Continual low-dose metronomic chemotherapy as potentially preferable to aggressive strategies

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Published: 10 Jul 2014
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Prof Yuval Shaked - Israel Institute of Technology, Haifa, Israel

Prof Shaked talks to ecancertv at the Metronomic Chemotherapy Meeting in Milan about the benefits of a metronomic chemotherapy regimen as a less aggressive treatment than high dose chemotherapy, and a more effective maintenance drug, preventing relapse and decreasing metastatic burden.

One of the problems in the field of metronomic chemotherapy is the fact that we do not really know how it works. Back then, in the past, it was the idea that it has an anti-angiogenic effect but there are a lot of studies now showing that it’s not only an anti-angiogenic effect, there are many other different effects such as stimulation of the immune system on one hand or effects that are related to maybe metabolism of the tumours and so on and so forth. What we put forward, further, is actually studying what happened to the tumour microenvironment after treatment with the maximum tolerated dose or with metronomic chemotherapy.

By way of example, previous studies that we published in this area showing that when you give a maximum tolerated dose, a high dose, regimen of chemotherapy what you will gain is obviously, on one hand, an anti-tumour activity, and that’s why these drugs are being used in the clinic. But at the same time you gain another thing which is for the benefit of the tumour and these are the host generates a pro-tumorigenic and pro-metastatic effect. In fact, if you precondition a mouse with chemotherapy, with high dose chemotherapy, and then you inject tumour cells into these mice, the mice that were treated with chemotherapy will succumb to metastases earlier than the mice that were not treated. That’s when you give a maximum tolerated dose chemotherapy. The reason is, again, because you eliminated the anti-tumour activity of the drug by introducing the tumour cells only after the chemotherapy. If obviously you did it before that then you will get the anti-tumour activity. So I would say clinicians or oncologists actually haven’t seen this phenomenon in the clinic but this phenomenon exists but is negated by the anti-tumour activity that we see. So this is in general what happened when you give a maximum tolerated dose.

So we took an advantage of these, as we called it, host response effects to maximum tolerated dose and we tested whether the same effect might happen when you give a metronomic chemotherapy regimen, when you give a continuous dosing of the drug in low doses. In fact, what we found was that there is no host pro-tumorigenic or pro-metastatic effect and that might explain why sometimes metronomic chemotherapy can be given as a maintenance treatment, can promote a stable disease and not an acute response effect but then regrowth. So we don’t see so much of a regrowth when using a metronomic chemotherapy.

We even took it a step further because we wanted to ask whether when you combine these types of treatment, when you take a high dose regimen on one hand and then you continue, at the drug free break period you continue with a low dose continuous regimen, as I mentioned, as a maintenance treatment, maybe you can blunt these host pro-tumorigenic effects or pro-metastatic effects. In fact what we found, and we actually published just recently with a pancreatic tumour model and we published it also ten years ago without understanding why we got these effects, is that we know now that the effects, the pro-tumorigenic effects, that we see after high dose chemo is being negated or being blunted by the metronomic chemotherapy regimen. That could explain, at least partially, why this type of combining regimen or chemo switch regimen from an MTD to a low dose regimen can have a greater efficacy in terms of treatment outcome, a decrease in metastasis burden and a decrease in metastasis spread, as we can see in our tumour models. Obviously these things should be tested further clinically.

Is timescale important?

What we did so far is actually we used the regimen of an MTD but instead of giving a drug holiday, as we can say that, instead of that we don’t give any drug holiday, we just continue with a low dose. To do this, and in order to reduce the toxicity, we didn’t use the high maximum tolerated dose, we used a mid-dose or a reduced dose because we wanted to reduce toxicity because we give both the MTD and the low dose metronomic chemo.

Would metronomic chemotherapy be better at immunomodulation than high dose chemotherapy?

I think so far in pre-clinical studies we see that metronomic chemotherapy actually activates the immune system. Actually it’s the T regulatory cells that are important regulators of the T cytotoxic cells so we know that it happens. We know that MTD chemotherapy is a myelosuppressive drug and when it’s a myelosuppressive drug it actually depletes many different cell types. So in addition, I guess, to the T regulatory cells it also causes the depletion of the T cytotoxic cells. So I think there is a difference between the two regimens in terms of immune modulation. I do believe that but still these things need to be further investigated. I do believe that the metronomic chemotherapy, in fact, activates the immune system against tumour cells.

Should we wait a little for the research to catch up?

The problem is that the metronomic chemotherapy is still a niche and, as I mentioned at the beginning, one of the reasons that it could be a niche is because we don’t really know how it works. I think that, yes, if we gain more understanding what is the mechanism of action or what are the mechanisms of action of metronomic chemotherapy obviously we’ll see more and more clinicians using this type of treatment regimen. Because the basic idea of metronomic chemotherapy is that you can use old drugs, off patent drugs, and you gain anti-tumour activity with these old drugs. So you don’t need to use sophisticated biological active drugs, you can use very old drugs and gain sometimes even the same treatment efficacy, at least pre-clinically and clinically it’s still on-going and being tested now in phase III clinical studies.

Anything else to add?

I think that the most important thing, in my view, in order to promote this field, and I think this is an important field because it’s usually not being supported by drug companies but can be supported by governments and institutions, the initiative that’s being taken of the Metronomic Global Health Initiative, it’s a great initiative in order to actually not only use metronomic chemotherapy in developed countries but also in developing countries and in mid- and low-economic countries. Because I think that with this type of treatment regimen we will be able to get access to more patients that need a cure and are not able to get a cure because of financial problems in these countries. So I think just for this it will be a great opportunity to try and develop and promote this type of treatment modality in the future and for the future of patients in low income countries.