Burden of Childhood Cancer in LMICs

In high-income countries (HICs), the annual incidence of childhood cancer is approximately 140 per 1 million children younger than age 15 years, although estimates vary between and within countries (Parkin and others 1998). Incidence rates from low- and middle-income country (LMIC) registries are generally significantly lower, as annual rates per 1 million children of 45.6 in Namibia and 64.4 in India, respectively, illustrate (Parkin and others 1998). Some of this variation may relate to differences in environmental exposures or to biologic susceptibility. However, deficiencies in diagnosis and registration likely contribute significantly to differences in the reported incidence of cancer, both overall and of particular subtypes, such as acute leukemias (Howard and others 2008).

Incidence data from high-quality cancer registries with complete population coverage are rare in LMICs. In 2006, only 8 percent of people in Asia and 11 percent in Sub-Saharan Africa were covered by population-based cancer registries; when only high-quality registries are considered, these rates are 4 percent and 1 percent, respectively (Ferlay and others 2010).

Multiple steps are required for children with cancer to be included in a registry (figure 7.1). Caregivers must seek medical attention for symptoms. Primary health care workers must appropriately refer patients to third-level centers capable of recognizing and diagnosing pediatric malignancies and then entering data into cancer registries. Breaks in the chain of events may occur at any step.

Figure 7.1

Links in the Chain of Childhood Cancer Diagnosis and Registration with Potential Barriers in Low- and Middle-Income Countries.

A comparison of leukemia and non-leukemia cancer incidence rates is instructive. Pediatric leukemia may present with a variety of nonspecific symptoms, such as fever, anemia, malaise, or hemorrhage; many of the symptoms are also associated with infections. Most non-leukemia cancers present with enlarging masses more easily recognizable as malignant. Accordingly, the magnitude of underdiagnosis would be expected to be greater in leukemia than in non-leukemia cancers; registry data bear this out. In the most recent global compilation of pediatric cancer data, leukemia incidence in low-income countries (LICs) averaged 16.4 per million children, far lower than the incidence rate of 36.5 in middle-income countries (MICs) and 40.9 in HICs (figure 7.2) (Howard and others 2008). The non-leukemia cancer incidence was broadly similar in all income groups: 85 in LICs, 70 in MICs, and 89 in HICs (Howard and others 2008). The underdiagnosis of childhood brain tumors is likely even greater; many regions report few or no incident cases of pediatric central nervous system malignancies (Parkin and others 1998).

Figure 7.2

Reported Incidence Rate of Childhood Leukemia and Its Association with 2005 Gross National Income, Selected Economies.

Underdiagnosis and underregistration are not uniform across all segments of the population. In Jordan and Honduras, higher leukemia incidence rates are reported in urban compared with rural districts (Al Sheyyab and others 2003; Metzger and others 2003). Comparing Indian cancer registries, the male-to-female ratio in acute lymphoblastic leukemia (ALL) incidence ranged from 1.7 per million in Mumbai to 2.6 in Delhi, compared with 1.3 in Canada during the same time period (Parkin and others 1998). At least in some cases, underdiagnosis may affect girls and rural children disproportionately.

In addition, not only is childhood cancer severely underrepresented in LMIC cancer registration; only a proportion of the children who are registered receive appropriate treatment. From a survey of health care workers in 10 LMICs, including Bangladesh, the Philippines, Tanzania, and Vietnam, 15–37 percent of the expected patients were seen (Ribeiro and others 2008). Including children missed by registries would lower this percentage even further.

Thus, the approximately 175,000 children diagnosed with cancer globally every year are likely to represent a significant underrepresentation of the worldwide incidence. Expansion of current cancer registries, improvement in diagnosis and registration, and novel methodologies are needed to establish the true pediatric cancer burden (Ferlay and others 2010; Magrath and others 2013). The International Agency for Research on Cancer is assembling an updated volume of the International Incidence of Childhood Cancer, drawn predominantly from registry data. Comparisons with previous editions will allow an assessment of progress.

Why Treat Childhood Cancer in LMICs?

Platforms for Childhood Cancer Treatment Delivery

Dedicated Centers

Childhood cancer treatment requires specialized diagnostic and therapeutic capabilities, as well as the ability to manage potential complications. Expensive, high-technology equipment is not required, however. Although volume-outcome relationships have not been convincingly demonstrated in pediatric oncology, the dominant paradigm is to manage care through a limited number of treatment centers in which resources and expertise are concentrated. Satellite centers can deliver some treatment, decreasing the burden on families, providing rapid management of complications and, in LMICs, decreasing abandonment of treatment (Metzger and others 2003; Pediatric Oncology Group of Ontario 2012).

