Aim of the review

The aim of this assessment was to review and update research evidence as necessary to inform National Institute for Health and Care Excellence (NICE) guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of erythropoiesis-stimulating agents (ESAs) for the treatment of cancer treatment-induced anaemia (CIA) (see Current service provision).

The previous guidance [technology appraisal (TA)142¹] was primarily based on evidence presented to NICE in the assessment report by Wilson and colleagues.² We have incorporated relevant evidence presented in the previous report and report new evidence gathered since 2004.

Description of the health problem

Anaemia is defined as ‘a reduction of the haemoglobin (Hb) concentration, red blood cell (RBC) count, or packed cell volume below normal levels’ (p. v244).³ A commonly used classification of anaemia according to Hb level is shown in Table 1.³

TABLE 1

Classification of anaemia

It is the most frequent haematological manifestation in patients with cancer; > 50% of all cancer patients will be anaemic, regardless of the treatment received, and approximately 20% of all patients undergoing chemotherapy will require a red blood cell transfusion (RBCT).⁴

The cause of anaemia is usually multifactorial and may be patient, disease or treatment related.⁴ The haematological features in anaemic patients depend on the different types of malignant disease, stage and duration of the disease, the regimen and intensity of tumour therapy and possible intercurrent infections or surgical interventions. Tumour-associated factors, such as tumour bleeding, haemolysis and deficiency in folic acid and vitamin B₁₂, can be acute or chronic. In the advanced stages of haematological malignancy, bone marrow involvement often leads to progressive anaemia. In addition, interaction between tumour cell populations and the immune system can lead to the release of cytokines, especially interferon-gamma, interleukin-1 and tumour necrosis factor. This disrupts endogenous erythropoietin synthesis in the kidney and suppresses differentiation of erythroid precursor cells in the bone marrow. As a result, patients with tumour anaemia may have relatively low levels of erythropoietin for the grade of anaemia observed. Moreover, activation of macrophages can lead to a shorter erythrocyte half-life and a decrease in iron utilisation.

Chemotherapy may cause both transient and sustained anaemia.⁴ Mechanisms of drug-induced anaemia in patients with cancer include stem cell death, blockage or delay of haematopoietic factors, oxidant damage to mature haematopoietic cells, long-term myelodysplasia and immune-mediated haematopoietic cell destruction.⁴ Patients treated with platinum-based regimens develop anaemia most often and frequently need transfusions.⁴ As a consequence, dose-intensified regimens or shortened treatment intervals, as well as multimodal therapies, are associated with a higher degree of anaemia.⁴ Anaemia can also compromise the effect of treatment because low tissue oxygenation is associated with a reduced sensitivity of tumours to radiation and some forms of chemotherapy, contributing to the progression of cancer and reduction in survival.⁴

Among those patients with solid tumours, the incidence of anaemia is highest in patients with lung cancer (71%) or gynaecological cancer (65%); these patients have the highest frequency of anaemia and the highest rate of transfusion requirements.^4,5 The frequency of RBCT requirements in these patients varies from 47% to 100% depending on the cumulative dose of platinum chemotherapy received and other risk factors, for example age, disease stage and pretreatment Hb level. In haematological cancers, anaemia is an almost invariable feature of the disease.⁴ In addition, some of the newer chemotherapeutic agents, such as taxanes or vinorelbine, are strongly myelosuppressive and frequently cause anaemia.⁶

The clinical manifestation and severity of anaemia can vary considerably among individual patients.⁴ Mild-to-moderate anaemia can typically cause such symptoms as headache, palpitations, tachycardia and shortness of breath.⁴ Chronic anaemia can result in severe organ damage affecting the cardiovascular system, immune system, lungs, kidneys and the central nervous system.⁴ In addition to physical symptoms, the subjective impact of cancer-related anaemia on quality of life, mental health and social activities may be substantial.⁴ A common anaemia-related problem is fatigue, which impairs the patient’s ability to perform normal daily activities.⁴

Relationship between cancer treatment-induced anaemia and survival

Although the evidence is uncertain, some researchers hypothesise that anaemia in cancer patients is associated with a worse prognosis. According to Bohlius and colleagues,⁷ one explanation may be that, as a result of a low Hb level, the tumour cells become hypoxic and are subsequently less sensitive to cytotoxic drugs, in particular oxygen-dependent chemotherapies.^8–10 Evidence for this, as reported in the study by Tonia and colleagues,¹¹ exists in studies in which tumour control and overall survival (OS) are improved in solid tumour patients with better tumour oxygenation.^10,12 There is also the practical implication that severe anaemia may require a dose reduction or delay of chemotherapy, subsequently leading to a poorer outcome. It is therefore plausible that efforts taken to reduce anaemia may improve tumour response and OS.⁷ That said, it should be noted that Hb levels elevated to > 14 g/dl in women and > 15 g/dl in men are undesirable and may lead to increased viscosity, impaired tumour oxygenation and thromboembolic events.¹³

