Metronomics Global Health Initiative

the International School of Metronomic Chemotheray - ISMe

2019-07-18T14:40:06Z

We are delightred to e to introduce you “The International School of metronomic chemotherapy – ISMe”. This initiative is being lead by Dr. Marina Elena Cazzaniga.

ISMe's Core Faculty are all well recognized experts in the field of metronomic chemotherapy or are active participants of ongoing trials exploring new areas of research.

ISME has the aim to improve the knowledge in this particular type of treatment, its characteristic mechanisms of action, the most recent results in different types of cancer, as well as contributing to scientific exchange among physicians, clinicians and basic researchers involved in this field.
By improving the skills of all health professionals dealing with cancer patients, ISMe helps shorten the time needed to transfer knowledge from research centres to daily practice.
Last but not least, is that the School has no charging fees.
ISMe planned to start activities in 20198, providing independent, evidence based, patient-oriented education to health professionals, including clinical and medical oncologists, radiation therapists, surgeons, nurses, patients advocates and medical students on the topic of metronomic chemotherapy.
Due to unmet educational needs outside Europe, ISMe will include the Eurasia region, Mediterranean region, North and South Africa, Middle East, South-East Asia, and Central/South America as part of a wider “cultural Europe” in its educational activities.
Education will be delivered through e-learning activities.

ISMe is a distance learning school completely focused on spreading knowledge on metronomic chemotherapy, both at a pre-clinical and a clinical level.
Depending on location ISMe will provide web-based training (WBT), or computer-based training (CBT). ISMe Educational Program is composed of 12 different Modules. Each Module is organized and chaired by a Faculty Member, previously presented and approved by the Scientific Committee. Each Module can be attended separately from the others, even if the suggestion of the School is to attend each of them in sequence.
The training material consist of webinar recordings, pdf, literature and case studies.
The school permits to obtain EACCME® credits, as long as the attendee performs at least 10 out of 12 online modules and relative tests (multiple choice).

Here are the planned topic modules :
1. Pre-clinical data (1) – Robert Kerbel, Eddy Pasquier

2. Pre-clinical data (2) – Yuval Shaked, Bertolini Francesco, J Ciccolini

3. Pre-clinical data (3) – Guido Bocci, Maria Grazia Cerrito

4. Breast cancer (1) – neo&adjuvant – E. Munzone ,E. Montagna, L. Sven, M. Cazzaniga

5. Breast cancer (2) – metastatic– M. Cazzaniga, E. Petru , P. Sanchez-Rovira, E. Munzone

6. Lymphomas – Pediatric cancer – Nicolas André, Cox Christina, F. Berthold, J. Sterba

7. Colon and gastrointestinal cancers–Piotr Wysocki, Woo In Sook

8. Gynecologic cancers – Piotr Wysocki, Łukasz Kwinta, Pawel Potocki

9. Prostate Cancer – Camerini Andrea, Urban Emmenegger

10. Lung cancer – Camerini Andrea, Francesco Grossi

11. Nursing care –Marina Cazzaniga, Lourein Smit

12. Pharmacoeconomic – M. Cazzaniga, R. Umberto, P. Pantziarka, E. Pasquier

You can find the dedicated website here

3rd Karton Kamen-MGHI Prize : call for abstracts

2017-11-21T08:20:05Z

We are very proud to launch the call for abstract for the Third Barton Kamen-MGHI prize

The prize is given in honor of Pr. Barton Kamen, pediatric oncologist, pioneer in the field of metronomic chemotherapy. Barton Kamen has been one of the leading force that has kept the field of metronomics alive when it was facing resistance/skepticism from clinicians. Barton has also been a source of inspiration for clinical colleagues, scientists and mentored many junior scientists. Barton Kamen was also the first very MGHI ambassador. Through this prize, we wish to acknowledge his critical role for the field of metronomics and maintain his legacy alive by rewarding a clinician or a scientist working in the field of metronomics. Priority will be given to work focusing on children living in low and middle countries

This prize is awarded to the author of the best submitted scientific article. The jury can also propose candidate. The winner will present his work and receive the prize during the 6th Metronomic Meeting that will take place in Grand Rapids in May 2018 (click here for more information) All accepted abstracts will be published on the MGHI website.

The dead-line for submission is 01/03/2018 Results will be given by email before the 10th of April.

