Discussion:
Why is adjuvant vaccination to cervical surgery an important issue? First, despite the availability of highly effective preventive vaccination, cervical dysplasia remains a massive problem worldwide, the HPV vaccination uptake in most countries is relatively low, estimated around 40% globally [28]. Secondly, most women are at reproductive age when diagnosed with cervical dysplasia. A relationship between cervical surgery and premature birth has been shown in many studies. The risk of premature birth is even higher after multiple treatments. Furthermore, the great emotional impact on the parents, the lifelong consequences in the prematurely born child with additional costs are considerably underestimated (15, 27).
The beneficial effect of prophylactic HPV vaccines for the primary prevention of HPV-related diseases has been confirmed by several studies (5). Still, the possible positive effect of adjuvant vaccination combined with surgical treatment has not been proven yet. Vaccination only in HPV-positive women with high grade cervical dysplasia did not reduce the incidence of cervical lesions (28). Nonetheless, there is increasing evidence that prophylactic HPV vaccinations in addition to usual treatment are of added value in the clinical manifestations of this virus. This holds not only for cervical premalignant lesions but also for other HPV-related clinical diseases.
The studies by Kang et al, and Ghelardi et al. both have their limitations regarding the methodology and outcome. In both studies, the women could decide for themselves whether to wanted be vaccinated, which may have resulted in selection bias. The study form Kang et al. concerned retrospective data and was primarily not designed to answer the question if adjuvant vaccination is beneficial. But despite the limitations, these studies show that vaccination is an independent risk factor for the recurrence of CIN2+ lesions. There is sufficient reason, there to further explore whether adjuvant vaccination is beneficial to prevent recurrence.
Joura et al. pooled data of 2 studies (FUTURE I and II); analysis revealed a significant decrease in the incidence of HPV-related diseases (cervical, vulvar and vaginal intraepithelial neoplasia and genital warts) when quadrivalent vaccination was given after LEEP treatment. This is a promising effect, which was only seen, irrespective of HPV type. The diseases related to the vaccine HPV-types, only the decrease in the occurrence of genital warts was significant. Although this study has some limitations, the authors concluded that vaccination has a positive effect to prevent recurrence possibly as a result of cross-protection. The subsequent abnormalities were predominantly low-grade abnormalities and occurred significantly less frequently with vaccination, especially after surgery. Like Joura et al. Garland et al., describe a promising ‘secondary’ benefit of vaccination for recurrent CIN2+ lesions, regardless of HPV-type. In contrast to Joura et al., however, they reported no reduction in the frequency of low-grade lesions but suggested a high chance for these lesions to regress spontaneously. The vaccine ought to protect against de novo HPV infection. The authors also suggest that the effect of cross-protection between different types of HPV may play a role. In addition, the effect relies on a possible boost of the immune response after vaccination.
Hildesheim et al., performed the same evaluation but found no evidence of viral clearance for the different HPV types and no difference in post-LEEP infections between the HPV types. Although they concluded that benefit of vaccination was not shown, both in results section and in the discussion section they refer to a significant vaccination effect to protect women for new HPV types. Furthermore they suggest possible selection bias. Characteristics of the two study groups were not similar at baseline and only 38% of the patients were HPV 16 or HPV 18 positive at baseline.
All three studies above mentioned studies were not designed nor intended to address the effect on the vaccination after LEEP and, in addition, were not powered for this aim. They included the same, young population with a follow-up until 48 months for the primary study. The recurrence after LEEP (or other treatment) was evaluated after 60 days. The HPV is more easily cleared in younger patients than older patients. The follow-up period was very short with difficulty whether it is recurrence or residual disease. Furthermore, the vaccination was not administered during LEEP treatment period. In all three studies, the LEEP performed, if needed, in the follow-up period. Both Garland et al. and Joura et al. concluded that women who undergo surgical therapy after prior HPV vaccination have a lower risk of developing subsequent residual/recurrent CIN2+ compared to non-vaccinated women.
The two cases reported by Giannella et al. nicely illustrate the skepticism towards administration of the HPV vaccine after LEEP treatment. As case reports may cause bias, this report was not included in our meta-analysis.
For our meta-analysis we chose to have two separate analyses. The three post-hoc analyses are comparable in design and method, as well as the studies from Kang et al. and Ghelardi et al.
The discussion about a possible positive effect of adjuvant vaccination additional to regular treatment is still ongoing. Investigators in search of a vaccine against HPV noted an increased immune response with higher CD4+ and CD8+ T-cell activity after vaccination for severe dysplasia of the cervix (29, 30). This would imply that women in whom the HPV was not spontaneously cleared now have the antibodies from the vaccine. Another logical explanation for the positive adjuvant vaccination effect is the prevention of de novo HPV infections and re-infections.