the United States, with the incidence having plateaued for decades. And yet, in 2019, more than 13,000 US women will be diagnosed with cervical cancer.¹ Globally, in 2018 almost 600,000 women were diagnosed with cervical cancer²; it is the fourth most frequent cancer in women. This is despite the fact that we have adequate primary and secondary prevention tools available to minimize—and almost eliminate—cervical cancer. We must continue to raise the bar for preventing, screening for, and managing this disease.

Human papillomavirus (HPV) vaccines provide a highly effective primary prevention strategy, but we need to improve our ability to identify and diagnose dysplastic lesions prior to the development of cervical cancer. Highly sensitive HPV testing and cytology is a powerful secondary prevention approach that enables us to assess a woman’s risk of having precancerous cells both now and in the near future. These modalities have been very successful in decreasing the incidence of cervical cancer in the United States and other areas with organized screening programs. In low- and middle-income countries, however, access to, availability of, and performance with these modalities is not optimal. Innovative strategies and new technologies are being evaluated to overcome these limitations.

Advances in radiation and surgical technology have enabled us to vastly improve cervical cancer treatment. Women with early-stage cervical cancer are candidates for surgical management, which frequently includes a radical hysterectomy and lymph node dissection. While these surgeries traditionally have been performed via an exploratory laparotomy, minimally invasive techniques (laparoscopic and robot-assisted surgical techniques) have decreased the morbidity with these surgeries. Notable new studies have shed light on the comparative effectiveness of minimally invasive technologies and have shown us that new is not always better.

The US Preventive Services Task Force (USPSTF) recently released its updated cervical cancer screening guidelines. The suggested approach to screening differs from previous recommendations. HPV testing as a primary test (that is, HPV testing alone or followed by cytology) takes the spotlight now, according to the analysis by the Task Force.

In this Update, we highlight important studies published in the past year that address these issues.

Continue to: New tech's potential to identify high-grade...

New tech's potential to identify high-grade cervical dysplasia may be a boon to low-resource settings 

Hu L, Bell D, Antani S, et al. An observational study of deep learning and automated evaluation of cervical images for cancer screening. J Natl Cancer Inst. 2019;doi:10.1093/jnci/djy225. 

When cervical screening tests like cytology and HPV testing show abnormal results, colposcopy often is recommended. The goal of colposcopy is to identify the areas that might harbor a high-grade precancerous lesion or worse. The gold standard in this case, however, is histology, not colposcopic impression, as many studies have shown that colposcopy without biopsies is limited and that performance is improved with more biopsies.^3,4 

Visual inspection with acetic acid (VIA) is an approach used often in low-resource settings where visual impression is the gold standard. However, as with colposcopy, a visual evaluation without histology does not perform well, and often women are overtreated. Many attempts have been made with new technologies to overcome the limitations of time, cost, and workforce required for cytology and histology services. New disruptive technologies may be able to surmount human limitations and improve on not only VIA but also the need for histology. 

Novel technology uses images to develop algorithm with predictive ability 

In a recent observational study, Hu and colleagues used images that were collected during a large population study in Guanacaste, Costa Rica.⁵ More than 9,000 women were followed for up to 7 years, and cervical photographs (cervigrams) were obtained. Well-annotated histopathology results were obtained for women with abnormal screening, and 279 women had a high-grade dysplastic lesion or cancer. 

Cervigrams from women with high-grade lesions and matched controls were collected, and a deep learning-based algorithm using artificial intelligence technology was developed using 70% of the images. The remaining 30% of images were used as a validation set to test the algorithm's ability to "predict" high-grade dysplasia without knowing the final result. 

Findings. Termed automated visual evaluation (AVE), this new technology demonstrated a very accurate ability to identify high-grade dysplasia or worse, with an area under the curve (AUC) of 0.91 from merely a cervicogram (FIGURE). This outperformed conventional Pap smears (AUC, 0.71), liquid-based cytology (AUC, 0.79) and, surprisingly, highly sensitive HPV testing (AUC, 0.82) in women in the prime of their screening ages (>25 years of age). 

Continue to: Data offer persuasive evidence...

Data offer persuasive evidence to abandon minimally invasive surgery in management of early-stage cervical cancer 

Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914. 

Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904. 

Over the past decade, gynecologic cancer surgery has shifted from what routinely were open procedures to the adoption of minimally invasive techniques. Recently, a large, well-designed prospective study and a large retrospective study both demonstrated worse outcomes with minimally invasive radical hysterectomy (MIRH) as compared with traditional open radical abdominal hysterectomy (RAH). These 2 landmark studies, initially presented at the Society of Gynecologic Oncology's 2018 annual meeting and later published in the New England Journal of Medicine, have really affected the gynecologic oncology community. 

Shorter overall survival in women who had MIRH 

Melamed and colleagues conducted a large, retrospective US-based study to evaluate all-cause mortality in women with cervical cancer who underwent MIRH compared with those who had RAH.⁶ The authors also sought to evaluate national trends in 4-year relative survival rates after minimally invasive surgery was adopted. 

The study included 2,461 women who met the inclusion criteria; 49.8% (1,225) underwent MIRH procedures and, of those, 79.8% (978) had robot-assisted laparoscopy. Most women had stage IB1 tumors (88%), and most carcinomas were squamous cell (61%); 40.6% of tumors were less than 2 cm in size. There were no differences between the 2 groups with respect to rates of positive parametria, surgical margins, and lymph node involvement. Administration of adjuvant therapy, in those who qualified, was also similar between groups. 

Results. At a median follow-up of 45 months, 94 deaths occurred in the minimally invasive group and 70 in the open surgery group. The risk of death at 4 years was 9.1% in the minimally invasive group versus 5.3% in the open surgery group, with a 65% higher risk of death from any cause, which was highly statistically significant. 

Prospective trial showed MIRH was associated with lower survival rates 

From 2008 to 2017, Ramirez and colleagues conducted a phase 3, multicenter, randomized controlled trial to prospectively establish the noninferiority of MIRH compared with RAH.⁷ The study included 631 women from 33 centers. The prespecified expected disease-free survival rate was 90% at 4.5 years. 

To be included as a site, centers were required to submit details from 10 minimally invasive cases as well as 2 unedited videos for review by the trial management committee. In contrast to Melamed and colleagues' retrospective study, of the 319 procedures that were classified as minimally invasive, only 15.6% were robotically assisted. Similarly, most women had stage IB1 tumors (91.9%), and most were squamous cell carcinomas (67%). There were also no differences in the postoperative pathology findings or the need for adjuvant therapy administered between groups. The median follow-up was 2.5 years. 

Results. At that time there were 27 recurrences in the MIRH group and 7 in the RAH group; there were also 19 deaths after MIRH and 3 after RAH. Disease-free survival at 4.5 years was 86% with MIRH versus 96.5% with RAH. Reported 3-year disease-free survival and overall survival were also significantily lower in the minimally invasive subgroup (91.2% vs 97.1%, 93.8% vs 99.0%, respectively). 

Study limitations. Criticisms of this trial are that noninferiority could not be declared; in addition, the investigators were unable to complete enrollment secondary to early enrollment termination after the data and safety monitoring board raised survival concerns. 

Many argue that subgroup analyses suggest a lower risk of poor outcomes in patients with smaller tumors (<2 cm); however, it is critical to note that this study was not powered to detect these differences. 

Continue to: USPSTF updated guidance on cervical cancer screening...

USPSTF updated guidance on cervical cancer screening 

Melnikow J, Henderson JT, Burda BU, et al. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;320:687-705. 

US Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686. 

Past guidelines for cervical cancer screening have included testing for high-risk HPV (hrHPV) as a cotest with cytology or for triage of atypical squamous cells of undetermined significance (ASCUS) in women aged 30 to 65 years.⁸ The American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology, with other stakeholder organizations, issued interim guidance for primary HPV testing--that is, HPV test first and, in the case of non-16/18 hrHPV types, cytology as a triage. The most recent evidence report and systematic review by Melnikow and colleagues for the USPSTF offers an in-depth analysis of risks, benefits, harms, and value of cotesting and other management strategies.⁹ 

Focus on screening effectiveness 

Large trials of cotesting were conducted in women aged 25 to 65.^10-13 These studies all consistently showed that primary hrHPV screening led to a statistically significant increased detection of cervical intraepithelial neoplasia (CIN) 3+ in the initial round of screening, with a relative risk of detecting CIN 3+ ranging from 1.61 to 7.46 compared with cytology alone. 

Four additional studies compared cotesting with conventional cytology for the detection of CIN 3+. None of these trials demonstrated a significantly higher detection rate of CIN 3+ with cotesting compared with conventional cytology testing alone. Notably, the studies reviewed were performed in European countries that had organized screening programs in place and a nationalized health care system. Thus, these data may not be as applicable to women in the United States, particularly to women who have limited health care access. 

Risks of screening 

In the same studies reviewed for screening effectiveness, the investigators found that overall, screening with hrHPV primary or cotesting was associated with more false-positive results and higher colposcopy rates. Women screened with hrHPV alone had a 7.9% referral rate to colposcopy, while those screened with cytology had a 2.8% referral rate to colposcopy. Similarly, the rate of biopsy was higher in the hrHPV-only group (3.2% vs 1.3%). 

Overall, while cotesting might have some improvement in performance compared with hrHPV as a single modality, there might be risks of overreferral to colposcopy and overtreatment with additional cytology over hrHPV testing alone. 

This evidence review also included an analysis of more potential harms. Very limited evidence suggests that positive hrHPV test results may be associated with greater psychological harm, including decreased sexual satisfaction, increased anxiety and distress, and worse feelings about sexual partners, than abnormal cytology results. These were assessed, however, 1 to 2 weeks after the test results were provided to the patients, and long-term assessment was not done. 

New recommendations from the USPSTF 

Based on these data, the USPSTF issued new recommendations regarding screening (TABLE).¹⁴ For women aged 21 to 29, cytology alone should be used for screening every 3 years. Women aged 30 to 65 can be screened with cytology alone every 3 years, with hrHPV testing alone every 5 years, or with cotesting every 5 years.   

Cervical cancer rates remain low in the United States, with the incidence having plateaued for decades. And yet, in 2019, more than 13,000 US women will be diagnosed with cervical cancer.¹ Globally, in 2018 almost 600,000 women were diagnosed with cervical cancer²; it is the fourth most frequent cancer in women. This is despite the fact that we have adequate primary and secondary prevention tools available to minimize—and almost eliminate—cervical cancer. We must continue to raise the bar for preventing, screening for, and managing this disease.

Human papillomavirus (HPV) vaccines provide a highly effective primary prevention strategy, but we need to improve our ability to identify and diagnose dysplastic lesions prior to the development of cervical cancer. Highly sensitive HPV testing and cytology is a powerful secondary prevention approach that enables us to assess a woman’s risk of having precancerous cells both now and in the near future. These modalities have been very successful in decreasing the incidence of cervical cancer in the United States and other areas with organized screening programs. In low- and middle-income countries, however, access to, availability of, and performance with these modalities is not optimal. Innovative strategies and new technologies are being evaluated to overcome these limitations.

Advances in radiation and surgical technology have enabled us to vastly improve cervical cancer treatment. Women with early-stage cervical cancer are candidates for surgical management, which frequently includes a radical hysterectomy and lymph node dissection. While these surgeries traditionally have been performed via an exploratory laparotomy, minimally invasive techniques (laparoscopic and robot-assisted surgical techniques) have decreased the morbidity with these surgeries. Notable new studies have shed light on the comparative effectiveness of minimally invasive technologies and have shown us that new is not always better.

