Reversible Posterior Leukoencephalopathy Syndrome and Bevacizumab
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《新英格兰医药杂志》
To the Editor: We would like to report the occurrence of reversible posterior leukoencephalopathy that we believe is directly attributable to bevacizumab (Avastin), a recombinant, humanized, monoclonal IgG1 antibody that binds and inhibits vascular endothelial growth factor (VEGF). A 59-year-old woman received seven infusions of bevacizumab at two-week intervals for the treatment of metastatic renal cancer, during which time her blood pressure remained within her usual range, at approximately 100/70 mm Hg. Eight days after the last infusion, she presented to the emergency room with severe lethargy. The physical examination was essentially normal except for a blood pressure of 168/88 mm Hg. Laboratory assessment was remarkable only for a white-cell count of 14,000 per cubic millimeter; urinalysis showed more than 100 white cells per high-power field and a moderate number of bacteria. The cerebrospinal fluid was clear, colorless, and acellular, with a total protein level of 78 mg per deciliter and a glucose level of 66 mg per deciliter. The patient was admitted to the hospital after a tonic–clonic seizure in the emergency room that was treated with lorazepam.
The patient's blood pressure initially fluctuated from 156 to 178 mm Hg systolic and from 70 to 98 mm Hg diastolic. Neurologic examination on the first hospital day revealed cortical blindness and extensor plantar responses. Magnetic resonance imaging (MRI) of the brain showed nonenhancing extensive leukoencephalopathy in the subcortical (distal vasculature) distribution (Figure 1). The patient had a normal brain MRI performed less than two months earlier.
Figure 1. MRI Scan of the Brain of a Patient with Leukoencephalopathy.
An axial FLAIR (fluid-attenuated inversion recovery) image shows symmetric frontal and parietal high-intensity lesions.
The patient made a rapid recovery, despite also having a small, left parieto-occipital hemorrhagic stroke. By hospital day 4, she was alert and able to read regular newsprint at 18 in., and plantar responses reverted to flexor. The blood pressure also returned to normal without treatment. Follow-up MRI six weeks later showed complete resolution of the leukoencephalopathy.
The reversible posterior leukoencephalopathy syndrome (RPLS) was initially reported by Hinchey et al. in 1996.1 We are aware of at least 82 reports in the English literature that associate this syndrome with various conditions, including chemotherapeutic drugs and immunosuppressants.2,3 We have found no reports of association with bevacizumab, which is approved for the treatment of metastatic colon and rectal cancer and is now being assessed in other oncologic settings. Reported adverse effects include hemorrhagic stroke, arterial thrombotic events, hypertension, and the nephrotic syndrome.
Since bevacizumab has a 20-day half-life, we believe this patient's reversible posterior leukoencephalopathy is attributable to bevacizumab. We speculate that this may have resulted from effects of this VEGF inhibitor on the blood–brain barrier. Because of the increasing use of this agent, clinicians should be aware of this potential association.
Peter Glusker, M.D., Ph.D.
Larry Recht, M.D.
Barton Lane, M.D.
Stanford University Medical Center
Stanford, CA 94305
pglusker@stanfordmed.org
References
Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494-500.
Garg RK. Posterior leukoencephalopathy syndrome. Postgrad Med J 2001;77:24-28.
Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a misnomer reviewed. Intern Med J 2005;35:83-90.
To the Editor: RPLS is a brain-capillary leak syndrome related to hypertension, fluid retention, and the cytotoxic effects of immunosuppressive agents on the vascular endothelium. Cyclosporine, tacrolimus, granulocyte colony-stimulating factor, cisplatin, epoetin, and immune globulin therapy have been associated with RPLS.1 We report a case of RPLS in association with bevacizumab, a monoclonal antibody directed at VEGF and its receptors.
A 52-year-old woman with hypertension and metastatic rectal adenocarcinoma who had received three cycles of chemotherapy with fluorouracil, leucovorin, and oxaliplatin presented with acute bilateral loss of vision, headache, and confusion 16 hours after her first dose of bevacizumab, which was administered with the fourth cycle of this chemotherapy regimen. The physical examination was unremarkable except for high blood pressure (172/100 mm Hg), hepatomegaly, and bilateral cortical visual loss with normal optic fundi. Laboratory studies, including cerebrospinal fluid and viral analyses, were unrevealing. However, T2-weighted MRI of the brain showed hyperintense areas at the posterior aspects of both occipital lobes. The patient's clinical presentation and imaging findings were characteristic of RPLS. With stringent blood-pressure control, her vision rapidly improved and recovered fully by the third day.
Bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure, and the number of viable, circulating endothelial and progenitor cells and increases the fraction of vessels with pericyte coverage in patients with rectal carcinoma.2 The drug improves survival and the rate of tumor regression in patients with colorectal carcinoma.3 However, bevacizumab-based combination chemotherapy is associated with a risk of grade 3 hypertension in up to 16 percent of patients, possibly secondary to vasospasm.4 Severe hypertensive encephalopathy leads to RPLS and vasogenic edema of the posterior cerebral white matter, induced by endothelial dysfunction and a disrupted blood–brain barrier. We speculate that bevacizumab may have induced vasospasm, which, coupled with hypertension in our patient, led to RPLS.
We suggest that RPLS is an important consideration in patients with poorly controlled hypertension who are treated with VEGF inhibitors. Clinicians should be aware of this potential complication and control blood pressure strictly during and after the bevacizumab infusion. Controlling hypertension and discontinuing the offending agent appear to help reverse this complication. It is important early in the clinical course to differentiate this syndrome from acute cerebral ischemia or thromboembolic phenomena, which are also associated with this agent, in order to avert permanent visual loss.
Cevher Ozcan, M.D.
Stuart J. Wong, M.D.
Parameswaran Hari, M.D.
Medical College of Wisconsin
Milwaukee, WI 53226
phari@mail.mcw.edu
References
Tam CS, Galanos J, Seymour JF, Pitman AG, Stark RJ, Prince HM. Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies. Am J Hematol 2004;77:72-76.
Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145-147.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342.
Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005;23:3697-3705.
The above letters were referred to Genentech, the manufacturer of bevacizumab, which offers the following reply: Genentech is committed to providing physicians and patients with important safety and efficacy information available for bevacizumab (Avastin). Avastin was approved in the United States in February 2004 for use in combination with intravenous fluorouracil chemotherapy for the treatment of newly diagnosed metastatic colorectal cancer. It is also approved in many other countries worldwide, and we estimate that more than 60,000 patients have been treated with Avastin globally.
The letters from Dr. Glusker and colleagues and Dr. Ozcan and colleagues provide valuable information about a very rare syndrome. We agree that the two patients reported meet the clinical criteria for RPLS. At this time, we are reviewing the global safety database to look for cases with clinical signs and symptoms associated with RPLS and are investigating one additional case.
We believe it is important for physicians to be cognizant of the signs and symptoms of this rare but reversible syndrome and its association with even moderate hypertension. Hypertension, a known adverse reaction associated with Avastin treatment, has been included in the Avastin package insert since the drug's approval in 2004. We plan to update the Avastin package insert in the United States to include a description of the syndrome and to recommend discontinuation of Avastin if RPLS is diagnosed. Our corporate partner, Roche, will implement appropriate actions outside of the United States.
Patient safety is of utmost importance to us, and Genentech encourages physicians to continue reporting RPLS and other adverse events observed during Avastin treatment.
Hal Barron, M.D.
Genentech
South San Francisco, CA 94080-4990
The patient's blood pressure initially fluctuated from 156 to 178 mm Hg systolic and from 70 to 98 mm Hg diastolic. Neurologic examination on the first hospital day revealed cortical blindness and extensor plantar responses. Magnetic resonance imaging (MRI) of the brain showed nonenhancing extensive leukoencephalopathy in the subcortical (distal vasculature) distribution (Figure 1). The patient had a normal brain MRI performed less than two months earlier.
Figure 1. MRI Scan of the Brain of a Patient with Leukoencephalopathy.
An axial FLAIR (fluid-attenuated inversion recovery) image shows symmetric frontal and parietal high-intensity lesions.
The patient made a rapid recovery, despite also having a small, left parieto-occipital hemorrhagic stroke. By hospital day 4, she was alert and able to read regular newsprint at 18 in., and plantar responses reverted to flexor. The blood pressure also returned to normal without treatment. Follow-up MRI six weeks later showed complete resolution of the leukoencephalopathy.
The reversible posterior leukoencephalopathy syndrome (RPLS) was initially reported by Hinchey et al. in 1996.1 We are aware of at least 82 reports in the English literature that associate this syndrome with various conditions, including chemotherapeutic drugs and immunosuppressants.2,3 We have found no reports of association with bevacizumab, which is approved for the treatment of metastatic colon and rectal cancer and is now being assessed in other oncologic settings. Reported adverse effects include hemorrhagic stroke, arterial thrombotic events, hypertension, and the nephrotic syndrome.
Since bevacizumab has a 20-day half-life, we believe this patient's reversible posterior leukoencephalopathy is attributable to bevacizumab. We speculate that this may have resulted from effects of this VEGF inhibitor on the blood–brain barrier. Because of the increasing use of this agent, clinicians should be aware of this potential association.
Peter Glusker, M.D., Ph.D.
