J Neurooncol (2012) 106:121–125 DOI 10.1007/s11060-011-0642-1
CLINICAL STUDY – PATIENT STUDY
Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients Andrew D. Norden • Julia Bartolomeo • Shota Tanaka • Jan Drappatz • Abigail S. Ciampa • Lisa M. Doherty • Debra C. LaFrankie • Sandra Ruland Eudocia C. Quant • Rameen Beroukhim • Patrick Y. Wen
•
Received: 13 April 2011 / Accepted: 17 June 2011 / Published online: 26 June 2011 Ó Springer Science+Business Media, LLC. 2011
Abstract Venous thromboembolic events (VTE) are common in glioma patients and are typically treated with anticoagulant medications. The anti-angiogenic agent bevacizumab (BVZ) increases the risks of both VTE and hemorrhagic complications. Little is known about the hemorrhagic risk of anticoagulation in glioma patients receiving BVZ. We reviewed medical records from 282 BVZ-treated patients at our center and identified 64 who received concurrent anticoagulant therapy. The risk and severity of hemorrhagic complications were assessed. Fisher’s exact test was used to compare the risk of hemorrhage between subjects who received and did not receive anticoagulants. Forty-seven patients (73%) had glioblastoma, 15 (23%) anaplastic glioma, and 2 (3%) other tumors. Thirteen (20%) and 51 (80%) patients received warfarin and low-molecular-weight heparin, respectively. The indication for anticoagulation was deep venous thrombosis in 37 patients (58%), pulmonary embolism in 22 (34%), and both in 5 (8%). Thirteen patients (20%) Andrew D Norden and Julia Bartolomeo contributed equally to this work. A. D. Norden J. Bartolomeo S. Tanaka J. Drappatz A. S. Ciampa L. M. Doherty D. C. LaFrankie S. Ruland E. C. Quant R. Beroukhim P. Y. Wen (&) Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA e-mail:
[email protected] A. D. Norden S. Tanaka J. Drappatz E. C. Quant R. Beroukhim P. Y. Wen Division of Neuro-Oncology, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA A. D. Norden J. Drappatz E. C. Quant R. Beroukhim P. Y. Wen Harvard Medical School, Boston, MA, USA
experienced hemorrhage, of which four hemorrhages (6%) were serious (grade C 3): one patient had grade 5 intracerebral hemorrhage (ICH), one grade 4 ICH, one grade 3 epistaxis, and one grade 3 gastrointestinal hemorrhage. ICH was seen in seven patients (11%), of which five (8%) were grade 1. Among 218 patients who did not receive anticoagulants, there were two (1%) serious hemorrhages (both grade 4 ICH). Both the serious hemorrhage rate and overall ICH rate were higher in patients who received anticoagulants (P = 0.03 and 0.02, respectively). Anticoagulant use during BVZ therapy may increase the risk of hemorrhage in glioma patients, although it is generally well tolerated. Keywords Glioma Glioblastoma Bevacizumab Anticoagulation Intracerebral hemorrhage
Background Venous thromboembolic events (VTE) are common in patients with high-grade gliomas (HGG) [1–3]. In a prospective study, the annual risk of deep vein thrombosis (DVT) was 18% [4]. Four percent of patients died of pulmonary embolism (PE) despite prospective surveillance for VTE. Other data suggest a lifetime risk of approximately 30% [5]. Bevacizumab (AvastinÒ; Genentech, Inc., South San Francisco, CA) (BVZ), a humanized monoclonal antibody to vascular endothelial growth factor (VEGF), received accelerated approval by the US Food and Drug Administration (FDA) for the treatment of recurrent glioblastoma (GBM) in 2009. Like other anti-angiogenic drugs, BVZ increases the risk of VTE. The reported incidence of VTE in BVZ-treated cancer patients ranges from 3 to 23% [6].
