Figure 1. Study selection process flow
diagram .
3.1. Public Assistance
Hill et al. in 201628addresses the development of a multidisciplinary and multisectoral
strategy embracing health professionals, students, survivors of RB,
their families, and members of the government of Kenya. It was
structured from annual meetings and resulted in the development of
National Retinoblastoma Strategy Guidelines, that counted with
facilitated access to government-subsidized health insurance, the
creation of a nursing home, centralization of the pathological diagnosis
of the disease, and the acquisition of artificial eyes for the children.
3.2. Surveillance
strategies
New software technologies like CRADLE® and MDEyeCare® have been
developed to detect leukocoria, the main and most early signal of RB20. Using
this principle, Bernard et al.3 with
their EyeScreen® mobile application, Vargas-Cuentas21 with
RetinoApp® and Khedekar et al20 with
MDEyeCare® demonstrated that mobile apps are promising screening
strategies. EyeScreen® application achieves a sensitivity of 87% and
specificity of 73% 8. RetinoApp®, associated with an
algorithm that detected leukocoria, correctly identified 93.33% of
cases and 95% of controls21.
MDEyeCare® had good results for advanced intraocular disease, but low
sensitivity for initial stages.
Ademola-Popoola, 201717evaluated the use of a cell phone’s basic camera’s photo and video
functions along with a 20D lens after eye dilation. Although images
captured through this approach were not as clear as those obtained
through fundoscopy, new camera technologies can overcome this
limitation.
Another strategy to enhance screening effectiveness relied on a clinical
assessment of the risk of harboring germline RB1 mutations. Kaliki et
al. (2019)19successfully executed this strategy by conducting ophthalmological
examinations on parents of children diagnosed with RB. If at least one
parent had a spontaneously regressed RB, there is a presumed risk of a
sibling having a germline RB1 mutation. Similarly, Yousef et al.22devised a calculated risk model based on factors such as family history,
the presence of affected family members, and the classification of
unilateral or bilateral disease. The study’s findings revealed that the
calculated risk model resulted in enhanced detection of the disease at
earlier stages, thereby providing increased opportunities for ocular
salvage.
3.3. International
partnership
In the study conducted by Qaddoumi et al.29, it
was observed that the twinning strategy facilitated the provision of
high-quality care and early identification of issues that could
potentially harm the patients. Furthermore, the training of skilled
professionals in developing countries was found to reduce the need for
sending professionals abroad for extended periods to enhance their
expertise, thereby reducing associated costs. Additionally, it is
crucial to support the development of a well-established infrastructure
to ensure effective multidisciplinary interventions.
In another study conducted by Wilimas, et al.16,
twinning strategies were implemented in Central America countries in
collaboration with St. Jude Children’s Research Hospital and the ocular
oncology team at the Hamilton Eye Institute (UTHEI). The primary focus
of the program was on early diagnosis and specialist referrals, and as
the program expanded, there was an increase in ocular salvage16.
However, the study also highlighted the need for additional resources
and inputs to support the program.
Jordan was another country that benefited from the twinning program with
the St. Jude Children’s Research Hospital. The study conducted by Yousef
et al. demonstrated improvements in mortality rates, ocular salvage, and
increased autonomy throughout the program, as well as successful
decision-making with the implementation of the telemedicine strategy30.
Another example of an international partnership was between the
Children’s Cancer Institute and St. Jude Children’s Research Hospital,
as described in the article by Al Haddad et al8. This
partnership aimed to address the needs of children with RB in Lebanon.
The study observed an annual increase in admissions of patients with RB;
however, there was a higher number of diagnoses of patients with locally
advanced tumors (stages D and E) and lower rates of ocular salvage for
those with early-stage disease (A, B, and C). Most cases of early-stage
disease were diagnosed in bilateral RB, with the second eye being more
advanced8.
The My Child Matters program, which supports projects in LMICs,
including the African Retinoblastoma Network also demonstrated promising
results. The program covers 55 projects in 42 countries and has
initiatives related to awareness of early diagnosis and training of
professionals in disease management. The program resulted in a reduction
of extraocular disease, increased survival, and ocular preservation15. The
Mali Retinoblastoma Program pioneered the strategies developed, had
substantial results, and was extended to the Democratic Republic of
Congo, Senegal, Côte d’Ivoire, and Madagascar15,31.
Finally, it is crucial to highlight a significant 20-year cooperation
between Garrahan Hospital in Argentina with Memorial Sloan Kettering
Cancer Center in New York, which serves as an exemplary model to be
followed. Throughout the stages of this process, it became evident that
the primary focus was on empowering the country to develop local
capabilities to deliver high-quality patient care. The program,
initiated in 1995, initially concentrated on medical education through
oncologist visits to New York, alongside the development of a protocol
aimed at enhancing ocular preservation and reducing late effects.
