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Clinical outcomes of cancer-associated isolated superficial vein thrombosis in daily practice

Open AccessPublished:November 04, 2022DOI:https://doi.org/10.1016/j.thromres.2022.10.022

      Highlights

      • In acute isolated SVT, the prevalence of cancer is almost 7 %.
      • Cancer increases the SVT-associated VTE risk at 3 and 12 months.
      • Cancer patients with isolated SVT may benefit from prolonged anticoagulation.

      Abstract

      Background

      Despite significant progress in the understanding of paraneoplastic deep vein thrombosis (DVT) and pulmonary embolism (PE), little is known about the outcomes of cancer-associated superficial vein thrombosis (SVT) in daily practice.

      Methods

      INSIGHTS-SVT was a prospective observational study on patients with acute isolated SVT. Primary outcome measure was symptomatic venous thromboembolism (VTE), a composite of DVT, PE, and SVT extension/recurrence, at 3 months. Clinically relevant bleeding was also assessed.

      Results

      Of 1151 patients included, 6.7 % either had active cancer at baseline or were diagnosed with cancer during 12 months of follow-up. At 3 months, symptomatic VTE had occurred in 13.0 % and 5.4 % of cancer and non-cancer patients, respectively (HR 2.6, 95 % CI 1.3–5.0). Regarding secondary outcomes, cancer patients had increased risks of DVT and PE (HR 3.9, 95 % CI 1.3–11.8) and hospitalization due to VTE (HR 11.0, 95 % CI 2.5–49.0). The rate of clinically relevant bleeding was numerically higher in the cancer cohort (3.9 % vs 1.3 %, HR 3.1, 95 % CI 0.9–10.7). At 12 months, the primary composite outcome had occurred in 15.6 % and 11.9 % of cancer and non-cancer patients, respectively (HR 1.9, 95 % CI 1.0–3.5). After adjusting for additional risk factors, including age, history of DVT/PE and cardiovascular risk factors/diseases, the association of cancer with the primary outcome remained statistically significant.

      Conclusion

      Cancer patients with isolated SVT are at significant risk of symptomatic VTE. While most events occur within 3 months, the VTE risk remains elevated up to one year of follow-up.
      ClinicalTrials.gov identifier: NCT02699151.

      Graphical abstract

      Keywords

      1. Introduction

      Cancer patients are at increased risk of venous thromboembolism (VTE), a composite of deep vein thrombosis (DVT) and pulmonary embolism (PE). The rates of cancer-associated thromboembolism (CAT) range from 4 % to 20 % [
      • Mulder F.I.
      • Horváth-Puhó E.
      • van Es N.
      • et al.
      Venous thromboembolism in cancer patients: a population-based cohort study.
      ], mainly dependent on the types of cancer, which can be divided into very high risk (i.e., pancreas, stomach, high-grade glioma), high risk (e.g., lung, colorectal, gynecological), and low risk (e.g., breast, prostate) entities [
      • Pabinger I.
      • van Es N.
      • Heinze G.
      • et al.
      A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts.
      ,
      • Ay C.
      • Dunkler D.
      • Marosi C.
      • et al.
      Prediction of venous thromboembolism in cancer patients.
      ]. This suggests that there are cancer type-specific pathways in CAT pathophysiology [
      • Hisada Y.
      • Mackman N.
      Cancer-associated pathways and biomarkers of venous thrombosis.
      ,
      • Riedl J.
      • Preusser M.
      • Nazari P.M.
      • et al.
      Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism.
      ]. Increased levels of leukocytes, platelets, plasma D-dimers, inflammatory cytokines, and tissue factor-positive microvesicles are among the many potential factors that alone or in combination may contribute to CAT development [
      • Hisada Y.
      • Mackman N.
      Cancer-associated pathways and biomarkers of venous thrombosis.
      ,
      • Dicke C.
      • Langer F.
      Pathophysiology of Trousseau's syndrome.
      ]. In addition, several patient- (e.g., history of VTE, thrombophilia, varicose veins) and treatment-related risk factors (e.g., surgery, hormone, chemo- and radiotherapy) are critically involved in CAT development [
      • Ay C.
      • Pabinger I.
      • Cohen A.T.
      Cancer-associated venous thromboembolism: burden, mechanisms, and management.
      ].
      Superficial vein thrombosis (SVT) is characterized by partial or total thrombotic obstruction of the lumen of the affected vein and by inflammatory alterations of the vessel wall [
      • Bauersachs R.M.
      Diagnosis and treatment of superficial vein thrombosis.
      ,
      • Decousus H.
      • Frappe P.
      • Accassat S.
      • et al.
      Epidemiology, diagnosis, treatment and management of superficial-vein thrombosis of the legs.
      ]. SVT is often perceived as a more benign condition than DVT or PE and has thus received less medical attention. However, it has become clear that SVT, DVT and PE are related entities, which may occur concomitantly or in sequence [
      • Di Minno M.N.
      • Ambrosino P.
      • Ambrosini F.
      • Tremoli E.
      • Di Minno G.
      • Dentali F.
      Prevalence of deep vein thrombosis and pulmonary embolism in patients with superficial vein thrombosis: a systematic review and meta-analysis.
      ]. A recent study has found an 8.7 % cancer prevalence in patients with SVT [
      • Hirmerova J.
      • Seidlerova J.
      • Subrt I.
      • Hajsmanova Z.
      Prevalence of cancer in patients with superficial vein thrombosis and its clinical importance.
      ]. In that study, cancer was the strongest determinant for the occurrence of concomitant DVT/PE.
      The management of cancer-associated VTE, including SVT, poses a challenge to the treating physician, because cancer patients are more prone to bleeding than non-cancer patients [
      • Farge D.
      • Frere C.
      • Connors J.M.
      • et al.
      2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.
      ]. In addition, the optimal type, duration, and intensity of anticoagulation in hematology-oncology patients with acute isolated SVT are unclear.
      Until today, the highly variable real-life management and outcomes of SVT are poorly defined. The prospective observational Investigating SIGnificant Health TrendS in the management of Superficial Vein Thrombosis (INSIGHTS-SVT) study aimed at collecting representative data on patient characteristics, diagnosis, management, and outcomes of acute isolated SVT in Germany under real-life conditions [
      • Bauersachs R.
      • Gerlach H.E.
      • Heinken A.
      • et al.
      Rationale, design, and methodology of the observational INSIGHTS-SVT study on the current state of care and outcomes of patients with superficial vein thrombosis.
      ,
      • Bauersachs R.
      • Gerlach H.E.
      • Heinken A.
      • et al.
      Management and outcomes of patients with isolated superficial vein thrombosis under real life conditions (INSIGHTS-SVT).
      ]. Here, we compare the subgroup of patients with cancer, either diagnosed or treated within 1 year prior to enrolment or diagnosed during 12 months of follow-up, with non-cancer patients to obtain additional information on treatment outcomes in this vulnerable patient population.