As an intervention used to increase Hb, and by association improve prognosis, some studies actually report a detrimental effect of ESAs on survival and tumour progression.^14–20 This effect is postulated to be caused by the presence of erythropoietin receptors on various cancers,^21–25 whereby the endogenously produced or exogenously administered erythropoietin promotes the proliferation and survival of erythropoietin receptor-expressing cancer cells.⁷ However, controversy about the functionality of these receptors remains^26–30 and several studies show no effect on tumour progression for patients receiving ESAs.^17,31–33

It should be noted that the majority of the studies examined in the systematic reviews by Bohlius and colleagues⁷ and Tonia and colleagues¹¹ used a wide range of administration frequencies and dosages of ESAs (generally exceeding the licence), which may result in an increase in adverse events (AEs) and mortality. This knowledge, along with the generally poor reporting and data omission on factors such as tumour stage and method of assessment, led to the conclusion by Tonia and colleagues¹¹ that no clear evidence was found to either exclude or prove a tumour-promoting effect of ESAs.

Current management

Erythropoietin-stimulating agents

Erythropoietin is an acidic glycoprotein hormone. Approximately 90% of the hormone is synthesised in the kidney and 10% is synthesised in the liver. Erythropoietin is responsible for regulating RBC production. Erythropoietin for clinical use is produced by recombinant DNA technology.¹

Exogenously administered erythropoietin is used to shorten the period of symptomatic anaemia in patients receiving cytotoxic chemotherapy. It is used in addition to, rather than as a complete replacement for, the existing treatments. Blood transfusion, in particular, may still be needed.¹

Marketing authorisations: haemoglobin levels

Initially, all ESAs were recommended for use at Hb levels of ≤ 11 g/dl, with target Hb levels not exceeding 13 g/dl. However, because of data showing a consistent, unexplained, excess mortality in cancer patients with anaemia treated with ESAs, a safety review of all available data on ESA treatment of patients with CIA was conducted in 2008 by the Pharmacovigilance Working Party at the request of the Committee for Medicinal Products for Human Use. As a result of this safety review, the European Medicines Agency (EMA) requested that the Summary of Product Characteristics (SPCs) for all ESAs be changed to highlight that ESAs should be used only if anaemia is associated with symptoms; to establish a uniform target Hb range for all ESAs; to mention the observed negative benefit risk balance in patients treated with high target Hb concentrations; and to include the relevant results of the trials triggering the safety review. SPCs for all ESAs were therefore revised in 2008 to decrease the Hb value for treatment initiation to ≤ 10 g/dl and to amend Hb treatment target values to 10–12 g/dl and Hb levels for stopping treatment to > 13 g/dl.

The EMA labels the use of ESAs as follows:

• in patients treated with chemotherapy and with a Hb level of ≤ 10 g/dl, treatment with ESAs might be considered to increase Hb (to within the target range of 10–12 g/dl) or to prevent further decline in Hb
• in patients not treated with chemotherapy, there is no indication for the use of ESAs and there might be an increased risk of death when ESAs are administered to a target Hb level of 12–14 g/dl
• in patients with curative intent, ESAs should be used with caution.

These changes to the licence (Table 2) were introduced subsequent to the previous NICE appraisal.

TABLE 2

Changes to marketing authorisations

Details of current licence recommendations are summarised in Table 3.

TABLE 3

Treatment recommendations according to licence

Current service provision

National Institute for Health and Care Excellence guidance (TA142)¹ currently recommends ESAs in combination with intravenous iron as an option for:

• the management of CIA in women receiving platinum-based chemotherapy for ovarian cancer who have symptomatic anaemia with a Hb level of ≤ 8 g/dl. The use of ESAs does not preclude the use of existing approaches to the management of anaemia, including blood transfusion when necessary
• people who cannot be given blood transfusions and who have profound cancer treatment-related anaemia that is likely to have an impact on survival.

When indicated, the ESA used should be the one with the lowest acquisition cost.

