15.1 Frequency and Causes of Anemia in Oncology

Anemia is a common manifestation in patients with cancer. More than 80% of cancer patients undergoing chemotherapy develop anemia (hemoglobin [Hb] level < 12 g/dL) [1]. Information on the prevalence and effects of anemia can be found in the literature from clinical trials of anemia treatments or chemotherapy [2,3,4,5,6,7]. The data generated by these studies came from well-designed and selected populations of patients. However, little was known about what happens day to day in doctors’ offices or hospitals until the European Cancer Anaemia Survey (ECAS) study was published [1]. This study, in which 15,367 patients were evaluated, is probably the best ever performed to understand the incidence and prevalence of anemia in cancer patients. This prospective study demonstrated a prevalence of anemia at enrollment of 39.3% (Hb < 10.0 g/dL, 10%) and 67.0% during the survey (Hb < 10.0 g/dL, 39.3%). Low Hb levels were found to correlate with poor performance status. Incidence of anemia was 53.7% (Hb < 19 g/dL, 15.2%).

Anemia in the cancer patient can be caused by a variety of conditions in what constitutes the so-called anemic syndrome, either caused by the same tumor or by the effects or complications of cancer treatments [1]. The causes of anemia are multifactorial: (1) bone marrow infiltration by cancer cells; (2) nutritional deficits such as vitamin B12, folic acid, or iron; (3) hemolysis; (4) myelosuppression secondary to chemotherapy or radiotherapy; (5) toxicity induced by the new antitargeted therapies; (6) low endogenous erythropoietin levels; and (7) anemia of chronic disease, also known as functional iron deficiency (Fig. 15.1). The unexpected finding of low erythropoietin levels in cancer patients by Miller et al. in 1990 [8], together with the toxicity induced by chemotherapy, sets the basis for the use of this agent in cancer patients. Vitamin B12, folic acid, and iron are necessary factors for red blood cell production. Blood loss can be a common association, particularly in colorectal cancer, endometrial cancer (bleeding), or lung cancer (hemoptysis). Anemia can be seen occasionally in cancer patients due to hemolysis secondary to particular chemotherapeutic agents. A short red blood cell half-life has also been reported [9].

Fig. 15.1
figure 1

Causes of anemia in the patient with cancer (adapted from [2, 8, 9])

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Anemia in cancer can also be caused indirectly by the same inflammatory process associated with the disease. In this case, cytokines are produced, with some of them having relevant biological effects with regard to anemia. Two of them, interleukin-1 (IL-1α [alpha], β [beta]) and tumor necrosis factor (TNF-α [alpha]), are known to inhibit the production of erythropoietin by the kidneys. Another important cytokine is IL-6, a proinflammatory factor that acts on the liver to induce the production of hepcidin, a small peptide that has an important role in iron metabolism [10, 11]. It is considered the most important factor in the anemia of chronic disease, also known as functional iron deficiency. Hepcidin induces the degradation of ferroportin, the iron transport protein from the gastrointestinal tract cells or from iron storage pools in reticuloendothelial cells, mainly macrophages. In other words, hepcidin works in the duodenum, inhibiting the oral absorption of iron, and in the bone marrow, blocking the release of the iron contained in the macrophages. It is understandable that with this scenario, the red blood cells’ progenitors lack the two major sources of iron for new red blood cell formation: the gastrointestinal tract, where the enterocytes are unable to absorb either nutritional or therapeutic iron, and the bone marrow, where the macrophages, scavenger cells, do not release the sequestrated iron obtained from the senescent red blood cells [12].

The fact that chemotherapy agents induce anemia is well known. Because dividing cells are targets for these agents, we observed cytotoxicity on cancer cells as well as toxicity in bone marrow cells (myelotoxicity), since most of these cells are in a constant proliferative state. However, we are now facing a quite different scenario in treating cancer since the arrival to our hospital pharmacies of the new targeted agents (tyrosine kinase inhibitors, mTOR inhibitors, monoclonal antibodies, antiangiogenics, etc.). Interestingly, some reports recently published show some of these new agents causing grade 1–2 anemia (range, 15–30%). Among the monoclonal antibodies, trastuzumab has been associated with mild anemia, and bevacizumab has a reduced risk of anemia effect [13,14,15,16,17]. The mechanism(s) of anemia are still unknown for all new targeted agents. Some recent publications established that many of these agents induce by themselves various degrees of fatigue, in some cases quite important, and independently of the level of Hb of the patient.

