Keywords
advanced stages - chemotherapy - childhood malignancy - retinoblastoma - survival
- treatment refusal
Introduction
Retinoblastoma (Rb) is a rare tumor and is also the most common intraocular malignancy
of childhood. The reported incidence worldwide is ∼1 in 18,000 live births.[1]
[2] In India, RB constitutes 3.1% of all childhood cancers in boys and 4.1% in girls
from 0 to 14 years of age group.[3]
RB most commonly presents with leukocoria followed by other symptoms including poor
vision, redness, squint, or proptosis.[2] The average age of diagnosis is 18 months, and unilateral cases are diagnosed later
than bilateral ones with average age of 24 months for unilateral versus 12 months
for bilateral cases.[4] The disease may be unilateral or bilateral; bilateral involvement is seen in 25
to 35% of cases.[4]
RB was associated with near certain death just over a century ago. Over the recent
years, treatment of RB has significantly improved. In the early stages, the main aim
is to preserve the globe as well as vision, with minimum treatment-related adverse
effects. This has been made feasible with the frequent use of intravenous chemotherapy
and focal treatment methods. Of the recent advancements, the use of targeted delivery
of chemotherapy to the eye in the form of intraarterial and intravitreal chemotherapy
has shown promising results.[5] Radiotherapy is beneficial in selected cases, either in the form of external beam
radiotherapy and stereotactic radiotherapy or plaque brachytherapy.[6]
[7] In cases of advanced orbital disease, a multimodal treatment protocol in the form
of systemic chemotherapy followed by either focal therapy or enucleation has improved
survival as well as globe and vision preservation to some extent. The disease being
potentially curable requires a multidisciplinary approach for appropriate treatment
and thus the prognosis is dependent on early diagnosis. Goals of therapy are life
salvage, followed by globe salvage, and vision preservation in decreasing priority.
However, challenges remain, especially for the developing world where most of the
cases are diagnosed in advance stages.
Methods
This study was designed as a retrospective study. Children who presented and underwent
treatment at the medical and pediatric oncology department of our center between 2004
and 2017 were recruited and analyzed retrospectively. The study received the institutional
ethics committee approval.
Objectives of the Study
The aim of this study was to analyze clinical and epidemiological profile and treatment
outcomes with special reference to eye and vision salvation in children presenting
with RB.
Inclusion Criteria
All children from 0 to 14 years of age group diagnosed by radiological and/or ophthalmological
examination are included for the study.
Exclusion Criteria
Children with relapsed RB at presentation, patient not received any treatment after
confirmation of the diagnosis, and patients who failed to undergo complete diagnostic
workup were excluded from the analysis. Clinicoepidemiological and treatment-related
data were collected from case files of the patients and health records available in
our hospital database and in collaboration with the Ophthalmology Center, Guwahati,
Assam, India.
After the diagnosis with the help of ophthalmologic examination under anesthesia and
ocular ultrasonography (bone scan), children underwent complete staging evaluation
using contrast enhanced magnetic resonance imaging (MRI) brain and orbits, chest X-ray
posteroanterior view and bone marrow aspiration and biopsy, lumbar puncture and radionuclide
bone scan in patients with extraorbital involvement along with complete hemogram,
liver and kidney function test, serum lactate dehydrogenase, viral serology as per
institution protocol. Children, thereafter, underwent staging using International
Classification of Intraocular Retinoblastoma.[8]
[9]
[10]
Statistical Analysis
The results are presented as descriptive statistics using methods of calculating central
deviation. Disease and patient characteristics were calculated in percentage and presented
in the form of pie chart. Association between use of chemotherapy and compliance to
treatment was analyzed using chi-squared test and presented in form of bar diagram.
Survival was analyzed with the Kaplan–Meier method and log-rank test. Calculations
were done using IBM SPSS version 16.0.
Results
A total of 206 patients of RB were registered at our institute during the study period
between April 1, 2004 to March 31, 2017. Out of 206 cases, 189 children were found
to be eligible for the study. Most of the ineligible patients were those who failed
to undergo complete diagnostic workup and lost to follow-up after first visit.
