17.1 Introduction

Eighty-five percent of the world’s children live in areas of limited resources. The poorest continent, Africa, accounts for 23% of pediatric disease but only employs 1.3% of the world’s health workers. Pediatric neuro-oncology requires highly specialized teams, and in countries where there are inadequate resources for even the most common diseases, such as infections, malnutrition, and HIV-related disease, it is understandable that children with central nervous system (CNS) tumors are not a priority.

According to the World Bank (TWB 2015a), there are 35 low income countries (LIC) with gross national income (GNI) per capita per year (Atlas Method) of less than $1500, 56 lower middle income countries (LMIC) (GNI per capita of $1500–$3975), 54 upper middle income countries (UMIC, GNI per capita of $3976–$12,275), and 50 high income countries (HIC, GNI per capita of >$12,275), see Table 17.1 and Fig. 17.1. This is reflected in the health expenditure per capita (TWB 2015b) (Table 17.2), which varies as a percentage of gross domestic product (GDP) and ranges from $13 per person per year in the Central African Republics to $9715 per person per year in Norway. The inequity of financial resources is reflected in the availability of doctors and other health workers (Table 17.2) and certainly in the availability of pediatric neuro-oncology facilities. It is estimated that at least 80% of children with brain tumors in the world do not receive adequate treatment (Friedrich et al. 2015; Hadley et al. 2012; Barr et al. 2011) and major efforts would be required to reverse the current situation. Ensuring that all children of the twenty-first century are able to receive basic treatment in the neglected domain of CNS tumors should be a priority for all pediatric oncology health workers.

Table 17.1 Tables showing countries in order as defined by Gross National Income (GNI) per capita
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Fig. 17.1
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World Map showing Gross National Income (GNI) (US dollars) per capita per year using the Atlas method (The World Bank 2015a)

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Table 17.2 Table showing health related parameters in countries as defined by the World Bank (TWB 2015b)
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The number of children in the world under the age of 15 years presenting each year with any cancer is estimated to be 160,000 (Ferlay 2004; Howard et al. 2008), although the accuracy of this figure is questionable due to the uncertain incidence in many LMIC and LIC. Extrapolating from US data, about one-fifth of these cancers are CNS cancers (Howard et al. 2008). However, the actual incidence of brain tumors in LIC and LMIC is very difficult to ascertain. Many children and young people are not diagnosed for a variety of reasons, including late presentation and lack of neuroimaging facilities. In addition, there is frequently a lack of trained clinicians, including radiologists, pathologists, neurosurgeons, and oncologists (Barr 1994), which adversely affects the ability to adequately diagnose brain tumors. True numbers of subtypes of brain tumors may not be possible to determine since a tissue diagnosis is seldom achieved. The prevalence of the different CNS tumor types as well as the biological subgroups may differ in LIC and LMIC from HIC, but this information is not readily available due to the factors mentioned above. In addition, a number of intracerebral lesions are labelled as brain tumors when in fact they are not (Mitra et al. 2012).

Globally, great advances have been made in the biological understanding of pediatric CNS tumors as well as treatment modalities and treatment stratification for children with CNS tumors, but these advances are not relevant to the majority of children with brain tumors in whom adequate access to the basic pillars of treatment are missing. Successful treatment of such children requires input from many different health professionals and is best coordinated by a formal and functioning multidisciplinary team. This can be difficult to achieve in LIC and LMIC where the number of health professionals varies widely (Table 17.2), with some countries having less than 0.2 doctors and 56 nurses per 100,000 population (TWB 2015b).

There are many factors important in setting up and maintaining a functioning program to adequately treat children with CNS tumors in LIC and LMIC. Some of these are outlined below.

17.2 Establishing a Neuro-Oncology Program in Low Income and Low Middle Income Countries

17.2.1 Political Will and Funding

Considerable investment is required to adequately care for children with brain tumors, but the commitment of different governments to their care varies. Not only are highly trained personnel required, but functioning tertiary facilities with adequate infrastructure and maintenance are needed as well. Nongovernmental organizations, including universities and charities from resource-rich countries, sometimes provide training, financial assistance, and equipment. However, the local government must be supportive in order to sustain effective programs.

