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Clinical Sciences |

Intravitreal Melphalan for Refractory or Recurrent Vitreous Seeding From Retinoblastoma FREE

Fariba Ghassemi, MD; Carol L. Shields, MD
[+] Author Affiliations

Author Affiliations: Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran (Dr Ghassemi); and Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania (Dr Shields).


Arch Ophthalmol. 2012;130(10):1268-1271. doi:10.1001/archophthalmol.2012.1983.
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Published online

Objective To evaluate the efficacy and complications of intravitreal chemotherapy for viable vitreous seeding from retinoblastoma.

Methods Intravitreal injection of melphalan (8-50 μg in 0.05 mL) followed by injection site cryotherapy.

Results Among 12 treated cases, success with control of vitreous seeds was achieved in 10 of 12 cases at immediate follow-up (0-3 months), 8 of 10 cases at short-term follow-up (3-6 months), and 6 of 10 cases at long-term (>6 months) follow-up. Among those 8 cases that received an 8- to 10-μg dose, control was achieved in 6 of 8 cases at immediate follow-up, 5 of 7 cases at short-term follow-up, and 3 of 7 cases at long-term follow-up. Complications with the 8- to 10-μg dose were minor and included preretinal hemorrhage and retinal vasculitis with retinal pigment epithelial alterations. Of those 4 that received a 50-μg dose, immediate, short-term, and long-term control was 100%, but complications of cataract, vitreous hemorrhage, subretinal hemorrhage, severe hypotonia, and phthisis lead to enucleation in 2 cases. There was no case of orbital tumor recurrence or retinoblastoma metastasis (follow-up range, 8-66 months).

Conclusions Intravitreal melphalan for recurrent vitreous seeds from retinoblastoma appears to provide vitreous seed control in some patients. A high dose (50 μg) of melphalan is toxic and should be avoided.

Figures in this Article

Retinoblastoma is generally managed with systemic chemotherapy.1 According to the International Classification of Retinoblastoma, standard intravenous chemoreduction is successful for 100% of group A, 93% of group B, 90% of group C, 48% of group D, and 25% of group E eyes.1,2 Adjuvant low-dose radiotherapy improves globe salvage of group E eyes to 83%.2 A newer method of intra-arterial chemotherapy has shown promise for salvage of group D and E eyes.3,4 One of the most challenging aspects of retinoblastoma therapy is control of persistent or recurrent viable vitreous or subretinal tumor seeds. A previous report on vitreous seed control revealed eye salvage in 64% of patients treated with chemotherapy (using carboplatin, etoposide, and vincristine) and whole-eye radiotherapy at 5 years.4 Intra-arterial chemotherapy offers control for subretinal seeds in 82% of patients and for vitreous seeds in 67% of patients.3 A few reports on intravitreal chemotherapy for viable vitreous seeds have been published using thiotepa,5 melphalan,6 and methotrexate.7 Herein, we share our experience with intravitreal melphalan in 12 eyes with viable retinoblastoma vitreous seeds.

