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.

Female Fertility Cryopreservation Outcomes in Childhood Cancer: A Systematic Review.

BACKGROUND AND AIMS: As survival rates in childhood cancer progress significantly, health outcomes in adulthood are pivotal to quality of life (QoL). Female patients undergoing chemotherapy and radiation for childhood cancer may experience adverse effects such as gonadotoxicity-related ovarian insufficiency. Ovarian tissue cryopreservation (OTC) is well studied in adults, but has only recently started to be explored in an effort to preserve fertility in young patients with childhood cancer. This systematic review aims to critically highlight contemporary outcomes of cryopreservation in female pediatric cancer patients. METHODS: A systematic search was conducted in PubMed, Embase, and Web of Science databases to identify English-language full text articles and abstracts published between 2004 and 2022 describing cryopreservation among female children (0-21 years old) with cancer. Abstracts and full-text articles were screened for inclusion. Subsequently, data from eligible studies was extracted and analyzed. Descriptive statistics were utilized to estimate overall outcomes of cryopreservation. RESULTS: Of 104 abstracts and 34 full-text articles, 12 studies were included. Data was collected from 7 world countries and involved some 612 pediatric and adolescent patients with malignant disease. Most common cancers included hematological malignant disease (81%), CNS nervous system malignant tumors (56%), and sarcomas (39%). Of the 6 studies with full reporting, OTC was undertaken in 501 patients, and 5.9% (30/501) of these patients underwent ovarian tissue transplantation (OTT). After OTT, 27 patients desired pregnancy and 33% (9/27) became pregnant. Six of these 9 patients (67%) had live births. CONCLUSIONS: Preliminary analysis showed that OTC has been successfully performed but not yet studied thoroughly in pediatric cancer patients in a longitudinal manner. This study has further shown that cryopreservation outcomes are mainly reported among adult patients living in high income countries, demonstrating a crucial need for long-term outcome studies focused on pediatric and prepuberal OTC, subsequent OTT, and potential pregnancy. This work is considered critical to aid standardize recommendations of fertility preservation in childhood cancer patients and to better inform the efficacy of these procedures to benefit patients in world nations of all fiscal income levels. LEVEL OF EVIDENCE: Level III.

Ideal vs Actual Timing of Palliative Care Integration for Children With Cancer in Latin America.

Importance: Early integration of pediatric palliative care (PPC) for children with cancer is critical for the quality of life of both patient and family. To improve access to PPC in resource-limited settings, barriers to early integration must be understood. Objectives: To evaluate the ideal vs actual timing of PPC integration for children with cancer and to uncover barriers to early integration identified by physicians in Latin America. Design, Setting, and Participants: The Assessing Doctors' Attitudes on Palliative Treatment (ADAPT) survey was distributed electronically from August 1, 2020, to January 31, 2021, to physicians who treat children with cancer in 17 countries in Latin America. Main Outcomes and Measures: The ADAPT survey queried for understanding of ideal vs actual timing of PPC for children with cancer and for identification of barriers to PPC integration. Descriptive statistics were used to summarize the data. For secondary analyses, a comparison of the associations of previous palliative care training with physician specialty was performed using the Pearson χ2 test or the Fisher exact test. The McNemar test was used to assess responses regarding the actual vs ideal timing of PPC consultation. Analysis of variance was used to compare mean values for perceived barriers by country income level. Answers to open-ended questions were analyzed qualitatively. Results: A total of 831 physicians (578 women [69.6%]; 275 physicians [33.1%] aged <35 years and 556 physicians [66.9%] aged ≥35 years) from 17 countries participated, with an overall response rate of 37.9% (831 of 2193) and a median country response rate of 51.4% (range, 22.2%-88.9%). Most respondents (572 [68.8%]) said that PPC should be involved from diagnosis, but only 117 (14.1%) stated that this occurred at their institution (P < .001). The most significantly ranked barriers to PPC were lack of home-based services (713 [85.8%]), personnel (654 [78.7%]), and knowledge about PPC (693 [83.4%]), along with physician (676 [81.3%]) and family (603 [72.6%]) discomfort about PPC involvement. In addition, these barriers were rated as more important in lower-middle income countries compared with upper-middle income countries and high-income countries. Conclusions and Relevance: This study highlights the discrepancy between ideal and actual timing of PPC for children with cancer and barriers to early PPC integration in Latin America. Interventions addressing access to PPC resources, didactic training, and clinical education (with a particular focus on equitable access to basic resources and support) are critical to improve the timing and quality of PPC in the region.

