As developing nations continue to improve their health status, the need to develop and maintain cancer programs is becoming more imperative. Globally, the number of new cancer cases at all ages will increase from 10 million in 2000 to 15 million in 2020 and 24 million in 2050, and close to 70% of those cases are expected to occur in low-income and middle-income countries (LMICs) . The rising proportion of cases in these countries is caused by population growth and aging, combined with reduced mortality from infectious diseases [2▪,3▪▪]. However, there is a dramatic inequity in the distribution of resources for cancer care and control worldwide. Although almost 80% of the disability-adjusted life-years lost worldwide to cancer are in LMICs, these countries have less than 5% of global resources for cancer [2▪]. The global economic cost of the 12.9 million new cancer cases in 2009 was US$ 286 billion (305 billion including cancer research funding). These costs disproportionally accrue to high-income countries (HICs), which account for 94% of the total estimated costs, well in excess of their 15% share of the world population and 39% of global cancer cases [3▪▪]. The medical spending per cancer case in HICs is 2.5 times the world average; further, that select group of countries account for nearly all of the world's spending on cancer research [3▪▪].
The cancer burden is therefore clearly shifted toward resource-limited countries. Pediatric cancer is not an exception; of the estimated more than 200 000 children and adolescents diagnosed with cancer every year, 80% live in countries with limited resources, which account for more than 90% of childhood cancer deaths . Moreover, the gap in survival between HICs and low-income countries (LICs) will only widen in coming years; on the basis of current population growth and decreased infant mortality rates, the number of children with cancer will increase by 30% by 2020.
In September 2000, the heads of state and government of 189 Member States gathered at the UN headquarters for the Millennium Summit and set down the millennium declaration, a series of collective priorities for peace and security, poverty reduction, the environment, and human rights. This resulted in the Millennium Development Goals (see list below); by 2015, the leaders pledged, the world would achieve measurable improvements in the most critical areas of human development. In 2008, the Union for International Cancer Control (UICC) issued the World Cancer Declaration, a consensus between government officials, public health experts, and cancer advocates from around the world, with the goal to help bring the growing cancer crisis to the attention of government leaders and health policy-makers and reduce the global cancer burden by 2020 through 11 key targets that require integration of health policy initiatives, cancer prevention, and early detection and treatment (see list below) . More recently, in September 2011, a high-level meeting of the United Nations General Assembly was dedicated to the prevention and control of noncommunicable diseases, including cancer, thus calling for action by global health agencies and governments. Importantly, reduction of child mortality is a Millennium Development Goal, and integration of pediatric cancer in broader global cancer initiatives is necessary. It is in this context that the pediatric oncology community should analyze the progress made and steps to take in the cure of pediatric cancer, worldwide.
Millennium Development Goals:
1. Eradicate extreme poverty and hunger;
2. Achieve universal primary education;
3. Promote sex equality and empower women;
4. Reduce child mortality;
5. Improve maternal health;
6. Combat HIV/AIDS, malaria, and other diseases;
7. Ensure environmental sustainability;
8. Develop a global partnership for development.
The World Cancer Declaration (UICC):
1. Sustainable delivery systems will be in place to ensure that effective cancer control programs are available in all countries.
2. The measurement of the global cancer burden and the impact of cancer control interventions will have improved significantly.
3. Global tobacco consumption, obesity, and alcohol intake levels will have fallen significantly.
4. Populations in the areas affected by human papillomavirus and hepatitis B virus will be covered by the universal vaccination programs.
5. Public attitudes toward cancer will improve and damaging myths and misconceptions about the disease will be dispelled.
6. Many more cancers will be diagnosed when still localized through the provision of screening and early detection programs and high levels of public and professional awareness about important cancer warning signs.
7. Access to accurate cancer diagnosis, appropriate cancer treatments, supportive care, rehabilitation services, and palliative care will have improved for all patients worldwide.
8. Effective pain control measures will be available universally to all cancer patients in pain.
9. The number of training opportunities available for health professionals in different aspects of cancer control will have improved significantly.
10. Emigration of health workers with specialist training in cancer control will have reduced dramatically.
11. There will be major improvements in cancer survival rates in all countries.
Globally, the percentage of children dying before the age of 5 years has decreased from 250 per 1000 live births to less than 70 over the last 50 years. However, regional variations still exist; while in Latin America and the Caribbean, for example, under-five mortality has decreased to below 20 per 1000 live births, in sub-Saharan Africa it remains consistently above 100 . The vast majority of under-five deaths occur in the setting of poverty, and most could have been prevented with simple public health services. Thus, in most parts of the world, resource allocation is a major issue, and support of pediatric oncology programs may not take priority. In an analysis of childhood cancer outcomes in 10 LMICs, Ribeiro et al.[7▪▪] showed the 5-year survival estimates to be directly proportional to several health indicators, such as number of physicians and nurses per 1000 population and annual government health-care expenditure per capita. In 2006, the Mexican government launched the Fund for Protection Against Catastrophic Expenditures, which includes childhood cancer. Coverage of new cancer cases increased from 3.3 to 55.3%; however, a preliminary analysis shows outcome estimates to be still suboptimal, particularly in the more deprived regions . Thus, although public investment to support access to pediatric cancer care is an important first step, it is clearly not sufficient. Strengthening of the healthcare systems as a whole through clear prioritization of key public health functions is required for sustainability, while research methods should be applied to scale-up health interventions.
THE GLOBAL IMPACT: EPIDEMIOLOGY OF PEDIATRIC CANCER
Cancer is the leading cause of death from illness in children in HICs. Unfortunately, very little is known about the epidemiology of pediatric cancer in LMICs. Cancer registries are almost nonexistent, and underdiagnosis and underregistration are additional barriers; the development of childhood cancer registries in LMICs should be prioritized.
