Disclaimer: This independent medical education article was commissioned by MSD Ireland.
Cervical cancer is predominantly a disease of younger women, with over 58 per cent of patients under the age of 50 years old at diagnosis. It is rare under the age of 25 years. It is the eighth most common cancer in Ireland and the National Cancer Registry Ireland records 262 new cases of invasive cervical cancer in Ireland each year.1 While it is the 12th most common cause of cancer mortality in Ireland, it is the second most common cause of cancer death in women aged 25-to-39 years.1 Globally, cervical cancer remains a major female health concern, with 85 per cent of cases occurring in developing countries and the extent of this inequity makes it the leading cause of cancer death in women in the world.2,3 Early diagnosis is the key to improved patient outcomes, and the introduction of the national cervical cancer screening programme CervicalCheck has resulted in a fairly constant decline in invasive cervical cancer diagnoses year-on-year in Ireland. During 2017-2019, almost one-third of invasive cervical cancer cases were diagnosed through CervicalCheck and at a much earlier stage than those cancers that present with symptoms.
Cervical cancer is primarily the result of persistent infection with the human papillomavirus (HPV).4,5 There are hundreds of HPV subtypes, but only a dozen are considered ‘high-risk’ for the development of cervical cancer. In particular, HPV-16 and HPV-18 infection results in up to 70 per cent of all cervical cancers. It is estimated that 75-to-80 per cent of women are infected by HPV during their lifetime, but most women successfully clear the virus with an appropriate immune response. In some women, however, the virus evades the host immune system and can result in the development of chronic infection with the potential initiation of carcinoma. Immunisation against specific HPV subtypes can prevent this infection and is expected to reduce cervical cancer incidence.6,7,8
Pathologically, cervical cancer is predominantly comprised of squamous cell carcinoma (80 per cent), although adenocarcinoma, adenosquamous, and other subtypes can occur, including neuroendocrine or undifferentiated cervical cancer. Cytological screening is not as effective for non-squamous histologies of the cervix as it is for squamous cell carcinoma.9,10,11 Risk factors for the development of invasive cervical cancer include multiple prior sexual partners, history of other sexually-transmitted infections, smoking, and a weakened immune system due to organ transplantation or other infection.12,13
Early cervical cancers and pre-invasive cervical intraepithelial neoplastic (CIN) lesions do not usually present with symptoms, underpinning the importance of cervical cancer screening. The most common symptoms of cervical cancer include vaginal discharge or bleeding between periods or after sex, pelvic pain, and pain/discomfort during sex. Because of the accessibility of the uterine cervix, cervical cytology or Papanicolaou (Pap) smear and cervical biopsies can usually result in an accurate diagnosis.
Work-up of patients with suspicious symptoms includes history and physical examination, blood tests (full blood count, renal and liver assessment), and consider radiologic imaging with CXR, CT, PET/CT, MRI as clinically indicated. Confirmed invasive cervical cancer requires MRI pelvis for accurate staging assessment and potentially other radiology after, as clinically indicated.
Cancer staging is performed using the T (tumour size) N (nodal status) M (metastasis) method according to the revised 2018 FIGO Staging System (Table 1).14 Accurate imaging is essential for precise staging and thus formulating an appropriate treatment strategy.
Fertility-sparing approaches may be considered in highly selected patients who have been thoroughly counselled regarding disease risk as well as pre- and peri-natal challenges.14
Very early-stage disease (stage IA1) can be considered for conisation with negative margins. Stage IA2 and IB1, especially cancers less than 2cm in diameter, may be eligible for conservative surgery in the form of a radical trachelectomy. However, trachelectomy is not suitable for neuroendocrine cancers and other rarer histological subtypes.15,16 Studies that examined pregnancy in women who underwent radical trachelectomy have provided differing success rates. One case series of 125 patients with cervical cancer who underwent vaginal radical trachelectomy reported 106 pregnancies among 58 women.17 In a systematic review of 413 women who underwent abdominal radical trachelectomy, 113 women attempted pregnancy and 67 (59 per cent) were successful in conceiving.18 However, miscarriage and pre-term labour rates are elevated among women who have undergone radical trachelectomy.19,20,21
Non-fertility sparing approaches to cervical cancer include simple hysterectomy, modified radical hysterectomy, and radical hysterectomy. Decisions regarding surgical approach are dependent upon accurate staging, histopathological subtype, and patient-related factors, including personal choice.