      2. Methods

      2.1 Study design

      The rationale, design and methods of the study have previously been reported in detail [
      • Bauersachs R.
      • Gerlach H.E.
      • Heinken A.
      • et al.
      Rationale, design, and methodology of the observational INSIGHTS-SVT study on the current state of care and outcomes of patients with superficial vein thrombosis.
      ].
      In brief, this was a prospective, multicenter, non-interventional (observational) study with a 1-year follow-up period. The study protocol was approved by the institutional review board of the physician chamber in Hessen, Germany, and all patients provided written informed consent. The study was registered by the regulatory authority (BfArM) under NIS 6781 and by ClinicalTrials.gov under NCT 02699151. The 3-month outcomes of the total patient cohort have recently been reported [
      • Bauersachs R.
      • Gerlach H.E.
      • Heinken A.
      • et al.
      Management and outcomes of patients with isolated superficial vein thrombosis under real life conditions (INSIGHTS-SVT).
      ].
      Hospital- and office-based physicians, who regularly treated patients with SVT and who were board-certified for compression ultrasound (CUS) diagnostics, were invited to participate in INSIGHTS-SVT, including vascular physicians, vascular surgeons, phlebologists, and general internists or practitioners.
      Patient inclusion criteria were as follows: objectively confirmed (by ultrasound, including CUS and duplex ultrasound [DUS]), acute (time interval between onset of SVT symptoms and study inclusion <3 weeks), isolated SVT of the lower extremities (concomitant DVT was excluded by CUS or DUS, and patients had no clinical symptoms of PE). Patients were ineligible, if they met any of the following exclusion criteria: proximal extension of SVT to ≤3 cm of the saphenofemoral junction (SFJ); subject unlikely to comply with the requirements of the protocol (e.g., due to cognitive and/or language limitations); subject likely not available for 1-year follow-up.
      Patients had a follow-up visit at 3 months and 1 year; optional visits were at 10 ± 3 days and 45 ± 3 days, respectively. Due to the observational nature of the study, ultrasound examinations and any other diagnostic or therapeutic decisions during the follow-up period were at the investigator's discretion. DUS refers to ultrasound systems with both pulsed-wave Doppler and color technology.
      Information on pharmacological and non-pharmacological therapy (i.e., the type of utilized drugs, their dosing and duration of application) was collected. Anticoagulant drugs were categorized as prophylactic (<50 % of full-therapeutic dose), intermediate (50–75 % of full-therapeutic dose) or therapeutic (>75 % of full-therapeutic dose). If no anticoagulant drugs were given, or if there was no treatment at all, this was also documented.
      This analysis of INSIGHTS-SVT compared cancer patients with non-cancer patients. Active cancer at study inclusion was defined by protocol as cancer diagnosed or treated within the previous 12 months. In addition, the cancer cohort in this report comprised patients diagnosed with new or recurrent cancer during 1 year of follow-up.

      2.2 Study outcomes

      The primary outcome measure was the incidence of symptomatic VTE, defined as a composite of DVT, PE and recurrent or extending SVT, at 3 months of follow-up. Secondary outcomes included recurrent SVT or extension of SVT into the deep vein system or to 3 cm or less from the SFJ, symptomatic PE, DVT, persistent SVT (i.e., SVT without clinical improvement), asymptomatic SVT, death, and hospitalization because of VTE.
      An additional outcome measure was the combination of major or clinically relevant non-major bleeding, with definitions based on American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (major bleeding) [
      • Schulman S.
      • Beyth R.J.
      • Kearon C.
      • Levine M.N.
      Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ] and the CALISTO trial (clinically relevant non-major bleeding) [
      • Decousus H.
      • Prandoni P.
      • Mismetti P.
      • et al.
      Fondaparinux for the treatment of superficial-vein thrombosis in the legs.
      ].

      2.3 Statistical analysis

      Patient characteristics and the onset of the defined outcomes were reported by standard descriptive statistics. Characteristics for patients with and without cancer were compared by chi2-test and t-test for categorical and continuously distributed variables, respectively. The cumulative incidence of the primary outcome during the 12-month follow-up period was estimated by Kaplan-Meier technique. The likelihood for the onset of outcomes was analyzed by fitting univariate Cox proportional hazards models. For composite outcomes, the first event among all events was considered in the time to event analyses. The risk for primary outcome between patients with and without cancer was also analyzed by a multivariable Cox proportional hazards model including the parameters age, previous DVT or PE, cardiovascular risk factors/diseases, and involvement of great saphenous vein only as a result of variable selection by LASSO (least absolute shrinkage and selection operator) method. A sensitivity analysis was performed in order to force to include the two parameters varicose veins and anticoagulation. The Cox proportional hazards assumption was checked by Schoenfeld residuals. The P value threshold for statistical significance was 0.05. All statistical analyses were performed with STATA 12.1.

