Abstract
Background: Previous randomized clinical trials did not support a benefit of screening for occult cancer after diagnosis of venous thromboembolism (VTE), although screening may be of potential benefit for selected high-risk patients.
Methods and Results: The COMMAND VTE Registry-2 enrolled consecutive patients with acute symptomatic VTE between 2015 and 2020 from 31 centers across Japan. The 3,706 patients in the registry without known active cancer at the time of VTE diagnosis were divided into 2 groups: those with (n=250) and without (n=3,456) newly diagnosed cancer during the follow-up period. The cumulative incidence of newly diagnosed cancer was 1.5% at 30 days, 3.7% at 1 year, and 7.0% at 3 years. The multivariable Cox proportional hazard model demonstrated that older age (hazard ratio [HR] 1.02 per 1 year increase; 95% confidence interval [CI] 1.01–1.03; P<0.001), a history of cancer (HR 3.57; 95% CI 2.73–4.64; P<0.001), autoimmune disorders (HR 1.48; 95% CI 1.06–2.02; P=0.02), a history of major bleeding (HR 1.64; 95% CI 1.04–2.48; P=0.04), and the absence of transient provoking risk factors for VTE (HR 1.44; 95% CI 1.08–1.92; P=0.01) were independently associated with newly diagnosed cancer.
Conclusions: The incidence of newly diagnosed cancer after VTE diagnosis was 3.7% at 1 year, and several independent risk factors for newly diagnosed cancer after VTE diagnosis were identified.
Cancer is a well-known risk factor for the development of venous thromboembolism (VTE), including pulmonary embolism and deep vein thrombosis,1 and VTE could be the first manifestation of cancer. Thus, clinicians often consider screening for occult cancer in VTE patients without known cancers. A 2017 meta-analysis reported that the incidence of occult cancer was approximately 5% in the 12-month period after the diagnosis of unprovoked VTE.2 To investigate the benefit of an extensive cancer screening strategy in VTE patients, several randomized clinical trials evaluated the utility of an extensive screening strategy, including computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scanning, which did not show a benefit compared with a limited screening strategy.3–5 Therefore, the current guidelines recommend a regular screening strategy for occult cancer in VTE patients, including medical history, physical examination, basic blood testing, chest radiography, and age- and sex-specific testing according to national recommendations.6 However, there may be a potential benefit of an extensive screening strategy for select patients with a high risk of occult cancer.
Several risk prediction scores for occult cancer have been reported,7,8 although their predictive performance was found to be poor in validation studies.9,10 A comprehensive investigation of more detailed clinical risk factors for occult cancer would be needed for more accurate identification of high-risk populations for occult cancer in current daily clinical practice. Therefore, we sought to investigate the risk factors for newly diagnosed cancer in VTE patients without known active cancers at the time of VTE diagnosis using a contemporary large-scale Japanese observational database of VTE.
Methods
Study Cohort
The Contemporary management and outcomes in patients with venous thromboembolism (COMMAND VTE) Registry-2 is a physician-initiated multicenter retrospective cohort study that enrolled consecutive patients with acute symptomatic VTE objectively confirmed by imaging examination or autopsy from 31 centers across Japan between January 2015 and August 2020 after the introduction of direct oral anticoagulants (DOAC) for the treatment of VTE in Japan. The design of the registry has been reported previously in detail.11 The present study was conducted in accordance with the principles of the Declaration of Helsinki. The relevant review board or ethics committee of all 31 participating centers (Supplementary Appendix 1) approved the research protocol. The requirement for written informed consent from each patient was waived because we used clinical information obtained from routine clinical practice, and none of the patients refused to participate in the study when contacted for follow-up. This method is concordant with the guidelines for epidemiological studies issued by the Ministry of Health, Labour and Welfare in Japan (https://www.mhlw.go.jp/content/001077424.pdf).
