Metronomics Global Health Initiative

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.

Slow and Steady Keeps Them in the Race: Metronomic Therapy in Children With Cancer

2020-06-16T17:14:20Z

An editorial entitled : Slow and Steady Keeps Them in the Race: Metronomic Therapy in Children With Cancer by SIDHARTH TOTADRI from the Pediatric Hematology-Oncology Unit, Department of Pediatrics, Christian Medical College and Hospital, Vellore, India has just been published in Indian Pediatrics.

It highlights the recent ancillary associated pediatric trial published in Jama Oncololgy (Pramanik R et al. Metronomic chemotherapy vs best supportive care in progressive pediatric solid malignant tumors: A randomized clinical trial. JAMA Oncol. 2017;3:1222-7.

In this ancillary study, no angiogenic biomarkers were identified but an decrease in TPS1 was observed in responders and an increase in non responders; confirming the role of angiognenesis on the anticancer effect of metronomic chemotherapy.

You can acces free full text here.

Metronomics for paediatric brain tumours at ISPNO 2018

2018-07-02T18:18:07Z

The International Symposium on Pediatric Neuro-Oncology (ISPNO) is the major biennial global meeting of the multi-disciplinary international community of professionals involved in the scientific research, diagnosis, treatment, rehabilitation of infants, children and young people with CNS tumors.
The ISPNO took place Friday, June 29 to Tuesday, July 3, 2018. in Denver.

Four communications concerned metronomics:

– 1 communication from the Tata Memorial in Mumbai presented un update of their experience with the modified COMBAT regimen as a maitenance for high-risk brain tumours.
– 1 communication from Buenos Aeres reported the use of a 5 drugs metronomic regimen combined with bevacizumab in children with recurrent ependymoma
– 2 communication from Hartfort for patients with refractory ependymoma treated according to the MEMMAT regimen.
– 1 communication from Vienna summarizing their experience with 71 patients treated with the MEMMAT regimen.

The detailed abstrcts are pasted bellow.

THE ROLE OF COMBAT (COMBINED ORAL METRONOMIC BIODIFFERENTIATING ANTIANGIOGENIC TREATMENT) IN HIGH-RISK AND RELAPSED MEDULLOBLASTOMA: A SINGLE INSTITUTION EXPERIENCE

Girish Chinnaswamy, Hari Sankaran, Vasudev Bhat, Anand KC, Megha Saroha, Maya Prasad, Tushar Vora, Ayushi Sahay, Rahul Krishnatry, Sona Pungavkar, Amit Janu, Tejpal Gupta, Rakesh Jalali, and Shripad Banavali; Tata Memorial Centre, Mumbai, India

OBJECTIVE: We retrospectively reviewed the ef cacy and feasibility of COMBAT metronomic chemotherapy in high risk and relapsed medul- loblastoma from April 2011 to December 2016. METHODS: Post-sur- gery high risk medulloblastoma or relapsed medulloblastoma who were started on COMBAT regimen after completion of conventional therapy were included in this analysis. COMBAT regimen consists of low dose temozolomide, etoposide, sodium valproate and 13-cisretinoic acid admin- istered in 12-weekly cycles. RESULTS: 39 children (median age, 9 years; median follow-up, 27.7 months; male:female ratio, 5.5:1) were started on COMBAT during the study period, of which 19 (48.7%) were started after completion of conventional therapy and 20 (51.3%) were started at relapse. Molecular data was available for 17 children (WNT – n=2; SHH, n=3; Group 3, n=5; Group 4, n =7). 2-year progression free sur- vival (PFS) after starting COMBAT was 83.9% (95%CI: 49.4–95.7) and 25.8% (95% CI: 6.5–51.1%) for upfront therapy and relapsed medullo- blastoma at presentation respectively. 2-year overall survival was 92.3% (95% CI: 56.6–98.9%) and 67.4% (95% CI: 41.0–84.0%) for upfront therapy and relapsed medulloblastoma at presentation respectively. Only 1 child developed secondary AML and warranted discontinuation of COM- BAT therapy. CONCLUSION: COMBAT regimen is a well-tolerated and effective treatment option after completion of conventional treatment for children with high risk medulloblastoma. Future ongoing studies will fur- ther delineate the role of COMBAT in high risk medulloblastoma based on molecular subtypes.

