Klinik I für Innere Medizin, Universitätsklinikum Köln, Köln, Germany
* Correspondence to: Prof. A. Engert, Klinik I für Innere Medizin, Universitätsklinikum Köln, Kerpener Str. 62, D-50924 Köln, Germany. Tel: +49-221-4785966; Fax: +49-221-4783778; E-mail: a.engert{at}uni-koeln.de
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Abstract |
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Key words: anaemia, cancer, darbepoetin alfa, erythropoietin
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Introduction |
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Although the use of red blood cell (RBC) transfusions is still quite common for the treatment of anaemia, this therapy has a number of drawbacks. Even today the risk of transmission of viral and bacterial infections cannot be ruled out. In 256 reports of transfusion-associated death received by the United States Food and Drug Administration (FDA) between 1976 and 1985, the majority (51%) were caused by acute haemolysis due to ABO incompatibility. Other causes included pulmonal injury, delayed haemolysis, bacterial infections and graft-versus-host reactions [6]. Transfusions can also cause immune suppression [7
].
With the introduction of human recombinant erythropoietin (rHuEPO) in oncology about 10 years ago, an alternative to RBC transfusion became available [8]. In addition to improving symptoms of anaemia, the use of erythropoietin might also influence overall QoL and the prognosis of patients. In order to give a framework for erythropoietin therapy, the American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) and, more recently, the European Organisation for Research and Treatment of Cancer (EORTC) developed evidence-based guidelines on the use of epoetin in cancer patients [9
, 10
].
To increase treatment efficacy and to improve patient compliance, a number of different administration regimes for rHuEPO are currently under evaluation, including less frequent dosing and loading-dose concepts. In addition, with the development of darbepoetin alfa, a genetically modified erythropoietin with longer half-life has become available [11]. Owing mainly to economical considerations, the general use of recombinant erythropoietin has not become common practice in the oncological setting.
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Erythropoietin: mechanism of action |
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In response to a decrease in tissue oxygenation, erythropoietin is released into the plasma and binds to erythropoietin receptors on the surface of red-blood cell precursors (BFU-e, CFU-e, erythroblasts) located in the bone marrow. As well as prolonging their survival, erythropoietin inhibits apoptosis of the precursor cells, thereby inducing their proliferation and differentiation [15].
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Causes of cancer-related anaemia |
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Some groups of cancer patients show particularly high incidences of anaemia during or after cytotoxic therapy. This is the case for 70% of myeloma patients and
50% of lung and ovarian cancer patients [19
]. Anaemia is also frequently observed in patients with head and neck tumours, breast cancer, genitourinary tumours and lymphomas [3
].
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Symptoms of anaemia |
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One of the most common anaemia-related problems is fatigue, a condition of exhaustion that cannot be improved by rest or sleep, impairing the patient's ability to perform normal daily activities. Studies have shown that 60% to 96% of patients undergoing chemotherapy suffer from this syndrome [22].
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Recombinant human erythropoietins |
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Like the native hormone, epoetin alfa and beta consist of 165 amino acids, but differ in their carbohydrate content, owing to differences in production and purification. After subcutaneous injection, which is the method of choice in cancer patients, epoetin alfa and beta have an average half-life of 8 h. The recently developed darbepoetin alfa has a higher molecular weight of 38 kDa. This is due to the fact that five amino acids have been exchanged by site directed mutagenesis, leading to two additional N-glycosylation sites, thereby increasing the number of sialic acid residues from
14 to
22. This modification leads to a longer terminal half-life of
49 h after subcutaneous injection, but resulted in a lower receptor binding capacity leading to lower biological activity in vitro [25
, 26
].
In addition to the standard regimen of 10 000 IU or 150 IU/kg thrice weekly, epoetin alfa and beta are also being administered once weekly. The recommended dose for darbepoetin alfa is 2.25 µg/kg per week [2325
].
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Treatment of cancer-related anaemia with erythropoietin |
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However, although several trials indicated a significant increase in the overall QoL, a systematic review on the effectiveness of erythropoietin with regard to QoL questioned the validity and reliability of the data reported in the literature [46]. One major limitation described is the lack of masked testing of patients. Other flaws presented included lack of definition of QoL and adequate power calculations, as well as incomplete reports on methods for handling of missing data. These findings have been supported by two systematic reviews published in 2001 [47
] and 2004 [48
].
