Orbital Retinoblastoma: From Palliation to Cure by Sequential Multimodal Multidisciplinary Therapy – A Case Report

Abstract

Introduction

Orbital retinoblastoma (RB) is a form of advanced-stage RB and typically carries poor prognosis, with mortality rates ranging from 25% to 100% [Br J Ophthalmol. 1990;74(2):97–8]. While new multimodal treatment protocols have been proposed, there remains a paucity of reported successful treatment outcomes before standard treatment protocols can be established. In many developing nations, orbital RB is frequently palliated due to presumed poor treatment outcomes.

Case Presentation

We highlight a case of a 6-year-old child who presented with a unilateral fungating orbital RB without regional or systemic spread. After 4 cycles of neoadjuvant chemotherapy, there was complete clinical regression of the tumour to within the globe. Following an ocular enucleation with histopathologic control, he underwent placement of a primary orbital implant followed by adjuvant proton beam therapy (PBT) to the orbit and remains well till this day.

Conclusion

This case underscores the importance of multimodal combination therapy in improving survival outcomes, highlighting the promising impact of neoadjuvant systemic chemotherapy in reducing tumour burden even in advanced RB. It also draws attention to the use of PBT as a superior alternative to conventional external beam radiotherapy, due to its ability to reduce dose splash to surrounding organs, reducing the chance of secondary malignancies [Indian J Ophthalmol. 2024;72(6):778–88]. Above all, this case challenges the historical prognosis of orbital RB, demonstrating that with a tailored and comprehensive approach, even children with advanced disease can attain disease-free survival. It serves as a call to action for the clinical community to continue pursuing evidence-based treatment protocols that can transform advanced RB care.

Introduction

Retinoblastoma (RB) is the most common primary intraocular malignant tumour in the paediatric group, comprising 2.5–4% of all paediatric malignancies [1]. It typically affects children less than 5 years of age and has an estimated incidence of 1 in 16,000–18,000 live births worldwide [2]. Classically, lesions appear as a discrete yellow-white retinal mass with dilated vessels, subretinal fluid/seeds, and vitreous seeds [2] from endophytic growth. However, with neglect or in low- and middle-income countries with various healthcare access and delivery limitations, progression to orbital RB, defined as clinically, radiologically or histopathologically detected extension of RB outside the confines of the eye, is not uncommon. Badhu et al. [3] reported the incidence of orbital RB in Nepal to be around 40%, while Kao et al. [4] from Taiwan reported an incidence rate of 36% in a large study. Orbital RB has conventionally carried poor prognosis with mortality rates ranging from 25% to 100% [5], with a significant burden arising from developing countries within Asia like India, China, Indonesia, Pakistan, Bangladesh and the Philippines. In areas with reduced access to healthcare and lower health literacy, cases of RB may have a delayed presentation with orbital involvement at diagnosis. Frequently reported or observed management in low- and middle-income countries include neglect, observation alone, palliative therapy or orbital exenteration.

Literature has demonstrated that combination therapy, consisting of local surgical excision, radical orbital radiotherapy, and systemic chemotherapy when used in conjunction, provide the best outcomes in achieving complete remission [5]. However, there is still a paucity of reported treatment outcomes in orbital RB, especially in the Asian population.

Singapore’s geographical location and developed healthcare within Southeast Asia has made it a preferred centre for referral of challenging and advanced medical conditions, including RB patients. We report a case of a unilateral Stage III A orbital RB which demonstrated excellent response to high-dose neoadjuvant chemotherapy, with no histopathological evidence of residual disease upon subsequent enucleation and orbital biopsy, highlighting the efficacy of systemic chemotherapy even in high stage/group RBs and restoration of normal appearance without disfiguration. To our knowledge, it is also the first known case in Asia to undergo proton beam therapy (PBT) post-enucleation for RB.

Case Report

A 6-year-old boy was referred to our institution with presumed advanced RB of 2 years duration without any previous treatment. He is the 5th child born to non-consanguineous parents, previously well, with no family history of RBs. He was noted to have a left leukocoria 2 years earlier with examination, then demonstrating a large intraocular tumour and was advised on enucleation. Deferred by the family and having received alternative therapy, he was noted to have a left proptosis and eventual fungating growth with failure to thrive and suffered social consequences prior to presentation.

