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Clinically evident venous thromboembolic events in children with brain tumors
CLINICALLY EVIDENT VENOUS THROMBOEMBOLIC EVENTS IN CHILDREN WITH BRAIN TUMORS STEVEN R. DEITCHER, MD, AMAR GAJJAR, MD, LARRY KUN, MD, AND RICHARD L. HEIDEMAN, MD
We evaluated the incidence and significance of central venous access device dysfunction and symptomatic major thrombosis in 253 pediatric patients with brain tumors. Central venous access device dysfunction was a common complication (28.4%) and was associated with major thrombosis development and a reduced overall survival rate. Major thrombosis was relatively uncommon (2.8%). (J Pediatr 2004;145:848-50)
rain tumors are the most common form of solid neoplasm in children.1 As survival improves, medical complications associated with these tumors and their treatment, such as central venous access device (CVAD) dysfunction and venous thrombosis, have become more important. Venous thromboembolic events (VTE) occur in up to 36% of adults with primary and metastatic brain tumors and are associated with neurosurgical interventions and tissue factor release from some tumors and surrounding cerebral tissue into the systemic circulation.2-4 This hypercoagulability may be facilitated by blood-brain barrier disruption and exacerbated by cytotoxic therapy and surgical manipulation.4 CVAD-associated thrombosis has been reported in up to 50% of children with cancer.5-7 In one study, 8.3% of children with acute leukemia or nonbrain solid tumors had symptomatic right atrial thrombosis.5 In another study, 12.5% of children treated for cancer had symptomatic thrombosis; 42.9% of asymptomatic patients were found to have CVAD-associated thrombosis by venography.7 We characterized the incidence and survival impact of CVAD dysfunction and major VTE in pediatric patients with brain tumor.
B
METHODS Medical, radiographic, and pharmacy records of 253 consecutive patients diagnosed and treated for brain tumors at St Jude Children’s Research Hospital with at least 6 months of follow-up were retrospectively reviewed. A subset of 190 patients who received systemic chemotherapy by means of CVAD was analyzed. Clinically evident CVAD dysfunction was defined as the inability to withdraw blood From the Section of Hematology and or infuse medication and blood products and the requirement for instillation of Coagulation Medicine, Department of a fibrinolytic agent to restore patency. Symptomatic major venous thrombosis was Hematology-Medical Oncology, The suspected in the setting of extremity pain and swelling, chest pain, acute onset dyspnea, and Cleveland Clinic Foundation, Cleveland, Ohio; the Divisions of NeuroCVAD dysfunction. All suspected thromboses were objectively evaluated. Fibrinolytic and oncology and Radiation Oncology, St antithrombotic therapies were identified through the use of pharmacy records. Jude Children’s Research Hospital, Memphis, Tennessee; and the Division Overall and major thrombosis-free survival analyses were performed by means of of Pediatric Hematology/Oncology, Kaplan-Meier curves and the log-rank test. x2 analysis and the Fisher exact test were used Children’s Hospital of New Mexico, where appropriate to compare the frequency of CVAD dysfunction and major thrombosis Albuquerque, New Mexico. Supported in part by the American in patient subsets. A value of P < .05 was considered significant.
RESULTS The cohort consisted of 122 (48%) girls, 192 (76%) whites, and 55 (21%) patients with metastatic disease. The most common histologies were astrocytoma (26.9%), medulloblastoma (20.9%), glioma (15.0%), ependymoma (8.3%), and oligodendroglioma (7.1%), accounting for more than 78% of cases; 87% of patients underwent some degree of surgical
CVAD
848
Central venous access device
VTE
Venous thromboembolic events
Lebanese Syrian Associated Charity (ALSAC). Submitted for publication Jan 26, 2004; last revision received Apr 14, 2004; accepted May 12, 2004. Reprint requests: Steven R. Deitcher, MD, 675 Almanor Ave, Sunnyvale, CA 94085. E-mail: sdeitcher@nuvelo. com. 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.05.055
Table. CVAD dysfunction and major thrombosis event rates in the study population and select subgroups CVAD dysfunction Patient group (n) Entire study population (253) Male (131) Female (122) White (192) Black (49) Asian (8) Hispanic (4) Nonchemotherapy (63) Chemotherapy (190) Astrocytoma* (55) Medulloblastoma* (44) Glioma (no histology)* (28) Ependymoma* (17) Oligodendroglioma* (16) Glioblastoma* (11) Other/unknown histologies* (19)
Major thrombosis n (%) 59 28 31 43 11 4 1 5 54 13 12 5 7 2 9 6
(23.3) (21.4) (25.4) (22.4) (22.5) (50.0) (25.0) (7.9) (28.4) (23.6) (27.3) (17.9) (41.2) (12.5) (81.8)y (31.6)
n (%) 7 (2.8) 4 (3.1) 2 (1.6) 3 (1.6) 2 (4.1) 0 (0.0) 1 (25.0) 1 (1.6) 5 (2.6) 1 (1.8) 1 (2.3) 1 (3.6) 0 (0.0) 2 (12.5) 0 (0.0) 0 (0.0)
*Chemotherapy patients only. yP < .001 for comparison between glioblastoma and nonglioblastoma histologies.
