Inequity in paediatric oncology in South Africa – The neuroblastoma case study

health of children is a national priority, it is therefore necessary to sensitise policymakers to the needs of children with cancer. in to 60 % by


Introduction
When the Republic of South Africa ratified the United Nations (UN) Convention on the Rights of the Child in 1995 and subsequently enshrined children's rights to health care in 1996 in its Constitution, the country committed to provide children with equitable health care. 1 Section 27 of the South African Constitution affords children access to health care as citizens of South Africa, and they have the right to basic healthcare services under section 28. 2 These two rights in the Bill of Rights facilitate the access to health care. 1 Children may lodge a claim against the state for the provision of healthcare services when their parents are unable to afford healthcare services. 1 The South African Constitution states that the state should also take reasonable action to comply with the provision of health care. 2,3 It does not fully define the nature of the healthcare services beyond emergency medical care and basic health services, which may be interpreted as primary health care or preventative health care. 4 Section 28 of the Bill of Rights stipulates that children have a right to basic nutrition, shelter, basic healthcare services and social services. 2 The Constitution protects the right to life, and as oncological diseases are life-threatening, oncological health care should be defined as an essential healthcare service. 2 The government should provide health care in accordance with its available resources but may not allocate a disproportionate share of the budget to one sector of health care, and thereby create shortages for other healthcare services. 4 To be able to prioritise healthcare services, major public health needs should be identified for state funding. 3 Childhood cancer is one of the leading causes of mortality in high-income countries. 5 Yet, 90% of the world's paediatric population lives in low-and middle-income countries (LMICs), where 84% of the global childhood cancer burden occurs. 6 This is the estimate, taking into account that there may be a 10%-45% underestimation of childhood cancer incidences, partially because of the lack of cancer registries and poor access to oncological health care. 6 In South Africa, the number of underdiagnosed patients is estimated to be in the same region as in other LMICs. 7 As section 37 of the Constitution states that emergency health care is a right, children with cancer should have the right to life-saving treatment regardless of where in South Africa they live.
According to the World Health Organization (WHO), the definition of access to medical care pertains to physical access, economic access and information about health care. 8 Physical access is defined as that 'health facilities, goods and services must be within safe physical reach for all sections of the population, especially vulnerable or marginalised groups'. Economic accessibility is defined as: [A] measure of people's ability to pay for services without financial hardship. It takes into account not only the price of the health services but also indirect and opportunity costs (e.g. the costs of transportation to and from facilities and of taking time away from work). 8 Access consists of services that can provide the needed care, timeliness of receiving the care when it is recognised, a workforce that can provide the care and coverage or the means to access health care. 9,10 We aimed to evaluate access to equitable paediatric oncology services for the treatment of neuroblastoma (NB), a childhood malignancy, in line with the stipulations of the South African Constitution. The three issues for evaluation were equal access to NB care, equal paediatric oncology services and other equal resources needed for childhood cancer diagnosis and treatment. Furthermore, we wished to determine whether the state had taken reasonable action for NB health care towards achieving the aim of the WHO International Society for Paediatric Oncology (SIOP) to improve childhood cancer survival in LMICs to 60% by 2030. 11

Materials and methods
Electronic literature reviews were conducted on the constitutional, legal and ethical issues pertaining to equality of medical care and access to medical care in the South African setting. Searches were conducted on PubMed, Google Scholar, WorldCat and JSTOR with search terms 'access to medical care', 'rights to medical care', 'equal medical care', 'cancer', 'children' and 'South Africa'. The reference lists of publications were screened to supplement the search results.

