Gynecologic oncologists seek balance as cervical cancer screening guidelines evolve

Once the leading cause of cancer death among U.S. women, cervical cancer incidence and mortality have decreased substantially over the past 40 years, largely due to screening.

Since the implementation of widespread screening, deaths associated with cervical cancer in the United States declined from 2.8 per 100,000 women in 2000 to 2.3 per 100,000 women in 2014, according to a 2018 U.S. Preventive Services Task Force recommendation.

Simply stated, screening saves lives.

In July, American Cancer Society (ACS) updated its guideline to recommend initiating cervical cancer screening at age 25 years, a change from the prior recommendation of 21 years. The society also recommended phasing out the Pap test and cotesting in favor of the HPV test alone, once every 5 years through age 65 years.

These changes have sparked controversy in the gynecologic oncology and OB/GYN fields.

“The suggestion that testing need only be performed every 5 years ... appears to be based in theoretical and economic benefit while unfortunately neglecting the other components of well-woman care and cancer prevention,” Jubilee Brown, MD, professor and division director of gynecologic oncology at Levine Cancer Institute at Atrium Health, and president of the AAGL, told HemOnc Today. “The elimination of cervical cytology and thereby ‘eliminating the Pap smear’ stands to risk the health of many unless we incorporate a significant public health and education initiative at the same time.”

In response to this criticism, Debbie Saslow, PhD, managing director of cancer control interventions for HPV and gynecologic cancers at ACS, told HemOnc Today that strong evidence supports the guideline changes.

“The update is based on decades of studies comparing the effectiveness of HPV testing with cytology and bolstered by evidence of the impact of HPV vaccination, including a dramatic decline in cervical precancers and, more recently, cervical cancers among young women,” she said. “Screening and management for the detection of cervical cancer and its precursors are based on a more robust understanding of the risk from persistent HPV infection.”

HemOnc Today spoke with gynecologic oncologists and cancer prevention experts about the implications of the changes to the American Cancer Society cervical cancer screening guidelines on current practice and well-woman care, how variations in guidelines from different medical societies contribute to confusion in this area, and the role of HPV vaccination in screening efforts.

Guideline variations

The intention of guideline recommendations is to maximize benefit while minimizing harm. But, guidance from medical societies on cervical cancer screening now vary in how they seek to achieve that.

Moreover, these societies are on different timelines to update their respective guidelines, which can add to the confusion.

ACS estimated that the switch to primary HPV testing starting at age 25 years would prevent 13% more cervical cancers and 7% more cervical cancer deaths than the previously recommended strategy of starting cytology — also known as Pap testing — at age 21 years.

The decision to push back screening initiation to age 25 years is based on a variety of factors, including the impact HPV vaccination has had in reducing the cervical cancer burden in younger women. Data published with the recommendation showed that only 0.8% of all new cervical cancer diagnoses occur among women aged 20 to 24 years, compared with 4% among those aged 25 to 29 years. Only 0.5% of cervical cancer deaths are attributed to those diagnosed among women aged 20 to 24 years, compared with 3% for those aged 25 to 29 years.

Following the update to ACS recommendations, Christopher M. Zahn, MD, FACOG, vice president of practice activities at American College of Obstetricians and Gynecologists (ACOG), released a statement that the organization would review its 2012 guidance to determine whether similar changes are needed.

“In the interim, ACOG affirms our current cervical cancer screening guidelines, which encompass all three cervical cancer screening strategies [high-risk HPV testing alone, cervical cytology alone and cotesting],” Zahn said. “ACOG’s current screening guidelines reflect a balance of benefit and potential harms and support shared decision-making between patients and their clinicians.

“The value of cervical cancer screening cannot be emphasized enough,” Zahn added. “The incidence of cervical cancer in the United States has decreased more than 50% in the past 30 years because of widespread screening. An evidence-based approach to cervical cancer screening will allow us to continue to build on this progress.”

