Description of the condition

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (2015, Issue 5) on palliative interventions for controlling vaginal bleeding in advanced cervical cancer (Eleje 2015). According to the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, cervical cancer ranks fourth for both incidence and mortality of cancer among women worldwide, with only breast cancer, colorectal and lung cancer occurring more frequently (Bhatla 2019; Bray 2018; Ferlay 2019). Worldwide, cervical cancer accounts for estimated 569,847 new diagnoses and 311,365 deaths every year (Bray 2018; Ferlay 2019).

Of the new cases, more than 85% occur in low‐ to middle‐income countries, and in some of these countries cervical cancer is the most common cancer in women (Ikechebelu 2010; Obiechina 2009; Sankaranarayanan 2008). Therefore, nearly 70% of the global burden occurs in the developing world and more than one‐fifth of all new cases are diagnosed in India (GLOBOCAN 2012). The highest regional incidence and mortality rates are seen in Africa, while in relative terms, the rates are 7 to 10 times lower in North America, Australia and New Zealand, and Western Asia (Bray 2018; Ferlay 2019).

Differences are largely affected by the availability of cervical screening. Studies in low‐ to middle‐income countries continue to show a low to moderate level of awareness and utilisation of cervical cancer screening services (Ajayi 1998; Asonganyi 2013; Ayinde 2004; Bradford 2013; Bukar 2012; Gamaoun 2018; Hyacinth 2012; Mukakalisa 2014). This lack of effective screening also explains why in low‐ to middle‐income countries over 75% of affected women present with an advanced stage, whereas in high‐income countries over 75% of affected women present with early‐stage disease (Ikechebelu 2010; NHSCSP 2007‐2010; Umezulike 2007). Despite advances in cervical cancer prevention and diagnosis, outcomes for patients given a diagnosis of advanced and recurrent or metastatic disease are poor, with 5‐year survival rates between 5% and 15% for such cases, and treatment options are very limited (Godoy‐Ortiz 2018; Rosen 2017). Older women, who are at risk for a poorer overall prognosis because of their age, often do not receive the appropriate treatment and are also dying more frequently because of advanced cervical cancer (Quinn 2019).

Early‐stage cancer of the cervix (stage I to IIa; Appendix 1), can be successfully treated by radical surgery (with or without neoadjuvant chemotherapy) or concomitant chemoradiation (FIGO Committee on Gynecologic Oncology 2014; Pecorelli 2009). For advanced cervical cancer (stages IIb to IVb; Appendix 1), the treatment is chemoradiotherapy or palliative chemotherapy with or without radiotherapy (Scatchard 2012). Women with advanced cancer of the cervix often need palliation for distressing symptoms, such as vaginal bleeding. In previous studies, the prevalence of vaginal bleeding in women with advanced cervical cancer ranged from 0.7% to 100% (Adewuyi 2008; Ikechebelu 2010; Shapley 2006; Tarney 2014; Umezulike 2007). Vaginal bleeding is the immediate cause of death in 6% of women with cervical cancer and its management often poses a challenge (Yennurajalingam 2009).

Description of the intervention

Due to the geographical differences in incidence, and with increased rates in low‐ to middle‐income countries, there is a need for different palliative options to treat vaginal bleeding across a variety of healthcare settings. These include: vaginal packing; use of formalin‐soaked vaginal packs; QuikClot combat gauze (Vilardo 2017); cautery; endoscopic haemostatic forceps (Kobara 2015); tranexamic acid; interventional radiology techniques, such as uterine artery embolisation; uterine artery resection; uterine artery ligation and ionising radiation/radiotherapy (Barbera 2010; Fletcher 2002; Pereira 2004; Seider 1988). Potentially helpful radiotherapy approaches include transvaginal orthovoltage treatment (cervical cone irradiation), high‐dose fraction external beam radiotherapy or brachytherapy (irradiation delivered directly into the cervix/vagina). The type and length of treatment will depend on the woman's Karnofsky performance status (a standard way of measuring the ability of people with cancer to perform ordinary tasks). In a woman with a reasonable performance status, stereotactic radiosurgery may be considered to control bleeding (Konski 2005).

In cases of uncontrollable bleeding, uterine artery embolisation may be required. This is a procedure performed using x‐ray imaging for guidance to block feeding blood vessels to the uterus and cervix with metal coils, foam or glue‐like agents. If radiographically directed embolisation is not available, laparotomy with ligation of uterine arteries or anterior divisions of the hypogastric arteries is an alternative, but is likely to be inappropriate in a palliative setting. However, a very few, well‐selected women may derive benefit. Symptomatic anaemia resulting from blood loss can be remedied with blood transfusions once bleeding is stopped (Barbera 2010; Konski 2005).

