Dramatic response to temozolomide, irinotecan, and bevacizumab for recurrent medulloblastoma with widespread osseous metastases

Bonney, Phillip A.; Santucci, Joshua; Maurer, Adrian J.; Sughrue, Michael E.; McNall-Knapp, René; Battiste, James

doi:10.1016/j.jocn.2015.10.022

Cited by 25 publications

(12 citation statements)

References 12 publications

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“…The TBI regimen produced moderate side effects including hypertension, leukopenia, and proteinuria. This study confirmed previous published results that TBI is a safe regimen with manageable and expected side effects (Supplement Table 1) (19–21, 23–27), which lends support to a proposed clinical trial testing this regimen in rGBM patients.…”

Section: Discussionsupporting

confidence: 90%

“…The TBI regimen was also well-tolerated among pediatric patients with medulloblastoma (42) and neuroblastoma (24). A dramatic response from TBI regimen therapy was reported in a patient diagnosed with recurrent medulloblastoma with widespread osseous metastases (23). Although these studies have small sample sizes, they have all demonstrated that the TBI regimen is safe for patient use.…”

Section: Discussionmentioning

confidence: 99%

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Triple-drug Therapy With Bevacizumab, Irinotecan, and Temozolomide Plus Tumor Treating Fields for Recurrent Glioblastoma: A Retrospective Study

Rao

Zhu

et al. 2019

Front. Neurol.

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Clinical studies treating pediatric and adult solid tumors, such as glioblastoma (GBM), with a triple-drug regimen of temozolomide (TMZ), bevacizumab (BEV), and irinotecan (IRI) [TBI] have demonstrated various efficacies, but with no unexpected toxicities. The TBI regimen has never been studied in recurrent GBM (rGBM) patients. In this retrospective study, we investigated the outcomes and side effects of rGBM patients who had received the TBI regimen. We identified 48 adult rGBM patients with a median age of 56 years (range: 26–76), who received Tumor Treating Fields (TTFields) treatment for 30 days or longer, and concurrent salvage chemotherapies. The patients were classified into two groups based on chemotherapies received: TBI with TTFields (TBI+T, N = 18) vs. bevacizumab (BEV)-based chemotherapies with TTFields (BBC+T, N = 30). BBC regimens were either BEV monotherapy, BEV+IRI or BEV+CCNU. Patients in TBI+T group received on average 19 cycles of TMZ, 26 and 21 times infusions with BEV and IRI, respectively. Median overall survival (OS) and progression-free survival (PFS) for rGBM (OS-R and PFS-R) patients who received TBI+T were 18.9 and 10.7 months, respectively. In comparison, patients who received BBC+T treatment had OS-R and PFS-R of 11.8 (P > 0.05) and 4.7 (P < 0.05) months, respectively. Although the median PFS results were significantly different by 1.5 months (6.6 vs. 5.1) between TBI+T and BBC+T groups, the median OS difference of 14.7 months (32.5 vs. 17.8) was more pronounced, P < 0.05. Patients tolerated TBI+T or BBC+T treatments well and there were no unexpected toxicities. The most common side effects from TBI+T treatment included grade III hypertension (38.9%) and leukopenia (22.2%). In conclusion, the TBI regimen might play a role in the improvement of PFS-R and OS-R among rGBM patients. Prospective studies with a larger sample size are warranted to study the efficacy and toxicity of TBI+T regimen for rGBM.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Triple-drug Therapy With Bevacizumab, Irinotecan, and Temozolomide Plus Tumor Treating Fields for Recurrent Glioblastoma: A Retrospective Study

Rao

Zhu

et al. 2019

Front. Neurol.