At presentation to our institution, the child was asthenic with a fungating, discharging left periorbital mass (Fig. 1a). Examination of the right eye was unremarkable, as was systemic examination, without regional lymphadenopathy. Staging workup included magnetic resonance imaging (MRI) of the face, orbits and brain, bilateral bone marrow biopsy, and cerebrospinal fluid analysis. MRI showed a large mass occupying and extending anteriorly from the left globe, with thickening of the adjacent extraocular muscles and the retrobulbar optic nerve without intracranial extension (Fig. 2a).

Fig. 1.

a Clinical photograph of the subject’s OS orbital RB at presentation. b Clinical photograph of the subject’s left eye after 3 cycles of neoadjuvant systemic chemotherapy. c Clinical photograph of the subject after having a custom prosthesis fitted post orbital enucleation, restoring ocular form, and aesthetics.

Fig. 2.

a MRI T1 axial cut with contrast taken before initiation of chemotherapy. It showed a large fungating mass fully occupying the entire left globe, with extraconal extension as well as post-laminar extension with involvement of the optic nerve. b MRI T1 axial cut with contrast taken after 3 cycles of vincristine, etoposide, and cyclophosphamide (VEC) chemotherapy. It showed significant interval decrease in size of his RB, with the tumour being confined to the orbit and preconal space. c Figure for 95% isodose distribution, where dose volume was extended along the optic nerve, to the optic chiasm. d Figure for 95% isodose distribution, where dose volume was extended medially and laterally from the orbit to cover potential sites of original involvement.

Cerebrospinal fluid analysis from lumbar puncture, bone marrow analysis from bilateral posterior iliac trephine, and whole-body positron emission tomography-computed tomography were all negative. He was diagnosed with left orbital RB (International Classification of Retinoblastoma [ICRB] Group E Stage 3B, T3N0M0). Genetic testing for RB1 germline mutation was also negative for any mutation.

Following detailed counselling the patient was initiated on chemotherapy consisting of vincristine, carboplatin, and etoposide. Following the first cycle, there was around 80% reduction of the periorbital mass. After completion of 3 cycles of vincristine, carboplatin, and etoposide and observed clinical regression of the mass lesion into the globe (Fig. 1b), a repeat MRI confirmed the clinical findings (Fig. 2b). In view of good clinical regression of his orbital RB after completion of the 4th cycle of chemotherapy, he underwent enucleation of the left eye with a long segment of the optic nerve (Fig. 3a), multiple biopsies of the extraocular muscles and orbital fat with primary socket reconstruction with a 20 mm acrylic sphere wrapped in donor sclera.

Fig. 3.

a Photograph of enucleated OS specimen with evidence of optic nerve thickening. b Histology slide (at ×40 magnification power) of enucleated OS specimen. Most notably, the posterior chamber of the eye was filled with a disorganised mass of calcification, fibrous tissue, foamy macrophages and giant cell reaction. There was no definite residual RB seen. Features suggestive of RB such as small round blue cells and rosettes were absent.

Histopathological examination of his chemoreduced globe showed no definite residual RB intraocularly and no extraocular extension (Fig. 3b). The optic nerve while atrophic had no evidence of viable tumour despite post-laminar involvement seen on imaging at presentation. Biopsy samples of the left perineural fat and extraocular muscles were also negative for malignancy.

