key: cord-1016543-0flic0sv
authors: Mosaad, Manar; Elnaem, Mohamed Hassan; Cheema, Ejaz; Ibrahim, Ismail; Ab Rahman, Jamalludin; Kori, Ahlam Naila; Hin, How Soon
title: Cancer-Associated Thrombosis: A Clinical Scoping Review of the Risk Assessment Models Across Solid Tumours and Haematological Malignancies
date: 2021-07-24
journal: Int J Gen Med
DOI: 10.2147/ijgm.s320492
sha: 04db5c21af091d466feb15f0af68395701d7ee7a
doc_id: 1016543
cord_uid: 0flic0sv

Cancer-associated thrombosis (CAT) is a leading cause of death in cancer patients receiving outpatient chemotherapy. The latest guidelines emphasize stratifying the patients in terms of CAT risks periodically. Multiple risk assessment models (RAMs) were developed to classify patients and guide thromboprophylaxis to high-risk patients. This study aimed to discuss and highlight different RAMs across various malignancy types with their related advantages and disadvantages. A scoping review was conducted using predefined search terms in three scientific databases, including Google Scholar, Science Direct, and PubMed. The search for studies was restricted to original research articles that reported risk assessment models published in the last thirteen years (between 2008 and 2021) to cover the most recently published evidence following the development of the principal risk assessment score in 2008. Data charting of the relevant trials, scores, advantages, and disadvantages were done iteratively considering the malignancy type. Of the initially identified 1115 studies, 39 studies with over 67,680 patients were included in the review. In solid organ malignancy, nine risk assessment scores were generated. The first and most known Khorana risk score still offers the best available risk assessment model when used for high-risk populations with a threshold of 2 and above. However, KRS has a limitation of failure to stratify low-risk patients. The COMPASS-CAT score showed the best performance in the lung carcinoma patients who have a higher prevalence of thrombosis than other malignancy subtypes. In testicular germ cell tumours, Bezan et al RAM is a validated good discriminatory RAM for this malignancy subtype. CAT in haematological malignancy seems to be under-investigated and has multiple disease-related, and treatment-related confounding factors. AL-Ani et al score performed efficiently in acute leukemia. In multiple myeloma, both SAVED and IMPEDED VTE scores showed good performance. Despite the availability of different disease-specific scores in lymphoma-related thrombosis, the standard of care needs to be redefined.

The link between cancer and its predisposing risk of thrombosis has been well identified. 1 Compared to the general population, cancer patients have a 7-times higher risk of thromboembolism. 2 Cancer-associated thrombosis (CAT) is the second most prevalent mortality cause in malignancy patients, following the mortality caused by the direct impact of cancer. 3 Mortality risk increases fourfold with advanced malignancy. Furthermore, CAT is a significant cause of morbidity for patients, resulting in a lower quality of life and more frequent hospitalization. 4 There is a 5-10% probability of developing CAT among patients on chemotherapy within the first year following the disease diagnosis. 5 The yearly incidence of CAT varies widely from 1.4% to 10% and up to 20% in specific cases attributed to a wide range of presentation variations such as the cancer type, stage, patient characteristics, and treatment protocols. 6 Since thromboprophylaxis may reduce CAT rates by up to 50% in high-risk patients, extensive research has been done to establish accurate and discriminative risk assessment models (RAM) that can distinguish high-risk CAT patients in whom thromboprophylaxis is most likely to confer significant benefits and overweight any possible risks. 7 Given the high CAT-related morbidity and mortality, thromboprophylaxis is recommended for moderate to high VTE risk ambulatory patients undergoing chemotherapy based on the type of malignancy or by using a valid risk evaluation model. 8, 9 The first risk assessment score was introduced in 2008 by Alok Khorana et al through the most known and validated model for risk evaluation, The Khorana Risk Score (KRS). 10 A systematic review evaluated the performance of the KRS from 2008 till 2018 and included 55 cohorts (N= 34,555) showed consistency in identifying ambulatory patients who are at high risk of developing VTE; however, patients with low scores (0 or 1) were still experiencing a significant rate of VTE incidence. 11 In the recent AVERT and CASSINI studies measuring the performance of thromboprophylaxis use of direct oral anticoagulant (DOAC) in ambulatory cancer patients, the used KRS ≥2 showed a substantial decline in the overall VTE burden. 12, 13 It was revealed that the KRS has numerous limitations, particularly in the low-risk group; thus, several risk assessment scores were also developed. Although the majority of the scores are pan-malignant RAM, other diseases specific RAM also developed. This raises concern about whether the availability of a more specific RAM would yield an even better risk reduction. Up to the best of the authors' knowledge, there is a lack of evidence to discuss and highlight different RAMs across various malignancy types with their related advantages and disadvantages. This review aimed to discuss and summarize available risk assessment models/scores in various malignancies and identify their relative performance and advantages.