Description of the technologies under assessment

Several short- and long-acting ESAs are available, including epoetin alfa, epoetin beta and darbepoetin beta. Since the last appraisal (2004) [the Health Technology Assessment (HTA) monograph relating to this was published in 2007²], an additional two ESAs have become available: epoetin theta and epoetin zeta. All are administered by subcutaneous injection. This technology assessment report will consider six pharmaceutical interventions: epoetin alfa (Eprex^®, Janssen-Cilag Ltd; Binocrit^®, Sandoz Ltd), epoetin beta (NeoRecormon^®, Roche Products Ltd), epoetin theta (Eporatio^®, Teva Pharmaceuticals Ltd), epoetin zeta (Retacrit^®, Hospira UK Ltd) and darbepoetin alfa (Aranesp^®, Amgen Inc.).¹ Two of the six ESAs, Binocrit and Retacrit, are biosimilars of epoetin alfa. A ‘biosimilar’ medicine is similar to a biological medicine (the ‘reference medicine’) that is already authorised in the European Union and contains a similar active substance to the reference medicine. The reference medicine for both Binocrit and Retacrit is Eprex/Erypo^®, which contains epoetin alfa. Unlike generic medicines, biosimilars are similar but not identical to the original biological medicine.^41,42 Treatment recommendations according to licence are summarised for each pharmaceutical intervention in Table 3.

This NICE appraisal focuses on the treatment of CIA. As such, the appraisal does not cover all aspects of the licensed indications, such as the prevention of anaemia or the treatment of symptomatic anaemia as a result of chronic renal failure.

Clinical guidelines

Existing evidence

Existing systematic reviews of effectiveness

There have been a number of well-conducted systematic reviews evaluating the effects of ESAs for treating CIA in cancer patients. We identified 11 systematic reviews (reported in 14 publications) that fulfilled the definition of a systematic review prespecified in the protocol; a summary of the eligible systematic reviews and a quality assessment [compared with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement⁴⁴] is provided in Appendix 1.

Cochrane review

The Cochrane review by Tonia and colleagues¹¹ was the most recent and authoritative review. The Cochrane review’s conclusions were that ESAs reduce the need for RBCTs but increase the risk for thromboembolic events and deaths. ESAs may improve quality of life but the effect of ESAs on tumour control is uncertain. The review concluded that ‘Further research is needed to clarify cellular and molecular mechanisms and pathways of the effects of ESAs on thrombogenesis and their potential effects on tumour growth (p. 2).¹¹

This was an update of a Cochrane review first published in 2004.⁷ Searches were conducted in the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE and other databases. Searches were carried out for the periods January 1985 to December 2001 for the first review, January 2002 to April 2005 for the first update and up to November 2011 for the most recent update. The authors of the review also contacted experts in the field and pharmaceutical companies [for access to individual patient data (IPD)]. Inclusion, quality assessment and data abstraction were undertaken in duplicate by several reviewers. Eligibility criteria are detailed and compared with those in the Peninsula Technology Assessment Group (PenTAG) review in Table 4. The Cochrane review differed from the PenTAG review in respect of the population (cancer-related anaemia vs. chemotherapy-induced anaemia) and the intervention [all ESAs irrespective of licence vs. ESAs within licence (defined based on start dose)].

TABLE 4

Differences between the systematic reviews of Tonia and colleagues and PenTAG

A total of 91 studies with 20,102 participants were included in the Cochrane review by Tonia and colleagues.¹¹ The results from the Cochrane review are summarised in Table 5 and compared with the results of the PenTAG HTA review throughout Chapter 3.

TABLE 5

Results: Cochrane review

Cochrane review: meta-analysis based on individual patient data

Another Cochrane review⁷ examined the effect of ESAs and identified factors that modify the effects of ESAs on OS, progression-free survival (PFS) and thromboembolic and cardiovascular events, as well as the need for transfusions and other important safety and efficacy outcomes in cancer patients. It concluded that ‘ESA treatment in cancer patients increased on study mortality and worsened OS. For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded’ (p. 2).

The review was conducted in 2009. Searches were conducted in The Cochrane Library, MEDLINE, EMBASE and conference proceedings for eligible trials and manufacturers of ESAs were contacted to identify additional trials. The review included randomised controlled trials (RCTs) comparing ESAs plus RBCT (as necessary) with RBCT (as necessary) alone to prevent or treat anaemia in adult or paediatric cancer patients with or without concurrent antineoplastic therapy. Inclusion, quality assessment and data abstraction were undertaken in duplicate by several reviewers. A meta-analysis of RCTs was conducted and patient-level data were obtained and analysed by independent statisticians.

