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Published on 2 November 2009

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The use of erythropoiesis stimulating agents in oncology

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Treating cancer patients with ESAs has been questioned because of data linking their use to adverse events. However, further research may prove them beneficial if guidelines are followed closely

Jim Janinis
MD

Director, Department of
Medical Oncology
Athens Medical Center
Athens, Greece

Anaemia is common in patients with malignancy and a frequent complication of the disease itself, as well as of the myelosuppressive chemotherapy delivered to treat it. It is estimated that more than 80% of cancer patients undergoing chemotherapy develop anaemia, with haemoglobin (Hb) levels <12 g/dl, requiring treatment.[1] Anaemia can impair the patient’s functional status, diminish physiologic reserve and cause fatigue that can be disabling. In addition to causing symptoms, the presence of anaemia has been associated with an adverse prognosis in several malignancies.

These observations have provided additional rationale for aggressively treating anaemia in patients receiving cancer therapy. Definitive therapy requires eradication of the underlying malignancy but, in many cases, this is not possible and short-term red blood cell (RBC) transfusion is needed in to provide symptomatic relief. However potential complications, such as transmission of infectious diseases and transfusion reactions, prompted the use of erythropoiesis stimulating agents (ESAs) as a safer alternative.

Erythropoiesis stimulating agent
The ESAs erythropoietin alfa (EPO) and darbepoetin alfa are widely used to treat anaemia in patients with cancer. These drugs received approval for cancer indications from the US Food and Drug Administration (FDA) in 1993 and 2002, respectively. In Europe the EMEA approved ESAs for cisplatin-related anaemia in 1994. In the early 2000s, ESAs were approved for all chemotherapy-related anaemia.

Multiple studies and subsequent meta-analyses have demonstrated that treatment with ESAs increases Hb levels and reduces the proportion of patients receiving red blood cell transfusions in cancer patients receiving chemotherapy.[2],[3] In one systematic review, data from a total of 9,353 cancer patients with breast, lung, and gastrointestinal tract malignancies, were used.[2] Treatment with epoetin (synthetic erythropoietin) or darbepoetin significantly reduced the need for transfusion (relative risk, 0.64; 95% confidence interval, 0.60-0.68), and the chance of achieving a haematologic response was consistent across tumour types. Patients treated with an ESA received one unit less of red blood cells on average than the control group. In an earlier meta-analysis of 22 trials, a statistically significant improvement in QOL was observed when the mean pretreatment HGB level was ≤ 10 g/dL.[3]

Data under scrutiny
Recently the use of ESAs has been questioned, because of data linking their use to an excess of venous thromboembolic events (VTE), inferior survival, and worse cancer outcomes (higher rates of locoregional failure), particularly when used in patients whose anaemia is unrelated to chemotherapy and in those receiving myelosuppressive chemotherapy with the intent of cure. Three large meta-analyses of 51-53 randomised trials have reported worsened health outcomes associated with the use of ESAs.4-6. In these meta-analyses VTE risk was increased by about 50-70% and mortality by 10-17% in patients receiving ESAs compared to placebo. In the most recent of these reports the researchers analysed individual data from 13,933 cancer patients participating in 53 trials, and found that ESAs increased the relative risk for mortality by 17%.[6] However, when they considered only cancer patients who were undergoing chemotherapy (10,441 patients in 38 trials), they found that ESAs increased the relative risk of on-study mortality by 10% with a Hazard Ratio (HR) of 1.10 (95% confidence interval 0.98-1.24), a difference which was not statistically significant.

