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.