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Article

Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy: A Systematic Review and Meta-Analysis

1
Global Health Neurology Lab, Sydney, NSW 2000, Australia
2
Neurovascular Imaging Laboratory, Clinical Sciences Stream, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
3
UNSW Medicine and Health, University of New South Wales (UNSW), South Western Sydney Clinical Campuses, Sydney, NSW 2170, Australia
4
Department of Neurology & Neurophysiology, Liverpool Hospital & South West Sydney Local Health District (SWSLHD), Liverpool, NSW 2170, Australia
5
NSW Brain Clot Bank, NSW Health Pathology, Sydney, NSW 2170, Australia
6
Stroke & Neurology Research Group, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
*
Author to whom correspondence should be addressed.
Current address: Department of Neurology & Neurophysiology, Clinical Sciences Building, Liverpool Hospital, Elizabeth St., Liverpool, NSW 2170, Australia.
Diagnostics 2022, 12(12), 2954; https://doi.org/10.3390/diagnostics12122954
Submission received: 23 September 2022 / Revised: 6 November 2022 / Accepted: 24 November 2022 / Published: 25 November 2022
(This article belongs to the Topic Thrombosis: From Basic Mechanisms to Saving Lives)

Abstract

:
Objective: Venous thromboembolism (VTE) is a life-threatening complication that may exacerbate cancer prognosis. Whilst some studies indicate an increased risk of VTE in cancer patients undergoing chemotherapy, the prevalence estimates on the pooled prevalence of VTE in cancer patients undergoing chemotherapy are not known. This study aims to calculate the pooled prevalence of VTE in chemotherapy-treated cancer patients. Methods: Studies on VTE occurrence in cancer patients undergoing chemotherapy were retrieved after database search. The terms used included “cancer”, “chemotherapy”, and “venous thromboembolism”. A random-effects meta-analysis was conducted to obtain a pooled estimate of VTE prevalence in cancer patients undergoing chemotherapy. Results: A total of 102 eligible studies involving 30,671 patients (1773 with VTE, 28,898 without) were included in the meta-analysis. The pooled estimate of VTE prevalence was found to be 6%, ranging from 6% to 7% (ES 6%; 95% CI 6–7%; z = 18.53; p < 0.001). Conclusions: The estimated pooled prevalence rate of VTEs was 6% in cancer patients undergoing CRT, which was higher than the overall crude prevalence rate (5.78%). Comprehensive cancer care should consider stratified VTE risk assessment based on cancer phenotype, given that certain phenotypes of cancer such as bladder, gastric and ovarian posing particularly high risks of VTE.

1. Introduction

Venous thromboembolism (VTE) is a major public health problem constituting a significant burden of disease [1,2]. There are around 10 million cases of VTE worldwide every year. After myocardial infarction and stroke, VTE is the third leading vascular disease [3]. In the first one to three months following a stroke, there is an increased risk of VTE, partly because of immobility brought on by the stroke [4]. Major venous and arterial thrombotic disorders share overlap in some key cardiovascular risk factors [5]. A higher risk of VTE is linked to specific cardiovascular risk factors such as older age, smoking, and greater adiposity [2,6]. Cancer, a leading cause of death and disability in the world [7,8], is known to potentiate the risk of VTE and roughly 20% of VTE are linked to cancer [9,10]. Thrombosis in cancer patients is a clinically challenging construct which is associated with poor outcomes despite therapy [11].
Recent studies have also indicated that cancer patients on chemotherapy may be at an increased risk of venous thromboembolism [12,13,14]. Assessment of VTE risk is critical for appropriate medical management and prophylactic treatment [15]. Given the lack of data on the prevalence estimates of VTE in cancer patients, especially in those receiving chemotherapy, further studies are required. Distinct cancer phenotypes may render cancer patients at varying levels of VTE risk [16,17,18]. Recent guidelines from American Society of Haematology published in early 2021 recommend stratifying cancer patients according to their VTE risk prior to the start of chemotherapy, as well as patient-specific factors, using the Khorana risk score, the major determinant of which is cancer phenotype [19]. This comes in the background of two landmark randomized clinical trials (RCTs), resulting in the change of guidelines, demonstrating VTE prophylaxis with direct oral anticoagulants (DOACs) following risk assessment lowered the incidence of VTE during chemotherapy [20,21,22]. Several societies or health systems beyond United States are yet to adopt these recommendations; besides, unwarranted variations in clinical care as well as poor adherence to recommendations or guidance vis à vis VTE risk assessment and optimal administration of thromboprophylaxis pose an ongoing real-world or systems challenge [23,24]. Moreover, literature is sparse when comparing the relative risk and prevalence of VTE across multiple cancer phenotypes—with studies only revealing VTE prevalence specific to a cancer phenotype and risk in homogenous cancer populations, vis à vis their ethnicity and treatment received. Understanding of, and estimates of, the pooled prevalence may also be useful to increase awareness on VTE risks in cancer patients undergoing chemotherapy as well to inform clinicians and patients on the quantum of the VTE prevalence/risks in cancer or across various types of cancer. This meta-analysis sought to investigate the pooled prevalence of venous thromboembolism in cancer patients receiving chemotherapy. There is also a gap in clinician knowledge pertaining to the specific risk that cancer phenotypes and chemotherapy poses to cancer patients. We have sought to address two key underlying questions through this meta-analysis:
(1)
what is the prevalence of VTE in cancer patients receiving chemotherapy?
(2)
what is the prevalence of VTE stratified by cancer phenotype in patients undergoing chemotherapy?

2. Materials and Methods

2.1. Literature Search: Identification and Selection of Studies

The primary search engine of this meta-analysis and systematic review was the PubMed database. Articles published between 2012 and October 2022 were included in the search. Search terms included: “cancer”, “chemotherapy” and “venous thromboembolism”. The complete search strategy is available in the Supplementary Information (Search Strategy). Studies were filtered to include those in the English language, conducted on humans, and restricted to disregard Phase I studies, accepting only those Phase II and above. Additional studies were also included through handsearching of references from included studies as well as from other sources such as Google Scholar and ResearchGate. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This study was registered in Open Science, registration number is “yn5br” (https://osf.io/yn5br/ (accessed on 6 November 2022)). The PRISMA flowchart shows the studies included in the meta-analysis (Figure 1). PRISMA checklist is also provided in the Supplementary Information (PRISMA Checklist).

2.2. Inclusion and Exclusion Criteria

Studies were eligible for inclusion if they met the following criteria: (1) age ≥ 18 years; (2) patients with a confirmed diagnosis of cancer; (3) patients receiving chemotherapy; (4) patients not on prophylactic anticoagulation concomitant to chemotherapy, (5) availability of data on VTE occurrence noted in patients; and (6) studies with a sample size of >20 patients. The exclusion criteria were (1) studies not in English, (2) animal studies, (3) duplicated publications, (4) systematic reviews, meta-analyses, or narrative reviews; and (5) studies whereby relevant data on VTE occurrence not available.

3. Data Extraction

Firstly, titles and abstracts were screened on EndNote™ (Clarivate, Philadelphia, PA, USA) to identify articles that were beyond the scope of this study, were systematic reviews of meta-analyses, or for other reasons failed to match the eligibility criteria before being excluded. Remaining articles were read in full-text and comprehensively assessed to determine eligibility for inclusion in this study, with screening conducted independently by two experienced investigators. In the case of disagreement between authors, a consensus was reached through discussion. A data extraction sheet was used to extract the following data from each study: (1) baseline demographics: author, year of publication, type of publication, country of lead author, study design, and study type; (2) study population: age of patients, sample size, baseline clinical characteristics, cancer phenotype, body location of cancer, cancer stage, and treatment agent, dose, duration, and frequency; (3) outcome measures: VTE occurrence. In the grading of VTE severity, most VTEs were classified as an adverse effect within a drug trial, and thus were graded via the Common Terminology Criteria for Adverse Events (CTCAE) scale of Grade 1 through 5. Although some studies were particular in grading each adverse event into individual categories of Grade 1/2/3/4/5, the majority of studies grouped Grades 1 and 2 together, and Grades 3/4/5 together. As such, in our meta-analysis, we have extracted data based on this later, more generalised method. Studies reporting on VTE in cancer, without prophylactic anticoagulation concomitant to chemotherapy, were included in the systematic review and meta-analysis.

Quality Assessment of Included Studies

Using the modified Jadad analysis (MJA) criterion, the methodological quality of each study was assessed [25]. The MJA evaluates the quality of studies based upon: randomisation, blinding, description of withdrawals/dropouts, inclusion/exclusion criteria, assessment of adverse events and methods used for statistical analysis. Studies receive a score from 0–8 based upon their ability to fulfil aforementioned criteria [26]. The complete quality assessment of each study is available in the Supplementary Information (Jadad Analysis). Each study was also separately assessed for risk of funding bias using a 2-point scale that scored studies from 0 (low potential for bias) to 2 (high potential for bias) [27]. The absence of industry funding was not taken to signify an absence of bias, but the presence of industry funding or conflicts of interest was assumed to be an indicator of bias.

4. Statistical Analysis

Statistical analysis was performed using STATA (Version 13.0, StataCorp LLC, College Station, TX, USA). The purpose of this study was to determine the prevalence of VTE in cancer patients undergoing chemotherapy. As a result, the “metaprop” STATA command was utilised, pooling prevalence by performing a random-effects meta-analysis of proportions obtained from the individual studies [28]. The DerSimonian and Laird method was used for random effects modelling. In presenting the overall effects, forest plots were generated. Heterogeneity across the studies was estimated from the inverse-variance fixed-effect model and quantified using the I2 measure (I2 < 40% = low, 30–60% = moderate, 50–90% = substantial, and 75–100% = considerable). An overall meta-analysis was performed stratified by cancer phenotype to estimate the pooled prevalence of VTE in cancer patients undergoing chemotherapy. Besides, meta-analysis for individual cancer phenotypes were also performed provided there were minimum of 4 studies. The estimate of between-study variance (tau-squared or τ2) was also reported. Significance tests in the form of z-statistics and p-values were also reported. p-values less than 0.05 were considered significant.

5. Results

A total of 2643 and 85 studies were identified from PubMed and other sources, respectively. On screening of 2723 titles/abstracts, 2172 studies were excluded. Out of these, full texts of 551 studies were assessed for eligibility. Overall, 102 studies were included in the final synthesis.

5.1. Description of Included Studies

This meta-analysis included 102 studies, which reported on VTE prevalence within cancer patients undergoing chemotherapy, with a cumulative cohort of 30,671 patients (1773 with VTE, 28,898 without). Within a cohort of 20,420 patients for which data on sex was reported, 53.11% were male (sex data on 10,251 patients were not reported). Age ranged from 18–93 years. The mean age within a cohort of 8159 patients on which age data was reported was 59.59 years (standard deviation (SD) 33.74). Twenty-two cancer phenotypes were identified including bladder, blood, brain, breast, cervical, colorectal, endometrial, gastric, germ cell, head and neck, liver, lung, lymph, mesothelial, mixed, neuroendocrine, oesophageal, ovarian, pancreatic, prostate, renal, and skin.
The clinical characteristics of all included studies are shown in Table 1. Table 2 and Table 3 further delineate treatment dose, duration, and frequency. Tabulated results for the estimated pooled prevalence and crude prevalence rates stratified by cancer phenotype are shown in Table 4. The MJA and funding bias analysis for each study can be found in Supplemental SI Tables S1 and S2.