Data obtained from population-based cancer registries, combined with medically certified death data, are key to producing statistics on the occurrence of cancer in a defined population in a specific time period and also to providing a framework for assessing and controlling the impact of cancer on the community. Furthermore, cancer registries are key tools for planning cancer control strategies, as they can measure cancer burden in populations and generate information that can be used for causative research [9,10▪,11]. Unfortunately, large portions of the world's population are not covered by the existing cancer registries; this is particularly true where the predictions indicate that the cancer burden is growing most rapidly. Data from the International Agency for Research on Cancer (IARC) indicate that, while the population covered by existing registries is around 90% in North America and Oceania, and 60% in Europe, it is only 21% in Central and South America, 11% in Africa, and 8% in Asia [10▪]. And, where those registries exist, death records are often inaccurate due to uncoordinated and fragmented vital registry systems [3▪▪]. Limitations of the existing diagnostic and treatment capacities, inaccurate population data, cultural taboos, and the consequences of political or economic instability and massive population movements result in incomplete registration and underestimation of the true cancer incidence [10▪]. Clearly, accurate population-based cancer registries need to be developed worldwide. The International Association of Cancer Registries (IACR) and IARC have produced recommendations regarding the data items to be collected [9,10▪,11].
The magnitude of this problem is magnified in pediatrics. Children's cancer registries differ from adult registries because of the relative rarity of pediatric cancer, the different spectrum of tumors, and the use of histology-based classifications, as opposed to site-specific classifications used to estimate cancer incidence and mortality in adults . In light of the difficulties, costs, and uncertainties associated with accurate population-based cancer registries, hospital-based registries could provide a reliable source of information for pediatric cancer, while serving as a practical first step toward a possible population-based assessment of cancer incidence rates [10▪,12]. Resources available for the development of cancer registration in LMICs are depicted in Table 1.
Epidemiology of childhood cancer
Data from adult cancers show global differences in cancer incidence and distribution, often denoting differences in interaction of ethnicity, environment, socioeconomic conditions, and biology [13,14▪▪]. Given the deficient cancer registry systems, whether the same paradigm is true for pediatric cancer is not known, although differences in incidence rates between HICs and LICs have been documented . Research in health disparities in HICs may provide a very solid evidence-based ground to lead epidemiology research initiatives in resource-limited settings . Incidence rates of cancer differ between various ethnic groups within a single country and between countries with similar ethnic compositions. Such differences may be the result of genetic predisposition, early or delayed exposure to infectious diseases, and other environmental factors . In a population-based case–control study examining cancer incidence by race in children in five USA states, Chow et al. showed that, compared with whites, blacks had a 28% decreased risk of cancer, whereas both Asians and Hispanics had an approximate 15% decrease. Children of mixed white and black ancestry also were found to be at decreased risk. Differences were found also for specific neoplasms; compared with whites, black and mixed white/black children had decreased odds ratio (OR) for acute lymphoblastic leukemia (ALL); Asian and mixed white/Asian children had decreased OR for brain tumors; and Hispanic and mixed white/Hispanic children had decreased OR for neuroblastoma, but increased incidence of ALL [16▪]. It is possible that a combination of genetic, ethnic, and socioeconomic factors is responsible for these differences; interestingly, similar trends have been noted recently in pilot epidemiology studies performed in LMICs, as summarized below.
The reported mean annual leukemia incidence per million children in LICs is significantly lower than in HICs (16.4 vs. 40.9, respectively) . These differences could represent underreporting, as the presentation of acute leukemia resembles acute infection, and early death could occur before cancer is suspected or diagnosed. In fact, LICs with the lowest reported incidence rates of leukemia have a very high incidence of malaria, which can be 10 000 times more common than leukemia in endemic areas . However, the observations of a markedly increased incidence rate of ALL in children between 2 and 5 years old in affluent societies, the lack of such an age peak in LICs, and occasional clustering of childhood ALL cases have fueled the infection-based theories of leukemogenesis, which attribute the peak incidence in industrialized countries to early infectious insulation that predisposes the immune system of susceptible individuals to aberrant or pathologic responses after subsequent or delayed exposure to common infections at an age commensurate with increased lymphoid cell proliferation [12,17]. In a recent study from Indonesia using a hospital-based registry in a referral center, the calculated age-adjusted annual incidence rate of ALL was 20.8 per million per year, significantly lower than in HICs, whereas the incidence of acute myeloid leukemia (AML) was similar to HICs (8.0 per million per year), thus suggesting that the lower incidence of ALL is not entirely attributable to underreporting because of death before diagnosis . The causes of these ethnic differences in the incidence of ALL thus remain uncertain, although both genetic and nongenetic differences are likely important. Genome-wide interrogations have recently identified genetic variations in ARID5B to be associated with susceptibility to childhood ALL. In a recent study conducted in North and Central American patients, several ARID5B polymorphisms were associated with ALL susceptibility in both whites and Hispanics, with risk alleles more frequent in children of Native American ancestry [19▪▪]. These data may help interpret the increased incidence of ALL in North American Hispanics reported by Chow et al.[16▪]. Taking these data one step further, differences in the outcome by ethnic group traditionally attributed to quality of care may need to be redefined as genomic-wide studies are conducted. Interrogating genome-wide germline single nucleotide polymorphism genotypes in an unselected large cohort of children with ALL, Yang et al. observed that the component of genomic variation that cosegregated with Native American ancestry was associated with the risk of relapse even after adjustment for known prognostic factors. This adds to the known differences in thiopurine methyltransferase (an enzyme involved in the metabolism of thiopurines used in ALL therapy) allele frequency and distribution of polymorphic low activity alleles in different ethnic groups that may be important for toxicity and outcome .
Differences in the incidence of embryonal tumors between countries and ethnic groups have been consistently reported over the last decades, particularly for neuroblastoma and retinoblastoma ; however, the deficiencies inherent in suboptimal cancer registries in LICs have made proper estimates difficult. Recently published studies add very valuable data to those suspected trends. In a country as ethnically diverse and socioeconomically heterogeneous as Brazil, population-based registries offer a great opportunity to investigate those hypotheses. De Camargo et al. calculated the age-adjusted incidence rates (AAIRs) of retinoblastoma in 20 population-based cancer registries in Brazil and noted higher AAIRs than those of developed countries. The AAIR for children 0–4 years of age was as high as 15 and 27 in Salvador and Bahia, respectively, two of the most deprived states in the country (vs. 10–12 in the USA and Europe). In a broader study testing the differences in the incidence of embryonal tumors and their correlation with socioeconomic status, the same group documented an inverse correlation between the incidence of retinoblastoma and socioeconomic index. Interestingly, the opposite was true for neuroblastoma, with higher incidence in Brazilian regions with high socioeconomic status . A similar phenomenon has been reported in Mexico, where a very low incidence of neuroblastoma has been documented, along with a higher incidence of retinoblastoma, particularly in deprived states such as Chiapas [24,25]. Conversely, in the USA, black and Native American patients with neuroblastoma have a higher prevalence of high-risk disease, with higher prevalence of late-occurring events among blacks suggesting increased resistance to chemotherapy .
