Venous Thromboembolism and Peri-Operative Chemotherapy for Muscle-Invasive Bladder Cancer: A Population-based Study

INTRODUCTION

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in patients with cancer [1]. Patients with bladder cancer have multiple risk factors for VTE. While several reports have described an increased risk of VTE due to major pelvic surgeries, such as cystectomy, [2–5] the risk of VTE during peri-operative chemotherapy has not been well characterized. Existing studies present conflicting results regarding the association between chemotherapy and VTE, have not been restricted to curative intent patients, or include only a small number of patients treated with chemotherapy [6–15]. Several studies conclude that neoadjuvant chemotherapy (NACT) is not associated with an increased risk of VTE after RC, [6, 13, 14] though these studies included only a small number of patients with NACT (sample size range 78–216). Conversely, a multi-institutional study of 761 patients receiving NACT followed by radical cystectomy (RC) report a VTE rate of 11% [16]. Fifty-eight percent of events occurred before RC. Our previous work did not identify an association between delivery of adjuvant chemotherapy (ACT) and VTE [13]. A systematic review and meta-analysis of 5082 of patients with bladder cancer treated with chemotherapy for any stage of disease describe an overall VTE rate of 7% [17].

A growing body of evidence supports the use of extended thromboprophylaxis treatment after cystectomy [6, 13–15]. Thromboprophylaxis treatment is not without risks, and therefore identifying patients at highest risk of VTE may guide decision-making. To address existing gaps in the literature we undertook a population-based study to describe VTE rates and the factors associated with VTE among patients treated with chemotherapy and cystectomy.

METHODS

RESULTS

VTE events

Nine percent (363/4205) of the study population experienced VTE within 6 months before or after cystectomy. The incidence rate of pre-operative and post-operative VTE was 1% and 8%, respectively. The incidence rate of VTE increased slightly over the study period (7% in 1994–1998 to 9% in 2009–2013, p = 0.019) (Supplemental eFigure 2).

The incidence rates of pre-operative and post-operative VTE in patients by treatment groups are shown in Fig. 1. Patients treated with NACT had a substantially higher rate of pre-operative VTE (4%) compared to patients not treated with pre-operative chemotherapy (0.5%, p <0.001). Post-operative rates of VTE within 6 months of cystectomy were comparable between patients treated with ACT and patients who did not receive chemotherapy (8% vs 8% p = 0.624). The cumulative rate of VTE within 6 months before and after cystectomy was substantially higher among those patients treated with NACT compared to patients with no chemotherapy or only ACT (12% vs 8% vs 9%, p = 0.002).

Fig.1

Crude incidence rates and timing of venous thromboembolism in 4205 patients with muscle-invasive bladder cancer treated with radical cystectomy by peri-operative chemotherapy groups in Ontario from 1994–2013. Abbreviations: VTE, venous thromboembolism NACT neoadjuvant chemotherapy, ACT, adjuvant chemotherapy, mos, Months. Post-cystectomy VTE rates are not cumulative and include VTEs that occurred during the hospital admission for cystectomy. Patients' earliest VTE is presented and those with pre-operative VTE are excluded from post-cystectomy VTE rates. Ranges are presented to prevent small cells from being calculated. The 57 patients who received neoadjuvant and adjuvant chemotherapy have been excluded from this figure to prevent numbers ≤6 from being calculated.

Timing of VTE relative to surgery is shown in Supplemental eFigure 3. Overall, 10%, 28% and 61% of VTEs were experienced before, during, and after the admission to hospital for cystectomy. Among patients treated with ACT, 51% of VTEs were experienced within 8 weeks and 82% within 16 weeks of starting chemotherapy (Supplemental eFigure 4).

