Pediatric low-grade glioma (LGG) was included in the World Health Organization (WHO) 2030 Global Initiative for Childhood Cancer (GICC) due to its relatively high incidence and high potential for cure, thereby possibly contributing to increasing the cure rates of all childhood cancers to 60% (1). Successful treatment requires comprehensive multidisciplinary care and multisectoral interventions (2). Pediatric LGG is a group of heterogeneous tumors originating from various neurological structures (3, 4), constituting up to 30%−40% of central nervous system (CNS) tumors in children globally (5). The tumors are classified as Grade I and II according to the WHO classification for their indolent pathophysiology and, in contrast to adult LGG, have low potential for malignant transformation (3, 4, 6). Approximately 75% of pediatric LGG are WHO grade 1 (6). Up to 30% of pediatric LGG can develop in supratentorial structures, 15% in deep midline structures, while < 10% develop in the optic pathway and brainstem, respectively (3, 4, 6), with metastatic disease present in < 5%−7% of patients (3, 4, 6). Neurofibromatosis type 1 and tuberous sclerosis are associated with distinct subtypes of LGG, such as optic pathway gliomas and subependymal giant cell astrocytomas, respectively (7).

Cure is possible following complete surgical resection with long-term overall survival (OS) exceeding 90% (3, 4, 7). However many of these tumors occur in anatomical areas of the brain not amenable to complete resection. Historically, focal radiotherapy was used if resection was incomplete or if progression occurred after three regimens of chemotherapy in a child older than 12 years with a tumor in a location amenable to radiation (8). However use of radiotherapy is controversial despite having better control rates and a shorter duration of treatment than chemotherapy, due to concerns of late sequelae (9). Chemotherapy is now advocated as front-line adjuvant therapy to defer radiotherapy in infants and young children (3, 4, 7). Chemotherapy is also the first-line treatment in gliomas of the optic pathways in an attempt to avoid radiotherapy or potential loss of vision during surgery (3). Chemotherapy protocols range from regimens with limited toxicity and easy accessibility, like vinblastine, vincristine, and carboplatin, to more toxic and harder-to-access options, such as thioguanine, procarbazine, lomustine, and vincristine (3, 4). Most chemotherapy regimens are given over an extended period of 12–18 months (3, 4). With increasing access to molecular diagnostics, the question arises whether targeted therapies or conventional chemotherapy should be administered as first-line chemotherapy (10). The best chance of cure and preservation of function in low- and middle-income countries (LMIC) relies on a multidisciplinary approach, cognizant of the burden of cancer care for families and with judicious combinations of minimally toxic chemotherapy, surgical resection, and radiotherapy when indicated (11).

There is limited data regarding the African pediatric LGG experience. Single-center survival outcomes have been reported from Egypt and Uganda, but they are not representative of their countries (12). Data from African childhood cancer registries show that fewer tumors are diagnosed than in high income countries, with a low proportion of CNS tumors, particularly LGG (13). Most publications from African countries included either adult patients (14, 15) or reported on different molecular alterations (16) and novel imaging modalities (17, 18) in pediatric LGG, but none have documented management approaches or treatment outcomes. An unpublished Master's thesis from the University of Cape Town, South Africa, documented the demographics of 86 patients with pediatric LGG between 2001 and 2017 (19, 20) with an estimated 5-year OS of 86.8% and progression-free survival (PFS) of 42.8% (19). An Egyptian study of 227 patients reported a 3-year OS of 87.3% and event-free survival (EFS) of 65.5% (21). Egypt, Tunisia, and Uganda reported respective outcomes of 87.3% (3-year OS), 78.5% (5-year OS), and 65.0% (3-year OS) (22). Three scoping reviews concluded that only epidemiology and management could be documented and that survival outcomes could not be reported (23) because too few publications contained African outcomes data. Another scoping review on the outcomes of brain tumors in children in Sub-Saharan Africa concluded that data were insufficient and inconsistent. The single-institution reports were not representative of the African situation, and data were limited to specific tumor types (24).

There may be epidemiological differences in CNS tumors in Africa compared to other continents, particularly regarding the distribution of histological subtypes (22). In a review of LGG in Africa, differences in tumor characteristics between adult LGG and pediatric LGG were highlighted (1). One example was a higher reported incidence of brainstem gliomas in children compare to adults in Africa and international literature (6, 22). Barriers like limited healthcare infrastructure and lack of robust registry systems in various African regions prevent comparison of results between African treatment centers while treatment strategies for pediatric LGG in Africa have been diverse and limited by resource constraints (6, 24). The GICC target of 60% refers to all index cancers combined rather than pediatric LGG alone (2, 24). To meet the ambitious targets of the WHO GICC, we questioned what the baseline survival of pediatric LGG was. In this study, we evaluated pediatric oncology units (POUs) as well as patient and tumor characteristics to determine the management resources, epidemiology, and baseline survival outcomes of pediatric LGG in Africa.