Trained health professionals in some LIC and LMIC countries receive limited salaries for their public work, resulting in them seeking employment outside of their countries or in the private sector where they are better remunerated. This may result in less time for treating the majority of children who require their expertise. Some practitioners use income from their private practice to fund patients unable to afford treatment, and nongovernmental organizations and charities may supplement salaries of key personnel in order to ensure that more time is spent looking after those who are less advantaged. The requirement for patients to pay for part of their treatment or for certain drugs or treatment modalities varies from country to country and may also have an effect on the delivery of care.

17.2.2 The Importance of the Multidisciplinary Team

Early discussion of each child with a CNS tumor results in a higher standard of care and a better outcome (Parkes et al. 2015). There are many aspects of care requiring involvement from many disciplines. Since they are interdependent, it is vital that coordinated care is discussed prior to definitive treatment. Interdisciplinary discussion is critical in order to maximize outcomes. An example of this is the decision to undertake curative surgery for a presumed medulloblastoma when there are no radiation facilities available. In some circumstances referral to the nearest tertiary unit with appropriate facilities should be encouraged. Lack of multidisciplinary team coordinated care is a major stumbling block to effective care in many LIC and LMIC centers.

17.2.3 The Value of Country-Wide Services and Common Protocols

Common treatment protocols used across a country or region allow a standard of care to be developed. Each LIC and LMIC should consider whether centralization of core neuro-oncology services, such as surgery and radiotherapy, would benefit the children of the region. A different solution may be necessary for each country or region. Twinning with regular online meetings with other centers or regions may also advance care. One such example is the weekly shared care telemedicine meeting run by the team at Red Cross Children’s Hospital in Cape Town where sub-Saharan centers in Africa discuss difficult cases. Others include wider initiatives such as Asociacion de Hemato-Oncologia Pediatrica de Centro America (AHOPCA), which is a collaboration between many countries in Central America (Barr et al. 2014).

17.2.4 Outside Support, Including Twinning

The International Society of Paediatric Oncology (SIOP) has a subgroup named Paediatric Oncology in Developing Countries (PODC). This latter group has been set up to aid health professionals working in the resource challenged world and to facilitate twinning between centers in resource challenged and resource rich countries. In addition, the development of treatment guidelines for specific tumor types appropriate to various settings is a priority. The first SIOP-PODC neuro-oncology guideline, namely that for standard risk medulloblastoma, was recently published (Parkes et al. 2015).

The American Society of Clinical Oncology (ASCO) has similar initiatives, as do a number of other organizations and institutions, particularly St. Jude Children’s Research Hospital (Ribeiro et al. 2008; Ribeiro 2012) in Memphis and Sick Kids Hospital (Qaddoumi et al. 2008) in Toronto. The majority of these programs aim to enable the local hospitals to lead the process and to develop their own long-term clinical and funding strategies.

There are many other examples of twinning and many large institutions in HIC have twinning partners. Twinning is individualized according to the centers involved and most programs encompass the exchange of ideas, regular video conferencing or teleconferencing with multidisciplinary teams (Ribeiro et al. 2008; Ribeiro 2012; Qaddoumi et al. 2008) and remote pathological diagnosis (Mitra et al. 2012; Carey et al. 2014; Fischer et al. 2011; Gimbel et al. 2012; Sirintrapun et al. 2012).

17.2.5 Development of Essential Infrastructure

There are a number of core facilities and infrastructure requirements for treatment of children with CNS tumors. SIOP PODC has produced a guideline for determining settings according to the facilities and expertise available in order to facilitate decisions about what treatment should be offered (Parkes et al. 2015) (Table 17.3). The temptation to offer treatment conceived in HIC that requires a high level of supportive care may paradoxically worsen the outcome in LIC and LMIC, because excessive toxic mortality outweighs any survival advantage (Magrath et al. 2013). Some of the essential infrastructure required is outlined below.

Table 17.3 Infrastructural and personnel service line levels for selection of SIOP PODC adapted treatment regimens for standard risk medulloblastoma
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17.2.5.1 Radiology

Accurate and detailed imaging is vital in diagnosis, decision-making, and follow-up of children with CNS tumors. The radiologist is a vital member of the multidisciplinary team. In most LIC and LMIC centers, reporting is done by a general radiologist. The experience of the radiologist may vary greatly depending on prior training opportunities. Hence, the guidance given to the surgeon, radiation oncologists, and oncologist varies. This must be taken into account when making decisions on when and how to treat children.

