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Primary Thromboprophylaxis and the Risk of Venous Thromboembolic Events in Patients With Testicular Germ Cell Tumors Treated With Cisplatinum-Based Chemotherapy

  • Angelika Terbuch
    Affiliations
    Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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  • Gudrun Walser
    Affiliations
    Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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  • Michael Stotz
    Affiliations
    Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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  • Armin Gerger
    Affiliations
    Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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  • Author Footnotes
    ⁎⁎ Florian Posch and Thomas Bauernhofer are co-last authors.
    Florian Posch
    Correspondence
    Address for correspondence: Florian Posch, MD, PhD, Division of Hematology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 38, 8036 Graz, Austria.
    Footnotes
    ⁎⁎ Florian Posch and Thomas Bauernhofer are co-last authors.
    Affiliations
    Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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  • Author Footnotes
    ⁎⁎ Florian Posch and Thomas Bauernhofer are co-last authors.
    Thomas Bauernhofer
    Footnotes
    ⁎⁎ Florian Posch and Thomas Bauernhofer are co-last authors.
    Affiliations
    Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
    Search for articles by this author
  • Author Footnotes
    ⁎⁎ Florian Posch and Thomas Bauernhofer are co-last authors.
Open AccessPublished:October 11, 2022DOI:https://doi.org/10.1016/j.clgc.2022.10.005

      Highlights

      • Testicular germ cell tumor (TGCT) patients undergoing cisplatinum-based chemotherapy have a high risk of venous thromboembolism (VTE).
      • Higher clinical tumor stage and a large retroperitoneal lymphadenopathy (RPLND >5 cm) are the strongest predictors of an elevated VTE risk.
      • TGCT patients undergoing cisplatinum-based chemotherapy have a significantly lower VTE risk when receiving primary thromboprophylaxis.
      • Given the low risk of bleeding in patients with TGCT, it might be worthwhile to consider thromboprophylaxis in patients of all clinical stages for the duration of cisplatinum-based chemotherapy.

      Abstract

      Background

      Cisplatinum-based chemotherapy is associated with an increased risk of venous thromboembolism (VTE). We hypothesized that primary thromboprophylaxis in patients with testicular germ cell tumors (GCT) undergoing cisplatinum-based chemotherapy can reduce the risk of VTE.

      Patients and Methods

      In this single-center retrospective cohort study, we investigated the increased use of primary thromboprophylaxis between January 2000 and December 2021 at our institution and its effect on the risk of VTE. Patients with GCT undergoing adjuvant or curative cisplatinum-based chemotherapy were included.

      Results

      Three hundred forty-six patients with GCT initiating a cisplatinum-based therapy were included in the study, of whom 122 (35%) were treated in the adjuvant and 224 (65%) in the curative setting, respectively. VTE events occurred in 49 (14.2%) patients. In univariable competing risk analysis, a higher clinical tumor stage and large retroperitoneal lymphadenopathy (RPLND >5 cm) were the strongest predictors of an elevated VTE risk (SHR for stage IIC - IIIC: 2.6 (95%CI: 5.0-24.7, P < .001), SHR for RPLN: 2.36 (95%CI: 1.27-4.4, P < .007)). The proportion of patients receiving primary thromboprophylaxis strongly increased over time and reached 100% in CS IIC-III patients from 2019 onwards. After adjusting for tumor stage, primary thromboprophylaxis was associated with a 52% relatively lower risk of VTE (SHR = 0.48, 95% CI: 0.24-0.97; P = .032).

      Conclusion

      In this retrospective cohort study, we showed that TGCT patients undergoing cisplatinum-based chemotherapy have a lower VTE risk when receiving primary thromboprophylaxis. For the duration of chemotherapy, primary thromboprophylaxis should be considered on a risk-benefit ratio.