      3. Results

      3.1 Patient characteristics

      Disposition and flow of INSIGHTS-SVT study participants are shown in Fig. 1. In total, 1159 patients with acute isolated SVT were prospectively enrolled between April 2016 and August 2017. Critical review of individual patient data at study inclusion revealed non-melanoma skin cancer or premalignant hematological conditions in 6 and 2 cases, respectively. These subjects were excluded from further analysis. In 3 additional cases, the presence of active cancer at baseline could not be confirmed. These subjects were included in the non-cancer cohort. Thus, this analysis is based on 1151 patients (100 %), of whom 77 (6.7 %) either had active cancer at baseline (n = 70) or were diagnosed with new or recurrent cancer during follow-up (n = 7), as compared to the previously published analysis of this study, which reported 81 patients with known active cancer at study inclusion [
      • Bauersachs R.
      • Gerlach H.E.
      • Heinken A.
      • et al.
      Management and outcomes of patients with isolated superficial vein thrombosis under real life conditions (INSIGHTS-SVT).
      ]. Tumor types included breast (n = 31), urogenital (n = 17), gastrointestinal (n = 15), hematological (n = 5), gynecological (n = 3) or head-and-neck cancer (n = 3), melanoma (n = 2), and cancer of unknown primary (n = 1). Specific information on tumor stage or treatment was not captured in case report forms (CRFs). Follow-up at 3 and 12 months was almost complete in the cancer cohort, while about 25 % of patients were lost to follow-up between 3 and 12 months in the non-cancer cohort (Fig. 1).
      Fig. 1
      Fig. 1Patient disposition and flow.
      Abbreviation: GI gastrointestinal.
      Demographic and clinical characteristics of cancer and non-cancer patients are compared in Table 1. Cancer patients were significantly older than non-cancer patients (65.5 ± 11.0 vs 59.7 ± 14.8 years, P < 0.001), but did not show statistically significant differences with respect to sex, ethnic background, or body mass index. Hormone replacement therapy (5.2 % vs 1.3 %, P = 0.008) and use of oral contraceptives (33.3 % vs 9.5 %, P < 0.001) were more frequent in the cancer than in the non-cancer cohort. Compared to patients without cancer, cancer patients were also more likely to suffer from hemiplegia (2.6 % vs 0.4 %, P = 0.032), immobility/bedriddenness (11.7 % vs 3.2 %, P < 0.001), or cardiovascular risk factors/diseases (66.2 % vs 51.1 %, P = 0.010) at the time of SVT diagnosis. Of note, cancer patients more frequently had major surgery during the preceding 12 weeks than non-cancer patients (11.7 % vs 3.4 %, P < 0.001). There were no differences in localization (proximal vs distal) or extension of SVT. Exclusive involvement of the great saphenous vein was less frequent in the cancer compared to the non-cancer cohort (24.7 % vs 39.4 %, P = 0.010).
      Table 1Demographic and clinical patient characteristics.
      Patients without cancerPatients with cancerP value
      n = 1074n = 77
      Age (years), mean ± SD59.7 ± 14.865.5 ± 11.0<0.001
      Age ≥ 65 years, n (%)431 (40.1)42 (54.6)0.013
      Women, n (%)694 (64.6)54 (70.1)0.327
      Body mass index (kg/m2), mean ± SD29.4 ± 6.428.7 ± 4.90.328
      Body mass index ≥30 kg/m2, n (%)398 (37.1)29 (37.7)0.916
      Caucasian, n (%)1069 (99.5)76 (98.7)0.327
      Chronic, dispositional risk factors for VTE, n (%)
       Varicose veins809 (75.3)62 (80.5)0.305
       History of thrombosis
      SVT321 (29.9)25 (32.5)0.633
      DVT or PE171 (15.9)6 (7.8)0.056
      VTE (SVT, DVT or PE)422 (39.3)28 (36.4)0.611
       Family history of DVT or PE177 (16.5)8 (10.4)0.160
       CVI/ulceration513 (47.8)45 (58.4)0.070
       Known thrombophilia53 (4.9)4 (5.2)0.919
       Hormone replacement therapy14 (1.3)4 (5.2)0.008
       Oral contraception66 (9.5)18 (33.3)<0.001
       Current smoking176 (16.4)13 (16.9)0.910
       Hemiplegia4 (0.4)2 (2.6)0.032
       Chronic inflammatory disease52 (4.8)5 (6.5)0.519
       Immobility/bedriddenness34 (3.2)9 (11.7)<0.001
       Cardiovascular risk factors/diseases
      Diabetes mellitus, arterial hypertension, coronary artery disease, cerebrovascular disease, peripheral artery disease, atrial fibrillation, renal failure.
      549 (51.1)51 (66.2)0.010
       Heart failure30 (2.8)1 (1.3)0.434
       Respiratory failure30 (2.8)4 (5.2)0.229
      Transient, expositional risk factors for VTE, n (%)
       Trauma (past 4 weeks)46 (4.3)0 (0.0)0.064
       Travel (>6 h by car or flight)91 (8.5)4 (5.2)0.313
       Major surgery (past 12 weeks)36 (3.4)9 (11.7)<0.001
       Severe systemic infection9 (0.8)2 (2.6)0.125
       Pregnancy8 (0.7)0 (0.0)0.447
       Postpartum13 (1.2)0 (0.0)0.332
      Number of chronic dispositional risk factors (other than cancer), n (%)
       0135 (12.6)9 (11.7)0.990
       1281 (26.2)20 (26.0)
       2409 (38.1)29 (37.7)
       3+249 (23.2)19 (24.7)
      Characteristics of SVT events
       Great or small saphenous vein, n (%)579 (53.9)45 (58.4)0.441
       Other veins, n (%)495 (46.1)32 (41.6)
       Great saphenous vein only, n (%)423 (39.4)19 (24.7)0.010
       Distance between thrombus and SFJ (cm), mean ± SD25.8 ± 14.833.1 ± 12.70.018
       Distance between thrombus and SFJ < 10 cm, n (%)49 (11.4)0 (0.0)0.080
       Distance between thrombus and SFJ ≥ 10 cm, n (%)382 (88.6)24 (100.0)
       Small saphenous vein only, n (%)55 (5.1)2 (2.6)0.324
       Number of affected veins (n), mean ± SD2.2 ± 1.01.5 ± 0.70.338
       Localization, n (%)
      Proximal only285 (27.3)16 (21.1)0.185
      Distal only559 (53.6)49 (64.5)
      Proximal and distal199 (19.1)11 (14.5)
       Extension (cm), mean ± SD14.6 ± 10.813.0 ± 9.40.207
      < 20 cm719 (67.3)55 (72.4)0.328
      ≥ 20 cm350 (32.7)21 (27.6)
      Abbreviations: VTE venous thromboembolism, DVT deep vein thrombosis, PE pulmonary embolism, SVT superficial vein thrombosis, SFJ saphenofemoral junction, SD standard deviation.
      a Diabetes mellitus, arterial hypertension, coronary artery disease, cerebrovascular disease, peripheral artery disease, atrial fibrillation, renal failure.