15.2 The Therapy of Anemia

15.2.1 Red Blood Cell Transfusions

Prior to the introduction of human recombinant epoetins, there were no other treatment options for the correction of anemia than red blood cell transfusions or iron; in many cases, the option was not to give anything. The AIDS epidemic puts blood transfusions under the magnifying glass, and although the safety of our modern blood banks has never been so good, still blood transfusions are associated with unwanted effects. A transfusion of red blood cells causes a sharp increase in Hb level as well as an increase in blood viscosity that varies with the number of units transfused. Interestingly, there has been no large clinical trial to demonstrate an improvement in quality of life after blood transfusions, as has been the case for epoetins.

15.2.2 Erythropoiesis-Stimulating Agents

Human recombinant epoetins were introduced in the early 1990s. Initially there were epoetin alfa and epoetin beta. Both agents are similar to the endogenous molecule, erythropoietin. Ten years later, a new modified erythropoietin molecule was introduced in our pharmacies, darbepoetin alfa. Since the three molecules stimulate erythropoiesis, they are currently called erythropoiesis-stimulating agents (ESAs) (Table 15.1). Over the last 20 years, more than 20,000 cancer patients with anemia have been enrolled in multiple clinical trials of ESAs to assess the efficacy, side effects, and quality of life. This massive clinical experience with ESAs has demonstrated that they are well tolerated and can effectively increase Hb levels and decrease transfusion use [3,4,5,6,7, 9, 18, 19]. Initially, epoetins were administrated three times weekly following the pattern used for dialysis in chronic renal failure patients. Lately, once-a-week administration has become the most popular schedule. In addition, darbepoetin alfa has an administration schedule of every 3 weeks, besides the once-a-week presentation [20]. In general, ESAs produce significant decreases in transfusion requirements and significant increases in Hb level (around 1 g/dL in 4 weeks), with hematopoietic response rates ranging from 55 to 74% [3,4,5,6,7, 9, 18, 19]. In addition, correction of the anemia by ESAs has been correlated, in a significant way, with improvement in the quality of life of cancer anemic patients. Fatigue is a major symptom of anemia. Cancer-related fatigue has a profound effect on patient quality of life, affecting physical and emotional well-being, as well as relationships with family and friends. The greatest incremental improvement in quality of life occurs when the Hb level increases from 11 to 12 g/dL (range, 11–13 g/dL) [21].

Table 15.1 Erythropoiesis-stimulating agents
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As a result of so many social and medical changes in attitude, anemia management practices have changed over the years. This is reflected by the guidelines for anemia treatment issued first by the American Society of Hematology (ASH) jointly with the American Society of Clinical Oncology (ASCO) [22], by the National Comprehensive Cancer Network (NCCN) [23], and, more recently, by the European Organisation for Research and Treatment of Cancer [24]. The three guidelines strongly recommended ESA treatment for cancer patients with anemia receiving chemotherapy who have a Hb level < 10 g/dL. However, the three guidelines differ somewhat regarding recommendations for treatment of patients with Hb levels of 10–12 g/dL. The correction of anemia should not go over 12 g/dL (Table 15.2) [28].

Table 15.2 Summary of international evidence-based guidelines for treating cancer-induced anemia
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Recently, a new generation of ESA-like agents has been approved by the European Regulatory Agency (EMA). The loss of the patent of the originals has produced a new generation of similar but not identical agents. These are called biosimilars in Europe or follow-on biologics in the United States [29]. Among the biosimilars for anemia, there are already three approved agents: HX575, XM01 (in reality, this agent is an original if one follows its clinical development), and SB309. All these agents receive different trade names in occasions with the same agent. For instance, HX575 has been registered with three different names: Binocrit (Sandoz, Princeton, NJ, USA), Epoetina Hexal (Hexal Biotech, Germany), and Abseamed (Medice Arzneimittel Putter, Germany). Another biosimilar, SB309, has been registered as epoetin zeta, and its trade names are Silapo (STADA, Bad Vilbel, Germany) and Retacrit (Hospira, Warwickshire, UK). The third biosimilar for anemia is epoetin theta. In fact, this agent is an original but generally is included in the biosimilar list, probably owing to the timing of its introduction to the market, the same as the real biosimilars. Its trade name is Eporatio (Ratiopharm-TEVA, Ulm, Germany) [29].

