Venous Thromboembolism Rate in Patients With Bladder Cancer According to the Type of Treatment: A Systematic Review

Bladder cancer (BC) is classified as a high-risk tumour type for venous thromboembolism (VTE). VTE presents an extra challenge in the management of patients with cancer, given the increase in morbidity and mortality on having both conditions. To summarise the contemporary evidence on the VTE rate in patients with BC according to the stage, type of anti-cancer treatment and highlight VTE rate in the UK and other countries. A systematic review was carried out, and an electronic search for publications between January 2000 and November 2021 was done. Studies recording VTE in BC patients were included, whilst paediatric patients, case reports, studies reporting on a mix of arterial and venous thrombosis, studies reporting DVT or PE only and recorded hospitalised VTE only were excluded. The rate of VTE, country of origin, risk factors and thromboprophylaxis duration for VTE in BC patients were identified. A total of 38 papers met the search criteria. All publications were original research papers (cohort studies). The overall VTE rate in patients with BC was estimated at 1.9% to 4.7%. For those patients undergoing cystectomy, the VTE rate ranged from 3% to 17.6%; however, the VTE rate in the metastatic stage of BC patients ranged from 3.1% to 5.1%. The rates of VTE in BC patients are high, further increased by interventions such as surgery and chemotherapy. Thromboprophylaxis measures should be optimised. This review highlighted the fact that the VTE rate in BC varies between studies due to the heterogeneity of risk factors reported.


Introduction And Background
Venous thromboembolism (VTE) is a disorder in which a thrombus forms, mostly in the deep veins of the lower or upper limbs, and is called deep vein thrombosis (DVT). The thrombus may travel to the pulmonary arteries where it lodges, causing a pulmonary embolism (PE). Together, DVT and PE are known as VTE. Cancer is an independent risk factor for VTE [1], and VTE is a major cause of morbidity and mortality in patients with cancer [2]. VTE negatively affects the quality of life and increases the risk of further complications such as recurrent VTE and bleeding [3]. In addition, the utilisation of health care resources in cancer patients who have VTE is high [3]. Cancer patients have a five to six-fold increased risk of developing VTE compared with the general population; this can reach seven-fold for cancers of the brain, ovary and pancreas [4]. The pathogenesis of VTE in cancer patients is complex, related to the interaction between the procoagulant properties of the malignant cells themselves, the haemostatic system and characteristics of the patient [5].
BC is categorised as a high-risk tumour type (for VTE) [6]. These authors found the six-month cumulative incidence of VTE in metastatic urothelial BC is 8.2%. VTE rates in patients with BC who have had a cystectomy range between 0.3% and 17.6% [7][8]. Furthermore, in a USA study, exploring VTE in BC patients, the VTE rate was 7.5% (5.5-9.9%) in USA and 3.8% (2.5-5.4%) in non-USA countries, P = 0.005. The standard treatment for muscle-invasive non-metastatic bladder cancer is cystectomy or multimodality treatment (surgery -transurethral resection of bladder tumour plus chemo-radiotherapy). Muscle-invasive BC is proven to increase the risk of VTE, and this risk becomes even higher after cystectomy [9].
This systematic review was undertaken to summarise the contemporary evidence on the VTE rate in patients with BC according to the type of anti-cancer treatment and highlight the VTE rate in the UK vs other countries.
The risk of VTE in BC may vary between different countries due to different guidelines followed in BC 1 1 2 1 management, e.g. European Society for Medical Oncology (ESMO) guidelines are generally used in Europe, National Comprehensive Cancer Network (NCCN) guidelines are used internationally, in particular in the USA and National Institute for Health and Care Excellence (NICE) guidelines are used in the UK, for example, using neoadjuvant chemotherapy or not before cystectomy. Different treatment regimens are preferred in different countries, e.g., the USA and using thromboprophylaxis for 14 or 28 days post cystectomy [10].
BC patients who are undergoing major surgery, e.g., radical cystectomy, are particularly at high risk for VTE; thus, most guidelines recommend pharmacological thromboprophylaxis for patients starting before surgery and continuing for four weeks post-surgery. Thromboprophylaxis for ambulatory BC patients who are receiving chemotherapy is not widely adopted or recommended by guidelines unless the patients have other risk factors [10].
It is important to have evidence on VTE incidence in patients with BC according to known confounding variables for VTE, in the UK and other countries, so that healthcare professionals and patients are informed and can take appropriate action. In practice, optimizing treatment plans to decrease VTE risk while also reducing bleeding risk is significant to patients and the healthcare system; thus, the decision to use pharmacological thromboprophylaxis needs a balance between the risk of VTE and major bleeding [11].
The clinician needs to consider the balance between the risk of VTE and the risk of bleeding before prescribing pharmacological thromboprophylaxis [9]. This systematic review also reveals the rate of VTE in BC patients according to the treatments and length of thromboprophylaxis in the UK and other countries to inform the optimisation of thromboprophylaxis

