March 27, 2024, by Edward Winstead

Most people with early-stage cervical cancer are treated with a radical hysterectomy. But doctors have long wondered whether a less extensive surgery could be a safe and effective alternative to the radical procedure.

According to the results of a large clinical trial, the answer seems to be yes. In the trial, 700 people with early-stage cervical cancer underwent either a radical hysterectomy or a more limited surgical procedure called a simple hysterectomy.

Three years after surgery, the cancer had come back in the pelvic area among less than 3% of the participants, regardless of which procedure they had undergone, researchers reported in the New England Journal of Medicine on February 29.

However, participants who had a simple hysterectomy experienced fewer side effects, such as urinary incontinence and urinary retention (trouble emptying all of the urine from the bladder), than those who had a radical hysterectomy. Measures of quality of life appeared to favor the simple over the radical hysterectomy, the researchers found.

“Both surgeries have similarly low rates of cancer recurrence,” said study leader Marie Plante, M.D., of Université Laval in Quebec. “But the less radical surgery was associated with fewer surgical complications and a better quality of life.”

The study was a noninferiority trial, meaning it was not designed to determine which procedure was better, Dr. Plante noted; rather, the goal was to determine whether a simple hysterectomy was not worse than the radical procedure for preventing a recurrence.

Pedro Ramirez, M.D., of Houston Methodist Hospital, who wrote an accompanying editorial, predicted that a simple hysterectomy will likely become the new standard treatment for people with early-stage, low-risk cervical cancer as defined in the trial.

The research, Dr. Ramirez explained, is part of an effort by cancer surgeons to de-escalate treatment, by shifting away from radical procedures toward more conservative approaches that may have fewer side effects.

“This trial so far shows that by de-escalating the treatment, we are not compromising outcomes for patients,” Dr. Ramirez said.

Complications, side effects, and limitations of the trial

During a simple hysterectomy, a surgeon removes the uterus and the cervix. By comparison, a radical hysterectomy involves removing the uterus, cervix, part of the vagina, and ligaments and tissues around the uterus (parametrium).

The radical surgery has long been the recommended treatment for people diagnosed with early-stage cervical cancers considered to be at low risk of the cancer spreading or coming back. Studies have suggested that only about 1% of low-risk, early-stage cervical cancers spread to the tissue near the cervix.

“We have wondered whether it’s necessary to do such a radical surgery for a cancer with such a low probability of spread to the surrounding tissues,” said Dr. Plante. Such questions were the basis for developing the SHAPE trial.

The Canadian Cancer Trials Group led the study, which was funded by the Canadian Institutes of Health Research and Canadian Cancer Society, in collaboration with the Gynecologic Cancer Intergroup.

Almost identical recurrence rates with simple hysterectomy

All participants in the trial had early-stage cervical cancer that met certain low-risk criteria (see box). All participants had surgery to remove lymph nodes in the pelvis (lymph node dissection) and then were randomly assigned to get a simple or radical hysterectomy.

Defining low-risk, early-stage cervical cancer

To participate in the SHAPE trial, participants’ tumors had to be:

• stage IA2 or IB1
• less than or equal to 2 cm
• grade 1, 2, or 3
• invading the cervix wall by less than 10 mm

With a median follow-up of 4.5 years, the 3-year pelvic recurrence rate was 2.52% in the simple hysterectomy group and 2.17% in the radical hysterectomy group.

There were more surgical complications in the radical hysterectomy group. Those participants had three times as many bladder injuries and nearly twice as many ureteral complications as participants who had a simple hysterectomy.

In addition, urinary incontinence was more common in the radical hysterectomy group (5.5% versus 2.4% within 4 weeks of surgery) and persisted over time (11% versus 4.7% beyond 4 weeks), the researchers found.

Urinary retention was also higher in the radical hysterectomy group (11% versus 0.6% within 4 weeks of surgery) and persisted over time (9.9% versus 0.6% beyond 4 weeks).

The researchers also assessed participants’ quality of life using questionnaires. People in the simple hysterectomy group had much more favorable responses to questions about topics such as sexual function, pain, and distress.

After extended follow-up, Dr. Plante and her colleagues plan to publish additional results related to quality of life. They also intend to analyze the relative costs of the two surgical procedures.

The researchers noted some limitations of the trial. Participants were primarily from Western Europe, South Korea, and Canada. Black women and Native Americans were underrepresented in the trial, and consequently the findings may not apply to these groups or to populations in developing nations, they wrote.

They also cautioned that the results could change with longer follow-up, though most recurrences occur within the first 2 years after surgery.

Patient selection for the simple hysterectomy is key

Dr. Plante stressed the need to carefully select patients for the simple hysterectomy.

“We have to ensure that their tumors meet the criteria established during this trial,” she said.

Dr. Ramirez agreed. He noted that half of the hysterectomies were done by laparoscopy (also called minimally invasive surgery), and those were split almost evenly between robotic procedures and traditional laparoscopic surgery.

“The SHAPE trial was not designed to determine whether one type of surgery for simple hysterectomy is better than another,” Dr. Ramirez said.

Nonetheless, the trial results will be “impactful for our patients,” he said.

“This research is a very positive step forward for people diagnosed with cervical cancer.”

September 1, 2023, by Linda Wang

Testing for the presence of cancer-causing types of the human papillomavirus (HPV) is now a standard part of screening for cervical cancer, some times with simultaneous Pap tests (known as co-testing). But cervical cancer screening is recommended to stop at age 65 in many places and, for a variety of reasons, many older adults stop getting screened for cervical cancer well before that age.

Results from a population-based study conducted in Denmark, however, suggest that it may be worthwhile for some individuals between ages 65 and 69 to get tested for HPV: those who haven’t had cervical cancer screening for at least 5 years.

In the new study, about 62% of women who were invited to undergo this “catch-up” testing for HPV (intervention group) had a test within the next year. In a comparison group of women not invited for catch-up testing, only about 2% had either a Pap test or an HPV test over the next year.

The rate of CIN2+ lesions diagnosed in the intervention group was significantly higher than in the comparison group (3.9 vs. 0.3 per 1,000 eligible women, respectively). CIN2+ lesions are often called precancers because these types of cell changes can go on to become cancer. Finding these lesions early allows doctors to remove them before they can progress.

Women who were furthest behind on regular screenings—that is, had one or no screenings since age 50—had nearly twice the rate of CIN2+ lesions as women who had been screened two or more times since age 50, the researchers found.

The study findings were published July 6 in PLOS Medicine.

“It may be time to reevaluate cervical cancer screening at older ages,” said lead investigator Mette Tranberg, Ph.D., of the University Research Clinic for Cancer Screening at Randers Regional Hospital in Denmark. “Our data show that it could really be beneficial to [offer catch-up HPV testing] for these older, insufficiently screened women.”

The findings support recommendations in some countries, such as the United States, where a history of negative screening results is recommended for stopping screening at age 65, after which the risk of a new HPV infection developing into cervical cancer is very low, said Nicolas Wentzensen, M.D., Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics (DCEG), who was not involved in the study.

Dr. Tranberg cautioned, however, that catch-up HPV testing could have potential downsides.

As with any screening approach, she said, it’s important to weigh the potential benefits of catching precancers or early cancers with the potential harms. Those harms include being treated for lesions that would never have developed into cancer during a woman’s lifetime.

Overall, Dr. Wentzensen said, the study reinforces the importance of women continuing to stay up to date on cervical cancer screening as they get older.

“This study was able to evaluate the prevalence of precancer in this specific population. Understanding the prevalence of precancer is one part of the puzzle to inform screening recommendations in an any age group,” he said. “This study clearly shows that there [are potential precancers over age 65] and that offering an HPV test in this population to identify those who may need treatment could be helpful.”

The challenges of screening older individuals

Almost all cervical cancers are caused by infection with high-risk types of HPV, particularly HPV 16 and HPV 18. Most HPV infections go away on their own, but for some people an infection can persist for years and lead to abnormal cervical cells that form cervical lesions. If left untreated, these lesions may progress to cervical cancer.