ANTIANGIOGENIC METRONOMIC THERAPY FOR CHILDREN WITH RECURRENT EPENDYMOMA

 Daniel Alderete, Lorena Baroni, Claudia Sampor, Candela Freytes, and Carla Pennella; Hospital Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina

Patients with relapse ependymoma have few therapy options and a short median survival time regardless of salvage treatment. The aim of this study is to evaluate the activity of multidrug antiangiogenic treatment in recurrent ependymoma patients. We evaluated the use of biweekly intravenous bevacizumab in combination with fivve oral drugs (thalidomide, celecoxib, fenofibrate, and oral etoposide/cyclophosphamide) in 9 recurrent ependymoma patients between September 2015 and August 2017. The median aged at beginning of treatment was 7.7y (3.7–11.8). 8 patients began therapy for progression disease (6 local/2 metastatic; 1 rst/7 multiple) and 1 because residual tumor after conventional treatment. Objective tumor response was 88% (8), including 5 with partial response and 3 with stable disease. Best response was observed 4.4 months (2.8–5.4) since starting treatment. The median treatment time was 10.6 months (3.4–21). Median time to progression(PFS) was 10.7 months. Median overall survival(OS) was 14.4 months (3.4–27.8). The OS and PFS after 6 months was 100% and 87% respectively; and after 12 months 50% and 37%. At last follow-up, 4 patients (44%) are alive including 2 still undergoing treatment. One patients remain alive and progression free at 16 months and another is alive with disease at 27 months. Therapy was generally well tolerated. This 5-drug regimen plus Bevacizumab produces objective responses with minimal toxicity in children with recurrent ependymoma. This antiangiogenic metronomic therapy could be an evolving alternative approach to recurrent ependymoma and it would be included as part of conventional treatment for unresectable ependymoma.

METRONOMIC THERAPY FOR RECURRENT EPENDYMOMA; PRELIMINARY RESULTS

 Eileen Gillan and Markus Bookland; Connecticut Children's Medical Center, Hartford, CT, USA

Recurrent ependymomas have a dismal prognosis (2 year survival rates 29% OS and 23% EFS) and are relatively resistant to conventional chemo- therapy. An alternative approach to conventional chemotherapy can be antiangiogenic or metronomic chemotherapy which inhibits endothelial cell function and resultant neovascularization. From November 2011 to Feb 2018 five patients (median age:28 months) with recurrent (3 first, 2 multiple) anaplastic ependymomal brain tumors were treated with an antiangiogenic multidrug combination regimen (bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide, and cyclophophamide) and additional intraventricular therapy (etoposide and liposomal cytarabine) for a median of 12 months. Currently all patients are alive without evidence of recurrent disease at a median of 14 months. Toxicities were manageable and therapy was generally well tolerated with the exception of 1 patient who suffered developmental regression necessitating discontinuation of treatment. Our results suggest that the chosen antiangiogenic drug combination is particularly bene cial for patients with recurrent ependymoma and warrants further investigation as an alternative to conventional chemotherapy in relapsed patients.

