Dr.RAKSHA RAO, Dr.Santosh G Honavar
Abstract:
Objectives: To study the clinical features contributing to failure of globe salvage in retinoblastoma group E eyes with neovascular glaucoma.
Design: Retrospective, comparative, interventional case series.
Intervention: Management by neoadjuvant systemic chemotherapy with or without enucleation.
Participants:Thirty-seven patients of retinoblastoma group E eyes with neovascular glaucoma.
Main Outcome Measures:Life salvage,globe salvage, and vision salvage.
Results:Of the 37 eyes managed by neoadjuvant systemic chemotherapy,secondary enucleation was necessary in 21 eyes for treatment failure (group 1), and globe salvage was possible in16eyes(group 2). A comparison of both groups revealed no difference inthe age at presentation (24.5 months vs 18 months, p=0.2204),sex (female 48% vs 44%, p = 1.000), laterality (left eye 62% vs 56%, p = 1.000), and the presenting symptom (leukocoria 86% vs 94%, p = 0.618).
However, there was significant difference with group 1 demonstratinggreater duration of symptoms (18.8weeksvs 5.4weeks,p=0.016), greater intraocular pressure (IOP) at presentation (36 mm Hg vs 30 mm Hg, p=0.044), greater increase in corneal diameter (1.52 mm vs 0.50 mm p=0.013), and the presence of sterile orbital cellulitis (9 vs 1, p=0.023). Further by univariate analysis, the study showed that the risk factors for secondary enucleation were age at diagnosis >6 months (p=0.055), duration of symptoms >10 weeks (p=0.003), presenting IOP >26 mm Hg (p=0.045), presence of buphthalmos (p=0.014), and presence of sterile orbital cellulitis (p=0.023). Ata mean follow-up of 20.5 months follow up, none of the patients in either groupdeveloped systemic metastasis. The mean visual acuity in the 16 eyes belonging to group 2 was 20/200 (median, 20/200; range, 20/60-PL+).
Conclusion:For retinoblastoma group E eyes presenting with neovascular glaucoma, the chance of globe salvage with neoadjuvant systemic chemotherapy is better if the age at diagnosis is <6 months, duration of symptoms is <10 weeks, IOP is <26 mm Hg, and in the absence buphthalmos and sterile orbital inflammation.
With the introduction of intra-arterial chemotherapy, there has been a paradigm shift in the management of retinoblastoma.1-3 Intra-arterial chemotherapy achieves excellent eye salvage rates, in both early and advanced retinoblastoma.1-3 However, standard triple drug (vincristine+carboplatin+etoposide) intravenous chemotherapy (IVC) continues to be the primary modality of treatment forretinoblastoma in many parts of the world.4-16IVC alone can achieve an impressive tumor control in less advanced cases, with aglobe salvage of 100%, 93% and 90% in international classification for retinoblastoma(ICRB) groups A, B and C, respectively.8When used as thefirst line of treatment in conjunction with the focalconsolidation therapies, IVC can achieve upto 47%-63% globe salvage in group D eyes.8,9
Regarding group E eyes, there are very few reports which have studied the efficacy of IVC in these eyes with advanced retinoblastoma, as most often they undergoprimary enucleation.8,10-12In one study that compared the management of group E eyes using IVC with and without radiation,the globe salvage rate at a mean follow-up of 63 monthswas reported to be 45% with the use of IVC alone, versus 83% with a combination of IVC and low-dose external radiotherapy.10However, this study did not include any group E eyes withneovascularization of iris (NVI), neovascular glaucoma (NVG), extensive hyphema, extensive vitreous hemorrhage, tumor invasion into the anterior chamber, iris, optic nerve, choroid, or eyes with massive tumor, total retinal detachment, extensive tumor seeding, or sterile orbital cellulitis.10Long-term results indicate that secondary enucleation isnecessary in many of the group E eyes for early and late treatment failure.8,10,13Despite this, IVC in group E eyes may stillbe indicated when there is bilateral group E disease, when it is the only eye of the patient, or when the opposite eye requires IVC for less advanced retinoblastoma and the involved group E eye can be monitored for any response.10,13
The term neoadjuvant chemotherapy has been used in oncology to refer to chemotherapy given before any local therapy.17In advanced retinoblastoma, neoadjuvant systemic chemotherapy is given with an intent to enucleate the eye, with a primary aim to control any immediate extraoculartumor extension, and thus protect the patient from possible metastatic disease.15 In addition, group E eyes with neovascular glaucoma have extremely thin sclera secondary to buphthalmos.11,16 Neoadjuvant chemotherapy reduces the tumor load within the eye and helps make enucleation safer.11,16Herein, we analyze theeffect of neoadjuvant chemotherapy in group E eyes with neovascular glaucoma and the clinical features contributing to failure of globe salvage in these eyes.
