Thromboembolism in Muscle-Invasive Bladder Cancer. A Population-based Nationwide Study

The bladder cancer data base Sweden (BladderBaSe)

The BladderBaSe was initiated in 2015 through linkage of the Swedish National Register for Urinary Bladder Cancer (SNRUBC) to a number of health care and demographic registers [25]. The project was approved by the Research Ethics Board at Uppsala University, Uppsala, Sweden (File No 2015/277).

We included all patients registered with primary tumours localized in the urinary bladder and with clinical stage T2-T4 UBC (stages II-IV) diagnosed from January 1, 1997 to December 31, 2014. The tumour, node and metastatic (TNM) classification, tumour grade and detailed information about Charlson Comorbidity Index (CCI), marital and educational status have been presented elsewhere [25, 26].

The patients’ ages were stratified by the median age ≤74 years and >74 years. Although most patients had cisplatin-based treatment, information about the type of chemotherapy and the curative intention, was not always available and therefore patients treated with any modality of chemotherapy were analysed together. Primary treatment was grouped as follows: radiotherapy with curative intent (RT), radical cystectomy (RC), chemotherapy in combination with radical cystectomy (Chemo-RC), other curative treatment (OCT), chemotherapy only (Chemo-only) and supportive management with best supportive care only.

We used all diagnoses of hospitalisations from 1987 until the end of 2014 in the previously validated In-Patient Registry [27]. VTE events and risk factors for VTE were registered at least 10 years before the diagnosis of UBC. Peripheral arterial thrombosis, considered to be dependent on local factors such as localized arterial stenosis were not included in the VTE group. To study background risk factors for VTE, the following codes in the hospital records were considered; coronary heart disease (IC10 codes I210-I259), stroke (ICD-10 codes I610-I649, I740-I749), hypertension (ICD 10 codes I110-I159). In case of registration of one or more of these conditions, the patient was considered to have a previous cardiovascular disease. Furthermore, diabetes mellitus (ICD-10 codes E109-E159) was analysed as a risk factor. Registered VTE events were pulmonary embolism (ICD-10 codes I260-I269) and venous thrombosis (ICD-10 codes I800-I809). Screening for VTE was not recommended during the studied period. Death and cause of death were registered until 31 December 2014 according to data from the National Causes of Death Register.

The national guidelines recommended prophylaxis against VTE with LMWH the day before RC and 14 days thereafter during the first part of the studied period, and later this recommendation was extended to 30 days. Information about the exact length of this prophylaxis for each patient was not available. At chemotherapy, no prophylaxis against VTE was recommended during the study period. A sub-group analysis, including only patients treated with RT, RC, Chemo-RC or Chemo-only with a known first treatment date, was used to relate VTE event to the date of treatment. In this analysis, patients with a treatment date after 30 November 2014 were excluded as the observation time from treatment was 31 days or less (Fig. 1).

Fig. 1

Diagram of studied groups of patients in those analysed for VTE after diagnosis and VTE after first treatment date, respectively, in all patients with stage T2-T4 urinary bladder cancer in Sweden 1997–2014.

Definitions of VTE occurrence

VTE before diagnosis was defined as all VTE events occurring prior to six months before diagnosis.

VTE at diagnosis was defined as all VTE events occurring from six months before diagnosis to 14 days after diagnosis.

VTE after diagnosis was defined as all VTE events occurring from 15 days after diagnosis until 24 months after diagnosis.

Late VTE was defined as all VTE events occurring from 24 months after diagnosis and onwards.

A second VTE event was defined as a VTE event occurring six months or more after the first VTE event.

Statistics

We investigated VTE events, patients and tumour characteristics, primary management and outcome. Differences between groups were studied using the chi squared test. A Cox Proportional Hazards analysis was used to study time to VTE, where patients were censored at the date of death or date of end of follow-up, if no VTE had occurred before this date. In a sub-group with a known first treatment date, a similar Cox analysis was carried out. A p-value <0.05 was considered to be statistically significant. Kaplan-Meier curves were used to illustrate the evolution of the cumulative incidence of VTE in the different treatment groups. Differences between groups were studied using the Log-rank test, and a p-value <0.05 was considered to be statistically significant.

