Pediatric Oncology in Countries with Limited Resources
Raul C. Ribeiro
Guillermo L. Chantada
Ramandeep S. Arora
Federico Antillon
Mariana Kruger
Ronald D. Barr
BACKGROUND
Since the last edition of this book, several biomedical milestones have been achieved, substantially advancing pediatric oncology. The human genome project has made breakthroughs possible in our understanding of the molecular basis of cancer and has allowed us to distinguish among phenotypically similar entities and develop more rational treatment strategies.1 Powerful genomic techniques have not only improved nosologic classification but also revealed new prognostic markers and potential targets for more closely targeted therapies.2 Drug discovery has been facilitated by high-throughput screening that can interrogate thousands of compounds in a relatively short period of time.3 During the coming decade, integration of these approaches into clinical pediatric oncology should help reduce both cancer mortality and the long-term side effects of conventional cancer treatments. However, the benefits we describe will be fully accessible only to selected patients who reside in affluent parts of the world. Meaningful access to effective therapies for all children remains a major challenge in pediatric oncology.
Each year, approximately 200,000 new cases of cancer are diagnosed worldwide in children and adolescents. Countries with large populations of children less than 15 years of age and a low general life expectancy have the highest percentage of cases of pediatric versus adult cancer.4 In fact, nearly 80% of children with cancer reside in low- to mid-income countries (LMIC).5 However, pediatric cancer is not among the main causes of childhood mortality in LMIC and is not included in the national health care agendas of most such countries. Although noncommunicable diseases, led by adult cancer, have become an increasingly important priority for the World Health Organization (WHO),6 pediatric cancer care in LMIC has emerged through the isolated initiatives of institutions and/or individuals. In many cases, the parents of children who received cancer treatment in a high-income country have developed philanthropic initiatives to assist local children with cancer. In these arrangements, public hospitals cover the costs of a specific number of beds for pediatric cancer and the salaries of a limited number of health care professionals, while families or philanthropic organizations pay for diagnostic procedures, medications, and other expenses. Sources of financial coverage of treatment vary among countries, ranging from complete national coverage to essentially no coverage at all. In the latter cases, only a few children receive treatment. In many LMIC, there is a combination of financial models that combine government, private, and philanthropic sources.7 However, despite such arrangements, the rate of abandonment of therapy is very high and adherence to treatment is poor owing to factors such as the families being unable to bear the cost of travel, not allocating time away from work, having to care for their other children, and having to create financial provision for other necessities.
Countries with populations greater than 30,000 are economically classified by the World Bank on the basis of gross national income (GNI) per capita. Of the 34 countries listed as low-income, 26 (76%) are in sub-Saharan Africa and 17 have a GNI per capita less than US$630, including Malawi ($270) and Burundi ($280) at the low end. Unfortunately, the gap between the richest and poorest countries continues to widen. Nine of the top 15 countries, with a GNI per capita greater than $50,000, are in Western Europe, while 16 (80%) of the 20 countries with half their population below the international poverty line (U.S. $1.25/day) are in sub-Saharan Africa. Other countries with more than half the population below the poverty level include Honduras (64.5%), Haiti (58.7%), Guatemala (53.7%), and Mexico (52.3%). Strengthening the overall health care systems of LMIC should improve the survival of children with cancer as well as the general quality of health care.
In this chapter, we discuss the status of pediatric oncology worldwide and review various strategies to extend cancer care to the largest possible number of children.
EPIDEMIOLOGY OF PEDIATRIC CANCER WORLDWIDE
Pediatric cancer is rare, accounting for 0.5% to 10% of cases, depending on the age distribution in various countries.8,9,10 Several pediatric cancers show substantial geographic and ethnic differences in their incidence.11,12 The distribution of various cancers within a geographic area (Fig. 54.1) reflects the interaction between constitutional/genetic and environmental factors that have been established over thousands of years as populations have expanded, adapted to their environment, and adopted occupational and lifestyle characteristics. While lifestyle factors such as cigarette smoking, occupation, and nutrition play an important role in cancer predisposition in adults, infection-related factors appear to be the strongest environmental determinants in the uneven geographic distribution of pediatric cancers.13 The contribution of Epstein-Barr virus to the pathogenesis of Burkitt lymphoma, Hodgkin lymphoma, extranodal NK-cell lymphoma of nasal type, and nasopharyngeal carcinoma is well established,14,15 as is the association between hepatitis B virus (with or without exposure to aflatoxin) and hepatocellular carcinoma.16 More recently, it has become clear that the prevalence of cervical carcinoma in adolescent females in developing countries is a consequence of infection with human papilloma virus, especially serotypes 16 and 18.17,18 Finally, the HIV/AIDS epidemic in sub-Saharan Africa has led to an increase in associated cancers, especially Kaposi sarcoma, which is associated with human herpes virus 8 (HHV8), and non-Hodgkin lymphoma (NHL),19,20 demonstrating how infection can alter the incidence of certain tumors over a relatively brief period and can play a crucial role in pediatric tumorigenesis.