Since there is no way to guarantee access to immediate radiotherapy in low‐ to middle‐income countries, the use of formalin‐soaked packs has been advocated for the treatment of haemorrhage associated with vaginal bleeding. Other vaginal packing procedures include the use of gauze (Vilardo 2017), lamb's wool or calcium alginate. Monsel's solution (i.e. ferric subsulphate) can also be used to stop vaginal bleeding from cervical cancer (Konski 2005).

Tranexamic acid can be given as an oral tablet or by injection to help to stabilise blood clots and stop bleeding by preventing fibrin degradation. It is effective in controlling blood loss in trauma situations and has been used to prevent blood loss during major surgery (CRASH‐2 Collaborators 2011; Hunt 2015; Ker 2014; Ng 2015).

How the intervention might work

Cervical cancer tends to spread locally before it metastases to distant organs. When the cancer is confined to the pelvis or regional lymph nodes cure is possible with radical hysterectomy, chemoradiotherapy or a combination of the two. In the presence of distant metastatic disease, cervical cancer is generally not curable and treatment is given with palliative intent. In low‐ to middle‐income countries, many women with cancer of the cervix present when the disease is already advanced and metastatic. At this stage, a degree of vaginal bleeding is almost inevitable. If there are distant metastases, there would be limited justification for embarking on aggressive surgical interventions such as bilateral ligation of the hypogastric arteries and so conservative approaches, such as packing of the vagina, use of haemostatic agents and palliative radiotherapy, are more appropriate (Konski 2005).

Oral or intravenous administration of tranexamic acid, three or four times per day, may be used to control/palliate mild‐to‐moderate vaginal bleeding. Tranexamic acid can have both direct and indirect actions. It antagonises the activation of plasminogen (mechanism for dissolving blood clots after they have been formed) by fastening to its kringle enzymatic domain (autonomous protein domains that fold into large loops, which are important in protein–protein interactions with blood coagulation factors). With this action, it reduces the conversion of plasminogen to plasmin. The inhibition of the formation of plasmin is important in controlling vaginal bleeding. In fibrinolysis (fibrin‐splitting), plasmin breaks up the fibrin in blood clots, fibrinogen and other proteins in the blood plasma, such as procoagulant factors V and VIII. In addition, tranexamic acid can antagonise the actions of plasmin directly, though a higher dosage is required to achieve this action than the dosage required to inhibit its action on plasminogen. As well as approaches used to palliate vaginal bleeding, the volume of blood loss needs to be replenished adequately, using plasma expanders or packed red blood cells (CRASH‐2 Collaborators 2011; Mishra 2011).

Tight vaginal packing with simple gauze rolls is a simple first‐aid measure to control haemorrhage. For vaginal packing to be effective, the lithotomy position (legs up in stirrups) is ideal, with the use of an instrument (speculum) to expose the superior part of the vagina aseptically. Sedation or short‐lasting general anaesthesia may be needed. The fornices of the vagina are tightly packed with the aim of maintaining an even pressure in the vagina. While the pack is in situ, the woman requires catheterisation, as she is likely to have difficulty in passing urine, due to compression on the urethra. Other simple measures, such as restricting that woman's mobility, foot‐end elevation of the bed or haemostatic agents (local, oral or parenteral), may enhance the effectiveness of the vaginal packing (Mishra 2011). As long as the vaginal pack is present, broad‐spectrum antibiotics, including metronidazole, may be helpful for treating any underlying infection, which is common with necrotic tumours and can contribute to haemorrhage.

Formalin also acts as a haemostatic agent by initiating a chemical cauterisation, reducing haemorrhage arising from small blood vessels (Chattopadhyay 2010; Vyas 2006). Formalin is an aqueous solution of the chemical compound formaldehyde. The formaldehyde in formalin is responsible for its cauterising property, while the water helps to dilute it, making the solution safer to use. A 4% solution of formalin has no toxic adverse effects (Vyas 2006). This concentration is well tolerated by women, and can help to control vaginal bleeding. Formalin contains noxythiolin (oxymethylenethiourea), tauroline (a condensate of two molecules of the aminosulponic acid taurine with three molecules of formaldehyde), hexamine (hexamethylenetetramine, methenamine), the resins melamine and urea formaldehydes, and imidazolone derivatives such as dantoin. These agents are claimed to be microbicidal, on account of the release of formaldehyde, as well as having some coagulase properties that allow the arrest of bleeding (Adebamowo 2000; Chattopadhyay 2010; Fletcher 2002).

