Canine (Pet Dog) Tumor Microsurgery and Intratumoral Concentration and Safety of Metronomic Chlorambucil for Spontaneous Glioma

A Phase I Clinical Trial

R. Timothy Bentley, Stephanie A. Thomovsky, Margaret A. Miller, Deborah W. Knapp, Aaron Cohen-Gadol

Research output: Contribution to journalArticle

Abstract

Objective: Metronomic (daily low-dose) chlorambucil requires further study before use in human patients with glioma. The aim of this study was to investigate distribution and safety of metronomic chlorambucil in naturally occurring canine glioma. Methods: Eight client-owned (pet) dogs with newly diagnosed spontaneous glioma were prospectively enrolled. Chlorambucil was administered preoperatively at 4 mg/m2 every 24 hours for ≥3 days and continued postoperatively until death or dose-limiting adverse events. Chlorambucil concentrations in the surgical glioma specimen, cerebrospinal fluid, and serum were analyzed. Dogs additionally received lomustine postoperatively. Dogs were monitored for seizures, myoclonus, cytopenias, and tumor recurrence. Results: Complete microsurgical resection was achieved in 7 oligodendrogliomas and 1 astrocytoma (6 high grade, 2 low grade). Median surgical glioma specimen chlorambucil concentration was 0.52 ng/g (range, 0–2.62 ng/g), or 37% (range, 0%–178%) of serum concentration. Median cerebrospinal fluid concentration was 0.1 ng/mL (range, 0–0.3 ng/mL). Chlorambucil was not associated with increase in seizure activity. Six dogs displayed prolonged seizure-free intervals. There was no myoclonus. Three dogs developed asymptomatic thrombocytopenia after 8–12 months of chlorambucil. Median progression-free survival was 253 days (range, 63–860 days). Median overall survival was 257 days (range, 64–860 days). Conclusions: The presence of intratumoral chlorambucil indicated an altered blood-brain barrier that varied from case to case. Despite sporadic previous reports of neurotoxicity, prolonged seizure-free intervals supported a high safety margin at this dose in this species. Metronomic chlorambucil was well tolerated. Spontaneous canine glioma offers a robust preclinical model.

Original languageEnglish (US)
JournalWorld Neurosurgery
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Chlorambucil
Clinical Trials, Phase I
Microsurgery
Glioma
Canidae
Dogs
Safety
Neoplasms
Seizures
Myoclonus
Cerebrospinal Fluid
Lomustine
Oligodendroglioma
Pets
Astrocytoma
Blood-Brain Barrier
Serum
Thrombocytopenia
Disease-Free Survival
Recurrence

Keywords

  • Astrocytoma
  • Blood-brain barrier
  • Dogs
  • Oligodendroglioma

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Canine (Pet Dog) Tumor Microsurgery and Intratumoral Concentration and Safety of Metronomic Chlorambucil for Spontaneous Glioma : A Phase I Clinical Trial. / Bentley, R. Timothy; Thomovsky, Stephanie A.; Miller, Margaret A.; Knapp, Deborah W.; Cohen-Gadol, Aaron.

In: World Neurosurgery, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "Objective: Metronomic (daily low-dose) chlorambucil requires further study before use in human patients with glioma. The aim of this study was to investigate distribution and safety of metronomic chlorambucil in naturally occurring canine glioma. Methods: Eight client-owned (pet) dogs with newly diagnosed spontaneous glioma were prospectively enrolled. Chlorambucil was administered preoperatively at 4 mg/m2 every 24 hours for ≥3 days and continued postoperatively until death or dose-limiting adverse events. Chlorambucil concentrations in the surgical glioma specimen, cerebrospinal fluid, and serum were analyzed. Dogs additionally received lomustine postoperatively. Dogs were monitored for seizures, myoclonus, cytopenias, and tumor recurrence. Results: Complete microsurgical resection was achieved in 7 oligodendrogliomas and 1 astrocytoma (6 high grade, 2 low grade). Median surgical glioma specimen chlorambucil concentration was 0.52 ng/g (range, 0–2.62 ng/g), or 37{\%} (range, 0{\%}–178{\%}) of serum concentration. Median cerebrospinal fluid concentration was 0.1 ng/mL (range, 0–0.3 ng/mL). Chlorambucil was not associated with increase in seizure activity. Six dogs displayed prolonged seizure-free intervals. There was no myoclonus. Three dogs developed asymptomatic thrombocytopenia after 8–12 months of chlorambucil. Median progression-free survival was 253 days (range, 63–860 days). Median overall survival was 257 days (range, 64–860 days). Conclusions: The presence of intratumoral chlorambucil indicated an altered blood-brain barrier that varied from case to case. Despite sporadic previous reports of neurotoxicity, prolonged seizure-free intervals supported a high safety margin at this dose in this species. Metronomic chlorambucil was well tolerated. Spontaneous canine glioma offers a robust preclinical model.",
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T2 - A Phase I Clinical Trial

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AU - Thomovsky, Stephanie A.

AU - Miller, Margaret A.

AU - Knapp, Deborah W.

AU - Cohen-Gadol, Aaron

PY - 2018/1/1

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AB - Objective: Metronomic (daily low-dose) chlorambucil requires further study before use in human patients with glioma. The aim of this study was to investigate distribution and safety of metronomic chlorambucil in naturally occurring canine glioma. Methods: Eight client-owned (pet) dogs with newly diagnosed spontaneous glioma were prospectively enrolled. Chlorambucil was administered preoperatively at 4 mg/m2 every 24 hours for ≥3 days and continued postoperatively until death or dose-limiting adverse events. Chlorambucil concentrations in the surgical glioma specimen, cerebrospinal fluid, and serum were analyzed. Dogs additionally received lomustine postoperatively. Dogs were monitored for seizures, myoclonus, cytopenias, and tumor recurrence. Results: Complete microsurgical resection was achieved in 7 oligodendrogliomas and 1 astrocytoma (6 high grade, 2 low grade). Median surgical glioma specimen chlorambucil concentration was 0.52 ng/g (range, 0–2.62 ng/g), or 37% (range, 0%–178%) of serum concentration. Median cerebrospinal fluid concentration was 0.1 ng/mL (range, 0–0.3 ng/mL). Chlorambucil was not associated with increase in seizure activity. Six dogs displayed prolonged seizure-free intervals. There was no myoclonus. Three dogs developed asymptomatic thrombocytopenia after 8–12 months of chlorambucil. Median progression-free survival was 253 days (range, 63–860 days). Median overall survival was 257 days (range, 64–860 days). Conclusions: The presence of intratumoral chlorambucil indicated an altered blood-brain barrier that varied from case to case. Despite sporadic previous reports of neurotoxicity, prolonged seizure-free intervals supported a high safety margin at this dose in this species. Metronomic chlorambucil was well tolerated. Spontaneous canine glioma offers a robust preclinical model.

KW - Astrocytoma

KW - Blood-brain barrier

KW - Dogs

KW - Oligodendroglioma

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