ESAs should be given to patients with chemotherapy-induced anemia to reduce blood transfusions and to increase quality of life. ESAs should not be given when there are other treatable causes of anemia, such as iron deficiency anemia or vitamin deficiencies. ESAs should not be given in radiotherapy when this treatment option is the only anticancer treatment or in anemia associated with cancer in the absence of any active anticancer treatment.

15.2.3 Iron

It is well known that ESAs have a response rate that is suboptimal, ranging from 55 to 74% in most published clinical trials [30]. Several explanations have been found, but in general it is accepted mostly due to functional iron deficiency. The remarkable improvement in the response rate observed with the concomitant administration of intravenous iron to ESAs strongly suggests this possibility. Functional iron deficiency (i.e., lack of bioavailable iron) is a clinical entity where erythropoiesis is impaired owing in part to the sequestration of iron [31] by the macrophages and a blockage of enteral iron absorption mostly mediated by hepcidin [31]. In other words, oral iron is poorly absorbed or not absorbed at all, and bone marrow iron, although present in the bone marrow, is not available to the making of red blood cells. Parenteral iron therapy has subsequently become an important adjunct to obtaining and maintaining adequate Hb levels in patients with cancer who are receiving chemotherapy. However, despite the good results observed with parenteral iron, many oncologists are still reluctant to use it because of the poor safety profile observed in the past with the old iron preparations, particularly high-molecular-weight dextran (HMWD). The new intravenous preparations (ferric gluconate, ferric carboxymaltose, iron isomaltoside, iron sucrose) show not only a much better safety profile but a much easier administration.

Over the last few years, nine studies on the use of intravenous iron supplementation have been conducted and their results published. In all cases, intravenous iron was delivered concomitantly with ESAs in the treatment of anemia secondary to chemotherapy [32,33,34,35,36,37,38]. Except in one study, the study by Steensma et al. [39], all others were favorable to the arm of intravenous iron. In this study, the authors compared parenteral, oral, or no iron supplementation in patients with chemotherapy-associated anemia treated with darbepoetin alfa [39]. Interestingly, the results contrast with the other six other publications [32,33,34,35,36,37,38] and two reported clinical trials [40, 41] on the benefits of supplementing iron intravenously in patients receiving a concomitant ESA. It is tempting to posit some potential explanations. The first likely explanation is that the total administered dose of iron seems to be low, approximately 650 mg total [42], compared to the Bastit study [35], which is very similar in design to the Steensma study [39]. In the former, the total iron dose delivered was 400 mg higher [42]. This fact has to do with the design of this study, which planned a total iron dose of 937.5 mg iron, which represents the second lowest dose of iron among the published trials (750–3000 mg). Furthermore, it would be the lowest dose when calculated on a weekly basis (62.5 mg/week). This, by itself, may have limited the potential benefit of intravenous iron supplementation in this particular study.

According to some authors [42, 43], the lack of response to intravenous ferric gluconate in the Steensma study [39] may be attributed to a suboptimal dosing regimen (i.e., a very low average dose but too high single doses) and a high proportion of dropouts rather than a lack of intravenous iron efficacy. In this regard, it is interesting to analyze the results from two recent meta-analyses that confirm the superiority of parenteral intravenous iron over oral or no iron supplementation in terms of better hematopoietic responses and a reduction in blood transfusions [44, 45]. These two meta-analyses had already included data of this trial as presented by Steensma et al. at the 2009 American Society of Hematology (ASH) Congress [46].

Many physicians are still reluctant to incorporate routine use of intravenous iron, largely because of poor understanding and misconceptions of the clinical nature of adverse events reportedly in the past. All of these adverse events were associated with the administration of HMW intravenous iron dextran. Because of that, parenteral iron is therefore underused in oncology patients with anemia. A large body of clinical evidence, with more than 1000 patients evaluated in clinical trials involving the use of intravenous iron, demonstrates an excellent safety profile and a substantial benefit with the new intravenous iron preparations. Interestingly, recently a few publications have reported that intravenous iron sucrose alone was given to patients with gynecological cancer who were receiving chemotherapy; these patients achieved a higher Hb and hematocrit than the control group [47] and had less transfusion requirements [48] and achieved correction of the anemia with ferric carboxymaltose alone [49]. Further research is required to elucidate a future role for intravenous iron in the management of chemotherapy-induced anemia in cancer patients.

