Treatment-related mortality in children with cancer in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Approximately 90% of children with cancer live in low-income and middle-income countries (LMICs), where 5-year survival is lower than 20%. Treatment-related mortality in high-income countries is approximately 3-5%; however, in LMICs, treatment-related mortality has been reported in up to 45% of children with cancer. This study aimed to systematically explore the burden of treatment-related mortality in children with cancer in LMICs and to explore the association between country income level and treatment-related mortality. METHODS: For this systematic review and meta-analysis we identified articles published between Jan 1, 2010, and June 22, 2021, describing treatment-related mortality in paediatric patients (aged 0-21 years) with cancer in LMICs. We searched PubMed, Trip, Web of Science, Embase, and the WHO Global Metric Index databases. The search was limited to full-text articles and excluded case reports (<10 patients) and haematopoietic stem-cell transplantation recipients. Two reviewers independently screened studies for eligibility, extracted data from included publications, and evaluated data quality. Random and mixed-effects models were used to estimate treatment-related mortality burden and trends. The Cochran-Q statistic was used to assess heterogeneity between studies. This study is registered on PROSPERO (CRD42021264849). FINDINGS: Of 13 269 identified abstracts, 501 studies representing 68 351 paediatric patients with cancer were included. The treatment-related mortality estimate was 6·82% (95% CI 5·99-7·64), accounting for 30·9% of overall mortality (4437 of 14 358 deaths). Treatment-related mortality was inversely related to country income. Treatment-related mortality was 14·19% (95% CI 9·65-18·73) in low-income countries, 9·21% (7·93-10·49) in lower-middle-income countries, and 4·47% (3·42-5·53) in upper-middle-income countries (Cochran-Q 42·39, p<0·0001). In upper-middle-income countries, the incidence of treatment-related mortality decreased over time (slope -0·002, p=0·0028); however, outcomes remained unchanged in low-income (p=0·21) and lower-middle-income countries (p=0·16). INTERPRETATION: Approximately one in 15 children receiving cancer treatment in LMICs die from treatment-related complications. Although treatment-related mortality has decreased in upper-middle-income countries over time, it remains unchanged in LMICs. There is an urgent need for targeted supportive care interventions to reduce global disparities in childhood cancer survival. FUNDING: American Lebanese Syrian Associated Charities and National Cancer Institute.

Prevalence and Associated Risk Factors of Anemia Among Hospitalized Children in a Tertiary Level Hospital in Botswana.

Anemia is a global health concern and has been associated with long term cognitive and behavioral adverse effects. A cross sectional study was conducted to determine the prevalence of and risk factors for anemia in infants and children between 6 months to 5 years of age admitted to a tertiary hospital in Botswana. Baseline full blood count of every patient admitted during the study period was assessed to determine if anemia was present. Data were collected from patient's medical inpatient chart, electronic medical record (Integrated Patient Management System (IPMS)), and through interviewing parents and caregivers. Multivariate logistic regression model was used to identify risk factors of anemia. A total of 250 patients were included in the study. Prevalence of anemia in this cohort was 42.8%. There were 145 (58%) males. Of the patients with anemia, 56.1%, 39.2%, and 4.7% had mild, moderate, and severe anemia, respectively. Microcytic anemia consistent with iron deficiency was identified in 61 (57%) patients. Age was the only independent predictor of anemia. Children aged 24 months and more had a 50% lower risk of having anemia than their younger counterparts (odds ratio (OR) 0.52; 95% Confidence Interval (95% CI) 0.30 to 0.89). The findings of this study demonstrate anemia as a serious health concern in the pediatric population in Botswana.

Association between Antiretroviral Therapy and Cancers among Children Living with HIV in Sub-Saharan Africa.

Approximately 91% of the world's children living with HIV (CLWH) are in sub-Saharan Africa (SSA). Living with HIV confers a risk of developing HIV-associated cancers. To determine the incidence and risk factors for cancer among CLWH, we conducted a nested case-control study of children 0-18 years from 2004-2014 at five centers in four SSA countries. Incident cases of cancer and HIV were frequency-matched to controls with HIV and no cancer. We calculated the incidence density by cancer type, logistic regression, and relative risk to evaluate risk factors of cancer. The adjusted incidence density of all cancers, Kaposi sarcoma, and lymphoma were 47.6, 36.6, and 8.94 per 100,000 person-years, respectively. Delayed ART until after 2 years of age was associated with cancer (OR = 2.71, 95% CI 1.51, 4.89) even after adjusting for World Health Organization clinical stage at the time of enrolment for HIV care (OR = 2.85, 95% CI 1.57, 5.13). The relative risk of cancer associated with severe CD4 suppression was 6.19 (p = 0.0002), 2.33 (p = 0.0042), and 1.77 (p = 0.0305) at 1, 5, and 10 years of ART, respectively. The study demonstrates the high risk of cancers in CLWH and the potential benefit of reducing this risk by the early initiation of ART.

