Metronomics Global Health Initiative

Safety and Efficacy of Vinorelbine and Continuous Low-Dose Cyclophosphamide Chemotherapy in Japanese Pediatric Patients With Relapsed or Refractory Rhabdomyosarcoma

2026-04-30T12:16:28Z

The team from the Department of Pediatric Oncology, National Cancer Center Japan, Tokyo, Japan.
and the Cancer Medicine, Cooperative Graduate School, The Jikei University Graduate School of Medicine, Tokyo, Japan have just published an article in Pediatric Blood and Cancer about a metronomic maitenance in RMS.

The authors Risa Yanai, Minako Sugiyama, Bunpei Miyazaki, Natsumi Kikuchi, Kosuke Tamefusa, Kayoko Tao, Eriko Uchida, Kiyotaka Isobe, Kan Yonemori, Ayumu Arakawa thus confirm the activity of the metronomicregimen in 18 relapsing and refractory RMS. Interstingly, they suggest starting at 80% of the dose.

Abstract

Background

: Relapsed or refractory rhabdomyosarcoma (RMS) has a poor prognosis, and optimal treatment remains an unmet need. Vinorelbine (VNR) and low-dose metronomic cyclophosphamide (CPM) have shown clinical efficacy and are used as maintenance therapy in localized and metastatic disease; however, dose reductions are frequently required due to myelosuppression. This study evaluated the safety, efficacy, and optimal dosing of VNR and CPM in pediatric patients with relapsed or refractory RMS.

Methods: Pediatric patients treated with VNR and CPM at our institution between March 2014 and May 2024 were retrospectively reviewed. Dosing was based on the RMS 2005 protocol, with dose reductions implemented before or during treatment to minimize treatment interruptions.

Results: Eighteen patients received 139 cycles of therapy (median age at initiation, 15.6 years; range, 7-21 years), including 13 relapsed and 5 refractory cases. The median number of cycles administered was 5.5 (range, 1-26), with a median interval of 28 days. The median adjusted dose ratios over three cycles were 55% for VNR and 53.5% for CPM. Disease control lasting longer than 10 months was achieved in six patients (33%). Neutropenia occurred in 89% of patients, whereas anemia and thrombocytopenia requiring transfusion occurred in 28% and 22%, respectively. No grade 4 non-hematologic toxicities or treatment-related deaths were observed after dose adjustment.

Conclusions: VNR and continuous low-dose CPM chemotherapy were safe and feasible with dose adjustments. In heavily pretreated patients, initiating therapy at approximately 80% of the standard dose may be appropriate.

A modified multi-drug metronomic antiangiogenic approach in recurrent pediatric embryonal central nervous system tumors: an institutional experience

2026-04-30T11:17:39Z

Katrina O'Halloran, Benjamin Fixman, Tom B. Davidson, Nathan J. Robison, Anat Erdreich-Epstein, Jemily Malvar, Kaaren Waters, Teresa Rushing, Mark D. Krieger, Jennifer Cotter ,Benita Tamrazi, S. Margol from the Cancer and Blood Disease Institute, the Keck School of Medicine, the Norris Comprehensive Cancer Center, the Department of Pathology, and the Division of Neurosurgery, Children's Hospital Los Angeles, Los Angeles, CA, USA have just published a article" A modified multi-drug metronomic antiangiogenic approach in recurrent pediatric embryonal central nervous system tumors: an institutional experience" in NeuroOncology Pediatrics.
It brings on additional data about the use of MEMMAT like treatment (triple IT therapy with araC, etoposide, topotecan) and report that overall response rate in our modified-MEMMAT experience is encouraging (Table 3). Similar to the
French “real life” experience, we showed somewhat lower EFS and OS compared to the Austrian studies.

Abstract
Background
Approximately one third of pediatric patients with embryonal tumors of the central nervous system will experience a recurrence, with poor prognosis. Patients with recurrent or progressive disease may be treated with multi-drug metronomic antiangiogenic approaches.
Methods
We performed a retrospective review of 13 patients treated at a single institution from 2010-2023 using a multimodal metronomic antiangiogenic regimen which includes oral thalidomide, celecoxib and fenofibrate, and alternating etoposide/cyclophosphamide, intravenous bevacizumab, and alternating intraventricular etoposide, cytarabine, and topotecan.