This study illustrates the heterogeneous resources, management and outcomes of pediatric LGG in Africa. Africa has fledgling multidisciplinary teams in many centers establishing neuro-oncology treatment approaches and many services that cannot offer all surgery, radiotherapy, or chemotherapy options. Diagnoses are still primarily made on imaging, and survival varies between and within countries. Providing adequate treatment and establishing dedicated long-term follow-up programs are challenging.

A key factor in evaluating tumor outcomes is the capacity to treat patients with neuro-oncological diseases (21). In many African settings, basic pediatric oncology services have not been established or have only recently been established, including the capacity to diagnose and treat children with LGG. Previously, children diagnosed with LGG were managed by neurosurgeons or adult oncology services. In our study, there is a significant heterogeneity in the availability of services. Excluding countries without pediatric oncology services, nearly 13% did not have neurosurgeons and radiotherapy facilities. In countries with radiotherapy services, challenges with maintenance contracts, workforces unaccustomed to treating pediatrics, and regulatory issues affecting access and availability limits optimal delivery of services (31). Nearly half of centers have to transport children to other hospitals to obtain radiotherapy services. Radiotherapy machines are inequitably distributed in the public and private sectors where private hospitals can only be accessed by self-funded patients or those who have private medical aid (31). In Africa, there is one radiotherapy center per 2.24 million children under the age of 15 years, one neurosurgeon per 304,685 children, and one pediatric neuro-oncology specialist for more than 150 million children. The majority of these services are concentrated in 7% of African countries. Many neuro-surgical and radiotherapy services are overburdened and primarily treat adult patients (30). In comparison, in the United States of America, there is one radiotherapy center per 28,000 children under the age of 15 years, one neurosurgeon per 15,468 children, and one pediatric neuro-oncology specialist per 373,330 children (25, 26).

In our study, the diagnosis of LGG was biopsy-confirmed in 65% of the cases, mainly in the three countries where neurosurgical services are concentrated (Egypt, South Africa, and Morocco). Morocco, Mali and several POUs in South Africa diagnosed 60% or more of pediatric LGG cases on imaging, which we postulate represents the greater African region in countries with limited resources. In hospitals where neurosurgeons deem tumors unresectable and refer patients to other centers, the number of image-diagnosed tumors is falsely elevated, and the primary tumor sites do not follow global trends (32). In the absence of an accurate tissue diagnosis, the optimal use of chemotherapy and targeted therapy options is limited. The matter is further complicated by late presentation and tumors that are deemed unresectable, which is often the case in Africa (33).

The most common primary site in this cohort was the brainstem compared to the cerebellum, optic tract and cerebrum in global reports (33). The high number of brainstem tumors in two South African centers and in Morocco skewed the overall results. The remaining countries reported primary tumors in the cerebellum, optic pathways and cerebrum, aligning with reports from the literature (8). One possible reason could be that diffuse midline gliomas may have been included in the sample in centers where diagnoses were based on imaging alone (34). The second possible reason is that fully resected tumors were not referred by neurosurgery in these centers. We do not believe that this represents a different demography of LGG by site in Africa.

Cases without a known histology, who was either not biopsied of diagnosed on radiological imaging, had a far inferior 5-year OS of 62.7% compared to cases with known histological results. Pilocytic astrocytoma was the most commonly reported histology in the entire sample, as well as in some individual countries, which is in line with global reports (34). There was a disproportionately high percentage of Grade II tumors in the African cohort. The majority (75%-80%) of pediatric LGG are WHO Grade I, compared to 65% in our study. A possible reason for this may be the accuracy of reports by pathologists, reflecting greater experience in diagnosing adult pathology rather than pediatric pathology. In our sample 13.6% of patients were older than 10 years and it may well be that some centers were reporting on an older group of pediatric LGG patients, resulting in a higher percentage of Grade II pathology. In our study obtaining a histological diagnosis was of prognostic significance. The limited pathology services in Africa frequently do not have access to central review services to verify diagnoses.

