Ashis Kumar Ghosh
Department
of Paediatric Haematology and Oncology, Institute of Cancer Research and
Hospital, Bangladesh
Health and Hope Hospital
152/2/G, Green Road,Panthapath, Dhaka-1205, Bangladesh
For Appointment: 01611131253, 01678131252. Sunday and Wednesday 2-5 pm. (Room no-311)
Abstract
Retinoblastoma is the most common primary intraocular
malignancy of childhood. A potentially curable cancer, its treatment has improved significantly over the last few decades. In developed world current treatment options aim to preserve the globe as well as vision with minimum morbidity. High
resolution imaging has improved tumor detection and is useful for
prognosticating cases and monitoring response to treatment. Targeted
chemotherapy has shown promising results and these routes are being
increasingly employed world-wide for globe preservation. Chemotherapy is
currently used as a first line approach for children
with this malignancy and can be delivered by intravenous, intra-arterial,
periocular, and intravitreal routes. The choice of route for chemotherapy
administration depends upon the tumor laterality and tumor staging. This review
aims to highlight newer advancements in the field of management of
retinoblastoma that have been introduced in recent times, with a special
emphasis on globe-preserving therapy.
Keywords: intra-arterial chemotherapy, intravitreal chemotherapy,
retinoblastoma
Volume
10 Issue 4 - 2020
Correspondence: Ashis Kumar Ghosh, Department of Paediatric Haematology
and Oncology, National Institute of Cancer Research and Hospital, Bangladesh,
Introduction
Retinoblastoma (RB) is the most common primary
intraocular malignancy of childhood worldwide with a uniform incidence rate
across population at 1 in 15000–20000 live birth corresponding to about 9000 new cases every year.1 With more than 90% of RB children living in under developed
nations.2 And 43% (3452 of 8099 children) of the global burden of RB lives in the 6
countries: 1486 children in India, 1103 children in China, 277 children in Indonesia, 260 children
in Pakistan, 184 children in Bangladesh, 142 children in Philippines.3 Even one century ago
Retinoblastoma was a fatal disease for the children. And major treatment for RB was eye removal and prognosis
was poor with outcome fatal for most children. The dramatic evolution, in a short period of time
across all fields of RB management, has resulted in nearly 100% survival in
developed countries and allowed eye salvage in many of the cases.4 So
in developed countries, the goal of treatment has shifted from
globe salvage to vision preservation.5,6 This
has been possible due to emerging trend of chemoreduction and local
consolidation therapy by intravenous chemotherapy along with focal therapy. But to reduce systemic side
effects associated with intravenous chemotherapy (IVC) and to increase salvage rate
of more advanced intraocular RB eyes, the era of targeted delivery of chemotherapy to the eye has born.
These include Intra- arterial
Chemotherapy, Intravitreal chemotherapy, Sub-conjunctival and sub-tenon
chemotherapy. While
exenterations, intervenous chemotherapy,external beam radiotherapy,laser
photocoagulation are still
the main stream of RB management in developing countries like Bangladesh.
The
recent advances such as detection of constitutional abnormalities of the
RB1 gene, replacement of external beam radiotherapy
by chemoreduction as the primary modality of management, use of chemoreduction
to minimize the size of the regression scar with consequent optimization of
visual potential,5–9 identification
of histopathologic high-risk factors following enucleation10 and
provision of adjuvant therapy to reduce the incidence of systemic metastasis,11 protocol-based management of retinoblastoma with
accidental perforation or intraocular surgery12,13 and
aggressive multimodal therapy in the management of orbital
retinoblastoma14–15 have contributed to improved outcome in terms of better survival, improved eye salvage and potential for optimal
visual recovery. In conclusion it can be say retinoblastoma (RB) has emerged as a malignancy with one of the highest survival rates among all pediatric cancers, owing
to improving treatment methods over the years.16,17 There is a
major shift from globe-sacrificing methods to globe-saving alternatives in the treatment of most
cases, using novel techniques
of chemotherapy. In this review, we will discuss the latest methods of
chemotherapy for the management of retinoblastoma Adatabase search was performed
using the terms “Retinoblastoma,” “chemotherapy,” “intravenous chemotherapy
(IVC),” “intra-arterial chemotherapy (IAC),” “periocular chemotherapy,” or “intravitreal chemotherapy”. English
language articles were extracted, reviewed, and referenced appropriately.