These variations in the incidence of leukemias and some embryonal tumors, which may be related to environmental factors and geographical and ethnic patterns, provide clues to causative diagnosis and point toward the need for dedicated global molecular epidemiology studies. Genome-wide interrogations may be needed to elucidate the genetic basis for those variations. Because childhood cancer is considered to be related in part to perinatal exposures, the range of those exposures in the developing world gives us the opportunity to explore hypotheses in ways that were not possible before.
THE CHILD WITH CANCER IN RESOURCE-LIMITED SETTINGS
Initiatives aimed at improving the outcomes for pediatric cancer in LMICs must consider its unique features; the host, the diseases, and the social, economic and cultural contexts are remarkably different from the adult. All the elements in cancer control, including primary prevention, early detection, diagnosis and treatment, survivorship, and palliative care, must be addressed from the unique pediatric perspective.
Late presentation and underdiagnosis
Lack of education, limited access to healthcare, and complex and deficient socioeconomic environment result in delayed and underdiagnosis in LMICs. The magnitude of the problem is difficult to ascertain given the paucity of population-based cancer registries. Clearly, the reasons for delayed and underdiagnosis are multiple and complex. Taking retinoblastoma as an example of a neoplasm in which timing of diagnosis is crucial, global studies indicate that, of the 8000 children diagnosed with retinoblastoma yearly, 66% live in LMICs, but those countries have 90% of the cases presenting with metastatic disease, revealing a significant deficiency in the early diagnosis and referral pathways . In LMICs, retinoblastoma educational and public awareness campaigns have been shown to increase referrals, decrease the rates of advanced disease, and improve outcomes . However, the level of awareness of the first contact health provider is critical. In a recent report from Mexico, Leal-Leal et al. surveyed a large cohort of students from 12 different medical schools in their last year of school and tested their knowledge on the basic signs of retinoblastoma as well as their proficiency in identifying the problem and making the appropriate referral. Only 3.3% of students obtained a proficiency grade; close to two-thirds of students did not know the common signs of retinoblastoma and, more importantly, fewer than 50% of students were able to diagnose a retinoblastoma when an image of leukocoria (an abnormal white reflection from the retina) was shown. This is particularly important because in Mexico, as in many other LMICs, newly graduated physicians are the first contact healthcare providers in most rural areas as part of the social services programs. The importance of medical delay is further documented by De Angelis et al. in their analysis of reasons for delayed presentation of children with AML in Nicaragua. The investigators compared time to diagnosis of children with AML between two referral centers in Nicaragua and Italy. Although the median time from symptoms to first medical assessment was similar in both centers (7 vs. 5 days), the median lag time to diagnosis was higher in Nicaragua than in Italy (29 vs. 14 days) and it was mainly because of physician delay (16.5 vs. 7 days). Importantly, the median lag time from symptoms to diagnosis was decreased in Nicaraguan districts, where a specific training program for childhood cancer had been implemented (20.5 vs. 40 days). The results of these studies emphasize the need to implement educational initiatives aimed at first contact healthcare workers.
Abandonment of therapy
Refusal and abandonment of therapy is a major cause of therapeutic failure in countries with limited resources, affecting up to 50–60% of children and thus often exceeding all other causes of failure [31▪,32]. Most patients abandon early, usually after induction remission in leukemias  or at the time of radical surgeries (enucleation or amputation) in solid malignancies [34,35]. Factors predisposing to abandonment are multiple and complex; however, while socioeconomic factors play a major role, studies have shown the importance of healthcare providers’ attitudes and communication, and the amelioration of quality of life through better supportive care [33,36]. The Abandonment of Treatment Working Group of the International Society of Pediatric Oncology (SIOP) Pediatric Oncology in Developing Countries (PODC) committee was recently created with the goals of heightening awareness of abandonment as a major cause of treatment failure in resource-poor countries, to elucidate the contributing factors, and to identify and widely disseminate effective solutions [31▪]. The following recommendations were proposed by the working group. First, abandonment of treatment should be defined as failure to either begin (refusal) or to continue the planned course (abandonment), because both are likely to have related underlying causes and could benefit from similar interventions. Second, abandonment should be documented as an adverse event in childhood cancer studies in resource-poor settings; patients who do not begin or complete treatment should not be excluded from survival analyses. The event-free survival (EFS) should be analyzed in two ways, by treating abandonment as an adverse event and by censoring cases at the time of abandonment; these two estimates will reflect the upper and lower bounds of the true EFS estimate. The concept ‘abandonment-sensitive survival’ has been proposed . Third, while treatment might be interrupted for various reasons, abandonment should be defined as a hiatus of 4 or more weeks in the scheduled treatment, as studies seem to indicate that patients are unlikely to return after this length of absence, and, even if they return, treatment effectiveness may be compromised. And, fourth, the concept of abandonment of treatment should only be applied in the context of treatment given with intention to cure [31▪].
The prevalence of malnutrition in children with cancer in LMICs reaches 50–70% [37,38▪]. Malnutrition is associated with higher toxicity rates, most notably chemotherapy-induced neutropenia and infectious complications, resulting in decreased survival rates [37,38▪]. Importantly, the impact of malnutrition in metabolism, distribution, and clearance of chemotherapeutic agents should not be underestimated. Malnutrition results in altered liver and renal function, alters body composition, and decreases plasma proteins. In a study comparing vincristine pharmacokinetics in children with Wilms tumor in Malawi and in the United Kingdom, malnutrition was associated with decreased vincristine clearance and increased systemic exposure . Initiatives aimed at local production and provision of ready-to-use therapeutic food for the treatment of malnutrition have been shown to be effective and should be considered as programs for pediatric oncology are developed . Combining mid-upper arm circumference, triceps skin fold thickness, and serum albumin values, Sala et al.[38▪] have proposed three categories of nutritional status that appear to correlate with the outcome and could be used in the initial assessment of children with cancer to outline nutritional intervention and adjust cancer treatment.