5.2. Overall Prevalence of VTE in Cancer Patients Undergoing Chemotherapy

One hundred and two included studies, encompassing 30,671 patients, reported on the prevalence of VTE in cancer patients receiving chemotherapy only. The meta-analysis revealed a pooled estimated prevalence of 6%, ranging from 6% to 7% (ES 6%; 95% CI 6–7%; z = 18.53; p < 0.001) (Table 4 and Figure 2). Notably, there was considerable heterogeneity between the included studies (I2 = 91.84%, p < 0.001). The estimate of between-study variance (τ2) was 0.04. The estimated pooled prevalence of VTE in cancer patients undergoing chemotherapy was higher than the crude prevalence rates of 5.78% observed in this study. The heterogeneity chi2 was 1237.89 (p < 0.001, d.f. = 101). Figure 3 provides findings of the overall meta-analysis on the pooled estimated prevalence stratified by cancer phenotype.

5.3. Prevalence of VTE in Cancer Patients Stratified by Cancer Phenotype

5.3.1. Prevalence of VTE in Bladder Cancer Patients

Four included studies encompassing 2700 patients reported on the prevalence of VTE in bladder cancer patients undergoing chemotherapy [35,87,91,116]. The meta-analysis revealed a pooled estimated prevalence of 18%, ranging from 10% to 28% (ES 18%; 95% CI 10–28%; z = 6.53; p < 0.001) (Table 4 and Supplemental SI Figure S1). Notably, there was considerable heterogeneity between the included studies (I2 = 95.85%, p < 0.001). The estimate of between-study variance (τ2) was 0.05. The estimated pooled prevalence of VTE in blood cancer patients (18%) was higher than the crude prevalence rate of 11.30% observed in this study. The heterogeneity chi2 was 72.22 (p < 0.001, d.f. = 3).

5.3.2. Prevalence of VTE in Blood Cancer Patients

Three included studies, encompassing 934 patients, reported on the prevalence of VTE in blood cancer patients [85,107,117]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in blood cancer patients was 10.81% (Table 4).

5.3.3. Prevalence of VTE in Brain Cancer Patients

Eight included studies encompassing 3177 patients reported on the prevalence of VTE in brain cancer patients undergoing chemotherapy [29,30,58,89,93,98,127,129]. The meta-analysis revealed a pooled estimated prevalence of 4%, ranging from 4 to 5% (ES 4%; 95% CI 4–5%; z = 17.72; p < 0.001) (Table 4 and Supplemental SI Figure S2). Notably, there was low heterogeneity between the included studies (I2 = 0.00%, p = 0.56). The estimate of between-study variance (τ2) was 0.00. The estimated pooled prevalence of VTE in brain cancer patients (4%) was lower than the crude prevalence rate of 5.19% observed in this study. The heterogeneity chi2 was 72.22 (p = 0.56, d.f. = 3).

5.3.4. Prevalence of VTE in Breast Cancer Patients

Eight included studies encompassing 3082 patients reported on the prevalence of VTE in breast cancer patients undergoing chemotherapy [36,37,46,69,76,103,104,112]. The meta-analysis revealed a pooled estimated prevalence of 1%, ranging from 0% to 3% (ES 1%; 95% CI 0–3%; z = 4.17; p < 0.001) (Table 4 and Supplemental SI Figure S3). Notably, there was substantial heterogeneity between the included studies (I2 = 73.31%, p < 0.001). The estimate of between-study variance (τ2) was 0.01. The estimated pooled prevalence of VTE in breast cancer patients (1%) was lower than the crude prevalence rate of 1.88% observed in this study. The heterogeneity chi2 was 26.23 (p < 0.001, d.f. = 7).

5.3.5. Prevalence of VTE in Cervical Cancer Patients

Two included studies, encompassing 716 patients, reported on the prevalence of VTE in cervical cancer patients [63,124]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in cervical cancer patients was 6.42% (Table 4).

5.3.6. Prevalence of VTE in Colorectal Cancer Patients

Fifteen included studies encompassing 5891 patients reported on the prevalence of VTE in colorectal cancer patients undergoing chemotherapy [34,42,44,53,55,59,88,102,106,110,111,118,122,125,126]. The meta-analysis revealed a pooled estimated prevalence of 5%, ranging from 3 to 7% (ES 5%; 95% CI 3–7%; z = 8.16; p < 0.001) (Table 4 and Supplemental SI Figure S4). Notably, there was substantial heterogeneity between the included studies (I2 = 85.28%, p < 0.001). The estimate of between-study variance (τ2) was 0.02. The estimated pooled prevalence of VTE in colorectal cancer patients (5%) was higher than the crude prevalence rate of 4.69% observed in this study. The heterogeneity chi2 was 95.10 (p < 0.001, d.f. = 14).

5.3.7. Prevalence of VTE in Endometrial Cancer Patients

Three included studies, encompassing 173 patients, reported on the prevalence of VTE in endometrial cancer patients [31,54,74]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in endometrial cancer patients was 11.56% (Table 4).

5.3.8. Prevalence of VTE in Gastric Cancer Patients

Seven included studies encompassing 4932 patients reported on the prevalence of VTE in gastric cancer patients undergoing chemotherapy [57,78,86,94,99,119,130]. The meta-analysis revealed a pooled estimated prevalence of 9%, ranging from 5% to 15% (ES 9%; 95% CI 5–15%; z = 5.89; p < 0.001) (Table 4 and Supplemental SI Figure S5). Notably, there was considerable heterogeneity between the included studies (I2 = 95.94%, p < 0.001). The estimate of between-study variance (τ2) was 0.05. The estimated pooled prevalence of VTE in gastric cancer patients (9%) was higher than the crude prevalence rate of 6.55% observed in this study. The heterogeneity chi2 was 147.92 (p < 0.001, d.f. = 6).

5.3.9. Prevalence of VTE in Germ Cell Cancer Patients

One included study, encompassing 193 patients, reported on the prevalence of VTE in endometrial cancer patients [65]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in germ cell cancer patients was 2.07% (Table 4).

5.3.10. Prevalence of VTE in Head and Neck Cancer Patients

Two included studies, encompassing 158 patients, reported on the prevalence of VTE in head and neck cancer patients [38,62]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in head and neck cancer patients was 1.27% (Table 4).

5.3.11. Prevalence of VTE in Liver Cancer Patients

Two included studies, encompassing 347 patients, reported on the prevalence of VTE in liver cancer patients [43,109]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in liver cancer patients was 5.19% (Table 4).

5.3.12. Prevalence of VTE in Lung Cancer Patients

Sixteen included studies encompassing 3228 patients reported on the prevalence of VTE in lung cancer patients undergoing chemotherapy [47,60,61,64,68,71,77,83,84,90,92,101,114,120,123]. The meta-analysis revealed a pooled estimated prevalence of 5%, ranging from 2 to 9% (ES 5%; 95% CI 2–9%; z = 4.32; p < 0.001) (Table 4 and Supplemental SI Figure S6). Notably, there was considerable heterogeneity between the included studies (I2 = 93.22%, p < 0.001). The estimate of between-study variance (τ2) was 0.08. The estimated pooled prevalence of VTE in lung cancer patients (5%) was higher than the crude prevalence rate of 3.97% observed in this study. The heterogeneity chi2 was 221.28 (p < 0.001, d.f. = 15).

5.3.13. Prevalence of VTE in Lymph Cancer Patients

Six included studies encompassing 699 patients reported on the prevalence of VTE in lymph cancer patients undergoing chemotherapy [41,45,50,51,72,97]. The meta-analysis revealed a pooled estimated prevalence of 4%, ranging from 2% to 7% (ES 4%; 95% CI 2–7%; z = 4.69; p < 0.001) (Table 4 and Supplemental SI Figure S7). Notably, there was substantial heterogeneity between the included studies (I2 = 54.86%, p = 0.05). The estimate of between-study variance (τ2) was 0.01. The estimated pooled prevalence of VTE in lymph cancer patients (4%) was higher than the crude prevalence rate of 3.58% observed in this study. The heterogeneity chi2 was 11.08 (p = 0.05, d.f. = 5).

5.3.14. Prevalence of VTE in Mesothelial Cancer Patients

Five included studies encompassing 1286 patients reported on the prevalence of VTE in mesothelial cancer patients undergoing chemotherapy [39,49,80,113,128]. The meta-analysis revealed a pooled estimated prevalence of 6%, ranging from 3% to 11% (ES 6%; 95% CI 3–11%; z = 5.24; p < 0.001) (Table 4 and Supplemental SI Figure S8). Notably, there was substantial heterogeneity between the included studies (I2 = 84.17%, p < 0.001). The estimate of between-study variance (τ2) was 0.02. The estimated pooled prevalence of VTE in mesothelial cancer patients (6%) was higher than the crude prevalence rate of 4.82% observed in this study. The heterogeneity chi2 was 25.27 (p < 0.001, d.f. = 4).

5.3.15. Prevalence of VTE in Neuroendocrine Cancer Patients

One included study, encompassing 113 patients, reported on the prevalence of VTE in neuroendocrine cancer patients [56]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in neuroendocrine cancer patients was 6.19% (Table 4).

5.3.16. Prevalence of VTE in Oesophageal Cancer Patients

Two included studies, encompassing 328 patients, reported on the prevalence of VTE in oesophageal cancer patients [52,67]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in oesophageal cancer patients was 9.76% (Table 4).

5.3.17. Prevalence of VTE in Ovarian Cancer Patients

Six included studies encompassing 718 patients reported on the prevalence of VTE in ovarian cancer patients undergoing chemotherapy [40,79,82,96,115,121]. The meta-analysis revealed a pooled estimated prevalence of 8%, ranging from 5% to 12% (ES 8%; 95% CI 5–12%; z = 7.47; p = 0.02) (Table 4 and Supplemental SI Figure S9). Notably, there was substantial heterogeneity between the included studies (I2 = 61.47%, p = 0.02). The estimate of between-study variance (τ2) was 0.01. The estimated pooled prevalence of VTE in ovarian cancer patients (8%) was lower than the crude prevalence rate of 8.22% observed in this study. The heterogeneity chi2 was 12.98 (p = 0.02, d.f. = 5).

5.3.18. Prevalence of VTE in Pancreatic Cancer Patients

Three included studies, encompassing 144 patients, reported on the prevalence of VTE in pancreatic cancer patients [32,33,81]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in pancreatic cancer patients was 28.47% (Table 4).

5.3.19. Prevalence of VTE in Prostate Cancer Patients

Three included studies, encompassing 1233 patients, reported on the prevalence of VTE in prostate cancer patients [95,100,108]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in prostate cancer patients was 2.11% (Table 4).

5.3.20. Prevalence of VTE in Renal Cancer Patients

Two included studies, encompassing 198 patients, reported on the prevalence of VTE in renal cancer patients [48,105]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in renal cancer patients was 11.11% (Table 4).

5.3.21. Prevalence of VTE in Skin Cancer Patients

One included study, encompassing 93 patients, reported on the prevalence of VTE in skin cancer patients [75]. However, a meta-analysis could not be performed due to insufficient number of studies. The crude prevalence rate of VTE in skin cancer patients was 7.53% (Table 4).

