Introduction

Chemotherapy induced alterations on  bone marrow function, including myelosuppression, anemia, and thrombocytopenia, continue to be the most common side effects of cancer treatment and also occur as a byproduct of the cancer or disease state itself. This year’s American society of Clinical Oncology (ASCO) meeting included a number of studies in the supportive care of bone marrow suppression which may lead to clinical practice changes.

Treatment of Chemotherapy Induced Anemia

Erythropoietic stimulating agents (ESAs) have been much in the news lately, driven by reports of lack of efficacy in non-approved settings such as anemia of cancer and potential safety signals proposed by recent clinical trials and some biological experiments.  There is concern that targeting higher hemoglobin levels may increase the risk of recurrence in patients with head and neck cancers,[1] non-small cell lung cancer[2] and breast cancer.[3],[4] There is much debate on both sides of the topic, with consideration being given to changes in the labeling and federal reimbursement strategies[5]. 

However, several facts are clear:  1) ESAs are safe when used in chemotherapy-induced anemia (CIA) as per the FDA label and NCCN / ASCO guidelines.  Several meta-analyses show no evidence that survival is compromised by ESAs. There is a 1.4-1.5 relative risk of thromboembolic events for CIA patients treated with ESAs across studies.  2) ESAs are effective at reducing transfusion requirements and improving quality of life in CIA.  An average 50% reduction in transfusions are shown across studies and multiple measures of quality of life, including FACT-F and LASA scores, demonstrate statistically and clinically improvements in fatigue and sense of well being.  3) Earlier usage of ESAs in CIA, (starting at hemoglobin levels of < 11 g/dL) rather than waiting until hemoglobin levels fall lower reduce the risk of transfusion and improve quality of life.  4) There is no convincing in vitro evidence that tumors with putative erythropoietin receptors are stimulated with pharmacologic doses of erythropoietin to increase tumor growth or reduce survival.  Nonetheless, many questions remain regarding the optimal usage of these agents in cancer related anemia. There were many presentations at ASCO 2007 which addressed several of these issues.

Prediction of First Cycle Chemotherapy-Induced Anemia

Researchers from Spain affiliated with the DELFOS study identified male gender, platinum-based chemotherapy and high baseline bilirubin levels as predictors for first cycle chemotherapy-induced anemia in patient with solid tumors.[6] They also reported that baseline hemoglobin values were inversely related to toxicity.

Effects of Erythropoietins on Outcomes of Patients with Localized Breast Cancer

The recent US Food and Drug Administration (FDA) ODAC meeting in May 2007 reviewed evidence which suggested that targeting high hemoglobin levels may increase relapses of some cancers and increase the incidence of clotting in patients treated with ESPs. The FDA cited data from a study carried out in Europe and Canada which reported that women with metastatic breast cancer who receive epoetin alfa to maintain hemoglobin levels between 12 and 14 g/dL have a decreased survival compared to control patients. This has prompted researchers to revaluate studies of erythropoietins in women with various stages of breast cancer. Researchers affiliated with CALGB have reported that the dose-dense adjuvant regimen ETC (epirubicin, paclitaxel, cyclophosphamide) supported by epoetin alfa significantly reduces the number of red blood cell infusions, prevents anemia and does not increase relapses or affect overall survival.[7] This study involved over 1,200 women who were randomly allocated to receive dose-dense ETC versus a standard sequential regimen of EC followed by T.

The 658 patients in the dose-dense ETC arm of the study were randomly allocated to receive epoetin alfa or no epoetin alfa. Transfusions were administered to 28% of the dose-dense ETC control patients compared to 13% of the epoetin alfa group. Hemoglobin levels in the epoetin alfa group were maintained at 12.4 g/dL while the control group had average hemoglobin levels of 10.7 g/dL despite receiving more blood transfusions. At a median follow-up of 62 months, the five year disease-free survival (DFS) was 71% for the control arm and 72% for the epoetin alfa arm while overall survival (OS) was 83% for the control arm and 83% for the epoetin alfa arm. These authors concluded that “the prevention of anemia has no influence on DFS and OS in the adjuvant treatment of breast cancer with dose-dense ETC.” These data strongly support other observations that epoetin alfa decreases transfusion requirements without increasing the relapse rate or increasing the rate of deaths from VTE in women with localized breast cancer.

