ECHOGRAPHIC LOCALIZATION OF PERIOCULAR CARBOPLATIN FOR TREATMENT OF ADVANCED RETINOBLASTOMA Colleen M. Cebulla, MD, PHD, Armando Alegret, MD, Fiona J. Ehlies, BSC, R. Prince Davis, II, MD, Ditte J. Hess, CRA, Timothy G. Murray, MD, MBA, the Echography Study Group
Purpose: To study ocular ultrasonography as a means to effectively localize periocular carboplatin in patients with advanced retinoblastoma. Methods: In a cases series, seven patients diagnosed with advanced retinoblastoma refractory to standard chemotherapy were treated with two to four periocular carboplatin injections. Echographic images were obtained before and after injection. Results: The periocular carboplatin depot was a discrete homogeneous structure with lower internal reflectivity than the surrounding orbital tissue. The mean maximal juxtascleral height of the drug depot ⫾ SD was 3.3 ⫾1.4 mm and was located directly posterior to the area of maximal intraocular tumor thickness in all seven patients. Moderate shadowing from calcification was present in one patient. Five patients had a pattern of a thinner pocket of drug visible after subsequent injections. Conclusions: Echography is a useful technique to study novel periocular drug delivery. It effectively images the drug in relation to the intraocular tumor, confirming the most effective drug placement for these resistant tumors. RETINAL CASES & BRIEF REPORTS 3:4 –7, 2009
From the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida.
trates the first echographic localization of periocular carboplatin for the treatment of advanced retinoblastoma.
P
eriocular carboplatin has been used as adjunctive treatment for resistant, advanced retinoblastoma.1 In particular, cases with extensive vitreous seeds may benefit from judicious use of this therapy. As sustained release formulations of periocular chemotherapy are developed, echography may be useful as a noninvasive technique to visualize the drug depot. To our knowledge, this case series of seven patients illus-
Methods Seven patients diagnosed with advanced retinoblastoma refractory to standard chemotherapy were treated with two to four periocular carboplatin injections. Carboplatin (2 mL of a 10 mg/mL solution) was delivered by creating a small incision with Westcott scissors in the conjunctiva and Tenon’s layer and injecting it through a cannula into the retrobulbar space. The drug was injected in the clock hour of maximal tumor thickness (i.e., behind the tumor). Echographic images were obtained before and after injection with an Innovative Imaging, Inc. (I3), ABD unit and a 10-MHz contact B-scan probe. The gain was medium to low, to show orbital structures better. This study was conducted with approval from the
The Echography Study Group includes Brandy Hayden, Patricia Superfine-Rivera, Linda Kelley, Ernesto Bermudez, and Maria Eugenia Bretana. T. G. M. 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. Reprint requests: Timothy G. Murray, MD, Bascom Palmer Eye Institute, PO Box 016880, Miami, FL 33101; e-mail: TMurray@ med.miami.edu
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ECHOGRAPHIC LOCALIZATION OF PERIOCULAR CARBOPLATIN IN ADVANCED RETINOBLASTOMA
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Table 1. Data for Seven Patients Treated With Periocular Carboplatin Injections
Patient 1 2 3 4 5 6 7
Age at Presentation 6d 23 mo 7 mo 10 mo 13 mo 9 mo 12 mo
ReeseEllsworth Group Vb Vb Vb Vb Vb Vb Vb
Chemotherapy (Total No. of Cycles) VEC VEC VEC VEC VEC VEC VEC
(13) ⫹ cyclosporine (9) ⫹ cyclosporine (9) ⫹ cyclosporine (8) ⫹ cyclosporine (9) ⫹ cyclosporine (10) ⫹ cyclosporine (10) ⫹ cyclosporine
Laser
Cryotherapy
Yes Yes Yes Yes Yes Yes Yes
Yes No No No No No No
No. of Injections (Cycle No. at First Injection) 4 4 3 2 2 4 4
(9) (8) (9) (7) (8) (7) (4)
Sequelae Mild conjunctival fibrosis and EOM restriction
VEC, vincristine, etoposide, and carboplatin; EOM, extraocular muscle.