6. Discussion

Our meta-analysis revealed an overall pooled estimated prevalence of VTEs in cancer patients undergoing chemotherapy, as well for various cancer phenotypes. Our findings indicate that the estimated pooled prevalence of VTEs in cancer patients undergoing chemotherapy is approximately 6%, ranging from 5% to 7%, which is higher than the crude prevalence rate of 5.78%. To the best of our knowledge, this is one of the first reports in which prevalence estimates of VTE have been conducted on a relatively large cohort of patients. Our findings also reveal phenotypic variability in VTE risk, indicating need for prophylactic management of VTE risk in cancer patients undergoing chemotherapy, with certain phenotypes of cancer such as bladder, gastric and ovarian posing particularly high risks of VTE.
One explanation for why cancer patients have a higher risk of having VTE is that tumours can express various procoagulant molecules and alter tissue factor expression [131,132]. Certain tumours may also raise the risk of thrombosis by compressing blood vessels, changing blood flow, or causing injury to the vascular endothelium through intravascular growth [9]. Subsequent cancer diagnosis within the first year of first VTE diagnosis have been reported in up to 10% of patients [133]. Therefore, VTE, especially in the lower limbs, can also be useful as marker for occult cancer [134].
This pooled estimate of 6% is higher than other estimates of 2.3% prevalence rates of VTE in cancer patients in the first 12 months after their diagnosis, with other estimates ranging from 4–20% of cancer patients developing VTE in their lifetime [12,135]. Amongst the normal population, VTE prevalence is at 1–2% [136]. In a retrospective study on 40,787,000 hospitalised cancer patients from 1979 through 1999, patients with malignancy were found to have a 2% prevalence of thromboembolism, although, were not necessarily on chemotherapy or radiotherapy treatment [137]. This suggests that cancer itself, without the interference of external treatment regimens, may not pose a significant risk to VTE but rather, it is the accompanying therapies which may confer additional VTE risk.
The prevalence of VTE may vary across cancer phenotype. This is of clinical interest as it may aid in the risk-staging and appropriate tailored management specific to cancer phenotype. We found that the pooled VTE prevalence varied across cancer phenotype in the range of 1–18%, with lowest prevalence of 1% observed in breast and head and neck cancer and highest prevalence of 18% observed in bladder cancer. This indicates a need for more aggressive VTE screening for specific cancer phenotypes. From a policy standpoint, beyond the hospital-based risk factors, such as recent surgery, cancer, and congestive heart failure, to prevent VTE, dietary counselling as well as public health strategies around encouraging the adoption of heart-healthy habits for cancer patients undergoing chemotherapy may be beneficial [138]. Moreover, concomitant preventative measures targeting arterial thrombosis and VTE are also important [2].

6.1. Pathophysiology of VTE in Cancer Patients

The pathophysiological process behind VTE prevalence in cancer patients is multifaceted and can be attributed to multiple aetiological pathways, spanning the hypercoagulable state induced by malignancy itself to the thrombotic risk posed by treatment regimens of chemotherapy and radiotherapy [139]. The inflammatory state induced by malignancy, stemming from tumour biology and activation of the coagulation cascade, increases cancer patients’ risk of VTE occurrence [139]. On a molecular level, several factors increase the risk of VTE, with increased concentrations of procoagulants on a cellular level amplifying thrombosis prevalence. These include tissue factor, microparticles, plasminogen activator inhibitor-1, cancer procoagulant, mucin, tumour-derived platelet agonists and inflammatory cytokines such as IL-6, IL-8 and IL-10 [140,141,142,143,144,145]. Alterations to thrombomodulin expression due to interference from tumour necrosis factor-a and IL-1B also contribute to a prothrombotic state [146].

6.2. Chemotherapy and VTE

Chemotherapy has been shown to increase VTE risk by six-fold in cancer patients [12]. Multiple chemotherapy drugs which are used to treat cancer are associated with increased thrombotic events [147]. Cisplatin is a major component of several treatment regimens—and its thrombotic potential and vascular toxicity has been identified since 1986 [148]. Through direct drug-induced damage to the endothelium and by indirectly increasing the expression of TF procoagulant activity of monocytes and macrophages, chemotherapy poses a serious risk of increasing VTE within a cancer patient [148].

7. Limitations

There are several limitations to this study due to variance across the quality of studies included and therefore ability to accurately process the data extracted. Firstly, the types of studies included vary from being retrospective in design to being randomised controlled trials (RCT)—therefore, whilst some studies noted VTE as one of multiple adverse effects within an RCT for a novel chemotherapy regimen, others purely sought to document VTE occurrence within a cohort of cancer patients which oftentimes varied in cancer phenotype, staging and treatment. Furthermore, whilst some studies were robust in being double-blinded, randomised, placebo-controlled and multi-institutional, others were single institution studies conducted on a relatively small cohort size, without an appropriate control group or blinding. As such, this wide variance in included study quality could confound the overall pooled estimated prevalence. Within these studies, their documentation of patients’ cancer history is highly limited. Reporting of time of diagnosis to treatment, the duration, drug regimen and frequency of previous treatments are inconsistent and rarely available. As such, it is difficult to determine whether previous treatment regimens played a confounding role in patients developing VTE. We are also unable to determine whether variance in time of diagnosis to treatment plays a role. Moreover, there was a lack of standardised reporting and insufficient detail in the description of VTEs across the studies. As the majority of studies included were RCTs, VTEs were often a side effect as opposed to the focus of the study, and thus less attention was given toward the VTE. VTE pooled prevalence stratified by cancer severity grade was not investigated in this meta-analysis. In few cases, studies neglected to document the severity of thrombotic events altogether—in which we have assumed a Grade 3/4/5 event in that case. Besides, detailed analysis into the association between severity of VTE event, and any relationship with cancer phenotype, time to treatment, staging, drug regimen, or patient profile could not be performed. Additionally, documentation on certain groups such as atrial fibrillation and VTE recurrence were not available across all studies. It would be ideal to understand whether VTE events occurred before therapy, during, or how long post-diagnosis and post-treatment. As such, more robust future studies with more detailed information and reporting on VTE occurrence, recurrence and adverse effects is necessary. Another limitation of this study and in the studies gathered is the lack of accounting for baseline underlying comorbidities in all the patients. Important factors such as atherosclerosis, cardiovascular disease, histories of smoking, histories of VTE, obesity and age were not detailed in the original studies.
Although patients on prophylactic anticoagulation concomitant to chemotherapy were not included in this study, we acknowledge that previous history of anticoagulation may presumably not have been reported in some studies. In light of recent guidelines [19], as adherence to prophylactic anticoagulation grows to reduce VTE risk, it is likely that VTE prevalence will show a downward trajectory. Finally, for the patients who did experience VTE prevalence, often these patients were not followed longitudinally for VTE recurrence, and specific time to disease progression and overall survival. Typically, follow-up was not provided for longer-term complications and recurrence. The discrepancy in protocol for VTE diagnosis and follow-up between hospitals and studies leads to the inconsistent reporting and treatment of patients across the clinical decision making, imaging and diagnosis pipeline. Despite these limitations, the use of random-effects modelling would have mitigated some of the random biases and risks above.

8. Conclusions

In conclusion, this meta-analysis demonstrated a pooled prevalence estimate of 6%, with a range of 5% to 7%, of VTEs amongst cancer patients undergoing chemotherapy. Our study indicates there is substantial risk of developing VTE as a cancer patient on chemotherapy showing a compelling need for robust screening and subsequent prophylactic management to prevent future VTE. More efforts should be undertaken to implement adherence of American Society of Haematology guidelines on VTE risks and management in cancer patients undergoing chemotherapy [19].

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/diagnostics12122954/s1, Figure S1: Forest plot showing the estimated pooled prevalence of VTE in bladder cancer patients; Figure S2: Forest plot showing the estimated pooled prevalence of VTE in brain cancer patients; Figure S3: Forest plot showing the estimated pooled prevalence of VTE in breast cancer patients; Figure S4: Forest plot showing the estimated pooled prevalence of VTE in colorectal cancer patients; Figure S5: Forest plot showing the estimated pooled prevalence of VTE in gastric cancer patients; Figure S6: Forest plot showing the estimated pooled prevalence of VTE in lung cancer patients; Figure S7: Forest plot showing the estimated pooled prevalence of VTE in lymph cancer patients; Figure S8: Forest plot showing the estimated pooled prevalence of VTE in mesothelial cancer patients; Figure S9: Forest plot showing the estimated pooled prevalence of VTE in ovarian cancer patients; Table S1: Modified Jadad Analysis for Methodological Quality; e.g., S2: Funding bias scores for studies.

Author Contributions

S.M.M.B. conceived the study, contributed to the planning, drafting, and revision of the manuscript; and supervision of the student. S.M.M.B. encouraged M.-Y.S. to investigate and supervised the findings of this work. M.-Y.S. and S.M.M.B. wrote the first draft of this paper. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no funding.

Institutional Review Board Statement

Ethical review and approval is not applicable for this study as all analyses were based on previously published studies; thus, no ethical approval or patient consent was required.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in the study are included in the article, and further inquiries can be directed to the corresponding author.