Adverse effects
The reasons for poorer outcomes with ESA treatment are under intense scrutiny. The documented increased incidence of VTEs in most studies is regarded as a very likely cause of morbidity and increased mortality. Interestingly, most studies included in the metaanalyses were not following current recommendations and guidelines on the use of ESAs. Baseline Hb levelsat initiation of ESA treatment as well as target Hb levels in many studies were considerably higher than current recommendations. In many studies off-label use of ESAs in non-chemotherapy related anaemia impacted negatively on survival. These observations are further supported by the Paladini et al meta-analysis (17 studies with 3,788 patients), which assessed the safety of ESAs when used according to label indications, in patients with chemotherapy-induced anaemia (instead of cancer-induced anaemia) with an Hb level <11 g/dl. In that meta-analysis, there was no difference in the mortality rate associated with the use of ESAs (relative risk, 0.95; 95% CI, 0.88–1.03; p =0.22), and the authors concluded that, when ESAs are used as indicated on the label, they are not associated with a higher mortality risk.[7]

Tumour cell receptors
Another proposed potential mechanism – to explain higher rates of locoregional failure, more rapid disease progression and shortened survival following treatment with ESAs – is the presence of erythropoietin receptors (EPO-Rs) on the surface of tumour cells. A number of tumours have been reported to possess cell surface EPO-Rs; these may promote angiogenesis,
tumour growth, and/or tumour cell survival. However, it is questionable whether EPO-Rs on tumour cells are functional and there is no evidence that ESAs (within the approved indication in patients receiving chemotherapy) can stimulate EPO-Rs on tumour cells in vivo.

Warnings and guidelines
Increased worldwide awareness regarding the potential adverse effects linked to the use of ESAs prompted the international regulatory authorities, FDA and EMEA, as well as major oncology groups – American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), European Organisation for Research and Treatment of Cancer (EORTC) – to issue warnings and clinical practice guidelines on the proper use of ESAs in cancer patients with anaemia. These recommendation can be summerised as follows:

  • Treatment with ESAs should be initiated when Hb levels are <10 g/dL, in order to increase and maintain steady state Hb levels and avoid packed RBC transfusions.
  • In case of less severe anaemia (Hb <12 and >10 g/dL), whether to initiate ESA treatment or to wait until Hb levels fall closer to 10 g/dL should be determined by clinical circumstances, such as presence of significant symptoms thought to be caused by the anaemia.
  • Target Hb levels should not exceed 12 g/dL, or should be maintained at such a level in order to avoid transfusions.
  • ESAs should not be preferred over transfusionsfor the management of anaemia caused bymyelosuppressive chemotherapy when there is areasonably long life-expectancy or the treatment goal is cure.
  • ESAs are contraindicated for the treatment of nonchemotherapy related anaemia of malignancy.

Further investigations
Treatment with ESAs is effective in producing a haematopoietic response, in reducing transfusion requirements and improving quality of life in patients with chemotherapy related anaemia. There is a favourable risk–benefit ratio associated with ESAs when used for labelled indications. It is believed that more controlled use of ESAs in line with current label guidance – using the lowest ESA dose needed to avoid RBC transfusion, avoiding high Hb target level, using ESAs only for treatment of anaemia resulting from concomitant myelosuppressive chemotherapy – will prove to be beneficial for management of chemotherapy-induced anaemia. However, there is need to investigate further the risk-benefit ratio of ESAs in this category with adequately- powered, well-designed trials that can detect differences in tumour response or survival in patients prescribed ESA to lessen the need for transfusion secondary to myelosuppressive chemotherapy.

References
1. Ludwig H, Van Belle S, Barrett-Lee P et al. The European Cancer Anaemia Survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence and treatment of anaemia in cancer patients. Eur J Cancer 2004; 40:2293–2306.
2. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006;98(10):708–14.
3. Seidenfeld J, Piper M, Flamm C, et al. Epoetin treatment of anaemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials. J Natl Cancer Inst 2001;93(16):1204–14.
4. Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anaemia. JAMA 2008;299(8):914–24.
5. Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms of erythropoiesis-stimulating agents for anaemia related to cancer: a meta-analysis. CMAJ 2009;180(11):62–71.
6. Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 2009;373(9674):1532–42.
7. Paladini L, Clark O, Clark L, et al. Erythropoiesis stimulating agents (ESA) for the treatment of chemotherapy induced anaemia in patients with hemoglobin levels (Hb)<11 g/dl—a systematic review and meta-analysis. Blood 2008;112:Abstract1305



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