Results
Toxicities included myelosuppression with at least one grade 3 hematologic toxicity in 11/12 (92%) patients. Other toxicities included infection, neurologic (cerebritis, irritability), hepatic (transaminitis), and a secondary leukemia. Seven patients required one or more drugs to be held or modified due to toxicity. The overall response rate was 69.2% (95% confidence interval (CI): 38.6%-90.9%) with median time to best response for patients who achieved CR or PR of 5 months. The median event-free survival (EFS) and overall survival (OS) time was 6 months (range: 1-21 months) and 15 months (range: 1.1-42.6 months), respectively. The 12-months EFS was 46.1% (95% CI: 19.2%-69.6%) with 12-months OS 83.9% (95% CI: 49.4%-95.7%).

Conclusion
Metronomic multi-drug approaches combining oral, intravenous and intraventricular/intrathecal therapy were generally well tolerated and provided a survival benefit.

you can have freely tho the full text here.

Real-life experience with a "modified-MEMMAT" regimen for relapsed medulloblastoma

Nicolas André — 2026-02-24T15:47:28Z

Thus a retrospective work lead by the Bambino Gesù Children's Hospital in Roma evaluating MEMMAT like combinations in medulloblastoma. The article is entitled : Experience with a "modified-MEMMAT" regimen for relapsed medulloblastoma and has been published in Ther Adv Med Oncol.

The authors (Antonella Cacchione, Giada Del Baldo, Federica D'Antonio, Valentina Di Ruscio , Giacomina Megaro, Chiara Pilotto, Assunta Tornesello, Alessandro Cocciolo, Sabina Vennarini, Silvia Chiesa, Andrea Carai, Andrea De Salvo, Giulia Albino, Giovanna Stefania Colafati, Irene Slavc, Angela Mastronuzzi from the Bambino Gesù Children's Hospital, the Sapienza University of Rome, the ASUFC Santa Maria Della Misericordia, Udine, the Ospedale Vito Fazzi, Lecce, the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Ithe Fondazione Policlinico Universitario "A. Gemelli," Catholic University of Sacred Heart, Rome,
the Medical University of Vienna, Austria confirm the promising antitumorali activity of the combination.

Background: Medulloblastoma (MB) relapse is typically resistant to available treatments. An emerging alternative strategy focuses on disrupting tumor angiogenesis at various stages, using a combined metronomic anti-angiogenic approach.

Objectives: The study aims to assess the efficacy and safety of this modified treatment approach in managing recurrent MB in the pediatric population.

Designs: This study is a retrospective observational analysis involving 14 pediatric patients diagnosed with first or multiple recurrences of MB.

Methods: We analyzed clinical, molecular, radiological, and outcome data of our cohort treated using a modified Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial (MEMMAT) strategy.

Results: Median age of patients was 11.6 years (range: 6.4-26 years). All 14 patients presented with a metastatic relapse after conventional treatments. The median time from primary diagnosis/prior relapse to the start of "modified MEMMAT" was 22 months (range: 2-60 months). Fifty-seven percent received the "modified MEMMAT" schema as second-line treatment, while 43% received it as third-line or beyond after recurrence. At a median follow-up of 17.9 months, the median overall survival (OS) from the MEMMAT start date was 18.2 months, and the median progression-free survival (PFS) was 12.8 months. OS at 12 and 24 months was 78.6% and 28.6%, respectively. PFS at 6 and 12 months was 100% and 55.0%, respectively. Treatment was globally well tolerated.