Diagnostic facilities vary greatly in LIC and LIMC. There may also be inequity in imaging facilities between the private and government sectors. In a survey of 104 SIOP PODC members, 93% of respondents had access to CT scans and 82% to MRI scans (77% in Africa, Table 17.4) (Parkes et al. 2015), but some of these centers did not have access to intravenous contrast agents. More refined techniques, such as magnetic resonance spectroscopy and diffusion weighted imaging were usually not available. Waiting times to access scans as well as the quality of the scans varies greatly. Twinning with a center in a HIC may be of some assistance since images may be shared and discussed remotely using telemedicine platforms (Mitra et al. 2012; Gimbel et al. 2012).

Table 17.4 Online survey of resources available in low and low middle income countries with regards to services essential for a pediatric neuro-oncology service
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17.2.5.2 Neurosurgery

Neurosurgical expertise is vital for the safe treatment of children and adolescents with CNS tumors. Children with CNS tumors are usually referred directly to the neurosurgical service and the willingness and ability of surgeons to refer these patients on to other members of the multidisciplinary team, including oncologists, may determine the feasibility of further curative treatment. In the SIOP PODC survey, only 76% of respondents had neurosurgical and oncology facilities available within the same hospital network (Parkes et al. 2015). In addition, neurosurgeons in LMIC frequently did not have vital equipment or adequate preoperative imaging, making definitive surgery more difficult. It may be appropriate in many LIC and LMIC centers to perform a temporary cerebrospinal fluid (CSF) diversion in order to enable transfer of the patient to another center with more expertise or facilities.

The experience and support of neurosurgeons varies greatly in terms of pediatric CNS tumor surgery in LIC and LMIC. Some surgeons may offer surgery without any knowledge of whether further treatment is available, and others may attempt surgery that is beyond the level of their expertise. The neuro-oncology units with the best outcomes for children have a multidisciplinary team in which there is a close collaboration between the neurosurgeon and other members of the wider team.

17.2.5.3 Pathology

The pathological diagnosis of children’s CNS tumors is complex. The majority of pathologists in LIC and LMIC are not subspecialized and see relatively few children’s CNS tumors. In the SIOP PODC survey, 96% of centers had access to morphology and 53% to subtyping, but in 39% the waiting time for a result was longer than 10 days (Parkes et al. 2015). Many immunocytochemistry tests essential for accurate diagnosis are not routinely available in LIC and LMIC. With the increasing reliance on molecular testing and the likely inclusion of these tests in the new World Health Organization (WHO) tumor classification (Gottardo et al. 2014), this gap will only increase.

Some HIC services offer remote pathological advice through web-based systems such as with scanners or simple microscope cameras with dropboxes (Mitra et al. 2012; Carey et al. 2014; Fischer et al. 2011; Gimbel et al. 2012; Sirintrapun et al. 2012). The alternative is that specimens are sent by courier to other centers or countries, but this may lead to a delay in diagnosis.

17.2.5.4 Radiotherapy

Availability of radiotherapy requires considerable investment. Because of this, many LIC and LMIC have a single center or limited numbers of centers that cater to all patients requiring radiotherapy. Distances to access such centers are huge, and since most radiotherapy courses require daily treatments for up to 6 weeks, patients have to be accommodated in or close to the center. Small children requiring daily radiotherapy treatments require sedation or anesthetics. This is resource-intense and time consuming. For this reason, some LIC and LMIC centers refer such cases to regional tertiary centers for treatment.

The radiotherapy technique used may determine the late side effect profile in the child. The ability to do at least 3-D conformal radiotherapy planning and treat patients on linear accelerators as opposed to 2-D planning and Cobalt treatment may significantly affect the future quality of life of survivors. Currently, less than 50% of centers within Africa are able to offer this (IAEA n.d.) (Fig. 17.2).

Fig. 17.2
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World Map showing the availability of radiotherapy machines per million people (IAEA n.d.)