123
122
A recent meta-analysis demonstrated an increased risk of VTE associated with BVZ therapy among cancer patients (relative risk 1.33 [95% confidence interval 1.13–1.56]; P \ 0.001) [7]. BVZ also increases the risk of hemorrhage. In clinical trials for HGG, BVZ-treated patients had a risk of severe (grade C 3) intracranial hemorrhage (ICH) of 2–5% [8–10]. One retrospective study reported an 18% risk of any hemorrhagic complications including epistaxis and rectal bleeding [11]. Little is known about the risk of hemorrhage for glioma patients receiving BVZ and therapeutic anticoagulation concurrently. One small retrospective study found that anticoagulation produced 1 (5%) symptomatic and 2 (10%) asymptomatic ICHs in 21 patients receiving BVZ [12]. We aimed to assess the hemorrhagic risk of concurrent use of BVZ and anticoagulants in glioma patients.
J Neurooncol (2012) 106:121–125 Table 1 Characteristics of the 64 glioma patients with concurrent use of bevacizumab and anticoagulants Patient characteristics Median age, years
55.5
Age range, years
31–84
Male:female ratio
48:16
Diagnosis Glioblastoma
47 (73)
Anaplastic astrocytoma
15 (23)
Low-grade glioma Reason for anticoagulation
2 (3)
DVT
37 (58)
PE
22 (34)
Both DVT and PE
5 (8)
Type of anticoagulant Enoxaparin Dalteparin Warfarin
Materials and methods
N (%)
Fondaparinux
49 (77) 1 (2) 13 (20) 1 (2)
DVT deep venous thrombosis, PE pulmonary embolism
This study was approved by our local institutional review board; informed consent was waived due to its minimal risk. Using our departmental database, we identified 282 consecutive glioma patients who were treated with BVZ at our institution. Of these patients, 64 (23%) received BVZ and anticoagulants concurrently. Anticoagulants included warfarin; low-molecular-weight heparins (LMWH) such as enoxaparin and dalteparin; and fondaparinux. Medical records were reviewed for the 282 patients, and the following data were recorded: age, sex, diagnosis, start and stop dates of BVZ, and anticoagulants (if applicable), type of anticoagulants used (if applicable), and type and severity of hemorrhagic complications. The severity was evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. We defined serious hemorrhage as any hemorrhage of grade 3 or greater. The risk and severity of hemorrhagic complications in patients with concurrent use of BVZ and anticoagulants were assessed. A two-tailed Fisher’s exact test was used to compare the risks of serious hemorrhage and ICH between patients who received and did not receive anticoagulants.
Results The characteristics of 64 patients receiving BVZ and concurrent anticoagulation are summarized in Table 1. Thirty-seven patients (58%) were placed on anticoagulants for DVT, 22 patients (34%) for PE, and 5 patients (8%) for both DVT and PE. The majority of patients (50, 79%) received LMWH. Thirteen (20%) received warfarin.
123
Fig. 1 Fatal intracerebral hemorrhage. a This T1-weighted, contrastenhanced MRI scan of the brain was obtained in a 72-year-old man with recurrent right parietal glioblastoma. The patient developed DVT in the lower extremity requiring dalteparin at 1 mg/kg twice daily. When his tumor progressed, BVZ was started at 10 mg/kg every 2 weeks. He also received irinotecan, which was subsequently switched to carboplatin for further progression. He had received a total of six doses of BVZ when he developed severe headache and vomiting followed by somnolence. b This non-contrast CT scan of the head revealed diffuse patchy hemorrhage within the tumor causing increased mass effect, midline shift, and uncal herniation. Palliative care was pursued and he expired on the following day
