Abstract
Purpose:
The “cavitary” form of retinoblastoma has historically demonstrated minimal treatment response with intravenous chemoreduction, showing less robust regression and less reductions in tumor size. Intra-arterial chemotherapy (IAC) has been reported to more effectively treat retinoblastoma, allowing many previously-unsalvageable eyes to now be saved. The purpose was to report treatment response of cavitary retinoblastoma tumors to IAC.
Design:
Retrospective case series
Subjects:
Patients presenting with cavitary retinoblastoma who were treated with IAC.
Methods:
Retrospective case series of all patients presenting with cavitary retinoblastoma between August 2015 and January 2019 who were treated with primary IAC.
Main Outcome Measures:
Tumor regression, recurrence, resolution of vitreous and subretinal seeds, number of treatments required, globe salvage, metastasis, and death.
Results:
Eight cavitary retinoblastoma tumors in 6 eyes of 4 patients were treated with IAC. One hundred percent of the cavitary tumors regressed (8/8 tumors, in 6/6 eyes), 100% of vitreous and subretinal seeds regressed, with 100% globe salvage. None of the tumors recurred, no patients developed metastases, and no patients died. Eyes were treated with a median of 4.5 cycles of IAC (range 1–7), with fewer IAC treatments used in the later patients (1–3 treatments per eye for the most recent 3 eyes, compared to 6–7 treatments per eye for the earliest 3 eyes). Mean reduction in thickness was 73.4% (range: 59.7–84.6%). Mean reduction in basal diameter was 45.5% (range: 24.8–56.0%).
Conclusions:
Treatment with IAC results in regression of cavitary retinoblastoma, often with greater reduction in tumor size than has been reported previously with intravenous chemotherapy. Using upfront triple therapy (such as melphalan [0.4mg/kg], carboplatin [50mg], and topotecan [2mg]) and noting certain subtle signs of early regression can help to minimize unnecessary additional cycles of treatment.
Précis:
Historically, cavitary retinoblastoma showed minimal regression with intravenous chemotherapy. We report excellent tumor control (8/8) and globe salvage (6/6) with intra-arterial chemotherapy. Many eyes showed greater reduction in size than typically reported for intravenous chemotherapy.
INTRODUCTION:
Cavities have been reported in about 2–4% of retinoblastoma (RB) tumors.1,2 These tumors are characterized by the presence of lucent cavities on funduscopy, are hypofluorescent on fluorescein angiography, and appear as acoustically hollow/hypoechoic cavities on ultrasound. “Cavitary” RB tumors are associated with highly-differentiated histopathology and slow growth.1 As with many other types of differentiated cancers, they have been found to be less-responsive to chemotherapy. In fact, Mashayekhi et al. described general chemoresistance of cavitary RB tumors,1 and Rojanaporn et al. reported minimal reduction in size of cavitary tumors following intravenous chemotherapy (IVC).2
Intra-arterial chemotherapy (IAC) has demonstrated greater efficacy for treatment of advanced RB tumors that were not previously salvageable with IVC.3–5 However, there is minimal literature on the efficacy of IAC for the treatment of cavitary RB. Given the minimal treatment response of cavitary RB with IVC, we sought to evaluate the efficacy of IAC for cavitary RB.
METHODS:
Vanderbilt University Medical Center Institutional Review Board approval was obtained. Informed consent was obtained from patients for all procedures performed. This study adhered to the tenets of the Declaration of Helsinki and was in accordance with the Health Insurance Portability and Accountability Act.
All newly-diagnosed patients with RB evaluated by the Vanderbilt Eye Institute’s Ocular Oncology Division from August 2014 to January 2019 were reviewed and patients diagnosed with cavitary RB were identified. All charts and imaging studies were then re-reviewed to confirm the presence of cavities within these tumors, and the number of distinct tumors with cavities in these patients. Cavities were diagnosed based on the presence on funduscopy and fundus photography of lucent spaces within tumors, and/or by the presence of hypoechoic spaces within tumors on ultrasonography. Treatment course was reviewed, and only those patients treated with IAC as first-line therapy for the cavitary RB were included (i.e., we did not include patients previously treated with IVC).