Conclusion: The modified MEMMAT strategy shows promise in treating recurrent MB, achieving a 12-month OS rate from date of starting treatment of 78.6%, with manageable toxicity. These findings suggest its potential as a viable option for heavily pre-treated pediatric patients, warranting further validation in larger prospective studies.

you can read the full paper here :

Building a new arsenal: repurposed drugs and metronomic chemotherapy against medulloblastoma

Nicolas André — 2026-02-24T15:46:31Z

In this review article, entitled : Building a new arsenal: repurposed drugs and metronomic chemotherapy against medulloblastoma published in Expert Rev Neurother
Donze C, Piris P, Leblond P, Matteudi M, Pasquier E, Carre M, and André N from Service d'Hématologie & Oncologie Pédiatrique, Timone Hospital, AP-HM, Marseille, the Reverse Molecular Pharmacology in Pediatric Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université́, CNRS, INSERM, SouthROCK Center of Excellence in Pediatric Oncology Research, Marseille, the IHOPe-Pediatric Hematology and Oncology Institute, Leon Berard Center, Lyon and the Metronomics Global Health Initiative, Marseille, France the authors summarize the current evidence regarding metronomic chemotherapy (MC) and drug repurposing in MB and discuss prospective future developments by searching the PubMed database from 1980 to 2025. Drug repurposing (DR), defined as the identification of novel therapeutic applications for existing pharmacological agents, presents a promising strategy to expedite the development of effective and well-tolerated treatments. Metronomic chemotherapy, characterized by the frequent administration of low-dose chemotherapeutic agents, exerts its therapeutic effects by targeting the tumor microenvironment and angiogenesis. Notably, metronomic chemotherapy, particularly in multidrug combinations incorporating repurposed agents, has demonstrated significant clinical activity in patients with relapsing/refractory MB.
Medulloblastoma (MB) represents the most prevalent malignant pediatric brain tumor. Although survival has greatly improved, the tumor and its treatments have devastating long-term side effects that negatively impact quality of survival. Consequently, there is a critical need for innovative therapeutic strategies aimed at enhancing patient outcomes and mitigating treatment-related toxicities.

Expert opinion: Data on MC and DR, published over the past decades, has confirmed their potential to prolong survival and potentially cure patients with refractory/relapsing MB. Randomized trials are now mandatory to generate higher levels of evidence.

yao can find the full article herehttps://www.tandfonline.com/doi/10....

Results of the Latin American Pediatric Oncology Group (GALOP) Trial for Patients With Metastatic Ewing Sarcoma: Multicentric Study of Interval-Compressed Multiagent and Metronomic Chemotherapy

Nicolas André — 2025-07-29T07:59:03Z

Adriana Rose , Lauro Jose Gregianin , Erica Boldrini , Carla Macedo , Sima Ferman , Tatiana El Jaick Bonifácio Costa , Marcelo Scopinaro , Algemir Lunardi Brunetto , André Tesainer Brunetto , Milena Villarroel on behalf of the GALOP Latin American Pediatric Oncology Group Ewing Sarcoma Investigators have published in Pediatric Blood and Cancer the result from an internaytional clinical trial entitled: Results of the Latin American Pediatric Oncology Group (GALOP) Trial for Patients With Metastatic Ewing Sarcoma: Multicentric Study of Interval-Compressed Multiagent and Metronomic Chemotherapy.

the full text of the paper can be foundhere

Abstract
Background: GALOP investigators developed a multicenter protocol to standardize treatment for newly diagnosed metastatic Ewing sarcoma (ES) in South America.

Methods: Prospective trial. Induction chemotherapy consisted of 9 alternating interval-compressed cycles (every 14 days) of vincristine, doxorubicin, cyclophosphamide, and ifosfamide-etoposide; local and metastatic site control; and 5 consolidation cycles (every 21 days), followed by MCT with cyclophosphamide and vinblastine for 1 year.

Results: Between 2011 and 2019, 198 patients were recruited from 34 centers in Argentina, Brazil, Chile, and Uruguay. Characteristics include: male patients (60.6%), median age of 12.3 years (range, 0.8-31.1); axial primary localization (62.1%), size >8 cm (70.2%); and bone origin (71.2%). Metastatic sites were lung, extra-lung, and combined in 43.4%, 31.3%, and 25.3%, respectively. The overall response rate was 79.3%, and local treatment was performed in 85.3% of patients. With a median follow-up of 65.1 months (95% CI: 53.9-76.4), the 5-year overall survival (OS) and event-free survival (EFS) were 33.1% (95% CI: 25.9-40.4) and 27.8% (95% CI: 21.5-34.3), respectively. The 5-year OS was 44.9%, 31.3%, and 15.6% for lung, extra-lung, and combined, respectively (p < 0.001). The median interval between induction chemotherapy cycles was 17 days, with a febrile neutropenia rate of 19.3%. Metronomic chemotherapy (MCT) was administered to 100 patients (50.5%), demonstrating good tolerability, with 58 patients completing at least 75% of the scheduled cycles.