Acknowledgments

Funding grant for the NSW Brain Clot Bank (Chief Investigator: S.M.M.B.) from the NSW Ministry of Health (2019–2022) is acknowledged. The funding body has no role in the study design, data collection, analysis, interpretation of findings and manuscript preparation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the affiliated/funding organisation/s.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. The PRISMA flowchart showing the steps followed during the study selection process. Abbreviations: N: number of studies; n: number of patients.
Figure 1. The PRISMA flowchart showing the steps followed during the study selection process. Abbreviations: N: number of studies; n: number of patients.
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Figure 2. Forest plot showing the estimated overall pooled prevalence of VTE in cancer patients undergoing chemotherapy [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128]. Abbreviations: VTE: venous thromboembolism.
Figure 2. Forest plot showing the estimated overall pooled prevalence of VTE in cancer patients undergoing chemotherapy [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128]. Abbreviations: VTE: venous thromboembolism.
Diagnostics 12 02954 g002aDiagnostics 12 02954 g002bDiagnostics 12 02954 g002c
Figure 3. Forest plot showing the estimated pooled prevalence of VTE in cancer patients stratified by cancer phenotype [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128]. Abbreviations: VTE: venous thromboembolism.
Figure 3. Forest plot showing the estimated pooled prevalence of VTE in cancer patients stratified by cancer phenotype [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128]. Abbreviations: VTE: venous thromboembolism.
Diagnostics 12 02954 g003aDiagnostics 12 02954 g003bDiagnostics 12 02954 g003c
Table 1. Clinical characteristics of studies included in the meta-analysis.
Table 1. Clinical characteristics of studies included in the meta-analysis.
Study IDAuthorYearStudy DesignStudy PhaseCountryCancer PhenotypeCancer Phenotype, BodyAge (Median)Age (Range)Number of Males (%)CNP
1Affronti et al. [29]2018Prospective, single centreIIUSARecurrent grade IV malignant gliomaBrain55.527–7461.1136411.11
2Alexander et al. [30]2012Prospective, single centreIIUSANewly diagnosed glioblastomaBrainN/AN/A628988.99
3Alvarez et al. [31]2014Prospective, single centreIIUSARecurrent or persistent endometrial carcinomaEndometrial6335–8004912.04
4Assenat et al. [32]2021aProspective, multicentreIIUSAMetastatic pancreatic cancerPancreas6034–7250581831.03
5Assenat et al. [33]2021bProspective, multicentreIIFranceMetastatic pancreatic cancerPancreas6235–7759.7622235.48
6Bai et al. [34]2015Prospective, single centreUnspecifiedChinaMetastatic colorectal cancerColorectal5520–7963.417510.57
7Balar et al. [35]2013Prospective, single centreIIUSAAdvanced unresectable/metastatic urothelial cancerBladder6742–8372.5511019.61
8Basso et al. [36]2013Prospective, multicentreUnspecifiedItalyLocally advanced/metastatic breast cancerBreast7870–9303239.38
9Bear et al. [37]2015Prospective, multicentreIIIUSAEarly HER2-negative breast cancerBreastN/AN/A01206373.07
10Buxo et al. [38]2018Retrospective, single centreUnspecifiedSpainRecurrent or metastatic head and neck squamous cell carcinomaHead and NeckN/AN/AN/A10410.96
11Campbell et al. [39]2012Prospective, multicentreIIUSAMalignant mesotheliomaMesotheliumN/AN/A845036.00
12Chekerov et al. [40]2018Prospective, multicentreIIGermanyPlatinum-resistant ovarian cancerOvaryN/AN/A0174105.75
13Chen et al. [41]2015Prospective, single centreIIUSARelapsed/refractory indolent non-Hodgkin lymphomaLymph6244–855428414.29
14Chibaudel et al. [42]2019Prospective, multicentreIIFranceMetastatic colorectal cancerColorectal62.932–8653.14812.08
15Ciombor et al. [43]2014Prospective, multicentreIIUSAHepatocellular carcinomaLiver5923–76.571.13812.63
16Cremolini et al. [44]2020Prospective, multicentreIIIItalyUnresectable metastatic colorectal cancerColorectalN/AN/AN/A672639.38
17de Vos et al. [45]2014Prospective, multicentreIIUSADiffuse large B-cell lymphomaLymph7218–85614636.52
18DeCensi et al. [46]2019Prospective, multicentreIIIItalyDuctal carcinoma in situBreastN/AN/A050020.40
19Deschenes-Simard et al. [47]2021Retrospective, multicentreUnspecifiedCanadaNon-small-cell lung cancerLung66.7N/A54.35936410.79
20Donskov et al. [48]2018Prospective, multicentreIIIbDenmarkMetastatic renal cell carcinomaRenalN/AN/AN/A1181512.71
21Dowell et al. [49]2012Prospective, multicentreIIUSAAdvanced malignant mesotheliomaMesothelium6624–818552713.46
22Dummer et al. [50]2012Prospective, multicentreIISwitzerlandPrimary cutaneous T-cell lymphoma, mycosis fungoidesLymphN/AN/AN/A4924.08
23Duvic et al. [51]2015Prospective, single centreIIUSACutaneous T-cell lymphoma and lymphomatoid papulosisLymph59.531–77544824.17
24Fehr et al. [52]2020Prospective, multicentreIIISwitzerlandLocally advanced oesophageal cancerOesophageal6136–7588300299.67
25Feliu et al. [53]2014Prospective, multicentreIISpainMetastatic colorectal cancerColorectal75.670.5–85.465681014.71
26Fleming et al. [54]2014Prospective, multicentreIIUSAEndometrial cancerEndometrialN/AN/A0711014.08
27Folprecht et al. [55]2016Prospective, multicentreIIGermanyMetastatic colorectal cancerColorectal62.529–8761235229.36
28Frizziero et al. [56]2019Retrospective, multicentreUnspecifiedUKPoorly differentiated neuroendocrine carcinomasNeuroendocrine65.824–8863.711376.19
29Fuchs et al. [57]2019Prospective, multicentreIIIUSAMetastatic, HER2-negative gastric or gastrooesophageal junction adenocarcinomaGastricN/AN/AN/A6459915.35
30Ghiaseddin et al. [58]2018Prospective, single centreIIUSARecurrent, grade 4 malignant gliomaBrain52.432–74604037.50
31Ghiringhelli et al. [59]2012Prospective, single centreIIFranceMetastatic colorectal cancerColorectal6325–79534912.04
32Goss et al. [60]2016Prospective, multicentreIICanadaEGFR Thr790Met-positive advanced non-small-cell lung cancerLung6435–883121010.48
33Gronberg et al. [61]2012Prospective, multicentreIINorwayBrain metastases from lung cancerLungN/AN/AN/A1071614.95
34Guigay et al. [62]2015Prospective, multicentreIIFranceRecurrent or metastatic head and neck squamous cell carcincomaHead and NeckN/AN/A96.35411.85
35He et al. [63]2020Retrospective, single centreUnspecifiedChinaAdvanced cervical cancerCervixN/AN/A0264249.09
36Hirsch et al. [64]2017Prospective, multicentreIIUSAAdvanced squamous cell non-small-cell lung cancerLungN/AN/AN/A10932.75
37Honecker et al. [65]2013Retrospective, multicentreUnspecifiedGermanyGerm cell tumourGerm Cell3518–83N/A19342.07
38Hu et al. [66]2015Prospective, single centreIIChinaAdvanced non-small-cell lung cancerLung59.632–8355.4561221.43
39Idelevich et al. [67]2012Prospective, single centreIIIsraelLocally advanced resectable esophageal cancerOesophagealN/AN/A8228310.71
40Ikemura et al. [68]2015Prospective, single centreIIJapanAdvanced non-small-cell lung cancerLung59.535–7480.63113.23
41Ishida et al. [69]2015Prospective, multicentreUnspecifiedJapanMetastatic breast cancerBreast6241–85011710.85
42Kakkos et al. [70]2020Prospective, multicentreUnspecifiedGreeceVarious—lung, pancreatic, ovarian, prostateMixedN/AN/AN/A231177.36
43Karavasilis et al. [71]2014Prospective, multicentreIIGreeceMetastatic non-small-cell lung cancerLung64N/AN/A5012.00
44Kim et al. [72]2018Prospective, multicentreUnspecifiedUSAPreviously treated cutaneous T-cell lymphomaLymphN/AN/AN/A37271.88
45Kitayama et al. [73]2017Prospective, single centreUnspecifiedJapanMixedMixed65N/A48.5972929.90
46Konecny et al. [74]2015Prospective, multicentreIIUSAMetastatic endometrial cancerEndometrialN/AN/A053916.98
47Kottschade et al. [75]2013Prospective, multicentreIIUSAUnresectable metastatic melanomaSkinN/AN/AN/A9377.53
48Lang et al. [76]2012Prospective, multicentreIIIHungaryLocally recurrent/metastatic breast cancerBreastN/AN/A056181.43
49Lara et al. [77]2016Prospective, multicentreIIUSAAdvanced non-small-cell lung cancerLungN/AN/AN/A5911.69
50Larsen et al. [78]2015Prospective, single centreUnspecifiedDenmarkGastric, esophageal, gastro-oesophagealGastric6435–8475.21292116.28
51Lee et al. [79]2020Prospective, multicentreIIUSARecurrent ovarian cancerOvaryN/A27–7905459.26
52Maio et al. [80]2017Prospective, multicentreIIbItalyRelapsed malignant mesotheliomaMesothelium6660–7274571172.98
53Makielski et al. [81]2015Prospective, multicentreIIUSAAdvanced pancreatic cancerPancreas6348–83N/A2414.17
54Matsumoto et al. [82]2015Prospective, multicentreIIJapanPlatinum-resistant taxane-pretreated ovarian cancerOvary5831–7506011.67
55Michelsen & Sorensen [83]2015Prospective, single centreUnspecifiedDenmarkAdvanced non-small-cell lung cancerLungN/AN/AN/A421023.81
56Mountzios et al. [84]2012Prospective, multicentreIIGreeceChemoresistant relapsed small cell lung cancerLung6443–82903013.33
57Nagane et al. [85]2012Prospective, single centreIIJapanRecurrent malignant gliomaBrain5423–7251.63113.23
58Okines et al. [86]2013Prospective, multicentreII/IIIUKLocalised gastro-oesophageal adenocarcinomaGastric6440–8082200157.50
59Ottosson et al. [87]2020Prospective, multicentreUnspecifiedSwedenMuscle-invasive urinary bladder cancerBladderN/AN/A80.61264535.71
60Peeters et al. [88]2013Prospective, multicentreIIBelgiumMetastatic colorectal cancerColorectalN/AN/AN/A144106.94
61Pitz et al. [89]2015Prospective, multicentreIICanadaGlioblastomaBrain5635–7863.63326.06
62Powell et al. [90]2013Prospective, single centreIIUSAAdvanced, refractory non-small-cell lung cancerLung62.536–8042.94212.38
63Ramos et al. [91]2017Retrospective, multicentreUnspecifiedUSAMetastatic urothelial carcinomaBladderN/AN/A77.517621448.17
64Reck et al. [92]2014Prospective, multicentreIIIGermanyNon-small-cell lung cancerLungN/AN/AN/A131430.23
65Reyes-Botero et al. [93]2018Prospective, multicentreIIFranceNewly diagnosed glioblastomaBrain7670–87366634.55
66Rivera et al. [94]2015Prospective, multicentreIISpainAdvanced gastric cancerGastric73.340–8774.418604654349.30
