Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab

Abstract

Systemic monotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as Irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma. Most patients tolerated these regimens well with well-established sides effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ-speci c toxicities have never been examined by postmortem studies. MethodsPostmortem tissues (from all major organs) were prospectively collected and examined by standard institution autopsy and brain cutting procedures from 76 decedents, including gliomas (N=68, 44/M, and 24/F) and brain metastases (N=8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin (H&E) were performed on all major organs and brain samples harvested. Electronic microscopic (EM) study was carried on selected subjects kidney samples per standard EM protocol. ResultsTwenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at glioma recurrence.Exposure to IRI signi cantly increased the frequency of CM (p=0.05). No unexpected adverse events were detected clinically or permenant end-organ damage by postmortem examination among subjects who received TIB compared to subjects who received standard of care (SOC) therapies. Among glioma decedents, the most common causes of death (COD) were tumor progression (63.2%, N=43), followed by aspiration pneumonia (48.5%, N=33). No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. ConclusionIRI, but not the extended use of TMZ, signi cantly increased CM in recurrent glioma patients. There is no permanent organ-speci c toxicity among glioma decedents who received prolonged BEV, TMZ or TIB regimen based chemotherapies except expected occasional myelosuppresson. COD are most commonly resulted from glioma tumor progression and aspiration pneumonia.

Comparative Study of Postmortem MRI and Pathological Findings in Malignant Brain Tumors

“…However, there is a time lag between the final imaging examination before death and at death, and the final imaging examination before death may not accurately assess the condition during an autopsy. An MRI examination of the autopsied brain can compensate for this time difference [ 3 , 9 ]. The benefits of postmortem MRI are that it produces a clear image without body motion or pulsating echoes of cerebrospinal fluid and blood, allowing for the comparison of images and pathology in the exact same plane, and does not consider the possibility of lesion progression or change between the time that the MRI is taken and the pathology specimen is examined.…”

“…In addition, tumor cell features such as high invasive capacity and proliferative ability can cause serious brain dysfunctions, such as paralysis and impaired consciousness. In such intractable tumors, brain specimens obtained at autopsies are useful not only for understanding the pathology of brain tumors but also for elucidating the effects of treatment and its relationship to the primary brain tissue [ 3 ]. However, final magnetic resonance imaging (MRI) before death does not accurately reflect the pathology at the time of autopsy because of the time difference between the time of autopsy and the time of final MRI.…”

Larotrectinib versus infigratinib for adult patients with both glioma and tyrosine kinase alterations after failure of initial therapies: Efficacy and safety analysis

“…The Common Terminology Criteria for Adverse Events, version 4.03, was used to evaluate adverse effects during the treatment(s) and follow-up period. 10 …”