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The ability to identify and manage late effects of radiotherapy may also be problematic in LIC and LMIC. Survivors of pediatric CNS tumors require long-term follow-up and management of various problems, including endocrinopathies, hearing and visual deficits, and neurocognitive problems. Poor diagnosis and management of these problems may impact significantly on quality of life for these patients.

17.2.5.5 Chemotherapy

Although surgery and radiotherapy are the mainstay of treatment for CNS tumors in children, chemotherapy plays an important role, especially in the very young and for chemosensitive tumors. Chemotherapeutic strategies need to be tailored in a risk-adapted way to take into account the availability of drugs and the supportive care available. Skilled and knowledgeable staff are required to deliver chemotherapy that is often complex to administer and requires close monitoring. In 21% of centers surveyed, there was no access to chemotherapy necessary to treat pediatric CNS tumors (Parkes et al. 2015). Of the 79% of centers that used chemotherapy for brain tumors, carboplatin was available in 86% of centers but lomustine in only 43%. The regimens used varied widely; some centers used locally adapted regimens, some developed protocols in discussion with their twinning partners, and some attempted to use protocols developed in HIC. Treating children with chemotherapy is best undertaken when the potential consequences of toxicity can be adequately managed (e.g., hearing aids when cisplatin may lead to deafness).

17.2.5.6 Supportive Care

Advances in supportive care have enabled more intensive therapies to be delivered safely. This is not always the case in LIC and LMIC where levels of supportive care vary widely; therefore, it is vital that the intensity of treatment offered to patients does not exceed the level of supportive treatment available.

Supportive care has many facets, especially for children with CNS tumors, and includes both short- and long-term issues. In the immediate diagnostic and management period when the children may be extremely unwell, the ability to monitor electrolytes 24 h a day, perform blood counts and neurological observations, and have access to antibiotics and antifungals as well as blood products is essential to safe management. Children may have electrolyte instabilities, either as a presenting feature or as a consequence of their surgery. This, coupled with possible hormone disorders, such as antidiuretic hormone (ADH) deficiency (diabetes insipidus) or inappropriate ADH secretion, may require specialist endocrine input. Intracranial bleeding, CSF leaks, development of raised intracranial pressure, or deterioration in neurological state require rapid recognition and response, especially in the acute setting. There needs to be rapid 24-h access to either CT or MRI scanning. Central venous catheters may need to be inserted to deliver some of this supportive care. The majority of children in the immediate postoperative phase are managed in an intensive care unit when the child is most susceptible to sudden deterioration. Supportive care drugs such as anti-emetics, opiates, and neuropathic analgesia play an important role in the comfort of the child.

After the immediate postoperative period, the ability to provide nutritional support (both enteral and parental) is an important adjunct to many treatment schedules and may limit the intensity of treatment that can be used. The access to visual and hearing aids for those children with compromised vision or hearing is necessary to ensure the quality of their life. The ability to measure and treat hormone deficiencies that were either present pre-surgery or developed post-surgery is essential.

In a survey by Parkes et al. (2015) (Table 17.4), only 45% of units surveyed were able to place central venous access devices (21% in Africa, 41% in Asia and 64% in Central and South America). Nutritional support was provided in 72% of centers and dietetic support in 67%. Physiotherapy was available in 78% of centers, occupational therapy in 47%, and play therapy in 33%. Dedicated pediatric oncology wards were present in 88%.

17.2.6 Developing Skills and Training Staff

Adequate training of all team members is one of the most vital aspects in both setting up a neuro-oncology service and in its continuing development. There are many training programs as well as twinning programs that are supported by governments from HIC or by nongovernmental organizations. It is important that the training should be appropriate to the setting in which the professionals are working and that specific issues relating to working in LIC and LMIC are addressed. Where training happens remotely, ongoing support from the host institutions must be provided in order to sustain this development.

In instances where expensive equipment needs to be procured for cancer services (e.g., radiotherapy equipment, neurosurgical equipment), it is prudent that the cost of training personnel, as well as the cost of maintaining such equipment, be included in the equipment tender. This requires commercial companies who supply such equipment to have a responsibility both in ensuring that the correct equipment is procured and that local staff are empowered to operate it optimally.