      3.2 Study outcomes

      Pre-analyses of the data aimed to test whether there was a selective drop-out during the 12-month follow-up period. We could not find statistically significant differences in terms of demographics. However, patients with 12-month assessment, as compared to patients with incomplete follow-up, showed slightly higher rates in history of thrombotic events and cardiovascular risk factors/diseases, while the index SVT was less often proximal.
      At 3 months of follow-up (Table 2), the primary composite outcome had occurred in 10 cancer patients (13.0 %) and 57 non-cancer patients (5.4 %), with a hazard ratio (HR) of 2.56 (95 % CI 1.31–5.01, P = 0.006). Regarding secondary outcomes at 3 months, cancer patients had increased risks of DVT and PE (HR 3.92, 95 % CI 1.30–11.80, P = 0.015), persistent SVT (HR 3.22, 95 % CI 1.42–7.31, P = 0.005), or hospitalization due to VTE (HR 10.96, 95 % CI 2.45–48.99, P = 0.002). The rate of clinically relevant bleeding was numerically higher in the cancer cohort (3.9 % vs 1.3 %, HR 3.08, 95 % CI 0.88–10.70, P = 0.077).
      Table 2Study outcomes after 3 months.
      Patients without cancerPatients with cancerP valueHR
      Cancer vs no cancer.
      95 % CI
      n = 1065n = 77
      n%n%
      Primary outcome
       Symptomatic VTE (DVT, PE, recurrent or extending
      Extension into the deep vein system or to ≤ 3 cm of the saphenofemoral junction.
      SVT)
      575.41013.00.0062.561.31–5.01
      Secondary outcomes
       SVT (recurrent or extending
      Extension into the deep vein system or to ≤ 3 cm of the saphenofemoral junction.
      )
      484.567.80.1861.770.76–4.14
       PE70.722.60.0774.120.86–19.84
       DVT141.333.90.0773.080.88–10.70
       DVT and PE151.445.20.0153.921.30–11.80
       Persistent SVT323.0810.40.0053.221.42–7.31
       Asymptomatic SVT
      Detectable only on compression or duplex ultrasound.
      20.200.0
       Death10.122.6
       Hospitalization due to VTE40.433.90.00210.962.45–48.99
      Bleeding141.333.90.0773.080.88–10.70
      Severe bleeding20.211.3
      Clinically relevant non-major bleeding121.122.60.2552.390.53–10.66
      Abbreviations: VTE venous thromboembolism, DVT deep vein thrombosis, PE pulmonary embolism, SVT superficial vein thrombosis, HR hazard ratio, CI confidence interval.
      a Extension into the deep vein system or to ≤ 3 cm of the saphenofemoral junction.
      b Detectable only on compression or duplex ultrasound.
      c Cancer vs no cancer.
      At 12 months of follow-up (Table 3), the primary composite outcome had occurred in 15.6 % of cancer patients and 11.9 % of non-cancer patients (HR 1.89, 95 % CI 1.04–3.45, P = 0.037), while rates of clinically relevant bleeding were 3.9 % and 1.9 %, respectively (HR 2.86, 95 % CI 0.83–9.87, P = 0.097).
      Table 3Study outcomes after 12 months.
      Patients without cancerPatients with cancerP valueHR
      Cancer vs no cancer.
      95 % CI
      n = 805n = 77
      n%n%
      Primary outcome
       Symptomatic VTE (DVT, PE, recurrent or extending
      Extension into the deep vein system or to ≤ 3 cm of the saphenofemoral junction.
      SVT)
      9611.91215.60.0371.891.04–3.45
      Secondary outcomes
       SVT (recurrent or extending
      Extension into the deep vein system or to ≤ 3 cm of the saphenofemoral junction.
      )
      759.3810.40.2351.560.75–3.22
       PE111.433.90.0343.981.11–14.25
       DVT151.933.90.0972.860.83–9.87
       DVT and PE283.545.20.1622.110.74–6.02
       Persistent SVT344.2810.40.0092.981.32–6.72
       Asymptomatic SVT
      Detectable only on compression or duplex ultrasound.
      50.600.0
       Death70.956.50.3641.790.51–6.25
       Hospitalization due to VTE50.633.90.0038.872.12–37.12
      Bleeding151.933.90.0972.860.83–9.87
      Severe bleeding20.311.3
      Clinically relevant non-major bleeding131.622.60.3032.190.49–9.69
      Abbreviations: VTE venous thromboembolism, DVT deep vein thrombosis, PE pulmonary embolism, SVT superficial vein thrombosis, HR hazard ratio, CI confidence interval.
      a Extension into the deep vein system or to ≤ 3 cm of the saphenofemoral junction.
      b Detectable only on compression or duplex ultrasound.
      c Cancer vs no cancer.
      Estimated cumulative incidence rates of the primary composite outcome are shown in Fig. 2. Cumulative incidence rates of symptomatic VTE at 3 and 12 months were 13.8 % (95 % CI 7.7–24.2 %) and 18.2 % (95 % CI 10.6–30.4 %), respectively, in the cancer cohort and 5.3 % (95 % CI 4.0–6.8 %) and 12.9 % (95 % CI 10.5–15.7), respectively, in the non-cancer cohort (HR 2.02, 95 % CI 1.11–3.70, P = 0.02).
      Fig. 2
      Fig. 2Cumulative incidence of the primary composite outcome.
      *Extension into the deep vein system or to ≤3 cm of the saphenofemoral junction.
      Abbreviations: VTE venous thromboembolism, DVT deep vein thrombosis, PE pulmonary embolism, SVT superficial vein thrombosis, HR hazard ratio, CI confidence interval, wo. without, w. with.
      After adjusting for additional risk factors (Table 4), the cancer-associated risk of the primary composite outcome remained statistically significant at 3 months (HR 3.63, 95 % CI 1.79–7.35, P < 0.001) and 12 months (HR 2.40, 95 % CI 1.30–4.45, P = 0.005). Findings were consistent when including varicose veins and anticoagulant therapy as additional variables in the Cox regression model (supplementary Table 1).
      Table 4Multivariable analysis of the primary composite outcome of symptomatic VTE (DVT, PE, recurrent or extending SVT
      Extension into the deep vein system or to ≤ 3 cm of the saphenofemoral junction.
      ).
      HR95 % CIP value
      After 3 months
       Cancer vs no cancer3.631.79–7.35<0.001
       Age (years)0.970.95–0.990.003
       Previous DVT or PE1.690.93–3.090.086
       Cardiovascular risk factors/diseases0.950.54–1.650.846
       Great saphenous vein only1.500.92–2.440.101
      After 12 months
       Cancer vs no cancer2.401.30–4.450.005
       Age (years)0.980.96–0.990.001
       Previous DVT or PE1.781.13–2.800.012
       Cardiovascular risk factors/diseases1.090.71–1.680.697
       Great saphenous vein only1.160.79–1.720.447
      Abbreviations: VTE venous thromboembolism, DVT deep vein thrombosis, PE pulmonary embolism, SVT superficial vein thrombosis, HR hazard ratio, CI confidence interval.
      a Extension into the deep vein system or to ≤ 3 cm of the saphenofemoral junction.

