MASCC 2018: Chemotherapy-induced neutropenia and the role of G-CSFs

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Published: 3 Jul 2018
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Prof Jean Klastersky and Prof Bernardo Rapoport

Prof Jean Klastersky and Prof Bernado Rapoport discuss chemotherapy-induced neutropenia and the place of G-CSF in modern oncology.

The introduction of G-CSF is noted as an important advance, as it can reduce the frequency of febrile neutropenia and its associated consequences “by 50%”. Prof Klastersky notes the utilisation of primary and secondary G-CSF prophylaxis, before focusing on the patients where treatment with G-CSF would be appropriate.

Prof Rapoport mentions guidelines that can help determine which patients should receive G-CSF, segmenting these into low, intermediate and high-risk patients.

Discussion then focuses on the formulation of G-CSF, noting how the mechanism of action with short-acting GCSF means daily injections and continuous monitoring is necessary.

Conversely, long-acting GCSF allows for one injection due to the “lack of renal excretion”, making ease of administration preferable and leading to improvements with compliance. It is suggested that these factors could have contributed to the benefits seen with long-acting vs short-acting G-CSF in a recent meta-analysis.

Commenting on the future use of these treatments, the importance of new formulations is noted as well as increasing access around the world.

Reasons are provided as to why in Belgian and South African clinical practice, long-acting G-CSF is used most often and is the “way to go in general oncology”.
 

The background of GCSF
Guidelines for use
Long-acting formulations of GCSF
Possible prophylactic use

Supported by the grant of Teva Pharmaceutical Industries Ltd

 

Prof Jean Klastersky – Institute Jules Bordet, Brussels, Belgium
Prof Bernardo Rapoport – The Medical Oncology Centre of Rosebank, Johannesburg, South Africa


BR: Good morning, I’m Professor Bernardo Rapoport from Johannesburg in South Africa, I’m a medical oncologist. I’m here with my friend Professor Jean Klastersky attending the MASCC meeting in Vienna, the Multinational Association of Supportive Care in Cancer. Jean, I have a question for you – would you give us the background on GCSF and what is its place in modern oncology?

JK: Yes, to understand that you have to realise what is one of the main complications of chemotherapy which is febrile neutropenia which usually means infection, severe infection. The GCSF will be there to prevent or to reduce the risk of febrile neutropenia. Why is febrile neutropenia so important? Well, it increases markedly the morbidity for the cancer patients; it increases probably also the mortality; it is an important cause for the delay or reduction of the dose of chemotherapy which might be detrimental and I suppose you will deal with that question a little bit later. Also, febrile neutropenia is associated with increased cost for the patient and also for society. The introduction of GCSF has been really wonderful because they reduce by at least 50% the frequency of febrile neutropenia and obviously of the consequences which are just mentioned. Basically, there are two types of use of prophylaxis with GCSF – the primary, which is the most commonly used, that means GCSF are given with the starting chemotherapy, and there is also another modality, the secondary, which is the use of GCSF when after one course of chemotherapy febrile neutropenia has occurred. So now, maybe, it’s time to say who are the patients who should receive GCSF and who are the patients who shouldn’t receive the GCSF.