Institutional Review Board at the University of Miami (Miami, FL). Results The clinical details for the patients are listed in Table 1. Echographic analysis of the periocular carboplatin depot revealed a discrete homogeneous structure with lower internal reflectivity than the surrounding orbital tissue. After the first injection, the location and maximal juxtascleral height of the drug depot were determined (Table 2). The depot was located adjacent to the area of maximal intraocular tumor thickness in all seven patients, and the mean maximal juxtascleral height ⫾ SD was 3.3 ⫾ 1.4 mm. Moderate shadowing from calcification was present in one patient (Fig. 1); however, this did not preclude measuring the juxtascleral height. The length of the drug depot extended from the optic nerve to the limbus in the quadrant of injection and was difficult to measure accurately because of the length of extension. Further pertinent echography details are listed separately.
and carboplatin and concurrent laser ablation of the tumor. Unfortunately, the patient developed late progression of vitreous seeding in the left eye (Fig. 2). Despite continued treatment with laser, cryotherapy, and two more cycles of vincristine, etoposide, and carboplatin plus cyclosporine, the vitreous seeds increased in size as the child approached 14 months of age. Because of vitreous seed progression, the patient was treated with periocular carboplatin. Subsequent examination during anesthesia revealed improvement in the size of vitreous seeds 1 month after the first carboplatin injection and disappearance of the vitreous seeds 1 month after the fourth injection (Fig. 2). Echographic imaging of the third injection showed the accumulation of drug in the Tenon’s space adjacent to the area with vitreous seeds (Fig. 2). As in all patients treated in this series, the patient developed mild conjunctival fibrosis and restriction as determined by forced duction testing (Table 1).
Case 2 A 23-month-old boy with stage Vb retinoblastoma had persistent vitreous and subretinal seeds despite treatment with nine cycles of vincristine, etoposide, and carboplatin plus cyclosporine and laser ablation of the tumor. The patient was treated with four periocular carboplatin injections, and the disease remained stable in the left eye. Ultrasonography revealed a large pocket of carboplatin after
Case Reports Case 1 A 6-day-old girl with group Vb retinoblastoma underwent systemic chemoreduction with nine cycles of vincristine, etoposide,
Table 2. Ultrasound Measurements of Periocular Carboplatin Patient 4 2 1 7 5 6 3
Location (Clock Hour) 10:30 7:30 10:30 6:00 5:00 6:00 5:00
Juxtascleral Height (mm) 6.0 4.0 3.6 3.2 2.5 2.1 2.0 3.3 (1.4)*
*Mean ⫾ SD.
Fig. 1. Calcific shadowing limits visualization of periocular carboplatin. Arrows mark the periocular drug, while an asterisk marks the shadowing from the intraocular tumor.
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Fig. 2. Improvement in vitreous seeding after periocular carboplatin injection. The patient’s resistant vitreous seeds are shown before periocular carboplatin (A) and have disappeared 1 month after the fourth injection (B). Echographic localization demonstrates vitreous seeds before the third injection (white arrow, C) and immediately after the third injection (small white arrow, D). The periocular carboplatin is well visualized (blue arrows, D) adjacent to the globe and optic nerve shadow (large white arrow, D).
the first injection; however, the drug depot became much thinner with subsequent injections, with the juxtascleral height of the carboplatin depot decreasing from 4 mm to 1 mm (Fig. 3). This pattern was noted in five cases in this series. In addition, an increase in echodensity in the area of the periocular depot was noted with time after some injections (large arrow, Fig. 3), likely due to precipitation of the drug in the periocular tissues.
Case 3 A 13-month-old boy with group Vb retinoblastoma in the left eye had a large macular tumor and vitreous seeding despite nine cycles of vincristine, etoposide, and carboplatin plus cyclosporine and laser ablation. Two periocular carboplatin injections were
delivered concurrent with his last two systemic treatments. The carboplatin depot clinically appeared to be located anteriorly, and the drug was visible as a bleb under the conjunctiva (Fig. 4). However, echography showed that a large posterior pocket of drug was also adjacent to the maximal thickness of the intraocular tumor (Fig. 4).
Discussion On the basis of preclinical models and clinical trials,1,2 periocular carboplatin injection may be an effective adjuvant strategy for advanced drug-resistant retinoblastoma. However, because there are reports of
Fig. 3. Periocular carboplatin volumes are more compressed with repeated injections. The periocular carboplatin is marked by white arrows and is a wider volume after the first injection (A) compared with the fourth injection (B). Echodense material (large white arrows) is visible in the area of the carboplatin depot after increasing time, a phenomenon seen with many injections.
