Expert insight: Managing neutropenia in breast cancer patients

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Published: 23 Jan 2018
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Dr Matti Aapro and Prof Hope Rugo

Dr Matti Aapro, a medical oncologist from the from the FMH Oncologie-Hématologie, Genolier, Switzerland, chaired a discussion at the 10th Breast, Gynaecological & Immunooncology International Cancer Conference (BGICC) in Cario, Egypt, alongside Professor Hope Rugo.

Dr Aapro and Professor Rugo discussed the use of Granulocyte-Colony Stimulating Factor (G-CSF) in breast cancer management, and the various methods used to reduce chemotherapy-induced neutropenia. The use of growth factor biosimilars, particularly in the U.S.A, and how they have been adopted into clinical practice was the first topic of conversation. They then spoke about chemotherapy dosing, in combination with growth factors, in patients who have neutropenia to ensure that the regime was tolerable to avoid delaying or missing the treatment schedule.

Dr Aapro and Professor Rugo then discussed neutropenia in the setting of CDK 4/6 inhibitors, and why the origin of neutropenia is difference with this class of drug due to its mechanism of action, and concluded the discussion by looking at long-acting single vs daily short acting injectables of growth factors, and the pros and cons associated with each e.g. cost management and adverse event control.


Dr Matti Aapro – Genolier Cancer Center, Genolier, Switzerland
Professor Hope Rugo – UCSF Medical Center, San Francisco, USA

MA: I’m Matti Aapro, I’m a medical oncologist based in Genolier in Switzerland and I’m here at the BGICC meeting in Cairo in Egypt joined by Professor Hope Rugo.

HR: I’m Dr Hope Rugo, I’m a breast medical oncologist as well and I work at the University of California San Francisco in San Francisco, California.

MA: And the topic that we would like to discuss with you is about the use of G-CSF, and all the varieties of G-CSF, in the setting of breast cancer treatment to prevent febrile neutropenia and other side effects related to chemotherapy.

HR: Indeed and I think it’s a critical issue for all of us as we are trying to do less is more but also understand where more intensive therapy is also important. Certainly in the United States where we’re also now incorporating biosimilars into our treatment, which I think you’ve been doing for many years.

MA: Indeed, in Europe we have had the opportunity to use biosimilars of growth factor, the poietins and G-CSF, for quite a few years. There was a considerable debate at the time and the debate has now faded away as everyone has seen that these agents are, indeed, just as good as the so-called original agents. But I understand that in the States it’s a little bit new for some of my colleagues and there are some questions. What are the key questions that you have in the United States about biosimilars?

HR: Overall with biosimilars the therapeutic agents are going to face more questions and need more education. The supportive care medications, the growth factors as you mentioned, there has been a little bit easier path towards acceptance but people are still getting used to using those agents. At our institution and with our insurers we’ve mostly switched over to using the biosimilars for most patients actually. Those are the drugs that get delivered to home etc. I think people just feeling comfortable that the studies have really shown equivalency and then using the drugs in practice and seeing that there are no additional side effects and that they seem to work just as well has improved comfort a lot. So I’ve seen in the last six months really the opinions have shifted tremendously. Still as people who are lower volume users are still getting used to it.

MA: Yes, that’s true. You have to have the hands on experience with all of these agents and we know that now they’re introducing other types of biosimilars in breast cancer the debate is going to restart again. But also we have to understand that the original products that we have today, it’s like the cars we have today - we still speak about the good old cars but they are not the same as they were ten years ago. The same is true for medication, the techniques change and under the supervision of the FDA or EMA in Europe these products evolve. So at the end, if I may, I know that many companies don’t like me to say this, today’s original product is a biosimilar of the original offered ten years ago.

HR: Yes, I would agree. It’s really interesting because as the user, on the user end, a lot of times we don’t understand issues like the fact that you have to get approval to get a drug in a country based on where it’s made. So there are already concerns even about simple chemicals so even more so with biologics. For example, if you got it from the EU plant in Spain versus the American plant in wherever it is, North Carolina, you actually have to think about these as being different agents as well. So it’s really an ongoing issue that people haven’t understood and I think it’s great to have the competition as well as drugs that are a little lower priced because for our patients, who have often a share of costs, it’s been a huge issue. We have all these issues about whether people get drugs at home or in an infusion centre, which I know don’t exist so much in Europe, but the other thing that comes up a lot is how we use growth factors, either short acting or long acting. In patients of early stage breast cancer are you giving weekly therapy, dose dense, every three weeks and how do you decide how to use the growth factors.