The US Preventive Services Task Force (USPSTF) recently released its updated cervical cancer screening guidelines. The suggested approach to screening differs from previous recommendations. HPV testing as a primary test (that is, HPV testing alone or followed by cytology) takes the spotlight now, according to the analysis by the Task Force.

In this Update, we highlight important studies published in the past year that address these issues.

Continue to: New tech's potential to identify high-grade...

New tech's potential to identify high-grade cervical dysplasia may be a boon to low-resource settings 

Hu L, Bell D, Antani S, et al. An observational study of deep learning and automated evaluation of cervical images for cancer screening. J Natl Cancer Inst. 2019;doi:10.1093/jnci/djy225. 

When cervical screening tests like cytology and HPV testing show abnormal results, colposcopy often is recommended. The goal of colposcopy is to identify the areas that might harbor a high-grade precancerous lesion or worse. The gold standard in this case, however, is histology, not colposcopic impression, as many studies have shown that colposcopy without biopsies is limited and that performance is improved with more biopsies.^3,4 

Visual inspection with acetic acid (VIA) is an approach used often in low-resource settings where visual impression is the gold standard. However, as with colposcopy, a visual evaluation without histology does not perform well, and often women are overtreated. Many attempts have been made with new technologies to overcome the limitations of time, cost, and workforce required for cytology and histology services. New disruptive technologies may be able to surmount human limitations and improve on not only VIA but also the need for histology. 

Novel technology uses images to develop algorithm with predictive ability 

In a recent observational study, Hu and colleagues used images that were collected during a large population study in Guanacaste, Costa Rica.⁵ More than 9,000 women were followed for up to 7 years, and cervical photographs (cervigrams) were obtained. Well-annotated histopathology results were obtained for women with abnormal screening, and 279 women had a high-grade dysplastic lesion or cancer. 

Cervigrams from women with high-grade lesions and matched controls were collected, and a deep learning-based algorithm using artificial intelligence technology was developed using 70% of the images. The remaining 30% of images were used as a validation set to test the algorithm's ability to "predict" high-grade dysplasia without knowing the final result. 

Findings. Termed automated visual evaluation (AVE), this new technology demonstrated a very accurate ability to identify high-grade dysplasia or worse, with an area under the curve (AUC) of 0.91 from merely a cervicogram (FIGURE). This outperformed conventional Pap smears (AUC, 0.71), liquid-based cytology (AUC, 0.79) and, surprisingly, highly sensitive HPV testing (AUC, 0.82) in women in the prime of their screening ages (>25 years of age). 

Continue to: Data offer persuasive evidence...

Data offer persuasive evidence to abandon minimally invasive surgery in management of early-stage cervical cancer 

Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914. 

Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904. 

Over the past decade, gynecologic cancer surgery has shifted from what routinely were open procedures to the adoption of minimally invasive techniques. Recently, a large, well-designed prospective study and a large retrospective study both demonstrated worse outcomes with minimally invasive radical hysterectomy (MIRH) as compared with traditional open radical abdominal hysterectomy (RAH). These 2 landmark studies, initially presented at the Society of Gynecologic Oncology's 2018 annual meeting and later published in the New England Journal of Medicine, have really affected the gynecologic oncology community. 

Shorter overall survival in women who had MIRH 

Melamed and colleagues conducted a large, retrospective US-based study to evaluate all-cause mortality in women with cervical cancer who underwent MIRH compared with those who had RAH.⁶ The authors also sought to evaluate national trends in 4-year relative survival rates after minimally invasive surgery was adopted. 

The study included 2,461 women who met the inclusion criteria; 49.8% (1,225) underwent MIRH procedures and, of those, 79.8% (978) had robot-assisted laparoscopy. Most women had stage IB1 tumors (88%), and most carcinomas were squamous cell (61%); 40.6% of tumors were less than 2 cm in size. There were no differences between the 2 groups with respect to rates of positive parametria, surgical margins, and lymph node involvement. Administration of adjuvant therapy, in those who qualified, was also similar between groups. 

Results. At a median follow-up of 45 months, 94 deaths occurred in the minimally invasive group and 70 in the open surgery group. The risk of death at 4 years was 9.1% in the minimally invasive group versus 5.3% in the open surgery group, with a 65% higher risk of death from any cause, which was highly statistically significant. 

Prospective trial showed MIRH was associated with lower survival rates 

From 2008 to 2017, Ramirez and colleagues conducted a phase 3, multicenter, randomized controlled trial to prospectively establish the noninferiority of MIRH compared with RAH.⁷ The study included 631 women from 33 centers. The prespecified expected disease-free survival rate was 90% at 4.5 years. 

To be included as a site, centers were required to submit details from 10 minimally invasive cases as well as 2 unedited videos for review by the trial management committee. In contrast to Melamed and colleagues' retrospective study, of the 319 procedures that were classified as minimally invasive, only 15.6% were robotically assisted. Similarly, most women had stage IB1 tumors (91.9%), and most were squamous cell carcinomas (67%). There were also no differences in the postoperative pathology findings or the need for adjuvant therapy administered between groups. The median follow-up was 2.5 years. 

Results. At that time there were 27 recurrences in the MIRH group and 7 in the RAH group; there were also 19 deaths after MIRH and 3 after RAH. Disease-free survival at 4.5 years was 86% with MIRH versus 96.5% with RAH. Reported 3-year disease-free survival and overall survival were also significantily lower in the minimally invasive subgroup (91.2% vs 97.1%, 93.8% vs 99.0%, respectively). 

Study limitations. Criticisms of this trial are that noninferiority could not be declared; in addition, the investigators were unable to complete enrollment secondary to early enrollment termination after the data and safety monitoring board raised survival concerns. 

Many argue that subgroup analyses suggest a lower risk of poor outcomes in patients with smaller tumors (<2 cm); however, it is critical to note that this study was not powered to detect these differences. 

Continue to: USPSTF updated guidance on cervical cancer screening...

USPSTF updated guidance on cervical cancer screening 

Melnikow J, Henderson JT, Burda BU, et al. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;320:687-705. 

US Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686. 

Past guidelines for cervical cancer screening have included testing for high-risk HPV (hrHPV) as a cotest with cytology or for triage of atypical squamous cells of undetermined significance (ASCUS) in women aged 30 to 65 years.⁸ The American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology, with other stakeholder organizations, issued interim guidance for primary HPV testing--that is, HPV test first and, in the case of non-16/18 hrHPV types, cytology as a triage. The most recent evidence report and systematic review by Melnikow and colleagues for the USPSTF offers an in-depth analysis of risks, benefits, harms, and value of cotesting and other management strategies.⁹ 

Focus on screening effectiveness 

Large trials of cotesting were conducted in women aged 25 to 65.^10-13 These studies all consistently showed that primary hrHPV screening led to a statistically significant increased detection of cervical intraepithelial neoplasia (CIN) 3+ in the initial round of screening, with a relative risk of detecting CIN 3+ ranging from 1.61 to 7.46 compared with cytology alone. 

Four additional studies compared cotesting with conventional cytology for the detection of CIN 3+. None of these trials demonstrated a significantly higher detection rate of CIN 3+ with cotesting compared with conventional cytology testing alone. Notably, the studies reviewed were performed in European countries that had organized screening programs in place and a nationalized health care system. Thus, these data may not be as applicable to women in the United States, particularly to women who have limited health care access. 

Risks of screening 

In the same studies reviewed for screening effectiveness, the investigators found that overall, screening with hrHPV primary or cotesting was associated with more false-positive results and higher colposcopy rates. Women screened with hrHPV alone had a 7.9% referral rate to colposcopy, while those screened with cytology had a 2.8% referral rate to colposcopy. Similarly, the rate of biopsy was higher in the hrHPV-only group (3.2% vs 1.3%). 

Overall, while cotesting might have some improvement in performance compared with hrHPV as a single modality, there might be risks of overreferral to colposcopy and overtreatment with additional cytology over hrHPV testing alone. 

This evidence review also included an analysis of more potential harms. Very limited evidence suggests that positive hrHPV test results may be associated with greater psychological harm, including decreased sexual satisfaction, increased anxiety and distress, and worse feelings about sexual partners, than abnormal cytology results. These were assessed, however, 1 to 2 weeks after the test results were provided to the patients, and long-term assessment was not done. 

New recommendations from the USPSTF 

Based on these data, the USPSTF issued new recommendations regarding screening (TABLE).¹⁴ For women aged 21 to 29, cytology alone should be used for screening every 3 years. Women aged 30 to 65 can be screened with cytology alone every 3 years, with hrHPV testing alone every 5 years, or with cotesting every 5 years.   

In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.

ASCCP releases updated quality guidelines for performing colposcopy

Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.

Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.

Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.

In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:

• establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting  
• the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
• both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.

Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.

Selected details of the 3 guideline reports

The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.

If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.

Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:

Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.

Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,^1,2 although consensus is lacking on the value of such interventions.

The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).³ Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.

Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.

Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:

• When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
• Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
• Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).  
• Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.

How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:

• precolposcopy evaluation
• the examination
• use of colposcopy adjuncts
• documentation
• biopsy sampling
• postcolposcopy procedures.

The constituent parts of these components are laid out in TABLE 2.⁴ A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.

The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.

Standards arrive for practice

Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)

What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.

Read about adherence to cervical cancer screening.

Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.

Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.

Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.

Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.

Details of the studies

Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.

At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.

Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.

Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.

In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.

Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.

What next?

Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16^INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.

We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.

Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.

Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.  

Read about the safety and efficacy of HPV vaccination.

Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program

Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.

Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.

The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.

Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.

Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.

Findings of the 2 studies

HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.

The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).

Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."

Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.

What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.

How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.

HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.

From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.

Summing up

This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.

ASCCP releases updated quality guidelines for performing colposcopy

Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.

Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.

Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.

In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:

• establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting  
• the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
• both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.

Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.

Selected details of the 3 guideline reports

The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.

If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.

Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:

Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.

Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,^1,2 although consensus is lacking on the value of such interventions.

The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).³ Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.

Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.

Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:

• When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
• Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
• Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).  
• Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.

How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:

• precolposcopy evaluation
• the examination
• use of colposcopy adjuncts
• documentation
• biopsy sampling
• postcolposcopy procedures.

The constituent parts of these components are laid out in TABLE 2.⁴ A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.

The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.

Standards arrive for practice

Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)

What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.

Read about adherence to cervical cancer screening.

Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.

Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.

Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.

Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.

Details of the studies

Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.

At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.

Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.

Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.

In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.

Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.

What next?

Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16^INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.

We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.

Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.

Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.  

Read about the safety and efficacy of HPV vaccination.

Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program

Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.

Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.

The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.

Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.

Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.

Findings of the 2 studies

HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.

The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).

Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."

Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.

What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.

How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.

HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.

From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.

Summing up

This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.

ASCCP releases updated quality guidelines for performing colposcopy

Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.

Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.

Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.

In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:

• establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting  
• the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
• both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.

Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.

Selected details of the 3 guideline reports

The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.

If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.

Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:

Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.

Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,^1,2 although consensus is lacking on the value of such interventions.

The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).³ Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.

Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.

Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:

• When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
• Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
• Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).  
• Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.

How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:

• precolposcopy evaluation
• the examination
• use of colposcopy adjuncts
• documentation
• biopsy sampling
• postcolposcopy procedures.

The constituent parts of these components are laid out in TABLE 2.⁴ A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.

The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.

Standards arrive for practice

Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)

What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.