      Keywords

      Introduction

      The risk of VTE is increased around 4 to 6 fold in cancer patients as compared to the general population.
      • Khorana A.A.
      • Connolly G.C.
      Assessing risk of venous thromboembolism in the patient with cancer.
      ,
      • Khorana A.A.
      • Kuderer N.M.
      • Culakova E.
      • Lyman G.H.
      • Francis C.W.
      Development and validation of a predictive model for chemotherapy-associated thrombosis.
      In patients receiving chemotherapy the risk seems to vary, ranging from 3% to 5% in patients with early-stage cancer to 30% in those with metastatic disease.
      • Rutjes A.W.
      • Porreca E.
      • Candeloro M.
      • Valeriani E.
      • Di Nisio M.
      Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.
      ,
      • Timp J.F.
      • Braekkan S.K.
      • Versteeg H.H.
      • Cannegieter S.C.
      Epidemiology of cancer-associated venous thrombosis.
      A very high incidence of thromboembolic events in patients has been observed in cancer patients receiving cisplatinum-based chemotherapy possibly due to its effect on vascular injury and endothelial dysfunction.
      • Herrmann J.
      Vascular toxic effects of cancer therapies.
      • Seng S.
      • Liu Z.
      • Chiu S.K.
      • et al.
      Risk of venous thromboembolism in patients with cancer treated with Cisplatin: a systematic review and meta-analysis.
      • Zahir M.N.
      • Shaikh Q.
      • Shabbir-Moosajee M.
      • Jabbar A.A.
      Incidence of Venous Thromboembolism in cancer patients treated with Cisplatin based chemotherapy - a cohort study.
      • Togna G.I.
      • Togna A.R.
      • Franconi M.
      • Caprino L.
      Cisplatin triggers platelet activation.
      • Terbuch A.
      • Posch F.
      • Annerer L.M.
      • et al.
      Long-term cardiovascular complications in stage I seminoma patients.
      Primary thromboprophylaxis is recommended for hospitalized cancer patients who have a low risk of bleeding.
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline Update.
      ,
      • Mandala M.
      • Falanga A.
      • Roila F.
      • Group E.G.W.
      Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines.
      For ambulatory patients with cancer receiving systemic therapy the recommendation of thromboprophaylaxis is based on risk-stratification factors like the Khorana score. High-risk outpatients with a Khorana score of 2 or higher may be offered thromboprophylaxis.
      • Key N.S.
      • Khorana A.A.
      • Kuderer N.M.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline Update.
      ,
      • Mandala M.
      • Falanga A.
      • Roila F.
      • Group E.G.W.
      Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines.
      However, prospective randomized clinical trials that investigated the role of thromboprophylaxis included different cancer types and patients with testicular germ cell tumors (TGCT) have been a minority in those trials.
      • Carrier M.
      • Abou-Nassar K.
      • Mallick R.
      • et al.
      Apixaban to prevent venous thromboembolism in patients with cancer.
      • Agnelli G.
      • Gussoni G.
      • Bianchini C.
      • et al.
      Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study.
      • Khorana A.A.
      • Soff G.A.
      • Kakkar A.K.
      • et al.
      Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer.
      As has been shown by Srikanthan et al and our group, tumor stage and the presence of large retroperitoneal lymphadenopathy provide a higher discriminatory performance with respect to VTE than the Khorana score for patients with TGCT.
      • Srikanthan A.
      • Tran B.
      • Beausoleil M.
      • et al.
      Large retroperitoneal lymphadenopathy as a predictor of venous thromboembolism in patients with disseminated germ cell tumors treated with chemotherapy.
      ,
      • Bezan A.
      • Posch F.
      • Ploner F.
      • et al.
      Risk stratification for venous thromboembolism in patients with testicular germ cell tumors.
      Since then, we have consequently assessed the risk of testicular GCT patients at our department and used primary thromboprophylaxis on basis of a risk-benefit-ratio for TGCT patients undergoing cisplatin-based chemotherapy. The aim of this study was to investigate the incidence of VTE in a large cohort of TGCT patients over a time period with a consequent increase of thromboprophylaxis and its effect on VTE risk.