In our study the WHO 2016 brain tumor classification was ideal because the International Classification of Childhood Cancer (ICCC-3) adopts more detailed categories including categories based on molecular results. The ICCC-3 however does not consider clinical tumor behavior which is a hallmark of the WHO grading system. Therefore, the ICCC-3 does not contain distinct entities for astrocytoma, limiting a separate analysis of low-grade and high-grade astrocytic tumors (35). Our study showed that there was a difference in survival between the astrocytoma subtypes where Pilocytic astrocytoma had the best overall survival. Girardi et al. incorporated tumor grade into ICCC-3 to overcome the limitations of the ICCC-3 and account for differences in cancer registration practices globally. This allowed them to report on low-grade astrocytoma for the first time. Although they reported a 5-year OS between 78%−97%, the data set consisted mostly of well-resourced settings. Our study reported a comparative 5-year OS of 87%−97% for grade I and II histology, but investing in molecular diagnostics of low-grade glioma may improve prognostication, identify individual targetable tumor characteristics and limit possible harmful treatments (34).

We postulate that referral patterns could influence the ratio of operable and inoperable tumors managed independently by neurosurgeons and pediatric oncologists. Completely resected LGGs may never be seen or managed by pediatric oncologists, while tumors such as optic gliomas that are mainly treated by chemotherapy are commonly managed by ophthalmologists and pediatric oncologists (32, 36). Only 3.6% of the African sample had metastatic disease. We postulate that inadequate diagnostic services such as lack of MRI in some countries may contribute to this low rate (37). Morocco was the only country with a similar metastatic disease prevalence as the 7%−10% global prevalence (3).

In the entire cohort, neurofibromatosis type I was reported in 6.8% of cases, and tuberous sclerosis in < 1%. This is generally much lower than the globally reported rates (38, 39). Since African patients are poorly represented in most global studies, it is possible that the prevalence of these syndromes is less, however another possible explanation could be missed diagnoses of these predisposition syndromes due to healthcare professionals, with a lack of awareness, overlooking the clinical stigmata of these syndromes. Respondents from Tunisia reported neurofibromatosis type I in 19% of patients, which is comparable to the 15%−20% global prevalence (38, 39).

Pediatric LGG has a highly favorable OS, exceeding 90% in well-resourced settings (40). Based on the SEER registry data, 20-year OS in high-income countries reached between 87%−92% (6). In our study, Egypt and Tunisia achieved similar results, with South Africa just falling short of 90%. Although Morocco and Uganda did not achieve similar survival rates, both countries achieved the GICC goal of 60% and compared favorably with the 69.2% 5-year OS obtained by other LMICs such as Thailand and the Caribbean islands (19). In well-resourced settings, nearly 40% of pediatric patients with LGG treated with chemotherapy will have disease progression or relapse (19). In our study, progression and relapse accounted for 28.1% of all events but varied considerably between countries, with Morocco reporting progression in half of patients and relapse in 6.7%. Tunisia and Uganda did not document any progressions or relapses, possibly due to death. Another contributing factor could be the combination or sequence of treatment: radiotherapy has higher control rates exceeding 80%. Vincristine combined with carboplatin provides a 2-year PFS rate between 40%−50%, sometimes reaching higher rates in younger patients. Vinblastine alone offers comparable PFS rates but with fewer side effects, making it a strong alternative in cases where carboplatin isn't well-tolerated (41). In the six African countries included in our study, 22.1% of patients were lost to follow-up, with the percentage of patients reaching 50% in Uganda and 61.5% in Mali. These factors contribute to poor outcomes and may be due to abandonment of long treatment protocols especially when centers are far away from patient's home, or due to the absence of long-term follow-up options in many African countries (40).

In Africa, underdiagnosis and poor referral rates are major challenges for all patients but particularly brain tumor patients, and the data in our study reflect only the survival rates of patients who were diagnosed. When considering global data that that 25% of childhood cancers are pediatric brain tumors, of which 40% are LGGs, then based on a conservative age-standardized rate (ASR) for childhood cancer of 100 per million children under 15 years annually, there should be ~10 diagnoses of LGGs per million children per year. Clearly, the numbers reflected in this report are considerably lower than expected. South Africa averaged 25 diagnoses per year. In 2013 there were ~15 million children under 15 years in South Africa (42). Based on the population the South African number of diagnoses should equate to at least 240 cases of LGG annually.

In order to improve care for LGG in Africa, more resources would need to be invested into neurosurgical care with dedicated operating time for neuro-oncology, independent from trauma and infectious cases (43), and diagnostics such as MRI and pathology services. Neurosurgery services can achieve a dual purpose of achieving complete resections and obtaining tissue for pathology and potential molecular diagnostics (34, 36). The co-management of neuro-oncology patients by an organized MDT would limit referral bias, and possibly increase biopsy rates. Not only would an increase in biopsy rates promote more accurate diagnoses, but increase molecular diagnoses (44). Due to lack of data, it is not currently known whether the molecular targets reported in studies in the global north, reflect the African situation and genetics, since studies in this area are lacking. Furthermore, for non-resectable tumors, since chemotherapy rarely leads to complete remission and relapses are frequent, pediatric LGG becomes a chronic condition requiring multiple regimens at different times. It is possible that radiotherapy provided earlier in the course of the disease, especially for older children, may decrease the burden of care for families and decrease abandonment, as well as providing a shorter duration of treatment and better local control. Late effects from radiotherapy are a risk and are well described, however this strategy is particularly worth considering when there is risk to function, such as vision, or when abandonment is considered a risk (11).