Pediatric Early Warning Systems (PEWS) improve provider-family communication from the provider perspective in pediatric cancer patients experiencing clinical deterioration.

BACKGROUND: Communication between providers and patients' families is an integral part of clinical care. Family concern is a validated component of Pediatric Early Warning Systems (PEWS); however, little is known about the impact of PEWS on provider-family communication. METHODS: Semi-structured interviews were conducted with 83 ward and Pediatric Intensive Care Unit (PICU) providers involved in the care of patients with deterioration at two pediatric oncology hospitals of different resource levels: St. Jude Children's Research Hospital (n = 42) in the United States and Unidad Nacional de Oncología Pediátrica (UNOP, n = 41) in Guatemala. Interviews were conducted in the participants' native language (English or Spanish), transcribed, and translated into English. Transcripts were coded by two researchers and analyzed for thematic content surrounding family communication and concern. RESULTS: All participants recognized patients' families as a valuable part of the care team, particularly during events requiring escalation of care. Perceived barriers to communication included limited time spent at the bedside, and, at UNOP, language and literacy challenges which occasionally limited providers' ability to assess family concern and involve families in patient care. Despite these barriers, providers perceived PEWS improved communication by facilitating more interaction with families, allowing for relationship-building, anticipatory guidance, and destigmatization of the PICU. PEWS assessments also allowed families to contribute to identification of deterioration. CONCLUSIONS: PEWS improve the quality of communication between providers and families by providing more opportunities for interaction, building relationships, and trust. These findings further support the use of PEWS in the care of children with cancer in hospitals of all resource-levels.

Stages of change: Strategies to promote use of a Pediatric Early Warning System in resource-limited pediatric oncology centers.

BACKGROUND: Pediatric Early Warning Systems (PEWS) assist early detection of clinical deterioration in hospitalized children with cancer. Relevant to successful PEWS implementation, the "stages of change" model characterizes stakeholder support for PEWS based on willingness and effort to adopt the new practice. METHODS: At five resource-limited pediatric oncology centers in Latin America, semi-structured interviews were conducted with 71 hospital staff involved in PEWS implementation. Purposive sampling was used to select centers requiring variable time to complete PEWS implementation, with low-barrier centers (3-4 months) and high-barrier centers (10-11 months). Interviews were conducted in Spanish, professionally transcribed, and translated into English. Thematic content analysis explored "stage of change" with constant comparative analysis across stakeholder types and study sites. RESULTS: Participants identified six interventions (training, incentives, participation, evidence, persuasion, and modeling) and two policies (environmental planning and mandates) as effective strategies used by implementation leaders to promote stakeholder progression through stages of change. Key approaches involved presentation of evidence demonstrating PEWS effectiveness, persuasion and incentives addressing specific stakeholder interests, enthusiastic individuals serving as models for others, and policies enforced by hospital directors facilitating habitual PEWS use. Effective engagement targeted hospital directors during early implementation phases to provide programmatic legitimacy for clinical staff. CONCLUSION: This study identifies strategies to promote adoption and maintained use of PEWS, highlighting the importance of tailoring implementation strategies to the motivations of each stakeholder type. These findings can guide efforts to implement PEWS and other evidence-based practices that improve childhood cancer outcomes in resource-limited hospitals.

The COVID-19 Pandemic's impact on sustainability and expansion of a Pediatric Early Warning System in resource-limited hospitals.