A total of 13,933 cancer patients from 53 trials were analysed; 1530 patients died on study and 4993 died overall. ESAs increased on-study mortality [combined hazard ratio (cHR) 1.17; 95% confidence interval (CI) 1.06 to 1.30] and worsened OS (cHR 1.06; 95% CI 1.00 to 1.12), with little heterogeneity between trials (I² = 0%, p = 0.87, and I² = 7.1%, p = 0.33 respectively). Thirty-eight trials enrolled 10,441 patients receiving chemotherapy (Table 6). The cHR for on-study mortality was 1.10 (95% CI 0.98 to 1.24) and that for OS was 1.04 (95% CI 0.97 to 1.11). There was little evidence of a difference between trials of patients receiving different cancer treatments (p-value for interaction = 0.42).

TABLE 6

Results: Cochrane review

Previous Health Technology Assessment review

The previous HTA review (Wilson and colleagues²) informed NICE guidance (TA142¹). It assessed the effectiveness and cost-effectiveness of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment. The review concluded that ESAs are effective in improving the haematological response and reducing RBCT requirements, but that the effect on health-related quality of life (HRQoL) is uncertain and the incidence of side effects and the effect on survival are highly uncertain. If there is no effect on survival it seems highly unlikely that ESAs would be considered a cost-effective use of health-care resources.

Using the Cochrane review⁴⁵ published in 2004 as the start point, Wilson and colleagues² conducted a systematic review of RCTs comparing ESAs with standard care. MEDLINE, EMBASE, The Cochrane Library and other databases were searched from 2000 (1996 in the case of darbepoetin alfa) to September 2004. Inclusion, quality assessment and data abstraction were undertaken in duplicate. Eligibility criteria are detailed and compared with those of the PenTAG review in Table 7. When possible, meta-analysis was employed. The economic assessment consisted of a systematic review of past economic evaluations, an assessment of economic models submitted by the manufacturers of the three ESAs and development of a new individual sampling model (see Chapter 4, Wilson and colleagues: summary).

TABLE 7

Differences between the systematic reviews of Wilson and colleagues and PenTAG

A total of 46 RCTs were included in the review, 27 of which had been included in the Cochrane review.⁷ All 46 studies compared ESA plus supportive care for anaemia (including transfusions) with supportive care for anaemia (including transfusions alone). Outcomes assessed were anaemia-related outcomes (haematological response, Hb change, RBCT requirements), malignancy-related outcomes (tumour response and OS), HRQoL and AEs.

Results from the previous HTA review² (Table 8) are compared with the results of the PenTAG review throughout Chapter 3.

TABLE 8

Results: Wilson and colleagues

Key points

• Anaemia is defined as a deficiency in RBCs. It is the most frequent haematological manifestation in patients with cancer; > 50% of all cancer patients will be anaemic, regardless of the treatment received, and approximately 20% of all patients undergoing chemotherapy will require a RBCT. The cause is multifactorial: patient, disease or treatment related.
• Anaemia is associated with many symptoms, all of which affect quality of life. These symptoms include dizziness, shortness of breath on exertion, palpitations, headache and depression. Severe fatigue is probably the most commonly reported symptom and can lead to an inability to perform everyday tasks. However, fatigue in people with cancer can also have other causes, for example the disease itself, chemotherapy, radiotherapy, anxiety or depression.
• Many people are anaemic when cancer is diagnosed, before any cancer treatment starts. The degree of anaemia caused by treatments such as chemotherapy often fluctuates depending on the nature of the treatment and the number of courses administered, but is typically at its worst 2–4 weeks after chemotherapy is given. Once cancer treatments are stopped, a period of ‘normalisation’ is likely, during which the Hb may return to pretreatment levels.
• Options available for the management of CIA include adjustments to the cancer treatment regimen, iron supplementation and blood transfusion. The majority of people who become anaemic do not receive any treatment for their anaemia, but those who become moderately or severely anaemic are usually given blood transfusions. Complications related to RBCT include procedural problems, iron overload, viral and bacterial infections and immune injury.
• Current evidence suggests that ESAs reduce the need for RBCT but increase the risk of thromboembolic events and death. There is suggestive evidence that ESAs may improve quality of life. Whether and how ESAs affect tumour control remains uncertain.
• Based on the previous assessment,² NICE guidance (TA142)¹ recommended the use of ESAs in combination with intravenous iron for the treatment of CIA in women with ovarian cancer receiving platinum-based chemotherapy with symptomatic anaemia (Hb ≤ 8 g/dl). The recommendation made in TA142 did not prohibit the use of other management strategies for the treatment of CIA, for example blood transfusion.¹ In addition, guidance set out in TA142 recommended ESAs in combination with intravenous iron for people with profound CIA who cannot be given blood transfusions.¹ The ESA with the lowest acquisition cost should be used.¹