For more information conctact: metronomicsghi@gmail.com

Abstract Requirements and Guidelines

Formatting Tips:

Abstracts must be submitted in English by email at metronomicsghi@gmail.com. Each abstract should consist of four separate paragraphs. These should be labeled Background, Methods, Results, and Conclusions. Each abstract should, briefly and concisely, describe the problem or issue being addressed, how the study was performed, the salient results or findings, and what the authors conclude from these results.

Abstracts are not to exceed 200 words, excluding title and authors.The length should correspond to approximately 1 pages, single-spaced, in a Word document Abstract titles are restricted to 25 words.. You will type the title, authors and keywords into individual fields, separately from the body of the abstract.

Abstracts must clearly define the objectives, status, methodology, findings, and significance of the investigation or stud

How Abstracts are Judged and Assigned

Abstracts submitted for presentation will be reviewed by the Scientific Committee in April. Notification of acceptance and schedule information will be sent in APRIL. Abstracts will be judged according to four criteria: scientific merit, originality, interest for metronomic

Drug repositioning- Frontiers in Oncology-call for papers

2017-01-13T11:22:18Z

Pan Pantziarka for the Anticancer Fund and Nicolas André from the Metronomic Global Health Initiative are organizing a Research Topic titled “Drug Repurposing” to be published in Frontiers in Medicine.

Drug repurposing, also known as drug repositioning, is a strategy that seeks to reuse existing, licensed medications for new medical indications, often in diseases with very different profiles to that for which the drug was originally developed. Repurposing offers a number of significant advantages in comparison with de novo drug development. These include the availability of extensive pharmacokinetic, pharmacodynamic and safety data, (with data on both common and rare adverse events) and an understanding of relevant molecular targets and mechanisms of action.

Additionally the repurposing of generic medications is appealing at a time when economic pressures are negatively impacting health systems globally. The potential for cheap generic medications to tackle cancer and other serious medical conditions in low and middle income countries is particularly appealing. The combination of drug repurposing and metronomic chemotherapy, often termed metronomics, is particularly appealing in this respect. However, more widespread adoption of the repurposing strategy is often hampered by a lack industry engagement and poor financial incentives. Therefore, while the advantages are clear, there are many challenges to overcome in order to show clinical efficacy, which is the most important criterion by which repurposing should be judged.

This Research Topic provides a focus on drug repurposing, particularly in a clinical context. Potential articles will focus on translational and clinical studies, case reports, trial rationales and so on. An additional focus will be on regulatory and institutional issues related to repurposing, including drug licensing, financial disincentives and other factors associated with translating trial results to clinical practice.

The project homepage with a full description of this project can be found here

Important Note: All contributions to this Research Topic must be in line with the scope of the specialty and field to which they are submitted, as defined in their mission statements. Manuscripts discovered during any stage of peer review to be outside of the scope may be transferred to a suitable section or field, or withdrawn from review.

The 2nd Barton Kamen-MGHI Prize has been attributed to Pr G. Saulnier-Sholler : DFMO in Neuroblastoma

2016-05-09T16:09:37Z

The Second Barton Kamen-MGHI Prize has been attributed to Pr Giselle Saulnier Sholler, during the 5th Metronomic Meeting that took place in Mumbai from the 6th to 8th of MAY 2016. Pr G. SAULINER is currently
Director of Pediatric Oncology Research
Head of the Pediatric Oncology Translational Research Laboratory
Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
Associate Professor, Michigan State University College of Human Medicine
Chair of the Neuroblastoma & Medulloblastoma Translational Research Consortium

The prize was given to her in recognition of her work on DFMO in neuroblastoma.

Read more about DFMO and the NMTCR here.

Second Barton Kamen-MGHI prize: call for abstract

2016-01-27T13:47:32Z

We are very proud to launch the call for abstract for the Second Barton Kamen-MGHI prize

The prize is given in honor of Pr. Barton Kamen, pediatric oncologist, pioneer in the field of metronomic chemotherapy. Barton Kamen has been one of the leading force that has kept the field of metronomics alive when it was facing resistance/skepticism from clinicians. Barton has also been a source of inspiration for clinical colleagues, scientists and mentored many junior scientists. Barton Kamen was also the first very MGHI ambassador. Through this prize, we wish to acknowledge his critical role for the field of metronomics and maintain his legacy alive by rewarding a clinician or a scientist working in the field of metronomics. For the first prize, priority will be given to work focusing on children living in low and middle countries

This prize is awarded to the author of the best submitted scientific article. The winner will present his work and receive the prize during the 5th Metronomic Meeting that will take place in Mumbai in May 2016 (click here for more information) All accepted abstracts will be published on the MGHI website.

