Should the ASCO/ASH Guidelines for the Use of Intravenous Iron in Cancer- and Chemotherapy-Induced Anemia Be Updated?

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  • a From Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; and Georgetown University School of Medicine, Washington, DC.

Coadministration of intravenous (IV) iron improves responses to erythropoiesis-stimulating agents (ESAs) in the treatment of cancer-associated (CAA) and chemotherapy-induced anemia (CIA). Twelve prospective studies have demonstrated synergy between parenteral iron and ESAs, with variable degrees of improved hemoglobin (Hgb) response rates, shorter times to target Hgb levels, and a lower ESA dose required for equivalent Hgb responses. Clinically significant adverse events (AEs) with currently available IV iron products are uncommon. Pretreatment serum hepcidin levels may predict response magnitude. Safety concerns among many oncologists are driven by reports of serious AEs from older IV iron formulations that are no longer available, and misinterpretation of the nature and frequency of minor infusion reactions. Premedication with antihistamines is of unproven benefit and can cause symptoms that mimic anaphylaxis, prompting intervention with vasopressors and converting self-limited reactions into hemodynamically significant AEs. Payer rules proscribing the administration of ESAs and IV iron on the same day also have limited the clinical adoption of IV iron and ESA coadministration. At a time when financial resources are scarce, the ability to reduce use of costly ESAs is beneficial. Despite a favorable risk/benefit ratio for IV iron in CAA and CIA, current IV iron recommendations in guidelines from ASCO/ASH, NCCN, and ESMO are inconsistent. The authors believe more routine use of IV iron for CAA and CIA is appropriate in view of existing evidence, and suggest reconsideration of the current ASCO/ASH guidelines, which state “there is insufficient evidence to consider the use of intravenous iron as a standard of care.”

More than a decade has passed since Auerbach et al1 presented the first study demonstrating synergy of intravenous (IV) iron with erythropoiesis-stimulating agents (ESAs) for correcting anemia in patients receiving chemotherapy for malignant disease. Subsequent to that presentation, 11 other prospective randomized trials (Table 1), which collectively enrolled more than 1500 patients with either chemotherapy-induced (CIA) or cancer-associated anemia (CAA), yielded similar results. Adverse events (AEs) associated with the IV iron preparations used in these trials were uncommon and serious AEs (SAEs) were rare.

However, despite the apparent favorable risk/benefit ratio for IV iron in most patients with CIA or CAA, the most current version of the ASCO/ASH Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin in Adult Patients With Cancer, published in late 2010, states that “there is insufficient evidence to consider the use of intravenous iron as a standard of care.”13 NCCN, in contrast, recommends consideration of IV iron with erythropoietic therapy when iron is indicated for “functional iron deficiency,” a state in which total body iron stores are normal or elevated, but bioavailable iron is inadequate to maintain erythropoiesis. Although several definitions of functional iron deficiency have been proposed, it is classified by NCCN when the serum ferritin level is between 30 and 800 ng/mL and transferrin saturation (TSAT) is between 20% and 50%; NCCN states that in these circumstances, “IV iron has superior efficacy and should be considered for supplementation. Oral iron has been more commonly used but is less effective.”3 Meanwhile, the European Society of Medical Oncology considers the use of IV iron in conjunction with ESAs to be a clinical practice with grade A, level I evidence (ie, from meta-analysis or high-quality randomized, controlled trials), but does not suggest specific ferritin or TSAT levels for treatment initiation.15

