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- Publisher
- Hindawi Publishing Corporation
- Copyright
- Copyright © 2012 Jeevan Kumar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
- ISSN
- 2090-6706
- eISSN
- 2090-6714
- DOI
- 10.1155/2012/695430
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- See Article on Publisher Site
Abstract
Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2012, Article ID 695430, 3 pages doi:10.1155/2012/695430 Case Report Bevacizumab-Induced Reversible Thrombocytopenia in a Patient with Adenocarcinoma of Colon: Rare Adverse Effect of Bevacizumab 1, 2 1 1 Jeevan Kumar, Manorama Bhargava, and Shyam Aggarwal Sir Ganga Ram Hospital, New Delhi 110060, India Department of Hematology, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi 110060, India Correspondence should be addressed to Jeevan Kumar, grgjvn@gmail.com Received 28 August 2012; Accepted 22 September 2012 Academic Editors: C. Gennatas and J. I. Mayordomo Copyright © 2012 Jeevan Kumar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report a case of bevacizumab- (BEV-) induced thrombocytopenia in a 59-year-old man with adenocarcinoma of colon. After colectomy, the patient was treated with twelve cycles of FOLFOX-4 (folinic acid, 5-fluorouracil, and oxaliplatin) regimen. On relapse, he was treated with FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) regimen along with BEV 10 mg/kg for 6 cycles. After that, BEV was continued for maintenance as a single agent at an interval of three weeks. After the13th cycle of BEV, the patient developed melena with epistaxis and thrombocytopenia, from which he recovered on withdrawal of BEV. On rechallenge with half the initial dose, there was once again a reversible drop in platelet count. The proposed mechanism of thrombocytopenia may be immune-mediated peripheral destruction of platelets. 1. Introduction patient suffered from melena, epistaxis, and thrombocytope- nia. Bevacizumab (BEV) is a humanized immunoglobulin mon- oclonal antibody that binds to and inhibits the activity of 2. Case Report vascular endothelial growth factor (VEGF). It can result in two distinct patterns of bleeding: minor hemorrhage, most In June 2008, the patient presented with subacute intestinal commonly grade 1 epistaxis; serious, and in some cases fatal, obstruction. On investigations, he was found to have mucin- hemorrhagic events. Severe or fatal hemorrhage, including secreting well-differentiated adenocarcinoma of colon Duke hemoptysis, gastrointestinal bleeding, hematemesis, CNS stage C. There were no liver nodules, ascites, and peritoneal hemorrhage, epistaxis, and vaginal bleeding has been dissemination. After hemicolectomy, the patient was treated reported up to fivefold more frequent in patients receiving with twelve cycles of FOLFOX-4 (folinic acid, 5-fluorouracil, BEV compared to those receiving chemotherapy alone [1–3]. and oxaliplatin) regimen. He received the last cycle of BEV also impairs wound healing. In a controlled clinical trial, chemotherapy in February 2009. A CT scan done after the the incidence of wound healing complications in patients completion of chemotherapy showed no mass or enlarged with metastatic colorectal cancer who underwent surgery lymph nodes. Postchemotherapy carcinoembryonic antigen during the course of BEV treatment was 15% as compared to (CEA) was 8 μg/L (0–5 μg/L). 4% in those who did not receive BEV. Serious and sometimes The patient remained asymptomatic till February 2010, fatal gastrointestinal perforation is more frequent in BEV- when he developed abdominal pain and ascites. PET-CT treated patients compared to controls [1]. We report here the showed omental thickening with few small nodular deposits case of a 59-year-old man with relapsed adenocarcinoma of in anterior abdominal wall with moderate ascites. Biopsy colon. After surgery and multiple chemotherapies, BEV was of nodular deposits in anterior abdominal wall and ascitic continued as a single agent. After the 13th cycle of BEV, the fluid examination revealed adenocarcinoma. The blood 2 Case Reports in Oncological Medicine investigations were CEA = 74.8 μg/L, Hb = 10.9 g/dL, TLC = 250,000 9,000/μL, and platelet count = 212,000/μL. This relapse was 224,000 treated with FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) regimen along with BEV 10 mg/kg for 6 cycles, 200,000 last cycle in July 2010. The patient responded quite well to 178,000 this regimen. The PET-CT scan showed reduction in omental 170,000 thickening and ascites. Investigations after chemotherapy 156,000 150,000 were CEA = 11 μg/L, Hb = 12.8 g/dL, TLC = 7,880/μL, and 142,000 136,000 platelet count = 191,000/μL. After that, BEV 10 mg/kg was continued as a single agent at an interval of three weeks. 