Tables 7.1 and 7.2 list the personnel and infrastructural requirements for an ideal LMIC center delivering pediatric cancer care; however, many institutions in LMICs deliver curative treatment in the absence of many of these elements (Harif and others 2008; Madani and others 2006; Pedrosa and others 2000). Such treatment must be adapted to local capabilities. For example, centers without an intensive care unit or ventilators will not be able to deliver as intensive chemotherapy as ones with these resources, but they will nonetheless be able to cure a portion of children.

Table 7.1

Examples of Essential Personnel for Ideal Pediatric Cancer Care in Low- and Middle-Income Countries.

Table 7.2

Infrastructure Needed to Deliver Ideal Pediatric Cancer Care in Low- and Middle-Income Countries.

It is worth highlighting the importance of stable drug supplies. Shortages of essential chemotherapy agents have been shown to impact pediatric survival, even in HICs (Metzger, Billett, and Link 2012). In LMICs, the impact of inconsistent chemotherapy availability is likely to be even greater.

In many LMICs, childhood cancer services are delivered through cancer hospitals serving primarily adult populations. In these instances, appropriately sized pediatric equipment and specific pediatric expertise are still required. Even when these requirements are met, the neglect of pediatric populations in the face of large volumes of adult patients may still adversely impact the quality of childhood cancer care.

General Principles of Treatment

Importance of Locally Adapted Treatment Protocols

Although not true for all cancers, increasing the intensity of treatment has increased cure rates (Matthay and others 1999; Womer and others 2012; Woods and others 1996). Different childhood cancers require different treatment intensities for maximum cure rates; for example, the chemotherapy for Wilms tumor is far less intense than for acute myeloid leukemia (AML). One of the great achievements of pediatric oncology in recent decades is the refinement of risk stratification systems, allowing for an assessment of the aggressiveness of a particular child’s cancer and for treatment intensity to be matched to disease risk, thereby reducing both undertreatment and overtreatment (Crawford, MacDonald, and Packer 2007; Maris 2010; Metzger and Dome 2005; Pui, Robison, and Look 2008).

Avoiding overtreatment is crucial in LMICs, since it carries with it an increased risk of treatment-related mortality (TRM), defined as death from complications of treatment, as opposed to the disease itself (Creutzig and others 2004; Ethier and others 2011; Gupta and others 2009; Gupta and others 2011; Prucker and others 2009). At some point, any benefit in disease control of intensifying treatment will be outweighed by an increase in TRM. Finding the balance point for each malignancy at each pediatric cancer center is key to optimizing therapy and curing the maximum number of children possible.

This ideal balance point depends on the malignancy in question, as well as a particular center’s ability to provide supportive care to prevent and manage treatment complications. The same high intensity chemotherapy delivered at two centers, one with 24-hour availability of intensive care and the other without, will result in higher TRM rates in the latter. In HICs, advances in supportive care have allowed the delivery of ever higher intensity treatments. Even in this context, however, the ideal balance has at times been difficult to find; intensifying treatment for AML initially resulted in high TRM rates in Europe and North America, which later decreased as cancer units developed the new level of supportive care required (Creutzig and others 2004; Lange and others 2008).

In many LMIC centers, supportive care capabilities lag behind those in HICs. Transposing treatment protocols designed for HIC levels of supportive care to LMIC centers is therefore almost certain to cause high levels of TRM (Gupta and others 2009; Gupta and others 2011). The possibility of doing more harm than good is significant. An important example is described in box 7.1, where decreasing treatment intensity actually led to higher cure rates. Questions to ask when trying to determine the supportive care capabilities of an individual institution include the following:

Box 7.1

Acute Promyelocytic Leukemia: Cost and Treatment Intensity.

• Are 24-hour nursing and medical coverage available for inpatients?
• How quickly can antibiotics be ordered, received, and given to patients when urgent treatment is necessary?
• How quickly can a blood transfusion be ordered, received, and given to patients when urgent treatment is necessary?

• Are basic radiographic, microbiologic, and hematologic diagnostic tests available?
• Is intensive care, including ventilator and inotropic support, available?
• What is the prevalence of malnutrition in the population? What programs are available in the pediatric cancer unit to address malnutrition?
• Are families able to reach medical attention quickly in case of a treatment complication?
• Where do outpatients go when emergencies develop after hours? Who treats them there? Are pediatric oncology professionals involved in their care after hours?