      Patients and Methods

      In this single-center cohort study consecutive patients with histologically confirmed TGCT, presenting to the Division of Oncology at the Medical University of Graz between January 2000 and December 2021, were identified (n = 1052). After a diagnosis of TGCT, patients were staged initially using computed tomographic (CT) scans of the abdomen, CT scan or X-ray of the chest, and postoperative tumor markers α-fetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH). Tumor markers within normal limits after orchiectomy and the absence of metastases on imaging defined Clinical Stage I (CSI). Patients with disseminated disease were risk-classified according to the International Germ Cell Cancer Collaborative group (IGCCCG).
      International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group.
      ,
      • Schmoll H.J.
      • Souchon R.
      • Krege S.
      • et al.
      European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG).
      Follow-up data were retrieved until January 2022. Follow up investigations at our center were performed according to a local protocol and were adapted in 2007 and 2012 according to recent publications.
      • Cathomas R.
      • Helbling D.
      • Stenner F.
      • et al.
      Interdisciplinary evidence-based recommendations for the follow-up of testicular cancer patients: a joint effort.
      ,
      • Rustin G.J.
      • Mead G.M.
      • Stenning S.P.
      • et al.
      Randomized trial of two or five computed tomography scans in the surveillance of patients with stage I nonseminomatous germ cell tumors of the testis: Medical Research Council Trial TE08, ISRCTN56475197–the National Cancer Research Institute Testis Cancer Clinical Studies Group.
      Electronic and paper medical records of all 1052 consecutive TGCT patients were retrospectively reviewed and thromboembolic events were documented in our in-house administrative system. Eligible events were symptomatic or incidental deep vein thrombosis (DVT), visceral thrombosis, and pulmonary embolism (PE). Occurrence of VTE had to be confirmed by objective methods, such as angiography, venous Doppler ultrasound, magnetic resonance imaging, computed tomography, ventilation/perfusion scan, and were adjudicated by an independent panel of local experts. Three hundred forty-six out of these 1052 patients received cisplatin-based chemotherapy as adjuvant or curative treatment and were included for further analysis (Supplementary Figure 1). Fourteen patients had a VTE event leading to the diagnosis of testicular cancer and were subsequently not counted as VTE events in this analysis. This study was approved by the Institutional Review Board of the Medical University of Graz (No. 26-196 ex 13/1).

      Statistical Methods

      All statistical analyses were performed with Stata 17.0 (Windows version, Stata Corp., Houston, TX). Continuous variables were reported as medians [25th-75th percentile], and count data as absolute frequencies (%). The distribution of variables between the 2 groups were compared with rank-sum tests, χ2-tests, and Fisher's exact tests, as appropriate. For time-to-VTE analyses, the date of chemotherapy initiation (either in the adjuvant or curative setting) was the baseline date. Risks of VTE were computed with 1-Kaplan-Meier estimators and competing risk cumulative incidence estimators, treating death-from-any-cause as the competing event. Comparisons of VTE risk between patients with and without primary thromboprophylaxis were performed with log-rank tests, log-rank tests stratified for clinical stage, and adjusted Wald tests. VTE risk was modeled in the uni- and multivariable setting with Fine & Gray competing risk regression models. To gauge whether the association between primary thromboprophylaxis and VTE risk may be modified by clinical stage, interactions between thromboprophylaxis and clinical stage were fitted within a Fine & Gray model, and cumulative VTE incidences by prophylaxis and clinical stage status directly predicted from this model. Missing data are reported in Table 1, and a complete case analysis was performed.
      Table 1Baseline Characteristics
      VariableNumber (% Missing)Overall (n = 346)No VTE During Follow-up (n = 297)VTE during Follow-up (n = 49)P*
      Demographic Characteristics
      Age346 (0%)35 [28-42]35 [28-42]34 [27-40].508
      BMI (kg/m²)311 (10%)25 [23-28]25 [23-28]25 [22-28].754
      Smoker or Ex-Smoker239 (31%)143 (60%)128 (61%)15 (54%).472
      Karnofsky Index <100%286 (17%)39 (14%)31 (12%)8 (22%).129
      Clinical variables
      Non-Seminomatous histology343 (1%)250 (73%)213 (72%)37 (77%).481
      Clinical tumor stage344 (1%)///.012
      —stage IA-IB/156 (45%)144 (49%)12 (25%)/
      —stage IS/10 (3%)9 (3%)1 (2%)/
      —stage IIA–IIC/103 (30%)85 (29%)18 (38%)/
      —stage IIIA–IIIC/75 (22%)58 (20%)17 (35%)/
      RPLN(>5 cm)340 (1%)57 (17%)41 (14%)16 (33%).001
      Primary metastatic disease346 (0%)190 (55%)153 (52%)37 (76%).002
      Initial treatment setting346 (0%)///.004
      —Active Surveillance/34 (10%)30 (10%)4 (8%)/
      —Adjuvant treatment/122 (35%)114 (38%)8 (16%)/
      —Curative treatment/190 (55%)153 (52%)37 (76%)/
      IGCCCG risk stratification190 (0%)///
      —Good risk/146 (77%)121 (79%)25 (68%)/
      —Intermediate risk/20 (11%)13 (9%)7 (19%)/
      —Poor risk/24 (13%)19 (12%)5 (14%)/
      Type of primary chemotherapy346 (0%)///.691
      —PEB/317 (92%)272 (92%)45 (92%)/
      —PE/23 (7%)20 (7%)3 (6%)/
      —PEI/3 (1%)3 (1%)0 (0%)/
      —Other/3 (1%)2 (1%)1 (2%)/
      Chemotherapy cycles given346 (0%)///.004
      —1 cycle/47 (14%)45 (15%)2 (4%)/
      —2 cycles/70 (20%)65 (22%)5 (10%)/
      —3 cycles/156 (45%)132 (44%)24 (49%)/
      —≥4 cycles/73 (21%)55 (19%)18 (37%)/
      IGCCCG, International Germ Cell Cancer Collaborative Group.