0.9 AA anaplastic astrocytoma, BVZ bevacizumab, DVT deep venous thrombosis, GBM glioblastoma, INR international normalized ratio, PE pulmonary embolism
350 Asymptomatic (grade 1) Intratumoral Carmustine, irinotecan q 2 weeks 12 0.5 mg/kg daily Dalteparin DVT M 50
GBM
1 300 Asymptomatic (grade 1) Intratumoral Irinotecan q 2 weeks 2 1 mg/kg bid Dalteparin DVT M 57
AA
NA 195 Asymptomatic (grade 1) Intratumoral Irinotecan q 2 weeks 6 1 mg/kg bid Dalteparin DVT F 51
GBM
1.1 150 Asymptomatic (grade 1) Intratumoral Irinotecan q 2 weeks 3 1 mg/kg bid Dalteparin DVT M 53
GBM
NA 125 Asymptomatic (grade 1) Intratumoral None q 2 weeks 3 0.5 mg/kg bid Dalteparin DVT M 60
GBM
NA NA Major deficit (grade 4) Intratumoral Irinotecan q 2 weeks
332 Death (grade 5) Intratumoral, intraventricular Irinotecan, carboplatin q 2 weeks 6
BVZ frequency Number of BVZ doses
5 1 mg/kg bid Dalteparin PE GBM
Thirteen patients (20%) experienced hemorrhage (Figs. 1, 2). None of the hemorrhages were provoked by apparent precipitating factors such as excessive anticoagulation or trauma. Because of small subject numbers in the warfarin and non-GBM groups, we did not assess hemorrhage risk based on the type of anticoagulant used or tumor histology. Out of four patients (6%) who experienced serious hemorrhage (grade C 3), one patient had grade 5 ICH, one grade 4 ICH, one grade 3 epistaxis, and one grade 3 gastrointestinal hemorrhage. Seven patients (11%)
M
0 (0)
51
1 (2)
1 mg/kg bid
5
Dalteparin
2 (1)
DVT
1 (2)
M
0 (0)
4
72
0 (0)
GBM
Platelet count (103/ll) Consequence 2 (1)
3
Concurrent chemotherapy
Type of bleeding 3 (1)
0 (0)
Anticoagulant dosage
5 (8)
2
Type of anticoagulant
1
DVT/ PE
No anticoagulant use N (%)
Pathology
Anticoagulant use N (%)
Sex
Grade of intracerebral hemorrhage
Age
Table 2 Grades of intracerebral hemorrhage stratified by the use of anticoagulants
Table 3 Treatment details for the seven glioma patients who experienced intracerebral hemorrhage
Fig. 2 Asymptomatic (grade 1) intracerebral hemorrhage. a, b This T1-weighted, pre- and post-contrast MRI scan of the brain was obtained in a 57-year-old man with recurrent anaplastic astroyctoma. The heterogeneously enhancing mass is apparent in the left temporal lobe. The patient also had a history of deep venous thrombosis in the lower extremity treated with dalteparin at 1 mg/kg twice daily. BVZ at 10 mg/kg every 2 weeks and irinotecan were started for radiographic progression. c After two doses of BVZ, this routine precontrast T1-weighted MRI of the brain revealed hemorrhagic change within the tumor and the resection cavity, not associated with edema or mass effect. d Post-contrast T1-weighted MRI after the hemorrhage
1
123 INR
J Neurooncol (2012) 106:121–125
123
124
experienced ICH of any grade (Table 2). Table 3 summarizes the treatment details in this cohort. All asymptomatic ICHs were managed conservatively. Anticoagulants were discontinued in these patients and inferior vena cava (IVC) filters were placed. BVZ was continued except in one patient whose tumor progressed on the subsequent scan. There was no association between duration of anticoagulation, duration of bevacizumab use, or duration of concurrent treatment and hemorrhage risk. Among 218 BVZ-treated patients who did not receive concurrent anticoagulants, two patients (1%) experienced serious hemorrhage (both grade 4 ICH). Any ICH was observed in seven of these patients (3%) (Table 2). Both the serious hemorrhage rate and ICH rate (any grade) were higher in patients who received concurrent anticoagulants than those who did not (P = 0.03 and 0.02, respectively). The type of anticoagulant (LMWH vs. warfarin) was not associated with the risk of hemorrhage (P = 0.27).
