Parth S. Mehta

Essential medicines for pediatric oncology in developing countries

The burden of cancer in children in low and middle income countries (LMICs) is substantial, comprising at least 80% of incident cases globally, and an even higher proportion of cancer‐related deaths. With survival rates exceeding 80% in high income countries, it is imperative to transfer these successes to LMICs. A major challenge is the poor availability of safe, cost‐effective chemotherapy. A list of 51 drugs—chemotherapeutics, infectious disease agents, and supportive care medications—is proposed as essential to improving the survival of children with cancer in LMICs with an additional 13 drugs identified as being of further value. Pediatr Blood Cancer 2013; 60: 889–891.

Clinical characteristics and outcomes of HIV-infected children diagnosed with Kaposi sarcoma in Malawi and Botswana.

Kaposi sarcoma (KS) is the most common HIV‐associated malignancy in sub‐Saharan Africa. The presentation and outcomes of pediatric KS are not well understood.

Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study.

Kaposi sarcoma (KS) is the most common HIV-associated malignancy in children and adolescents in Africa. Pediatric KS is distinct from adult disease. We evaluated the clinical characteristics associated with long-term outcomes. We performed a retrospective observational analysis of 70 HIV-infected children and adolescents with KS less than 18 years of age diagnosed between 8/2010 and 6/2013 in Lilongwe, Malawi. Local first-line treatment included bleomycin and vincristine plus nevirapine-based highly active anti-retroviral therapy (HAART). Median age was 8.6 years (range 1.7–17.9); there were 35 females (50%). Most common sites of presentation were: lymph node (74%), skin (59%), subcutaneous nodules (33%), oral (27%), woody edema (24%), and visceral (16%). Eighteen (26%) presented with lymphadenopathy only. Severe CD4 suppression occurred in 28%. At time of KS diagnosis, 49% were already on HAART. Overall, 28% presented with a platelet count < 100 x 109/L and 37% with hemoglobin < 8 g/dL. The 2-year event-free (EFS) and overall survival (OS) were 46% and 58% respectively (median follow-up 29 months, range 15–50). Multivariable analysis of risk of death and failure to achieve EFS demonstrated that visceral disease (odds ratios [OR] 19.08 and 11.61, 95% CI 2.22–163.90 and 1.60–83.95 respectively) and presenting with more than 20 skin/oral lesions (OR 9.57 and 22.90, 95% CI 1.01–90.99 and 1.00–524.13 respectively) were independent risk factors for both. Woody edema was associated with failure to achieve EFS (OR 7.80, 95% CI 1.84–33.08) but not death. Univariable analysis revealed that lymph node involvement was favorable for EFS (OR 0.28, 95% CI 0.08–0.99), while T1 TIS staging criteria, presence of cytopenias, and severe immune suppression were not associated with increased mortality. Long-term complete remission is achievable in pediatric KS, however outcomes vary according to clinical presentation. Based on clinical heterogeneity, treatment according to risk-stratification is necessary to improve overall outcomes.

Early antiretroviral therapy is protective against epilepsy in children with human immunodeficiency virus infection in botswana.

Background: Seizures are common among patients with HIV/AIDS in the developing world and are associated with significant morbidity and mortality. Early treatment with combination antiretroviral therapy (cART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy. Methods: A case–control study of new-onset epilepsy among children aged 0–18 years with perinatally acquired HIV/AIDS followed in Gaborone, Botswana, during the period 2003–2009 was conducted. Children with epilepsy were identified and compared with age- and sex-matched controls without epilepsy with respect to timing of cART initiation. Early treatment was defined as treatment with cART before the age of 12 months, at a CD4% of greater than 25 in children aged 1–5 years, or at an absolute CD4 count of >350 cell per cubic millimeter in children aged 5 years and older. Results: We identified 29 cases of new-onset epilepsy and 58 age- and sex-matched controls. The most common identified etiologies for epilepsy were central nervous system infections and direct HIV neurotoxicity. Only 8 (28%) of the children who developed epilepsy received early treatment compared with 31 (53%) controls (odds ratio: 0.36, 95% confidence interval: 0.14 to 0.92, P = 0.03). This effect was primarily driven by differences in rates of epilepsy among children who initiated treatment with cART between the ages of 1 and 5 years (11% vs. 53%, odds ratio: 0.11, 95% confidence interval: 0.01 to 1.1, P = 0.06). Conclusions: Earlier initiation of cART may be protective against epilepsy in children with HIV.