67Saad et al. [95]2021Prospective, multicentreIIICanadaMetastatic, castration-resistant prostate cancerProstateN/AN/A100982151.53
68Salinaro et al. [96]2020Prospective, multicentreUnspecifiedUSAAdvanced epithelial ovarian cancerOvary64.834–840230166.96
69Salles et al. [97]2020Prospective, multicentreIIFranceRelapsed or refractory diffuse large B-cell lymphomaLymph7262–765415674.49
70Seidel et al. [98]2012Prospective, multicentreUnspecifiedGermanyGliomaBrainN/AN/AN/A28551435.01
71Slagter et al. [99,100]2020Prospective, multicentreUnspecifiedNetherlandsGastric cancerGastricN/AN/AN/A781789.99
72Sonpavde et al. [100]2012Prospective, multicentreIIUSAMetastatic castration-resistant prostate cancerProstateN/AN/A10022094.09
73Stevenson et al. [101]2012Prospective, single centreIIUSAAdvanced, non-squamous non-small-cell lung cancerLung65.335–80464037.50
74Tahover et al. [102]2015Prospective, single centreUnspecifiedIsraelMetastatic colorectal cancerColorectalN/AN/AN/A308206.49
75Tan et al. [103]2021Prospective, multicentreIIIUSAHER2-positive early breast cancerBreastN/AN/A050040.80
76Tryfonidis et al. [104]2013Prospective, multicentreIIGreeceMetastatic breast cancer HER-2 negativeBreast6223–7508311.20
77Tunio et al. [105]2012Prospective, single centreIIPakistanMetastatic renal cell carcinomaRenal51.1123–7373.88078.75
78Uetake et al. [106]2015Prospective, multicentreIIJapanMetastatic colorectal cancerColorectal62.539–8058.74512.22
79Usmani et al. [107]2019Prospective, multicentreIIIUSAMultiple myelomaBloodN/AN/AN/A30120.66
80Vaishampayan et al. [108]2014Prospective, single centreIIUSAMetastatic castrate-resistant prostate cancerProstate6750–851003126.45
81Valle et al. [109]2021Prospective, multicentreIIUKLocally advanced or metastatic biliary tract cancerLiverN/AN/AN/A309175.50
82Wolff et al. [110]2012Prospective, multicentreIIUSAMetastatic colorectal cancerColorectalN/AN/AN/A117108.55
83Yamazaki et al. [111]2016Prospective, multicentreIIIJapanMetastatic colorectal cancerColorectalN/AN/AN/A395266.58
84Yardley et al. [112]2012Prospective, multicentreIIUSAAdvanced breast cancerBreastN/A35–8308322.41
85Zalcman et al. [113]2016Prospective, multicentreIIIFranceNewly diagnosed pleural mesotheliomaMesotheliumN/AN/AN/A448153.35
86Baggstrom et al. [114]2017Prospective, multicentreIIIUSANon-small cell lung cancerLung6625–895621010.48
87Chavan et al. [115]2017Retrospective, single-centreUnspecifiedChinaEpithelial ovarian cancerOvaryN/A26–7501442013.89
88Duivenvoorden et al. [116]2016Retrospective, multicentreUnspecifiedUSAMuscle invasive bladder cancerBladderN/AN/A74.876110613.93
89Gay et al. [117]2010Retrospective, multicentreUnspecifiedUSANewly diagnosed multiple myelomaBloodN/AN/AN/A4114911.92
90Hong et al. [118]2012Prospective, multicentreIISouth KoreaMetastatic colorectal cancerColorectal5731–7551.37611.32
91Kang et al. [118]2012Retrospective, single-centreUnspecifiedSouth KoreaAdvanced gastric cancerGastric5718–886630951033.33
92Li et al. [119]2017Prospective, multicentreIIUSAMetastatic gastroesophageal adenocarcinomaGastric6227–7979%3937.69
93Martella et al. [85]2022Retrospective, multicentreUnspecifiedItalyNewly diagnosed adult acute myeloid leukaemiaBloodN/AN/A522225022.52
94Matikas et al. [120]2016Prospective, multicentreIVGreeceAdvanced non-small cell lung cancerLung6338–8474.831492.87
95Monk et al. [121]2018Prospective, multicentreIIUSARecurrent or persistent platinum-resistant ovarian, fallopian tube or primary peritoneal cancerOvaryN/AN/A056712.50
96Slavicek et al. [122]2014Retrospective, multicentreUnspecifiedCzech RepublicMetastatic colorectal cancerColorectalN/AN/A62.631871053.29
97Tachihara et al. [123]2020Prospective, multicentreIIJapanResected nonsquamous non-small celll lung cancerLung6657–7557.12114.76
98Tewari et al. [124]2018Prospective, multicentreIIIUSAAdvanced cervical cancerCervixN/AN/A0452224.87
99Yildiz et al. [125]2012Retrospective, multicentreUnspecifiedTurkeyMetastatic colorectal cancerColorectal5318–7461.733241.20
100Lee et al. [126]2013Prospective, multicentreUnspecifiedTaiwanMetastatic colorectal cancerColorectal5732–8762.54012.50
101Reynes et al. [127]2016Prospective, multicentreIIUKRecurrent glioblastomaBrain5642–7770.42713.70
102Pinto et al. [128]2021Prospective, multicentreIIItalyMalignant pleural mesotheliomaMesothelium6944–81741652012.12
Abbreviations: C: total number of patients, N: number of venous thromboembolism cases, P = crude prevalence of venous thromboembolism in individual studies, GI: gastrointestinal, VTE: venous thromboembolism, II: phase-two study, III: phase-three study.
Table 2. Prevalence of venous thromboembolism stratified by treatment regimen.
Table 2. Prevalence of venous thromboembolism stratified by treatment regimen.
Study IDAuthorYearCancer Phenotype, BodyTreatment AgentCNPGrade 1/2 (n)Grade 3/4/5 (n)
1Affronti et al. [29]2018BrainBevacizumab with rilotumumab36411.1104
2Alexander et al. [30]2012BrainThalidomide8988.9908
3Alvarez et al. [31]2014EndometrialBevacizumab + temsirolimus4912.0401
4Assenat et al. [32]2021aPancreasNab-paclitaxel/gemcitabine and FOLFIRINOX581831.03810
5Assenat et al. [33]2021bPancreasGemcitabine, trastuzumab plus erlotinib622235.48022
6Bai et al. [34]2015ColorectalmFOLFOX-6 or XELOX or FOLFIRI with bevacizumab17510.5701
7Balar et al. [35]2013BladderGemcitabine, carboplatin and bevacizumab511019.61010
8Basso et al. [36]2013BreastLiposomal doxorubicin3239.3821
9Bear et al. [37]2015BreastVarious1206373.07037
10Buxo et al. [38]2018Head and NeckCarboplatin, cetuximab and tegafur10410.9601
11Campbell et al. [39]2012MesotheliumCediranib5036.0003
12Chekerov et al. [40]2018OvarySorafenib plus topotecan versus placebo plus topotecan174105.7555
13Chen et al. [41]2015LymphVorinostat and rituximab28414.2904
14Chibaudel et al. [42]2019ColorectalAflibercept with FOLFOX (folinic acid, fluorouracil, oxaliplatin) followed by maintenance with fluoropyrimidine4812.0801
15Ciombor et al. [43]2014LiverBortezomib plus doxorubicin3812.6301
16Cremolini et al. [44]2020ColorectalmFOLFOX6 and bevacizumab followed by FOLFIRI plus bevacizumab after disease progression, or FOLFOXIRI and bevacizumab, followed by the same regimen after disease progression672639.383231
17de Vos et al. [45]2014LymphDacetuzumab4636.5203
18DeCensi et al. [46]2019BreastTamoxifen50020.4002
19Deschenes-Simard et al. [47]2021LungVarious immune checkpoint inhibitors including nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, and M7824.5936410.79064
20Donskov et al. [48]2018RenalInterleukin-2 and interferon-a with or without bevacizumab1181512.71015
21Dowell et al. [49]2012MesotheliumCisplatin, pemetrexed and bevacizumab52713.4607
22Dummer et al. [50]2012LymphPegylated liposomal doxorubicin4924.0802
23Duvic et al. [51]2015LymphBrentuximab Vedotin4824.1702
24Fehr et al. [52]2020OesophagealDocetaxel and cisplatin,300299.671316
25Feliu et al. [53]2014ColorectalBevacizumab, oxaliplatin and oral capecitabine681014.7137
26Fleming et al. [54]2014EndometrialTemsirolimus plus megestrol acetate/tamoxifen711014.08010
27Folprecht et al. [55]2016ColorectalmFOLFOX6 with or without aflibercept235229.36121
28Frizziero et al. [56]2019NeuroendocrineCarboplatin and etoposide11376.1907
29Fuchs et al. [57]2019GastricCisplatin and capecitabine, and either ramucirumab or placebo6459915.35099
30Ghiaseddin et al. [58]2018BrainBevacizumab and vorinostat4037.5012
31Ghiringhelli et al. [59]2012ColorectalBevacizumab and FOLFIRI-3 regimen (irinotecan, leucovorin and 5-fluorouracil)4912.0401
32Goss et al. [60]2016LungOsimertinib21010.4801
33Gronberg et al. [61]2012LungEnzastaurin1071614.95016
34Guigay et al. [62]2015Head and NeckCetuximab, docetaxel and cisplatin5411.8501
35He et al. [63]2020CervixCisplatin and paclitaxel chemotherapy with or without bevacizumab264249.09024
36Hirsch et al. [64]2017LungOnartuzumab, paclitaxel and carboplatin/cisplatin or placebo plus paclitaxel and carboplatin/cisplatin10932.7503
37Honecker et al. [65]2013Germ CellCisplatin-based chemotherapy19342.0704
38Hu et al. [66]2015LungNab-paclitaxel561221.4348
39Idelevich et al. [67]2012OesophagealCisplatin, 5-FU, bevacizumab28310.7103
40Ikemura et al. [68]2015LungS-1 and irinotecan3113.2301
41Ishida et al. [69]2015BreastFulvestrant and trastuzumab (if HER2-positive disease)11710.8501
42Kakkos et al. [70]2020MixedVarious231177.36017
43Karavasilis et al. [71]2014LungErlotonib and docetaxel5012.0001
44Kim et al. [72]2018LymphMogamulizumab or vorinostat37271.8807
45Kitayama et al. [73]2017MixedVarious972929.90029
46Konecny et al. [74]2015EndometrialDovitinib53916.9836
47Kottschade et al. [75]2013SkinTemozolomide and bevacizumab or nab-paclitaxel, carboplatin and bevacizumab9377.5307
48Lang et al. [76]2012BreastBevacizumab and capecitabine or paclitaxel56181.4308
49Lara et al. [77]2016LungErlotinib or erlotinib plus carboplatin/paclitaxel5911.6901
50Larsen et al. [78]2015GastricVaried1292116.28021
51Lee et al. [79]2020OvaryBevacizumab and sorafenib5459.2605
52Maio et al. [80]2017MesotheliumTremelimumab571172.98017
53Makielski et al. [81]2015PancreasSorafenib and oxaliplatin and capecitabine2414.1701
54Matsumoto et al. [82]2015OvaryEtoposide plus irinotecan6011.6701
55Michelsen & Sorensen [83]2015LungPlatinum-vinorelbine plus bevacizumab with/without pemetrexed421023.81010
56Mountzios et al. [84]2012LungBevacizumab and paclitaxel3013.3301
57Nagane et al. [85]2012BrainBevacizumab3113.2301
58Okines et al. [86]2013GastricEpirubicin, cisplatin and capecitabine plus bevacizumab200157.50015
59Ottosson et al. [87]2020BladderVaried1264535.71045
60Peeters et al. [88]2013ColorectalTrebananib and FOLFIRI144106.94010
61Pitz et al. [89]2015BrainPX-8663326.0602
62Powell et al. [90]2013LungTopotecan4212.3801
63Ramos et al. [91]2017BladderVaried17621448.170144
64Reck et al. [92]2014LungDocetaxel plus nintedanib or docetaxel plus placebo131430.2303
65Reyes-Botero et al. [93]2018BrainTemozolomide plus bevacizumab6634.5503
66Rivera et al. [94]2015GastricReduced dose docetaxel, oxaliplatin and capecitabine4349.3004
67Saad et al. [95]2021Prostate 982151.53015