Read about adherence to cervical cancer screening.

Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.

Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.

Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.

Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.

Details of the studies

Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.

At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.

Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.

Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.

In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.

Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.

What next?

Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16^INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.

We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.

Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.

Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.  

Read about the safety and efficacy of HPV vaccination.

Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program

Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.

Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.

The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.

Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.

Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.

Findings of the 2 studies

HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.

The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).

Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."

Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.

What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.

How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.

HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.

From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.

Summing up

This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Realistic prospective performance data are needed to quantify the additional benefit of the cytology component of cotesting on top of what is already known to be highly sensitive molecular HPV testing. While the addition of cytology to HPV testing can add performance, it also can add further costs and the potential for unnecessary colposcopies for what are merely cytomorphologic manifestations of an active HPV infection. Frequent invasive procedures such as colposcopy, which can be costly and lead to anxiety and distress in generally young women and the potential for overtreatment of likely regressive lesions, has been defined as a harm of screening by the US Preventive Services Task Force (USPSTF).

Details of the study

In a cohort from Kaiser Permanente Northern California, 1,208,710 women aged 30 years or older were screened with cotesting from 2003 to 2015. Those who cotested HPV negative and cytology negative were offered triennial screening. Positive cotest results were managed according to Kaiser protocol. Women with cytologic abnormalities were referred for colposcopy. Those with HPV positive/cytology negative results or HPV negative/cytology equivocal results underwent accelerated testing at 1 year. A total of 623 cervical cancers were identified and included in the analyses.

Using multiple analyses, Schiffman and colleagues demonstrated the sensitivity advantage of HPV testing. They clearly showed that the cytology component to cotesting performance over many years is very limited for detecting precancers and early curable cancers. For example, prediagnostic HPV testing (76.7%) was more likely to be positive than cytology (59.1%; P<.001 for paired comparison); 82.6% of all prediagnostic cotests were positive by HPV and/or cytology; and only 5.9% of the cotests were positive by cytology alone (HPV negative.)

Primary HPV testing is recommended as a potential screening strategy by an interim guidance group led by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and it is the primary cervical cancer screening recommendation of USPSTF draft guidelines.¹ There have been reports that reliance on primary HPV testing would encourage cervical cancer mortality; Schiffman and colleagues point out, however, that according to their study data, such reports are overstated.

Despite these data, practically speaking, shifting away from standard cotesting poses numerous challenges for clinicians and laboratories alike; however, these data clearly show the limited value of cytology and, due to the overtreatment of likely regressive cervical intraepithelial neoplasia grade 2, the possible increased risk of preterm birth and its subsequent harm as well.

Study strengths and weaknesses

The authors examined the long-term relative history of HPV testing and cytology prior to cancer diagnosis in a large, prospectively followed US cohort where hundreds of women in this cohort developed cancer. There will not be a validation study of this size and scale in the near future. Further, the authors showed that the relative value of cytology to cotesting is minimal. Multiple subsequent rounds of cotesting after negative results also can be questioned. 

One weakness of the study is that the data were collected from only one health care system and therefore may not be representative of all populations. Additionally, cotesting was performed on 2 separately collected specimens, which may have reduced HPV testing performance.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Realistic prospective performance data are needed to quantify the additional benefit of the cytology component of cotesting on top of what is already known to be highly sensitive molecular HPV testing. While the addition of cytology to HPV testing can add performance, it also can add further costs and the potential for unnecessary colposcopies for what are merely cytomorphologic manifestations of an active HPV infection. Frequent invasive procedures such as colposcopy, which can be costly and lead to anxiety and distress in generally young women and the potential for overtreatment of likely regressive lesions, has been defined as a harm of screening by the US Preventive Services Task Force (USPSTF).

Details of the study

In a cohort from Kaiser Permanente Northern California, 1,208,710 women aged 30 years or older were screened with cotesting from 2003 to 2015. Those who cotested HPV negative and cytology negative were offered triennial screening. Positive cotest results were managed according to Kaiser protocol. Women with cytologic abnormalities were referred for colposcopy. Those with HPV positive/cytology negative results or HPV negative/cytology equivocal results underwent accelerated testing at 1 year. A total of 623 cervical cancers were identified and included in the analyses.

Using multiple analyses, Schiffman and colleagues demonstrated the sensitivity advantage of HPV testing. They clearly showed that the cytology component to cotesting performance over many years is very limited for detecting precancers and early curable cancers. For example, prediagnostic HPV testing (76.7%) was more likely to be positive than cytology (59.1%; P<.001 for paired comparison); 82.6% of all prediagnostic cotests were positive by HPV and/or cytology; and only 5.9% of the cotests were positive by cytology alone (HPV negative.)

Primary HPV testing is recommended as a potential screening strategy by an interim guidance group led by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and it is the primary cervical cancer screening recommendation of USPSTF draft guidelines.¹ There have been reports that reliance on primary HPV testing would encourage cervical cancer mortality; Schiffman and colleagues point out, however, that according to their study data, such reports are overstated.

Despite these data, practically speaking, shifting away from standard cotesting poses numerous challenges for clinicians and laboratories alike; however, these data clearly show the limited value of cytology and, due to the overtreatment of likely regressive cervical intraepithelial neoplasia grade 2, the possible increased risk of preterm birth and its subsequent harm as well.

Study strengths and weaknesses

The authors examined the long-term relative history of HPV testing and cytology prior to cancer diagnosis in a large, prospectively followed US cohort where hundreds of women in this cohort developed cancer. There will not be a validation study of this size and scale in the near future. Further, the authors showed that the relative value of cytology to cotesting is minimal. Multiple subsequent rounds of cotesting after negative results also can be questioned. 

One weakness of the study is that the data were collected from only one health care system and therefore may not be representative of all populations. Additionally, cotesting was performed on 2 separately collected specimens, which may have reduced HPV testing performance.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Realistic prospective performance data are needed to quantify the additional benefit of the cytology component of cotesting on top of what is already known to be highly sensitive molecular HPV testing. While the addition of cytology to HPV testing can add performance, it also can add further costs and the potential for unnecessary colposcopies for what are merely cytomorphologic manifestations of an active HPV infection. Frequent invasive procedures such as colposcopy, which can be costly and lead to anxiety and distress in generally young women and the potential for overtreatment of likely regressive lesions, has been defined as a harm of screening by the US Preventive Services Task Force (USPSTF).

Details of the study

In a cohort from Kaiser Permanente Northern California, 1,208,710 women aged 30 years or older were screened with cotesting from 2003 to 2015. Those who cotested HPV negative and cytology negative were offered triennial screening. Positive cotest results were managed according to Kaiser protocol. Women with cytologic abnormalities were referred for colposcopy. Those with HPV positive/cytology negative results or HPV negative/cytology equivocal results underwent accelerated testing at 1 year. A total of 623 cervical cancers were identified and included in the analyses.

Using multiple analyses, Schiffman and colleagues demonstrated the sensitivity advantage of HPV testing. They clearly showed that the cytology component to cotesting performance over many years is very limited for detecting precancers and early curable cancers. For example, prediagnostic HPV testing (76.7%) was more likely to be positive than cytology (59.1%; P<.001 for paired comparison); 82.6% of all prediagnostic cotests were positive by HPV and/or cytology; and only 5.9% of the cotests were positive by cytology alone (HPV negative.)

Primary HPV testing is recommended as a potential screening strategy by an interim guidance group led by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and it is the primary cervical cancer screening recommendation of USPSTF draft guidelines.¹ There have been reports that reliance on primary HPV testing would encourage cervical cancer mortality; Schiffman and colleagues point out, however, that according to their study data, such reports are overstated.

Despite these data, practically speaking, shifting away from standard cotesting poses numerous challenges for clinicians and laboratories alike; however, these data clearly show the limited value of cytology and, due to the overtreatment of likely regressive cervical intraepithelial neoplasia grade 2, the possible increased risk of preterm birth and its subsequent harm as well.

Study strengths and weaknesses

The authors examined the long-term relative history of HPV testing and cytology prior to cancer diagnosis in a large, prospectively followed US cohort where hundreds of women in this cohort developed cancer. There will not be a validation study of this size and scale in the near future. Further, the authors showed that the relative value of cytology to cotesting is minimal. Multiple subsequent rounds of cotesting after negative results also can be questioned. 

One weakness of the study is that the data were collected from only one health care system and therefore may not be representative of all populations. Additionally, cotesting was performed on 2 separately collected specimens, which may have reduced HPV testing performance.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Vaccination against human papillomavirus (HPV) infection and periodic cervical screening have significantly decreased the incidence of invasive cervical cancer. But cancers still exist despite the availability of these useful clinical tools, especially in women of reproductive age in developing regions of the world. In the 2016 update on cervical disease, I reviewed studies on 2 promising and novel immunotherapies for cervical cancer: HPV therapeutic vaccine and adoptive T-cell therapy. This year the focus is on remarkable advances in the field of genomics and related studies that are rapidly expanding our understanding of the molecular characteristics of cervical cancer. Rewards of this research already being explored include novel immunotherapeutic agents as well as the repurposed use of existing drugs.

But first, with regard to cervical screening and follow-up, 2 recent large studies have yielded findings that have important implications for patient management. One pertains to the monitoring of women who have persistent infection with high-risk HPV but cytology results that are negative. Its conclusion was unequivocal and very useful in the management of our patients. The other study tracked HPV screening performed every 3 years and reported on the diagnostic efficiency of this shorter interval screening strategy.

Read about persistent HPV infection and CIN

Persistent HPV infection has a higher risk than most clinicians might think

Elfgren K, Elfström KM, Naucler P, Arnheim-Dahlström L, Dillner J. Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J Obstet Gynecol. 2017;216(3):264.e1-e7.

It is well known that most cases of cervical cancer arise from persistent HPV infection, with the highest percentage of cancers caused by high-risk types 16 or 18. What has been uncertain, however, is the actual degree of risk that persistent infection confers over time for the development of cervical intraepithelial neoplasia (CIN) or worse when a woman's repeated cytology reports are negative. In an analysis of a long-term double-blind, randomized, controlled screening study, Elfgren and colleagues showed that all women whose HPV infection persisted up to 7 years developed CIN grade 2 (CIN2+), while those whose infection cleared in that period, or changed genotype, had no precancerous lesions out to 13 years of follow-up.

Related Article:
It is time for HPV vaccination to be considered part of routine preventive health care

Details of the study

Between 1997 and 2000, 12,527 Swedish women between the ages of 32 and 38 years who were undergoing organized cervical cancer screening agreed to participate in a 1:1-randomized prospective trial to determine the benefit of screening with HPV and cytology (intervention group) compared with cytology screening alone (control group). However, brush sampling for HPV was performed even on women in the control group, with the samples frozen for later testing. All participants were identified in the Swedish National Cervical Screening Registry.

Women in the intervention group who initially tested positive for HPV but whose cytology test results were negative (n = 341) were invited to return a year later for repeat HPV testing; 270 women returned and 119 had type-specific HPV persistence. Of those with persistent infection, 100 agreed to undergo colposcopy; 111 women from the control group were randomly selected to undergo sham HPV testing and colposcopy, and 95 attended. Women with evident cytologic abnormalities received treatment per protocol. Those with negative cytology results were offered annual HPV testing thereafter, and each follow-up with documented type-specific HPV persistence led to repeat colposcopy. A comparable number of women from the control group had repeat colposcopies.

