Optimal authoritative risk assessment score of Cancer-associated venous thromboembolism for hospitalized medical patients with lung Cancer

A retrospective study was performed to explore which one of the currently authoritative risk assessment scores for VTE including PE and/or DVT had the optimal assessment accuracy for the development of VTE in hospitalized medical patients with primary lung cancer. We reviewed consecutive patients with lung cancer who had undergone VTE investigation including computed tomography pulmonary angiography (CTPA), compression ultrasonography (CUS) of lower and upper extremities, and/or planar ventilation/perfusion (V/Q) scan [21, 22] during a medical hospitalization which implied a higher probability of VTE than ambulatory outpatients. Medical hospitalization denotes the hospitalization in which chemotherapy, radiotherapy, targeted therapy, immunotherapy, and/or other medical treatment were administered to patients. Patients underwent all of the aforementioned three investigations unless there was a contraindication to CTPA. The patients were assigned into the lung cancer (LC) and lung cancer-VTE (LC-VTE) groups according to whether or not they had been diagnosed with VTE till the present study or death prior to the present study after the diagnosis of lung cancer. In the meantime of VTE diagnostic investigation, all patients received thromboprophylaxis through discharge unless there was a contraindication. The follow-up period commenced from the diagnosis of lung cancer to the present study or the death of patients, whereas the post hoc analysis period initiated from lung cancer diagnosis to the last time of VTE testing in hospitalization prior to the present study.

In the current study, the likelihood of VTE in patients were reassessed with the Khorana score, the PROTECHT score, the CONKO score, the ONKOTEV score, the COMPASS-CAT score, and the CATS/MICA score, thereby comparing their assessment accuracy for the development of VTE. The Khorana score comprises variables including primary site of cancer (very high risk [2 points] or high risk [1 point]), prechemotherapy platelet count of 350 × 10⁹ /L or more (1 point), hemoglobin level less than 100 g/L and/or use of red cell growth factors (1 point), leukocyte count more than 11 × 10⁹ /L (1 point), and body mass index (BMI) of 35 kg/m² or more (1 point). A total score of 3 or more was defined as high risk of VTE [11]. The PROTECHT score consists of Khorana score, gemcitabine chemotherapy (1point), and platinum-based chemotherapy (1point). A total score of 3 or more was defined as high risk of VTE [13]. The CONKO score is also a revised Khorana score in which BMI is replaced by the Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status ≥2 (1 point). A total score of 3 or more was defined as high risk of VTE [14]. The ONKOTEV score is based on a Khorana score > 2(1 point), metastatic disease (1point), previous VTE (1point), and vascular/lymphatic macroscopic compression (1point). A total score of 2 or more was defined as high risk of VTE [15]. The COMPASS-CAT score includes anti-hormonal or anthracycline therapy (6 points), time since cancer diagnosis ≤6 months (4 points), central venous catheter (3 points), advanced stage of cancer (2 points), cardiovascular risk factors (5 points), recent hospitalization (5 points), personal history of VTE (1 point), and platelet count ≥350 × 10⁹ /L (2 points). A total score of 7 or more was defined as high risk of VTE [16]. The CATS/MICA score comprises one tumor-site category and D-dimer level. A 6-month cumulative risk of VTE ≥ 10%(or a total score ≥ 110) was defined as high risk of VTE [18].

The patients with high risk of VTE assessed by each score were defined as VTE likely, whereas those with non-high risk of VTE were defined as VTE unlikely. Then such dichotomy was contrasted with the actual presence and absence of VTE confirmed by CTPA, V/Q scan, and CUS, so as to compare the assessment accuracy for VTE development among these risk assessment scores. The parameter values at admission were adopted for the variables involved in these scores. For patients who had been diagnosed with VTE prior to the present study, the data of the hospitalization in which VTE was initially diagnosed was incorporated into the present study as one case, whereas for those who had not been diagnosed with VTE until the present study, the data in the hospitalization in which the last time of VTE diagnostic testing was performed prior to the present study was adopted as one case. For each patient, all these VTE risk assessment scores were performed post hoc based on the data in the same hospitalization. One patient could not be counted as more than one case. All data were retrieved from the Electronic Medical Record (EMR) of three hospitals in Shanghai, including Shanghai Xinhua Hospital, Shanghai Pulmonary Hospital, and Shanghai Punan Hospital. The protocol was approved by the institutional review boards of these hospitals.

In terms of inclusion and exclusion criteria, we incorporated eligible patients into the current study. The inclusion criteria comprised: 1) all eligible patients were 18 years old or older; 2) all eligible patients had a definite histopathological diagnosis of primary lung cancer; 3) all eligible patients with lung cancer underwent CTPA, CUS and/or V/Q scan that could confirm the presence or absence of VTE during the hospitalizations of diagnoses or medical treatment of lung cancer, or an acute medical illness; 4) all eligible patients had complete information required for the study. The exclusion criteria comprised: 1) patients who had other known primary cancers apart from lung cancer were excluded; 2) patients who had a history of chronic VTE or thrombophilia were excluded; 3) patients who had undergone major surgery or trauma within previous month prior to the diagnoses of VTE were excluded.