15.3 Side Effects of the Treatments of Anemia

15.3.1 Red Blood Cell Transfusions

Red blood cell transfusions are safer than ever. However, complications from blood transfusions still remain a major concern: infections (viral, bacterial contamination), acute and delayed hemolytic reactions, and acute lung injury are among the most frequent complications. Therefore, blood transfusions are reserved for critical situations but not for mild to moderate degrees of anemia [50]. Recently, some alarm signals have appeared with the use of red blood cell transfusions related to their storage time at the blood bank. Several publications, mainly in the fields of intensive care, cardiology, and trauma, have reported on these complications [51,52,53]. Most results imply the development of severe complications when blood is older than 2 weeks (see Table 15.3) [56, 57].

Table 15.3 Red blood cell transfusions: risks of complications
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Modified from Goodnough et al. [54] and Klein et al. [55]

References [50,51,52]

15.3.2 Erythropoiesis-Stimulating Agents

Over the last 10 years, more than 15,000 patients have participated in clinical trials with different ESAs. The massive clinical experience with these agents has demonstrated that they are well tolerated and safe if used according to registry. Efficacy has been proven in several randomized, placebo-controlled trials [58,59,60,61,62]. These agents decrease the number of blood transfusions and improve the quality of life. All data have been collected and summarized in meta-analysis [63, 64].

15.3.3 Pure Red Cell Anemia

A potential adverse event in the administration of biopharmaceuticals, due to their molecular complexity and their laborious fabrication, is immunogenicity, the possibility of inducing antibody formation. This was the case with epoetin alfa (during the years 1998 and 2003). Only chronic renal patients receiving epoetin alfa were affected [65]. No oncology patients were reported. The condition is called pure red cell anemia (PRCA), and it is caused by antibodies against endogenous erythropoietin. As expected, this medical condition results in no available erythropoietin, associated with severe anemia. The clinical course of antibody-mediated anemia is characterized by a sudden fall in hemoglobin concentration despite ESA therapy, with reticulocyte counts declining to very low levels < 20 × 109/L. Affected patients, due to the severity of the anemia, rapidly become transfusion dependent. A bone marrow aspiration shows the absence or near absence of erythroid progenitor cells. The confirmation of PRCA is the detection in the serum of these patients of neutralizing antibodies that not only neutralize the biological activity of the exogenous ESA but also endogenous erythropoietin, thus preventing red cell production in the bone marrow.

PRCA related to ESA therapy is a very rare medical entity, with an exposure-adjusted incidence of 0.02–0.03 per 10,000 patient-years [66]. The peak incidence of PRCA related to ESA therapy occurred during 2002 and 2003, following the report of few cases of chronic renal patients [67]. The cause of this disease has remained elusive, although several factors are believed to have been implicated [65]. The initial most obvious cause was the removal of human serum albumin (HSA) from the epoetin alfa preparation (Eprex, Janssen-Ortho, Toronto, Canada), which was a requirement by the European authorities due to the concern about the transmission of Creutzfeldt-Jakob disease (prions). HSA was replaced by polysorbate 80, and it was initially thought that this vehicle itself might be involved in PRCA development. Another hypothesis is the so-called rubber leachates. The company had introduced a preloaded syringe with a rubber stop. It was not until after the company replaced the rubber stop with one made of Teflon that the cases began to decrease. A third hypothesis, very plausible at the time, was that it was due to a break in the cold storage chain, which rendered the protein molecule less stable. This fact leads to conformational changes in the tertiary structure of the molecule that was the ultimate cause for its immunogenicity. In total more than 200 cases were reported.

