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.