Radical retreatment of localised cervical cancer recurrences can include surgery or radiotherapy and/or chemotherapy. After treatment for relapse, long-term disease-free survival (DFS) rates of approximately 40 per cent have been reported.22 Pelvic exenteration may be an option for recurrent or persistent cervical cancer that is confined to the central pelvis and may be a potential curative therapy.23,24 Various surgical approaches are available, however, pelvic exenteration is an extensive surgical procedure and can result in substantial morbidity, often requiring stoma formation and ureter resection and ileal conduit formation with a mortality rate of ~5 per cent.25,26,27 Thus, discussions regarding the potential for cure balanced against the potential for harm need to be carefully discussed by specialist surgeons in this field.
Sentinel lymph node (SLN) mapping is the surgical assessment of cancer nodal spread by identifying and removing the draining lymph node(s) using techniques such as blue dye/radiocolloid or indocyanine green tracers.28,29 SLN detection is feasible in cervical cancer and may safely avoid removal of a larger group of lymph nodes in early-stage cervical cancer and the potential morbidity that comes with nodal removal; for example, lower limb lymphoedema. Using nodal assessment techniques to accurately assess spread to the para-aortic lymph node basin in more locally-advanced cancers can help in radiotherapy planning – supporting the benefit of extended radiation therapy with known para-aortic nodal involvement. A randomised study, LiLACS, examining surgical versus radiologic staging and treatment of para-aortic lymph node involvement is ongoing.30
While there has been a surgical move towards more minimally-invasive surgical approaches, either using conventional or robotic techniques over open approaches in many cancers, the recent results of the prospective LACC study in locally-advanced cervical cancer queried the appropriateness of this.31 LACC randomised patients to minimally-invasive versus open surgical approaches and reported a lower rate of DFS with the minimally-invasive group compared with the open surgical group. Three-year DFS was 91.2 per cent for the minimally-invasive approach versus 97.1 per cent for the open group. Additionally, there was a reduction in the overall survival of those who had undergone the minimally-invasive approach (three-year overall survival of 93.8 per cent (minimally invasive) vs 99 per cent (open surgery)). Two subsequent epidemiological studies have supported these results and reported a shorter overall survival for patients who underwent minimally-invasive treatment.32,33 This has led to a global move away from minimally-invasive surgery in locally-advanced cervical cancer, except perhaps for the earliest of cancers, although women should be carefully counselled regarding the oncological risks of different surgical approaches.
Concurrent chemoradiotherapy utilises platinum-based cisplatin chemotherapy delivered weekly during daily radiotherapy (RT) and is the treatment of choice for stage IB3 to IVA disease based on the results of five randomised control trials.34,35 These trials have shown superiority of survival with concurrent chemoradiotherapy over radiotherapy alone in the range of 30-to-50 per cent.36,37 Pelvic radiotherapy or chemoradiation invariably leads to ovarian failure in pre-menopausal women. To preserve intrinsic hormonal function, ovarian transposition may be considered before pelvic RT for select women younger than 45 years of age with squamous cell cancers.38,39 Radiotherapy is usually followed by brachytherapy, a type of internal radiation therapy. Patients with positive pelvic or para-aortic lymph nodes and negative workup for more distant metastatic disease, ideally using PET CT, should receive extended-field external beam radiotherapy, concurrent platinum chemotherapy, and subsequent brachytherapy. Radiotherapy or chemoradiotherapy may also be recommended postoperatively, depending upon the final histological findings and surgical margins.
Trials are ongoing to ascertain the benefit of adding immune checkpoint inhibitors such as the PD-1 inhibitors, pembrolizumab or durvalumab, to chemoradiotherapy. The phase 3 randomised clinical trial, KEYNOTE-A18 (please note this is off-label in Ireland), was open in Ireland and recruited until November 2022 (NCT04221945) and CALLA presented its early interim findings at the 2022 European Society for Medical Oncology (ESMO) Annual Congress. More mature survival data is required to assess whether this approach is superior to the current concurrent chemoradiation standard of care.
