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Figure 1. Cavitary retinoblastomas before treatment. The tumors display gray lucent cavities (arrows) on clinical examination (A), shown as hypofluorescence (arrows) on fluorescein angiography (B). More pronounced gray lucent cavities (arrows) are demonstrated after chemoreduction (C) and on the optical coherence tomographic image (D).

Figure 1. Cavitary retinoblastomas before treatment. The tumors display gray lucent cavities (arrows) on clinical examination (A), shown as hypofluorescence (arrows) on fluorescein angiography (B). More pronounced gray lucent cavities (arrows) are demonstrated after chemoreduction (C) and on the optical coherence tomographic image (D).

Figure 2. Clinical course of cavitary retinoblastoma during chemotherapy in 3 cases. Findings are shown before treatment (A, D, and G), after 6 cycles of systemic chemotherapy (B, E, and H), and at the last follow-up visit (C, F, and I). Minimal to moderate change in tumor size is seen after treatment. The arrows indicate the cavities.

Figure 2. Clinical course of cavitary retinoblastoma during chemotherapy in 3 cases. Findings are shown before treatment (A, D, and G), after 6 cycles of systemic chemotherapy (B, E, and H), and at the last follow-up visit (C, F, and I). Minimal to moderate change in tumor size is seen after treatment. The arrows indicate the cavities.