Table 1

Intravenous Iron Studies

Table 1

The ASCO/ASH guidelines for treatment of CIA and CAA are of special interest in light of the February 2008 Centers for Medicare & Medicaid Services (CMS) guidance for ESA use, which was issued as a result of 8 controlled studies that showed poorer outcomes in patients with cancer treated with ESAs compared with ESA-unexposed controls. Four of these studies targeted hemoglobin (Hgb) levels of 13 or greater, and the other half studied levels of 12 g/dL or greater, which are greater than those of existing recommendations. A patient-level meta-analysis of 13,933 patients with CIA/CAA in 53 ESA studies16 showed increased mortality and disease progression with ESA use during the on-study period, but no statistically significant difference in overall survival at the latest available follow-up with ESAs compared with controls. In comparison, subsequent meta-analysis of randomized prospective studies in advanced lung cancers17 and 2 large randomized prospective trials in adjuvant dose-dense chemotherapy for breast cancer with a Hgb target of 12.0 to 13.0 g/dL showed no increase in mortality or disease progression.18,19 Nevertheless, current ESA labels and clinical guidelines are more conservative than those of a decade ago, and recommend avoidance of ESAs when cure is a goal, delay of therapy until the Hgb level is less than 10 g/dL, and cessation of therapy when Hgb is greater than that level. This article attempts to summarize the existing data regarding the concomitant role of IV iron in CIA and CAA to support a recommendation for a change in the ASCO/ASH guidelines.

Seven IV iron formulations have been approved in the United States, Canada, Europe, Asia, and South America (Table 2), including high-molecular-weight iron dextran (HMW ID), low-molecular-weight (LMW) ID, ferric gluconate, iron sucrose, and 3 newer formulations: ferumoxytol, ferric carboxymaltose, and iron isomaltoside, which features tighter elemental iron binding to novel carbohydrate cores and can be administered as a full, or near-full, replacement dose in only 15 minutes. Because the preponderance of published literature reports that HMW ID is associated with a significantly higher incidence of AEs and SAEs compared with other preparations, this preparation is not discussed further.20

The first prospective study demonstrating synergy of IV iron with ESAs in CIA was presented at the December 2002 ASH annual meeting and published in the Journal of Clinical Oncology in 2004.1 Some observers criticized the eligibility criteria for this trial, stating that patients who had not just functional iron deficiency but true total-body iron deficiency were also treated. Enrollment required a serum ferritin level of less than 200 ng/mL or less than 300 ng/mL, with a TSAT of less than 19%. Nonetheless, the mean serum ferritin level across the 4 arms of the study was greater than 200 ng/mL. Subjects were required to be actively receiving chemotherapy and anemic, and were randomized to 40,000 U/wk of epoetin alfa subcutaneously with or without oral iron, with IV LMW ID as a 100-mg bolus to a calculated deficit, or with the same dose administered as a single total dose infusion. The results of this prospective, randomized, multicenter trial of 157 patients revealed a greater than 3-fold benefit of IV iron plus ESA over ESA alone or ESA with oral iron in Hgb increment. The method of administration of IV iron, via total dose infusion or multiple infusions, made no difference in rate of response.

To address the criticisms of the first trial, Henry et al2 performed a prospective study that used more restrictive entrance criteria. In this open-label, multicenter, randomized trial, 187 patients with CIA were required to have a serum ferritin level greater than 100 ng/mL and a TSAT greater than 15%. Consistent with the previous study, epoetin alfa was administered as 40,000 U/wk subcutaneously, either alone or with either 125 mg IV ferric gluconate once weekly for 8 weeks or with oral ferrous sulfate 3 times daily. It should be noted that the 2 iron salts, ferric gluconate and iron sucrose (not used in this study), should not be administered in single doses of greater than 200 or 300 mg, respectively, because of a high incidence of vasoactive infusion reactions, ostensibly because of free-iron release from the less tightly binding carbohydrate carriers.21 In the efficacy analysis, the mean increase in Hgb was 2.4 g/dL for those who received IV iron compared with 1.6 g/dL with oral iron and 1.5 g/dL with no iron. These results, with a reported 93.3% adherence to oral iron, corroborated the first published conclusions that IV and not oral iron is necessary to optimize responses to ESAs (P=.0099 for ferric gluconate vs oral iron and P=.0029 for ferric gluconate vs no iron).

Despite the evidence from these 2 prospective randomized trials, erythropoiesis experts still believed a large percentage of those who received iron in these studies were overtly iron-deficient rather than functionally iron-deficient. Additional studies with stricter inclusion criteria were designed to address these concerns.