Conclusion: The implementation of a multicenter protocol incorporating MCT for metastatic ES proved feasible across Latin America.

Maintenance therapy for pediatric sarcoma: full throttle ahead?

Nicolas André — 2025-07-29T07:49:49Z

We are delighted to announcve a new Metronomics Global Health Initiative publication !

Maintenance therapy for pediatric sarcoma: full throttle ahead? has been publisahed in Current opinion in Oncology as part of a sarcoma special issue.
The piece has been written with Nadege Corradini from the HOPe-Pediatric Hematolgy and Oncology Institute, Leon Berard Center, Lyon.and Daniel Orbach from the SIREDO Oncology Center , Institut Curie, PSL University, Paris, France.

Abstract

Purpose of review: Maintenance therapy (MT), particularly antiangiogenic approaches such metronomic chemotherapy (MC), correspond to the continuous administration of low-dose anticancer agents in a context of minimal residual disease. While widely used in pediatric acute lymphoblastic leukemia for decades, MT has recently shown promise in solid tumors. Additionally, antivascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) are increasingly explored in pediatric sarcomas.

Recent findings: This review summarize current evidence on MT efficacy in pediatric sarcomas, focusing on MC and TKIs. It examines their impact on the tumor microenvironment and cancer progression, as well as potential future applications, including standalone use or combination with targeted therapies, immunotherapies and/or drug repurposing.

Summary: MT has been demonstrated to improve outcomes in specific sarcomas, especially high-risk localized rhabdomyosarcoma, and has therefore become a standard of care. Its role in other sarcomas, such as Ewing sarcoma and osteosarcoma, is under investigation. However, critical challenges remain, including optimizing drug selection, treatment duration, and patient stratification to maximize benefits.

Myelodysplastic syndrome-post-cytotoxic therapy for pediatric low-grade glioma

Nicolas André — 2025-07-29T07:43:09Z

A case report entitled : Myelodysplastic syndrome-post-cytotoxic therapy for pediatric low-grade glioma authored by Phoebe Power, Susannah Payne, Rebecca Walsh, Adam Nelson & Neevika Manoharan from Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA and Kids Cancer Centre, Sydney Children's Hospital, Australia has been published in Child's Nervous System

The full text is freely avaliable here

Abstract

Myeloid neoplasms-post cytotoxic therapy (MN-pCT, previously therapy-related myeloid neoplasms/tMN), are secondary malignancies associated with prior chemotherapy treatment, historically carrying a very poor prognosis. These are rarely associated with primary central nervous system (CNS) tumors, usually high-grade CNS malignancies requiring intensive multimodal treatment. Pediatric low-grade gliomas (pLGGs) are the most common childhood CNS tumors, and up to 50% of patients will require adjuvant therapy, which has traditionally consisted of low-dose metronomic chemotherapy, though the recent identification of key molecular drivers of pLGG means targeted therapies are changing this paradigm. We present a novel case of a 17-year-old girl with therapy-related myelodysplastic syndrome following chemotherapeutic treatment for pLGG. Given the poor prognosis of MN-pCTs, this case represents an important note of caution when choosing appropriate therapy for pLGG, especially considering the evolving role for targeted treatments in this disease.

Infantile myofibromatosis: Small bumps pose big problems

2025-03-25T10:17:14Z

Hillary C Lee, Amee A Amin, Kudakwashe R Chikwava, Valeria R Smith, and Caraciolo J Fernandes from
the Section of Neonatal-Perinatal Medicine, Department of Pediatrics, the Department of Pathology and Immunology, and the Division of Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine/Texas Children's Hospital, Houston, TX, USA.
have just published in Neonatal Perinatal Medicine a brief report entitled :
Infantile myofibromatosis: Small bumps pose big problems

It reports about a preterm, male infant with a trichorionic, triamniotic pregnancy following preterm labor. Within the first week of life, several well-circumscribed, smooth, non-tender, and soft nodules with some mobility were noticed along the border of the ribs, across the trunk, back, and lower extremities. Ultrasound imaging confirmed well-circumscribed hypoechoic, intramuscular nodules, and biopsy evaluation showed atypical spindle cell proliferation. The biopsied lesion was PDGFRB-mutated on molecular genetic studies, confirming a diagnosis of myofibromatosis. The infant developed mixed lytic and sclerotic deformities of a variety of bones, necessitating treatment given disease progression.

