Kondwani Banda

Kaposi’s sarcoma in children: An open randomised trial of vincristine, oral etoposide and a combination of vincristine and bleomycin

INTRODUCTION Kaposis sarcoma (KS) is a common childhood cancer in places where HIV is endemic and access to antiretroviral therapy (ART) is delayed. Despite this there are no randomised trials to compare and assess chemotherapeutic regimens. METHOD An open label, randomised trial comparing intravenous vincristine alone, vincristine and bleomycin and oral etoposide, was carried out in children with Kaposis sarcoma in the Queen Elizabeth Central Hospital, Blantyre, Malawi. HIV infected children were given ART after 2-3 courses of chemotherapy if they were not already on treatment. Neither HIV nor widespread KS are curable and treatment is aimed at disease reduction and improved quality of life. Tumour reduction was assessed by measuring the size of sentinel KS nodules and quality of life (QoL) by using the Lansky score. Follow up was until death or for one year. FINDINGS 92 children were enrolled of whom 46% were naïve to ART; 10 (11%) were HIV negative. Survival was not influenced by age or gender but was better in the oral etoposide and the vincristine and bleomycin groups. P=0.0045. The group receiving oral etoposide had a better quality of life. Toxicity was not significant, and any drop in haemoglobin or white cell count could have been causally related to HIV infection rather than cytotoxic therapy. CONCLUSION Oral etoposide is a safe, effective treatment to contain KS and improve QoL which can be achieved without many visits to the hospital and intravenous injections.

Preoperative chemotherapy for patients with Wilms tumor in Malawi is feasible and efficacious

Wilms tumor has a survival rate of 85–90% in well resourced countries but in low income countries survival is lower. Malawi is a country with very limited resources. We studied the feasibility, toxicity and efficacy of preoperative chemotherapy for Wilms tumor in Malawian children.

Bezafibrate and medroxyprogesterone acetate in resistant and relapsed endemic Burkitt lymphoma in Malawi; an open‐label, single‐arm, phase 2 study (ISRCTN34303497)

Endemic Burkitt lymphoma (eBL) accounts for half of childhood cancers where malaria is holoendemic (Molyneux et al, 2012). Limited healthcare resources preclude intensive chemotherapy, restricting cure rates to <50% vs. >90% for children in high income countries (Patte et al, 2001). Intensification of chemotherapy in Africa has produced 20% infection-related mortality rates (Harif et al, 2008; Hesseling et al, 2013). Malnutrition, late stage presentation and co-infections are compounding problems for managing eBL even with non-intensive regimens (Israels et al, 2009; Hesseling et al, 2013). Our laboratory studies showed BaP [Bezafibrate (Bez) and Medroxyprogesterone acetate (MPA)] had potent anti-eBL activity and thus might provide affordable, non-toxic therapy (Fenton et al, 2003). Concurrently we have shown BaP has activity against other blood cancers in the laboratory and in clinical trials (Desmond et al, 2003; Khanim et al, 2009; Murray et al, 2010 and ISRCTN99131400). Over 5 years, from February 2007, 95 children with relapsed or resistant eBL were recruited to assess three doses of BaP for toxicty and anti-eBL activity. At first diagnosis these children had received cyclophosphamide (CPM) 40 mg/kg i.v. on day 1 and CPM 60 mg/kg orally on days 8, 18 and 28, with intrathecal methotrexate and hydrocortisone (i.t. MTX/HC) both at 12 5 mg on days 1, 8, 18 and 28. Twenty-five patients had also received vincristine 1 5 mg/m iv on days 1, 8, 18 and 28. BaP was administered daily from study entry to end of all therapy. Low dose BaP comprised 4 mg/kg MPA twice daily with Bez 200 mg once daily for patients <20 kg, or twice daily if >20 kg. Both intermediate and high dose BaP comprised MPA at 20 mg/kg once daily. For intermediate dose BaP, Bez was one 400 mg tablet/10 kg daily and twice that for high dose BaP. In 61 patients, BaP was given alone for a week before starting CPM 60 mg/kg orally plus vincristine 1 5 mg/m on days 8, 18 and 28; in 34 patients BaP and chemotherapy were started concurrently. There was no significant difference in patient characteristics between the low, intermediate and high BaP dose cohorts (Table I). Overall median age was 8 years (range 1–14); male:female ratio 58:37; resistant:relapsed disease ratio 24:71; weight <3rd centilein 68% patients. No toxicity occurred during BaP therapy alone (61 patients, 16 of whom received high dose BaP. A further 34 children received BaP therapy concurrently with chemotherapy from day 1 when the tumour burden was high, and no evidence of tumour lysis was seen. During all periods of concomitant administration of BaP and chemotherapy (95 patients) diarrhoea, vomiting, infection requiring antibiotics and blood transfusions occurred at the expected rates for chemotherapy alone with the only difference being a trend to more vomiting when taking high dose BaP. No patients stopped BaP therapy because of adverse events. Overall, 58% took BaP for 3–4 weeks and 24% for 2–3 weeks. It is important to note that laboratory assessment of toxicity was limited. However, only one death occurred during therapy in 95 children, which was less than expected with chemotherapy alone (Hesseling et al, 2013) and considerably less than the 25% treatment-related mortality encountered when applying more intensive chemotherapy in the Blantyre unit (Hesseling et al, 2013). The diagnosis of eBL can be difficult to make quickly and confidently in new patients in Africa (Naresh et al, 2011) but in this study this had been achieved at least some weeks prior to study entry with resistant or relapsed disease. The response of eBL to BaP was assessed directly in 61 patients receiving BaP alone for the first 7 d before adding standard rescue chemotherapy on day 8. Early assessment of lymphoma response can be difficult and was limited by lack of radiology. However progressive disease (PD) was defined as any clinical enlargement of the tumour or worsening of signs or symptoms. When PD was suspected during the first week of BaP therapy alone, standard rescue therapy was commenced immediately. PD was seen in only 7/24 evaluable children on low dose BaP and in none of the patients on intermediate or high dose BaP (Table II). No Clinical Change (NCC) was considered to be significant evidence of BaP anti-eBL activity because eBL normally increases in size substantially in a week without anti-BL therapy. NCC was seen in 11/24 (46%) of the evaluable low dose BaP cohort patients. In the intermediate and high dose groups this percentage increased to 22/31 (71%) alongside a reduction in PD from 29% to 0% (Table II). Comparing the four response groups between the three cohorts, there was a significant difference driven by the difference in PD in the patients receiving low dose (Fishers exact test, P = 0 04). In the low and intermediate BaP dose cohorts, complete clinical response (CCR) at the end of BaP plus rescue chemotherapy was seen in 39% of patients [95% confidence correspondence

