7th November 2010
Key to Participants:
MA: Matti Aapro - University of Geneva, Switzerland
JF: Joachim Fandrey - Essen University, Germany
DS: Dirk Schrijvers - Middelheim Hospital, Antwerp
AO: Anders Österborg - Karolinska Hospital, Stockholm
MA: Good Afternoon. I’m Matti Aapro, a medical oncologist based in Genolier in Switzerland and it’s my pleasure to be welcoming you to this ecancer session. We are here in Amsterdam at a meeting on anaemia in cancer called Anaemia Management Update, an international expert forum on blood transfusion and ESAUs. This meeting has been made possible thanks to a grant from Janssen Pharmaceutical and we have had quite a few colleagues discussing many areas around anaemia management. And now I have the pleasure to have three of them with me here to discuss some of the highlights of this meeting that has lasted almost a full day. So the first, to my left here, is Joachim Fandrey, so could you present yourself to our colleagues out there?
JF: Yes, my name is Joachim Fandrey. I’m a physiologist from Essen University in Germany and the topic of our work in my department is hypoxia in tumour tissue but also erythropoiesis and erythropoietin receptor signalling which is probably my role today to discuss.
MA: So the next one sitting here with us comes from Belgium, so why don’t you introduce yourself?
DS: Yes, my name is Dirk Schrijvers, I’m a medical oncologist working at Middelheim Hospital in Antwerp, Belgium. My main topic is supportive care, head and neck cancer and prostate cancer, that was why I was participating in this meeting.
MA: And now we go to the northern part of Europe where my family comes from and Sweden.
AO: My name is Anders Österborg, I’m an oncologist working at the Karolinska Hospital in Stockholm with a long-lasting interest in developing immunotherapy in lymphoproliferative malignancies.
MA: Very good. So, as you saw, we are four of mainly medical oncology and physiology background but the meeting was not only about oncology, we also had colleagues from the surgical field, from anaesthesiology, also from nephrology of course and we had some lively discussions. We will concentrate on the cancer side of anaemia, but we will also be mentioning some of the highlights of the meeting in the setting of these other specialities and actually starting by something which is common to all of us and that is transfusions. How frequently do we transfuse patients and what other data on, not the short-term safety of transfusions - we know that in Europe, at least, and in most countries of the world the transfusion safety is, in the short term, without any discussion. But we have some questions about long-term safety of transfusions. So who among you would like to tackle this? Dirk, what about you?
DS: So we did a study at the beginning of the 2000s in patients with cancer, the e-cancer study, and there we saw that around 40% of cancer patients have anaemia. When we looked at the treatment of these patients we saw that 15% of them were being treated with transfusions. There are also some data in different tumour types that anaemia impacts the outcome of cancer treatment and we looked at the impact of transfusions on the outcome of cancer treatment. There we saw that in some tumour types there may be a negative effect on the outcome when these patients are given transfusions. So although we don’t have long-term data on the outcome of transfusions in cancer patients, I think that we should be very careful when we are using transfusions to increase the haemoglobin level.
MA: Isn’t this somewhat of a paradox that you are telling us that transfusions might have a negative effect in some cancer patients and then we have the regulatory authorities telling us that for safety reasons we should first think about transfusions? Anders, what is your take on this?
AO: Well I think it’s hard to really tell what is what and what is what in a situation like this. But just the fact that someone’s getting a transfusion might reflect that the patient has a poor prognosis by itself; it might be finding something that is related to poor prognosis. I’m not that perfectly convinced that you will affect prognosis in a negative way by giving a transfusion. Accordingly I think we have slightly higher trigger levels for transfusions in my area compared to many others, partly also because we don’t have such a lack of anucleate red cells.
MA: We also had discussions earlier this morning with our colleagues, some data in other fields than cancer, and it was quite striking to see that there are some data in patients with cardiac questions where transfusions in intensive care units actually led to a worse outcome compared to patients who are not transfused. There it’s difficult to understand why and one of the points that was made is maybe we should look at the quality of the blood which is being transfused, maybe it’s important to have fresh blood transfusions rather than all red blood cells. Joachim, would you like to comment on the quality of red blood cells when they have been for a few weeks standing in some fridge in some type of artificial fluid?