Aims
The aims of this review are to find (a) the incidence rate of venous thromboembolism (VTE) according to the anti-cancer treatments received, in and out of the UK; (b) the VTE rate differences between the UK and global data.

Objectives
To explore (a) the VTE rate in BC patients in the UK and other countries; (b) the evidence available on VTE rate in non-muscle-invasive, muscle-invasive, and metastatic BC patients in the UK and non-UK countries; (c) the influence of the duration of pharmacological thromboprophylaxis on VTE rate in patients with BC undergoing cystectomy; (d) the knowledge gaps of VTE in BC that demand further studies in the UK and non-UK countries.

Methods for systematic review
The Centre for Reviews and Dissemination (CRD) Guidance for Undertaking Reviews in Healthcare (CRD, 2008) was utilised to guide this systematic review. A search was conducted on the PubMed and Embase electronic databases (Appendix 1). In addition, conference proceedings of the American Society of Clinical Oncology and the American Urological Association, the two largest international meetings of cancer and urology, were screened for potentially relevant records.

Search inclusion and exclusion criteria
The main outcome of interest was any VTE, which included symptomatic or incidentally detected DVT and PE, diagnosed in patients with BC.

Data sources and searches
The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines and checklist were followed to develop this review [12]. The following terms were used: (('bladder cancer' OR bladder carcinoma' OR 'bladder tumour' OR 'bladder urothelial carcinoma' OR 'transitional cell carcinoma') AND ('VTE' OR 'DVT' OR 'PE' OR 'venous thromboembolism' OR 'thrombosis' OR 'thromboembolism' OR 'deep vein thrombosis' OR 'pulmonary embolism' OR 'lung embolism')).
Publications from January 2000 to June 2020 were included (Appendix 1). Data on overall VTE incidence in BC patients were extracted from all related publications. These were the source data for the primary objective -incidence of VTE in BC patients. Reference list checking was carried out to identify further relevant studies. All titles and abstracts from the search were evaluated independently by two reviewers (DP and IM) and disagreements were resolved by a third arbitrator (AY).

Study quality assessment for systematic review
For each of the included studies, the risk of bias was evaluated using the Newcastle-Ottawa Scale (NOS) and Agency for Healthcare Research and Quality (AHRQ) standards and classified as good, fair, and poor. The NOS assigns up to a maximum of nine points for the least risk of bias in three domains: 1) selection of study groups (four points); 2) comparability of groups (two points); and 3) ascertainment of exposure and outcomes (three points) for cohort studies.
A maximum score of 2 can be awarded for comparability and a maximum score of 1 can be given for each of the remaining points. A study can have the maximum possible quality score of 9. Thresholds for converting the NOS to AHRQ standards were applied to have a clear view of quality assessment for each study (Appendix 2).

Ethical considerations for systematic review
Ethics committee approval was not required for this systematic review, as this methodology utilises only previously published material, is not primary research and does not involve humans or data collection.

Descriptive Characteristics
Of the 2921 publications, a total of 38 studies met the inclusion criteria and were selected for this systematic review. All stages of the extraction process are shown in the PRISMA flow diagram ( Figure 1).

FIGURE 1: Study selection process of systematic review
In the current systematic review, all papers with one exception have good and fair quality according to the Newcastle-Ottawa Scale and AHRQ standards. All publications were original research papers (cohort studies) in which the VTE rate was clearly stated. The cohort studies were generated in different countries: 'USA', 'Canada', 'Germany', 'France', 'Denmark', 'Netherlands', 'UK', 'Australia', 'Turkey', and 'Egypt'. The majority of the studies were carried out in the USA. The country of origin is summarised in Figure 2.