Study Population
After screening 51,313 patients with suspected VTE for eligibility through chart review by physicians at each participating institution, 5,197 patients with acute symptomatic VTE were enrolled in the registry. After excluding 1,491 patients with known active cancer at the time of VTE diagnosis, the present study population consisted of 3,706 patients without known active cancer at the time of VTE diagnosis. These 3,706 patients who were divided into 2 groups: those with and those without newly diagnosed cancer during the entire follow-up period (Figure 1).
Data Collection and Definitions of Patient Characteristics
Data on patient characteristics were collected from hospital charts or hospital databases according to the prespecified definitions using an electronic case report form in a web-based database system. The physicians at each participating institution were responsible for data entry, and data were automatically checked for missing or contradictory inputs and values out of the expected range. Additional editing checks were performed at the registry’s general office.
Patients with active cancer were defined as those receiving treatment for cancer, such as chemotherapy or radiotherapy, those scheduled to undergo cancer surgery, those with metastasis to other organs, and/or those with terminal cancer (expected life expectancy ≤6 months) at the time of diagnosis.12 We defined active cancer diagnosed before the diagnosis of VTE diagnosis as “known active cancer,” and active cancer that was diagnosed simultaneously with VTE diagnosis as “no known active cancer.” Detailed definitions of other patient characteristics are provided in Supplementary Appendix 2.
Clinical Follow-up and Endpoints
Follow-up information was primarily collected via review of hospital charts, with additional follow-up information collected through contact with patients, relatives, and/or referring physicians by telephone and/or mail with questions regarding vital status, clinical events, invasive procedures, and the status of anticoagulation therapy. In this cohort study, the final data collection for follow-up events was performed between September 2021 and April 2022. The median follow-up period was 909 days (interquartile range 405–1,511 days), with a follow-up rate of 83.2% at 1 year.
The primary outcome measure in this study was the development of newly diagnosed cancer during the follow-up period. Cancer diagnosis was based on clinical diagnosis by oncologists at each participating institution according to imaging examinations and/or histological examinations. We considered all types of active malignancies as newly diagnosed cancer.12 The secondary outcome measure was all-cause death. The independent clinical event committee (Supplementary Appendix 3), unaware of patient characteristics, reviewed the detailed clinical course and adjudicated the clinical events. Detailed definitions of clinical events are presented in Supplementary Appendix 4.
Statistical Analysis
Categorical variables are presented as numbers and percentages. Continuous variables are presented as the mean ± SD or median and interquartile range according to data distribution. Categorical variables were compared using the Chi-squared test. Continuous variables were compared using Student’s t-test or the Wilcoxon rank-sum test according to data distribution. The Kaplan-Meier method was used to estimate the cumulative incidence of newly diagnosed cancer throughout the follow-up period, with the significance of differences between subgroups assessed using log-rank test. We constructed a multivariable Cox proportional hazard model to estimate hazard ratios (HR) and 95% confidence intervals (CI) of the potential risk factors for the newly diagnosed cancer. Considering that there have been no risk factors established, we comprehensively selected 13 potential variables, including age, sex, and type of VTE, as well as all variables with P≤0.20 in the univariate Cox proportional hazard models. In addition, because a new diagnosis of cancer could be influenced by the initial screening strategy for cancer after VTE diagnosis, we conducted a landmark analysis at 30 days as a sensitivity analysis and investigated the risk factors for newly diagnosed cancer beyond 30 days. In this analysis, we excluded those patients with newly diagnosed with cancer within 30 days of VTE diagnosis. Furthermore, we conducted an exploratory analysis according to the site of the thrombus at the time of VTE diagnosis. We also estimated the risk of newly diagnosed cancer after VTE for subsequent all-cause death with the multivariable Cox proportional hazard model. We incorporated newly diagnosed cancer after VTE into the multivariable Cox model as time-updated covariates together with the 19 clinically relevant risk-adjusting factors listed in Table 1. All statistical analyses were performed using JMP version 15.2.0 (SAS Institute Inc., Cary, NC, USA) and EZR (Jichi Medical University Saitama Medical Center, Saitama, Japan). All reported P values are 2-tailed, and statistical significance was set at P<0.05.
Table 1.
