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Risk Factors for Venous Thromboembolism in Patients Treated for Differentiated Thyroid Carcinoma

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Risk Factors for Venous Thromboembolism in Patients Treated for Differentiated Thyroid Carcinoma 246 T van der Boom et al. Risk factors for venous 24:6 267–273 Research thromboembolism in DTC Risk factors for venous thromboembolism in patients treated for differentiated thyroid carcinoma Trynke van der Boom1,2, Esther N Klein Hesselink1,2, Hilde A M Kooistra3, Karina Meijer3, Anouk N A van der Horst-Schrivers2, Joop D Lefrandt1 and Thera P Links2 1Department of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands 2Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Correspondence the Netherlands should be addressed 3Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, to T P Links the Netherlands Email [email protected] Abstract Although cancer in general is a strong risk factor for developing venous thromboembolism Key Words (VTE), the risk factors for venous thromboembolic events in patients with differentiated f differentiated thyroid thyroid carcinoma (DTC) have never been assessed. This is remarkable, as several parts of the carcinoma treatment comprise a hypercoagulable state that could in subgroups of DTC patients lead f venous thromboembolism to an increased risk of VTE. The aim of this study was to assess which risk factors could cause f risk factors Endocrine-Related Cancer Endocrine-Related DTC patients to develop VTE. We performed a nested case–control study, involving cases of DTC patients treated between 1980 and 2014 with confirmed VTE after diagnosis of DTC. Controls were defined as DTC patients without VTE. In all subjects, we collected information about thyroid cancer characteristics, treatment characteristics, traditional risk factors for VTE and additional clinical data, and we performed univariable and multivariable regression analyses. We included 28 cases and 56 controls matched for age at DTC diagnosis, sex and date of DTC diagnosis. In the univariable regression analysis, histology, distant metastases, DTC risk classification, recent surgery and other active malignancy were associated with VTE. In the multivariable analysis, distant metastases (odds ratio 7.9) and recent surgery (odds ratio 6.1) were independently associated with VTE. In conclusion, surgery and presence of distant metastases are independent risk factors for developing VTE in DTC patients. The risk factors identified in this study could be considered when making decisions regarding thromboprophylaxis for patients with thyroid cancer. Endocrine-Related Cancer (2017) 24, 267–273 Introduction Cancer is a strong risk factor for developing venous of cancer, depending mostly on the growth rate and the thromboembolism (VTE), and VTE is an important cause presence of metastases (Khorana & Rao 2007, Lyman 2011). of death in cancer patients (Lyman 2011, Deng et al. Thyroid carcinoma is the most common 2014). The risk of developing VTE varies among subgroups endocrine malignancy with an estimated 56,870 new http://erc.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-17-0013 Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 07:50:47AM via free access 10.1530/ERC-17-0013 Research T van der Boom et al. Risk factors for venous 24:6 268 thromboembolism in DTC cases in the United States each year (https://seer. Materials and methods cancer.gov/statfacts/html/thyro.html). Moreover, Patients and controls the incidence rate of thyroid cancer is rising, with an average annual increase of 5.3% (95% confidence We performed a nested case–control study in patients with interval (CI), 4.8–5.7%) over the last two decades DTC. Data were retrieved from a document pertaining (Magreni et al. 2015). thyroid cancer patients treated and/or in follow-up at the Differentiated thyroid carcinoma (DTC) comprises University Medical Center Groningen (UMCG) between papillary and follicular thyroid carcinomas (PTC January 1980 and December 2014. Deceased patients and FTC). DTC patients have a favorable prognosis were eligible. At the UMCG, patients are treated with after treatment with total thyroidectomy, iodine-131 total thyroidectomy and lymph node dissection when ablation and subsequent thyroid hormone suppression indicated. They are subsequently treated with Iodine-131 therapy (THST) (Schlumberger 1998). In low-risk ablation therapy after thyroid hormone withdrawal. patients, there is a tendency to use less aggressive Recombinant human (rh)TSH ablation is performed only treatment (ATA et al. 2009). The rationale for THST, if withdrawal is contraindicated. advocated in high-risk patients, is to minimize Cases were defined as patients with PTC or FTC, with potential tumor growth (Pujol et al. 1996). However, confirmed VTE after DTC diagnosis. VTE was defined as deep the downside of this therapy is that it results in venous thrombosis or pulmonary embolism confirmed