The Society of Gynecologic Oncology (SGO) guidelines align with those of ACOG and the American Society of Colposcopy and Cervical Pathology (ASCCP), which recommend screening starting at age 21 years and continuing every 3 years until age 30 years. From age 30 to 65 years, women may switch to cotesting with the Pap plus HPV test every 5 years, or use the Pap test alone every 3 years if the HPV test is unavailable.

SGO, ACOG and ASCCP are now actively working on an update to their screening guidelines in response to ACS’s new recommendations, according to Amelia Jernigan, MD, division director of the department of gynecology oncology and associate professor of gynecologic oncology at LSU Healthcare Network in New Orleans.

“Cervical cancer screening recommendations evolve for a number of reasons — as certain factors change in the general population and as technology becomes more sophisticated, we change how frequently to screen and which screening tests to use,” Jernigan told HemOnc Today. “There will be tremendous resistance to the new American Cancer Society update within the gynecology community. Many were upset about pushing cervical cancer screening to age 21 years, so there will certainly be pushback about starting screening at age 25 years. Personally, I am not going to move the screening age to 25 years yet. But, it is coming, and we are going in that direction.”

Saslow said evidence shows many gynecologists were supportive of the prior change to start screening at age 21 years.

“Within 1 year of the recommendation, there was a 90% drop in screening prior to age 21 years, whereas usually it takes about 10 years for clinicians to change practice in response to a new guideline,” she said. “This is because the vast majority of gynecologists knew that screening prior to age 21 was harmful and was not beneficial.”

Yet another set of guidelines, from USPSTF, support cervical cancer screening via cervical cytology every 3 years among women aged 21 to 29 years. The guidance includes three sets of options for women aged 30 to 65 years: screening every 3 years with cervical cytology alone; HPV testing alone every 5 years; or cotesting — use of both the HPV test and Pap test — every 5 years.

“Recommendations will continue to evolve as new data evolve. Once published research meet our criteria, the USPSTF will review the topic again or if new data are not published within 5 to 6 years, we will review topics at that time,” Melissa A. Simon, MD, task force member and vice chair for clinical research in the department of obstetrics and gynecology at Northwestern University, told HemOnc Today. “Right now, there are several studies being conducted on HPV self-sampling and as those studies are published, then we would reevaluate the data and see if they will change our recommendations on cervical cancer screening. For now, it may still be another 2 years before we start the process of a new update to our most recent recommendations, published in 2018. It will then take another 2 years to go through the process to published an updated recommendation.”

Simon added that it is important to understand that these main recommendations are for asymptomatic women.

“If there is a symptom or a problem that a woman is presenting with, that places them in a separate category for screening altogether,” she said.

Jernigan said despite these variations in recommendations, one of the most important things for women to do in addition to receiving the HPV vaccine is to be seen regularly for wellness exams.

“The intervals in between screenings have become so lengthy that it is likely that recommendations will change between one cervical cancer screening and the next,” she said. “The most important thing to note is that a negative test does not mean that the patient does not need to come back to the office for another 5 years — women should continue to participate in annual exams for a variety of reasons other than an HPV test.

“We can certainly anticipate that as more individuals get vaccinated and as screening methods become more sophisticated, we will see these recommendations change in terms of how frequently we perform them, how they are administered and what type of follow-up is needed for an abnormal result,” Jernigan added.

HPV test ‘is simply better’

The Pap test had long been the standard for cervical cancer screening. However, studies have suggested cytology-based screening is less efficient for those who have undergone HPV vaccination, resulting in a high rate of false-positive results.

The HPV test emerged as an alternative — given that most cervical cancers are caused by HPV — after the FDA approved the test in 2014 and Huh and colleagues released guidance representing several medical societies on its use in 2015.

The rationale for recommending the HPV test as a primary screening tool is that it is superior to the Pap test, according to Bradley J. Monk, MD, FACS, FACOG, professor in the division of gynecologic oncology of Arizona Oncology-US Oncology Network at University of Arizona College of Medicine in Phoenix.

