Keywords
COVID-19 - children - retinoblastoma - lockdown - travel restrictions
Introduction
The coronavirus disease 2019 (COVID-19) pandemic has created a significant void in
the availability and accessibility of treatment modalities and timely intervention
for children with cancer. The lockdown with travel restrictions and financial constraints
has been a major cause. Furthermore, in retinoblastoma (RB) already a strong disparity
exists between the delay in diagnosis, stage of presentation, abandonment, and survival
in the developing and developed countries prior to the COVID-19 pandemic.[1] Despite the development of healthcare in diagnosis and treatment, 50% of children
with RB in developing countries present at a more advanced stage and succumb to the
disease, whereas in developed countries, it is less than 5%.[2]
[3] The COVID-19 pandemic has caused an additional strain on the diagnosis and treatment
process of RB children. There are multifactorial reasons for treatment delay including
hospital resource constraints, affordability of transport, financial constraints along
with the fear among parents regarding the implications of COVID-19 rather than RB.[4]
[5] The major reason is the inability to reach their respective health centers leading
to interruption of treatment.[6]
[7] Our study is to assess the challenges of the COVID-19-related nationwide lockdown
on disruption of access to healthcare and its impact on the management of children
with RB and the strategies we developed to overcome these challenges.
Materials and Methods
This is a cross-sectional study of 104 children with RB, who presented within the
1-year study period (May 2020–April 2021) to Sankara Nethralaya (SN) tertiary referral
eye hospital in Tamil Nadu. These children were collectively managed by both the pediatric
oncology unit in Sri Ramachandra Institute of Higher Education and Research (SRIHER),
and SN. The demographic details, clinical presentations, initiation delay and interruptions
of treatment, and the outcome of treatment during this lockdown period were collected.
Initiation delay was defined as time from onset of symptoms to initiation of treatment
of more than 4 weeks. Interruptions are defined as a delay of more than 2 weeks during
therapy. The examination included comprehensive eye evaluation under anesthesia (EUA),
ultrasonography of the eye to measure the tumor dimensions, RetCam imaging, magnetic
resonance imaging of the brain and orbit to assess the optic nerve status, and presence
of the primary neuroendocrine tumor. Children diagnosed with RB but continued treatment
in their native place were excluded from study.
The staging was based on International Intraocular Retinoblastoma Classification (IIRC)
in SN; patients were referred to the pediatric hemato oncology unit in SRIHER for
staging evaluations, intravenous chemotherapy, and radiotherapy.[8] Metastatic work if needed included bone marrow aspiration and lumbar puncture for
cerebrospinal fluid analysis. The treatment modalities consisted of focal therapy,
intravenous, intra-arterial, intravitreal chemotherapy, radiotherapy, and enucleation
as per staging after the discussion in the combined institutional tumor board. The
outcome was measured based on vision salvage, globe salvage, and life salvage.
Chemotherapy regimens commonly used are of two types: standard dose VEC (vincristine,
etoposide, carboplatin) for intraocular RB and high-dose VEC for extraocular RB. For
metastatic and trilateral RB, four drug regimen was used: vincristine (1.5 mg/m2) and cyclophosphamide (600 mg/m2) followed by cisplatin (80 mg/m2) and etoposide (200 mg/m2). Enucleation was performed when required. The enucleated eyes were analyzed for
high-risk features, which were involvement of optic nerve, choroid invasion, anterior
segment, scleral, and extrascleral involvement.
The impact of lockdown on delay in diagnosis, interruption of treatment, and outcome
was studied. The reasons for treatment interruption like transport restrictions, financial
constraints, and accommodation difficulty were analyzed. The residence of the RB children,
the distance needed to travel to reach the treating hospital during the lockdown times,
financial constraints, difficulty in accommodation during the lockdown, and the challenges
faced were obtained. History pertaining to COVID-19 infection in any of the family
members was obtained. The treatment outcome was measured in terms of vision salvage,
globe salvage, and life salvage.
