Retinoblastoma (RB) is the most common malignant tumor in children, accounting for 2% of all pediatric cancers (1), although it is still considered a rare disease (2). The disease mainly occurs in children under the age of five, with approximately 90% of cases diagnosed before the age of three (3). Its incidence is about 1 case per 15,000 to 18,000 babies born alive, and no significant differences have been observed between different races or genders (4). RB is an invasive eye cancer that can lead to death within 1 to 2 years if not treated (5). In addition, delayed or inadequate treatment may lead to vision loss, which seriously affects the patient’s quality of life (6).

In May 2025, the World Health Assembly adopted a resolution on rare diseases, emphasizing the burden faced by patients with rare diseases, especially children, and the importance of addressing the issue of health equity (7, 8). However, due to the uneven distribution of medical resources (9, 10), there is a significant variation in the global burden of RB. In high-income countries, there are advanced treatment options, including techniques like intravitreal or intra-arterial chemo (11), and the overall 5-year survival rate can reach 94–95% (12). A small number of early cases can preserve eyeballs and vision through local treatment (13). Conversely, in low and middle income countries, insufficient screening and delayed diagnosis frequently result in patients receiving treatment at advanced stages, leading to a poor prognosis and an approximate survival rate of 50% (14).

Following established disease burden research frameworks (15, 16), this study uses data from the Global Disease Burden (GBD) database to systematically analyze the incidence, prevalence, disability-adjusted life years (DALYs), and death of RB from 1990 to 2021. Building on previous studies, we further examine cross-national inequalities in RB burden and explore the effect of public health policies and project disease burden trends to 2035.

Although there are differences in RB incidence, prevalence, DALYs, and death from country to country, the overall global RB burden has shown a trend of increasing and then gradually decreasing between 1990 and 2021. Projections suggest that although the number of incidence and prevalence is expected to decline slightly every year between 2022 and 2035, the number of DALYs and deaths will continue to rise. This suggests that the control and management of RB will remain a focus of global public health efforts in the coming decades. Transnational inequality analysis shows that low-SDI countries bear a disproportionately higher burden of rare diseases, and the relative inequality associated with SDI has intensified over time. In terms of rare disease policy formulation, countries with high and middle SDI have established more complete systems, while countries with low SDI still have limited scope and progress.

Although RB is a rare disease with a relatively low incidence and prevalence, its burden of disease is still quite heavy. For example, in 2021, the total DALYs reached 279,066 (95% confidence interval: 159,656–365,150). There are significant differences between different regions and countries, and sub-Saharan East Africa ranks first in all four indicators. India reported the highest number of incidence and deaths, while China has the highest prevalence and number of DALYs. The Republic of Malawi has the largest ASDR, whereas Tokelau has the largest ASIR, ASR-DALY, and ASPR. Regions with a relatively heavy burden of these diseases require more attention and targeted interventions. Analysis of SDI strata indicates that nations with low SDI experience a greater disease burden in terms of quantity. As far as ASR is concerned, low SDI deaths and DALYs are the highest, highlighting significant health inequalities associated with RB, which may be attributed to factors such as war (27), armed conflict, and economic crises (28, 29).

From an overall temporal perspective, global RB incidence and prevalence increased, whereas ASR-DALY and ASDR declined. With the exception of Sub-Saharan Africa, all other regions showed a decline in ASR-DALY, and ASDR decreased across all regions, with Central Europe showing the most significant downward trends. Furthermore, ASR-DALY decreased in 180 countries (88.23%), and ASDR decreased in 181 countries (88.73%). These widespread declines are closely linked to advances in RB diagnosis and treatment, as well as improvements in rare disease policy. Between 1990 and 2021, the widespread application of intravenous chemotherapy (30, 31), intra-arterial chemotherapy, intravitreal chemotherapy, and combined local radiotherapy significantly improved local control and eye preservation rates, leading to marked reductions in death and years lived with disability (32, 33). Declines in mortality and DALYs reflect not only medical progress but also the critical role of neonatal screening, referral systems, and treatment infrastructure established in recent years (34). Particularly in Central Europe, most countries gradually introduced neonatal red reflex or “leukocoria” screening in the late 20th and early 21st centuries (35), incorporating it into national child health programs. Combined with rare ocular tumor registries and multinational clinical research networks, these measures enabled standardized clinical guidelines and knowledge sharing (36). In addition, universal health insurance coverage reduced treatment abandonment due to financial barriers (37), thereby improving patient outcomes at a population level. By contrast, resource-limited regions such as Sub-Saharan Africa continue to experience high ASR-DALY/ASDR and poorer survival outcomes due to delayed diagnosis and limited treatment access, underscoring substantial policy and resource gaps (38).

Segmented trend analysis reveals that the growth rates of ASIR and ASPR varied from 1990 to 2003, 2003–2015, and 2015–2019, with the growth trend accelerating over time. Due to the genetic characteristics of RB, this trend may reflect the improvement of diagnostic and screening capabilities and the enhancement of public awareness, thus increasing the case detection rate rather than the real increase in the risk of disease (39). From 2019 to 2021, ASIR and ASPR decreased slightly, which may be due to external factors such as disruptions in healthcare services, delayed diagnosis, and underreporting during the COVID-19 pandemic affecting cancer detection and surveillance worldwide (40). In contrast, ASR-DALY and ASDR are generally on a downward trend, but their change patterns are more complex. Both indicators rose slightly from 2002 to 2014 but declined sharply after 2014, accelerating from 2019 to 2021. These changes are closely related to the adoption of multidisciplinary management models and the emergence of new local treatments, particularly intra-arterial chemotherapy and intravitreal chemotherapy, which have substantially improved survival outcomes as well as eye- and vision-preservation rates, thus effectively reducing the burden of disease caused by death and disability (33). Overall, the period between 1990 and the early 2000s was characterized by inadequate diagnostic and curative capacity, resulting in fluctuations or increases in the disease burden. In contrast, the past decade has shown a continuous downward trend, mainly due to advances in healthcare levels and resources. These changes highlight the importance of policies such as promoting early screening, simplifying referral processes, and centralized treatment.