Subsequently, with financial support, the program facilitated the
research and treatment protocol for RB in Latin America, leading to the
incorporation of the first center in the region capable of performing
intra-arterial chemotherapy. One notable impact of the program has been
the significant improvement in the survival and ocular preservation of
patients afflicted with the disease, resulting in a three-year
probability of disease-free survival, which rose from 0.84 before
program implementation to 0.9714,32,33.
3.4. Education
In the study conducted by Elfalah et al.25educating medical students about RB resulted in significantly improved
knowledge about the disease, particularly in terms of its severity and
diagnosis, following the intervention25.
Another example of medical education was developed by Hill et al.26 in
Kenya. They designed a comprehensive and interactive workshop on RB
genetics, followed by discussions of patient case studies. The study
revealed that participants felt more confident in discussing genetics
with patients and improving genetic counseling as a result of this
training26. This
strategy is of great importance in the country, as there is evidence
indicating that the second and third children with RB are often
diagnosed at an advanced stage of the disease, highlighting a failure in
genetic counseling. Therefore, this tool shows promise in expanding the
knowledge of healthcare professionals regarding the disease. However,
knowledge assessments conducted one year after the workshop showed low
scores, suggesting the need for frequent reinforcement of knowledge.
Concerning familiar awareness about the disease, Soliman et al.34 and
Nawaiseh et al18demonstrated that increased knowledge of the disease among parents who
had a first affected child led to improved care for subsequent children.
In Honduras, the integration of an RB education program into a
nationwide vaccination campaign resulted in a reduction in the
occurrence of extraocular disease27.
Similar findings were observed in the study of Antonelli et al.24 in
Brazil, where campaigns involved publishing articles in non-medical
magazines, placing billboards at strategic locations in the city,
providing guidance to medical professionals through courses offered at
medical schools, and publishing findings in a medical journal to raise
awareness of the disease, resulted in a reduction of referral time and,
consequently, an increase in the number of detected intraocular tumors.
3.5. Genetic counseling
Joseph et al., 2004, compared the costs of genetic testing and a
clinical strategy based on familiar risk assessment. Significant cost
savings of 3.5 times for the proband and 6.1 times for the family were
observed9.
Thirumalairaj et al.23observed in their study that the genetic analysis of RB is hindered in
developing countries due to the extensive size of the gene and the
presence of multiple dispersed exons. This results in time-consuming and
costly procedures, as demonstrated by the comprehensive DNA sequencing
model developed by Joseph et al. in 200613, which
leads to an average delay of 84 days in obtaining results and subsequent
management, particularly in India. Consequently, Thirumalairaj’s study
emphasizes the need for alternative approaches that can offer faster and
more efficient outcomes. The strategy they developed is based on
prioritizing analysis based on the local frequencies of mutations
reported in the literature and genetic databases23.
3.6. Other studies and
initiatives
Despite not meeting our inclusion criteria (see Appendix II), we came
across other relevant studies that warrant mention. One, the ’One World,
One Vision’ symposium in January 2007, presented a global perspective on
RB assistance disparities, showcasing successful case studies. The
symposium catalyzed advancements in the field and aimed to explore
country-specific RB programs 35. The ’Grupo Mexicano
de Retinoblastoma’ (RtbMex), established in January 2003, educated
health professionals, provided national RB guidelines, and conducted
early diagnosis campaigns 36. The CureAll framework,
supported by the WHO Global Initiative for Childhood Cancer, aims to
improve children’s cancer outcomes globally, prioritizing childhood
cancer through regional, national, and global action plans. The initial
focus is on six main childhood cancer types, including RB, to assess
care landscapes and identify areas for improvement, with the goal of
achieving a minimum 60% survival rate worldwide and reducing overall
suffering 37.
3.7. Assessment of the risk of bias of the included
studies.
Qaddoumi, 200829, the
only cohort study, was considered as of moderate quality. The most
significant issue identified was related to the identification and
strategies for addressing confounding factors. Participants were not
clearly free from the outcome at the beginning of the study, and it was
unclear whether strategies were employed to manage follow-up losses.
Among the twelve cross-sectional studies evaluated, most demonstrated
moderate to high methodological quality3,9,17,20,21,23,25,27,28,30.
The primary issues identified pertained to insufficient detail in the
study sample and a failure to identify strategies for managing
confounding factors. Four case series studies were assessed, with the
majority exhibiting high methodological quality (3 out of 4 studies)18,19,22.
The main problem identified was a lack of clarity regarding the
consecutive inclusion of participants (See Appendix III).
DISCUSSION
In the current systematic review, we aimed to find and evaluate
strategies to improve access to diagnosis and treatment in LMICs.
Retinoblastoma is a tumor which diagnosis and treatment require a
multidisciplinary team that includes an ophthalmologist, oncologist,
pathologist, and specialized geneticist38,39.
Nationally coordinated strategies are important to build this
integration and a chain of care. Public policies need to be guided by
experts’ knowledge and require governmental funds and when possible, it
is important to establish cooperation with high-income countries.
