Quality of life and cost advantages of metronomics and drug repurposing

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Published: 10 Jul 2014
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Dr Lisa Hutchinson - Editor of Nature Reviews, London, UK

Dr Hutchinson talks to ecancertv at the Metronomic Chemotherapy Meeting in Milan about the work of her journal, Nature Reviews Clinical Oncology, and the benefits of metronomic chemotherapy and drug repurposing, whilst noting the challenges facing it such as a lack of rigorous definitions and terminology, limited knowledge about dosage efficacy, and difficulties surrounding funding.

I was fortunate enough to be invited to do a talk here at this meeting by Nicolas André. He’d actually written an article that was published in our journal back in 2010 and we felt that that particular topic was worthy four years ago and we wanted to have an update of that. So Nicolas and Eddy wrote very recently, just online a couple of weeks ago, a lovely article for our journal on metronomic chemotherapy and said to me last year would I be willing to do a talk. So I basically predicated the talk around the first half to give a bit of an overview, background, of metronomic chemotherapy, the mechanisms behind it, the data that we have in the clinic for adults and paediatrics, a little bit of background to do with why there is a bit of cynicism or why it’s an underappreciated field, and then a couple of slides to talk through the ways forward.

The second half of the talk I gave was more focussing on why we selected this topic to be covered in the journal, why it was important, how it filled a gap in the field, and then I went on to talk a little bit about what Nature Reviews staff do at the journal, what the importance of a review article does, how it lends an extra component in the secondary content area to the field. The other thing that we also wanted to cover in this talk was to give a nice overview of how we do commissioning peer review, why it’s important to attend conferences to understand more of the basic research and the clinical side of this area and so that was the talk really.

Can you tell us a little about metronomic chemotherapy?

Basically metronomic chemotherapy is the use of chemotherapy but at a much lower dose than maximum tolerated dose with no drug free intervals, so it’s fairly continuous. So a frequent dosing means that the idea there is that it’s based around several components of its mechanism. So it has an anti-angiogenic component, it also targets the immune system and it also is basing its action on tumour initiating cells, some of the cancer stem cells, and it also has effects on hypoxia and tumour associated macrophages. So three or four areas, so it’s effectively a multi-target type of therapy, it’s not just singular therapy like targeted therapy. There has been a lot of data in the last decade actually, both in adults and in paediatrics, that are coming out showing that this approach is less toxic for the patient, that patients can endure therapy for a longer period so there is a lack of tumour regrowth between drug breaks because obviously it’s being continuously dosed at a lower level. So it means that it can be helpful in the relapse and recurrent setting and for maintenance. The other attraction is, of course, it’s using chemotherapy drugs that are off patent or that are very low cost so therefore there is an advantage in low and middle income countries as well as for developed countries.

Are the drugs specifically for certain types of cancer?

Some of them are specific to certain cancers so some of the original data we’re using cytotoxic drugs in breast cancer for that disease, but we’ve actually had other studies doing repositioning of drugs or repurposing where drugs that are not used for the original therapeutic area in which they were initially developed are now being repurposed and used either in a metronomic fashion or in combination with normal conventional cytotoxic therapy or, indeed, angiogenic therapy or even immunomodulators so that they can actually effectively be prolonging survival in some of these patients.

But it is not totally accepted?

The dosing that is used for metronomic chemotherapy is fairly empiric so it’s not really well defined in the way that perhaps maximum tolerated dosing occurs in trials. So one of the issues is essentially that we still need to understand a lot more about how we dose, how frequently we dose, with this type of therapy. So it’s not necessarily as straightforward or as well defined. The other thing is metronomics as an actual term is not very well published in the literature so an awful lot of people are reading papers on metronomic chemotherapy not even realising it’s metronomic because titles of papers say ‘low dose’ or ‘continuous’ or whatever. So there’s a lack of appreciation of that particular type of therapy in the field.  The other cynicism to do with metronomic chemotherapy is that effectively it’s not actually being as embraced by the oncology community as it should be because also there are, unfortunately, funding issues so perhaps the use of metronomic chemotherapy is not quite as attractive from an industry perspective because obviously it’s using drugs that aren’t quite as expensive as some of these other, newer therapies. So a combination of definitions, how we dose, and the fact that the terminology is perhaps not as well known within the field have hampered its uptake. Plus, in addition, we have a limited number of randomised controlled trial data with metronomic chemotherapy. That is beginning to now shift and we are getting more data but compared to conventional it’s still lower.