Methods:
Our retrospective, comparative, interventional case series included 59 eyes of 59patients with ICRB group E retinoblastoma with neovascular glaucoma. The study setting was a tertiary care eye hospital with an integrated retinoblastoma management centre. Institutional review board approval was obtained.
The clinical data weretabulated and analyzed with regard to the main outcome measures–life salvage, globe salvage, and vision salvage. All statistical calculations were performed using Microsoft Excel 2013 software (Microsoft, Redmond, Washington, USA) and GraphPad software (GraphPad Software Inc., California, USA). The outcomes from each group were evaluated using the 2-tailed Fisher exact test for categorical variables. For continuous variables, the student t-test was employed. P values of 0.05 or lower were considered statistically significant.
Results:
The mean age at presentation of groups 1 and 2 was 24.5 and 18 months, respectively. Demographic features did not statistically differ among the groups. The mean visual acuity in both groups was no fix and follow to light. A comparison of tumor features (group 1 vs group 2) demonstrated a significant difference between the two groups with regard to the mean duration of symptoms (18.8 weeks vs 5.4 weeks, p = 0.016), mean presenting IOP (30 mm Hg vs 26 mm Hg, p = 0.045), and mean difference in corneal diameter (1.5 mm vs 0.5 mm, p = 0.014). There was also a significant difference with regard to the presence of lid edema (9 vs 1, p = 0.023) and sterile orbital cellulitis (9 vs 1, p = 0.023) at presentation. No other tumor features showed any significant difference.
There was no significant difference between the two groups with regard to the number of cycles of neoadjuvant chemotherapy received and adjuvant treatment (TTT/cryotherapy, POC, intravitreal topotecan, and plaque brachytherapy). Regarding group 1, the eyes were secondarily enucleated for suboptimal response to neoadjuvant chemotherapy or tumor recurrence (13/21, 62%), phthisis (7/21, 33%), and vitreous haemorrhage (1/21, 5%). Of these, 5 (24%) had histopathological high-risk factors for which the patients further received adjuvant chemotherapy.
In group 2 eyes, main tumor recurrence was seen in 11 eyes (69%), subretinal seed recurrence in 5 eyes (31%), and vitreous seed recurrence in 5 eyes (31%), and all were successfully treated. The final mean visual acuity at the last follow-up was 20/200 (median 20/200, range 20/60-light perception). There was no difference between groups 1 and 2 with regard to life salvage (100% vs 100%, p = 1.000).
The clinical risk factors that are predictive of a more aggressive clinical course in retinoblastoma with neovascular glaucoma that would eventually require secondary enucleation areas follows. While age at presentation > 6 months (p = 0.055) showed a borderline significance as a risk for enucleation, the other factors with definite significance were duration of symptoms > 10 weeks (p = 0.003), presenting IOP > 26 mm Hg (p = 0.045), difference between the corneal diameters of both eyes ≥ 0.5 mm (p = 0.015), and presence of sterile orbital cellulitis (p = 0.023).