DISCUSSION

In this population-based study, we describe incident rates of VTE among patients with bladder cancer treated with cystectomy and peri-operative chemotherapy in routine clinical practice. VTE events were identified using diagnostic codes from hospital admissions and/or emergency room visits. Accordingly, the events captured in this study and were likely symptomatic events and not incidental VTE identified on surveillance imaging. Several important findings have emerged. First, the incidence of any VTE within 6 months of surgery was 9% among all patients. Second, these rates have remained stable over the study period. Third, among patients treated with chemotherapy, the VTE rate was highest with NACT compared to ACT (12% vs 9%). Fourth, length of hospitalization and stage of disease are strongly associated with VTE risk independent of chemotherapy exposure. Finally, most VTEs were experienced after discharge for cystectomy.

Our results are consistent with several smaller studies reporting VTE rates of 9–18% [9, 11, 23–25]. These existing reports are limited by their small size, limited generalizability (i.e. single centre), often not describing in detail how VTEs were identified (symptom-driven vs incidental). Duivenoorden and colleagues have recently reported a multi-institutional study of 761 bladder cancer patients treated with NACT and cystectomy. In their study the VTE incidence rate was 11%; half of these events occurred before surgery which is very comparable to our study which reported a 4% VTE rate before cystectomy [9]. A retrospective chart review study of 202 patients treated with cystectomy at two centres in Canada reported an overall arterial/venous thrombosis rate of 8%; higher rates were observed with NACT(19%) [12].

In a retrospective cohort study of 1581 bladder cancer patients under age 65 by James et al., the incidence of VTE at three months post-RC was 10% and 45% of events occurred in the outpatient setting. Fourteen percent (216/1581) of patients received NACT, which was not found to be associated with VTE (OR1.57 95% CI 0.99–2.50) [6]. Vandlac et al. studied 1307 patients in a retrospective cohort study using chart data, and reported a VTE incidence of 6% (78/1307) after cystectomy with 55% diagnosed in the outpatient setting. Similar to the aforementioned study, NACT was not found to be associated with VTE, which the authors attributed to small numbers [14].

A systematic review and meta-analysis by Gopalakrishna et al., aimed to determine the rate of VTE in patients receiving systemic therapy for urothelial carcinoma. Included studies were published from 1985 to 2015 and a wide distribution of VTE rates was found across studies. 5082 patients were identified from 62 studies, with a median age of 65 and 55% of patients underwent surgery. The VTE rate was found to be 7%. Important limitations of this review were the heterogeneity in the study population, and incomplete information on several variables of interest and timing of systemic therapy and VTE in the included studies. Finally, rates of VTE did not significantly change over time, which the authors suggest may be related to poor development of guidelines and adherence for prophylaxis treatment [17].

Current guidelines recommend perioperative VTE prophylaxis for bladder cancer patients undergoing RC while in hospital [26–29]. Although there is a lack of consensus across all guidelines, recent guideline updates are support extended thromboprophylaxis [30, 31]. The 2012 American College of Chest Physicians guidelines [26], the 2017 European Association of Urology guidelines [32] and the 2018 NCCN guidelines [33] recommend 4 weeks of prophylaxis for patients undergoing major abdominal or pelvic surgery for cancer, while the American Urological Association [27] does not recommend extended duration prophylaxis. The Level 1 evidence supporting the use of extended thromboprophylaxis has largely been from studies of non-urologic cancer [34–36]. This combined with the variable recommendations for extended prophylaxis and provider concerns of post-operative hemorrhage might explain the lower compliance and slow uptake of extended thromboprophylaxis treatment for bladder cancer patients [37, 38].

Several studies have shown that a large proportion (45%–55%) of VTEs occur after discharge from hospital, [6, 14] including our previous work, [13]; this observation lends support to the role of extended thromboprophylaxis. In the present study, we found that 61% of VTE events occur after discharge. In 2017, a retrospective study by Pariser et al., of 402 RC patients, examined the post-RC VTE rate before and after the implementation of an extended enoxaparin prophylaxis regimen at their institution. The VTE rate before and after the regimen implementation was 28/234 (12%) and 9/168 (5%) (p = 0.024). Post-discharge VTE rates within 90 days of RC decreased from 6% to 2% (p = 0.039) and transfusion rates were similar across both time periods 44% vs 49% (p = 0.342) [15].