Table 2

List of Intravenous Iron Preparations

Table 2

Hedenus et al3 randomized 67 patients with anemia and a history of lymphoproliferative malignancy not on chemotherapy to receive either epoetin beta alone or 100 mg of iron sucrose weekly on the same day. If hyporesponsiveness to therapy was observed (defined as a failure to demonstrate a Hgb increment of >1 g/dL after 4 weeks), the dose of epoetin was doubled from 30,000 U to 60,000 U. Uniquely among studies to date, a positive hemosiderin stain (stainable iron after Perls’ Prussian blue reaction of a marrow aspiration sample), which is the gold standard definition of iron repletion, within 1 month of trial enrollment was an entrance criterion. No baseline differences in iron parameters were present among the 2 groups. A statistically significant increment in Hgb levels was noted in the IV iron group compared with the no-iron group, and no difference in AEs was seen between arms. Pedrazzoli et al5 prospectively evaluated 149 patients on chemotherapy for lung, gynecologic, breast, and colorectal cancers, who were treated at 33 different institutions. The entrance criteria included both a serum ferritin level greater than 100 ng/mL and TSAT greater than 20%, and those with ferritin levels greater than 800 ng/mL or TSATs greater than 40% were excluded. Patients were randomized to darbepoetin alfa (DA) alone or with 125 mg of IV ferric gluconate weekly. Statistically significant Hgb increments and fewer dose escalations were observed in the IV iron group compared with the no-iron group, and the authors concluded that, in those with CIA and no iron deficiency, IV iron still reduces DA failures. An interesting observation in this Italian trial was that nonresponders at 4 weeks in the DA/iron arm were far more likely (P=.0199) to respond to a subsequent doubling of DA (68.2% vs 32.0%).

In the same issue of Journal of Clinical Oncology that the Pedrazzoli et al5 study appeared in, Bastit et al4 reported the first prospective study examining IV iron’s synergy with ESAs that was powered to show a difference in red blood cell transfusions during CIA. The investigators randomized 396 patients with nonmyeloid malignancies to either DA alone or with IV iron administered as 200 mg of either iron sucrose or ferric gluconate every 3 weeks. Absolute iron deficiency (ferritin <10 ng/mL and TSAT <15%) and iron overload (ferritin >800 ng/mL) were exclusion criteria. Supporting previously published evidence, the DA/IV iron arm was associated with an increased hematopoietic response. However, unique to this trial, a statistically significant reduction in red blood cell transfusions (9 vs 20; P=.005) was observed. Considering the cost of transfusions and ESAs at the time of the publication, the routine use of IV iron saved more than $1300 per patient per 12-week period.

Despite published evidence supporting the safety, efficacy, and ease of administration of IV iron when added to the treatment paradigm of CIA or CAA, safety concerns have lingered. Some investigators have expressed concern that IV iron may contribute to long-term toxicity, similar to that seen in patients with hereditary hemochromatosis, by causing free radical-induced DNA damage by Fenton chemistry. Although none of the IV iron studies reviewed earlier had long-term cancer outcomes as a primary end point, post hoc analyses uncovered no differences in response rate1 or oncologic outcomes.2 At the 2008 ASH annual meeting, Beguin et al22 shared results from 127 patients with lymphoproliferative malignancies who underwent autologous bone marrow transplants and remained anemic. Subjects were randomized to ESA alone or with IV iron. Consistent with the other published evidence, a clear improvement in Hgb response was observed, as was a 50% reduction in transfusion, in the IV iron/ESA group. However, unlike the other studies, the investigators followed subjects for an additional 5 years and noted no differences in survival or increases in relapse in the IV iron-treated group. Although this was one of the smaller IV iron studies, it is the one that followed patients the longest.