The framework for performing scoping reviews was the main methodological base for performing this scoping review. We followed the stepwise illustrated approach as proposed by H. Arksey & L. O'Malley and advanced further by Levac et al. 14, 15 Identifying the Research Questions This review focussed on studying the risk assessment models of cancer-associated thrombosis. The following research questions guided the process of including studies, extracting and summarising assessment models, and their main characteristics, advantages, and disadvantages:

What are available risk assessment models for cancerassociated thrombosis in ambulatory cancer patients undergoing chemotherapy?

Which score has the most comparative discriminative performance among risk assessment models in each malignancy type among ambulatory cancer patients?

We included original research articles published between January 2008 and January 2021 that reported risk assessment models in cancer-associated thrombosis ( Table 1) . The search for studies was restricted to the last thirteen years to review the most recently published evidence following the development of the principal risk assessment score in 2008. (Table 2) . A comprehensive search in three databases, Google Scholar, PubMed, and ScienceDirect, was performed to retrieve relevant studies using predefined terms. 

The search terms included ("cancer-associated thrombosis"), ("CAT"), ("risk assessment model"), ("risk assessment score"), ("RAM"), ("risk stratification"), ("prediction tool"), and ("predictive score"). Figure 1 shows the flow chart of the process of inclusion of the studies.

Two independent reviewers performed the initial identification of studies for potential inclusion at this stage according to the predefined inclusion criteria presented in Table 1 . As suggested by the followed methodological approach, meetings were conducted regularly to select the studies. Further involvement of an independent reviewer was considered to resolve any conflicts or discrepancies in the included studies. Finally, full-text articles published in the last thirteen years that met the inclusion criteria were considered for inclusion (Table 1) .

An iterative pattern of charting the data was adopted using a form specifically to extract relevant information consistent with the above-mentioned research questions. The included variables were study author, year, main score components, advantages, disadvantages, conducted validation trials, and the key findings. Independent data extraction for the first five studies was performed and evaluated. A consistent data extraction pattern was then completed for the remaining included studies concerning the designed extraction form.

A descriptive analysis of the retrieved data was conducted. Reporting the key findings was done in a reliable pattern to the proposed research questions and the main work objectives. Based on the malignancy subtypes, a summary of the advantages and disadvantages of the risk assessment models was discussed and tabulated. For cancer-associated thrombosis, the performance of the risk assessment models compared to others was highlighted.

Of the initially identified 1115 studies, 39 studies with over 67,680 patients were included in the review.

Overall, the review identified three major malignancy subtypes with well-defined dedicated risk assessment models: solid organ, lung, and haematological malignancies. Few RAMs that have been validated for use across all 

The initial risk assessment model, KRS (2008), was pancancerous for all types of malignancies and not diseasespecific. However, the validation studies showed suboptimal KRS performance in certain malignancies such as lung carcinoma and haematological malignancies that will be individually discussed later. The RAMs currently available for thrombosis risk stratification in solid organ malignancy are KRS being the first and most known score, Khorana modification scores (CATS Score, PROTECHT Score, CONKO Score, TiC-Onco risk score, and ONKOTEV Score), and the new generation models (The COMPASS-CAT score, new Vienna-CATS score, and The MDACC CAT model). These scores have similarities and unique features for each of them, as shown in Table 2 .

