Postmortem Evaluation of Kidney and Other End-Organ Toxicity in Glioblastoma Patients Treated with Bevacizumab
Xuejun Tian, Jay Jiguang Zhu, Nadine Linendoll, Rolf Pfannl, Monika Pilichowska. Tufts Medical Center, Tufts Medical School, Boston, MA
Background: Bevacizumab (BEV) alone or in combination with temozolomide (TMZ) and/or irinotecan is the main chemotherapy option for progressive glioblastoma (GBM). BEV containing regimens are also widely used for metastatic kidney, breast, colon and lung cancers. There are concerns of permanent organ damage from long term use of BEV containing regimens. However, post-mortem examination of end-organ toxicity has not been reported.
Design: Postmortem organ specific morphologic studies including electron microscopy (EM) and immunofluorescence (IF) were performed in 10 cases of progressive GBM treated with TMZ and BEV containing regimens. 9 male and 1 female subjects were included, ranging from 50 to 77 years of age (median 57 years old). All subjects were treated at Tufts Medical Center, Boston and received palliative care prior to their death. All patients initially received standard treatment for GBM with subsequent monthly TMZ. After GBM progression they received BEV every the other week at 10 mg/kg with TMZ or irinotecan (5-49 treatments, median 17 treatments). Medical records of all 10 subjects were reviewed. Clinical toxicities and laboratory abnormalities were documented. Institutional review board (IRB) clearance and autopsy consents form the next of kin were obtained.
Results: The cause of death in most patients was bronchopneumonia (8/10). Clinically, apart from symptoms related to tumor progression in relevant cases, 8 subjects receiving BEV treatment developed proteinuria (trace to 3+) and 4 subjects developed hypertension. In 9 out of 10 unlimited autopsies (one was brain and kidney only). There was no significant morphologic evidence of TMZ/BEV-related injury in heart, liver, adrenal glands, thyroid, pancreas, spleen, or bone marrow. In all subjects the glomeruli revealed diffuse variable degree of glomerular basement membrane thickening with segmental to global double contours and without proliferative lesions. EM examination of the kidneys showed homogenized substructure and subendothelial rarefaction with some wrinkling of the glomerular basement membrane. The vasculature showed variable mural thickening as observed in hypertensive changes. IF examination showed no immune complex depositions.
Conclusions: With the exception of the kidneys, there appears to be no significant end-organ damage associated with treatment with TMZ and BEV of variable durations. Renal toxicity manifests as mild-to-moderate endothelial damage which was clinically associated with variable proteinuria and hypertension.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 7, Wednesday Morning