JF: Sure. From the physiology standpoint there is clear evidence that blood ages when it is stored. We’ve seen these electron-microscopic slides this morning where you can see the morphological differences and even on the storage and the fluid in which the red blood cells are stored, and also the energy homeostasis, will change over time. We know from the physiological aging that energy homeostasis affects function and particularly of red blood cells. So I think it’s not surprising that older blood cells will do not do the job as young blood cells. The problem for the usual day to day is to identify young and old and obviously the storage of blood to just have blood for transfusion requires to store it for some time and that will be a problem.
MA: It will be in the interest for everyone to know that another discussion point we had today was that there are some remarkable data showing that the use of blood in different centres throughout the same country or between countries is quite different. Transfusions are very frequent in some centres for patients operated, for example, for hip replacement and very infrequent in other centres and it is difficult to understand why. There are many reasons of course but it has been made quite clear to us by a presentation from one of our colleagues, Axel Hoffman, that you can tackle this issue and there has been a major effort conducted under the leadership of the Australian government in Australia that has led to an improvement in the use of blood with less differences now among centres and a decrease in the use of blood, a precious commodity that should be used only when it is needed and not be just stored somewhere eventually if it should be needed but only used, as I said earlier, for the appropriate patients, the appropriate time.
Joachim, the area of oncology and anaemia has been an area in which there have been some discussions in the past few years about the safety, not of blood, but of ESAs, of erythropoiesis stimulating agents. There have been some discussions that maybe some of the data showing that in some studies patients have a worse outcome when they receive an ESA is related to some enhancement of tumour growth by ESAs because of so-called EPO receptors. You are an expert in this field, can you tell us briefly what is this EPO receptor story?
JF: I want to introduce a growth factor and ESAs are growth factors for red blood cell growth into the tumour field. From the very beginning you have the concern that you might also affect the tumour cells. And so there are basically two problems, as I see them. One is in vitro studies with tumour cells, so tumour cell lines, and the other is the putative detection of EPO receptors on tumour cells. Now for the first topic, tumour cells that we all use in basic science tumour cell lines, they are heterogeneous and they are good models for some questions but they do not reflect the in vitro situations. So some of the studies really lacked adequate controls and they were not reproducible in that one group reported results that were not compatible with the results of others. So there was one recent survey that included 209 cell lines that was published in Blood earlier this year, so the usual cell lines that were used for these studies. In this particular publication it was shown that tumour cell lines did not respond to erythropoietin and did not show the receptor protein on the surface. The particular emphasis on this study is that a new antibody was generated that could actually detect the receptor protein.
So the second problem in the past was that antibodies that were not specific to the EPO receptors were used for immunohistochemistry and then a correlation was made between this immune reactivity and the patient outcome. And I believe this is obvious if you have reagents that are non-specific you are not allowed to draw any firm conclusions. So this has certainly caused some confusion in the field, particularly since these studies were mostly published in basic science journals and so not every clinician has the time and the opportunity to go over all the basic data.
AO: If I could just add to that, in a way we’re also concerned about all these pre-clinical trials on the EPO receptor expressions and we really tried to do our best in our lab to address these questions using all the readouts we could possibly think of. In no way were we able to detect an EPO receptor and the stimulation of erythropoietin in large systems. Even the most recent papers that have been published, do you think are there any publications that really indicate that there are functional EPO receptors on the tumour, on the surface of any tumour cells?
JF: I do not believe so and I think since these papers that appeared earlier this year in Blood, so a well-known and peer-reviewed journal, are a very good overview and the experiments were performed under well-controlled conditions. These studies were made by scientists from the Amgen company, but on the other hand they had the opportunity to use all the controls we were asking in the review of other papers, for example, to use the formula, the preparation of EPO that is used in the drug EPO except the active peptide. So then you have the formulation buffer as an appropriate control, you can exclude any unspecific effects. As I said, 209 cell lines including all the previous models in one group tested under controlled circumstances is good evidence that these cell lines that were tested do not respond to EPO.