The dead-line for submission is 1/04/2016 Results will be given by email before the 10th of April.

For more information conctact : metronomicsghi@gmail.com

Abstract Requirements and Guidelines

Formatting Tips:

Abstracts must clearly define the objectives, status, methodology, findings, and significance of the investigation or stud

How Abstracts are Judged and Assigned

the MGHI metronomics in LMIC survey

2016-01-03T09:25:00Z

MGHI is launching an international survey to know more about the use of metronomic chemotherapy and drug repositioning to treat children with cancer in LMIC.
The questioned have been developed by Dr Gabriel Revon-Rivière and Dr Nicolas André.
We aim at sending the survey in central and South America, Africa (GFAOP), Iran, Uganda, Tanzania and India.
This survey has 18 items, it is to be answered on-line and requires 10 minutes to be filled.
You may be contacted soon by email.

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Metronomic therapy can increase quality of life during paediatric palliative cancer care, but careful patient selection is essential.

2016-01-01T10:32:00Z

Porkholm M, Toiviainen-Salo S, Seuri R, Lönnqvist T, Vepsäläinen K, Saarinen-Pihkala UM, Pentikäinen V, Kivivuori SM from the Division of Hematology-Oncology and Stem Cell Transplantation, the Division of Child Neurology, the Division of Pediatrics and the Department of Pediatric Radiology from the University of Helsinki and Helsinki University Hospital, Helsinki, Finland. have just published an article entitled "Metronomic therapy can increase quality of life during paediatric palliative cancer care, but careful patient selection is essential." in Acta Paediatrica.

They report on 17 children with refractory or high-risk malignancies who were treated with a maintenance therapy that consisted of metronomic thalidomide, etoposide and celecoxib. The endpoints of the study were overall and progression-free survival, changes in the Karnofsky-Lansky scores from baseline to the end of the study therapy and radiological responses.
The median overall survival after the start of the study therapy was 6.2 months (range 2.0-57.7) and the six, 12 and 24-month survival rates were 59%, 18% and 18%, respectively. The median progression-free survival was 3.2 months (range 0.3-17.8). The Karnofsky-Lansky scores increased significantly during the study therapy (p=0.02), with 35% of the patients having a transient improvement in their clinical status. Radiologically, one partial response and two disease stabilisations were encountered. Grade III-IV adverse events occurred in 76% of the patients.
This report highlight that metronomics can increase the quality of life during palliative care for childhood cancer, but requires careful patient selection to minimise the risk of serious adverse events.

You can access the full text on the website of the journal here

PROVIN : Phase I study of a propranolol (Hemangiol®) and oral metronomic vinorelbine (Navelbine®) combination for children and teenagers with refractory/relapsing solid tumors

2015-10-05T09:25:25Z

With 2 grants obtained from the PHRC-K national grants and "l'Etoile de Martin" and drugs provided by Pierre Fabre Oncology we are ready to start our latest pediatric metronomics trial that will combine oral propranolol and oral metronomic navelbine in children with refractory/relapsing solid tumours. The trial is called PROVIN and should start recruiting patients Q2 2016. Pierre Fabre has agreed to provide drugs for the trial.
The trial will be opened in 10 pediatric oncology centres in France.

PROVIN : Phase I study of a propranolol (Hemangiol®) and oral metronomic vinorelbine (Navelbine®) combination for children and teenagers with refractory/relapsing solid tumors

BACKGROUND: Cancer remains the first cause of death due to disease in children and adolescents despite important progress and 70% of the survivors present one or more chronic health conditions as a result of treatment. It is therefore mandatory to generate new and preferably less toxic treatment strategies relying on new anticancer agents, and/or new combinations or new schedules of administered compounds.