Table 1. Demographic and Clinical Features of Patients Undergoing Chemotherapy for Cavitary Retinoblastoma
Table 1. Demographic and Clinical Features of Patients Undergoing Chemotherapy for Cavitary Retinoblastoma
Table 2. Ocular Symptoms in Patients With Cavitary Retinoblastoma
Table 2. Ocular Symptoms in Patients With Cavitary Retinoblastoma
Table 3. Treatment of Cavitary Retinoblastoma
Table 3. Treatment of Cavitary Retinoblastoma
Table 4. Long-term Chemotherapy Resultsa
Table 4. Long-term Chemotherapy Resultsa
Table 5. Globe Salvage and Enucleation
Table 5. Globe Salvage and Enucleation
1.
Shields CL, Palamar M, Sharma P,  et al.  Retinoblastoma regression patterns following chemoreduction and adjuvant therapy in 557 tumors.  Arch Ophthalmol. 2009;127(3):282-290PubMedArticle
2.
Shields CL, Ramasubramanian A, Thangappan A,  et al.  Chemoreduction for group E retinoblastoma: comparison of chemoreduction alone versus chemoreduction plus low-dose external radiotherapy in 76 eyes.  Ophthalmology. 2009;116(3):544.e1-551.e1PubMedArticle
3.
Lumbroso-Le Rouic L, Aerts I, Lévy-Gabriel C,  et al.  Conservative treatments of intraocular retinoblastoma.  Ophthalmology. 2008;115(8):1405-1410, 1410.e1-1410.e2PubMedArticleArticle
4.
Menon BS, Juraida E, Alagaratnam J,  et al.  Chemoreduction for intraocular retinoblastoma in Malaysia.  J Pediatr Hematol Oncol. 2007;29(1):2-4PubMedArticle
5.
Gombos DS, Chevez-Barrios AP. Current treatment and management of retinoblastoma.  Curr Oncol Rep. 2007;9(6):453-458PubMedArticle
6.
Shields CL, Mashayekhi A, Au AK,  et al.  The International Classification of Retinoblastoma predicts chemoreduction success.  Ophthalmology. 2006;113(12):2276-2280PubMedArticle
7.
Antoneli CB, Ribeiro KC, Steinhorst F, Novaes PE, Chojniak MM, Malogolowkin M. Treatment of retinoblastoma patients with chemoreduction plus local therapy: experience of the AC Camargo Hospital, Brazil.  J Pediatr Hematol Oncol. 2006;28(6):342-345PubMedArticle
8.
Shields JA, Shields CL, Meadows AT. Chemoreduction in the management of retinoblastoma.  Am J Ophthalmol. 2005;140(3):505-506PubMedArticle
9.
Shields CL, Mashayekhi A, Cater J, Shelil A, Meadows AT, Shields JA. Chemoreduction for retinoblastoma: analysis of tumor control and risks for recurrence in 457 tumors.  Am J Ophthalmol. 2004;138(3):329-337PubMedArticle
10.
Shields CL, Mashayekhi A, Demirci H, Meadows AT, Shields JA. Practical approach to management of retinoblastoma.  Arch Ophthalmol. 2004;122(5):729-735PubMedArticle
11.
Moll AC, Imhof SM, Schouten-van Meeteren AY, Boers M, van Leeuwen F, Hofman P. Chemoreduction for retinoblastoma [comment].  Arch Ophthalmol. 2003;121(10):1513PubMedArticle
12.
Sussman DA, Escalona-Benz E, Benz MS,  et al.  Comparison of retinoblastoma reduction for chemotherapy vs external beam radiotherapy.  Arch Ophthalmol. 2003;121(7):979-984PubMedArticle
13.
Shields CL, Honavar SG, Meadows AT, Shields JA, Demirci H, Naduvilath TJ. Chemoreduction for unilateral retinoblastoma.  Arch Ophthalmol. 2002;120(12):1653-1658PubMedArticle
14.
Ghose S, Nizamuddin SH, Sethi A,  et al.  Efficacy of induction chemotherapy in retinoblastoma, alone or combined with other adjuvant modalities.  J Pediatr Ophthalmol Strabismus. 2002;39(3):143-150PubMed
15.
Friedman DL, Himelstein B, Shields CL,  et al.  Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma.  J Clin Oncol. 2000;18(1):12-17PubMed
16.
Greenwald MJ, Goldman S, Strauss LC. Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma.  Ophthalmology. 1998;105(9):1579-1581PubMedArticle
17.
Shields CL, Shields JA, Needle M,  et al.  Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma.  Ophthalmology. 1997;104(12):2101-2111PubMed
18.
Murphree AL, Villablanca JG, Deegan WF III,  et al.  Chemotherapy plus local treatment in the management of intraocular retinoblastoma.  Arch Ophthalmol. 1996;114(11):1348-1356PubMedArticle
19.
Shields CL, De Potter P, Himelstein BP, Shields JA, Meadows AT, Maris JM. Chemoreduction in the initial management of intraocular retinoblastoma.  Arch Ophthalmol. 1996;114(11):1330-1338PubMedArticle
20.
Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience.  Arch Ophthalmol. 2011;129(6):732-737PubMedArticle
21.
Shields CL, Shields JA. Intra-arterial chemotherapy for retinoblastoma: the beginning of a long journey.  Clin Experiment Ophthalmol. 2010;38(6):638-643PubMedArticle
22.
Abramson DH, Dunkel IJ, Brodie SE, Marr B, Gobin YP. Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery).  Ophthalmology. 2010;117(8):1623-1629PubMedArticle
23.
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):1399-1406PubMedArticle
24.
Shields CL, Bianciotto CG, Jabbour P,  et al.  Intra-arterial chemotherapy for retinoblastoma: report No. 2, treatment complications.  Arch Ophthalmol. 2011;129(11):1407-1415PubMedArticle
25.
Aziz HA, Boutrid H, Murray TG,  et al.  Supraselective injection of intraarterial melphalan as the primary treatment for late presentation unilateral multifocal stage Vb retinoblastoma.  Retina. 2010;30(4):(suppl)  S63-S65PubMedArticle
26.
Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy.  Curr Opin Ophthalmol. 2010;21(3):203-212PubMedArticle
27.
Mashayekhi A, Shields CL, Eagle RC Jr, Shields JA. Cavitary changes in retinoblastoma: relationship to chemoresistance.  Ophthalmology. 2005;112(6):1145-1150PubMedArticle
28.
Palamar M, Pirondini C, Shields CL, Shields JA. Cavitary retinoblastoma: ultrasonographic and fluorescein angiographic findings in 3 cases.  Arch Ophthalmol. 2008;126(11):1598-1600PubMedArticle
29.
Ts’o MO, Zimmerman LE, Fine BS. The nature of retinoblastoma, I: photoreceptor differentiation: a clinical and histopathologic study.  Am J Ophthalmol. 1970;69(3):339-349PubMed
30.
Ginsberg J, Spaulding AG, Asbury T. Cystic retinoblastoma.  Am J Ophthalmol. 1975;80(5):930-934PubMed
31.
Demirci H, Eagle RC Jr, Shields CL, Shields JA. Histopathologic findings in eyes with retinoblastoma treated only with chemoreduction.  Arch Ophthalmol. 2003;121(8):1125-1131PubMedArticle
32.
Shields CL, Mashayekhi A, Cater J,  et al.  Macular retinoblastoma managed with chemoreduction: analysis of tumor control with or without adjuvant thermotherapy in 68 tumors.  Arch Ophthalmol. 2005;123(6):765-773PubMedArticle
Clinical Sciences
May 2012

