Thrombosis Research 133 (2014) 154–157
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
High prevalence of recurrent thrombosis in subsets of cancer patients with isolated gonadal vein thrombosis: A single center retrospective study Suebpong Tanasanvimon a,c, Naveen Garg b, Chitra Viswanathan b, Mylene Truong b, Harmeet Kaur b, Bryan K. Kee c, Ibrahim H. Sahin c, Milind M. Javle c, Christopher R. Garrett c,⁎ a b c
Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand Department of Diagnostic Radiology, UT MD Anderson Cancer Center, Houston, Texas Department of Gastrointestinal Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas
a r t i c l e
i n f o
Article history: Received 8 July 2013 Received in revised form 6 August 2013 Accepted 17 October 2013 Available online 24 October 2013 Keywords: Cancer Venous Thrombosis Surgery Pulmonary Embolism CAT Scan
a b s t r a c t Purpose: Cancer patients are a high-risk population for venous thromboembolism (VTE); the natural history of gonadal vein thrombosis (GVT) occurring in cancer patients is not well described in the medical literature. Methods: Utilizing a software program the computerized tomographic scan reports of patients at a single cancer center from January 1, 2004 to June 30, 2011 were searched for the term GVT. Patients included in this analysis had a diagnosis of cancer, an isolated GVT (i.e. no evidence of thrombosis at another site), no symptoms referable to the GVT, and at least six months of follow-up information. All subsequent recurrent VTE events were confirmed by imaging studies. Results: 196 cancer patients with GVT were identified. The majority of patients in this analysis had metastatic disease (118, 61.2%) as well as active cancer (167, 85.2%). Twenty patients (10.8%) developed recurrent VTE (median follow-up 14.5 months); median time to recurrent VTEs was 5.5 months (range 0–19 months). When considering only patients with without a recent history of gynecologic surgery, VTE recurrence rates were 14.3%. Active cancer was the only risk factor significantly associated with recurrent VTE (P = 0.047). Conclusions: Based upon the patient’s risk factors for VTE, treatment of an incidentally detected GVT in cancer patients with anticoagulation, as per guidelines for other VTE sites, may be indicated in certain high risk subgroups, especially those patients with active cancer who have not had prior pelvic surgery. © 2013 Published by Elsevier Ltd.
Introduction Cancer is a well-known prothrombotic condition with an overall incidence of venous thromboembolism reported in the literature to be as high as 20% [1]; this is more than double the incidence of VTE in patients without cancer [2]. The explanation for this increased risk is multifactorial, but is associated with changes in blood flow, damage to the vascular endothelium, and changes to the plasmatic clotting factors (these three factors are known as “Virchow’s triad”) [3]. Due to the significant morbidity associated with VTE in patients with cancer [4], and the fact that it is a common cause of death in cancer patients [5], guidelines have been developed regarding the appropriate treatment and subsequent prophylaxis of VTE [6–10]. There is significant heterogeneity in the clinical features in which a thrombotic event occurs in a patient. The site of thrombosis may impact the subsequent treatment approach of a thrombotic event. The gonadal ⁎ Corresponding author at: Department of Gastrointestinal Medical Oncology, UT MD Anderson Cancer Center, Unit 426, 1515 Holcombe Boulevard, Houston, Texas, 77030–4009. Fax: + 1 713 792 4032. E-mail address: [email protected] (C.R. Garrett). 0049-3848/$ – see front matter © 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.thromres.2013.10.027
vein is an uncommon site of thrombosis, and thrombosis in this vein is associated with pregnancy [11,12] and the postpartum period [13,14], gastrointestinal inflammation [15], pelvic infection [16], following gynecologic surgery [17], or it may be without a discernible cause (idiopathic) [18,19]. In a single institution retrospective analysis of 35 patients with GVT, 12 (34%) had a history of cancer [20]. This study compared the thrombosis recurrence rates in these patients with GVT with 114 randomly selected females with lower extremity deep venous thrombosis, and found the VTE recurrence rates to be similar. Currently no guidelines currently exist regarding the treatment of isolated GVT occurring in the setting of patients with cancer. To better understand the natural history and rethrombosis rate in patients with radiographically detected GVT we studied the outcome of patients with a diagnosis of GVT seen at MD Anderson between 2004–2011. Patients and Methods Patient Selection Following IRB expedited approval for the study (PA12 − 0730) a software program was utilized in order to search the computerized
S. Tanasanvimon et al. / Thrombosis Research 133 (2014) 154–157
tomography (CT) scan reports of patients seen at University of Texas MD Anderson Cancer Center from January 1, 2004 to June 30, 2011 for the words “gonadal vein thrombosis”. Patients included in this analysis had: a) a diagnosis of cancer and, b) isolated GVT (i.e. no evidence of thrombosis at another site before or at the time GVT reported). All medical records were reviewed for relevant data. All subsequent VTE events were documented by imaging studies. Statistical Plan IBM SPSS (version 19.0) statistical software was utilized for all statistical analysis. The χ2 or Fisher’s exact test was used to compare recurrent VTE rates following GVT between the different subgroups. To analyze the associated factors for recurrent VTE in cancer patients with isolated GVT we included only patients having at least one follow-up evaluation. According to previous report of GVT being a common radiologic finding in patients following hysterectomy and oophorectomy, we compared cancer patients with or without history of hysterectomy and/or oophorectomy. For six-month recurrent VTE analysis, we included only patients with at least six month follow-up evaluations. Active cancer was defined as current cancer diagnosis, local cancer recurrence, metastatic disease (distant relapse), or treatment for cancer within the previous six months. Statistical significance would be reached if the P value was less than 0.05 for any comparison. Results Baseline Patient Characteristics We identified 412 CT reports of GVT. After exclusion of duplication (multiple CT reports on the same patient) and ineligible cases (mostly non-isolated GVT and uncertain diagnosis of GVT), we identified 196 cancer patients with CT reported isolated GVT (Fig. 1).
