We have started with metronomic chemotherapy as a salvage or palliative setting for relapsed refractory cases and we were surprised by a very good clinical tolerance and overall efficacy in several remarkable cases. So we started to work on it a little bit more and in 2004, ten years ago, we had developed our COMBAT protocol which means combined oral metronomic bio-differentiating anti-angiogenic treatment. In 2006 we published our first series of patients underlying good tolerance, a high quality of life and affordability of this treatment compared to modern and much more sexy targeted and modern therapies.
Which drugs do you use?
We used a lower dose of temozolomide but metronomic prolonged exposure of temozolomide, VP16 in a very low dose, 25mg/m2, and celecoxib and the retinoic acid as a [combo] but in a lower dose than it is usually given for neuroblastoma. Those are drugs normally used but not in such a combo as a cocktail. We were surprised by several very nice responses and I was summarising our clinical experience which could be concentrated in several points. One is that for brain tumours we need compartmental treatment; we need to treat our compartment, especially for some embryonal tumours like medulloblastoma where the second pattern of progression is leptomeningeal so we have to address the leptomeningeal compartment via intra-articular application of chemotherapy. Then the question comes what it should be, if it should be expensive liposomal Ara-C or just a normal methotrexate or normal VP16. It’s one of the important points and another important point is that the best survival we can report today from a real life clinical scenario are patients where we, after discussion with parents and family, parents were offered to use metronomic chemotherapy as a maintenance where they were just in some good partial remission or just partial remission at the end of the planned treatment. Those patients, those very high risk patients with a very low probability to sustain, to remain in their first PR, they are doing best.
A point I may underline is very good tolerability and potential to combine metronomic treatment with targeted therapies and with immune approaches. We have piloted a combination of metronomic chemotherapy with dendritic cell vaccine and that’s what we are working on recently.
Probably the last point I may make is my experience from the European Regulatory Agency, from EMEA, as a several years member of the paediatric committee that there is almost no interest coming from companies to support paediatric metronomic trials despite they are very promising definitely, very cheap, affordable. However, the regulation applied to such low risk trials is completely the same as for trials backed by rich pharma companies.
What will the outcome be if drug companies don’t support the trials?
We have to apply for some charities, European agencies, national agencies. We have to do our best to get that money because we have to comply with regulations.
What other options would there be for these patients if they cannot access metronomic therapy?
Simply, they will get metronomic but out of clinical trials. They will get it off patent, off label, but we are wasting the data we could use for further development.
What’s the future of metronomics?
The future of metronomics, at least in my eyes, it’s a combination with some personalised medicine principles to know to whom to give which drug in which dose and the possibility to combine metronomic treatment especially with some immunomodulation approaches. This is probably the new avenue forward.