Intravenous Chemoreduction or Intra-arterial Chemotherapy for Cavitary RetinoblastomaLong-term Results

Author Affiliations

Author Affiliations: Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.

Arch Ophthalmol. 2012;130(5):585-590. doi:10.1001/archophthalmol.2011.2825
Abstract

Objective To assess the long-term results of chemotherapy for cavitary retinoblastoma.

Methods Retrospective, nonrandomized, interventional case series of 26 cavitary retinoblastomas in 25 eyes of 24 patients. Retinoblastomas were treated with intravenous chemoreduction and/or intra-arterial chemotherapy. Main outcome measures included tumor control, globe salvage, and metastasis.

Results Of 24 patients with cavitary retinoblastoma, the mean age at diagnosis was 16 months. The mean number of cavitary tumors per eye was 1 (median, 1; range, 1-2), with a mean tumor basal diameter of 13 (median, 13; range, 7-24) mm and mean tumor thickness of 7 (median, 6; range, 3-17) mm. The mean number of cavities per tumor was 2 (median, 2; range, 1-5), with a mean cavity diameter of 3 (median, 2; range, 1-10) mm. Related features included vitreous seeds in 7 tumors (27%), subretinal seeds in 6 (23%), and subretinal fluid in 13 (50%). Intravenous chemoreduction was used in 23 tumors (88%); intra-arterial chemotherapy, in 2 (8%); and both, in 1 (4%). After treatment, the mean reduction in tumor base was 22% and mean reduction in tumor thickness was 29%. Despite minimal reduction, tumor recurrence was noted in only 1 eye (4%), globe salvage was achieved in 22 (88%), and there were no cases of metastasis or death during 49 (range, 6-189) months of follow-up.

Conclusion Despite minimal visible tumor response to chemotherapy, cavitary retinoblastoma displays relatively stable long-term results.

Retinoblastoma is a life-threatening malignant neoplasm that manifests in the eye with features of painless leukocoria or strabismus. Intravenous chemotherapy or chemoreduction (CRD)119 and intra-arterial chemotherapy (IAC)2026 currently play an important role in the management of retinoblastoma. For CRD, chemotherapeutic agents (vincristine sulfate, etoposide, and carboplatin) are given through an intravenous route, whereas for IAC, chemotherapy (usually melphalan hydrochloride) is delivered directly into the ophthalmic artery. In classic cases, clinically visible dramatic tumor regression is seen after CRD1,9,12,14,1719 and IAC,20,22,23,25 with reduction of tumor thickness of 50% or more, leaving a partially calcified remnant in most cases.

Cavitary retinoblastoma, a rare low-grade variant of retinoblastoma2730 with ophthalmoscopically visible cavitary spaces, shows minimal response to CRD.27,28 Despite its more subtle immediate reduction after CRD, the long-term results remain unclear. In this report, we specifically review our long-term experience with CRD and IAC for cavitary retinoblastoma.

