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.

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.

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.

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.

Extramedullary hematopoiesis of the liver in a child with sickle cell disease: A rare complication.

We present the case of a 7-year-old Cameroonian girl with sickle cell disease (SCD) who presented with progressive abdominal distension, fever, severe anemia, respiratory distress, and fatigue. Abdominal ultrasound showed a 15.3 cm × 11.5 cm × 15.5 cm solid echogenic mass within the left lobe of the liver. Fine-needle aspiration showed features of extramedullary hematopoiesis (EMH). Despite transfusions, antibiotics, and initiation of hydroxyurea the patient died of respiratory failure during the hospital stay. There is a paucity of information on EMH in the pediatric sickle cell population, especially from resource-limited settings such as western Africa. EMH, however, is a known complication of SCD and should be considered in patients presenting with mass lesions in the setting of chronic anemia. With limited therapeutic interventions for EMH, including radiation and hydroxyurea, the emphasis should be on improving overall treatment of patients with chronic and untreated hemolytic anemia, especially in low-income countries.

Disparities in pediatric oncology patient education and linguistic resources: results of a national survey of pediatric oncologists.

BACKGROUND: Extensive patient and family education is required at the time of a new diagnosis of pediatric cancer yet little data exist regarding the availability and linguistic competency of new cancer diagnosis education provided by pediatric oncology institutions. PROCEDURE: Using the American Society of Pediatric Hematology/Oncology (ASPHO) membership list, a web-based survey was conducted among a cohort of pediatric oncologists to determine pediatric oncologists' assessment of institutional resources for new cancer diagnosis education and the availability of linguistically appropriate education. RESULTS: Of 1,294 ASPHO members sent email survey invitations, 573 (44.3%) responded with 429 meeting eligibility criteria. Oncologists at academic institutions reported their institutions had more availability of resources for new diagnosis education compared with those from non-academic institutions (mean 78.6 vs. 74.3; 0 [not at all]-100 [well equipped]; P = 0.05). The mean score increased with volume of new cancer diagnoses/year: small (<75) = 73.4; medium (75-149) = 76.7; large (>150) = 84.5 (P < 0.001). Oncologists at large volume institutions reported more availability of an established patient education protocol (50.8% vs. 38.1%, P < 0.001) and increased use of dedicated non-physician staff (79.9% vs. 66.1%, P = 0.02), but less use of websites for patient education (17.2% vs. 33.3%, P = 0.001). Availability of linguistically appropriate education improved with increasing institution size: small (76.4), medium (82.3), and large (84.0) patient volume (P < 0.011). CONCLUSION: According to pediatric oncologists, a disparity in educational and linguistic resources for new pediatric cancer diagnosis education exists depending on institution type and size.

Idiopathic myelofibrosis in children: primary myelofibrosis, essential thrombocythemia, or transient process?

We report 3 pediatric cases of primary/idiopathic myelofibrosis (PMF/IMF). Two cases exhibited clinical courses not typically observed in adult patients in whom this process is much more common. One of these cases exhibited spontaneous clinical and bone marrow resolution, whereas the other case achieved near resolution of myelofibrosis in response to cytoreductive therapy alone. However, the third case of IMF that met diagnostic criteria for essential thrombocythemia with a JAK2V617F mutation had central venous thrombosis that resulted in blindness. PMF/IMF, a rare finding in children, does not seem to portend the same level of risk as seen in adults with the same process, thus less aggressive management may be appropriate. However, delayed diagnosis of mutation-associated PMF or essential thrombocythemia can lead to devastating consequences. We review the literature and discuss the complexities surrounding diagnosis, risk stratification, and management of pediatric PMF/IMF.

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.

Neuroendocrine carcinoma in an adolescent with hypercortisolemia.

We present a 16-year-old boy with weakness, hypercortisolemia, and markedly elevated adrenocorticotropic hormone. Computed tomographic imaging revealed hepatic lesions and a calcified pancreatic mass. Biopsy of the hepatic lesions revealed moderately differentiated neuroendocrine carcinoma. The primary tumor could not be determined. The patient received neoadjuvant chemotherapy with carboplatin and etoposide followed by therapeutic bilateral adrenalectomy and tumor debulking. Despite significant clinical improvement, restaging revealed progressive hepatic disease. The patient died 9 months after diagnosis. Autopsy revealed disseminated neuroendocrine carcinoma. The rarity of this tumor compels a cooperative investigational model involving pediatric and adult oncologists.

Use of Paclitaxel to Successfully Treat Children, Adolescents, and Young Adults with Kaposi Sarcoma in Southwestern Tanzania.

Treating Kaposi sarcoma (KS) in children, adolescents, and young adults (AYA) remains a challenge in low- and middle-income countries (LMIC) where chemotherapy options and availability are limited. We describe a retrospective cohort review of pediatric patients with KS treated with paclitaxel in Mbeya, Tanzania, between 1 March 2011 and 31 December 2019. Paclitaxel was given to patients who had KS relapse, a contraindication to bleomycin, vincristine, and doxorubicin (ABV), special circumstances in which a clinician determined that paclitaxel was preferable to ABV, or experienced treatment failure, defined as persistent KS symptoms at the completion of treatment. All patients also received multidisciplinary palliative care. Seventeen patients aged 5.1-21.3 years received paclitaxel, of whom 47.1% (8/17) had treatment failure, 29.4% (5/17) received paclitaxel as initial treatment, and 23.5% (4/17) had relapsed. All HIV positive patients (16/17) were given anti-retroviral therapy (ART) and 87.5% (14/16) achieved viral load <1000 cp/mL. At censure, 82.3% (14/17) of patients were alive-71.4% (10/14) achieved complete clinical remission and 28.6% (4/14) achieved a partial response. The median follow up was 37.3 months (range 8.0-83.5, IQR 19.7-41.6), and no patients were lost to follow up. In this cohort, high rates of long-term survival and favorable outcomes were possible with paclitaxel treatment.

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.

Perspective: Creating the Evidence Base for Nutritional Support in Childhood Cancer in Low- and Middle-Income Countries: Priorities for Body Composition Research.

There is a striking disparity in survival rates for children in low- and middle-income countries (LMICs) compared with high-income countries (HICs). Many of the contributing factors are preventable, including the comorbidity of malnutrition. There are emerging data that malnutrition, as reflected in body composition changes, impacts survival of cancer. However, not enough priority is given to nutrition management of children with cancer, particularly in LMICs. The primary purpose of this article is to review the current knowledge on childhood cancer and body composition in LMICs and identify priorities for future research into the interlinking associations between cancer, body composition, and clinical outcomes for childhood cancer patients. Evidence will ensure feasible and effective nutrition management is prioritized in childhood cancer centers in LMICs and contribute to improving outcomes for children with cancer.

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.