PMID- 36203027 OWN - NLM STAT- MEDLINE DCOM- 20221102 LR - 20221102 IS - 1573-7373 (Electronic) IS - 0167-594X (Linking) VI - 160 IP - 1 DP - 2022 Oct TI - Postmortem study of organ-specific toxicity in glioblastoma patients treated with a combination of temozolomide, irinotecan and bevacizumab. PG - 221-231 LID - 10.1007/s11060-022-04144-y [doi] AB - 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. CI - (c) 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. FAU - Lu, Guangrong AU - Lu G AD - The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth(R)) McGovern Medical School and Memorial Hermann Hospital at Texas Medical Center, 6400 Fannin Street, Suite 2800, Houston, TX, 77030, USA. FAU - Zhu, Ping AU - Zhu P AD - The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth(R)) McGovern Medical School and Memorial Hermann Hospital at Texas Medical Center, 6400 Fannin Street, Suite 2800, Houston, TX, 77030, USA. AD - Department of Neurosurgery, University of Minnesota, Minneapolis, MN, 55455, USA. FAU - Rao, Mayank AU - Rao M AD - The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth(R)) McGovern Medical School and Memorial Hermann Hospital at Texas Medical Center, 6400 Fannin Street, Suite 2800, Houston, TX, 77030, USA. FAU - Linendoll, Nadine AU - Linendoll N AD - Department of Hematology-Oncology, Tufts Medical Center, Boston, MA, 02111, USA. FAU - Buja, L Maximilian AU - Buja LM AD - Department of Pathology and Laboratory Medicine, UTHealth(R) McGovern Medical School, Houston, TX, 77030, USA. FAU - Bhattacharjee, Meenakshi B AU - Bhattacharjee MB AD - Department of Pathology and Laboratory Medicine, UTHealth(R) McGovern Medical School, Houston, TX, 77030, USA. FAU - Brown, Robert E AU - Brown RE AD - Department of Pathology and Laboratory Medicine, UTHealth(R) McGovern Medical School, Houston, TX, 77030, USA. FAU - Ballester, Leomar Y AU - Ballester LY AD - The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth(R)) McGovern Medical School and Memorial Hermann Hospital at Texas Medical Center, 6400 Fannin Street, Suite 2800, Houston, TX, 77030, USA. AD - Department of Pathology and Laboratory Medicine, UTHealth(R) McGovern Medical School, Houston, TX, 77030, USA. FAU - Tian, Xuejun AU - Tian X AD - Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, USA. AD - Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, 10467, USA. FAU - Pilichowska, Monika AU - Pilichowska M AD - Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, USA. FAU - Wu, Julian K AU - Wu JK AD - Department of Neurosurgery, Tufts Medical Center, Boston, MA, 02111, USA. FAU - Hergenroeder, Georgene W AU - Hergenroeder GW AD - The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth(R)) McGovern Medical School and Memorial Hermann Hospital at Texas Medical Center, 6400 Fannin Street, Suite 2800, Houston, TX, 77030, USA. FAU - Glass, Williams F AU - Glass WF AD - Department of Pathology and Laboratory Medicine, UTHealth(R) McGovern Medical School, Houston, TX, 77030, USA. FAU - Chen, Lei AU - Chen L AD - Department of Pathology and Laboratory Medicine, UTHealth(R) McGovern Medical School, Houston, TX, 77030, USA. FAU - Zhang, Rongzhen AU - Zhang R AD - Department of Pathology and Laboratory Medicine, UTHealth(R) McGovern Medical School, Houston, TX, 77030, USA. FAU - Pillai, Anil K AU - Pillai AK AD - Diagnostic & Interventional Imaging, UTHealth(R) McGovern Medical School, Houston, TX, 77030, USA. FAU - Hunter, Robert L AU - Hunter RL AD - Department of Pathology and Laboratory Medicine, UTHealth(R) McGovern Medical School, Houston, TX, 77030, USA. FAU - Zhu, Jay-Jiguang AU - Zhu JJ AUID- ORCID: 0000-0003-4635-0914 AD - The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston (UTHealth(R)) McGovern Medical School and Memorial Hermann Hospital at Texas Medical Center, 6400 Fannin Street, Suite 2800, Houston, TX, 77030, USA. jay.jiguang.zhu@uth.tmc.edu. LA - eng PT - Journal Article DEP - 20221006 PL - United States TA - J Neurooncol JT - Journal of neuro-oncology JID - 8309335 RN - YF1K15M17Y (Temozolomide) RN - 2S9ZZM9Q9V (Bevacizumab) RN - 7673326042 (Irinotecan) SB - IM MH - Humans MH - Temozolomide/therapeutic use MH - *Glioblastoma/therapy MH - Bevacizumab/therapeutic use MH - Irinotecan/therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - Neoplasm Recurrence, Local/drug therapy MH - *Brain Neoplasms/therapy MH - *Glioma/drug therapy MH - *Pneumonia, Aspiration OTO - NOTNLM OT - Autopsy OT - Bevacizumab OT - Brain metastasis OT - Chemotherapy OT - End-organ toxicity OT - Glioblastoma (GBM) OT - Glioma OT - Irinotecan OT - Myelosuppression OT - Postmortem OT - Temozolomide EDAT- 2022/10/07 06:00 MHDA- 2022/11/03 06:00 CRDT- 2022/10/06 23:35 PHST- 2022/01/10 00:00 [received] PHST- 2022/09/20 00:00 [accepted] PHST- 2022/10/07 06:00 [pubmed] PHST- 2022/11/03 06:00 [medline] PHST- 2022/10/06 23:35 [entrez] AID - 10.1007/s11060-022-04144-y [pii] AID - 10.1007/s11060-022-04144-y [doi] PST - ppublish SO - J Neurooncol. 2022 Oct;160(1):221-231. doi: 10.1007/s11060-022-04144-y. Epub 2022 Oct 6.