155
Table 1 Clinical characteristics of overall cancer patients with isolated GVT. Age
57.5 ± 12.7 years
Cancer -Breast -Hematologic malignancy -GI -GU -Gynecologic -Miscellaneous Chemotherapy Hormonal therapy Abdominal surgery (within 6 months prior GVT) Hysterectomy and/or oophorectomy history Cancer stage -Locoregional -Distant Cancer status -Active -Non-active GVT site -Right -Left -Bilateral Anticoagulant therapy
21 (10.7%) 9 (4.6%) 55 (28.1%) 7 (3.6%) 87 (44.4%) 16 (8.2%) 106 (54.1%) 21 (10.7%) 159 (81.1%) 151 (77.0%) 78 (39.8%) 118 (61.2%) 29 (14.8%) 167 (85.2%) 114 (58.2%) 69 (35.2%) 13 (6.6%) 23 (11.7%)
Baseline patient characteristics are demonstrated in Table 1. Although gynecologic cancer was the most frequent cancer identified in this cohort, 55.6% of patients had other cancers, and of these gastrointestinal cancers accounted for the majority of cases (50.9%). Three-fourths of patients had a prior history of hysterectomy and/ or oophorectomy. Most patients had active cancer (85.2%) as well as distant metastatic disease (60.2%). All reported isolated GVT were incidental CT findings without any symptoms referable to the thrombosis. More than half of patients had right sided GVT and 6.6% of cases had bilateral GVT. Only 11.7% of patients received anticoagulant therapy. With median follow up time of 14.5 (0–71) months, recurrent VTE occurred in 20 out of 185 patients (10.8%) all of whom had at least one follow-up evaluation. The most common recurrent VTE site was pulmonary embolism (PE) present in 10 (5.4%) patients. Other sites of recurrent VTE included deep vein thrombosis of extremities (DVT) in 6 (3.2%) patients, inferior vena cava thrombosis in two (1.1%) patients, renal vein thrombosis in one (0.5%) patient and internal jugular vein thrombosis in one (0.5%) patient. The median time to event was 5.5 (0–19) months. The overall recurrent VTE rate was significantly higher in patients with active cancer (Table 2). There were no other significantly associated factors including gynecologic surgery history.
Table 2 Association between clinical characteristics and recurrent VTE incidence.
Fig. 1. Consort diagram of the study population.
Cancer Status -Active cancer -No evidence of disease Chemotherapy -Yes -No Cancer Type -Gynecologic -Non-Gynecologic Gynecologic Surgery Hx -Yes -No Cancer Stage -Distant -Locoregional
Recurrent VTE
P Value
20/146 0/28
0.047
13/101 7/84
0.32
7/83 13/102
0.35
14/143 6/42
0.41
14/112 6/73
0.36
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S. Tanasanvimon et al. / Thrombosis Research 133 (2014) 154–157
Table 3 Comparison of clinical characteristics between patients with and without history of gynecologic surgery (n = 196).