Two studies have examined IV iron administration without ESAs in patients with gynecologic malignancies undergoing chemoradiation therapy. In the first of these, Kim et al9 randomized 75 patients to IV iron alone or no treatment and observed a 24% transfusion decrement in the IV iron arm compared with no treatment. In the second, Dangsuwan and Manchana10 randomized previously transfused patients to oral or IV iron, again without ESAs. Consistent with the results of the first study, a decrement in transfusions from 63.6% to 22.7% was observed in the IV iron group. The fact that transfusion requirements were decreased in these 2 trials supports the use of IV iron for CIA, even without ESAs. These results were corroborated in a recent publication by Steinmetz et al8 using the new preparation ferric carboxymaltose. Although the FDA-approved labeled indication for this formulation is 750 mg administered over 15 minutes, the investigators administered ferric carboxymaltose at a median dose of 1000 mg over 15 minutes, and noted a substantial Hgb increase and stabilization to the 11 to 12 g/dL range without ESAs. Furthermore, supporting the results of the other investigators, these benefits occurred irrespective of baseline iron parameters, whether iron replete, iron deficient, or in the zone where functional iron deficiency is possible but true iron deficiency unlikely.

To examine the effect of IV iron supplementation with up-front DA dosing, Auerbach et al6 randomized 237 patients to either 300 or 500 mcg of DA every 3 weeks (double-blind), with or without 2000 mg of LMW ID administered as 400 mg IV every 3 weeks with the DA dose (open-label). Strikingly, the higher dose of DA alone resulted in only a marginal benefit, whereas, irrespective of DA dose, the addition of IV iron decreased time to target Hgb and improved responses. A reported result of this trial that could potentially extrapolate to huge cost savings in the management of CIA was that studied subjects in the 500 mcg DA alone arm had responses of lower magnitude than those who received 300 mcg plus IV iron. This outcome was not routinely addressed in most of the reported CIA trials. At first glance this finding may appear contradictory to the those of Pedrazzoli et al,5 who reported that high doses of ESA up-front did not produce the same effect as high doses of ESA at day 42 (6 weeks). However, in the Auerbach trial, both doses of ESA were used upfront with or without IV iron.6 IV iron proved to be the driving force for increased response, corroborating the data from the trial by Pedrazzoli et al.5

Examining a different model of IV iron synergy, Anthony et al11 evaluated whether IV iron added to ESAs could restore responsiveness in established ESA snonresponders. Both responders and nonresponders were then randomized to continue ESAs alone or with 1500 mg of iron sucrose. Both IV responders and nonresponders had statistically significantly increased Hgb responses compared with the ESA-alone group.

The only prospective study thus far that did not show a statistically significant benefit with IV iron in ESA synergy was presented at the 2009 ASH annual meeting and published in the Journal of Clinical Oncology in 2011.23 This was a cooperative group study (Mayo Clinic Cancer Research Consortium) of 502 patients with CIA who were randomized to either DA with IV ferric gluconate, oral ferrous sulfate, or oral placebo. The oral placebo was included to compare the AE profile of oral iron supplementation with IV and no iron. At entry, no baseline differences were seen in Hgb or iron parameters. Unique to all other studies, pretreatment and posttreatment hepcidin levels were measured. After a 16-week study period, no differences were observed in Hgb or hematopoietic response, DA dose, or quality of life parameters (measured using validated tools) among those who received IV iron compared with the other groups. A small but statistically significant increase in minor reactions was noted in the IV iron arm, but this may have been from premedication with diphenhydramine, given at the discretion of the investigators, before the IV iron infusion.

The investigators, in a preplanned analysis, then stratified the intention-to-treat arm of the IV iron group into those who received at least 80% of the planned dose versus those who received less, and created a second stratification based on pretreatment serum hepcidin levels.12 Consistent with all of the other studies, a hematopoietic response of 80% was achieved among patients in the IV iron group who actually received most or all of the preplanned dose, compared with 56% in those who did not receive IV iron. Oral iron added nothing to DA alone. A novel finding from this study was that low pretreatment hepcidin levels were associated with an erythropoietic response of 92% to 95%, compared with 69% among patients with high pretreatment hepcidin levels. Furthermore, those with low hepcidin levels who received IV iron received no allogeneic blood, whereas transfusions were required in all of the other groups.