The ability to provide state-of-the-art curative treatments for children with cancer in LMICs is severely limited by lack of proper infection control programs and transfusional support, among others. Further, in many areas of the world, the high prevalence of HIV/AIDS creates a complex environment . Death from infection during neutropenic episodes is significantly higher in countries with limited resources, and, although the rate of microbiologically documented infections may be similar, the proportion of polymicrobial and Gram-negative infections is higher in LMICs [42▪,43,44]. The control of nosocomial infections is key in those settings, and yet resource-poor hospitals have many barriers to proper hand hygiene. Alcohol-based hygiene can compensate for inadequate infrastructure and supplies. Caniza et al. evaluated the implementation of alcohol-based hand hygiene in five high-risk wards of a pediatric hospital in El Salvador. Placement of 35 gel dispensers using local providers increased the ratio of hand hygiene stations to beds from 1 : 6.2 to 1 : 1.8; hand hygiene practice increased from 33.8 to 40.5%, and the use of the correct technique increased from 73.8 to 95.2% . Thus, alcohol gel hand hygiene can address some of the barriers to effective hand washing at resource-poor institutions, and its cost may be offset by the reduction of nosocomial infections. This is the method recommended by the WHO; guides to local production of WHO-recommended hand rub formulations have been developed . Availability of safe blood products is another major limitation to successful cancer care in LMICs. About 92 million blood donations are collected every year worldwide; however, approximately half of these blood donations are collected in HICs, home of 15% of the world's population. Although 78% of countries have national-specific guidelines on the appropriate clinical use of blood products, only 13% of LMICs have a national hemovigilance system to monitor and improve the safety of the transfusion process, and only 53% of the donations are screened following basic quality procedures. Furthermore, the source of donations is very limited; 36% of blood products in countries with limited resources come from family replacement or paid donations, compared with only 0.3% in HICs [47▪▪]. The development of regional and national programs to improve availability and safety of blood products is a priority of international healthcare organizations.
A key principle of successful pediatric cancer treatment is the delivery of care by skilled professional nurses. Hospitals in HICs routinely offer pediatric oncology-specific nursing education and training, and require chemotherapy certification to ensure nursing competency in the care of children with cancer. However, specialized education and training are generally unavailable for nurses in LMICs, contributing to the disparity in outcomes and overall survival. Challenges to the education and retention of nurses in LMICs include inadequate financial support for salaries and training, inaccessibility of academic nursing programs, and cultural and organizational barriers preventing nurses from being recognized as valued members of the multidisciplinary team. Nurse workload is another critical factor in patient outcomes. Inadequate nurse staffing has proven to result in longer hospital stays, increased risk for complications, and an increase in patient mortality [48▪▪]. Day et al. proposed the development of nursing educators to reside within the pediatric oncology unit to promote the provision of quality nursing care. Principal responsibilities of the nurse educator include the development of a curriculum for newly hired nurses and the promotion of continuing education for all nursing staff. The curriculum includes essential elements of pediatric oncology nursing care, such as courses in chemotherapy administration and management of central lines. Day et al. later evaluated the effectiveness of this initiative in the pediatric oncology unit in Guatemala by measuring the completion of an education course by all nurses, chemotherapy and central line competency, continuing nursing education, and cost. All newly hired nurses completed the education course – of the nurses employed, 86% participated in the chemotherapy courses and 93% achieved competency; 57% participated in the central line course, and 79% achieved competency. Nurses completed a mean of 26 h of continuing education yearly. Annual direct cost of the educator was $244 per nurse; this approach may be an effective and sustainable means to educate nurses in resource-limited settings. While methods for monitoring and assessing the quality of nursing care in countries with limited resources are developed, the Joint Commission International Standards can be a useful tool .
Countries with limited resources carry the largest pediatric cancer burden; most children with cancer live in those settings and the majority of them die. The implementation of palliative care programs should thus be a priority, and their integration early in the disease process, regardless of the expected outcome, should be the norm ; however, most LMICs lack properly developed and implemented palliative care programs. In a survey of 58 countries with different developmental levels, the availability of specialized palliative care services, pain management, bereavement care, and institutional or national decision-making support were inversely related to income level. Availability of high-potency opiates and adjuvant drugs was also significantly less in LMICs [53▪]. The large number of patients, lack of specialized palliative care teams and trained nurses, poor government support, and highly restricted access to morphine are major barriers; however, even considering those limitations, the development of quality palliative care programs is possible [54,55]. The International Network for Cancer Treatment and Research (INCTR) has produced a palliative care handbook for countries with limited resources that includes recommendations for program building and patient care (Table 1). Lack of adequate pain control is at the core of deficient palliation in LMICs; pain management initiatives may be available in fewer than 50% of pediatric oncology units, and high-potency opiates and adjuvant medications for neuropathic pain are available in fewer than 15% of the countries [53▪]. Although morphine is in the WHO list of essential medications , it is regulated by international drug conventions, and its importation, manufacture, and distribution are under exclusive government control. Unfortunately, access is often limited by lack of government policies and education. The vast majority of morphine and other narcotics are consumed in industrialized countries. According to the data from the International Narcotics Control Board (INCB), of the 39 723 doses of all opiate analgesics administered per million habitants per day worldwide during 2007–2009, 98.6% were consumed in North America, Europe, and Oceania; South America, Asia, Central America and Caribbean, and Africa accounted for only 0.5, 0.2, 0.1, and 0.1% of the total amount, respectively . Clearly, the medical need for opiates is not fully met, and the problem may be magnified when the care of children with cancer is considered. The collaboration between WHO and INCB has led to successful examples in Africa, and similar initiatives should be explored .