Patient Characteristics in Patients With and Without Newly Diagnosed Cancer
| |
Patients with newly
diagnosed cancer
(n=250) |
Patients without newly
diagnosed cancer
(n=3,456) |
P value |
| Baseline characteristics |
| Age (years)A |
71.6±11.8 |
67.2±17.0 |
<0.001 |
| No. womenA |
151 (60) |
2,079 (60) |
0.94 |
| Body weight (kg) |
57.3±12.8 |
60.1±15.0 |
0.004 |
| Body mass index (kg/m2) |
22.9±4.2 |
23.8±4.6 |
0.004 |
| Body mass index ≥30 kg/m2 A |
11 (4.4) |
248 (7.2) |
0.10 |
| Comorbidities |
| History of cancerA |
88 (35) |
366 (11) |
<0.001 |
| HypertensionA |
128 (51) |
1,533 (44) |
0.04 |
| DiabetesA |
52 (21) |
539 (16) |
0.03 |
| Dyslipidemia |
73 (29) |
916 (27) |
0.35 |
| Chronic kidney diseaseA |
52 (21) |
664 (19) |
0.54 |
| Dialysis |
3 (1.2) |
40 (1.2) |
0.95 |
| Chronic heart diseaseA |
21 (8.4) |
362 (10) |
0.30 |
| Chronic lung diseaseA |
34 (14) |
375 (11) |
0.18 |
| History of strokeA |
25 (10) |
353 (10) |
0.91 |
| Liver cirrhosisA |
2 (0.8) |
26 (0.8) |
0.93 |
| Autoimmune disorderA |
50 (20) |
465 (13) |
0.004 |
| Varicose veinA |
12 (4.8) |
173 (5.0) |
0.89 |
| History of VTEA |
26 (10) |
254 (7.4) |
0.08 |
| History of major bleedingA |
23 (9.2) |
230 (6.7) |
0.12 |
| Transient provoking risk factors for VTEA |
72 (29) |
1,360 (39) |
<0.001 |
| Major transient provoking risk factors |
31/72 (43) |
488/1,360 (36) |
0.22 |
| Minor transient provoking risk factors |
41/72 (57) |
872/1,360 (64) |
| Presentation |
| PE with or without DVTA |
138 (55) |
1,889 (55) |
0.87 |
| DVT onlyA |
112 (45) |
1,567 (45) |
| Hypoxemia in PE |
54/138 (39) |
876/1,889 (46) |
0.10 |
| Shock in PE |
10/138 (7.3) |
227/1,889 (12) |
0.09 |
| Cardiac arrest/collapse in PE |
4/138 (2.9) |
115/1,889 (6.1) |
0.24 |
| Proximal DVT in lower extremities in DVT only |
64/112 (57) |
928/1,567 (59) |
0.67 |
| Imaging examinations for VTE diagnosis |
| Computed tomography |
176 (70) |
2,457 (71) |
0.82 |
| Ultrasound examination for lower extremities |
163 (65) |
2,224 (64) |
0.79 |
| Laboratory tests at diagnosis |
| AnemiaA |
127 (51) |
1,602 (46) |
0.17 |
| ThrombocytopeniaA |
12 (4.8) |
133 (3.9) |
0.46 |
| D-dimer (μg/mL; n=3,541B) |
8.8 [4.6–17.9] |
8.9 [4.1–17.5] |
0.97 |
| Hereditary thrombophilia |
7 (2.8) |
149 (4.3) |
0.25 |
Unless indicated otherwise, data are given as the mean ± SD, median [interquartile range], or n (%). ARisk-adjusting variables for the multivariable Cox regression model to estimate the risk of all-cause death. BThere were 165 missing values for D-dimer levels: 9 among patients with newly diagnosed cancer and 156 among patients without newly diagnosed cancer. Chronic heart disease was defined as persistent heart disorders including heart failure, history of myocardial infarction, and atrial fibrillation. Chronic lung disease was defined as persistent lung disorders such as asthma, chronic obstructive pulmonary disease, and restrictive lung diseases. Autoimmune disorder was defined as immune-mediated diseases, such as inflammatory bowel disease, rheumatoid arthritis and antiphospholipid syndrome. A history of major bleeding was diagnosed if the patient had a history of International Society of Thrombosis and Hemostasis major bleeding. Hypoxemia was defined as PaO2 <60 mmHg or percentage saturation of hemoglobin with oxygen of <90%. Shock was defined as systolic blood pressure <90 mmHg for at least 15 min, a pressure drop of ≥40 mmHg for at least 15 min, or requiring inotropic support. Proximal deep vein thrombosis (DVT) in the lower extremities was defined as a venous thrombosis that was located in the popliteal, femoral, or iliac veins. Anemia was defined as a hemoglobin level <13 g/dL for men and <12 g/dL for women. Thrombocytopenia was defined as a platelet count <100×109/L. Hereditary thrombophilia included protein C deficiency, protein S deficiency, and antithrombin III deficiency. PE, pulmonary embolism; VTE, venous thromboembolism.