The majority of these RAMs have been derived through retrospective statistical analysis of ambulatory cancer patient cohorts subsequently validated. We reviewed all these trials with over 41,896 patients in derivation and validation studies. These RAMs vary widely; hence while some are feasible, some have limitations and disadvantages if considering the real-life setting, as discussed below. A list of the studies involved different RAMs and a summary of their key findings, advantages, and disadvantages are provided in Table 3 .

KRS was developed in 2008 with a cohort of around 4000 ambulatory cancer patients. Two-thirds of the population was included in the derivation of the score, and then the remaining one-third was used to validate it. Median follow-up was 73 days only. The score was composed of the tumour site, patient body mass index, and pre-chemotherapy blood counts. Throughout the last decade, numerous amounts of validation trials were performed. Some were disease-specific such as Srikanthan et al for germ cell tumour, 30 and Santai et al, who did pooled analysis for lymphoma. 31 In 2019, Mulder et al enrolled 34,555 from 55 cohorts of ambulatory cancer patients assessing the six-month incidence of thrombosis and KRS performance in a systematic review and metaanalysis. The authors concluded that KRS could be used to select cancer patients at high VTE risk for thromboprophylaxis; however, most CAT events take place outside this high-risk group. 11 It was also noted that reducing the threshold of KRS score to two points was 2, 19, 20 ONKOTEV score is easily applicable and have good predictability in a score of 2 and more and offers better stratification than KRS however shares the same limitation of failing to identify cases in the low-risk group.

The COMPASS-CAT Score

The COMPASS-CAT score was developed to improve CAT risk assessment for colon, lung, ovarian, and breast cancers. This score includes cancer-associated factors (time since diagnosis, stage), patient-related characteristics (cardiovascular risk factors, platelet count, history of VTE, recent hospitalization), and treatment-associated aspects (anthracycline or anti-hormonal therapy, central venous catheter). The risk of VTE was 1.7% in the low/intermediate-risk group, while in the high-risk population, it was 13.3%. The score had a good discriminatory capacity (AUC 0.85). 23 Retrospective validation of 3814 patients concluded that model discrimination was moderate and calibration was poor; however, the model had a good negative predictive value. 27 On the contrary, two validation studies involving lung carcinoma patients showed good outcomes, which will be discussed later in this work. 

Lung carcinoma is a distinctive group of solid organ malignancy given the disease nature and the proximity to major vessels and treatment protocols. Lung cancer has been associated with a high incidence of VTE compared to other malignancy groups; this led to more research in this subgroup of patients. 42, 43 Table 4 shows several RAMs were studied explicitly for lung carcinoma with a total population of 4161 patients.

A meta-analysis evaluated 3293 patients, of which 1913 were lung cancer patients. In the analysis, the Khorana score was incapable of stratifying patients with lung cancer based on their VTE risk compared to other malignancy groups. 44 

Despite the performance in the overall solid organ malignancy validation study, COMPASS-CAT score in lung carcinoma in specific has a superiority study in which Rupa-Matysek et al; compared Khorana risk score (KRS), COMPASS-cancer associated thrombosis score (COMPASS-CAT), PROTECHT score and CONKO score. Moreover, it involved 118 patients with lung cancer.

The COMPASS-CAT model was the most precise predictor of VTE incidence in patients with lung malignancy with a C statistic of 0.89. The score was able to detect 100% of patients with established VTE.

