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Treatment of childhood Hodgkin lymphoma in sub-Saharan Africa : A report from the French-African Paediatric Oncology Group ( GFAOP )

Hodgkin lymphoma (HL) is a B-cell line lymphoma, characterised histologically by the presence of large, atypical cells called ReedSternberg cells. The first histological description dates back to 1832 by Thomas Hodgkin.[1] Epstein-Barr virus (EBV) is an important factor in the pathogenesis of HL and it is detected in Reed-Sternberg cells in the vast majority of HL specimens from developing countries, but much less frequently in high-income countries.[2] The incidence of HL is 1.2 per 100 000 children and represents the most common malignant tumour in adolescents in high-income countries, and the majority of cases are diagnosed at an early stage of disease.[3] Hodgkin’s disease is more common in children under 10 years of age in developing countries. HL is a malignant but highly curable tumour and its treatment is one of the success stories of modern medicine. The use of chemotherapy combined with radiotherapy has greatly improved the survival rate of advanced stages of the disease. In high-income countries, the event-free survival and overall survival rates are 85% and 90%, respectively.[4,5] The reported results of therapy of HL in lowand middle-income countries (LMICs) are not as good, due to several factors.[6,7] One of the key reasons is that radiation therapy centres in sub-Saharan Africa are rare, but efforts are underway to address this issue.[8,9] Studies from one institution using chemotherapy alone in the treatment of HL have shown encouraging results.[10,11] This therapeutic strategy has been adopted by the French-African Paediatric Oncology Group (GFAOP) to improve the treatment of children with HL in sub-Saharan Africa. In this article, we present the results of a prospective, collaborative, multicentre study on the management of HL using only chemotherapy in GFAOP institutions.


RESEARCH
with HL and the associated epidemiological and therapeutic aspects. Patients from seven oncology centres of the GFAOP in sub-Saharan Africa were included. Participating centres were located in Burkina Faso, Cameroon, Mali, Madagascar and Senegal.

Patient selection
The study was conducted between 1 October 2006 and 30 November 2012. Patients younger than 18 years with histologically confirmed HL were enrolled in the study. The histological criteria established by the World Health Organization were used for the diagnosis. [12] In addition, enrolled patients should not previously have been treated with chemotherapy or radiotherapy, had to be HIV negative and should not have had any major contraindication for treatments. Signed consent of the child's parents or legal guardian was obtained prior to their enrolment in the study.
All the patients underwent complete clinical examination, including reporting the number and size of superficial lymph nodes (>1 cm) on a body schema, measurement of liver and spleen size and a routine blood check. The blood analysis included complete blood count, erythrocyte sedimentation rate, Rhesus grouping, renal and hepatic function tests, an HIV test and a hepatitis B (HbsAg) test. Echocardiography, chest X-rays (CXR) with the mediastinal-thoracic index (MTI) measured (≥0.45 considered a large mediastinum), abdominal ultrasound, chest-abdominal computed tomography scan (if possible and repeatable), bone marrow aspiration and biopsy were performed in all patients enrolled in the study. The staging of patients was performed according to the Ann Arbor classification. [13] The letter B was added as suffix to the stage of patients if weight loss (>10% of the weight of the body during the last 6 months) or fever (>38°C for at least a week or night sweats) was observed. The absence of these signs was noted by the suffix A on the stage of disease.
Patients were divided into two treatment groups according to the prognosis at initial diagnosis: favourable (G1) and unfavourable (G2).
The criteria for group G1 were: stages I and IIA, MTI <0.45, lymphadenopathy <6 cm, and no contiguous involvement. Criteria for group G2 were: stages IIB, III or IV, MTI ≥0.45, lymphadenopathy ≥6 cm or presence of visceral involvement.

Chemotherapy strategies
The treatment strategy was based on GFAOP guidelines for the treatment of HL. All patients received COPP/ABV hybrid chemotherapy according to their assigned therapeutic group and the response at evaluation. Chemotherapy was administered as follows: vincristine 1.5 mg/m 2 intravenously and cyclophosphamide 650 mg/m 2 intravenously on day 1, procarbazine 100 mg/m 2 orally on days 1 -8, adriamycin 35 mg/m 2 , vinblastine 6 mg/m 2 and bleomycin 10 mg/m 2 all intravenously on day 8, and prednisone 40 mg/m 2 orally on days 1 -14 (Fig. 1). The effectiveness of the treatment was evaluated after every two cycles of chemotherapy by physical examination, CXR and abdominal ultrasound.
Treatment of patients with a favourable prognosis at diagnosis (group G1) All patients in this group received two COPP/ABV courses followed by an evaluation. Good responders to treatment received two further cycles of therapy according to the protocol. After the first assessment, poor responders received two additional COPP/ABV courses, followed by a second assessment. If an insufficient response was found at this second evaluation, the treatment was stopped. If a good response was found, patients received two complementary courses and then treatment was stopped (Fig. 2).