|
Indications of
chemotherapy for Retinoblastoma.18 |
|||
|
Chemotherapy |
Indication |
||
|
Intravenous |
Intraocular RB especially
bilateral cases Orbital RB High-risk RB Metastatic RB |
||
|
Intra-arterial |
Intraocular RB as primary
treatment Refractory intraocular RB
as secondary treatment |
||
|
Periocular |
Recurrent or residual
vitreous seeds Bilateral RB with poor
prognosis at diagnosis In cases with
contraindication of systemic chemotherapy |
||
|
Intravitreal |
Recurrent or residual
vitreous seeds |
||
Intra-arterial chemotherapy
Injection of a chemotherapeutic agent into the carotid
artery was first attempted
by Reese in 195719 Later, the Japanese revisited this delivery technique in 1993,20 followed
by the Americans.19 In this procedure, chemotherapy is given
directly in the ophthalmic artery with the help of an interventional
radiologist. The various agents used for IAC in RB include melphalan,
carboplatin, topotecan, and methotrexate.21 The
advantages of IAC include: Control of intraocular tumor, Resolution of
retinal detachment (RD),Globe salvage and Minimal systemic side-effects. And
various studies have shown that IAC can be used as primary treatment or
secondary treatment in eyes with recurrent/residual RB.22 In
a 3-year experience with this technique
on advanced retinoblastoma, only 1 of 28 eyes required enucleation and none
required adjuvant systemic chemotherapy or radiation.23
In a study of selective IAC with melphalan Figure 1 in
408 eyes of 343 patients by Suzuki et
al. globe salvage was achieved in 100% group A, 88% group B, 65% group C,
45% group D, and 30% group E eyes. Visual acuity of 20/40 or better was
achieved in 51% eyes.24 Gobin reported their experience in 95
eyes with supraselective IAC, with 82% globe salvage when used as primary
treatment and 58% globe salvage when used as secondary treatment.25 Shields et
al. reported their experience in 70 consecutive patients treated with
supraselective IAC, with 72% globe salvage when used as primary treatment and
62% globe salvage when used as secondary treatment
Systemic side effects of Intra-arterial chemotherapy (IAC)
are minimum. Transient neutropenia develops in 11% patients after IAC
that does not require transfusion.27 Owing to minimal systemic absorption of drugs, IAC
offers no protection against systemic metastasis, pinealoblastoma, and second
cancers. Of 78 patients treated with IAC, two children developed systemic metastasis.27 Local
side-effects at the injection site and carotid spasm can also occur. Ocular
complications with IAC are well-documented.28 Less severe, temporary side-effects
include periorbital edema, periocular hyperemia, madarosis, and ocular
dysmotility. More severe complications include vitreous hemorrhage in 13-27%, Retinal
detachment in 15 to 27%, retinal pigment
epithelial changes occur in 5-53%, retinal ischemia in 4-24%, and
chorioretinal atrophy in <1 to
29% cases.21,25 All these changes occur either secondary to drug toxicity or competency of
ophthalmic artery catheterization resulting in structural and vascular damage
of the retina causing visual loss.29
Intravitreal chemotherapy
Intravitreal chemotherapy (IVitC) is another
well-established targeted therapy accounting for one of the important current
treatment modalities for retinoblastoma manifesting vitreous seeds but did not
gain popularity due to the risk of tumor metastasis. Seregard. demonstrated the
absence of local recurrence Figure 2 and metastatic disease following
administration of intravitreal thiotepa.30 Initial
reports on IVitC date back
to the 1960s where thiotepa was injected into the vitreous cavity of six eyes
with retinoblastoma; yet the results were inconclusive due to the limited
number of treated eyes.31 Later Inomata and Kaneko found
melphalan to be the most sensitive
chemotherapeutic agent against RB based on in vitro testing of 12 agents, and a
dose of 4 ug/ml achieved complete tumor suppression.32–34 In
the rabbit model, the concentration of 5.9 µg/ ml showed no retinal toxicity,
and this correlates to human vitreous doses of 20-30ug. These findings have prompted