Further consequences stem from the principle that increased intensity and cost of treatment can do more harm than good. Many diagnostic modalities are utilized to classify the extent of disease, including stage and risk group, of particular patients. For example, in ALL, the most common childhood cancer in many countries, flow cytometry and cytogenetics help to identify high-risk subgroups, such as T-cell or hypodiploid ALL (Pui, Robison, and Look 2008). Children with these high-risk subgroups are treated with higher intensity protocols. In a center in which higher intensity therapy leads to unacceptable TRM rates, spending limited resources on developing these diagnostic modalities is difficult to justify. However, making a correct diagnosis (such as distinguishing between myeloid and lymphoblastic leukemia) is often life-saving and cost-effective (Howard and others 2005).

Abandonment of Therapy

Abandonment is defined as the “failure to start or complete [potentially] curative treatment” (Mostert and others 2011, 719). The phenomenon of abandonment, virtually unknown in HICs, is a significant problem in LMICs; in some contexts, it constitutes the most common cause of treatment failure (Arora, Eden, and Pizer 2007). The importance of this issue led SIOP to establish the Abandonment of Treatment Working Group (Mostert and others 2011). A systematic review of pediatric acute lymphoblastic leukemia in LMICs found that abandonment rates ranged from 3 percent to an astonishing 74 percent (Gupta and others 2013). None of 83 published reports of abandonment were from LICs, so the review likely underestimates the global incidence of abandonment.

Many reasons for abandonment have been cited, including a lack of financial resources, poor disease comprehension, cultural factors, belief in alternative medicines, fear of treatment toxicity, inadequate care on the part of health care workers, and decreased awareness of aid programs (Bonilla and others 2009; Howard and others 2004; Kulkarni and Marwaha 2010; Luo and others 2009a; Mostert and others 2006). Interestingly, even in the context of a treatment program in which chemotherapy, supportive care, lodging, and transport were provided at no cost to families, families of low socioeconomic status were still at higher risk of abandonment (Bonilla and others 2009). Various efforts in LMICs have decreased abandonment rates, including providing financial support, adapting treatment protocols based on a family’s financial resources, providing parental education, and establishing a social work program (box 7.2) (Bonilla and others 2009; Howard and others 2004; Luo and others 2008; Mostert and others 2010).

Box 7.2

Examples of Successful Efforts to Decrease the Abandonment of Therapy in Children with Cancer.

Thus, just as some level of basic supportive care capacity is necessary to treat children with cancer, basic educational and aid programs aimed at preventing abandonment are also imperative.

Treatment of Specific Cancers

The ideal malignancy targeted for treatment in LMICs would be one that accounts for a significant proportion of the local cancer burden and that is curable with either simple surgery or short-course chemotherapy alone. The treatment of this ideal target would involve minimal acute toxicity and few chronic late effects—survivorship issues specific to LMIC children are unstudied. Of course, no single malignancy perfectly fits this profile. Which malignancies should be treated in a particular LMIC center depends on the local incidence, the available treatment modalities, the institutional level of supportive care possible, and theoretically attainable cure rates.

A center that is only beginning to treat childhood cancer could start with malignancies for which cure is possible with relatively simple and low-intensity chemotherapy, such as BL or Hodgkin lymphoma (HL). A center that has achieved significant cure rates in these cancers could then address malignancies requiring more complex chemotherapy (for example, ALL) and multimodality treatment (for example, Wilms tumor) and could eventually advance to treatment of sarcomas, brain tumors, and diseases that require high levels of supportive care (for example, AML, high-risk neuroblastoma). Table 7.3 lists characteristics of 13 of the most common childhood cancers; this information should be considered before deciding which malignancies to treat and which resources to develop in a specific setting. For each type of cancer, the elements required for successful treatment may differ based on stage and risk group. For example, while intensive chemotherapy, surgery, radiation, and autologous stem cell transplantation cure only a minority of advanced-stage neuroblastoma in older children, surgery alone may cure localized and biologically favorable neuroblastoma in a younger child.

Table 7.3

Characteristics of Childhood Cancers to Consider When Determining Which Malignancies Are Appropriate for Treatment in a Particular Resource-Constrained Setting.