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Darbepoetin alfa |
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In most phase III studies using darbepoetin alfa, a starting dose of 2.25 µg/kg per week was used. One example is the application trial for patients with solid tumours, enrolling 320 patients with lung cancer who had Hb levels 11 g/dl [50
]. Patients received either darbepoetin alfa or placebo for a period of 12 weeks during platinum-containing chemotherapy. In addition to a significant reduction in the proportion of patients transfused during weeks 512 (27% versus 52%), patients under darbepoetin alfa had a higher haematopoietic response (66% versus 24%) defined as an increase in Hb level of >2 g/dl or achieving a Hb level of 12 g/dl. Fifty-one percent of the patients (n = 80) showed an increase in Hb of >2 g/dl. Improvement in fatigue symptoms (FACT-Fatigue) was better in the darbepoetin alfa arm (56% versus 44%), but did not quite reach statistical significance (P = 0.052). This might in part be due to the delayed increase in the average Hb level after 4 and after 12 weeks, respectively (Figure 4) [51
]. A dose escalation to 4.5 µg per week was applied in 43% of patients.
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In a dose-finding study [53], darbepoetin alfa was administered every 3 weeks. Doses of 4.5, 6.75, 9, 12, 13.5 and 15 µg/kg as well as placebo were given for 12 weeks (Table 2). Patients (n = 249) with solid tumours and a baseline Hb level of
11 g/dl were included. The best results were observed in the group receiving 12 µg/kg, which showed a response rate of 71% and a final increase in Hb of 2.64 g/dl. Similar results were observed in another dose-finding study [53
] for the administration of darbepoetin alfa every 4 weeks, comparing placebo and doses of 9, 12, 15 and 18 µg/kg in 145 patients (Table 3). While the highest response rate and increase in Hb was achieved with a dose of 15 µg/kg, a dose of 18 µg/kg gave worse results. Because the less obvious doseresponse relationship might be due to the limited number of patients in these two studies, it seems that additional data are needed to show the best dose for every 3 weeks and every 4 weeks administration of darbepoetin alfa.
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Loading-dose concepts |
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A recently published study by Glaspy et al. [54] including 127 patients with solid tumours compared three different doses of darbepoetin alfa with epoetin alfa per week. Patients in the three darbepoetin groups (Hb
11 g/dl) received a loading dose of 4.5 µg/kg per week until a Hb value of 12 g/dl was achieved (group 1) or for 4 weeks (groups 2 and 3). Treatment was continued until week 12 with a maintenance dose of 1.5 µg/kg per week (group 1), or for 8 weeks with doses of 2.25 µg/kg per week (group 2) and 3 µg/kg every 2 weeks (group 3). Patients in the epoetin arm received 40 000 IU epoetin alfa per week, with a dose escalation to 60 000 IU after 6 weeks in non-responders.
Although initially equal doses of darbepoetin alfa were administered, the average increase in Hb values differed in the three groups (0.53, 0.70 and 0.90 g/dl). This was also the case after 12 weeks, where the Hb increases of 1.35, 1.35 and 1.28 g/dl did not reach the 8-week benchmark of 2 g/dl. Response rates ranged between 58% and 65% (
Hb
2 g/dl). The median time to response in groups 1 and 2 was shorter than in group 3 (50 versus 78 days), suggesting a faster onset of action. The investigators observed an improvement of fatigue symptoms in all three groups but did not provide data to show significance.
Similar loading-dose trials were also performed using epoetin alfa. In a study by Cortesi et al. [55], 19 patients with solid tumours and an initial Hb level <9 g/dl received a total of five injections of 40 000 IU epoetin alfa on days 1, 4, 7, 10 and 13 of chemotherapy (group A). They were compared with a historical group of 19 patients, who received 10 000 IU epoetin alfa three times per week without dose escalation for their entire treatment time of 45 days (group B). While the mean increase in Hb at day 15 was 1.7 g/dl for group A versus 0.4 g/dl in group B (P = 0.0042), average
Hb values of 2.9 versus 0.8 were observed at day 45 (Figure 5). Response rates (
Hb
2) at day 15 and day 45 were 37% and 84% in group A versus 16% and 21% in the control group, resulting in a lower transfusion rate and a better performance score for patients in the front-loading group.