Effects of Erythropoietins on Venous Thromboembolism

Venous thromboembolism due to erythropoietins is difficult to evaluate as there is an increased incidence in cancer patients not receiving erythropoietins. However, the higher mortality rates of erythropoietin treated patients reported in some studies could be due to an increased incidence of VTE. Researchers affiliated with the Research on Adverse Drug Events and Reports (RADAR) project reported data at ASCO 2007 based on various metanalyses of clinical trials of various erythropoietins (epoetin alfa and beta and darbepoetin alfa) on the risk of VTE.[8] These studies concluded that the relative risk of VTEs for patients taking epoetin alfa, epoetin beta or darbepoetin alfa ranged from 1.2 to 1.8. These studies included 2 Cochrane reports, an FDA study, and pharmaceutical reports from Amgen, Johnson&Johnson/Ortho, and Roche. This study did not address mortality associated with VTE. No new safety signals for overall mortality were noted.

Effects of Intravenous Iron Supplementation on Response to Erythropoietins

It is well established that not all patients treated with ESAs have a hematopoietic response to therapy and there is room for improvement in the delivery of these drugs.  One potential reason relates to iron incorporation into hemoglobin in patients with cancer.  Growing evidence suggests that many patients with CIA have a functional iron deficiency.  Previous studies have demonstrated that the addition of intravenous iron along with erythropoietin can improve the erythropoietic response as well as the proportion of responders.  Additional evidence supporting the practice of intravenous iron comes from three moderately sized randomized trials reported at ASCO this year.

An interim analysis of a European randomized trial presented at ASCO 2006 concluded that the combination of darbepoetin alfa and intravenous iron (ferrous gluconate) may increase the proportion of patients with chemotherapy-induced anemia who achieve target hemoglobin levels, and decrease the proportion of patients requiring a blood transfusion.[9] This study was based on the results in 196 patients. At ASCO 2007, these same investigators reported the outcomes of 396 patients in this same study. Patients were randomly allocated to receive darbepoetin alfa 500 mcg every three weeks with either intravenous iron (200 mcg every three weeks on the same schedule as darbepoetin alfa, or, if required, as two doses (200 mcg total) within a three-week period) or with iron administered according to standard practice (oral iron or no iron).[10]

Outcomes were assessed between week five and the end of treatment and results were compared in two groups of patients: those with a hemoglobin of <10 and those with an initial hemoglobin >10 g/dL at baseline. Target hemoglobin level was 11 g/dL.

Table 1. No or Oral Iron versus IV iron in patients with a baseline hemoglobin <10 g/dL

Adapted from Burnell, et al¹⁹

Table 2. No or Oral Iron versus IV iron in patients with a baseline hemoglobin =10 g/dL

Adapted from Burnell, et al¹⁹

These authors concluded that IV iron improved clinical outcomes, especially in patients with a baseline hemoglobin <10 g/dL. They suggest initiating darbepoetin alfa before the hemoglobin falls below 10 g/dL.

Researchers involved in a multicenter trial evaluated the addition of IV ferrous sucrose (Ferrlecit®) for the treatment of chemotherapy induced anemia.[11] This study enrolled 375 patients with hemoglobin levels <10 g/dL. This was a two phased study with patients being categorized as initial responders to darbepoetin alfa or epoetin alfa or deemed failures of therapy. Failures to initial treatment were then randomly allocated to receive further doses of darbepoetin alfa or epoetin alfa alone or with the addition of IV iron. These researchers reported that IV iron improved hemoglobin and fatigue responses compared to no iron. They also stated that baseline iron status did not predict response to IV iron therapy. These authors concluded that supplemental IV iron increased hemoglobin levels and improved iron stores in patients not responding to initial therapy with erythropoietins.

Researchers affiliated with the Ferrlecit Cancer Study Group reported quality of life measurements in patients with chemotherapy induced anemia who were randomly allocated to receive IV ferrous sucrose, oral iron or no iron supplementation in addition to epoetin alfa.[12] Patients receiving IV iron had a 2.4 g/dL increase in hemoglobin by the end of the study compared to 1.6 and 1.5 for oral and no iron, respectively. These authors reported that only patients receiving IV iron had significant improvements in quality of life scores. They concluded that the IV iron plus epoetin alfa was the only group with improved fatigue scores.

All of these studies showed similar effects – the use of IV iron increases the proportion of patients with hematopoietic responses, increases hemoglobin levels to higher levels and improves fatigue scores better than patients treated with no iron or oral iron.  Both iron sucrose and ferrous gluconate appeared effective and both offer the advantages of reduced risk of anaphylaxis compared to iron dextran, although the maximum dose of the formulations that can be delivered in one setting is limited. 

Importantly, no additional safety concerns were identified when IV iron was added to erythropoietin.  These studies also support the concept that oral iron achieves little or nothing and should not be recommended to improve efficacy and efficiency of ESAs.  Future trials could study reduced doses or longer interval between doses of ESAs in conjunction with IV iron. This study design could yield a combination regimen that is more cost effective and potentially safer, an attractive combination.