The 117 patients with VTE events from six months before to 14 days after diagnosis were not included in the analyses of treatment-related VTE. All time to event analyses were limited to 24 months after diagnosis, restricting the study period to the most relevant one for treatment-associated VTE. Models were specified by using an a priori Diagnostic Acyclic Graph (DAG) displaying how different co-variates may influence the association between type of treatment and risk of VTE [28].

Results of the study in relation to previous findings

In this study a substantial number of patients with UBC had VTE shortly before or at the time of diagnosis and sometimes leading to diagnosis of UBC [2]. Therefore, all VTE events from six months before diagnosis until two weeks after diagnosis were considered to be related to the disease per se and not to treatment. In contrast, in most comparable series such stratification was not reported [5, 14, 15, 19, 20, 22, 23].

We considered the time period for VTE after diagnosis up to 24 months after the start of first treatment, which is a longer period than in other series [19, 22–23, 29, 30]. In contrast to our findings of increased cumulative incidence during 24 months after treatment, others have found the incidence of VTE to decrease after six months [20, 29, 30], possibly due to differences in how VTE was reported. In our series the diagnosis of VTE came from all hospitalisations and most outpatient care services covering all hospital facilities in the country, while other studies may have reported only from to the institution providing the bladder cancer treatment.

In the RC treatment group, we observed the majority of VTE events more than 30 days after surgery, favouring a longer LMWH prophylaxis in line with other authors. James et al. [14] found in 1581 patients the cumulative incidence of VTE to be 2.9%during hospitalisation and 3.3%from the end of hospitalisation up to 90 days after surgery. VanDlac et al. [15] found in 1307 patients a 30-day cumulative incidence of VTE in 6%and the majority occurred after hospital discharge. Schomburg et al. [20] observed, in a small randomised study comparing 30-day prophylaxis with prophylaxis during hospitalisation, a 90-day cumulative incidence of VTE of 5%and 17.6%, respectively. No increased risk of bleeding complications was observed with 30 days of LMWH prophylaxis [7, 20].

The results in the present and other series indicate that neoadjuvant or adjuvant chemotherapy might have a further prolonged effect on the occurrence of VTE [20–23, 29–31], possibly due to cisplatin-induced apoptosis and vascular necrosis mediated by the cytotoxic effect of caspases and calpain or vascular damage from central venous catheters or other mechanisms of hypercoagulability [17, 18]. Similar results have been found with carboplatin and gemcitabine [19]. However, due to a lack of complete data on date of initiation of chemotherapy, a comparison between occurrence of VTE after neoadjuvant vs adjuvant chemotherapy in conjunction with radical cystectomy was not possible.

The lower risk of VTE in patients with previous cardiovascular disease stands in contrast with previous findings [8, 23]. Reasons for this, besides the possible differences in compliance with guidelines by the risk group, might be that in Sweden a systematic approach to the treatment and prophylaxis of other cardiovascular events has been adopted since the nineties, including Warfarin medication on wide indications [32, 33]. Many patients with previous cardiovascular disease may have had Warfarin or LMWH medication throughout the observation period. The observed increased risk with later years of diagnosis might be due to a trend over time for wider indications for radical treatment including increased use of neoadjuvant chemotherapy [34].

The reported 9.6–26%cumulative incidence of VTE in the case of palliative chemotherapy [19, 22], and the observed high risk for VTE in our small Chemo-only group, might be dependent on factors such as progressive disseminated disease, immobilisation and comorbidity besides the given systemic chemotherapy, as seen in our supportive management group, where 67%of the VTE events occurred within three months before death as part of the progressive disease. A higher risk among married patients cannot be fully explained by insufficient adjustment for the known higher treatment intensity in this patient group [35] since the higher risk is still obvious in the adjusted analyses. A higher propensity to seek advice for symptoms and thus a higher diagnostic activity is a more likely explanation.