      3.3 Anticoagulant treatment of SVT

      As initial anticoagulant therapy, about 65 % of cancer and non-cancer patients each were treated with fondaparinux. Only 3.9 % of cancer patients did not receive any anticoagulant, as compared to 6.6 % of non-cancer patients (Table 5). When considering all drugs used for initial anticoagulant therapy, there was no difference in the duration or intensity of anticoagulation between the two groups. However, treatment duration with low-molecular-weight heparin (LMWH) was significantly longer in the cancer than in the non-cancer cohort (36.8 ± 32.4 vs 25.3 ± 21.9 days, P = 0.034).
      Table 5Initial anticoagulant and physical therapy.
      Patients without cancer n = 1074Patients with cancer n = 77P value
      Medical therapy duration (days), mean ± SD32.1 ± 20.334.4 ± 26.10.409
       ≥4 weeks, n (%)53149.43545.50.499
       ≥6 weeks, n (%)27926.02127.30.803
       ≥3 months, n (%)232.145.20.087
       ≥12 months, n (%)00.000.0
      Dosing regimen, n (%)
       Prophylactic79774.25976.60.365
       Intermediate15814.71418.2
       Therapeutic494.611.3
       No anticoagulant706.533.9
      Fondaparinux, n (%)71965.45064.90.886
       Duration (days), mean ± SD33.7 ± 16.632.3 ± 17.20.510
      LMWH, n (%)25122.82026.00.487
       Duration (days), mean ± SD25.3 ± 21.936.8 ± 32.40.034
      Others (UFH, VKA, NOAC), n (%)565.145.20.994
       Duration (days), mean ± SD42.4 ± 39.148.5 ± 68.40.775
      No anticoagulant, n (%)736.633.90.362
      Physical therapy
       Compression83577.75368.80.147
       Cooling40637.81823.40.013
       Other716.645.20.669
      Abbreviations: LMWH low-molecular-weight heparin, UFH unfractionated heparin, VKA vitamin K antagonist, NOAC non-vitamin K-dependent oral anticoagulant, SD standard deviation.

