Management of Anemia in Cancer Patients

Aknar Calabrich; Artur Katz

Disclosures

Future Oncol. 2011;7(4):507-517. 

In This Article

Erythropoiesis-stimulating Agents

Initially, ESAs were used to correct anemia in patients with chronic renal failure. Three agents, epoetin-α, epoetin-β and darbepoetin-α, have demonstrated similar efficacy and display similar limitations, and the available data suggest that these agents are safe when used in agreement with current recommendations.[10] Several studies have also demonstrated the benefit of these agents in patients with cancer.[11] These trials have demonstrated that the use of recombinant human EPO to treat anemia in cancer patients increases hemoglobin levels, reduces transfusion requirements and improves QOL, predominantly by reducing fatigue.[12] Moreover, EPO therapy may also improve cognitive function in patients receiving chemotherapy.[13] However, clinical data indicate that more than 50% of anemic cancer patients are not treated.[14]

Despite the benefits resulting from the use of ESAs in anemic cancer patients, in the current medical community, there is a question about the safety of these agents because some recent studies have demonstrated a negative impact on cancer control and survival. A recent review, based on several published Phase III studies and a meta-analysis, has demonstrated an enhanced risk of venous thromboembolism and a reduced survival in anemic cancer patients treated with ESAs.[15] However, there is great variability in therapeutic goals and in the characteristics of patients who undergo treatment with ESAs; therefore, careful analysis of the currently available data on the efficacy and safety of these agents is required.[16]

Without doubt, ESAs are capable of increasing hemoglobin levels in most anemic patients with cancer.[17–20] A systematic review of 57 studies and a total of 9353 patients with cancer has demonstrated that treatment with ESAs reduced the need for blood transfusion by 36% and increased the rate of hematological response, defined as hemoglobin increases of more than 2 g/dl, when compared with no treatment with ESAs.[21] With regard to improvements in QOL, the results were somewhat controversial. However, a systematic review has evaluated the different agents that are available for the treatment of cancer-related fatigue. The analysis of ten studies with EPO, involving 2226 patients with cancer receiving chemotherapy and with hemoglobin levels of less than 12 g/dl, has demonstrated a significant reduction in symptoms of fatigue related to cancer (p = 0.008). The same improvement in fatigue was demonstrated with the use of darbepoetin, compared with placebo, in four studies totaling 964 patients (p = 0.05).[22]

Littlewood and colleagues have assessed the response to EPO in patients with hematological malignancies.[23] Cancer patients with anemia undergoing non-platinum-based chemotherapy who were enrolled in a multinational, double-blind, randomized, placebo-controlled trial were prospectively stratified with respect to tumor type (hematological or solid tumors). The mean increase in hemoglobin levels among patients with hematological malignancies was greater with EPO than with placebo treatment (2.2 vs 0.3 g/dl). Patients treated with EPO had improved QOL, while patients treated with placebo had decreased QOL. Even though the study had not been powered for survival, statistical estimates demonstrated a trend in overall survival favoring EPO in the full study cohort and in the hematological malignancy subgroup. In another study, Osterborg and colleagues have investigated the effect of EPO in severely anemic patients with chronic lymphocytic leukemia (n = 126), low-grade non-Hodgkin's lymphoma (n = 106) and multiple myeloma (n = 117).[24] Transfusion-free survival (p = 0.0012) and transfusion- and severe anemia-free survival (p = 0.0001), response rate (p < 0.0001) and QOL (p < 0.05) were significantly greater in the EPO group were compared with placebo. The observed improvement in QOL was correlated with an increase in hemoglobin concentrations of greater than or equal to 2 g/dl. ESAs were able to improve anemia-related outcomes in breast cancer patients receiving chemotherapy in a randomized trial that included women with hemoglobin levels of less than or equal to 12 g/dl.[25]