The prospective ROADMAP-CAT study detected two biomarkers of hypercoagulability, the mean rate index (MRI) of the propagation phase of thrombin generation and the procoagulant phospholipid-dependent clotting time (Procoag-PPL). These have been clinically significant for stratifying ambulatory cancer patients with lung 

adenocarcinoma who had received a maximum of one chemotherapy cycle into high and intermediate/low risk for VTE. This score's positive predictive value (PPV) was 25%, and the negative predictive value (NPV) was 97%. 26 In the same study, the research team studied the association of the Procoag-PPL and MRI with the COMPASS-CAT RAM, which added to its accuracy with PPV of 70% and NPV of 97%. Although this result is promising, the Procoag-PPL and MRI testing feasibility in the real-life setting as a standard of care in all cancer patients is questionable.

In a retrospective analysis of 1980 patients with lung cancer, the study concluded that current or former smokers, older age, chronic obstructive pulmonary disease, ECOG PS ≥2, no prior cancer surgery, and metastatic disease are predictive of VTE in lung carcinoma patients; however, a validation study is required.

Testicular germ cell tumours are among the most common malignancies affecting adolescents and young adults. 45 In this group of malignancy, thrombosis events cover up to 8.4% and increase to 17% in patients ongoing cisplatinbased chemotherapy, 45, 46 hence some research was directed to thrombosis risk assessment.

Aside from the pancancerous KRS, two risk assessment model was developed:

A single parameter risk identifier by Srikanthan et al in a cohort of 216 patients concluded that large retroperitoneal lymphadenopathy (RPLN) more than 5 cm with metastatic disease in patients receiving first-line cisplatin-based chemotherapy is associated with high thrombosis risk (AUROC 0.61 vs 0.57 for KRS). 30 

In derivation cohort 657 and validation cohort 349, Bezan et al. developed a disease-specific RAM. The findings underpinned higher tumour stage and a large RPLN as the significant predictors of VTE. The score has good risk discrimination in comparison to the previously mentioned RPLN-VTE risk classifier (AUC-ROC:0.75 vs.0.63). 46

Patients with haematological malignancy tend to be underrepresented groups in thrombosis research since this population incline to have variable characteristics and blood parameters. Also, this group of patients remains vulnerable to thrombosis predisposed by potentially thrombogenic therapy. Several works aimed to construct risk assessment models (RAM) to guide patients' risk stratification and treatment. Noticeably, lymphoma and multiple myeloma have more RAM-related research in comparison to acute leukaemia. 47 Summary of the RAMs categorized under each haematological malignancy with a total population of 20,383 patients, and their performance is provided in Table 5 .

A misconception that thrombosis risk in patients with leukaemia was lower than that of solid tumours 48 is being replaced by recent studies which showed the incidence of thrombosis to be similar or even higher than in those with solid tumours. 49 The prevalence of thrombosis in acute myelocytic leukemia (AML) varies. In a cohort of 5394 cases, the largest cohort of AML, the 2-year cumulative incidence of deep vein thrombosis and/or pulmonary embolism was 5.2%. 47 While acute promyelocytic leukemia (APL), the incidence of thrombosis increases to 10-15% compared to other types of acute myeloid leukaemia due to distinct molecular, morphologic, clinical characteristics, procoagulant and fibrinolytic properties of pathological promyelocytes. 50 In acute lymphocytic leukemia (ALL), a study conducted by Ku et al among 2482 cases with ALL, the 2-year incidence of VTE was 4.5%. Also, as reported by Grace et al, the ratio could increase to 42% in adults with ALL during chemotherapy. 51, 52 This significantly increased risk is attributed to asparaginase and central venous catheters, being major risk factors for thrombosis in ALL. Other risk factors are older age and the number of chronic comorbidities. 51, 53 Risk assessment models in leukemia are as follows:

In a study conducted by Mirza et al, 867 AML patients were included from 2000 to 2018. There was no statistically significant increment in the risk of thrombosis associated with a higher KRS in AML patients with a KRS of 1 to 3. Of notice, only a few patients were found to have a KRS > 3. This was mainly due to cytopenias that are common in AML. Therefore, Khorana was not the optimum risk score for AML. 