Median age of presentation for the study group was 14 months with slightly male preponderance
(1.2:1) ([Table 1]). Median duration from symptom onset to presentation at healthcare facility was
found to be of 49 days. Family history of RB and of other malignancies was elicited
in 0.5 and 4% of children, respectively.
Table 1
Baseline demographic profile
|
Median age (mo)
|
14
|
|
Male:female
|
1.2:1
|
|
Median duration from symptom (d)
|
49 (SD ± 79)
|
|
Family history of RB (%)
|
0.5
|
|
Family history of other cancers (%)
|
4
|
Abbreviations: RB, retinoblastoma; SD, standard deviation.
In this study, three-fourth of all children had unilateral disease ([Table 2]), and the most common presenting symptom was leukocoria (60%) followed by red eye
(5%). Of all children included in this study, 87% were diagnosed based on ultrasound.
Staging workup included computed tomography (CT) and MRI scan, which were performed
in 66 and 16% of the children, respectively. Most of the children included in the
study presented with an advanced disease (stage D—21% and stage E—76%) with evidence
of extraocular disease spread present in 29% of children.
Table 2
Baseline disease characteristics
|
Unilateral vs. bilateral (%)
|
73 vs. 27
|
|
Presentation with leukocoria
|
113 (60%)
|
|
Ultrasound-based diagnosis (%)
|
87
|
|
CT scan
|
124 (66%)
|
|
MRI
|
30 (16%)
|
|
Stage E
|
144 (76%)
|
|
Stage D
|
39 (21%)
|
|
Extraocular disease
|
55 (29%)
|
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging.
Regarding treatment characteristics ([Table 3]), of all children found to be eligible for the study, 33(18%) of them refused to
take any form of treatment and were lost to follow-up. Of remaining 156 children who
underwent treatment at our institute, 100 (64%) received some form of chemotherapy
(including neoadjuvant and/or adjuvant). Out of these 100 children who received chemotherapy,
68 (68%) underwent neoadjuvant chemotherapy and remaining received only adjuvant chemotherapy.
Since most of the children presented in an advanced stage, in spite of using neoadjuvant
chemotherapy, only 33 (21%) children were eligible for and underwent focal therapy.
Most common mode of focal therapy used was external beam radiotherapy in 13 (39%)
children followed by cryotherapy in 11 (33%) children. Of 156 children who received
treatment, eyeball salvation was achieved in 20 (13%) children and vision salvation
in 19 (12%) children. In this study, chemotherapy was found to be associated with
improved survival in children with advance disease. Median survival in children who
received some form of chemotherapy was not reached as compared with 27 months in children
who did not receive any form of chemotherapy (p = 0.02).
Table 3
Treatment characteristics
|
Refusal to treatment
|
33 (18%)
|
|
Chemotherapy (n = 156)
|
100 (64%)
|
|
Focal therapy (n = 156)
|
33 (21%)
|
|
External beam RT (n = 33)
|
13 (39%)
|
|
Cryotherapy (n = 33)
|
11 (33%)
|
|
Globe salvation (n = 156)
|
20 (13%)
|
|
Vision salvation (n = 156)
|
19 (12%)
|
|
Overall survival (mo)
|
40
|
|
Median survival without CT (mo)
|
27 NR
|
p = 0.02
|
|
Median survival with CT (mo)
|
Abbreviations: CT, computed tomography; RT, radiotherapy.
Discussion
RB is the most thoroughly studied example of heritable cancers and is also the most
common intraocular tumor in the children. Most of these malignancies are sporadic
and unilateral, in nearly 60% of the cases. The remaining 40% are inherited, with
bilateral presentation seen in 25% of the cases.[11] The median age at presentation in our study was found to be 14 months, which is
lower than 3.5 years reported by the study from Sahu et al[12] and 30 months reported in the study from Postgraduate Institute of Medical Education
and Research (PGIMER), Chandigarh, India.[13] and is similar to the study by Padma et al.[14] Our study found slightly male predominance with a male to female ratio of 1.2:1,
which was similar to that reported from other Indian studies.[12]
[14 ] The median duration of illness in our study group is 1.5 months, with a family history
of RB and of other malignancy found is 0.5 and 4%, respectively. Study from Tata Memorial
Hospital, Mumbai, Maharashtra, India, reported a longer duration of illness (i.e.,
8 months) before presentation and similar family history of malignancy, as compared
with our study.[12] This may be due to complete ignorance of symptoms for longer duration by the parents.
