Abstract
Background:
There has been no effective method for treating newly visible (“new”) sub-retinal seeding in retinoblastoma except enucleation. The objective of this report is to determine whether intravitreal chemotherapy combined with 810nm indirect laser can successfully treat retinoblastoma eyes with “new” sub-retinal seeding which appeared after intra-arterial chemotherapy (Ophthalmic Arterial Chemosurgery: OAC).
Material and Methods:
Single center retrospective study from a tertiary cancer hospital of a case series of 14 eyes treated with combined intravitreal chemotherapy and laser from 2012–2017. Ocular salvage, patient survival, recurrence-free ocular survival, metastases and extraocular extension were assessed.
Results:
A total of 14 eyes in 13 unilateral or bilateral retinoblastoma patients with “new” sub-retinal seeding after initial eye salvage therapy were treated with combined intravitreal injection of Melphalan (30ug) or Melphalan (30ug) and Topotecan (20ug) and with 810nm indirect continuous wave laser. All eyes were salvaged. Only two eyes (14%) recurred again for sub-retinal seeds after 6 and 8 months, respectively, and required additional cycles of intravitreal injections and laser. Combined intravitreal injection of Melphalan or Melphalan plus Topotecan with 810 nm indirect continuous wave laser was not associated with any metastatic events, patient deaths, extraocular extension or need for enucleation.
Conclusion:
There has been no effective treatment for “new” sub-retinal seeding after OAC except enucleation or second course OAC. Combined intravitreal chemotherapy with 810 nm indirect laser may be an effective and safe alternative to enucleation.
Keywords: Retinoblastoma, Newly visible sub-retinal seeds, Intravitreal Chemotherapy, Laser, Ocular Salvage
Introduction:
The greatest challenge to saving an eye with intraocular retinoblastoma has been the presence of seeding (vitreous and sub-retinal). Pioneering studies by Reese revealed that eyes developing vitreous seeding (VS) after external irradiation were “least favorable to treat” (“Vb”), with only 25% of those eyes salvaged after radiation therapy1. All three International Classification schemes acknowledge that sub-retinal seeds (SRS) are also a poor prognostic sign for ocular salvage after intravenous based chemotherapy1,2. Thus (worldwide) the majority of eyes with “D” classification (Children’s Oncology Group/COG) are enucleated primarily, while of those treated with systemic chemotherapy, fewer than 50% are salvaged3.
The introduction of intraarterial chemotherapy (ophthalmic artery chemosurgery/OAC) and, subsequently, intravitreal chemotherapy completely reversed this 100 year experience4. With OAC, the majority of “D” eyes have been saved without compromising patient survival4. In the initial reports using OAC, 60% of eyes with VS were salvaged without compromising patient survival5 and since then 80% of those eyes have been salvaged3. When intravitreal Melphalan was added to OAC, the ocular salvage rates increased, time to cure decreased and the overall patient exposure to chemotherapy decreased6. It is now common to save >90% of Stage D eyes that 10 years ago were routinely enucleated, without compromising patient survival or extraocular extension of tumor from injection7.
SRS at diagnosis has remained the limiting feature and it is difficult to cure in retinoblastoma eyes. Systemic chemotherapy has rarely saved those eyes and focal techniques are equally ineffective. That is why eyes with SRS have been routinely enucleated for 100 years, until the introduction of OAC. With OAC alone the majority of eyes with SRS have been salvaged without sacrificing patient survival5. Human and animal studies showed that intraarterial drug collects in the sub-retinal space working like a “depot” delivery system and effectively bathing the seeds in chemotherapy for many hours8,9.
In some eyes, however, SRS appear after what was thought to be successful OAC (which is why we refer to them as “new” SRS). There has been no effective treatment at this stage and no study has focused on the issue of management of “new” SRS10,11.
Here, we report on our 5-year experience in managing “new” SRS in eyes treated with OAC utilizing combined intravitreal chemotherapy and laser.
Material and methods:
Single center, IRB approved retrospective series of patients with “new” SRS (newly seen SRS that were not previously noted in an eye that received OAC) managed with combined intravitreal chemotherapy (Melphalan 30ug or Melphalan 30ug plus Topotecan 20ug) and 810nm indirect laser (continuous wave). Filtered Melphalan (30ug/0.07mL) was injected 3mm from the limbus in an area devoid of active seeding after lowering intraocular pressure with digital massage and ultrasonic biomicroscopic exam (UBM), done prior to lowering the pressure, showed no tumor in the needle path. Before removing the needle, cryotherapy was applied to seal and sterilize the needle site. Indirect 810nm laser was done (usually at the same session just before the intravitreal injection) with a 20-diopter lens on continuous wave laser and titrated till visible burns were evident.