A risk assessment model was developed by Al-Ani et al in a cohort of 501 leukemia patients, of these, 74 were having ALL. It is a simple score with three components, previous history of VTE (three points), ALL (two points) and platelet count >50 x 109 (one point). A score of three and more indicates a high risk. The score is statistically significant with a C-statistic of 0.664 (95% CI: 0.590-0.738) and ongoing external validation. 49 International Society on Thrombosis and Haemostasis Disseminated Intravascular Coagulation Score (ISTH DIC)

The score which was initially derived for DIC risk assessment was investigated in a prospective study in a cohort of 272 adult patients by Libourel et al, and it was noted that it significantly predicted arterial and venous thrombosis with a hazard ratio (HR) for a high DIC score ( ‡5) of 4.79 (1.71-13.45). 63 A validation cohort of 132 elderly patients with AML confirmed the finding (HR 11.08 [3.23-38.06]). 63 D-dimer levels were the most predictive for thrombosis. This study excluded APL, which is highly associated with DIC. In another cohort by Mitrovic et al, 63 consecutive de novo APL patients were included. Thrombosis events were reported in 13 cases (20.6%). Initial ISTH DIC score was predictive for venous TE (P = 0.001). 50 However, in a study by Al-Ani et al, the parameters were not predictive of thrombosis, but that study lacked D-dimer level sampling. 49 Table 6 present the parameters and their assigned scores for the ISTH DIC score.

Lymphomas are the most prevalent haematological malignancies globally and at higher VTE risk than different 

cancer types, particularly solid tumours. 64 Aggressive lymphomas occur in 10-15% incidence of CAT in the first year of diagnosis. 65 Hodgkin lymphoma (HL) accounts for nearly 10% of all lymphomas. Thrombosis events vary from 5.0% to 59.5% in lymphomas and are more significant in non-Hodgkin than in HL. 66 As with other haematological malignancies, anticoagulation for treatment or prophylaxis is challenging because of the thrombocytopenia, which is either disease-related or treatment-related. In the recent Cassini trial that compared rivaroxaban 10 mg once-daily versus placebo for prophylaxis of outpatients with Khorana score (≥2) receiving chemotherapy, 7% were lymphoma cases. The findings showed reductions of approximately 60% of thrombotic events. 36 Risk assessment models for thrombosis risk in lymphoma are more than other haematological malignancies. Examples of RAMs for lymphoma are as follows:

In the initial cohort during the development of the score, 12.6% had lymphomas. Subsequently, several studies have specifically studied KRS in lymphoma. The majority of them concluded that the KRS did not adequately predict VTE events in patients at a higher VTE risk. However, in a pooled analysis of 12 lymphoma studies by Santi et al, the findings showed that a Khorana score of 3 and more was associated with VTE incidence. 31 Later, several Khorana modification scores were developed; however, lymphoma patients were not represented. 65, 67, 68 Thrombosis Lymphoma-ThroLy Score TiC-ONCO-Associated Lymphoma Score (TiC-Lympho)

A lymphoma-specific RAM was developed as a variant of the TIC-ONCO score for solid organ tumours risk stratification. The F5 rs6025, F5 rs4524, F13 rs5985, SERPINA10 rs2232698, additionally some clinical variables (immobilization, Ann Arbor stage mediastinum extension, tumour type, and personal thrombotic history) were significantly related to CAT. The study found that incorporating genetic-clinical data to assess VTE risk is relevant to lymphoma. The predictive capacity for VTE in the lymphoma population exceeds that achieved by the Khorana and ThroLy scores. 59 However, a validation study is required, especially to 

In a study involving 144 patients in a prospective risk assessment to detect patients with MM at risk for CAT, the findings demonstrated that longer Procoagulant phospholipid clotting time (Procoagulant-PPL) and lower endogenous thrombin potential (ETP) could significantly predict thrombosis. However, a powered study is required for validation.