Results
Patient Characteristics
In this study, the mean age of the study population was 67.5±16.7 years, 60% were women, and the mean body weight and body mass index were 59.9±14.9 kg and 23.7±4.6 kg/m2, respectively. Among the 3,706 patients, 250 (6.7%) had newly diagnosed cancer (Figure 1). The cumulative incidence of newly diagnosed cancer was 1.5% at 30 days, 3.7% at 1 year, 7.0% at 3 years, and 16.0% at 7 years (Figure 2). Among the 250 patients with newly diagnosed cancer, cancer was newly diagnosed in 55 (22%) patients within 30 days after VTE diagnosis and in 68 (27%) patients between 31 and 365 days after VTE diagnosis. The detailed types of newly diagnosed cancer are presented in Table 2. For each type of newly diagnosed cancer, the proportion of patients with a history of that type of cancer is presented in Supplementary Table 1.
Table 2.
Types of Newly Diagnosed Cancer Overall and According to the Timing of Cancer Diagnosis
| Type of cancer |
OverallA
(n=250) |
Cancer diagnosis relative to VTE diagnosisB |
Within 30 days
(n=55) |
Between 31 and
365 days (n=68) |
Beyond 366 days
(n=127) |
| Colon |
43 (17.2) |
7/43 |
12/43 |
24/43 |
| Lung |
37 (14.8) |
3/37 |
14/37 |
20/37 |
| Blood |
20 (8.0) |
13/20 |
2/20 |
5/20 |
| Stomach |
18 (7.2) |
3/18 |
5/18 |
10/18 |
| Breast |
18 (7.2) |
3/18 |
4/18 |
11/18 |
| Uterus |
14 (5.6) |
1/14 |
5/14 |
8/14 |
| Ovary |
13 (5.2) |
5/13 |
3/13 |
5/13 |
| Prostate |
13 (5.2) |
0/13 |
5/13 |
8/13 |
| Kidney/ureter |
12 (4.8) |
1/12 |
4/12 |
7/12 |
| Bladder |
10 (4.0) |
2/10 |
3/10 |
5/10 |
| Gall bladder/bile duct |
7 (2.8) |
2/7 |
2/7 |
3/7 |
| Pancreas |
6 (2.4) |
3/6 |
0/6 |
3/6 |
| Thyroid gland |
6 (2.4) |
2/6 |
2/6 |
2/6 |
| Brain |
5 (2.0) |
2/5 |
3/5 |
0/5 |
| Esophagus |
5 (2.0) |
2/5 |
0/5 |
3/5 |
| Skin |
3 (1.2) |
0/3 |
1/3 |
2/3 |
| Liver |
1 (0.4) |
0/1 |
0/1 |
1/1 |
| Multiple |
2 (0.8) |
0/2 |
0/2 |
2/2 |
| Others |
17 (6.8) |
6/17 |
3/17 |
8/17 |
AData are presented as n (%). BData are presented as n/N.