Postoperatively the boy underwent 45 Gy in 1.8 Gy fractions of PBT to the affected orbit, including the orbital apex, optic canal up to the chiasm and the orbital fissures (Fig. 2c). The PBT dose distribution was extended both laterally and medially to cover sites of potential original involvement (Fig. 2d), based on signal changes seen on MRI. As the boy sustained mild acute kidney injury from the previous cycles of neoadjuvant high-dose chemotherapy, he was switched to the Children’s Oncology Group (COG) ARET0321 Protocol [6], where the addition of cyclophosphamide allowed for an overall reduction in number of adjuvant chemotherapy cycles, thus minimising nephrotoxicity. He has since completed 2 cycles of adjuvant chemotherapy, as part of consolidation therapy of the COG protocol and has successfully completed his chemotherapy regime. He was also fitted with a customised ocular prosthesis with restoration of normal form and appearance (Fig. 1c) and has remained well since. A recent surveillance positron emission tomography-computed tomography scan 3.5 months post-operation showed no tumour recurrence or activity in his left orbit or elsewhere in the body. He remains under regular follow up every 6–12 months until 10 years of age and will require annual follow up on a lifelong basis for loco-regional and distant spread, treatment-related side effect surveillance including neurocognitive and neuroendocrine deficiencies.

The CARE Checklist has been completed by the authors for the aforementioned case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000549400).

Discussion

Orbital RB has historically carried a dismal prognosis and continues to be a high-risk diagnostic factor for mortality at presentation, especially in the developing world. Although there are no universally accepted protocols for management, current preferred management is sequential multimodal therapy consisting of neoadjuvant chemotherapy, followed by surgery, adjuvant chemotherapy, and external beam radiotherapy (EBRT) [7]. Honavar and Singh have proposed a treatment protocol comprising initial triple drug high-dose chemotherapy followed by appropriate surgery, orbital radiotherapy, and an additional 12 cycle standard dose chemotherapy [8]. This case has shed light on the efficacy and safety of systemic chemotherapy in orbital RB even in the developing world where there are numerous challenges. In general, chemotherapy (systemic or intra-arterial) is well known to achieve considerable tumour control in early-stage RB, while treatment outcomes for ICRB Group E and advanced-stage RB remain poor. A study of 101 eyes in 101 patients with unilateral RB (21 group C, 40 group D, 40 group E by ICRB) reported that intensified chemotherapy with periocular carboplatin resulted in eye salvage in 20 (95%) group C, 34 (85%) group D, and 23 (57.5%) group E eyes [9]. Fewer than 25% of RBs were found to have been cured by chemotherapy with or without focal techniques, with most cured patients classified as having ICRB group A and B tumours. Chemotherapy alone was reported to have failed in 40% of group C and the majority of D and E eyes, necessitating enucleation or radiation [9].

In accordance with the literature, our case has shown that while chemotherapy, EBRT, enucleation, or exenteration alone is unlikely to be therapeutic in the treatment of orbital RB, a well-planned and executed sequential multimodal therapy can yield excellent outcomes. Although the child eventually required enucleation and underwent subsequent radiation, the case has demonstrated the efficacy of high-dose chemotherapy in reducing tumour burden after 4 cycles, with complete absence of demonstrable residual histopathological evidence of RB despite suggestive radiologic findings at presentation. This suggests that neoadjuvant systemic chemotherapy can achieve excellent tumour-reduction outcomes, with adjuvant chemotherapy being tailored to clinico-radiologic and pathologic response to reduce systemic side effects and improve compliance with recommended treatment and follow-up. Selective intra-arterial chemotherapy, in which fluoroscopy-guided microcatheterization is used to deliver chemotherapeutic agents in a targeted manner was not utilised in this case as there was no intention for globe salvage and available systemic chemotherapeutic services in the geographical region but remains an alternative in more advanced nations with expertise. This is especially so in Groups B-D RB, with globe salvage success rates reaching 100% in non-germline, unilateral Groups B and C RB, and 94% in Group D RB respectively [10].

Furthermore, this case has highlighted the utility of PBT in treatment of advanced RB. Conventional EBRT has been shown to cause side effects intra-cranially and to the contralateral globe and orbit, alongside ocular complications including dry eye, cataracts, radiation retinopathy, vitreous haemorrhage, and glaucoma [11]. EBRT is also generally avoided due to the risk (53% at the age of 50 years) of developing secondary malignancies in the field of radiation in germline mutations [10]. By delivering energy from the heavier subatomic particles more precisely to the residual tumour bed and orbit and with less scattering to surrounding tissues [12], a retrospective analysis of patients with RB treated with PBT showed that the former significantly reduced the rate of secondary malignancy [13]. However, the number of RB patients treated with PBT reported in literature remains small. Till date, this is the first reported case of PBT in Asia used to treat orbital RB. It provides a viable alternative to conventional EBRT – for the same dose of radiation administered; PBT can achieve a similar chance of cure while reducing late-onset toxicity, which can post significant burden for childhood cancer survivors.