by (subclinical) hyperthyroidism, which is associated compression ultrasonography, computed tomography (CT) with adverse cardiovascular effects and mortality angiography, magnetic resonance imaging (MRI) or digital (Klein Hesselink et al. 2013, Danzi & Klein 2014). subtraction angiography (DSA). Controls were defined as Walker and coworkers assessed the incidence of VTE DTC patients without VTE after diagnosis of DTC. Controls in 83,203 cancer patients and 577,207 controls. The were derived from the same patient cohort as cases. Cases study included 503 thyroid cancer patients in whom and controls were excluded if younger than 18 years old an absolute increased incidence of VTE was not found when diagnosed with DTC, and when follow-up records, (Walker et al. 2013). However, as histological subgroups thyroid cancer characteristics, or treatment modalities of thyroid cancer were not defined, a subgroup of thyroid were not present in the electronic patient files. In general, cancer patients may have increased the risk of VTE. follow-up visits of DTC patients took place at least once a DTC patients may have an increased risk of developing Endocrine-Related Cancer Endocrine-Related year. Correspondence from both the UMCG and regional VTE as known (treatment-related) risk factors for VTE, hospitals regarding outpatient clinic visits was available including surgery (Bates et al. 2012) and (subclinical) in the electronic patient files. Each case was matched to hyperthyroidism, are inevitable during treatment of DTC. two controls. First, for each case, the period between DTC Although hypothyroidism is associated with increased diagnosis and VTE diagnosis was calculated. A patient was bleeding risk, hyperthyroidism is associated with a eligible to be matched to a case if he or she had clinical hypercoagulable state (Franchini et al. 2011, Kootte et al. follow-up records for at least the DTC-VTE duration of the 2012, Horacek et al. 2015). In overt hyperthyroidism, case. Second, cases and controls were matched according to increasing levels of FT4 are a risk factor for VTE (van sex. Third, to correct for evaluating treatment strategies and Zaane et al. 2010). In contrast to patients with overt standard of care between 1980 and 2014, the difference in hyperthyroidism, patients on THST are maintained in a date of DTC diagnosis between cases and controls was not less toxic state of hyperthyroidism, but potentially for a allowed to exceed 10 years. Finally, we chose the control much longer time. Horne and coworkers found that DTC whose age at DTC diagnosis was closest to that of the case patients on THST have an increased thrombin production upon DTC diagnosis. We calculated an index date for each and reduced plasminogen activation. This would suggest control; we used the date as long after their DTC diagnosis that patients on THST are predisposed to VTE (Horne et al. as the length of time between the corresponding case’s DTC 2004, Franchini et al. 2011, Horacek et al. 2015). In diagnosis and VTE diagnosis. conclusion, certain subgroups of DTC patients, depending on the histological findings, metastases, THST and recent Data collection surgery, may be more at risk than others of developing VTE. Therefore, the aim of this study was to identify the Data on tumor histology (papillary or follicular thyroid risk factors for VTE in patients with DTC. carcinoma, including Hürthle) and TNM classification http://erc.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-17-0013 Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 07:50:47AM via free access Research T van der Boom et al. Risk factors for venous 24:6 269 thromboembolism in DTC Table 1 Characteristics of cases and controls at DTC diagnosis. Cases (n = 28) Controls (n = 56) Parameter No./median %/IQR No./median %/IQR Sex (male) 10 35.7 20 35.7 Age (years) 58 43–67 58 43–67 Histology Papillary 13 46.4 37 66.1 Follicular 15 53.6 19 33.9 Hürthle 4 14.2 6 10.7 TNM stage Tx–T2 6 21.4 14 25 T3–T4 22 78.6 42 75 Nx–N0 19 67.9 14 25 N1 9 32.1 42 25 Mx–M0 20 71.4 51 91.1 M1 8 28.6 5 8.9 DTC risk classification Low (Tx–T2, Nx–N0, Mx–M0) 9 32.1 28 50 Intermediate (any T3 or N1 tumor) 9 32.1 13 23.2 High (any T4 or M1 tumor) 10 35.7 15 26.8 History of VTE before DTC diagnosis 1 3.6 1 1.8 DTC, differentiated thyroid carcinoma; IQR, inter quartile range; VTE, venous thromboembolism. were collected upon VTE diagnosis/index date. All malignancies other than thyroid cancer. Body mass index subjects were scored according to the postoperative (BMI) was collected as closely as possible to the time of TNM classification. Until 2006, the fifth edition of TNM VTE diagnosis or index date. Smoking was scored at VTE Classification of Malignant Tumors was used. Between diagnosis or index date as never, former, current and not 2006 and 2010, the sixth edition was used, and thereafter, recorded. Additionally, we collected data about the use of the seventh edition.
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