Unlike Pap tests, which look for abnormal cells in a sample of cervical cells, an HPV test checks the cells for the presence of genetic material (DNA or RNA) from high-risk HPV types.

Many countries, including the United States, have begun transitioning to HPV testing as the primary approach to cervical cancer screening. Women who test positive for HPV are referred for follow-up testing, which may include a Pap test or colposcopy (visual inspection of the cervix under magnification) and a biopsy to see how abnormal the cells are and how much of the cervical tissue is affected.

HPV tests are very good at detecting infection with the virus, but because these tests have only been available for the past 10 or so years, most women over age 65 have never had one. Instead, most older women have had Pap tests for routine cervical cancer screening.

However, Pap tests are less effective in older women compared to younger women because physiological changes after menopause make it more difficult for doctors to collect samples from the part of the cervix where cell changes typically start.

Even though cervical cancer tends to be diagnosed at younger ages than many cancers—in the United States the median age at diagnosis is 50 years—it does affect older women.

Experts say new approaches to prevent cervical cancer in women over the age of 65 are needed because women over this age continue to be diagnosed with and die from the disease. In the United States, for example, women 65 and older account for more than 20% of new cases of cervical cancer and around 37% of deaths from the disease.

Dr. Tranberg and her colleagues wondered whether giving women over age 65, particularly those who have fallen behind on screening, a catch-up HPV test could help bridge this gap in cervical cancer prevention.

Catching up with an HPV test

In the study, more than 11,000 Danish women aged 65 to 69 from one region of Denmark were invited to get an HPV test. They were able to choose between having a cervical sample collected by their doctor or using a vaginal self-collection kit to be mailed back for testing, known as self-sampling.

Women were included if they had no record of screening in the past 5.5 years. A comparison group of about 33,400 Danish women from Denmark’s remaining four regions were offered usual care, which included getting a Pap test or HPV test as needed—for example, if they had vaginal bleeding.

About 62% of women in the catch-up testing group had an HPV test within 12 months, while only 2% of women in the comparison group got either a Pap test or HPV test within the same time frame.

Using patient records from a centralized data network in Denmark, the researchers compared the rates CIN2+ lesions diagnosed in the two groups. In the catch-up group, 3.9 out of every 1,000 eligible women were found to have a CIN2+ lesion, compared with 0.3 out of every 1,000 eligible women in the comparison group.

Those who had rarely or never been screened in their 50s and early 60s (“insufficiently screened”) were more than twice as likely to have CIN2+ lesions as those who had been screened at least twice during that same time (“routinely screened”).

Overall, more women in the catch-up testing group chose to get a cervical sample collected by a clinician than to do self-sampling. But those who were insufficiently screened were much more likely to choose self-collection than those who were routinely screened.

Among the 2,000 women who conducted the testing via self-collection at home, 161 were found to be HPV-positive. Of this group, all except one completed follow-up testing with their doctor within the next 6 months.

This finding, Dr. Tranberg said, suggests that offering the opportunity for self-collection may be appealing to women who prefer not to get screening from a provider.

Balancing risk versus benefit

The study's findings, Dr. Wentzensen said, highlight the importance of the recommendation in US cervical cancer screening guidelines that calls for women over 65 to continue screening until they have a series of normal results.

“We know there is risk [in this age group],” he said. “So clinicians need to work with patients to make sure they have had several consecutive normal HPV test results. For their patients who haven’t, he added, “you can’t just release them from screening.”

However, he cautioned that CIN2+ is not the best indicator of cervical cancer risk, because many of these lesions will never progress to cancer. A better measure, he said, would be CIN3+ lesions, which are much more likely to develop into cancer.

Dr. Tranberg acknowledged that CIN3+ would have been a better primary measure but, from a statistical standpoint, would have required an even larger study. However, the researchers did find that rates of CIN3+ were higher in the catch-up testing group than the comparison group.

Ultimately, Dr. Tranberg said, better tests and biomarkers are needed to differentiate between abnormalities that are harmless and abnormalities that will progress to cancer.

She also pointed out that given the potential harms of screening, such as overdiagnosis and overtreatment, it’s important to determine who would benefit most from receiving a catch-up HPV test.

One approach might be to offer catch-up testing to only those older women who have been insufficiently screened, and to make self-collection kits more widely available. HPV self-collection kits are already being used in several countries, including Denmark, and are under FDA review in the United States.

Meanwhile, Dr. Wentzensen and other DCEG colleagues are engaged in several collaborative efforts related to cervical cancer screening. They include initiatives to improve screening in communities where screening rates continue to lag (see below).

Screening centered around HPV testing “is now the preferred approach in most places in the world, and now it’s really a question of implementation and making sure that new developments reach the populations that need them the most,” he said.

NCI Collaborates on Efforts to Improve Cervical Cancer Screening and Prevention

NCI’s Division of Cancer Epidemiology and Genetics is collaborating with other organizations to improve cervical cancer screening guidelines and accelerate the dissemination of new screening approaches.

They include the following efforts:

• The Enduring Consensus Cervical Cancer Screening and Management Guidelines is a collaborative effort to continuously monitor the field for new technologies and approaches that can help health care providers stay up to date with the latest cervical cancer screening guidelines.
• The Federal Cervical Cancer Collaborative, a Cancer Moonshot initiative, developed a toolkit for clinicians to help speed the adoption of the new clinical management and screening guidelines in communities where screening uptake is particularly low. A patient-focused toolkit is under development.
• The American Cancer Society’s National Roundtable on Cervical Cancer is a coalition of organizations aimed at tackling disparities in cervical cancer prevention, screening, and treatment. The Roundtable was created after the 2-year ACS Cervical Cancer Screening Initiative to accelerate the transition to primary HPV screening in the United States.

June 3, 2022, by Elia Ben-Ari

New results from a study in Kenya add to growing evidence that a single dose of human papillomavirus (HPV) vaccine is highly effective in protecting young women against cervical infection with cancer-causing HPV types.

Certain types of HPV cause almost all cases of cervical cancer. Vaccines that protect against these HPV types can greatly reduce the risk of developing cervical cancer, as well as other cancers caused by long-lasting HPV infections. But globally, HPV vaccination rates are low, especially in countries with high rates of cervical cancer and limited health care resources.

Giving just one HPV vaccine dose instead of the two or three doses currently recommended would reduce the cost and simplify the logistics of vaccination, which could allow more girls worldwide to be vaccinated, said Aimée Kreimer, Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics.

The new findings are from the KEN SHE study, a randomized clinical trial comparing HPV infection rates in girls and young women ages 15–20 who received a single dose of HPV vaccine with rates in those who received a meningitis vaccine and 18 months later received an HPV vaccine.

The trial “is part of a global effort by researchers to make HPV vaccines more accessible to girls around the world,” said Dr. Kreimer. She leads several NCI-sponsored HPV vaccine clinical trials in Costa Rica in collaboration with Agencia Costarricense de Investigaciones Biomédicas.

In the KEN SHE trial, a single dose of either of two HPV vaccines provided 97.5% protection against new persistent infections with HPV 16 and 18, the two HPV types that cause about 70% of all cervical cancers, reported the study’s principal investigator Ruanne Barnabas, M.D., Ph.D., chief of infectious diseases at Massachusetts General Hospital, and her colleagues.

The results were published April 11 in NEJM Evidence.

Along with earlier findings from observational studies, including those from an extended follow-up of the Costa Rica HPV Vaccine Trial and recent results from a study in India, the KEN SHE results “have moved us another step closer to the important goal of increasing the accessibility of HPV vaccines,” Dr. Kreimer said. “And more data are coming from other studies that we hope will take us the rest of the way.”