DEVELOPING ADAPTED TREATMENTS
Aims and priorities of pediatric cancer programs in countries with limited resources should be in accordance with the level of complexity of their healthcare system, and stepwise improvements should integrate with its growth (Fig. 1). Once basic concepts of therapy and key trained personnel are available, and principles of palliative care are incorporated, cure of children with cancer in a cost-effective manner is possible even in the most deprived settings. In tropical Africa, for example, studies conducted over the last two decades have demonstrated the possibility of designing effective regimens for Burkitt lymphoma, one of the most common cancers in the region, adapted to the socioeconomic conditions, the available supportive care, and the patients’ comorbidities. In Malawi, a simple protocol including intravenous cyclophosphamide 40 mg/kg on day 1, followed by oral cyclophosphamide 60 mg/kg on days 8, 18, and 28, including intrathecal hydrocortisone and methotrexate, resulted in 1-year survival of 48%, with a treatment-related mortality rate of only 5% . Importantly, the cost of a 28-day cycle was less than US$50. Similar survival rates were reported by the French African Group of Pediatric Oncology in a prospective multicenter study in six countries ; however, this regimen included higher doses of cyclophosphamide and resulted in toxic death rates of 21%. Overall, those results are particularly remarkable considering the limitations in diagnosis, staging, and supportive care in sub-Saharan Africa, but underscore the need to develop the necessary infrastructure and supportive care required for more successful outcomes . As shown by the Burkitt lymphoma experience and others, the direct translation of protocols that are effective in HICs to children in LMICs is simply not possible; treatments need to be adapted and new evidence needs to be generated. In a study performed in Russia in the 1990s, 713 patients with ALL were randomized between a standard ALL treatment protocol widely used in Western Europe (ALL BFM-90m) and a more feasible and less intensive regimen (ALL-MB91), which limited the administration of high-dose therapies, anthracyclines, and cranial irradiation. The 7-year EFS estimates were 67 and 68% for patients treated on the ALL-MB91 and ALL-BFM-90m regimens, respectively; however, the adapted regimen resulted in lower myelosuppression and hospitalization rates and less resource utilization . Thus, a systematic and graduated approach to diagnosis, risk classification, and treatment of childhood cancers in LMICs should be implemented. Even with adjusted regimens, treatment-related mortality is significant [42▪,44] and a very careful design of gradual protocols should be performed. Following this rationale, Hunger et al.[62▪▪] have proposed intensity-adjusted treatment strategies for ALL with simple stratification algorithms and a standard base treatment upon which intensity is increased gradually as safety and feasibility are documented and treatment-related mortality is decreased. As these approaches are implemented, it is important to build data management infrastructures. The application of the selected regimens should be uniform, with prospective documentation of all events, including toxicities, abandonment, and relapses . Modifications to the regimens can then be made on the basis of periodic review of local outcomes, and a stepwise increment in diagnostic and stratification complexity and treatment intensity can then be done. Here again, research done in the health disparities field is very relevant; in North America, among children and adolescents treated on a Children's Oncology Group ALL protocol, adherence to daily oral 6-mercaptopurine therapy was significantly lower in Hispanics, and a progressive increase in relapse was observed with decreasing adherence . Clearly, psychosocial support and parent and patient education need to be included as treatments are developed if an impact is to be made .
Treatment of solid malignancies in countries with limited resources may be more challenging; a more multidisciplinary approach with surgery, pathology, diagnostic imaging, and radiation oncology is essential, and a complex infrastructure is required. While steady and consistent improvements in outcome for children with ALL have been documented over the last two decades , outcomes for children with most solid malignancies have not followed a parallel evolution . Delayed and deficient diagnosis, lack of coordinated multidisciplinary care, and high abandonment rates at time of surgical interventions (often radical and mutilating) result in clearly suboptimal outcomes; this is particularly noticeable in retinoblastoma , sarcomas , and brain tumors , in which the complexity of care is high. To address some of these issues, graduated intensity treatment guidelines are being developed by the SIOP PODC Committee . Furthermore, access to safe and modern radiation facilities is a major impediment to the care of a large proportion of children with solid malignancies. The International Atomic Energy Agency (IAEA) has launched the Programme of Action for Cancer Therapy (PACT) to assist in the assessment and capacity building of radiation centers in countries with limited resources (Table 1). Despite these limitations, successful outcomes have been documented for solid malignancies such as retinoblastoma , sarcomas [70,71], or Wilms tumor , particularly when treatments and resources are carefully adapted to the local conditions. In this regard, the creation of regional centers of excellence that concentrate expertise and resources may be a very cost-effective model to follow [73▪]. As countries build capacity, outcomes improve, and complexity of care increases, high-level programs such as hematopoietic stem cell transplant can be developed; an example of such a successful model has been recently reported by Palma et al.[74,75] in Chile, where haploidentical transplants are now performed.
As global health initiatives for pediatric cancer are becoming more solid and models for intervention are developed, parallel work in nonmalignant hematology should be incorporated. Similarly to cancer, approximately 80% of the annual births of infants with hemoglobinopathies occur in LMICs. And again, as the population size of these regions grows and the healthcare systems improve, children with those conditions will require the development of dedicated programs that integrate diagnostic, therapeutic, and support facilities . The integration of those programs with ongoing childhood cancer control initiatives and the development of broader pediatric hematology–oncology regional and national programs is necessary.
PROGRAM BUILDING AND INTEGRATION OF EDUCATION AND RESEARCH
The low incidence of childhood cancer provides the rationale for the development of dedicated pediatric oncology centers with wide reach and which could grow to become regional or national centers of excellence. International partnerships that integrate twinning between institutions in HICs and LMICs along with commitment from local governments and participation of global health agencies, advocacy groups, and local foundations have proven to be very successful models for building sustainable programs [66,77,78]. The baseline status is very different in each country, and a detailed analysis of the situation must be performed before priorities are set. Different scenarios may apply to each country or center, and the recognition of the main problem is the first step toward the development of a program. Priorities are then established, and a gradual process of program building follows (Table 2).
For these initiatives to be successful, the incorporation of strong educational and research components is key. Similarly to adult cancer, pediatric cancer diagnosis, treatment, and support require a sophisticated integration of multiple specialties, including (but not limited to) nursing, pediatric and radiation oncology, surgery, pathology, infection control, laboratory and imaging medicine, psychosocial, and palliative care. Adequate training for all those healthcare professionals is difficult (and often inadequate) in HICs, and often nonexistent in LMICs, where services are often provided by adult specialists. Web-based training provides a unique tool to implement education on a global scale and facilitate interaction with mentors. The application of medical telecommunications to the development of oncology programs and all its related disciplines can potentially enhance access to and quality of clinical cancer care as well as improving education and training (Table 1) [73▪,79,80].