      4. Discussion

      More than 150 years ago, the French Physician Armand Trousseau described the association of cancer with superficial migratory thrombophlebitis [
      • Trousseau A.
      ]. Today, the term Trousseau's syndrome is used for virtually all clinically relevant coagulation abnormalities, including SVT, in patients with malignancies [
      • Dicke C.
      • Langer F.
      Pathophysiology of Trousseau's syndrome.
      ]. Despite significant progress in the understanding of paraneoplastic DVT and PE, including pathophysiology, epidemiology, and pharmacological treatment, less is known about the clinical presentation, management, and outcomes of cancer-associated SVT in daily practice.
      In INSIGHTS-SVT, out of 1151 patients included in this analysis, 70 patients (6.1 %) had active cancer at baseline, while new cancer was revealed during follow-up in an additional 7 patients (0.6 %). Thus, in 6.7 % of patients, an underlying malignancy likely contributed to SVT pathogenesis. Tumor entities detected after SVT diagnosis comprised colorectal (n = 2), pancreatic, ovarian, breast, lung, and head-and-neck cancer (n = 1 each). Importantly, 6 out of the 7 newly diagnosed malignancies were detected within 3 months of follow-up (supplementary Table 2), further supporting a pathophysiological link between cancer and SVT development.
      In earlier randomized controlled trials (RCTs) on the initial treatment of DVT or PE, the proportions of patients with active or previous cancer were 10–12 % and 5–7 %, respectively [
      • Buller H.R.
      • Davidson B.L.
      • Decousus H.
      • et al.
      Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.
      ,
      • Buller H.R.
      • Davidson B.L.
      • Decousus H.
      • et al.
      Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial.
      ]. Regarding the prevalence of underlying malignancy in patients with acute isolated SVT, active cancer was an exclusion criterion in the CALISTO fondaparinux RCT, which, in the placebo arm, included the largest prospective cohort of patients with spontaneous SVT not receiving anticoagulant treatment [
      • Decousus H.
      • Prandoni P.
      • Mismetti P.
      • et al.
      Fondaparinux for the treatment of superficial-vein thrombosis in the legs.
      ]. However, about 2 % of patients in CALISTO had a history of cancer. In the recently published open-label, randomized, non-inferiority phase-3b trial that compared rivaroxaban with fondaparinux for the treatment of proximal SVT, 45 out of 472 patients (9.5 %) had active cancer or a history of cancer at study inclusion [
      • Beyer-Westendorf J.
      • Schellong S.M.
      • Gerlach H.
      • et al.
      Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open-label, randomised, non-inferiority SURPRISE phase 3b trial.
      ].
      Before INSIGHTS-SVT, evidence from observational studies involving patients with isolated SVT was predominantly limited to the situation in France. In POST, out of 634 patients with isolated SVT, 24 (3.8 %) and 29 patients (4.6 %) had active or previous cancer, respectively [
      • Decousus H.
      • Quéré I.
      • Presles E.
      • et al.
      Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study.
      ]. In OPTIMEV, out of 556 patients with isolated SVT, 28 patients (5.0 %) had active cancer, and 16 patients (2.9 %) had a history of cancer [
      • Galanaud J.P.
      • Sevestre M.A.
      • Pernod G.
      • et al.
      Long-term risk of venous thromboembolism recurrence after isolated superficial vein thrombosis.
      ,
      • Galanaud J.P.
      • Bosson J.L.
      • Genty C.
      • et al.
      Superficial vein thrombosis and recurrent venous thromboembolism: a pooled analysis of two observational studies.
      ]. In PERSEUS, out of 978 patients with isolated SVT, 29 patients (3.0 %) had active cancer, and 66 patients (6.7 %) had a history of cancer [
      • Blin P.
      • Sevestre M.A.
      • Pouchain D.
      • Gillet J.L.
      Management and 3-month outcomes of isolated superficial vein thrombosis of the lower limb: a real-world cohort study.
      ].
      It is important to point out that there is no universally accepted definition of the term ‘active cancer’ [
      • Voigtlaender M.
      • Langer F.
      Direct oral anticoagulants for the treatment of cancer-associated venous thromboembolism. What do we know so far?.
      ]. In most contemporary RCTs on anticoagulant treatment of VTE, active cancer is defined as follows: cancer diagnosed or treated within the previous 6 months (excluding non-melanoma skin cancer); recurrent, locally advanced, or metastatic solid cancer; hematological cancer not in complete remission. A more stringent definition of patients with active cancer includes patients with measurable tumor manifestations and ongoing (or an indication for) specific anticancer therapy. The risk of recurrent VTE is generally considered to be lower in patients with a history of cancer, while some evidence indicates that patients with cancer diagnosed or treated within the previous 2 years have a risk of VTE recurrence that is in the same magnitude as the risk of VTE recurrence in patients with active cancer [
      • van Es N.
      • Di Nisio M.
      • Bleker S.M.
      • et al.
      Edoxaban for treatment of venous thromboembolism in patients with cancer. Rationale and design of the Hokusai VTE-cancer study.
      ]. Patients diagnosed with cancer during follow-up (i.e., within 6–12 months after VTE occurrence) are at exceedingly high risk for both VTE recurrence and bleeding [
      • Prins M.H.
      • Lensing A.W.
      • Brighton T.A.
      • et al.
      Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials.
      ], because these patients may not only have particularly aggressive malignancies, but may also undergo diagnostic or therapeutic procedures requiring interruption of anticoagulant therapy. Consistent with this notion, 3 out of 6 patients, whose cancer was diagnosed within 3 months after the index SVT event, experienced symptomatic VTE during follow-up (supplementary Table 2).
      Following critical review of individual CRFs we feel that the final cohort of cancer patients reported herein adequately reflects the impact of malignancy and its treatment on SVT outcomes in daily practice, even though we cannot comment on clinical tumor stages or specific anticancer therapies.
      The term Trousseau's sign of malignancy implicates the diagnosis of hitherto hidden cancer after SVT occurrence. In a population-based study from Denmark, the risk of cancer during the first year of follow-up was 2.2 % in patients with SVT, corresponding to a standardized incidence ratio (SIR) of 2.46 (95 % CI 2.10–2.86) and being similar to the risk of subsequent cancer in patients with DVT (SIR 2.75, 95 % CI 2.60–2.90) or PE (SIR 3.27, 95 % CI 3.03–3.52) [
      • Sørensen H.T.
      • Sværke C.
      • Farkas D.K.
      • et al.
      Superficial and deep venous thrombosis, pulmonary embolism and subsequent risk of cancer.
      ]. From these data it may be concluded that the 0.6 % risk of new cancer detection during 1 year of follow-up, as observed in INSIGHTS-SVT, is close to what might be expected in the general population. This hypothesis is supported by a case-control study of 737 consecutive patients with isolated SVT not involving the saphenofemoral junction, of whom 3.5 % were diagnosed with cancer during 26 ± 8 months (range, 3–45 months) of follow-up, as compared to 3.9 % of 1438 controls [
      • Prandoni P.
      • Casiglia E.
      • Tikhonoff V.
      • Leizorovicz A.
      • Decousus H.
      The risk of subsequent cancer and arterial cardiovascular events in patients with superficial vein thrombosis in the legs.
      ]. Albeit limited by a quite small sample size, an observational study from the Netherlands has also not found an increased risk of subsequent cancer in 250 patients with a first episode of unprovoked SVT [
      • van Doormaal F.F.
      • Atalay S.
      • Brouwer H.J.
      • van der Velde E.F.
      • Büller H.R.
      • van Weert H.C.
      Idiopathic superficial thrombophlebitis and the incidence of cancer in primary care patients.
      ].
      The risk of an underlying malignancy, however, may be dependent on certain SVT characteristics, such as absence of varicose veins [
      • Decousus H.
      • Epinat M.
      • Guillot K.
      • Quenet S.
      • Boissier C.
      • Tardy B.
      Superficial vein thrombosis: risk factors, diagnosis, and treatment.