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“…Prior reports demonstrated some efficacy of these agents alone or in combination, 46–48 but this report is the largest cohort to date. In an Italian multi‐institutional phase II trial, Cefalo et al 49 .…”

Section: Discussionmentioning

confidence: 75%

Temozolomide with irinotecan versus temozolomide, irinotecan plus bevacizumab for recurrent medulloblastoma of childhood: Report of a COG randomized Phase II screening trial

Levy

Krailo

Chi

et al. 2021

Pediatric Blood & Cancer

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Background: Approximately 30% of children with medulloblastoma (MB) experience recurrence, which is usually incurable. This study compared the overall survival (OS) of patients receiving temozolomide (TMZ) and irinotecan with that of patients receiving TMZ, irinotecan, and bevacizumab for recurrent MB/central nervous system (CNS) primitive neuroectodermal tumor (PNET). Methods: Patients with relapsed/refractory MB or CNS PNET were randomly assigned to receive TMZ (150 mg/m2/day PO on days 1–5) and irinotecan (50 mg/m2/day IV on days 1–5) with or without bevacizumab (10 mg/kg IV on days 1 and 15). Results: One hundred five patients were eligible and treated on study. Median OS was 13 months in the standard arm and 19 months with the addition of bevacizumab; median event‐free survival (EFS) was 6 months in the standard arm and 9 months with the addition of bevacizumab. The hazard ratio for death from the stratified relative‐risk regression model is 0.63. Overall, 23 patients completed 12 courses of planned protocol therapy, 23% (12/52) in the experimental arm with bevacizumab versus 21% (11/53) in the standard arm. Toxicity profiles were comparable in both treatment arms. The estimate of the incidence of feasibility events associated with the bevacizumab arm is three of 52 (5.8%) (95% CI 1.2–16%). Events included myelosuppression, electrolyte abnormalities, diarrhea, and elevated transaminases. One intracranial hemorrhage event was observed in each arm. Conclusion: The addition of bevacizumab to TMZ/irinotecan significantly reduced the risk of death in children with recurrent MB. The combination was relatively well tolerated in this heavily pretreated cohort. The three‐drug regimen demonstrated a sufficient risk reduction to warrant further investigation.

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“…For recurrent glioblastoma multiforme (GBM), the median overall survival was 8.63 months for patients treated with bevacizumab, an anti-VEGF antibody, and 8.91 months when bevacizumab was combined with irinotecan, a chemotherapeutic agent [62] Thus, this study showed bevacizumab alone is beneficial for GBM. Interestingly, recent clinical trials have also demonstrated the efficacy of bevacizumab for the treatment of recurrent MB when combined with chemotherapeutic agents temozolomide and irinotecan or with stereotactic radiosurgery [63,64]. Despite this promise, clinical use of antiangiogenic agents has not evolved [65,19].…”

Section: Discussionmentioning

confidence: 99%

REST promotes ETS1‐dependent vascular growth in medulloblastoma

et al. 2021

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Expression of the RE1 ‐silencing transcription factor (REST), a master regulator of neurogenesis, is elevated in medulloblastoma (MB) tumors. A cell‐intrinsic function for REST in MB tumorigenesis is known. However, a role for REST in the regulation of MB tumor microenvironment has not been investigated. Here, we implicate REST in remodeling of the MB vasculature and describe underlying mechanisms. Using REST TG mice, we demonstrate that elevated REST expression in cerebellar granule cell progenitors, the cells of origin of sonic hedgehog (SHH) MBs, increased vascular growth. This was recapitulated in MB xenograft models and validated by transcriptomic analyses of human MB samples. REST upregulation was associated with enhanced secretion of proangiogenic factors. Surprisingly, a REST‐dependent increase in the expression of the proangiogenic transcription factor E26 oncogene homolog 1, and its target gene encoding the vascular endothelial growth factor receptor‐1, was observed in MB cells, which coincided with their localization at the tumor vasculature. These observations were confirmed by RNA‐Seq and microarray analyses of MB cells and SHH‐MB tumors. Thus, our data suggest that REST elevation promotes vascular growth by autocrine and paracrine mechanisms.

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Dramatic response to temozolomide, irinotecan, and bevacizumab for recurrent medulloblastoma with widespread osseous metastases

Cited by 25 publications

References 12 publications

Triple-drug Therapy With Bevacizumab, Irinotecan, and Temozolomide Plus Tumor Treating Fields for Recurrent Glioblastoma: A Retrospective Study

Triple-drug Therapy With Bevacizumab, Irinotecan, and Temozolomide Plus Tumor Treating Fields for Recurrent Glioblastoma: A Retrospective Study

Temozolomide with irinotecan versus temozolomide, irinotecan plus bevacizumab for recurrent medulloblastoma of childhood: Report of a COG randomized Phase II screening trial

REST promotes ETS1‐dependent vascular growth in medulloblastoma

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