Retinoblastoma is a rare ocular tumour that develops in the retina and is usually diagnosed in the early years of a child's life. Worldwide it affects about 8,000 children each year, with an incidence of 1 in every 16,000 to 18,000 live births.
In more than 95% of cases, the tumour arises due to biallelic loss of the oncosuppressor gene RB1, followed by further genetic and epigenetic changes.
Non-inherited retinoblastoma comprises the majority of cases (60%), with both RB1 alleles locally mutated in the affected retina. Hereditary retinoblastoma (40%) is associated with a predisposing variant in the line germinal RB1 and the subsequent somatic inactivation of the other allele. For this reason, cases of retinoblastoma non hereditary retinoblastoma occur as unilateral tumours, unlike hereditary retinoblastoma which often develops bilaterally and multifocally.1 Once the tumour develops, the first clinical sign immediately observed among patients is a white pupillary reflex, known as leukocoria.
If treated promptly, retinoblastoma is a curable form of cancer with ocular survival, but it can be fatal if left untreated. In fact, this tumour risks developing metastases if treatment is delayed.
Current treatment modalities for retinoblastoma
The primary goals in the treatment of retinoblastoma are the prevention of metastases, preservation of the eyeball and optimisation of vision. Currently used therapies maintain excellent survival rates when the disease is identified in the localised intraocular phase. In addition, the most recent therapies focused on improving results in terms of preservation of the ocular globe and to achieve the best possible result for visual acuity.2
The treatment of choice for retinoblastoma depends on2:
- -from staging based on the International Classification of Retinoblastoma (ICRB)
- -by the presence or absence of extraocular clinical factors
- -from family history and germ line test results
In order to decide on the desired extent of treatment and avoid unnecessary side effects, a thorough initial evaluation of the disease is important. If the germline is confirmed, genetic testing is advisable in all cases of retinoblastoma, both for the patient and the rest of his or her family. Moreover, the response to the first treatment can guide long-term results.
Intravenous chemotherapy (IVC)
Introduced in the early 1990s, systemic intravenous chemotherapy remains an essential tool for the treatment of retinoblastoma. It usually consists of 2, 3 or 4 chemotherapy agents administered monthly through a central or peripheral catheter for a total of 6-9 consecutive cycles. The most frequently used regimen includes three drugs: vincristine, etoposide and carboplatin. Because of its ability to reduce tumour size, intravenous chemotherapy is sometimes referred to as 'chemoreduction'. Current indications include patients with bilateral disease, confirmed germline mutation, family history of retinoblastoma, or cases with suspected optic nerve or choroidal invasion. In addition, intravenous chemotherapy plays a protective role in the prevention of second long-term tumours, metastases and pineoblastoma. Other indications for IVC include patients weighing less than 6 kg awaiting intra-arterial chemotherapy (IAC). As with most systemic chemotherapies, they canor transient alopecia, cytopenia and fever occur. However, systemic IVC toxicity for retinoblastoma is generally mild.
Intra-arterial chemotherapy (IAC)
IAC is a complex procedure performed in an angiographic suite by an experienced neurosurgeon or interventional neuroradiologist, in which a microcatheter is guided by fluoroscopy to deliver chemotherapeutic agents supra-selectively into the ophthalmic artery. Given the success of IAC for saving the eyeball in advanced cases and refractory tumours, this treatment modality has become more widely used in the last decade. Compared to IVC, IAC allows a 10-fold higher dose of chemotherapy to be administered directly into the eye. The main indications for IAC include both first-line and salvage therapy of the eyeball. Chemotherapy generally consists of one, two or three drugs (melphalan, topotecan or carboplatin), typically administeredonce a month for an average of three sessions. Despite localised administration of chemotherapeutic agents, systemic toxicity was observed after IAC.
Intravitreal chemotherapy
Intravitreal chemotherapy (IvitC) is a type of intraocular chemotherapy that is useful in combination with IAC as an ocular globe salvage therapy. The most commonly used drugs in IvitC are melphalan and topotecan, alone or in combination. Serious ocular adverse events may be associated with IvitC.
In recent years, two variants of IvitC have been introduced: precision intravitreal chemotherapy (p-IvitC) and intracameral chemotherapy (IcamC).
Focal therapies
Focal therapies are often used as consolidation therapies in combination with IVC or IAC. Currently used focal therapies mainly include cryotherapy and transpupillary thermotherapy (TTT).
- -Cryotherapy
Cryotherapy is a reliable and regularly used treatment in the management of retinoblastoma. Currently, it is rarely used as a stand-alone therapy and is most frequently used in combination with chemotherapy, most commonly the IVC.
- -Transpupillary thermotherapy (TTT)
Transpupillary diode laser thermotherapy can be used in combination with chemotherapy as primary treatment for small tumours less than 3 mm in diameter and 2 mm thick. TTT is usually administered by indirect ophthalmoscopy, using an 810 nm diode laser in continuous mode.
External beam radiotherapy (EBRT)
Before the introduction of IVC, external beam radiotherapy (EBRT) was used as a salvage therapy for the eye globe. Today, EBRT is less widely used due to the numerous associated side effects and the better results obtained from chemotherapy. However, EBRT still maintains a role in the context of extraocular tumour extension, orbital recurrence and positive optic nerve margin after enucleation.
Radiotherapy with plates
Currently, plaque radiotherapy, or brachytherapy, is typically used as a secondary treatment of medium-sized chemoresistant tumours following recurrence after IVC or IAC. Plaque radiotherapy can also be used to manage diffuse anterior segment retinoblastoma, with or without IVC, in the absence of choroid or retinal tumours. Compared to EBRT, many serious side effects are also avoided.
Despite great advances in the management of retinoblastoma, enucleation of the eyeball still remains a current treatment. It is usually reserved for massive group E tumours, poor visualisation of the tumour (e.g. due to vitreous haemorrhage), presence of extraocular extension, suspected optic nerve or choroid invasion, or recalcitrant tumours refractory to previous globe salvage therapy. Removal of the eye globe can lead to debilitating functional, physical and psychological effects and, therefore, prosthetic rehabilitation is crucial.
Bibliography:
Dr. Carmelo Chines
Direttore responsabile
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