Approval for this retrospective study was received by the Farabi Hospital Review Committee of Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran, and by institutional review board of Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Criteria for inclusion were eyes with viable vitreous seeds for which standard chemotherapy and/or radiotherapy methods failed and for which enucleation was the remaining option. Success was defined as stabilization or regression of vitreous seeds and was categorized into immediate, (0-3 months) short-term (3-6 months), and long-term (>6 months) control. Failure was defined as growth of vitreous seeds or appearance of new vitreous seeds based on funduscopic examination (Figure 1 and Figure 2). After informed consent, under sterile technique, intravitreal melphalan (8-50 μg in 0.05 mL) was prepared in the operating room. Dosages were initiated at 8 μg in the first 2 patients (by C.L.S.), and later dosage increase was explored (by F.G.) owing to poor control, and dosage was adjusted based on amount of seeding. The freeze-dried powder melphalan (Alkeran; Aspen Pharmacare Australia Pty Ltd) was prepared using the provided sterile diluent. The medication was immediately injected through the peripheral cornea and iris root (at Wills Eye Institute) into anterior vitreous or through the pars plana (3 mm from limbus, beveled approach) (at Farabi Hospital) superotemporally using 30-gauge needle (Table). Cryotherapy at injection site was performed as single freeze-thaw cycle. There was no aqueous humor tap. Forceps-induced globe jiggling for 10 seconds to disperse vitreous chemotherapy was performed. Intraocular pressure was monitored 2 hours after injection and at each follow-up. Patient examination was performed every 3 to 4 weeks under general anesthesia with repeated injection if needed at the time of examination under anesthesia until vitreous seed control was achieved.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Vitreous seed control with low-dose (8 μg) intravitreal melphalan. A and B, Following chemoreduction and external beam radiotherapy delivered elsewhere, this patient was referred with approximately 70 viable recurrent vitreous seeds appearing as soft white translucent tumors floating in the vitreous gel. Melphalan at a dose of 8 μg was injected into the vitreous by transcorneal route. C and D, Two weeks after the first injection, the seeds are nearly resolved. E and F, Four months after 8 injections, the seeds are completely resolved, leaving clear vitreous.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Complications of vitreous melphalan injection. A and B, At first examination, the macula showed minor retinal pigment epithelial (RPE) alterations (A), presumably from previous serous retinal detachment and radiotherapy, with window defects and blockage on fluorescein angiography (B). C and D, Following 8 melphalan injections, the macula shows more obvious RPE alterations (C) with pigment hyperplasia and subtle retinal vascular staining (D).

Table Graphic Jump LocationTable. Outcomes of 12 Patients With Retinoblastoma and Refractory or Recurrent Vitreous Tumor Seeding Managed With Intravitreal Melphalan

Over the past 6 years, 12 eyes of 12 patients received intravitreal melphalan for active vitreous seeding from retinoblastoma (Table). All patients had received 6 to 8 cycles of standard chemotherapy, and 2 received additional external radiotherapy. At the time of injection, no patient was on systemic chemotherapy. Following injection, there was no prolonged elevation of intraocular pressure.

Overall, success with control of vitreous seeds was achieved in 10 of 12 cases (83%) at immediate follow-up, 8 of 10 cases (80%) at short-term follow-up, and 6 of 10 cases (60%) at long-term follow-up. Among those 8 cases that received an 8- to 10-μg dose, control was achieved in 6 of 8 cases (75%) at immediate follow-up, 5 of 7 cases (71%) at short-term follow-up, and 3 of 7 cases (43%) at long-term follow-up. Complications with an 8- to 10-μg dose were minor and included preretinal hemorrhage (n = 1) and retinal vasculitis with retinal pigment epithelial alterations (n = 1). Of those 4 patients who received the 50-μg dose, immediate, short-term, and long-term control was 100%, but complications of cataract, vitreous hemorrhage, subretinal hemorrhage, severe hypotonia, and phthisis lead to enucleation in 2 cases. There were no viable vitreous seeds histopathologically. Of the total 12 eyes, all facing enucleation as the main alternative, 4 were ultimately spared enucleation by intravitreal melphalan. The 8 that came to enucleation were for reasons of new retinoblastoma (n = 1), recurrent solid retinoblastoma and vitreous seeds (n = 2), recurrent vitreous seeds (n = 2), phthisis bulbi (n = 2), and chemotherapy intolerance/family preference (n = 1). There were no cases of orbital or systemic retinoblastoma recurrence over a mean 32 months' follow-up (median, 32.5 months; range, 8-66 months).

Intravitreal chemotherapy was explored by Ericson and Rosengren in 1961 using thiotepa for treatment of retinoblastoma in 6 cases, achieving success in 4 cases.5 They further investigated intravitreal injection of several chemotherapeutic agents in rabbit eyes using nitrogen mustard, cyclophosphamide, methotrexate, and thiotepa and established ocular toxicity levels.8 They observed the main adverse effect of vitreous opacification.8

Inomata and Kaneko found in vitro that retinoblastoma was most sensitive to melphalan, compared with vincristine, bleomycin, 5-fluorouracil, methotrexate, dacarbazine, and cytosine arabinoside.9 Kaneko10 performed intravitreal injection of 8- to 30-μg of melphalan combined with ocular hyperthermia for vitreous tumor seeding in 41 eyes, and unpublished results revealed an eye-preservation rate of nearly 51%. Munier11 studied 23 cases of recurrent vitreous seeds treated with up to 8 weekly intravitreal melphalan (8-30 μg) injections and found 87% control at 17 months. Although it is difficult to accurately compare results with unpublished data, this information is the only available data at this time. The 2 unpublished series mentioned above used 8 to 30 μg of melphalan. Because there is no published data, we cannot compare complications by dosage.

