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Summary

In a comprehensive review, Velentzis and colleagues addressed a very topical issue, namely the prophylactic use of the HPV vaccine after treatment for high-grade cervical intraepithelial neoplasia (CIN) [1]. As pointed out by the authors, the percentage of recurrence of CIN2+ after treatment ranges from 2.5% to 18% [2, 3]. Furthermore, it is reported that up to 23.1% of women undergoing excisional treatment reveal positive surgical margins, which, in addition to the persistence of HPV infection, represent the two main predictors of disease recurrence [4]. Finally, it is stressed that women treated for high-grade CIN are more at risk of subsequent cervical cancer than the general population for the next 10-25 years [5]. Given the “numbers” mentioned above, the evaluation of a possible role of HPV vaccines to further reduce post-treatment CIN2+ has its rationale. The studies on the effectiveness of HPV vaccines after local treatment have been reported. In a non-randomized observational study including 737 women, Kang et al. showed a lower recurrence rate of high-grade lesions in vaccinated women (quadrivalent vaccine) than in non-vaccinated women (2.5% versus 7.2%, respectively) [6]. Likewise, in a similar study, other authors found a decreased recurrence of CIN2+ in vaccinated women (quadrivalent vaccine) compared to non-vaccinated women in a sample of 350 patients (1.2% versus 6.4%, respectively) [7]. The authors rightly conclude that, although there is evidence that the post-treatment HPV vaccine reduces recurrences, the lack of a randomized controlled trial represents a significant gap.

Commentary

This is a fascinating article addressing a topic of keen interest based on the evidence present in the literature. Women undergoing excisional treatment for high-grade CIN represent a high-risk group of patients with cervical disease [8]. Besides, women with disease recurrence are particularly sensitive to post-treatment HPV infections [9]. The latter could be infections due to incomplete excision of the primary cervical lesion or by new acquisition. To date, there is indirect evidence on the efficacy of the post-treatment HPV vaccine [9]. The absence of a randomized controlled trial on this topic represents a relevant gap that needs to be filled [1]. In this regard, the NOVEL trial, scheduled to begin on November 1, 2019, and will be completed on July 31, 2023 (https://clinicaltrials.gov/ct2/show/NCT03979014) will hopefully shed some light on the subject. An Italian randomized controlled trial (HOPE9, https://clinicaltrials.gov/ct2/show/NCT03848039?term=ghelardi&rank=1), the aim of which is to evaluate the efficacy of 9-valent HPV vaccination in preventing recurrence of CIN2+ in participants treated for high-grade CIN, is also under way. It will be interesting to know if the vaccination is cost-effective for all women undergoing local treatment, or only for those women with post-treatment negative HPV. However, in the meantime, while awaiting the results of these studies, post-treatment HPV vaccination should be offered to women, provided that a correct counselling is made about the available evidence of efficacy.

Author(s)

  • Luca Giannella
    Woman’s Health Sciences Department, Gynecologic Section, Polytechnic University of Marche, Ancona, Italy.

Citations

  1. Velentzis LS, Brotherton JML, Canfell K. Recurrent disease after treatment for cervical pre-cancer: determining whether prophylactic HPV vaccination could play a role in prevention of secondary lesions. Climacteric 2019; 22:596-602.
    https://www.ncbi.nlm.nih.gov/pubmed/31030590
  2. Tan JH, Garland SM, Tabrizi SN, Moore EE, Danielewski JA, Quinn MA. Hybrid Capture II testing for high-risk human papillomavirus DNA in the follow-up of women treated for high-grade cervical intraepithelial neoplasia. J Low Genit Tract Dis 2013;17:308–14.
    https://www.ncbi.nlm.nih.gov/pubmed/23552206
  3. Arbyn M, Ronco G, Anttila A, Meijer CJ, Poljak M, Ogilvie G, Koliopoulos G, Naucler P, Sankaranarayanan R, Peto J. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine 2012;30: Suppl F88–99.
    https://www.ncbi.nlm.nih.gov/pubmed/23199969
  4. Arbyn M, Redman CWE, Verdoodt F, Kyrgiou M, Tzafetas M, Ghaem-Maghami S, Petry KU, Leeson S, Bergeron C, Nieminen P, Gondry J, Reich O, Moss EL. Incomplete excision of cervical precancer as a predictor of treatment failure: a systematic review and meta-analysis. Lancet Oncol 2017;18:1665–79.
    https://www.ncbi.nlm.nih.gov/pubmed/29126708
  5. Kocken M, Helmerhorst TJ, Berkhof J, Louwers JA, Nobbenhuis MA, Bais AG, Hogewoning CJ, Zaal A, Verheijen RH, Snijders PJ, Meijer CJ. Risk of recurrent high grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol 2011;12:441–50.
    https://www.ncbi.nlm.nih.gov/pubmed/21530398
  6. Kang WD, Choi HS, Kim SM. Is vaccination with quadrivalent HPV vaccine after loop electrosurgical excision procedure effective in preventing recurrence in patients with high-grade cervical intraepithelial neoplasia (CIN2-3)? Gynecol Oncol. 2013;130:264-8.
    https://www.ncbi.nlm.nih.gov/pubmed/23623831
  7. Ghelardi A, Parazzini F, Martella F, Pieralli A, Bay P, Tonetti A, Svelato A, Bertacca G, Lombardi S, Joura EA. SPERANZA project: HPV vaccination after treatment for CIN2. Gynecol Oncol. 2018;151:229-234.
    https://www.ncbi.nlm.nih.gov/pubmed/30197061
  8. Ebisch RMF, Rutten DWE, IntHout J, Melchers WJG, Massuger LFAG, Bulten J, Bekkers RLM, Siebers AG. Long-lasting increased risk of human papillomavirus-related carcinomas and premalignancies after cervical intraepithelial neoplasia grade 3: a population-based cohort study. J Clin Oncol. 2017; 35: 2542–2550.
    https://www.ncbi.nlm.nih.gov/pubmed/28541790
  9. Joura EA, Kyrgiou M, Bosch FX, Kesic V, Niemenen P, Redman CW, Gultekin M. Human papillomavirus vaccination: The ESGO-EFC position paper of the European Society of Gynaecologic Oncology and the European Federation for colposcopy. Eur J Cancer 2019;116:21-26.
    https://www.ncbi.nlm.nih.gov/pubmed/31163338
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