      ]. In INSIGHTS-SVT, the prevalence of varicose veins was similar between cancer (80.5 %) and non-cancer patients (75.3 %). In addition, there was no clear evidence for increased thrombus burden or other SVT characteristics suggestive of a more aggressive clinical presentation in the cancer cohort (Table 1). Taken together, findings from our analysis and other studies do not support an extensive screening strategy for occult cancer in unselected patients with acute isolated SVT.
      Despite initial anticoagulant and non-pharmacological treatment, 15.6 % of the cancer patients in INSIGHTS-SVT experienced a thromboembolic event up to 12 months of follow-up, including recurrent or extending SVT (10.4 %), DVT (3.9 %), and PE (3.9 %). Thus, our analysis shows that active cancer, as defined before, is a substantial and independent risk factor for symptomatic VTE in patients with isolated SVT, both after 3 months (HR 3.63, 95 % CI 1.79–7.35, P < 0.001) and after 12 months (HR 2.40, 95 % CI 1.30–4.45, P = 0.005). This finding is consistent with a pooled analysis of POST and OPTIMEV, according to which cancer is a risk factor for recurrent VTE, including DVT, PE or new SVT, at 3 months of follow-up (HR 2.31, 95 % CI 1.03–5.22) [
      • Galanaud J.P.
      • Bosson J.L.
      • Genty C.
      • et al.
      Superficial vein thrombosis and recurrent venous thromboembolism: a pooled analysis of two observational studies.
      ]. Similarly, a longitudinal analysis of ICARO, involving 411 patients with isolated SVT and sufficient follow-up, identified active solid malignancies as an independent risk factor for DVT or PE, with model-dependent adjusted HRs of 3.12 (95 % CI 1.11–8.93) and 4.62 (95 % CI 1.48–14.42) [
      • Barco S.
      • Pomero F.
      • Di Minno M.N.D.
      • et al.
      Clinical course of patients with symptomatic isolated superficial vein thrombosis: the ICARO follow-up study.
      ]. Finally, in SURPRISE, the composite efficacy endpoint of symptomatic DVT or PE, progression or recurrence of SVT, and all-cause mortality occurred in 20 % (9/45) of cancer and 5.4 % (23/427) of non-cancer patients during the entire observation period of 90 days, with DVT/PE incidences of 6.7 % (3/45) and 1.2 % (5/427), respectively [
      • Beyer-Westendorf J.
      • Schellong S.M.
      • Gerlach H.
      • et al.
      Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open-label, randomised, non-inferiority SURPRISE phase 3b trial.
      ]. Based on these findings and our observations from INSIGHTS-SVT [
      • Bauersachs R.
      • Gerlach H.E.
      • Heinken A.
      • et al.
      Management and outcomes of patients with isolated superficial vein thrombosis under real life conditions (INSIGHTS-SVT).
      ], it is tempting to speculate that cancer patients with acute isolated SVT may benefit from prolonged, e.g. up to 3 months, and more intensive anticoagulation, e.g. with intermediate or therapeutic dosages, to sufficiently control the hypercoagulable state. In support of this hypothesis, although the risk of VTE remained elevated during the entire observation period of 1 year, most events in the cancer cohort occurred within the first 3 months, suggesting that cancer drives VTE occurrence during the early phase, while other established risk factors continue to play a role during the later phase of follow-up. It is important to point out that due to the multifactorial pathogenesis of CAT it is highly likely that risk factors in addition to the cancer itself, such as surgery, immobility/bedriddenness, cardiovascular risk factors/diseases and hormone therapy (Table 1), significantly contributed to VTE development in the cancer cohort.
      Albeit not statistically significant, we observed an increased all-cause mortality in the cancer (6.5 %) versus the non-cancer (0.9 %) cohort (HR 1.79, 95 % CI 0.51–6.25, P = 0.364). Considering average 6-month mortality rates of 20–30 % in recent CAT trials [
      • Young A.M.
      • Marshall A.
      • Thirlwall J.
      • et al.
      Comparison of an Oral factor xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D).
      ,
      • Agnelli G.
      • Becattini C.
      • Meyer G.
      • et al.
      Apixaban for the treatment of venous thromboembolism associated with cancer.
      ], this finding points to the inclusion of patients with less advanced malignancies in INSIGHTS-SVT. Other studies have linked lower-limb venous thrombosis, including DVT and SVT, to poor survival in patients with cancer [
      • Barco S.
      • Pomero F.
      • Di Minno M.N.D.
      • et al.
      Clinical course of patients with symptomatic isolated superficial vein thrombosis: the ICARO follow-up study.
      ,
      • Galanaud J.P.
      • Blaise S.
      • Sevestre M.A.
      • et al.
      Long-term outcomes of isolated superficial vein thrombosis in patients with active cancer.
      ,
      • Gary T.
      • Belaj K.
      • Steidl K.
      • et al.
      Asymptomatic deep vein thrombosis and superficial vein thrombosis in ambulatory cancer patients: impact on short-term survival.
      ].
      Our study has several limitations. First, a general shortcoming of observational studies such as ours is lack of randomization. However, we prospectively followed a large and broad spectrum of consecutive patients with acute isolated SVT in a real-world setting, which is consistent with our previous conclusions and may be considered a strength of our study. Second, a substantial number of non-cancer patients were lost to follow-up at 12 months, which may be a source of bias. However, we did not find any significant differences between patients with and without 12-month assessment in demographics. In fact, patients with available 12-month follow-up appeared to have a slightly more severe risk profile. Third, the relatively high event rate in our study could be explained by the setting (secondary care level): general practitioners may have only referred patients with an advanced age or other factors determining higher risk to the specialists for confirmation of SVT, while keeping lower risk patients in their own management [
      • Geersing G.J.
      • Cazemier S.
      • Rutten F.
      • Fitzmaurice D.A.
      • Hoes A.W.
      Incidence of superficial venous thrombosis in primary care and risk of subsequent venous thromboembolic sequelae: a retrospective cohort study performed with routine healthcare data from the Netherlands.
      ]. Finally, as discussed before, we cannot comment on important tumor characteristic such as clinical stage or specific anticancer treatment.
      In addition to the prospective study design and large patient cohort, strengths of INSIGHTS-SVT include high data completeness [
      • Bauersachs R.
      • Gerlach H.E.
      • Heinken A.
      • et al.
      Management and outcomes of patients with isolated superficial vein thrombosis under real life conditions (INSIGHTS-SVT).
      ], with a lost to follow-up at 3 months of only 0.4 %, which is lower compared to 4.8 % in PERSEUS [
      • Blin P.
      • Sevestre M.A.
      • Pouchain D.
      • Gillet J.L.
      Management and 3-month outcomes of isolated superficial vein thrombosis of the lower limb: a real-world cohort study.
      ] and 2.3 % in POST [
      • Decousus H.
      • Quéré I.
      • Presles E.
      • et al.
      Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study.
      ]. Data reporting was supported through monitoring with source data verification. Furthermore, 3-month data were documented based on personal contacts of patients with their physicians (before the COVID-19 restrictions), and selected centers all had CUS devices. Study participants, however, may represent a positive selection in terms of patient adherence and of compliant physicians, who have a higher-than-average level of expertise, who are interested in scientific research, and who are willing to undergo quality control measures, such as on-site monitoring visits with source data verification.
      In summary, the prospective INSIGHTS-SVT registry shows that cancer patients are exposed to a high risk for thromboembolic complications during real-life management of acute isolated SVT despite antithrombotic treatment. While most events occurred within 3 months, the risk remained elevated up to 1 year of follow-up. The study thus underlines the need to keep the high VTE risk of cancer patients in mind and to consider prolonged and more intensive anticoagulation on an individual basis.

