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Keywords:

  • cancer-related anaemia;
  • erythropoiesis stimulating agents;
  • intravenous iron;
  • predictive markers

Summary

  1. Top of page
  2. Summary
  3. Baseline and early predictors of response to ESA
  4. Predictors of iron availability and markers of FID
  5. The use of IV iron in conjunction with ESA in cancer and treatment-related anaemia
  6. Conclusions
  7. References

Cancer and treatment-related anaemia is a significant clinical problem. Erythropoiesis stimulating agents (ESA) improve anaemia and ultimately enhance patients’ quality of life. However, about one-third of patients do not respond to ESA administration, mostly because of the impaired supply of iron to the erythroid marrow (functional iron deficiency). Concomitant administration of intravenous (IV) iron may improve responsiveness. The use of baseline predictors of response to ESA and of indicators of appropriateness of response and iron availability should allow targeted therapeutic interventions with both ESA and IV iron. Several biochemical and haematological indicators of response and of iron balance have been studied, but firm criteria for their use have not yet been rigorously established. The commonly used early predictive markers of response to ESA, such as baseline endogenous erythropoietin levels and an increase in haemoglobin, reticulocytes, and soluble transferrin receptor levels during ESA treatment, have not proved reliable due to their low sensitivity and specificity. Traditional markers of iron availability, such as serum ferritin and transferrin saturation display interpretation pitfalls. The need for predictors and indicators of responsiveness to ESA and IV iron is still current and clinically relevant.

Erythropoietin stimulating agents (ESA) have been successfully used in the management of cancer and treatment-related anaemia for more than 15 years. Since the first published study showing their efficacy (Ludwig, 1990), several studies have demonstrated the ability of ESA to increase haemoglobin levels and reduce the need for red-cell transfusions, leading to an improvement in patient quality of life (Glaspy et al, 1997; Siedenfeld et al, 2001; Hedenus et al, 2003). However, the impact of anaemia improvement on overall survival is not clear (Glaspy, 2002). Although a small number of studies have suggested a trend toward improved survival with administration of ESA (Littlewood et al, 2001), other studies have not confirmed this finding (Osterborg et al, 2005). Furthermore, a recently published large meta-analysis showed no clear survival benefit (Bohlius et al, 2006). This meta-analysis also demonstrated that ESA increase the relative risk for venous thrombosis, raising further concerns about the use of these agents (Bohlius et al, 2006). A recent meta-analysis (Bennett et al, 2008) confirmed that ESA are associated with increased risk for deep vein thrombosis and showed, in addition, that these agents are associated with increased mortality risk. Several recent studies have also addressed the possible negative impact of ESAs on overall survival, particularly in patients with solid tumours (Henke et al, 2003; Leyland-Jones et al, 2005; Goldberg, 2007; Wright et al, 2007), although the mechanisms that explain the possible negative impact of ESA on overall survival have not yet been clarified. Henke et al (2006), suggested that tumour cells bear functional erythropoietin receptors (EPOR). However, a later study questioned this observation, demonstrating in vitro that EPOR on tumour cell lines are not functional (Laugsch et al, 2007). Furthermore, the currently available anti-EPOR antibodies are not of sufficient quality to detect EPOR on tumour cells and the data are not convincing enough to support the correlation of EPOR status with the clinical outcome in patients treated with ESA (Sinclair et al, 2007). In March, 2007, the United States Food and Drug Administration (FDA), based on the four published studies on solid tumours (Henke et al, 2003, 2006; Leyland-Jones et al, 2005; Goldberg, 2007; Wright et al, 2007), as well as on two unpublished studies (the Anemia of Cancer Study and the Lymphoid Cancers Anemia Study) instituted the addition of a black-box warning about the potential for tumour promotion and thromboembolic events. FDA instructions required ESA to be withheld from patients whose haemoglobin level exceeded 120 g/l until the level fell below 110 g/l. Furthermore, as discussed and suggested at a meeting of the FDA’s Oncologic Drugs Advisory Committee (2007) in May 2007 (http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-00-index.htm), the risks associated with raising and maintaining haemoglobin levels at a point higher than is needed in order to avoid transfusions should be considered “unacceptable.” The recently updated American Society of Clinical Oncology/American Society of Haematology (ASCO/ASH) 2007 clinical practice guidelines on the use of epoetin and darbepoetin in cancer-related anaemia, following the FDA instructions, suggested that haemoglobin levels should not exceed 120 g/l (Rizzo et al, 2008). They also addressed the fact that clinicians should carefully weigh the risks of thromboembolism in patients for whom epoetin or darbepoetin are prescribed, especially when ESA are administered concomitantly with the combination of immunomodulatory drugs (thalidomide or lenalidomide) and dexamethasone or anthracyclines, as is usually the case in patients with multiple myeloma. These guidelines underscore the fact that physicians caring for patients with non-myeloid haematological malignancies should consider starting with chemotherapy and follow the haematological outcomes achieved through tumour reduction before deciding on ESA administration (Rizzo et al, 2008).

