Approach

Treatment aims to save lives, save eyes, and save vision. These goals underpin the treatment approach, which is typically highly individualised and planned by an experienced ocular oncologist. Early diagnosis and prompt treatment in specialist paediatric hospitals can save a child’s life and the eye globe, while frequently retaining useful vision.[21]

Globe-salvaging modalities are used increasingly where facilities are available (e.g., middle- to high-income countries; tertiary care) and disease is less advanced (e.g., International Classification of Retinoblastoma grades A to C).[57]

Treatment options vary considerably by availability, but typically include:[58]

  • Surgical enucleation (plus adjuvant chemotherapy if there is increased risk of relapse after enucleation, or potentially external beam therapy [EBRT] if presumed residual microscopic disease)

  • Modalities with globe salvage intent

    • ophthalmic artery chemosurgery (also known as intra-arterial chemotherapy)

    • intravenous chemotherapy (with focal consolidation)

    • intravitreal chemotherapy

    • focal therapy destructive to tumour cells (e.g., cryopexy, laser photocoagulation, hyperthermia, and plaque irradiation)

    • external beam radiotherapy (EBRT) if there is no response to other treatments or microscopic residual disease remains after enucleation

The management of retinoblastoma should include a multi-speciality team comprising an ocular and/or paediatric oncologist, a pathologist, and an interventional radiologist, where available.

Vitreous seeding present

Characterised by tumour cells floating within the vitreous cavity; a potentially limiting factor for globe salvage therapy.

Globe enucleation

  • Enucleation (surgical removal of the eye without resection of the lids or extraocular muscles) is a recommended first-line treatment, especially for unilateral advanced disease (e.g., International Classification of Retinoblastoma grades D and E).

  • Subsequent histopathological examination, performed by an experienced ocular pathologist, determines the presence of high-risk pathological features, including:[57][59]​​​

    • invasion of the anterior chamber, iris, ciliary body, trabecular medhwork, and Schlemm's canal;

    • involvement of the optic nerve surgical resection margin;

    • retrolaminar optic nerve invasion;

    • intrascleral invasion;

    • massive choroidal invasion;

    • extraocular spread.

  • If any of these features are noted, patients receive adjuvant chemotherapy.[60]​ This typically involves high-dose combinations of carboplatin, etoposide, and vincristine, with some centres adding additional agents.

  • Advances in eye salvage therapy mean that enucleation is used less frequently. However, it remains an important option for cases where eye salvage is not possible and there is a low chance of fellow-eye involvement. Cure rates >90% have been reported for patients with advanced unilateral intraocular retinoblastoma undergoing enucleation.[61][62]

Globe-salvaging treatments

  • Can be attempted in the absence of complicating factors, but these interventions are increasingly used as a first-line option where facilities are available and disease is less advanced (e.g., International Classification of Retinoblastoma grades A to C).

  • First-line treatments vary widely:

    • Systemic chemotherapy plus focal therapy, where chemotherapy usually consists of 6 to 9 cycles of a 3- or 4-drug systemic intravenous regimen (i.e., carboplatin, vincristine, etoposide, and possibly ciclosporin) accompanied by focal therapy.[63]​ Focal therapy usually involves cryotherapy or laser therapy and is synergistic if performed on the same day as chemotherapy.

    • Ophthalmic artery chemosurgery (also known as intra-arterial chemotherapy) for unilateral and bilateral retinoblastoma.[64][65][66]​​​​​ Performed by an interventional neuroradiologist or interventional neurosurgeon and involves the insertion of a microcatheter via the femoral artery to the ostium of the ophthalmic artery. The most commonly used agent is melphalan; however, melphalan, carboplatin, and topotecan have been used alone or in combination.[67]​ The procedure is repeated as often as necessary, with a fundus examination under anaesthesia repeated before each cycle. Studies suggest that rates of global salvage (e.g., International Classification of Retinoblastoma grades D and E) are greater with ophthalmic artery chemosurgery than with intravenous chemotherapy.[68][69]​​ Common ocular complications reported with melphalan-based ophthalmic artery chemosurgery include retinopathy and palpebral oedema; systemic complications include nausea and vomiting.[70]