Patients with newly diagnosed cancer were older (71.6 vs. 67.2 years; P<0.001) and had a lower body weight (57.3 vs. 60.1 kg; P=0.004) than those without newly diagnosed cancer (Table 1). Patients with newly diagnosed cancer were more likely to have a history of cancer, hypertension, and diabetes, and less likely to have transient provoking risk factors for VTE, than those without newly diagnosed cancer.
Risk Factors for Newly Diagnosed Cancer After VTE
The multivariable Cox proportional hazard model revealed that older age (HR 1.02 per 1 year; 95% CI 1.01–1.03; P<0.001), a history of cancer (HR 3.57; 95% CI 2.73–4.64; P<0.001), autoimmune disorder (HR 1.48; 95% CI 1.06–2.02; P=0.02), a history of major bleeding (HR 1.64; 95% CI 1.04–2.48; P=0.04), and the absence of transient provoking risk factors for VTE (HR 1.44; 95% CI 1.08–1.92; P=0.01) were independently associated with the development of newly diagnosed cancer after VTE (Table 3).
Table 3.
Multivariable Analysis of Risk Factors for Newly Diagnosed Cancer After Diagnosis of VTE
| |
Univariate |
Multivariable |
| Crude HR (95% CI) |
P value |
Adjusted HR (95% CI) |
P value |
| Age (per 1 year) |
1.02 (1.02–1.03) |
<0.001 |
1.02 (1.01–1.03) |
<0.001 |
| Female sex |
1.03 (0.80–1.33) |
0.80 |
1.00 (0.77–1.31) |
0.99 |
| Body mass index ≥30 kg/m2 |
0.57 (0.29–0.98) |
0.04 |
0.67 (0.34–1.19) |
0.18 |
| History of cancer |
3.97 (3.05–5.14) |
<0.001 |
3.57 (2.73–4.64) |
<0.001 |
| Hypertension |
1.32 (1.03–1.69) |
0.03 |
1.03 (0.79–1.34) |
0.84 |
| Diabetes |
1.41 (1.03–1.89) |
0.03 |
1.30 (0.94–1.77) |
0.11 |
| Chronic lung disease |
1.30 (0.89–1.83) |
0.17 |
1.08 (0.74–1.55) |
0.68 |
| Autoimmune disorder |
1.43 (1.04–1.93) |
0.03 |
1.48 (1.06–2.02) |
0.02 |
| History of VTE |
1.33 (0.87–1.96) |
0.18 |
1.26 (0.82–1.87) |
0.28 |
| History of major bleeding |
1.56 (0.99–2.34) |
0.057 |
1.64 (1.04–2.48) |
0.04 |
| Absence of transient provoking risk factors for VTE |
1.51 (1.16–2.00) |
0.002 |
1.44 (1.08–1.92) |
0.01 |
| PE with or without DVT (vs. DVT only) |
1.05 (0.82–1.35) |
0.68 |
1.17 (0.90–1.51) |
0.23 |
| Anemia |
1.29 (1.00–1.65) |
0.047 |
1.22 (0.93–1.58) |
0.15 |
Crude and adjusted HR and 95% CI were estimated by the Cox proportional hazard models. CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.
Landmark Analysis Beyond 30 Days After VTE Diagnosis and Exploratory Analysis
Landmark analysis at 30 days revealed that the cumulative incidence of newly diagnosed cancer was 2.2% at 1 year, 5.7% at 3 years, and 14.7% at 7 years (Supplementary Figure 1). The results of multivariable Cox proportional hazard model beyond 30 days were essentially consistent with those of the main analysis, although the absence of transient provoking risk factors for VTE was no longer significantly associated with newly diagnosed cancer (Supplementary Table 2). The results of the exploratory analysis according to the site of the thrombus at the time of VTE diagnosis were consistent with the main results, regardless of thrombus site (Supplementary Figure 2).