      Results

      Baseline Characteristics

      Three hundred forty-six patients receiving a platinum-based therapy were included in the study (Table 1), of whom 122 (35%) were treated in the adjuvant and 224 (65%) in the curative setting, respectively. As only patients treated with cisplatin-based chemotherapy were included in the study, clinical stage (CS) I seminoma as well as CS II seminoma treated with radiotherapy and patients treated with retroperitoneal lymphadenectomy only were excluded (Supplemental Data Figure 1). The cohort for the final analysis included 93 patients with metastatic seminoma, 3 patients with GCT of unknown type and 250 patients with nonseminoma of. One hundred fifty-six patients (45%) presented with CS I of whom 122 patients received adjuvant chemotherapy. Thirty-four patients with CS I were managed with active surveillance initially and received curative chemotherapy for disease relapse. One hundred ninety-patients (55%) presented with primary metastatic disease, 30% of those having CS II, 22% CS III and 3% having CS IS disease. Fifty-seven patients (17%) had bulky retroperitoneal disease larger than 5 centimeters.
      Figure 1
      Figure 1Proportion of patients with primary thromboprophylaxis during the inclusion period – Distribution by clinical stage.

      VTE Events

      Median follow-up for VTE was 50.6 months, and 75% and 25% of the cohort had follow-up intervals of at least 31.3 and 74.4 months, respectively. During the prespecified VTE observation period of 6 months after chemotherapy initiation, 49 patients (14%) developed VTE. These events included pulmonary embolism (PE, n = 31 (63%)), PE and deep vein thrombosis (PE+DVT, n = 8 (16%)), DVT (n = 6 (12%)), and VTE events at other sites (n = 4 (8%)). This corresponded to 1-, 2-, 3-, and 6-month cumulative VTE incidences of 2.0% (95%CI: 0.9-4.0), 8.4% (5.8-11.7), 12.3% (9.1-16.1), and 13.2% (9.9-17.1), respectively (Supplemental Data Figure 2). On average, patients who developed VTE had higher clinical tumor stages, a higher probability of stage IIC disease, and received more platinum-based chemotherapy cycles than patients who did not develop VTE, respectively. In CS I disease VTE events occurred in 9% of patients without thromboprophylaxis compared to 3% of patients with thromboprophylaxis. In CS IIC disease 50% of patients developed a VTE compared to 15% of patients with thromboprophylaxis. In CSIII 30% of patients without thromboprophylaxis suffered from a VTE event compared to 13% of patients with thromboprophylaxis. Only in CS IS-IIB disease more, VTE events happened in the group with thromboprophylaxis (Supplemental Data Table 1).
      Figure 2
      Figure 2Primary thromboprophylaxis and risk of VTE in patients with TGCT undergoing platinum-based therapy. Data represent 1-Kaplan-Meier estimtators and a log-rank test stratified by clinical tumor stage (IA-IIB vs. IIC-IIIC).