The management of this case has also underscored the utility of having a Retinoblastoma Response Evaluation Criteria in Solid Tumors (RB-RECIST) specific for orbital extension of the disease. Thus far, there exist response criteria for intraocular RB proposed by Berry et al. [14] using fundus photography and ultrasound imaging to evaluate response in intraocular tumours, vitreous seeds, and subretinal seeds. However, no corresponding criteria for extraocular RB have been put forward. As such, treatment outcomes still largely rely on indirect measures of therapeutic response such as progression free survival. Specific, standardised RB-RECIST criteria targeted at extraorbital RB would be an important pillar in the standardisation and assessment of tumour response in orbital RB and would be beneficial for the ongoing development of standardised treatment protocols for orbital extension disease.

An important factor in managing the socket in RB is to restore normal structure and aesthetics post-enucleation. Anophthalmic sockets face complications such as implant exposure, migration, extrusion, socket contracture, and finally poor cosmesis [15]. Optimal structural, cosmetic, and thus psychosocial rehabilitation is essential for the afflicted children to lead stigma-free normal lives into adulthood. Our case has thus demonstrated that ensuring negative tumour margins, appropriate socket reconstruction with adequate volume replacement and customised prosthesis not only restores lost volume but also reinstates oculofacial aesthetics, an important factor in convincing parents to proceed with recommended management, while renewing self-esteem to the affected child.

In conclusion, this case of orbital RB brings to light a few key points. First, it supports present literature of utilising multimodal combination therapy to attain best survival outcomes in orbital RB. Second, it highlights the efficacy of neoadjuvant chemotherapy in tumour burden reduction, suggesting a possibility that future treatment protocols involving fewer sessions of chemotherapy can be developed, balancing the risks of systemic toxicity against the risks of recurrence. This case is notable in terms of its drastic response to 4 initial cycles of chemotherapy, which managed to shrink the orbital RB significantly with no viable RB detected in the enucleated sample on histopathological analysis. Additionally, the use of PBT over conventional EBRT to achieve similar therapeutic effects while reducing overall SEs is worth exploring in future with larger cohort numbers.

Finally, this case has demonstrated that hope is not lost even in the most advanced orbital RB. Apart from adding to current limited treatment outcomes of orbital RB, it also serves as a clarion call for definitive standardised management protocols to be proposed. Where previously orbital RB was associated with high fatality rates, this case has highlighted that with appropriate protocol-based sequential multimodal and multidisciplinary management, children with orbital RB can achieve excellent outcomes and lead disease-free, stigma-free lives with treatment complications brought to a minimum. RB, especially advanced and complex cases requiring multiple treatment modalities, should ideally be managed at tertiary dedicated centres with synergistic inter-speciality cooperative workflows to maximise outcomes.

Statement of Ethics

This study was performed in accordance with the Declaration of Helsinki. Ethical approval was not received for this human study because Ethical approval is not required for this study in accordance with local guidelines. Written informed consent in accordance with BMJ Case Reports informed consent guidelines was obtained from the parents of the subject of this case report for publication of the details of his medical case, as well as any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

V.W.W.N. and D.N.H.T. – substantial contributions to acquisition of case report details and revising the manuscript critically for important intellectual content. M.S.K. – substantial contributions to medical co-management of the subject in the case report. W.S.L. – substantial contributions to provision of details regarding PBT treatment rendered, revising the manuscript critically for important intellectual content. D.L. – substantial contributions to acquisition of case report histopathology images. G.S. – substantial contributions to acquisition of case report details, surgical co-management of the subject in the case report, revising the manuscript critically for important intellectual content. All authors listed have given final approval of the version to be published.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

References made in this article are readily available on the Internet and can be obtained from reputable research databases like PubMed. Further enquiries can be directed to both the corresponding and submitting author.