Factors that influence responsiveness to ESA are the type and stage of the underlying malignancies, the type of therapy, and the co-existence of other causes of anaemia. The updated ASCO/ASH 2007 clinical practice guidelines suggest that continuing epoetin or darbepoetin treatment beyond 6–8 weeks in the absence of response (e.g. 10–20 g/l rise in Hb or no attenuation of clinical conditions requiring blood transfusion) does not appear to be beneficial, and thus ESA therapy in this case should be discontinued. Patients who do not respond should be investigated for underlying tumour progression, iron deficiency, or other aetiologies for anaemia (Rizzo et al, 2008).

One of the most important causes of ESA unresponsiveness is iron-restricted erythropoiesis or functional iron deficiency (FID), which is defined as an imbalance between iron requirements and iron supply to the erythroid marrow in the presence of adequate iron stores in the reticuloendothelial system (Goodnough, 2007). Iron-restricted erythropoiesis may occur at diagnosis as a result of the shift of the circulating iron into the reticuloendothelial system due to inflammatory cytokines and the hormone hepcidin (Weiss & Goodnough, 2005), or during ESA treatment due to the excess of stimulation of erythropoiesis (Cavill, 2002; Goodnough, 2007). Several studies have suggested benefits for the use of IV iron concomitant with ESA therapy in anaemia of cancer (Auerbach et al, 2004; Hedenus et al, 2007; Henry et al, 2007).

Baseline and early predictors of response to ESA

  1. Top of page
  2. Summary
  3. Baseline and early predictors of response to ESA
  4. Predictors of iron availability and markers of FID
  5. The use of IV iron in conjunction with ESA in cancer and treatment-related anaemia
  6. Conclusions
  7. References

During the last two decades, several predictive models have been proposed in an attempt to identify patients who could benefit from ESA administration (Ludwig et al, 1994; Cazzola et al, 1995, 1996, 2003; Hellstrom-Lindberg, 1995;Henry et al, 1995; Osterborg et al, 1996; Hellstrom-Lindberg et al, 1997;Italian Cooperative Study Group for rHuEpo in Myelodysplastic Syndromes, 1998; Park et al, 2008) (Table I). The most significant and widely used predictor of response to ESA is baseline endogenous erythropoietin (EPO) levels. Several published studies supported the predictive value of this marker in both solid tumours and haematological malignancies (Cazzola et al, 1995, 1996, 2003; Osterborg et al, 1996), including myelodysplastic syndromes (Hellstrom-Lindberg, 1995; Hellstrom-Lindberg et al, 1997; Italian Cooperative Study Group for rHuEpo in Myelodysplastic Syndromes, 1998; Terpos et al, 2002; Park et al, 2008). However, outside the myelodysplastic syndrome setting, the value of endogenous EPO has not been consistently confirmed (Hedenus et al, 2003; Steinmetz et al, 2007). Neither endogenous EPO nor all of the other predictors mentioned above have been evaluated prospectively in large studies and their reliability has been disputed. The meta-analysis reported by Littlewood (2003) demonstrated that none of the commonly used predictors of response to ESA treatment (e.g. baseline endogenous EPO, serum ferritin and transferrin saturation levels (TSAT%), increase in haemoglobin and absolute reticulocyte number, and changes in serum ferritin and TSAT% levels after 2 or 4 weeks of ESA treatment) approached the required 80–90% levels of sensitivity and specificity that are generally regarded as appropriate for clinically useful predictive tests or screening techniques. The use of predictive markers with >50% of false negative results would result in omitting an effective treatment in a large number of patients. Furthermore, the high percentage of false-positive results would lead to overuse of a very expensive drug not yet proven to be risk-free. Additionally, none of these predictive markers reflect with accuracy and without interpretation pitfalls the functional iron status, which plays an important role in the pathogenesis of cancer-related anaemia. The most widely available markers reflecting the functional iron status of the body are TSAT% and serum ferritin. These markers have been incorporated in the recent National Cancer Comprehensive Network (NCCN) criteria (http://www.nccn.org, v2, 2007) for cancer and treatment-related anaemia, guiding physicians in their decisions concerning iron supplementation. However, these parameters display certain disadvantages: TSAT% is strongly influenced by the daily fluctuations of serum iron, whereas serum ferritin is an acute phase protein and thus can be increased during inflammation (Cavill, 2002; Coyne, 2006). Furthermore, soluble transferrin receptor (sTfR), which has been incorporated in predicting models of response to ESA based on its capacity to reflect erythropoiesis (Cazzola et al, 1996), is also a useful parameter of iron-deficient erythropoiesis caused by the true absence of iron stores, or by impaired iron supply due to anaemia of chronic disease. However, as a single marker, sTfR cannot discriminate between these two causes of iron-deficient erythropoiesis (Chang et al, 2007).

