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.