Planning for radiotherapy in cervical cancer must take into account the potential impact on surrounding critical structures such as rectum, sigmoid, bladder, small bowel, and bone. Acute side-effects such as diarrhoea, bladder irritation, and fatigue can be managed with medications and supportive care and generally resolve soon after completion of radiation. Longer-term, chronic issues can occur that can substantially affect women following cervical radiotherapy and can have a marked impact on their well-being and psychosocial and psychosexual functioning. Some of the side-effects can develop many years after exposure to radiotherapy for cervical cancer.
Late side-effects may include potential injury to bladder, rectum, bowel, and pelvic skeletal structures.40,41 The risk of major complications such as fibrosis, necrosis, and fistula are related to the volume, total dose, dose per fraction, and specific intrinsic radiosensitivity of the normal tissue irradiated.42,43 In addition, patient-related conditions such as inflammatory bowel disease (IBD), collagen vascular disorders, multiple pelvic/abdominal surgeries, history of pelvic inflammatory disease, and diabetes can influence the long-term effects of treatment.
Vaginal stenosis results from the post-radiotherapy scarring after external beam radiotherapy or brachytherapy. The vaginal canal narrows and becomes less able to stretch or even shorter, which can make sex painful. Regular vaginal dilation using dilators can improve this. Vaginal dryness can be aided by topical oestrogens administered per vagina. Rectal bleeding and/or stenosis can be painful and require careful expert management. Radiation to the pelvis can also cause chronic radiation cystitis presenting as irritable bladder, blood in urine, or more frequent urination. Fistulation may also rarely occur following radiation: Fistula tracts can connect the vagina with the bladder, rectum or other nearby structure. The bones can also weaken after exposure to radiotherapy and this can lead to fractures and pain of the pelvis or hips. Bone density assessment may be beneficial to measure bone strength and monitor risk of fracture. Lymphoedema of the lower limbs is also a risk in particular when lymph nodes in the pelvis and para-aortic basin are irradiated.
Patients with metastatic disease or advanced disease not suitable for surgery or radiation receive platinum-based chemotherapy alone as palliative intent to control rather than eradicate the disease. The current cytotoxic treatment for advanced and metastatic disease has not changed since 2009, when the GOG-204 trial established cisplatin with paclitaxel as first-line chemotherapy.44 In 2014, the addition of bevacizumab, an antiangiogenic agent, was noted to improve overall survival by almost four months as part of the GOG-240 trial and the three compounds are now considered international gold standard.45 Nevertheless, bevacizumab is not suitable for all patients. The potential increased risk of bleeding, thrombotic events, impaired wound healing, renal injury, high blood pressure, fistulation, and gastrointestinal perforation may preclude a substantial cohort of patients. Cervical cancer by itself, regardless of treatment, poses a risk of fistulation into adjacent structures and the addition of bevacizumab can contribute to this.
Chemotherapy compounds after failure of platinum and paclitaxel are less effective and no superior regimen has been noted. Options include irinotecan, gemcitabine, vinorelbine, pemetrexed, docetaxel, and fluorouracil among others. The unmet need for additional therapy options in metastatic disease has driven much research and clinical trials in this space. Over the past number of years, the emergence of alternative strategies and agents has brought hope to the future management of advanced, metastatic cervical cancer.
Immunotherapy using immune checkpoint inhibitors (ICI) has risen substantially to the fore in cancer therapy in recent years. These compounds, most commonly targeting the receptors PD-1, PD-L1, and CTLA-4, release the brakes on the host immune system that prevent an innate immune response against cancer cells (Figure 1). By inhibiting these receptors, the immune system can attempt to eradicate cancer cells from the body. Measurement of the PD-L1 receptor either on the cervical cancer itself or the surrounding immune cell environment (combined positive score (CPS)) is used as an imperfect biomarker to predict response to ICI. However, while high tumour PD-L1 expression can result in greater tumour responses to ICI treatment, it is by no means guaranteed.
Following early signals of pembrolizumab efficacy in advanced, metastatic cervical cancer (KEYNOTE-028),46 the larger phase 2 KEYNOTE-158 reported a tumour response rate of 14.3 per cent with pembrolizumab alone following standard platinum-based chemotherapy regimens (NCT02628067) (please note both KEYNOTE-028 and KEYNOTE-158 are off-label in Ireland).47 A subgroup analysis of those with PD-L1 expression of 1 per cent or above increased this to 17.1 per cent. Based on these results, the US Food and Drug Administration (FDA) approved pembrolizumab for use in metastatic cervical cancer following failure of chemotherapy in those cancers over-expressing PD-L1 in at least 1 per cent of the sampled tumour or immune cells.