“Although cervical cancer screening is a shared decision-making process, it becomes challenging because there are a lot of factors to consider that are beyond a patient’s capacity to adjudicate,” Monk told HemOnc Today. “The overall message here should not be whether or not we perform the Pap test, but that the American Cancer Society reaffirms the importance that every patient who wants to be screened for cervical cancer needs an HPV test.

“With this being said, the value of the test among those aged younger than 25 years is limited because most of the tests will be false positives and associated with harm, hence the reason for upping the recommended age for screening,” Monk added. “Cervical cancer is extremely rare among those younger than 25 years and the risks associated with a false-positive test do not outweigh the benefit. The HPV test is a key component of cervical cancer screening in my practice.”

In response to a joint call to action by ASCO, USPSTF and ASCCP for clinical trials to assess primary HPV testing alone, Ogilvie and colleagues of the HPV FOCAL study compared the effect of primary HPV testing alone with liquid-based cytology screening for the prevention of grade 3 or higher cervical intraepithelial neoplasia (CIN3+) after 48 months.

Results, published in 2018 in JAMA, showed HPV testing within an organized cervical cancer screening program in Canada led to earlier detection of precancers than the Pap test.

Women screened for cervical cancer via primary HPV testing had a lower likelihood of developing CIN3+ lesions at 48 months than women who underwent standard cytology testing (incidence rate per 1,000, 2.3 vs. 5.5; RR = 0.42; 95% CI, 0.25-0.69). Ogilvie and colleagues also reported a reduction in CIN2+ lesions (incidence rate per 1,000, 5 vs. 10.6; RR = 0.47; 95% CI, 0.34-0.67).

“Whatever we do as physicians has to balance the benefit and potential harms,” Monk said. “The HPV test is proven to be more sensitive than cytology, detects more cancerous and precancerous lesions, and is simply better than the Pap test. The value in all of this is that it reinforces the importance of performing an HPV test at the recommended screening visit and it is irrational to perform a Pap test alone because the HPV test is more sensitive and finds more cases that cytology would miss. We should perform the HPV test alone, in combination with the Pap test, or only perform the Pap test if the HPV test comes back positive.”

Brown said the proposed idea of using HPV testing as a screening tool prior to performing cervical cytology is valid and that decreasing the frequency of HPV screening also may be economically appropriate and scientifically valid.

“From a scientific standpoint, HPV infects up to 80% of the population, often in adolescence and early adulthood, and is usually cleared prior to causing any abnormality,” Brown said. “Abnormal cytology found on a Pap smear is unlikely to be clinically relevant without a concurrent or preceding high-risk HPV test.”

Before a primary HPV test received FDA approval, cotesting originally was recommended by ACS in 2002 no more often than every 3 years for women aged 30 to 65 years, as it combines the sensitivity of the HPV test with the standard use of the Pap test.

However, data have suggested the combination approach does not improve the identification of cancers, while increasing costs and false-positive results.

Results of a study by Schiffman and colleagues showed that cotesting women for cervical cancer did not detect cancers that could not be identified by HPV screening alone. Prediagnostic HPV testing appeared more clinically sensitive than cytology for identifying women later diagnosed with cancer (76.7% vs. 59.1%; P < .001) and precancer (83.8% vs. 61.9%; P < .001).

Role of vaccination

Although ACS cites HPV vaccination as a reason for later screening initiation and longer intervals between screenings, most experts with whom HemOnc Today spoke cautioned that HPV vaccination rates are still not at their targets.

“The notion that HPV vaccination is one reason for screening later does not make sense because we have not achieved our national goal for HPV vaccination,” Anna R. Giuliano, PhD, founding director of the Center for Immunization and Infection Research in Cancer at Moffitt Cancer Center, told HemOnc Today. “If we were to reach our goal of 80% of vaccinating all males and females, then all the more reason why the HPV test as a primary test makes sense.”

ACS also updated its guideline on HPV vaccination in early July, stating that health care providers should begin offering routine HPV vaccination to children as young as age 9 years in order to increase rates of on-time administration.