Electroretinogtrams (ERG) were performed as previously described by our group 10 utilizing 30Hz flicker responses. The change in ERG amplitude (30Hz flicker) between measurements obtained the day of the first injection, or immediately prior to that, and the ones obtained at the visit immediately following the last injection was reported. ERG was considered stable if the change was within 25 uV, improved in cases where an increment of at least 25 uV was observed, and worse in cases with a decrement of at least 25uV.
Results:
Fourteen eyes from 13 patients, treated with intravitreal injection of Melphalan and/or Topotecan combined with indirect 810nm laser for the treatment of “new” SRS were analyzed. Patients’ details and treatment parameters are presented in Table 1. Thirty-six percent of the eyes were from bilateral cases and all of them exhibited advanced disease (defined as Reese-Ellsworth Groups “Va” or “Vb”, or ICRb COG Classification Groups “D” or “E”). The mean age of patients at the time of injection was 22 months and the mean time of follow up was 17 months. All eyes were previously treated: 100% of them had received OAC and, among them, 7% had also received intravitreal injection of Melphalan and/or Topotecan for the management of VS. In addition to OAC, 57% of the eyes had received prior focal therapy (laser or cryotherapy). All eyes were treated with combined intravitreal injection of Melphalan and/or Topotecan and indirect 810nm laser for the management of “new” SRS, with a mean of 2 laser sessions and 3 injections per eye. Two eyes also received cryotherapy. None of them received concomitant OAC.
Table 1:
Eyes Characteristics
|
all eyes |
|
|---|---|
| Number (n) of eyes | 14 |
| Mean Age at first injection (mth) | 22 (10–61) |
| Sex (Female) n (%) | 6 (43) |
| Advanced Eyes n (%) | 14 (100) |
| Laterality (bilateral) n (%) | 5 (36) |
| Mean follow up (mth) | 17 (6–38) |
| Response | |
| Mean regression time (d) | 41 (21–69) |
| Mean interval Injections session (d) | 24 (7–35) |
| Mean number of injections | 3 (2–5) |
| Mean number of drugs injected | 1 (1–2) |
| Recurrences n (%) | 2 (14) |
| Mean time to recurrence (mth) | 7 (6–8) |
| Treatment | |
| Prior OAC n (%) | 14 (100) |
| Prior focal therapy n (%) | 8 (57) |
| Prior IVT n (%) | 1 (7) |
| Concurrent Laser n (%) | 14 (100) |
| Mean number of laser sessions | 2 (1–3) |
| Concurrent Cryo n (%) | 2 (14) |
| ERG | |
| Stable n (%) | 10 (72) |
| Improved n (%) | 2 (14) |
| Worsening n (%) | 2 (14) |
OAC= Intra-arterial Chemotherapy; IVT= Intra-vitreal Chemotherapy
ERG=Electroretinogram; mth=months
The mean interval time between injections was of 24 days (7–35) and the mean regression time was 41 days (21–69). Most eyes received injection of one drug per session (Melphalan); two eyes were treated with dual injection of Topotecan and Melphalan. After treatment the 30Hz Flicker response ERG was the same in the majority of eyes (72%), improved in 14% and diminished in 14%.
In 13 eyes the SRS were completely calcified or scar-like (Figure 1). One eye showed fish-flesh material and was further treated with additional cycles of laser and cryo. Two eyes (14%) recurred again with SRS (after 6mo and 8mo) and received additional sessions of intravitreal injections and laser. The Kaplan-Meier estimate of recurrence-free ocular survival was 92.9% (95% Confidence Interval [CI] 66.22-93.90) at 6mo and 82.54 % (95% CI 62.60-87.06 %) at 12mo. There were no cases of metastatic events, deaths or extraocular extension at the needle site, and all eyes have been salvaged (Figure2).
Figure 1: “New” sub-retinal seeds before (A) and after treatment (B). OCT of SRS after combined treatment.
Figure 2: Kaplan-Meier Curves.
Discussion:
Until the introduction of OAC, seeding has been difficult to cure in patients with retinoblastoma and because of inadequate success of external beam radiation, systemic chemotherapy (<25%) and focal techniques (laser or cryotherapy), these eyes have been enucleated primarily. Initial published ocular salvage rates with OAC demonstrated that the majority of those eyes could be salvaged12 and, with additional experience, more than 75% of those eyes are now routinely saved3. There are few options for eyes that develop VS after initial chemotherapy (intravenous or intra-arterial). It is often impossible to see all SRS at diagnosis, but if seeds appear beneath a retina that was previously ophthalmoscopically normal, we call them “new” seeds, though they are potentially present at diagnosis. We have previously reported that some of these eyes can be salvaged with a second (or a third) course of OAC10. In addition, we previously reported encouraging success in 4 patients with SRS utilizing intravitreal injections of Melphalan13, but, since then, there have been no reported successes in the management of “new” SRS.