resection. Chemotherapy was used in 75.1% of patients and was a component of multimodal therapy in 182 patients. Radiation therapy was received by 65.6% of patients. No patient received CVAD primary thromboprophylaxis or had a prior personal or family history of VTE (Table). CVAD dysfunction warranting fibrinolytic instillation was reported in 54 of 190 (28.4%) patients who had central lines placed to support chemotherapy. Thrombotic occlusion was objectively confirmed in 17 of 54 (31.5%) patients with CVAD dysfunction. Seven episodes of major VTE were detected in 6 patients, for an overall episode rate of 2.8%. Major thromboses involved the leg deep veins (n = 2), internal jugular veins (n = 2), superior vena cava (n = 3), and right atrium (n = 1). Major thromboses were detected an average of 17.7 months (range, 2 to 46 months) after tumor diagnosis and were not temporally related to neurosurgical procedures. The major thromboses involving the internal jugular vein, superior vena cava, and right atrium developed in patients with a history of CVAD placement. The CVAD dysfunction rate was significantly higher in patients with glioblastoma (81.8%) compared with those with nonglioblastoma histologies. Major thrombosis was more likely to develop in patients with CVAD dysfunction (4 of 59) than in those without CVAD dysfunction (2 of 194) (P = .028). Major thrombosisfree survival was significantly shorter in patients with CVAD dysfunction (P = .006). CVAD dysfunction but not major thrombosis was associated with a significantly reduced overall survival rate (P < .0000001 and P = .1351, respectively).
Figure. Chemotherapy patient survival as a function of having had central venous access device dysfunction.
In the patients with CVAD to support chemotherapy administration (n = 190), major thrombosis was not more likely to develop in patients with CVAD dysfunction (3 of 54) compared with those without CVAD dysfunction (2 of 136) (P = .139). Major thrombosis was more likely to develop in patients with documented CVAD thrombotic occlusion (4 of 17) compared with those without (1 of 173) (P = .00021). Thrombosis-free survival was significantly reduced in patients with CVAD dysfunction (P = .0002). In this population, CVAD dysfunction but not major thrombosis was associated with a shorter overall survival rate (P = .00004 and P = .1326, respectively) (Figure).
DISCUSSION These data suggest that CVAD dysfunction and CVAD thrombotic occlusion are common complications in children with brain tumors and were significant risk factors for the development of major VTE primarily involving the upper extremities and superior vena cava. In contrast to adult brain tumor patients, major VTE were uncommon in our pediatric cohort and occurred, on average, almost 18 months after initial diagnosis by biopsy and surgical debulking. CVAD dysfunction predicted not only development of major thrombosis but, more unexpectedly, an unfavorable patient outcome. Fifty-nine percent of patients with CVAD who had dysfunction were alive at 2 years compared with 81% of those without documented dysfunction. Only 41% of those with confirmed thrombotic dysfunction were alive at 2 years. CVAD dysfunction is caused by fibrin deposition or thrombosis in at least 60% of cases. It must be considered that patients with a more aggressive tumor and more aggressive therapy (ie, glioblastoma) may exhibit enhanced hypercoagulability leading to greater CVAD dysfunction and thrombosis. Conversely, fibrin sheath formation and nonocclusive thrombus might promote angiogenesis and tumor progression. This hypothesis is supported by observations that some patients with acute VTE have markedly elevated plasma vascular endothelial growth factor levels, both platelet-rich
Clinically Evident Venous Thromboembolic Events in Children with Brain Tumors
849
and platelet-poor plasma clots promote neovessel formation in a chick chorioallantoic (CAM) assay system, and antithrombotic agents such as low-molecular-weight heparins that effectively prevent CVAD-associated and other thromboses can improve survival in certain subsets of patients with cancer, with and without clinically evident thrombosis.8-11 VTE prevention is strongly advocated in high-risk populations versus a ‘‘watch, wait, and treat’’ management approach.4 Anticoagulant-based prophylaxis is frequently avoided because of the fear of excessive central nervous system bleeding.12 This study describes a potential additional incentive for the prevention of thrombosis in children with brain tumors, namely, reduction in mortality rate. Study of prophylactic antithrombotic therapy in children with brain tumors and CVAD, including an analysis of survival impact, appears to be indicated.
