The data and material included in this manuscript is original and has not been previously published. An abstract of these data was presented at the 9th Congress of the European Haematology Association (Geneva, 10–13 June 2004).
Impact of epoetin-β on survival of patients with lymphoproliferative malignancies: long-term follow up of a large randomized study*
Article first published online: 29 MAR 2005
British Journal of Haematology
Volume 129, Issue 2, pages 206–209, April 2005
How to Cite
Österborg, A., Brandberg, Y. and Hedenus, M. (2005), Impact of epoetin-β on survival of patients with lymphoproliferative malignancies: long-term follow up of a large randomized study. British Journal of Haematology, 129: 206–209. doi: 10.1111/j.1365-2141.2005.05440.x
- Issue published online: 6 APR 2005
- Article first published online: 29 MAR 2005
- Received 17 November 2004; accepted for publication 28 January 2005
Recent studies have suggested that epoetin treatment of anaemia may influence the survival of patients with cancer. We conducted an analysis of long-term survival in patients with lymphoproliferative malignancies treated with epoetin-β or placebo in a large-scale study. This was a randomized, double-blind trial in which patients with transfusion-dependent anaemia and lymphoproliferative malignancy received epoetin-β 150 IU/kg or placebo three times weekly for 16 weeks. Long-term survival data were analysed by standard Kaplan–Meier methods and differences between groups were assessed using a log-rank test. The intention-to-treat population consisted of 343 patients (epoetin-β, n = 170; placebo, n = 173). There were no major differences between the two treatment groups in demographic or clinical characteristics/prognostic factors. A total of 110 (65%) patients died in the epoetin-β group (censored, n = 60) and 109 (63%) died in the placebo group (censored, n = 64) up to the end of long-term follow up. Kaplan–Meier curves for survival were similar in both groups. Median survival was 17 months with epoetin-β and 18 months with placebo. A log-rank test indicated no significant difference in survival (P = 0·76). This long-term follow up indicated that epoetin-β has no significant effect on survival compared to placebo in anaemic patients with lymphoproliferative malignancies.
Many patients with cancer experience anaemia, either as a result of their underlying malignancy or anticancer therapy. Because anaemia is associated with a variety of symptoms that include fatigue, depression and impaired cognitive function, it has a profound negative effect upon patients’ quality of life (QoL; Cella et al, 2002). Moreover, anaemia is widely recognized as an adverse prognostic factor, numerous studies having shown that low haemoglobin (Hb) levels before and during treatment are correlated with reduced locoregional disease control and survival in patients with a variety of cancer types (Caro et al, 2001).
This correlation between anaemia and treatment outcomes has led to the suggestion that correction of the anaemia could improve prognosis. Recombinant human erythropoietin (epoetin) is a well-established therapy for anaemia in patients with cancer. Randomized, placebo-controlled studies have shown that treatment with epoetin raises Hb levels, reduces transfusion requirements and improves QoL in patients with solid tumours (Littlewood et al, 2001) and lymphoproliferative malignancies (Österborg et al, 2002; Hedenus et al, 2003). Data from some studies have also shown a trend towards improved survival in patients treated with epoetin (Antonadou et al, 2001; Littlewood et al, 2001; Vansteenkiste et al, 2002). However, two recently published trials in which survival was a primary end-point have raised concerns that epoetin may have a significant negative impact on survival (Henke et al, 2003; Leyland-Jones, 2003). Furthermore, erythropoietin receptors have been detected on various tumour types, including multiple myeloma (MM), and a tumour-stimulating effect of epoetin in vitro has been reported in some tumour cell lines (Acs et al, 2001; Yasuda et al, 2003). In addition, an angiogenic effect of epoetin has also been reported (Ribatti et al, 2003).
As the safety of treatment with epoetin is of major importance, we performed a long-term follow-up survival analysis of patients with lymphoproliferative malignancies treated with epoetin-β (NeoRecormon®, F. Hoffmann-La Roche, Basel, Switzerland) in a large-scale, placebo-controlled study.
This was a randomized, double-blind trial in which transfusion-dependent patients with severe anaemia and B-cell chronic lymphocytic leukaemia (CLL), low-grade non-Hodgkin's lymphoma (NHL) or MM received either subcutaneous epoetin-β 150 IU/kg (c. 30 000 IU/week) or placebo three times weekly for 16 weeks. For inclusion, patients needed a Hb level of <10 g/dl and a red blood cell transfusion requirement of ≥2 U in the 3 months before the study. In addition, patients were scheduled to receive anticancer therapy during the study, had a World Health Organization performance status of 0–3 and a life-expectancy of at least 4 months. Randomization was stratified by malignancy type and study centre. Patients were followed up for at least 1 year after finishing the 16-week course of treatment. Survival data were analysed by standard Kaplan–Meier methods and differences in survival between groups were assessed using a log-rank test. The study design and methods have previously been reported in more detail (Österborg et al, 2002).
A total of 349 patients were randomized into the study. Six patients withdrew before receiving study medication so the intention-to-treat and safety populations consisted of 343 patients (epoetin-β, n = 170; placebo, n = 173). There were no major differences between the two treatment groups in baseline demographic or clinical characteristics. The majority of patients had advanced disease (MM: 72% Durie-Salmon stage III; NHL: 93% Ann Arbor stages III and IV; CLL: 100% Rai stages III and IV) and 59% had a performance status of 2–3. Type and frequency of antitumour therapy was similar in both treatment groups.