Table I.   Predictors of response to ESA treatment in cancer and treatment-related anaemia.
StudyPatients (n)BaselineAfter 2 weeksAfter 4 weeks
  1. Hb, haemoglobin; ESA, erythropoietic stimulating agents; s-EPO, serum erythropoietin; s-ferritin, serum ferritin; sTfR, soluble transferrin receptor; retics, reticulocytes; G-CSF, granulocyte-stimulating fact.

Haematological malignancies and/or solid tumours with or without chemotherapy
 Ludwig et al (1994) 40 s-EPO <100 U/l; Hb increase ≥5·0 g/l; s-Ferritin <400 μg/l 
 Cazzola et al (1996) 48s-EPO <100 U/lSerum sTfR increase ≥25%Hb increase ≥10 g/l; retics increase ≥40 × 109/l
 Henry et al (1995)206  Hb increase ≥10 g/l; retics increase ≥40 × 109/l
Multiple myeloma and non-Hodgkin lymphoma with or without chemotherapy
 Cazzola et al (1995) 57s-EPO ≤50 U/lHb increase ≥3·0 g/l 
 Cazzola et al (2003)241s-EPO ≤41 U/l  
 Osterborg et al (1996) 82s-EPO <50 U/l; platelet count >100 × 109/l  
Myelodysplastic syndromes
 Hellstrom-Lindberg (1995)205s-EPO ≤200 U/l; no transfusions; no RARS  
 Hellstrom-Lindberg et al (1997) (ESA plus G-CSF) 98s-EPO <100 U/l; <2 transfusions/month  
 Italian Cooperative Study Group for rHuEpo in Myelodysplastic Syndromes, (1998) 44s-EPO <100 U/l  
Park et al, (2008) (ESA plus G-CSF)433s-EPO <200 U/l  

Predictors of iron availability and markers of FID

  1. Top of page
  2. Summary
  3. Baseline and early predictors of response to ESA
  4. Predictors of iron availability and markers of FID
  5. The use of IV iron in conjunction with ESA in cancer and treatment-related anaemia
  6. Conclusions
  7. References

In order to better define FID, novel erythrocyte indices, which give important information about erythrocyte haemoglobinization and iron status, have been proposed recently (Brugnara, 2003). These indices comprise the percentage of hypochromic erythrocytes (HYPO%) (Macdougall et al, 1992), the reticulocyte Haemoglobin Content (CHr) (Brugnara, 2000) and, more recently, the reticulocyte Haemoglobin equivalent (Ret He) (Brugnara et al, 2006). The first two indices are available for use on the ADVIA analyzers (Siemens Medical Solutions, Tarrytown, NY, USA), whereas the last is provided by the Sysmex XE 2100 (Sysmex Corporation, Kobe, Japan). In contrast with traditional markers that are not informative unless definite signs of iron-deficient anaemia occur, these novel indices display changes very early in the course of the development of iron deficiency and thus offer important information concerning iron status and erythrocyte haemoglobinization. HYPO% and CHr have been established as reliable markers of FID in haemodialysis patients exhibiting high specificity and sensitivity in the management of IV iron therapy (Fishbane et al, 1997; Tessitore et al, 2001; Bovy et al, 2007). A 6-week study of ESA administration in anaemic patients with multiple myeloma and lymphomas demonstrated that baseline HYPO% alone or in combination with an increase of the absolute number of reticulocytes of ≥50 × 109/l after 2 weeks of ESA treatment predicted therapeutic response, exhibiting high sensitivity and specificity (Katodritou et al, 2007a). The same study also demonstrated that baseline HYPO ≥5% was superior to serum ferritin <100 μg/l or TSAT% <20% in recognizing FID in anaemic patients with myeloma and lymphoma with a 100% specificity and positive predictive value, based on the response to IV iron administration. Previous studies failed to show a value for sTfR in predicting and/or managing response to ESA therapy (Beguin, 1995;Pettersson et al, 1996; Ahluwalia, 1997; Cazzola et al, 2003), whereas the sTfR-F index, defined as the ratio of sTfR to the logarithm of ferritin, was shown to be useful for the sequential monitoring of response to ESA (Katodritou et al, 2007b). According to some authors, this marker displayed changes reflecting functional iron status during ESA treatment, indicating the appropriate time for IV iron administration (Katodritou et al, 2007b). Furthermore, Thomas and Thomas (2002) evaluated the role of red cell haemoglobinization markers (HYPO% and CHr) in combination with the sTfR-F index in 442 patients with various disease-specific anaemias. In this study the authors proposed a diagnostic plot combining the sTfR-F index with CHr, which distinguished iron deficiency from anaemia of chronic disease (ACD) as well as from the combined state of FID/ACD with high sensitivity and specificity. In a following study, a modified plot combining the sTfR-F index with HYPO% proved useful in predicting response to ESA and in recognizing FID, when applied to anaemic patients with multiple myeloma (Katodritou et al, 2006). Although these plots are very useful in identifying the type of anaemia and in predicting response to ESA, they are not yet applicable in every-day practice. The recently updated European Organization for Research and Treatment of Cancer (EORTC) guidelines for the use of erythropoietic proteins in anaemic patients with cancer highlight the importance of recognizing FID and recommend that it should be treated with IV iron (Bokemeyer et al, 2007). Appropriate studies to assess the suitability of erythrocyte haemoglobinization markers like CHr and HYPO% for future guidelines concerning the management of FID in cancer-related anaemia still need to be performed.