Infantile myofibromatosis is characterized by proliferation of benign myofibroblastic tumors that typically manifest as solitary or multiple nodules in the skin, muscle, bone, subcutaneous tissues, and visceral organs and can pose significant morbidity and mortality risks, particularly in cases involving visceral organs or causing functional impairment. These soft tissue lesions are the most prevalent benign fibrous tumors that present before age two and can undergo spontaneous regression or are amenable to surgical resection.

Conclusion: Successful clinical management with low-dose metronomic chemotherapy (methotrexate and vinblastine) is possible and can treat extensive disease, as seen in our patient.

The full text of the article is available here

Metronomic chemotherapy in pediatric neuroblastoma

Nicolas André — 2024-11-29T08:33:00Z

A review about metronomic chemotherapy and neuroblastoma written by Yi Jiang, Chengjun Xi, Chao Yang from the Children's Hospital of Chongqing Medical University, Chongqing, China
The review is entitled : Metronomic chemotherapy in pediatric neuroblastoma and has been published in Pediatric Discovery.

The full text is freely available here

Abstract

Metronomic chemotherapy (MC) is an innovative therapeutic approach that involves the chronic administration of low doses of chemotherapy agents. This strategy aims to sustain prolonged and active plasma levels of drugs, which can result in favorable tolerability. MC has shown promise in the treatment of hematologic and solid tumors, including high‐risk neuroblastoma and relapsed/refractory (R/R) neuroblastoma. In the contemporary management of neuroblastoma, MC stands as a viable maintenance therapy for newly diagnosed patients lacking access to autologous stem cell transplantation or immunotherapy, particularly in resource‐constrained regions. Furthermore, it serves as a pragmatic alternative for individuals intolerant to intensified regimens or undergoing palliative care for R/R neuroblastoma. Nevertheless, the quest for the optimal MC regimen persists, necessitating comprehensive investigations to delineate standardized protocols. Moreover, the identification of potential biomarkers or prognostic indicators assumes paramount significance in refining MC strategies for future breakthroughs in this domain. This review embarks on a comprehensive exploration of MC in neuroblastoma, offering insights into its historical underpinnings, diverse applications, adverse effect and future prospects, endeavoring to enrich our understanding of MC role in neuroblastoma management.

Retrospective experience of children with relapsed brain tumors treated with oral combination of axitinib and metronomic etoposide

2024-05-23T14:57:47Z

Caroline Donzé, Gabriel Revon-Rivière, Morgane Pondrom, Arnauld Verschuur, Pierre Leblond, Nicolas André from the Pediatric Oncology Department of of the Hopital pour enfants de la Timone APHM Marseille, the IHOPE Lyon, the Pediatric Oncology Department , CHU Nice, and the Metronomic Global Health Initiative, France have just published a short article in Pediatric Blood and Cancer entitled : Retrospective experience of children with relapsed brain tumors treated with oral combination of axitinib and metronomic etoposide.

In this article they're report their preliminary experience of the combination of axitinib and metronomic etoposide given as as an “off-label” combination in 6 children and young adults with medulloblastoma (5 patients) or ATRT (1 patient).
Interestingly, 3 patients with medulloblastoma experienced partial response; one patient with atypical teratoid rhabdoid tumor (ATRT) displays an ongoing stable disease (12 months); two patients with medulloblastoma had progressive disease. Grade 3–4 toxicities were observed in two patients (thrombocytopenia, anemia, diarrhea, fatigue). The axitinib–etoposide combination shows signals of efficacy in heavily pretreated patients with relapsed/refractory brain tumors. These results were based on real-world observation and will need formal evaluation in a phase I/II trial.The full text of the article is freely available here