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ICMR releases draft guidelines for managing eye cancer in children

Laxmi Yadav, Mumbai
Friday, August 12, 2022, 08:00 Hrs  [IST]

The Indian Council of Medical Research (ICMR) has released a draft consensus document for management of retinoblastoma (RB) which is the most common malignant intraocular neoplasm in children.
This draft of the consensus document has been formulated by ICMR’s expert group and the scientific community has been asked to submit their comments on it by August 28, 2022.
Retinoblastoma constitutes 2.5 per cent to 4 per cent of all paediatric cancers with 11 per cent occurring in less than one year of age. About 8000 children worldwide are diagnosed with RB each year with an estimated incidence in India being 1500 cases annually. In India, as in many other low middle income countries (LMICs), the median age of diagnosis of unilateral and bilateral RB is 30 months and 18-24 months, respectively. 63 per cent of RB is diagnosed in the intra-ocular stage, with one-third presenting as locally advanced or metastatic disease. Two thirds of the retinoblastoma children have unilateral disease. A positive family history of retinoblastoma is noted in only 5 per cent of cases.
Although long-term survival has improved to well-over 90 per cent with multimodality therapy in the developed world, it still causes fatalities in the LMICs because of delayed presentation (leading to advanced disease) and treatment abandonment. The RB therapy not only preserves life and the eye but also optimizes residual vision and decreases second malignancies. Early diagnosis of RB with the disease contained within the eye is key to better survival.
India has a major burden of RB and the delay in diagnosis is attributed to socio-economic barriers, leading to a large proportion of advanced disease presentations resulting in poorer survival outcomes.

RB is the first tumour where a genetic origin was identified. Retinoblastoma is caused by mutation in the RB1 tumour suppressor gene at chromosome 13q14.2. RB occurs when both copies are lost or mutated.
When a child is diagnosed with RB, it is important to determine if it is the heritable form or the non-heritable form of the disease. Unilateral tumours affect one eye and could be hereditary or sporadic retinoblastoma, whereas bilateral tumours which affect both eyes are of the hereditary subtype. It however must be emphasized that not all hereditary retinoblastomas are bilateral when they are found. Bilateral or multifocal RB is due to a germline RB1 mutation that can be passed to the next generation. Heritable (germline) mutation in RB1 gene usually affects about 90 per cent of cases that develop RB in early infancy, making genetic analysis an important aspect of management of the disease. 25 per cent of germline retinoblastomas are acquired from a carrier parent (who was diagnosed with RB during childhood) and 75 per cent germline retinoblastoma occur during embryogenesis (no family history of retinoblastoma). In this situation, a new mutation that arose at random around the time of conception has ultimately led to the occurrence of RB. Long-term side effects of radiation and chemotherapy may cause second malignancies in retinoblastoma patients.

The draft guidelines stressed on the need for the family of a child with retinoblastoma to have genetic testing.

A single genetic test is unlikely to detect all germline RB1 gene mutations. It is necessary to combine various modalities such as DNA sequencing, FISH, MLPA, PCR, Methylation studies to increase the sensitivity of detection of RB1 gene mutation to 90 per cent to 95 per cent, it stated.
“Plaque brachytherapy can be effective in the early stage of the disease when other forms of local therapies have failed to control the tumour. Though latest RT techniques including intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) can significantly improve conformity and spare surrounding organs at risks, these techniques should be used carefully in these children due to increased risk of second malignancies because of increased low dose bath. Unique property in reducing exit dose in proton beam therapy has the potential to reduce side effects, however cost and limited availability remains a significant issue,” added the draft guidelines.
RB arises from the sensory retina and grows initially into the intraocular compartments like choroid, vitreous, and anterior chamber. There are two growth patterns of RB, exophytic (away from vitreous) and endophytic (towards vitreous). Ocular USG is usually the first imaging performed in a suspected case of retinoblastoma. The ideal management of RB requires a multi-speciality team including ocular oncologist, paediatric oncologist, pathologist, radiologist, radiotherapist and interventional radiologist, it stated.
Enucleation remains the most common treatment for unilateral advanced intraocular retinoblastoma in LMIC. The treatment of intraocular retinoblastoma primarily depends on the intraocular tumour grading/ classification, presence of germline mutations, disease laterality, multifocality in case of unilateral disease, psychosocial situation of the family, compliance issues and existing institutional resources. Treatment modalities employed in management of intraocular retinoblastoma (IORB) comprise of- Enucleation, Examination under anaesthesia (EUA) for administering focal treatment to retinal tumour like cryotherapy, transpupillary thermotherapy (TTT) or laser photocoagulation and targeted treatment for vitreous seeds with intravitreal chemotherapy, Systemic chemotherapy (IVC: intravenous chemotherapy or IAC: intraarterial chemotherapy) for reducing tumour volume (chemoreduction) or adjuvant treatment (IVC) in case of histopathological high risk factors after enucleation, Plaque brachytherapy for residual/ recurrent retinal tumours. External beam radiotherapy (EBRT) for globe salvage in cases not responding to other treatment or microscopic residual disease (MRD) after enucleation.
There are few recent small case series showing better outcomes in advanced RB with multimodality treatment.
Treatment of bilateral retinoblastoma is more challenging than unilateral retinoblastoma due to several reasons. It indicates presence of a germline mutation and hence such patients are at an increased risk of trilateral retinoblastoma and secondary malignancies. Intravenous chemotherapy may offer systemic protective effects against development of systemic metastasis and pinealoblastoma.
“The management of extraocular retinoblastoma is multi-modality involving chemotherapy, radiotherapy, and surgery. The panel recommends only palliative RT in metastatic RB due to insufficient data and poor prognosis. Consensus guidelines say whenever indicated, RT should be delayed till the child attains 12 months of age, unless palliative. RT should be given within 4-6 weeks of surgery. Consensus guidelines say though there is no strong evidence, it was recommended to give RT to initially involved nodal region. Though there is no strong evidence, it has been recommended that if cut end of optic nerve is positive, entire orbit along with the optic nerve and proximal chiasma should be irradiated as there is potential for subclinical spread that is not visible on an MRI,” said the ICMR guidelines.
The available data suggest that patients with extra-ocular RB can be cured with intensive treatment that includes systemic chemotherapy and external beam radiation therapy. Therefore, all patients with orbital disease should receive RT.


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