The use of IV iron in conjunction with ESA in cancer and treatment-related anaemia

  1. Top of page
  2. Summary
  3. Baseline and early predictors of response to ESA
  4. Predictors of iron availability and markers of FID
  5. The use of IV iron in conjunction with ESA in cancer and treatment-related anaemia
  6. Conclusions
  7. References

The role of IV iron supplementation in optimizing response to ESA was initially demonstrated in the research field of dialysis patients (Eschbach et al, 1987). Subsequently, Fishbane et al (1995) demonstrated a significant improvement in responsiveness to ESA treatment when IV iron dextran was concomitantly administered. The same authors showed that IV iron dextran co-administration with ESA resulted in a reduction of dosage and duration of ESA treatment, while oral iron was not effective in this group of patients due to poor compliance and impaired absorption (Fishbane et al, 1996). The superiority of IV iron over the oral form was also confirmed in several studies in dialysis and predialysis (Hudson & Comstock, 2001; Charytan et al, 2005) as well as in peritoneal dialysis patients (Johnson et al, 2001).

Recently, five published studies have addressed the efficacy of IV iron supplementation to ESA treatment of cancer and treatment-related anaemia. Auerbach et al (2004) demonstrated in a randomized study that the addition of IV iron dextran significantly improved response compared to oral supplementation or ESA alone. However, the design of this study has been criticized (Beguin, 2005; Rizzo et al, 2008), as the study was closed before reaching the enrollment targets, and the inclusion criteria did not allow physicians to define the proportion of patients who had documented iron-restricted erythropoiesis but not true iron deficient anaemia by using accepted definition criteria (TSAT% <20% and/or serum ferritin <100 μg/l in the presence of stainable iron in the bone marrow). The study by Henry et al (2007) confirmed the results reported by Auerbach et al (2004). To avoid inclusion of true iron-deficient patients, participants in the later study were required to have serum ferritin level ≥100 μg/l or TSAT% >15%, but bone marrow iron staining studies were not performed (Henry et al, 2007). At variance, the inclusion criteria for the study reported by Hedenus et al (2007) included the documentation of stainable iron in the bone marrow without considering serum ferritin or TSAT% levels. Anaemia response in this latter study was evaluated after 16 weeks of continuous ESA treatment: the response rate was unexpectedly low in patients treated with ESA (53%), although they had a stable disease and were off chemotherapy. We would suggest that the low response rate may have been due to the gradual development of FID during the 16-week course of ESA treatment. The study by Bastit et al, 2008 demonstrated that addition of IV iron to ESA in patients with chemotherapy-induced anaemia, resulted in an improved haematopoietic response rate and lower incidence of transfusions compared with ESA alone. This study displays certain limitations: the inclusion of patients with serum ferritin <l00 μg/l or TSAT <20%, without evaluation of the iron stores in the bone marrow, may have resulted in the enrolment of patients with overt or functional iron deficiency in both arms. Pedrazzoli et al, 2008 also demonstrated that in patients with chemotherapy-related anaemia and no iron deficiency, IV iron supplementation significantly reduces treatment failures to ESA, without additional toxicity. The latter study was the first study which excluded true or functional iron deficient patients by using both serum ferritin levels >100 μg/l and TSAT% >20% as an inclusion criterion. However, considering the accepted limitations of serum ferritin and TSAT% (Coyne et al, 2006), it is redoubtable to define iron repletion by using these particular iron status indices, especially in the context of a clinical trial for cancer-related anaemia. In addition to the different inclusion criteria of the five mentioned studies, it is important to note that IV iron was not administered according to the same therapeutic schedule. The appropriate dose and timing of IV iron administration in cancer-related anaemia have not yet been firmly defined. We suggest that IV iron should be administered concomitantly with ESA, in patients with confirmed FID at diagnosis, while in patients with no definite FID criteria it should be started soon after signs of FID are observed, concomitantly with ESA administration. The iron dose may be reasonably calculated with the common formula for calculating the deficit of iron according to the desired haemoglobin levels (Auerbach et al, 2004). If iron sucrose is used, the total dose should be divided in to doses of 200 mg and administered at 48-h intervals, until reaching the total dose. After this loading procedure, iron sucrose should be continued in a maintenance dose of 100 mg per week during ESA administration. If low-molecular-weight iron dextran is used, the total dose should be administered as a single infusion (Auerbach et al, 2007) after the confirmation of FID. Maintenance with iron dextran would be also reasonable. The use of IV iron up front could also be an effective option; however, this approach needs to be explored in future prospective studies.