17.3 Factors Affecting the Program

17.3.1 Delayed Recognition

The successful treatment of CNS tumors is reliant on early diagnosis and timely intervention. Delays are more often the result of nonrecognition by medical personnel rather than non-presentation by parents (Dang-Tan et al. 2007; Stefan et al. 2011; Abdelkhalek et al. 2014). It is important for the multidisciplinary team to work with the general pediatric and surgical services to continue to educate them about the warning signs of CNS tumors, and to be accessible to provide advice to referring centers as well as to expedite potential referrals.

17.3.2 Cultural Factors

In some poorly developed countries, prompt management is delayed due to families presenting to traditional healers first. However, traditional healers play an important role in many cultures and respect for these professionals must be maintained. Some countries, such as India, have chosen to promote such healers (Kumar 2000) and embed them in their health system. A partnership with such healers may have multiple benefits, such as mutual respect and trust allowing for prompt referral in both directions. Gender bias in some societies may also be a barrier to effective and prompt treatment for some (Arora et al. 2010).

17.3.3 Financial Factors

The financial implications of having a child with a brain tumor cannot be overstated, especially in regions of extreme poverty. There is a wide variation within regions and countries as to the cost of healthcare to the patients themselves. Some countries have free healthcare but others require the parent to contribute, and often require them to pay for medications. This leads to further inequity of healthcare as the poorest families are not able to afford treatment.

Food and transport to and from the hospital is expensive. Since children with CNS tumors need to be treated at a central hospital, many parents in rural LMICs have to travel vast distances in order to be present for treatment. The child may require prolonged stays in the hospital with a caregiver present. This adds to the family’s financial burden since the parent who is the primary caregiver is unable to work during this time. Additional caregivers may also need to be employed to care for siblings remaining at home.

17.3.4 Comorbidities

The treatment of children with CNS tumors in LMIC may be confounded by the presence of comorbidities making optimal treatment excessively toxic. Underlying nutritional status has major implications and although this has best been described for non-CNS tumors, the same principles apply (Israëls et al. 2008). There may be a decreased ability to tolerate some drugs, such as cardio- and nephrotoxic drugs. The children may also be unable to mount an adequate response to infection in the face of chemo- or radiotherapy-induced myelosuppression. Additionally, HIV infection is prevalent in many LIC and LMIC. It does not appear to play a major causative role in most primary pediatric CNS tumors, but it may significantly complicate the treatment of affected children.

17.4 Decision-Making and Service Development

17.4.1 Deciding Who to Treat and When

The key when developing a neuro-oncology service is to set realistic expectations and goals. One of the most challenging decisions is to decide what diagnoses are able to be treated safely and what level of treatment should be offered in a center. The balance of manageable toxicity versus potential curability needs to be carefully considered. It is tempting to try to offer advanced treatment to everyone in every setting, but the toxic death and morbidity rate may result in an overall poorer outcome. It is important that the whole team supports this concept. A suggestion would be that each unit uses setting tables such as those developed by SIOP PODC (Table 17.3) to realistically select the optimal treatment regimen for their patients. With limited resources, children who have tumors that are potentially curable should be prioritized. However, it is important that all children should be offered a good standard of clinical care, whether it be radical or palliative.

17.4.2 Preventing Treatment Abandonment

The failure to complete treatment for nonmedical reasons (also known as treatment abandonment) is a long-standing concern, especially in LIC and LMIC. In a recent survey it was estimated that 99% of cases in which children fail to complete treatment occur in LIC and LMIC (Friedrich et al. 2015). The number of children failing to complete treatment is approximately equal to the number of children treated in HIC. There are many reasons, but the predominant ones are failure of caregivers to understand the reasons for treatment, financial concerns, need to care for other children, and lack of transport (Friedrich et al. 2015; Wang et al. 2015; Salaverria et al. 2015). There have been many efforts across many countries to tackle the issue of abandonment and great strides have been made. These are most successful when having government backing with national investment; an example is state-sponsored treatment for children with acute lymphoblastic leukemia in Mexico (Rivera-Luna et al. 2014). Since complex treatments and rehabilitation are required for many children with CNS tumors, active efforts must be made to address parents’ concerns from the start of treatment.