Mapping the Epidemiology of Kaposi Sarcoma and Non-Hodgkin Lymphoma Among Children in Sub-Saharan Africa: A Review

Children with human immunodeficiency virus (HIV) have an increased risk of developing Kaposi Sarcoma (KS) and non‐Hodgkin lymphoma (NHL) compared to HIV‐negative children. We compiled currently published epidemiologic data on KS and NHL among children in sub‐Saharan Africa (SSA). Among countries with available data, the median incidence of KS was 2.05/100,000 in the general pediatric population and 67.35/100,000 among HIV‐infected children. The median incidence of NHL was 1.98/100,000 among the general pediatric population, while data on NHL incidence among HIV‐infected children were lacking. Larger regional studies are needed to better address the dearth of epidemiologic information on pediatric KS and NHL in SSA.

Reply to “Childhood cancer in Africa”

To the Editor: We were pleased to see the recent comprehensive and informative review by Kruger et al. [1] entitled Childhood Cancer in Africa. However, we feel compelled to address an important omission that, per Figure 1 from Childhood Cancer in Africa, erroneously indicated there are no pediatric cancer services available in Botswana. In fact, Botswana has an active pediatric hematology/oncology program through partnership between its Ministry of Health (MOH), Baylor College of Medicine (BCM), Texas Children’s Cancer Center (TCCC), Baylor International Pediatric AIDS Initiative (BIPAI), and the Texas Children’s Hospital Global Health Service Corps. Partnership in pediatric HIV care between the MOH and BIPAI began in 1999 when Botswana had the highest adult prevalence of HIV in the world at 35.8% [2]. With assistance from Bristol-Myers Squibb, the Botswana-Baylor Children’s Clinical Centre of Excellence (BBCCOE) was later constructed and opened in 2003 in Gaborone on the campus of PrincessMarina Hospital (PMH), the country’s largest referral hospital. The BBCCOE was the first comprehensive pediatric HIV clinic in sub-Saharan Africa, served as a model for subsequent clinics, and still provides care to thousands of children. Currently, Botswana has the highest antiretroviral therapy coverage for HIV-positive children in subSaharan Africa [3]. With the benefit of the clinical infrastructure, existing partnership with the MOH, and evident need to treat both HIV-associated malignancies and other pediatric hematology/ oncology diagnoses, BIPAI, BCM, and TCCC have had a pediatric hematologist/oncologist in Botswana since 2007. This expanded a previously existing but small pediatric hematology–oncology program at PMH. With a fully nationalized health service, Botswana provides all health care free of charge for citizens including transportation to and from PMH for therapy. The Botswana model concurs with the World Health Organization (WHO) recommendation for universal coverage in low-income countries to promote and sustain health by providing timely access to care [4]. Thus, abandonment of pediatric oncology treatment is nearly non-existent, which differs significantly from rates reported in other resource-limited settings. Chemotherapy is provided free through the government formulary; surgical services are rendered by pediatric surgeons, orthopedic surgeons and neurosurgeons on the PMH staff; and radiation therapy is provided at a local private hospital through a guarantee of payment from the MOH. Additionally, a small number of children are referred to partner institutions in South Africa for interventions unavailable in Botswana. Numerous educational symposia, both in Botswana and in Houston, Texas, have created training opportunities for Batswana healthcare providers and have increased local capacity. A pediatric hematology–oncology fellowship training program is being planned to obviate the need for expatriate pediatric hematologist/oncologists. The program is also making significant scholarly contributions to the literature [5]. In their conclusion, Kruger et al. [1] suggest partnering with the established framework of the HIV/AIDS infrastructure in Africa to address pediatric cancer care. Botswana serves as a striking example of the feasibility and success of such collaboration.

Beyond Endemic Burkitt Lymphoma: Navigating Challenges of Differentiating Childhood Lymphoma Diagnoses Amid Limitations in Pathology Resources in Lilongwe, Malawi:

Background. Although Burkitt lymphoma (BL) is the most common childhood lymphoma in sub-Saharan Africa, Hodgkin lymphoma (HL) and other non-Hodgkin lymphomas occur. Diagnosing non-jaw mass presentations is challenging with limited pathology resources. Procedure. We retrospectively analyzed 114 pediatric lymphomas in Lilongwe, Malawi, from December 2011 to June 2013 and compared clinical versus pathology-based diagnoses over two time periods. Access to pathology resources became more consistent in 2013 compared with 2011-2012; pathology interpretations were based on morphology only. Results. Median age was 8.4 years (2.1-16.3). The most common anatomical sites of presentation were palpable abdominal mass 51%, peripheral lymphadenopathy 35%, and jaw mass 34%. There were 51% jaw masses among clinical diagnoses versus 11% in the pathology-based group (P < .01), whereas 62% of pathology diagnoses involved peripheral lymphadenopathy versus 16% in the clinical group (P < .01). The breakdown of clinical diagnoses included BL 85%, lymphoblastic lymphoma (LBL) 9%, HL 4%, and diffuse large B-cell lymphoma (DLBCL) 1%, whereas pathology-based diagnoses included HL 38%, BL 36%, LBL 15%, and DLBCL 11% (P < .01). Lymphoma diagnosis was pathology confirmed in 19/66 patients (29%) in 2011-2012 and 28/48 (60%) in 2013 (P < .01). The percentage of non-BL diagnoses was consistent across time periods (35%); however, 14/23 (61%) non-BL diagnoses were pathology confirmed in 2011-2012 versus 16/17 (94%) in 2013. Conclusions. Lymphomas other than Burkitt accounted for 35% of childhood lymphoma diagnoses. Over-reliance on clinical diagnosis for BL was a limitation, but confidence in non-BL diagnoses improved with time as pathology confirmation became standard. Increased awareness of non-BL lymphomas in equatorial Africa is warranted.

Lessons from pediatric HIV: A case for curative intent in pediatric cancer in LMICs

* Abbreviations: ALL — : acute lymphoblastic leukemia ARV — : antiretroviral medication BL — : Burkitt lymphoma CLHIV — : children living with HIV HIC — : high-income country LMIC — : low- and middle-income country Antiretroviral medications (ARVs) are now being provided to nearly 50% of children living with HIV (CLHIV) in low- and middle-income countries (LMICs), an increase of 30% in the past 5 years.1 The provision of ARVs in LMICs demonstrates that effective therapy can be delivered to children with complex medical issues. An estimated 96% of CLHIV and 80% of children <15 years of age living with cancer reside in LMICs, where 94 900 pediatric AIDS deaths and 120 000 pediatric cancer deaths occur annually.2,3 The health system infrastructure gains in the fight against HIV and other communicable diseases represent a promising platform for long-overdue, transformational cancer care in LMICs. Similar to combination antiretroviral therapy in the context of pediatric HIV, the advent of combination chemotherapy in the mid-1960s revolutionized pediatric cancer treatment. Before chemotherapy, pediatric cancer was uniformly fatal, and care was focused on palliation. By the 1970s, over half of children diagnosed with cancer in high-income countries (HICs) were cured. … Address correspondence to Henry Miller, Office of HIV/AIDS, United States Agency for International Development, 1300 Pennsylvania Ave, NW, Washington, DC 20523. E-mail: hmiller{at}usaid.gov

Increasing Numbers of New Kaposi Sarcoma Diagnoses in HIV-Infected Children and Adolescents Despite the Wide Availability of Antiretroviral Therapy in Malawi

To the Editor—It is with great interest that we read the recently published manuscript on Kaposi sarcoma (KS) risk in human immunodeficiency virus (HIV)–infected children worldwide [1]. The particularly high incidence rate of pediatric KS reported in eastern Africa is striking. The experience in our pediatric HIV-related malignancy program in Lilongwe, Malawi, is consistent with the epidemiologic data from the Pediatric AIDS-Defining Cancer Project Working Group. In eastern and central Africa— where human herpesvirus 8 (HHV-8) is endemic and prevalence rates are highest in the world—KS is among the 3 most common childhood cancers overall [2–5]. With the increased availability of combination antiretroviral therapy (cART) in sub-Saharan Africa over the past decade, it is important to determine trends in KS. Data from South Africa and Zambia demonstrate that in adults, the risk for KS and incidence rates remain high despite increased cART coverage [6, 7]. We retrospectively investigated trends in pediatric KS from 2006 to 2015 in our pediatric (<18 years of age) HIV-related malignancy program at the Baylor College of Medicine International Pediatric AIDS Initiative Center of Excellence in Lilongwe, Malawi. The scale-up in delivering cART to children in the Malawian national antiretroviral program began in 2005. Since then, >50 000 children have been initiated on cART, including 3964 at our center. Despite the substantial increase in cART coverage in Malawi, the annual number of new KS diagnoses in HIVinfected children and adolescents has steadily increased over the past decade (Figure 1). The average annual number of new pediatric KS diagnoses from 2006 to 2010 (n = 89) was 17.8 cases per year, compared to 25.2 cases per year from 2011 to 2015 (n = 126). We also compared numbers of new KS diagnoses in HIV-infected children and adolescents from our 2 published cohorts [8, 9]. In the recent cohort, 70 patients were diagnosed with KS over 34 months from 2010 to 2013. That represented 5.2% (70/1359) of all children initiated on cART at our center [9]. The historical control reported 72 patients with KS from 2003 to 2009 (total duration 80 months), representing 3.2% (72/2241) of cART initiations [8]. The older cohort averaged 0.9 new KS diagnoses per month vs 2.1 new KS diagnoses per month more recently. It is evident that the number of new pediatric KS diagnoses in Malawi is not yet decreasing despite wider availability of cART. Recent data from Blantyre, Malawi, reveal similar numbers [10]. Several factors that may contribute to the current increased numbers of pediatric KS diagnoses include improved referral networks via outreach to regional healthcare professionals, facilities, and patients through our Tingathe Community Outreach Program, improved infrastructure to establish definitive diagnoses via biopsies (especially in lymph node KS), and persistent gaps in access to cART. Despite great efforts to reduce the severe complications of pediatric HIV infection with cART, KS still remains an important complication in HHV-8– endemic regions of Africa. Our experience has demonstrated that long-term complete remission may be achieved in childhood KS with the combination of relatively moderate chemotherapy and