Statistical Analysis
The data collected was entered in MS Excel and the mean, percentage, and statistical
analysis were performed by SPSS version 20.1
Ethics
Ethics clearance was obtained from both the institutional ethics committee (SN and
SRIHER- CSP-MED/21/JUN/69/97) in accordance with the 1964 Helsinki Declaration and
its later amendments. Informed consent was obtained from either of the parents prior
to enrolment.
Results
A total of 104 children were treated during this period from May 2020 to April 2021.
This included both newly diagnosed cases and follow-up children already on treatment.
The total number of children who underwent EUA was 122 in the previous year (pre-COVID-19
lockdown) and the newly diagnosed was 67 as compared with 60 during the lockdown period
(May 2020–April 2021).
Of the 152 eyes of 104 children, 52% were unilateral RB and 48%were bilateral RB in
which four children had metastatic disease and one child had trilateral RB. The mean
age at diagnosis was 34 months (range: 1–132 months), with 52% males and 48% females.
Leukocoria was the most common presenting feature (94%). Family history of RB was
positive in only 7.5% (n = 8) ([Table 1]). The cases were classified based on IIRC, and majority were in groups D (42%; n = 64 eyes) and E (25%; n = 38 eyes). Almost, half of the children 51% (n = 53) underwent enucleation. Overall, the vision was preserved in 32% of the children.
The globe salvage was achieved in 49% of children, of which 29 children had unilateral
and 22 had bilateral RB. In comparison, globe salvage was achieved in 54% of children
in the previous year. Eleven children (10.5%) succumbed to the disease due to disease
progression.
Table 1
Demographic and clinical details
|
Demographics
|
n = 104 children (%)
|
95% CI
|
|
Age at diagnosis
|
34 months (range: 1–132 months)
|
|
|
Gender
|
Male
|
54 (52)
|
(42.3, 61.5)
|
|
Female
|
50 (48)
|
(38.4, 57.6)
|
|
Distance needed to travel
|
<500 km
|
26 (25)
|
(16.7, 33.3)
|
|
500–1,000 km
|
6 (7)
|
(1.2, 10.3)
|
|
>1,000 km
|
72 (68)
|
(60.3, 78.1)
|
|
Family history of RB
|
Yes
|
8 (7.5)
|
(2.57, 12.8)
|
|
No
|
96 (92.5)
|
(87.2, 97.4)
|
|
Laterality
|
Unilateral
|
54 (52)
|
(42.3, 61.5)
|
|
Bilateral
|
50 (48)
|
(38.5, 57.7)
|
|
Vision salvage
|
43 (32)
|
(31.9, 50.8)
|
|
Globe salvage
|
51 (49)
|
(39.4, 58.7)
|
|
Life salvage
|
94 (90)
|
(84.7, 96.1)
|
|
Death
|
10 (10)
|
(3.9, 15.3)
|
Abbreviations: CI, confidence interval; RB, retinoblastoma.
We developed a protocol to contact the patients telephonically periodically to prevent
abandonment. We also made efforts to arrange transport for families to reach the hospital
with special permissions and coordinated accommodation with the help of the home-away-home
program and coordinated nongovernment organizations (NGO) support for funding for
invisible expenses also like food. Financial assistance for EUA, local therapy, chemotherapy,
and radiotherapy treatment was completely supported by both hospitals together with
NGOs. Whenever required transport and rent allowance for the extended stay during
locked down were also supported by NGOs.
Majority of children, 69% (n = 72) had to travel more than or equal to 1,000 km for the treatment ([Table 2]). About 57% (n = 60) of children were newly diagnosed during the lockdown period and due to the
travel restrictions, they had a mean delay of 2.2 months (range: 0–15 months) in starting
treatment and 27% (n = 29) of children on treatment had an interruption of treatment. Only three of our
children had tested positive for COVID-19 during routine screening. When the children
were positive, we withheld treatment for 2 weeks. They were asymptomatic and continued
treatment after the resolution of COVID-19 infection.
Table 2
Impact of lockdown on RB follow-up
|
(n, %)
|
|
Loss to follow-up
|
29, 27
|
|
Travel restrictions
|
18, 62
|
|
Financial constraints
|
8, 28
|
|
COVID-19 positivity in family
|
3, 10
|
Abbreviations: COVID-19, coronavirus disease 2019; RB, retinoblastoma.