The risks of death and thromboembolic events (TEs) have been evaluated in a meta-analysis published by Bennett and colleagues in 2008.[26] A total of 13,611 patients from 51 Phase III studies were analyzed for survival and 8172 patients from 38 studies were evaluated for the risk of TEs. The meta-analysis has demonstrated an increased risk of TEs, with a relative risk (RR) of 1.57 (95% CI: 1.31–1.87), and an overall increased risk of death, with a hazard ratio (HR) of 1.10 (95% CI: 1.01–1.20; p = 0.03). However, there was no statistically significant increase in mortality when the analysis was restricted to patients who were undergoing active treatment with chemotherapy or radiotherapy (HR: 1.09; 95% CI: 0.99–1.19). Eight studies, which were identified in security alerts from the US FDA, have individually demonstrated an increase in the rate of progression and death associated with the use of ESAs, but all of these studies aimed to maintain normal hemoglobin levels of at least 13 g/dl.[27–33,102] Some data suggest that the higher the levels of hemoglobin, the greater the chances of TEs and hypertension.[34,35] It is important to mention that none of these studies were adequately powered to specifically address this question, and in most studies, all that was observed were safety signals that could suggest the occurrence of potentially harmful adverse events. A recent systematic review of published and unpublished randomized controlled trials that assessed mortality, cardiovascular events, hypertension, blood transfusions, QOL, tumor response and serious adverse events identified 52 trials that enrolled a total of 12,006 patients.[36] According to this review, the pooled all-cause mortality during treatment was significantly higher in the ESA group when compared with the control group (RR: 1.15; 95% CI: 1.03–1.29). The use of ESAs was also related to an increased risk of TEs (RR: 1.69; 95% CI: 1.27–2.24) and serious adverse events (RR: 1.16; 95% CI: 1.08–1.25). The authors suggested that ESAs should not be used routinely as a substitute to blood transfusion in patients with anemia related to cancer.

The largest meta-analysis of individual patient data was published in 2009 and assessed a total of 13,933 patients from 53 studies.[37,38] The use of ESAs was associated with an increased risk of death during the active period of the study (HR: 1.17; 95% CI: 1.06–1.30; p = 0.003) and an increased overall mortality (HR: 1.06; 95% CI: 1.00–1.12; p = 0.046). When 38 studies that only enrolled patients receiving chemotherapy were analyzed, there was a relative increase in mortality of 10%, but that increase was not statistically significant (p = 0.12). It is worth emphasizing that the study that contributed nearly 20% of the statistical weight evaluated the use of EPO in women with breast cancer, aiming to maintain hemoglobin levels between 12 and 14 g/dl. When this study was excluded from the analysis, the risk of death with ESAs was no longer significant (HR: 1.03; 95% CI: 0.90–1.18). Another important finding was the demonstration of the correlation between the risk of death and baseline hemoglobin. Patients with baseline hemoglobin of less than or equal to 10 g/dl had no increase in mortality with treatment with ESAs, unlike those with higher baseline hemoglobin levels.

To date, there has been no study demonstrating an increased mortality when the target hemoglobin levels during treatment with ESAs were less than 12 g/dl in patients receiving anticancer treatment. The studies that have demonstrated increased mortality with the use of ESAs used higher baseline hemoglobin levels, higher doses of EPO or darbepoetin or higher targets for hemoglobin values in comparison with those recommended by international consensus and approved by the FDA. In a meta-analysis of 12 studies and 2297 patients, subjects with baseline hemoglobin levels of less than or equal to 11 g/dl had no increased risk of death when treated with EPO in comparison with those receiving placebo.[35] Similarly, a Brazilian study, presented at the 2008 meeting of the American Society of Hematology (ASH), evaluated mortality exclusively in cancer patients receiving chemotherapy for whom treatment with an ESAs was indicated when the hemoglobin level was lower than 11 g/dl.[39] In total, the 17 studies analyzed included 3788 patients with such characteristics and found no increase in the risk of death associated with ESA treatments (RR: 0.95; p = 0.22). Similarly, when the cutoff value of hemoglobin was reduced to 10 g/dl, capable results were demonstrated (RR: 0.97; p = 0.52).[39]