The development of successful pediatric oncology programs in LMICs should progressively incorporate clinical research into their practices. In this context of limited resources, clinical research is not only possible, but also necessary. The design and conduct of clinical research should focus on the epidemiologic, biologic, clinical, and psychosocial questions relevant to the advancement of local care, the development of treatment guidelines and interventions, and to guiding public health priorities . Again, the importance of incorporating solid data management programs early in the process of program building should be emphasized. In this regard, web-based technologies can assist countries with limited resources by enhancing the quantity and quality of clinical data and can support international clinical collaborations to facilitate protocol-based treatment for children with cancer. An example of such possibility is the web-based, free access, pediatric oncology network database (www.POND4kids.org), a multilingual clinical database created for use by pediatric oncology units in countries with limited resources to meet various clinical data management needs including cancer registration, data collection, and changes in treatment outcome. This is an excellent tool to store patient data for easy retrieval and analysis and to achieve uniform data collection to facilitate meaningful comparison of information among centers .
ESSENTIAL MEDICINES FOR CHILDHOOD CANCER
The WHO list of essential chemotherapy drugs guides many international organizations, nongovernmental organizations, and charities. In 2007, the WHO launched a parallel essential medicines list for children, including an expanded list of chemotherapy drugs, which has been updated every 2 years . Although this list is mainly intended for the treatment of hematologic malignancies, it provides a good framework on which to work and expand, as a large number of LMICs restrict drug importation to those drugs specified on the WHO list. The Essential Medicines list has been incorporated into the UN Committee on Economic, Social and Cultural Rights defining the right to health. All drugs included in the Essential Medicines list for childhood cancer are commonly used in the treatment of adult cancer and thus are not unique to the pediatric population; therefore, procurement of drugs for the treatment of childhood cancer should benefit from policies and procedures implemented for adult cancer.
In 2004, the Ponte di Legno Working Group representing 15 study groups and institutions issued a statement to prompt WHO and other national and international agencies to provide the necessary drugs at affordable cost worldwide, emphasized the right of all children in the world to full access to the essential treatment of cancer, and called upon the authorities concerned to recognize and support all measures that promote this right to a chance of cure . Recent shortages in drug availability and the disparity with which they have impacted the care of children with cancer in different regions highlights the importance of developing initiatives to ensure the availability of safe and affordable drugs for all children.
Advances in cancer control and treatment are often measured by the progress made in the developed world. However, a true impact in cancer outcomes will not occur until we commit resources and intellectual power to address the burden of cancer in LMICs and develop global initiatives. International partnerships facilitating the processes that build capacity while incorporating epidemiology and health services research and implementing intensity-graduated treatments have been shown to be effective. Major academic centers involved in cancer care should assume the responsibility to lead the way and be convinced that serious global initiatives will represent the breakthrough in cancer treatment and control for the next century. A global cancer initiative should be recognized as part of the mission of the institution, shared by all cancer programs, and integrated into their strategic planning.
The authors want to acknowledge the inspiration provided by so many unfortunate children who suffer and succumb to cancer in countries with limited resources, and by the many anonymous doctors, nurses and parents who fight tirelessly for their lives.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 145–146).
1. Brown M, Goldie S, Draisma G, et al.
Health service interventions for cancer control in developing countries. In: Jamison DT, Breman JG, Measham AR, et al.
, editors. Disease control priorities in developing countries. 2nd ed. Washington, DC: World Bank; 2006. Chapter 29. Available from http://www.ncbi.nlm.nih.gov.ezp-prod1.hul.harvard.edu/books/NBK11756/
. [Accessed October 2012]
2▪. Farmer P, Frenk J, Knaul FM, et al. Expansion of cancer care and control in countries of low and middle income: a call to action. Lancet 2010; 376:1186–1193.
A call to action from leading global and academic organizations to implement cancer control systems in LMICs.
An in-depth analysis of the cancer burden globally.
4. Kellie SJ, Howard SC. Global child health priorities: what role for paediatric oncologists? Eur J Cancer 2008; 44:2388–2396.
7▪▪. Ribeiro RC, Steliarova-Foucher E, Magrath I, et al. Baseline status of paediatric oncology care in ten low-income or mid-income countries receiving My Child Matters support: a descriptive study. Lancet Oncol 2008; 9:721–729.
Analysis shows correlation between pediatric cancer outcomes and healthcare indicators.
8. Pérez-Cuevas R, Doubova SV, Zapata-Tarres M, et al. Scaling up cancer care for children without medical insurance in developing countries: the case of Mexico. Pediatr Blood Cancer 2013; 60:196–203.
9. Curado M, Voti L, Sortino-Rachou A. Cancer registration data and quality indicators in low and middle income countries: their interpretation and potential use for the improvement of cancer care. Cancer Causes Control 2009; 20:751–756.
10▪. Valsecchi MG, Steliarova-Foucher E. Cancer registration in developing countries: luxury or necessity? Lancet Oncol 2008; 9:159–167.
Importance of cancer registration to build base for future interventions and guidelines to develop population-based and hospital-based registries.
11. Parkin DM. The evolution of the population-based cancer registry. Nat Rev Cancer 2006; 6:603–612.
12. Howard SC, Metzger ML, Wilimas JA, et al. Childhood cancer epidemiology in low-income countries. Cancer 2008; 112:461–472.
13. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 61:69–90.
14▪▪. Bray F, Jemal A, Grey N, et al. Global cancer transitions according to the Human Development Index (2008–2030): a population-based study. Lancet Oncol 2012; 13:790–801.
A description of international cancer incidence variations and their correlation with human development.
15. Bhatia S. Disparities in cancer outcomes: lessons learned from children with cancer. Pediatr Blood Cancer 2011; 56:994–1002.
16▪. Chow EJ, Puumala SE, Mueller BA, et al. Childhood cancer in relation to parental race and ethnicity. Cancer 2010; 116:3045–3053.
Variations in cancer incidence by ethnicity in the United States may help understand international variations.
17. Greaves M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer 2006; 6:193–203.
18. Supriyadi E, Widjajanto PH, Purwanto I, et al. Incidence of childhood leukemia in Yogyakarta, Indonesia, 1998–2009. Pediatr Blood Cancer 2011; 57:588–593.
