Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

with vitreous seeding

1st line – enucleation

Back
ACUTE
|
with vitreous seeding
|
globe-salvaging procedures not available or suitable
1st line – 

enucleation

Enucleation is surgical removal of the eye without resecting the lids or extraocular muscles.

Primary enucleation is the preferred option for unilateral advanced disease (e.g., International Classification of Retinoblastoma grades D and E). Cure rates >90% have been reported for patients with advanced unilateral intraocular retinoblastoma undergoing enucleation.[60][61]

There are no major adverse effects if surgery is done correctly, the correct orbital implant is used, and there is good prosthesis management.

Consider – postoperative systemic chemotherapy

Back
ACUTE
|
with vitreous seeding
|
globe-salvaging procedures not available or suitable
Consider – 

postoperative systemic chemotherapy

Treatment recommended for SOME patients in selected patient group

If postoperative histopathologic examination of the enucleated specimen by an experienced ocular pathologist confirms the presence of high-risk pathologic features, patients receive a course of adjuvant chemotherapy.[59]

High-risk features include: invasion of the anterior chamber, iris, ciliary body, trabecular meshwork and Schlemm’s canal; involvement of the optic nerve surgical resection margin; retrolaminar optic nerve invasion; intrascleral invasion; massive choroidal invasion; extraocular spread.[56][58]​​

Adjuvant chemotherapy in this circumstance typically involves high-dose combinations of carboplatin, etoposide, and vincristine, with some centers adding additional agents.

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

etoposide

and

vincristine

1st line – systemic chemotherapy or ophthalmic artery chemosurgery

Back
ACUTE
|
with vitreous seeding
|
globe-salvaging procedures available or suitable
1st line – 

systemic chemotherapy or ophthalmic artery chemosurgery

Globe-salvaging procedures are appropriate where facilities are available (e.g., middle- to high-income countries) and for less advanced disease (e.g., International Classification of Retinoblastoma grades A to C).[56]​ First-line treatment in this situation varies widely. Check local guidance.

Systemic treatment usually consists of chemotherapy with 6 to 9 cycles of a 3- or 4-drug intravenous regimen (i.e., carboplatin, vincristine, etoposide, ± cyclosporine) accompanied by focal therapy with laser ablation or cryotherapy.[62] The number of drugs and number of cycles used varies widely by institution.[76]

Ophthalmic artery chemosurgery is increasingly used in specialist centers.[63]​ This procedure is 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.[66]​ The procedure is repeated as often as necessary, with a fundus examination under anesthesia 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.[67][68]

Patients undergo regular, frequent examinations under anesthesia to assess the response to treatment.

See local specialist protocol for dosing guidelines.

Primary options

Systemic chemotherapy

carboplatin

and

vincristine

and

etoposide

OR

Systemic chemotherapy

carboplatin

and

vincristine

and

etoposide

and

cyclosporine modified

OR

Ophthalmic artery chemosurgery

melphalan

and/or

carboplatin

and/or

topotecan

Consider – intravitreal chemotherapy

Back
ACUTE
|
with vitreous seeding
|
globe-salvaging procedures available or suitable
Consider – 

intravitreal chemotherapy

Treatment recommended for SOME patients in selected patient group

Intravitreal chemotherapy (e.g., melphalan) may be used to control vitreous seeding following ophthalmic artery chemosurgery or systemic chemoreduction.[64][70]​​

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 with fewer recurrences.[65][71][72]​​

Although there are concerns about tumor dissemination along the needle track leading to metastasis, the risk appears to be negligible with modern strategies.[73][74][75]

See local specialist protocol for dosing guidelines.

Primary options

melphalan

Plus – concurrent laser ablation or cryotherapy

Back
ACUTE
|
with vitreous seeding
|
globe-salvaging procedures available or suitable
Plus – 

concurrent laser ablation or cryotherapy

Treatment recommended for ALL patients in selected patient group

Focal therapy, such as diode laser therapy, is synergistic if performed on the same day as chemotherapy.