METHODS

We reviewed the medical records of patients with retinoblastoma that was managed at the Oncology Service of the Wills Eye Institute from January 1, 1999, through July 31, 2011. Patients with the diagnosis of cavitary retinoblastoma and treatment with CRD or IAC were selected for further analysis (Figure 1 and Figure 2). This was a retrospective, nonrandomized, noncomparative interventional case series. Institutional review board approval was obtained.

The patient data were reviewed for demographic information, clinical findings, treatment, and outcome. Each patient underwent evaluation for age at diagnosis (in months), sex (male or female), race (white, African American, Hispanic, or Asian), and hereditary pattern (familial or sporadic). Results of genetic testing (germline or somatic) were recorded whenever available. All prior treatments of the eye and previous CRD or IAC were recorded. A comprehensive ocular examination under anesthesia was performed with assessment for laterality (unilateral or bilateral); intraocular pressure (measured by means of Schiøtz tonometry); status of the anterior chamber, iris, ciliary body, optic nerve, choroid, retina, and vitreous; overall tumor growth pattern (exophytic, endophytic, or combined exophytic-endophytic); total number of tumors per eye; total number of cavitary tumors per eye; location of cavitary tumor; total number of cavities within each tumor; size of cavities; and location of cavities within each tumor. Each tumor was measured for greatest basal dimension and thickness using indirect ophthalmoscopy and ultrasonography; the presence of associated vitreous seeds (present or absent), percentage of retinal detachment (0-100%), and presence of subretinal tumor seeds (present or absent) were recorded. All findings were documented by large fundus drawing, fundus photography with a commercially available fundus camera (RetCam; Massie Industries), fluorescein angiography, and ultrasonography (Figure 1).

All patients were scheduled to receive CRD or IAC. For CRD, 6 monthly cycles of systemic intravenous chemotherapy with vincristine sulfate (0.05 mg/kg), etoposide (5 mg/kg), and carboplatin (18.6 mg/kg) were delivered. For IAC, 3 monthly cycles of melphalan hydrochloride (5 mg) were given. At the end of each chemotherapy cycle, ocular oncologic follow-up was performed by means of examination under anesthesia (Figure 2).

At each examination, the individual tumor response was judged as complete (no viable tumor), partial (some residual viable tumor), or none (completely viable tumor). On funduscopic examination, the tumor was determined to be viable if there was no change in the funduscopic appearance of the tumor. The tumor was considered to be nonviable or to demonstrate complete tumor response when it showed decreased basal dimensions and thickness, total or partial calcification, decrease in the associated subretinal fluid, and surrounding areas of retinal pigment epithelial changes without areas of growth or recurrence.

Each cavitary tumor was measured for the greatest basal dimension, thickness, tumor regression pattern, and percentage of tumor replaced with calcium. The status of vitreous seeds (present, absent, or calcified), the status of subretinal seeds (present, absent, or calcified), and the percentage of residual subretinal fluid was noted. The percentage of decrease or increase in tumor base and thickness at the completion of chemotherapy and at the last follow-up date were calculated. Patient status at the last follow-up examination was also recorded (alive without metastasis, alive with metastasis, dead due to metastasis, or dead due to unrelated causes).

RESULTS

Of 1591 patients with newly diagnosed retinoblastoma that was managed at the Oncology Service of the Wills Eye Institute from 1999 through 2011, 37 (2.3%) had cavitary retinoblastoma. Of these 37 patients, 13 were excluded because they had not received CRD or IAC or had a follow-up duration of less than 6 months. The remaining 24 patients displayed 26 cavitary retinoblastomas in 25 eyes. The mean patient age at presentation was 16 (median, 15; range, 6-35) months. The demographic data are listed in Table 1.