Metronomic chemotherapy (MC) consists in giving low doses of anticancer agents on a daily/weekly basis. Low doses of chemotherapeutic drugs are therefore continuously administered to cancer patients. MC has been showed to be a safe and effective way to administer chemotherapy to obtain anti-cancer effects through news mechanisms of action. The higher frequency and lower dose targets distinct features of tumor biology. Thus MC has been shown to inhibit tumor angiogenesis at least in part by decreasing thrombospondin-1, VEGF and circulating endothelial progenitor cells as well as killing endothelial cells and blocking their pro-angiogenic functions. The immune system can also be stimulated through multiple mechanisms (e.g selective depletion in regulatory T cells, modulation of myeloid-derived suppressor cells or maturation of dendritic cells) (Pasquier 2010, André 2014). Some studies have also demonstrated an effect of MC on cancer stem cells (André 2014).
Additionally, MC is often combined in the clinic with drug repositioning (DR). DR consists in using already approved drugs for which novel anti-cancer properties have been unveiled (Blatt 2013). Using non anticancer drugs per se allows adding more agents with at the same time very little toxicity and targeted effect like. This approach has already been used successfully in pediatric oncology and represents an interesting way to introduce medications with new mechanisms of action (Blatt 2013).
Among the drugs that can be repositioned for cancer treatment, propranolol is a non selective beta-blocker initially used to treat hypertension but its potent anticancer properties have been recently uncovered The potential of beta-blockers as anticancer agents is supported both by preclinical and epidemiological data. We have shown for instance that the use of beta-blockers could sensitize breast cancer, angiosarcoma and neuroblastoma cells to chemotherapy in vitro and in vivo at least in part via anti-angiogenic mechanisms (Pasquier 2011, Pasquier 2013, Banavali 2015). Moreover, preclinical studies in breast cancer, neuroblastoma, angiosarcoma have shown synergy between betablockers and several anti-tubulin agents including vincristine, vinorelbine and paclitaxel (Pasquier 2011, Pasquier 2013, Bouche 2014) both in vitro, and in vivo.
There are currently 15 clinical trials prospectively evaluating their potential in adults with cancer (Clinicaltrials.gov) but only one in children with PEComa, a rare tumor mainly affecting children with tuberous sclerosis. The therapeutic potential of beta-blockers against the most frequent and refractory childhood cancer remains however totally unexplored.

AIMS: to determine the MTD of a combination of oral metronomic vinorelbine alone and in combination with daily oral propranolol.

METHODS: Phase I trial with a “rolling six” design and a 3 levels dose escalation (10, 20 and 30 mg/m² of thrice weekly oral vinorelbine only plus addition of daily oral propranolol (1.5mg/kg/day BID) after completion of the first cycle. PK analysis of vinorelbine and propranolol will be performed. Once the recommended dose of the combination established 4 extension cohorts of 9 patients (neuroblastoma, rhabdomyosacoma, Ewing sarcoma, miscellaneous tumors) will be added. Potential biomarkers (beta-adrenergic receptors on the tumors, B-tubulin isotypes in the tumor) will also be evaluated.

IMPACT: Overall, the PROVIN project displays 3 innovative aspects:
1) Use of β-blockers as anticancer agents through drug repositioning
2) Use of oral metronomic chemotherapy
3) Genesis of a multi-targeted precision medicine treatment combining a targeted agent and broad spectrum treatment with metronomic chemotherapy.
This approach aims at providing an “all oral” treatment (easy to administer, no need for hospitalization or central lines) with very little toxicity for pediatric patients. It can therefore contribute both to reduce the toxicity of anti-cancer treatments as well as to increase the quality of life of the patients. Eventually this trial will provide a well tolerated, all oral combination for patients with refractory/relapsing tumors. This combination could also be then proposed as maintenance for instance in patients with neuroblastoma or rhabdomyosarcoma or for patients living in low- and middle-income countries

Update about the Moroccan Society of Pediatric Hematology/Oncology Phase II metronomic trial.

2015-07-10T10:47:33Z

Cure rates in pediatric cancer can reach 80% in high income countries (HIC). However, 80% children are living low income countries where cure rates often don't exceed 35%. Children with metastatic, unresectable, or recurrent cancer continue to have poor prognosis and the treatment of these patients with second-line intensive or experimental treatments with new expensive drugs, as it is done in HIC nonrealistic option in most of the African countries.

In Morocco, we have previously reported cases of disease stabilization and/or second complete remission in children with recurrent or relapsed malignant disease (SIOP Africa Ghana 2005) under prolonged low dose of cyclophosphamide treatment. Besides, a study from Mali, another LMIC African country, reported the efficacy and safety of a vincristine/cyclophosphamide/methotrexate MC regimen given to children with refractory cancer of various tumor types. These findings led pediatricien from Morroco to look closely at the concept of metronomic chemotherapy (MC) for children with cancer treated in Morocco.

Pr Laila Hessissen and Pr Maria El Kababri with the help of MGHI therefore initiated in 2014 a prospective multicentre metronomic phase II trial with a cyclophosphamide, etoposide, and valproic acid combination in children with either a relapsing/refractory tumors or a very advanced disease. This project is conducted by The Moroccan Society of Pediatric Hematology/Oncology with the financial support of the Lalla Salma Foundation Prevention and Treatment of Cancer.