The subsequent sections discuss five childhood cancers often targeted by LMIC centers because of their high potential cure rates with relatively low intensity treatment regimens. In addition, these five cancers collectively account for a significant portion of pediatric malignancies: ALL, HL, Wilms tumor, BL, and retinoblastoma. Each section outlines aspects of diagnosis and treatment and how both may be adapted to local resource constraints.

Hodgkin Lymphoma

Monika L. Metzger¹

¹Division of Leukemia/Lymphoma, St. Jude Children’s Research Hospital, Memphis, TN, United States.

In HICs, over 80 percent of children with HL survive long-term. In LMICs, survival has been lower because of lack of adequate staging, drug shortages, inadequate access to radiotherapy, delays in therapy, and social hardship leading to abandonment of therapy. Most children with HL in LMICs present to medical attention with advanced-stage disease and a long history of symptoms. Despite these obstacles, many LMIC patients can still be cured with basic chemotherapy, with or without consolidative radiotherapy. HL is curable, diagnosable without expensive technology, and constitutes an important portion of children with cancer.

Epidemiology and Prognostic Factors

Childhood HL rarely presents before five years of age in HICs; however, in LMICs it can be seen in children as young as age one year. In HICs, HL has a bimodal age distribution in early adulthood and after the age of 50 years. The age distribution is shifted toward younger ages in LICs, and it often occurs before adolescence. Furthermore, in LMICs, HL is most often Epstein-Barr virus-positive and of mixed cellular histology (Siddiqui and others 2006). Disease stage and bulk, as well as the presence of “B-symptoms” (fevers, drenching night sweats, or greater than 10 percent weight loss in the past six months) are established prognostic factors. Other potential prognostic factors include the erythrocyte sedimentation rate and low hemoglobin and albumin levels, although these may be less reliable indicators in children suffering from chronic malnutrition or parasitic infections.

Diagnosis of HL

An excisional lymph node biopsy is recommended, as fine-needle aspirates are often inadequate for diagnosis. This is, in fact, the only surgical procedure routinely required in the treatment of HL. Pathology is basic; the diagnosis can be confirmed with a simple hematoxylin and eosin stain without the need for immunohistochemistry.

Staging and Treatment Options

In HICs, the ideal initial evaluation of children for HL includes computed tomography of the neck, chest, abdomen, and pelvis, accompanied by FDG-positron emission tomography. Staging and the presence of B-symptoms allow risk stratification with therapy tailored according to risk of relapse and adapted based on disease response after two cycles of chemotherapy. Risk-stratified, response-adapted therapy offers the potential to maximize cure and minimize toxicity (Hodgson, Hudson, and Constine 2007).

In LMICs with limited availability of diagnostic imaging, a thorough physical examination for determination of all pathologic peripheral adenopathy, chest radiograph for extent of mediastinal involvement, and ultrasonography for intra-abdominal adenopathy can be sufficient for staging. Bone marrow biopsy is not recommended for most patients, since it is expensive, painful, and rarely affects risk classification or therapy (Hines-Thomas and others 2010). In some cases, a positive bone marrow biopsy may actually harm the patient by leading to the false perception that bone marrow involvement is incurable or that consolidative radiation therapy is not indicated.

In cases of limited staging evaluation, the treatment approach must account for incomplete ascertainment of affected areas. Accordingly, more weight must be placed on effective chemotherapy and less on local control with radiotherapy, which would not be applied to disease sites undetected by incomplete staging evaluations. Furthermore, radiation therapy is often unavailable, inconsistently available, or too toxic when given by radiation oncologists without pediatric expertise. Risk stratification in many LMICs should also be broader, similar to early HIC chemotherapy-only trials. Table 7.4 provides examples of chemotherapy-only and combined modality treatment regimens used successfully in LMICs.

Table 7.4

Treatment Results of Pediatric Hodgkin Lymphoma Trials in Low- and Middle-Income Countries.

During HL treatment, the minimum necessary supportive care consists of antibiotics and antiemetics, blood products are rarely needed, and therapy can be administered in the outpatient setting without the need for growth factors.

Costs of HL Treatment

The bulk of the cost of HL therapy is due to pathologic evaluation, radiation therapy, and diagnostic imaging studies; chemotherapy and supportive care constitute a far smaller portion. In a study evaluating the cost of therapy in Sub-Saharan Africa for a child with stage II disease and followed for two years, the total cost was more than US$6,500 in a continent where the annual gross domestic product (GDP) per inhabitant is usually less than US$2,000 (Stefan and Stones 2009). However, these costs can be significantly reduced by carefully choosing the minimal necessary diagnostic imaging techniques required for staging and chemotherapy regimens that will permit the omission of radiotherapy. The most important cost to avoid is that of relapse.

