Thromboembolic disease (VTED) is a frequent event in cancer patients. It is related to cancer treatment interruption, a decrease in quality of life and an increase in comorbidity, morbidity and mortality. It also increases hospital stay and healthcare costs.1–6

This relationship between VTED and cancer is bidirectional. The presence of active cancer increases the risk of VTED by 9 times compared to the general population. The incidence of VTED in cancer patients have practically been tripled in the last two decades.7

Current clinical guidelines do not recommend the routine use of thromboprophylaxis in cancer primary unselected patients.8–10 Identifying cancer patients who could be beneficiaries of thrombotic prophylaxis is a real challenge. That is why the Khorana score was developed as a validated tool incorporated into thromboprophylaxis guidelines, which assesses the risk of developing VTED in cancer patients before starting chemotherapy.9,11 This score evaluates five clinical and analytical parameters prior to chemotherapy (Table 1), classifying patients as low (0 points), intermediate (1–2 points) or high risk (≥3 points) for VTED.12

Several authors and guidelines have suggested that primary thromboprophylaxis should be considered only in selected patients in the high risk group (Khorana ≥3).13–16 Recently, two randomised controlled trials have demonstrated the efficacy and safety of thromboprophylaxis with apixaban and rivaroxaban in cancer patients classified in the intermediate or high risk group of VTED (Khorana score ≥2).17–20 After that, new guidelines recommend thromboprophylaxis in patients with ≥2 points on this score.8–11 Although it is currently well known that thromboprophylaxis reduces the risk of VTED,21 there are certain limitations in the available literature and clinical practice guidelines do not provide solid recommendations in certain situations in cancer patients. Furthermore, the current adherence of clinicians to the predictive risk scores for thrombosis associated with cancer and the prescription of thromboprophylaxis in high risk patients are not well established.

The aim of our study is to analyse the application of the Khorana risk prediction score in cancer patients. Our study also tries to evaluate the prescription of primary thromboprophylaxis in cancer patients at risk of VTED.

A retrospective observational survival study was carried out from January 2009 to March 2018. There were included those patients admitted at the Hospital Central de la Defensa for any cause diagnosed with acute pulmonary embolism (PE) by computed tomographic pulmonary angiography and/or ventilation perfusion scan, according to the Spanish Pulmonology and Thoracic Surgery Society clinical practice guidelines of 201322 and the European Cardiology Society guidelines of 2014.23 A comprehensive search was performed in the registry of medical records during this period of patients diagnosed with PE in the emergency department or in the hospital ward. A non-probabilistic consecutive sampling was executed.

This population was classified into two groups: tumour PE (TPE) and no tumour PE (nTPE).

In addition, a case-control study was carried out by TPE patients (cases) and no PE cancer patients (nPEC). The registry of medical records was accessed by performing a deep search during this period of the different cancer Committees of the Hospital Central de la Defensa of patients diagnosed of cancer (gynaecological, lung, digestive, urological, haematological, and other tumour types) without VTED. The prevalence was maintained in both groups.

There were excluded from the study: patients diagnosed with an incidental pulmonary embolism (IPE) and incomplete clinical information cases, patients with prior anticoagulant treatment with poor adherence or infratherapeutic blood levels, pregnant women, children, patients with a difficult follow-up and those cases with a doubtful diagnosis.

VTED has experienced an increase in its incidence in hospitalised patients in recent years, with greater comorbidity and lower mortality over time.24–26 VTED is the second cause of death in cancer patients.27 Patients with TPE present greater comorbidity measured by the ChI compared to patients with nTPE,1 and this consideration is reflected in the present study. Regarding primary thromboprophylaxis in cancer patients, there is currently an open debate on the optimal way to identify cancer patients at high risk of VTED. Because of the recent publication of two trials,17,18 several guidelines recommend thromboprophylaxis in patients with a score of ≥2 on the Khorana score,8–11 so indication for thromboprophylaxis in cancer patients would increase significantly.28

This study aims to analyse this aspect when evaluating the usefulness of the Khorana predictive score in hospitalised cancer patients and the prescribing of thrombotic prophylaxis in the oncologic patient with high and intermediate-high risk of VTED using this score.

Although it is true that this predictive score was validated as a predictive tool in ambulatory cancer patients, numerous studies have evaluated its predictive capacity in hospitalised patients.29,30

When evaluating and comparing the Khorana score in patients with TPE and nPEC in our study, we found that it had predictive capacity, with intermediate risk prevailing in both groups. The high risk group (≥2 points) was more frequent in patients with TPE. The intermediate to high risk group (≥2 points) was also more frequent in the TPE group, both with statistically significant differences. The sensitivity of this score is modest in our series, since 90% and 74% of the thromboembolic events did not occur in the high risk and intermediate to high risk groups, respectively.