68Salinaro et al. [96]2020OvaryNeoadjuvant230166.96016
69Salles et al. [97]2020LymphTafasitamab and lenalidomide15674.4925
70Seidel et al. [98]2012BrainBevacizumab28551435.010143
71Slagter et al. [99,100]2020GastricEpirubicin, cisplatin, oxaliplatin and capecitabine781789.9901
72Sonpavde et al. [100]2012ProstateDocetaxel plus prednisone with placebo or AT-10122094.0909
73Stevenson et al. [101]2012LungBevacizumab plus pemetrexed and carboplatin followed by maintenance BVZ4037.5003
74Tahover et al. [102]2015ColorectalBevacizumab with other chemotherapies308206.49020
75Tan et al. [103]2021BreastPertuzumab and trastuzumab50040.8004
76Tryfonidis et al. [104]2013BreastDocetaxel, epirubicin and bevacizumab8311.2001
77Tunio et al. [105]2012RenalThalidomide8078.7507
78Uetake et al. [106]2015ColorectalmFOLFOX6 + bevacizumab4512.2201
79Usmani et al. [107]2019BloodPembrolizumab plus lenalidomide and dexamethasone30120.6602
80Vaishampayan et al. [108]2014ProstateBevacizumab and satraplatin in docetaxel-pretreated3126.4502
81Valle et al. [109]2021LiverAll patients received intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles + additional treatment309175.50017
82Wolff et al. [110]2012ColorectalEnzastaurin with 5-FU/leucovorin plus bevacizumab117108.55010
83Yamazaki et al. [111]2016ColorectalBevacizumab + FOLFIRI or Bevacizumab + mFOLFOX6395266.58026
84Yardley et al. [112]2012BreastSunitinib8322.4102
85Zalcman et al. [113]2016MesotheliumBevacizumab, pemetrexed and cisplatin448153.35015
86Baggstrom et al. [114]2017LungSunitinib after platinum-based chemotherapy21010.4800
87Chavan et al. [115]2017OvaryVarious1442013.89020
88Duivenvoorden et al. [116]2016BladderVarious76110613.930106
89Gay et al. [117]2012BloodThalidomide or lenalidomide, and dexamethasone4114911.92049
90Hong et al. [118]2012ColorectalBevacizumab plus doublet combination chemotherapy7611.3201
91Kang et al. [118]2012GastricVarious30951033.330103
92Li et al. [119]2017GastricModified FOLFOX63937.6903
93Martella et al. [85]2022BloodVarious2225022.52050
94Matikas et al. [120]2016LungBevacizumab-containing chemotherapy treatments, in conjunction with paclitaxel/docetaxel/cisplatin/carboplatin31492.8709
95Monk et al. [121]2018OvaryPaclitaxel and elesclomol sodium56712.5052
96Slavicek et al. [122]2014ColorectalVarious31871053.290105
97Tachihara et al. [123]2020LungCisplatin-based adjuvant chemotherapy and pemetrexed2114.7601
98Tewari et al. [124]2018CervixVarious regimens involving cisplatin/paclitaxel/topotecan/bevacizumab452224.87022
99Yildiz et al. [125]2012ColorectalFOLFIRI and bevacizumab33241.2004
100Lee et al. [126]2013ColorectalBevacizumab and standard chemotherapy combinations4012.5001
101Reynes et al. [127]2016BrainTemozolomide and irinotecan2713.7001
102Pinto et al. [128]2021MesotheliumGemcitabine with/without ramucirumab1652012.12155
Abbreviations: GI: gastrointestinal, VTE: venous thromboembolism, C: total number of patients, N: number of venous thromboembolism cases, P = crude prevalence of venous thromboembolism in individual studies.
Table 3. Study characteristics stratified by frequency, dosage, and duration of treatment regimen.
Table 3. Study characteristics stratified by frequency, dosage, and duration of treatment regimen.
Study IDAuthorYearTreatment DoseTreatment DurationTreatment Cycle Frequency
1Affronti et al. [29]2018Bevacizumab (10 mg/kg IV) and Rilotumumab (20 mg/kg IV)Bevacizumab (every 2 weeks for up to 12 cycles, with three infusions of Avastin every 2 weeks). Rilotumumab (every 2 weeks following the administration of Avastin for up to 12 cycles. Three infusions of Avastin at 10 mg/kg followed by rilotumumab at 20 mg/kg)6 weeks
2Alexander et al. [30]2012Thalidomide (200 mg daily drom Day 1 of radiation therapy, increasing by 100–200 to 1200 mg every 1–2 weeks until tumour progression or unacceptable toxicity)N/RN/R
3Alvarez et al. [31]2014Bevacizumab (10 mg/kg IV every other week, e.g., day 1 and 15) plus temsirolimus (25 mg IV weekly, e.g., day 1, 8, 15 and 22) or a 4 week cycleUntil disease progression or adverse event prohibits further therapy4 weeks
4Assenat et al. [32]2021aPatients received AG [IV injection of nab-paclitaxel over 30 min followed by gemcitabine] at day 1, 8 and 15, while FFX was delivered at day 29 and 43 (IV injection of oxaliplatin for 2 h, irinotecan for 90 min and leucovorin for 2 h after 1 h rest, followed by fluorouracil bolus injection and then continuous 46 h infusion).Median of 4 (1–9) cycles in 8.5 months (0.5–19.8 months)N/R
5Assenat et al. [33]2021bPatients received 1000 mg/m2 IV gemcitabine, 30 minutes infusion, on days 1, 8, 15, 22, 29, 36 and 43, during the first 8 weeks of treatment, then on days 1, 8 and 15, 3 weeks out of a 4-week cycle. They also received weekly IV trastuzumab, 4 mg/kg 90 min infusion on Day 1, 2 mg/kg on Days 8 and 15, 30 min infusion, and 100 mg/day erlotinib per os.Median duration of 16.1 weeksN/R
6Bai et al. [34]2015mFOLFOX-6 (oxaliplatin 85 mg/m2 dL 5-FU bolus 400 mg/m2 d1, 5-FU 2400 mg/m2 continuous infusion for 46 h, every 2 weeks), XELOX (oxaliplatin 130 mg/m2 d1, capecitabine 2000 mg/m2 d1–14 every 3 weeks), or modified FOLFIRI (irinotecan 180 mg/m2 d1, 5-FU bolus 400 mg/m2 d1, 5FU 2400 mg/m2 continuous infusion for 46 h every 2 weeks), in combination with bevacizumab 5 mg/kg every 2 weeks (5-FU-based regimens) or 7.5 mg/kg every 3 weeks (capecitabine-based regimens).N/RN/R
7Balar et al. [35]2013Patients initially received bevacizumab 10 mg/kg intravenously (IV) followed 2 weeks later with combination therapy. Gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin IV at area under the [concentration-time] curve (AUC) 5.0 on day 1 were administered every 21 days. Bevacizumab 15 mg/kg IV was administered on day 1 of each 21-day cycleMedian of 6 cycles administered3 weeks
8Basso et al. [36]2013PLD was administered at 20 mg/mq every two weeks for a maximum of 12 cycles.Mean of 7.8 cycles2 weeks
9Bear et al. [37]2015Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m2) with addition of capecitabine (825 mg/m2) oral twice daily days 1–14, 75 mg/m2) docetaxel) or with addition of gemcitabine (1000 mg/m2) days 1 and 8 intravenously, 75 mg/m2 docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m2) and 600 mg/m2) intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses.VariousVarious
10Buxo et al. [38]2018Carboplatin IV at an area under the curve of 5 mg/mL/min on day 1; cetuximab at an initial dose of 400 mg/m2 IV as a 2 h intravenous infusion, followed by 250 mg/m2 IV weekly as a 1 h infusion; and oral tegafur 500 mg/m2 every 12 h for 21 consecutive daysMedian of 4.5 cycles, for 13.5 weeksN/R
11Campbell et al. [39]2012Administered orally once daily on days 1 through 28 of a 28-day cycle. Cediranib was initially dosed at 45 mg daily, but due to substantial rates of toxicity the protocol was amended in June 2007 to decrease the starting dose to 30 mg daily.Median of 2 cycles, range 1–14N/R
12Chekerov et al. [40]2018Topotecan (1.25 mg/m2 on days 1–5) plus either oral sorafenib 400 mg or placebo twice daily on days 6–156 cycles3 weeks
13Chen et al. [41]2015One cycle of therapy consisted of oral vorinostat 200 mg twice daily for 14 days followed by a 7-day break, and intravenous rituximab 375 mg/m2 on day 1 of a 21-day cycle.Median of 11.5 cycles, range 1–69, median duration is 17.8 monthsN/R
14Chibaudel et al. [42]2019Modified FOLFOX7 (5-FU/folinic acid and oxaliplatin) with aflibercept at 4 mg/kg every 2 weeks followed by maintenance therapy with fluoropyrimidine with aflibercept until disease progression or limiting toxicity.6 cycles2 weeks
15Ciombor et al. [43]2014Bortezomib was administered at a dose of 1.3 mg/m2 IV push over 3–5 s on days 1, 4, 8, 11 of a 21-day cycle. Doxorubicin was administered at a dose of 15 mg/m2 IV over 5–15 min on days 1, 8 of each 21-day cycle. The first dose of doxorubicin was administered on day 8 of cycle 1 after the first two doses of bortezomib (cycle 1, day 8). On days when both bortezomib and doxorubicin were administered (days 1 and 8), doxorubicin was administered before bortezomib. Patients continued to receive chemotherapy until progression. Doxorubicin discontinued after receiving 12 cycles, regardless of response.12 cycles maximum, median 3.83 weeks
16Cremolini et al. [44]2020In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression.Maximum 8 cycles2 weeks
17de Vos et al. [45]2014For Cycle 1, all patients were treated using an intra-patient dose-escalation schedule. 1 mg/kg Day 1, 2 mg/kg Day 4, 4 mg/kg Day 8, 8 thereafter. Subsequent cycles consisted of 4 doses of 8 mg/kg on Days 1, 8, 15, and 22. Patients were treated with 2 cycles after a complete remission (CR) or until disease progression for a maximum of 12 cycles.up to 12 cycles6 weeks
18DeCensi et al. [46]20195 mg/daily3 yearsDaily
19Deschenes-Simard et al. [47]2021VariousN/RN/R
20Donskov et al. [48]2018IFN 3 MIU subcutaneously (SC) daily and IL2 2.4 MIU/m2 sc twice daily, 5 days per week for two consecutive weeks every 28-day-cycle, for 9 months; or supplemented with BEV 10 mg/kg, every 2 weeks intravenously (IV) until progression, unacceptable toxicity, or 1 year following no evidence of disease (NED)9 months4 weeks
21Dowell et al. [49]2012Previously untreated MM patients with advanced, unresectable disease received cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg) intravenously every 21 days for a maximum of 6 cycles. Patients with responsive or stable disease received bevacizumab (15 mg/kg) intravenously every 21 days until progression or intolerance.Median of 6 cycles of chemotherapy3 weeks
22Dummer et al. [50]2012PLD 20 mg/m2 on days 1 and 15Maximum 6 cycles4 weeks
23Duvic et al. [51]2015Brentuximab vedotin was administered intravenously at 1.8 mg/kg every 21 days for a maximum of eight doses. Patients with partial or stable response were eligible to receive up to eight additional doses. Patients with complete response could receive two additional doses. Patients with breakthrough lesions could receive 1.2 mg/kg every 2 weeks at the discretion of the principal investigator.Maximum 8 cycles3 weeks