Although some women were lost to clinical follow-up throughout the trial, all 195 who attended the first colposcopy were followed for at least 5 years in the Swedish registry, and 191 were followed in the registry for 13 years. Of 102 women with known HPV persistence at baseline (100 in the treatment group; 2 in the randomly selected control group), 31 became HPV negative, 4 evidenced a switch in HPV type but cleared the initial infection, 27 had unknown persistence status due to missed HPV tests, and 40 had continuously type-specific persistence. Of note, persistent HPV16 infection seemed to impart a higher risk of CIN development than did persistent HPV18 infection.

All 40 participants with clinically verified continuously persistent HPV infection developed CIN2+ within 7 years of baseline documentation of persistence (FIGURE 1). Among the 27 women with unknown persistence status, risk of CIN2+ occurrence within 7 years was 50%. None of the 35 women who cleared their infection or switched HPV type developed CIN2+.

Read about HPV-cytology cotesting

HPV−cytology cotesting every 3 years lowers population rates of cervical precancer and cancer

Silver MI, Schiffman M, Fetterman B, et al. The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: reduced cervical cancer risk and decreased yield of precancer per screen. Cancer. 2016;122(23):3682−3686.

Current guidelines on screening for cervical cancer in women 30 to 65 years of age advise the preferred strategy of using cytology alone every 3 years or combining HPV testing and cytology every 5 years.¹ These guidelines, based on data available at the time they were written, were meant to offer a reasonable balance between timely detection of abnormalities and avoidance of potential harms from screening too frequently. However, many patients are reluctant to postpone repeat testing to the extent recommended. Several authorities have in fact asked that screening intervals be revisited, perhaps allowing for a range of strategies, contending that the level of protection once provided by annual screening should be the benchmark by which evolving strategies are judged.² Today, they point out, the risk of cancer doubles in the 3 years following an initial negative cytology result, and it also increases by lengthening the cotesting interval from 3 to 5 years. They additionally question the validity of using frequency of colposcopies as a surrogate to measure harms of screening, and suggest that many women would willingly accept the procedure's minimal discomfort and inconvenience to gain peace of mind.

The study by Silver and colleagues gives credence to considering a shorter cotesting interval. Since 2003, Kaiser Permanente Northern California (KPNC) has implemented 3-year cotesting. To determine actual clinical outcomes of cotesting at this interval, KPNC analyzed data on more than 1 million women in its care between 2003 and 2012. Although investigators expected that they might see decreasing efficiency in cotesting over time, they instead found an increased detection rate of precancerous lesions per woman screened in the larger of 2 study cohorts.

Related Article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Details of the study

Included were all women 30 years of age or older enrolled in this study at KPNC between 2003 and 2012 who underwent HPV−cytology cotesting every 3 years. The population in its entirety (1,065,273 women) was deemed the "open cohort" and represented KPNC's total annual experience. A subset of this population, the "closed cohort," was designed to gauge the effect of repeated screening on a fixed population and comprised only those women enrolled and initially screened between 2003 and 2004 and then followed longitudinally until 2012.

For each cohort, investigators calculated the ratios of precancer and cancer diagnoses to the total number of cotests performed on the cohort's population. The 3-year testing periods were 2004−2006, 2007−2009, and 2010−2012. Also calculated in these periods were the ratios of colposcopic biopsies to cotests and the rates of precancer diagnoses (TABLE). 

In the open cohort, the biopsy rate nearly doubled over the course of the study. Precancer diagnoses per number of cotests rose by 71.5% between the first and second testing periods (P = .001) and then eased off by 10% in the third period (P<.001). These corresponding increases throughout the study yielded a stable number of biopsies (16 to 22) needed to detect precancer.

In the closed long-term cohort, the biopsy rate rose, but not as much as in the open cohort. Precancer diagnoses per number of cotests rose by 47% between the first and second periods (P≤.001), but in the third period fell back by 28% (P<.001) to a level just above the first period results. The number of biopsies needed to detect a precancerous lesion in the closed cohort rose from 19 to 33 over the course of the study, suggesting there may have been some loss of screening efficiency in the fixed group.

Read about molecular profiling of cervical cancer

Molecular profiling of cervical cancer is revolutionizing treatment

The Cancer Genome Atlas Research Network. Integratedgenomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378−384.

Effective treatments for cervical cancer could be close at hand, thanks to a recent explosion of knowledge at the molecular level about how specific cancers arise and what drives them other than HPV. The Cancer Genome Atlas Research Network (TCGA) recently published the results of its genomic and proteomic analyses, which yielded distinct profiles for 178 cervical cancers with important patterns common to other cancers, such as uterine and breast cancer. These recently published findings on cervical cancer highlight areas of gene and protein dysfunction it shares with these other cancers, which could open the doors for new targets for treatments already developed or in the pipeline.

Related Article:
2016 Update on cervical disease

How molecular profiling is paying off for cervical cancer

Cancers develop in any given tissue through the altered function of different genes and signaling pathways in the tissue's cells. The latest extensive investigation conducted by the TCGA network has identified significant mutations in 5 genes previously unrecognized in association with cervical cancer, bringing the total now to 14.

Several highlights are featured in the TCGA's recently published work. One discovery is the amplification of genes CD274 and PDCD1LG2, which are involved with the expression of 2 cytolytic effector genes and are therefore likely targets for immunotherapeutic strategies. Another line of exploration, whole-genome sequencing, has detected an aberration in some cervical cancer tissue with the potential for immediate application. Duplication and copy number gain of BCAR4, a noncoding RNA, facilitates cell proliferation through the HER2/HER3 pathway, a target of the tyrosine-kinase inhibitor, lapatinib, which is currently used to treat breast cancer.

The integration of data from multiple layers of analysis (FIGURE 2) is helping investigators identify variations in cancers. DNA methylation, for instance, is a means by which cells control gene expression. An analysis of this process in cervical tumor tissue has revealed additional cancer subgroups in which messenger RNA increases the transition of epithelial cells to invasive mesenchymal cells. Targeting that process in these subgroups would likely enhance the effectiveness of novel small-molecule inhibitors and some standard cytotoxic chemotherapy.  

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Vaccination against human papillomavirus (HPV) infection and periodic cervical screening have significantly decreased the incidence of invasive cervical cancer. But cancers still exist despite the availability of these useful clinical tools, especially in women of reproductive age in developing regions of the world. In the 2016 update on cervical disease, I reviewed studies on 2 promising and novel immunotherapies for cervical cancer: HPV therapeutic vaccine and adoptive T-cell therapy. This year the focus is on remarkable advances in the field of genomics and related studies that are rapidly expanding our understanding of the molecular characteristics of cervical cancer. Rewards of this research already being explored include novel immunotherapeutic agents as well as the repurposed use of existing drugs.

But first, with regard to cervical screening and follow-up, 2 recent large studies have yielded findings that have important implications for patient management. One pertains to the monitoring of women who have persistent infection with high-risk HPV but cytology results that are negative. Its conclusion was unequivocal and very useful in the management of our patients. The other study tracked HPV screening performed every 3 years and reported on the diagnostic efficiency of this shorter interval screening strategy.

Read about persistent HPV infection and CIN

Persistent HPV infection has a higher risk than most clinicians might think

Elfgren K, Elfström KM, Naucler P, Arnheim-Dahlström L, Dillner J. Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J Obstet Gynecol. 2017;216(3):264.e1-e7.

It is well known that most cases of cervical cancer arise from persistent HPV infection, with the highest percentage of cancers caused by high-risk types 16 or 18. What has been uncertain, however, is the actual degree of risk that persistent infection confers over time for the development of cervical intraepithelial neoplasia (CIN) or worse when a woman's repeated cytology reports are negative. In an analysis of a long-term double-blind, randomized, controlled screening study, Elfgren and colleagues showed that all women whose HPV infection persisted up to 7 years developed CIN grade 2 (CIN2+), while those whose infection cleared in that period, or changed genotype, had no precancerous lesions out to 13 years of follow-up.

Related Article:
It is time for HPV vaccination to be considered part of routine preventive health care

Details of the study

Between 1997 and 2000, 12,527 Swedish women between the ages of 32 and 38 years who were undergoing organized cervical cancer screening agreed to participate in a 1:1-randomized prospective trial to determine the benefit of screening with HPV and cytology (intervention group) compared with cytology screening alone (control group). However, brush sampling for HPV was performed even on women in the control group, with the samples frozen for later testing. All participants were identified in the Swedish National Cervical Screening Registry.

Women in the intervention group who initially tested positive for HPV but whose cytology test results were negative (n = 341) were invited to return a year later for repeat HPV testing; 270 women returned and 119 had type-specific HPV persistence. Of those with persistent infection, 100 agreed to undergo colposcopy; 111 women from the control group were randomly selected to undergo sham HPV testing and colposcopy, and 95 attended. Women with evident cytologic abnormalities received treatment per protocol. Those with negative cytology results were offered annual HPV testing thereafter, and each follow-up with documented type-specific HPV persistence led to repeat colposcopy. A comparable number of women from the control group had repeat colposcopies.

Although some women were lost to clinical follow-up throughout the trial, all 195 who attended the first colposcopy were followed for at least 5 years in the Swedish registry, and 191 were followed in the registry for 13 years. Of 102 women with known HPV persistence at baseline (100 in the treatment group; 2 in the randomly selected control group), 31 became HPV negative, 4 evidenced a switch in HPV type but cleared the initial infection, 27 had unknown persistence status due to missed HPV tests, and 40 had continuously type-specific persistence. Of note, persistent HPV16 infection seemed to impart a higher risk of CIN development than did persistent HPV18 infection.

All 40 participants with clinically verified continuously persistent HPV infection developed CIN2+ within 7 years of baseline documentation of persistence (FIGURE 1). Among the 27 women with unknown persistence status, risk of CIN2+ occurrence within 7 years was 50%. None of the 35 women who cleared their infection or switched HPV type developed CIN2+.

Read about HPV-cytology cotesting

HPV−cytology cotesting every 3 years lowers population rates of cervical precancer and cancer

Silver MI, Schiffman M, Fetterman B, et al. The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: reduced cervical cancer risk and decreased yield of precancer per screen. Cancer. 2016;122(23):3682−3686.

Current guidelines on screening for cervical cancer in women 30 to 65 years of age advise the preferred strategy of using cytology alone every 3 years or combining HPV testing and cytology every 5 years.¹ These guidelines, based on data available at the time they were written, were meant to offer a reasonable balance between timely detection of abnormalities and avoidance of potential harms from screening too frequently. However, many patients are reluctant to postpone repeat testing to the extent recommended. Several authorities have in fact asked that screening intervals be revisited, perhaps allowing for a range of strategies, contending that the level of protection once provided by annual screening should be the benchmark by which evolving strategies are judged.² Today, they point out, the risk of cancer doubles in the 3 years following an initial negative cytology result, and it also increases by lengthening the cotesting interval from 3 to 5 years. They additionally question the validity of using frequency of colposcopies as a surrogate to measure harms of screening, and suggest that many women would willingly accept the procedure's minimal discomfort and inconvenience to gain peace of mind.

The study by Silver and colleagues gives credence to considering a shorter cotesting interval. Since 2003, Kaiser Permanente Northern California (KPNC) has implemented 3-year cotesting. To determine actual clinical outcomes of cotesting at this interval, KPNC analyzed data on more than 1 million women in its care between 2003 and 2012. Although investigators expected that they might see decreasing efficiency in cotesting over time, they instead found an increased detection rate of precancerous lesions per woman screened in the larger of 2 study cohorts.