Recommendations for treating life-threatening Kaposi sarcoma during pregnancy in HIV-positive women in low income countries.

In areas of high HIV and human herpes virus 8 prevalence, life-threatening forms of Kaposi sarcoma (KS) can occur in HIV-positive women during pregnancy. Treating KS in pregnancy must balance both the well-being of the mother with the health of the fetus, yet data and recommendations on the best treatment approach for KS during pregnancy are limited. Without effective treatment, which can be difficult to obtain in low income countries (LICs), the mother and infant are at risk for poor outcomes. A successful case report is used as teaching example, followed by a detailed review of the literature that culminates in recommendations for treating KS during pregnancy among HIV-positive women in LICs. A 31-year-old HIV-positive woman presented for care in April 2016 at 28 weeks gestation with extensive KS skin lesions, KS lymphadenopathy, and a large oropharynx KS lesion causing partial airway obstruction. She had initiated antiretroviral therapy (ART) months prior and was virally suppressed, suggesting KS-immune reconstitution inflammatory syndrome. Due to the severity of KS and her third trimester status, combination chemotherapy was initiated using bleomycin, vincristine, and doxorubicin followed by maintenance therapy with paclitaxel. She showed remarkable response to the chemotherapy and had a normal vaginal delivery of a healthy baby at full term. Full clinical remission was achieved, and her baby was HIV-negative with no negative health effects of the KS or the chemotherapy. Review of the sparse existing literature demonstrates the importance, safety, and effectiveness of treating KS during pregnancy. We offer simple adaptable treatment recommendations for use in treating HIV-positive women with KS during pregnancy in LICs. Life-threatening KS can be treated using chemotherapy and ART in resource-limited settings, allowing for good outcomes in mother and infant. While monotherapy with liposomal doxorubicin or paclitaxel is preferred, these are often not available in LICs. As alternatives, bleomycin, vincristine, and doxorubicin can be safely used during the second and/or third trimesters for treating KS. Following a simple treatment approach can be an effective way to treat KS in pregnancy for pregnant women living with HIV in an LIC setting.

Factors influencing diagnostic delays of pediatric cancers in Botswana.

BACKGROUND: A major barrier in improving cancer outcomes in Botswana and other low- and middle-income countries is timely access to care. Understanding time to diagnosis of pediatric cancers in Botswana and evaluating factors contributing to delays was necessary to inform interventions. METHODS: A retrospective cohort study of children diagnosed with cancer at Princess Marina Hospital from 2008 to 2015 was performed utilizing the Botswana Pediatric Oncology Database. The time to diagnosis, pretreatment center delay, and pathology turnaround time were calculated. Time to diagnosis was analyzed using univariate and multivariate analyses to determine association with age, sex, distance to a treatment center, HIV status, cancer type, outcome, and presence of metastasis at diagnosis. RESULTS: The median time to diagnosis was 10.7 weeks, median pretreatment center delay was 9.6 weeks, and median pathology turnaround time was 3 weeks. Longer time to diagnosis was significantly correlated with presence of metastasis at diagnosis. Age, sex, distance to a treatment center, HIV status, cancer type, and outcome were not significantly associated with diagnostic delay. CONCLUSION: Children with cancer in Botswana have more than three months of symptoms prior to diagnosis, which is associated with metastasis at diagnosis. Efforts should be made to empower and promote awareness of pediatric cancer symptoms among caregivers and community healthcare providers in order to shorten time to presentation at a treatment center.

Establishing a Pediatric Hematology-Oncology Program in Botswana.

