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

  • Clinical Study
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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.

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Data availability

This manuscript has processed data included as electronic supplementary material. The datasets (raw data) generated during and/or analyzed during the current study are available from the corresponding author upon request.

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Acknowledgements

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

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

Author information

Authors and Affiliations

  1. The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth®) McGovern Medical School and Memorial Hermann Hospital at Texas Medical Center, 6400 Fannin Street, Suite 2800, Houston, TX, 77030, USA

    Guangrong Lu, Ping Zhu, Mayank Rao, Leomar Y. Ballester, Georgene W. Hergenroeder & Jay-Jiguang Zhu

  2. Department of Hematology-Oncology, Tufts Medical Center, Boston, MA, 02111, USA

    Nadine Linendoll

  3. Department of Pathology and Laboratory Medicine, UTHealth® McGovern Medical School, Houston, TX, 77030, USA

    L. Maximilian Buja, Meenakshi B. Bhattacharjee, Robert E. Brown, Leomar Y. Ballester, Williams F. Glass, Lei Chen, Rongzhen Zhang & Robert L. Hunter

  4. Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, USA

    Xuejun Tian & Monika Pilichowska

  5. Department of Neurosurgery, Tufts Medical Center, Boston, MA, 02111, USA

    Julian K. Wu

  6. Diagnostic & Interventional Imaging, UTHealth® McGovern Medical School, Houston, TX, 77030, USA

    Anil K. Pillai

  7. Department of Neurosurgery, University of Minnesota, Minneapolis, MN, 55455, USA

    Ping Zhu

  8. Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, 10467, USA

    Xuejun Tian

Authors
  1. Guangrong Lu
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Contributions

All authors contributed to the study. J-JZ initiated the project and mobilized resources for the study at Tufts Medical Center first, then at University of Texas Health Science Center at Houston (UTHealth®) McGovern Medical School and Memorial Hermann at Texas Medical Center. JK. Wu and J-JZ were investigators at Tuft Medical Center and University of Texas Health Science Center at Houston (UTHealth®) McGovern Medical School and Memorial Hermann at Texas Medical Center; respectively. Autopsies, tissue collections, storage and retrieval, gross anatomy and microscopic analysis of tissues were performed at the Department of Pathology, supervised by MB, MBB, LYB, REB, XT, MP, GWH, RZ, and RLH. Ultrasound guided kidney biopsy in cadaver was performed by AKP. Slides review and pathology reports were issued by MB, MBB, LYB, XT, MP, RLH. WFG and LC. Clinical data collection and analysis were performed by GL, MR, NL and J-JZ. Stiatistical analysis was performed by PZ. The first draft of the manuscript was written by GL. J-JZ, GL, and PZ had worked on all versions of the manuscript. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Jay-Jiguang Zhu.

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Conflicts of interest

The authors have no relevant financial or non-financial interests to disclose.

Research involving human participants

This study used postmortem human specimens and had reviewed medical records from deceased subjects. The study was performed in line with the principles of the Declaration of Helsinki. It is approved by the Health Sciences Institutional Review Board (IRB) at Tufts Medical Center. The same study protocol was also approved by the Committee for the Protection of Human Subjects (CPHS) at the University of Texas Health Science Center at Houston (UTHealth) (HSC-MS-11–0133).

Informed consent

Consents for autopsy examination were obtained from all participants, either from patients when patients were alive or from the next of kin after subjects had deceased before autopsy [full autopsies (N = 69), restricted autopsies to the brain (N = 6) and restricted to the brain and kidney (N = 1)].

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Lu, G., Zhu, P., Rao, M. et al. Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab. J Neurooncol 160, 221–231 (2022). https://doi.org/10.1007/s11060-022-04144-y

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  • DOI: https://doi.org/10.1007/s11060-022-04144-y

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