BR: The idea of giving GCSF is attractive because of the indications that you mentioned, that you can prevent one of the most important complications which is febrile neutropenia. Now, the patients, there are very specific guidelines. Doctors in the beginning used to give GCSF to everyone. Now, in order to establish if the patient requires GCSF or not we have the ESMO guidelines, we have also the ASCO guidelines and we have also the NCCN guidelines. There is a little bit of concordance on all three because the regimes that are utilised to treat cancer patients can be classified into low, intermediate or high risk patients. The low risk is when you are giving a treatment that the chance of developing febrile neutropenia is approximately 10% or less. The very high risk are those ones that the chance of getting febrile neutropenia is 20% or more. If you’re treating breast cancer with combination chemotherapy like TAC, for example, the chances of getting febrile neutropenia is approximately 20-25% or if you’re treating patients with germ cell tumours which you give treatment with a combination BEP is 20%. Now, if you’re using regimes that are 10% or less it includes treatments like for breast cancer with CMF - cyclophosphamide, methotrexate and 5-fluourouracil. From the point of view of who should receive GCSF, definitely the group of patients with the high risk of more than 20% is a concordance on the three guidelines, that people should receive that type of treatment to prevent febrile neutropenia. The second one is the group of patients that have 10% or less, they should not be given GCSF because you will have to treat a lot of patients to benefit only one. It’s not cost effective also. The intermediate group is a question that is always difficult because is 10% near the low risk or 20% or 18% near the high risk? If you take into account ESMO and EORTC guidelines, take into account the risk factors of the patient also, just like a formula that says 10%, 20%, 25%, 10%, 6% or whatever. It also varies according to the patients that you treat. Elderly patients are at higher risk so if you have a patient with a regime that is 10-20% chance of febrile neutropenia and you have a patient with comorbidities or the patient also with other problems like age group and if they’ve had febrile neutropenia before in the past, the guidelines give you all the risk factors and then you take into account two or three of those risk factors then you should give GCSF. If the patient doesn’t have any risk factors probably you shouldn’t use GCSF on the intermediate risk group. Tell us more, Jean, about what is the situation with the formulation of GCSF - it used to be short-acting in the beginning, now there are long-acting formulations. Maybe you should mention a couple of words about that?

JK: One should realise that the relatively small molecule filgrastim, which is the short-acting preparation, is cleared mainly by the renal route. There is another mechanism which is an inhibition or destruction of the molecule by the rising leucocytes but this is minimal. Because the renal excretion is so important for the small, short-acting molecule, it has to be given every day by injection, subcutaneously or intravenously, and it also requires monitoring of the leucocyte and watching when the leucocytes start to rise because the daily injection must be given as long as the neutrophils do not rise again. Now, with the long-acting form, which is a pegylated form which means that a kind of chemical tail protects the molecule against renal excretion, the only mechanism to destroy the molecule is the metabolism of the rising leucocyte. So it becomes an auto-controlled system which doesn’t require any control and also allows because of the lack of renal excretion one single injection. So the ease of the administration is much better and the compliance of the patient is also much better. Having said that, probably if you give the short-acting for ten or eleven days until the white cells rise, it’s probably as effective as the long-acting although meta-analyses show a small benefit for the long-acting form but that might be related to the ease of administration of that form of GCSF. Having said that, I think that we need a few comments about the future – what will happen during the next years with the use of this prophylactic GCSF.

BR: The current guidelines, in my opinion, they are evolving and they are based mainly on the cost. It’s not based on the medical indications. To me, one of the things that is important is now there are new formulations, more formulations in the market and, of course, you have the development of all the biosimilars coming in. So we envisage that in the past it used to be a very selective group of patients being treated, then a wider group of patients, now it’s going to be almost every patient that needs treatment because the cost of the drugs are going to go down and it’s not going to be an issue like it used to be in the past. For example, there are indications that we didn’t mention that you shouldn’t use GCSF at all where patients have a low white cell count or complicated febrile neutropenia; there, even if the cost is low, you shouldn’t be using it anyway. But there are a lot of patients, especially in the emerging markets and the developing world that don’t receive treatment and they have curable conditions. For example, to maintain the dose intensity of a curable cancer when you’re dealing with lymphomas or germ cell tumours or even Hodgkin’s disease. So now the good news for us is that the development of biosimilars, which are very good drugs, they will help a lot of the patients around the world.

JK: I fully agree with what you said and actually they are changing patterns of the use of these drugs. In Belgium, for instance, the long-acting are practically the only ones which are used and very recently the rules for reimbursement have been changed allowing to broaden the indication.

BR: The spectrum, yes.

JK: Absolutely.

BR: The short-acting, in my opinion, has a place in the haematology setting for mobilisation of stem cells and during the recovery period of auto-transplantation in patients with myeloma or lymphomas. Now, we use in South Africa mainly the long-acting for a number of reasons – for convenience, number one, number two – the compliance is really important, it’s a very important aspect because some of the patients hate injecting themselves. One of the side effects in some patients is with expansion of the bone marrow you get bone pain and they stop taking the treatment so that’s a problem of compliance also. So the long-acting is the way to go in the general oncology set-up.

JK: Yes, absolutely. We had a good discussion about that and thank you for listening to us.