REFERENCES 1. Packer RJ. Brain tumors in children. Curr Opin Pediatr 1995;7:64-72. 2. Dhami MS, Bona RD, Calogero JA, Hellman RM. Venous thromboembolism and high grade gliomas. Thromb Haemost 1993;70:393-6. 3. Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol 1983;13:334-6.
850
Deitcher et al
4. Deitcher SR. Cancer-related deep venous thrombosis: clinical importance, treatment challenges, and management strategies. Semin Thromb Hemost 2003;29:247-58. 5. Korones DN, Buzzard CJ, Asselin BL, Harris JP. Right atrial thrombi in children with cancer and indwelling catheters. J Pediatr 1996; 128:841-6. 6. Wilimas JA, Hudson M, Rao B, Luo X, Lott L, Kaste SC. Late vascular occlusion of central lines in pediatric malignancies. Pediatrics 1998; 101:e7. 7. Glaser DW, Medeiros D, Rollins N, Buchanan GR. Catheter-related thrombosis in children with cancer. J Pediatr 2001;138:255-9. 8. Deitcher SR, Goldman CK, Ruiter K. Vascular endothelial growth factor (VEGF) levels in patients with idiopathic acute proximal deep venous thrombosis. Thromb Haemost 2001;86(Suppl):P1517. 9. Trikha M, Nakada MT. Platelets and cancer: implications for antiangiogenesis therapy. Semin Thromb Hemost 2002;28:39-44. 10. Kakkar AK, Kadziola Z, Williamson RCN, Levine MN, Low V, Lemoine NR. Low molecular weight heparin therapy and survival in advanced cancer. Blood 2002;100:148a (abstract 557). 11. Lee AY, Julian JA, Levine MN, et al. Impact of dalteparin lowmolecular-weight heparin (LMWH) on survival: results of a randomized trial in cancer patients with venous thromboembolism (VTE). Proc Am Soc Clin Oncol 2003;22:211 (abstract 846). 12. Carman TL, Kanner AA, Barnett GH, Deitcher SR. Prevention of thromboembolism after neurosurgery for brain and spinal tumors: a survey. South Med J 2003;96:17-22.
The Journal of Pediatrics December 2004
We evaluated the incidence and significance of central venous access device dysfunction and symptomatic major thrombosis in 253 pediatric patients with brain tumors. Central venous access device dysfunction was a common complication (28.4%) and was associated with major thrombosis development and a reduced overall survival rate. Major thrombosis was relatively uncommon (2.8%). (J Pediatr 2004;145:848-50)
rain tumors are the most common form of solid neoplasm in children.1 As survival improves, medical complications associated with these tumors and their treatment, such as central venous access device (CVAD) dysfunction and venous thrombosis, have become more important. Venous thromboembolic events (VTE) occur in up to 36% of adults with primary and metastatic brain tumors and are associated with neurosurgical interventions and tissue factor release from some tumors and surrounding cerebral tissue into the systemic circulation.2-4 This hypercoagulability may be facilitated by blood-brain barrier disruption and exacerbated by cytotoxic therapy and surgical manipulation.4 CVAD-associated thrombosis has been reported in up to 50% of children with cancer.5-7 In one study, 8.3% of children with acute leukemia or nonbrain solid tumors had symptomatic right atrial thrombosis.5 In another study, 12.5% of children treated for cancer had symptomatic thrombosis; 42.9% of asymptomatic patients were found to have CVAD-associated thrombosis by venography.7 We characterized the incidence and survival impact of CVAD dysfunction and major VTE in pediatric patients with brain tumor.
B
METHODS Medical, radiographic, and pharmacy records of 253 consecutive patients diagnosed and treated for brain tumors at St Jude Children’s Research Hospital with at least 6 months of follow-up were retrospectively reviewed. A subset of 190 patients who received systemic chemotherapy by means of CVAD was analyzed. Clinically evident CVAD dysfunction was defined as the inability to withdraw blood From the Section of Hematology and or infuse medication and blood products and the requirement for instillation of Coagulation Medicine, Department of a fibrinolytic agent to restore patency. Symptomatic major venous thrombosis was Hematology-Medical Oncology, The suspected in the setting of extremity pain and swelling, chest pain, acute onset dyspnea, and Cleveland Clinic Foundation, Cleveland, Ohio; the Divisions of NeuroCVAD dysfunction. All suspected thromboses were objectively evaluated. Fibrinolytic and oncology and Radiation Oncology, St antithrombotic therapies were identified through the use of pharmacy records. Jude Children’s Research Hospital, Memphis, Tennessee; and the Division Overall and major thrombosis-free survival analyses were performed by means of of Pediatric Hematology/Oncology, Kaplan-Meier curves and the log-rank test. x2 analysis and the Fisher exact test were used Children’s Hospital of New Mexico, where appropriate to compare the frequency of CVAD dysfunction and major thrombosis Albuquerque, New Mexico. Supported in part by the American in patient subsets. A value of P < .05 was considered significant.