The use of anthracyclines in the treatment of endemic Burkitt lymphoma

Burkitt lymphoma is the most common malignancy in children in Malawi, the worlds poorest country, where there is a long history of treating this disease using a 28‐day cyclophosphamide‐based protocol. Stage III/IV disease has had poor outcomes. In an attempt to improve the outcome for higher stage disease, anthracyclines were added to the existing protocol. The disease‐free (DFS) and overall survival (OS) of 58 children with cytologically confirmed Burkitt lymphoma admitted during 2012–2014 and treated using this protocol were calculated. Six (10%) children had stage I disease, ten (17%) stage II and 42 stage III or IV (73%). Overall 12‐month DFS (OS) was 68·5% (72·9%); for stage I disease 100% (100%), stage II 56·2% (60%), stage III/IV 66·3% (72·2%). The DFS was significantly improved from the previous protocol (P = 8 × 10−4). The addition of doxorubicin to stage III and IV disease resulted in a markedly improved DFS. Anthracyclines are deliverable in resource‐poor settings and possibly improve the survival of children with Burkitt lymphoma.

Outcome is unchanged by adding vincristine upfront to the Malawi 28-day protocol for endemic Burkitt lymphoma

We previously reported a 28‐day treatment protocol for children with endemic Burkitt lymphoma (BL) which included four doses of cyclophosphamide (CPM), intrathecal methotrexate and hydrocortisone (IT MTX/HC) at Queen Elizabeth Central Hospital (QECH) in Malawi which resulted in an Event‐Free Survival (EFS) of 50% at 1 year.

Treating childhood acute lymphoblastic leukemia in Malawi

Pediatric acute lymphoblastic leukemia (ALL) can now been cured in the vast majority of cases diagnosed in the developed world. However, the treatment regimes rely on good supportive care and multi-agent chemotherapy; and cannot be delivered in poor countries like Malawi. Therefore, many patients

Central nervous system lesions in Malawian children: identifying the treatable.

In Malawi, children with central nervous system (CNS) tumours are seldom able to be treated with curative intent. A study was undertaken of 29 children who underwent CNS MRI during a two year period. A combination of neoplastic and non-neoplastic diagnoses were noted, seven of which were revised on review. As a result an effective system has been set up for remote urgent review to guide prognosis and treatment. The opinion of a paediatric neuro-radiologist greatly assists in differentiating infectious and non infectious causes of CNS lesions and can enable the local team to effectively triage patients.

Kaposi sarcoma in HIV-seronegative children presenting to the paediatric oncology ward in The Queen Elizabeth Central Hospital, Blantyre, Malawi during 2002–2014

One of the most common malignancies in HIV-endemic, resource-poor countries is Kaposi sarcoma (KS). It is an AIDS-defining disease and as Malawi’s incidence and prevalence of HIV is high, KS is now the most common cancer in adult male Malawians and the second most common in women and children. Most attention has focused on HIV-seropositive adults as their number far outweighs those of children. This audit concerns the presentation and outcome of HIV-seronegative children with KS who presented in a 12-year period (2002–2014) to The Queen Elizabeth Central Hospital. Twenty (10.5%) of the 191 children with KS presenting to the paediatric oncology ward during 2002–2014 were HIV-seronegative. They were usually younger than seropositive children and 62% had severe anaemia. The main presenting complaints in the HIV-seronegative group were woody oedema, commonly of a limb, and lymphadenopathy. Woody oedema was common in children with or without HIV infection. Seronegative children with KS were less likely to have oral KS than HIV infected children. Of 11 children who completed courses of chemotherapy, seven (63%) had complete cure sustained over a 1-year follow-up period. KS is potentially curable in this group of children. Chemotherapy regimens are equally effective in HIV-seropositive and HIV-seronegative children. The presentation of HIV-seronegative children with KS differs from adults and HIV-seropositive children. Further research is necessary to determine possible triggers for developing KS in HIV-seronegative children.

Wilms tumour in Malawi: surgical staging to stratify postoperative chemotherapy?

Wilms tumour postoperative chemotherapy is ideally stratified according to the pathologists assessment of tumour stage and risk classification (tumour type). In sub‐Saharan Africa results are often not available in time to influence therapy and in Malawi surgical staging has been used to stratify postoperative chemotherapy. Here we compare the results from surgical and both local pathology and central pathology review.