Impact of Newly Diagnosed Cancer After VTE on Subsequent Mortality
The time-updated multivariable Cox proportional hazard model revealed that newly diagnosed cancer after VTE was strongly associated with subsequent mortality risk (crude HR 8.53; 95% CI 6.75–10.77; P<0.001; adjusted HR 7.08; 95% CI 5.53–9.08; P<0.001). Among patients with newly diagnosed cancer, the majority of deaths were due to cancer (76.3%); in contrast, among those without newly diagnosed cancer, the majority of deaths were due to non-cardiac, non-cancer causes (61.3%; Table 4).
Table 4.
Causes of Death
| |
Patients with newly
diagnosed cancer
(n=250) |
Patients without newly
diagnosed cancer
(n=3,456) |
| All-cause deaths (n) |
97 |
367 |
| Specific causes of death |
| PE-related death |
2/97 (2.1) |
60/367 (16.4) |
| Bleeding |
4/97 (4.1) |
14/367 (3.8) |
| Cancer |
74/97 (76.3) |
0/367 (0) |
| Cardiac death |
3/97 (3.1) |
47/367 (12.8) |
| Non-cardiac, non-cancer death |
9/97 (9.3) |
225/367 (61.3) |
| Unknown |
5/97 (5.2) |
21/367 (5.7) |
Unless indicated otherwise, data are presented as n/N (%). PE, pulmonary embolism.
Discussion
The main findings of the present study are as follows: (1) the cumulative incidence of newly diagnosed cancer was 1.5% at 30 days and 3.7% at 1 year after VTE diagnosis; (2) independent risk factors for newly diagnosed cancer were older age, a history of cancer, autoimmune disorder, a history of major bleeding, and the absence of transient provoking risk factors for VTE; and (3) newly diagnosed cancer after VTE diagnosis was associated with a worse mortality outcome than no newly diagnosed cancer, primarily because of deaths due to cancer.
The reported incidence of occult cancer after the diagnosis of VTE varied widely in previous studies. For example, a study in the 1990s reported that the incidence of cancer diagnosis was 3.3% at the time of VTE diagnosis and 7.6% during a 2-year follow-up period among patients with unprovoked VTE.13 A recent meta-analysis reported that the incidence of cancer after unprovoked VTE diagnosis was 5.2% during a 1-year follow-up period, which could vary depending on limited vs. extensive screening strategies for cancer.2 Another study reported that the incidence of occult cancer after VTE plateaued beyond 3 months after VTE diagnosis, with a rate of approximately 1–2% per year.14 These results could be influenced by the type of VTE and the screening strategies for cancer in each study, as well as by temporal changes in the diagnosis of cancer. The present study showed that the incidence rates of occult cancer after VTE diagnosis were 1.5% at 30 days and 3.7% at 1 year, which appear relatively lower than those reported in the previous studies. This could be partly because the present study evaluated all types of VTE, including provoked and unprovoked VTE, and most patients did not undergo an extensive screening strategy for cancer unless there was no clinical suspicion of occult cancer. These incidence rates could reflect the current real-world status and may be clinically useful for understanding the risk of occult cancer in current daily clinical practice and for considering the validity of additional extensive screening strategies for cancer.
Although there has been no risk score established for predicting occult cancer, previous studies have reported the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) and The Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) scores as potential risk scores.7,8 The RIETE score includes male sex, old age, chronic lung disease, anemia, a high platelet count, the absence of a history of VTE, and the absence of postoperative VTE; the SOME score includes old age, current smoking, and a history of provoked VTE. However, previous validation studies reported that the predictive performance of both scores was poor, and only old age could have a relatively significant effect on predictive ability, which resulted in the limited utility of these scores in daily clinical practice.9,10 The present comprehensive study, including all potential variables, revealed several risk factors for occult cancer, with some being consistent with previous reports and some being novel variables. This could be partly due to differences in study populations and racial differences. In particular, a history of cancer was identified as a significant and strong independent risk factor for occult cancer. This may reflect the importance of the recurrence of previous cancer along with the development of VTE. Of note, the types of newly diagnosed cancer after a diagnosis of VTE seemed to be line with the incidence of different types of cancer in the general population in Japan as reported by the Ministry of Health, Labour and Welfare.15 Considering that patients who were newly diagnosed with cancer after a VTE diagnosis had worse mortality, primarily due to cancer death, early diagnosis could have the potential benefit of improving mortality rates through early treatment for cancer, which may suggest the potential utility of extensive screening strategies for selected high-risk populations. Extensive screening strategies may be reasonable for patients with high-risk characteristics, such as old age, a history of cancer, and overlapping risk factors. Further clinical trials are warranted to validate this concept arising from the present study.