24Fehr et al. [52]2020Docetaxel 75 mg/m2 and cisplatin 75 mg/m2 (duration of cycle 3 weeks)2 cyclesN/R
25Feliu et al. [53]2014Intravenous bevacizumab 7.5 mg kg−1 and oxaliplatin 130 mg m−2 on day 1 of each cycle, plus oral capecitabine 1000 mg m−2 twice daily (BID) on days 1–14 of each cycle (patients with a baseline creatinine clearance of 30–50 mL min−1 had a 25% reduction in their initial capecitabine dose to 750 mg/m2 BID). Treatment was repeated every 3 weeks for 6 cycles. After 6 cycles, oxaliplatin was discontinued and patients continued to receive bevacizumab and capecitabine following the same regimen until progression or study discontinuationMedian of 6.8 months, range 0.2–25.23 weeks
26Fleming et al. [54]2014Temsirolimus 25 mg IV weekly plus megestrol acetate 80 mg orally twice a day for 3 weeks alternating with tamoxifen 20 mg orally twice a day for 3 weeks3 weeksTwice a day
27Folprecht et al. [55]2016MFOLFOX6 (5 mg/m2 oxaliplatin [2 (h) IV)] together with 350 mg/m2 leucovorin (2 h IV) followed by 5-FU (400 mg/m2 as bolus and 2400 mg/m2 IV over 46 h). Patients in the experimental arm received 4 mg/kg aflibercept (1 h IV) before chemotherapy.The median number of aflibercept cycles was 7.0 (range 1–43). In the mFOLFOX6 and the aflibercept/mFOLFOX6 arms, the median number of oxaliplatin cycles was 10.0 (1–31) and 9.0 (1–40), and the median number of 5-FU cycles was 11.0 (1–43) and 10.0 (1–44), respectively. The median duration of exposure to aflibercept was 17.1 weeks (range 2–94). In the mFOLFOX6 and the aflibercept/mFOLFOX6 arms, the median duration of exposure to oxaliplatin was 23.2 (2–77) and 22.0 (2–84), and to 5-FU was 25.9 (2–95) and 24.1 (2–106) weeks, respectively.N/R
28Frizziero et al. [56]2019CarboEtop-1; etoposide 50 mg twice daily orally from day 1 to day 7 (inclusive) followed by carboplatin area under the curve (AUC) 5, intravenously on day 8, every 28 days; CarboEtop-2; etoposide 120 mg/m2 intravenously on days 1, 2, and 3, and carboplatin AUC 5 or 6 intravenously on day 1, every 21 days; CarboEtop-3; etoposide 100 mg/m2 intravenously on days 1, 2, and 3, and carboplatin AUC 4 or 5 intravenously on day 1, every 21 days; A higher proportion of patients received intravenous etoposide compared to oral etoposide, both in first-line (54.7% versus 45.3%) and second/third-line (58.8% versus 41.2%).Median of 3.6 months, range 0.4–9.9Various
29Fuchs et al. [57]2019Temsirolimus 25 mg IV weekly plus megestrol acetate 80 mg orally twice a day for 3 weeks alternating with tamoxifen 20 mg orally twice a day for 3 weeks3 weeksTwice daily
30Ghiaseddin et al. [58]2018Bevacizumab, 10 mg/kg IV every 2 weeks combined with VOR 400 mg PO daily for 7 days, then 7 days off in a 28-day cycle, vorinostat VOR 400 mg PO daily for 7 days, then 7 days off, in a 28-day cycleN/R4 weeks
31Ghiringhelli et al. [59]2012Bevacizumab given at a dose of 5 mg/kg on day 1 every 2 weeks. FOLFIRI-3 regimen was given every 14 days as follows: on day 1, irinotecan 100 mg/m2 as a 1 h infusion, running concurrently with leucovorin 200 mg/m2 as a 2 h infusion via a Y-connector, followed by 5-FU 2000 mg/m2 as a 46 h infusion using an electric pump. On day 3, irinotecan 100 mg/m2 as a 1 h infusion was repeated, at the end of 5-FU infusion.N/R2 weeks
32Goss et al. [60]2016Osimertinib 80 mg orally once dailyN/RDaily
33Gronberg et al. [61]2012Oral maintenance enzastaurin (1125 mg on Day 1 followed by 500 mg daily) or placeboN/RDaily
34Guigay et al. [62]2015docetaxel 75 mg/m2 IV day 1, cisplatin 75 mg/m2 IV day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 IV day 1 of cycle 1 and 250 mg/m2 IV weekly on subsequent administrations) 4 weeks
35He et al. [63]2020Intravenous chemotherapy regimen consisted of cisplatin (at a dose of 50 mg per square metre of body surface area) plus paclitaxel (at a dose of 175 mg/m2 on day 1); the intravenous BEV regimen was a dose of 15 mg/kg on day 1N/R3 weeks
36Hirsch et al. [64]2017N/RN/RN/R
37Honecker et al. [65]2013Carboplatin was applied either as single-agent adjuvant treatment for pure seminoma or combined with etoposide as high-dose first-salvage treatment after cisplatin-based chemotherapy. Cisplatin-based combination chemotherapy consisted of 2 cycles with etoposide and bleomycin (PEB) as adjuvant therapy in nonseminoma or of 3–4 cycles combined with etoposide plus bleomycin (PEB), etoposide plus ifosfamide (VIP), or ifosfamide plus paclitaxel (TIP) for metastatic disease.N/RN/R
38Hu et al. [66]2015Nab-paclitaxel 100 mg/m2 (IV) on days 1, 8 and 15 of a 28-day cycleup to 6 cycles4 weeks
39Idelevich et al. [67]2012Bevacizumab 7.5 mg/kg followed by cisplatin 80 mg/m2 infusion on day 1 followed by 5-FU 1000 mg/m2 as a 96 h continuous infusion on days 1–4, separated by a 3-week interval.4 days per cycle3 weeks
40Ikemura et al. [68]2015Irinotecan was administered at 60 mg/m2 on Days 1 and 8. Oral S-1 was administered on Days 1–14 every 3 weeks at 80 mg/day for patients with a body surface area of <1.25 m2, 100 mg/day for patients with a body surface area of 1.25–1.5 m2 and 120 mg/day for patients with a body surface area of >1.5 m2N/R3 weeks
41Ishida et al. [69]2015fulvestrant 500 mg as two 5-mL intramuscular injections, one in each buttock, on days 0, 14, and 28 and every 28 days thereafter. 4 weeks
42Kakkos et al. [70]2020VariousN/RN/R
43Karavasilis et al. [71]2014Erlotinib for 12 consecutive days prior to docetaxel (Arm A) or after docetaxel (Arm B). Erlotinib was taken orally at a dose of 150 mg every day for 12 consecutive days and docetaxel was administered intravenously at a dose of 75 mg/m2.N/R3 weeks
44Kim et al. [72]2018Mogamulizumab (1 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily)N/R4 weeks
45Kitayama et al. [73]2017VariousN/RN/R
46Konecny et al. [74]2015Dovitinib (500 mg per day, orally, on a 5 days-on and 2 days-off scheduleN/RN/R
47Kottschade et al. [75]2013Temozolomide (200 mg/m2 on d. 1–5) and bevacizumab (10 mg/kg IV d. 1 and 15) every 28 days (Regimen temozolomide/bevacizumab [TB]) or nab-paclitaxel (100 mg/m2 [80 mg/m2 post addendum 5-secondary to toxicity] days 1, 8 and 15), bevacizumab (10 mg/kg on days 1 and 15), and carboplatin (AUC 6 day 1 [AUC 5 post addendum 5]) every 28 days (Regimen ABC)N/R4 weeks
48Lang et al. [76]2012Arm A: bevacizumab 10 mg/kg days 1 and 15; paclitaxel 90 mg/m2 days 1, 8, and 15, every 4 weeks; or Arm B: bevacizumab 15 mg/kg day 1; capecitabine 1000 mg/m2 BID, days 1–14, every 3 weeks, until disease progression, unacceptable toxicity or consent withdrawal.VariousVarious
49Lara et al. [77]2016Erlotinib 150 mg orally daily (Arm 1) or erlotinib 150 mg orally daily on days 2–16 plus 4 cycles of carboplatin (AUC 5 day 1) and paclitaxel (200 mg/m2 IV day 1), followed by erlotinib 150 mg orally (Arm 2)N/RN/R
50Larsen et al. [78]2015VariousN/RN/R
51Lee et al. [79]2020Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off.N/RN/R
52Maio et al. [80]2017Intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met.N/RVarious
53Makielski et al. [81]2015Sorafenib 200 mg orally twice daily along with oxaliplatin 85 mg/m2 IV on days 1 and 15, followed by capecitabine 2250 mg/m2 orally every 8 h for six doses starting on days 1 and 15 of a 28-day cycleN/R4 weeks
54Matsumoto et al. [82]2015Oral etoposide (50 mg/m2 once a day) from day 1 to day 21 and IV irinotecan (70 mg/m2) on days 1 and 15up to 6 cycles4 weeks
55Michelsen & Sorensen [83]2015VariousN/RN/R
56Mountzios et al. [84]2012Aclitaxel (90 mg/m2, days 1, 8 and 15) along with bevacizumab (10 mg per kg of body weight, days 1 and 15) in cycles of 28 days.N/R4 weeks
57Nagane et al. [85]201210 mg/kg bevacizumab as an intravenous infusion administered over 90 (±15) min on Day 1 of each cycle, which could be reduced to 30 min by Cycle 3 if no infusion reactions occurred.N/RN/R
58Okines et al. [86]2013ECX comprises 3-weekly epirubicin 50 mg/m2 and cisplatin 60 mg/m2 IV (day 1), with capecitabine 1250 mg/m2/day (divided doses days 1–21), plus bevacizumab 7.5 mg/kg IV (day 1) added in the ECX-B arm. Surgery was scheduled 5 to 6 weeks after the last capecitabine dose of the third cycle and postoperative chemotherapy (three cycles) restarted 6–10 weeks after surgery. ECX-B patients then received six 3-weekly cycles of maintenance bevacizumab 7.5 mg/kg IVN/RN/R
59Ottosson et al. [87]2020VariousN/RN/R
60Peeters et al. [88]2013Intravenous trebananib 10 mg kg−1 once weekly (QW) (Arm A) or placebo QW (Arm B)N/RWeekly
61Pitz et al. [89]20158 mg dailyN/R8 weeks
62Powell et al. [90]2013topotecan (4.0 mg/m2) on days 1, 8, and 15, and bevacizumab (10 mg/kg) on days 1 and 15 as intravenous infusions on a 28-day treatment cycleN/R4 weeks
63Ramos et al. [91]2017Gemcitabine, cisplatin, nonplatinum regimens, etc.N/RN/R
64Reck et al. [92]2014Nintedanib 200 mg orally twice daily or matching placebo on days 2–21N/R3 weeks
65Reyes-Botero et al. [93]2018TMZ administered at 130–150 mg/m2 per day for 5 days every 4 weeks plus Bev administered at 10 mg/kg every 2 weeksN/RN/R
66Rivera et al. [94]2015“miniDOX” regimen (D: 40 mg/m2 IV, day 1; O: 80 mg/m2 IV, day 1; C: 625 mg/m2 PO BID, day 1 to day 21, every 21 days; after six courses, only C was maintained)N/R3 weeks
67Saad et al. [95]2021Oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone-prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone-prednisone group)N/R4 weeks
68Salinaro et al. [96]2020VariousN/RN/R
69Salles et al. [97]2020Afasitamab was administered intravenously at a dose of 12 mg/kg, over approximately 2 h. For cycles 1–3, tafasitamab was administered weekly on days 1, 8, 15, and 22; an additional loading dose was administered on day 4 of cycle 1. From cycle 4, tafasitamab was administered every 14 days,17 on days 1 and 15 of each cycle. Patients self-administered lenalidomide capsules orally, starting with 25 mg daily on days 1–21 of each 28-day cycle. A stepwise dose reduction (decrease by 5 mg per day in each step, only once per cycle, without re-escalation) of lenalidomide was done in cases of protocol-defined toxicities.N/R4 weeks