Treatment of patients with an unfavourable prognosis at diagnosis (group G2)
All patients received two COPP/ABV courses followed by an evaluation. Good responders to treatment received four additional cycles of chemotherapy, after which treatment was stopped. Patients who did not respond well at the first assessment received two additional COPP/ABV courses. Continuation of therapy was decided at a subsequent evaluation. If the response was deemed to be good after this second round of treatment, another four courses were administered and then treatment was stopped (Fig. 3).

Response criteria
Complete remission was defined as the disappearance of all clinical, biological and visual signs of disease on imaging. A good response was defined as a 75% reduction of the sum of the diameters of all measurable lesions. Partial remission was defined as the disappearance of the biological and clinical signs and a reduction of at least 50% of all measurable targets. Tumour progression was defined as an increase of more than 25% in the size of at least one measurable lesion or the reappearance of the general signs. Patients who achieved complete remission or showed good response to the treatment were defined as good responders. Biopsy and histological examination confirmed relapse.
Assessment after treatment had been completed included a full physical examination, a CXR and abdominal ultrasound. The schedule of surveillance after the complete treatment was every 6 weeks during the first 6 months, then every 3 months until 1 year

Data collection and analysis
Each centre sent their collected data electronically to the GFAOP data manager. Data were analysed in SPSS version 20 (IBM Corp., USA). The Kaplan-Meier method was used to estimate survival and the logrank test to compare the survival of different groups of treated patients. [14] Ethical considerations The consent of the patient's legal guardian was obtained before enrolment in the study. The ethics committees of each participating country gave their consent for the study.

Results
A total of 127 patients were registered for the study, of whom 21 patients were excluded for the following reasons: two cases of undifferentiated carcinoma of nasopharyngeal type; one case of nodular paragranuloma; one case of anaplastic lymphoma; one case of lymph node metastasis of a melanoma; patients previously treated by another protocol (n=6); incomplete data (n=7); one case of cardiomyopathy; one case of association of HL with tuberculosis; and one case of unknown reason. No HIV-positive cases were found. The remaining 106 patients were therefore included in the analysis. The distribution of patients according to their country of origin was as follows: Senegal: n=45 (42.5%); Mali: n=26 (24.5%); Madagascar: n=25 (23.6%); Cameroon: n=6 (5.7%); Burkina Faso: n=4 (3.8%).

Response to treatment
After two cycles of chemotherapy, 90 patients were evaluated by physical examimation and imaging (CXR and abdominal ultrasonography). Of these, 80 patients were considered to be good responders and 10 were poor responders. The intermediate evaluation after four cycles of chemotherapy found 72 cases of good response and 5 cases of insufficient response. After six cycles, 51 patients were deemed to have responsed well and 4 patients showed insufficient

Toxicity of COPP/ABV treatment
Grade III anaemia with haemoglobin <5 g dL was observed in 15 patients. Grade III neutropenia, with a neutrophil count <500 mm 3 was observed in 13 patients. One patient developed severe and prolonged pancytopenia. Sixteen patients had a severe infection associated with neutropenia. Pneumonia was noted in seven patients and urinary tract infection also in seven patients. Two patients developed severe sepsis at the end of treatment, and subsequently died. All the urinary tract infections were associated with Escherichia coli, as was one case of sepsis. Plasmodium falciparum malaria was diagnosed in two cases. The outcome of these infectious episodes was favourable, except for the two cases of sepsis. One case of grade III vomiting was noted. One case of dilated cardiomyopathy was noted and led to the withdrawal of adriamycin from the patient's treatment.

Relapses
A total of 17 patients relapsed. The median time to relapse was 13 months (range 4 -41 months). Of these patients, 15 were from group G2 (unfavourable prognosis at diagnosis); 11 of these patients were in stage IIIB and 4 were in stage IVB. Two patients of group G1 (favourable initial prognosis) relapsed. One of these patients was 2 years old at diagnosis, had chronic otitis and a primary immune system deficiency was subsequently diagnosed; the second was 17 years old and was retrospectively diagnosed with bulky disease. This patient was erroneously assigned to the group with favourable prognoses. All cases of relapse were confirmed by biopsy. The initial treatment was completed in 12 patients before relapse and interrupted in 5 patients on medical decision. Seventeen patients presented with a relapse site identical to that involved at initial diagnosis. One patient, who was in stage IVB with liver involvement, had an isolated splenic relapse, which was different from the site of initial diagnosis. In the cohort of patients who relapsed, seven had bulky disease at diagnosis.
Second-line chemotherapy treatment was used to treat seven patients, two of whom are still in a second stable remission.

Deaths
A total of 20 deaths (18.9%) were recorded, of which four were toxic deaths: a 16-yearold stage IIIB patient, splenectomised at diagnosis and in complete remission, died of a severe neurological form of malaria 7 months after completing treatment; one patient with a multidrug-resistant E. coli infection died at the end of the treatment; a 9-year-old patient with stage IIIB HL died during treatment owing to multidrugresistant tuberculosis; and an 11-year-old patient with stage IIIB HL died owing to severe digestive and haematologic toxicity. Sixteen patients died after relapse.

