Rabbit Model of Intra-Arterial Chemotherapy Toxicity Demonstrates Retinopathy and Vasculopathy Related to Drug and Dose, Not Procedure or Approach

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Abstract

Purpose

To use our intra-arterial chemotherapy (IAC) rabbit model to assess the impact of IAC procedure, drug, dose, and choice of technique on ocular structure and function, to study the nature and etiology of IAC toxicity, and to compare to observations in patients.

Methods

Rabbits received IAC melphalan (0.4-0.8 mg/kg), carboplatin (25–50 mg), or saline, either by direct ophthalmic artery cannulation, or with a technique emulating nonocclusion. Ocular structure/function were assessed with examination, electroretinography (ERG), fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography, prior to and 5 to 6 weeks after IAC. Blood counts were obtained weekly. We reviewed our last 50 IAC treatments in patients for evidence of ocular or systemic complications.

Results

No toxicity was seen in the saline control group. With standard (0.4 mg/kg) melphalan, no vascular/microvascular abnormalities were seen with either technique. However, severe microvascular pruning and arteriolar occlusions were seen occasionally at 0.8 mg/kg doses. ERG reductions were dose-dependent. Histology showed melphalan dose-dependent degeneration in all retinal layers, restricted geographically to areas of greatest vascular density. Carboplatin caused massive edema of ocular/periocular structures. IAC patients experienced occasional periocular swelling/rash, and only rarely experienced retinopathy or vascular events/hemorrhage in eyes treated multiple times with triple (melphalan/carboplatin/topotecan) therapy. Transient neutropenia occurred after 46% of IAC procedures, generally after triple therapy.

Conclusions

IAC toxicity appears to be related to the specific drug being used and is dose-dependent, rather than related to the IAC procedure itself or the specific technique selected. These rabbit findings are corroborated by our clinical findings in patients.

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Most cited references 29

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Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience.

Y. Pierre Gobin, Brian Marr, D Abramson … (2011)

To determine whether intra-arterial chemotherapy is safe and effective in advanced intraocular retinoblastoma. Retinoblastoma often presents with advanced intraocular disease and, despite conventional treatment with intravenous chemotherapy and external beam radiation therapy, may still require enucleation. Single-arm, prospective registry from May 30, 2006, to May 30, 2010, at an ophthalmic oncology referral center with ambulatory care. A total of 95 eyes of 78 patients with unilateral or bilateral retinoblastoma were treated. The intervention was selective catheterization of the ophthalmic artery and injection of chemotherapy, usually melphalan with or without topotecan. Drug dosage was determined by age and angioanatomy. The main outcome measures were procedural success, event-free (enucleation or radiotherapy) ocular survival, and ocular and extraocular complications. Catheterization succeeded in 98.5% of procedures. There were 289 chemotherapy injections (median, 3 per eye). The Kaplan-Meier estimates of ocular event-free survival rates at 2 years were 70.0% (95% confidence interval, 57.9%-82.2%) for all eyes, 81.7% (95% confidence interval, 66.8%-96.6%) for eyes that received intra-arterial chemotherapy as primary treatment, and 58.4% (95% confidence interval, 39.5%-77.2%) for eyes that had previous treatment failure with intravenous chemotherapy and/or external beam radiation therapy. There were no permanent extraocular complications. Our experience suggests that intra-arterial chemotherapy is safe and effective in the treatment of advanced intraocular retinoblastoma.

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Complications of modern diagnostic cerebral angiography in an academic medical center.

J Fifi, Steven P. Meyers, John Pile-Spellman … (2009)

Catheter cerebral angiography and noninvasive cerebral imaging have steadily improved in the past several decades. Now, catheter angiography is frequently reserved for treatment planning. To remain relevant as a diagnostic modality, catheter angiography must be safe, even in critically ill patients. The present report describes the complication rate of catheter cerebral angiography performed by neurointerventional specialists at an academic medical center. From July 2001 through June 2007, 3,636 diagnostic catheter cerebral angiograms were obtained at a large academic institution. Complication data were prospectively acquired according to institutional policy and New York Patient Occurrence Reporting and Tracking System criteria. Data collected included patient age, sex, indication for the procedure, operator, and nature of adverse event, including need for treatment. Clinical predictors of complications were evaluated with logistic regression. Among 3,636 diagnostic cerebral angiograms obtained in 6 years, there were 11 clinical complications (0.30%). One patient (0.03%) had magnetic resonance imaging-detected stroke with no apparent clinical deterioration. Iatrogenic dissections were seen in five arteries (0.14%). No patient developed neurologic symptoms. Nonneurologic complications occurred in five patients (0.14%) who had arteriotomy site-related complications: one femoral abscess, two occlusions of the femoral artery with leg ischemia requiring surgical revascularization, one dissection with pseudoaneurysm formation requiring percutaneous thrombin injection, and one retroperitoneal hemorrhage requiring transfusion. Three of these patients were treated with an arterial closure device. Age greater than 65 years was associated with development of complications (P = .03). Modern catheter cerebral angiography performed by neurointerventionalists is associated with a low complication rate of 0.30%, even in a highly complex patient population.

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Unilateral Retinoblastoma Managed With Intravenous Chemotherapy Versus Intra-Arterial Chemotherapy. Outcomes Based on the International Classification of Retinoblastoma

Emil Anthony T. Say, George Magrath, Carol L. Shields … (2016)

The objective of this study was to compare outcomes after intravenous chemotherapy (IVC) versus intra-arterial chemotherapy (IAC) for unilateral retinoblastoma.

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Author and article information

Journal

Journal ID (nlm-ta): Invest Ophthalmol Vis Sci

Journal ID (iso-abbrev): Invest. Ophthalmol. Vis. Sci

Journal ID (hwp): iovs

Journal ID (pmc): Invest Ophthalmol Vis Sci

Journal ID (publisher-id): IOVS

Title: Investigative Ophthalmology & Visual Science

Publisher: The Association for Research in Vision and Ophthalmology

ISSN (Print): 0146-0404

ISSN (Electronic): 1552-5783

Publication date (Print): March 2019

Volume: 60

Issue: 4

Pages: 954-964

Affiliations

[1 ]Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States

[2 ]Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, United States

[3 ]Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States

[4 ]Cerebrovascular Program, Vanderbilt University Medical Center, Nashville, Tennessee, United States

[5 ]Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States

[6 ]Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States

[7 ]Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States

[8 ]Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States

[9 ]Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee, United States

[10 ]Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States

Author notes

Correspondence: Anthony B. Daniels, Vanderbilt Eye Institute, Vanderbilt University Medical Center, 2311 Pierce Avenue, Nashville, TN 37232, USA; anthony.b.daniels@ 123456vumc.org , anthony.b.daniels@ 123456gmail.com .

Article

Serial Item and Contribution ID: iovs-60-02-17 Publisher ID: IOVS-18-25346R2

DOI: 10.1167/iovs.18-25346

PMC ID: 6424472

PubMed ID: 30882851

SO-VID: 231d0480-b8c6-4d9b-9856-54c052db5413

License:

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Rabbit Model of Intra-Arterial Chemotherapy Toxicity Demonstrates Retinopathy and Vasculopathy Related to Drug and Dose, Not Procedure or Approach

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Abstract

Purpose

Methods

Results

Conclusions

Related collections

Animal models of intrauterine growth restriction (IUGR)

Most cited references 29

Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience.

Complications of modern diagnostic cerebral angiography in an academic medical center.

Unilateral Retinoblastoma Managed With Intravenous Chemotherapy Versus Intra-Arterial Chemotherapy. Outcomes Based on the International Classification of Retinoblastoma

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