Improving our use of biomarkers to identify the subgroup of patients who could derive clinical benefit from the use of ICII is essential for more efficacious delivery of ICIs.
Another PD-1 inhibitor, cemiplimab, with data recently reported in the EMPOWER-Cervical 1 trial, has been found to confer a survival benefit over chemotherapy in the second-line setting.48 Median overall survival for those receiving cemiplimab was 12 months compared with 8.5 months in the chemotherapy arm. The drive to further improve patient outcome has led to immunotherapy compounds being tested earlier in the disease course. KEYNOTE-826 reported an improvement of carboplatin, paclitaxel and pembrolizumab +/- bevacizumab over carboplatin and paclitaxel +/- bevacizumab alone, increasing median overall survival to 24.4 months compared with 16.5 months with chemotherapy alone.49 This was regardless of PD-L1 expression levels. Both of these regimens have been recently National Cancer Control Programme (NCCP) approved for prescription in Ireland.
Other novel agents are also in development for cervical cancer. While targeting cancer mutations has been disappointing overall, there are still efforts ongoing to identify a cohort of patients who may benefit. The National Cancer Institute (NCI)-MATCH study in the US revealed potentially actionable or targetable mutations in 28 per cent of advanced cervical cancers. This suggests there is a future for precision oncology in this cancer subtype, although how that is best delivered and with what drug combinations are best is still being elicited. Some mutations of ongoing interest include HER2 mutations with compounds such as neratinib and trastuzumab deruxtecan being currently explored in trials. Targeting PI3 kinase and mTOR pathway abnormalities are also being trialled with compounds such as taselisib (PI3K inhibitor), copanlisib (PI3K inhibitor), capivasertib (AKT inhibitor), and ipatasertib (AKT inhibitor) in development.
Much excitement has surrounded a novel antibody drug conjugate (ADC) compound called tisotumab vedotin, which is now approved by the US FDA for the management of metastatic cervical cancer following platinum-based chemotherapy first-line. Tisotumab vedotin is an ADC directed against tissue factor (TF), which is expressed across multiple solid tumour types and is associated with poor clinical outcome. ADC compounds specifically target receptors that are expressed upon the surface of cancer cells to attach and subsequently deliver potent cytotoxic chemotherapy directly into the cancer cells themselves. Tisotumab vedotin is also being explored in combination with a variety of agents through the ENGOT-cx8 clinical trial such as bevacizumab, pembrolizumab, and carboplatin with some very promising tumour response rates.50,51
Cervical cancer remains a serious global problem. HPV vaccination programmes have set out to reduce the incidence of HPV and consequently cervical cancer; however, there remains marked global inequities in access to immunisation initiatives. Screening programmes continue to be vital in the early diagnosis of cervical cancer. Prevention and earlier diagnosis remain the key to substantially reducing the impact of this disease.
Management strategies for cervical cancer include surgery, (chemo)radiation and chemotherapy alone. The multidisciplinary decision depends heavily upon the accurate and precise staging of this cancer. Despite curative treatment strategies, cancer recurrence and de novo metastatic disease remain a treatment challenge. Nevertheless, a busy drug development pipeline and increasing access to next-generation sequencing for solid tumours will result in further compounds being developed in cervical cancer, in particular drugs precisely targeted against identified mutations and immunotherapy agents. The identification of biomarkers that predict response to particular treatments such as ICI are critical in better selecting the subgroups of patients that may respond to these immunotherapy agents.
Data available at www.ncri.ie
Cervical cancer: Estimated incidence, mortality, and prevalence worldwide in 2012. International Agency for Research on Cancer and World Health Organisation. 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
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Vergote I, Mirza MR, Sehouli J, et al. Trial in progress update on ENGOT-cx8/GOG-3024/novaTV205 addition of a new cohort with first-line (1L) tisotumab vedotin (TV) + pembrolizumab (pembro) + carboplatin (carbo) +/- bevacizumab (bev) recurrent metastatic cervical cancer. J Clin Oncol. 2022; 40 (16): TPS5603
DR DEARBHAILE COLLINS, Consultant Medical Oncologist, Cork University Hospital, and Senior Lecturer in Cancer Research, University College Cork
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