By Brendan Guercio

Dr. Nicolas André, MD, PhD,  is a pediatric oncologist in the Department of Hematology & Pediatric Oncology in the “Hôpital pour Enfants de La Timone” and CRO2-UMR INSERM 911- (Centre de Recherche en Oncologie Biologique et Oncopharmacologie) in Marseille. He is the former president of the “Société Francophone de Recherche en Pédiatrie” and the current leader and co-founder of the “Metronomics-Global-Health Initiative.” His research centers on rare pediatric tumors, brain tumors and the pharmacology of anticancer agents.

In his recent article, “Has the time come for metronomics in low-income and middle-income countries?”, Dr. André and his co-authors propose a strategy to address the rising need for cancer care in low and middle-income countries (LMICs) (Lancet Oncol 2013; 14:e239-48). André and his colleagues argue that the most feasible approach to cancer care in LMICs may be metronomic chemotherapy–using frequent, low-dose, and minimally toxic treatments of cheap, oral chemotherapeutic agents–coupled with drug repositioning strategies–wherein old drugs are used for new purposes (e.g. NSAIDs in the prevention of colorectal cancer.) The central obstacle now is a lack of resources to conduct further research on these promising strategies; new business models involving partnerships between private and public sector entities may ultimately solve this dilemma.

How did you first become interested in metronomics and drug repositioning as viable strategies for treating cancer? When did you first perceive them as useful approaches to oncology in low and middle-income countries (LMICs)?

After obtaining my PhD in pharmacotherapy a student in my lab doing research on low-dose anti-cancer therapies clued me in to the potential for metronomic chemotherapy. We were doing some critical work on anti-tumor agents, but at the time I had not yet read any papers on the topic of metronomic therapy. When I started my first rotations in pediatric oncology, we used oral etoposide in palliative care. I was surprised to find that it worked, especially in patients who previously received “high dose chemotherapy.” But no one could really tell me how it worked. So I had that in my mind as something to work on in the lab where we discovered different mechanisms of action.

Then, as it was so cheap and well-tolerated, I thought metronomics could be useful for LMICs. We have a twinning program with the GFAOP (http://www.gfaop.fr/),  an African, French-speaking  pediatric oncology group. Physicians from this group come to France for training, and one of them, Fousseyni Traore, said “Nicolas, I think metronomics could be useful for my patients.” We constructed a metronomic protocol that he could use with his patients in Mali. That pilot study was published 2 to 3 years ago and he has continued that work, using valproic acid on top of the original protocol. And it seems to be returning positive results.

What are the important differences for readers to know between traditional chemotherapy and the metronomic/drug repositioning approach?

The first difference is the way you give the treatment. It’s oral, and you give the drugs frequently so there is continuous exposure of the tumor to the medications. It has very moderate toxicity. Then in terms of biology,  the same drug used more frequently or at a lower dosage works through different mechanisms, allowing you to target the microenvironment of cancer cells. Initially people thought this only worked through anti-angiogenesis, but now we know that the drugs also work through the immune system or even more sophisticated mechanisms on the cancer cells themselves.

Why is it important to approach cancer care differently in LMICs, and how do metronomic chemotherapy and drug repositioning address these issues? What are the long-term goals of your research?

The aim is not to do things differently, but to take into account the context of cancer care in LMICs, because we cannot try to force other countries to overcome the same barriers we face in the same ways we do. These countries do not have a lot of money, they do not have the same health systems we have, and toxicity can be a major issue for someone living in a disadvantaged neighborhood in India or favelas in South America. We are trying to come up with a treatment that is realistic and effective. The goal right now is to demonstrate that the metronomic approach works in these countries in comparison to traditional chemotherapies which they cannot access.

What are the most promising examples of metronomic treatment and drug repositioning to date?

Historically, the maintenance treatment for patients with leukemia is metronomic, using frequent and low dose methotrexate and low dose of Purinethol.

In pediatric oncology, Wilm’s tumor is treated with vincristine and dactomycin frequently, and it works very well. We also know that in palliative care, oral etoposide and oral cyclophosphamide are good drugs when given metronomicaly. There are multiple metronomic treatment options for breast cancer as well.