In experienced hands, such an approach can result in avoidance of 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.[62]

2nd line – external beam radiation therapy (EBRT)

Back
ACUTE
|
with vitreous seeding
|
globe-salvaging procedures available or suitable
2nd line – 

external beam radiation therapy (EBRT)

Globe-salvaging procedures are appropriate where facilities are available (e.g., middle- to high-income countries) and for less advanced disease (e.g., International Classification of Retinoblastoma grades A to C). First-line treatment in this situation varies widely. Check local guidance.

EBRT is typically avoided if possible because it increases risk for secondary cancers. But it may be considered in the treatment of recurrent tumors and seeding.[43][78][79]​ Eyes with diffuse seeds are at higher risk of EBRT treatment failure compared with eyes with focal seeds.[80]

An 83% 3-year eye preservation rate was observed in a large series of Group IV and V eyes treated with a standard lateral beam approach.[104]​ A study of Reese-Ellsworth Group Vb eyes demonstrated an 81% 1-year ocular survival rate and a 53% 10-year ocular survival.[105]

Short-term adverse-effects of EBRT include periorbital redness and edema, dry eye, and cataracts. Longer-term adverse effects include secondary cancers and temporal bony hypoplasia, particularly in children radiated at ages <6 months.

3rd line – periocular carboplatin therapy

Back
ACUTE
|
with vitreous seeding
|
globe-salvaging procedures available or suitable
3rd line – 

periocular carboplatin therapy

Globe-salvaging procedures are appropriate where facilities are available (e.g., middle- to high-income countries) and for less advanced disease (e.g., International Classification of Retinoblastoma grades A to C). First-line treatment in this situation varies widely. Check local guidance.

For patients with noncalcified vitreous seeds, where external beam radiation has not produced a satisfactory result, periocular carboplatin therapy may be an option before enucleation.[81]

Periocular carboplatin is effective for noncalcified 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.[82][83]

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

4th line – enucleation

Back
ACUTE
|
with vitreous seeding
|
globe-salvaging procedures available or suitable
4th line – 

enucleation

Enucleation is performed when tumors do not respond to attempts at globe-salvaging therapy.

without vitreous seeding

1st line – systemic chemotherapy or ophthalmic artery chemosurgery

Back
ACUTE
|
without vitreous seeding
|
tumor >2 disc diameters in size
1st line – 

systemic chemotherapy or ophthalmic artery chemosurgery

Treatment usually consists of chemotherapy with 6 to 9 cycles of a 3- or 4-drug systemic intravenous regimen (i.e., carboplatin, vincristine, etoposide, ± cyclosporine) accompanied by focal therapy with laser ablation or cryotherapy.[62] The number of drugs and number of cycles varies widely by institution.[76]

Ophthalmic artery chemosurgery is increasingly used in specialist centers (e.g., melphalan, carboplatin, or topotecan, either used alone or together).[63]

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.[67][68]

Patients undergo regular, frequent examinations under anesthesia to assess the response to treatment.

See local specialist protocol for dosing guidelines.

Primary options

Systemic chemotherapy

carboplatin

and

vincristine

and

etoposide

OR

Systemic chemotherapy

carboplatin

and

vincristine

and

etoposide

and

cyclosporine modified

OR

Ophthalmic artery chemosurgery

melphalan

and/or

carboplatin

and/or

topotecan

Plus – concurrent laser ablation or cryotherapy

Back
ACUTE
|
without vitreous seeding
|
tumor >2 disc diameters in size
Plus – 

concurrent laser ablation or cryotherapy

Treatment recommended for ALL patients in selected patient group

Focal therapy, such as diode laser therapy, is synergistic if performed on the same day as chemotherapy.