In our 12 cases, the patients were facing enucleation and had received numerous previous treatments of systemic chemotherapy/external radiotherapy for advanced retinoblastoma. All were treated with intravitreal melphalan for recurrent vitreous seeds. Of those 8 eyes that received 8- to 10-μg doses of melphalan, vitreous seed control was found in 71% of cases at short-term follow-up and 43% of cases at long-term follow-up, and there were minor ocular toxicities. For the 4 eyes that received a 50-μg dose, control was achieved in 100% cases at both short-term and long-term follow-up, but serious adverse effects of hypotony/phthisis bulbi were noted. There was no case of orbital tumor recurrence or retinoblastoma metastasis. There was no tumor in the needle tract on histopathology in any eye that came to enucleation. A more detailed histopathologic study of these eyes will be published separately.

In conclusion, our mean 3-year experience shows that intravitreal melphalan for recurrent vitreous retinoblastoma seeds following failed systemic chemotherapy appears to provide vitreous seed control in some patients. Further studies on pharmacokinetics of vitreous melphalan at varying dosages and the anticipated complications should be performed. Investigation should be made into more effective agents with a longer half-life and higher therapeutic indices. From this small cohort, it appears that a high dose (50 μg) of melphalan is toxic and should be avoided.

Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Institute, 840 Walnut St, Ste 1440, Philadelphia, PA 19107 (carol.shields@shieldsoncology.com).

Submitted for Publication: December 23, 2011; final revision received May 3, 2012; accepted May 7, 2012.

Financial Disclosure: None reported.

Shields CL, Mashayekhi A, Au AK,  et al.  The International Classification of Retinoblastoma predicts chemoreduction success.  Ophthalmology. 2006;113(12):2276-2280
PubMed   |  Link to Article
Shields CL, Ramasubramanian A, Thangappan A,  et al.  Chemoreduction for group E retinoblastoma: comparison of chemoreduction alone vs chemoreduction plus low-dose external radiotherapy in 76 eyes.  Ophthalmology. 2009;116(3):544.e1-551.e1
PubMed
Shields CL, Bianciotto CG, Jabbour P,  et al.  Intra-arterial chemotherapy for retinoblastoma: report No. 1, control of retinal tumors, subretinal seeds, and vitreous seeds.  Arch Ophthalmol. 2011;129(11):1399-1406
PubMed   |  Link to Article
Kingston JE, Hungerford JL, Madreperla SA, Plowman PN. Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma.  Arch Ophthalmol. 1996;114(11):1339-1343
PubMed   |  Link to Article
Ericson LA, Rosengren BH. Present therapeutic resources in retinoblastoma.  Acta Ophthalmol (Copenh). 1961;39:569-576
PubMed   |  Link to Article
Kaneko A, Suzuki S. Eye-preservation treatment of retinoblastoma with vitreous seeding.  Jpn J Clin Oncol. 2003;33(12):601-607
PubMed   |  Link to Article
Kivelä T, Eskelin S, Paloheimo M. Intravitreal methotrexate for retinoblastoma.  Ophthalmology. 2011;118(8):1689-1689.e6
PubMed   |  Link to Article
Ericson LA, Karlberg B, Rosengren BH. Trials of intravitreal injections of chemotherapeutic agents in rabbits.  Acta Ophthalmol (Copenh). 1964;42(4):721-726
PubMed   |  Link to Article
Inomata M, Kaneko A. Chemosensitivity profiles of primary and cultured human retinoblastoma cells in a human tumor clonogenic assay.  Jpn J Cancer Res. 1987;78(8):858-868
PubMed
Kanecko A. How to perform vitreous injection of melphalan to treat recurrent vitreous seeding of retinoblastoma. http://members3.jcom.home.ne.jp/akiakikaneko/image/616312Poster200&100V-PVI-070216.pdf. Accessed July 13, 2012
Munier FL. Intravitreal chemotherapy with melphalan for vitreous disease in advanced retinoblastoma: evidence for safety and efficacy. Paper presented at: Biennial International Society of Ocular Oncology; November 16, 2011; Buenos Aires, Argentina

