3.3 Effect of erythropoiesis- stimulating agents and iron

3.3.1 Cancer

Evidence Statements – cancer (erythropoiesis-stimulating agents)
ES3.1	In anaemic adults with cancer, ESA therapy increases the risk of all-cause mortality; this effect appears to be greater in patients with a Hb concentration > 100 g/L.
ES3.2	In adult cancer patients with non chemotherapy-induced anaemia, ESA therapy increases the risk of all-cause mortality.
ES3.3	In adult cancer patients with chemotherapy-induced anaemia, the effect of ESA therapy on mortality is uncertain.	X
ES3.4	In anaemic adults with cancer, ESA therapy reduces transfusion incidence and volume.
ES3.5	In anaemic adults with cancer, ESA therapy increases the risk of thromboembolic events.
ES3.6	In anaemic adults with cancer, ESA therapy may improve functional or performance status; however, the magnitude of this effect appears slight.	X

Evidence Statements – cancer (iron therapy)
ES3.7	In anaemic adults with cancer receiving ESAs, the effect of IV iron versus oral or no iron on short-term mortality is uncertain.		NA
ES3.8	In adults with cancer-related anaemia receiving ESAs, IV iron may reduce the incidence of RBC transfusion.
ES3.9	In anaemic patients with gynaecological cancer receiving chemotherapy, IV iron may reduce the incidence and volume of RBC transfusion.	NA
ES3.10	In adults with chemotherapy-induced anaemia receiving ESAs, the effect of IV iron versus oral or no iron on the incidence of thromboembolic events is uncertain.		NA
ES3.11	In adults with non-myeloid malignancies and chemotherapy-induced anaemia receiving ESAs, IV iron versus oral or no iron appears to have no effect on functional or performance status.	NA	NA
ES3.12	In anaemic patients with gynaecological cancer receiving chemotherapy, the effect of IV iron versus oral iron on functional or performance status is uncertain.	NA	NA

ES, evidence statement; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; IV, intravenous; RBC, red blood cell

=A; =B; =C; NA,not applicable (see Table 2.1)

Recommendation – cancer
R2 Grade A	In cancer patients with anaemia, the routine use of ESAs is not recommended because of the increased risks of mortality and thromboembolic events.

Practice Points – cancer
PP8^a	In patients with cancer, the aetiology of anaemia is often multifactorial; where appropriate, reversible causes should be identified and treated.
PP12	In anaemic patients with cancer receiving ESAs, evaluate iron status to guide adjuvant iron therapy.

^a Repeated from Section 3.2.4, above

ESA, erythropoiesis-stimulating agent; PP, practice point; R, recommendation

Erythropoiesis-stimulating agents – cancer

In patients with cancer, anaemia may be due to inflammation, chemotherapy, bone marrow infiltration by malignancy or haematinic deficiency (e.g. iron deficiency). Patients with haematological malignancies form a separate subgroup, because they have potentially defective erythropoiesis and therefore a reduced capacity to respond to ESAs.

A systematic review of RCTs (Level I)⁹⁴ evaluated the effectiveness of ESAs in individuals with nonhaematological malignancies. The study documented a significant increase in the risk of mortality with ESA treatment among cancer patients; this was confirmed by a meta-analysis that included five studies published subsequently. There was a nonsignificant trend towards a higher risk of mortality among patients with higher baseline Hb who received ESA treatment.

Meta-analyses of the studies from Tonelli et al⁹⁴ and two fair-to-poor-quality RCTs (Level II)^95,96 identified benefits in patients with cancer receiving ESAs. There was a significantly lower likelihood of transfusion among patients treated with ESAs if the baseline Hb was 120 g/L or lower; in addition, the mean RBC transfusion volume among all patients who received ESAs was 0.8 units less than in untreated patients. There was a favourable effect on functional or performance status. However, a meta-analysis of studies – including those identified by Bohlius et al,⁹⁷ Tonelli et al,⁹⁴ Hoskin⁹⁵ and Tsuboi⁹⁶ – found an increased risk of thromboembolic events among cancer patients treated with ESAs.

Based on these analyses, it is not possible to draw conclusions for patients with specific cancer subtypes; it is also not possible to distinguish between patients with different pretransfusion Hb concentrations, or between patients being treated with curative rather than palliative intent. In view of the increased mortality and incidence of thromboembolic events among cancer patients treated with ESAs, decision making should be individualised in patients with cancer. ESAs are not currently listed on the Pharmaceutical Benefits Scheme (PBS) for reimbursement for patients with cancer.

Intravenous iron – cancer

The literature review identified five RCTs (Level II) that evaluated the use of iron therapy in anaemic patients with cancer. All of the studies compared intravenous (IV) iron with either oral iron or no iron therapy. Participants received adjuvant darbepoetin in three of the studies, which were of fair or good quality,^98-100 and adjuvant erythropoietin in one study,¹⁰¹ which was of poor quality.

Of the four RCTs that reported mortality,^98-101 no significant difference was found in patients treated with IV iron compared to patients who received oral or no iron therapy; however, the studies were underpowered. No significant difference was found after meta-analysis.

Two studies^99,102 found that, compared with patients who did not receive IV iron, patients treated with IV iron had both a significantly lower incidence and median volume of RBC transfusion. There was no significant difference in functional status (Functional Assessment of Cancer Therapy (FACT) score) between the groups in both studies. One of these studies¹⁰² compared IV iron alone to oral iron in gynaecologic cancer patients with anaemia (Hb <100 g/L) who underwent primary surgery and were receiving platinum-based chemotherapy.

Of the three studies reporting thromboembolic events, there was no significant difference between patients treated with darbepoetin plus IV iron and those treated with darbepoetin plus oral iron or no iron, including after meta-analysis.^98-100

Risks associated with ESAs include increased mortality, venous thromboembolism, tumour progression and stroke. With the growing awareness of these risks, the role of iron therapy (alone or in combination with lower doses of ESAs) in selected patients requires further study. While iron therapy is generally recommended to augment the response in ESA recipients with iron deficiency, there is insufficient evidence to recommend the routine use of IV iron. Patients with cancer and anaemia should be evaluated and treated for iron deficiency before ESAs are initiated; these patients should be re-evaluated periodically during the course of therapy. IV iron may be required when oral administration is not possible or is ineffective.