Discussion
COVID-19 was declared a pandemic by the World Health Organization) on March 11, 2020.
Following this, many countries went into complete lockdown. India declared lockdown
on March 24, 2020, leading to transport restrictions and the inability to reach the
healthcare facilities. Children with life-threatening diseases in need of continued
hospital care like our oncology patients were affected the most.[9] Children with pediatric solid tumors, transplant recipients, and ocular cancers
such as RB faced a major difficulty in continuing their treatment, majorly due to
the inability to reach their healthcare providers.[10]
[11]
Pediatric cancers have also been observed to affect the low (41%) and middle socioeconomic
(43%) class more than the upper class (16%), and 90% of the global cancer deaths are
from low- and middle-income countries.[12]
[13] Similarly, RB accounts for 2.5 to 4% of all childhood cancers in most developed
countries, and a two- to threefold increase has been reported in India.[14] India accounts for nearly one-third of RB cases in the Asia-Pacific region. The
survival of RB is between 95 and 100% in developed countries; however, in parts of
Asia and Africa, it is between 30 and 60%.[15] With the already existing social issues prepandemic, the lockdown has caused more
strain on the developing counties. Multifactorial reasons have been identified for
treatment delay—financial constraints, transport restriction, accommodation issues,
and no caregiver to accompany.
Fabien et al in their global RB study from 94 countries have reported approximately
42.3% of families had delays in treatment due to travel restrictions during the current
pandemic as compared with only 10% before the pandemic. They also mentioned that the
availability of life-saving treatment modalities such as EUA, enucleation, intravenous
chemotherapy, and intraarterial chemotherapy have significantly dropped from 95.9
to 55.2%, 100 to 89.6%, 96.9 to 93.8%, and 49.7 to 37.8%, respectively, before and
after the pandemic.[16] Similarly, Gupta et al had reported an average duration of delay in follow-up was
14 days (7–20 days) during pre-COVID-19, as compared with 336 days (56–560 days) during
the lockdown period.[17]
This COVID-19 lockdown situation has led many ophthalmic and pediatric oncology centers
to revise the policy of examining, treating, and admitting their patients. One such
study by Hadjistilianou et al, from Italy, has studied the policies adopted during
the COVID-19 pandemic and RB patients. They have observed a wide disparity between
various ophthalmology tertiary care centers as to when and who should be tested for
COVID-19. Although swab testing was mandatory to ensure the safety of both patients
and healthcare workers, only 2 out of 16 institutions they reviewed had ensured mandatory
testing in all centers.[18] In our center, mandatory testing was done for both patients and the accompanying
attenders and 3 were found to be COVID-19 positive.
During the era of global lockdown and travel restrictions, to help flatten the COVID-19
curve, telemedicine has been fundamental in connecting patients to their healthcare
providers. This helped in triaging the patients, hence identifying those requiring
immediate medical assistance and others to continue the medical care through teleconsultations.[19]
The COVID-19 pandemic and the nationwide lockdown have created a negative impact on
overall healthcare in particular on chronic diseases needing long-term management.
Hence, it is imperative to establish a network with necessary support across the hospitals,
with the help of government, nongovernment social organizations, shared care with
primary practitioners and telemedicine, keeping in mind the psychological impact of
the pandemic on the families.
Future Research Directions
Future Research Directions
A multicentric study, comparing the RB children during the COVID-19 lockdown period
with the non-COVID-19 period in various countries, would help us understand the support
system across the centers that can help in preparedness future pandemics.
Limitations of the Study
It is a single-center experience with a limited study population.
Conclusion
Our study has shown that providing collaborative care has enabled 73% of patients
to receive emergent care and continue their treatment. Through our study, we advocate
that with the involvement of NGOs and meticulous planning of funding support we can
provide a structured management strategy during global pandemics. In conclusion, there
is a delicate balance of risk assessment and management of RB patients during the
pandemic. The decision-makers should make bold new policies weighing the risks and
benefits of the situation.