As has been previously reported (Österborg et al, 2002), more patients achieved a haematological response (≥2 g/dl increase in Hb without transfusion) with epoetin-β compared with placebo (67% vs. 27%; P < 0·0001) after 16 weeks. Patients treated with epoetin-β also reported a significantly improved QoL compared with placebo, as measured with the Functional Assessment of Cancer Therapy (FACT) scale (P < 0·05).
The majority of patients (68%) were classed as having either stable disease or partial remission in both treatment groups after 16 weeks. Nine patients (5%) in the epoetin-β group and five patients (3%) in the placebo group achieved a complete remission while progressive disease was reported for 18% of epoetin-β-treated patients and 23% of placebo-treated patients.
The minimum length of follow up was approximately 17·5 months in both treatment groups, with only four patients in each group having a follow up of shorter duration. Median time to patients being censored was 27·8 months in the epoetin-β group and 27·5 months in the placebo group.
The total number of deaths was similar between the two groups; 110 (65% of patients) died in the epoetin-β group (censored, n = 60) and 109 (63%) died in the placebo group (censored, n = 64) up to the end of long-term follow up. Kaplan–Meier curves for survival were also similar in both treatment groups (Fig 1) with median survival of 17·4 months [95% confidence interval (CI): 15·0–20·5] with epoetin-β and 18 months (95% CI: 16·0–22·3) with placebo [hazard ratio (HR): 1·04, 95% CI: 0·80–1·36]. Log-rank test indicated no significant difference in survival (P = 0·76).
The impact of epoetin on the survival of anaemic patients with cancer remains the focus of considerable debate. Some preclinical data suggest that epoetin may improve cyto- and radio-sensitivity and impair progression of various tumours (Thews et al, 2001; Stuben et al, 2003), including MM (Mittelman et al, 2001). However, other studies have suggested that epoetin may promote tumour cell growth in vitro (Acs et al, 2001; Yasuda et al, 2003) and angiogenesis (Ribatti et al, 2003), while one case report suggested that epoetin may have stimulated myeloma tumour growth in vivo (Olujohungbe et al, 1997).
Several clinical studies provide evidence that epoetin may have a potential beneficial effect on survival (Antonadou et al, 2001; Littlewood et al, 2001; Vansteenkiste et al, 2002). In a randomized-controlled trial of 385 patients with various pelvic malignancies who were receiving radiotherapy, treatment with epoetin improved tumour control and survival (Antonadou et al, 2001). Also a randomized study of 90 patients with locally advanced head and neck cancers receiving non-platinum-based chemotherapy plus radiation, treatment with epoetin was associated with a non-significant trend towards improved progression-free survival (Rosen et al, 2003). A trend towards improved survival with epoetin has also been suggested by two randomized, double blind, placebo-controlled trials of patients with solid or non-myeloid haematological malignancies receiving chemotherapy (Littlewood et al, 2001; Vansteenkiste et al, 2002). However, neither of these studies were powered for survival as an end-point. In addition, a recent meta-analysis of randomized-controlled trials has also reported a trend towards increased survival in epoetin-treated patients (HR: 0·81, 95% CI: 0·67–0·99, n = 2865; Bohlius et al, 2004).
In contrast, significantly reduced survival in patients receiving epoetin has been reported by two prospective, randomized trials in which survival was a primary end-point (Henke et al, 2003; Leyland-Jones, 2003). The first of these studies, which included patients with normal Hb levels (>13 g/dl) and metastatic breast cancer receiving first-line chemotherapy, was terminated early because of an observed higher mortality with epoetin-α than placebo in the first 4 months (Leyland-Jones, 2003). In the other study, treatment with epoetin-β was associated with reduced locoregional progression-free survival and overall survival compared with placebo in 351 head and neck cancer patients undergoing radiotherapy (Henke et al, 2003). These data, together with recent reports on epoetin-induced tumour progression in vitro and epoetin-induced stimulation of angiogenesis, have started an intensive debate on the safety of epoetin. However, as has been highlighted (Kaanders & van der Kogel, 2004; Leyland-Jones & Mahmud, 2004), the results of both these studies need to be interpreted with caution. In particular, baseline imbalances in prognostic factors may have favoured the placebo groups in both studies. Despite this, the possibility of a negative treatment effect of epoetin in these trials cannot be entirely excluded.
In the present analysis, treatment of severe, transfusion-dependent anaemia with epoetin-β had no significant effect on the risk of progressive disease or long-term survival in patients with lymphoproliferative malignancies. This finding supports the view that treatment of severe anaemia with epoetin does not have a negative effect on survival in patients with haematological cancers, although a limitation of these data is that the 16-week epoetin treatment period was relatively short compared with the median survival time of patients. Further prospective clinical trials, such as the BReast cancer – Anaemia and the Value of Erythropoietin (BRAVE) trial of epoetin-β in patients with metastatic breast cancer, which are specifically designed to address survival end-points are currently ongoing and will hopefully provide further evidence on whether anaemia correction with epoetin influences prognosis in various tumour types and clinical settings.
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