ECHOGRAPHIC LOCALIZATION OF PERIOCULAR CARBOPLATIN IN ADVANCED RETINOBLASTOMA
7
Fig. 4. Anterior localization of periocular carboplatin. The periocular drug appears to be very anterior, with a conjunctival bleb shown by photography (arrow, A); however, a large amount of the drug travels near the posterior pole and is visualized with echography (arrows, B). The optic nerve is marked with an asterisk.
complications such as optic neuropathy, conjunctival fibrosis, and ocular motility restriction, its use is limited.3,4 Improved periocular treatments are being investigated, including carboplatin in fibrin sealant, which would provide slow sustained drug release and potentially reduce the number of injections.5 To determine whether ultrasonography could effectively image the periocular drug depot in relation to the intraocular tumor, seven patients with group Vb disease (International Classification E) who received two to four adjuvant periocular carboplatin injections were studied. In each patient, the carboplatin depot was a discrete homogeneous structure with greatest juxtascleral height adjacent to the maximal thickness of the intraocular tumor. The height was measurable, despite moderate shadowing from calcification in one patient. Five patients had a pattern of a compressed pocket of drug after the second injection. This finding was attributed to conjunctival or Tenon layer fibrosis limiting the expansion of the drug. It is interesting that there was also the observation of increasing echodensity of the carboplatin depot with time after the injection. Presumably, this is due to interaction of the drug with the periocular tissues. Future studies could address whether the echodense areas and shrinking drug pocket size may be markers for greater fibrosis or toxicity. This small case series demonstrates that despite some limitations from calcific shadowing, echography
is a useful technique to study novel periocular drug delivery. An interesting question for future study is whether more precise ultrasound-guided drug placement with a different more cohesive formulation of carboplatin could reduce side effects such as optic neuropathy. In conclusion, echography effectively images the drug in relation to the intraocular tumor, assuring the most effective drug placement for these resistant tumors. Key words: periocular carboplatin, retinoblastoma, ultrasound localization, echography. References 1.
2.
3.
4.
5.
Abramson DH, Frank CM, Dunkel IJ. A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 1999;106:1947–1950. Hayden BH, Murray TG, Scott IU, et al. Subconjunctival carboplatin in retinoblastoma: impact of tumor burden and dose schedule. Arch Ophthalmol 2000;118:1549–1554. Schmack I, Hubbard GB, Kang SJ, et al. Ischemic necrosis and atrophy of the optic nerve after periocular carboplatin injection for intraocular retinoblastoma. Am J Ophthalmol 2006;142: 310–315. Mulvihill A, Budning A, Jay V, et al. Ocular motility changes after subtenon carboplatin chemotherapy for retinoblastoma. Arch Ophthalmol 2003;121:1120–1124. Van Quill KR, Dioguardi PK, Tong CT, et al. Subconjunctival carboplatin in fibrin sealant in the treatment of transgenic murine retinoblastoma. Ophthalmology 2005;112:1151–1158.
Purpose: To study ocular ultrasonography as a means to effectively localize periocular carboplatin in patients with advanced retinoblastoma. Methods: In a cases series, seven patients diagnosed with advanced retinoblastoma refractory to standard chemotherapy were treated with two to four periocular carboplatin injections. Echographic images were obtained before and after injection. Results: The periocular carboplatin depot was a discrete homogeneous structure with lower internal reflectivity than the surrounding orbital tissue. The mean maximal juxtascleral height of the drug depot ⫾ SD was 3.3 ⫾1.4 mm and was located directly posterior to the area of maximal intraocular tumor thickness in all seven patients. Moderate shadowing from calcification was present in one patient. Five patients had a pattern of a thinner pocket of drug visible after subsequent injections. Conclusions: Echography is a useful technique to study novel periocular drug delivery. It effectively images the drug in relation to the intraocular tumor, confirming the most effective drug placement for these resistant tumors. RETINAL CASES & BRIEF REPORTS 3:4 –7, 2009
From the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida.
trates the first echographic localization of periocular carboplatin for the treatment of advanced retinoblastoma.
