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

Abstract

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.

Figure 1:. Study selection

*Deduplicated using Covidence software.

Figure 2:. Map of included studies

World map depicting number of studies included in this systematic review from each country. Countries in grey represent those without included published studies.

Figure 3:. Estimated treatment-related mortality by cancer diagnosis

Forest plot of estimated treatment-related mortality by cancer diagnosis by use of a mixed-effects model. Estimated treatment-related mortality is shown with 95% CIs. The size of the square representing the estimate corresponds to the sample size of patients. The vertical dotted line represents the aggregated treatment-related mortality estimate for all patients included in this systematic review and meta-analysis. *Treatment-related mortality estimates based on random-effects model. †Subcategories of diagnoses with a small number of studies, where treatment-related mortality could not be estimated.

Figure 4:. Trends in treatment related-mortality over time

The figure depicts treatment-related mortality by study mid-year, calculated as the middle year of study conduct (average between start and stop of study inclusion years). Treatment-related mortality rates are depicted for all study patients (A), patients receiving treatment in low-income countries (B), patients receiving treatment in lower-middle-income countries (C), and patients receiving treatment in upper-middle-income countries (D). The size of the circle represents the size of the study sample. Mixed-effects model was used to explore the relationship between treatment-related mortality estimates and the year of study conduct (as depicted by the trend line shown).