Chemoresistance in Cervical Cancer Therapy
Currently, invasive cervical cancer is treated with surgery or radiation
combined with a platinum-based chemotherapy. The most effective
chemotherapeutic agent used in cervical cancer treatment is Cisplatin,
which can be used either as a single agent or in combination with other
therapeutic agents, e.g. 5-Fluorouracil 29. More
advanced stages of cervical cancer are treated by chemotherapy,
including metastatic disease, as well as patients with persistent, or
recurrent disease. Unfortunately these patients typically have a poor
prognosis because cancer cells can develop resistance to the
chemotherapy agents 30. One of the main obstacles in
the treatment of late-stage cervical cancer is resistance which develops
to chemotherapeutic agents 31. An increase in the
number of available chemotherapeutic agents has resulted in increased
resistance in cancer cells as more exposure to medications makes tumour
cells more prone to developing drug resistance which subsequently leads
to widespread metastasis 29.
Cisplatin interacts with DNA molecules to form cross-linked DNA
“adducts” which in turn activate several downstream molecular pathways
including p53 and MAPK, ultimately resulting in apoptosis29. Chemo-resistance arises in cancer cells via the
downregulation of tumour suppressors and the stabilization or activation
of cell survival factors 32 including increased DNA
repair, decreased uptake of drug into the tumour cells and increased
inactivation of drug 29. These mechanisms lead to less
apoptosis in cancer cells, resulting in unchecked tumour replication and
spread of malignancy 33,34.
Most women in Africa present with late-stage cervical cancer when
chemo-radiotherapy becomes the only option for curative or palliative
treatment. A recent study of 2760 patients from 11 African countries
found that 65.8% had stage III-IV disease 35. In
Zimbabwe, 76% of women present at the later stages of the disease37. Patients who present with late stage disease have
poorer outcomes. The 5-year overall survival for stage III-IV cervical
cancer as determined from nine African registries was 20.5%36 compared to 50.3% for stage I-II cervical cancer35. Moreover, it is estimated that only 8% of The
International Federation of Gynaecologists and Obstetricians (FIGO)
stage I-III patients in Africa receive guideline-adherent care due to
lack of access to treatment facilities. While an estimated 55% of new
of cancer diagnoses in Africa could be treated by radiotherapy, there
are no available radiation facilities in 26 of 54 African countries38. In countries where they do exist, they are
inaccessible to most patients because they are either located in
tertiary institutions, are non-functional or poorly maintained, or they
are available only in the private sector at a cost out of reach for most
patients 38. Late-stage disease presentation in
addition to poor access to radiotherapy means that therapeutic options
for advanced presentations are increasingly limited to chemotherapy
alone, further compounding the problem of chemoresistance.
Overcoming drug resistance is an important approach in cancer research,
and various agents including phytochemicals have been investigated as
potential bioactive agents in the arsenal of the war against cancer. For
example, curcumin sensitizes cervical cancer cells to paclitaxel
treatment and inhibits pathways involved in cellular proliferation and
survival in vivo 39. It also plays a role in
the reversal of resistance to cisplatin in cervical cancer cells40. An indirect but logical way of mitigating the
effects of multi drug resistance in cervical cancer is to focus on early
detection of cervical lesions and early intervention to prevent
progression to late-stage disease. This strategy has a three-fold
advantage. Firstly, targeting early lesions which have not breached the
basement membrane and are contained to the epithelium offer a
pharmacokinetic advantage for a loco-regional therapy as drug will be
penetrating a thin layer of cells with less chance of pharmacokinetic
drug resistance developing. Secondly, treating the disease at the early
stages negates the use of chemotherapy and hence abrogating the factors
that lead to the development of chemoresistance. Thirdly, and more
pertinent to LMIC treating early-stage disease removes the financial and
resource burden associated with treating late-stage disease, thus making
the disease eminently more treatable with rapid and better patient
outcomes.
The concept for developing a locoregional therapy for cervical cancer in
LMIC would focus treatment directly onto the pre-neoplastic lesion
leading to local control of the disease and effectively preventing
recurrence. It would be particularly applicable in the case of HIV
positive women for whom treatment is associated with high recurrence
rates, and for whom treatment resistance is a problem. In a country like
Zimbabwe where HIV prevalence rates are around 15%41, this would apply to a significant proportion of
women. Locoregional therapy as part of a “screen and treat” strategy
would also reduce the need for yearly cervical screens following a
diagnosis and treatment of high-grade cervical dysplasia (CIN2+).
Importantly, any treatment that negates the use of excisional or
ablative methods would be beneficial as it would also reduce the
incidence of obstetric complications, in women of reproductive age.
There is a clear rationale for developing loco-regional therapies for
treating cervical cancer, particularly in the rural areas of LMIC where
access or travel to medical facilities can be problematical.