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F.I. Mulder et al.
points), platelet count of 350x109/L or more (+1 point), hemoglobin concentration of 100 g/L or lower or use of erythropoiesis-stimulating agents (+1 point), leukocyte count of 11x109/L or higher (+1 point), and a Body Mass Index of 35 kg/m2 or higher (+1 point) (Table 1).7 A sum score of 0 points classifies patients as being at low risk of VTE, 1 or 2 points at intermediate risk, and those with 3 or more points at high risk. The Khorana score is endorsed by the latest guideline updates of the American Society of Clinical Oncology and the National Comprehensive Cancer Network to select ambulatory cancer patients for thromboprophylaxis.6,8
Over 50 studies have evaluated the score since its publi- cation, but reported results were often conflicting. A clear interpretation of these findings is further hampered by the substantial variation in study design, cancer types includ- ed, and duration of follow up, ranging from a median of 2 to 79 months.9,10
To obtain valid and interpretable summary estimates of the performance of the Khorana score, based on the evi- dence available, we performed a systematic review and meta-analysis, specifically focusing on 6-month follow-up outcomes of all published relevant studies by obtaining additional data, thereby minimizing between-study het- erogeneity. Our findings provide physicians with clinically useful data on the absolute risks of VTE associated with a low-, intermediate-, and high-risk Khorana score in ambu- latory patients with cancer.
Methods
This report adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance (See checklist in Online Supplementary Table S1).11
Search strategy and data collection
A comprehensive search was performed in Embase and MED- LINE from January 2008 to June 2018 to identify studies that had evaluated the Khorana score in ambulatory cancer patients. In addition, studies presented as abstracts at conferences of the American Society of Hematology (ASH) or the International Society on Thrombosis and Haemostasis (ISTH) were identified by a manual search. Two reviewers (FIM and MC) independently screened studies and assessed bias with the Quality in Prognosis Studies (QUIPS) tool.12 The search strategy is shown in Online Supplementary Table S2, and a full explanation of study selection, data extraction, and bias assessment is provided in Online Supplementary list 1.
Additional data
Because the number of events are expected to increase with the duration of follow up, we evaluated the incidence of VTE during a pre-specified follow-up duration to minimize between-study heterogeneity in observation time. Since the majority of venous thromboembolic events occur in the first six months after start of chemotherapy,1 this 6-month follow-up period was considered most relevant. Corresponding authors of included studies not reporting the 6-month period were contacted and invited to pro- vide additional data for this period.
Statistical analysis
The primary outcome measure was the proportion of cancer patients who developed VTE during the first six months of study follow up in those with a low (0 points), intermediate (1-2 points),
Table 1. Khorana risk score. Patients’ characteristics
Risk score
Site of cancer
Very high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecological, bladder, or testicular) 1
Prechemotherapy platelet count ≥350 x 109/L 1 Prechemotherapy hemoglobin level <100 g/L 1 or use of red cell growth factors
Prechemotherapy leukocyte count >11 x 109/L 1 Body Mass Index ≥35 kg/m2 1
or high (3 or more points) Khorana score. VTE was defined as the composite of radiologically confirmed symptomatic or incidental distal or proximal lower-extremity deep-vein thrombosis, upper- extremity deep-vein thrombosis, or pulmonary embolism. Studies with a fixed follow-up time less than six months in their study design were not included in the analysis of the 6-month outcomes. The derivation cohort of the Khorana score was excluded from analysis.7 As currently ongoing clinical trials (clinicaltrials.gov identi- fier: 02048865 and 02555878) select patients with a score of 2 or more for thromboprophylaxis; the primary outcome was also assessed for this alternative positivity threshold. Secondary out- come measures included the proportion of patients with VTE dur- ing overall follow up, the proportion of VTE occurring in the high- risk group, and the relative risk of VTE for patients with a high- risk score (≥3 points) versus those with a low-to-intermediate risk score (0-2 points) in the first six months and during complete fol- low up. A sensitivity analysis was performed restricted to studies not judged to be at high risk of bias in any of the domains.
A random effects model with logit transformation and inverse variance weighting was used to calculate summary estimates. Forest plots are presented with back-transformed study-specific estimates and corresponding 95% confidence and prediction inter- vals. Between-study heterogeneity was assessed by calculating tau-squared (τ2) using restricted maximum likelihood estimation. Differences between subgroups were tested for significance with a χ2 test. P<0.05 was considered statistically significant. Publication bias was explored with a funnel plot using the relative risk between high- and low-to-intermediate risk patients on the x- axis.13 Analyses were performed with R computing software, ver- sion 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria; www.r-project.org), in particular using the meta package version 4.9-0.
Results
Search results
The database and manual search yielded 1,826 unique articles and 53 abstracts, of which 1,641 were excluded on the basis of title and abstract (Figure 1). Another 50 studies were excluded after full-text assessment because the Khorana score was not reported (n=31), VTE incidence was not reported (n=6), the study population only com- prised patients with VTE (n=6), the cohort was a duplicate report (n=5), or the study had a case-control design (n=2).
A total of 45 articles and eight abstracts were included in the analysis, comprising 55 cohorts and 34,555 ambula- tory cancer patients, of whom 2,386 (6.9%) were diag- nosed with VTE during follow up. Most studies included patients with various tumors (n=22; 42%), while others had confined recruitment to patients with gastrointestinal
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haematologica | 2019; 104(6)