Pediatric Burkitt lymphoma is the classic example of multiple, complex interactions between genetic and environmental factors.21,22 Although cytogenetic studies consistently show translocation of the MYC oncogene to one of the genes encoding the immunoglobulin chains, the incidence, presenting clinical features, and response to chemotherapy of this cancer vary geographically. The high incidence of childhood Burkitt lymphoma in sub-Saharan Africa is associated with equatorial climate
characteristics, including infection with mosquito-borne arboviruses, Epstein-Barr virus, and malaria.23,24 In the United States and Europe, Burkitt lymphoma is associated with none of these factors,25 whereas in some Latin American regions it is associated with Epstein-Barr virus infection and equatorial climate but not with malaria. There is limited evidence showing that prevention of malaria reduces the incidence of Burkitt lymphoma, as does the presence of protective antibodies to Plasmodium falciparum.26,27 People of African descent born in the United States are not predisposed to Burkitt lymphoma, corroborating the impact of environmental factors; in fact, the incidence of Burkitt lymphoma in Black children is half that in non-Hispanic White children in the United States.
characteristics, including infection with mosquito-borne arboviruses, Epstein-Barr virus, and malaria.23,24 In the United States and Europe, Burkitt lymphoma is associated with none of these factors,25 whereas in some Latin American regions it is associated with Epstein-Barr virus infection and equatorial climate but not with malaria. There is limited evidence showing that prevention of malaria reduces the incidence of Burkitt lymphoma, as does the presence of protective antibodies to Plasmodium falciparum.26,27 People of African descent born in the United States are not predisposed to Burkitt lymphoma, corroborating the impact of environmental factors; in fact, the incidence of Burkitt lymphoma in Black children is half that in non-Hispanic White children in the United States.
 Figure 54.1 Distribution of cancer in children less than 15 years of age in selected populations. |
Genetic factors also influence the incidence of pediatric cancers in diverse geographic regions. The expansion of the African population that arrived in the United States during the 1700s and the relative absence of racial mixing resulted in a large number of Black individuals residing in different environments. Analysis of population-based registries has shown that acute lymphoblastic leukemia (ALL), the most common pediatric cancer, is significantly less common in Black than in White children.28 Remarkably, this difference can be explained by the absence of the peak in ALL incidence between ages 2 and 4 years that is typical in White children in affluent countries. The relatively recent immigration of Hispanic people to the United States, who now comprise about 17% of the country’s population (52 million people), has also provided insight into the impact of genetic ancestry on pediatric cancer incidence. An analysis of cases of acute leukemia in 17 population-based cancer registry areas of the Surveillance, Epidemiology and End Results (SEER) Program during 2001 to 2007 revealed that Hispanics had a significantly higher incidence of progenitor B-cell ALL (incidence ratio rate [IRR] = 1.64) and acute promyelocytic leukemia (IRR = 1.28) than did non-Hispanic Whites, while Blacks had a lower incidence of all acute leukemia subtypes investigated.29 Recent genome-wide association studies have suggested that inherited variations in the genes ARID5B, IKZF1, CEBPE, CDKN2A, and BMI1-PIP4K2A are associated with childhood predisposition to ALL.30 One of these variants, the ARID5B single nucleotide polymorphism (SNP) 10821936, has been found to increase the risk of ALL across racial, ethnic, and geographic groups.31 Geographic and racial/ethnic differences in the incidence of pediatric cancer offer opportunities to investigate the basic mechanisms of tumorigenesis and, most importantly, provide a strong rationale for individualized approaches to implementing national pediatric cancer programs, depending on the country or continent.