Despite the obvious limitations of these three studies, it is important to highlight that they all demonstrate the effectiveness of IV iron in cancer-related anaemia. However, the widespread administration of IV iron during ESA therapy advocated by these latest studies, which were performed in the absence of laboratory criteria to guide its use, may not be entirely harmless (Huang, 2003; Weiss & Gordeuk, 2005).

In the past, anaphylactic reactions were considered a major problem for IV iron administration, particularly when iron dextran was widely used. This problem has been eliminated with the introduction of low molecular iron dextrans, iron sucrose, and iron saccharate (Bailie, 2005; Chertow et al, 2006). Possible long-term toxicities of intravenous iron have not been properly addressed and currently remain largely undefined and unexplored. Free-iron resulting from transferrin oversaturation may enhance tumour growth, as was demonstrated in several types of solid tumours (Huang, 2003). The molecular mechanisms which govern iron carcinogenesis include iron-induced oxidative stress and iron-induced oxidative-responsive transcription factors, which are responsible for tumour cell survival (Huang, 2003). Free-iron may also exacerbate certain infections, as iron is essential for intracellular bacteria to grow and survive in the cell (Collins, 2003). Furthermore, free-iron induces the generation of free radicals that increase oxidative stress, potentially leading to atherosclerosis and cardiotoxicity, especially in cancer patients receiving cardiotoxic chemotherapeutic drugs (Sengölge et al, 2005; Cavill et al, 2006). The idea that iron is safe is still a hidden assumption (Sullivan, 2004, 2007). The detrimental impact of excess iron storage in patients with FID is still a concern. Despite the fact that patients with cancer-related anaemia have impaired iron supply to the erythroid marrow, there is still a risk of iron accumulation in vital organs, given that intravenous iron is initially delivered to the reticuloendothelial system and cannot be rapidly mobilized in order to reach the erythroid compartment of the bone marrow (Beamish et al, 1971). Therefore, a cautious approach for the administration of intravenous iron in cancer patients and the use of proper laboratory criteria to guide iron replacement therapy should still be advocated.

Conclusions

  1. Top of page
  2. Summary
  3. Baseline and early predictors of response to ESA
  4. Predictors of iron availability and markers of FID
  5. The use of IV iron in conjunction with ESA in cancer and treatment-related anaemia
  6. Conclusions
  7. References

Although ESA-therapy has been shown to be effective in the treatment of certain types of anaemia of cancer, a significant number of patients do not respond or respond poorly, probably because of iron-restricted erythropoiesis. Considering the cost of both ESA and IV iron therapies, and their relative known and potential short-term and long-term toxicities, it would be prudent to establish a reliable set of biomarkers guiding these therapies, rather than merely advocating IV iron therapy for all patients with cancer treated with ESA. Prospective trials that will focus on the identification of the most reliable predictive markers of response to both ESA and IV iron are needed.

References

  1. Top of page
  2. Summary
  3. Baseline and early predictors of response to ESA
  4. Predictors of iron availability and markers of FID
  5. The use of IV iron in conjunction with ESA in cancer and treatment-related anaemia
  6. Conclusions
  7. References
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