Demographic information was collected including age at diagnosis, sex, race, presenting symptoms, and pattern of heredity. Tumor characteristics recorded included laterality, number of cavitary tumors in each eye, total number of tumors in each eye, as well as the presence or absence of vitreous seeds, subretinal seeds, and subretinal fluid. Tumor basal diameter and thickness were obtained from b-scan ultrasound images when available. Eyes were classified using both the International Classification of RB (ICRB)3,6 and the International Intraocular RB Classification (IIRC)7. Regression was evaluated based on operative reports from examinations under anesthesia and confirmed by review of all subsequent imaging studies during and after treatment with IAC.
IAC was performed using either melphalan, carboplatin, topotecan, or a combination of the above agents. Local consolidative therapy, including transpupillary thermotherapy (TTT) or cryotherapy, was performed as deemed necessary.
Outcome measures were tumor regression, recurrence, resolution of vitreous and subretinal seeds, number of treatments required, globe salvage, metastasis, and death.
RESULTS:
Eight cavitary RB tumors occurred in 6 eyes of 4 patients. The mean follow-up was 37 months (median: 34 months, range: 14–66 months). Mean age at diagnosis was 15 months (median: 34 months, range: 11–20 months). Three patients were male and one was female. Strabismus was the presenting symptom in three cases and failed vision screening was the presenting symptom in one case. Two patients had germline RB with bilateral disease, both of whom had at least one cavitary tumor in each eye.
One eye had 3 cavitary tumors, while the other 5 eyes had 1 cavitary tumor each. The cavitary tumors contained an average of 5 cavities per tumor (range 3–9). Four eyes contained additional noncavitary tumors, but at least 1 cavitary tumor was found in each eye affected by RB (i.e., no patient had cavitary RB in one eye and exclusively noncavitary tumors in the other eye). It was the larger tumors within each eye in which cavities were observable, while no cavities could be definitively discerned in smaller tumors. Prior to treatment, 3 eyes had vitreous seeds, 5 eyes had subretinal seeds, and 4 eyes had subretinal fluid. Four eyes (comprising 4 of the cavitary tumors) were group C and 2 eyes (comprising 4 of the cavitary tumors) were group D (Table 1). All eyes presenting with cavitary tumors during the study period were treated with IAC, and there were no eyes with cavitary tumors that were enucleated primarily. There were no cavitary group E eyes during the study period.
Table 1:
Tumor characteristics.
| Patient # | Eye | Tumor # | Eye Group* | Treatment | Initial tumorsize (mm)** | Seeds at presentation | Final tumor size (mm)** | Seeds after treatment |
|---|---|---|---|---|---|---|---|---|
| 1 | OD | 1 | C | 7 cycles IAC | ---‡ | Yes | 5.1x1.9 § | No |
| 1 | OS | 2 | D | 7 cycles IAC | --- | Yes | 9.5x2.2 | No |
| 1 | OS | 3 | D | 7 cycles IAC | --- | Yes | 6.4x2.2 | No |
| 1 | OS | 4 | D | 7 cycles IAC | --- | Yes | 6.4x1.7 | No |
| 2 | OS | 5 | D | 6 cycles IAC | 13.7x6.2 | Yes | 10.3x2.5 | No |
| 3 | OD | 6 | C | 2 cycles IAC | 12.5x6.2 | Yes | 5.5x1.2 | No |
| 3 | OS | 7 | C | 1 cycle IAC | 7.0x6.5 | No | 3.7x1.0 §§ | No |
| 4 | OS | 8 | C | 3 cycles IAC | 12.8x5.1 | Yes | 5.9x1.6 | No |
Eyes were classified by both the ICRB = International Classification of Retinoblastoma [Philadelphia/shields classification) and International Intraocular Retinoblastoma Classification (Murphree/CHLA). There were no eyes that were discordant based on classification system used.
