Socioeconomic constraints to effective management of Burkitt's lymphoma in south-eastern Nigeria

Authors


Authors
M.M. Meremikwu, E.E. Udoh and E.O. Alaje, Department of Paediatrics, University of Calabar Teaching Hospital, PMB 1278, Calabar, Cross Rivers State, Nigeria. Tel.: +234 87 210 403; Fax: +234 87 236-208; E-mail: mmeremiku@yahoo.co.uk
J.E. Ehiri, Department of Maternal and Child Health, School of Public Health, University of Birmingham at Alabama, 1665 University Boulevard, Ryals Building 320, Birmingham, Alabama 35294-0022, USA. Tel.: +1 205 975 7641; Fax: +1 205 934 8248; E-mail: jehiri@uab.edu (corresponding author)
D.G. Nkanga, Department of Ophthalmology, University of Calabar Teaching Hospital, PMB 1278, Calabar, Cross Rivers State, Nigeria. Tel.: +234 87 222 408 (ext. 236); Fax: +234 87 222 205; E-mail: dennisnkanga@yahoo.com
O.F. Ikpatt, Department of Pathology, University of Calabar Teaching Hospital, PMB 1278, Calabar, Cross Rivers State, Nigeria. Tel.: +234 87 222 408 (ext. 236); Fax: +234 87 222205; E-mail: ofrikpatt@yahoo.com

Summary

This paper presents health outcomes and associated socioeconomic factors of 41 children admitted to a tertiary care institution in south-east Nigeria with Burkitt's lymphoma (BL) between 1987 and 2004. BL responds well to chemotherapy and does not pose a significant threat to health in industrialized nations. However, in resource-poor settings where it is endemic, socioeconomic factors significantly affect access to care for affected children, making this readily treatable condition a cause of considerable distress and early death in affected children. Half of the children reported in this paper presented with late stage disease. Although laboratory facilities were available, they were not accessible to all the children. Nearly a quarter of parents of these children could not afford the cost of confirmatory tests, and about a fifth (n = 8; 19.5%) of the children received no chemotherapy because of their parents’ inability to pay. Only 21 of 41 children (51.2%) remained on treatment long enough (at least 12 weeks) to enable them to be confirmed either as short-term cure (n = 9; 64.3%), or as early relapse (n = 2; 4.9%). Owing to financial constraint, 13 of the parents (31.7%) withdrew their children against medical advice (n = 7; 17.1%) or left the hospital (n = 6; 14.6%). To address the challenge posed by these factors, we call for the establishment of a regional BL programme in Africa to help establish a critical mass of resources (human and material) to facilitate the development of an effective and accessible control programme in the region.

Introduction

Dennis Burkitt, a British physician, first described Burkitt's lymphoma (BL) among Ugandan children in 1958 (Burkitt 1958, 1985). Within the intervening 44 years, the disease has provided scientists with valuable insight into the pathogenesis of cancers, including the possibility of a link with a virus (Ambinder 2003). BL affects the body's lymph system and results in tumours composed of lymphocytes. Burkitt's tumours arise and grow rapidly. However, they respond very well to chemotherapy, and although BL is not a major problem in industrialized societies, proposals for the development of novel therapeutic approaches using molecular genetic technology are already under discussion in these nations (Campo 2003). But in poor countries where it is endemic, many affected families can hardly afford even the cost of basic laboratory diagnostic tests, and this readily treatable condition can be a cause of considerable distress and early death in affected children. Our aim is to present an overview of some of the challenges encountered by children and their families in accessing care for BL in south-eastern Nigeria and the impact of this on the disease outcome for the children.

Burkitt's lymphoma is the commonest childhood cancer in tropical Africa (Aderele & Antia 1983; Daniel 1990). It predominantly affects the jaw and abdominal organs (Burkitt 1958). Although BL is also seen in adults, it is primarily a disease of children, especially those aged between 4 and 8 years (Wright 1997). It is classified as a high-grade type of small cell lymphoma. In tropical Africa and Papua New Guinea where the tumour is endemic, it has been strongly associated with malaria and Epstein–Barr virus infections (Cool & Bitter 1997), and constitutes over 50% of all childhood malignancies (Makata et al. 1996; Sandlund et al. 1996; Xue et al. 2002). The tumour is known to grow very rapidly and can be fatal if untreated. Fortunately, BL is highly chemosensitive and over 75% of limited stage disease has been known to achieve long periods of event-free cure (Sandlund et al. 1996). Despite the availability of chemotherapy and the high cure rate, the outcome of treatment in many parts of Africa remains sub-optimal for reasons ranging from poor health-seeking behaviour to poor economic conditions (Meremikwu & Ikpatt 1997).