In experienced hands, such an approach can result in avoidance of 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.[62]

2nd line – external beam radiation therapy (EBRT)

Back
ACUTE
|
without vitreous seeding
|
tumor >2 disc diameters in size
2nd line – 

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 tumors and seeding.[43][78][79]

Rates of eye preservation with external beam radiation are as high as 95% for Reese-Ellsworth Group I to III eyes. An 83% 3-year eye preservation rate was observed in a large series of Group IV and V eyes treated with a standard lateral beam approach.[104] A study of Reese-Ellsworth Group Vb eyes demonstrated a 81% 1-year ocular survival rate and a 53% 10-year ocular survival.[105]

3rd line – periocular carboplatin therapy

Back
ACUTE
|
without vitreous seeding
|
tumor >2 disc diameters in size
3rd line – 

periocular carboplatin therapy

For patients with noncalcified vitreous seeds, where external beam radiation has not produced a satisfactory result, periocular carboplatin therapy may be an option before enucleation.[81]

Periocular carboplatin is effective for noncalcified 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.[82][83]

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

4th line – enucleation

Back
ACUTE
|
without vitreous seeding
|
tumor >2 disc diameters in size
4th line – 

enucleation

Enucleation is performed when tumors do not respond to attempts at globe-salvaging therapy.

1st line – focal laser ablation alone

Back
ACUTE
|
without vitreous seeding
|
tumor 2 disc diameters or less in size
1st line – 

focal laser ablation alone

Patients with a family history of retinoblastoma are normally screened from birth, allowing many tumors to be detected when very small (2 disc diameters or smaller). These tumors can often be treated successfully with focal laser alone.[77]

2nd line – systemic chemotherapy or ophthalmic artery chemosurgery

Back
ACUTE
|
without vitreous seeding
|
tumor 2 disc diameters or less in size
2nd line – 

systemic chemotherapy or ophthalmic artery chemosurgery

Treatment usually consists of chemotherapy with 6 to 9 cycles of a 3- or 4-drug systemic intravenous regimen (i.e., carboplatin, vincristine, etoposide, ± cyclosporine) accompanied by focal therapy with laser ablation or cryotherapy.[62] The number of drugs and number of cycles varies widely by institution.[76]

Ophthalmic artery chemosurgery is increasingly used in specialist centers (e.g., melphalan, carboplatin, or topotecan, either used alone or together).[63]

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.[67][68]

Patients undergo regular, frequent examinations under anesthesia to assess the response to treatment.

See local specialist protocol for dosing guidelines.

Primary options

Systemic chemotherapy

carboplatin

and

vincristine

and

etoposide

OR

Systemic chemotherapy

carboplatin

and

vincristine

and

etoposide

and

cyclosporine modified

OR

Ophthalmic artery chemosurgery

melphalan

and/or

carboplatin

and/or

topotecan

Consider – concurrent laser ablation or cryotherapy

Back
ACUTE
|
without vitreous seeding
|
tumor 2 disc diameters or less in size
Consider – 

concurrent laser ablation or cryotherapy

Treatment recommended for SOME patients in selected patient group

Focal therapy, such as diode laser therapy, is synergistic if performed on the same day as chemotherapy.

In experienced hands, such an approach can result in avoidance of 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.[62]

3rd line – external beam radiation therapy (EBRT)

Back
ACUTE
|
without vitreous seeding
|
tumor 2 disc diameters or less in size
3rd line – 

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 tumors and seeding.[43][78][79]

An 83% 3-year eye preservation rate was observed in a large series of Group IV and V eyes treated with a standard lateral beam approach.[104]​ A study of Reese-Ellsworth Group Vb eyes demonstrated an 81% 1-year ocular survival rate and a 53% 10-year ocular survival.[105]

Short-term adverse-effects of EBRT include periorbital redness and edema, dry eye, and cataracts. Longer-term adverse effects include secondary cancers and temporal bony hypoplasia, particularly in children radiated at ages <6 months.