Intravitreal injections of Melphalan are now routinely used worldwide for the management of VS but not SRS14,15. A large international survey of more than 3000 injections reported no extraocular extension and a predicted rate of <0.08% of such events 16. In murine models, intravitreal Melphalan is associated with high levels of drug in the retina within 15 minutes of injection8. High levels remain longer in the retina than vitreous (12h vs. 5h), suggesting a role for intravitreal Melphalan in the management of SRS.
Our clinical experience with intravitreal injections alone or laser alone for “new” SRS was disappointing, so 5 years ago we began combining the two with the hope of saving eyes. This combination proved to be effective and safe but we do not know the relative contribution of each modality on success rate. The absence of extraocular extension, metastatic events or deaths, combined with success, offer clinicians an option to save eyes with “new” SRS.
ACKNOWLEDGEMENTS
Funding: This work was supported by the Fund for Ophthalmic Knowledge, Inc. (no grant number; philanthropic fund) and Perry’s Promise Fund (no grant number; philanthropic fund), and funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Footnotes
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References:
- 1.Reese AB. Retinoblastoma: past, present and future. Bibl Ophthalmol. 1968;75:138–141. [PubMed] [Google Scholar]
- 2.Dimaras H, Corson TW, Cobrinik D, et al. Retinoblastoma. Nat Rev Dis Primers. 2015;44:15021–15023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Scelfo C, Francis JH, Khetan V, et al. An international survey of classification and treatment choices for group D retinoblastoma. Int J Ophthalmol. 2017; 10 (6):961–967. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Abramson DH. Retinoblastoma: saving life with vision. Annu Rev Med. 2014;65(1):171–184. [DOI] [PubMed] [Google Scholar]
- 5.Abramson DH, Marr BP, Dunkel IJ, et al. Intra-arterial chemotherapy for retinoblastoma in eyes with vitreous and/or subretinal seeding: 2-year results. Br J Ophthalmol. 2012;96(4):499–502. [DOI] [PubMed] [Google Scholar]
- 6.Francis JH, Brodie SE, Marr B MS et al. Efficacy and Toxicity of Intravitreous Chemotherapy for Retinoblastoma: Four-Year Experience. Ophthalmology. 2017; 124(4):448–495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Abramson DH, Shields CL, Munier FL, Chantada GL. Treatment of Retinoblastoma in 2015: Agreement and Disagreement. JAMA Ophthalmol. 2015;133(11):1341–1347. [DOI] [PubMed] [Google Scholar]
- 8.Schaiquevich P, Fabius AW, Francis JH, et al. OCULAR PHARMACOLOGY OF CHEMOTHERAPY FOR RETINOBLASTOMA. Retina 2017: 37 (1): 1–10. [DOI] [PubMed] [Google Scholar]
- 9.Materin MA, Kuzmik GA, Jubinsky PT, et al. Verification of supraselective drug delivery for retinoblastoma using intra-arterial gadolinium. J NeuroIntervent Surg. 2013;5(6):e42–e42. [DOI] [PubMed] [Google Scholar]
- 10.Francis JH, Abramson DH, Gobin YP et al. Efficacy and Toxicity of Second-Course Ophthalmic Artery Chemosurgery for Retinoblastoma. Ophthalmology. 2015;122(5):1016–1022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Schields CL, Honavar SG, Schield JA et al. Factors Predictive of Recurrence of Retinal Tumors, Vitreous Seeds, and Subretinal Seeds Following Chemoreduction for Retinoblastoma. Arch Ophthalmol. 2002; 120 (4):460–464. [PubMed] [Google Scholar]
- 12.Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology. 2008;115(8):1398–1404. [DOI] [PubMed] [Google Scholar]
- 13.Francis JH, Marr BP, Brodie SE et al. INTRAVITREAL MELPHALAN AS SALVAGE THERAPY FOR REFRACTORY RETINAL AND SUBRETINAL RETINOBLASTOMA. Retin Cases Brief Rep; 2016: 10 (4): 357–360. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Munier FL. Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24th 2013. Ophthalmic Genet. 2014;35(4):193–207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Schields CL, Douglass AM, Beggache M et al. INTRAVITREOUS CHEMOTHERAPY FOR ACTIVE VITREOUS SEEDING FROM RETINOBLASTOMA. Retina 2016; 36(6):1184–1190. [DOI] [PubMed] [Google Scholar]
- 16.Francis JH, Abramson DH, Ji X, et al. Risk of Extraocular Extension in Eyes With Retinoblastoma Receiving Intravitreous Chemotherapy. JAMA Ophthalmol. 2017;135(12):1426–1429. [DOI] [PMC free article] [PubMed] [Google Scholar]