Low global rates of HPV vaccination

Cervical cancer is one of the leading causes of cancer death in women in low- and middle-income countries, including in sub-Saharan Africa. Most new cases of cervical cancer worldwide—about half a million each year—occur in these countries, as do almost 90% of cervical cancer deaths.

One motivation for conducting the KEN SHE study, Dr. Barnabas said, was a visit she and the study’s co-principal investigator, Nelly Mugo, M.D., M.P.H., of the Kenya Medical Research Institute (KEMRI), made to the cervical cancer ward at a hospital in Nairobi.

“We’ve had the HPV vaccine since 2006, and we could have prevented those women from developing cervical cancer,” she said.

HPV vaccination can prevent infection with HPV types that cause most cervical cancers. Because HPV is transmitted sexually, vaccine programs generally aim to vaccinate girls and younger adolescents.

However, in 2019, only about 15% of adolescent girls worldwide had received two doses of HPV vaccine, and that rate fell to 13% during the COVID-19 pandemic, said Dr. Barnabas, who was at the University of Washington at the time the KEN SHE study was being conducted.

Many low-resource countries do not have HPV vaccination programs or the health infrastructure to offer routine cervical cancer screening. And rates of HPV vaccination in many countries that do have ready access to the vaccines, including the United States, remain less than optimal.

Looking at the protection from one HPV vaccine dose

Health officials in Kenya had planned a national HPV vaccination program for 9- to 14-year-old girls. However, due to limited supply, the vaccine has been made available only to 10-year-old girls. Although some girls up to age 14 may eventually be able to get vaccinated, HPV vaccination is not provided for those 15 and older in Kenya, Dr. Barnabas said.

“These women who are just older than 15 years have decades of life ahead of them, so we wanted to test whether a single HPV vaccine dose could reduce their risk of acquiring HPV,” she continued. Vaccination provides the most benefit if a person has not yet been infected with one or more of the high-risk HPV types targeted by the vaccines.

The KEN SHE trial, which was primarily funded by the Bill & Melinda Gates Foundation, enrolled 2,275 girls and young women ages 15–20 years at three sites in Kenya. Participants needed to be sexually active but with no more than five lifetime partners, HIV negative, and not previously vaccinated against HPV. Just over 60% of participants reported having had only one lifetime sexual partner.

Participants were randomly assigned to one of three groups:

• One group received a single dose of the bivalent HPV vaccine (Cervarix), which prevents infection with HPV 16 and 18.
• A second group received one dose of the nonavalent HPV vaccine (Gardasil 9), which protects against HPV 16, 18, and five other cancer-causing, or high-risk, HPV types.
• A third group received a vaccine that protects against meningococcal disease, a common cause of bacterial meningitis in teens and young adults.

Dr. Barnabas’s team had originally planned to give all participants in the meningococcal vaccine group one of the HPV vaccines at the end of the study, 3 years after enrollment.

However, she said, once it became clear, after 18 months of follow up, that a single dose of HPV vaccine was protective, the girls and young women in this group received an HPV vaccine.

Both HPV vaccines sharply reduced risk of infection

At enrollment, participants were tested for HPV infections of the cervix. During the study, participants received regular HPV testing and Pap tests. They also were offered sexual and reproductive health services, including family planning and testing and treatment for sexually transmitted infections including HIV.

The primary outcome of the study was vaccine efficacy—that is, the incidence of new persistent infections with an HPV type targeted by the vaccine—at 18 months. Participants who, within the first 3 months of the study, did not yet have an HPV infection with one or more of the HPV types targeted by the vaccine were included in this analysis.

Those who were infected with any of these HPV types in the first 3 months remained in the study, and all women with an abnormal Pap test are being followed until their infection clears or they receive treatment, Dr. Barnabas said.

At 18 months after enrollment, 36 of 473 women (7.6%) who received the meningococcal vaccine (control group) had a new persistent cervical HPV 16/18 infection, compared with only 2 of 985 women (0.2%) who received one of the two HPV vaccines. The efficacy of both vaccines against HPV 16/18 was 97.5%.

The KEN SHE team is continuing to follow all participants for a total of 3 years to see how long the protection against HPV infection lasts.

More data to come on single-dose vaccination

Longer-term data from the KEN SHE trial and from other randomized clinical trials involving younger girls will become available over the coming years, and will aim to answer questions about the durability of single-dose HPV vaccination and to determine how one dose compares to two doses, Dr. Kreimer said.

Current evidence that a single dose of HPV vaccine is as effective as two or three doses comes from previous studies that were not specifically designed to investigate the efficacy of one dose, but in which some participants ended up receiving only a single dose.

One trial specifically testing whether one dose is as effective as two doses is the NCI-sponsored ESCUDDO trial in Costa Rica, which Dr. Kreimer leads. Results from ESCUDDO are expected in 2025, she said.

Another important study, the DoRIS trial, is taking place in Tanzania, Dr. Kreimer said. This trial is studying the immune response to see how one, two, and three doses of the bivalent and nonavalent HPV vaccines work in young girls. The trial will indirectly assess the protection that vaccination provides by comparing the immune response in young girls in Tanzania to the immune response in participants in the KEN SHE trial, and the Costa Rica and India studies, she explained. Results are expected this year.

Meanwhile, on April 11, a World Health Organization (WHO) advisory group issued a provisional recommendation to update HPV vaccine schedules to one or two doses for most girls and young women 9–20 years old, based on results of the KEN SHE trial and other emerging evidence. A final recommendation is expected in June.

WHO has set a goal of vaccinating 90% of girls worldwide against HPV by age 15 by 2030.

In addition, in February, a United Kingdom advisory committee on vaccination issued an interim recommendation to change the HPV vaccination schedule from two doses to one in the UK’s routine vaccination program for adolescents up to age 14.

Stakeholders in KEN SHE trial shared common agenda

The KEN SHE trial was designed in close collaboration with the Kenyan Ministry of Health, KEMRI, and other study partners, Dr. Barnabas said. In addition, an outside group, the Institute for Ethics and Policy Innovation at McMaster University, conducted a formal ethics review.

All the stakeholders in the KEN SHE study “had the same agenda, with the outcome being increased access to HPV vaccination throughout the world,” she said. “That includes here in the United States, where there continue to be disparities in access to HPV vaccines and a single dose of a highly effective HPV vaccine could yield the same benefits” as were seen in Kenya.

She noted that in Australia, where a universal HPV vaccination program has sharply reduced infection with cancer-causing HPV types, “they will probably eliminate cervical cancer by 2025.

Meanwhile, we have 90% of the burden of cervical cancer in low- and middle-income countries. The disparities are really striking, and it doesn’t need to be this way.”

February 22, 2022, by Edward Winstead

Cervical cancer screening has dramatically reduced new cases and deaths from the disease over the past 50 years. But the percentage of women in the United States who are overdue for cervical cancer screening has been growing, and the reasons have not been clear.

To better understand the decline in cervical screening, researchers analyzed data on more than 20,000 women who were eligible for screening in the United States. Between 2005 and 2019, the analysis showed, the rates of timely cervical cancer screening fell overall.

In addition, the analysis showed disparities among groups of women. In 2019, compared with non-Hispanic White women, Asian and Hispanic women were more likely to be overdue for screening, as were women who lived in rural areas, lacked insurance, or identified as lesbian, gay, bisexual, queer, other, or unsure (LGBQ+).

The most common reason study participants gave for not receiving timely screening was lack of knowledge about screening or not knowing they needed screening, according to findings published in JAMA Network Open on January 18.

“Cervical cancer is preventable,” said lead investigator Ryan Suk, Ph.D., of the University of Texas Health Science Center in Houston. “But the incidence of the disease is higher than it should be, and there are large disparities in the rates of timely screening among women of different sociodemographic groups.”

The new findings highlight how important it is for health care providers to recommend cervical cancer screenings to their patients, Dr. Suk continued. Awareness campaigns that use culturally appropriate messages are needed to promote cervical screening to groups with lower-than-optimal screening rates, she added.

