Current Treatments for Cervical Dysplasia and their Limitations
Treatments for pre-cancerous cervical lesions developed over the past
five decades, are responsible for reducing the incidence and mortality
of cervical cancer in developed countries over the same period of
time12,13 (Kitchener et al., 2006; Peto et al., 2004).
Essentially, treatment uses ablative methods such as cryotherapy, laser
ablation and electrocautery. Alternatively, excisional methods such as
loop electrosurgical excision procedure (LEEP) (or large loop excision
of the transformation zone (LLETZ)) and cold knife cone biopsy (CKC)
(also known as conization) can be used, depending on the extent and
severity of the lesion. Ablative methods destroy the precancerous cells
in the transformation zone by necrosis, with no anaesthetic required,
and no tissue is removed. Excisional methods involve removal of the
precancerous lesion under either local or general anaesthetic, together
with a margin of healthy tissue, which can be sent for histological
evaluation. LEEP and CKC are performed by an experienced clinician,
generally an obstetrician/gynaecologist who can recognize and manage
complications, and in a facility where surgical back-up is available if
required 14. This limits the use of excisional methods
as treatments in LMICs 14. Whilst these surgical
procedures remove the neoplasia, they do not target the cause of these
lesions, which is persistent HPV infection. Recurrence rates for
cervical intraepithelial neoplasia (CIN) after treatment is between
5-26% 15,16.
There are advantages and disadvantages associated with each of the
techniques used, for example there is an increase in major and minor
bleeding with LEEP compared to CKC, however there is a decreased risk of
major infection with LEEP compared with CKC 17. CKC
has the lowest recurrence rate of CIN 2+ when compared with LEEP and
cryotherapy 17. However, CKC is associated with other
complications such as major infection (including pelvic inflammatory
disease) and increased risk of premature labour 17. A
meta-analysis on perinatal mortality and adverse pregnancy outcomes
showed that cold knife conization, laser conization and radical
diathermy were associated with a significantly increased risk of
peri-natal mortality, pre-term delivery, low birthweight18,19, premature rupture of membranes and caesarean
section 18. While the literature is not consistent
about effects of excisional therapy on fertility, and a meta-analysis20 found no evidence to support an effect on fertility
outcomes, there was evidence that excisional therapy increased the risk
of a second trimester miscarriage possibly due to cervical incompetence
after large excisions.
A further complication in LMIC is that while excisional therapy is
effective treatment for cervical dysplasia in immunocompetent patients,
it seems to be effective only in slowing progression to cervical cancer
in HIV positive women. The recurrence rates for women with HIV are much
higher than for HIV negative women, even in the Highly Active
Anti-retroviral Therapy (HAART) era, with studies showing recurrence
rates of up to 63% 21–24. Fruchter et al., reported
that 90% of HIV-infected women with CD4 counts less than 200
cellsmm-3 developed recurrent dysplasia at 3 years21. While antiretroviral therapy may delay the
recurrence of HPV-related disease in HIV positive women, immune
restoration on HAART is insufficient to clear HPV because HPV DNA
persists in patients on HAART 25. Furthermore, the
incidence of invasive cervical cancer has remained constant since the
introduction of HAART 26, and treatment with HAART has
failed to eradicate CIN in many HIV-infected women 27.
As a result, definitive management with hysterectomy has been advocated
for eradication of cervical dysplasia in HIV positive women.
Recent data suggests that most CIN2 lesions regress spontaneously,
particularly in young women, under 30 years 28. This
means that the reclassification of CIN2 and CIN3 as high grade squamous
intraepithelial lesion (HSIL) has huge implications for many women,
especially young women in their reproductive years. There is a
possibility that spontaneously regressing lesions could be classified as
high grade lesions that warrant treatment and the attendant increased
risks of reproductive morbidity 1817. Taken together, there is a clear case for
developing locoregional medical therapies in LMIC based on the “screen
and treat” approach. Simple screening using VIA combined with
application of the treatment directly to the surface of the cervix,
would circumvent the issues of delayed diagnosis, low follow-up rates,
the high risk of infection or adverse pregnancy outcomes attendant with
current practice.