Febrile neutropenia and neutropenia are a relatively common event in cancer treatments depending on the intensity of the treatment. If you look at radiation therapy, if you radiate enough of the bone marrow you will have profound effects on the activity of the bone marrow; it’s very rare but it does happen. We also have to think of several types of cancer treatments, classically chemotherapy and nowadays the CDK4 and CDK6 inhibitors, which will, on one side, decrease the white blood cell counts, that’s neutropenia, and in some instances this profound neutropenia will mean fever and that is febrile neutropenia.
Neutropenic events with cancer treatments vary depending on what cancer treatment is given to the patients and we have extensive listings in different sources that will give an idea of what the risk is for the patient. So it can vary from almost nothing to more than 40-50% of the patients having a risk of febrile neutropenia. Neutropenia can be much more common as it is, for example, with CDK4 and CDK6 inhibitors that elicit neutropenia in more than 80% of the patients but it is extremely rare that it is a febrile neutropenia.
Neutropenia by itself has an impact that is relatively modest except if non-experienced oncologists, which I hope don’t exist anymore, are treating the patients and become nervous about neutropenia. What is really important is the length of the neutropenia and the risk of febrile neutropenia and the febrile neutropenia itself. This can then mean that the patients will not be dosed with the adequate amount of treatment and this can lead them to subsequent consequences.
What is the clinical importance of chemotherapy dose time, and relative dose intensity?
If we adapt the treatment of our cancer patients to the fact that they have had neutropenia by delaying the treatment or decreasing the amount of the chemotherapy, this can be of extreme importance in the settings of curative treatments of chemosensitive tumours. There has been clear demonstration in the adjuvant setting of breast cancer treatment and in the treatment of non-Hodgkin lymphoma that decreasing dose intensity to less than 80% will basically mean that the chemotherapy is useless. So we have to be very careful dose-wise. On the other hand, if it’s only palliative treatment just to help the patients survive somewhat longer from the cancer then we can use other types of treatments where the patients will not have neutropenia, and the eventual consequence – febrile neutropenia, but in that setting there is no implication for patient survival.
The prediction of febrile neutropenia risk is, in theory, relatively easy because you look at studies and you look at the percentage of patients that presented without preventative treatment febrile neutropenia. But actually this is not that easy because the studies have inclusion/exclusion criteria which mean that you’ll have lots of patients that are not included and these are the ones that are at risk of febrile neutropenia. Elderly patients – clear increased risk of febrile neutropenia; patients that have a poor performance status – clearly increased risk; patients that have some co-medication that will influence the intensity of the chemotherapy with a change of the area of the curve, all of these situations need to be taken into account in order to decide what is the level of risk of febrile neutropenia for the patient.
What should the treatment strategies be for these groups?
Today most guideline groups divide patients into three different categories when we think of prevention of febrile neutropenia: the low risk group, which is felt to be less than 10% risk; the median risk group which is 10-20% risk of febrile neutropenia and the high risk group – more than 20% risk. But what we have to take into account is that this is related to the chemotherapy itself, then we have to adapt this to the reality of the patient. So a typical example is you have a young lady who is going to have adjuvant treatment for breast cancer where we know that dose intensity is important. We don’t want her to have a problem and if we have in her history that she has, like some ladies have, someone who has urinary tract infections on a recurrent basis you know that she should not have a neutropenia because then she is at high risk of febrile neutropenia and even a septicaemia. So you will be doing preventative treatment for this lady, even if she is in the middle group of 10-20% risk.
What does this preventative treatment look like?
Today in the drugs that are registered for prevention of febrile neutropenia we have the GCSFs and we have two types of GCSF grossly: the short-acting ones where you have to repeat the injection over several days, ideally beyond neutropenia nadir, which means to eight, ten, eleven days, which many oncologists don’t do, then the long-acting drugs which allow with one single injection to cover all of that period and not put the patient at risk. Because we have evidence that if you don’t treat high risk patients with adequate, at least 7-10 days, of treatment, there is a higher risk of febrile neutropenia nevertheless.
What are the barriers to effective management?
Oncologists today don’t follow guidelines as they should do, at least coming from someone who is a member of guidelines committees, for several reasons. One of the reasons is that febrile neutropenia is a relatively rare event and they don’t perceive that the patients are really at risk of febrile neutropenia. Many believe that because they have been using a package, a package is five ampoules of the short-acting compounds, and that is enough, they think that it’s not a problem. Actually we have data to say that it is a problem when there is a high risk of febrile neutropenia. Then there is another factor which has been cost and today, thanks to development of biosimilars, we see that in many countries where there were limitations to the use of GCSF, these limitations have been now withdrawn and the agents are used in the preventative way as per guidelines much more frequently.
How does management vary internationally?
Worldwide there are quite a few different guidelines that exist and the application in different countries depends very much on what is available in these countries. So there will be some variations in the types of agents used but, on the other hand, they are relatively similar. What continues to happen in many countries, for example in Europe, is that there are sometimes strange limitations – in some countries patients have had to have a previous event of febrile neutropenia in order to be treated afterwards for the subsequent cycles. From the point of view of the ESMO and EORTC committees in Europe we believe this is wrong. The risk of febrile neutropenia is rare but is a risk of death for the patients so this should never happen if it can be prevented.
What more needs to be done to improve treatment and management of febrile neutropenia?
Prevention of febrile neutropenia is extremely important in order to assure when the patient has chemosensitive disease the adequate dose intensity of chemotherapy. This is now recognised in most instances and, for example, recently in the setting of adjuvant treatment of breast cancer we had a communication at the San Antonio meeting at the end of 2017 showing that dose intense treatments actually made a difference even in patients where we thought it might not make a difference because we believe that endocrine sensitive breast cancer is not that chemosensitive. But it seems, at least from the initial data that was presented, this was important.
So clinicians throughout the world are recognising this point. What is also happening is that, as I alluded to earlier, access to these drugs is becoming easier because of the development of biosimilars. Finally, we also know that there are other agents that are being developed, they are not yet licensed, and this is going, probably, to change also a little bit the approach to the prevention of febrile neutropenia.
And a last point: antibiotic use for prevention of febrile neutropenia is a no, no, no, by all guidelines.