      Primary Thromboprophylaxis

      One hundred seven patients (31%) received primary thromboprophylaxis (Table 2), of whom n = 106 (99%) received a low-molecular-weight heparin (LMWH) and n = 1 (1%) received a direct oral anticoagulant (DOAC). LMWH doses were prophylactic in n = 87 patients, semitherapeutic in n = 11 patients, and unknown in n = 8 patients, respectively. The proportion of patients receiving primary thromboprophylaxis strongly increased over time (P < .0001) in both patients with and without CS IIC-III disease (P for interaction= .104) and reached 35% in CS IA-IIB patients and 100% in CS IIC-III patients from 2019 onward (Figure 1). On average, patients receiving primary thromboprophylaxis had lower Karnofsky indices, higher clinical tumor stages, were more likely to have primary metastatic disease, were less likely to have IGCCCG good-risk disease, and received more chemotherapy cycles in primary platinum-based treatment (Table 2). The strongest predictor of primary thromboprophylaxis was clinical tumor stage. In detail, 54 (23%) patients with CS IA-IIB disease and 53 (50%) of patients with cS IIC-III received primary thromboprophylaxis (P < .0001).
      Table 2Patient Characteristics overall and distributed by primary thromboprophylaxis
      VariableNumber (% missing)Overall (n = 346)No Primary Thrombo-prophylaxis (n = 239)Primary Thrombo-prophylaxis (n = 107)P*
      Demographic Characteristics
      Age346 (0%)35 [28-42]34 [28-41]37 [28-45].119
      BMI (kg/m²)311 (10%)25 [23-28]25 [23-28]25 [23-28].667
      Smoker or Ex-Smoker239 (31%)143 (60%)108 (61%)35 (57%).650
      Karnofsky Index <100%286 (17%)39 (14%)23 (11%)16 (21%).033
      Clinical variables
      Non-Seminomatous histology343 (1%)250 (73%)190 (80%)60 (57%)<.0001
      Clinical tumor stage344 (1%)///<.0001
      —stage IA-IB/156 (45%)125 (53%)31 (29%)/
      —stage IS/10 (3%)10 (4%)0 (0%)/
      —stage IIA–IIC/103 (30%)60 (25%)43 (41%)/
      —stage IIIA–IIIC/75 (22%)43 (18%)32 (30%)/
      RPLN(>5 cm)340 (1%)57 (17%)23 (10%)34 (33%)<.0001
      Primary metastatic disease346 (0%)190 (55%)114 (48%)76 (71%)<.0001
      Initial treatment setting346 (0%)///<.0001
      —Active Surveillance/34 (10%)23 (10%)11 (10%)/
      —Adjuvant treatment/122 (35%)102 (43%)20 (19%)/
      —Curative treatment/190 (55%)114 (48%)76 (71%)/
      IGCCCG risk stratification⁎⁎190 (0%)///.010
      —Good risk/146 (77%)96 (84%)50 (66%)/
      —Intermediate risk/20 (11%)7 (6%)13 (17%)/
      —Poor risk/24 (13%)11 (10%)13 (17%)/
      Chemotherapy cycles given346 (0%)///<.0001
      —1 cycle/47 (14%)39 (16%)8 (7%)/
      —2 cycles/70 (20%)62 (26%)8 (8%)/
      —3 cycles/156 (45%)106 (44%)50 (47%)/
      —≥4 cycles/73 (21%)32 (13%)41 (38%)/
      IGCCCG, International Germ Cell Cancer Collaborative Group.