Wilms Tumor

Trijn Israels¹

¹Department of Pediatric Hematology/Oncology, VU University, Amsterdam, The Netherlands.

Wilms tumor is relatively common, accounting for 5–7 percent of all childhood cancers (Stiller and Parkin 1996). In many settings, Wilms tumor is the most common malignant abdominal tumor. As treatment programs for pediatric oncology are developed, Wilms tumor should be one of the first tumors targeted because of its frequency and curability. Treatment also requires the development of multidisciplinary capacities that may benefit other children and programs across the hospital.

Great progress has been made in the treatment of children with Wilms tumor in recent decades. The survival rates in HICs now exceed 85 percent. Multidisciplinary treatment combines surgery and chemotherapy, with radiotherapy in a selected group of patients (Graf, Tournade, and de Kraker 2000; Green 2004). Two treatment strategies have been used for Wilms tumor worldwide. The first operates on tumors upfront, as practiced by the Children’s Oncology Group in North America, followed by chemotherapy; the second starts with preoperative chemotherapy, as practiced in Europe (SIOP). Both strategies result in similar long-term survival for HIC patients (Graf, Tournade, and de Kraker 2000; Green 2004). Preoperative chemotherapy, however, reduces surgical complications, such as tumor rupture, and downstages the tumor at surgery, thereby allowing for lower intensity, postoperative chemotherapy and reducing the need for radiotherapy. This is a sensible strategy for many LMIC patients, who often present with large tumors in settings where supportive care is limited and radiotherapy may not be available.

Survival rates in LMICs are lower than in HICs, ranging from 11 percent to 81 percent (Abuidris and others 2008; Israels 2012; Israels and others 2012; Moreira and others 2012; Wilde and others 2010). Known challenges are late presentation with advanced disease, malnutrition, abandonment of treatment, and poor facilities for specific cancer treatment and supportive care (Abuidris and others 2008; Harif and others 2005; Moreira and others 2012). Capacity building, earlier presentation, a multidisciplinary approach, social support, improved supportive care, and treatment adapted to local circumstances are key to improving results (Hadley 2010; Hadley, Rouma, and Saad-Eldin 2012; Israels and others 2012).

Treatment Settings

The facilities and resources available for the care of children with Wilms tumor vary among centers, but they can be defined using the following settings (table 7.5):

Table 7.5

Classification of Different Settings Providing Care for Children with Wilms Tumor.

• Setting 1 is one in which the minimal requirements for treatment with curative intent are available.
• Setting 3 is one where all state-of-the-art facilities are available.
• Setting 2 is in between.

Diagnosis

The diagnosis of Wilms tumor can be made with reasonable certainty based on history, physical examination, and ultrasonography of the abdomen. The typical presentation of a child with Wilms tumor in low-income settings is that of a malnourished young child with a large abdominal or flank mass, who is relatively well without acute pain or severe general malaise, but with hematuria and hypertension (Green 2004; Israels 2012). Ultrasonography of the abdomen is extremely useful to confirm the diagnosis (De Campo 1986; Hartman and Sanders 1982; Lowe and others 2000). An x-ray should be done to detect chest metastases.

In HICs, pathology is useful to confirm the diagnosis and, in addition to stage, to help risk stratify children and determine postoperative chemotherapy. In many LMICs, however, the availability of pathologists with pediatric expertise is limited and pathology results often are available too late to effect clinical decision making. Other challenges include the appropriate processing of specimens and the availability of special stains and immunohistochemistry, although central pathology review or telepathology may be helpful (Vujanic and others 2009). Fortunately, a diagnosis can often be made with some certainty based on clinical findings and ultrasonography. Postoperative chemotherapy can be based on surgical staging, only if needed.

A diagnostic biopsy before preoperative chemotherapy is not standard practice in current SIOP Wilms protocols; it is only recommended in LMICs when there is serious doubt about the diagnosis (Vujanic and others 2003). Such biopsies may result in bleeding, infection, or tumor spillage with consequent upstaging.

Treatment of Wilms Tumor

Preoperative chemotherapy should be used for children with Wilms tumor in LMICs, even in cases of small, seemingly easily resectable tumors (Lemerle and others 1983). Preoperative chemotherapy reduces surgical complications, downstages the tumor, and allows for less intense postoperative chemotherapy and the potential avoidance of radiotherapy (Graf, Tournade, and de Kraker 2000). Reliable and continuous access to the chemotherapeutic drugs such as vincristine, actinomycin D, and doxorubicin is essential.