RESPONSE OF RECURRENT MALIGNANT CHILDHOOD CNS TUMORS TO A MEMMAT BASED METRONOMIC ANTIANGIOGENIC COMBINATION THERAPY VARIES DEPENDENT ON TUMOR TYPE: EXPERIENCE IN 71 PATIENTS

Irene Slavc1, Andreas Peyrl1, Monika Chocholous1, Dominik Reisinger1, Lisa Mayr1, Amedeo Azizi1, Karin Dieckmann1, Christine Haberler1,
and Thomas Czech1; 1Medical University of Vienna, Department of Pediatrics, Vienna, Austria, 2Medical University of Vienna, Department of Radiotherapy., Vienna, Austria, 3Medical University of Vienna, Institute of Neurology, Vienna, Austria, 4Medical University of Vienna, Department of neurosurgery, Vienna, Austria

Patients with recurrent malignant CNS tumors have a poor prognosis irrespective of salvage therapy applied. We used a metronomic antiangio- genic combination therapy and report on the response of individual tumor types to this approach. Since 2006, 81 patients with various recurrent malignant brain tumors started treatment with an antiangiogenic multidrug- regimen at the Medical University of Vienna. Therapy consisted of daily oral thalidomide, feno brate, celecoxib, and 21-day cycles of low dose oral etoposide alternating with cyclophosphamide augmented with IV bevaci- zumab and intraventricular therapy (etoposide and liposomal cytarabine). Excluding the 10 patients with recurrent medulloblastoma treated in the formal international protocol (MEMMAT; ClinicalTrials.gov Identi er: NCT01356290), 71 patients were treated according to the same strategy “off trial”. Diagnoses were medulloblastoma (n=20), atypical teratoid rhab- doid tumor (ATRT) (n=11), ependymoma (n=9), high grade glioma/diffuse intrinsic pontine glioma (HGG/DIPG) (n=9), and various other entities in the remaining patients. As of the end of 2017, 3-year and 5-year OS for the 20 patients with recurrent medulloblastoma was 64.2 ± 10.9% and for the 11 patients with recurrent ATRT 45.7 ± 16.6% and 30.5 ± 16.7%, respec- tively. Remission could be maintained after discontinuation of treatment in a certain percentage of patients with medulloblastoma, ATRT and epend- ymoma. Patients with HGG and DIPG did not respond to this approach. The proposed antiangiogenic regimen seems most promising in medulloblastoma and ATRT and possibly also ependymoma. In a number of other tumor enti- ties time to progression could be prolonged while maintaining good quality of life.

METRONOMIC CHEMOTHERAPY AND THE USE OF A NOVEL APP (CAREZONE) FOR FACILITATION OF MEDICATION ADMINISTRATION AND COMPLIANCE

 Eileen Gillan, Jeanne Walczak, and Heather Rea; Connecticut Children's Medical Center, Hartford, CT, USA

Metronomic chemotherapy can be an alternative approach to conven- tional chemotherapy by inhibition of endothelial cell function and result- ant neovascularization. During the last 3 years our center has successfully treated 5 patients with either high grade glioma or recurrent ependymomal brain tumors. The antiangiogenic multidrug combination regimen consists of IV bevacizumab, 5 oral drugs; thalidomide, celecoxib, feno brate, etopo- side, and cyclophophamide plus intraventricular therapy (etoposide and liposomal cytarabine). This drug regimen has a complicated schedule with the administration of 5 oral drugs on varying schedules with modi cations based on blood counts plus IV and IT medications. In an effort to improve patient/parent understanding of regimen and subsequent compliance we chose a mobile app for iOS and Android. named CareZone. Based upon patient and staff comments the CareZone app was the most comprehensive in simplifying this regimen with improved patient sati cation and adher- ence to drug administration. This app has the following features that are desirable in our pediatric oncology population: 1) the bottle barcode can be photographed and converted directly into text 2) roadmaps and other documents can be photographed into app 3) reminders for med adminis- tration with administration documentation is available to share with other caregivers and providers, 4) reminders for drug re ll dates and speciality pharmacy contact information 5) lab owsheets are to be added by devel- oper for oncology population. Mobile apps are familiar with patient and care providers and simplify complicated metronomic drug administration and compliance data for physicians.