      Predictors of VTE Risk

      Higher clinical tumor stage was the strongest univariable predictor of VTE risk (Table 3). In univariable analysis, primary thromboprophylaxis was not associated with VTE risk (Subdistribution hazard ratio (SHR) = 0.68, 95%CI: 0.35-1.32, P = .251), but was strongly associated with a lower risk of VTE after adjusting for the confounding influence of clinical stage (Adjusted SHR = 0.48, 95% CI: 0.24-0.97; stage-stratified log-rank P = .032 (Figure 2), Wald test P = .042 (Figure3)). As the presence of a retroperitoneal lymph node bulk (CS IIC) and stage III were the strongest predictor of VTE, while being highly correlated with primary thromboprophylaxis, we assessed the association of primary thromboprophylaxis with VTE risk separately for patients with CS I-IIB and patients with CS IIC-III within an interaction analysis. Here, we did not observe that the relative association between primary thromboprophylaxis and a lower risk would be different in patients with clinical stage IA-IIB and clinical stage IIC-III disease (P for interaction = .310), although interaction-adjusted regression coefficients indicated a potentially much greater relative risk reduction with thromboprophylaxis in patients with clinical stage IIC-III disease (SHR 0.37, 95% CI 0.16-0.87, P = .023) vs. stage IA-IIB disease patients (SHR 0.76, 95%CI: 0.26-2.25, P = .625, Supplemental Data Figure 3).
      Table 3Predictors of VTE - univariable competing risk regression
      VariableSHR95%CIP
      Main study exposure
      Primary thromboprophylaxis0.680.35 - 1.32.251
      Demographic characteristics
      Age (per 5 years increase)0.970.85 - 1.12.725
      BMI (per 5kg/m² increase)0.960.70 - 1.32.821
      Smoker/Ex-Smoker vs never smoker0.600.27 - 1.31.200
      Karnofsky Index <100%1.840.79 - 4.28.156
      Clinical variables
      Non-Seminomatous histology1.300.65 - 2.62.460
      Clinical stage IIC–IIIC2.601.45 - 4.66.001
      RPLN(>5 cm)2.361.27 - 4.40.007
      Primary metastatic disease2.241.15 - 4.37.018
      IGCCCG risk stratification⁎⁎
      Good riskRef.Ref.Ref.
      —Intermediate risk and poor risk1.450.70 - 2.99.322
      Chemotherapy cycles in primary platinum-based treatment
      —1 cycleRef.Ref.Ref.
      —2 cycles1.610.30 - 8.59.576
      —3 cycles3.240.74 - 14.18.119
      —≥4 cycles5.031.13 - 22.45.034
      IGCCCG, International Germ Cell Cancer Collaborative Group.
      Figure 3
      Figure 3Predicted risk of VTE according to primary thromboprophylaxis and clinical stage in patients with TGCT undergoing platinum-based therapy. Curves represent cumulative incidence functions that were predicted from a Fine & Gray competing risk regression model with 2 variables (primary prophylaxis and clinical stage IA-IIB vs. IIC-IIIC). The Wald-test P-value represents the stage-adjusted P-value for thromboprophylaxis (overall model P-value = .001). This model constrains the relative risk reduction of thromboprophylaxis to be similar in patients with stage IA-IIB and stage IIC-IIIC disease.