BACKGROUND: The COVID-19 pandemic impacted healthcare delivery worldwide, including pediatric cancer care, with a disproportionate effect in resource-limited settings. This study evaluates its impact on existing quality improvement (QI) programs. METHODS: We conducted 71 semi-structured interviews of key stakeholders at five resource-limited pediatric oncology centers participating in a collaborative to implement Pediatric Early Warning System (PEWS). Interviews were conducted virtually using a structured interview guide, recorded, transcribed, and translated into English. Two coders developed a codebook of a priori and inductive codes and independently coded all transcripts, achieving a kappa of 0.8-0.9. Thematic analysis explored the impact of the pandemic on PEWS. RESULTS: All hospitals reported limitations in material resources, reduction in staffing, and impacts on patient care due to the pandemic. However, the impact on PEWS varied across centers. Identified factors that promoted or limited ongoing PEWS use included the availability of material resources needed for PEWS, staff turnover, PEWS training for staff, and the willingness of staff and hospital leaders to prioritize PEWS. Consequently, some hospitals were able to sustain PEWS; others halted or reduced PEWS use to prioritize other work. Similarly, the pandemic delayed plans at all hospitals to expand PEWS to other units. Several participants were hopeful for future expansion of PEWS post-pandemic. CONCLUSION: The COVID-19 pandemic created challenges for sustainability and scale of PEWS, an ongoing QI program, in these resource-limited pediatric oncology centers. Several factors mitigated these challenges and promoted ongoing PEWS use. These results can guide strategies to sustain effective QI interventions during future health crises.

Impact of hospital characteristics on implementation of a Pediatric Early Warning System in resource-limited cancer hospitals.

Background: Pediatric Early Warning Systems (PEWS) aid in identification of deterioration in hospitalized children with cancer but are underutilized in resource-limited settings. Proyecto EVAT is a multicenter quality improvement (QI) collaborative in Latin America to implement PEWS. This study investigates the relationship between hospital characteristics and time required for PEWS implementation. Methods: This convergent mixed-methods study included 23 Proyecto EVAT childhood cancer centers; 5 hospitals representing quick and slow implementers were selected for qualitative analysis. Semi-structured interviews were conducted with 71 stakeholders involved in PEWS implementation. Interviews were recorded, transcribed and translated to English, then coded using a priori and novel codes. Thematic content analysis explored the impact of hospital characteristics and QI experience on time required for PEWS implementation and was supplemented by quantitative analysis exploring the relationship between hospital characteristics and implementation time. Results: In both quantitative and qualitative analysis, material and human resources to support PEWS significantly impacted time to implementation. Lack of resources produced various obstacles that extended time necessary for centers to achieve successful implementation. Hospital characteristics, such as funding structure and type, influenced PEWS implementation time by determining their resource-availability. Prior hospital or implementation leader experience with QI, however, helped facilitate implementation by assisting implementers predict and overcome resource-related challenges. Conclusions: Hospital characteristics impact time required to implement PEWS in resource-limited childhood cancer centers; however, prior QI experience helps anticipate and adapt to resource challenges and more quickly implement PEWS. QI training should be a component of strategies to scale-up use of evidence-based interventions like PEWS in resource-limited settings.

Multilevel impacts of a pediatric early warning system in resource-limited pediatric oncology hospitals.

Background: Pediatric Early Warning Systems (PEWS) reduce clinical deterioration, improve interdisciplinary communication, and provide cost savings; however, little is known about how these impacts are achieved or related. This study evaluates the multi-level impacts of PEWS in resource-limited pediatric oncology centers. Methods: We conducted 71 semi-structured interviews including physicians (45%), nurses (45%), and administrators (10%) from 5 resource-limited pediatric oncology centers in 4 Latin American countries. Interviews were conducted in Spanish, transcribed, and translated into English. A code book was developed using a priori and inductively derived codes. Transcripts were independently coded by 2 coders, achieving a kappa of 0.8-0.9. Thematic content analysis explored perceived impacts of PEWS at the level of the patient, clinician, healthcare team, and institution. Results: PEWS improved the quality of attention for patients, reducing morbidity and mortality. Clinicians felt more knowledgeable, confident, and empowered providing patient care, resulting in greater job satisfaction. PEWS affected team dynamics by improving interdisciplinary (ward and intensive care unit) and interprofessional (physicians and nurses) relationships and communication. This ultimately led to institutional culture change with emphasis on patient safety, collaboration with other centers, and receipt of institutional awards. Together, these impacts led to hospital-wide support of ongoing PEWS use. Conclusions: In resource-limited hospitals, PEWS use results in multi-level positive impacts on patients, clinicians, teams, and institutions, creating a feedback loop that further supports ongoing PEWS use. These findings can guide advocacy for PEWS to various stakeholders, improve PEWS effectiveness, and inform assessment of other interventions to improve childhood cancer outcomes.