Study Limitations
The present study has several limitations. First and most importantly, the present study was an observational study with limitations inherent to the observational study design. The decisions, including screening strategies for cancer, were left to the discretion of the attending physician, which could influence the diagnosis of occult cancer. In particular, detection bias could have been introduced by unmeasured variables that induced physicians to more extensively screen specific patients for occult cancer. Second, the demographics, practice patterns, and diagnostic strategies for cancer in Japan may differ from those outside Japan. In particular, regular health checks among the general population are common in Japan, which could influence the early diagnosis of active cancer. Third, there could be a different follow-up status between patients with and without newly diagnosed cancer, which could have some effect on the present results. Finally, we evaluated the long-term development of newly diagnosed cancer. However, newly diagnosed cancers far beyond the index VTE diagnosis could not be related to the pathogenesis of the index VTE.
Conclusions
In this large real-world VTE registry in the current era, the incidence of newly diagnosed cancer after VTE diagnosis was 1.5% at 30 days and 3.7% at 1 year. Old age, a history of cancer, autoimmune disorder, a history of major bleeding, and the absence of transient provoking risk factors for VTE were found to be independent risk factors for newly diagnosed cancer.
Acknowledgments
The authors appreciate the support and collaboration of the coinvestigators who participated in the COMMAND VTE Registry-2.
Sources of Funding
The COMMAND VTE Registry-2 was supported, in part, by JSPS KAKENHI Grant Number JP 21K16022. The funding body had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, or the preparation, review, or approval of the manuscript.
Disclosures
K. Ono is a member of Circulation Journal’s Editorial Team. Y.Y. has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo, as well as grant support from Bayer Healthcare and Daiichi-Sankyo. T.M. reports having received lecturer fees from Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray, as well as manuscript fees from Bristol-Myers Squibb and Kowa, and sitting on the advisory board for Sanofi. Y.N. has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. N.I. has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. S.I. has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, and Daiichi-Sankyo. Y.O. has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo, as well as research funds from Bayer Healthcare and Daiichi-Sankyo. N.K. has received lecture fees from Bayer Healthcare and grant support from Pfizer. K. Kaneda has received lecture fees from Bristol-Myers Squibb, Pfizer, and Daiichi-Sankyo. All other authors have no relationships relevant to the contents of this paper to disclose.
Author Contributions
Y.Y. has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Y.Y.; acquisition, analysis, or interpretation of data: all authors; drafting of the manuscript: Y.Y., T.M., T.K.; critical revision of the manuscript for important intellectual content: all authors; statistical analysis: Y.Y., T.M.; administrative, technical, or material support: all authors; study supervision: T.M., T.K.
IRB Information
The relevant review boards or ethics committees in all 31 participating centers (Supplementary Appendix 1) approved the research protocol.
Data Availability
The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. However, if the relevant review board or ethics committee approves data sharing and all investigators of the COMMAND VTE Registry-2 provide consent, the deidentified participant data will be shared on a request basis through the principal investigator. The study protocol will also be available. The data will be shared as Excel files via email during the period that considered necessary for the research.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-24-0786
References
- 1.
Falanga A, Ay C, Di Nisio M, Gerotziafas G, Jara-Palomares L, Langer F, et al. Venous thromboembolism in cancer patients: ESMO clinical practice guideline. Ann Oncol 2023; 34: 452–467, doi:10.1016/j.annonc.2022.12.014.
- 2.
van Es N, Le Gal G, Otten HM, Robin P, Piccioli A, Lecumberri R, et al. Screening for occult cancer in patients with unprovoked venous thromboembolism: A systematic review and meta-analysis of individual patient data. Ann Intern Med 2017; 167: 410–417, doi:10.7326/M17-0868.