Setting
South Africa consists of nine provinces, subdivided into nearly 300 districts. 12,13 The health care in the country is administrated by three systems: The national, provincial and the district health systems. 12,13 The National Department of Health (DoH) coordinates with the public and private healthcare services at national, provincial and district levels, whilst administrative, financial and supportive services are regulated at the provincial and district levels. 14 In 2012, South Africa's DoH initiated a National Health Insurance (NHI) plan as an efficient, equitable and sustainable health system. 15 This social health insurance plan was developed to make health care more accessible and affordable for citizens who have no other way of funding such care individually, but it has not yet been implemented because of the funding still being sourced. 15

Data
Based on the South African Children's Cancer study group's retrospective study of the management and outcomes of NB between 2000 and 2014, we evaluated the burden of three prognostic factors, age at diagnosis, stage and risk stratification, associated with NB in each province of South Africa. Furthermore, we evaluated the human resources and paediatric oncology services during this period by comparing the provincial paediatric oncology services that manage children diagnosed with NB. Paediatric oncology services were evaluated according to the SIOP resource settings for NB diagnosis, staging and risk stratification (Appendix 1). 16 A multi-disciplinary team including subspecialist doctors, nurses and laboratory staff was involved in managing childhood malignancies. 16 We surveyed only former and current paediatric oncologists and paediatric surgeons attached to paediatric oncology services to establish the number of physicians working in paediatric oncology associated with individual paediatric oncology units (POUs), where possible, annual departmental hospital reports were cross-referenced for confirmation. To evaluate access to POUs, three random furthest points with a named settlement in each province were chosen. The distance and travel duration between the settlement and the nearest paediatric POU were determined with Google Maps®. 17

Statistical analysis
Data from a retrospective study on the management and outcomes of South African children diagnosed with NB between 2000 and 2014 were used to determine the overall survival (OS) and associated 95% confidence intervals (CI) for each province. These data were described using Kaplan Meier curves with differences evaluated using log rank tests. The Kaplan Meier curves were assessed using IBM SPSS Version 25 (IBM Corporation, USA) statistical software. 18 For all calculations, a p-value less than 0.05 was considered significant.

Geographic characteristics
Nearly a third (n = 124, 32.2%) of the 385 children diagnosed with NB in South Africa between 2000 and 2014 ( Figure 1) were treated in the Western Cape (WC), 114 (29.6%) were treated in Gauteng (GP) and 62 (16.1%) in the Free State (FS), followed by KwaZulu-Natal (KZN) (n = 55, 14.3%) and the Eastern Cape (EC) (n = 30, 7.8%). Data from Limpopo (LP) were not included in this study because permission to access data could not be obtained.

Age at diagnosis
The median age at diagnosis for the total cohort was 39.

Tumour staging at diagnosis
Stage 4 or metastatic disease was the most prevalent (n = 273, 70.9%) ( Table 3). All provinces predominantly

Risk stratification at diagnosis
High-risk (HR) disease was the most prevalent (n = 294, 76.4%) ( Table 5). All provinces predominantly had HR     (Table 7) GP was the province with the smallest surface area (

National access to neuroblastoma care
Based on geographical distances in South Africa (Figure 1), road access and travelling time to cover the distances as well as transport options for patients -timeliness (Table 7) of access to care were not equal. The Constitution guarantees the facilitation of gaining access to health care. 2 Both the 2009 public inquiry into access to healthcare services and the 2017 Foundation for Human Rights paper on monitoring the right of access to health care in South Africa documented ongoing limited resources and access to both patient transport services and emergency transport. 19,20 The greatest burden fell on children and patients from rural areas who needed inter-provincial transfers. 21,22 Not only did patients in MP, NC and NW not have NB medical services in their own provinces, but there was also limited transport for them to access NB care in other provinces.
Anti-neoplastic agents are important for the treatment of NB. 21 Until 2016, approximately 20 basic and essential antineoplastic agents listed in the WHO essential anti-cancer medications had not been listed on the South African Essential Drugs list. 23 Subsequent Essential Medicines Formularies for Tertiary and Quaternary Care did also not include antineoplastic agents as needed for childhood malignancies. 24,25   A multi-disciplinary team is crucial for the management of NB. The disciplines should include paediatric oncologists, paediatric surgeons, radio-oncologists, radiologists, pathologists, nuclear physicians, bone marrow transplant specialists and supportive care services (blood transfusion services, pharmacy services and dieticians), but of special importance is the nursing staff. 16 If the provinces without paediatric oncology services are not taken into account, GP and WC that had the smallest percentage of children under the age of 15 years (respectively, 24.5% and 26.7%), 26 had the best access to health care between 2000 and 2014, with more paediatric oncologists and paediatric surgeons than any of the other provinces (Tables 8 and 9). Even in the context of this disproportionate distribution of human resources, both the 2009 public inquiry and the 2017 Foundation for Human Rights working paper concluded that there was a shortage of skilled healthcare workers, especially nursing staff, in the public sector and that their numbers were still decreasing. 20,27 Equality of the paediatric oncology services delivering neuroblastoma care The management of NB includes chemotherapy, surgery and radiotherapy. 28,29 In localised NB, trimodal therapy is curative, but in metastatic NB or NB with adverse biology, trimodal therapy leads to a survival of only 20%. 16,28,29 An autologous bone marrow transplant preceded by ablative bone marrow therapy, immunotherapy and maturation therapy with cisretinoic acid is vital, but was not available in South Africa during this time. 28,29 Between 2000 and 2014, the POUs in South Africa delivered different levels of neuroblastoma management based on the available healthcare resources in each hospital ( The existence of a facility does not, however, guarantee access to it, or that access to it would be gained. 30 In South Africa, when a paediatric surgeon was not available, a general surgeon performed surgical interventions when diagnosing NB with the aid of a biopsy or operated on the primary tumour. Radiotherapy services did not routinely reserve time for paediatric NB patients who needed irradiation. Moreover, in both these situations, children had to compete not only for resources, but also with the adult population to gain access to life-saving services. 31 High-risk NB had poor outcomes, high relapse rates and a high need for resources. 16 When the justice principle is applied for access to limited surgical, radiotherapy and transplantation services, these characteristics might work against patients with NB because of competition for resources rather allocated to burden of disease of adult noncommunicable diseases. This situation was compounded when paediatric oncology services competed with adult services. 31