Assessment of Barriers and Enablers to Implementation of a Pediatric Early Warning System in Resource-Limited Settings.

Importance: Pediatric early warning systems (PEWS) aid with early identification of clinical deterioration and improve outcomes in children with cancer hospitalized in resource-limited settings; however, there may be barriers to implementation. Objective: To evaluate stakeholder-reported barriers and enablers to PEWS implementation in resource-limited hospitals. Design, Setting, and Participants: In this qualitative study, semistructured stakeholder interviews were conducted at 5 resource-limited pediatric oncology centers in 4 countries in Latin America. Hospitals participating in a multicenter collaborative to implement PEWS were purposefully sampled based on time required for implementation (fast vs slow), and stakeholders interviewed included physicians, nurses, and administrators, involved in PEWS implementation. An interview guide was developed using the Consolidated Framework for Implementation Research (CFIR). Interviews were conducted virtually in Spanish, audiorecorded, and professionally transcribed and translated into English. A codebook was developed a priori using the CFIR and supplemented with codes inductively derived from transcript review. Two coders independently analyzed all transcripts, achieving a κ of 0.8 to 0.9. The study was conducted from June 1 to August 31, 2020. Main Outcomes and Measures: Thematic analysis was conducted based on CFIR domains (inner setting, characteristics of individuals, outer setting, intervention characteristics, and implementation process) to identify barriers and enablers to PEWS implementation. Results: Seventy-one staff involved in PEWS implementation were interviewed, including 32 physicians (45%), 32 nurses (45%), and 7 administrators (10%). Of these, 50 were women (70%). Components of the 5 CFIR domains were mentioned by participants as barriers and enablers to PEWS implementation at both fast- and slow-implementing centers. Participants emphasized barriers at the level of the clinical staff, hospital, external factors, and PEWS intervention. These barriers included staff resistance to change, inadequate resources, components of health systems, and the perceived origin and complexity of PEWS. At all centers, most barriers were successfully converted to enablers during the implementation process through targeted strategies, such as early stakeholder engagement and adaptation, including adapting PEWS to better fit the local context and changing the hospital setting to support ongoing use of PEWS. Conclusions and Relevance: To date, this is the first multicenter, multinational study describing barriers and enablers to PEWS implementation in resource-limited settings. Findings suggest that many barriers are not immutable and can be converted to enablers during the implementation process. This work can serve as a guide for clinicians looking to implement evidence-based interventions to reduce global disparities in patient outcomes.

Physician Perceptions of Palliative Care for Children With Cancer in Latin America.