- 3.
Carrier M, Lazo-Langner A, Shivakumar S, Tagalakis V, Zarychanski R, Solymoss S, et al. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med 2015; 373: 697–704, doi:10.1056/NEJMoa1506623.
- 4.
Robin P, Le Roux PY, Planquette B, Accassat S, Roy PM, Couturaud F, et al. Limited screening with versus without 18F-fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: An open-label randomised controlled trial. Lancet Oncol 2016; 17: 193–199, doi:10.1016/S1470-2045(15)00480-5.
- 5.
Prandoni P, Bernardi E, Valle FD, Visona A, Tropeano PF, Bova C, et al. Extensive computed tomography versus limited screening for detection of occult cancer in unprovoked venous thromboembolism: A multicenter, controlled, randomized clinical trial. Semin Thromb Hemost 2016; 42: 884–890, doi:10.1055/s-0036-1592335.
- 6.
Delluc A, Antic D, Lecumberri R, Ay C, Meyer G, Carrier M. Occult cancer screening in patients with venous thromboembolism: Guidance from the SSC of the ISTH. J Thromb Haemost 2017; 15: 2076–2079, doi:10.1111/jth.13791.
- 7.
Jara-Palomares L, Otero R, Jimenez D, Carrier M, Tzoran I, Brenner B, et al. Development of a risk prediction score for occult cancer in patients with VTE. Chest 2017; 151: 564–571, doi:10.1016/j.chest.2016.10.025.
- 8.
Ihaddadene R, Corsi DJ, Lazo-Langner A, Shivakumar S, Zarychanski R, Tagalakis V, et al. Risk factors predictive of occult cancer detection in patients with unprovoked venous thromboembolism. Blood 2016; 127: 2035–2037, doi:10.1182/blood-2015-11-682963.
- 9.
Mulder FI, Carrier M, van Doormaal F, Robin P, Otten HM, Salaun PY, et al. Risk scores for occult cancer in patients with unprovoked venous thromboembolism: Results from an individual patient data meta-analysis. J Thromb Haemost 2020; 18: 2622–2628, doi:10.1111/jth.15001.
- 10.
Kraaijpoel N, van Es N, Raskob GE, Buller HR, Carrier M, Zhang G, et al. Risk scores for occult cancer in patients with venous thromboembolism: A post hoc analysis of the Hokusai-VTE study. Thromb Haemost 2018; 118: 1270–1278, doi:10.1055/s-0038-1649523.
- 11.
Kaneda K, Yamashita Y, Morimoto T, Chatani R, Nishimoto Y, Ikeda N, et al. Anticoagulation strategies and long-term recurrence in patients with venous thromboembolism in the era of direct oral anticoagulants. Eur J Intern Med 2023; 118: 59–72, doi:10.1016/j.ejim.2023.08.007.
- 12.
Chatani R, Yamashita Y, Morimoto T, Mushiake K, Kadota K, Kaneda K, et al. Cancer-associated venous thromboembolism in the direct oral anticoagulants era: Insight from the COMMAND VTE Registry-2. Thromb Res 2024; 234: 86–93, doi:10.1016/j.thromres.2023.12.016.
- 13.
Prandoni P, Lensing AW, Buller HR, Cogo A, Prins MH, Cattelan AM, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992; 327: 1128–1133, doi:10.1056/NEJM199210153271604.
- 14.
Douketis JD, Gu C, Piccioli A, Ghirarduzzi A, Pengo V, Prandoni P. The long-term risk of cancer in patients with a first episode of venous thromboembolism. J Thromb Haemost 2009; 7: 546–551, doi:10.1111/j.1538-7836.2008.03268.x.
- 15.
Cancer and Disease Control Division, Ministry of Health, Labour and Welfare. Cancer incidence of Japan 2020 [in Japanese]. https://www.mhlw.go.jp/content/10900000/001231386.pdf (accessed October 30, 2024).