In a MM validation cohort that enrolled 2874 patients with a six month follow up, Khorana score failed to predict VTE accurately. 60

The risk of venous thromboembolism VTE is up to 7-fold higher in cancer patients. 2 Cancer-associated thrombosis (CAT) is the second prevalent cause of mortality in cancer patients. Thromboprophylaxis in ambulatory cancer patients is associated with a 50% decrement of CAT occurrence in a high-risk population, 3 hence the need to stratify patients to high and low risk. Since 2008, numerous RAM has been developed.

In solid organ malignancy, to our knowledge, nine risk assessment scores were generated. The first and most known Khorana risk score still offers the best available risk assessment model when used with the threshold of 2 and above as a cut point for high-risk populations. 11 However, KRS has two major limitations: failure to stratify low-risk patients and performing poorly in certain malignancy subtypes such as lung, urothelial, and haematological malignancies. ONKOTEV score is a Khorana score modification with better performance and easy applicability but shares the same limitation as KRS. 41 The addition of genetic factors to stratify patients, although promising, is faced by the applicability restrains. 28 The lung carcinoma population has a higher prevalence of thrombosis than other subtypes. The risk assessment model aims to stratify lung malignancy patients. The COMPASS-CAT score performed the best. 24 If a large cohort trial confirmed the current finding, it should be used as a standard of care. In testicular germ cell tumour 

Bezan et al RAM is a validated good discriminatory RAM for this malignancy subtype. 46 Cancer-associated thrombosis in haematological malignancy is under-investigated. Thrombosis in these subtypes has multiple confounding factors such as disease-related factors, eg, thrombocytopenia, and treatment-related factors like Treatment with l asparaginase. In acute leukaemia, Al-Ani et al developed a simple predictive tool that may be used as standard of care but is awaiting ongoing external validation. 49 Despite the availability of different disease-specific scores in lymphoma-related thrombosis, in multiple myeloma, both SAVED and IMPEDED VTE scores performed better than currently used guidelines and can be used in risk stratification of patients with MM. 61, 72 The guidelines already recommend the thromboprophylaxis of high-risk patients, given the significant reduction in mortality and morbidity. Using the KRS, which is already proved to have a substantial limitation, has considerably reduced the VTE burden. Therefore, a better RAM is likely to have a more favourable outcome. Meanwhile, the clinician knowledge and application remain limited mainly due to the lack of a standard score or easily accessible system that calculates different risks. We believe that the currently allocated risk factors might be sufficient to stratify the patient. Having a pan-cancerous score for all types of malignancy might be challenging to achieve because of the broad disease characteristics. The future research should be directed to focus on the applicability rather than derivation of new parameters that later on would be faced with the limitation of feasibility and availability in solid organ malignancy; we looked at the different RAM components, the similarities with one or two factors distinctive for each score. Some of these factors are very academic or not readily practised in the general clinical setting others easy applicable. We suggest using all these feasible and practical factors to create a new combined score that might have better sensitivity and specificity and has less limitation to have better RAM. Future research could be directed to examine the use of telemedicine applications to help in patients' risk stratification and treatment guidance considering the current changes in the healthcare delivery model imposed by the covid19 pandemic.

CAT, cancer-associated thrombosis; RAM, risk assessment model; VTE, venous thromboembolism; PE, pulmonary embolism; KRS, Khorana risk score; DOAC, direct oral anticoagulant; BMI, body mass index; MM, multiple myeloma; HR, hazard ratio; ESA, erythrocyte stimulating agent; ECOG PS, Eastern Cooperative Oncology Group Performance Status; NNP, negative predictive value; PPV, Positive predictive value; OR, odds ratio; AML, acute myeloid leukaemia; APL, acute promyelocytic leukaemia; ALL, acute lymphoblastic leukaemia; NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; AUC, area under the curve.

This study did not require ethics approval.

The authors report no conflicts of interest in this work.

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