In addition, the role of clinicians in contributing to improvements in cervical screening rates deserves further study, according to the study authors.

“The increase in the proportion of women who said they did not know screening was needed or that they did not have a recommendation from a health care provider is surprising and concerning,” said Veronica Chollette, R.N., of NCI’s Health Systems and Interventions Research Branch, who was not involved in the research.

The marked decline in up-to-date screening for cervical cancer over time occurred even as new legislation was expanding access to effective screening tests. For example, the expansion of Medicaid in many states and certain provisions of the Affordable Care Act have increased coverage of recommended screenings.

As access to care continues to improve, Dr. Suk said, recommendations from health professionals for their patients to get screened will likely become increasingly important for improving screening rates.

Defining up-to-date screening for cervical cancer

Nearly all cases of cervical cancer are caused by persistent infection with high-risk types of human papillomavirus (HPV). For decades, screening with the Pap test (cytology) has allowed doctors to detect precancerous changes that could lead to cancer or the disease in its early stages, when it is most treatable. More recently, HPV testing and HPV/Pap cotesting have become available for cervical cancer screening.

While previous studies have reported declines in up-to-date screening for cervical cancer, Dr. Suk and her colleagues wanted to assess patterns of cervical screening in the United States by sociodemographic groups and try to learn why many women were overdue for screening.

To do so, they used data from the National Health Interview Survey for 2005 and 2019. Participants in the survey answered questions about various demographic, health behavior, and health care characteristics in a structured face-to-face interview.

The researchers defined being up to date on screening based on the US Preventive Services Task Force (USPSTF) recommendations that were in effect in 2005 and 2019. In 2005, that meant screening women aged 21 to 65 with a Pap test every 3 years.

Over time, the USPSTF recommendations evolved. In 2019 (and in 2022), up-to-date screening was defined as screening women aged 21 to 29 every 3 years with a Pap test alone and for women aged 30 to 65 screening every 3 years with a Pap test alone or every 5 years with HPV testing or HPV/Pap cotesting.

Changes to the guidelines during the study period may have caused confusion among patients and doctors about the timing and recommended intervals for screening, according to the researchers.

Results on cervical screening from the National Health Interview Survey

Using the National Health Interview Survey data, the researchers found that the percentage of women overall who were not up to date on screening jumped from 14% in 2005 to 23% in 2019.

When the findings were analyzed by race and ethnicity, Asian women were most likely to be overdue for screening in 2019 (31%). Although the reasons for that aren’t clear, the incidence of cervical cancer among Asian women is not as high as in other groups, so these women might not think they’re at high risk, Dr. Suk noted.

“Nonetheless,” she continued, “Asian women still need to be screened for this potentially deadly cancer.”

Rates of overdue screening were also higher among women who identified as LGBQ+ than among heterosexual women in 2019 (32% versus 22%). The National Health Interview Survey offers only two gender categories, male or female, so the researchers could not identify transgender individuals.

“The inclusion of women identifying as LGBQ+ in the study is particularly important,” said Ms. Chollette. “The number of individuals identifying as LGBQ+ is rising, and reasons for their low cervical cancer screening rates are poorly understood and largely unexplored.”

Possible reasons for not being up to date on cervical screening

The researchers also investigated potential reasons for the decrease in timely screening rates over time. Among the women who were not up to date on screening, 60% of women aged 21 to 29 years and 55% of women aged 30 to 65 years said “not knowing they needed screening” was the reason for being overdue for screening.

“Not knowing they needed screening” was the most common reason for being overdue across all groups, ranging from 47.2% of women identifying as LGBQ+ to 64.4% of women with Hispanic ethnicity.

Just 1% of women aged 21 to 29 reported that receiving the HPV vaccine was the main reason for not being up to date on screening. People who have been vaccinated against HPV still should be screened for cervical cancer because current vaccines do not protect against all HPV types that cause cervical cancer.

Over time, lack of access declined as a reason for being overdue for cervical screening, the researchers noted. From 2005 to 2019, the proportion of women aged 30 to 65 years who reported lack of access as a primary reason for not receiving screening decreased from 22% to 10%.

During this period in this population, however, lack of knowledge about screening as the primary reason increased (from 45% to 55%), as did not receiving recommendations from health care professionals (from 6% to 12%).

The fact that “not knowing that screening was needed” increased over time as a reason for not being up to date on screening across most sociodemographic groups underscores the need to develop strategies to increase screening awareness for all women, according to the study authors.

Improving cervical cancer screening rates among diverse populations

A limitation of the study was that participants could select only one response as the primary reason for not being up to date on cervical screening, the study authors acknowledged. Many women, including those who lack insurance, those from racial and ethnic minority groups, and those who identify as LGBQ+, may experience multiple barriers to screening, they noted.

The authors also cautioned that reducing the burden of cervical cancer will involve more than just improving timely cervical cancer screening rates. Another challenge is ensuring that women follow up with their health care providers after abnormal findings from cervical screening.

The pandemic has likely worsened the situation documented in the study, Ms. Chollette said. Once the pandemic hit, screening for all cancers dropped off as many people delayed or cancelled their scheduled appointments.

Future studies could focus on why current approaches for informing people about cervical screening (e.g., electronic reminders from health care professionals, chart reviews prior to appointments, and posters in waiting rooms) have failed to improve screening rates, Ms. Chollette said.

If a primary reason for the decline in cervical cancer screening is due to women not being aware that screening is needed, she added, “then researchers need to explore why providers are not recommending cervical cancer screening.”

Primary care physicians need to keep track of screening schedules for multiple cancers, Dr. Suk acknowledged.

“We need more effective and efficient tools and systems that help clinicians stay up to date on screening guidelines,” she continued. “We also need more research on the barriers that prevent clinicians from administering cervical cancer screening.”

September 18, 2020, by NCI Staff

Routine cervical cancer screening is very effective for preventing cervical cancer and deaths from the disease. On July 30, the American Cancer Society (ACS) published an updated guideline for cervical cancer screening. The guideline’s recommendations differ in a few ways from ACS’s prior recommendations and those of other groups. An expert on cervical cancer screening, Nicolas Wentzensen, M.D., Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics, explains the changes.

How have the cervical cancer screening recommendations changed?

The American Cancer Society’s new guideline has two major differences from previous guidelines. One is to start screening at a slightly older age, and the other is to preferentially recommend a type of screening test called an HPV test.

ACS recommends cervical cancer screening with an HPV test alone every 5 years for everyone with a cervix from age 25 until age 65. If HPV testing alone is not available, people can get screened with an HPV/Pap cotest every 5 years or a Pap test every 3 years.

These recommendations differ slightly from those given by ACS in 2012 and by the US Preventive Services Task Force (USPSTF) in 2018.

What’s the difference between an HPV test, a Pap test, and an HPV/Pap cotest?

A Pap test, often called a Pap smear, looks for abnormal cells that can lead to cancer in the cervix. An HPV test looks for the human papillomavirus, a virus that can cause cervical cancer. For an HPV/Pap cotest, an HPV test and a Pap test are done together.

For a patient at the doctor’s office, an HPV test and a Pap test are done the same way—by collecting a sample of cervical cells with a scraper or brush.

The Pap test has been the mainstay of cervical cancer screening for decades. HPV tests are a newer method of cervical cancer screening. Two HPV tests have been approved by the Food and Drug Administration (FDA) for use as a primary HPV test, meaning it is not part of an HPV/Pap cotest. Other HPV tests are approved as part of an HPV/Pap cotest.

Why does the new guideline recommend an HPV test over a Pap test or HPV/Pap cotest?

All three tests can find cervical cancer precursors before they become cancer. But studies have shown that HPV tests are more accurate and more reliable than Pap tests. Also, you can rule out disease really well with HPV tests so they don’t have to be repeated as frequently.