Maximizing the Impact of a Pediatric Hematology-Oncology Twinning Program

To the Editor: In 2007, Baylor College of Medicine (BCM) and the Texas Children’s Cancer and Hematology Centers (TXCH) established a comprehensive pediatric hematology-oncology program at Botswana’s primary government referral hospital, Princess Marina Hospital (PMH).[1] The PMH program remains the only center, public or private, that provides services to children with cancer and blood disorders in Botswana. The barriers to diagnosis, management, and survival of pediatric cancer in low and middle income countries (LMIC) have been described in many studies and include abandonment of treatment, late presentation, lack of diagnostic and treatment options, limited supportive care, and toxicity from treatment. Thus, survival from pediatric cancer in LMIC lags far behind high income countries. Creative approaches are necessary to achieve the best possible outcomes in LMIC as resources common in modern pediatric cancer centers are typically lacking. Since the program’s inception, the pediatric hematologyoncology program at PMH through BCM/TXCH has relied primarily on one full-time pediatric hematologist-oncologist (PHO) with periodic visiting PHOs. With high patient volumes in addition to various administrative, research and teaching responsibilities, interventions were necessary to maximize the impact of the twinning program at PMH with limited resources. In 2013, adapting a successful model from high income countries, the position of a Care Coordinator (CC)/Project Manager (PM) was created. The role of the CC is to organize patient care activities and facilitate appropriate healthcare services through the exchange of information among participants with the goal of achieving timely, high quality, and cost-effective healthcare with optimal outcomes. The PM role focuses on program development, patient education, and research infrastructure. In the 2 years since the establishment of the CC/PM position, many advances have been made including the following: creating referral and orders management systems to reduce abandonment of treatment or lost to follow-up of survivors; coordination of both local and international referrals for services unavailable at PMH; the development of patient educationmaterials for 13 malignancies and seven blood disorders and a handbook for all new oncology patients; creating standardized inpatient and outpatient clinical note forms; establishment of a comprehensive pediatric oncology database with enrollment of over 200 pediatric cancer patients for both clinical and research purposes that will soon provide the first data on pediatric cancer from the PMH program; editing a comprehensive pediatric hematology-oncology supportive care handbook that is nearing completion; liaising with philanthropists and non-governmental organizations offering support to patients and families; leading psycho-social efforts to decrease the negative impact of prolonged hospitalization; collaborating with colleagues at the twinning institution (BCM/TXCH) to appropriately leverage the twinning institution’s experience and resources; and education of local staff, especially nurses and dietitians, with limited pediatric cancer experience. The CC/PM has liaised with local benefactors for the donation of 14 televisions throughout PMH’s pediatric medical and surgical wards, wheelchairs to patients with disabilities, and recently, the donation of over 600 child-friendly pillow cases. Utilizing the role of the CC/PM, the above accomplishments were possible in spite of a growing clinical service that saw almost 25% increases in the average daily inpatient census and new patient referrals from 2013 to 2014. Pediatric oncology programs in high income countries are successful due to a multi-disciplinary approach with specialized staff including PHOs, nurses, social workers, care coordinators, child life specialists, and many other essential staff. A low cost and high impact option in LMIC is the employment of nurses and/or social workers in the non-clinical CC/PM role serving to maximize the impact of the twinning program.