      Discussion

      In this retrospective cohort study, we showed that TGCT patients undergoing cisplatinum-based chemotherapy have a lower VTE risk when receiving primary thromboprophylaxis. The main risk factors for VTE in TGCT patients are the clinical stage and the presence of large retroperitoneal lymphadenopathy as has been shown previously by our group and Srikanthan et al in 2015.
      • Srikanthan A.
      • Tran B.
      • Beausoleil M.
      • et al.
      Large retroperitoneal lymphadenopathy as a predictor of venous thromboembolism in patients with disseminated germ cell tumors treated with chemotherapy.
      ,
      • Bezan A.
      • Posch F.
      • Ploner F.
      • et al.
      Risk stratification for venous thromboembolism in patients with testicular germ cell tumors.
      Since then, the use of primary thromboprophylaxis has increased significantly at our institution and has reached one hundred percent in CS IIC-IIIC disease in recent years (Figure 1). Thromboprophylaxis in cancer patients has been investigated in several trials and resulted in a relative risk reduction of 30% to 60% in VTE.
      • Carrier M.
      • Abou-Nassar K.
      • Mallick R.
      • et al.
      Apixaban to prevent venous thromboembolism in patients with cancer.
      • Agnelli G.
      • Gussoni G.
      • Bianchini C.
      • et al.
      Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study.
      • Khorana A.A.
      • Soff G.A.
      • Kakkar A.K.
      • et al.
      Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer.
      TGCT patients have been under-represented in all trials. Only three patients with TGCT were included in the AVERT trial comparing apixaban with placebo in a population consisting of 563 cancer patients.
      • Carrier M.
      • Abou-Nassar K.
      • Mallick R.
      • et al.
      Apixaban to prevent venous thromboembolism in patients with cancer.
      Ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score ≥2) and were initiating chemotherapy were included. Apixaban resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy (4.2% vs. 10.2%; HR 0.41; P < .001).
      • Carrier M.
      • Abou-Nassar K.
      • Mallick R.
      • et al.
      Apixaban to prevent venous thromboembolism in patients with cancer.
      A retrospective study by Gizzi et al suggests a similar effect of primary thromboprophylaxis on VTE in TGCT patients although this did not reach statistical significance.
      • Gizzi M.
      • Oberic L.
      • Massard C.
      • et al.
      Predicting and preventing thromboembolic events in patients receiving cisplatin-based chemotherapy for germ cell tumours.
      The risk factors for stratification in this study were elevated serum lactate dehydrogenase and high body surface area (BSA). Thromboprophylaxis was associated with a numerically but not statistically significant reduced incidence of thromboembolic events (9.2% in patients with risk factors receiving LMWH vs. 16.6% in patients with risk factors not receiving LMWH, P = .23).
      • Gizzi M.
      • Oberic L.
      • Massard C.
      • et al.
      Predicting and preventing thromboembolic events in patients receiving cisplatin-based chemotherapy for germ cell tumours.
      In our study, the incidence of VTE was 14.2% which is similar to that observed in other studies with a range from 8% to 19%.
      • Khorana A.A.
      • Kuderer N.M.
      • Culakova E.
      • Lyman G.H.
      • Francis C.W.
      Development and validation of a predictive model for chemotherapy-associated thrombosis.
      ,
      • Piketty A.C.
      • Flechon A.
      • Laplanche A.
      • et al.
      The risk of thrombo-embolic events is increased in patients with germ-cell tumours and can be predicted by serum lactate dehydrogenase and body surface area.
      We assessed the association of primary thromboprophylaxis with VTE risk according to clinical tumor stage because the presence of a large retroperitoneal lymphadenopathy and visceral metastases were the strongest predictors of VTE. After adjusting for the confounding influence of clinical stage, primary thromboprophylaxis was strongly associated with a 52% risk reduction of VTE (P = .032, Figure 2). To gauge whether the potential efficacy of primary thromboprophylaxis may be higher in patients with more advanced disease, we fitted an interaction between thromboprophylaxis and disease stage in our VTE risk models. These models did not yield statistical significance at the 5% level that the relative association between primary thromboprophylaxis and a lower risk would be different in patients with clinical stage IA-IIB and clinical stage IIC-III disease (P for interaction = .310), although interaction-adjusted regression coefficients indicated a potentially much greater relative risk reduction with thromboprophylaxis in patients with clinical stage IIC-III disease (Supplemental Data Figure 3). Primary thromboprophylaxis might increase the risk of bleeding events. We have not recorded any major bleeding complications in our patient population. However, as this is a retrospective data collection there is the possibility of missing such a bleeding event. In a retrospective analysis by Fankhauser et al the risk of bleeding in patients with testicular cancer was <1%.