So I believe the pre-clinical models will help for some studies but, as I said, they cannot replace the in vivo situation. So far I do not see proof of the full signalling cascade from the receptors through the signalling pathways and then to proliferative changes as we know them from erythro-progenitor cells.
DS: The problem, of course, came with the FDA black box warning because there were six studies studying the use of ESAs and saw a higher mortality in patients treated with ESAs. But these were studies using mainly off label indications and not a strict upper limit of haemoglobin levels. So it may be a confounding factor but we had the black box warning by the FDA that we should be very careful by using ESAs.
MA: We had a presentation today by Mario Dicato looking at data that has come after this decision by the authorities. We had a summary of the work of Professor Ludwig and colleagues on one of the ESAs, Darbepoetin, looking at all the studies that show that there’s no difference in terms of survival between the patients receiving Darbepoetin and not receiving Darbepoetin. There has also been a very interesting publication about some data from Medicare that has shown that patients whoever received in the Medicare setting, and these are patients above the age of 65 in the United States, erythropoietin, actually if you look at the long-term survival, those whoever received erythropoietin do not have a worse survival, actually in that publication they have a better survival, whatever that means.
So there are some data that tell us that there might be in some specific settings something that could go wrong and we have to be very careful but overall the signalling today, including for head and neck cancer, seems to be not as dramatic as it used to be maybe three or four years ago. There has been a publication for a third study in head and neck cancer which, contrary to other ones, is absolutely negative, there is no signal whatsoever and it’s just as small or just as large as the other two studies. So we are in a situation in which we certainly need to be careful but when appropriately used according to the guidelines it seems that these agents are useful and should not be withheld from the patients who might need them.
DS: Nevertheless there was a decrease of the use of ESAs and what we see is that this led to an increase of 30% of transfusions. So we still are facing patients with anaemia and with complications and while in the past we were using mainly ESAs we are now going back to transfusions and that’s why it’s so important that we again have access to safe transfusions and that we know what the impact is on long-term.
MA: And especially that we look at the long-term effect of transfusions and for which patients really safe and not safe to use them.
One of the issues with ESAs has been that not all patients respond to ESAs and Anders, you have participated in one major study with the use of ESAs and iron and you reviewed this earlier this morning, all the studies, most of them positive and one negative for the use of iron. Could you comment on that?
AO: Most of these trials were designed in a perspective way so we could rely quite a lot on the results and we have six trials which are phase III trials and five of them, as you say, were positive and one showed no difference between intravenous iron and erythropoietic agents alone. Some of these trials also had a third arm with oral iron and the take home message from these three trials is that you will get more patients responding by adding intravenous iron to erythropoietic agents but there is not such an effect with oral iron in the same situation. And this is also reflected, the most recent guideline from ASH and ASCO that they consider that we should more consider adding intravenous iron together with erythropoietic agents, even though it’s not yet standard of care.
MA: The issue of IV versus oral iron was also for discussion with our colleagues in nephrology and in that field it’s clear that patients who are under dialysis benefit in terms of an improved response to ESAs from iron. Again in that setting it was also emphasised that we need to have long-term follow-up of these patients in order to be certain that there is not some organ damage related to iron or misuse of iron, too much iron, and these are issues that need to be discussed in the future.
The nephrologists have also been discussing the use of erythropoietic stimulating agents and a couple of years ago they had a publication in New England Journal of Medicine of a study called TREAT which led finally to a hearing by the FDA very recently in order to see whether or not there should be a change in the use of erythropoietins in the setting of nephrology. It seems that this FDA hearing came to the conclusion that the data was such that there should be no change as long as the patients are treated according to the guidelines. Any comment from any of you?