Reported as (largest basal diameter x height [mm])
Preoperative measurements were not obtained for patient 1
Following completion of IAC and regression of the tumor, the residual tumor was treated with cryotherapy.
Following near-complete regression of the tumor with a single IAC treatment, cryotherapy was applied to the tiny residual calcified tumor.
IAC = intra-arterial chemotherapy
Each eye was treated with a median of 4.5 cycles of chemotherapy (range 1–7) (Table 2). These treatments consisted of the following drugs and doses, alone or in combination: melphalan (dose was based on the child’s weight at the time of treatment, at 0.4mg/kg), and/or carboplatin (50mg), and/or topotecan (2mg). “Tandem therapy,” with both eyes treated during the same IAC procedure, was used for both patients with bilateral disease. Choice of agents for a given eye was partly dictated by the presence of tumors in the other eye (i.e., all three agents could not be used for the right eye if the left eye also required IAC at the same time, but rather 2 drugs were given to one eye and the third drug was given to the second eye). However, with experience, we began to favor triple therapy (using all 3 drugs) as first line for unilaterally-affected patients with cavitary tumors. For one eye with three large cavitary tumors, 2 small noncavitary tumors, and extensive vitreous seeds, penetration of chemotherapy into the vitreous was augmented by application of cryotherapy to the anterior periphery (away from the tumors), akin to what has been described to increase vitreous drug levels with IVC.8 For two of the small cavitary tumors (in two different patients), following dramatic tumor regression with IAC, local consolidation was performed using cryotherapy. No cavitary tumors received TTT, although TTT was applied to subretinal seeds adjacent to some treated cavitary tumors in one eye.
Table 2:
Treatment Regimens
| Patient # | Eye | Treatment | |||
|---|---|---|---|---|---|
| Cycle # | Melphalan Dose [mg] | Carboplatin Dose [mg] | Topotecan Dose [mg] | ||
| 1 | OD | 1* | -- | 50 | -- |
| 2 | -- | 50 | 2 | ||
| 3 | 4.5 | -- | -- | ||
| 4 | -- | 50 | -- | ||
| 5 | 4.5 | -- | 2 | ||
| 6 | -- | 50 | 2 | ||
| 7 | 4.8 | -- | 2 | ||
| 1 | OS | 1 | 4.0 | -- | 2 |
| 2 | 4.0 | -- | -- | ||
| 3 | -- | 50 | 2 | ||
| 4 | 4.5 | -- | 2 | ||
| 5 | -- | 50 | -- | ||
| 6 | 4.8 | -- | -- | ||
| 7 | -- | 50 | -- | ||
| 2 | OS | 1 | 4.0 | 50 | 2 |
| 2 | 4.0 | 50 | 2 | ||
| 3 | 4.4 | 50 | 2 | ||
| 4 | 4.4 | 50 | 2 | ||
| 5 | 4.5 | 50 | 2 | ||
| 6 | 4.5 | 50 | 2 | ||
| 3 | OD | 1 | 4.2 | -- | 2 |
| 2 | -- | 50 | 2 | ||
| 3 | OS | 1 | -- | 50 | -- |
| 4 | OS | 1 | 3.5 | 50 | 2 |
| 2 | 3.5 | 50 | 2 | ||
| 3 | 4.0 | 50 | 2 | ||
-- no dose given
For all patients with bilateral disease, both eyes were treated at the same time (“tandem therapy”), and so cycle #1 OD occurred at the same time as cycle #1 OS. For patient #3, cycle #1 OD and cycle #1 OS were simultaneous tandem therapy, but OS required no further treatments, and so cycle #2 is listed only for OD.