The right to life -A right to be treated for neuroblastoma and treatment-related complications
Worldwide localised NB without adverse biology (low-and intermediate-risk disease) had 5-year OS rates of upwards from 80%. 16,28,29 In metastatic NB or NB with adverse biology (high-risk disease) with multi-modal therapy, including autologous stem cell transplant (ASCT) and immunotherapy, the 5-year OS rates were 60%. 15,27,28 In South Africa, with limited access to ASCT and no immunotherapy, the 5-year OS was approximately 20%. 32 The inequitable distribution of NB management-related resources had an impact on the survival, as the two provinces GP and WC, with a full range of healthcare services, had survival rates above the national average of 22.6% (Table 11). KZN did not have a paediatric oncologist to complement the multi-disciplinary team until 2013 (the end of the study period) and had the lowest survival rate of 5.5% (Figure 2). The effect of inequitable access to NB care could be demonstrated by comparing Pretoria and Soweto with Johannesburg. All are Setting 3 paediatric oncology services, but during the study period, Johannesburg received referrals from Southern GP (roughly 9088 km 2 ) and Soweto received referrals from Southern GP and NW (113 970 km 2 ), whilst Pretoria received referrals from Northern GP, MP and LP (until a POU was opened in Ga-Rankuwa) (roughly 211 337 km 2 ), which were significantly further away from the child's residence. This potentially may have led to late diagnoses and delays in referrals to central hospitals, contributing to a poorer 10-year

Chronic care or long-term life-saving health care
Since 2009, non-communicable diseases in South Africa, including cancer, have contributed the greatest percentage to the burden of disease in the country. 20 It is estimated that one in every five children up to late adolescence in South Africa was in need of long-term life-saving health care or chronic health care because of a previously life-limiting condition, such as with cancer and palliative care. 33 Yet, when the right to life-saving health care on the basis of a chronic condition was challenged in the constitutional court in the Soobramoney case: Soobramoney vs Minister of Health (KwaZulu-Natal) 1998 (1) SA 765 (CC), the court decided that emergency medical treatment did not include chronic treatment. 34 Therefore, ASCT, which contributes a 15%-20% increase in survival in high-risk NB, 16 is not guaranteed as a right to life under the determination of the constitutional court and neither is any part of paediatric oncology care apart from acute life-threatening emergencies such as acute emergencies at diagnosis which include spinal cord compression symptoms and respiratory distress or neutropaenic fever, heart failure caused by chemotherapy-induced anaemia, bleeding because of thrombocytopaenia. 16

