The Feasibility, Implementation, and Safety of High-Dose Methotrexate for the Treatment of Pediatric Burkitt Lymphoma in Mwanza, Tanzania

Abstract

Introduction: Despite the excellent outcomes achieved for pediatric patients with Burkitt lymphoma (BL) in high income countries (HICs), survival remains <50% in many low- and low middle-income countries (LMICs). High-dose methotrexate (HD-MTX), though proven to be highly efficacious for the treatment of BL, has been infrequently used in LMICs due to its historically resource intensive supportive care regimen and potential associated toxicities. Though there have been a few reports of HD-MTX use in resource limited settings, there has been no literature to date detailing the implementation methods needed to introduce HD-MTX in a resource limited setting. Subsequently, at our site, Bugando Medical Centre (BMC), located in Mwanza, Tanzania, efforts were taken to explore the feasibility, implementation methods, and safety of introducing HD-MTX for the treatment of pediatric BL and a related condition, diffuse large B-cell lymphoma (DLBCL). Methods: Feasibility and pre-implementation planning were both addressed using methods and tools from the Active Implementation Framework (AIF). Feasibility assessments included a fit analysis, cost analysis, and resource mapping. Subsequent pre-implementation efforts included the identification and engagement of key stakeholders, the formation of an implementation team, and the development of an educational curriculum. Continuing education resources and decision support tools were also developed. Protocol fidelity monitoring was also developed and included the creation of bedside tracking sheets. Once HD-MTX was introduced, recurrent errors identified using the fidelity assessments were addressed using quality improvement methodology. Feedback from key stakeholders was also collected and analyzed. Safety of HD-MTX was assessed via a prospective observational study that collected both provider assessments as well as patient reported outcomes (PROs) data. This study was opened prior to the introduction of HD-MTX at BMC in order to collect safety comparative data from the prior standard of care chemotherapy. Collected data was recorded in a secure REDCap database. A descriptive statistical analysis was performed. Results: Pre-implementation evaluation supported the intervention fit and feasibility of the use of HD-MTX at BMC. Cost analysis revealed a typical maximum cost per cycle of 72,000 Tanzanian shillings ($28.80 USD), but that for many patients the cost would be far less thanks to support from local non-governmental organizations (NGOs). Resource mapping revealed that most all physical and human resources needed for using HD-MTX at BMC were already in place. Early implementation efforts to date have included the administration of 13 cycles of HD-MTX to date at BMC. Overall, fair protocol fidelity has been observed with all cycles generally following the supportive care protocol as written. Key recurrent issues have included delays in methotrexate being prepared from pharmacy and delayed or missed serum creatinine checks at the 48-hour mark. Safety evaluation to date has revealed that the HD-MTX at a dose of 1g/m2 has been overall well tolerated, with only 1 attributable grade III adverse event (AE), mucositis. Conclusions: Overall, HD-MTX at a dose of 1g/m2 appears feasible and safe at BMC. A robust implementation strategy has been developed to support its introduction at BMC. The context at BMC is likely similar to that at many low resource cancer centers, and subsequently the success of the use of HD-MTX at BMC to date likely supports its use at other LMIC cancer centers. There are several generalizable themes learned from the efforts at BMC that apply to any cancer center and could be used to inform and facilitate the introduction of HD-MTX at those centers.