One-hundred percent (8/8) of cavitary tumors regressed, 100% of vitreous and subretinal seeds regressed and 100% (6/6) of eyes were salvaged (Figures 1 and 2). No tumors recurred, no patients developed metastases, and no patients died. Mean pre-treatment thickness was 6.0 mm, and mean pre-treatment basal diameter was 11.5 mm. Mean post-treatment thickness was 1.8 mm, and mean post-treatment basal diameter was 6.6 mm (Figure 2). The average reduction in thickness was 73.1% (median: 74.0%, range: 59.5–84.7%). The average reduction in basal diameter was 45.5% (median: 50.5%, range: 24.8–56.0%).
Figure 1:
Fundus photos of representative patients prior to, and after, treatment with IAC.
A-B) Patient #3. A) At presentation, there was a large cavitary tumor obscuring view of the optic nerve, and with subretinal fluid and subtle subretinal seeds extending under the fovea. B) After two cycles of IAC (melphalan/topotecan, then carboplatin/topotecan), the tumor showed dramatic regression. The optic nerve is now visible (and normal in appearance), and the subfoveal seeds and fluid have completely resolved.
C-D) Patient #1. C) At presentation, large cavities were noted in all three large tumors in this eye. This is best appreciated in the current photograph in the temporal-most tumor. The two very small peripheral tumors in this eye did not show obvious cavities. D) Four years after completion of therapy, the tumors are regressed. Note that in this patient, the tumors did not show massive regression as in patient #3 (parts A-B of this figure), but rather slow gradual regression that continued even after cessation of active treatment. This response is more akin to that traditionally seen with intravenous chemotherapy for cavitary retinoblastoma (see manuscript text for discussion). This patient was treated with 7 cycles of IAC. Final visual acuity in this eye was 20/80.
Figure 2:
B-scan ultrasounds of two representative patients, demonstrating the obvious lucent cavities at presentation.
A-B) Patient #4. A) At presentation, a large tumor measuring 12.8mm in largest basal diameter and 5.1mm in height was seen in the central macula, with lucencies corresponding to the clinically-observed cavities, and with hyperechogenicities consistent with calcium. B) After 3 cycles of triple therapy with melphalan/carboplatin/topotecan, there was dramatic regression of the tumor, which now measures 5.9mm in largest basal diameter and 1.6mm in height.
C-D) Patient #3. C) Another nice example of lucent cavities seen in a different patient at the time of presentation. This B-scan corresponds to the fundus photos presented in Figure 1A, where the details of the case are described. D) After 2 cycles of triple therapy with melphalan/carboplatin/topotecan, there was a dramatic regression in tumor size which now measures 5.5mm in largest basal diameter and 1.2mm in height (vs. 12.5mm in basal diameter and 6.2mm in height prior to treatment). Neither one of these patients received consolidation to the tumor with laser or cryotherapy, and so the tumor responses observed are solely due to the IAC.
DISCUSSION:
This series of patients demonstrates that IAC can be effective to treat cavitary RB, a highly-differentiated form of RB that historically has shown relatively modest treatment response with IVC. While there are many reports of the efficacy of IAC for even advanced cases of RB,4,5 there is a paucity of literature related to IAC for the treatment of cavitary RB. In the large case series of chemotherapy for cavitary RB by Rojanaporn et al.,2 only three tumors were treated with IAC, and the outcomes of IAC-treated tumors were grouped together with the IVC-treated eyes (which formed 90% of the cohort). Fuller et al.9 described imaging findings in a single case of cavitary RB after treatment with IAC. Thus, to our knowledge, this study constitutes the single largest series of the results of IAC treatment for this rare, and notoriously hard-to-treat, form of RB.
A few series have explored the results of IVC for cavitary RB, and they have generally noted a lack of reduction in tumor size with IVC, sometimes resulting in enucleation. In their report of IVC for cavitary RB, Mashayekhi et al.,1 reported that 3 of their 16 eyes (19%) required enucleation. Similarly, 3 of the 26 eyes with cavitary RB treated by Rojanaporn2 required enucleation. In contrast, we found that all 8/8 cavitary tumors could be successfully treated with IAC, with all eyes being saved.