Radiotherapy is used in patients with advanced-stage or unfavorable histology disease in centers with advanced capabilities. Unfortunately, safe radiotherapy for children is often unavailable in developing countries. The recent National Wilms Tumor Study and SIOP studies have shown that omitting or decreasing radiation therapy may not compromise cure rates, but these studies have not been done in children with very advanced disease or large tumors. Studies from Morocco and Nicaragua have demonstrated that cure can be achieved in some patients with advanced disease without radiotherapy (Baez and others 2002; Madani and others 2006). Higher cure rates in these populations may, however, require radiotherapy.

Table 7.6 shows some elements of the therapy used and the results from selected countries with limited resources. More detailed treatment recommendations can be found in a recently published SIOP guideline developed for use in LMICs (Israels and others 2013).

Table 7.6

Reported Outcomes of Patients with Wilms Tumor Treated in Low- and Middle-Income Countries.

Cost of Wilms Treatment

To date, cost analyses related to the treatment of children with Wilms tumor in LMICs have not been reported. Although of relatively long duration (six months to two years), treatment is of relatively low intensity and does not involve expensive chemotherapeutic agents. The costs of surgery are likely to be high. Social support enabling parents to complete treatment is very likely to be cost-effective in LMICs.

Burkitt Lymphoma

Mhamed Harif¹

¹Unité Hématologie et Oncologie Pédiatrique, Centre d’Oncologie et Hématologie, Centre Hospitalier Mohammed VI, Marrakech, Morocco.

BL is a mature B-cell neoplasm that arises in lymphoid tissue, commonly in the jaw or abdomen. Described first in 1957 by Denis Burkitt in Uganda, it remains the most common pediatric cancer in malaria-endemic regions of Sub-Saharan Africa (Burkitt 1958; Lewis and others 2012). BL invariably arises from chromosomal translocations in which an oncogene (c-myc) is juxtaposed with genes encoding immunoglobulins. These translocations lead to an overexpression of monoclonal surface immunoglobulins in malignant cells, which is important for diagnosing and distinguishing it from other lymphoid cancers.

Although more than 90 percent of children with BL in HICs can be cured, doing so requires timely, accurate diagnosis and risk-directed treatment with high intensity chemotherapy and well-developed supportive care (Patte and others 2007). In many LMICs with limited supportive care, delivery of such therapy causes excessive toxic death; adapted regimens are necessary to cure as many patients as possible (Hesseling, Israels, and others 2012). Nevertheless, in even the most resource-constrained environment, a simplified protocol for patients with BL can cure 50 percent (Hesseling and others 2009). Indeed, treatment of BL is likely to be highly cost-effective in all settings (Bhakta and others 2012).

Diagnosis

Suspected BL is a medical emergency. BL is the fastest growing human malignancy, in some cases doubling its volume every 24 hours. The risks of tumor lysis syndrome (TLS)—a collection of metabolic derangements caused by the rapid turnover of malignant cells, disease progression, nutritional deterioration, and concomitant infection—make diagnosis and therapy critical. Indeed, any child from an endemic region presenting with massive facial swelling or an abdominal mass requires immediate physical and laboratory evaluation for any of these complications.

Biopsy of the suspected tumor is recommended for diagnosis, but extensive surgery is contraindicated. The top priority must always be to make a diagnosis in the fastest, least invasive way possible and to initiate therapy rapidly. In rare cases, BL cells may be seen in the peripheral blood, as in Burkitt leukemia, obviating the need for a biopsy. A fine-needle aspiration may be sufficient in patients whose clinical features are consistent with BL (Razack and others 2011). When possible, the presence of mature B-cell markers (for example, CD20, immunoglobulin) and proliferative markers, such as Ki67, should be verified to differentiate BL from other small, round, blue cell tumors.

In cases in which the diagnosis is very likely and pathologic confirmation will be delayed, chemotherapy with cyclophosphamide, vincristine, and prednisone (COP) may be initiated empirically in potentially life-threatening situations. These agents have low toxicity and are active for most lymphomas. The benefits of prompt therapy initiation greatly outweigh the risks, as delayed therapy can lead to metabolic complications such as TLS that can be rapidly fatal.

