Metronomic Chemotherapy for Children in Low- and Middle-Income Countries: Survey of Current Practices and Opinions of Pediatric Oncologists

Abstract

PURPOSE Low- and middle-income countries (LMICs) experience the burden of 80% of new childhood cancer cases worldwide, with cure rates as low as 10% in some countries. Metronomics combines frequent administrations of low-dose chemotherapy with drug repurposing, which consists of using already-approved drugs for new medical applications. With wide availability, limited costs, and little infrastructure needs, metronomics can be part of constraint-adapted regimens in these resource-limited settings—with the understanding that metronomics shall not be a substitute for standard treatments when available and doable. Our study aims to describe the experience, practices, opinions, and needs in metronomics of physicians working in LMICs. METHODS An online questionnaire was sent to more than 1,200 physicians in pediatric oncology networks in LMICs. Items included the type of center, physician’s demographics, experience in pediatric oncology, and experience with current knowledge of metronomics. Opinions and perspectives were explored using multiple-answer and open questions. RESULTS Of physicians, 17% responded. Of respondents, 54.9% declared that they had already used a metronomic regimen. The most frequently cited repositioned drugs were celecoxib (44%) followed by propranolol and valproic acid (17%). Respondents highlighted the advantages of outpatient use (20%) and expected low toxicity (24%). In considering the drawbacks of metronomics, 47% of responses highlighted the lack of scientific evidence or guidelines, 33% the availability or affordability of drugs, and 18% the problem of acceptance or compliance. Of physicians, 79% believed that use of metronomics will spread in LMICs in the near future and 98% of them were willing to participate in international metronomic protocols or registries. CONCLUSION Metronomics is already used in LMICs and is a potential answer to unmet needs in pediatric oncology. There is room for improvement in the availability of drugs and a necessity to develop collaborative protocols and research to generate level A evidence.

Drug Repurposing of β-blocker Propranolol in Osteosarcoma: Preclinical Antitumor Efficacy Alone or in Combination with Chemotherapy.

“…OSA is fatal for about one-third of the patients worldwide. However, prognosis is signi cantly poorer for LMICs [9]. Higher mortality rates are mainly due to economic inequalities and ine cient health-care systems, resulting in diagnosis at advanced stages and poor access to treatment resources, including surgery, radiotherapy and high-cost novel cancer drugs [2].…”

“…Higher mortality rates are mainly due to economic inequalities and ine cient health-care systems, resulting in diagnosis at advanced stages and poor access to treatment resources, including surgery, radiotherapy and high-cost novel cancer drugs [2]. As previously introduced, metronomics combines drug repurposing with metronomic chemotherapy and could act as a substitute for standard treatments when unavailable or undoable [9]. PPN is a low-cost widely-available FDA-approved drug and its repositioned use in oncology is gaining strength as high quality preclinical and clinical evidence accumulates.…”

“…Moreover, seeking for enhanced therapeutic bene ts, repurposed drugs are often combined with metronomic chemotherapy, consisting in frequent administrations of low-dose chemotherapy, with no sustained drug-free breaks [8]. This treatment strategy is called "metronomics", and stands as an interesting therapeutic approach to especially implement in LMICs as its reduced costs and fewer infrastructure needs can be easily adapted in resource-limited countries [9].…”

Metro‐SMHOP 01: Metronomics combination with cyclophosphamide‐etoposide and valproic acid for refractory and relapsing pediatric malignancies

“…4 Over the last few years, a growing number of publications have investigated the potential role of metronomics for children in LMIC, 4,14,20,24,[26][27][28] and a recent international survey has confirmed the interest of pediatric oncologists working in LMIC for this approach, especially for palliative care or as a maintenance for patients with high-risk disease. 29 Indeed, access to newer therapies such as targeted therapies or immunotherapies is very limited in LMIC. Consequently, for these patients, metronomics represents a way to respond to patients' unmet needs and to families who want something to be done for their children.…”

Widely disseminated metastatic Ewing sarcoma: Sustained, complete metabolic response to first‐line oral metronomic chemotherapy

“…Metastatic ES essentially needs a personalized risk‐adapted approach 1 . OMCT is an intelligent way of providing effective, yet less toxic treatment with requirement of less supportive measures and fulfills an unmet need in LMICs 5,21 . In this case, OMCT was used in the upfront setting with documentation of excellent and sustained response even after stopping all treatment.…”