The effects of BL depend on the site of the tumour in the body. In African BL, the jaw is the commonest site, where it causes visible swelling of the cheek and loosening of the teeth (Ong et al. 2001). In non-African BL, the tumour commonly arises in the abdomen where it causes swelling and discomfort (Cavdar et al. 1994). Diagnosis is by biopsy from the suspected disease site. Common tests include a complete blood count (CBC), a platelet count, a bone marrow aspiration and biopsy, and lumbar puncture. Further tests may include radiographic examinations such as CT scan to identify occult masses, but extensive X-ray procedures are not usually needed.

Materials and methods

The study was undertaken at the University of Calabar Teaching Hospital (UCTH), a tertiary referral centre that serves a catchment area of over 4 million people in four states within south-eastern Nigeria – Akwa Ibom, Abia, Rivers, and Cross River. The area is located in the tropical rain forest belt, with an average annual rainfall of 1500–2000 mm and is holoendemic for malaria. Ethical approval for the study was obtained from the Ethics Committee of UCTH.

The study was retrospective and covers the period January 1987 to June 2004. Included in this report are children under 15 years of age who had clinical and histopathologic diagnosis of BL and complete hospital records (sociodemographic and medical). Some cases of jaw tumour were not confirmed by histopathology because the parents had no money for this and other laboratory tests. Those whose histopathology was diagnosed in our centre (UCTH) on the request of clinicians working in other hospitals were excluded from this report. The staging of the disease was as proposed by Magrath (1991).

Data collection

Data collected from each child's record included: basic sociodemographic data, medical history, patient's clinico-pathological profile, chemotherapeutic regimen, duration of hospitalization and outcome. The usual protocol adopted for treatment in our centre was a combination of intravenous cyclophosphamide (1 g/m2 body surface area), intravenous vincristine (1.4 mg/m2) and intra-thecal methotrexate (6.5 mg). Depending on the stage of the disease, two to six cycles of this course was given. However, given the fee-for-service system of care, the ability of patients to purchase the drugs actually determined whether or not a child would receive appropriate course of treatment. We computed direct cost of treatment to the parents to include cost of drugs, laboratory tests, and in most cases, blood transfusion services. All cost calculations shown in Table 1 were based on the prevailing rates as of September 2004.

Table 1.  Direct costs of treating a 7-year-old with Burkitt's lymphoma in Nigeria
ItemsUnit costs/details (local currency, Naira)Total cost per child treated (Naira)Cost per child treated (US$)
Laboratory tests at first diagnosis: haematology, histopathology, biochemistry, X-ray, ultra soundCBC = 350245018.9
Histopathology = 500
X-ray = 600
Ultrasound = 500
Biochemistry = 500
Laboratory tests during follow-up 12509.6
Cost of cytotoxic drugs (for 6-course treatment regimen): vincristine, cyclophosphamide, methotrexateCyclophosphamide (1000 × 6) = 600013 500103.8
Vincristine (900 × 6) = 5400
Methotrexate (350 × 6) = 2100
Other patient costs: bed fee, drips, infusion sets, including cross-match and screening blood for transfusion (1 unit)Drips (@ 80 × 6) = 320410031.5
Infusion sets (@ 40 × 7) = 280
Bed fee (@ 50 × 28) = 1400
Blood transfusion (cross-match, screening for hepatitis B and HIV) = 2100
Total direct cost per child treated bsl0008221 300US$163.8

Results

During the 15-year period, a total of 62 children were diagnosed with BL, but only 41 (66.1%) of these were included in this report. Of the 21 excluded from our analysis, nine had incomplete records and 12 were referred by other centres, and were therefore, treated by those centres.

Sociodemographic characteristics

Table 2 shows the sociodemographic characteristics and health-seeking behaviour of caregivers of the 41 children. Most of the children (n = 27; 65.9%) were aged between 5 and 10 years, and the mean age was 7.4 years, ranging from 3 to 15 years (SD = 3.1). Nine (22.0%) were under 5 years of age, while five (12.2%) were aged over 10 years. There were more males (n = 27; 65.9%) than females (n = 14; 34.1%). Most of the children belong to the lower social class – using education and occupation as proxies for economic status. The fathers of nine (22.0%) of 41 children had no school education, and these were among the 15 (36.6%) whose major occupation was subsistence farming. Eighteen (43.9%) of the mothers had no school education.