IV iron administration may also have a salutary effect on the incidence of venous thromboembolism, a highly significant AE routinely seen with ESAs. Two publications note that thrombocytosis associated with ESA therapy is modulated by iron supply. Loo and Beguin24 noted a statistically significant reduction in platelet counts in rats administered IV iron with ESAs compared with ESAs alone, and concluded that the effect of recombinant human erythropoietin on platelet counts is strongly modulated by the adequacy of iron supply. More recently, in a post hoc exploratory analysis of their prospective study showing synergy of ferric gluconate with ESA in iron-replete patients with CIA, Henry et al25 noted a reduction in platelet counts and venous thromboembolic events in the IV iron-treated group.

Two meta-analyses examining the role of IV iron as part of the paradigm for CIA have been published. In 2012, Petrelli et al26 performed a meta-analysis on 1606 patients included in 8 trials. They assessed IV iron in conjunction with ESAs. A relative risk (RR) of hematopoietic response (defined as an Hgb level increase by ≥2 g/dL or an increase >12 g/dL) of 1.29 (P=.0001) with IV iron and 1.04 (P=.59) for oral iron, compared with no iron, was reported. The transfusion rate was reduced with IV iron versus no iron (RR, 0.77; P=.02) but not with oral iron (RR, 0.68; P=.08). The time to reach hematopoietic responses was 1 month shorter in the IV iron arm, and no increased toxicity was seen with iron supplementation via either route. The investigators concluded that overall IV iron reduces risk of transfusions by 23% and increases the chance of hematopoietic response by 29% when compared with ESAs alone. Conversely, they noted that oral iron does not increase hematopoietic response or decrease the transfusion rate.

In the second meta-analysis, Gafter-Gvili et al27 noted that current guidelines are inconclusive regarding IV iron in the treatment of CIA. This meta-analysis involved 1681 patients included in 11 trials, most of which examined the addition of IV iron to ESAs (1562 patients; 92.9%), but trials without ESAs were also included. Consistent with other reports, the investigators concluded that IV iron significantly increased hematopoietic response (RR, 1.28; 95% CI, 1.125-1.45; Figure 1) and decreased transfusions in trials with ESAs (RR, 0.76; 95% CI, 0.61-0.95) and those without (RR, 0.52; 95% CI, 0.34-0.80). A novel finding in this analysis was that the increase in hematopoietic response was correlated with cumulative IV iron dose, irrespective of baseline iron status, supporting the conclusions of the prospective studies. In addition, in the IV iron arm, a significant increase was seen in the number of patients showing improvement on quality of life scales for cancer (RR, 1.25; 95% CI, 1.05, 1.49). Another important finding was no observed difference in the occurrence of thromboembolic events (RR, 1.03; 95% CI, 0.59, 1.80). No difference in mortality or AEs was noted.

With such compelling data, it is reasonable to explore reasons for widespread reluctance to incorporate IV iron as a standard in the treatment paradigm for CIA and CAA. Unlike patients with pregnancy, heavy uterine bleeding, hereditary hemorrhagic telangiectasias, inflammatory bowel disease, or severe malabsorption, in whom a single IV iron infusion markedly simplifies care, the frequent necessary visits of patients with CIA and CAA to the infusion centers during chemotherapy allow virtually any schedule of administration to be practical. Therefore, concerns about safety, and not convenience, are likely primarily responsible for the failure to use a modality that has been shown to be safe and effective. In more than 2000 patients in the 12 reported trials, only 1 SAE was observed in 1 of 2 patients who received HMW ID during a short period in 1997 when LMW ID was not available.1 The other formulations are associated only with extremely rare SAEs, and in all head-to-head comparisons and intrainstitutional retrospective analyses no significant difference in efficacy or safety has been observed.