15.3.4 Thromboembolic Events

The use of ESAs has been associated with a higher incidence of thromboembolic events (TEs). In general there is an increased risk of around 1.5–3% [68, 69]. A recent meta-analysis of all randomized, controlled studies of epoetin beta (n = 12) [70] evaluated the impact of therapy at different hemoglobin-initiation levels and to different target Hb levels on overall survival, tumor progression, and TEs. An analysis of risk factors predisposing patients to TEs under epoetin beta therapy was also performed. A total of 2297 patients were included in the analysis. The study showed a significantly increased TE rate with epoetin beta compared with control (0.22 events/patient-year vs. 0.14 events/patient-year) and an increased risk of TEs with this agent. These results are consistent with those reported by the meta-analyses of the Cochrane Collaboration [68, 69]. Subgroup analyses based on hemoglobin-initiation level indicate a correlation between hemoglobin-initiation level and risk of TE. This increased TE risk is seen in all of these agents, and it is adequately reflected in the product labeling for all approved ESAs. Among the several risk factors shown for TEs, the most relevant include increasing age (>65), prolonged immobility, malignant disease, multiple trauma, major surgery, previous venous TE, and chronic heart failure [71]. Another meta-analysis to evaluate venous TEs associated with ESA administration reviewed 38 trials including 8172 patients and found a risk rate of 1.57 (CI 95% of 1.31–1.87) [69]. A study-level and patient-level meta-analysis on the benefits and risks of using ESAs in lung cancer patients reported a 10.5% for darbepoetin alfa versus 7.2% for the placebo arm. The study evaluated 9 (n = 9) trials with a total of 2342 patients [70]. A recent publication reported an association between RBC and platelet transfusions and an increased risk of TEs and mortality in cancer patients [72]. Interestingly, another recent publication by Fujisaka et al. [73], treating 186 patients with cancer receiving epoetin beta 36,000 IU or placebo weekly for 12 weeks according to the European regulation, showed no significant differences in adverse events; the incidence of TE was 1.1% in both groups. One has to be careful with these data owing to the low number of patients included in this study. A provocative explanation for the high risk for thrombocytosis and venous thromboembolism in cancer patients with chemotherapy-induced anemia has been given recently by Henry et al. [74]. These authors suggest that these events may be related to ESA-induced iron-restricted erythropoiesis, which, interestingly, is reversed by intravenous administration of iron.

Finally, it is worth noting the results of a prospective, multicenter observational study of venous TE in cancer patients receiving chemotherapy. It was observed that those patients with platelet counts ≥350,000/mm3 were associated with a higher incidence of thrombosis independent of recombinant EPO therapy [75]. These results suggest that a high prechemotherapy platelet count could be a marker to identify patients at risk for venous thrombosis (Table 15.4) [75].

Table 15.4 Adverse effects associated with erythropoiesis-stimulating agents
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15.3.5 Increased Mortality

In the early 2000s, two publications reported positive clinical outcomes in cancer patients receiving epoetins treated with chemotherapy. One clinical trial used epoetin alfa and the other used darbepoetin alfa; both were compared to a placebo arm [3, 61]. Although both trials did not have survival as an end point, both were highly favorable to the ESA arm in terms of survival. This fact reinforced many old theoretical arguments of the past that suggested that ESAs, by correcting the anemia, would improve tissue oxygenation. As a consequence, tumor tissues would be rendered more sensitive to cancer treatments: radiotherapy and chemotherapy. The follow-up of this rationale was that by maintaining higher Hb levels (higher oxygenation) during the course of the cancer treatment, one should expect better outcomes. This situation led to a series of clinical trials aimed not only at the correction of the anemia but to its prevention. Unfortunately, many of the trials were poorly designed, and soon some of these newly designed clinical trials were showing, unexpectedly, better outcomes in the placebo arm. In particular, the results of two of them showed, for the first time, an association between erythropoietin treatment and increased mortality [76, 77]. The results raised concerns about the safety of ESAs when targeting high Hb levels (13–14 g/dL or higher). A critical analysis of these publications [76, 77] presents serious methodological limitations. The first was an off-label use of epoetin beta using only radiotherapy for head and neck cancer achieving Hb levels of 14–15.5 g/dL and higher, and the second was an anemia-prevention study, also an off-label use, with epoetin alfa in breast cancer patients. The design of these two clinical trials could have confounded the results and probably influenced the conclusions [78, 79]. In addition, three more studies have been recently published that report a detrimental impact of ESA treatment on survival [80,81,82]. Many interpretations of these unexpected findings [83, 84] suggest that increased mortality may be because of a higher risk of TEs with the use of ESA therapy. These agents used off label may have caused blood hyperviscosity due to the high hematocrits achieved. Another explanation, very popular until recently, has been that ESAs may promote tumor growth through erythropoietin receptor (EpoR) activation and/or stimulation of angiogenesis [85,86,87,88]. This issue has been and still is very controversial due to the detection by some authors [86] of EpoRs on the surface of cancer cells using an anti-EpoR polyclonal antibody (A-20). Some recent publications argue against the validity of these data. One report suggested that the polyclonal antibody (A-20) recognizes heat shock protein-70 (HSP-70) and not the real EpoR. The same authors have identified some genetic homologies between the two molecules [89]. The same authors have published the results on a KO mouse, for EpoR shows staining with the polyclonal antibody A-20 in both the KO mouse and in the control, which clearly suggests nonspecific binding of A-20 [89]. More recently, a monoclonal antibody against the EpoR (A82) [90] has failed to identify any EpoR in 67 human cell lines of different tumor pathologies [91] and in 182 fresh human tissue samples from different patients with different types of cancer [92].