Did this start off in humans and then go back to the lab?

Yes, certainly there’s a translational component, if you like, to metronomic chemotherapy. So, as is often the case with cancer, the bench to bedside and back again approach is actually letting us understand the biology of the cancer in a better way. Certainly metronomic chemotherapy is not an exception in that regard at all. I think that we are finding that some of the mouse models that we’re doing and I think there needs to be more pre-clinical research actually in the drug development process, both using conventional chemotherapy and/or conventional agents, but certainly with metronomic chemotherapy this is an area that we need to have, perhaps, a greater amount of investment in in terms of resourcing and funding. But also I think it’s providing us, actually, with some really intriguing data and things we’re seeing in the clinic, some of the successes are actually being shown subsequently with retrospective pre-clinical work to give us a better understanding of how this type of chemotherapy is working which is great.

What do you think the future holds for metronomic therapy?

I think metronomic chemotherapy has a very integral and important and vital part of our future in oncology. I’ve been to conferences in the last two years, ASCO, ESMO, and one of the biggest drivers of the discussions at these conferences has been we cannot afford cancer care anymore at the level we’ve been doing it for the past decade, it has spiralled out of control. Metronomic chemotherapy doesn’t only offer cancer patients potentially response rates and survival benefits, it’s doing so at a lower toxicity, it’s also potentially beneficial in frail or elderly patients because those patients that perhaps cannot tolerate standard maximum tolerated dose chemotherapy however will benefit from metronomic chemotherapy. And let’s not forget that cancer is a disease of the aging and it’s becoming ever more important in patients of sixty and seventy years and older. Therefore, I think that the future for this particular treatment is going to be extremely important in terms of a fairly holistic approach and, indeed, because of its cost saving opportunities.

What interested you about attending this meeting?

My interest in coming to this meeting is that I can learn more about some of the scientific research and clinical advances that are taking place in this area that I would not have managed to have obtained just through reading the literature alone. So a lot of our commissioning that we do on the journal is predicated around making sure that we network with the community and attend conferences to get ideas, not only from listening to talks but actually from networking. Networking is the best way, really, in many respects to get ideas for the journal. And already in the session breaks I’ve had some fantastic conversations with some of the speakers and attendees at this conference and I’m already thinking of other ways in which we would like to cover this particular topic in the journal over the next two or three years and in the future.

What is your career background?

My career track or background is that I did a PhD at the Institute of Cancer Research, Royal Marsden; it was actually to do with the Wnt signalling pathway in the breast cancer area but it was very, very pre-clinical, I was doing mouse work and cell line work. But after leaving my PhD I decided I wanted to have a career probably in publishing because I decided that I didn’t want to stay in the bench and I wanted to use my science background but in a way where I can potentially use it for the community in an area that I enjoyed, which was, in fact, writing up my thesis. So I started at Breast Cancer Research as the editor of that journal for two to three years then did a little stint for a medical communications agency so I got exposure to the pharmaceutical pipeline and understood product lifecycles much better than I would have done if I’d stayed just in academia. Then after that I joined the Nature Publishing Group and I’ve been there ten years.

What are your plans for the future?

I still love working on the journal; we’re celebrating our anniversary decade issue in November this year and I think that oncology actually is really exciting but it’s reached a frustrating crossroads. I think that the oncology community is actually faced with a lot of challenges, not just things we’ve talked about with metronomic chemotherapy with cost issues, but the drug development pipeline, how we conduct our clinical trials, has to change compared to the days when we did this in a more systematic way with our older chemotherapy drugs. Maybe that returning back to old ways might actually be some of the ways in which we can advance the field actually. I think we can learn from the past as well as some of the exciting present stuff that’s happening with some of our newer agents and with the genomics.