INTERNATIONAL DISPARITIES AND BARRIERS TO PROGRESS
Population Dynamics and Health Care Delivery
The barriers to progress in pediatric oncology are daunting, in view of both economic and health system dimensions.32,33 Nonetheless, strategies to improve outcomes are being implemented. As Sullivan et al.34 noted, “Policies to increase social capital—i.e., the development of social relations and networks that produce strong societal bonding, mutuality, and solidarity—around children with cancer will play a major part in the delivery of better access and services.” The International Society of Pediatric Oncology (SIOP) and the International Confederation of Childhood Cancer Parents’ Organizations have collaborated in the development of policy issues to improve access to care (Table 54.1).35
Recently, the role of health care systems in LMIC has been the focus of intense discussions by advocacy groups and global health experts.36 It appears clear, at least at the disadvantaged end of the spectrum, that postulated 5-year survival rates for children with cancer are directly proportional to several health indicators, including GNI per capita, the number of physicians per 1,000 population, and, most significantly, the annual government expenditure on health care per capita (Fig. 54.2).37 A recent report by the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries38 has included childhood cancers in a set of candidate cancers for which there are “compelling cancer care and control opportunities for immediate action to expand treatment” and which are “ideal targets for advocacy and action in LMIC.” By using recent delivery options, including international partnerships and twinning with the aid of information and communications technology and telemedicine, the cancer divide between high-income countries and LMIC can be bridged and the barriers to effective cancer care and control (Table 54.1) can be overcome. The report calls for increased availability of global and domestic funding for health information systems and for research on cancer in LMIC.
Cost of Treatment
Treatment of pediatric cancer is expensive. Because of the rarity of childhood cancer and its small impact on the overall under-5 mortality rates, many LMIC have not budgeted for the treatment of children with cancer. A study in the mid-1980s estimated the mean cost of treating diverse pediatric cancers (n = 569 children) in the United States to be about $30,000 per patient-year.39 The mean annual hospital inpatient cost was $15,500; the mean ambulatory care cost, $4,000; and the related family out-of-pocket expenses, $10,000. Family out-of-pocket expenses and lost wages comprised about 50% of the total cost of care. However, public, private, and charitable payers covered about 95% of all medical costs. Out-of-pocket medical expenses for which the family was responsible were about $1,000 each year. For reference, in 1985, the per capita United States health expenditure was $1,721, the under-5 mortality rate was about 15 per thousand live births, and overall survival for pediatric cancer was 70% (77% for ALL). Cancer was the second overall and the first disease-related cause of death in children 0 to 14 years of age. Many LMIC are recapitulating the childhood health milestones observed in the United States in the 1970s, which consisted of a dramatic reduction of under-5 and infectious disease-related mortality. Largely as a consequence of these successes, the relative importance of childhood cancer has increased in at least some countries. For example, cancer is now the most common cause of disease-related death in children of school age in China and in parts of Latin America. These data suggest that implementation of pediatric cancer care programs at a national level is critical, but it depends on several factors, including progress in overall child health and partnerships involving government, the private sector, and philanthropic agencies. The medical costs and family out-of-pocket expenses during and after treatment of pediatric cancer have not been examined carefully in LMIC but may be similar to that in the United States in the early 1980s.40,41,42
TABLE 54.1 Key Policies to Improve Care for Children with Cancer and Barriers to Effective Cancer Care and Control Planning | ||||
|---|---|---|---|---|
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During the transition phase in which countries are attempting to reduce their under-5 mortality rates but lack the economic resources to implement a national pediatric cancer program, it is time to determine whether an attempt should be made to establish adequate diagnosis and curative treatment of pediatric cancer. Our position has been that at least one pediatric oncology unit should be implemented in every country. This initiative can demonstrate to the community that pediatric cancer is manageable and can be cured (even if infrequently). The pediatric oncology unit also serves as a site for the training of health care professionals in pediatric oncology and can attract the attention of government and community leaders to pediatric oncology as a distinct pediatric
specialty. From this initial demonstration project, which can be implemented at relatively low cost, general guidelines and broad partnerships including governmental and public organizations can emerge and lead to a national pediatric cancer care plan.43
specialty. From this initial demonstration project, which can be implemented at relatively low cost, general guidelines and broad partnerships including governmental and public organizations can emerge and lead to a national pediatric cancer care plan.43
