A Phase I/II Study of Direct Intraarterial (Ophthalmic Artery) Chemotherapy with Melphalan for Intraocular Retinoblastoma: Initial Results

doi:10.1016/j.ophtha.2007.12.014

Ophthalmology

Volume 115, Issue 8, August 2008, Pages 1398-1404.e1

https://doi.org/10.1016/j.ophtha.2007.12.014 Get rights and content

Objective

To develop a technique that would allow us to cannulate repeatedly the ophthalmic artery of young children with advanced retinoblastoma, to find a dose of melphalan that would be tolerable and tumoricidal for retinoblastoma when given intraarterially, and to study the local ocular and systemic side effects of intraarterial melphalan in these children.

Design

Phase I/II clinical trial.

Participants

Ten children with advanced retinoblastoma (Reese–Ellsworth V) eyes who were indicated for enucleation were entered into an institutional review board–approved protocol of ophthalmic artery infusion of melphalan to avoid enucleation.

Methods

Cannulation of the ophthalmic artery was performed by a femoral artery approach using microcatheters while the children were under anesthesia and anticoagulated. Chemotherapy (melphalan) was infused into the artery over a 30-minute period.

Main Outcome Measures

Ophthalmic examinations, retinal photography, and electroretinograms were used to document local toxicity, whereas physical examinations and complete blood counts were used to measure systemic toxicity.

Results

The ophthalmic arteries were successfully cannulated in 9 cases (total, 27 times), as many as 6 times in 1 patient. Dramatic regression of tumors, vitreous seeds, and subretinal seeds were seen in each case. No severe systemic side effects (sepsis, anemia, neutropenia, fever, or death) occurred. No transfusions were required (red cells or platelets). Three patients developed conjunctival and lid edema that resolved without treatment. There was no toxicity to the cornea, anterior segment, pupil, or motility. One (previously irradiated) eye developed retinal ischemia; another eye had no toxicity after intraarterial chemotherapy but did develop a radiationlike retinopathy after brachytherapy. Vision stabilized or improved in all but 1 patient after treatment. Electroretinograms were generally poor (advanced eyes were treated), but in 2 cases, the electroretinogram improved after treatment (and resolution of a retinal detachment). Seven eyes avoided enucleation. Two intraarterially treated eyes were enucleated, with no viable tumors identified pathologically.

Conclusions

We developed a technique of direct ophthalmic artery infusion of melphalan for children with retinoblastoma. The technique had minimal systemic side effects (one patient had grade 3 neutropenia) and minimal local toxicity. Among the first 9 cases treated with this technique, 7 eyes destined to be enucleated were salvaged.

Section snippets

Materials and Methods

Under general anesthesia, the femoral artery (alternatively right or left) was punctured and a 4-French (F) arterial sheath was placed. Anticoagulation was obtained with intravenous heparin (75 IU/kg). The 4-F (1.3-mm diameter) catheter was guided into the ipsilateral internal carotid artery. An arteriogram was performed to visualize the eye and cerebral vasculature and to select the best incidence showing the takeoff of the ophthalmic artery from the internal carotid. Using fluoroscopy and

Results

This report summarizes our experience in the first 10 patients with Reese–Ellsworth V eyes (Vb, 9; Va, 1) who were enrolled on the protocol (Table 1). An attempt at catheterization was unsuccessful in 1 patient because of a vascular anomaly (ophthalmic artery arising from the middle meningeal artery). Every other attempt in every child was successful in cannulating the ophthalmic artery. Overall, 27 separate infusions were performed in 9 patients. The mean follow-up is 8.8 months, and the

Discussion

This report summarizes our experience with a novel approach for advanced intraocular retinoblastoma utilizing a technique of selective ophthalmic artery infusion with locally high-dose chemotherapy. The standard management of an eye with advanced intraocular retinoblastoma (Reese–Ellsworth Va and Vb) is enucleation,¹⁰ which is effective in preventing progression to clinical metastatic disease in >95% of cases. During the past 30 years, unilateral retinoblastoma has also been managed in

References (23)

D.S. Gombos et al.
Secondary acute myelogenous leukemia in patients with retinoblastomaIs chemotherapy a factor?
Ophthalmology
(2007)
D.H. Abramson et al.
A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma
Ophthalmology
(1999)
T. Yamane et al.
The technique of ophthalmic artery infusion therapy for patients with intraocular retinoblastoma
Int J Clin Oncol
(2004)
A.B. Reese et al.
The treatment of retinoblastoma by X-ray and triethylene melamine
AMA Arch Ophthalmol
(1958)
M. Kiribuchi
Retrograde infusion of anti-cancer drugs to ophthalmic artery for intraocular malignant tumors [in Japanese]
Nippon Ganka Gakkai Zasshi
(1966)
A. Kaneko et al.
Chemo-thermotherapy was successful in two cases of recurrence of intraocular retinoblastoma after irradiation [in Japanese]
Rinsho Ganka
(1990)
M. Mohri
The technique of selective ophthalmic arterial infusion for conservative treatment of recurrent retinoblastoma [in Japanese]
Keio Igaku (J Keio Med Soc)
(1993)
M. Ueda et al.
Study on conservative treatment of retinoblastoma–effect of intravitreal injection of melphalan on the rabbit retina [in Japanese]
Nippon Ganka Gakkai Zasshi
(1995)
A. Kaneko et al.
Eye-preservation treatment of retinoblastoma with vitreous seeding
Jpn J Clin Oncol
(2003)
S. Suzuki et al.
Management of intraocular retinoblastoma and ocular prognosis
Int J Clin Oncol
(2004)

A. Kaneko

Japanese contributions to ocular oncology

Int J Clin Oncol

(1999)

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Supported in part by a grant from the Fund for Ophthalmic Knowledge, Inc., New York, New York.

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Original articleA Phase I/II Study of Direct Intraarterial (Ophthalmic Artery) Chemotherapy with Melphalan for Intraocular Retinoblastoma: Initial Results

Objective

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Materials and Methods

Results

Discussion

Ophthalmology

Ophthalmology

Int J Clin Oncol

The treatment of retinoblastoma by X-ray and triethylene melamine

AMA Arch Ophthalmol

Retrograde infusion of anti-cancer drugs to ophthalmic artery for intraocular malignant tumors [in Japanese]

Nippon Ganka Gakkai Zasshi

Chemo-thermotherapy was successful in two cases of recurrence of intraocular retinoblastoma after irradiation [in Japanese]

Rinsho Ganka

The technique of selective ophthalmic arterial infusion for conservative treatment of recurrent retinoblastoma [in Japanese]

Keio Igaku (J Keio Med Soc)

Study on conservative treatment of retinoblastoma–effect of intravitreal injection of melphalan on the rabbit retina [in Japanese]

Nippon Ganka Gakkai Zasshi

Eye-preservation treatment of retinoblastoma with vitreous seeding

Jpn J Clin Oncol

Management of intraocular retinoblastoma and ocular prognosis

Int J Clin Oncol

Japanese contributions to ocular oncology

Int J Clin Oncol

Original article
A Phase I/II Study of Direct Intraarterial (Ophthalmic Artery) Chemotherapy with Melphalan for Intraocular Retinoblastoma: Initial Results