Promoting comprehensive registration of neuro-oncological cases that includes clinical data would enable a more accurate assessment of the pediatric LGG burden and a more accurate evaluation of tumor characteristics compared to international reports. Development of an African pediatric oncology research platform or network would also assist in development and standardization of protocols, treatment guidelines and in publication of relevant local data to inform future studies and clinical approaches (45). Such a network should be established to foster collaboration, and improve research capacity, which may benefit not only LGG but all pediatric cancers (46). The most important is to conduct more prospective studies and collecting clinical and outcome data in real-time.

This data would in turn support effective resource planning, including chemotherapy procurement and the development of radiotherapy services (7). Such planning may be hindered by patients seeking cross-border care (47). Patients not treated in their home countries have a higher chance of abandoning treatment, contributing to poor survival outcomes (47). This is one possible reason for the higher loss-to-follow-up and death rates in South Africa and Uganda, who serve patients from neighboring countries without or limited services.

Establishing strong long-term follow-up programs and rehabilitation services could reduce patient loss to follow-up and improve daily functioning for those with oncological sequelae, ideally through an MDT approach (44, 48). This should include ophthalmology consultations for optic tract gliomas to preserve vision or prevent further vision loss.

The retrospective nature of this study contributed to limitations in data analysis and interpretation. LGG is an indolent tumor, so patients who were lost to follow-up may have lived longer than was censored in this study, creating a falsely lower EFS and OS. This may also have falsely decreased the number of patients at risk when evaluating survival curves. Events were not always dated, and some were collected retrospectively, with a potential recall bias. The majority of countries were not represented by the total number of POUs, mainly because these countries did not have established pediatric oncology programs during the study period and so this data is likely to reflects the centers with at least some resources and may not reflect the continent as a whole. All POUs from each country did not participate, therefore data are not representative of a whole country.

The use of hospital-based survival data in this study introduces potential biases compared to population-based data, due to differences in patient selection and access to health care. Our hospital-based survival data may provide a skewed view of pediatric LGG in each country that may not be generalizable to each national population or the African continent as a whole. Hospital data may represent outcomes influenced by selection, referral, and treatment biases. While hospital data is useful for evaluating specific treatments or settings, and in this study provides novel data, population-based data provide a more accurate and generalizable survival outcomes (49, 50).

Despite these limitations, the data provided from six African countries spanning low-, lower-middle- and upper-middle-income countries contribute to a greater understanding of the available resources and the resource constraints in the region. The survey respondents from 41 countries represented both the state and private sectors, and included pediatric oncologists, neurosurgeons and radiation oncologists, providing a broad perspective on the management of children with LGG across the continent. We have provided as comprehensive an overview as possible of the resources available to treat LGG based on the perspectives of clinicians working at the ground level. The findings on the numbers of patients with specific histological subtypes contribute to a better understanding of tumor characteristics in the African context and establish a base-line for future evaluations in achieving the goals set out by the WHO GICC.

This study highlights the significant deficits and disparities in resources, management and outcomes for pediatric LGG across six African countries. While some countries have begun to establish multidisciplinary teams for neuro-oncology, many still face limitations in surgery, radiotherapy, and chemotherapy options. The reliance on imaging for diagnosis, coupled with a lack of adequate treatment and long-term follow-up programs, pose substantial challenges in improving patient outcomes. Despite some successes, such as the high OS rates in Egypt and Tunisia, many children continue to be lost to follow-up, adversely affecting survival data. The stark contrast in resources and access to care when compared to high-income countries further emphasizes the urgent need for investment in pediatric oncology services in under-resourced settings. Strengthening neurosurgical capabilities and fostering multidisciplinary collaboration could improve diagnostic accuracy and treatment efficacy for pediatric LGG. Additionally, comprehensive data registration and resource planning are crucial to address the pediatric cancer burden in Africa. Establishing robust follow-up programs will help track patient outcomes and enhance the quality of care. Finally, creating pediatric oncology research networks could facilitate the development of standardized treatment protocols, ultimately benefiting all pediatric cancer patients across the continent and other similar resource settings globally. Addressing these issues holistically is essential to advance the care and outcomes for children with LGG in Africa.