P
eriocular carboplatin has been used as adjunctive treatment for resistant, advanced retinoblastoma.1 In particular, cases with extensive vitreous seeds may benefit from judicious use of this therapy. As sustained release formulations of periocular chemotherapy are developed, echography may be useful as a noninvasive technique to visualize the drug depot. To our knowledge, this case series of seven patients illus-
Methods Seven patients diagnosed with advanced retinoblastoma refractory to standard chemotherapy were treated with two to four periocular carboplatin injections. Carboplatin (2 mL of a 10 mg/mL solution) was delivered by creating a small incision with Westcott scissors in the conjunctiva and Tenon’s layer and injecting it through a cannula into the retrobulbar space. The drug was injected in the clock hour of maximal tumor thickness (i.e., behind the tumor). Echographic images were obtained before and after injection with an Innovative Imaging, Inc. (I3), ABD unit and a 10-MHz contact B-scan probe. The gain was medium to low, to show orbital structures better. This study was conducted with approval from the
The Echography Study Group includes Brandy Hayden, Patricia Superfine-Rivera, Linda Kelley, Ernesto Bermudez, and Maria Eugenia Bretana. T. G. M. 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. Reprint requests: Timothy G. Murray, MD, Bascom Palmer Eye Institute, PO Box 016880, Miami, FL 33101; e-mail: TMurray@ med.miami.edu
4
ECHOGRAPHIC LOCALIZATION OF PERIOCULAR CARBOPLATIN IN ADVANCED RETINOBLASTOMA
5
Table 1. Data for Seven Patients Treated With Periocular Carboplatin Injections
Patient 1 2 3 4 5 6 7
Age at Presentation 6d 23 mo 7 mo 10 mo 13 mo 9 mo 12 mo
ReeseEllsworth Group Vb Vb Vb Vb Vb Vb Vb
Chemotherapy (Total No. of Cycles) VEC VEC VEC VEC VEC VEC VEC
(13) ⫹ cyclosporine (9) ⫹ cyclosporine (9) ⫹ cyclosporine (8) ⫹ cyclosporine (9) ⫹ cyclosporine (10) ⫹ cyclosporine (10) ⫹ cyclosporine
Laser
Cryotherapy
Yes Yes Yes Yes Yes Yes Yes
Yes No No No No No No
No. of Injections (Cycle No. at First Injection) 4 4 3 2 2 4 4
(9) (8) (9) (7) (8) (7) (4)
Sequelae Mild conjunctival fibrosis and EOM restriction
VEC, vincristine, etoposide, and carboplatin; EOM, extraocular muscle.
Institutional Review Board at the University of Miami (Miami, FL). Results The clinical details for the patients are listed in Table 1. Echographic analysis of the periocular carboplatin depot revealed a discrete homogeneous structure with lower internal reflectivity than the surrounding orbital tissue. After the first injection, the location and maximal juxtascleral height of the drug depot were determined (Table 2). The depot was located adjacent to the area of maximal intraocular tumor thickness in all seven patients, and the mean maximal juxtascleral height ⫾ SD was 3.3 ⫾ 1.4 mm. Moderate shadowing from calcification was present in one patient (Fig. 1); however, this did not preclude measuring the juxtascleral height. The length of the drug depot extended from the optic nerve to the limbus in the quadrant of injection and was difficult to measure accurately because of the length of extension. Further pertinent echography details are listed separately.
and carboplatin and concurrent laser ablation of the tumor. Unfortunately, the patient developed late progression of vitreous seeding in the left eye (Fig. 2). Despite continued treatment with laser, cryotherapy, and two more cycles of vincristine, etoposide, and carboplatin plus cyclosporine, the vitreous seeds increased in size as the child approached 14 months of age. Because of vitreous seed progression, the patient was treated with periocular carboplatin. Subsequent examination during anesthesia revealed improvement in the size of vitreous seeds 1 month after the first carboplatin injection and disappearance of the vitreous seeds 1 month after the fourth injection (Fig. 2). Echographic imaging of the third injection showed the accumulation of drug in the Tenon’s space adjacent to the area with vitreous seeds (Fig. 2). As in all patients treated in this series, the patient developed mild conjunctival fibrosis and restriction as determined by forced duction testing (Table 1).
Case 2 A 23-month-old boy with stage Vb retinoblastoma had persistent vitreous and subretinal seeds despite treatment with nine cycles of vincristine, etoposide, and carboplatin plus cyclosporine and laser ablation of the tumor. The patient was treated with four periocular carboplatin injections, and the disease remained stable in the left eye. Ultrasonography revealed a large pocket of carboplatin after
Case Reports Case 1 A 6-day-old girl with group Vb retinoblastoma underwent systemic chemoreduction with nine cycles of vincristine, etoposide,
Table 2. Ultrasound Measurements of Periocular Carboplatin Patient 4 2 1 7 5 6 3
Location (Clock Hour) 10:30 7:30 10:30 6:00 5:00 6:00 5:00
Juxtascleral Height (mm) 6.0 4.0 3.6 3.2 2.5 2.1 2.0 3.3 (1.4)*
*Mean ⫾ SD.
Fig. 1. Calcific shadowing limits visualization of periocular carboplatin. Arrows mark the periocular drug, while an asterisk marks the shadowing from the intraocular tumor.