Related Article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Details of the study

Included were all women 30 years of age or older enrolled in this study at KPNC between 2003 and 2012 who underwent HPV−cytology cotesting every 3 years. The population in its entirety (1,065,273 women) was deemed the "open cohort" and represented KPNC's total annual experience. A subset of this population, the "closed cohort," was designed to gauge the effect of repeated screening on a fixed population and comprised only those women enrolled and initially screened between 2003 and 2004 and then followed longitudinally until 2012.

For each cohort, investigators calculated the ratios of precancer and cancer diagnoses to the total number of cotests performed on the cohort's population. The 3-year testing periods were 2004−2006, 2007−2009, and 2010−2012. Also calculated in these periods were the ratios of colposcopic biopsies to cotests and the rates of precancer diagnoses (TABLE). 

In the open cohort, the biopsy rate nearly doubled over the course of the study. Precancer diagnoses per number of cotests rose by 71.5% between the first and second testing periods (P = .001) and then eased off by 10% in the third period (P<.001). These corresponding increases throughout the study yielded a stable number of biopsies (16 to 22) needed to detect precancer.

In the closed long-term cohort, the biopsy rate rose, but not as much as in the open cohort. Precancer diagnoses per number of cotests rose by 47% between the first and second periods (P≤.001), but in the third period fell back by 28% (P<.001) to a level just above the first period results. The number of biopsies needed to detect a precancerous lesion in the closed cohort rose from 19 to 33 over the course of the study, suggesting there may have been some loss of screening efficiency in the fixed group.

Read about molecular profiling of cervical cancer

Molecular profiling of cervical cancer is revolutionizing treatment

The Cancer Genome Atlas Research Network. Integratedgenomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378−384.

Effective treatments for cervical cancer could be close at hand, thanks to a recent explosion of knowledge at the molecular level about how specific cancers arise and what drives them other than HPV. The Cancer Genome Atlas Research Network (TCGA) recently published the results of its genomic and proteomic analyses, which yielded distinct profiles for 178 cervical cancers with important patterns common to other cancers, such as uterine and breast cancer. These recently published findings on cervical cancer highlight areas of gene and protein dysfunction it shares with these other cancers, which could open the doors for new targets for treatments already developed or in the pipeline.

Related Article:
2016 Update on cervical disease

How molecular profiling is paying off for cervical cancer

Cancers develop in any given tissue through the altered function of different genes and signaling pathways in the tissue's cells. The latest extensive investigation conducted by the TCGA network has identified significant mutations in 5 genes previously unrecognized in association with cervical cancer, bringing the total now to 14.

Several highlights are featured in the TCGA's recently published work. One discovery is the amplification of genes CD274 and PDCD1LG2, which are involved with the expression of 2 cytolytic effector genes and are therefore likely targets for immunotherapeutic strategies. Another line of exploration, whole-genome sequencing, has detected an aberration in some cervical cancer tissue with the potential for immediate application. Duplication and copy number gain of BCAR4, a noncoding RNA, facilitates cell proliferation through the HER2/HER3 pathway, a target of the tyrosine-kinase inhibitor, lapatinib, which is currently used to treat breast cancer.

The integration of data from multiple layers of analysis (FIGURE 2) is helping investigators identify variations in cancers. DNA methylation, for instance, is a means by which cells control gene expression. An analysis of this process in cervical tumor tissue has revealed additional cancer subgroups in which messenger RNA increases the transition of epithelial cells to invasive mesenchymal cells. Targeting that process in these subgroups would likely enhance the effectiveness of novel small-molecule inhibitors and some standard cytotoxic chemotherapy.  

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Vaccination against human papillomavirus (HPV) infection and periodic cervical screening have significantly decreased the incidence of invasive cervical cancer. But cancers still exist despite the availability of these useful clinical tools, especially in women of reproductive age in developing regions of the world. In the 2016 update on cervical disease, I reviewed studies on 2 promising and novel immunotherapies for cervical cancer: HPV therapeutic vaccine and adoptive T-cell therapy. This year the focus is on remarkable advances in the field of genomics and related studies that are rapidly expanding our understanding of the molecular characteristics of cervical cancer. Rewards of this research already being explored include novel immunotherapeutic agents as well as the repurposed use of existing drugs.

But first, with regard to cervical screening and follow-up, 2 recent large studies have yielded findings that have important implications for patient management. One pertains to the monitoring of women who have persistent infection with high-risk HPV but cytology results that are negative. Its conclusion was unequivocal and very useful in the management of our patients. The other study tracked HPV screening performed every 3 years and reported on the diagnostic efficiency of this shorter interval screening strategy.

Read about persistent HPV infection and CIN

Persistent HPV infection has a higher risk than most clinicians might think

Elfgren K, Elfström KM, Naucler P, Arnheim-Dahlström L, Dillner J. Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J Obstet Gynecol. 2017;216(3):264.e1-e7.

It is well known that most cases of cervical cancer arise from persistent HPV infection, with the highest percentage of cancers caused by high-risk types 16 or 18. What has been uncertain, however, is the actual degree of risk that persistent infection confers over time for the development of cervical intraepithelial neoplasia (CIN) or worse when a woman's repeated cytology reports are negative. In an analysis of a long-term double-blind, randomized, controlled screening study, Elfgren and colleagues showed that all women whose HPV infection persisted up to 7 years developed CIN grade 2 (CIN2+), while those whose infection cleared in that period, or changed genotype, had no precancerous lesions out to 13 years of follow-up.

Related Article:
It is time for HPV vaccination to be considered part of routine preventive health care

Details of the study

Between 1997 and 2000, 12,527 Swedish women between the ages of 32 and 38 years who were undergoing organized cervical cancer screening agreed to participate in a 1:1-randomized prospective trial to determine the benefit of screening with HPV and cytology (intervention group) compared with cytology screening alone (control group). However, brush sampling for HPV was performed even on women in the control group, with the samples frozen for later testing. All participants were identified in the Swedish National Cervical Screening Registry.

Women in the intervention group who initially tested positive for HPV but whose cytology test results were negative (n = 341) were invited to return a year later for repeat HPV testing; 270 women returned and 119 had type-specific HPV persistence. Of those with persistent infection, 100 agreed to undergo colposcopy; 111 women from the control group were randomly selected to undergo sham HPV testing and colposcopy, and 95 attended. Women with evident cytologic abnormalities received treatment per protocol. Those with negative cytology results were offered annual HPV testing thereafter, and each follow-up with documented type-specific HPV persistence led to repeat colposcopy. A comparable number of women from the control group had repeat colposcopies.

Although some women were lost to clinical follow-up throughout the trial, all 195 who attended the first colposcopy were followed for at least 5 years in the Swedish registry, and 191 were followed in the registry for 13 years. Of 102 women with known HPV persistence at baseline (100 in the treatment group; 2 in the randomly selected control group), 31 became HPV negative, 4 evidenced a switch in HPV type but cleared the initial infection, 27 had unknown persistence status due to missed HPV tests, and 40 had continuously type-specific persistence. Of note, persistent HPV16 infection seemed to impart a higher risk of CIN development than did persistent HPV18 infection.

All 40 participants with clinically verified continuously persistent HPV infection developed CIN2+ within 7 years of baseline documentation of persistence (FIGURE 1). Among the 27 women with unknown persistence status, risk of CIN2+ occurrence within 7 years was 50%. None of the 35 women who cleared their infection or switched HPV type developed CIN2+.

Read about HPV-cytology cotesting

HPV−cytology cotesting every 3 years lowers population rates of cervical precancer and cancer

Silver MI, Schiffman M, Fetterman B, et al. The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: reduced cervical cancer risk and decreased yield of precancer per screen. Cancer. 2016;122(23):3682−3686.

Current guidelines on screening for cervical cancer in women 30 to 65 years of age advise the preferred strategy of using cytology alone every 3 years or combining HPV testing and cytology every 5 years.¹ These guidelines, based on data available at the time they were written, were meant to offer a reasonable balance between timely detection of abnormalities and avoidance of potential harms from screening too frequently. However, many patients are reluctant to postpone repeat testing to the extent recommended. Several authorities have in fact asked that screening intervals be revisited, perhaps allowing for a range of strategies, contending that the level of protection once provided by annual screening should be the benchmark by which evolving strategies are judged.² Today, they point out, the risk of cancer doubles in the 3 years following an initial negative cytology result, and it also increases by lengthening the cotesting interval from 3 to 5 years. They additionally question the validity of using frequency of colposcopies as a surrogate to measure harms of screening, and suggest that many women would willingly accept the procedure's minimal discomfort and inconvenience to gain peace of mind.

The study by Silver and colleagues gives credence to considering a shorter cotesting interval. Since 2003, Kaiser Permanente Northern California (KPNC) has implemented 3-year cotesting. To determine actual clinical outcomes of cotesting at this interval, KPNC analyzed data on more than 1 million women in its care between 2003 and 2012. Although investigators expected that they might see decreasing efficiency in cotesting over time, they instead found an increased detection rate of precancerous lesions per woman screened in the larger of 2 study cohorts.

Related Article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Details of the study

Included were all women 30 years of age or older enrolled in this study at KPNC between 2003 and 2012 who underwent HPV−cytology cotesting every 3 years. The population in its entirety (1,065,273 women) was deemed the "open cohort" and represented KPNC's total annual experience. A subset of this population, the "closed cohort," was designed to gauge the effect of repeated screening on a fixed population and comprised only those women enrolled and initially screened between 2003 and 2004 and then followed longitudinally until 2012.

For each cohort, investigators calculated the ratios of precancer and cancer diagnoses to the total number of cotests performed on the cohort's population. The 3-year testing periods were 2004−2006, 2007−2009, and 2010−2012. Also calculated in these periods were the ratios of colposcopic biopsies to cotests and the rates of precancer diagnoses (TABLE). 

In the open cohort, the biopsy rate nearly doubled over the course of the study. Precancer diagnoses per number of cotests rose by 71.5% between the first and second testing periods (P = .001) and then eased off by 10% in the third period (P<.001). These corresponding increases throughout the study yielded a stable number of biopsies (16 to 22) needed to detect precancer.

In the closed long-term cohort, the biopsy rate rose, but not as much as in the open cohort. Precancer diagnoses per number of cotests rose by 47% between the first and second periods (P≤.001), but in the third period fell back by 28% (P<.001) to a level just above the first period results. The number of biopsies needed to detect a precancerous lesion in the closed cohort rose from 19 to 33 over the course of the study, suggesting there may have been some loss of screening efficiency in the fixed group.

Read about molecular profiling of cervical cancer

Molecular profiling of cervical cancer is revolutionizing treatment

The Cancer Genome Atlas Research Network. Integratedgenomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378−384.

Effective treatments for cervical cancer could be close at hand, thanks to a recent explosion of knowledge at the molecular level about how specific cancers arise and what drives them other than HPV. The Cancer Genome Atlas Research Network (TCGA) recently published the results of its genomic and proteomic analyses, which yielded distinct profiles for 178 cervical cancers with important patterns common to other cancers, such as uterine and breast cancer. These recently published findings on cervical cancer highlight areas of gene and protein dysfunction it shares with these other cancers, which could open the doors for new targets for treatments already developed or in the pipeline.