Frugal Innovation in Medicine

2017-02-27T14:02:32Z

Frugal Innovation in Medicine

This is a very interesitng website that aims at sharing ideas, realizations of frugal innovations in medicine and ultimately facilitate their dissemination and use worldwide. Indeed, one of the main issue is that many frugal innovations remain local and rarely spread to others who might face similar challenges.
Frugal innovations in medicine, is of partuivlar interest for low & middle Income countries.

What is Frugal innovation?
Frugal innovation provides effective functional solutions to common problems encountered by “the many”, with a minimal use of resources. In healthcare, these innovations frequently arise when usual solutions are too expensive or not available, and are especially helpful in and for developing countries.

Four types of frugal innovations can be identified:

- Lean tools and techniques refer to the simplification and adaptation of existing technologies to drastically reduce costs and provide health innovations to everyone.

– Opportunistic solutions refer to the clever use of modern, cheap, and available-for-everyone technologies to tackle “old problems”.

– Contextualized adaptations refer to the diversion of existing techniques, materials or tools for completely different purposes.

– Bottom-up innovations refer to original, simple – and even simplistic- ideas to obtain results unattainable before.

Check the website here

ET HEALTHWORLD INTERVIEW OF DR EDDY PASQUIER

2016-12-20T18:21:24Z

In an interview with ETHealthworld, Eddy Pasquier, Founder, Metronomics Global Health Initiative, France, talks about the research and drug developments taking place for finding better cures in childhood cancer.
More specifically, he talk about drug repositioning and his work on propranolol for angiosarcoma.

ETHealth Wordl interview of Dr. Nicolas Andre : The field of metronomics in cancer is moving towards precision medicine

2016-10-08T12:50:32Z

People are getting used to the ideal of using metronomic chemotherapy and drug repositioning to treat refractory disease.

Dr. Nicolas Andre, Pediatric Oncologist, Hospital Pour Enfants De La Timone Marseille, France, talks to ETHealthworld about the latest finding from researches and clinical trials in metronomic chemotherapy.

Edited excerpts:

What is Metronomics Global Health Initiative?

Metronomics Global Health Initiative is something that we launched four years ago. We are working on metronomic chemotherapy with a view that this kind of treatment could be really useful for cancer patient living in low and middle income countries. When you live in a poor country you don't have a dedicated infrastructure, you may live far way from a cancer centre, you may not have a healthcare coverage or be poorly nourished due to which you may not be able to tolerate the treatment, so for all these reasons metronomic chemotherapy seems to fit well. We launched the website to put information about clinical trials, about the scientific data that would be available and we started to build the network of clinicians, people and institutions that would share the view about the potential of this treatment. We also do some pre-clinical research; we help setting clinical trials and organizing meetings for promoting this approach.

Tell us about the clinical trials and researches that you have undertaken?

We have been able to generate some knowledge and identify some new drugs. We work on metronomic chemotherapy but also drug repositioning – which involves using drugs that were not designed to be anticancer agents but do have anticancer properties. We have worked a lot on propenol and showed that it could work on some pediatric and adult cancers. So now we are moving to the clinical trials.

In France we currently have three metronomic trials going on and one has just stopped. We at this stage are validating activity on soft combinations and are trying to demonstrate new combinations that are based on pure drug repositioning. People are getting used to the ideal of using metronomic chemotherapy and drug repositioning to treat refractory disease.

How is this helping patients in low and middle income countries?

In low and middle income countries we published two trails about metronomic chemotherapy for children in Mali. It was successful as we managed to develop protocols that could be given to patients where disease would either relapse, which didn't have any potential treatment otherwise and also to patients who come to the hospital with too advanced disease. So we would not tolerate toxic chemotherapy. We generated this alternative and now it is used on daily basis in the centre.

How do you see the future of cancer treatment?