MA: That’s right. One of the questions that many of our colleagues ask when we discuss with them is the lack of data on the weekly chemotherapy and how do you use the growth factor, of course a short acting one, in that setting to support weekly treatment in settings where it is important to keep the dose intensity. So what’s your take on that?

HR: So we use weekly therapy in the neoadjuvant and adjuvant setting with weekly paclitaxel. It’s been a long time since I’ve given dose dense paclitaxel and certainly docetaxel outside of a specific regimen. So weekly paclitaxel if I’m going to give an anthracycline or with trastuzumab and then docetaxel cyclophosphamide every three weeks for patients who we’re not giving an anthracycline to. With weekly therapy, as you know, most people tolerate the weekly therapy without growth factors but in situations where neutropenia is an issue, and we really want to keep up that dose schedule and intensity because it’s important for the outcome which, of course, is disease free survival, we give a single dose of G-CSF on day three usually. That would be the most that I would do in that setting because then there’s something wrong, you have to be looking into what’s going on to try not to miss a dose and try not to dose delay. I would say I almost have never dose reduced in the curative setting. But when we’re giving drugs in the metastatic setting we tend to give a week off and this was something that developed over time simply due to tolerance and it seems to work OK. We’re never going to compare continuous dosing because it’s not feasible. So I tend to switch, so if I’m giving three weeks on, one week off and somebody doesn’t tolerate it well I’ll go to two weeks on, one week off and then I add in growth factors. The most I’ve added is two days, day three, four, for a patient who really has neutropenia all the time that’s delaying things. But it’s a balance, as I know you have a lot of opinions about, in terms of balancing cost and efficacy.

MA: Yes, you’re absolutely right, it’s a question of balance. It’s also if you look at guideline committees and the ESMO committee and the EORTC in Europe have come to the conclusion that in the setting of metastatic disease it’s very difficult to find a setting in which it is very important to keep the dose intensity. So we would say in those settings try to find if there’s another well tolerated and efficacious treatment for these patients and nowadays we have so many choices that sometimes we can do these treatments without the use of a growth factor. But there are also some interesting settings nowadays where we speak about neutropenia. Just yesterday I got again a call from one of the nurses, a patient arrived in the clinic and she is on one of the CDK4/6 inhibitors and she had neutropenia. This new nurse in our unit was all nervous and, ‘Oh, neutropenia… cancer treatment… Doctor, what should I do?’ So what about with CDK4/6?

HR: Of course we know that the neutropenia that is generated from CDK4/6 inhibitors is through actually a different mechanism than by cytotoxic chemotherapy where you destroy the progenitors and in this situation you’re really inhibiting the cell cycle. But when you remove the drug the effect is gone so you don’t have the same degree of neutropenia so therefore because recovery is faster you don’t have the same issue about recovery time. But there’s something else in there which is that when you give cytotoxic chemotherapy and you get neutropenic, the combination of that cytotoxic effect and neutropenia, as we all know from having seen this before growth factor time, causes mouth sores and infections and risks that you just don’t see with these CDK4/6 inhibitors. You don’t see the mucosal damage and it’s really because the drugs themselves work differently, they’re not causing the overall cell kill. What’s fascinating to me, and I was already a faculty member, was when we started using growth factors for every three week and now every two week chemotherapy is we stopped seeing mouth sores, essentially. We stopped seeing the same kinds of toxicity that we had before we had growth factors. So clearly that absence of neutrophils that’s caused by overall cell death is different than what we’re seeing with the CDK4/6 inhibitors where you’re simply impacting the progenitors that are dependent on that enzyme.

MA: You’re slowing them down, you’re not blocking them.

HR: And then they start up again and it takes them about a week to ten days to recover.