 Figure 54.2 Postulated 5-year survival of children with cancer according to annual government spending on health care. |
Access to Medication
A key to the success of childhood cancer treatment is early diagnosis; for this purpose, the WHO includes the early signs of childhood cancer in its Integrated Management of Childhood Illnesses program to assist primary health care workers in early recognition and referral.44 The next step, to ensure access to the necessary medicines for childhood cancer treatment, is often limited by high drug costs.45 The WHO Essential Medicines List includes all drugs considered necessary for treatment and palliation of childhood cancer; it provides important guidance to policy makers in prioritizing drugs for the needs of their populations.46,47 This list can be used together with the modified SIOP Pediatric Oncology in Developing Countries (PODC) treatment guidelines for common childhood cancers, which prescribe use of the drugs on the Essential Medicines List.20,48,49
Limitation and Suboptimal Utilization of Resources
LMIC have too few specialized physicians and they are usually concentrated in cities, although much of the population may reside in rural areas and smaller towns. Access to trained specialists is limited further by these physicians’ need to spend most of their time in private practice to augment the inadequate income provided by public health care systems. For example, a regional approach to training in Central America offers young physicians from several countries the opportunity for fellowship training in pediatric oncology in Guatemala, after which they practice in their home countries.50 The WHO has taken a tough stance against the recruitment by affluent countries of physicians from resource-poor countries.51 In many cases, nurses are undereducated and unable to meet the demands of providing complex care to children with cancer. As specialized nursing is a cornerstone of pediatric oncology, this deficit is widely recognized, and numerous efforts are under way to implement intensive local training with the aid of expert nurses from larger centers in more affluent countries. For example, the International Outreach Program of St. Jude Children’s Research Hospital has engaged in such training activities in Latin America.52 Not surprisingly, many allied health professions are also grievously underrepresented. Social workers, clinical pharmacists, dietitians, and child life specialists are rarely found. Psychologists, physiotherapists, and other support specialists are similarly scarce. In the face of such shortages, it is especially troublesome to learn that different levels of care are provided according to socioeconomic status (SES), as described, in Indonesia.53
Unfortunately, diagnostic capabilities are both quantitatively and qualitatively lacking in many countries with limited resources. Laboratories offer very little by way of immunohistochemistry, flow cytometry, ultrastructural analysis, karyotyping, and molecular genetics. Similarly, diagnostic capabilities and expertise pertaining to radiology, computed tomography, magnetic resonance imaging, and nuclear medicine are severely limited, notably so in much of Africa. Such specialties and capabilities are crucial to the correct diagnosis and classification of pediatric cancers and thus for appropriate treatment. However, correct diagnosis of pediatric malignancies remains a major challenge in LMIC. In a recent review of diagnoses in several countries, mostly LMIC, approximately 30% of the reviewed cases had been misdiagnosed and therefore inadequately treated.54 Moreover, diagnosis of the complications of cancer treatment, particularly infections, is also poorly supported in LMIC hospitals. Hence, improvement of clinical laboratory services is necessary. These deficits impose major limitations on diagnostic accuracy, thereby jeopardizing decisions about the appropriate therapies. Solutions include the development of regional facilities and expertise, as exemplified by a flow cytometry center serving several Latin American countries.55,56,57 Training and education of clinical anatomic pathologists, improvement of laboratory infrastructure, and regionalization of services have had positive effects.58 Correct diagnosis is also crucial for cancer registry initiatives. Pediatric cancer registries are essential to determine not only the incidence and mortality of malignancies but also the causes of treatment failure. One example of successful pediatric population-based registry is the Argentinean Onco-Pediatric Registry.59
On the topic of therapeutic modalities, the resource-intensive aspects of surgical and radiation oncology require immediate attention. Radiation oncology is virtually unavailable in much of sub-Saharan Africa. Approximately 80% of Africans have no access to radiotherapy, and 40 of 190 countries have reported to the International Atomic Energy Agency that they have no radiotherapy units at all.60 Similarly, sophisticated neurosurgical techniques and limb salvage procedures are almost unknown in large portions of the developing world, although substantial progress has been achieved in both areas in mid-income South American countries.61 An assessment of pediatric oncology resources in mid-income countries revealed a correlation between the level of infrastructure and the outcomes of pediatric solid tumors.62,63 Likewise, in the absence of radiotherapy in a much poorer country—Nicaragua—good results have been obtained in treating Wilms tumor and Hodgkin lymphoma.64,65
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