Staging Evaluations and Risk Stratification

Staging evaluations in HICs includes a detailed physical examination to document peripheral adenopathy and testicular involvement; computed tomography imaging of the neck, chest, abdomen, and pelvis to define all sites of adenopathy; and the evaluation of cerebrospinal fluid, bone marrow aspirates, and biopsies. Ideally, lumbar punctures are delayed until a diagnosis is made, so that intrathecal therapy can be administered at the time of the diagnostic puncture. The Murphy (St. Jude) staging system is most commonly used to classify the extent of disease (Murphy 1978). In LMICs, a physical examination, chest radiograph, abdominal ultrasound, bone marrow aspiration, and lumbar puncture may provide sufficient staging information (Marjerrison and others 2012).

Disease risk assignment, and thus treatment intensity, is determined mainly by disease stage. Lactate dehydrogenase level indicates disease activity and affects risk group assignment in some, but not all, HIC protocols. Inadequate response to treatment, defined in HICs as less than 20 percent reduction in tumor size after the initial chemotherapy cycle or residual cancer after the first intense blocks of therapy, require intensification of therapy. Different definitions of inadequate response have been used in resource-constrained settings (Hesseling, Israels, and others 2012). In either case, the dimensions of all masses must be documented at presentation.

Treatment

The optimal treatment regimen for a particular patient depends on disease stage, as well as the environment of care. Families with high socioeconomic status, good transportation, and proximity to a pediatric cancer unit with excellent infrastructure and supportive care can be treated on an HIC regimen, including intensive- and short-duration therapy with vincristine, cyclophosphamide, doxorubicin, cytarabine, high-dose methotrexate, and intrathecal agents. Duration and intensity vary according to risk group, but overall the therapy produces a 90 percent cure rate (Patte and others 2007). However, this treatment approach in settings with limited supportive care exposes patients to high rates of mortality and abandonment.

In LMICs and even in very poor settings, it has been shown that at least 50 percent of children with BL and up to 70 percent of children with localized stage I or stage II disease can be cured with intravenous or oral cyclophosphamide in combination with intrathecal methotrexate (Harif and others 2008; Hesseling and others 2009; Traore and others 2011). Treatment with simplified regimens is feasible everywhere and should always be attempted (table 7.7).

Table 7.7

Selected Cohorts and Outcomes of Children with Burkitt Lymphoma Treated in Low- and Middle-Income Countries with Locally Adapted Protocols of Lower Intensity.

In all cases, optimizing supportive care includes the prevention and treatment of TLS, infection, and vomiting. TLS is the most common cause of early death in patients with BL (Howard, Jones, and Pui 2011). Aggressively hydrating (three liters/m²/day), frequently monitoring urine output and serum chemistry values, and controlling uric acid with rasburicase (where available) or allopurinol can prevent acute kidney injury in most cases. Nutritional support and the prompt diagnosis and treatment of febrile neutropenia and mucositis are the mainstays of supportive care after the first week. Family education, written care pathways, and creative nutritional supplements can produce remarkable results, even in LMICs (Gavidia and others 2012; Israels and others 2009).

Relapses are usually seen during the first six months and are rare after one year. Follow-up after one year focuses on identifying late toxicities and assisting with reintegration into society. In LMICs, recruiting survivors to improve community awareness of pediatric cancer care and the possibility of cure is essential.

More detailed treatment recommendations can be found in a published SIOP guideline developed for use in LMICs (Hesseling, Israels, and others 2012).

Costs of BL Treatment

As in other pediatric malignancies, data on the cost-effectiveness of treatment are rare. Given that a small number of doses of cyclophosphomide, a relatively inexpensive drug, can cure a significant portion of children, the treatment of BL is likely to be highly cost-effective. A paper using data from Malawi demonstrated that using the World Health Organization (WHO) definition, treatment costs under US$14,243 per case would be considered very cost-effective (Bhakta and others 2012). Actual estimated costs of treatment per case, at US$50, were far lower, although this figure only accounted for the costs of chemotherapy and is likely an underestimate.

Cost-Effectiveness of Treating Childhood Cancer

Financial objections are often raised to the treatment of childhood cancer in resource-constrained settings; policy makers and lay persons may assume that any such treatment is prohibitively expensive. However, this assumption is often unsupported.