    • Intravitreal chemotherapy (e.g., melphalan) may be used to control vitreous seeding following ophthalmic artery chemosurgery or systemic chemoreduction.[65][71]​​​ Adjuvant intravitreal chemotherapy (both treatment naïve and previously treated retinoblastoma) with or without periocular chemotherapy, and combined with either systemic chemotherapy or ophthalmic artery chemosurgery, can improve regression rates and lead to fewer recurrences.[66][72][73]​​​ Although there are concerns about tumour dissemination along the needle track leading to metastasis, the risk appears to be negligible with modern treatment strategies.[74][75][76]

No vitreous seeding present

Management options are informed by tumour size (disc diameters).

Tumours >2 disc diameters in size

  • First-line treatment usually involves 6 to 9 cycles of a 3- or 4-drug intravenous chemotherapy regimen (i.e., carboplatin, etoposide, vincristine, and possibly ciclosporin), accompanied by focal laser ablation or cryotherapy.[63] The number of drugs and number of cycles varies widely by institution.[77]

  • Alternatively, consideration may be given to one or more cycles of ophthalmic artery chemosurgery with one or more of the following agents: melphalan, carboplatin, or topotecan.[64]

  • Patients undergo regular, frequent eye examinations under anaesthesia to assess treatment response. In experienced hands, this approach can avoid the need for external beam radiation and enucleation at 3 years in 100% of patients with Reese-Ellsworth Group I to IV disease and 83% of patients with Reese-Ellsworth Group V disease.[63]

Tumours 2 disc diameters or less in size

  • Patients with a family history of retinoblastoma are normally screened from birth, allowing many tumours to be frequently detected when very small (e.g., 2 disc diameters or smaller). These tumours can often be treated successfully with focal laser therapy alone.[78] Chemotherapy is recommended if this is not successful.

  • Patients are typically followed up with an examination under anaesthesia every month for at least 1 year, after which the interval between follow-up visits is gradually extended.

Vitreous seeding after chemotherapy and/or focal therapy

Treatment options in this clinical setting include external beam radiation therapy or intravitreal chemotherapy. Enucleation is performed when tumours do not respond satisfactorily to globe-salvaging therapies.

External beam radiation therapy (EBRT)

EBRT is typically avoided if possible because it increases risk for secondary cancers. But it may be considered in the treatment of recurrent tumours and seeding.[44][79][80]​​​ Eyes with diffuse seeds are at higher risk of EBRT treatment failure compared with eyes with focal seeds.[81]​ Short-term adverse effects of external beam radiation include periorbital redness and oedema, dry eye, and cataracts. Longer-term adverse effects include secondary cancers and temporal bony hypoplasia, particularly in children radiated at aged <6 months.

For patients with non-calcified vitreous seeds, where external beam radiation has not produced a satisfactory result, periocular carboplatin therapy may be an option before enucleation.[82]​ Periocular carboplatin is effective for non-calcified vitreous seeds, but not against subretinal seeds. Periocular carboplatin can cause major ocular adverse effects such as fibrosis of the extraocular muscles and optic nerve atrophy.[83][84]

Intravitreal chemotherapy

Intravitreal chemotherapy (e.g., melphalan) may be used to control vitreous seeding, including after recurrence, previous ophthalmic artery chemosurgery, or systemic chemoreduction.[71]​ Adjuvant intravitreal chemotherapy with or without periocular chemotherapy, and combined with either systemic chemotherapy or ophthalmic artery chemosurgery, can improve regression rates and lead to fewer recurrences.[72][73]​ Although concerns exist about tumour dissemination along the needle track leading to metastasis, the risk appears to be negligible risk with modern treatment strategies.[74][75][76]

Metastatic retinoblastoma

Extraocular and metastatic disease are rare in the US, but are a common problem in developing countries.[21]​ Treatment options depend on the location of the metastases.

Optic nerve/choroidal invasion

  • There is debate regarding the associated mortality rates and, by extension, the need for chemotherapy in patients with histopathological confirmation of tumour extension into the choroid and optic nerve after enucleation.[85][86][87]​​[88]​​ Four degrees of tumour extension are commonly acknowledged:[85]

    • choroidal invasion;

    • tumour anterior to, or up to, the lamina cribrosa;

    • tumour beyond the lamina cribrosa, but not reaching the surgical margin; and

    • tumour at the surgical margin.