With regard to drug repositioning, there is thalidomide for myeloma, metformin as an anti-cancer drug for breast cancer, and emerging data on beta-blockers improving chemotherapy outcomes in ovarian, prostate, melanoma, or breast cancer. We have just published a paper showing  that beta-blockers may have efficacy in  neuroblastoma too.  The use of retinoic acid for maintenance of neuroblastoma is another good example of drug repositioning.

What obstacles face the advancement of research in metronomics and drug repositioning and the implementation of these treatment strategies in both high and low income countries?

In the so-called high income countries, the main barrier is lack of funding for research. These drugs are cheap sopharmaceutical companies will not fund trials to research their efficacy in new regimens. The other issue is that my generation has grown-up with the idea that the more chemotherapy you give the better. It’s difficult to change the thinking on this topic, because it has almost become dogma. The funny thing is that we all agree targeted therapy has to be given daily; they would never give targeted therapy at the highest doses possible every three weeks. So there is this disconnect, where everyone says targeted therapy should be given daily at low doses and chemotherapy should be given infrequently at high doses, and the two lines of thought do not intersect. So that’s a switch in our thinking that has to occur. People see the two strategies as enemies, i.e. metronomics and drug repositioning against traditional chemotherapeutics. But they are not enemies; they are simply different tools which can be used to complement one another. We shouldn’t use metronomics for the sake of using metronomics; we should use whatever is the best treatment for our patients in a given context.

How do high income countries in particular stand to benefit from research in metronomics and drug repositioning?

The aim is to get a benefit for patients: by creating cheaper, less toxic treatments that do not require them to go to the hospital or deal with the complications and hassle of having a central catheter. Ultimately, this is better for the patient, family, and providers, whether in high or low-income countries.

There are several randomized studies currently comparing traditional chemotherapy to metronomic therapy for prostate cancer and breast cancer.If one of these studies shows positive results for metronomics, it will demonstrate that it is a viable option in some contexts. Interestingly, one of these studies deals with children and shall start soon in India.

In your article, you note that poor patient compliance may be an obstacle to metronomic therapy for two reasons: (1) metronomics requires longer duration of treatment and more frequent doses and (2) monitoring patient compliance is difficult when drugs are taken orally at home, as in metronomic regimens. What strategies might be used to overcome these obstacles and is there any active research in this area?

There is some research going on in this area. We have the same problems with targeted therapies. When you have a GIST, you have to take Gleevec® every day for three years, but we know patients usually do not actually take Gleevec® consistently. How to overcome that: first, we must educate the patient, so they understand why it is so important to take the drug and what is at stake. But sometimes that is not enough, especially when the patients are children. To ensure compliance, the treatment also has to be well tolerated, the pills must be as easy to swallow as possible and patients must have adequate follow-up. In low income countries specifically, there have been efforts to use cellular phones to deliver reminder messages every day to patients to encourage them to take their treatments. In addition to these obstacles, there is not yet any clear methodology to document how well patients are complying with their prescribed drug regimen. It is not an easy thing to monitor.

You also note that, while most drugs used in metronomic protocols are cheap and off patent, some are still on patent and costly. In the past, some pharmaceutical countries have made charitable efforts to assist public health efforts in low-income countries. For example, Merck & Co. have donated ivermectin to treat river blindness. Could similar charitable actions by pharmaceutical companies assist in the implementation of metronomic therapies to fight cancer in LMICs?

One of the differences between river blindness and metronomic therapy now is that river blindness has a known treatment, while many metronomic therapies are still in development. If companies were to make charitable efforts to improve their image, they might be more willing to put their efforts into donating drugs with known effects. Since metronomic therapy is still in the research phase of development, the benefits of investing are less certain.

You argue that more financial support from the public and non-profit sectors will be needed to fund metronomic clinical studies in LMIC settings. What efforts are being made to procure such funds? What more can be done now and in the future?

