Is 58% sensitivity for detection of cervical intraepithelial neoplasia 3 and invasive cervical cancer optimal for cervical screening?

Abstract

Recent Food and Drug Administration (FDA) approval of a Roche cobas human papillomavirus (HPV) test application as a first line primary cervical screening tool in women 25 and older introduces a new era of complex cervical screening choices. Perhaps the most surprising findings in Roche's supporting ATHENA trial data were the unexpectedly low verification bias-adjusted CIN3+ sensitivities documented by the FDA for both the proposed cobas HPV testing algorithm (58.26%) and Pap testing algorithm (42.63%). These unexpectedly low sensitivity estimates suggest intuitively that there is still considerable room for improvement in cervical screening, and available data from large systems point to routine cytology and HPV co-testing as offering the greatest protection against development of cervical cancer. Observational studies of large populations screened over time remain essential to document actual protection from development of cervical cancer with any new cervical screening options, as natural history studies and available data from large systems indicate that most CIN2/3 cases detected in short term clinical trials would not progress to invasive cervical cancer. Interpretation of ATHENA trial data and its application to routine clinical practice is further limited by published studies which document that a significant proportion of CIN2/3 biopsy diagnoses in the ATHENA trial could not be confirmed as accurate when evaluated with p16 immunohistochemistry and that cytology laboratory performance in the trial was notably suboptimal.

Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices

“…HPV‐only primary screening for cervical cancer presents many challenges for clinicians. Questions arise regarding its effectiveness, its long‐term risk, and when it is the best option for a particular patient . Clinicians had similar questions when cotesting was first recommended for women aged ≥30 years in 2006.…”

“…With more than 250,000 samples, we sought to compare the 3 screening approaches based on cervical biopsy results, including squamous cell carcinoma, adenocarcinoma, and cervical intraepithelial neoplasia (CIN) grade 3 or greater (≥CIN3). Our objective was to provide practical clinical data to inform the discussion regarding the choice of an appropriate cervical cancer screening methodology and to help determine the most effective screening method for the early detection and appropriate treatment of cervical cancer …”

PAX1 and SOX1 methylation as an initial screening method for cervical cancer: a meta-analysis of individual studies in Asians

“…The introduction of cytology screening (Pap smear) has greatly reduced the mortality and morbidity rates for patients with invasive cervical cancers in the past decades. However, it has been demonstrated that the accuracy of Pap smear test ranged from 20% to 80%, and the results varied substantially in areas with different screening infrastructures, which therefore limited its efficacy for cervical cancer diagnosis (3)(4)(5)(6). Persistently infected by human papillomavirus (HPV) with high risk type remains the major pathogens of cervical cancer, as a result, HPV DNA testing has been adopted for the triage of patients with atypical squamous cells of undetermined significance (2,4,(7)(8)(9).…”

Relevance of the Pap Test: A Report of HPV-DNA Test-Negative High-Grade Squamous Intraepithelial Lesions of the Female Lower Genital Tract

“…Primary screening with only HPV testing has been challenged by some authors who have highlighted the improved detection by cotesting and suggested it is insufficiently sensitive alone [19,27,28,29]. Amidst the controversy, the characteristics of HPV screening test-negative cases with cytology positive for dysplasia remain ill-defined.…”