Age GVT site -Right -Left -Bilateral Anticoagulant (treatment dosage) Thromboembolic Events (185 available f/u data) -PE -DVT -IVC Thrombosis -Others Chemotherapy Hormonal Rx Cancer stage -Locoregional -Distant Cancer active Median F/U Median time to event
GynSx Hx (n = 151)
NoGynSx Hx (n = 45)
P value
57.76 ± 12.82
56.73 ± 12.46
0.64
85 54 12 16 (10.6%) 14 (9.3%)
29 15 1 7 (15.6%) 6 (13.3%)
0.34
7 4 2 0 82 (54.3%) 17 (11.3%)
3 2 0 1 24 (53.3%) 4 (8.9%)
0.91 0.65
25 (16.6%) 17 7
4 (8.9%) 10 1
0.24 0.01 § 0.03⁎
0.36 0.41
§ non-parametric test. ⁎ log rank test.
The baseline characteristics were not different between patients with and without gynecologic surgery (Table 3). There was no significant difference in overall recurrent VTE rates between these two groups. Median time to VTE was significantly shorter in patients without gynecologic surgery history (1 vs 7 months, P = 0.027). Of the analyzed associated factors associated with a six-month recurrence of VTE, gynecologic surgery history was the only significant factor associated with lower risk of recurrent VTE within six months (Table 4). There was no other significantly-associated factors identified associated with higher risk of recurrent VTE within six months.
Discussion At this time there are no standard recommendations for the management of patients who develop an isolated GVT. As VTE are a common cause of morbidity in cancer patients [21], it is not clear at this time whether cancer patients who develop a GVT would benefit from anticoagulation. Given the relatively infrequent incidence of GVT, prospective clinical trials are unlikely be performed to determine the optimal clinical management of isolated GVT. Therefore evaluation of
Table 4 The association between clinical characteristics and recurrent VTE within six months (n = 152).
Cancer Status -Active cancer -NED Chemotherapy -Yes -No Cancer Type -Gynecologic -Non-Gynecologic Gynecologic Surgery Hx -Yes -No Cancer Stage -Distant -Locoregional
Recurrent VTE within six monts
P Value
10/124 0/28
0.21
8/86 2/66
0.12
6/88 4/64
0.89
5/117 5/35
0.04
7/89 3/63
0.45
existing clinical databases may provide useful information to better guide therapy of cancer patients who develop isolated GVT. This retrospective study of 196 patient’s medical data demonstrated a low overall incidence of recurrent VTE in cancer patients with isolated GVT. However certain subgroups of patients appear to be at much higher risk of rethrombosis, and an isolated GVT may be the first indication of this prothrombotic risk. Patients with active cancer but without a recent history of gynecologic surgery history had a significantly higher risk of recurrent VTEs. Based on this data, the anticoagulation of patients with isolated GVT, such as would be performed for patients with a deep vein thrombosis, may be clinically indicated, particularly for those patients who have an active cancer but who have not had recent gynecologic surgery. To our knowledge, this is the largest case series reporting isolated GVT in cancer patients. Previous reports were limited by either short follow-up time or small cohort of patients analyzed. One series of GVT in cancer patients showed no GVT-related complications in six cancer patients with the median follow-up time of three months [22]. Another series reported on GVT in female cancer patients who underwent total abdominal hysterectomy and bilateral oophorectomy with retroperitoneal lymph node dissection; with three-month interval follow-up after surgery for 3–24 months, there was also noted no GVT-related complications [20]. A comparison study of GVT and DVT from the Mayo clinic reported two recurrent VTE in twelve cancer patients with GVT [23]. Although these series demonstrated a low rethrombosis rate, our data limited to a larger cohort of cancer patients, with a longer follow-up time, was associated with an overall 10% incidence of recurrent VTE in patients with an isolated GVT. The characteristics of GVT in our cancer patients were similar to previous reports. Approximately 60% of patients had right sided GVT, consistent with previous reports, and consistent with the anatomic explanation of right gonadal vein being associated with higher risk of thrombosis (“right ovarian vein syndrome”) [24,25]. As with the other reports in the medical literature, GVT in cancer patients was more commonly an incidental finding with no related symptoms. Interestingly, approximately half of the patients had a non-gynecologic cancer, especially gastrointestinal cancer, which accounted approximately 25% of our cohort. Moreover, there was no difference in risk of recurrent VTE between gynecologic and