Although the Pap test has led to huge drops in rates of cervical cancer and death from the disease, it has some limitations. Pap tests have lower sensitivity compared with HPV tests, so they may miss some precancers and have to be repeated frequently. They also detect a range of abnormal cell changes, including some minor changes that are completely unrelated to HPV. So, many people who get an abnormal Pap test result actually have a very low chance of developing cervical cancer.

HPV/Pap cotesting is only slightly more sensitive than HPV testing, but it is less efficient because it requires two tests. And it detects a lot of minor changes that have a very low risk of turning into cancer. For an entire population, that’s a lot of additional effort and cost.

Screening with an HPV test alone was not recommended by ACS in 2012 because that approach wasn’t yet approved by FDA. The 2018 USPSTF guideline included HPV testing alone, cotesting, and Pap testing as equal options. The difference in the new ACS guidelines is that they elevate HPV testing alone over the other two tests.

Why does the new guideline recommend screening starting at age 25, instead of age 21?

Using information from new studies, ACS concluded that the benefits of cervical cancer screening do not outweigh the harms for people aged 21 to 24 years old.

This is an important change that is related to HPV vaccines. The first cohort of women who received the HPV vaccine when they were younger are now in their 20s and are eligible for cervical cancer screening. HPV vaccines are very good at preventing HPV infections, particularly infection with HPV types 16 and 18, the types that cause most cervical cancers. So, the vaccines have led to a drop in HPV infections and cervical precancer in this age group.

Also, in young women, most HPV infections go away on their own. Screening people in this age group often leads to unnecessary treatment, which can have side effects. That’s why ACS recommends starting screening at age 25.

Have the recommendations for those who are 65 years old or older changed?

No, the recommendations for this age group are the same as before. If you’ve had a series of normal screening test results over a long period of time, then you can stop screening at age 65. If, in the past, you had an abnormal result or anything suspicious on a screening test, or had treatment for cervical cancer or precancer, then you should continue to be screened.

The recommended age limit for cervical cancer screening has been consistent across different guidelines over the years. But there are current efforts to study the age limit more because it’s an area where we have less data. There is more interest now in looking at people who had an abnormal screening test result at an older age to see if they require more years of screening or more frequent screening.

If these screening tests save lives, isn’t it better for people to get tested more often and with more tests?

No. As with many tests, there is the potential to do more harm than good if they are applied too frequently. There are a few risks that come with cervical cancer screening tests.

Screening tests and follow-up tests can cause physical discomfort. There’s also the possibility of added anxiety and other emotions from incorrect, or false-positive, test results. And if you have an incorrect result, you may end up getting unnecessary follow-up tests or even unnecessary treatment.

Treatment for cervical cancer or precancer can permanently alter the cervix. That may raise the risk of serious complications in a future pregnancy, including pregnancy loss and preterm birth.

So, while testing more often or with more tests may seem like a good idea, it can actually lead to more harms. ACS carefully evaluated the potential benefits and harms of each screening test for each age group to come up with their updated recommendations.

Do people who got the HPV vaccine still need to get cervical cancer screening?

Yes, the new guideline recommends screening for those who have had the HPV vaccine. It does not recommend making a screening decision based on whether an individual has had the vaccine.

But, over time, as rates of HPV vaccination increase among people who are eligible for cervical cancer screening, we may see more changes in screening recommendations down the road.

Why do the guidelines for cervical cancer screening keep changing?

It’s a very dynamic situation, and that’s for multiple reasons. One is we have amazing results from the HPV vaccine, so that continually changes the picture for screening.

We also have seen great development of new technologies like HPV testing and improvement in some of the secondary tests that are used for following up after screening.

All these improvements have allowed us to make more accurate predictions of a person’s chances of getting cervical precancer and cancer. We also have new evidence from large studies that really give us the assurance that we can update screening practices to provide better outcomes for women and for the health care system.

What happens after someone gets an abnormal cervical screening test result?

If something abnormal or suspicious was found, also called a positive test result, you will typically get a second test. The standard approach is to do a Pap test, but there is also a new FDA-approved test, called dual stain. The dual stain test uses two biomarkers that can give a more accurate sign that precancer is present.

The results of the second test will help decide if you need a colposcopy—a procedure to look at the cervix with a magnifying lens and take samples from spots on the cervix that look abnormal.

ASCCP (formerly known as The American Society of Colposcopy and Cervical Pathology) recently published updated guidelines for the care of patients with abnormal cervical screening test results. This was a large consensus effort involving several clinical organizations, federal agencies, and patient representatives. Several NCI scientists, including myself, performed extensive risk assessment and systematic literature reviews to support the development of the guidelines.

Using all the information that we have on the risk of cervical cancer and precancer, the guidelines create a framework that helps doctors make decisions about follow-up care based on a patient’s total risk level.

The 2012 ASCCP guidelines were based on which test a patient got and what the results were. The new recommendations are more precise and tailored to many factors that determine a person’s risk of cervical cancer and precancer, such as their age and past test results.

Now, doctors can use any combination of test results to determine an individual’s risk and decide whether that person should, for example, get a colposcopy or come back in a year to repeat the screening test.

May 25, 2021, by Carmen Phillips

Nearly 3 years ago, results from a large clinical trial showed that minimally invasive surgery was inferior to traditional open surgery for women with early-stage cervical cancer. In the trial, called LACC, women with early-stage cervical cancer who had less invasive surgery, including robotic surgery, were more likely to have their cancer come back than those who had open surgery and were less likely to be alive 3 years after their surgery.

A new study shows that the LACC trial’s results appear to have changed surgeons' treatment choices for women in the United States with early-stage cervical cancer. In the 18 months after the LACC results were published, the percentage of women who had minimally invasive surgery to remove the uterus and nearby structures, known as a radical hysterectomy, decreased from 58% to 43%, researchers reported April 29 in the New England Journal of Medicine.

The findings are in line with those from a study published last year, which showed a similar drop in the number of women with early-stage cervical cancer who underwent a minimally invasive radical hysterectomy since early 2018, when the LACC results were initially presented at a large research meeting.

The new study also found that the number of minimally invasive radical hysterectomies has dropped far more dramatically at large academic medical centers than at smaller hospitals.

Although not entirely unexpected, the discrepancy “suggests an opportunity to improve outcomes” for women with early-stage cervical cancer, study co-leader Patrick Lewicki, M.D., of New York-Presbyterian Hospital, and his colleagues wrote.

Several other large studies have linked minimally invasive radical hysterectomy with a higher risk of the cancer returning and death in women with early-stage cervical cancer, said Pedro Ramirez, M.D., professor of gynecologic oncology at the University of Texas MD Anderson Cancer Center, the LACC trial's lead investigator.

As a result, Dr. Ramirez explained, clinical guidelines from multiple US and European medical groups now recommend open surgery—known as a laparotomy—as the standard approach for radical hysterectomy in women with early-stage cervical cancer.

At this point, for this group of patients, “I don’t think there is a role for minimally invasive surgery outside of a clinical study,” he said.

But that doesn’t mean minimally invasive surgery will never have a role in treating early-stage cervical cancer, said Emma Rossi, M.D., a gynecologic oncologist from the University of North Carolina School of Medicine.

“The LACC trial’s findings are valid and real,” Dr. Rossi said. But she noted that minimally invasive surgeries, particularly performed with robotic systems, have proven to be both safe and effective for numerous gynecologic conditions. And although the LACC trial and other studies consistently show worse outcomes with it in cervical cancer, she continued, “they failed to explain why.”

So, more research is needed, she said, “to see if we can find … ways to continue offering [minimally invasive surgery] while avoiding the negative effects.”

The Data on Open versus Minimally Invasive Radical Hysterectomy

Thanks to effective screening and prevention programs, cervical cancer has become fairly rare in the United States, with approximately 14,000 women diagnosed each year. Nearly half of cervical cancers are diagnosed at an early stage, meaning the tumors are small and have not spread beyond the cervix.

Although there are other treatment options, radical hysterectomy is the most common treatment for early-stage disease, and cure rates for the disease are around 80%.