100,000 The patient had recurrent episodes of epistaxis after starting BEV. 82,000 78,000 73,000 In November 2010, the patient again reported with 68,000 abdominal pain. CT scan of the abdomen showed extensive 50,000 peritoneal and omental deposits. External beam radiother- apy was given to omental plaques. In March 2011, the patient developed jaundice. CT scan of abdomen showed dilatation of intrahepatic biliary radicals with soft tissue density lesion Baseline 0 28 56 61 77 82 98 104 120 127 at the confluence of right and left hepatic ducts causing Time (days) extrinsic compression. The blood investigations were Hb = Figure 1: Changes in platelet count in relation to treatment with 10.7 g/dL, TLC = 10,700/μL, and platelet count = 224,000/μL. Bevacizumab. Arrows indicate injection of bevacizumab (5 mg/kg). Patient recovered after percutaneous transhepatic biliary drainage (PTBD). In July 2011, the patient started to have melena along 3. Discussion with epistaxis two days after completion of the 13th cycle of BEV as a single agent. On investigations Hb was 5.2 g/dL, Our patient developed melena with epistaxis and thrombo- TLC was 14,000/μL (neutrophils 85%, lymphocytes 11%, cytopenia, attributable to BEV. Thrombocytopenia is a rare monocytes 02%, myelocytes 01%, and metamyelocytes adverse effect of BEV that has only few case reports in the 01%), and platelet count was 10,000/μL. A repeat platelet literature. Leal et al. reported a case of bevacizumab-induced count on the same day was 6,000/μL. Bone marrow examina- reversible thrombocytopenia in a patient with recurrent tion showed cellular marrow with all hemopoietic elements high-grade glioma [4]. In their case report, the patient had with increased megakaryocytes. No bone marrow infiltration no bleeding and platelet count was mildly dropped, but our was seen. The patient was receiving no other known patient had melena, epistaxis with severe thrombocytopenia. medications that could be linked to the development of drug- Bevacizumab is a recombinant humanized monoclonal induced thrombocytopenia. He did not have a central venous neutralizing antibody against vascular endothelial growth access and was not receiving heparin. Antiplatelet antibodies factor (VEGF), which has shown clinical benefits and efficacy were absent on two separate occasions. Other hematologic in several types of malignancies including metastatic colorec- parameters, fibrinogen, fibrin monomer, D-dimer, PT/aPTT, tal and lung cancer [2]. Treatment with BEV is associated peripheral smear, bilirubin, LDH, antinuclear antibodies with increased rates of arterial and venous thromboem- (ANAs), and haptoglobin were unremarkable on two sepa- bolism and hemorrhage. In a large observational treatment rate occasions. study in patients with metastatic colorectal cancer, the inci- For epistaxis nasal packing was done. One unit platelet dence rate of clinically significant bleeding associated with apheresis and two units of packed red blood cells were trans- BEV was 2.4% [5]. fused. Two additional units of packed red blood cells were In the study of Hurwitz et al. [2, 3], grade 1 or 2 hem- transfused the next day. BEV was discontinued. The patient orrhagic events were more frequent in patients receiving was given injection methylprednisolone 1 g intravenously irinotecan, bolus fluorouracil, and leucovorin (bolus-IFL) daily for three days. Epistaxis and melena stopped on the plus BEV when compared to those receiving bolus-IFL second day. Platelet count on the second day was 38,000/μL. plus placebo and included gastrointestinal hemorrhage (24% His platelet count started rising, and after 4 weeks it was versus 6%), minor gum bleeding (2% versus 0), and vaginal 136,000/μL. After 8 weeks, when his platelet count was hemorrhage (4% versus 2%). Incidence of epistaxis was 178,000/μL, he was rechallenged with half the dose (5 mg/kg) higher (35% versus 10%) in patients receiving bolus-IFL of BEV (Figure 1). There was once again a drop in platelet plus BEV compared with patients receiving bolus-IFL plus count to 73,000/μL, which rose to 156,000/μLafter 3weeks. placebo. Impaired wound healing had contributed to these Again 5 mg/kg of BEV was given, and platelet count dropped hemorrhagic events. Incidence of grade 1 or 2 thrombo- to 82,000/μL. Since the platelet count recovered after 3 weeks, cytopenia was higher (5% versus 0%) in patients with BEV 5 mg/kg was continued every 3 weeks (if platelet count metastatic colorectal cancer receiving bolus-IFL plus BEV was above 100,000/μL) along with monitoring of platelet compared with patients receiving bolus-IFL plus placebo count. [2, 3]. Various clinical trials showed that addition of BEV Platelet count Case Reports in Oncological Medicine 3 to chemotherapy did not significantly alter the incidence of [3] H. I. Hurwitz, L. Fehrenbacher, J. D. Hainsworth et al., “Beva- cizumab in combination with fluorouracil and leucovorin: an thrombocytopenia [6–8]. active regimen for first-line metastatic colorectal cancer,” Jour- The pathophysiological mechanisms leading to these side nal of Clinical Oncology, vol. 23, no. 15, pp. 3502–3508, 2005. effects are poorly understood. Data from in vitro experi- [4] T. Leal and H. I. Robins, “Bevacizumab induced reversible