non-gynecologic cancer patients. The very low rate of anticoagulant therapy used in our series of patients reflected the current perception of clinical insignificant implications of GVT in cancer patients. This retrospective series, with its longer follow-up time and larger number of patients, was notable for an overall 10% incidence of recurrent VTE in cancer patients with isolated GVT. The VTE rate at six months of 5.9% was comparable to prior series of patients with DVT (6.4%, n = 51,233) and PE (5.8%, n = 21,625) [26]. However the 8.1% of one-year VTE recurrence rate (data was not shown) was much less than 14.1% per year in cancer patients with VTEs [27]. In this cohort, the presence of an isolated GVT seemed to increase only the short term recurrent VTE risk, but not long term risk. However, when we considered only patients without a recent history of gynecologic surgery, the six-month and one-year VTE recurrent rates were 11.9% and 14.3% (n= 42), respectively. Corresponding to previous reports, as well as anecdotal evidence, this data confirmed that GVT in patients is a relatively common postoperative occurrence following gynecologic surgery, and the risk of GVT-related complications is low. Therefore, gynecologic surgery-related and non-surgery related GVTs appear to have different rethrombosis rates with the latter having a much higher recurrent VTE risk. This study is limited by the lack of long-term follow-up (greater than 2 years) and the fact that it is a retrospective evaluation. This study would not be able to address the long term VTE recurrence risk that an isolated GVT may be associated with, although it is likely to be relatively low. Currently there is a paucity of literature to guide the appropriate medical management of cancer patients who experience an
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incidental and asymptomatic isolated GVT; this data set provides useful clinical information to guide decision making regarding anticoagulation. Taking into account the incidental asymptomatic nature of isolated GVT and relatively low risk for recurrent VTE, anticoagulant therapy cannot be recommended for all patients. Subsets of patients with high risk features (such as those with active cancer and who do not have surgery-related GVT), anticoagulation as per current consensus guidelines for VTE could be considered. Risk adapted approaches should be utilized to determine the appropriate therapy of isolated incidental GVT detected in cancer patients, in order to reduce the risk of recurrent VTE. We believe this data is helpful in determining risk of recurrent VTE by identifying high risk features. Conflict of Interest Statement None of the authors have any conflict of interest to disclose. Addendum Substantial Contribution to Concept and Design (S. Tanasanvimon, N. Garg, C.R. Garrett3), Analysis and/or Interpretation of Data (S. Tanasanvimon, C.R. Garrett), Critical Writing or Revising of the Intellectual Content (S. Tanasanvimon, N. Garg, C. Viswanathan, M. Truong, I.H. Sahin, C.R. Garrett), Final Approval of the Version to be Published (S. Tanasanvimon, N. Garg, C. Viswanathan, M. Truong, H. Kaur, B.K. Kee, I.H. Sahin, M.M. Javle, C.R. Garrett). References [1] Chew HK, Wun T, Harvey D, Zhou H, White R. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006;166:458–64. [2] Falanga A, Russo L. Epidemiology, risk and outcomes of venous thromboembolism in cancer. Hamostaseologie 2012;32:115–25. [3] Brotman DJ, Deitcher SR, Lip GY, Matzdorff AC. Virchow's triad revisited. South Med J 2004;97:213–4. [4] Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res 2010;125:490–3. [5] Ambrus JL, Ambrus CM, Mink IB, Pickren JW. Causes of death in cancer patients. J Med 1975;6:61–4. [6] Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013;11:56–70.
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[7] Mandalà M, Falanga A, Roila F. ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2011;22:85–92. [8] Lyman GH, Kuderer NM. Prevention and treatment of venous thromboembolism among patients with cancer: the American Society of Clinical Oncology Guidelines. Thromb Res 2010;125:S120–7. [9] Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:381S–453S. [10] National Comprehensive Cancer Network (NCCN). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Venous Thromboembolic Disease, version 1. Available at: http://www.nccn.org/professionals/physician_gls/pdf/vte. pdf; 2013. (accessed March 30, 2013). [11] Bertsch NM, Mastrobattista JM, Kawashima A, Kramer LA. Antepartum bilateral ovarian vein thrombosis: magnetic resonance imaging diagnosis. Am J Perinatol 1997;14:597–9. [12] Sher MH. Management of antepartum thrombophlebitis. Am Surg 1971;37:587–9. [13] Dunnihoo DR, Gallaspy JW, Wise RB, Otterson WN. Postpartum ovarian vein. thrombophlebitis: a review. Obstet Gynecol Surg 1991;46:415–27. [14] Heavrin BS, Wrenn K. Ovarian vein thrombosis: a rare cause of abdominal pain outside the peripartum period. J Emerg Med 2008;34:67–9. [15] Schwartz JH, Sclafani SJ, Glass TA, Sewell PE. Acute gonadal vein thrombosis secondary to terminal ileitis and thrombophilia. J Urol 2008;180:1124. [16] Teh HS, Chiang SH, Tan AG, Sng LH, Oh HM. A case of right loin pain: septic ovarian vein thrombosis due to Campylobacter fetus bacteraemia. Ann Acad Med Singapore 2004;33:385–8. [17] Murphy CS, Parsa T. Idiopathic ovarian vein thrombosis: a rare cause of abdominal pain. Am J Emerg Med 2006;24:636–7. [18] Tsiouris A, Karam J, Shepard D. Incidental diagnosis of idiopathic gonadal vein thrombosis. Vasa 2012;41:67–9. [19] Yildirim E, Kanbay M, Ozbek O, Coskun M, Boyacioglu S. Isolated idiopathic ovarian vein thrombosis: a rare case. Int Urogynecol J Pelvic Floor Dysfunct 2005;16:308–10. [20] Jacoby WT, Cohan RH, Baker ME, Leder RA, Nadel SN, Dunnick NR. Ovarian vein thrombosis in oncology patients: CT detection and clinical significance. Am J Roentgenol 1990;155:291–4. [21] Falanga A, Marchetti M, Russo L. Venous thromboembolism in the hematologic malignancies. Curr Opin Oncol 2012;24:702–10. [22] Yassa NA, Ryst E. Ovarian vein thrombosis: a common incidental finding in patients who have undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy with retroperitoneal lymph node dissection. Am J Roentgenol 1999;172:45–7. [23] Wysokinska EM, Hodge D, McBane II RD. Ovarian vein thrombosis: incidence of recurrent venous thromboembolism and survival. Thromb Haemost 2006;96:126–31. [24] Brown TK, Munsick RA. Puerperal ovarian vein thrombophlebitis: a syndrome. Am J Obstet Gynecol 1971;109:263–73. [25] Reynolds SR. Right ovarian vein syndrome. Obstet Gynecol 1971;37:308–13. [26] Murin S, Romano PS, White RH. Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism. Thromb Haemost 2002;88:407–14. [27] Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond WD, Enright P, et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004;117:19–25.
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
High prevalence of recurrent thrombosis in subsets of cancer patients with isolated gonadal vein thrombosis: A single center retrospective study Suebpong Tanasanvimon a,c, Naveen Garg b, Chitra Viswanathan b, Mylene Truong b, Harmeet Kaur b, Bryan K. Kee c, Ibrahim H. Sahin c, Milind M. Javle c, Christopher R. Garrett c,⁎ a b c
Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand Department of Diagnostic Radiology, UT MD Anderson Cancer Center, Houston, Texas Department of Gastrointestinal Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas
a r t i c l e
i n f o
Article history: Received 8 July 2013 Received in revised form 6 August 2013 Accepted 17 October 2013 Available online 24 October 2013 Keywords: Cancer Venous Thrombosis Surgery Pulmonary Embolism CAT Scan
a b s t r a c t Purpose: Cancer patients are a high-risk population for venous thromboembolism (VTE); the natural history of gonadal vein thrombosis (GVT) occurring in cancer patients is not well described in the medical literature. Methods: Utilizing a software program the computerized tomographic scan reports of patients at a single cancer center from January 1, 2004 to June 30, 2011 were searched for the term GVT. Patients included in this analysis had a diagnosis of cancer, an isolated GVT (i.e. no evidence of thrombosis at another site), no symptoms referable to the GVT, and at least six months of follow-up information. All subsequent recurrent VTE events were confirmed by imaging studies. Results: 196 cancer patients with GVT were identified. The majority of patients in this analysis had metastatic disease (118, 61.2%) as well as active cancer (167, 85.2%). Twenty patients (10.8%) developed recurrent VTE (median follow-up 14.5 months); median time to recurrent VTEs was 5.5 months (range 0–19 months). When considering only patients with without a recent history of gynecologic surgery, VTE recurrence rates were 14.3%. Active cancer was the only risk factor significantly associated with recurrent VTE (P = 0.047). Conclusions: Based upon the patient’s risk factors for VTE, treatment of an incidentally detected GVT in cancer patients with anticoagulation, as per guidelines for other VTE sites, may be indicated in certain high risk subgroups, especially those patients with active cancer who have not had prior pelvic surgery. © 2013 Published by Elsevier Ltd.