A total of 1370 patients with lung cancer from Jan, 2013 through Dec, 2020 were incorporated into the current study based on the inclusion criteria. According to the exclusion criteria, 29 patients who had other known primary cancers apart from lung cancer, 37 patients who had a history of chronic VTE or thrombophilia and 41 patients who had undergone major surgery or trauma within previous month prior to the diagnoses of VTE were excluded. Finally, 1263 patients were determined to be in the analysis of current study. The mean age of all patients was 70.4 years old. The number of female and male patients were 550 and 713, respectively. Among a total of 1263 patients with primary lung cancer who underwent VTE-confirming investigations, all patients underwent CUS and V/Q scan, and 1092 patients underwent CTPA whereas 171 patients did not due to contraindications.

Taken together, among 1263 patients with lung cancer, 173 patients (13.7%) had VTE, whereas 1090 ones had not. Among 173 patients with established VTE, 79 and 57 ones solely had PE and DVT, respectively, whereas 37 ones had both PE and DVT. For 173 patients with established PE, 155 patients were diagnosed with CTPA and/or V/Q scan, whereas 18 patients were diagnosed with sole V/Q scan due to the contraindications to CTPA. For 1090 patients whose VTE diagnoses were excluded, 937 patients had negative results of CTPA, V/Q scan and CUS, whereas 153 patients had negative results of V/Q scan and CUS due to the contraindications to CTPA. The median time from lung cancer diagnosis to the hospitalization in which the last time of VTE diagnostic testing was performed prior to the present study in LC and LC-VTE groups were 13.3(7.6–19.0) and 15.9(9.1–22.7) months, respectively.(p = 0.868) The median time from lung cancer diagnosis to the hospitalization in which data were analyzed in LC and LC-VTE groups were 13.3(7.6–19.0) and 11.8(5.2–18.4) months, respectively (p = 0.357) The demographic and clinical characteristic of patients were summarized in Table 1.

True Positive, False Positive, False Negative, and True Negative of all Risk Scores.

The VTE possibility of all patients in the final analyses were reassessed with the Khorana score, the PROTECHT score, the CONKO score, the ONKOTEV score, the COMPASS-CAT score, and the CATS/MICA score, then were contrasted with the actual VTE establishment, to determine the number of TP, FP, FN, and TN resulted from each risk score. The number of TP, FP, FN, and TN of all risk scores are demonstrated in Table 2. In contrast with the actual VTE prevalence of 13.7%, the diagnostic VTE prevalence by the Khorana score, the PROTECHT score, the CONKO score, the ONKOTEV score, the COMPASS-CAT score, and the CATS/MICA score were 27.5, 26.5, 27.4, 22.6, 31.4, and 18.3%, respectively. The Pairwise difference of number of TP, FP, FN, TN between every two risk scores are demonstrated in Fig. 1.

Base on the number of TP, FP, FN, TN of each risk score, the assessment accuracy for VTE development among all risk scores were compared. The ratio of actual VTE prevalence in patients predicted as VTE-positive over that in those predicted as VTE-negative by the Khorana score, the PROTECHT score, the CONKO score, the ONKOTEV score, the COMPASS-CAT score, and the CATS/MICA score were 7.08(36.3% vs 5.13%), 9.21(39.7% vs 4.31%), 8.02(37.6% vs 4.69%), 15.1(49.5% vs 3.27%), 8.61(34.8% vs 4.04%), 2.75(28.6% vs 10.4%), respectively. The ratio of actual VTE exclusion in patients predicted as VTE-negative over that in those predicted as VTE-positive by the Khorana score, the PROTECHT score, the CONKO score, the ONKOTEV score, the COMPASS-CAT score, and the CATS/MICA score were 1.49(94.9% vs 63.7%), 1.59(95.7% vs 60.3%), 1.53(95.3% vs 62.4%), 1.91(96.7% vs 50.5%), 1.47(96.0% vs 65.2%), 1.25(89.6% vs 71.4%), respectively.

The sensitivity, specificity, PPV, NPV, FPR, FNR, PLR, NLR, DOR, CA, AA, and Youden index for VTE assessment by all VTE risk assessment scores involved in the present study are demonstrated in Table 3. The comparison of assessment efficiency for VTE occurrence showed that the adjusted agreement of the Khorana score, the PROTECHT score, the CONKO score, the ONKOTEV score, the COMPASS-CAT score, and the CATS/MICA score were 70.9, 73.4, 72.1, 78.6, 71.7, and 60.3%, respectively. The ONKOTEV score had the highest Youden index which was 0.68, followed by the PROTECHT score (0.58), the COMPASS-CAT score (0.56), the CONKO score (0.55), the Khorana score (0.53), and the CATS/MICA score (0.23).