20-30 ug melphalan as the drug of choice for intravitreal chemotherapy, with
minimal ocular complications and no significant electroretinogram changes at
this dose.35,36 Dose greater than 50 ug is associated with
severe ocular complications.35 Satisfactory
results have also been reported with an intravitreal
methotrexate, carboplatin and topotecan.37 In the recent times,
the use of intravitreal chemotherapy through pars plana route for
recurrent/residual vitreous seeds has shown promising results.37–40
Extraocular tumor dissemination through the needle track with subsequent metastasis was perhaps
the most feared serious event limiting the use of this treatment modality in
the past. However, a meta-analysis examining published studies on this matter
revealed that the risk of systemic spread is very low (two cases out of 1304
injections, proportion of extraocular spread secondary to injections was 0.007) especially when the appropriate safety enhancing injection
techniques are applied. Therefore, IVitC can
be utilized unreservedly whenever needed after proper patient selection.41 Ocular
side effects are generally
uncommon in patients receiving IVitC. The major factor influencing the risk of
complications and local ocular toxicity is the dose of administered medication where toxicity is more likely with melphalan doses
higher than 30 μg.42 Among the most frequent side effects is retinal pigment
epithelium changes (salt and pepper retinopathy), which is believed to
represent a form of chemical burn to the retinal at the area where the drug is
concentrated the most.43,44 Retinal function decline due to toxicity, usually
highlighted on electroretinography (ERG), is a possible complication of
melphalan although the results are conflicting in the literature where one
study showed no effect on ERG (dose: 20–30 μg) while another reported
non-progressive decreased ERG amplitudes of approximately 5μV (equivalent to 5%
retinal response) with every 30 μg melphalan injection.45,46
Periocular chemotherapy
Complications of periocular chemotherapy
Due to
carboplatin, tissues in and around the eye can become very fibrosis and fat
cells may die to necrosis. This may restrict eye movement and cause a sunken
appearance. Topotecan does not any tissues effect. The other side effects
include ocular motility changes, orbital fibrosis, optic atrophy, pseudo
preseptal cellulitis, and rarely ophthalmic arterial alterations.53Conclusion The management of retinoblastoma is
particularly complex, requiring a multidisciplinary team, including Pediatric
oncologist, Ophthalmologist, Retina specialist, Radiation oncologist,
Anesthesiologist. With emerging trend of chemoreduction and increasing globe
salvage, local consolidation treatment is being increasingly popular in
developed countries. These include Intraarterial Chemotherapy, Intravitreal
chemotherapy, trans-scleral cryotherapy ,Sub-conjunctival /sub-tenon
chemotherapy. While other modalities of management like exenterations,
intravenous chemotherapy, external beam radiotherapy and laser photocoagulation
are using in developing countries like Bangladesh. Genetic protocols is an
establish method of prenatal diagnosis of retinoblastoma. Early diagnosis and
furtherance of focal therapy have resulted in improve eye and vision salvage.
Post-enucleation protocol, including recognition of histopathological high-risk
properties and provision of adjuvant therapy has resulted in notable reduction
in the incidence of systemic metastasis. The irritating retinoblastoma may seem
to have a cure finally with the combative multimodal approach. Future holds
promise for the treatment of retinoblastoma of further advancement in focal
therapy and targeted drug delivery.
Acknowledgments None.
Conflicts of interest
The
authors declare there are no conflicts of interest.
Citation: Ghosh AK, Gupta DSP. New
approach of chemotherapy for the treatment of retinoblastoma: a review. J
Pediatr Neonatal Care. 2020;10(4):98‒ 102. DOI: 10.15406/jpnc.2020.10.00419
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