70Seidel et al. [98]2012Bevacizumab 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks until disease progression or treatment-limiting toxicityN/R2 weeks
71Slagter et al. [99,100]2020Epirubicin (50 mg/m2 on day 1), cisplatin (60 mg/m2 on day 1), or oxaliplatin (130 mg/m2 on day 1), and capecitabine (either 1000 mg/m2 twice daily on day 1–14 in combination with epirubicin and cisplatin or 625 mg/m2 twice daily on day 1–21 in combination with epirubicin and oxaliplatin) (ECC/EOC)3 cycles3 weeks
72Sonpavde et al. [100]2012Docetaxel (75 mg/m2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1–3N/R3 weeks
73Stevenson et al. [101]2012Bevacizumab 15 mg/kg, pemetrexed 500 mg/m2 and carboplatin at an area under the concentration-time curve of 6 intravenously on day 1 every 21 days. Responding or stable patients who completed 6 cycles then received bevacizumab maintenance every 21 days until disease progression.N/R3 weeks
74Tahover et al. [102]2015Bevacizumab was administered in combination with FOLFOX (modified FOLFOX6–oxaliplatin, leucovorin, 5-fluorouracil [5-FU]) in 40.3%, FOLFIRI (leucovorin, 5-FU, irinotecan) in 19.8%, FOLFOX-FOLFIRI/FOLFIRI-FOLFOX in sequence in 24.0%, CapeOx (oxaliplatin, capecitabine) in 6.5%, and 5-FU/LV or capecitabine monotherapy in 9.4%.N/RN/R
75Tan et al. [103]2021Intravenous pertuzumab (840 mg loading dose, followed by 420 mg maintenance doses) plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance doses) or the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (1200 mg pertuzumab plus 600 mg trastuzumab loading dose in 15 mL, followed by 600 mg pertuzumab plus 600 mg trastuzumab maintenance doses in 10 mL)N/R3 weeks
76Tryfonidis et al. [104]2013received B (15 mg/kg), E (75 mg/m2) and D (75 mg/m2) with prophylactic G-CSF support every 3 weeks (q3w) for up to 9 cycles followed by B (15 mg/kg q3w) until disease progressionup to 9 cycles3 weeks
77Tunio et al. [105]2012Treatment consisted of gemcitabine in a 6 h infusion on days 1 and 8, and cisplatin at 75 mg/m on day 2 of a 3-week cycle. During phase I of the trial, the dose of gemcitabine was escalated from 130 to 170, 210 and 250 mg/m. In phase I of the trial, groups of six, seven, eight and eight patients were treated at the four dose levels of gemcitabine. In phase II, the remaining 32 patients all received gemcitabine at 250 mg/m.N/RDaily
78Uetake et al. [106]2015On day 1, bevacizumab (5 mg/kg), levohorinate (200 mg/m2), 5-fluorouracil ([5-FU]; 400 mg/m2), and oxaliplatin (85 mg/m2) were rapidly injected intravenously, followed by a 46 h continuous intravenous infusion of 5-FU (2400 mg/m2). Each cycle of the treatment steps was repeated every 2 weeks.N/R2 weeks
79Usmani et al. [107]2019Oral lenalidomide 25 mg on days 1–21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 every 4 weeks, with or without intravenous pembrolizumab 200 mg every 3 weeksN/R4 weeks
80Vaishampayan et al. [108]2014Bevacizumab treatment was administered at 10 mg/kg intravenously on day 1, and 15 mg/kg on day 15, of each 35-day cycle. Premedications were allowed at the treating physician’s discretion. Satraplatin 80 mg/m2 was taken orally with fasting for 1 h prior, and 2 h after dosing. Prednisone 5 mg twice daily was taken with meal.N/R35 days
81Valle et al. [109]2021Intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cyclesMaximum 8 cycles3 weeks
82Wolff et al. [110]2012Both arms received LV5FU2 plus bevacizumab (Genentech/Roche, South San Francisco, CA, USA) on day 1 of each cycle (2 weeks): leucovorin 400 mg/m2 intravenously (IV), then 5-fluorouracil 400-mg/m2 bolus followed by 2400 mg/m2 IV over 46 h, and bevacizumab 5 mg/kg IV.N/R2 weeks
83Yamazaki et al. [111]2016Bevacizumab (5 mg/kg) followed by FOLFIRI (irinotecan 150 mg/m2; l-leucovorin 200 mg/m2; intravenous bolus of fluorouracil 400 mg/m2, continuous infusion of fluorouracil 2400 mg/m2), or bevacizumab followed by mFOLFOX6 (oxaliplatin 85 mg/m2 instead of irinotecan)N/R2 weeks
84Yardley et al. [112]2012Sunitinib monotherapy at a starting dose of 37.5 mg orally on a continuous daily dosing schedule; one treatment cycle was considered to be 4 weeks.N/R4 weeks
85Zalcman et al. [113]2016Intravenously 500 mg/m2 pemetrexed plus 75 mg/m2 cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumabMaximum 6 cycles3 weeks
86Baggstrom et al. [114]2017Patients received maintenance sunitinib, 37.5 mg/d continuously, or placebo until disease progression or intolerable toxicity.N/RN/R
87Chavan et al. [115]2017VariousVariousVarious
88Duivenvoorden et al. [116]2016VariousVariousVarious
89Gay et al. [117]2012Thalidomide was given at a dose ranging from 100 mg/day to 400 mg/day continuously; lenalidomide dose was 25 mg/day, days 1 to 21 on a 28-day cycle. All patients received dexamethasone, either at high dose (40 mg orally on days 1–4, 9–12, and 17–20) or at low dose (40 mg orally on days 1, 8, 15, and 22).N/R4 weeks
90Hong et al. [118]2012FOLFOX or FOLFIRI consisted of leucovorin 200 mg/m2 on day 1, 5-FU 400 mg/m2 bolus infusion on day 1, and 5-FU 2400 mg/m2 continuous infusion for 46 h, either with oxaliplatin 85 mg/m2 or with irinotecan 150 or 180 mg/m2 on day 1, respectively, and repeated every 2 weeks. CapeOX consisted of capecitabine 1000 mg/m2 twice daily on days 1–14 and oxaliplatin 130 mg/m2 on day 1 and again every 3 weeks.N/RN/R
91Kang et al. [118]2012VariousVariousVarious
92Li et al. [119]2017mFOLFOX6 (leucovorin 400 mg/m, fluorouracil 400 mg/m bolus and 2400 mg/m continuous infusion over 46 h, oxaliplatin 85 mg/m) and bevacizumab (10 mg/kg) every 2 weeks until disease progression or intolerance.Median 12 cycles, range 4–862 weeks
93Martella et al. [85]2022VariousVariousVarious
94Matikas et al. [120]2016VariousVariousVarious
95Monk et al. [121]2018Paclitaxel 80 mg/m2 and elesclomol sodium 200 mg/m2 (equivalent of free elesclomol) were administered as two separate 1 h IV infusions weekly × 3 with a one-week restVariousweeks
96Slavicek et al. [122]2014VariousVariousVarious
97Tachihara et al. [123]2020Adjuvant chemotherapy with four cycles of cisplatin-based treatment (75 mg/m2) plus pemetrexed (500 mg/m2) with vitamin supplementation every three weeks.N/RN/R
98Tewari et al. [124]2018VariousVariousVarious
99Yildiz et al. [125]2012VariousVariousVarious
100Lee et al. [126]2013Eligible patients received bevacizumab (Avastin, Roche Products Ltd.), plus standard 5-fluoropyrimidine (5-FU)-based chemotherapy per physician’s choice (single-agent 5-FU or 5-FU plus oxaliplatin or irinotecan) until disease progression, unacceptable toxicity or death. The bevacizumab dose was fixed at 5 mg/kg every 2 weeks.VariousVarious
101Reynes et al. [127]2016All patients received oral TMZ at a fixed and continuous dose of 50 mg/m2 divided into three daily intakes, except for a single 100 mg/m2 dose, administered between 3 and 6 h before every irinotecan infusion. Irinotecan was given intravenously at the previously established dose of 100 mg/m2 on days 8 and 22 of 28-day cycles.N/R4 weeks
102Pinto et al. [128]2021Patients received intravenous gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks, combined with either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of a 3-week cycle, until progressive disease, unacceptable toxicity, or withdrawal of consent to treatment occurred.N/R3 weeks
Abbreviations: N/R: not reported; IV: intravenous; SC: subcutaneous; CR: complete remission; NED: no evidence of disease; 5-FU: 5-fluoropyrimidine; PO: medication taken orally; BID: medication taken twice a day; FOLFOX: 5-fluorouracil/leucovorin combined with oxaliplatin; FOLFIRI: 5-fluorouracil/leucovorin combined with irinotecan; TMZ: Temozolomide; CapeOx: oxaliplatin and capecitabine.
Table 4. Pooled and crude prevalence of venous thromboembolism across various cancer phenotypes.
Table 4. Pooled and crude prevalence of venous thromboembolism across various cancer phenotypes.
Cancer PhenotypeNumber of Studies
(N)
Total Number of Patients
(n)
Crude Prevalence RatePooled Prevalence Rate (Derived from Meta-Analysis)95% CIz-Scorep-Value
Overall102306715.78%6%0.06–0.0718.53<0.001
Cancer Phenotype
Bladder4270011.30%18%0.10–0.286.53<0.001
Blood393410.81%N/AN/AN/AN/A
Brain831775.19%4%0.04–0.0517.72<0.001
Breast830821.88%1%0.00–0.034.17<0.001
Cervical27166.42%N/AN/AN/AN/A
Colorectal1558914.69%5%0.03–0.078.16<0.001
Endometrial317311.56%N/AN/AN/AN/A
Gastric749326.55%9%0.05–0.155.89<0.001
Germ Cell11932.07%N/AN/AN/AN/A
Head and Neck21581.27%N/AN/AN/AN/A
Liver23475.19%N/AN/AN/AN/A
Lung1632283.97%5%0.02–0.094.32<0.001
Lymph66993.58%4%0.02–0.074.690.05
Mesothelial512864.82%6%0.03–0.115.24<0.001
Mixed232814%N/AN/AN/AN/A
Neuroendocrine11136.19%N/AN/AN/AN/A
Oesophageal23289.76%N/AN/AN/AN/A
Ovarian67188.22%8%0.05–0.127.470.02
Pancreatic314428.47%N/AN/AN/AN/A
Prostate312332.11%N/AN/AN/AN/A
Renal219811.11%N/AN/AN/AN/A
Skin1937.53%N/AN/AN/AN/A
Abbreviations: CI: confidence interval, N: number of studies, n: number of patients. Note: N/A = could not be generated as meta-analysis could not be performed due to limited number of studies (minimum of four studies required).
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Sun, M.-Y.; Bhaskar, S.M.M. Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy: A Systematic Review and Meta-Analysis. Diagnostics 2022, 12, 2954. https://doi.org/10.3390/diagnostics12122954

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Sun M-Y, Bhaskar SMM. Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy: A Systematic Review and Meta-Analysis. Diagnostics. 2022; 12(12):2954. https://doi.org/10.3390/diagnostics12122954

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Sun, Ming-Yee, and Sonu M. M. Bhaskar. 2022. "Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy: A Systematic Review and Meta-Analysis" Diagnostics 12, no. 12: 2954. https://doi.org/10.3390/diagnostics12122954

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