Discussion Cancer in general [13] and high-grade glioma in particular [2, 3] confer an increased risk of VTE. The procoagulant state observed in cancer patients may relate to increased expression of tissue factor and subsequent activation of protease receptors on cell surfaces followed by fibrin generation and VEGF release [14, 15]. Tissue factor expression levels correlate with the stage of cancer [16] and the grade of glioma [17]. In glioma patients, neurosurgical procedures, chemotherapy, and immobility due to neurological deficits or steroid myopathy may further increase the risk of VTE [2]. The standard management of VTE in glioma patients is therapeutic anticoagulation, although historically many physicians have chosen IVC filter placement instead of anticoagulation for fear of ICH [2]. The risk of ICH in brain tumor patients on therapeutic anticoagulation is estimated to be 2% [18], and thus anticoagulants can be used safely in many glioma patients [19]. Furthermore, IVC filter placement carries the inherent risks of recurrent VTE and filter thrombosis. Regarding the choice of anticoagulant, Meyer and colleagues performed a randomized clinical trial in cancer patients with VTE. The results indicated that LMWH is safer and more effective than warfarin [20]. It should be noted that this trial included only a small proportion of brain tumor patients; the extent to which these results can be generalized to the brain tumor population is uncertain, but no data specific to the brain tumor population have been reported. In a subsequent trial, patients with cancer and objectively confirmed VTE who received dalteparin were 50% less likely to develop
123
J Neurooncol (2012) 106:121–125
recurrent VTE than those randomized to receive warfarin [21]. Bevacizumab is the first anti-angiogenic drug to receive FDA approval for use in recurrent HGG [22]. Like other drugs in this class, BVZ is associated with increased risks of both VTE and hemorrhage, apparently by virtue of its tendency to cause abnormal endothelial cell apoptosis. This can result both in exposure of the prothrombotic basement membrane (resulting in thrombosis) and loss of microvascular integrity (resulting in hemorrhage) [6]. Another purported mechanism of thrombosis is loss of the VEGFdependent production of the platelet inhibitors prostaglandin I-2 and nitric oxide [23]. The risk of VTE is reported to range from 7 to 32% in patients with GBM who are not receiving anti-angiogenic agents [8, 9, 24]. The decision to start anticoagulation in a HGG patient on BVZ who develops VTE provokes anxiety in clinicians. Limited data are available concerning the risk of hemorrhage in HGG patients on concurrent BVZ and anticoagulation. In a study of 21 such patients, five were found to have ICH, but only one of these was symptomatic [12]. In the current study, we identified 64 such patients and compared them to 218 patients who were treated with BVZ and no anticoagulants. The ICH rate reported here for patients on BVZ alone (3%) is consistent with another recent report, in which the rate was 1.9% [25]. The rate of ICH of any grade in our population was significantly higher among patients on concurrent anticoagulants compared with those who were not. However, the rate of serious ICH was not significantly higher among patients on anticoagulants compared with those who were not. Even in the concurrently treated cohort, the rate of serious ICH was low (2/64, 3%) and within the range of what most would consider acceptable in light of the risks of the underlying disease. Additionally, the study design employed here cannot exclude the possibility of a bias toward calling asymptomatic hemorrhages on MRI in concurrently treated patients, which would falsely elevate the reported hemorrhage rate in this population. Obvious limitations of this study include its retrospective nature, the small number of patients that were studied, and the lack of active surveillance for asymptomatic hemorrhages. A randomized prospective clinical trial would be required to precisely quantify the risk of hemorrhage in patients on BVZ who are treated with or without anticoagulants. Since no effective salvage therapy exists for BVZ-treated recurrent HGG patients and the risk of serious hemorrhage is low even when these patients receive anticoagulants, we do not consider BVZ use a contraindication to therapeutic anticoagulation for VTE in glioma patients. The results of this study suggest that the concurrent use of BVZ and anticoagulants is safe for the large majority of patients. In particular, these data support the
J Neurooncol (2012) 106:121–125
use of therapeutic anticoagulation simultaneously with BVZ when progressive tumor and symptomatic VTE warrant the use of both.
125
12.
13.
