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

Guangrong Lu, Ping Zhu, Mayank Rao, Nadine Linendoll, L. Maximilian Buja, Meenakshi B. Bhattacharjee, Robert E. Brown, Leomar Y. Ballester, Xuejun Tian, Monika Pilichowska, Julian K. Wu, Georgene W. Hergenroeder, Williams F. Glass, Lei Chen, Rongzhen Zhang, Anil K. Pillai, Robert L. Hunter, Jay Jiguang Zhu

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Systemic chemotherapy including 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 (GBM). Most patients tolerated these regimens well with known side effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ- or system- specific toxicities from chemotherapy agents have never been examined by postmortem study. This is the largest cohort used to address this issue in glioma patients. Methods: Postmortem tissues (from all major systems and organs) were prospectively collected and examined by standard institution autopsy and neuropathological procedures from 76 subjects, 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 including brain specimens. Electronic microscopic (EM) study was carried out on 14 selected subject’s kidney samples per standard EM protocol. Medical records were reviewed with adverse events (AEs) analyzed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A swimmer plot was utilized to visualize the timelines of patient history by treatment group. The binary logistic regression models were performed to explore any associations between treatment strategies and incident myelosuppression. Results: Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1–25) cycles] at tumor recurrence. Exposure to IRI significantly increased the frequency of CM (p = 0.05). No unexpected adverse events clinically, or permanent end-organ damage during postmortem examination was identified in glioma subjects who had received standard or prolonged duration of BEV, TMZ or TIB regimen-based chemotherapies except rare events of bone marrow suppression. The most common causes of death (COD) were tumor progression (63.2%, N = 43) followed by aspiration pneumonia (48.5%, N = 33) in glioma subjects. 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. Conclusion: There is no organ or system toxicity by postmortem examinations among glioma subjects who received BEV, TMZ or TIB regimen-based chemotherapies regardless of durations except for occasional bone marrow suppression and reversible myelosuppression clinically. IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. COD most commonly resulted from glioma tumor progression with infiltration to brain stem and aspiration pneumonia.

Original languageEnglish (US)
Pages (from-to)221-231
Number of pages11
JournalJournal of neuro-oncology
Volume160
Issue number1
DOIs
StatePublished - Oct 2022

Bibliographical note

Funding Information:
We are very grateful to pathology attending physicians and residents from both Tufts Medical Center and UTHealth McGovern Medical School/Memorial Hermann Hospital at Texas Medical Center. We appreciate the technical assistance of sample preparation for electron microscope examination by Ms. Patricia Navarro at the Pathology Department and sample preparation for IDH study by Mr. Yu Cai of Radiology Department of UTHealth. We are very thankful to Drs. Bihong Zhao and Joanna S. O'Leary at UTHealth for their editorial assistances.

Funding Information:
This study is partially funded by the Dr. Marnie Rose Foundation (J-J Z).

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

  • Autopsy
  • Bevacizumab
  • Brain metastasis
  • Chemotherapy
  • End-organ toxicity
  • Glioblastoma (GBM)
  • Glioma
  • Irinotecan
  • Myelosuppression
  • Postmortem
  • Temozolomide

PubMed: MeSH publication types

  • Journal Article

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