ments and animal models point to a possible influence of thrombocytopenia in a patient with recurrent high-grade bevacizumab in primary hemostasis and platelet function. glioma: a case report,” Cancer Chemotherapy and Pharmacol- Recently VEGF and VEGF receptors (VEGF-Rs) have been ogy, vol. 65, no. 2, pp. 399–401, 2010. found to be relevant mediators of platelet aggregation [9, 10]. [5] A. Grothey, M. M. Sugrue, D. M. Purdie et al., “Bevacizumab Both of these targets represent potential sites at which beva- beyond first progression is associated with prolonged over- cizumab could potentially interact with primary hemostasis. all survival in metastatic colorectal cancer: results from a A proposed mechanism of thrombocytopenia was large observational cohort study (BRiTE),” Journal of Clini- described by Meyer et al. [10]. BEV forms immune com- cal Oncology, vol. 26, no. 33, pp. 5326–5334, 2008. [6] B. J. Giantonio, P. J. Catalano, N. J. Meropol et al., “Beva- plexes (ICs) with VEGF, a heparin-binding protein. In pres- cizumab in combination with oxaliplatin, fluorouracil, and ence of heparin, BEV+VEGF immune complexes activate leucovorin (FOLFOX4) for previously treated metastatic col- platelets via the IgG receptor FcγRIIa—a mechanism similar orectal cancer: results from the Eastern Cooperative Oncology to that observed with antibodies from patients with heparin- Group Study E3200,” Journal of Clinical Oncology, vol. 25, no. induced thrombocytopenia (HIT). VEGF can directly anchor 12, pp. 1539–1544, 2007. to platelet surface-bound platelet factor-4 (VEGF binds [7] H. S. Hochster, L. L. Hart, R. K. Ramanathan et al., “Safety and platelet factor-4 with high affinity) [11], which may explain efficacy of oxaliplatin and fluoropyrimidine regimens with heparin-independent BEV+VEGF activity. Meyer et al. [10] or without bevacizumab as first-line treatment of metastatic provided evidence that BEV immune complexes can directly colorectal cancer: results of the TREE study,” Journal of Clinical induce platelet aggregation and granule release in vitro and Oncology, vol. 26, no. 21, pp. 3523–3529, 2008. cause thrombocytopenia and thrombosis in vivo in a murine ´ [8] L.B.Saltz,S.Clarke, E. Dıaz-Rubio et al., “Bevacizumab in model. combination with oxaliplatin-based chemotherapy as first- line therapy in metastatic colorectal cancer: a randomized Thrombocytopenia can also be because of bevacizumab phase III study,” Journal of Clinical Oncology, vol. 26, no. 12, causing platelet dysfunction and consumption leading to pp. 2013–2019, 2008. shortened platelet half-life. It seems that overt thrombocy- [9] F. Selheim, H. Holmsen, and F. S. Vassbotn, “Identification of topenia would then develop once the compensatory mecha- functional VEGF receptors on human platelets,” FEBS Letters, nisms of the bone marrow became exhausted, particularly in vol. 512, no. 1–3, pp. 107–110, 2002. a patient who has had multiple prior therapies. [10] T. Meyer, L. Robles-Carrillo, T. Robson et al., “Bevacizumab A meta-analysis by Kut et al. [12] concluded that VEGF in immune complexes activate platelets and induce thrombosis cancer patients is mostly concentrated in the platelets within in FCGR2A transgenic mice,” Journal of Thrombosis and the blood compartment and that the cancer itself is not the Haemostasis, vol. 7, no. 1, pp. 171–181, 2009. main source of VEGF in the body. In vitro tests have shown [11] A. Bikfalvi, “Recent developments in the inhibition of angio- a stimulatory effect of VEGF on thrombin-induced platelet genesis: examples from studies on platelet factor-4 and the activation. This suggests that the endogenously secreted VEGF/VEGFR system,” Biochemical Pharmacology, vol. 68, no. 6, pp. 1017–1021, 2004. platelet VEGF may function as a positive feedback regulator [12] C. Kut, F. MacGabhann, andA.S.Popel,“WhereisVEGF during platelet activation [9]. Theoretically, the interaction in the body? A meta-analysis of VEGF distribution in cancer,” of bevacizumab with the platelet VEGF during platelet British Journal of Cancer, vol. 97, no. 7, pp. 978–985, 2007. activation could result in impaired primary hemostasis, increasing the risk of hemorrhage. Since the platelet counts recovered after methylpred- nisolone and bone marrow had shown increase in megakary- ocytes, the proposed mechanism of thrombocytopenia in our patient may have been immune-mediated peripheral destruction of platelets. It is of course possible that other mechanisms could also have contributed to thrombocytope- nia as an additive effect. High degree of awareness is required to this potential complication, which may have significant implications for clinical care and ongoing research. References [1] Avastin Prescribing Information, Genentech, 2011. [2] H. Hurwitz, L. Fehrenbacher, W. Novotny et al., “Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer,” New England Journal of Medicine, vol. 350, no. 23, pp. 2335–2342, 2004. 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Published: Oct 10, 2012