The guideline — published in CA: A Cancer Journal for Clinicians — continues to recommend providers inform individuals aged 22 to 26 years that vaccination may not prevent as many cancers as it would for children and teens. It also does not support the 2019 Advisory Committee on Immunization Practices recommendation that vaccination be considered for certain adults aged 27 to 45 years.

“I do not agree with the American Cancer Society position on HPV vaccination for those aged older than 26 years — which is contrary to CDC guidelines for this age group — to not even discuss the opportunity with their providers. We do not have enough data for individuals aged older than 26 years to make a definitive statement for or against vaccine effectiveness,” Giuliano told HemOnc Today. “For mid-adult men, there is no way to prevent oropharyngeal cancer caused by HPV other than to vaccinate. As the median age at diagnosis of oropharyngeal cancer is 60 years, it is likely that vaccination for those aged 27 to 45 years may have a positive impact on the rising incidence of this cancer, which affects more than 12,000 men per year in the U.S. alone.

“HPV vaccine effectiveness data to date support this concept, and every study that has examined population-level effectiveness of the vaccine to prevent oral HPV infection has found profound reductions among vaccinated populations,” Giuliano added.

Moreover, a study published last month in The New England Journal of Medicine confirmed HPV vaccination prevents invasive cervical cancer. Lei and colleagues reported that receiving at least one dose of the quadrivalent HPV vaccine led to lower incidence of cervical cancer after adjustment for age at follow-up compared with no vaccination (incidence rate ratio, 0.51; 95% CI, 0.32-0.82).

Jernigan said no matter when cervical cancer screening is initiated, HPV vaccination is paramount.

“For any woman aged younger than 25 years, the most important thing we can do for them is vaccinate them — we need to make sure we are vaccinating women,” Jernigan said.

Monk agreed.

“We should emphasize that the best approach to cervical cancer prevention is vaccination,” he said. “We are all currently sitting here awaiting a COVID-19 vaccine to become available, but we have a life-saving HPV vaccine that people are not getting. It is irrational to not vaccinate a child against cancer.”

Access to preventive care

Experts with whom HemOnc Today spoke said extended intervals between cervical cancer screenings could prevent timely access to preventive care for many women.

“The authors of the American Cancer Society guidelines fail to realize that ‘going for a Pap smear’ is more than a cytological evaluation and that it is often the only time that a young woman seeks health care,” Brown said. “The gynecologist often is her only physician and her only portal to medical care. It is through the gynecologist that contraception is discussed, family planning occurs, endometriosis and other maladies are detected, and early obstetrical care is delivered — all on a scheduled annual basis.”

Saslow said the recommendations do not take away women’s access.

“We deliberately retained suboptimal screening strategies (cotesting and the Pap test alone) as acceptable options so that no one would have a problem accessing cervical screening,” Saslow said. “The American Cancer Society will be working with our partners and the health community from now until the next guideline update to ensure a transition to primary HPV testing with the goal of complete access so that we can discontinue cotesting and cytology.”

In the absence of a significant public health educational campaign, the elimination of the Pap smear in favor of an HPV test performed at infrequent intervals may prompt a significant decline in preventive health care, Brown said.

“This is a very slippery slope, and the long-term outcomes not only for cervical cancer incidence, but also for population health, may be devastating,” she said. “The economic gains of eliminating the Pap may be quickly outpaced by unforeseen costs due to a decrease in preventive care, cancer screening and contraception. Therefore, to suggest an abrupt change in cervical cancer screening may have long-lasting, unanticipated effects. Prior to adoption of a health care model, the downstream effects of such changes require extensive discussion from experts in the field of gynecology and public health that focus on the woman as a whole person and not just the cells of her cervix.”

Saslow said the ACS guideline calls for a transition period in order to incorporate public health and education initiatives, allowing for Pap testing during that transition.

“HPV testing is far superior to Pap testing and will only stand to benefit health, not risk it,” she added.

Giuliano said it is understandable that gynecologists may be wary of the longer time between screenings because they want to be able to have contact with their patients annually.