In our study cohort, 27% of the children had bilateral disease, similar to the study
by Chawla et al and Naik et al, which reported 25% of cases with bilateral tumors.[11]
[15] The most common mode of presentation was leukocoria in 60% of children followed
by red eye in 5%, which is similar to other reported Indian studies. Further staging
workup in form of contrast-enhanced CT scan and MRI of brain and orbit was performed
in 66 and 16% of children. Most of the children in our study presented at an advance
stage (stage D—21% and stage E–76%) as compared with 78% reported in study from PGIMER,
Chandigarh, India.[13] Extraocular disease at presentation was found in 29% of children similar to 27%
reported from PGIMER, Chandigarh, India[13] but was found to be less than as compared with 57 to 58% reported in study by Sahu
et al and Padma et al.[12]
[13]
[14] However, these figures are in contrast to the Western world,[16] where the incidence of extraocular disease has been reported to be less than 5%.
Therefore, a major challenge in our country is the implementation of an early detection
program to minimize the progression of RB to advanced stages and allow for the treatment
at earlier stages of disease and have better treatment outcomes.
In our study, 33(18%) children after registration did not receive any form of treatment
and were lost to follow-up. Lost to follow-up rate in our study is found to be lower
than the report from PGIMER, Chandigarh, India (25.6%).[13] This further explains the lack of awareness among parents regarding this curable
disease. As compared with study by Padma et al, where only 55% children agreed to
and underwent treatment, in our study 82% children underwent treatment.[14] One more possible reason of declining treatment by parents is the counseling regarding
enucleation for advanced disease. A study from Malaysia[17] reported that most families refuse treatment upon counseling in favor of enucleation.
In our study population, 97% of children had advanced disease at presentation of which
64% received systemic chemotherapy either in neoadjuvant or adjuvant setting. Of these
children, 68% received neoadjuvant and remaining 32% received adjuvant systemic chemotherapy.
Most commonly employed regimen for chemotherapy was vincristine, etoposide, carboplatin
regimen.
In spite of using systemic therapy, only 21 and 39% of children were found to be suitable
for focal therapy and external beam radiotherapy, respectively. This resulted in eyeball
salvation rate of 13% and vision salvation rate of 12% in our study population. In
our study, we found significantly lower rates of eyeball salvation and vision salvation
as compared with the study from other developing countries like Thailand, which found
globe salvation rates of 52%[18] and globe salvation rate of 100% in studies from developed countries.[9]
[19]
[20] Similar to our study, rate of globe salvation reported in the study from PGIMER,
Chandigarh, India, was only 17%.[13] Median overall survival of the entire study group was found to be 40 months. In
cohort of children who received systemic chemotherapy median overall survival was
significantly higher than those who did not receive any form of systemic chemotherapy.
This finding highlights the importance of systemic chemotherapy in treatment of RB
and more so in cohort of children with advanced disease at presentation.
Conclusion
In developing countries, RB is mostly detected in advanced stages resulting in poor
outcomes. Increased awareness and accessibility to dedicated centers for treating
childhood malignancy can lead to early diagnosis, better prognosis, and increased
vision salvage. Fortunately, an early diagnosis[21] will lead to many eyes that can be treated safely and support a lifetime of good
vision, thus pointing to the key elements for national and global focus: awareness,
collaboration, and affordable expert care. Initiative for screening like Photo Red
India, an innovative study that trained healthcare professionals to use flash photography
and to identify childhood eye diseases, including RB, is much warranted.[22]