Related Article:
2016 Update on cervical disease

How molecular profiling is paying off for cervical cancer

Cancers develop in any given tissue through the altered function of different genes and signaling pathways in the tissue's cells. The latest extensive investigation conducted by the TCGA network has identified significant mutations in 5 genes previously unrecognized in association with cervical cancer, bringing the total now to 14.

Several highlights are featured in the TCGA's recently published work. One discovery is the amplification of genes CD274 and PDCD1LG2, which are involved with the expression of 2 cytolytic effector genes and are therefore likely targets for immunotherapeutic strategies. Another line of exploration, whole-genome sequencing, has detected an aberration in some cervical cancer tissue with the potential for immediate application. Duplication and copy number gain of BCAR4, a noncoding RNA, facilitates cell proliferation through the HER2/HER3 pathway, a target of the tyrosine-kinase inhibitor, lapatinib, which is currently used to treat breast cancer.

The integration of data from multiple layers of analysis (FIGURE 2) is helping investigators identify variations in cancers. DNA methylation, for instance, is a means by which cells control gene expression. An analysis of this process in cervical tumor tissue has revealed additional cancer subgroups in which messenger RNA increases the transition of epithelial cells to invasive mesenchymal cells. Targeting that process in these subgroups would likely enhance the effectiveness of novel small-molecule inhibitors and some standard cytotoxic chemotherapy.  

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Advances in cervical cancer screening continue apace. We are fortunate that these advances are based on a substantial amount of high-quality prospective evidence. Many of these advances are designed to target the women who have clinically relevant disease while minimizing harm and anxiety caused by unnecessary procedures related to cervical screening test abnormalities that have little clinical relevance.

With clinicians being regularly judged on performance and outcomes, adoption of advances and new guidelines should be ­considered relatively quickly by women’s health providers.

In this article, I focus on two significant advances of the past (and coming) year:

• recent application and unanimous approval by a Food and Drug Administration (FDA) expert panel for the use of the cobas human papillomavirus (HPV) DNA test as a primary cervical cancer screen
• the latest update of guidelines on the management of abnormal cervical screening tests from the American Society for Colposcopy and Cervical Pathology (ASCCP).

cobas HPV TEST IS POISED FOR FDA APPROVAL AS A PRIMARY SCREEN FOR CERVICAL CANCER

Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46.e1–e11.

An FDA expert panel unanimously approved the cobas (Roche Molecular Diagnostics; Pleasanton, California) HPV DNA test on March 12, 2014. The FDA will decide on potential approval within the coming months. Although the FDA sometimes reaches a different decision from one of its advisory committees when it comes to a final vote on a product or device, most often the FDA concurs with the committee’s judgment. Therefore, approval of the cobas HPV test as a primary screen is likely.

Related article: FDA Advisory Committee recommends HPV test as primary screening tool for cervical cancer  Deborah Reale (News for your Practice, March 2014)

The cobas HPV test yields a pooled result for 12 high-risk HPV types (hrHPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), as well as individual results for types 16 and 18; it also has an internal control for specimen adequacy. HPV 16 and 18 account for roughly 70% of all cases of cervical cancer, and infection with both types are known to place women at high risk for having clinically relevant disease—more so than the other hrHPV types.

COMMITTEE REVIEWED DATA FROM ATHENA IN VOTING FOR APPROVAL
In considering the cobas HPV test, the advisory committee reviewed data from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial, a prospective, multicenter, US-based study of 47,208 women aged 21 and older. These women were recruited at the time of undergoing routine screening for cervical cancer; only 2.6% had been vaccinated against HPV. All were screened by liquid-based cytology and an HPV test. Those who had abnormal cytology or a positive test for a high-risk HPV type underwent colposcopy, as did a randomly selected group of women aged 25 or older who tested negative on both tests.

The prevalence of abnormal findings was:

• 7.1% for liquid-based cytology
• 12.6% for pooled high-risk HPV
• 2.8% for HPV 16
• 1.0% for HPV 18.

As expected, cytologic abnormalities and infection with high-risk HPV types declined with increasing age. The adjusted prevalence of cervical intraepithelial neoplasia (CIN) grade 2 or higher in women aged 25 to 34 years was 2.3%; it declined to 1.5% among women older than age 34. Of note, approximately 500,000 US women are given a diagnosis of CIN 2 or CIN 3 each year in the United States.

WHY ATHENA IS IMPORTANT
This US-based trial was designed to assess the medical utility of pooled high-risk HPV DNA in addition to genotyping for HPV 16 and 18 in three populations:

• women aged 21 and older with a cytologic finding of atypical squamous cells of undetermined significance (ASC-US)
• women aged 30 and older with normal cytology
• women aged 25 and older in the overall screening population with any cytologic finding.

Investigators were particularly interested in the use of the HPV test as:

• a triage for women with abnormal cytologic findings
• an adjunct to guide clinical management of women with negative cytology results
• a potential front-line test in the screening of women aged 25 and older.

Related article: Endometrial cancer update: The move toward personalized cancer care  Lindsay M. Kuroki, MD, and David G. Mutch, MD (October 2013)

The participants of the ATHENA trial were representative of women undergoing screening for cervical cancer in the United States—both in terms of demographics and in the distribution of cytologic findings. For example, recent US census data indicate that the female population is 79% white, 13% black, and 16% Hispanic or Latino—figures comparable to the breakdown of race/ethnicity in the ATHENA trial.

The trial was conducted in a baseline phase (published in 2012) and a 3-year follow-up phase (not yet published). The 3-year data were reviewed by the FDA advisory committee during its consideration of the cobas HPV test as a primary screen.

DESPITE PROBABLE APPROVAL, INCREMENTAL CHANGE IS LIKELY
Although a move to the HPV test as the primary screen is a definite paradigm shift for what has been cytology-based screening since the initiation of cervical cancer screening, the changeover from primary cytology to primary HPV testing likely will be slow. It will require education of clinicians as well as patients, and a shift in many internal procedures for pathology laboratories.

The ATHENA trial also leaves some intriguing questions unanswered:

• How do we transition women into the new screening strategy? Many women today still undergo cytology screening with reflex HPV testing, as appropriate, and an increasing number of women aged 30 and older undergo cotesting with both cytology and HPV testing. When should they begin screening in a primary HPV testing setting? And what screening intervals will be recommended? If a woman already has been screened with cytology, how should she transition into and at what interval should she begin primary HPV screening?
• How should we manage women’s care after the first round of primary HPV testing? The ATHENA trial so far only has outcomes data after one round of HPV testing. While some data are available from Europe, we do not know what happens after two or three rounds of screening with primary HPV testing in a large US-based cohort. We clearly will be identifying and treating many women with preinvasive disease from screening after one round of testing, at a rate likely higher than with cytology alone—a good thing. We also likely will be reducing the number of unnecessary colposcopies for cytology that are not related to hrHPV.

What this EVIDENCE means for practice
Screening women using the cobas HPV test as a primary screen will require considerable education of providers and patients to explain how this change will affect how a woman will be managed after being screened for cervical cancer. Though much remains to be determined about this new cervical cancer screening paradigm (eg, logistics, timing, use of secondary tests), it should reduce the number of screening tests and colposcopies necessary to detect clinically relevant disease.

UPDATED ASCCP GUIDELINES EMPHASIZE EQUAL MANAGEMENT FOR EQUAL RISK

Massad LS, Einstein MH, Huh WK, et al; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27.

In formulating this latest set of guidelines for the management of abnormal cervical cancer screening tests and cancer precursors, the ASCCP led a conference consisting of scientific stakeholders to perform a comprehensive review of the literature. Also, with study investigators at Kaiser Permanente Northern California (KPNC) and the National Cancer Institute, the guidelines panel also modeled and assessed data on risk after abnormal tests from almost 1.4 million women followed over 8 years in the KPNC Medical Care Plan—this cohort has provided us with “big data.”

The sheer size of the Kaiser Permanente population made it possible for the ASCCP-led panel to validate its previous guidelines or to modify them, where needed. It also made risk-based stratification possible for even rare abnormalities and clinical outcomes.

Although findings from the KPNC population may not be fully generalizable to the US population as a whole, they enhance our understanding of the optimal management of abnormal cervical cancer screening tests and cancer precursors. More widely dispersed study cohorts on a similar scale in the United States are unlikely in the near future.

Related article: Update on cervical disease  Mark H. Einstein, MD, MS, and J. Thomas Cox, MD (May 2013)

SEVERAL SIGNIFICANT MODIFICATIONS
Although the ASCCP reaffirmed most elements of its 2006 consensus management guidelines, it did make a number of changes:

• Women who have ASC-US cytology but test HPV-negative now should be followed with cotesting at 3 years rather than 5 years before they return to routine screening.
• Women near age 65 who have a negative finding on ASC-US cytology and HPV testing should not exit screening.
• Women who have ASC-US cytology and test HPV-positive should go to immediate colposcopy, regardless of hrHPV results, including genotyping.
• Women who test positive for HPV 16 or 18 but have negative cytology should undergo immediate colposcopy.
• Women aged 21 to 24 years should be managed as conservatively and minimally invasively as possible, especially when an abnormality is minor.
• Endocervical curettage reported as CIN 1 should be managed as CIN 1, not as a positive endocervical curettage.
• When a cytologic sample is unsatisfactory, sampling usually should be repeated, even when HPV cotesting results are known. However, negative cytology that lacks sufficient endocervical cells or a transformation zone component usually can be managed without frequent follow-up.

Related article: New cervical Ca screening guidelines recommend less frequent assessment  Janelle Yates (News for your Practice; April 2012)

EQUAL MANAGEMENT SHOULD BE PERFORMED FOR ABNORMAL TESTS THAT INDICATE EQUAL RISK
The ASCCP-led management panel unanimously agreed to several basic assumptions in formulating the updated guidelines. For example, they concurred that achieving zero risk for cancer is impossible and that attempts to achieve zero risk (which typically means more frequent testing) may cause harm. They also cited the 2011 American Cancer Society/ASCCP/American Society for Clinical Pathology consensus screening document, which stated: “Optimal prevention strategies should identify those HPV-related abnormalities likely to progress to invasive cancers while avoiding destructive treatment of abnormalities not destined to become cancerous.”¹

The panel also agreed that CIN 3+ is a “reasonable proxy for cancer risk.” When ­calculating risk, the KPNC data were modeled for all combinations of cytology and HPV testing, using CIN 3+ for many of the outcomes, and when outcomes were rare, using CIN 2+. The theme of equal management for equal risk was the rationale behind the management approaches detailed in the TABLE. Risks were deemed to be low and return to normal screening was recommended when the risks were similar to the rate of CIN 3+ 3 years after negative cytology or 5 years after negative cotesting. However, immediate colposcopy was recommended when the 5-year risk of CIN 3+ for the combination of cytology and hrHPV testing, when indicated, exceeded 5%. A 6-month to 12-month return (intermediate risk) is indicated with a risk of CIN3+ of 2% to 5%.

An emphasis on avoiding harms
Abnormal findings at the time of cervical cancer screening can lead to a number of harms for the patient, including anxiety and emotional distress, particularly when colposcopy is necessary, as well as time lost from home and work life. For this reason, the guidelines panel emphasized that colposcopy and other interventions should be avoided when the risk of CIN 3+ is low and when the cervical screening abnormalities are likely to resolve without treatment.

However, women who experience postcoital bleeding, unexplained abnormal vaginal bleeding, pelvic pain, abnormal discharge, or a visible lesion should be managed promptly on an individualized basis.

