HPV TESTING FOR WOMEN OVER 35

January 21, 2010 — For women 35 years of age or older, human papillomavirus (HPV)-based screening is more effective in detecting high-grade lesions and preventing invasive cervical cancer than cytology. However, this screening modality is less effective in younger women because it can lead to overdiagnosis of cervical intraepithelial neoplasia (CIN), which is likely to regress on its own.

In a study published online January 19 in the Lancet Oncology, the researchers conclude that for women older than 35 years, HPV testing should replace cytology in routine screening.

An accompanying editorial notes that HPV testing "shows a great deal of promise to revolutionize cervical cancer screening, especially in developing countries."

In the first part of the trial, a similar number of invasive cancers were detected in the group screened with cytology (n = 9) and that screened with HPV testing (n = 7). But in the second round of screening, there were no invasive cancers detected in the HPV group and 9 in the cytology group, suggesting that HPV-based screening is more effective in preventing progression to cancer because of earlier detection of clinically relevant lesions and treatment of precancers.

"I think that there is sufficient evidence to shift to stand-alone HPV testing," said lead author Guglielmo Ronco, MD, from the Centro per la Prevenzione Oncologica in Turin, Italy. "Cytology should be used only to triage HPV-positive women."

In countries that have population-based screening programs, plausible pilot programs are advisable for making the transition, he told Medscape Oncology. This will help to assess costs and quality assurance and to determine the best method of communicating with women.

"In addition," explained Dr. Ronco, "there is a need for training professionals; the application of appropriate assessment protocols of HPV-positive women is crucial."

Extended Screening Intervals and No Changes for Younger Women

Dr. Ronco does not recommend any changes in the screening paradigm for younger women. "For the moment, they should continue with Pap [tests]," he said. "In the future, research on biomarkers could allow us to identify which CIN2 cases have the potential to progress, so as to avoid overtreatment."

"However," he added, "that is not possible at the moment."

The researchers also conclude that intervals between screenings can be extended with HPV testing, but more follow-up is needed to define how long screening intervals can be safely extended. "In my view, there is already evidence to say that 5-year intervals are safe," said Dr. Ronco.

HPV testing is more sensitive but less specific than cytology for detecting high-grade CIN. As previously reported by Medscape Oncology, when HPV DNA testing is used as a primary screening strategy, followed by cytological triage and repeat screening for persistent HPV type-specific infection, the accuracy of cervical cancer screening could be increased.

HPV testing might also be the most effective method of cervical cancer screening in low-resource settings, where it has been shown to significantly reduce the incidence of invasive cervical cancer (N Engl J Med. 2009;360:1385-1394).

Improved Detection With HPV Test

In the current study, Dr. Ronco and colleagues assessed the efficacy of different HPV-based screening policies and the most appropriate age of application. Their large phase 3 randomized trial consisted of 2 rounds of screening for each of 2 separate recruitment phases. The primary end point was the detection of CIN2/3 and invasive cervical cancers during the first and second screening rounds.

For both trial phases, 47,001 women were randomly assigned to cytology and 47,369 to HPV testing. Of this group, 33,851 women from the cytology group and 32,998 from the HPV-testing group participated in a second round of screening.

During the first phase, HPV-positive women 35 to 60 years old were referred to colposcopy, whereas those 25 to 34 years old were referred to colposcopy only if cytology was abnormal or HPV testing was persistently positive. In the second phase, participants in the HPV group were referred for colposcopy if the HPV test was positive. Each phase consisted of 2 rounds of screening, and all women underwent cytology testing only in the second round.

In the 2 rounds of screening, 18 invasive cancers were detected in the cytology group and 7 were detected in the HPV group (P = .028). All participants who were subsequently diagnosed with invasive carcinoma in the second round had normal cytology in the first round.

For women 35 to 60 years of age, the detection of CIN2 or CIN3 was significantly higher in the HPV group than in the cytology group, with a detection ratio of 2.03 (95% confidence interval [CI], 1.60 - 2.57), during the first screening round. Conversely, in the second round, the relative detection ratio for CIN2/3 was significantly lower in the HPV group than in the cytology group (detection ratio, 0.51; 95% CI, 0.28 - 0.93).

Overall, the ratio between the HPV group and the cytology group was 1.66 (95% CI, 1.34 - 2.06) for the total detection of disease during the first 2 screening rounds, and results were similar for the detection of CIN2 and CIN3.

Among women 25 to 34 years of age, the researchers observed a significant difference between the 2 recruitment phases in the relative detection of CIN3 with HPV testing. In phase 1, the detection ratio between groups was close to 1 during both the first and the second rounds. In the second phase, the detection of CIN3 was much higher in the HPV group than in the cytology group during the first screening round, and lower in the second round.

In phase 2, the total detection ratio of CIN3 for both screening rounds was 2.14 (95% CI, 1.28 - 3.59) for HPV vs cytology. For CIN2, when both phases were pooled, the detection ratio was 4.09 (95% CI, 2.24 - 7.48) for HPV vs cytology in round 1, and 0.64 (95% CI, 0.23 - 1.27) in round 2.

Shows Promise, Research Needed to Optimize Strategy

In an accompanying editorial, Philip E. Castle, PhD, MPH, and Hormuzd A. Katki, PhD, both from the National Cancer Institute in Bethesda, Maryland, write that HPV testing has the potential to "revolutionize" cervical cancer screening. However, there is still room for improvement, they add, by reducing the number of prophylactic treatment procedures and improving the management of equivocal disease of low invasive potential.

"We advocate that clinical management be based on estimating a woman's individual risk of cervical precancer, rather than complex algorithms," they write. "Data from the current study could be used to develop risk estimates to make the promise of more effective and cost-effective cervical cancer prevention a reality."

Dr. Ronco agrees. "We are conducting a full cost-effectiveness analysis and, clearly, prolonged screening intervals will contribute to reducing the overall costs," he said. "Another point is the economic and human cost of diagnostic work-up and treatment."

"Appropriate management of HPV-positive women is crucial and, clearly, these women should not be directly referred to colposcopy," Dr. Ronco added. "Nevertheless, there is a need for research in order to optimize screening, and I expect substantial improvements in this field in the near future."

The study was funded by the European Union; the Italian Ministry of Health; the Regional Health Administrations of Piemonte, Tuscany, Veneto, and Emilia-Romagna; and the Public Health Agency of Lazio. Dr. Ronco reports being an occasional adviser to Gen-Probe. One of his coauthors, Jack Cuzick, PhD, from Queen Mary University in London, United Kingdom, reports being an occasional adviser to Qiagen, Roche, Gen-Probe, and Abbot, another coauthor, Francesca Carozzi, PhD, from the Institute for Cancer Study and Prevention in Florence, Italy, reports being an occasional adviser to Gen-Probe, Abbott, Sanofi, and GlaxoSmithKline. The editorialists have disclosed no relevant financial relationships.

Lancet Oncol. Published online January 19, 2010.