Minimally invasive surgery, which can also be called laparoscopic surgery, has been used to perform radical hysterectomies in women with early-stage cervical cancer for several decades. A minimally invasive procedure can be performed manually or with the use of robotic systems.

Its use for radical hysterectomies increased substantially in the late 2000s and 2010s, Dr. Rossi explained. That trend was driven by several factors, including the greater availability of robotic surgery and data indicating that it was as effective as open surgery and had some advantages for patients, including lower risk of complications during surgery and shorter postsurgical hospital stays.

By the time the LACC trial results were published in November 2018, robotic surgeries represented the lion’s share of radical hysterectomies in women with early-stage cervical cancer, Dr. Ramirez explained.

However, most (84%) of the minimally invasive procedures in the LACC trial were performed with traditional laparoscopic surgery rather than with robotic surgery. That led some oncologists who specialize in treating gynecologic cancers to argue that the trial did not reflect real-world practice.

Two population-based studies—conducted in Sweden and Denmark—appeared to offer some support for those criticisms. Neither found that robotic radical hysterectomy was linked with higher risk of recurrence or death in patients with early-stage cervical cancer.

However, most other studies have reported findings that are consistent with those from the LACC trial. A large US study involving 2,400 women and another US-based study conducted at three Mayo Clinic hospitals reached the same conclusion: women who had robotic radical hysterectomies for early-stage cervical cancer had a higher risk of the cancer returning and worse survival.

The LACC trial’s findings were “shocking” to many gynecologic oncologists, Dr. Rossi said. But the consistency of the findings with those from other population-based studies can’t be dismissed, and, given the attention the research received in the medical community and in news stories, she noted, doctors and patients were going to respond.

Rapid, but Uneven, Change in Surgical Choice

To conduct the new study, Dr. Lewicki and his colleagues looked at data on nearly 2,500 women with early-stage cervical cancer from a large database that covers approximately 25% of the hospitals in the United States.

Their review included women treated between November 2015 and March 2020, spanning several years before and approximately 1.5 years after the publication of the LACC trial’s results. To compensate for the time it can take for clinicians to learn about newly published research findings, the review excluded the 3 months immediately following the publication of the trial results.

In the period before the results were published, 58% of radical hysterectomies for early-stage cervical cancer were performed with minimally invasive surgery. By March 2020, use of the minimally invasive procedure had dropped to 45%.

Academic centers were far more likely to change practice, with a much steeper decline in minimally invasive radical hysterectomy compared with what was seen at smaller community hospitals.

It will likely take some time for practice to change among surgeons at smaller hospitals, said David Sheyn, M.D., of the Case Western Reserve University School of Medicine, and part of the research team.

“It can sometimes take 5 to 6 years for [research] findings to make their way down to the community setting,” Dr. Sheyn said. Nevertheless, some surgeons who feel they get the best results with the robotic procedure may be “less likely to pivot” from their usual patterns of care, he continued, or at least not as quickly.

The slow pace of change at nonacademic centers may also reflect the different practice environment at smaller hospitals, said Dr. Rossi, where continuing education and collaborative efforts such as tumor boards are less common.

Why Worse Survival with Minimally Invasive Surgery?

One burning question on many researchers’ minds is why minimally invasive surgery would be less effective than open surgery in this particular situation and not for other gynecologic conditions (e.g., uterine cancer).

One of the most prominent theories places the blame on devices called uterine manipulators, which are sometimes used during minimally invasive procedures to improve surgeon’s ability to access and visualize the uterus and surrounding structures. This disruption to the uterus, the thinking goes, may be causing some cancer cells to become dislodged and escape into adjacent areas.

Drs. Ramirez and Sheyn agreed that this idea of cancer cell “spillover” is a theoretical concern that would be difficult to prove.

Dr. Rossi echoed a sentiment that other gynecologic oncologists have proposed: the problem may be the surgeons. Unlike drugs, which are consistent in how they are made and delivered, “that’s not true for surgery,” she said. “Different surgeons can have different outcomes, even with the same technique.”

And compared with open surgery, minimally invasive radical hysterectomy is a much more technically challenging procedure, she said, raising the question: “Is this possibly a technique-driven effect?”

That’s a subject for more research, Dr. Rossi continued, one that could open the door to reintroducing minimally invasive surgery for early-stage cervical cancer “in a safe way.”

Increasing Open Surgery at Smaller Hospitals?

For the time being, Dr. Ramirez stressed, the overwhelming evidence of worse outcomes with minimally invasive surgery for women with early-stage cervical cancer makes changing clinical practice an imperative.

He expressed concerns at the slow transition from minimally invasive to open radical hysterectomy at smaller hospitals. What will it take to speed things up?

“We have to continue to educate the public and educate doctors,” Dr. Ramirez said. “It’s also the responsibility of hospitals to ensure that standard practices are being followed.”

Dr. Sheyn said he expects surgeons at smaller hospitals to continue to decrease their use of minimally invasive procedures for early-stage cervical cancer. But, for a variety of reasons, he continued, “there may still be some holdouts.”

One important source of change will be younger surgeons, Dr. Rossi said. Because many younger surgeons at smaller hospitals are often trained at large academic centers, they are likely to be taught to perform open surgeries for this particular procedure.

“That tells me that this is going to be an enduring effect,” Dr. Rossi said, because academic centers “are where the [gynecologic surgeons] of tomorrow are going to be training.”

October 11, 2018, by NCI Staff

UPDATE: On March 11, 2020, the Food and Drug Administration (FDA) approved the first dual-stain test for women who have tested positive for HPV. The test, called CINtec® PLUS Cytology, is used to help doctors decide if an HPV-positive woman should have a biopsy to look for cervical precancer or cancer.

A new test, called dual stain, may help improve how doctors care for women who test positive for human papillomavirus (HPV) infection during routine cervical cancer screening, an NCI-led study has shown. HPV tests detect infections with the cancer-causing types of HPV.

For most women, HPV infections go away on their own. But for some, the infection leads to precancerous growths that can progress to cervical cancer. To better care for women who are HPV positive, researchers have been exploring ways to help tell whether an HPV infection is likely to cause precancer.

As HPV testing becomes a more common method of cervical cancer screening, “the challenge is how to best manage, or triage, HPV-positive women,” said the study’s senior investigator, Nicolas Wentzensen, M.D., Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics (DCEG).

Doctors usually use a Pap test, also called a Pap smear, to determine whether an HPV infection is likely to cause precancer and help decide whether a woman should get a biopsy. But, according to the NCI study, the dual-stain test was better than the Pap test at predicting whether HPV-positive women developed cervical precancer within 5 years.

The findings suggest that HPV-positive women with a positive dual-stain test result should get a biopsy to check for cervical precancer or cancer, the study authors concluded, whereas those with a negative result can safely wait 3 years before getting screened again. Results from the prospective study were reported October 11 in JAMA Oncology.

“This is a very important study,” said Mark Stoler, M.D., associate director of Surgical Pathology and Cytopathology at the University of Virginia School of Medicine. It’s the first study performed in the United States, Dr. Stoler continued, “that really provides the assurance that [dual stain] is a better triage test” than the Pap test.

Cervical Cancer Screening in the United States

There are around 12 different types of HPV that can cause cervical and other types of cancer. HPV infections that aren’t controlled by the immune system are the cause of nearly all cervical cancers. Cervical cancer screening tests look for disease in people who have no symptoms.

Current US guidelines for cervical cancer screening recommend one of three approaches: an HPV test alone, a combination of HPV and Pap tests (an HPV/Pap cotest), or a Pap test alone.

According to the US Preventive Services Task Force, women age 30 to 65 years at average risk of cervical cancer can be safely screened with an HPV test or HPV/Pap cotest every 5 years.

Although HPV/Pap cotesting has improved the accuracy of cervical cancer screening and helped to greatly reduce the incidence of cervical cancer, it has some limitations.