In the past, it is possible that some of the enucleated IVC-treated eyes had actually been treated successfully. However, because of the slow rate of regression seen with IVC for cavitary RB, these slowly-regressing tumors might have been mistaken for tumors that were failing to respond. Nowadays, where the slow rate of regression with IVC for cavitary RB is well-recognized, it is possible that some of those reported enucleated eyes might not have been removed.
Previous studies, predominantly utilizing IVC for the treatment of cavitary RB tumors, found an average reduction in tumor thickness of 18%1 and 29%.2 In contrast, the 73.1% mean reduction in tumor thickness and 45.5% mean reduction in basal diameter that we observed with IAC exceeded mean reductions in historical reports of tumors managed with IVC. We observed two scenarios of response: while 2 patients showed relatively modest reduction in tumor size during treatment, with continued gradual shrinkage over the years following treatment (akin to the pattern reported previously with IVC), the other 2 patients (3 eyes) showed dramatic tumor regression. For the patients with slow tumor regression, we suspect that the tumors were actually successfully treated (and nonviable) earlier in the course of treatment. However, because of the relatively minor clinical response, we continued to treat these patients with additional cycles of IAC (7 and 6 cycles, respectively). It is likely that we could have stopped treatment earlier, and in that sense, this probable overtreatment is not that different from what has happened with IVC in the past. Supporting this fact, our subsequent 3 eyes were treated with only 1–3 cycles of IAC.
Therefore, we now have adopted two ways to minimize the number of cycles of IAC required. First, we identified secondary signs indicating that IAC is working (regression of seeds or subretinal fluid, or regression of other noncavitary tumors elsewhere in the eye), which may be noticeable before shrinkage of the large cavitary tumor becomes apparent. When present, these findings served as a reassuring sign of the eye’s response to IAC, and we feel much more comfortable foregoing additional treatments if we see this secondary evidence of tumor response early on. Second, we favor upfront triple therapy with melphalan, carboplatin, and topotecan, to achieve the maximum effect and to maximize the likelihood of visible regression early on. Thus, the fact that eyes treated later in this study required fewer cycles likely arises from a combination of these two factors: triple therapy to increase the likelihood of seeing regression or secondary signs of tumor response, combined with increased faith that a tumor treated with (triple therapy) IAC was likely to be nonviable even if it did not shrink dramatically at first, if these signs of regression were seen.
Interestingly, there was variability in the timing of regression seen in cavitary tumors treated with IAC. Some eyes regressed slowly, while others regressed almost completely after only a single treatment. With non-cavitary RB, it is very common for tumors to respond with dramatic reductions in size after only 1–2 IAC treatments.10 In our study, some cavitary tumors displayed a similar immediate response, while others did not demonstrate this rapid response, and there was not necessarily perfect correlation with the number of drugs used. We did not vary the interval between IAC treatments based on this rate of regression. The interval between IAC and tumor regression was 4 weeks (range 3–5 weeks) in all patients, which is our standard protocol for both cavitary and non-cavitary tumors. On the one hand, one might argue that waiting longer between cycles gives more time for subtle changes of regression to become visible. However, we found that those tumors that regressed slowly, continued to regress slowly even if additional IAC treatments were given. On the other hand, there is reason to be aggressive and “hit the tumors hard” with cycles in rapid succession, when one is dealing with a difficult-to-treat RB tumor like cavitary RB. In addition, there is data from the New York group that outcomes are better when the interval between IAC treatments is not extended much beyond 4 weeks.11
We hypothesize that the greater regression and reductions in tumor size seen with IAC compared to IVC are related to the higher concentrations of drugs that reach the ocular tissues with IAC. Using a rabbit model of IAC, we have demonstrated that IAC achieves very high drug concentrations in both retina and vitreous,12 that these levels are much higher with IAC than with IVC,13 and that efficacy (and toxicity) is dose-dependent.12,14 As to why triple therapy might be particularly effective, it may not just be a case of “more drugs are better than fewer drugs”, but might relate to the specific effects of carboplatin itself, when used in combination with other agents. It is known that subretinal seeds respond particularly well to IAC, and this may be due to high drug levels concentrating within the subretinal space. We recently demonstrated that intra-arterial carboplatin causes vasotoxicity, leading to increased exudation and tissue edema,14,15 and we and others have observed retinal detachments forming transiently following intra-arterial carboplatin administration.16 It is possible that triple therapy may create a transient situation where carboplatin-induced exudation leads to increased local concentration of melphalan (and topotecan) within ocular tissues, thus potentiating their effects. However, further studies are needed to explore this mechanistic hypothesis.