At this point, my own metronomic studies are funded by traditional grants from the French government, from our scientific society for pediatric oncology, and one from a foundation called Reliable Cancer Therapies (http://www.reliablecancertherapies.com) located in Belgium. We don’t have any funding from pharmaceutical companies. We are hoping to study a patented drug that can be given orally to study its efficacy in conjunction with a repositioned drug. Because it is patented, it is still quite expensive, so I am working with the company to see if they will donate the drug for such research efforts.

With regard to LMICs, investigators at such sites are funding their research with funds from the governments of those countries and from philanthropic and charitable organizations local to those areas.  The funds are not generally coming from high income countries. Funds from high income countries could make a major impact.

In your article, you discuss at length the importance of developing new business models to research and implement metronomic therapies in LMICs. What sorts of individuals might have experiences which could lend insight to these efforts and what kinds of collaborations can be forged to develop such models?

People with experience in the world of philanthropy or health politics; people from  government; academics from for instance Harvard Global Health Initiative or the Saint Jude Outreach Program; people on site in LMICs; andpeople currently working on HIV and infectious disease, as they already have the know-how to develop the kinds of strategies needed. The tricky thing is that we are still trying to demonstrate that metronomics is a potentially attractive therapy that warrants and deserves more research. This is a major hurdle.

Even if we demonstrate that metronomic therapy works, we need to determine how businesses can profit by it. These drugs are very cheap: 50 tablets of cyclophosphamide in France might cost 12 euros. So in LMICs such as India, companies must charge a very low price and make little profit.  On the other hand, treating patients in LMICs is an important emerging market because he majority of the patients live in these countries.

That’s why we need a new business model to incentivize pharmaceutical companies to get involved.  The company might not make money directly from drug sales but would still receive some compensation; other parties, such as governments and philanthropic organizations, could collaborate in such business models to make this happen.

For example, governments or international institutions could offer a deal where, if the company provides a new drug for free or at discount or conducts a study in LMICs, they could receive an extension on their patent in a high income country. High income countries are already doing this in pediatric oncology. If company’s take drugs already in use by adults and then create new studies to better understand their potential for treatment in pediatrics, the pharmaceutical companies are rewarded by allowing an extension of their patent for that drug This couples the opportunity for pharmaceutical companies to do something good with something profitable at the same time.

Many might see parallels between your vision for cost-efficient cancer treatment in LMICs and what has been achieved in implementing HAART to combat the AIDS epidemic, like reducing cost of treatment in LMICs to $1 a day. How are these similar? What obstacles make combating cancer in LMICs different from implementing HAART to treat AIDS?

Both movements want to bring treatment to people who need it but who do not have the resources to afford such treatment on their own. The difference however lies in the fact that HAART is proven as a highly effective treatment for HIV and is the standard of care, while evidence for metronomics is still building. The second difference is that using metronomic therapy requires a change in how people think about cancer treatment, because it is so different from traditional chemotherapy. Proposing something new and different makes the situation more difficult. And we need more studies to demonstrate how metronomic therapy will affect morbidity and survival outcomes.

Do you have any advice for students interested in learning more about metronomics and global oncology?

Get involved!  It is easy to get in touch with scientists by e-mail. But if you want to become involved in metronomics, you must be aware that it is not a well-recognized field. Becoming involved is more risky than working on “hot topics”; it may be more difficult to get published in top journals. It’s “easier” to research new drug development and the use of targeted therapies and the role of stem cells for instance. But when you are looking at the intersection of metronomic therapy and global oncology, there is huge room for improvement. Right now, it is something that has to be built; it’s more risky, but that is also why it is very exciting. I think we need to reprioritize the way we are doing research now. We are always focusing on making things that are new; creating more cell lines, more new technology, more sophisticated techniques.  Barton Kamen would have said “don’t confuse trivial and simple.” We can still learn so much from things that are already around us and optimize them, without spending so much money to advance the medical frontier. And we should not think of this problem as metronomic therapy in opposition to the rest of the world; I love scientific progress and I love targeted therapies. It’s simply important for us to not forget that there is also other work to be done outside of the research topics that are currently fashionable.

Thank you very much!