The tumor features are listed in Table 2. The mean number of cavitary retinoblastomas per eye was 1 (median, 1; range, 1-2), the mean tumor basal diameter was 13 (median, 13; range, 7-24) mm, and the mean tumor thickness was 7 (median, 6; range, 3-17) mm. The mean number of cavities per tumor was 2 (median, 2; range, 1-5), with a mean cavity diameter of 3 (median, 2; range, 1-10) mm. Treatment variables are listed in Table 3. Twenty-three tumors (88%) were treated with CRD, 2 (8%) with IAC, and 1 (4%) with CRD and IAC. Adjuvant therapies are also listed in Table 3.

The mean percentage reduction in tumor diameter was 22% (median, 20%; range, 0-50%), and the mean percentage reduction in tumor thickness was 29% (median, 27%; range, 0-64%) during a mean follow-up duration of 49 (median, 20; range, 6-189) months. Outcomes are listed in Table 4. All 24 patients had at least 6 months of follow-up; 18 (75%), more than 1 year; 12 (50%), more than 3 years; and 9 (38%), more than 5 years. On follow-up, complete tumor response was found in 15 of 18 tumors (83%) at 1 year and in 9 of 9 tumors (100%) at 5 years. Overall, globe salvage was achieved in 22 eyes (88%). Enucleation was necessary for tumor recurrence (n = 1), neovascular glaucoma (n = 1), and optic nerve enhancement with suspected recurrence (later findings were negative) (n = 1) (Table 5). We reviewed pathology results of the 3 enucleated eyes. In all 3 eyes, tumors were well differentiated with extensive areas of photoreceptor differentiation and had no viable tumor at the edges of the cavities. Of these 3 eyes, 1 had extensive focus of necrotic retinoblastoma with scattered foci of viable retinoblastoma in the anterior retina and subretinal space, and the remaining 2 eyes had no viable retinoblastoma. No metastasis or death occurred in any case.

COMMENT

Retinoblastoma is known to respond dramatically to chemotherapy, including CRD1,9,12,14,1719 and IAC.20,22,23,25,26 In a series of 457 tumors reported by Shields and associates,9 the mean tumor reduction in basal diameter and thickness after CRD was 43% and 50%, respectively, with a tumor recurrence rate of 20%. Similar dramatic tumor responses have been found after IAC.20,22,23,25 In a previous report of tumor response after CRD for cavitary retinoblastoma, the mean tumor reduction was 19% in basal diameter and 18% in tumor thickness, without tumor recurrence during a mean follow-up of 32 months.27

Cavitary retinoblastoma is a rare variant of retinoblastoma, which has ophthalmoscopically visible lucent cavities within the tumor.27 The cavitary spaces appear hollow on ultrasonography and hypofluorescent on angiography (Figure 1).28 Histopathologically, the cavitary spaces have been shown to represent areas of photoreceptor differentiation. Ts’o and colleagues29 reviewed 300 eyes with retinoblastoma and found 18 tumors with associated photoreceptor differentiation in the adjacent area of cavitary spaces. Demirci et al31 reviewed histopathologic findings in eyes with retinoblastoma treated with CRD and reported mean tumor reductions in basal diameter and thickness of only 17% and 32%, respectively, in well-differentiated tumors and, in contrast, tumor reductions of 35% in basal diameter and 55% in thickness in tumors that were not well differentiated. In 2004, our group27 reported clinical features in 15 patients with cavitary retinoblastoma, and we found a relatively poor immediate clinical response of this variant to CRD. We concluded that cavitary retinoblastoma shows minimal visible response after CRD but speculated that this could be a sign of tumor differentiation. In a separate analysis of 68 cases of macular retinoblastoma treated with CRD and thermotherapy, tumor recurrence was found in 6 of 40 tumors (15%).32 However, those tumors classified as cavitary showed only 1 recurrence in 26 tumors (4%) at 4 years.