The field of cancer is moving towards precision medicine and that is one of the drawbacks of metronomic chemotherapy. We don't really know how it works in a given patient. I guess metronomic chemotherapy is going to be combined with the new sophisticated treatment and it is a good candidate as it has an activity of its own and its non toxic so it can match well with targeted therapy

Death of Evangelos Briassoulis (1953-2016)

2016-09-28T19:05:56Z

Defeated by cancer, Pr Evangelos Briassoulis died at the age of 62 years.
Evangelos Briasoulis was director of the Hematology Clinic of the University Hospital, while he directed the Interdisciplinary Laboratory of Molecular Oncology of the University Cancer Center biobanks in University of Ioannina and also participated as a member of the European Network biobank.
He was one of the ambassador of MGHI and a pioneer of the use of metronomic navelbine.
The void he leaves behind is irreplaceable. We have a though for his family and friends
RIP Evangelos....

Metronomic Chemotherapy and the immune system: Pr David Waxman on ETHealthWord.com

2016-09-19T19:30:23Z

During the Metronomic@Mumbai2016, Pr David Waxman, Prof. of Cell and Molecular Biology, Boston University, USA, gave an interview to ETHealthworld to tell them about the major advancements made in the field of metronomic chemotherapy more specifically about his work on the impact of metronomic chemotherapy on the immune system and the importance of schedule even when chemotherapy is given in a metronomic manner.

MGHI on Facebook

2016-07-24T08:49:01Z

Thanks to the help of Dr Bishal Gyawali, the Metronomics Global Health Initiative has now a facebook page. He will be in charge of the Facebook page.
All the news will now be posted on both Facebook and the website.
Here is the link to our facebookpage.

Enjoy !

Metronomics Global Health Initiative

Yuval Shaked ETHealthWorld.com interview: Cancer will not be a disease in the next 100 years

2016-06-26T08:56:00Z

Yuval Shaked, Associate Prof. Dept of Molecular Pharmacology, The Ruth & Bruce Rappaport Faculty of Medicine, ISRAEL, talks to ETHealthworld about the latest researches in cancer treatment.

you can access the full text on the ETWORLDHEALTH website here

What are the main focus areas of your ongoing research?

Our research focuses mainly on studying cancer treatment but the way we do it is basically not looking at how the treatment affect cancer cells but rather how they affect the host. We are interested to see how the treatments cause side effects to the host but not the regular side effects that we see like vomiting, hair loss or suppression but rather other silent side effects that can rather change the way the tumour cells behave.

Tell us about your findings so far?

We found that after giving the treatment the hosts react the way the tumour reacts so in terms of the tumour you can obviously see tumour cell death, anti tumour activity of the drug but when you look at the host definitely there are some activities.

When you talk about chemotherapy there are activities of a host cell but in addition to that you cause damage to the tumour and the cells and immediately there is a response from the host that generate factors and processes that may try to heel the damage that is caused. All types of treatment for cancer that cause damage to the tumour will trigger a reaction of the host to that treatment and will heal the tumour. So that would explain why tumour sometimes re-grow or become resistant of the tumours to the treatment.

What are the newer treatment modalities that have been identified as better options in treating cancer?

One way is where you give drugs which could be off-patent and very cheap drugs that can improve treatment efficacy and basically patient can have them for longer periods of time.

With other acute treatments these patients will actually not have the same side effects that you will see with patients that get other treatment modalities for cancer. So in addition to metronomic chemotherapy we actually identified some of these host effects. We now can identify drugs that are already in the market for other indications and repurpose or reposition into cancer drugs when you give them with conventional treatment.

How do you see the future of oncology?

In the last couple of years we have made a lot of breakthroughs in cancer treatments especially with immunomodulatory drugs. Metronomic chemotherapy for example is another way to show immunomudulation because these types of treatment promote immune cells against tumour cells. So I think in the near future we will see more and more progress not only in cancer research but also in cancer therapy. The future is bright for cancer and we now know much better than what we knew before and I think that cancer will not be a disease in the next 100 years.