19▪▪. Xu H, Cheng C, Devidas M, et al. ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 2012; 30:751–757.
Genetic polymorphisms may help explain differences in cancer incidence and outcomes between ethnic groups.
20. Yang J, Cheng C, Devidas M, et al. Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat Genet 2011; 43:237–241.
21. Parkin D, Stiller C, Draper G, Bieber C. The international incidence of childhood cancer. Int J Cancer 1988; 42:511–520.
22. de Camargo B, de Oliveira Santos M, Rebelo M, et al. Cancer incidence among children and adolescents in Brazil: first report of 14 population-based cancer registries. Int J Cancer 2010; 126:715–720.
23. de Camargo B, de Oliveira Ferreira J, de Souza Reis R, et al. Socioeconomic status and the incidence of noncentral nervous system childhood embryonic tumours in Brazil. BMC Cancer 2011; 11:160.
24. Fajardo-Gutierrez A, Juarez-Ocana S, Gonzalez-Miranda G, et al. Incidence of cancer in children residing in ten jurisdictions of the Mexican Republic: importance of the Cancer registry (a population-based study). BMC Cancer 2007; 7:68.
25. Juarez-Ocana S, Palma-Padilla V, Gonzalez-Miranda G, et al. Epidemiological and some clinical characteristics of neuroblastoma in Mexican children (1996–2005). BMC Cancer 2009; 9:266.
26. Henderson TO, Bhatia S, Pinto N, et al. Racial and ethnic disparities in risk and survival in children with neuroblastoma: a Children's Oncology Group Study. J Clin Oncol 2011; 29:76–82.
27. Chantada GL, Qaddoumi I, Canturk S, et al. Strategies to manage retinoblastoma in developing countries. Pediatr Blood Cancer 2011; 56:341–348.
28. Leander C, Fu LC, Pena A, et al. Impact of an education program on late diagnosis of retinoblastoma in Honduras. Pediatr Blood Cancer 2007; 49:817–819.
29. Leal-Leal CA, Dilliz-Nava H, Flores-Rojo M, Robles-Castro J. First contact physicians and retinoblastoma in Mexico. Pediatr Blood Cancer 2011; 57:1109–1112.
30. De Angelis C, Pacheco C, Lucchini G, et al. The experience in nicaragua: childhood leukemia in low income countries-the main cause of late diagnosis may be ‘medical delay’. Int J Pediatr 2012; 2012:129707.
31▪. Mostert S, Arora RS, Arreola M, et al. Abandonment of treatment for childhood cancer: position statement of a SIOP PODC Working Group. Lancet Oncol 2011; 12:719–720.
Importance of assuming abandonment as a major cause of treatment failure and developing initiatives to combat it.
32. Bonilla M, Rossell N, Salaverria C, et al. Prevalence and predictors of abandonment of therapy among children with cancer in El Salvador. Int J Cancer 2009; 125:2144–2146.
33. Sitaresmi MN, Mostert S, Schook RM, et al. Treatment refusal and abandonment in childhood acute lymphoblastic leukemia in Indonesia: an analysis of causes and consequences. Psychooncology 2010; 19:361–367.
34. Friedrich P, Ortiz R, Strait K, et al. Pediatric sarcoma in Central America. Cancer 2012. [Epub ahead of print]
35. Luna-Fineman S, Barnoya M, Bonilla M, et al. Retinoblastoma in Central America: report from the Central American Association of Pediatric Hematology Oncology (AHOPCA). Pediatr Blood Cancer 2012; 58:545–550.
36. Sitaresmi M, Mostert S, Gundy C, et al. Health-related quality of life assessment in Indonesian childhood acute lymphoblastic leukemia. Health Qual Life Outcomes 2008; 6:96.
37. Israëls T, van de Wetering MD, Hesseling P, et al. Malnutrition and neutropenia in children treated for Burkitt lymphoma in Malawi. Pediatr Blood Cancer 2009; 53:47–52.
38▪. Sala A, Rossi E, Antillon F, et al. Nutritional status at diagnosis is related to clinical outcomes in children and adolescents with cancer: a perspective from Central America. Eur J Cancer 2012; 48:243–252.
Importance of malnutrition as comorbidity that affects outcome in children with cancer in LMICs.
39. Israels T, Damen CWN, Cole M, et al. Malnourished Malawian patients presenting with large Wilms tumours have a decreased vincristine clearance rate. Eur J Cancer 2010; 46:1841–1847.
40. Israëls T, Borgstein E, Jamali M, et al. Acute malnutrition is common in Malawian patients with a Wilms tumour: a role for peanut butter. Pediatr Blood Cancer 2009; 53:1221–1226.
41. Stefan DC, Wessels G, Poole J, et al. Infection with human immunodeficiency virus-1 (HIV) among children with cancer in South Africa. Pediatr Blood Cancer 2011; 56:77–79.
42▪. Gupta S, Antillon FA, Bonilla M, et al. Treatment-related mortality in children with acute lymphoblastic leukemia in Central America. Cancer 2011; 117:4788–4795.
Treatment-related mortality in LMICs is high despite intensity-graduated treatments.
43. Gupta S, Bonilla M, Gamero M, et al. Microbiology and mortality of pediatric febrile neutropenia in El Salvador. J Pediatr Hematol Oncol 2011; 33:276–280.
44. Gupta S, Bonilla M, Valverde P, et al. Treatment-related mortality in children with acute myeloid leukaemia in Central America: incidence, timing and predictors. Eur J Cancer 2012; 48:1363–1369.
45. Caniza MA, Duenas L, Lopez B, et al. A practical guide to alcohol-based hand hygiene infrastructure in a resource-poor pediatric hospital. Am J Infect Control 2009; 37:851–854.
48▪▪. Needleman J, Buerhaus P, Pankratz VS, et al. Nurse staffing and inpatient hospital mortality. N Engl J Med 2011; 364:1037–1045.
A study showing correlation between nursing staffing and patient outcomes that could be very relevant to pediatric oncology units in LMICs.
49. Day SW, Segovia L, Viveros P, et al. Development of the Latin American Center for pediatric oncology nursing education. Pediatr Blood Cancer 2011; 56:5–6.