Palliative‐dose radiotherapy can be an effective treatment of vaginal bleeding in cancer of the cervix. The standard curative treatment fraction of radiotherapy is 1.8 Gy to 2.0 Gy in a single fraction. In palliative care, enhanced doses are given with fewer fractions (Mishra 2011).

When vaginal packing fails and radiotherapy is not feasible or available, measures aimed at decreasing the pulse pressure of the blood vessels feeding the cervical tumour can be implemented. These approaches largely comprise surgical interventions or interventional radiology procedures. However, in advanced disease there is often extensive neovascularisation from a variety of feeding vessels, limiting the utility of this approach. Therefore, for meaningful benefit, appropriate patient selection is essential. If excessive bleeding occurs in an end‐of‐life situation, anxiolytics and analgesics to relieve discomfort and distress are important palliative measures, as is psychological and supportive care of the woman and her relatives (Barbera 2010; Mishra 2011).

Mohs' paste works by releasing zinc ions when in contact with a cervical cancer tumour (Yanazume 2013a). Following contact, it precipitates wound proteins to aid haemostasis. These wound proteins include fibrin sealants, thrombin and platelet gels that provide activity during the augmentation or propagation, or both, phase of haemostasis (Glick 2013).

Monsel's solution (ferric subsulphate) is a haemostatic agent that can be applied directly to the bleeding cervix (Davis 1984; Jetmore 1993; Manca 1997; Ratliff 1992; Soyle 1992; Spitzer 1996). It can also be applied in addition to a gauze pack. It works by coagulating proteins, leading to tissue necrosis and eschar formation, enhancing thrombus formation and haemostasis (Glick 2013).

Platinum‐based chemotherapy works by slowing down cancer cell growth and can improve survival and quality of life in advanced disease, with relatively minimal toxicity (Scatchard 2012). However, in cancers, new feeding blood vessels may be abnormal and inadequate leading to lower perfusion of the cancer cells. This may result in a reduced concentration of cytotoxic agents within the tumour. The resulting hypoxia from poor blood supply may lower the proliferating fraction of cancer and reduce the potential cytotoxic effects of platinum‐based chemotherapeutic agents (Lorusso 2014).

Bilateral ligation of the internal iliac arteries (main arteries feeding the pelvis) may work to control intractable bleeding from advanced cervical cancer, especially when vaginal tamponade and blood transfusion are ineffective (Gassibe 1997). However, this requires major surgery and general anaesthetic, which may not be appropriate in a palliative setting.

Endoscopic haemostatic forceps work by soft coagulation which is non‐invasive (Kobara 2015), while QuikClot combat gauze is a synthetic haemostatic dressing used for haemorrhage control (Vilardo 2017).

One further supportive treatment is vitamin K. Vitamin K is essential for the hepatic (liver) production of a number of clotting factors, including factors II, VII, IX and X. Vitamin K treatment may be helpful if there is bleeding in the presence of a derangement of these factors or excessive warfarin therapy (which acts by inhibiting vitamin K‐dependent clotting factor production by the liver) in women with advanced cancer (Shafi 2012).

Why it is important to do this review

Palliative measures to control bleeding in women with advanced cervical cancer are often needed (Barbera 2010; Fletcher 2002; Konski 2005). The intervention chosen is likely to be dependent on the severity of bleeding, but should also take account of effectiveness and the woman's wishes, and those of her family, especially in a palliative or potentially terminal care setting. Radiotherapy may not be suitable (if previously used in the treatment pathway) or may not be readily available, due to limitations in the healthcare setting. However, although there are benefits of non‐invasive or minimally invasive palliative interventions, as compared with more invasive interventions, vaginal packing (non‐invasive intervention) can be painful and distressing and may require sedation or general anaesthesia, whereas other simple measures, such as tranexamic acid, can also have harms associated with them.

There is currently no systematic review that addresses palliative interventions for controlling vaginal bleeding caused by advanced cervical cancer. Systematic reviews on the use of ionising radiation for controlling bleeding show that it can be associated with serious adverse consequences, such as bowel toxicity (Green 2005; Symonds 2004). This damage causes symptoms such as diarrhoea, mucous discharge, cramping, bloating, tenesmus and anal pain or incontinence (Luna‐Pérez 2002). Vaginal bleeding remains a common consequence of advanced cervical cancer. Knowledge of the effectiveness of the interventions to reduce vaginal bleeding in women with advanced cervical cancer is essential to enable evidence‐based clinical decisions. A systematic evaluation of other alternative palliative interventions is therefore warranted to inform decision‐making for this important and distressing health need.