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Vitreous seed control with low-dose (8 μg) intravitreal melphalan. A and B, Following chemoreduction and external beam radiotherapy delivered elsewhere, this patient was referred with approximately 70 viable recurrent vitreous seeds appearing as soft white translucent tumors floating in the vitreous gel. Melphalan at a dose of 8 μg was injected into the vitreous by transcorneal route. C and D, Two weeks after the first injection, the seeds are nearly resolved. E and F, Four months after 8 injections, the seeds are completely resolved, leaving clear vitreous.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Complications of vitreous melphalan injection. A and B, At first examination, the macula showed minor retinal pigment epithelial (RPE) alterations (A), presumably from previous serous retinal detachment and radiotherapy, with window defects and blockage on fluorescein angiography (B). C and D, Following 8 melphalan injections, the macula shows more obvious RPE alterations (C) with pigment hyperplasia and subtle retinal vascular staining (D).

Tables

Table Graphic Jump LocationTable. Outcomes of 12 Patients With Retinoblastoma and Refractory or Recurrent Vitreous Tumor Seeding Managed With Intravitreal Melphalan

References

Shields CL, Mashayekhi A, Au AK,  et al.  The International Classification of Retinoblastoma predicts chemoreduction success.  Ophthalmology. 2006;113(12):2276-2280
PubMed   |  Link to Article
Shields CL, Ramasubramanian A, Thangappan A,  et al.  Chemoreduction for group E retinoblastoma: comparison of chemoreduction alone vs chemoreduction plus low-dose external radiotherapy in 76 eyes.  Ophthalmology. 2009;116(3):544.e1-551.e1
PubMed
Shields CL, Bianciotto CG, Jabbour P,  et al.  Intra-arterial chemotherapy for retinoblastoma: report No. 1, control of retinal tumors, subretinal seeds, and vitreous seeds.  Arch Ophthalmol. 2011;129(11):1399-1406
PubMed   |  Link to Article
Kingston JE, Hungerford JL, Madreperla SA, Plowman PN. Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma.  Arch Ophthalmol. 1996;114(11):1339-1343
PubMed   |  Link to Article
Ericson LA, Rosengren BH. Present therapeutic resources in retinoblastoma.  Acta Ophthalmol (Copenh). 1961;39:569-576
PubMed   |  Link to Article
Kaneko A, Suzuki S. Eye-preservation treatment of retinoblastoma with vitreous seeding.  Jpn J Clin Oncol. 2003;33(12):601-607
PubMed   |  Link to Article
Kivelä T, Eskelin S, Paloheimo M. Intravitreal methotrexate for retinoblastoma.  Ophthalmology. 2011;118(8):1689-1689.e6
PubMed   |  Link to Article
Ericson LA, Karlberg B, Rosengren BH. Trials of intravitreal injections of chemotherapeutic agents in rabbits.  Acta Ophthalmol (Copenh). 1964;42(4):721-726
PubMed   |  Link to Article
Inomata M, Kaneko A. Chemosensitivity profiles of primary and cultured human retinoblastoma cells in a human tumor clonogenic assay.  Jpn J Cancer Res. 1987;78(8):858-868
PubMed
Kanecko A. How to perform vitreous injection of melphalan to treat recurrent vitreous seeding of retinoblastoma. http://members3.jcom.home.ne.jp/akiakikaneko/image/616312Poster200&100V-PVI-070216.pdf. Accessed July 13, 2012
Munier FL. Intravitreal chemotherapy with melphalan for vitreous disease in advanced retinoblastoma: evidence for safety and efficacy. Paper presented at: Biennial International Society of Ocular Oncology; November 16, 2011; Buenos Aires, Argentina

Correspondence

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