50. Day SW, Garcia J, Antillon F, et al. A sustainable model for pediatric oncology nursing education in low-income countries. Pediatr Blood Cancer 2012; 58:163–166.
51. Day SW, McKeon LM, Garcia J, et al. Use of joint commission international standards to evaluate and improve pediatric oncology nursing care in Guatemala. Pediatr Blood Cancer 2012. [Epub ahead of print]
52. Wolfe J. Recognizing a global need for high quality pediatric palliative care. Pediatr Blood Cancer 2011; 57:187–188.
53▪. Delgado E, Barfield RC, Baker JN, et al. Availability of palliative care services for children with cancer in economically diverse regions of the world. Eur J Cancer 2010; 46:2260–2266.
Limited access to palliative care and pain management in LMICs.
54. Shad A, Ashraf MS, Hafeez H. Development of palliative-care services in a developing country: Pakistan. J Pediatr Hematol Oncol 2011; 33:S62–S63.
55. Ddungu H. Palliative care: what approaches are suitable in developing countries? Br J Haematol 2011; 154:728–735.
58. Hesseling P, Molyneux E, Kamiza S, et al. Endemic Burkitt lymphoma: a 28-day treatment schedule with cyclophosphamide and intrathecal methotrexate. Ann Trop Paediatr 2009; 29:29–34.
59. Traoré F, Coze C, Atteby J-J, et al. Cyclophosphamide monotherapy in children with Burkitt lymphoma: a study from the French-African Pediatric Oncology Group (GFAOP). Pediatr Blood Cancer 2011; 56:70–76.
60. Molyneux EM, Rochford R, Griffin B, et al. Burkitt's lymphoma. Lancet 379:1234–1244.
61. Karachunskiy A, Herold R, von Stackelberg A, et al. Results of the first randomized multicentre trial on childhood acute lymphoblastic leukaemia in Russia. Leukemia 2008; 22:1144–1153.
62▪▪. Hunger SP, Sung L, Howard SC. Treatment strategies and regimens of graduated intensity for childhood acute lymphoblastic leukemia in low-income countries: a proposal. Pediatr Blood Cancer 2009; 52:559–565.
Intensity-graduated treatment guidelines for ALL as a way of progressive increase in treatment complexity while decreasing toxicity.
63. Sitaresmi MN, Mostert S, Gundy CM, et al. Health-care providers’ compliance with childhood acute lymphoblastic leukemia protocol in Indonesia. Pediatr Blood Cancer 2008; 51:732–736.
64. Bhatia S, Landier W, Shangguan M, et al. Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the Children's Oncology Group. J Clin Oncol 2012; 30:2094–2101.
65. Mostert S, Sitaresmi MN, Gundy CM, et al. Comparing childhood leukaemia treatment before and after the introduction of a parental education programme in Indonesia. Arch Dis Childhood 2010; 95:20–25.
66. Masera G. Bridging the childhood cancer mortality gap between economically developed and low-income countries. J Pediatr Hematol Oncol 2009; 31:710–712.
67. Ekenze SO, Ekwunife H, Eze BI, et al. The burden of pediatric malignant solid tumors in a developing country. J Trop Pediatr 2010; 56:111–114.
68. Qaddoumi I, Unal E, Diez B, et al. Web-based survey of resources for treatment and long-term follow-up for children with brain tumors in developing countries. Childs Nerv Syst 2011; 27:1957–1961.
69. Israels T, Moreira C, Scanlan T, et al. SIOP PODC: clinical guidelines for the management of children with Wilms tumour in a low income setting. Pediatr Blood Cancer 2013; 60:5–11.
70. Al-Jumaily U, Ayyad O, Masarweh M, et al. Improved care of rhabdomyosarcoma in Jordan using less intensive therapy. Pediatr Blood Cancer 2013; 60:53–58.
71. Rivera GK, Quintana J, Villarroel M, et al. Transfer of complex frontline anticancer therapy to a developing country: the St. Jude osteosarcoma experience in Chile. Pediatr Blood Cancer 2008; 50:1143–1146.
72. Israels T, Chagaluka G, Pidini D, et al. The efficacy and toxicity of SIOP preoperative chemotherapy in Malawian children with a Wilms tumour. Pediatr Blood Cancer 2012; 59:636–641.
73▪. Wilimas JA, Wilson MW, Haik BG, et al. Development of retinoblastoma programs in Central America. Pediatr Blood Cancer 2009; 53:42–46.
A model for building regional centers of excellence for pediatric cancers.
74. Palma J, Mosso C, Paris C, et al. Establishment of a pediatric HSCT program in a public hospital in Chile. Pediatr Blood Cancer 2006; 46:803–810.
75. Palma J, Salas L, Carrión F, et al. Haploidentical stem cell transplantation for children with high-risk leukemia. Pediatr Blood Cancer 2012; 59:895–901.
76. Weatherall DJ. The challenge of haemoglobinopathies in resource-poor countries. Br J Haematol 2011; 154:736–744.
77. Ribeiro R, Pui C-H. Treatment of acute lymphoblastic leukemia in low- and middle-income countries: challenges and opportunities. Leuk Lymphoma 2008; 49:373–376.
78. Scanlan T, Kaijage J. From Denis Burkitt to Dar es Salaam. What happened next in East Africa? – Tanzania's story. Br J Haematol 2012; 156:704–708.
79. Hazin R, Qaddoumi I. Teleoncology: current and future applications for improving cancer care globally. Lancet Oncol 2010; 11:204–210.
80. Santiago TC, Jenkins JJ, Pedrosa F, et al. Improving the histopathologic diagnosis of pediatric malignancies in a low-resource setting by combining focused training and telepathology strategies. Pediatr Blood Cancer 2012; 59:221–225.
81. Denburg AE, Joffe S, Gupta S, et al. Pediatric oncology research in low income countries: ethical concepts and challenges. Pediatr Blood Cancer 2012; 58:492–497.
82. Quintana Y, Patel A, Naidu P, et al. POND4Kids: a web-based pediatric cancer database for hospital-based cancer registration and clinical collaboration. In: Borycki EM, et al., editors. International perspectives in health informatics 2011. IOS Press; 2011. pp. 227–231.
83. Eden T, Pui C-H, Schrappe M, et al. All children have a right to full access to treatment for cancer. Lancet 2004; 364:1121–1122.