Introduction Cancer is a well-known prothrombotic condition with an overall incidence of venous thromboembolism reported in the literature to be as high as 20% [1]; this is more than double the incidence of VTE in patients without cancer [2]. The explanation for this increased risk is multifactorial, but is associated with changes in blood flow, damage to the vascular endothelium, and changes to the plasmatic clotting factors (these three factors are known as “Virchow’s triad”) [3]. Due to the significant morbidity associated with VTE in patients with cancer [4], and the fact that it is a common cause of death in cancer patients [5], guidelines have been developed regarding the appropriate treatment and subsequent prophylaxis of VTE [6–10]. There is significant heterogeneity in the clinical features in which a thrombotic event occurs in a patient. The site of thrombosis may impact the subsequent treatment approach of a thrombotic event. The gonadal ⁎ Corresponding author at: Department of Gastrointestinal Medical Oncology, UT MD Anderson Cancer Center, Unit 426, 1515 Holcombe Boulevard, Houston, Texas, 77030–4009. Fax: + 1 713 792 4032. E-mail address: [email protected] (C.R. Garrett). 0049-3848/$ – see front matter © 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.thromres.2013.10.027
vein is an uncommon site of thrombosis, and thrombosis in this vein is associated with pregnancy [11,12] and the postpartum period [13,14], gastrointestinal inflammation [15], pelvic infection [16], following gynecologic surgery [17], or it may be without a discernible cause (idiopathic) [18,19]. In a single institution retrospective analysis of 35 patients with GVT, 12 (34%) had a history of cancer [20]. This study compared the thrombosis recurrence rates in these patients with GVT with 114 randomly selected females with lower extremity deep venous thrombosis, and found the VTE recurrence rates to be similar. Currently no guidelines currently exist regarding the treatment of isolated GVT occurring in the setting of patients with cancer. To better understand the natural history and rethrombosis rate in patients with radiographically detected GVT we studied the outcome of patients with a diagnosis of GVT seen at MD Anderson between 2004–2011. Patients and Methods Patient Selection Following IRB expedited approval for the study (PA12 − 0730) a software program was utilized in order to search the computerized
S. Tanasanvimon et al. / Thrombosis Research 133 (2014) 154–157
tomography (CT) scan reports of patients seen at University of Texas MD Anderson Cancer Center from January 1, 2004 to June 30, 2011 for the words “gonadal vein thrombosis”. Patients included in this analysis had: a) a diagnosis of cancer and, b) isolated GVT (i.e. no evidence of thrombosis at another site before or at the time GVT reported). All medical records were reviewed for relevant data. All subsequent VTE events were documented by imaging studies. Statistical Plan IBM SPSS (version 19.0) statistical software was utilized for all statistical analysis. The χ2 or Fisher’s exact test was used to compare recurrent VTE rates following GVT between the different subgroups. To analyze the associated factors for recurrent VTE in cancer patients with isolated GVT we included only patients having at least one follow-up evaluation. According to previous report of GVT being a common radiologic finding in patients following hysterectomy and oophorectomy, we compared cancer patients with or without history of hysterectomy and/or oophorectomy. For six-month recurrent VTE analysis, we included only patients with at least six month follow-up evaluations. Active cancer was defined as current cancer diagnosis, local cancer recurrence, metastatic disease (distant relapse), or treatment for cancer within the previous six months. Statistical significance would be reached if the P value was less than 0.05 for any comparison. Results Baseline Patient Characteristics We identified 412 CT reports of GVT. After exclusion of duplication (multiple CT reports on the same patient) and ineligible cases (mostly non-isolated GVT and uncertain diagnosis of GVT), we identified 196 cancer patients with CT reported isolated GVT (Fig. 1).
155
Table 1 Clinical characteristics of overall cancer patients with isolated GVT. Age
57.5 ± 12.7 years
Cancer -Breast -Hematologic malignancy -GI -GU -Gynecologic -Miscellaneous Chemotherapy Hormonal therapy Abdominal surgery (within 6 months prior GVT) Hysterectomy and/or oophorectomy history Cancer stage -Locoregional -Distant Cancer status -Active -Non-active GVT site -Right -Left -Bilateral Anticoagulant therapy
21 (10.7%) 9 (4.6%) 55 (28.1%) 7 (3.6%) 87 (44.4%) 16 (8.2%) 106 (54.1%) 21 (10.7%) 159 (81.1%) 151 (77.0%) 78 (39.8%) 118 (61.2%) 29 (14.8%) 167 (85.2%) 114 (58.2%) 69 (35.2%) 13 (6.6%) 23 (11.7%)
Baseline patient characteristics are demonstrated in Table 1. Although gynecologic cancer was the most frequent cancer identified in this cohort, 55.6% of patients had other cancers, and of these gastrointestinal cancers accounted for the majority of cases (50.9%). Three-fourths of patients had a prior history of hysterectomy and/ or oophorectomy. Most patients had active cancer (85.2%) as well as distant metastatic disease (60.2%). All reported isolated GVT were incidental CT findings without any symptoms referable to the thrombosis. More than half of patients had right sided GVT and 6.6% of cases had bilateral GVT. Only 11.7% of patients received anticoagulant therapy. With median follow up time of 14.5 (0–71) months, recurrent VTE occurred in 20 out of 185 patients (10.8%) all of whom had at least one follow-up evaluation. The most common recurrent VTE site was pulmonary embolism (PE) present in 10 (5.4%) patients. Other sites of recurrent VTE included deep vein thrombosis of extremities (DVT) in 6 (3.2%) patients, inferior vena cava thrombosis in two (1.1%) patients, renal vein thrombosis in one (0.5%) patient and internal jugular vein thrombosis in one (0.5%) patient. The median time to event was 5.5 (0–19) months. The overall recurrent VTE rate was significantly higher in patients with active cancer (Table 2). There were no other significantly associated factors including gynecologic surgery history.