Indeed, preliminary evidence suggests that treating childhood cancer may be highly cost-effective. Standard WHO methodology defines cost-effectiveness as the ratio of the cost required to avert one disability-adjusted life year to the annual per capita GDP of the area (WHO 2003). Ratios of 3:1 are considered cost-effective, while ratios of 1:1 are considered very cost-effective. Bhakta and others found that the amount that could be spent on a single case and still remain under the very cost-effective threshold was US$257,000 for ALL in Brazil and US$14,243 for BL in Malawi (Bhakta and others 2012). Although treatments costing these theoretical thresholds may still be unachievable for many LMICs, Bhakta and others also found that these cancers could be treated for a fraction of the threshold values: US$16,400 and less than US$50, respectively. Table 7.8 and figure 7.3 illustrate cost-effective thresholds for several malignancies in various countries and compare them with actual costs, when available. These figures, however, do not account for the initial expenditures associated with developing new pediatric oncology treatment centers, such as the initial training of personnel or acquisition of infrastructure. Further data on theoretical cost-effectiveness thresholds and real costs are needed to aid LMIC policy makers.

Table 7.8

Comparison of Cost-Effectiveness Thresholds among Common Childhood Cancers, Selected Countries.

Figure 7.3

Cost-Effective Thresholds Compared with Actual Costs in Selected Pediatric Malignancies.

Discussions of cost and cost-effectiveness in pediatric oncology should consider three additional factors.

• First, adapted treatment regimens of lower intensity can cure a significant proportion of children, with further increases in intensity delivering real, but diminishing, gains. This observation suggests that in most LMICs, an initial modest commitment of funds to childhood cancer will result in a dramatic increase in survival, although further improvements will require significant additional resources.
• Second, traditional cost-effective models assume a finite resource pool; funding one intervention requires cutting another. This zero-sum assumption may not be applicable to childhood cancer. In multiple LMICs, largely through the efforts of nongovernmental organizations, private funds that otherwise may have remained outside the health system have instead been allocated to pediatric oncology centers. The success of Unidad Nacional de Oncología Pediátrica (UNOP) in Guatemala provides an example of how multiple sectors can be mobilized, creating a positive-sum scenario. An initial outlay of funds to UNOP through a twinning program was leveraged into additional resources from government and private donors. The creation of an independent fundraising organization (Fundación Ayúdame a Vivir, http://ayuvi.org.gt) was essential to this outcome. Figure 7A.1 in the online annex illustrates the results of this process.
• Finally, determining whether resources should be allocated to the treatment of childhood cancer may be more complex than simple analyses of cost and cost-effectiveness. Arguments pertaining to justice, equity, and the non-monetary value of children to society may well hold resonance for governments, policy makers, health care workers, and the general public.

Conclusions and Future Directions

Although the advances in pediatric oncology in HICs have not been fully realized in most LMICs, significant progress has been achieved in some pediatric cancer units. The challenge remains to extend this progress to all cancer centers in LMICs and to close the survival gap. The following steps are key prerequisites:

• The development of national childhood cancer strategies is needed to move beyond the twinning paradigm and to increase cure rates for entire populations. Lobbying of governments by clinicians and parent groups is required, as are strengthening links between childhood cancer advocates in HICs and LMICs.
• To better inform governments and health officials, further research into the cost and cost-effectiveness of treatment is necessary. Without such data, the misconception of childhood cancer treatment as unaffordable will persist.
• The outcomes of children with cancer should be monitored by individual treatment centers using data entry systems. These data should be used continually to evaluate and modify the local implementation of therapeutic interventions. Governments can encourage this process through national childhood cancer strategies that include high-quality pediatric registries.
• Further research is needed into how to effectively treat various different childhood malignancies in settings of different resource constraints. Studies identifying how to prevent common causes of treatment failure in LMICs should be conducted.
• The formation of cooperative groups of LMIC centers should be encouraged as forums for protocol evaluation and advocacy; AHOPCA, the French-African Pediatric Oncology Group, and the Brazilian Childhood Cooperative Group for ALL Treatment are three excellent examples. Collaborations with HIC cooperative groups may aid this process.

Pediatric oncology treatment can create a cohort of cancer survivors in LMICs while building cancer management capacity and galvanizing cancer advocacy efforts more generally. Closing the pediatric oncology survival gap will help not only the more than 150,000 children in LMICs who develop cancer every year; it will also have long-lasting benefits for the societies to which they belong.

Note

World Bank income classifications as of July 2014 are as follows, based on estimates of gross national income per capita for 2013:

• Low-income countries: US$1,045 or less
• Middle-income countries:
  • Lower-middle-income: US$1,046–US$4,125
  • Upper-middle-income: US$4,126–US$12,745
• High-income countries: US$12,746 or more

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