RESULTS The cohort consisted of 122 (48%) girls, 192 (76%) whites, and 55 (21%) patients with metastatic disease. The most common histologies were astrocytoma (26.9%), medulloblastoma (20.9%), glioma (15.0%), ependymoma (8.3%), and oligodendroglioma (7.1%), accounting for more than 78% of cases; 87% of patients underwent some degree of surgical
CVAD
848
Central venous access device
VTE
Venous thromboembolic events
Lebanese Syrian Associated Charity (ALSAC). Submitted for publication Jan 26, 2004; last revision received Apr 14, 2004; accepted May 12, 2004. Reprint requests: Steven R. Deitcher, MD, 675 Almanor Ave, Sunnyvale, CA 94085. E-mail: sdeitcher@nuvelo. com. 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.05.055
Table. CVAD dysfunction and major thrombosis event rates in the study population and select subgroups CVAD dysfunction Patient group (n) Entire study population (253) Male (131) Female (122) White (192) Black (49) Asian (8) Hispanic (4) Nonchemotherapy (63) Chemotherapy (190) Astrocytoma* (55) Medulloblastoma* (44) Glioma (no histology)* (28) Ependymoma* (17) Oligodendroglioma* (16) Glioblastoma* (11) Other/unknown histologies* (19)
Major thrombosis n (%) 59 28 31 43 11 4 1 5 54 13 12 5 7 2 9 6
(23.3) (21.4) (25.4) (22.4) (22.5) (50.0) (25.0) (7.9) (28.4) (23.6) (27.3) (17.9) (41.2) (12.5) (81.8)y (31.6)
n (%) 7 (2.8) 4 (3.1) 2 (1.6) 3 (1.6) 2 (4.1) 0 (0.0) 1 (25.0) 1 (1.6) 5 (2.6) 1 (1.8) 1 (2.3) 1 (3.6) 0 (0.0) 2 (12.5) 0 (0.0) 0 (0.0)
*Chemotherapy patients only. yP < .001 for comparison between glioblastoma and nonglioblastoma histologies.
resection. Chemotherapy was used in 75.1% of patients and was a component of multimodal therapy in 182 patients. Radiation therapy was received by 65.6% of patients. No patient received CVAD primary thromboprophylaxis or had a prior personal or family history of VTE (Table). CVAD dysfunction warranting fibrinolytic instillation was reported in 54 of 190 (28.4%) patients who had central lines placed to support chemotherapy. Thrombotic occlusion was objectively confirmed in 17 of 54 (31.5%) patients with CVAD dysfunction. Seven episodes of major VTE were detected in 6 patients, for an overall episode rate of 2.8%. Major thromboses involved the leg deep veins (n = 2), internal jugular veins (n = 2), superior vena cava (n = 3), and right atrium (n = 1). Major thromboses were detected an average of 17.7 months (range, 2 to 46 months) after tumor diagnosis and were not temporally related to neurosurgical procedures. The major thromboses involving the internal jugular vein, superior vena cava, and right atrium developed in patients with a history of CVAD placement. The CVAD dysfunction rate was significantly higher in patients with glioblastoma (81.8%) compared with those with nonglioblastoma histologies. Major thrombosis was more likely to develop in patients with CVAD dysfunction (4 of 59) than in those without CVAD dysfunction (2 of 194) (P = .028). Major thrombosisfree survival was significantly shorter in patients with CVAD dysfunction (P = .006). CVAD dysfunction but not major thrombosis was associated with a significantly reduced overall survival rate (P < .0000001 and P = .1351, respectively).
Figure. Chemotherapy patient survival as a function of having had central venous access device dysfunction.