FIGURE 2: Summary of studies according to country of origin
The majority of papers included patients who had undergone cystectomy (n=33) ( Figure 3). The further risk of VTE in patients receiving neoadjuvant or adjuvant chemotherapy (with curative intent) was only mentioned in four of the 33 papers [13][14][15][16]. There are no data on VTE in patients having multimodality treatments. Only two papers discussed the VTE risk in patients receiving chemotherapy only [17][18]; two papers compared VTE rates in using thromboprophylaxis (TP) for two weeks and an extended duration of four weeks [19][20]; one paper included patients having a transurethral resection bladder tumour (TURBT) only [21].

VTE rate in patients with bladder cancer
This review identified 38 studies specifying the VTE rate in BC patients, with a total of 172,380 BC patients being included, according to the type of treatments ( Figure 3) and country of origin; however, two studies stated the overall VTE rate with no data on anti-cancer therapies or TP regimes [22][23]. A cohort study conducted in the UK explored the VTE rate in all cancer patients, including 3152 BC patients, and the absolute rate per 1000 person-years of VTE in BC was 15 [24]. Regarding thromboprophylaxis post-cystectomy, 30 studies did not clearly discuss thromboprophylaxis regimens for BC patients undergoing cystectomy. However, two studies from the USA explored thromboprophylaxis effectiveness in BC patients with cystectomy in the post-surgical period. These two studies grouped patients by receiving thromboprophylaxis for 14 days or 28 days post-cystectomy. The patients were followed for 90 days duration. A substantial reduction in VTE rate (from 17.6% to 5%) was recorded in the extended thromboprophylaxis (28 days) group in comparison to the control group (14 days); extended chemoprophylaxis significantly reduced the incidence of VTE (P-value=0.021) [20]. No UK studies explored the impact of using extended thromboprophylaxis on the VTE rate in BC patients who have had cystectomy.
VTE in bladder cancer patients undergoing chemotherapy: Only two studies exploring the VTE in muscleinvasive BC who received chemotherapy were found, and the VTE rates were 5.1% and 8.1% (mean=6.6%) [17][18]. The VTE rate within six months from diagnosis of metastatic urothelial cancer (not specifically bladder cancer) is 3.2%, and the VTE rate in metastatic urothelial cancer and receiving chemotherapy is 5.1% [18]. No data exclusively relating to patients with BC who have had chemotherapy only were found to assess the benefits or drawbacks of thromboprophylaxis in this population.
The mean of VTE rates in BC patients who had undergone radical cystectomy in the UK was lower than in non-UK countries as a group (Figure 4).