These data reflect how our series significantly increases the proportion of cancer patients who could benefit from thromboprophylaxis by prescribing it in patients with 2 points on the Khorana scale based on recent guidelines.8–11 This increase is comparable to that described by Mulder et al,28 who observed that the indication for thromboprophylaxis would increase from 17% to 47%28 when prescribing it in patients with ≥2 points.

Recently, several meta-analyses have analysed this aspect, finding results in the same direction, but with higher percentages in the intermediate to high and high risk groups. According to Mulder et al,28 64% of the 35,000 cancer patients were classified as intermediate risk, 17% as high risk, and 47% had ≥2 points. On the other hand, according to Bosch et al,31 64% of cancer patients presented ≥2 points.

It is essential to note that in this review one of the six studies analysed, unlike ours, considered very high risk brain tumour and high risk myeloma.18,28 Another aspect that could explain these striking differences is that in our study the most common tumour was gynaecological, followed by urological (mostly prostate), lung and digestive. On the other hand, in other studies, digestive, lung and gynaecological tumours were more frequent, implying higher score on Khorana score. Taking into account the histological types, in the recent study of the CARAVAGGIO registry, which included 1155 patients with TPE, the most frequent tumour was colorectal, followed by lung and breast.32 Similar results were obtained in the TESEO registry, with colon cancer being the most frequent followed by lung and breast.33 In contrast, in the RIETE registry, the most frequent associated cancer was lung, followed by breast and colorectal.34

Our TPE patients with lung cancer survived less than those with gynaecological tumours, who had the longest survival. The RIETE registry35 has described similar results, with survival being lower in patients with lung and digestive cancer, and higher in neoplasms of mammary origin. It should be mentioned that neoplasms with a high capacity to produce PE have recently been described, such as biliary tumour and non-small cell lung carcinoma.7 Furthermore, it is worth noting the growing importance of molecular biology in cancer (specifically the rearrangements of the ROS1 and ALK biomarkers in non-small cell lung cancer) due to its increased risk of producing PE.7,36

Continuing with our work and the history of thromboprophylaxis, only 7.4% of the TPE group had received it, corresponding to 8 patients. Of these, half, four patients were classified in the low risk group on the Khorana score and only one patient in the high risk group, with 3 patients scoring ≥2 points on the Khorana score. Of the 100 patients who had not received thromboprophylaxis, 9% had an indication of thromboprophylaxis with a score of ≥3 points and 24% had an indication based on the most recent guidelines with ≥2 points. This reflects a low prescription of thrombotic prophylaxis and limited adherence to this predictive score in our experience.

Evidence of this underutilisation of thromboprophylaxis in our series and poor adherence to this predictive score are other studies in cancer patients,37 such as that of Parker et al.,29 in which out of 1398 hospitalised cancer patients, 34.5% received thrombotic prophylaxis. In this study, unlike ours, patients with high risk of VTED on the Khorana score received more thromboprophylaxis than those at low risk (46.4% vs 23.9%).29

The present study has several limitations as it is a single-centre study and its design. It would require validation in future prospective studies. In addition, our sample with TPE is small, 108 patients, which could limit finding conclusions. Furthermore, in this study we have applied broad exclusion criteria, which could lead to a selection bias in the sampling. Likewise, the relative scarcity of similar studies that analyse the Khorana score in patients with TPE and nPEC limits the possibility of establishing large comparisons and parallels. Another limitation of this work is that we have not included certain treatments that are involved in the development of VTED, such as immunotherapy, protein kinase inhibitors, and angiogenic therapy.7

We have not analysed the Khorana score in the incidental pulmonary embolism (IPE). Numerous studies have not distinguished between IPE and TPE,7 or have not evaluated the usefulness of the Khorana score in the IPE, although this aspect could have been studied since the clinical characteristics do not differ significantly with respect to TPE.38 Regarding survival in this population, there are discordant results in this aspect, because while some studies have reported a similar prognosis in IPE and TPE,39 in a recent study by the RIETE registry have shown a lower mortality in IPE than in clinically suspected PE.40

Although we have not been able to conclude that the Khorana score constitutes a prognostic factor for VTED, based on the obtained results, thromboprophylaxis should be indicated in patients with intermediate (1–2 points) risk of VTED.

In conclusion, this study reflects the underutilisation of thromboprophylaxis in cancer patients and mainly in patients at high risk of VTED. Furthermore, there is little adherence to the Khorana score in our series, indicating the need for greater application and knowledge of this predictive score in clinical practice. More studies are needed to validate these findings and to optimise predictive strategies in the management of these patients.

Each of the authors of the article has contributed substantially to the elaboration of the manuscript: the design of the study or acquisition data, or analysis and interpretation of data, drafting the article or revising it deeply and critically for important intellectual content, final approval of the version to be submitted.

The authors declare that they have no conflict of interest directly or indirectly related to the contents of the manuscript.