Table 2 Association between clinical characteristics and recurrent VTE incidence.
Fig. 1. Consort diagram of the study population.
Cancer Status -Active cancer -No evidence of disease Chemotherapy -Yes -No Cancer Type -Gynecologic -Non-Gynecologic Gynecologic Surgery Hx -Yes -No Cancer Stage -Distant -Locoregional
Recurrent VTE
P Value
20/146 0/28
0.047
13/101 7/84
0.32
7/83 13/102
0.35
14/143 6/42
0.41
14/112 6/73
0.36
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S. Tanasanvimon et al. / Thrombosis Research 133 (2014) 154–157
Table 3 Comparison of clinical characteristics between patients with and without history of gynecologic surgery (n = 196).
Age GVT site -Right -Left -Bilateral Anticoagulant (treatment dosage) Thromboembolic Events (185 available f/u data) -PE -DVT -IVC Thrombosis -Others Chemotherapy Hormonal Rx Cancer stage -Locoregional -Distant Cancer active Median F/U Median time to event
GynSx Hx (n = 151)
NoGynSx Hx (n = 45)
P value
57.76 ± 12.82
56.73 ± 12.46
0.64
85 54 12 16 (10.6%) 14 (9.3%)
29 15 1 7 (15.6%) 6 (13.3%)
0.34
7 4 2 0 82 (54.3%) 17 (11.3%)
3 2 0 1 24 (53.3%) 4 (8.9%)
0.91 0.65
25 (16.6%) 17 7
4 (8.9%) 10 1
0.24 0.01 § 0.03⁎
0.36 0.41
§ non-parametric test. ⁎ log rank test.
The baseline characteristics were not different between patients with and without gynecologic surgery (Table 3). There was no significant difference in overall recurrent VTE rates between these two groups. Median time to VTE was significantly shorter in patients without gynecologic surgery history (1 vs 7 months, P = 0.027). Of the analyzed associated factors associated with a six-month recurrence of VTE, gynecologic surgery history was the only significant factor associated with lower risk of recurrent VTE within six months (Table 4). There was no other significantly-associated factors identified associated with higher risk of recurrent VTE within six months.
Discussion At this time there are no standard recommendations for the management of patients who develop an isolated GVT. As VTE are a common cause of morbidity in cancer patients [21], it is not clear at this time whether cancer patients who develop a GVT would benefit from anticoagulation. Given the relatively infrequent incidence of GVT, prospective clinical trials are unlikely be performed to determine the optimal clinical management of isolated GVT. Therefore evaluation of
Table 4 The association between clinical characteristics and recurrent VTE within six months (n = 152).