Discussion of the systematic review
This review explored the mean of VTE rates within and outside the UK and found the difference with the mean of VTE rates in non-UK countries according to the types of treatments or VTE risk factors in patients with BC. The VTE rates were explored in BC patients according to the risk factors impacting the rate of VTE such as surgery, chemotherapy and thromboprophylaxis in the UK and non-UK countries, where possible.
The review of the VTE rate in patients with BC elicited 38 prospective and retrospective studies that demonstrated VTE rates in different follow-up periods among BC patients who have had a radical cystectomy. Each study has a different rate of VTE and therefore a wide range of VTE rates in patients having cystectomy is noted (1.3% to 23.2%) in this current review. Regarding UK studies, they were only two studies that collected data on the VTE rate in BC patients who have had cystectomy in the UK, and these studies were carried out some years ago (2012 and 2013). Hence, due to the lack of new and enough studies (more than four studies) in recent years, it would be unlikely to be beneficial to carry out a meta-analysis of VTE rate in BC patients based on country (the UK vs non-UK countries). It is important to undertake new studies exploring the VTE rate in BC patients in the UK.
A previous systematic review was carried out on the risk of VTE and bleeding in patients having open radical cystectomy [9]. Many studies included in Tikkinen's systematic review were occasionally reported the VTE rate as one of the adverse effects of surgery, and it seems that these studies did not check for VTE events carefully. These data may be at risk of information bias [9].
The timing of follow-up differs between surgical studies. The minimum follow-up duration of patients undergoing cystectomy was 28 days, and the VTE rates were 3% -7.7% (mean=5.6%). In this review, we excluded studies that only drew on data relating to VTE during in-hospital admission because the vast majority of VTEs (82.6%) occur after discharge from the hospital; in other words, there was an inadequate follow-up for VTE in patients undergoing cystectomy [28]. In our current review, the data from three studies that followed up the patients for three months after cystectomy revealed that VTE rates were still high; this may be due to patients having further treatment and hospitalisation [15,18,50]. According to the study by , the VTE rate peaks at 20 days after cystectomy in BC patients; however, patients continue to be at risk of VTE long after surgery [16]. As found in this review, BC patients who had undergone cystectomy have an elevated risk of VTE for up to three months after surgery [13]. Consideration should thus be given to offering thromboprophylaxis measures and caring for longer than 28 days post cystectomy, in particular, if chemotherapy has been added to the treatment plan or patients have other risk factors for VTE. The majority of BC guidelines typically suggest extended thromboprophylaxis for pelvic surgery, including cystectomy for up to four weeks post-discharge [51]. Interestingly, the mean of VTE rates in patients who have had cystectomy with chemotherapy is 5.0% [13,15,34], suggesting that systemic chemotherapy did not increase the VTE rate more than the already increased rate imposed by surgery.
Brennan and his team (2018) also mentioned that chemotherapy is not associated with an increased risk of VTE after RC [15]. The presence of metastatic disease increases the VTE rate to the same extent as cystectomy by 5.1% [15]. However, patients with metastatic BC who did not receive chemotherapy had an absolute VTE incidence rate of 3.2% [18]. The VTE rate in patients with metastatic BC who receive systemic chemotherapy further increased to 5.1% within six months. VTE rates based on the chemotherapy group demonstrated no statistical difference when gemcitabine/cisplatin was used as the comparator [18]. Gopalakrishna et al. (2016) mentioned that the VTE rate differed significantly by country of origin among BC patients [53]. This is likely to be due to differences in patients' characteristics, using preoperative chemotherapy, recording issues and using different protocols of thromboprophylaxis. Thus, it is of value to find the VTE rate in the UK and not depend on the data from non-UK countries, in order to scope the problem and strive to protect the patients from this debilitating condition. The VTE rates were 2.5% and 2.9% within one-year post-cystectomy as the UK study found [25][26]. Table 1 lists the studies that provided information on the VTE rate in bladder cancer patients receiving thromboprophylaxis while Table 2 lists those included information on the VTE rate in bladder patients undergoing cystectomy and/or chemotherapy treatment.   The VTE rate in BC patients varies according to the type of treatment and the use of thromboprophylaxis. Additionally, the mean of VTE rates in BC patients in the UK is lower than the mean of non-UK countries, which indicates that there is a variation in VTE rates in BC patients between the UK and non-UK countries ( Figure 4).
According to the author, the VTE rate in BC patients in the UK seems lower than that of non-UK countries, perhaps due to the extended thromboprophylaxis regimens applied post-cystectomy. More data in the UK are required to document the VTE rate in patients who have had a cystectomy and patients treated with cystectomy and chemotherapy. This current review has some limitations, however, as many studies included did not report all variables of interest, e.g., thromboprophylaxis measures and chemotherapy prescribed, but mainly reported VTE rate and the country origin of study. The strengths of this current systematic review include the comprehensive search strategy, the risk of bias assessment and exploring other risk factors for VTE in the BC population.
In summary, this review found the VTE rates in patients with BC who have had cystectomy or chemotherapy are around 2.7% and 5.2%, respectively. There are no data on VTE in BC patients who have had radiotherapy, and very limited data regarding VTE in BC patients who have had cystectomy and chemotherapy in the UK. No data explored the radiotherapy risk factors for the VTE in BC patients.

Conclusions
This review highlights the fact that the VTE rate in BC varies between studies due to the heterogeneity of risk factors (cystectomy, chemotherapy and thromboprophylaxis) reported. The mean of VTE rates in BC patients who have had cystectomy in the UK seems lower than in non-UK countries. In the UK, there are only two studies that explored the VTE incidence in patients with BC. BC patients have variable regimens and drugs for thromboprophylaxis. VTE rates in patients with BC are affected by the duration of thromboprophylaxis in patients who have had cystectomy. Given the VTE rates in this review, longer-term thromboprophylaxis should be considered postoperatively, so this study supports extended anti-clotting prophylaxis in patients undergoing cystectomy.
Further studies to explore the VTE rate in patients with BC, undergoing cystectomy or receiving multimodality bladder preservation treatment, should be carried out in the UK, to garner more robust data to better protect patients from this debilitating condition.