  • One study suggests that only patients who have either scleral involvement or post-laminar optic nerve involvement, with either associated choroidal involvement or a positive surgical margin, require adjuvant chemotherapy. Patients with fewer histopathological risk factors were rescued with intensive chemotherapy at the time of extraocular recurrence.[89] Currently, the only histopathological criteria on which clinicians universally agree is that systemic chemotherapy is necessary in the presence of tumour at the surgical margin, as these patients are at high risk for central nervous system (CNS) metastases.

  • Chemotherapeutic regimens are not standardised across centres. The most commonly used agents in patients with high-risk histopathological features include carboplatin, etoposide, vincristine, cyclophosphamide, and doxorubicin. Intrathecal agents may also be administered, the most common regimen consisting of methotrexate, cytarabine, and a corticosteroid.

Orbital invasion

  • Studies have demonstrated the successful use of aggressive chemotherapy in conjunction with radiotherapy in this patient group.[90][91][92][93]

  • In the largest of these studies, patients underwent various treatments including orbital exenteration and/or external beam radiotherapy.[91] All patients received systemic chemotherapy with 1 to 5 agents including etoposide, cisplatin, vincristine, doxorubicin, and cyclophosphamide. Orbital disease carries a high risk of mortality, and aggressive, multimodal therapy is warranted.

  • Several groups have reported good outcomes for patients with just local nodal disease extension. These patients should not be grouped together with patients who have CNS or haematogenously spread distant metastases.

CNS invasion

  • Prognosis remains poor for these patients, with very few survivors reported, even among patients treated with aggressive multimodal therapy including intensive chemotherapy, intrathecal chemotherapy, and craniospinal irradiation.[94][95]

  • Unfortunately, the young age of most of these patients makes the use of craniospinal radiation extremely toxic to normal development, and severe developmental delay and intellectual impairment are frequent sequelae. High-dose chemotherapeutic regimens such as carboplatin, etoposide, and cyclophosphamide have not improved the prognosis for these patients.[96]

  • Protection of the CNS with intrathecal therapy in advanced disease has some rationale.[97][98]​ 

Bone marrow, bone, and soft-tissue invasion

  • The most successful published strategies for patients with metastatic disease at sites other than the CNS involve high-dose chemotherapy with stem-cell rescue, with or without radiation.

  • Radiotherapy is avoided or delayed as long as possible in the absence of CNS progression. Several reports demonstrating this approach have been published.[96][99][100][101][102] Agents used include vincristine, doxorubicin, cyclophosphamide, etoposide, thiotepa, and either cisplatin or carboplatin.

Recurrence: post-globe-salvaging therapy

If a patient develops a focal, non-macular, circumscribed tumour with no associated vitreous seeds following treatment with other modalities, brachytherapy may be used to treat the lesion.

Although not often used for this disease, iodine or ruthenium brachytherapy can occasionally be useful for these particular tumours. Iodine-125 is currently the most commonly used isotope in brachytherapy for retinoblastoma. The main advantage of this isotope is that radioactive seeds can be placed into a custom-built plaque designed to match the size of the lesion.

A tumour recurrence rate of 12% at 1 year post-treatment has been reported when plaques are used as primary treatment for retinoblastoma.[103] Radioactive plaques can also be successful when used as salvage therapy for eyes that have failed other treatment methods.[103][104] Intravitreal chemotherapy (e.g., melphalan) may be used to control vitreous seeding after recurrence.​[71]​​​[72][73][74][75][76]

Recurrence: post-enucleation

If recurrence occurs within the orbit post-enucleation, first-line therapy is with external beam radiation. Depending on the extent of the orbital recurrence, some patients may also receive a course of systemic chemotherapy.

Trilateral retinoblastoma

This signifies bilateral retinoblastomas and a concomitant pineal primitive neuroectodermal tumour (PNET) or pinealoma.[14]​ Patients have their retinoblastomas treated according to the principles above. In addition, the pinealoma is treated by surgical excision followed by radiotherapy. This may be supplemented by a second-look surgical procedure and re-excision.

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