Long-term effects of HPV vaccination are unknown
Among the areas that remain to be addressed are the unknown effects of widespread prophylactic HPV vaccination over the long term. We also lack full understanding of whether and how HPV vaccination will alter the incidence and management of cytologic and histologic abnormalities. Given the low rates of vaccination against HPV in the United States at present, this will need to be re-evaluated in the future.

What this EVIDENCE means for practice
The updated ASCCP guidelines are inherently complex, but their complexity arises from a large body of high-quality prospective data from a large population of women. Equal risk should result in equal management of cervical screening test abnormalities. Practitioners need not feel obligated to memorize the guidelines, owing to the availability of algorithms for specific findings in specific populations at the ASCCP Web site (www.asccp.org/consensus2012). Apps also are available for the iPhone, iPad, and Android.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter and in a future issue. Send your letter to: obg@frontlinemedcom.com Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

Advances in cervical cancer screening continue apace. We are fortunate that these advances are based on a substantial amount of high-quality prospective evidence. Many of these advances are designed to target the women who have clinically relevant disease while minimizing harm and anxiety caused by unnecessary procedures related to cervical screening test abnormalities that have little clinical relevance.

With clinicians being regularly judged on performance and outcomes, adoption of advances and new guidelines should be ­considered relatively quickly by women’s health providers.

In this article, I focus on two significant advances of the past (and coming) year:

• recent application and unanimous approval by a Food and Drug Administration (FDA) expert panel for the use of the cobas human papillomavirus (HPV) DNA test as a primary cervical cancer screen
• the latest update of guidelines on the management of abnormal cervical screening tests from the American Society for Colposcopy and Cervical Pathology (ASCCP).

cobas HPV TEST IS POISED FOR FDA APPROVAL AS A PRIMARY SCREEN FOR CERVICAL CANCER

Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46.e1–e11.

An FDA expert panel unanimously approved the cobas (Roche Molecular Diagnostics; Pleasanton, California) HPV DNA test on March 12, 2014. The FDA will decide on potential approval within the coming months. Although the FDA sometimes reaches a different decision from one of its advisory committees when it comes to a final vote on a product or device, most often the FDA concurs with the committee’s judgment. Therefore, approval of the cobas HPV test as a primary screen is likely.

Related article: FDA Advisory Committee recommends HPV test as primary screening tool for cervical cancer  Deborah Reale (News for your Practice, March 2014)

The cobas HPV test yields a pooled result for 12 high-risk HPV types (hrHPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), as well as individual results for types 16 and 18; it also has an internal control for specimen adequacy. HPV 16 and 18 account for roughly 70% of all cases of cervical cancer, and infection with both types are known to place women at high risk for having clinically relevant disease—more so than the other hrHPV types.

COMMITTEE REVIEWED DATA FROM ATHENA IN VOTING FOR APPROVAL
In considering the cobas HPV test, the advisory committee reviewed data from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial, a prospective, multicenter, US-based study of 47,208 women aged 21 and older. These women were recruited at the time of undergoing routine screening for cervical cancer; only 2.6% had been vaccinated against HPV. All were screened by liquid-based cytology and an HPV test. Those who had abnormal cytology or a positive test for a high-risk HPV type underwent colposcopy, as did a randomly selected group of women aged 25 or older who tested negative on both tests.

The prevalence of abnormal findings was:

• 7.1% for liquid-based cytology
• 12.6% for pooled high-risk HPV
• 2.8% for HPV 16
• 1.0% for HPV 18.

As expected, cytologic abnormalities and infection with high-risk HPV types declined with increasing age. The adjusted prevalence of cervical intraepithelial neoplasia (CIN) grade 2 or higher in women aged 25 to 34 years was 2.3%; it declined to 1.5% among women older than age 34. Of note, approximately 500,000 US women are given a diagnosis of CIN 2 or CIN 3 each year in the United States.

WHY ATHENA IS IMPORTANT
This US-based trial was designed to assess the medical utility of pooled high-risk HPV DNA in addition to genotyping for HPV 16 and 18 in three populations:

• women aged 21 and older with a cytologic finding of atypical squamous cells of undetermined significance (ASC-US)
• women aged 30 and older with normal cytology
• women aged 25 and older in the overall screening population with any cytologic finding.

Investigators were particularly interested in the use of the HPV test as:

• a triage for women with abnormal cytologic findings
• an adjunct to guide clinical management of women with negative cytology results
• a potential front-line test in the screening of women aged 25 and older.

Related article: Endometrial cancer update: The move toward personalized cancer care  Lindsay M. Kuroki, MD, and David G. Mutch, MD (October 2013)

The participants of the ATHENA trial were representative of women undergoing screening for cervical cancer in the United States—both in terms of demographics and in the distribution of cytologic findings. For example, recent US census data indicate that the female population is 79% white, 13% black, and 16% Hispanic or Latino—figures comparable to the breakdown of race/ethnicity in the ATHENA trial.

The trial was conducted in a baseline phase (published in 2012) and a 3-year follow-up phase (not yet published). The 3-year data were reviewed by the FDA advisory committee during its consideration of the cobas HPV test as a primary screen.

DESPITE PROBABLE APPROVAL, INCREMENTAL CHANGE IS LIKELY
Although a move to the HPV test as the primary screen is a definite paradigm shift for what has been cytology-based screening since the initiation of cervical cancer screening, the changeover from primary cytology to primary HPV testing likely will be slow. It will require education of clinicians as well as patients, and a shift in many internal procedures for pathology laboratories.

The ATHENA trial also leaves some intriguing questions unanswered:

• How do we transition women into the new screening strategy? Many women today still undergo cytology screening with reflex HPV testing, as appropriate, and an increasing number of women aged 30 and older undergo cotesting with both cytology and HPV testing. When should they begin screening in a primary HPV testing setting? And what screening intervals will be recommended? If a woman already has been screened with cytology, how should she transition into and at what interval should she begin primary HPV screening?
• How should we manage women’s care after the first round of primary HPV testing? The ATHENA trial so far only has outcomes data after one round of HPV testing. While some data are available from Europe, we do not know what happens after two or three rounds of screening with primary HPV testing in a large US-based cohort. We clearly will be identifying and treating many women with preinvasive disease from screening after one round of testing, at a rate likely higher than with cytology alone—a good thing. We also likely will be reducing the number of unnecessary colposcopies for cytology that are not related to hrHPV.

What this EVIDENCE means for practice
Screening women using the cobas HPV test as a primary screen will require considerable education of providers and patients to explain how this change will affect how a woman will be managed after being screened for cervical cancer. Though much remains to be determined about this new cervical cancer screening paradigm (eg, logistics, timing, use of secondary tests), it should reduce the number of screening tests and colposcopies necessary to detect clinically relevant disease.

UPDATED ASCCP GUIDELINES EMPHASIZE EQUAL MANAGEMENT FOR EQUAL RISK

Massad LS, Einstein MH, Huh WK, et al; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27.

In formulating this latest set of guidelines for the management of abnormal cervical cancer screening tests and cancer precursors, the ASCCP led a conference consisting of scientific stakeholders to perform a comprehensive review of the literature. Also, with study investigators at Kaiser Permanente Northern California (KPNC) and the National Cancer Institute, the guidelines panel also modeled and assessed data on risk after abnormal tests from almost 1.4 million women followed over 8 years in the KPNC Medical Care Plan—this cohort has provided us with “big data.”

The sheer size of the Kaiser Permanente population made it possible for the ASCCP-led panel to validate its previous guidelines or to modify them, where needed. It also made risk-based stratification possible for even rare abnormalities and clinical outcomes.

Although findings from the KPNC population may not be fully generalizable to the US population as a whole, they enhance our understanding of the optimal management of abnormal cervical cancer screening tests and cancer precursors. More widely dispersed study cohorts on a similar scale in the United States are unlikely in the near future.

Related article: Update on cervical disease  Mark H. Einstein, MD, MS, and J. Thomas Cox, MD (May 2013)

SEVERAL SIGNIFICANT MODIFICATIONS
Although the ASCCP reaffirmed most elements of its 2006 consensus management guidelines, it did make a number of changes:

• Women who have ASC-US cytology but test HPV-negative now should be followed with cotesting at 3 years rather than 5 years before they return to routine screening.
• Women near age 65 who have a negative finding on ASC-US cytology and HPV testing should not exit screening.
• Women who have ASC-US cytology and test HPV-positive should go to immediate colposcopy, regardless of hrHPV results, including genotyping.
• Women who test positive for HPV 16 or 18 but have negative cytology should undergo immediate colposcopy.
• Women aged 21 to 24 years should be managed as conservatively and minimally invasively as possible, especially when an abnormality is minor.
• Endocervical curettage reported as CIN 1 should be managed as CIN 1, not as a positive endocervical curettage.
• When a cytologic sample is unsatisfactory, sampling usually should be repeated, even when HPV cotesting results are known. However, negative cytology that lacks sufficient endocervical cells or a transformation zone component usually can be managed without frequent follow-up.

Related article: New cervical Ca screening guidelines recommend less frequent assessment  Janelle Yates (News for your Practice; April 2012)

EQUAL MANAGEMENT SHOULD BE PERFORMED FOR ABNORMAL TESTS THAT INDICATE EQUAL RISK
The ASCCP-led management panel unanimously agreed to several basic assumptions in formulating the updated guidelines. For example, they concurred that achieving zero risk for cancer is impossible and that attempts to achieve zero risk (which typically means more frequent testing) may cause harm. They also cited the 2011 American Cancer Society/ASCCP/American Society for Clinical Pathology consensus screening document, which stated: “Optimal prevention strategies should identify those HPV-related abnormalities likely to progress to invasive cancers while avoiding destructive treatment of abnormalities not destined to become cancerous.”¹

The panel also agreed that CIN 3+ is a “reasonable proxy for cancer risk.” When ­calculating risk, the KPNC data were modeled for all combinations of cytology and HPV testing, using CIN 3+ for many of the outcomes, and when outcomes were rare, using CIN 2+. The theme of equal management for equal risk was the rationale behind the management approaches detailed in the TABLE. Risks were deemed to be low and return to normal screening was recommended when the risks were similar to the rate of CIN 3+ 3 years after negative cytology or 5 years after negative cotesting. However, immediate colposcopy was recommended when the 5-year risk of CIN 3+ for the combination of cytology and hrHPV testing, when indicated, exceeded 5%. A 6-month to 12-month return (intermediate risk) is indicated with a risk of CIN3+ of 2% to 5%.

An emphasis on avoiding harms
Abnormal findings at the time of cervical cancer screening can lead to a number of harms for the patient, including anxiety and emotional distress, particularly when colposcopy is necessary, as well as time lost from home and work life. For this reason, the guidelines panel emphasized that colposcopy and other interventions should be avoided when the risk of CIN 3+ is low and when the cervical screening abnormalities are likely to resolve without treatment.

However, women who experience postcoital bleeding, unexplained abnormal vaginal bleeding, pelvic pain, abnormal discharge, or a visible lesion should be managed promptly on an individualized basis.

Long-term effects of HPV vaccination are unknown
Among the areas that remain to be addressed are the unknown effects of widespread prophylactic HPV vaccination over the long term. We also lack full understanding of whether and how HPV vaccination will alter the incidence and management of cytologic and histologic abnormalities. Given the low rates of vaccination against HPV in the United States at present, this will need to be re-evaluated in the future.