International partnerships can bring the quality of care from
high-income countries closer to children around the world8,30,36,40,41.
This has been achieved through cooperative programs known as twinning,
which involve partnerships between a developing country and a mentoring
institution from a developed country. This collaboration has become
possible due to the advancement of communication technology on a global
scale.
Telemedicine serves as an alternative for extending services to regions
lacking specialists by integrating virtual education, mentoring, and
case discussions. It also provides an opportunity for professionals to
enhance their skills and receive training in their home country.
Concerning strategies of diagnosis, typically, an ophthalmologist can
diagnose RB using indirect ophthalmoscopy with a dilated pupil38.
However, in resource-limited areas, accessing an ophthalmoscope can be
challenging, along with other restrictions such as the need for sedation
and technical expertise for diagnosis. Beyond screening, smartphones are
being tested for fundus examination. Since they are more accessible,
portable, and compatible with teleconsultation, they can be a
cost-effective strategy compared to traditional ophthalmoscopy.
Promising results have been reported in the current literature, as also
reviewed elsewhere42. It is
essential to emphasize that healthcare professionals using these devices
should receive proper instructions for use and interpretation.
Furthermore, expanding the use of the applications for screening to
family members or individuals without medical training can increase the
chances of early diagnosis, but at the same time, may increase testing
anxiety and false positive rates. New studies are needed to evaluate
this possibility before implementation.
In our review, we did not find studies on the screening benefits in the
general population of LMICs, possibly due to the rarity of the disease
and the scarcity of ophthalmology services. Additionally, there is a
lack of secure access to anesthesia and genetic testing in these regions43.
However, it is important to emphasize the relevance of routine ocular
health evaluation early in childhood for the diagnosis of other
conditions, which can also provide an opportunity for the diagnosis of
RB 44.
There are several ways to enhance the diagnosis and access to treatment
for RB through education, whether by guiding the general population or
individuals at higher risk regarding the signs and symptoms of the
disease or by offering guidance to healthcare professionals. Medical
education interventions play a fundamental role because, in numerous
countries, newly trained doctors play a pivotal role in healthcare
facilities, and the general practitioner will likely be the first
healthcare professional to evaluate a child with suspected RB45. For
this reason, a clinician’s ability to identify RB when first assessing a
child and to make a timely referral needs to be trained24. Thus,
it is important to improve teaching strategies, adding information about
the disease and its warning signs to the medical curriculum. There is
evidence that frequent reinforcement of knowledge is necessary, since
important concepts may be lost over time. Continued medical education
can be achieved by promoting periodic educational workshops26.
Furthermore, increasing family awareness about the disease also plays a
fundamental role. By being well-informed about the disease and its
potential risks, parents can take proactive measures to ensure the
well-being of their children and seek appropriate medical attention at
the earliest possible
stage18.
Studies that identified education strategies for the general
population’s awareness of the disease have yielded positive results in
reducing extraocular disease upon diagnosis24,27,
indicating that this approach has the potential to be implemented in
countries where late diagnosis is prevalent.
In patients at higher risk of the disease due to positive family
history, there are two ways to conduct screening: through genetic
counseling and by using risk models calculated based on clinical
assessment. Genetic counseling is important for the control and
management of RB, identifying individuals at increased risk, and guiding
screening and education for healthy lifestyles. RB is primarily caused
by biallelic inactivation of the RB1 gene in a precursor retinal cell,
followed by progressive mutations in other specific genes. Only a small
number of relatives will carry the mutation. However, every child born
to a parent with a germline RB1 mutation has a 50% chance of inheriting
the mutation22.
In most LMICs, widespread access to genetic testing for RB is limited
due to the absence of advanced technology capable of detecting RB1
mutations. Consequently, researchers have suggested calculated risk
models to identify patients at a high risk of RB1 mutations, who could
benefit from targeted screening programs19,22.
However, findings from this review indicated that genetic testing
incurred lower costs when compared to calculated risk models. This can
be explained, because the latter approach often led to unnecessary and
expensive repetitive ophthalmological examinations. Those unnecessary
exams also cause heightened concerns among family members, and increase
the risk of complications related to anesthesia9.
Therefore, implementing a genetic screening model would not only enable
more accurate and cost-effective care for patients with a higher
susceptibility to cancer but also aid family decision-making regarding
future pregnancies.
4.1. Improvement
opportunities
Despite facing numerous challenges, the initiatives identified in this
review highlight important acts that may improve the time to diagnosis
and access to treatment. By implementing these acts collectively, we
have the potential to not only preserve the lives of children but also
enhance their overall quality of life by avoiding treatment late
effects; and preserving functionality and facial aesthetics. Drawing
upon the extracted data, we propose a comprehensive chain of initiatives
(Fig. 2) that we believe can yield improved clinical outcomes for
patients with RB.