Table 2.  Socioeconomic characteristics of patients’ families
CharacteristicsFrequency (N = 41)
  1. Values are presented as n (%).

Age
 3.0–4.9
  Males8 (19.5)
  Females1 (2.4)
 5.0–6.9
  Males6 (14.6)
  Females2 (4.9)
 7.0–8.9
  Males5 (12.2)
  Females5 (12.2)
 9.0–10.9
  Males4 (9.8)
  Females5 (12.2)
 11.0–15
  Males4 (9.8)
  Females1 (2.4)
Family size (no. of children)
 <412 (29.3)
 4–620 (48.8)
 7–99 (22.0)
Father's education
 No school education9 (22.0)
 Primary7 (17.1)
 Secondary9 (22.0)
 Tertiary3 (7.3)
 Deceased/unknown13 (31.7)
Mother's education
 No school education18 (43.9)
 Primary10 (24.4)
 Secondary5 (12.2)
 Unknown8 (19.5)
Father's occupation
 Farming (subsistence)15 (36.6)
 Low-level civil servant10 (24.4)
 Petty trading or artisan3 (7.3)
 Deceased/unemployed13 (31.7)
Mother's occupation
 Farming (subsistence)18 (43.9)
 Petty trading9 (22.0)
 Low-cadre civil servant1 (2.4)
 Unemployed/housewife13 (31.7)
Treatment-seeking behaviour
 Consulted a traditional or spiritual (church) healer first11 (26.8)
 Consulted unorthodox practitioner/drug seller13 (31.7)
 Sought help from a health centre/clinic/general hospital17 (41.5)

Clinico-pathological profile, management and outcome

Thirty-two (78.1%) of the patients had pathologic confirmation of their diagnosis. The diagnoses of the nine cases (22.0%) whose parents could not afford the fees for laboratory tests were based on clinical judgment. One of these patients included in this report on account of clinical judgment (in the absence of histopathology) received empiric cytotoxic therapy, and responded favourably. The parents of the other eight could not pay for treatment, and took these sick children away against medical advice. Table 3 shows the clinical picture and haematological profile of the children on admission. The jaw (n = 20; 48.8%), abdomen (n = 16; 39.0%) and the orbit (n = 9; 22.0%) were the commonest sites. Bone marrow and the central nervous system (CNS) were less frequently involved. Most of the children (n = 18; 43.9%) presented within 1 month of the onset of illness. About half of the cases (n = 21; 51.2%) were limited-stage disease (A-B) while the other half were advanced stage (B and C). Underweight (n = 18; 43.9%), fever (n = 8; 19.5), abdominal pain (n = 8; 19.5), ascites (n = 7; 17.1%), splenomegaly, (n = 7; 17.1%) and hepatomegaly (n = 6; 14.6%) were other notable clinical features observed. Most of the children (n = 26; 63.4%) were anaemic on admission. Leucopenia and thrombocytopenia were detected in 17.1% (n = 7) and 9.8% (n = 4) of the patients respectively at the time of admission.

Table 3.  Clinical pattern and diagnosis
Pathological profile and outcomeNo. of patients (%) (N = 41)
  1. * Some of the children had more than one affected site.

  2. † Some of the children had more than one abnormality.

  3. ESR, erythrocyte sedimentation rate.

Pathological confirmatory diagnosis made
 Yes32 (78.0)
 No9 (22.0)
Clinical stage of disease
 A8 (18.5)
 AR0 (0.0)
 B13 (31.7)
 C15 (36.6)
 D5 (12.2)
Sites affected*
 Jaw20 (48.8)
 Orbit9 (22.0)
 Abdomen16 (39.0)
 CNS3 (7.3)
 Bone marrow3 (7.3)
Duration of illness at presentation (month)
 <118 (43.9)
 1–216 (39.0)
 >27 (17.1)
Clinical features observed on presentation
 Jaw swelling20 (48.8)
 Underweight18 (43.9)
 Abdominal swelling14 (34.1)
 Fever10 (24.4)
 Abdominal pain8 (19.5)
 Proptosis8 (19.5)
 Ascites7 (17.1)
 Splenomegaly7 (17.1)
 Hepatomegaly6 (14.6)
Haematologic profile†
 Anaemia (PCV <30%)26 (63.4)
 Leucopenia (WBC <4 × 109/l)7 (17.1)
 Thrombocytopenia (<100 × 109/l)4 (9.8)
 Raised ESR (>20 mm/1 h)11 (26.8)
Diagnostic method
 Fine needle aspiration26 (63.4)
 Excision biopsy6 (14.6)
 Clinical diagnosis with no laboratory confirmation (parents could not afford cost of laboratory tests)9 (22.0)