For example, some women who test positive for HPV and who have minor abnormalities on a Pap test are referred for colposcopy, a procedure in which biopsies are taken of abnormal areas in the cervix (visit NCI's page on cervical screening tests for the most up-to-date recommendations).

But only a small percentage of Pap test abnormalities turn out to be cervical precancer or cancer, meaning most of these women had an unnecessary colposcopy, Dr. Wentzensen explained. Because of these limitations, “there is a big effort to find better markers that allow us to triage HPV-positive women more efficiently,” he said.

In terms of potential triage approaches for HPV-positive women, dual-stain testing “is probably the most advanced method available,” said the study’s lead investigator, Megan Clarke, Ph.D., M.H.S., also of DCEG. The new study adds to that body of evidence, she said.

The dual-stain approach has been under study for more than a decade, Dr. Stoler said. It measures the presence of two specific proteins, p16 and Ki-67, in a sample of cervical cells. The expression of p16 is strongly linked with HPV infection, and Ki-67 is used as a biomarker for the rapid cell division seen in precancers and cancer.

Previous studies have provided some evidence that dual-stain testing is better at identifying HPV-positive women who have precancers than Pap testing, but none followed patients forward in time for more than 3 years.

Searching for a Better Triage Test for HPV-Positive Women

To conduct this new study, the investigators followed 1,549 women aged 30 or older who had tested positive for HPV (on a test that gives combined results for 13 cancer-causing types) while undergoing routine HPV/Pap cotesting at Kaiser Permanente Northern California between January and May 2012. Dual-stain testing was performed on participants’ cervical cell samples at the beginning of the study.

Women with a normal Pap test result were advised to repeat the cotest in 1 year, whereas women with an abnormal result were referred for immediate colposcopy and biopsy. Biopsy results can reveal a range of disease states, including normal, low-grade to high-grade precancer, and cancer.

Overall, 46% of women in the study had a positive dual-stain test result and 51% had an abnormal Pap test result. More women with severely abnormal Pap test results than women with normal Pap results had a positive dual-stain test result. Over the 5-year study period, 77% of women found to have a high-grade precancer and 91% found to have cancer had a positive dual-stain test result.

Compared with Pap test results, dual-stain test results were far more indicative of the 5-year risk of cervical precancer, the team found. For example, women with a positive dual-stain test result had a higher risk of developing cervical precancer over the next 5 years than women with a positive Pap test result.

Conversely, women with a negative dual-stain test result had a lower risk of developing cervical precancer within 5 years, compared with women with a normal Pap test result.

This means that a negative dual-stain test result gives greater reassurance than a normal Pap test result that precancer won’t develop during the ensuing 5 years, Dr. Wentzensen explained.

Dr. Clarke said that the study also addressed a critical question: “How often and at what time interval should HPV-positive women who test negative with dual stain come back for repeat screening?”

Based on the 5-year risks of cervical precancer, the researchers determined that HPV-positive women with a negative dual-stain result can safely wait 3 years before being screened again.
Together, the findings suggest that using the dual-stain test to triage HPV-positive women might lead to fewer unnecessary colposcopies, Dr. Clarke noted.

The higher sensitivity (i.e., better at identifying women with a higher risk of having precancer) and specificity (i.e., better at identifying those with a low risk) of the dual stain-test compared with the Pap test is impressive, Dr. Stoler said.

“It’s very hard to have a test that improves sensitivity and specificity, but dual stain does it because of the biology behind the development of the test,” he explained.

Learning More About Dual Stain

The dual-stain test is already being marketed and used in several countries, including Canada, Europe, and Australia, Dr. Stoler said. The clinical trial that would form the basis of FDA clearance for the dual-stain test in the United States is currently ongoing, he added.

In the future, HPV testing followed by dual stain for primary cervical cancer screening may be a more efficient alternative to HPV/Pap cotesting, Drs. Wentzensen and Clarke said.

The manufacturer of the dual-stain test is analyzing the development of cervical precancer in HPV-positive women who have a positive test result from either dual stain or Pap in an ongoing study. In addition, Dr. Wentzensen and his colleagues are investigating the results of dual stain testing in a large population of women, including many who are HPV negative.

“I think there will be sufficient data to change practice based on these observational studies,” said Dr. Wentzensen.

And the test may soon have other attractive qualities, the investigators noted. A major advantage of the dual-stain test, said Dr. Wentzensen, is that abnormal cells are highlighted with a colored stain and are therefore easier to detect and quantify than cells stained for a Pap test.

“Currently, the dual-stain test is evaluated manually, but we are working on an automated evaluation of this assay and we have exciting results,” he added. Automation of the dual-stain test would enhance its reliability and make it easier to use, he said.

August 2, 2018, by NCI Staff

UPDATE: On October 13, 2021, the Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) in combination with chemotherapy to treat advanced cervical cancer. Under the approval, the combination can be given with or without bevacizumab (Avastin). FDA also granted regular approval for pembrolizumab to be used alone for people with advanced cervical cancer whose tumors grew despite chemotherapy treatment. Pembrolizumab received accelerated approval in June 2018 as a single agent for this indication. Both approvals are for people whose tumors express the protein PD-L1.

Both approvals are based on results from a large phase 3 trial called KEYNOTE-826, in which adding pembrolizumab to chemotherapy led to longer overall survival, more tumor responses to treatment, and responses that lasted longer.

In June, the Food and Drug Administration (FDA) further expanded the approved uses of the immunotherapy drug pembrolizumab (Keytruda). The two recent approvals cover the use of pembrolizumab for some women with advanced cervical cancer and for adults and children with relapsed or treatment-resistant primary mediastinal large B-cell lymphoma (PMBCL), a rare type of aggressive non-Hodgkin lymphoma.

Both actions by FDA were accelerated approvals, meaning further studies are needed to confirm the drug’s clinical benefit in patients with these cancers.

Pembrolizumab is a type of immunotherapy called an immune checkpoint inhibitor. It works by blocking the binding of PD-1, a protein expressed on cytotoxic T cells, to the PD-L1 protein expressed on some cancer cells, an interaction that acts as a brake on the immune system and prevents T cells from attacking the cancer.

First Approval of a PD-1 Inhibitor for Cervical Cancer

On June 12, FDA approved pembrolizumab to treat women with cervical cancer that has recurred or spread (metastasized) to other parts of the body and gotten worse during or after chemotherapy. The approval makes pembrolizumab the first immune checkpoint inhibitor approved to treat cervical cancer.

Under the approval, patients' tumors must express PD-L1, as determined by an FDA-approved laboratory test. FDA simultaneously approved the PD-L1 IHC 22C3 pharmDx test (manufactured by Dako North America, Inc.), as a companion diagnostic test for women with cervical cancer.

The accelerated approval was based on results from a single cohort of 98 women with cervical cancer who were enrolled in an ongoing phase 2 clinical trial of pembrolizumab for the treatment of several cancer types. The trial, called Keynote-158, is sponsored by Merck, the drug’s manufacturer.

Of the 98 women, 77 had tumors that expressed PD-L1. Two of these women had their tumors disappear completely (complete responses) and nine had their tumors shrink by 30% or more (partial responses), for an overall response rate of 14.3%. In 10 of the 11 women who responded to pembrolizumab, the responses lasted 6 months or longer, and after nearly 12 months of follow-up, the median duration of response had not been reached. None of the women with PD-L1–negative tumors responded to pembrolizumab.

Nearly 40% of the women experienced serious side effects, including anemia (7%), fistula (4%), infection (4%), or hemorrhage (4%), and 8% of the patients had to stop treatment because of them. The most common side effects included fatigue, pain, nausea and vomiting, and difficulty breathing (dyspnea).

The current standard of care for women with cervical cancer that has recurred or metastasized after previous treatment is chemotherapy in combination with bevacizumab (Avastin). FDA approved the combination regimen in 2014 based on results of an sponsored randomized phase 3 trial showing a 3.7-month improvement in median overall survival with the addition of bevacizumab to chemotherapy.