      CRediT authorship contribution statement

      FL, RB, and DP developed the concept for the present analysis and wrote the first draft of the manuscript. All authors are members of the Steering Committee and contributed to the design, the data collection form, and the analysis plan. JK performed the statistical analyses.
      All members of the Steering Committee contributed to the interpretation of results, revised, and approved all versions of the manuscript, and vouch for the accuracy and completeness of the reported data and the fidelity of this article to the study protocol.

      Funding

      The INSIGHTS-SVT study was funded by Aspen Germany GmbH, Munich . The present analysis was funded by Mylan Germany GmbH (a Viatris company).

      Compliance with ethical standards

      The study fully complies with ethical standards (as described in the methods section).

      Declaration of competing interest

      FL has received honoraria for lectures or consultancy from Aspen, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, LEO, Pfizer, Sanofi, and Viatris.
      HG has received honoraria for lectures and advisory boards from Aspen, Bayer, Boehringer-Ingelheim and Leo Pharma.
      AS is full-time employee of Mylan Pharmaceuticals GmbH, Germany.
      AH was at the time of the study full-time employee of Aspen Pharma GmbH, Munich, and is now employee of Amgen GmbH, Germany.
      UH has received research support and honoraria for lectures and advisory boards from Bayer HealthCare Pharmaceuticals, Bristol-Myers-Squibb, Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Leo Pharma and Aspen.
      TN has received honoraria for consultancy from Medi Bayreuth, honoraria for presentations from Aspen, Bayer, and Bristol-Myers Squibb.
      DP has received honoraria for consultancy, advisory boards, or lectures by Actelion, Bayer, Biogen, Aspen, Amgen, Boehringer Ingelheim, Novartis, Daiichi Sankyo, Genzyme.
      JK reports no conflict of interest related to this study.
      ER has received honoraria for lectures and advisory boards from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Leo Pharma and Pfizer.
      RB has received research support and honoraria for lectures and advisory boards from Aspen, Bayer HealthCare Pharmaceuticals, Bristol- Myers Squibb, and Daiichi Sankyo.

      Acknowledgments

      We acknowledge the efficient project administration by Mrs. Linda Kottke and Mrs. Romy Wagner, GWT-TUD GmbH, Dresden.

      Investigator list

      The following investigators/sites documented patients: Christian Schnabl (Berlin), Tina Winterbauer (Birkenau), Norbert Schön (Mühldorf), Harriet Simone Werno (Nürnberg), Georg Herman (Augsburg), Oliver Schmidt (Erlangen), Beate Dietrich (Gera), Martin Schünemann (Nörten-Hardenberg), Eberhard Rieker (Lauffen), Ulrich Ruppe (Berlin), Gabriele Betzl (München), Thomas Noppeney (Nürnberg), Peter Heilberger (Nürnberg), Dimitrios Tsantilas (Augsburg), Andreas Köpp (Braunschweig), Lutz Forkmann (Chemnitz), Andreas Willeke (Darmstadt), Gabriele Rothenbücher (Dornstadt), Karl Förster (Ehringshausen), Jeanette Kießling (Erfurt), Gesche Junge (Heidelberg), Ina Wittig (Leipzig), Dagmar Wilms (Leverkusen), Christoph Schulte (Limburg), Stephan Flüchter (Mannheim), Martina Kneist (Mühlhausen), Ulrike Kirsch (Oranienburg), Thomas Herrmann (Weinheim), Alexandra Turowski (Berlin), Karsten Hartmann (Freiburg), Wolfram Oettler (Görlitz), Heike Nelles (Altenburg), Jürgen Frank (Baesweiler), Savvas Apostolidis (Frankfurt/Main), Dag-Alexander Keilhau (Hamburg), Renate Murena Schmidt (Köln), Iris Rocha Rivera-Reuver (Köln), Kerstin Augustin (Mosbach), Diethard Predel (Nordhausen), Thomas Hertel (Zwickau), Ursula Schmeink (Aachen), Simone Seibt (Berlin), Jürgen Schreiner (Dachau), Christine Zollmann (Jena), Eckart Möbius (Schwerin), Thomas Vollmer (Bruchsal), Roswitha Brettschneider (Düren), Sabine Raulin (Karlsruhe), Siamak Pourhassan (Oberhausen), Gerlind Läger (Oelsnitz), Robert Brandl (Passau), Rainer Schmiedel (Kaiserslautern), Karoline Jager (Saarbrücken), Erika Mendoza (Wunstorf), Jörg Schwuchow (Neuruppin), Jan-Peter Siegers (Otterndorf), Peter Gätzschmann (Viechtach), Dimitrios Zgouras (Wiesbaden), Werner Lang (Erlangen), Arne Clasing (Lüneburg), Anatoli Ananin (Nürnberg), Jörg Rutkowski (Traunstein), Christoph Kalka (Brühl), Frank Ackermann (Greiz), Fred Peter (Bamberg), Patricia Schaub (Limburg), Jan Beyer-Westendorf (Dresden), Bernadette Brado (Heidelberg), Mario Schöniger (Nordendorf), Sven Köpnick (Wuppertal), Ferenc Biro (Köln), Birgit Linnemann (Frankfurt am Main).

      Appendix A. Supplementary material

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