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Although larger, randomised trials are still needed, the results from these studies suggest that loading-dose concepts with a less frequent maintenance regimen might allow for a more rapid increase of Hb levels in anaemic cancer patients.
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Predicting and optimising erythropoietin treatment |
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In patients with a serum erythropoietin level of <100 mU/ml, a rise in Hb of >0.5 g/dl in the first 2 weeks of chemotherapy has been found to be a valuable early indicator for response to epoetin treatment (95% accuracy). Vice versa, an increase of <0.5 g/dl after 2 weeks in patients with a serum erythropoietin level of >100 mU/ml predicts lack of response with 93% accuracy [57]. Other predicting factors for response are an increase in the number of reticulocytes to more than 40 000/µl and a higher concentration in soluble transferrin receptors (>25%).
Serum ferritin levels of <100 µg/l and a transferrin saturation of >20% before the start of epoetin treatment might impair efficacy. In those patients a daily iron substitution of 100300 mg is recommended. Owing to the elevation in iron metabolism, the prophylactic application of iron might also be advisable. Another factor that might blunt response to erythropoietin is low serum folate, which therefore should be measured initially [59].
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Pharmacoeconomics |
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Pure red cell aplasia |
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Until 1998 there were only a few single reports on PRCA. French investigators identified 13 chronic dialysis patients who developed severe transfusion-dependent anaemia between 1998 and 2000 after treatment with epoetin for 367 months [62]. It could be shown that these patients had developed antibodies against epoetin, which also cross-reacted with the native hormone, thus inhibiting erythropoiesis.
Between January 1998 and April 2004 worldwide 180 cases of PRCA with anti-erythropoietin antibodies were reported in patients with chronic renal failure (CRF) treated with epoetin alfa, and 11 cases with epoetin beta. However, after procedures were adopted to ensure appropriate storage and handling, the incidence of PRCA in CRF patients decreased [63]. No further cases of PRCA in patients suffering from CRF have been reported in Europe since January 2003. No cases of PRCA have been reported so far in oncology. This might be due to the fact that the immune system of cancer patients is more disturbed by the disease or suppressed by cytotoxic therapy. In addition, compared with patients with CRF, erythropoietin therapy in cancer patients is much shorter.
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Influence of erythropoietin therapy on survival |
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Some studies suggest that the prophylactic use of erythropoeitin in cancer patients may improve prognosis. In the Littlewood et al. study [39], the median survival in the epoetin alfa group was 17 months, compared with 11 months for patients receiving placebo, hence this was not statistically significant (P = 0.13). As this study was not designed with survival as an end point, this result must be interpreted with care. Properly designed randomised controlled trials are necessary to test the hypothesis of whether erythropoeitin may indeed improve overall survival.
Casas et al. [66] reported effects of erythropoietin on the prognosis of 51 patients with small-cell and non-small-cell lung cancer stage IIIA/B. After initial cisplatin therapy, patients with Hb level <11 g/dl received epoetin alfa (150 IU/kg three times per week) concurrent with the ongoing radiochemotherapy. While 33.8% of the patients with an increase in Hb levels during radiochemotherapy reached 2-year survival, this was only the case for 1.5% of the patients with stable or decreasing Hb levels. Patients with an increase in Hb also had a significant improvement in their Karnofsky index (P = 0.001).
A recently closed trial by Blohmer et al. [67] investigated the impact of epoetin alfa in patients with high-risk carcinoma of the uterine cervix (n = 257) treated with sequential chemoradiotherapy. The first interim report might indicate an improvement in relapse-free survival for patients treated with epoetin alfa (10 000 IU three times per week) (17% versus 25%). Again, this observation is statistically not significant (P = 0.058; Figure 6) and these studies are not sufficiently powered to detect meaningful differences.