In the last 7 years, there have been an important number of trials on ESAs in cancer patients with a variety of outcomes. As a consequence, several meta-analyses have been performed to bring some light to the field. A meta-analysis published by Bohlius et al. [69] collected the data of 57 trials and 9353 cancer patients. The analysis included randomized, controlled clinical trials on treatment as well as on prophylaxis (off-label) and in cancer patients with anemia without concurrent anticancer treatment (off-label). The effect on overall survival gave an HR of 1.08 (95% CI, 0.99–1.18). In 2009, an individual patient-based meta-analysis was published by Bohlius et al. [63]. The number of patients analyzed was 13,933 from 53 trials. The final outcomes on overall survival resulted in a worse outcome for the patients enrolled in the ESA group (HR, 1.06, 95% CI, 1.00–1.12). On-study mortality HR for the total group of patients was 1.17 (95% CI, 1.06–1.30). Interestingly, for the 10,441 patients who received only chemotherapy, the HR for overall survival was 1.04 (95% CI, 0.97–1.11). In their publication, the authors state that ESAs are safe for chemotherapy-induced anemia. Six other meta-analyses have been performed: five showing a neutral effect of the ESA group (no significant effect on overall survival) [64, 93,94,95,96] and one [97] showing a worse overall survival in the group who received ESA.

Ross et al. analyzed 21,378 patients from 49 studies and found no differences in TEs or mortality between the ESA arm and the control arm [93]. Aapro et al. [94] analyzed 1413 patients from 8 studies (epoetin beta, n = 800; control, n = 613). There was a significantly reduced risk of rapidly progressive disease for epoetin beta (RR 0.78; 95% CI, 0.62, 0.99; P = 0.042). Glaspy et al. [64] evaluated 15,323 cancer patients with anemia receiving chemotherapy/radiotherapy, radiotherapy-only treatment, or anemia of cancer receiving no treatment from 60 studies. Results indicated that ESA use did not significantly affect mortality (60 studies, OR = 1.06; 95% CI, 0.97–1.15) or disease progression (26 studies: OR = 1.01; 95% CI, 0.90–1.14).

In a pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa, Ludwig et al. [95] found that this agent did not increase mortality and affected neither progression-free survival nor disease progression. Overall survival and progression-free survival seemed to be better in those patients who achieved Hb >12 or >13 g/dL as compared with those who did not [95]. The same authors investigated the effect of blood transfusions on rates of Hb increase. In the absence of transfusions, the percentage of patients with >1 g/dL in 14 days or >2 g/dL in 28 days increase in Hb was 68.8% for darbepoetin alfa and 52.3% for placebo or 39.1% for darbepoetin alfa and 19.2% for placebo, respectively. Interestingly, the results show that an increase of 1 or 2 g/dL in Hb levels resulting from blood transfusions was associated with an increased risk of death and disease progression. Furthermore, when blood transfusions were excluded from the analysis, the increase in Hb rates was not associated with an increased risk for disease progression or death. In summary, blood transfusions were associated with a greater risk for disease progression and death in both treatment arms and with a greater risk for embolism/thrombosis in the darbepoetin-alfa arm.