In our present analysis, we confirm persistent long-term stability of cavitary retinoblastoma after CRD or IAC. Despite the relatively blunted clinical response with less dramatic shrinkage, long-term tumor control is typically achieved. We also observed that cavitary retinoblastoma was less likely to display intrinsic calcification, subretinal fluid, vitreous seeds, or subretinal seeds.

In summary, we herein report a series of 26 cavitary retinoblastomas treated with chemotherapy (CRD and/or IAC), of which most showed only slight clinical reduction in tumor size. Despite minimal visible response to chemotherapy, cavitary retinoblastoma has a favorable long-term outcome with stable tumor regression and globe salvage. Based on these findings, aggressive or prolonged chemotherapy or adjunctive therapies are generally not necessary for cavitary retinoblastoma, although a dramatic response is not achieved. Long-term follow-up is advised for all cases because of the small risk of recurrence.

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Article Information

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: August 3, 2011; final revision received November 7, 2011; accepted November 8, 2011.

Author Contributions: Dr Shields had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the Eye Tumor Research Foundation (Dr Shields).

Role of the Sponsors: The sponsor had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

References
1.
Shields CL, Palamar M, Sharma P,  et al.  Retinoblastoma regression patterns following chemoreduction and adjuvant therapy in 557 tumors.  Arch Ophthalmol. 2009;127(3):282-290PubMedArticle
2.
Shields CL, Ramasubramanian A, Thangappan A,  et al.  Chemoreduction for group E retinoblastoma: comparison of chemoreduction alone versus chemoreduction plus low-dose external radiotherapy in 76 eyes.  Ophthalmology. 2009;116(3):544.e1-551.e1PubMedArticle
3.
Lumbroso-Le Rouic L, Aerts I, Lévy-Gabriel C,  et al.  Conservative treatments of intraocular retinoblastoma.  Ophthalmology. 2008;115(8):1405-1410, 1410.e1-1410.e2PubMedArticleArticle
4.
Menon BS, Juraida E, Alagaratnam J,  et al.  Chemoreduction for intraocular retinoblastoma in Malaysia.  J Pediatr Hematol Oncol. 2007;29(1):2-4PubMedArticle
5.
Gombos DS, Chevez-Barrios AP. Current treatment and management of retinoblastoma.  Curr Oncol Rep. 2007;9(6):453-458PubMedArticle
6.
Shields CL, Mashayekhi A, Au AK,  et al.  The International Classification of Retinoblastoma predicts chemoreduction success.  Ophthalmology. 2006;113(12):2276-2280PubMedArticle
7.
Antoneli CB, Ribeiro KC, Steinhorst F, Novaes PE, Chojniak MM, Malogolowkin M. Treatment of retinoblastoma patients with chemoreduction plus local therapy: experience of the AC Camargo Hospital, Brazil.  J Pediatr Hematol Oncol. 2006;28(6):342-345PubMedArticle
8.
Shields JA, Shields CL, Meadows AT. Chemoreduction in the management of retinoblastoma.  Am J Ophthalmol. 2005;140(3):505-506PubMedArticle
9.
Shields CL, Mashayekhi A, Cater J, Shelil A, Meadows AT, Shields JA. Chemoreduction for retinoblastoma: analysis of tumor control and risks for recurrence in 457 tumors.  Am J Ophthalmol. 2004;138(3):329-337PubMedArticle
10.
Shields CL, Mashayekhi A, Demirci H, Meadows AT, Shields JA. Practical approach to management of retinoblastoma.  Arch Ophthalmol. 2004;122(5):729-735PubMedArticle
11.
Moll AC, Imhof SM, Schouten-van Meeteren AY, Boers M, van Leeuwen F, Hofman P. Chemoreduction for retinoblastoma [comment].  Arch Ophthalmol. 2003;121(10):1513PubMedArticle
12.