Importance: The World Health Organization (WHO) designates early integration of palliative care as an ethical responsibility in the treatment of children with serious illness. Although structural barriers may influence provision of pediatric palliative care (PPC) for children with cancer in resource-limited settings, underlying physician perceptions may also impede early integration of PPC in cancer care. Objective: To investigate perceptions among physicians in Latin America about the integration of palliative care for children with cancer. Design, Setting, and Participants: This survey study used the Assessing Doctors' Attitudes on Palliative Treatment (ADAPT) survey, which was developed for physicians who care for children with cancer and was initially distributed in Eurasia. The survey was modified for use in Latin America, including translation into Spanish and adaptation for cultural context. The survey was distributed between August 21, 2020, and January 31, 2021, to physicians treating children with cancer in 17 Latin American countries. Each country had a specific survey distribution method based on guidance of local experts. Main Outcomes and Measures: The ADAPT survey evaluated physicians' understanding of palliative care principles, comfort in addressing patient and family suffering, and identification of barriers to PPC integration for children with cancer. Univariate and multivariable linear regression analyses were used to assess factors associated with physicians' knowledge about and comfort with PPC practice and whether independent physician variables were associated with survey response alignment with WHO guidance on PPC. Open-ended questions were analyzed qualitatively to supplement the quantitative data. Results: A total of 874 physicians from 17 countries participated, with an overall response rate of 39.9% (874 of 2193) and a median country response rate of 51.4% (range, 23.7%-100%). Most respondents were aged 35 years or older (577 [66.0%]), and 594 (68.0%) identified as female. Most physicians (486 [55.6%]) had no formal PPC training, and 303 (34.7%) had no access to PPC experts for consultation. Physician perspectives on PPC were generally aligned with WHO guidance (mean [SD] alignment, 83.0% [14.1%]; range among respondents, 24.0%-100%). However, only 438 respondents (50.1%) felt comfortable addressing physical symptoms of patients receiving PPC, 295 (33.8%) felt comfortable addressing emotional symptoms, and 216 (24.7%) felt comfortable addressing grief and bereavement needs of the patient's family. A total of 829 participants (94.8%) desired further education and training in PPC. Conclusion and Relevance: Although physicians' perspectives aligned well with WHO guidance for PPC, this survey study identified opportunities for improving physician training in symptom management and emotional support for children with cancer and their families. These findings may inform the development of targeted interventions to improve the quality of PPC for children with cancer in Latin America.

Challenges to sustainability of pediatric early warning systems (PEWS) in low-resource hospitals in Latin America.

Background: Sustainability, or continued use of evidence-based interventions for long-term patient benefit, is the least studied aspect of implementation science. In this study, we evaluate sustainability of a Pediatric Early Warning System (PEWS), an evidence-based intervention to improve early identification of clinical deterioration in hospitalized children, in low-resource settings using the Clinical Capacity for Sustainability Framework (CCS). Methods: We conducted a secondary analysis of a qualitative study to identify barriers and enablers to PEWS implementation. Semi-structured interviews with PEWS implementation leaders and hospital directors at 5 Latin American pediatric oncology centers sustaining PEWS were conducted virtually in Spanish from June to August 2020. Interviews were recorded, professionally transcribed, and translated into English. Exploratory thematic content analysis yielded staff perceptions on PEWS sustainability. Coded segments were analyzed to identify participant perception about the current state and importance of sustaining PEWS, as well as sustainability successes and challenges. Identified sustainability determinants were mapped to the CCS to evaluate its applicability. Results: We interviewed 71 staff including physicians (45%), nurses (45%), and administrators (10%). Participants emphasized the importance of sustaining PEWS for continued patient benefits. Identified sustainability determinants included supportive leadership encouraging ongoing interest in PEWS, beneficial patient outcomes enhancing perceived value of PEWS, integrating PEWS into the routine of patient care, ongoing staff turnover creating training challenges, adequate material resources to promote PEWS use, and the COVID-19 pandemic. While most identified factors mapped to the CCS, COVID-19 emerged as an additional external sustainability challenge. Together, these challenges resulted in multiple impacts on PEWS sustainment, ranging from a small reduction in PEWS quality to complete disruption of PEWS use and subsequent loss of benefits to patients. Participants described several innovative strategies to address identified challenges and promote PEWS sustainability. Conclusion: This study describes clinician perspectives on sustainable implementation of evidence-based interventions in low-resource settings, including sustainability determinants and potential sustainability strategies. Identified factors mapped well to the CCS, however, external factors, such as the COVID pandemic, may additionally impact sustainability. This work highlights an urgent need for theoretically-driven, empirically-informed strategies to support sustainable implementation of evidence-based interventions in settings of all resource-levels.