More recently, Aapro et al. reported results of an updated meta-analysis of 12 randomized, controlled studies of epoetin beta conducted in 2301 patients undergoing cancer therapy [96], including three recently completed trials with longer-term follow-up in patients with head and neck cancer [76], patients with metastatic breast cancer [98], and patients with cervical cancer [99]. The results of this meta-analysis based on individual patient-level data showed no statistically significant difference between patients receiving epoetin beta and standard treatment in terms of overall survival. In fact, the authors describe a favorable trend with respect to the risk of disease progression for patients receiving this agent [96]. Bennett et al. [97] reported a meta-analysis of phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer. A total of 13,611 patients included in 51 clinical trials were evaluated for survival. Patients with cancer who received ESAs had increased mortality risks (HR = 1.10, 95% CI, 1.01–1.20) than the placebo or the standard of care arm.

Interestingly, over the last few years, several studies have been reported with a major aim being the safety of ESAs. Results show either a neutral clinical outcome or a beneficial one [19, 73, 100,101,102,103,104,105].

In any event, a major consequence of the safety concerns raised by some studies on ESAs in the treatment of cancer-induced anemia has been the requirement, by the European regulatory authorities, to introduce a warning on the product labels for marketed ESAs to be restricted to a hemoglobin-initiation level <10 g/dL and a Hb target not to exceed 12 g/dL. However, the updated EORTC treatment guidelines recommend the initiation of ESA therapy at Hb levels between 9 and 11 g/dL and the target for treatment with ESAs to achieve a Hb level of ∼12 g/dL [106]. ASCO guidelines recommend the initiation of ESA therapy at Hb level < 10 g/dL and to use ESA to achieve the lowest Hb concentration needed to avoid transfusions [22]. ESMO guidelines also recommend starting ESAs at Hb ≤ 10 g/dL and Hb target not to exceed 12 g/dL (see Table 15.4) [25].

Further research is required to elucidate these still unanswered issues regarding the safety of ESAs for correction of chemotherapy-induced anemia. Two large, multicenter clinical trials with a major aim in survival were initiated few years ago: one in breast cancer using epoetin alfa and the other in lung cancer using darbepoetin alfa. The results from the former were recently published [107]. Interestingly, the primary end point, PFS based on investigator-determined PD, did not meet noninferiority criteria. However, the PFS based on independent review committee-determined PD met noninferiority criteria. For the clinical point of view, the results will not impact in clinical practice. The study in lung cancer is still ongoing until the patient recruitment goal is achieved.

15.3.6 Iron

The old preparations of intravenous iron, particularly high-molecular-weight dextran (HMWD), presented serious adverse effects ranging from allergies to anaphylactic reactions. This is the reason why many oncologists currently are reluctant to use it. The poor safety profile observed in the past with the old iron preparations was well documented. The new intravenous preparations (ferric gluconate, ferric carboxymaltose, iron isomaltoside, iron sucrose) show not only a much better safety profile but a much easier administration. Adverse effects are related to non-transferrin-bound iron (NTBI): toxicity occurs from the release of weakly bound iron. This is what occurred with the old preparations such as HMWD; the new preparations have a very strong iron-binding capacity that translates into much less free iron, the critical point for the serious events of the past, in particular anaphylaxis. The most common adverse effects of the new preparations are back pain, dyspnea, and hypotension [39]. Other adverse effects associated with intravenous iron in the past (e.g., myalgia, pruritus, rash) were not more common than with oral iron or placebo.

In nine published randomized trials, there was no difference in adverse events in the intravenous iron group compared with the no iron or oral iron groups [32,33,34,35,36,37,38,39]. There was no evidence for (1) increased risk of infection, (2) increase in cardiovascular morbidity, or (3) increase in tumor incidence or progression. The incidence of life-threatening adverse events with intravenous iron was <1:700,000 when high MW iron dextran was avoided [108].

Recently, a new preparation of oral iron has been approved (Sucrosomial Iron®)—it is a preparation of ferric pyrophosphate covered by phospholipids plus sucrose esters of fatty acid matrix This allows the molecule to be absorbed by the gastrointestinal tract independently of hepcidin and as such to get absorbed by cancer patients. Since it is a sort of liposomal iron, this does not causes the common side effects associated to oral iron. A recent publication [109] shows that Sucrosomial Iron® (Sideral®) is significantly more bioavailable than microencapsulated ferric pyrophosphate ingredients, Lipofer® and Sunactive®, and ferrous sulfate in a Caco-2 cell model.