What this EVIDENCE means for practice
The updated ASCCP guidelines are inherently complex, but their complexity arises from a large body of high-quality prospective data from a large population of women. Equal risk should result in equal management of cervical screening test abnormalities. Practitioners need not feel obligated to memorize the guidelines, owing to the availability of algorithms for specific findings in specific populations at the ASCCP Web site (www.asccp.org/consensus2012). Apps also are available for the iPhone, iPad, and Android.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter and in a future issue. Send your letter to: obg@frontlinemedcom.com Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

Advances in cervical cancer screening continue apace. We are fortunate that these advances are based on a substantial amount of high-quality prospective evidence. Many of these advances are designed to target the women who have clinically relevant disease while minimizing harm and anxiety caused by unnecessary procedures related to cervical screening test abnormalities that have little clinical relevance.

With clinicians being regularly judged on performance and outcomes, adoption of advances and new guidelines should be ­considered relatively quickly by women’s health providers.

In this article, I focus on two significant advances of the past (and coming) year:

• recent application and unanimous approval by a Food and Drug Administration (FDA) expert panel for the use of the cobas human papillomavirus (HPV) DNA test as a primary cervical cancer screen
• the latest update of guidelines on the management of abnormal cervical screening tests from the American Society for Colposcopy and Cervical Pathology (ASCCP).

cobas HPV TEST IS POISED FOR FDA APPROVAL AS A PRIMARY SCREEN FOR CERVICAL CANCER

Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46.e1–e11.

An FDA expert panel unanimously approved the cobas (Roche Molecular Diagnostics; Pleasanton, California) HPV DNA test on March 12, 2014. The FDA will decide on potential approval within the coming months. Although the FDA sometimes reaches a different decision from one of its advisory committees when it comes to a final vote on a product or device, most often the FDA concurs with the committee’s judgment. Therefore, approval of the cobas HPV test as a primary screen is likely.

Related article: FDA Advisory Committee recommends HPV test as primary screening tool for cervical cancer  Deborah Reale (News for your Practice, March 2014)

The cobas HPV test yields a pooled result for 12 high-risk HPV types (hrHPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), as well as individual results for types 16 and 18; it also has an internal control for specimen adequacy. HPV 16 and 18 account for roughly 70% of all cases of cervical cancer, and infection with both types are known to place women at high risk for having clinically relevant disease—more so than the other hrHPV types.

COMMITTEE REVIEWED DATA FROM ATHENA IN VOTING FOR APPROVAL
In considering the cobas HPV test, the advisory committee reviewed data from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial, a prospective, multicenter, US-based study of 47,208 women aged 21 and older. These women were recruited at the time of undergoing routine screening for cervical cancer; only 2.6% had been vaccinated against HPV. All were screened by liquid-based cytology and an HPV test. Those who had abnormal cytology or a positive test for a high-risk HPV type underwent colposcopy, as did a randomly selected group of women aged 25 or older who tested negative on both tests.

The prevalence of abnormal findings was:

• 7.1% for liquid-based cytology
• 12.6% for pooled high-risk HPV
• 2.8% for HPV 16
• 1.0% for HPV 18.

As expected, cytologic abnormalities and infection with high-risk HPV types declined with increasing age. The adjusted prevalence of cervical intraepithelial neoplasia (CIN) grade 2 or higher in women aged 25 to 34 years was 2.3%; it declined to 1.5% among women older than age 34. Of note, approximately 500,000 US women are given a diagnosis of CIN 2 or CIN 3 each year in the United States.

WHY ATHENA IS IMPORTANT
This US-based trial was designed to assess the medical utility of pooled high-risk HPV DNA in addition to genotyping for HPV 16 and 18 in three populations:

• women aged 21 and older with a cytologic finding of atypical squamous cells of undetermined significance (ASC-US)
• women aged 30 and older with normal cytology
• women aged 25 and older in the overall screening population with any cytologic finding.

Investigators were particularly interested in the use of the HPV test as:

• a triage for women with abnormal cytologic findings
• an adjunct to guide clinical management of women with negative cytology results
• a potential front-line test in the screening of women aged 25 and older.

Related article: Endometrial cancer update: The move toward personalized cancer care  Lindsay M. Kuroki, MD, and David G. Mutch, MD (October 2013)

The participants of the ATHENA trial were representative of women undergoing screening for cervical cancer in the United States—both in terms of demographics and in the distribution of cytologic findings. For example, recent US census data indicate that the female population is 79% white, 13% black, and 16% Hispanic or Latino—figures comparable to the breakdown of race/ethnicity in the ATHENA trial.

The trial was conducted in a baseline phase (published in 2012) and a 3-year follow-up phase (not yet published). The 3-year data were reviewed by the FDA advisory committee during its consideration of the cobas HPV test as a primary screen.

DESPITE PROBABLE APPROVAL, INCREMENTAL CHANGE IS LIKELY
Although a move to the HPV test as the primary screen is a definite paradigm shift for what has been cytology-based screening since the initiation of cervical cancer screening, the changeover from primary cytology to primary HPV testing likely will be slow. It will require education of clinicians as well as patients, and a shift in many internal procedures for pathology laboratories.

The ATHENA trial also leaves some intriguing questions unanswered:

• How do we transition women into the new screening strategy? Many women today still undergo cytology screening with reflex HPV testing, as appropriate, and an increasing number of women aged 30 and older undergo cotesting with both cytology and HPV testing. When should they begin screening in a primary HPV testing setting? And what screening intervals will be recommended? If a woman already has been screened with cytology, how should she transition into and at what interval should she begin primary HPV screening?
• How should we manage women’s care after the first round of primary HPV testing? The ATHENA trial so far only has outcomes data after one round of HPV testing. While some data are available from Europe, we do not know what happens after two or three rounds of screening with primary HPV testing in a large US-based cohort. We clearly will be identifying and treating many women with preinvasive disease from screening after one round of testing, at a rate likely higher than with cytology alone—a good thing. We also likely will be reducing the number of unnecessary colposcopies for cytology that are not related to hrHPV.

What this EVIDENCE means for practice
Screening women using the cobas HPV test as a primary screen will require considerable education of providers and patients to explain how this change will affect how a woman will be managed after being screened for cervical cancer. Though much remains to be determined about this new cervical cancer screening paradigm (eg, logistics, timing, use of secondary tests), it should reduce the number of screening tests and colposcopies necessary to detect clinically relevant disease.

UPDATED ASCCP GUIDELINES EMPHASIZE EQUAL MANAGEMENT FOR EQUAL RISK

Massad LS, Einstein MH, Huh WK, et al; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27.

In formulating this latest set of guidelines for the management of abnormal cervical cancer screening tests and cancer precursors, the ASCCP led a conference consisting of scientific stakeholders to perform a comprehensive review of the literature. Also, with study investigators at Kaiser Permanente Northern California (KPNC) and the National Cancer Institute, the guidelines panel also modeled and assessed data on risk after abnormal tests from almost 1.4 million women followed over 8 years in the KPNC Medical Care Plan—this cohort has provided us with “big data.”

The sheer size of the Kaiser Permanente population made it possible for the ASCCP-led panel to validate its previous guidelines or to modify them, where needed. It also made risk-based stratification possible for even rare abnormalities and clinical outcomes.

Although findings from the KPNC population may not be fully generalizable to the US population as a whole, they enhance our understanding of the optimal management of abnormal cervical cancer screening tests and cancer precursors. More widely dispersed study cohorts on a similar scale in the United States are unlikely in the near future.

Related article: Update on cervical disease  Mark H. Einstein, MD, MS, and J. Thomas Cox, MD (May 2013)

SEVERAL SIGNIFICANT MODIFICATIONS
Although the ASCCP reaffirmed most elements of its 2006 consensus management guidelines, it did make a number of changes:

• Women who have ASC-US cytology but test HPV-negative now should be followed with cotesting at 3 years rather than 5 years before they return to routine screening.
• Women near age 65 who have a negative finding on ASC-US cytology and HPV testing should not exit screening.
• Women who have ASC-US cytology and test HPV-positive should go to immediate colposcopy, regardless of hrHPV results, including genotyping.
• Women who test positive for HPV 16 or 18 but have negative cytology should undergo immediate colposcopy.
• Women aged 21 to 24 years should be managed as conservatively and minimally invasively as possible, especially when an abnormality is minor.
• Endocervical curettage reported as CIN 1 should be managed as CIN 1, not as a positive endocervical curettage.
• When a cytologic sample is unsatisfactory, sampling usually should be repeated, even when HPV cotesting results are known. However, negative cytology that lacks sufficient endocervical cells or a transformation zone component usually can be managed without frequent follow-up.

Related article: New cervical Ca screening guidelines recommend less frequent assessment  Janelle Yates (News for your Practice; April 2012)

EQUAL MANAGEMENT SHOULD BE PERFORMED FOR ABNORMAL TESTS THAT INDICATE EQUAL RISK
The ASCCP-led management panel unanimously agreed to several basic assumptions in formulating the updated guidelines. For example, they concurred that achieving zero risk for cancer is impossible and that attempts to achieve zero risk (which typically means more frequent testing) may cause harm. They also cited the 2011 American Cancer Society/ASCCP/American Society for Clinical Pathology consensus screening document, which stated: “Optimal prevention strategies should identify those HPV-related abnormalities likely to progress to invasive cancers while avoiding destructive treatment of abnormalities not destined to become cancerous.”¹

The panel also agreed that CIN 3+ is a “reasonable proxy for cancer risk.” When ­calculating risk, the KPNC data were modeled for all combinations of cytology and HPV testing, using CIN 3+ for many of the outcomes, and when outcomes were rare, using CIN 2+. The theme of equal management for equal risk was the rationale behind the management approaches detailed in the TABLE. Risks were deemed to be low and return to normal screening was recommended when the risks were similar to the rate of CIN 3+ 3 years after negative cytology or 5 years after negative cotesting. However, immediate colposcopy was recommended when the 5-year risk of CIN 3+ for the combination of cytology and hrHPV testing, when indicated, exceeded 5%. A 6-month to 12-month return (intermediate risk) is indicated with a risk of CIN3+ of 2% to 5%.

An emphasis on avoiding harms
Abnormal findings at the time of cervical cancer screening can lead to a number of harms for the patient, including anxiety and emotional distress, particularly when colposcopy is necessary, as well as time lost from home and work life. For this reason, the guidelines panel emphasized that colposcopy and other interventions should be avoided when the risk of CIN 3+ is low and when the cervical screening abnormalities are likely to resolve without treatment.

However, women who experience postcoital bleeding, unexplained abnormal vaginal bleeding, pelvic pain, abnormal discharge, or a visible lesion should be managed promptly on an individualized basis.

Long-term effects of HPV vaccination are unknown
Among the areas that remain to be addressed are the unknown effects of widespread prophylactic HPV vaccination over the long term. We also lack full understanding of whether and how HPV vaccination will alter the incidence and management of cytologic and histologic abnormalities. Given the low rates of vaccination against HPV in the United States at present, this will need to be re-evaluated in the future.

What this EVIDENCE means for practice
The updated ASCCP guidelines are inherently complex, but their complexity arises from a large body of high-quality prospective data from a large population of women. Equal risk should result in equal management of cervical screening test abnormalities. Practitioners need not feel obligated to memorize the guidelines, owing to the availability of algorithms for specific findings in specific populations at the ASCCP Web site (www.asccp.org/consensus2012). Apps also are available for the iPhone, iPad, and Android.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter and in a future issue. Send your letter to: obg@frontlinemedcom.com Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!