Although some studies and one meta-analysis have suggested that ESAs may negatively affect survival and disease control in patients with cancer, a recent meta-analysis of individual patient data from darbepoetin studies has been conducted.[40] Data from a total of 2122 patients enrolled in randomized, double-blind, placebo-controlled trials comparing darbepoetin-α (n = 1200) with placebo (n = 912) were pooled for analysis. This meta-analysis has demonstrated that, when the approved indication for darbepoetin-α in cancer treatment is followed, there is no association between the use of this agent and risk of disease progression or death.[40] Moreover, a recent study of cervical cancer has demonstrated no positive correlation between hemoglobin increases and clinical outcomes.[41] In this study, patients received radiochemotherapy and were randomized to EPO at 150 IU/kg three times a week (n = 34) or standard care (control; n = 40) for up to 12 weeks. Median baseline hemoglobin was 11.4 g/dl for the EPO group and 11.6 g/dl in the control group. At the end of the study, median hemoglobin increased by 1.3 g/dl with EPO and decreased by 0.7 g/dl in the control group (p < 0.0001). This analysis of clinical outcomes suggested no significant correlation between hemoglobin increases and anticancer treatment failure. In addition, there were no differences between EPO and control groups in progression- or relapse-free survival (p = 0.96), overall survival (p = 0.22) or complete response rates (p = 0.86).[41] At present, there are no persuasive data to support a significant impact on overall survival or mortality for cancer patients receiving ESAs within guidelines and labeling. Nevertheless, based on the currently existing data, the use of ESAs has to be considered carefully, taking into account any possible increase in risk of mortality.[42]

The use of ESAs should be discouraged in cancer patients who are not undergoing treatment with chemotherapy or radiotherapy. This recommendation is based primarily on a large, randomized, Phase III, double-blind study in which 989 patients with various nonmyeloid malignancies and anemia were randomized to darbepoetin or placebo for 16 weeks. All patients had hemoglobin levels of less than or equal to 11 g/dl, and none of them were receiving chemotherapy or radiotherapy. The primary objective – the reduction in the incidence of a first blood transfusion – was not achieved (19 vs 24% in the placebo group; p = 0.07), and there was an increase in adverse cardiovascular events and TEs, as well as in mortality.[31]

Bokemeyer and colleagues have performed a systematic literature review on the use of EPO in patients with cancer to create the European Organisation for Research and Treatment of Cancer (EORTC) evidence-based guidelines.[34] A total of 3 years later, the same authors published an update based on further accumulated evidence.[43] They confirmed the recommendation that treatment with ESAs in cancer patients receiving chemotherapy or radiotherapy should be initiated at a hemoglobin level of 9–11 g/dl based on symptoms related to anemia, rather than on predetermined hemoglobin concentrations. When the hemoglobin level is less than 9 g/dl, the patient should first be evaluated for the need for blood transfusions, potentially followed by ESA administration. The prophylactic use of EPO to prevent anemia was not recommended in patients who have normal hemoglobin levels and are undergoing chemotherapy or radiotherapy. Moreover, the use of higher than standard initial doses of ESAs to produce higher hematological responses was not recommended. A more recent meta-analysis of 12 randomized controlled studies has indicated that when ESAs are used within EORTC guidelines, it has no negative impact on the incidence of TEs, rate of tumor progression or duration of survival.[35] Another recent review has also found that when ESAs are used as indicated, they are valuable and safe drugs for the treatment of anemia in cancer patients.[44]

Based on the results of several studies, guidelines have defined the criteria to be used in selecting cancer patients for treatment with ESAs. Table 2 summarizes recommendations for the use of ESAs according to different organizations. Based on the recommendations set forth by the ASH and the American Society of Clinical Oncology (ASCO),[45] as well as the data discussed previously, both EPO and darbepoetin are indicated for the treatment of anemia in patients with nonmyeloid malignancies in whom anemia is related to chemotherapy. Treatment should be initiated when hemoglobin levels are lower than 10 g/dl. The dose should be reduced if there is an increase in hemoglobin level by 1 g/dl in 2 weeks. Hemoglobin should be increased to the lowest concentration needed to avoid transfusion. Treatment should also be discontinued if no response (increase in hemoglobin levels by 1–2 g/dl) is achieved after 6–8 weeks of treatment. All other causes of anemia should be investigated and corrected prior to the use of an ESA. Cancer patients with anemia not receiving chemotherapy should not be treated with ESAs. For patients with nonmyeloid malignancies who are undergoing chemotherapy with the goal of cure, the use of ESAs is controversial and should be evaluated with caution. Moreover, a review of 11 studies has suggested that the best clinical gain from EPO treatment of chemotherapy-induced anemia may be achieved through early intervention, as there was a reduction in the risk of both transfusions and hemoglobin levels falling to less than 10 g/dl with early intervention when compared with late use of ESAs.[46]

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