AO: It’s hard to comment on nephrology when you’re an oncologist or haematologist but generally speaking I think it’s the same situation as we have in oncology. Even if you read the largest meta-analysis on the individual patient data in oncology, if you look at the data another way in patients who are treated according to the approved labels then there is not much of a safety issue. All this we discussed earlier on, all the safety warnings have emerged when we tried to extend, to go beyond the approved labels in oncology, haematology.
DS: But the nephrology has also one side effect which we don’t see so much in oncology that’s pure red cell aplasia and that was seen in the period when they still gave subcutaneous ESA compared to an intravenous one. Now they’ve changed completely to intravenous administration of ESAs and according to them the problem has been solved.
MA: Yes, the problem seems to be absolutely solved in the nephrology field and indeed we do not encounter it in solid tumour oncology or haematological oncology.
JF: I have one comment with respect to the pre-dialysis treatment with EPO. From the physiology standpoint this is not too farfetched since the cells that produce erythropoietin in the kidney, they may well be damaged before the patient has to go on dialysis. So if the anaemia occurs due to lack of EPO it makes absolute sense to replace the EPO and correct for the anaemia, even if the patient is not yet on dialysis. So this is something that, from the physiology or pathophysiology makes sense and, as we said, within the indication that would ,be a true replacement therapy of lack of the endogenous hormone.
MA: This reminds me of a discussion we had in which it was emphasised that it seems that, at least in that area of medicine, it’s important to look at circulating EPO levels and it is with myelodysplastic syndrome patients. Anders, would you like to comment on MDS, one of the world experts being a Swede?
AO: Well I’m not an MDS doctor actually so it’s not a special indication, well we definitely have data supporting that EPO plus DSFF might work in a fraction of the patients but unfortunately the major effect is in the fraction of patients who have not that very poor prognosis. It’s still a great unmet medical need in patients with poor prognosis MDS and who have special problems that they need transfusions for a very long time, who have problems with iron overload and things like that.
MA: Indeed the MDS is often an indication which is not recognised and certainly the experts in that field are trying to make it clear for which patients we should or should not be using erythropoietins. And they have some specific guidelines and our colleague from Italy presented us with the Italian guidelines and also the guidelines in different other countries.
Coming back to the beginning of our discussion and to the fact that we have many surgeons among us and that we saw these variations and that we have this Australian data showing how you can improve on this, I think for us it’s quite important to realise that they insisted on the fact that the patients should be evaluated correctly before a surgical procedure that could lead to anaemia. This is also true for our patients in haematology oncology. Shouldn’t we always evaluate the iron reserves, the vitamin B12 at the foliate levels of a patient when we start them on chemotherapy because they can run into anaemia very quickly and we could do something to prevent that if we identify the problem first?
DS: Yes, of course. Before starting a treatment you should always evaluate the correctable causes and these three things you mentioned, they are for sure correctable. Also causes of bleeding should also be excluded in patients because patients can have other reasons of bleeding so we should always look at that. And then, as you told us, we have some guidelines but they are mainly looking at the cut-off value and I think that other factors are also important in trying to improve the anaemia in our patients because we should look at quality of life but that’s very difficult because we mainly use this as an outcome in clinical trials and clinical practice, we don’t have all these nice IT devices to evaluate the impact of our treatments on quality of life. But I think there is a need of adaption of our guidelines to involve more clinical in all the endpoints.
MA: Are there any comments that you would like to make about our session today or the discussions we had? Also in the breakouts, anything that I forgot to ask you or comment upon?
DS: In future we will see more and more elderly patients and that’s a big group that will become part of our society but also in oncology. These patients will have specific needs because, for instance, when you are giving a transfusion you are also causing overload, volume overload, and we will have to deal with that also. I think we should look at these elderly patients, how to manage anaemia in this group.
MA: Thank you very much, Dirk, for having mentioned the elderly patients who indeed are becoming the major part of our cancer patients because of an aging population. I’d like to thank you all for your attention to this ecancer session and welcome you to the next one you might want to participate in. Thank you.