Intravenous Etoposide is used by oral route because oral form is not available in Morocco.
The primary objective of the protocol is to evaluate the anti-tumor effect defined by:
– Progression free survival (PFS) after 4 months (4 cycles), 8 and 12 months of treatment.
– Response rate after 4 months, 8 and 12 months of treatment.
The secondary objectives are:
– Evaluate the tolerance of treatment
– Evaluate the quality of life (at D0 and every 4 months)
– Evaluate the analgesic consumption and the transfusion requirements

The study is ongoing and 20 patients from 3 out of the 4 Moroccan pediatric oncology centers have been included so far. Tolerance of treatment and compliance are excellent.

Treated patients:
– Ewing : 4 patients
– Osteosarcoma : 3
– Neuroblastome : 2
– Rhabdomyosarcoma : 4
– MGT : 2
– Nephroblastoma : 2
– UCNT : 1
– Medulloblastoma : 1
– STS : 1

Dose-Finding of Propranolol in combination with metronomic fixed oral cyclophosphamide based on Bivariate efficacy-tolerability outcome in patients with locally advanced or metastatic angiosarcoma : A collaborative and innovative phase I-II sequential trial

2015-02-26T11:07:27Z

The Pr Sébastien Salas from the Adult Oncology Unit, CHU La Timone, AP-HM, Marseille, France has obtained funding for the PROPAN study (Dose-Finding of Propranolol in combination with metronomic fixed oral cyclophosphamide based on Bivariate efficacy-tolerability outcome in patients with locally advanced or metastatic angiosarcoma : A collaborative and innovative phase I-II sequential trial ).

Adrenergic processes stimulated by epinephrine and neorepinephrine drive the development of tumor growth and metastatis. Beta-adrenergic receptor (BAR) antagonists have shown efficacy against melanoma, breast cancer and prostate cancer. The non-specific BAR inhibitor propranolol has been utilized as the gold standard treatment in pediatric patients with benign infantile hemangioma which express high levels of beta adrenergic receptors potentially explaining their sensitively to propranolol. BAR have been shown to be expressed across a diverse panel of vascular tumors, with the highest expression in malignant vascular tumors including angiosarcomas. Several reports indicate positive results from beta-blockade in patients with moderately threatening vascular tumors. It remains to be determined if more malignant vascular tumor such as the angioasarcomas are susceptible to propranolol. Besides, due to the lack of adequate therapies for angiosarcomas (doxorubicin or paclitaxel and finally cyclophosphamide in third line) and to the poor prognosis of this rare and agressive tumor, there is a strong need for the development of treatments against this tumor type.
Recently using a panel of angiosarcoma cell lines, Stiles et al. demonstrate that beta-adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Moreover, using in vivo tumor models they demonstrate that propranolol shows remarkable efficacy in reducing the growth of angiosarcoma tumors.
Based on these proofs of mechanisms in vitro and in vivo and due to the well established safety propranolol in humans, we propose to determine among a wide range of propranolol dose (80 mg/d ; 120 mg/d and 160 mg/d) the optimal one based on bivariate efficacy-toxicity outcome in patients with angiosarcoma treated by cyclophosphamide.
Because these these 2 agents have different pharmacological mechanisms, the aim is to determine the optimal dose of propranolol having the best systemic cardiovascular tolerability and the best potential antiangiogenic effect in addition with cyclophosphamide. Due to recent preclinical papers demonstrating the selective cytotoxicity and tumor suppressive ability of beta adrenergic inhibition on angiosarcoma in dose dependant manner, we propose here for the first time to assess the synergy of propranolol and fixed dose of oral cyclophosphamide among patients with advanced angiosarcoma, using an innovative design modeling both toxicity and efficacy outcomes (dose finding combined phase I-II sequential trial using a bivariate continual reassessment method). Because this tumor is very rare leading to a limited number of patients and because an efficient therapeutic is lacking, this design is particular of interest in order to determine more quickly the potential dose of propranolol to be tested in the pivotal phase III.

This trial will be a joint effort from the GSF/GETO, the SFCE and MGHI and will include adults and teenagers from French centers.
In this dose-finding design up to 24 patients will be required to find the dose level satisfying the requirements in terms of toxicity and efficacy.
The study shall be opened for recruitement by mid 2015.