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Erythropoiesis-Stimulating Protein Support and Survival

Erythropoiesis-Stimulating Protein Support and Survival

ABSTRACT: Anemia is common in many patients with cancer treated with chemotherapy. One option for managing chemotherapy-induced anemia (CIA) is erythropoiesis-stimulating proteins (ESPs), which are indicated for the treatment of CIA in patients with most types of cancer. They have been shown to be safe and effective in numerous well-documented studies, and their side effects are well known. The rate of thrombotic events with the long-acting ESP darbepoetin alfa (Aranesp) has been consistent in studies conducted before and after its approval. The association of thrombotic events with high hemoglobin levels or rapid increases in its levels in patients with cancer remains controversial. Adjusting the dose of the ESP to maintain and monitor a target hemoglobin level of 11 to 12 g/dL is certainly prudent and may help prevent or minimize these events. Chemotherapy-induced anemia has been associated with shorter survival in patients with cancer, and the relation is likely multifactorial. Data on the treatment of CIA with ESPs have not shown a consistent effect on survival. Two studies in patients with hemoglobin levels above the target level showed that survival was shorter in the patients treated with ESPs. A review of data from other trials found no effect of ESPs on survival, and other trials suggested a positive effect. This article reviews data on survival in patients treated with ESPs and discusses five large randomized controlled trials of darbepoetin alfa that are addressing this issue.


Anemia is common in patients with cancer who are treated with chemotherapy.[1] In addition to the physical symptoms and the diminished quality of life in patients with anemia, there is also evidence that the greater tumor hypoxia due to anemia may result in a poorer response to chemotherapy. Anemia is a risk factor for early mortality in nearly all cancers in which it has been studied, with a hazard ratio (HR) of 1.65.[2] Several preclinical studies have found correlations between anemia, tumor oxygenation, tumor response, and survival.[3-5] Strategies to lessen chemotherapy-induced anemia (CIA) may not only alleviate anemia-related symptoms and improve quality of life, but also increase tumor responses and possibly increase survival. Erythropoiesis-stimulating proteins (ESPs) are indicated for the treatment of CIA in patients with most types of cancer.

The efficacy and safety of ESPs have been well studied, but there are questions about their association with thrombotic events and survival. An association of higher thrombotic rates with high hemoglobin (Hgb) levels or a rapid rise in Hgb level has been described in patients who undergo renal dialysis. This is implicated in the population of patients with cancer, in whom the thrombotic risk is increased by the cancer, its treatment, and comorbidities. In trials in patients with CIA treated with ESPs, the risk of thrombotic events was identified. These rates have remained consistent across preapproval and postapproval studies.

There has also been concern that treatment with ESPs may promote tumor growth, possibly owing to the greater delivery of oxygen to tumor cells as a result of higher Hgb levels.[6] The binding of ESPs to erythropoietin receptors may also promote the proliferation of endothelial cells, tumor angiogenesis, and vasculogenesis. Preclinical studies have reported high levels of erythropoietin and erythropoietin receptors in tumor cells. Erythropoiesis-stimulating proteins may directly promote tumor proliferation and survival of tumor cells that express erythropoietin receptors. Two clinical studies have shown lower survival in patients treated with ESPs,[7,8] but other data indicate that treatment with ESPs has either no effect or the possibility of a beneficial effect on survival.[9] To address the issue of ESP tumor-related stimulation, most studies have not shown a detrimental effect on tumor progression with treatment for anemia. In this article, I review data on survival in patients treated with ESPs and discuss five ongoing large randomized controlled trials that are investigating the association between treatment with ESPs and survival.


Lower Survival in Patients Treated with ESPs

Two studies have reported lower survival in patients with anemia treated with ESPs than in those treated with placebo[7,8]; both trials were terminated early for that reason. One of these trials[7] investigated the effect of the use of ESPs to maintain normal Hgb levels (> 12 g/dL and < 14 g/dL) on survival in 939 patients with metastatic breast cancer and Hgb levels of 13 g/dL. This trial was to have lasted 12 months, but it was terminated early because of early mortality, particularly in the first 4 months. Survival at 12 months was 6 percentage points higher with placebo than with epoetin alfa (Epogen) (76% vs 70%; P = .012). However, follow-up beyond the treatment period, at 19 months, showed convergence of the survival rates.

In an analysis of early death rates, there was a higher incidence of disease progression in the epoetin alfa group than in the placebo group (6% vs 3%) and a greater incidence of thrombotic and vascular events (1% vs 0.2%). However, time to disease progression was not different in the two groups. In addition, the results in this trial may not be conclusive because of imbalances between the epoetin alfa and placebo groups. Only the presence of metastases was stratified, and not at every study center. Characteristics such as prognostic factors, risk factors, age, performance status, extent of disease at study entry, and risk factors for thrombovascular events were not balanced in the two groups.

Another randomized, double-blind, placebo-controlled trial also found lower survival with ESPs than with placebo.[8] This study investigated whether treatment with epoetin beta could increase the control of cancer and survival in 351 patients with head and neck cancer. Treatment with epoetin beta did increase Hgb levels, but tumor control and survival were not greater. The Hgb levels were ≥ 14.5 g/dL in 82% of the patients treated with epoetin beta but in only 15% of those treated with placebo. Overall survival was significantly greater in patients treated with placebo than in those treated with epoetin beta (relative risk [RR] of death, 1.39; 95% confidence interval [CI] = 1.05-1.84; P = .02). Median progression-free survival was also significantly longer in those treated with placebo (745 vs 406 days; RR of progression-free survival, 1.62; P < .001). The high final Hgb levels in the patients treated with epoetin beta in this trial (mean, 15.4 g/dL) are a possible cause of the higher number of thrombovascular events, and they may have had a negative effect on the comorbidities as well.

In the updated meta-analysis by Bohlius and colleagues of 225 randomized controlled trials in 4,307 cancer patients receiving epoetin or darbepoetin, treatment with ESPs increased the risk of thromboembolic complications (RR, 1.67; 95% CI = 1.35-2.06).[9]


Survival Impact WithESP Treatment


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