Table 4 shows the treatment, pattern of post-diagnosis behaviour and outcome. Thirty-two (78.1%) children had chemotherapy with either combined therapy (n = 26; 63.4%) or monotherapy with only cyclophosphamide (n = 7; 17.1%). Monotherapy is not recommended in the treatment protocol used in this hospital, but was used when parents could only afford to buy this one medication.

Table 4.  Treatment, post-diagnosis behaviour and outcome
TreatmentNo. of patients (%) (N = 41)
  1. * Analysis does not include fatal cases.

Chemotherapy given32 (80.5)
No treatment (could not afford cost of care)8 (19.5)
Surgery (debulking ocular) plus chemotherapy1 (2.4)
Outcome
 Remission without early relapse19 (46.3)
 Early relapse2 (4.9)
 Absconded/left against advice13 (31.7)
 Treatment ongoing1 (2.4)
 Died6 (14.6)
Post-diagnosis behaviour of caregivers*
 Left against medical advice7 (17.1)
 Absconded from hospital6 (14.6)
 Lost to follow-up12 (29.3)
 Kept appointments10 (24.4)

Seventeen (41.5%) children with advanced disease (including two relapsed cases) received 2–6 courses. Eight children did not receive chemotherapy because their parents could not afford the recommended drugs. These children's parents later left the hospital against medical advice.

Remission of tumour without relapse in the first 12 weeks of treatment was observed in 19 (46.3%) of the 41 children; thirteen others (31.7%) discharged themselves before or too soon after onset of chemotherapy and no further information was available regarding them. Six of the children (18%) died while in the hospital. Among these were the two that relapsed after initial treatment and remission.

Assessment of the attitude of the parents in the post-diagnosis period shows that irregular discharges (n = 13; 31.7%) were rampant while follow-up was very poor.

Socioeconomic constraints to effective management

Parents of 11 (26.8%) children consulted traditional or spiritual healers, while 13 (31.7%) sought help from unorthodox practitioners and drug sellers before presenting to the hospital (Table 2). Close to half of the patients (n = 20; 48.8%) presented with late stages C and D (Table 3). The time interval between the first appearance of signs of the disease and attendance at our hospital was over 1 month in about half of the children (n = 23; 56.1%). The time interval was longer for illiterate (−5.9 days, SD = 3.9) than literate mothers (−3.8 days, SD = 1.7).

Facilities for laboratory confirmation were available but nine (22.0%) of the parents could not afford the fee. One of these parents had their child treated on the basis of clinical assessment only, but eight (19.5%) children could not receive any treatment because the parents could not afford the cost. Frustrated by this experience, the parents either absconded or left against medical advice (Table 4). Seven (17.1%) other cases had monotherapy (only cyclophosphamide), as the parents had only enough money to buy this.

Abnormal discharge.  Seven parents (17.1%) took their children away against medical advice, while six (14.6%) absconded from the hospital. The parents involved in abnormal discharge were mostly those who could not afford the drugs at all (eight) and those whose children had only minimal response to therapy (three). No obvious explanations were available for two cases of abnormal discharges.

Loss to follow-up.  Twelve (57.1%) of the 22 properly discharged survivors did not keep any follow-up appointments. The reasons for failing to keep appointments were not determined, but were most likely to be cost of transport to the hospital, or concern about possible hospital charges. No visits were made to ascertain whether the children relapsed, deteriorated or died.

Cost of treatment.  The total direct cost to parents of treating BL based on current retail prices of drugs and hospital fees was US$103.8 per child, with 63% made up of the cost of drugs. The cost of treatment is more than twice the minimum monthly wage of US$42.3 for state employees. The income of subsistence farmers who constitute the majority is often far less than the minimum wage.

Discussion

This report confirms the characteristics of the disease as a rapidly growing facial or abdominal tumour. It provides only a snapshot assessment of the difficulties of parents of children affected by BL face in this part of the world given the small sample size. The relatively low prevalence of the disease in our study setting accounts for the small sample size. It is also important to note that our assessment used a very rough indicator of socioeconomic status – education and occupation. Within the context of Nigeria, education and occupation have often provided a reasonable measure of people's economic status and has been widely used in other studies (Adegoke 1992; Uzochukwu & Onwujekwe 2004). There is no reason to believe that the observations reported in this paper are different from the situation in similar settings in other parts of Nigeria and similar settings in many less developed countries.