Previous studies, using the Bayesian age-period-cohort (BAPC) model, have suggested that ASIR, ASPR, and ASR-DALY would show modest increases from 1990 to 2021, while ASDR may decline slightly (15). Extending this evidence, this study projected the number of incidence, prevalence, DALYs, and deaths for global RB through 2035. The results indicate that while the numbers of incidence and prevalence of RB may gradually decline, the numbers of DALYs and deaths are projected to continue increasing, highlighting the persistent global health burden of the disease. This differs somewhat from previous studies on the increase in ASIR and ASPR, primarily due to demographic changes, as the high-risk group—namely children—is expected to decrease due to persistently low fertility rates. Furthermore, this discrepancy suggests that future related projection research should focus not only on predicting ASR but also on predicting its number.

Crude rates can more directly reflect the actual burden of populations in different countries or regions (41). The inequality analysis using the crude DALYs rate showed that low SDI countries bear a more serious burden of rare diseases. Between 1990 and 2021, absolute inequality has narrowed, indicating that the global burden of rare diseases has generally improved, and the absolute gap between countries with high SDI and countries with low SDI has reduced. However, relative inequality has increased, because the improvement of countries with high SDI is faster than that of countries with low SDI, thus widening the proportional difference. This aligns with Li et al. (42) who similarly reported widening relative inequalities in ASR-DALY. Based on the comparison of rare disease policies, our research results show that high-income countries have launched rare disease policies earlier and established perfect screening, diagnosis, treatment capabilities and health care security systems. Middle-income countries are quickly following suit, while low-income countries are still lagging behind and independent. These studies suggest that health inequalities are partly due to inadequate policy coverage.

The use of novel therapeutic agents (e.g., topotecan) (43) and the optimization of treatment strategies [e.g., avoiding decentralized and overly aggressive treatment approaches (44)] have played a significant role in improving survival outcomes for patients with RB. However, existing research results show that RB patients have reduced survival rates. Research shows that medical progress must be combined with institutional and policy support to translate into practical patient benefits (45). The results of this study’s analysis of the effects of policy on disease burden indicate a clear association between policy development and trends in the burden of RB. Further integrating the findings of this study on regional trends in the burden of RB, we observed that from 1990 to 2021, ASIR and ASPR in high and high-middle SDI strata showed an increasing trend, while ASR-DALY and ASDR declined most markedly. This aligns with the policies of systematic neonatal screening, centralized treatment centers, national registration systems, and rare disease medical insurance policies in high-income countries, which enhance the timeliness and accessibility of medical services, ultimately improving patient prognosis. In contrast, the World Health Assembly resolution on rare diseases emphasized that inadequate screening items and uneven diagnostic resources may be the leading causes of delayed diagnosis (7, 8). Between 1990 and 2021, the ASIR and ASPR of other SDIs exhibited an upward trend, whereas the ASIR and ASPR of low SDI showed a downward trend. The decline in ASR-DALY and ASDR with low SDI is relatively small, which may reflect significant policy deficiencies, leading to limited screening, reduced treatment opportunities, and low affordability for medical expenses, thus exacerbating the structural root causes of health inequality (46). Therefore, the future RB prevention and control strategy should not only focus on promoting medical intervention, but also strengthen and implement public health policies. Systematic policy development and global collaboration (47, 48) are critical to narrowing regional disparities and sustaining a sustained decline in the global RB disease burden. Significantly, such policy improvements can not only improve the survival rate and quality of life of RB patients but also provide valuable experience for managing other rare diseases, thus helping to enhance the well-being of patients with rare diseases worldwide and promote health equity.

This study also has several limitations. First, it is based on the GBD database and may be affected by uncertainties and underreporting. Second, further rigorous causal inference studies on policy effects are needed in the future.

In summary, although RB is a rare tumor, it continues to impose a substantial global disease burden with pronounced regional disparities. From 1990 to 2021, incidence and prevalence exhibited an overall upward trend, while death and DALYs rates declined, suggesting improvements in diagnostic and therapeutic capacity. However, projection trends indicate that the number of DALYs and deaths will continue to rise in the coming decades, underscoring that RB prevention and control remain a critical global public health challenge. Notably, regions such as Central Europe have achieved significant reductions in disease burden through comprehensive policy frameworks and standardized management, highlighting the pivotal role of policy interventions and systemic measures in mitigating disease burden. In contrast, RB patients in low SDI countries continue to face disproportionate burdens due to limited resources and inadequate policy support, with health inequities remaining particularly acute. Moving forward, it is imperative to strengthen policy development related to rare diseases globally, especially in underdeveloped regions. Such policies and measures would narrow regional gaps, alleviate disease burden, and provide valuable lessons for the management of other rare diseases and the advancement of health equity.