Sussman DA, Escalona-Benz E, Benz MS,  et al.  Comparison of retinoblastoma reduction for chemotherapy vs external beam radiotherapy.  Arch Ophthalmol. 2003;121(7):979-984PubMedArticle
13.
Shields CL, Honavar SG, Meadows AT, Shields JA, Demirci H, Naduvilath TJ. Chemoreduction for unilateral retinoblastoma.  Arch Ophthalmol. 2002;120(12):1653-1658PubMedArticle
14.
Ghose S, Nizamuddin SH, Sethi A,  et al.  Efficacy of induction chemotherapy in retinoblastoma, alone or combined with other adjuvant modalities.  J Pediatr Ophthalmol Strabismus. 2002;39(3):143-150PubMed
15.
Friedman DL, Himelstein B, Shields CL,  et al.  Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma.  J Clin Oncol. 2000;18(1):12-17PubMed
16.
Greenwald MJ, Goldman S, Strauss LC. Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma.  Ophthalmology. 1998;105(9):1579-1581PubMedArticle
17.
Shields CL, Shields JA, Needle M,  et al.  Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma.  Ophthalmology. 1997;104(12):2101-2111PubMed
18.
Murphree AL, Villablanca JG, Deegan WF III,  et al.  Chemotherapy plus local treatment in the management of intraocular retinoblastoma.  Arch Ophthalmol. 1996;114(11):1348-1356PubMedArticle
19.
Shields CL, De Potter P, Himelstein BP, Shields JA, Meadows AT, Maris JM. Chemoreduction in the initial management of intraocular retinoblastoma.  Arch Ophthalmol. 1996;114(11):1330-1338PubMedArticle
20.
Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience.  Arch Ophthalmol. 2011;129(6):732-737PubMedArticle
21.
Shields CL, Shields JA. Intra-arterial chemotherapy for retinoblastoma: the beginning of a long journey.  Clin Experiment Ophthalmol. 2010;38(6):638-643PubMedArticle
22.
Abramson DH, Dunkel IJ, Brodie SE, Marr B, Gobin YP. Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery).  Ophthalmology. 2010;117(8):1623-1629PubMedArticle
23.
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):1399-1406PubMedArticle
24.
Shields CL, Bianciotto CG, Jabbour P,  et al.  Intra-arterial chemotherapy for retinoblastoma: report No. 2, treatment complications.  Arch Ophthalmol. 2011;129(11):1407-1415PubMedArticle
25.
Aziz HA, Boutrid H, Murray TG,  et al.  Supraselective injection of intraarterial melphalan as the primary treatment for late presentation unilateral multifocal stage Vb retinoblastoma.  Retina. 2010;30(4):(suppl)  S63-S65PubMedArticle
26.
Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy.  Curr Opin Ophthalmol. 2010;21(3):203-212PubMedArticle
27.
Mashayekhi A, Shields CL, Eagle RC Jr, Shields JA. Cavitary changes in retinoblastoma: relationship to chemoresistance.  Ophthalmology. 2005;112(6):1145-1150PubMedArticle
28.
Palamar M, Pirondini C, Shields CL, Shields JA. Cavitary retinoblastoma: ultrasonographic and fluorescein angiographic findings in 3 cases.  Arch Ophthalmol. 2008;126(11):1598-1600PubMedArticle
29.
Ts’o MO, Zimmerman LE, Fine BS. The nature of retinoblastoma, I: photoreceptor differentiation: a clinical and histopathologic study.  Am J Ophthalmol. 1970;69(3):339-349PubMed
30.
Ginsberg J, Spaulding AG, Asbury T. Cystic retinoblastoma.  Am J Ophthalmol. 1975;80(5):930-934PubMed
31.
Demirci H, Eagle RC Jr, Shields CL, Shields JA. Histopathologic findings in eyes with retinoblastoma treated only with chemoreduction.  Arch Ophthalmol. 2003;121(8):1125-1131PubMedArticle
32.
Shields CL, Mashayekhi A, Cater J,  et al.  Macular retinoblastoma managed with chemoreduction: analysis of tumor control with or without adjuvant thermotherapy in 68 tumors.  Arch Ophthalmol. 2005;123(6):765-773PubMedArticle
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