      • Fankhauser C.D.
      • Tran B.
      • Pedregal M.
      • et al.
      A risk-benefit analysis of prophylactic anticoagulation for patients with metastatic germ cell tumours undergoing first-line chemotherapy.
      The simulated cumulative VTE incidence from prophylactic anticoagulation for patients on or after chemotherapy translated into a number needed to treat 45 and a number needed to harm of 186.
      • Bezan A.
      • Posch F.
      • Ploner F.
      • et al.
      Risk stratification for venous thromboembolism in patients with testicular germ cell tumors.
      Given the low risk of bleeding in patients with TGCT, it might be worthwhile to consider thromboprophylaxis in patients of all clinical stages undergoing cisplatinum based chemotherapy in the absence of risk factors for bleeding complications such as chemotherapy-induced thrombocytopenia, chorioncarcinoma histology and tumor invasion of an adjacent organ.
      • Bezan A.
      • Posch F.
      • Ploner F.
      • et al.
      Risk stratification for venous thromboembolism in patients with testicular germ cell tumors.
      ,
      • Fankhauser C.D.
      • Tran B.
      • Pedregal M.
      • et al.
      A risk-benefit analysis of prophylactic anticoagulation for patients with metastatic germ cell tumours undergoing first-line chemotherapy.
      • Massard C.
      • Plantade A.
      • Gross-Goupil M.
      • et al.
      Poor prognosis nonseminomatous germ-cell tumours (NSGCTs): should chemotherapy doses be reduced at first cycle to prevent acute respiratory distress syndrome in patients with multiple lung metastases?.
      • Fankhauser C.D.
      • Oldenburg J.
      • Albers P.
      • et al.
      Recommendations to balance benefits and risks of thromboprophylaxis and to avoid central venous-access devices during first-line chemotherapy in men with metastatic germ cell tumors: The European Association Of Urology Testicular Cancer Panel Position in 2021.
      The risk of VTE increases immediately after the initiation of chemotherapy and is negligible after the end of treatment. As cisplatinum-based chemotherapy achieves high cure rates in patients with TGCT already with first-line treatment consisting of three to 4 cycles of chemotherapy, the duration of thromboprophylaxis would be limited for 2 to 3 months in most cases.
      • Bezan A.
      • Posch F.
      • Ploner F.
      • et al.
      Risk stratification for venous thromboembolism in patients with testicular germ cell tumors.
      ,
      • Tran B.
      • Ruiz-Morales J.M.
      • Gonzalez-Billalabeitia E.
      • et al.
      Large retroperitoneal lymphadenopathy and increased risk of venous thromboembolism in patients receiving first-line chemotherapy for metastatic germ cell tumors: a study by the global germ cell cancer group (G3).
      • Solari L.
      • Kronig M.
      • Ihorst G.
      • et al.
      High rates of thromboembolic events in patients with germ cell cancer undergoing cisplatin-based polychemotherapy.
      • Honecker F.
      • Koychev D.
      • Luhmann A.D.
      • et al.
      Venous thromboembolic events in germ cell cancer patients undergoing platinum-based chemotherapy.
      The major limitation of the present analysis is its retrospective data collection. However, given the low incidence of metastatic germ cell tumors, prospective randomized trials of VTE prophylaxis are unlikely to be performed. Therefore, this analysis represents the best evidence so far that primary thromboprophylaxis leads to a risk reduction of VTE in patients with testicular GCT undergoing cisplatinum-based chemotherapy.

      Conclusion

      TGCT patients undergoing cisplatinum-based chemotherapy have a lower VTE risk when receiving primary thromboprophylaxis. For the duration of chemotherapy, primary thromboprophylaxis should be considered on a risk-benefit ratio.

      Clinical Practice Points

      • Primary Thromboprophylaxis in cancer patients has been investigated in several trials and resulted in a relative risk reduction of 30-60% in VTE. TGCT patients have been under-represented in all trials. To our knowledge, this retrospective cohort study is the best evidence so far supporting primary thromboprophylaxis in TGCT patients undergoing adjuvant or curative cisplatinum-based chemotherapy.

      Author contribution

      AT, FP, and TB conceived and designed the study. AT, FP and TB interpreted the results. All authors collected data and contributed patients, wrote the first draft of the manuscript and agree with the manuscript's results and conclusions and ICMJE criteria for authorship read and met.

      Disclosure

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Appendix. Supplementary materials

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