Long-term toxicity of bevacizumab therapy in neurofibromatosis 2 patients.
OBJECTIVE
Bevacizumab treatment is associated with tumor shrinkage and hearing improvement in about 50 % of neurofibromatosis 2 (NF2) patients with progressive vestibular schwannomas. Hypertension and proteinuria are common side effects of treatment. However, the long-term toxicity of bevacizumab in this population has not been reported.


METHODS
We reviewed the medical records of all NF2 patients treated with compassionate care bevacizumab at our institution. Hypertension was defined as a systolic blood pressure ≥140 or a diastolic blood pressure ≥90. Proteinuria was measured by urine dipstick. Time-to-event analyses were conducted for hypertension and proteinuria. The relationship of cumulative dose of bevacizumab to mean arterial pressure (MAP) was examined using mixed model analysis, while the relationship to urine protein was examined using generalized estimating equations.


RESULTS
Thirty-three patients (median age 28 years) were included in the study, with a median treatment time of 34.1 months. 15/26 (58 %) patients became hypertensive and 18/29 (62 %) developed proteinuria during treatment. Median time to develop hypertension was 12.8 months. Median time to develop 1+ and 2+ proteinuria was 23.7 and 31.9 months, respectively. Eight patients required treatment holidays for proteinuria (median length 3.2 months). A significant positive relationship existed between cumulative bevacizumab dose and MAP (p < 0.0001) but not between cumulative dose and proteinuria (p > 0.30).


CONCLUSIONS
In our cohort of NF2 patients, extended use of bevacizumab was associated with manageable toxicity. However, bevacizumab treatment still requires careful monitoring of blood pressure and proteinuria, and future studies should investigate optimal dosing schedules to minimize long-term toxicity.
Center for Neurofibromatosis and Allied Disorders, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
Katherine M
KM
Slusarz
Vanessa L
VL
Merker
Alona
A
Muzikansky
Sanjeev A
SA
Francis
Scott R
SR
Plotkin
D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects*; D000068258:Bevacizumab; D002648:Child; D015331:Cohort Studies; D057176:Compassionate Use Trials / Q000009:adverse effects / Q000379:methods; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D016518:Neurofibromatosis 2 / Q000188:drug therapy*; D011507:Proteinuria / Q000139:chemically induced; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab