2016 Update on cervical disease

Primary HPV screening shows up to 70% greater protection against invasive cervical cancer than cytology
_{Ronco G, Dillner J, Elfstrom KM; International HPV Screening Working Group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383(9916):424-532.}

In my 2015 "Update on Cervical Disease,"⁸ I discussed the newly published interim guidance for managing abnormal screening results for cervical cancer from a collective expert panel from the American Society for Colposcopy and Cervical Pathology, Society of Gynecologic Oncology, the American College of Obstetricians and Gynecologists, and 4 more societies.⁹ The guidelines support use of HPV testing alone or with the Papanicolaou test. In 2016, follow-up data from 4 RCTs provide long-term data on the efficacy of HPV primary testing.

Details of the trial
Incidence of invasive cervical cancer was the endpoint in 4 European trials comparing HPV-based with cytology-based screening. In total, 176,464 women aged 20 to 64 years were randomly assigned to either screening strategy. Median follow-up was 6.5 years (1,214,415 person-years). Using screening, pathology, and cancer registries investigators identified 107 invasive cervical carcinomas, with masked review of histologic specimens and reports.

Investigators calculated the rate ratios (defined as the cancer detection rate in the primary HPV testing-based versus cytology-based arms) for incidence of invasive cervical cancer. During the first 2.5 years of follow-up, detection of invasive cancer was similar between screening methods (0.79, 0.46-1.36). Thereafter, however, cumulative cancer detection was lower in the primary HPV testing-based arm (0.45; 95% CI, 0.25-0.81).

At 3.5 and 5.5 years after a negative cytology test on entry, cumulative cancer incidence was 15.4 per 10⁵ (95% CI, 7.9-27.0) and 36.0 per 10⁵ (23.2-53.5), respectively. At 3.5 and 5.5 years after a negative HPV test on entry, cumulative cancer incidence was 4.6 per 10⁵ (1.1-12.1) and 8.7 per 10⁵ (3.3-18.6), respectively (FIGURE 3).

FIGURE 3 Cumulative detection of invasive cervical carcinoma

*Observations are censored 2.5 years after CIN2 or CIN3 detection, if any. Experimental arm = primary HPV testing−based screening; control arm = cytology-based screening. Reprinted from The Lancet, 383(9916), Ronco G, Dillner J, Elfstrom KM; International HPV Screening Working Group, Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomized controlled trials, 424–532, Copyright 2014, with permission from Elsevier. The rate ratio for invasive cervical carcinoma among all women from recruitment to end of follow-up was 0.60 (95% CI, 0.40-0.89), with no heterogeneity between studies (P = .52). Detection of invasive cervical carcinoma was similar between screening methods during the first 2.5 years of follow-up (0.79, 0.46-1.36) but was significantly lower in the experimental arm thereafter (0.45, 0.25-0.81). Among women with a negative screening test at entry, the rate ratio was 0.30 (0.15-0.60). Ronco and colleagues concluded that primary HPV testing-based screening provides 60% to 70% greater protection against invasive cervical cancers than cytology.

What this EVIDENCE means for practice
The 4 studies in this report were completed across Europe (in England, Netherlands, Sweden, and Italy): different regions, different sites, hospitals, and screening systems. The women in Europe are not any different than the women in the United States in terms of rates of HPV and age and incidence of HPV. Therefore, these results are globally generalizable.

The US trial by Wright and colleagues10 that led to US Food and Drug Administration approval of HPV primary testing was different than this European study in that all trial sites had to perform screening in the same way. In addition, the end point was high-grade dysplasia; in this trial by Ronco and colleagues the end point is cancer. These current investigators found no difference with either screening arm in terms of detection of invasive cervical cancer. Even more interesting is that, over time, the cervical cancer rates in the primary HPV testing-based arm were much less than that in the cytology-based arm.

The real strengths of this study are the long-term follow-up and the study size. We are not likely to see validation cohorts this big again. This study demonstrates that, overall, we should be able to continue to reduce the incidence of invasive cervical cancer with a primary HPV testing-based screening strategy.

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