PURPOSE: Annually, 300,000 children are diagnosed with cancer, and the majority of these children live in low- and middle-income countries (LMICs). Currently, there is incomplete information on pediatric cancer incidence, diagnosis distribution, and treatment outcomes in Africa. Since 2007, a pediatric hematology-oncology program has been operating in Botswana through a partnership between the Botswana government, Baylor College of Medicine, and Texas Children's Hospital. METHODS: To better understand patient characteristics and outcomes at Botswana's only pediatric cancer program, a hospital-based data base-the Botswana Pediatric Oncology Database-was established in 2014. Children younger than 18 years of age at the time of diagnosis who presented between 2008 and 2015 were included. Data for this study were extracted in February 2016. RESULTS: Of the 240 potential enrollees, 185 (77%) children met eligibility for this study. The median age was 6.4 years, and 50.8% were male. Leukemia was the most common malignancy representing 18.9% of the cohort and 88.1% of the total cohort had a histopathologic diagnosis. HIV seropositivity was confirmed in 13.5%. The 2-year overall survival of all pediatric cancer diagnoses was 52.4%. Abandonment of treatment occurred in 3.8% of patients. CONCLUSION: In the first 9 years of the program, capacity has been developed through a longstanding partnership between Botswana and Baylor College of Medicine/Texas Children's Hospital that has led to children receiving care for cancer and blood disorders. Although continued improvements are necessary, outcomes to date indicate that children with cancer in Botswana can be successfully diagnosed and treated.

A 14-Year-Old Boy With Fevers, Cytopenias, and Neurocognitive Decline.

A 14-year-old boy presented to our institution with a 1-month history of neurocognitive decline and intermittent fevers. His history was significant for fevers, headaches, and a 10-lb weight loss. Previous examinations by multiple medical providers were significant only for bilateral cervical lymphadenopathy. Previous laboratory workup revealed leukopenia, neutropenia, and elevated inflammatory markers. Despite improvement in his laboratory values after his initial presentation, his fevers persisted, and he developed slowed and "jerky" movements, increased sleep, slurred speech, delusions, visual hallucinations, and deterioration in his school performance. A brain MRI performed at an outside hospital before admission at our institution was concerning for patchy, increased T2 and fluid-attenuated inversion recovery signal intensity in multiple areas, including the basal ganglia. After transfer to our institution and admission to the pediatric hospital medicine team, the patient had an acute decompensation. Our subspecialists will discuss the initial evaluation, workup, differential diagnosis, definitive diagnosis, and subsequent management of this patient.

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.

Cryptogenic Cirrhosis and Hepatopulmonary Syndrome in a Boy with Hepatic Hemangioma in Botswana: A Case Report and Review of the Literature.

Hepatic hemangiomas are considered to be the most common benign tumors of the liver. They are often found incidentally while investigating for other causes of liver disease. Hemangiomas that are less than 10 cm are not expected to cause any problems. Typically, they do not enlarge and, apart from regular follow-up, no definitive treatment is indicated. This is a posthumous case report of a male child with a medium-sized hemangioma from infancy, complicated by cryptogenic cirrhosis and hepatopulmonary syndrome. It demonstrates the challenges of managing a child with such complicated conditions in a resource-limited setting.

Profound Vitamin B12 Deficiency in a 1-Year-Old Child in Botswana: A Call to Initiate Early Empiric Therapy.

Vitamin B12 deficiency is a rare diagnosis in young children. We present the case of a 1-year-old Zimbabwean child with profound anemia. Further testing revealed undetectable levels of vitamin B12 and positive intrinsic factor antibodies that were drawn after the initiation of empiric treatment with parenteral vitamin B12. We report the evaluation and management of vitamin B12 deficiency in a resource-limited setting. Vitamin B12 deficiency should be considered in children presenting with unexplained cytopenias with consideration of empiric treatment with parenteral vitamin B12, as developmental and neurological complications of vitamin B12 deficiency can be devastating and permanent.

Pediatric Cancer Recognition Training in Botswana.

Delayed presentation of children with cancer is a significant barrier to improving the survival from children's cancer in low- and middle-income countries (LMICs). Botswana, a country of approximately 2 million people in southern Africa, has only 1 pediatric cancer treatment program, based at Princess Marina Hospital (PMH) in the capital of Gaborone. A pediatric cancer recognition training program was developed that reached 50% of the government hospitals in Botswana teaching 362 health care workers how to recognize and refer children with cancer to PMH. Through evaluation of attendees, limitations in pediatric cancer training and general knowledge of pediatric cancer were identified. Attendees demonstrated improvement in their understanding of pediatric cancer and the referral process to PMH following the workshop.

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.

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.