Cancer Status -Active cancer -NED Chemotherapy -Yes -No Cancer Type -Gynecologic -Non-Gynecologic Gynecologic Surgery Hx -Yes -No Cancer Stage -Distant -Locoregional
Recurrent VTE within six monts
P Value
10/124 0/28
0.21
8/86 2/66
0.12
6/88 4/64
0.89
5/117 5/35
0.04
7/89 3/63
0.45
existing clinical databases may provide useful information to better guide therapy of cancer patients who develop isolated GVT. This retrospective study of 196 patient’s medical data demonstrated a low overall incidence of recurrent VTE in cancer patients with isolated GVT. However certain subgroups of patients appear to be at much higher risk of rethrombosis, and an isolated GVT may be the first indication of this prothrombotic risk. Patients with active cancer but without a recent history of gynecologic surgery history had a significantly higher risk of recurrent VTEs. Based on this data, the anticoagulation of patients with isolated GVT, such as would be performed for patients with a deep vein thrombosis, may be clinically indicated, particularly for those patients who have an active cancer but who have not had recent gynecologic surgery. To our knowledge, this is the largest case series reporting isolated GVT in cancer patients. Previous reports were limited by either short follow-up time or small cohort of patients analyzed. One series of GVT in cancer patients showed no GVT-related complications in six cancer patients with the median follow-up time of three months [22]. Another series reported on GVT in female cancer patients who underwent total abdominal hysterectomy and bilateral oophorectomy with retroperitoneal lymph node dissection; with three-month interval follow-up after surgery for 3–24 months, there was also noted no GVT-related complications [20]. A comparison study of GVT and DVT from the Mayo clinic reported two recurrent VTE in twelve cancer patients with GVT [23]. Although these series demonstrated a low rethrombosis rate, our data limited to a larger cohort of cancer patients, with a longer follow-up time, was associated with an overall 10% incidence of recurrent VTE in patients with an isolated GVT. The characteristics of GVT in our cancer patients were similar to previous reports. Approximately 60% of patients had right sided GVT, consistent with previous reports, and consistent with the anatomic explanation of right gonadal vein being associated with higher risk of thrombosis (“right ovarian vein syndrome”) [24,25]. As with the other reports in the medical literature, GVT in cancer patients was more commonly an incidental finding with no related symptoms. Interestingly, approximately half of the patients had a non-gynecologic cancer, especially gastrointestinal cancer, which accounted approximately 25% of our cohort. Moreover, there was no difference in risk of recurrent VTE between gynecologic and non-gynecologic cancer patients. The very low rate of anticoagulant therapy used in our series of patients reflected the current perception of clinical insignificant implications of GVT in cancer patients. This retrospective series, with its longer follow-up time and larger number of patients, was notable for an overall 10% incidence of recurrent VTE in cancer patients with isolated GVT. The VTE rate at six months of 5.9% was comparable to prior series of patients with DVT (6.4%, n = 51,233) and PE (5.8%, n = 21,625) [26]. However the 8.1% of one-year VTE recurrence rate (data was not shown) was much less than 14.1% per year in cancer patients with VTEs [27]. In this cohort, the presence of an isolated GVT seemed to increase only the short term recurrent VTE risk, but not long term risk. However, when we considered only patients without a recent history of gynecologic surgery, the six-month and one-year VTE recurrent rates were 11.9% and 14.3% (n= 42), respectively. Corresponding to previous reports, as well as anecdotal evidence, this data confirmed that GVT in patients is a relatively common postoperative occurrence following gynecologic surgery, and the risk of GVT-related complications is low. Therefore, gynecologic surgery-related and non-surgery related GVTs appear to have different rethrombosis rates with the latter having a much higher recurrent VTE risk. This study is limited by the lack of long-term follow-up (greater than 2 years) and the fact that it is a retrospective evaluation. This study would not be able to address the long term VTE recurrence risk that an isolated GVT may be associated with, although it is likely to be relatively low. Currently there is a paucity of literature to guide the appropriate medical management of cancer patients who experience an
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incidental and asymptomatic isolated GVT; this data set provides useful clinical information to guide decision making regarding anticoagulation. Taking into account the incidental asymptomatic nature of isolated GVT and relatively low risk for recurrent VTE, anticoagulant therapy cannot be recommended for all patients. Subsets of patients with high risk features (such as those with active cancer and who do not have surgery-related GVT), anticoagulation as per current consensus guidelines for VTE could be considered. Risk adapted approaches should be utilized to determine the appropriate therapy of isolated incidental GVT detected in cancer patients, in order to reduce the risk of recurrent VTE. We believe this data is helpful in determining risk of recurrent VTE by identifying high risk features. Conflict of Interest Statement None of the authors have any conflict of interest to disclose. Addendum Substantial Contribution to Concept and Design (S. Tanasanvimon, N. Garg, C.R. Garrett3), Analysis and/or Interpretation of Data (S. Tanasanvimon, C.R. Garrett), Critical Writing or Revising of the Intellectual Content (S. Tanasanvimon, N. Garg, C. Viswanathan, M. Truong, I.H. Sahin, C.R. Garrett), Final Approval of the Version to be Published (S. Tanasanvimon, N. Garg, C. Viswanathan, M. Truong, H. Kaur, B.K. Kee, I.H. Sahin, M.M. Javle, C.R. Garrett). References [1] Chew HK, Wun T, Harvey D, Zhou H, White R. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006;166:458–64. [2] Falanga A, Russo L. Epidemiology, risk and outcomes of venous thromboembolism in cancer. Hamostaseologie 2012;32:115–25. [3] Brotman DJ, Deitcher SR, Lip GY, Matzdorff AC. Virchow's triad revisited. South Med J 2004;97:213–4. [4] Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res 2010;125:490–3. [5] Ambrus JL, Ambrus CM, Mink IB, Pickren JW. Causes of death in cancer patients. J Med 1975;6:61–4. [6] Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013;11:56–70.
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