Discussion
Neuroblastoma is a childhood malignancy of the neuroendocrine system, contributing 15% of the total deaths in the paediatric oncology population and only 20% of cases survive for longer than 5 years because of late diagnosis and advanced disease in LMICs. 16,35 The 5-year OS rate in South Africa is 27%, whilst the country has a youthful population, with 34.3% of the population being under the age of 15 years. 21,32 Since the start of democracy in 1994, the DoH has developed beneficial programmes for children, which include the national integrated nutrition programme, the programme for the prevention of maternal HIV to child transmission and the early childhood development and basic education programmes. 32 Free basic child healthcare services for children under the age of 5 years are included in these programmes. A bias in favour of younger children and preventative medicine is evident in all these programmes, with the health needs of children with chronic diseases, older children and adolescents being neglected. 36 26 Yet both provinces had the most resources to manage NB. Mpumalanga, with 8.1% of the children under 15 years, and Limpopo with 11.6%, were the two provinces with the least resources and had a fifth of the children in the country. 26 In 2020, Mpumalanga still had no paediatric oncology services and referred children with NB to Pretoria.
The WHO-SIOP joint goal is to achieve a 60% childhood cancer cure rate worldwide. 11, 36 The South African government lacked the stewardship to implement National Core Standards, including programmes related to cancer care, in the country. 37 Most cancer-related programmes were adultcentred. 38 The Ministerial Advisory Committee on the Prevention and Control of Cancer (MACC) was established in 2013 and the Strategic Plan for the Prevention and Control of Non-Communicable Diseases ran from 2013 to 2017, but childhood cancer was not a priority, as the focus was again on prevention rather than cure, which is not applicable in childhood cancer. 38 In the 2017-2022 National Cancer Strategic Framework for South Africa, the commitment to paediatric cancers was not stated beyond a paragraph on childhood cancer epidemiology. 39 Therefore, although NB has a peak incidence of cancer in children between the ages of 2 years and 5 years, 16 the paediatric programmes' bias in favour of younger children does not include noncommunicable disease management. Access to treatment in the private healthcare setting for childhood cancers, thus for NB, is better than in the public setting. The two-tiered health system benefits the financially independent population or those who can afford private health insurance. 15 Although NB is classified as a rare disease, 40,41 optimising its management in South Africa is important from the principle of justice as part of setting a basic standard of health care for rare diseases. 42 The international age-standardised rate of NB in countries with standardised cancer registries is 10.5 cases per million. 43 In South Africa, with at least a 50% underdiagnosis of childhood malignancies, 7 the incidence is far less, at 2.7 cases per million. 7 Therefore, improving the quality of awareness of neuroblastoma, as with all childhood cancers, improving diagnostic capabilities and bringing  The absence of a definition in the Bill of Rights for 'basic health care services' as they pertain to children may be because of the relatively young Constitution or a means for the government not to commit to defined services. As a signatory of the UN Convention on the Rights of the Child, the South African government must prioritise the needs of children as the most vulnerable members of the South African society. 31 Section 7(2) of the Constitution requires the state to 'respect, protect, promote and fulfil the rights in the Bill of Rights'. Concerning the right of access to healthcare services, respect determines that the state not unreasonably limits people's access to healthcare services, whether in the public or private sector. 34 Thus, a reasonable measure to ensure that children, including children with malignancies, not only survive, but also thrive and reach their full capabilities according to the UN Convention, is to address discriminatory policies and practices 34 : defining basic health care for children and acknowledge the need for chronic healthcare services for children in South Africa. After 25 years of democracy, the scope of paediatric oncology should be acknowledged and a separate national cancer control plan for children should be formulated to address the paediatric epidemiology, pathophysiology and management needs of children with cancer.

Conclusion
In the case study of children diagnosed with neuroblastoma, it was determined that the patients were not afforded equitable access to care, were not afforded the same level of care based on resources and were not afforded the right to life by means of access to medical services as laid down by the South African Constitution. This case of neuroblastoma illustrates the measure of access to care for all paediatric malignancies in South Africa, which is currently a low priority in national cancer control because of the paucity of initiatives by policymakers for children with oncological diseases.