References 1. Marras LC, Geerts WH, Perry JR (2000) The risk of venous thromboembolism is increased throughout the course of malignant glioma: an evidence-based review. Cancer 89:640–646 2. Jenkins EO, Schiff D, Mackman N, Key NS (2010) Venous thromboembolism in malignant gliomas. J Thromb Haemost 8:221–227 3. Semrad TJ, O’Donnell R, Wun T, Chew H, Harvey D, Zhou H, White RH (2007) Epidemiology of venous thromboembolism in 9,489 patients with malignant glioma. J Neurosurg 106:601–608 4. Brandes AA, Scelzi E, Salmistraro G, Ermani M, Carollo C, Berti F, Zampieri P, Baiocchi C, Fiorentino MV (1997) Incidence of risk of thromboembolism during treatment high-grade gliomas: a prospective study. Eur J Cancer 33:1592–1596 5. Drappatz J, Schiff D, Kesari S, Norden AD, Wen PY (2007) Medical management of brain tumor patients. Neurol Clin 25(4):1035–1071, ix 6. Zangari M, Fink LM, Elice F, Zhan F, Adcock DM, Tricot GJ (2009) Thrombotic events in patients with cancer receiving antiangiogenesis agents. J Clin Oncol 27:4865–4873 7. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S (2008) Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 300:2277–2285 8. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740 9. Lai A, Tran A, Nghiemphu PL, Pope WB, Solis OE, Selch M, Filka E, Yong WH, Mischel PS, Liau LM, Phuphanich S, Black K, Peak S, Green RM, Spier CE, Kolevska T, Polikoff J, Fehrenbacher L, Elashoff R, Cloughesy T (2011) Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 29:142–148 10. Raizer JJ, Grimm S, Chamberlain MC, Nicholas MK, Chandler JP, Muro K, Dubner S, Rademaker AW, Renfrow J, Bredel M (2010) A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer 116:5297–5305 11. Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari
14. 15. 16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
S, Wen PY (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70:779–787 Nghiemphu PL, Green RM, Pope WB, Lai A, Cloughesy TF (2008) Safety of anticoagulation use and bevacizumab in patients with glioma. Neuro Oncol 10:355–360 Blom JW, Doggen CJ, Osanto S, Rosendaal FR (2005) Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293:715–722 Rickles FR, Patierno S, Fernandez PM (2003) Tissue factor, thrombin, and cancer. Chest 124:58S–68S Fernandez PM, Patierno SR, Rickles FR (2004) Tissue factor and fibrin in tumor angiogenesis. Semin Thromb Hemost 30:31–44 Callander NS, Varki N, Rao LV (1992) Immunohistochemical identification of tissue factor in solid tumors. Cancer 70:1194–1201 Hamada K, Kuratsu J, Saitoh Y, Takeshima H, Nishi T, Ushio Y (1996) Expression of tissue factor correlates with grade of malignancy in human glioma. Cancer 77:1877–1883 Wen PY, Schiff D, Kesari S, Drappatz J, Gigas DC, Doherty L (2006) Medical management of patients with brain tumors. J Neurooncol 80:313–332 Gerber DE, Grossman SA, Streiff MB (2006) Management of venous thromboembolism in patients with primary and metastatic brain tumors. J Clin Oncol 24:1310–1318 Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, SolalCeligny P, Le Maignan C, Extra JM, Cottu P, Farge D (2002) Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 162:1729–1735 Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M (2003) Lowmolecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146–153 Cohen MH, Shen YL, Keegan P, Pazdur R (2009) FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14:1131–1138 Yang R, Thomas GR, Bunting S, Ko A, Ferrara N, Keyt B, Ross J, Jin H (1996) Effects of vascular endothelial growth factor on hemodynamics and cardiac performance. J Cardiovasc Pharmacol 27:838–844 Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745 Fraum TJ, Kreisl TN, Sul J, Fine HA, Iwamoto FM (2011) Ischemic stroke and intracranial hemorrhage in glioma patients on antiangiogenic therapy. J Neurooncol
123