Regarding the classification of eyes, we classified all eyes according to both the ICRB3,6 and IIRC7 systems. While the discordance between these classification systems has been reported,17,18 for the 6 eyes included in this study, there was complete concordance (i.e., each eye maintained its classification regardless of which system was used).
Lastly, although this represents the largest study describing IAC as treatment for cavitary RB, the study’s limitations, including small overall sample size and retrospective nature, must be considered when interpreting results and drawing conclusions. Larger, multi-institutional studies should be considered in the future.
In conclusion, IAC may be a successful option in treating cavitary RB, which historically had shown relatively modest and slow treatment response with IVC. While a fraction of IAC-treated tumors showed a similar slow response, other cavitary tumors treated with IAC showed dramatic and rapid regression of the tumors and rapid resolution of subretinal and vitreous seeds, with as few as 1–3 IAC treatments. Using upfront triple therapy when possible, and noting early signs of tumor response, both can help to minimize the number of IAC treatments required.
Acknowledgments
Financial Support: This work was funded by the National Institutes of Health / National Eye Institute (Bethesda, Maryland), grant number 5K08EY027464-02 [ABD], by a Career Development Award [ABD] from Research to Prevent Blindness (New York, New York), and by an unrestricted grant from Research to Prevent Blindness to the Vanderbilt Department of Ophthalmology and Visual Sciences. The funding organizations had no role in the design or conduct of this research.
Author Disclosures: ABD and DLF have an unrelated patent with Vanderbilt University Medical Center. ABD receives research funding from Spectrum Pharmaceuticals, Inc., which is not related to the work described herein. MTF receives research funding from Genentech, Stryker, Medtronic, Microvention, and EndoPhys and serves as a consultant for Balt USA, Corindus, Genentech, Medtronic, Stryler, and Viz.ai. None of the other authors has any conflicts to report.
Abbreviations/Acronyms:
- IAC
intra-arterial chemotherapy
- RB
retinoblastoma
- IVC
intravenous chemotherapy
- ICRB
International Classification of Retinoblastoma
- IIRC
International Intraocular Retinoblastoma Classification
- TTT
transpupillary thermotherapy
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
REFERENCES:
- 1.Mashayekhi A, Shields CL, Eagle RC Jr., Shields JA. Cavitary changes in retinoblastoma: relationship to chemoresistance. Ophthalmology. 2005;112(6):1145–1150. [DOI] [PubMed] [Google Scholar]
- 2.Rojanaporn D, Kaliki S, Bianciotto CG, Iturralde JC, Say EA, Shields CL. Intravenous chemoreduction or intra-arterial chemotherapy for cavitary retinoblastoma: long-term results. Arch Ophthalmol 2012;130(5):585–590. [DOI] [PubMed] [Google Scholar]
- 3.Shields CL, Jorge R, Say EA, et al. Unilateral Retinoblastoma Managed With Intravenous Chemotherapy Versus Intra-Arterial Chemotherapy. Outcomes Based on the International Classification of Retinoblastoma. Asia Pac J Ophthalmol (Phila). 2016;5(2):97–103. [DOI] [PubMed] [Google Scholar]