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NUMBER 1
Fig. 2. Improvement in vitreous seeding after periocular carboplatin injection. The patient’s resistant vitreous seeds are shown before periocular carboplatin (A) and have disappeared 1 month after the fourth injection (B). Echographic localization demonstrates vitreous seeds before the third injection (white arrow, C) and immediately after the third injection (small white arrow, D). The periocular carboplatin is well visualized (blue arrows, D) adjacent to the globe and optic nerve shadow (large white arrow, D).
the first injection; however, the drug depot became much thinner with subsequent injections, with the juxtascleral height of the carboplatin depot decreasing from 4 mm to 1 mm (Fig. 3). This pattern was noted in five cases in this series. In addition, an increase in echodensity in the area of the periocular depot was noted with time after some injections (large arrow, Fig. 3), likely due to precipitation of the drug in the periocular tissues.
Case 3 A 13-month-old boy with group Vb retinoblastoma in the left eye had a large macular tumor and vitreous seeding despite nine cycles of vincristine, etoposide, and carboplatin plus cyclosporine and laser ablation. Two periocular carboplatin injections were
delivered concurrent with his last two systemic treatments. The carboplatin depot clinically appeared to be located anteriorly, and the drug was visible as a bleb under the conjunctiva (Fig. 4). However, echography showed that a large posterior pocket of drug was also adjacent to the maximal thickness of the intraocular tumor (Fig. 4).
Discussion On the basis of preclinical models and clinical trials,1,2 periocular carboplatin injection may be an effective adjuvant strategy for advanced drug-resistant retinoblastoma. However, because there are reports of
Fig. 3. Periocular carboplatin volumes are more compressed with repeated injections. The periocular carboplatin is marked by white arrows and is a wider volume after the first injection (A) compared with the fourth injection (B). Echodense material (large white arrows) is visible in the area of the carboplatin depot after increasing time, a phenomenon seen with many injections.
ECHOGRAPHIC LOCALIZATION OF PERIOCULAR CARBOPLATIN IN ADVANCED RETINOBLASTOMA
7
Fig. 4. Anterior localization of periocular carboplatin. The periocular drug appears to be very anterior, with a conjunctival bleb shown by photography (arrow, A); however, a large amount of the drug travels near the posterior pole and is visualized with echography (arrows, B). The optic nerve is marked with an asterisk.
complications such as optic neuropathy, conjunctival fibrosis, and ocular motility restriction, its use is limited.3,4 Improved periocular treatments are being investigated, including carboplatin in fibrin sealant, which would provide slow sustained drug release and potentially reduce the number of injections.5 To determine whether ultrasonography could effectively image the periocular drug depot in relation to the intraocular tumor, seven patients with group Vb disease (International Classification E) who received two to four adjuvant periocular carboplatin injections were studied. In each patient, the carboplatin depot was a discrete homogeneous structure with greatest juxtascleral height adjacent to the maximal thickness of the intraocular tumor. The height was measurable, despite moderate shadowing from calcification in one patient. Five patients had a pattern of a compressed pocket of drug after the second injection. This finding was attributed to conjunctival or Tenon layer fibrosis limiting the expansion of the drug. It is interesting that there was also the observation of increasing echodensity of the carboplatin depot with time after the injection. Presumably, this is due to interaction of the drug with the periocular tissues. Future studies could address whether the echodense areas and shrinking drug pocket size may be markers for greater fibrosis or toxicity. This small case series demonstrates that despite some limitations from calcific shadowing, echography
is a useful technique to study novel periocular drug delivery. An interesting question for future study is whether more precise ultrasound-guided drug placement with a different more cohesive formulation of carboplatin could reduce side effects such as optic neuropathy. In conclusion, echography effectively images the drug in relation to the intraocular tumor, assuring the most effective drug placement for these resistant tumors. Key words: periocular carboplatin, retinoblastoma, ultrasound localization, echography. References 1.
2.
3.
4.
5.
Abramson DH, Frank CM, Dunkel IJ. A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 1999;106:1947–1950. Hayden BH, Murray TG, Scott IU, et al. Subconjunctival carboplatin in retinoblastoma: impact of tumor burden and dose schedule. Arch Ophthalmol 2000;118:1549–1554. Schmack I, Hubbard GB, Kang SJ, et al. Ischemic necrosis and atrophy of the optic nerve after periocular carboplatin injection for intraocular retinoblastoma. Am J Ophthalmol 2006;142: 310–315. Mulvihill A, Budning A, Jay V, et al. Ocular motility changes after subtenon carboplatin chemotherapy for retinoblastoma. Arch Ophthalmol 2003;121:1120–1124. Van Quill KR, Dioguardi PK, Tong CT, et al. Subconjunctival carboplatin in fibrin sealant in the treatment of transgenic murine retinoblastoma. Ophthalmology 2005;112:1151–1158.