A male:female ratio of about 2:1 has been described in most studies (Burkitt 1958; Aderele & Antia 1983). Half of the children presented as late stage disease. Late presentation has been identified as a major problem in the management of childhood cancer in Nigeria (Johnson & William 1984; Meremikwu & Ikpatt 1997). Late presentation is known to be associated with poor prognosis in BL and other childhood cancers (Sandlund et al. 1996). Efforts to improve the ability of health workers and parents to recognize the features of BL for early referral to specialized centres would prevent late presentation. It has recently been reported that a BL project in Malawi which among other things, sought to enhance early detection and referral has resulted in a remarkable drop in the number of late stages of BL seen at treatment centres.

Availability of diagnostic facilities and necessary chemotherapeutic agents at affordable cost are vital for effective management of BL. In this report, although laboratory facilities were available, they were not accessible to all the patients. Nearly a quarter of the parents could not afford the costs of confirmatory laboratory tests. One child was treated without pathologic confirmation because of the parent's inability to bear the laboratory costs. This practice, although predicated by the difficult situation in which the attending paediatrician found himself, cannot be recommended as the use of cytotoxic agents on children without histopathological confirmation would expose misdiagnosed cases to adverse effects of these agents with no clinical benefits at all.

Rather than adopt this potentially harmful strategy, further effort should be made to subsidize the cost of diagnosis of paediatric cancer patients and discourage imposition of excessive costs on parents of these children. We have advocated this earlier (Meremikwu & Ikpatt 1997).

Sadly about a fifth of the children received no chemotherapy because their parents could not afford the cost, and in their frustration, took their sick children away, presumably to die at home, or to seek help from traditional healers or spiritual churches. Similar findings have been noted in reports from other parts of Nigeria (Fasola et al. 2002).

This study has shown that the current cost of treatment for BL may not be affordable to a good proportion of parents of affected children who earn little or no regular cash income. We recognize that poor households in low-income countries also experience difficulties with paying for cost of essential drugs for treating other common diseases including malaria, tuberculosis and HIV/AIDS. The establishment of the global fund to fight AIDS, tuberculosis and malaria (GFATAM) is a strong signal that the global community is responsive to the calls to increase access of the poor to effective health care. BL affects fewer children than these infections diseases but still accounts for many preventable deaths if treatment is delayed or denied. BL is a disease of the poor but unlike malaria, TB and HIV/AIDS, it is currently a neglected disease. This paper draws attention to the constraints posed by poor economic and social situation of communities in which BL is endemic. Providing subsidies for the cytotoxic drugs (which make up about two-thirds of the cost of treatment) would significantly reduce the cost burden on affected households.

Burkitt's lymphoma is curable and over 75% of early stage disease is known to achieve long periods of event-free remission (Sandlund et al. 1996). Among the 32 children treated during our reporting period, 21 (51.2%) stayed long enough (at least 12 weeks) to be confirmed as short-term cure (46.3%) or early relapse (4.9%). The cure rate is bound to improve if cases present early and are adequately treated. This calls for a better organization of cancer care for children in Nigeria and other parts of Sub-Saharan Africa. Self-discharge against medical advice can be reduced if parents are adequately educated and assured of affordable and effective treatment for their children (Sandlund et al. 1996). The tendency for parents to consult traditional and other alternative providers of healthcare services may have partly contributed to the delay in presentation. This health-seeking behaviour is related both to ignorance and to parental concern about cost of care in hospitals. Community education and effective integration of alternative health practitioners into the health system will go a long way in preventing undue delay in such places.

Some of the problems highlighted in this report also exist in many other resource-poor countries (Johnson & William 1984). In an earlier paper (Meremikwu & Ikpatt 1997), we drew attention to the deteriorating situation caused by the introduction of user fees for anticancer drugs that were provided free of charge by the government prior to the structural adjustment programme in Nigeria. The data we present in this current paper drives home the reality and extent of the problem that families confronted with this treatable condition face in our study locale and similar resource-poor settings. We recommend that efforts be made to overcome these obstacles. One of such efforts would be the actualization of our earlier call for a regional BL programme in Africa, which would facilitate the establishment of a critical mass of resources (human and material) from within and outside the continent in order to help develop an accessible and effective BL control programme for the region.

Ancillary