Larry Recht, M.D.
Barton Lane, M.D.
Stanford University Medical Center
Stanford, CA 94305
pglusker@stanfordmed.org
References
Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494-500.
Garg RK. Posterior leukoencephalopathy syndrome. Postgrad Med J 2001;77:24-28.
Stott VL, Hurrell MA, Anderson TJ. Reversible posterior leukoencephalopathy syndrome: a misnomer reviewed. Intern Med J 2005;35:83-90.
To the Editor: RPLS is a brain-capillary leak syndrome related to hypertension, fluid retention, and the cytotoxic effects of immunosuppressive agents on the vascular endothelium. Cyclosporine, tacrolimus, granulocyte colony-stimulating factor, cisplatin, epoetin, and immune globulin therapy have been associated with RPLS.1 We report a case of RPLS in association with bevacizumab, a monoclonal antibody directed at VEGF and its receptors.
A 52-year-old woman with hypertension and metastatic rectal adenocarcinoma who had received three cycles of chemotherapy with fluorouracil, leucovorin, and oxaliplatin presented with acute bilateral loss of vision, headache, and confusion 16 hours after her first dose of bevacizumab, which was administered with the fourth cycle of this chemotherapy regimen. The physical examination was unremarkable except for high blood pressure (172/100 mm Hg), hepatomegaly, and bilateral cortical visual loss with normal optic fundi. Laboratory studies, including cerebrospinal fluid and viral analyses, were unrevealing. However, T2-weighted MRI of the brain showed hyperintense areas at the posterior aspects of both occipital lobes. The patient's clinical presentation and imaging findings were characteristic of RPLS. With stringent blood-pressure control, her vision rapidly improved and recovered fully by the third day.
Bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure, and the number of viable, circulating endothelial and progenitor cells and increases the fraction of vessels with pericyte coverage in patients with rectal carcinoma.2 The drug improves survival and the rate of tumor regression in patients with colorectal carcinoma.3 However, bevacizumab-based combination chemotherapy is associated with a risk of grade 3 hypertension in up to 16 percent of patients, possibly secondary to vasospasm.4 Severe hypertensive encephalopathy leads to RPLS and vasogenic edema of the posterior cerebral white matter, induced by endothelial dysfunction and a disrupted blood–brain barrier. We speculate that bevacizumab may have induced vasospasm, which, coupled with hypertension in our patient, led to RPLS.
We suggest that RPLS is an important consideration in patients with poorly controlled hypertension who are treated with VEGF inhibitors. Clinicians should be aware of this potential complication and control blood pressure strictly during and after the bevacizumab infusion. Controlling hypertension and discontinuing the offending agent appear to help reverse this complication. It is important early in the clinical course to differentiate this syndrome from acute cerebral ischemia or thromboembolic phenomena, which are also associated with this agent, in order to avert permanent visual loss.
Cevher Ozcan, M.D.
Stuart J. Wong, M.D.
Parameswaran Hari, M.D.
Medical College of Wisconsin
Milwaukee, WI 53226
phari@mail.mcw.edu
References
Tam CS, Galanos J, Seymour JF, Pitman AG, Stark RJ, Prince HM. Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies. Am J Hematol 2004;77:72-76.
Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004;10:145-147.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342.
Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005;23:3697-3705.
The above letters were referred to Genentech, the manufacturer of bevacizumab, which offers the following reply: Genentech is committed to providing physicians and patients with important safety and efficacy information available for bevacizumab (Avastin). Avastin was approved in the United States in February 2004 for use in combination with intravenous fluorouracil chemotherapy for the treatment of newly diagnosed metastatic colorectal cancer. It is also approved in many other countries worldwide, and we estimate that more than 60,000 patients have been treated with Avastin globally.
The letters from Dr. Glusker and colleagues and Dr. Ozcan and colleagues provide valuable information about a very rare syndrome. We agree that the two patients reported meet the clinical criteria for RPLS. At this time, we are reviewing the global safety database to look for cases with clinical signs and symptoms associated with RPLS and are investigating one additional case.
We believe it is important for physicians to be cognizant of the signs and symptoms of this rare but reversible syndrome and its association with even moderate hypertension. Hypertension, a known adverse reaction associated with Avastin treatment, has been included in the Avastin package insert since the drug's approval in 2004. We plan to update the Avastin package insert in the United States to include a description of the syndrome and to recommend discontinuation of Avastin if RPLS is diagnosed. Our corporate partner, Roche, will implement appropriate actions outside of the United States.
Patient safety is of utmost importance to us, and Genentech encourages physicians to continue reporting RPLS and other adverse events observed during Avastin treatment.
Hal Barron, M.D.
Genentech
South San Francisco, CA 94080-4990