- 4.Abramson DH, Fabius AW, Issa R, et al. Advanced Unilateral Retinoblastoma: The Impact of Ophthalmic Artery Chemosurgery on Enucleation Rate and Patient Survival at MSKCC. PLoS One. 2015;10(12):e0145436. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Abramson DH, Daniels AB, Marr BP, et al. Intra-Arterial Chemotherapy (Ophthalmic Artery Chemosurgery) for Group D Retinoblastoma. PLoS One. 2016;11(1):e0146582. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113(12):2276–2280. [DOI] [PubMed] [Google Scholar]
- 7.Linn Murphree A Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am 2005;18(1):41–53, viii. [DOI] [PubMed] [Google Scholar]
- 8.Wilson TW, Chan HS, Moselhy GM, Heydt DD Jr., Frey CM, Gallie BL. Penetration of chemotherapy into vitreous is increased by cryotherapy and cyclosporine in rabbits. Arch Ophthalmol 1996;114(11):1390–1395. [DOI] [PubMed] [Google Scholar]
- 9.Fuller TS, Alvi RA, Shields CL. Optical Coherence Tomography of Cavitary Retinoblastoma. JAMA Ophthalmol 2016;134(5):e155355. [DOI] [PubMed] [Google Scholar]
- 10.Shields CL, Kaliki S, Shah SU, et al. Minimal exposure (one or two cycles) of intra-arterial chemotherapy in the management of retinoblastoma. Ophthalmology. 2012;119(1):188–192. [DOI] [PubMed] [Google Scholar]
- 11.Francis JH, Levin AM, Zabor EC, Gobin YP, Abramson DH. Ten-year experience with ophthalmic artery chemosurgery: Ocular and recurrence-free survival. PLoS One. 2018;13(5):e0197081. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Daniels AB, Froehler MT, Pierce JM, et al. Pharmacokinetics, Tissue Localization, Toxicity, and Treatment Efficacy in the First Small Animal (Rabbit) Model of Intra-Arterial Chemotherapy for Retinoblastoma. Invest Ophthalmol Vis Sci 2018;59(1):446–454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Daniels AB, Froehler MT, Pierce JM, et al. Efficacy, Toxicity and Biodistribution of Intra-arterial vs. Intravenous Chemotherapy in a Rabbit Retinoblastoma Model. Invest Ophthalmol Vis Sci 2018;59(9):1642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Daniels AB, Froehler MT, Nunnally AH, et al. Rabbit Model of Intra-Arterial Chemotherapy Toxicity Demonstrates Retinopathy and Vasculopathy Related to Drug and Dose, Not Procedure or Approach. Invest Ophthalmol Vis Sci 2019;60(4):954–964. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Oatess TL, Chen PH, Daniels AB, Himmel LE. Severe Periocular Edema after Intraarterial Carboplatin Chemotherapy for Retinoblastoma in a Rabbit (Oryctolagus cuniculus) Model. Comp Med 2020;70(2):176–182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Friedman EL, Froehler MT, Daniels AB. Orbital swelling in a child with retinoblastoma following intra-arterial chemotherapy. JAMA Ophthalmol [In Press]. [DOI] [PubMed] [Google Scholar]
- 17.Novetsky DE, Abramson DH, Kim JW, Dunkel IJ. Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies--an analysis of impact. Ophthalmic Genet 2009;30(1):40–44. [DOI] [PubMed] [Google Scholar]
- 18.Kim JW, Shah SN, Green S, O’Fee J, Tamrazi B, Berry JL. Tumour size criteria for Group D and E eyes in the International Classification System for Retinoblastoma: effects on rates of globe salvage and high-risk histopathologic features. Acta Ophthalmol 2020;98(1):e121–e125. [DOI] [PMC free article] [PubMed] [Google Scholar]