Another possible explanation may be the misinterpretation and misinformation concerning the nature and frequency of minor infusion reactions.19 Because antihistamines are sometimes used as premedication before the administration of IV iron preparations, adverse reactions from antihistamines may be misattributed to IV iron. Diphenhydramine can potentiate hypotension, somnolence, tachycardia, and diaphoresis, mimicking anaphylaxis and prompting intervention with more antihistamines, fluid challenge, and other medications, including vasopressors, converting a self-limited event during IV iron administration to a hemodynamically significant SAE. What is important to note, and not widely disseminated, is that all of the IV iron formulations may be infrequently associated with the acute onset of chest and back tightness without signs of true allergic reaction (tachypnea, tachycardia, hypotension, wheezing, stridor, or periorbital edema). These reactions abate without therapy and rarely recur with rechallenge. They are more frequent in those with an allergic diathesis (>1 drug allergy or asthma), in which case premedication with methylprednisolone may decrease the frequency. A few patients may experience self-limited arthralgias and myalgias the day after the infusion, both of which abate within 24 hours without therapy. Adding anti-inflammatory drugs may shorten their duration.28

Figure 1
Figure 1

Intravenous iron versus standard of care. Rate of patients who achieved a hematopoietic response.26 Black squares represent the point estimate, their sizes represent their weight in the pooled analysis, and the horizontal bars represent the 95% CI. The black diamond at the bottom represents the pooled point estimate.

Abbreviations: IV, intravenous; RR, relative risk; STD, standard.

From Anat Gafter-Gvili, Benaya Rozen-Zvi, Liat Vidal, et al. Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia - systematic review and meta-analysis of randomised controlled trials. Acta Oncol 2013;52:25, ©2013. Reproduced with permission of Informa Healthcare.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 5; 10.6004/jnccn.2014.0069

A third possibility behind the reluctance to use IV iron is concern about reimbursement. CMS rules have to date disallowed payment for IV iron co-administered on the same day as an ESA to avoid wasteful administration of ESAs to truly iron-deficient patients unlikely to experience a response to ESA therapy. These outdated rules must continue to be challenged, but the frequency with which most patients in oncology practice are seen in the clinic means that IV iron can, in most cases, be given on a different day and that practices will not lose money on this infusion.

In summary, at a time when resources are scarce and expensive therapy such as with ESAs can be substantially improved by adding much less expensive IV iron preparations, which in 12 studies have consistently improved Hgb responsiveness, decreased time to therapeutic target, and reduced cost without causing additional AEs, the authors believe that IV iron should be added to the standard paradigm for management of CIA and CAA, and that the current ASCO/ASH guideline stating that “there is insufficient evidence to recommend the routine use of intravenous iron for chemotherapy induced anemia” should be revisited. Although no negative long-term safety signals with IV iron have been reported in any population, it is reasonable to administer IV iron when cure is not possible, palliation takes precedence over cure, and long-term safety with IV iron with or without ESAs may be of less concern. When absolute iron deficiency coexists with settings in which cure is a goal, the decision to use IV iron must be individualized.

Dr. Steensma has disclosed that he has participated in a data safety monitoring committee for an Amgen study of darbepoetin in myelodysplastic syndromes, and is on the advisory board for Novartis. Drs. Gafter-Gvili and Auerbach have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

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Correspondence: Michael Auerbach, MD, Georgetown University School of Medicine, 5233 King Avenue #308, Baltimore, MD 21237. E-mail: mauerbachmd@abhemonc.com
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    Intravenous iron versus standard of care. Rate of patients who achieved a hematopoietic response.26 Black squares represent the point estimate, their sizes represent their weight in the pooled analysis, and the horizontal bars represent the 95% CI. The black diamond at the bottom represents the pooled point estimate.

    Abbreviations: IV, intravenous; RR, relative risk; STD, standard.

    From Anat Gafter-Gvili, Benaya Rozen-Zvi, Liat Vidal, et al. Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia - systematic review and meta-analysis of randomised controlled trials. Acta Oncol 2013;52:25, ©2013. Reproduced with permission of Informa Healthcare.

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