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Correction of Hb levels beyond anaemia |
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The second study recently published included 939 women with first-line metastatic breast cancer (BEST) who were prospectively randomised in a multinational multicentre study to receive epoetin alfa or placebo [69]. This study was terminated prematurely by an independent data monitoring committee based on first 4 months' safety data. There was a small but significant survival difference between patients receiving epoetin alfa (70%) and those in the placebo group (76%) at 12 months. This difference was due to an increased mortality in the first 4 months (41 versus 16). In particular, there was a higher incidence of fatal thrombotic and cardiovascular events (2.3% with erythropoietin versus 0.4% with placebo). The number of deaths related to disease progression in the epoetin alfa arm, however, were smaller than originally attributed by the investigators. In addition, there was a convergence of survival curves at 19 months. Although there were considerable imbalances between groups and methodological flaws, this study also suggests a higher risk of thromboembolic events in patients with higher Hb levels.
Apart from methodological limitations, the results of the studies published by Henke and Leyland-Jones may partly be explained by the increased incidence of thromboembolic complications. Interestingly, studies evaluating erythropoietin to maintain different hematocrit levels in end-stage renal failure patients and pronounced cardiovascular risk factors, showed that there is an increased mortality due to thrombovascular and cardiac events in those patients with higher hematocrit levels [70]. In patients with malignant diseases, which are often associated with an increased risk for thromboembolic complications, this concern might be even more important [71
].
The reduced tumour control claimed in the studies published by Henke [68] and Leyland-Jones [69
] raised additional pathophysiological discussion concerning the potential for erythropoietin to promote tumour growth. As preclinical studies reported high levels of erythropoietin and erythropoietin receptors in breast cancer cells and other malignancies, both endogenously and exogenously administered erythropoietin could theoretically promote the proliferation and survival of erythropoietin receptor expressing cancer cells [72
75
]. However, these preclinical might have no or very little clinical relevance until proven otherwise.
Taken together, these studies raised concern about the safety of erythropoietins, particularly in clinical trials aimed at correcting the Hb beyond anaemic levels. These questions were discussed during a comprehensive FDA hearing on 4 May 2004 (http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037b2.htm). At that meeting three company-sponsored meta-analyses focusing on safety and survival of patients treated with erythropoietins were presented (http://www.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Committees/Oncologic+Drugs/050404_Aranesp/050505_AranespR.htm). The discussion highlighted the difference between studies performed according to the current ASCO/ASH guidelines [9] and those aimed beyond correction of anaemia. Clinical studies aimed at maintaining a higher Hb level such as those published by Henke [68
] and Leyland-Jones [69
] indicated a higher risk of thrombovascular events. As a consequence, three other studies with similar concepts were closed prematurely.
The Oncologic Drugs Advisory Committee concluded that the data available at that time were insufficient to clarify the influence of erythropoietins on tumour growth and survival. However, they did not apply restrictions on the adequate use of erythropoietin and highlighted the need for further research to clarify these questions. Important questions in future studies will focus on possible mechanism involved and on the impact of the additional iron supplementation in erythropoietin-treated patients. Iron itself may be associated with detrimental coronary outcomes [76, 77
] and increase the risk of infection [78
] and tumour progression [79
]. In the meantime it is recommended to use erythropoietins only according to evidence-based guidelines and according to the indications granted by the regulatory agencies. Outside these indications erythropoietins should be considered only under monitored conditions in well designed controlled clinical trials.
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Systematic review on erythropoietin in patients with malignancies |
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Evidence-based guidelines for erythropoietin treatment |
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Conclusions |
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In order to improve efficacy and convenience of erythropoietin treatment, a number of different administration regimens are currently being tested, ranging from less frequent application of higher doses to loading-dose and early intervention concepts. Although initial promising results have been observed, the value of these concepts still has to be shown in larger randomised trials. Comparing the efficacy of the different epoetins is difficult due to a lack of large randomised head-to-head studies; so far, the three erythropoietins available have to be regarded as one class of drugs. Costs for erythropoietin treatment can be lowered if predictive factors for response are implemented and followed. In management of anemic patients, physicians should follow closely the ASCO/ASH guidelines. Clinical trials with erythropoietins aimed at correction of Hb levels beyond anaemia indicated a higher risk of thrombovascular events. Thus, treatment of patients beyond anaemia has to be regarded as experimental, and should only be conducted within clinical trials. Larger meta-analyses are needed to fully elucidate the impact of erythropoietin dosing and Hb levels on outcome.
Received for publication July 29, 2004. Revision received January 17, 2005. Revision received March 23, 2005. Accepted for publication April 12, 2005.
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