MA: Absolutely. What you mention is very important in the use of growth factors. We have always concentrated because of the label that they are against neutropenia but I remember years ago when Miguel Martin did one of the studies using chemotherapy with and without growth factors he indeed indicated very clearly what you just said, that not only do we reduce neutropenia but we reduce these ulcerations and we reduce diarrhoea. So there’s also that benefit for the patients that I think is very important to highlight.  But what about the use of the daily injections versus the long acting, in which settings would you prefer long acting?

HR: It’s such an interesting question because there’s a financial aspect to it too which thankfully is going to go away with the advent of biosimilars and these drugs going off patent. We have always favoured the long acting single injection of growth factor for regimens that have a reasonable, following the guidelines, 18-22% risk of febrile neutropenia. The toxicity that goes along with it, that you just mentioned, that makes it so hard for patients to get through their treatment and really delays recovery and increases hospitalisation. So we find it much easier to just have a patient come in the next day or have the drug delivered for regimens that are every two to three weeks in schedule. But others have used the daily injection simply for cost control with the idea that you might be able to give five to seven doses of G-CSF instead. It hasn’t been really a tolerable approach with our patients. It’s interesting, now that you can give the whole idea of whether it’s the biosimilar, the generic or how you’re doing it, we’re not going to have generics for growth factors, the biosimilars are our category of generics. But one way to get around that is to change the delivery system. So now we have this agent where you put, what I refer to as a cockroach, but a little white bug on your skin and it injects the next day and it doesn’t hurt and it’s really easy for patients. That’s actually ended up being our go to now for using long acting growth factors. So dose dense EC and for docetaxel cyclophosphamide we tend to use that. Now, docetaxel and cyclophosphamide in somebody who is healthy and doesn’t have problems, hasn’t gotten prior chemo, which is most of them, I can give five days of G-CSF and they’ll be fine. So I do tend to do that sometimes to avoid the bone pain.

MA: You just mentioned about the duration of G-CSF, the guidelines say that we should respect the label which says beyond neutropenia. We have very little studies about five days versus respecting the label but some of these studies, which are, admittedly, retrospective for most of them, indicate that nevertheless it’s better to continue in really neutropenic chemotherapies beyond this five days and that’s where the long acting steps in. We have data comparing long acting and short acting which tends to show that long acting in those settings where the chemotherapy is really giving neutropenia to the patient is a better product. What’s your take on this one?

HR: I agree in most settings. Docetaxel and cyclophosphamide for four cycles seems to be something that’s in the middle, that’s been my experience. So when I give a long acting growth factor to a healthy young person they get a lot of bone pain despite using antihistamines, which work really well for bone pain, and are not universally used for some unclear reason. I think it’s mainly knowledge and not being on a label but really a very useful symptom control mechanism for somewhat unclear reasons. I don’t know if you have insight into that. So we give the long acting growth factor in situations where the treatment is more intensive and you know it has that greater than 20% risk but docetaxel cyclophosphamide falls in the middle. It’s too much febrile neutropenia to not give it – the first two patients I treated I remember they didn’t use the drug, both were admitted with febrile neutropenia. It’s like, ‘OK, this is not a good idea.’ But on the other hand, giving five days of G-CSF seems to have completely eliminated the problem so that’s been trial and error. So that’s a unique regimen, all other situations like that I tend to use the long acting growth factor.

MA: You just mentioned younger patients and, of course, you know my interest for our older patients. Guidelines indicate that patients above the age of 65, which is an artificial definition of older people, we should be more careful – do you agree with this?

HR: I do and I think we tend to already do that. That doesn’t mean in a curative setting, which I’ve seen a lot and I know you have as well, that you start with inadequate chemo. That seems to me like you’re shooting yourself in the foot, why would you give something you don’t know is as effective? So I tend to try and maintain the dose intensity but I use more supportive care and we check in much more frequently. It’s an interesting question, you really have to be very, very cautious and in somebody who doesn’t tolerate it I’d rather take off the last dose rather than dose reduce and give the same amount.

MA: I think we would do the same also in my centre and in European centres. Well, thank you Hope. As usual a very nice discussion with you. Any topic we can always have a good exchange.

HR: We call always discuss. Very nice to talk to you too across the ocean.

MA: Thank you. Bye bye.

HR: Bye bye.