Discussion:
According to International Classification of Retinoblastoma, group E eyes are defined as eyes with extensive retinoblastoma occupying >50% globe, media opacity secondary tovitreous haemorrhage or hyphema, presence of anterior segment invasion, presence of sterile orbital cellulitis, phthisis bulbi, and presence of neovascular glaucoma.8The incidence of neovascularization of iris (NVI) with secondary glaucoma in retinoblastoma is approximately 12%.11,12,18,19Neovascular glaucoma in retinoblastoma occurs secondary to peripheral anterior synechiae formation, which results from neovascularization of iris due to retinal ischaemia caused by occlusion of the central retinal vesselsby the large tumors.19Less frequently, glaucoma in retinoblastoma may also occur secondary to massive retinal detachment with subsequent pupillary block, and clogging of the trabecular meshwork by the tumor cells.12.19 Although medical management can be initiated for glaucoma in retinoblastoma, the presence of neovascular glaucoma generally indicates poor prognosis and subsequent need for enucleation.11,20
In oncology practice, neoadjuvant chemotherapy offers several advantages.17,21-23Apart from reducing the tumorvolume and helping in tumor consolidation withfocal therapies, it offers a possibility for organ salvage.17,18-21 Systemic chemotherapy, with or without radiotherapy, when initiated before any local therapy, reduces the chances of local and systemic tumor spread and improves the overall patient survival.17,21-23In a meta-analysis of the effect of neoadjuvant chemotherapy in advanced bladder cancer,neoadjuvant systemic chemotherapy was shown to have a significant benefit with reduction in risk of death and improved survival.21,22 Similar survival benefit was reported for patients with head and neck cancer.23The study further showed that organ preservation after neoadjuvant chemotherapy did not have any deterrent effect on patient survival.23
In ophthalmic oncology, neoadjuvant systemicchemotherapy has been tried successfully in primary and secondary orbital tumorsin an attempt to avoid exenteration, thus allowing for local tumor resection and reducing morbidity to the patients.24-26Systemic chemotherapy has also been shown to be beneficial in advanced retinoblastoma.11,15 In 2016, Shields et al published a case series of 3 patients in whom globe salvage and visual preservation was obtained in eyes with diffuse anterior retinoblastoma.15All 3 cases presented withclouds of anterior chamber seeds without a retinal focus, and the diagnosis of diffuse anterior retinoblastoma was established by FNAB.15While 2 of the patients received systemic chemotherapy followed by plaque radiotherapy, 1 patient was managed solely with plaque radiotherapy.15At a mean follow-up of 35 months, tumor regression was maintained, and there was no orbital recurrence and systemic metastasis.15
Traditionally, eyes with advanced retinoblastoma presenting with neovascular glaucoma are enucleated.8,11,12In 2009, Parvus et al reported a single patient with bilateral retinoblastoma havingbuphthalmos from secondary glaucoma in one eye.11 The patient received IVC for a total of 6 cycles with focal consolidating therapies, and at 18 months follow-up, the buphthalmic eye remained stable with complete tumor regression and normal IOP.11In this series, neoadjuvant systemic chemotherapy was started for patients with an intent for safer enucleation.16,18 By reducing the tumor volume and intraocular inflammation, possible scleral perforation and risk of orbital seeding during enucleation in a buphthalmic eye are avoided.11,16 Surprisingly, however, neoadjuvant chemotherapy allowed for globe salvage in16 of 37 eyes (43%) that received protocol-based neoadjuvant chemotherapy, retaining a mean visual acuity of 20/200.
The study also recognizes certain clinical features in eyes whereglobe salvage is plausible in advanced retinoblastoma with neovascluar glaucoma. In this series, eyes which were secondarily enucleated had one or more of the following risk factors which includedage at presentation>6 months, greater duration of symptoms (>10 weeks), greater presenting IOP (≥26 mm Hg), presence of buphthalmos, and presence of sterile orbital cellulitis. In a study of 105 eyes managed by systemic chemotherapy, Gunduz et al reported that older age at presentation is a risk factor predictive of enucleation.27The authors speculated that older age essentially implies late diagnosis and hence, larger tumors at presentation.27Increased corneal diameter has been described as a risk factor for early treatment failure with IVC by Fabian et al in their study on group D eyes.9Greater age at presentation, greater duration of symptoms, higher IOP, and presence of buphthalmosare likely to be indicative of larger and aggressive tumors, thus leading to failure of treatment with IVC.Ten patients (n=10/37, 27%) in the serieshadsterile orbital cellulitis at presentation. Sterile orbital cellulitis in retinoblastoma occurs due to tumor necrosis, and the associated necrotic changes in the iris and ciliary body subsequently result in orbital inflammation.28With chemotherapy, 9 eyes with severe orbital inflammation turnedphthisical which were enucleated safely, while one eye with milder inflammation could be salvaged with chemotherapy and concomitant systemic steroids.
In summary, globe salvage in advanced retinoblastomausing neoadjuvant systemic chemotherapy is possible. Identifying the factors that are high risk for secondary enucleation can help categorize the patients and shorten the overalltreatment time. However, use of systemic chemotherapy in advanced retinoblastoma as an eye salvage therapy must be undertaken with watchful monitoring,and only after ruling out the presence of extraocular extension and tumor invasion into the optic nerve. Cautious planning in conjunction with a medical oncologist and close follow-ups are necessary to prevent orbital and systemic spread.
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