“The gynecologic community needs to come together and figure out the additional tests and procedures that they perform in addition to the HPV test and/or Pap test, and they should communicate this to women to encourage them to come in for an office visit annually, instead of once every 5 years,” she said. “This will create balance. Women will still have a routine schedule to see a physician once per year and connect with health care, and we will also have the optimal approach to cervical cancer screening at the same time. There are other reasons why a woman needs to seek a health care provider annually other than cervical cancer screening.”

There are many reasons for a woman to go a physician outside of getting a Pap test, Monk said.

“Women need mammograms, birth control pills, cholesterol checks, bone densitometry and more,” he said. “The idea that the only health care a 40-year-old woman needs is a Pap test is misguided. When a woman goes in for her annual exam, she needs a comprehensive physical examination, not just cervical cancer screening. There was a time when ACOG recommended gynecologists to be prepared and trained to perform a comprehensive evaluation. This has evolved and the opposite is now true where the primary care provider needs to be prepared to conduct an HPV test on the cervix.”

Saslow noted that, despite these debates, the ACS guidelines were the product of a multiorganization collaboration.

“SGO and ACOG, along with more than two dozen other organizations, reviewed and provided feedback that was incorporated into the ACS recommendations,” she said. “Many of their members served as individual expert reviewers. These organizations have partnered with ACS on cervical cancer screening issues for at least as long as I have been doing this work at ACS, which is since 1997. The emphasis should be on building support for improving women’s health and the vast amount of evidence that supports the recommendations, not on controversy.”

Overall wellness should not be ignored, Simon said.

“It is unfortunate that annual well-woman checkups are linked to one screening test, because going to a physician is not just about cervical cancer screening,” she said. “Annual check-ups should include a broader discussion about total overall health.

“A cervix is only one body part of many that need attention,” Simon added. “The thought process behind women not going to the doctor every year because they are not getting a Pap test does not make sense, and I hope that individuals can move forward with the approach to total overall health. It makes me sad to hear that it may be the only time a woman seeks care. Total body health care needs to be thought of more than only the health of a cervix.”

References:

ACOG statement on cervical cancer screening guidelines. Available at: www.acog.org/news/news-releases/2020/07/acog-statement-on-cervical-cancer-screening-guidelines. Accessed Oct. 5, 2020.

Fontham ETH, et al. CA Cancer J Clin. 2020;doi:10.3322/caac.21628.

Huh WK, et al. Gynecol Oncol. 2015;doi:10.1016/j.ygyno.2014.12.022.

Lei J, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1917338.

Massad LS. JAMA. 2018;doi:10.1001/jama.2018.7911.

Ogilvie GS, et al. JAMA. 2018;doi:10.1001/jama.2018.7464.

Saslow D, et al. CA Cancer J Clin. 2020;doi:10.3322/caac.21616.

Schiffman M, et al. J Natl Cancer Inst. 2017;doi:10.1093/jnci/djx225.

USPSTF. JAMA. 2018;doi:10.1001/jama.2018.10897.

For more information:

Jubilee Brown, MD, can be reached at Levine Cancer Institute at Atrium Health, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: jubilee.brown@atriumhealth.org.

Anna R. Giuliano, PhD, can be reached at Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612.

Amelia Jernigan, MD, can be reached at LSU Healthcare Network, 8585 Picardy Ave., Suite 313, Baton Rouge, LA 70809; email: amelia.jernigan@gmail.com.

Bradley J. Monk, MD, FACS, FACOG, can be reached at Phoenix - Biltmore Cancer Center, 2222 E. Highland Ave. #400, Phoenix, AZ 85016 ; email: bmonk@gog.org.

Debbie Saslow, PhD, can be reached at American Cancer Society, 250 Williams St., Suite 600, Atlanta, GA 30303; email: debbie.saslow@cancer.org.

Melissa A. Simon, MD, can be reached at Northwestern University, 633 N. St. Clair St., Suite 1800, Chicago, IL 60611.