Although current guidelines have mixed recommendations, [26, 27] a growing body of literature exists to support the use of extended prophylaxis in patients undergoing RC for bladder cancer [6, 13, 14]. While an established threshold risk has not been agreed on, a VTE risk of at least 10% has been used for justification for primary thromboprophylaxis in several settings [39–43].

In the absence of a randomized trial to strengthen the quality of current evidence, and non-negligible bleeding risks accompanying prophylaxis treatment, identifying high risk VTE patients is one possible approach for selecting patients who would benefit most from extended thromboprophylaxis treatment. Our findings suggest there is a group of identifiable patients who are experiencing VTE after discharge with several key risk factors including advanced disease, extended hospital admissions and potentially receipt of chemotherapy. In addition, the association with higher surgeon volume likely reflects more complex patients receiving treatment at larger centers. It may also reflect differences in use of radiologic testing that may increase the proportion of patients diagnosed with low-volume VTE.

This study has limitations that merit comment. Incidence rates of VTE are potentially underestimated due to the requirement of a hospital interaction for data capture. However, it is worth noting that VTE events in our study were likely symptomatic since they were associated with a visit to the Emergency Room and/or admission to hospital. It is therefore likely that our data under-estimate the true risk as VTE managed in out-patient clinics is not captured. The available data-sets also do not allow us to identify those patients who were treated with anticoagulants or whom may have had a more remote VTE. We also did not have granular clinical information such as use of central venous catheters of laboratory indices (i.e. Khorana risk factors) to include in the models. As with all retrospective observational studies, unmeasured confounding variables could not be accounted for in the adjusted analyses. It is possible that some cases classified as having ACT were in fact being treated with palliative intent chemotherapy for early recurrent disease. Due to missing drug name/number of cycles we were also unable to explore the association between chemotherapy intensity/duration and VTE. In the present study, the incidence of any VTE within 6 months of cystectomy was found to be 10% in patients treated with chemotherapy and 8% in patients not treated with chemotherapy. Patients who do not receive chemotherapy are often older, have more comorbidity, and longer hospital admissions for cystectomy. The resulting higher baseline of rate of VTE in patients who do not receive chemotherapy, makes it difficult to demonstrate the additional increase in risk of VTE due to chemotherapy when comparing patient groups. Importantly, data regarding adherence to and methods of mechanical and pharmacological VTE prophylaxis and data regarding patients’ perioperative mobility were unavailable. It is unlikely during the study period (pre-2014) that there was widespread utilization of extended thromboprophylaxis among patients treated with RC. Although the rate of pre-operative VTE was much higher among those patients with NACT, it is not clear whether this is being driven by pro-thrombotic factors related to chemotherapy, the presence of central venous lines, or by the presence of more advanced disease. In this study we did not explore arterial thrombotic events; this is an area that required further study. Despite these limitations, in addition to the large sample size, a strength of this study is the fact that the study population included all cases of bladder cancer treated with curative intent within Ontario and was therefore unselected. By including the entire population of interest it is possible to minimise the selection biases that affect traditional institution-based observational studies.

In summary, our data suggest that a substantial proportion of patients with bladder cancer treated with peri-operative chemotherapy will develop VTE. The majority of these occur after discharge from hospital following cystectomy. Further work is needed to understand whether there is a role for thromboprophylaxis during neoadjuvant chemotherapy. Extended thromboprophylaxis after RC for high-risk patients including those who receive peri-operative chemotherapy should be considered.

FUNDING

Dr. Booth is supported as a Canada Research Chair in Population Cancer Care. This work was also supported by the Canada Foundation for Innovation and the Canadian Cancer Society Research Institute.

CONFLICTS OF INTEREST

The authors report no conflicts of interest.