The clinical trials that led to the approvals of bevacizumab and pembrolizumab for cervical cancer that recurs or spreads and worsens during or after chemotherapy had different designs and goals, so “it’s not possible to compare the two regimens given the data currently available,” said Elise Kohn, M.D., Gynecologic Cancer Therapeutics Lead in NCI’s Cancer Therapy Evaluation Program.

“We now have two very different approved therapeutic options for these patients,” she said, “so patients should discuss the pros and cons of each regimen with their physicians before deciding on their treatment.”

Dr. Kohn stressed that patients and clinicians need to weigh the risks of side effects when considering the treatment options.

“Although the patterns of toxicity are different, they are not insignificant for either option,” she explained.

New Treatment Option for Rare Lymphoma

On June 13, FDA approved pembrolizumab for the treatment of adult and pediatric patients with PMBCL that is resistant to available treatments (refractory) or returned following treatment with two prior therapies.

The accelerated approval was based on results from a multicenter single-arm phase 2 trial called Keynote-170. The trial, sponsored by Merck, included 53 patients between the ages of 20 and 61 with relapsed or refractory PMBCL.

Although there were no children in the trial, “efficacy for pediatric patients with PMBCL was extrapolated from the results in the adult PMBCL population,” according to a Merck news release, and safety was determined based on “a study of 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors” who were treated with pembrolizumab.

The overall response rate in the Keynote-170 trial was 45%, with 11% of patients achieving a complete response and 34% experiencing a partial response. At an average follow-up of nearly 10 months, the median duration of response had not yet been reached.

In its approval notice, FDA stated that pembrolizumab should not be used in patients who have an urgent need for surgery to reduce a PMBCL mass that may be compressing a major blood vessel or other critical structure within the mediastinum.

The most common side effects of pembrolizumab in the Keynote-170 trial included musculoskeletal pain, upper respiratory tract infection, fever, fatigue, and dyspnea. Serious side effects occurred in 26% of patients, causing 15% to interrupt therapy and 8% to discontinue treatment with pembrolizumab entirely. Twenty-five percent of patients had side effects that required treatment with corticosteroids.

“In the short follow-up thus far, there haven’t been signs of increased toxicity compared to other trials of PD-1 inhibitors,” said Mark Roschewski, M.D., of the Lymphoid Malignancies Branch in NCI’s Center for Cancer Research. “But PMBCL patients are often young and female, so longer follow-up will be important for these patients because their lifetime risk of developing autoimmune diseases is much higher” than older patients treated with PD-1 inhibitors, he emphasized.

The distinction between patients with refractory PMBCL after first-line therapy and those who have relapsed or still have refractory disease following two previous lines of therapy is important, said Dr. Roschewski. Patients who have not been cured despite two previous lines of therapy—the patients covered by this approval—have a very poor prognosis.

“These patients need better therapies,” he said. “Now that we have an approved drug in PMBCL, it opens the possibility of combination therapy studies, such as pembrolizumab and CAR T-cell therapy, for example.”

October 5, 2017, by NCI Staff

NCI researchers have found that for the most common high-risk type of human papillomavirus (HPV) to cause cervical cancer, an important viral gene may need to have a precise DNA sequence. The findings, the researchers believe, contribute to a better understanding of HPV biology and may have implications for cervical cancer prevention and treatment.

The study investigators analyzed the genomes of HPV type 16—one of the most potent human carcinogens—from more than 5,000 infected women around the world, making it the largest genomic study of HPV16 to date. Some of the women in the study had cervical cancer while others did not.

They found that the sequence of a viral oncogene called E7 was almost identical among women with cervical cancer but had many different mutations among those without cancer.

“We knew that E7 was important, but we didn’t realize that its genetic conservation might be critical for HPV16 to cause cancer,” said lead investigator Lisa Mirabello, Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “Conservation” refers to whether the sequence of a gene remains unchanged over time.

The new findings were reported online on September 7 in Cell.

“This study really nicely shows that E7 is a very important, arguably the most important, oncogene for HPV16-associated cervical cancer development,” said Dohun Pyeon, Ph.D., associate professor of immunology and microbiology at the University of Colorado, who was not involved in the study.

Genetic Alterations in HPV16

Persistent infection with one of a dozen high-risk HPV types can lead to cervical, anal, oropharyngeal, and other cancers. HPV16, however, is the cause of half of all cervical cancers and an even larger fraction of other HPV-related cancers.

Although it is estimated that roughly 40% of women will be infected with a high-risk type of HPV at some point in their lives, most of these infections are successfully controlled by the immune system. Scientists do not fully understand why only some HPV infections persist and lead to cervical precancer or cancer.

Dr. Mirabello and her colleagues obtained cell or tissue samples from about 3,960 HPV16-infected women in the United States or Costa Rica who had benign infections, advanced cervical precancer, or cancer. Advanced cervical precancer (also called CIN 3) can turn into cancer, and in the United States, it is treated to prevent progression to cancer.

They found a high amount of diversity between the HPV16 genomes of all the samples; only about a quarter of the HPV16 genomes were exactly the same between two or more women in the study. When they looked at the quantity of mutations, they found that the HPV16 genomes from women with benign infections had more mutations than those from women who had precancer or cancer.

Both E6 and E7 are viral oncogenes that are thought to be responsible for cancer development in HPV16-infected women. The researchers found a similar amount of mutations in E6 among the women with cancer or precancer and the women with benign infections.

However, they found far fewer mutations in E7 among women who had precancer or cancer compared with women who had benign infections. In fact, for women who had precancer or cancer, E7 had the fewest mutations compared with any other gene in the HPV16 genome.

The researchers found similar patterns when they analyzed HPV16 genomes from more than 1,600 cervical cancer samples obtained from women in 39 different countries.

The team’s findings strongly suggest that “the uniquely potent” cancer-causing ability of HPV16 “hinges on the E7 protein remaining in its exact form,” said the study’s senior author, Mark Schiffman, M.D., also of DCEG, in a Cell press release.

Next, the researchers investigated how mutations in E7 may arise. They turned to a family of enzymes in human cells, called APOBEC3, which fight infections by introducing mutations into viral DNA. If unrepaired, these mutations could potentially impair the virus’s ability to survive in human cells. Several studies have shown that APOBEC3 enzymes may help cells resist HPV16 infection.

APOBEC3 enzymes tends to introduce mutations within a specific short DNA sequence. Dr. Mirabello and her colleagues found that, in the HPV16 genomes from women with benign infections, mutations in E7 often appeared in this APOBEC3-associated DNA sequence. This raises the possibility that mutations in E7 may be caused by an APOBEC3 enzyme, they wrote.

Understanding the Role of E7 in Cervical Cancer

The researchers are now taking a closer look at the mutations that may be induced by APOBEC3. By comparing these mutations across the viral genomes of women with and without cancer or precancer, their goal is “to try and understand which mutations are having a negative effect on the carcinogenic potential of the virus,” Dr. Mirabello said.

Identifying a genetic biomarker (such as a specific mutation) “that could suggest which HPV16 infections are likely to progress to cancer would be of tremendous clinical benefit,” Elizabeth White, Ph.D., of the University of Pennsylvania, and Karl Munger, Ph.D., of Tufts University wrote in an accompanying commentary. It might, for example, help identify HPV16-infected women who should have more frequent cervical cancer screenings.

Exactly how E7 mutations may reduce the cancer-causing potential of HPV16 is also unknown. A better understanding could come from an analysis of the effects of E7 mutations on proteins in human cervical cells, said Dr. Pyeon.

“The E7 protein binds to dozens, possibly hundreds, of proteins in human cells,” he explained. For example, E7 binds to and prompts degradation of pRB, a human protein that plays a major role in controlling cell growth. Genetic mutations could potentially disrupt or enhance E7’s binding to these target proteins.