Outcome
At the final treatment assessment, the eventfree and overall survival rates were 67% and 82%, respectively, at a median follow-up of 30 months (Fig. 4).

Discussion
HL in children is a poorly studied cancer in sub-Saharan Africa, with little data available on its treatment. It is possible that the frequency of the disease is underestimated because of difficulties in histological diagnosis.
HL is a highly curable disease, but unfortunately there are many challenges related to histological diagnosis, metastatic work-up and treatment in sub-Saharan Africa. Our study included patients with histological diagnosis of HL and who received treatment over a period of 6 years. In high-income countries, HL is typically a disease of teenagers and young adults, with a peak frequency in the 17 -19-year age groups. [15] HL appears to occur at an earlier age in developing countries than in high-income countries. [16,17] In our series, the median age was 10 years (range: 2 -18 years), with a predominance of children between 5 and 10 years (n=41; 38.7%). In studies from Morocco and India, the age group 6 -14 years was the most affected. [18,19] The early onset of HL in children in LMICs is thought to be due to early infection with EBV, although the role of the virus in the pathogenesis of HL remains partly enigmatic. [20,21] EBV was found in 68% and 93% of paediatric HL cases in South Africa and Malaysia, respectively. [22,23] An association of HL with EBV infection was also found in Mexico and Peru. [24,25] The male preponderance found in our series (76%) is similar to what has been reported elsewhere in literature. [26,27] In LMICs, the advanced disease stages seen in patients are likely due to late diagnosis and late referral. [28,29] In our series, 44% of patients were identified to be in stage IIIB, and the group with an unfavourable prognosis (G2) accounted for 85.8% of patients. In studies from Brazil and India, stages III and IV accounted for ~50% of patients. [30,31] It is important to note that there was no centralised review of histology in this study; ideas for including such a review in future studies are beign considered. Mixed cellularity HL is the predominant histologic subtype of HL in LMICs, and thought to be associated with low socioeconomic conditions and early EBV infection. [32,33] In contrast, the nodular sclerosis form is predominantly seen in high-income countries. However, we found 36% nodular sclerosis forms and 20% mixed cellularity forms. It should be noted that a significant proportion of histological subtypes were not specified. In high-income countries, the overall survival rate of HL treatment with combined chemo-and radiotherapy is greater than 90%. [34][35][36]  use of radiotherapy for early stages of disease, which respond well to initial chemotherapy. [37] The current European protocols indicate radiotherapy for the territories initially affected according to the therapeutic response. Application of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is useful for assessing the initial response to treatment and therefore to determine the use of radiotherapy. [38] Radiotherapy is available in North Africa and South Africa, and overall survival rates for HL are greater than 80%.
Our study was conducted in sub-Saharan African countries with very low incomes. The anticancer drugs were graciously donated by the GFAOP. For a sustainable treatment of paediatric cancers, each GFAOP partner country must ensure the supply of anticancer drugs to support the development of paediatric oncology. Delayed diagnosis, inaccessibility to chemotherapy and unavailability of radiotherapy are the main obstacles in the treatment of HL. [39] It has been known for many years that using chemotherapy alone is effective in curing HL, supported by evidence from countries with no availability or access to radiotherapy. At the time of this study, radiotherapy was not available in the countries that participated in this multicentre study.
The choice of the hybrid COPP/ABV chemotherapy protocol was based mainly on the remarkable results with regard to tolerance and efficacy obtained with this approach in LMICs. [40,41] Three-year event-free survival in the Baez series in Nicaragua was found to be 100% for stages I, II and IIIA, and 74.9% for stage IIIB. [10] In our series, we found an overall survival rate of 82% and an event-free survival rate of 67% across all stages combined after 30 months of follow-up. A better initial risk stratification and early evaluation of the therapeutic response of patients can improve overall survival. The low level of supportive care has a major influence on the outcomes of childhood cancer treatment in sub-Saharan Africa, partly explaining the difference between the overall survival rate in our study and that seen in Nicaragua when the same therapeutic strategy was used. In a study from Egypt, the event-free survival rate was found to be 96.6% with a protocol based on chemotherapy and radiotherapy. [42] In our series, the toxicity of chemotherapy was haematologic, resulting in anaemia and neutropenia. Four toxic deaths were noted and were due to issues with supportive care.
The median time to relapse was 13 months. The majority of patients who relapsed were considered good responders at the first assessment. We did not find a statistically significant correlation between the histological subtype and the occurrence of relapse (p=0.72). Second stable remission was obtained in two patients by second-line chemotherapy. Late relapse seems to be a better prognosis according to some authors. [43] In this study, the number of patients lost to follow-up during treatment was not significant.

Conclusion
This study demonstrates the feasibility of using chemotherapy alone as an effective strategy for treating HL in sub-Saharan Africa, as shown in multiple centres. The enhancement of supportive care and the availability of radiotherapy centres will lead to better results. It is important to improve the initial stratification but also the early evaluation of the therapeutic response of patients.