4th line – periocular carboplatin therapy

Back
ACUTE
|
without vitreous seeding
|
tumor 2 disc diameters or less in size
4th line – 

periocular carboplatin therapy

For patients with noncalcified vitreous seeds, where external beam radiation has not produced a satisfactory result, periocular carboplatin therapy may be an option before enucleation.[81]

Periocular carboplatin is effective for noncalcified 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.[82][83]

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

5th line – enucleation

Back
ACUTE
|
without vitreous seeding
|
tumor 2 disc diameters or less in size
5th line – 

enucleation

Enucleation is performed when tumors do not respond to attempts at globe-salvaging therapy.

metastatic disease

1st line – multimodal therapy

Back
ACUTE
|
metastatic disease
1st line – 

multimodal therapy

Extraocular and metastatic disease are rare in the US, but are a common problem in developing countries.[20]​ Treatment depends on the location of the metastases. 

Optic nerve/choroidal invasion: chemotherapy is the treatment of choice (e.g., carboplatin, etoposide, vincristine, cyclophosphamide, doxorubicin). However, there is debate regarding the associated mortality rates and, by extension, the need for chemotherapy in patients with histopathologic confirmation of tumor extension into the choroid and optic nerve after enucleation.[84]​[85]​[86]​[87]​ 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 (e.g., etoposide, cisplatin, vincristine, doxorubicin, cyclophosphamide) in conjunction with radiation therapy (external beam radiation therapy).[89][90][91][92]

Central nervous system invasion: prognosis remains poor for these patients, with very few survivors reported, even among patients treated with aggressive multimodal therapy including intensive chemotherapy (e.g., carboplatin, etoposide, cyclophosphamide), intrathecal chemotherapy, and craniospinal irradiation.[93][94]

Bone marrow, bone, and soft-tissue invasion: involves high-dose chemotherapy (e.g., vincristine, doxorubicin, cyclophosphamide, etoposide, thiotepa, cisplatin, carboplatin) with stem-cell rescue, with or without radiation.[95][98][99][100][101]

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

OR

cisplatin

OR

etoposide

OR

vincristine

OR

cyclophosphamide

OR

doxorubicin

OR

methotrexate

OR

cytarabine

OR

thiotepa

ONGOING

recurrence

1st line – brachytherapy

Back
ONGOING
|
recurrence
|
post globe-salvaging therapy
1st line – 

brachytherapy

Used for focal, nonmacular, circumscribed tumors with no associated vitreous seeds appearing after treatment with other modalities.

Although not often used for this disease, iodine or ruthenium brachytherapy can occasionally be useful for these particular tumors. 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 tumor recurrence rate of 12% at 1 year posttreatment has been reported when plaques are used as primary treatment for retinoblastoma.[102]​ There are minimal adverse effects, with almost no radiation exposure to the surrounding tissues or contralateral orbit. Generally an inpatient admission of several days is required due to radiation safety laws, which can be difficult for a young child.

Consider – intravitreal chemotherapy

Back
ONGOING
|
recurrence
|
post globe-salvaging therapy
Consider – 

intravitreal chemotherapy

Treatment recommended for SOME patients in selected patient group

Intravitreal chemotherapy (e.g., melphalan) may be used to control vitreous seeding after recurrence.​[70]​​​[71][72][73][74][75]

Although concerns exist about tumor dissemination along the needle track leading to metastasis, the risk appears to be negligible risk with modern treatment strategies.[73][74][75]

See local specialist protocol for dosing guidelines.

Primary options

melphalan

1st line – external beam radiation therapy

Back
ONGOING
|
recurrence
|
post enucleation
1st line – 

external beam radiation therapy

If recurrence occurs post enucleation, first-line therapy is external beam radiation.

Consider – systemic chemotherapy

Back
ONGOING
|
recurrence
|
post enucleation
Consider – 

systemic chemotherapy

Treatment recommended for SOME patients in selected patient group

Depending on the extent of the orbital recurrence, some patients may receive a course of systemic chemotherapy, in addition to radiation therapy.

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

vincristine

and

etoposide

OR

carboplatin

and

vincristine

and

etoposide

and

cyclosporine modified

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Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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