17.4.3 Follow-Up and Management of Late Effects

One of the major challenges faced by units in LIC and LMIC is the ability to manage the late effects of treatment of children with CNS tumors. These children often have major difficulties in later life and it is crucial that support is available to help them. The tumors and treatment can cause a range of problems including motor difficulties, cognitive problems, hearing and visual deficits, endocrinopathies, and growth disturbances (Laughton et al. 2008; Palmer et al. 2013; Ullrich et al. 2007). These can significantly affect school performance, the ability to gain employment, interpersonal relationships, and reproductive ability. All of the above may result in depression and loss of self-worth requiring counselling and possibly intervention.

Treating the tumor is only the beginning of the child and family’s journey. It is just as important that resources are used in this area as it is in the acute care of children with CNS tumors. However, many LIC and LMIC centers do not have the facilities, staffing levels, or training to provide follow-up.

17.4.4 Measuring Outcomes

Measuring outcomes is a fundamental cornerstone in developing and improving a neuro-oncology service. Outcomes should include not only survival but also morbidity and toxicity of treatment. Follow-up in LIC and LMIC can be challenging since patients may not return and considerable effort is required to make contact with the families in order to assess survival and impact of treatment. Many units employ a data manager or follow-up nurse/social scientist for this task. A robust and well backed-up database is essential and there are a number of web-based and stand-alone software solutions available (e.g., POND database from Cure 4 Kids based at St. Jude) (Quintana et al. 2013).

17.4.5 Registries and Tumor Banks

A national, regional, or even a center tumor registry is a worthwhile investment for the future. It allows the incidences of various CNS tumor types to be calculated, and records treatment details, toxicities, and outcomes. A registry takes a lot of effort, but is extremely beneficial in the long term. Similarly, although storing tumor samples for future research is a low priority for most LIC and LMIC, it is valuable for future translational research. It does need to go hand in hand with a tumor registry to ensure that appropriate clinical data is collected alongside the tumor sample. If possible, constitutional DNA in the form of blood should be collected at the same time.

17.4.6 Research

Research, mainly in the form of clinical trials or translational research, is an important aspect of the development of neuro-oncology services. Research conducted in resource-constrained countries fosters improved care and outcomes for children; most examples of this are found in leukemia (Carey et al. 2014; Magrath et al. 2005) but it is just as important in children with CNS tumors. It has been well shown that participation in clinical trials improves the outcome of children with cancer (Magrath et al. 2013; Howard et al. 2005). While it is important to foster and encourage research in LIC and LMIC, this should not be the primary aim of a developing service. It is equally important that institutions from HIC do not use developing countries as testing grounds or a means of improving their institution’s research portfolio and journal outputs. The local institution should have a local principal investigator who has equal rights, including senior authorship. The development of local principal investigators is important for long-term sustainability, growth, and ownership of neuro-oncology services.

Technological developments and equipment may help centers in LIC and LMIC, but these should be coupled with improvements in all aspects of care; for example, subgrouping of medulloblastoma is only of use if there is adequate surgery, radiotherapy, and supportive care. It is also important that any financial contribution from research to the care of the patients be spread among all the patients in the unit and not be used exclusively for those on the study, as this encourages differential levels of care.

17.4.7 The Wider Multidisciplinary Team

There are many other members of the wider multidisciplinary team who perform important roles in the functioning of a neuro-oncology service (Fig. 17.3). These may include physiotherapists and occupational therapists, dieticians, speech and language therapists, play therapists (very useful in helping children through various procedures and treatments such as radiotherapy), social workers, chaplains and equivalents in other religious faiths. A palliative care team that may double as a pain management team is vital in a context where a number of patients will not survive.

Fig. 17.3
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(a) The essential core members of any neuro-oncology multidisciplinary team, ensuring that the patient is the focal point. (b) Suggested members of a wider multidisciplinary team that can optimize therapy and outcome for children with CNS tumors

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Conclusion

Treating children with CNS tumors in an LIC or LMIC setting is challenging, but with an effective multidisciplinary team and realistic decision-making the best possible outcomes can be achieved. Treating children with CNS tumors should only be undertaken if the side effects of treatment are manageable. Irrespective of experience, consulting with others outside one’s own center is often beneficial.