In the patients with CVAD to support chemotherapy administration (n = 190), major thrombosis was not more likely to develop in patients with CVAD dysfunction (3 of 54) compared with those without CVAD dysfunction (2 of 136) (P = .139). Major thrombosis was more likely to develop in patients with documented CVAD thrombotic occlusion (4 of 17) compared with those without (1 of 173) (P = .00021). Thrombosis-free survival was significantly reduced in patients with CVAD dysfunction (P = .0002). In this population, CVAD dysfunction but not major thrombosis was associated with a shorter overall survival rate (P = .00004 and P = .1326, respectively) (Figure).
DISCUSSION These data suggest that CVAD dysfunction and CVAD thrombotic occlusion are common complications in children with brain tumors and were significant risk factors for the development of major VTE primarily involving the upper extremities and superior vena cava. In contrast to adult brain tumor patients, major VTE were uncommon in our pediatric cohort and occurred, on average, almost 18 months after initial diagnosis by biopsy and surgical debulking. CVAD dysfunction predicted not only development of major thrombosis but, more unexpectedly, an unfavorable patient outcome. Fifty-nine percent of patients with CVAD who had dysfunction were alive at 2 years compared with 81% of those without documented dysfunction. Only 41% of those with confirmed thrombotic dysfunction were alive at 2 years. CVAD dysfunction is caused by fibrin deposition or thrombosis in at least 60% of cases. It must be considered that patients with a more aggressive tumor and more aggressive therapy (ie, glioblastoma) may exhibit enhanced hypercoagulability leading to greater CVAD dysfunction and thrombosis. Conversely, fibrin sheath formation and nonocclusive thrombus might promote angiogenesis and tumor progression. This hypothesis is supported by observations that some patients with acute VTE have markedly elevated plasma vascular endothelial growth factor levels, both platelet-rich
Clinically Evident Venous Thromboembolic Events in Children with Brain Tumors
849
and platelet-poor plasma clots promote neovessel formation in a chick chorioallantoic (CAM) assay system, and antithrombotic agents such as low-molecular-weight heparins that effectively prevent CVAD-associated and other thromboses can improve survival in certain subsets of patients with cancer, with and without clinically evident thrombosis.8-11 VTE prevention is strongly advocated in high-risk populations versus a ‘‘watch, wait, and treat’’ management approach.4 Anticoagulant-based prophylaxis is frequently avoided because of the fear of excessive central nervous system bleeding.12 This study describes a potential additional incentive for the prevention of thrombosis in children with brain tumors, namely, reduction in mortality rate. Study of prophylactic antithrombotic therapy in children with brain tumors and CVAD, including an analysis of survival impact, appears to be indicated.
REFERENCES 1. Packer RJ. Brain tumors in children. Curr Opin Pediatr 1995;7:64-72. 2. Dhami MS, Bona RD, Calogero JA, Hellman RM. Venous thromboembolism and high grade gliomas. Thromb Haemost 1993;70:393-6. 3. Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol 1983;13:334-6.
850
Deitcher et al
4. Deitcher SR. Cancer-related deep venous thrombosis: clinical importance, treatment challenges, and management strategies. Semin Thromb Hemost 2003;29:247-58. 5. Korones DN, Buzzard CJ, Asselin BL, Harris JP. Right atrial thrombi in children with cancer and indwelling catheters. J Pediatr 1996; 128:841-6. 6. Wilimas JA, Hudson M, Rao B, Luo X, Lott L, Kaste SC. Late vascular occlusion of central lines in pediatric malignancies. Pediatrics 1998; 101:e7. 7. Glaser DW, Medeiros D, Rollins N, Buchanan GR. Catheter-related thrombosis in children with cancer. J Pediatr 2001;138:255-9. 8. Deitcher SR, Goldman CK, Ruiter K. Vascular endothelial growth factor (VEGF) levels in patients with idiopathic acute proximal deep venous thrombosis. Thromb Haemost 2001;86(Suppl):P1517. 9. Trikha M, Nakada MT. Platelets and cancer: implications for antiangiogenesis therapy. Semin Thromb Hemost 2002;28:39-44. 10. Kakkar AK, Kadziola Z, Williamson RCN, Levine MN, Low V, Lemoine NR. Low molecular weight heparin therapy and survival in advanced cancer. Blood 2002;100:148a (abstract 557). 11. Lee AY, Julian JA, Levine MN, et al. Impact of dalteparin lowmolecular-weight heparin (LMWH) on survival: results of a randomized trial in cancer patients with venous thromboembolism (VTE). Proc Am Soc Clin Oncol 2003;22:211 (abstract 846). 12. Carman TL, Kanner AA, Barnett GH, Deitcher SR. Prevention of thromboembolism after neurosurgery for brain and spinal tumors: a survey. South Med J 2003;96:17-22.
The Journal of Pediatrics December 2004