Erythropoietic Growth Factors for Children With Cancer: a Systematic Review of the Literature

By Mystakidou, Kyriaki Potamianou, Anna; Tsilika, Eleni

Key words: Anaemia – Erythropoiesis – Erythropoietin – Oncology – Paediatrics ABSTRACT

Objective: To review evidence on the use of erythropoietic stimulating agents (erythropoietin or darbepoetin) in children with cancer.

Methods: A systematic review of the published literature was performed using MEDLINE (1966-July 2007) and references from a Cochrane systematic review (focusing mainly on adults) published in 2006.

Results. The review identified 12 studies, comprising five randomized trials, six case control studies and one open-label, dose- escalation study. All the studies that used adequate doses of recombinant human erythropoietin (rhEPO) (usually 150 IU/kg three times per week) demonstrated benefits for rhEPO except for one study in which rhEPO was added to G-CSF in children with high-risk neuroblastoma. Despite the heterogeneity of the populations studied, in terms of age, tumour type and chemotherapy regimen, rhEPO use was associated with consistent benefits in terms of reduced transfusion requirements and improved haematological parameters. Only one case of darbepoietin use was reported.

Conclusions: While more studies are required, it appears that rhEPO is safe in this vulnerable patient group and can benefit children with cancer by preventing or ameliorating anaemia.

Introduction

The use of erythropoietic stimulating agents (ESAs, i.e. recombinant human erythropoietin [rhEPO] and darbepoetin) is now well-established in the prevention and treatment of anaemia in adult cancer patients. A systematic review showed that use of ESAs significantly reduced the need for blood transfusions and improved haematological status and/or response in patients with chemotherapy- induced anaemia1.

As with adults, a high proportion of children receiving treatment for cancer will become anaemic2. One study found that almost 60% of children receiving intensive chemotherapy required a blood transfusion because of anaemia3. However, there have been few definitive, large-scale, well-controlled trials of the use of ESAs in children with cancer and no review of existing studies has been published in English recently. A systematic review of published evidence on the use of ESAs in children with cancer was, therefore, performed.

Methods

MEDLINE was searched from 1966 to July 2007 using the search terms ‘erythropoietin’ or ‘darbepoetin’ and ‘cancer’ limited to human studies involving the 0-18 year age group, but with no language restrictions. The reference lists of the systematic (Cochrane) review and previous literature reviews were also searched1,4-7. Since the Cochrane review (published in 2006) had used several databases (e.g. EMBASE, the Cochrane register) and hand searching, these were not repeated. Studies published in full (i.e. not only as abstracts) in any language were included.

Results

The search identified 254 potential articles. Twelve of these were studies, comprising five randomized trials, six case control studies and one open-label uncontrolled study. All studies used erythropoietin (rhEPO) except for a single case in one case series where darbepoetin was received. The study findings are summarized below and in Tables 1 and 2.

Randomized trials

Csaki et al. reported findings from an open-label, prospective, randomized pilot study of 20 children aged 4-18 years with solid tumours and haemoglobin (Hb) concentration < 12 g/dL of whom 15 were evaluable for response8. Eight children received rhEPO (150 IU/kg, three times per week for 12 weeks or over three chemotherapy cycles) and seven acted as controls. At Week 8, the rhEPO group had significantly higher haematocrit (39.3% vs. 33.2%) and Hb concentration (13.11 g/dL vs. 11.06 g/dL) than the control group. There was a non-significant trend towards reduction of transfusion requirements by 3 months.

Porter et al. studied 24 children receiving chemotherapy for sarcoma, of whom 10 received rhEPO and 10 received placebo injections and were evaluable for response9. rhEPO was given at a dose of 150 IU/kg, three times per week for 16 weeks and the dose could be increased by 50 IU/kg/dose until the patient was transfusion independent or a maximum dose of 300 IU/kg had been reached. Both groups received oral iron (6 mg/kg/day). During the 16 weeks, the EPO group had significantly fewer RBC and platelet transfusions than the placebo group (median 4.5 vs. 13 RBC transfusions, median amount transfused 23 mL/kg vs. 80mL/kg) and, therefore, significandy fewer ‘donor exposures’.

Razzouk et al. performed the largest trial, involving over 200 children who were randomized to receive either rhEPO (111) or placebo (111)10. Participants were anaemic patients between 5 and 18 years old (mean age 11 years) receiving myelosuppressive chemotherapy for non-myeloid malignancies. Patients with brain tumours were excluded. All received intravenous rhEPO 600-900 IU/kg or placebo once weekly for 16 weeks. Those who received rhEPO had significantly greater increases in Hb and were more likely to be transfusion independent after 4 weeks (38.7% vs. 22.5%, p = 0.01). Significantly more children in the EPO group than in the placebo group had Hb level increases of at least 2 g/dL (56% vs. 35%, respectively, p = 0.002) and this difference was particularly marked in the 5-7 year age group (92% vs. 41%, N = 47 in this sub-group). No difference was detected in quality of life scores completed by the children and their parents. However, changes in Hb were correlated with changes in quality of life scores in the rhEPO, but not in the placebo, group. Adverse events were similar for rhEPO and placebo groups.

Varan et al. studied 34 children receiving chemotherapy for solid tumours, randomized to receive rhEPO (17) or be in the control group (17)11. All participants had normal Hb concentrations at the time of diagnosis. They received rhEPO (150 IU/kg, three times a week for 2 months) when Hb fell below 10 g/dL. The rhEPO group required significantly fewer blood transfusions than the control group (1/17 vs. 8/17, p = 0.008) and mean Hb concentration after treatment was higher in the rhEPO group (10.21 g/dL vs. 8.41 g/dL). However, the authors noted that the response in patients receiving regimens including cisplatin (n = 15) was lower than in those receiving other types of chemotherapy and suggested that higher doses of rhEPO may be needed for patients receiving platinum-based chemotherapy.

Wagner et al. randomized 38 children with high-risk neuroblastoma receiving intensive induction chemodierapy to receive granulocyte colony stimulating factor (G-CSF) alone (20) or G-CSF plus rhEPO (18)12. This was a younger population than other studies, with a median age of 3 years (range 1-19 years) and 80% of the study participants were under 5 years of age. Children in the EPO group received 200 IU/kg rhEPO daily if their Hb concentration was up to 10 g/dL or the same dose, three times per week, if their Hb concentration was > 10 g/dL. Treatment with rhEPO started on Day 6 of the first chemotherapy cycle and then 24 h after completion of chemotherapy in subsequent cycles. Blood transfusions were given if Hb concentrations fell below 8 g/dL. Addition of rhEPO to G-CSF gave no benefit in terms of the number of blood transfusions required.

Non-randomized trials

Bolonaki et al. studied 15 children ranging from 1 to 17 years of age13. Of these, six had haematological malignancies (including five cases of acute lymphoblastic leukaemia) and nine had solid tumours. All received 150 IU/kg rhEPO subcutaneously, three times per week plus oral iron for 8 weeks. The rhEPO dose could be increased to 250 or 400 IU/kg if there was no response. Haematological response for the chemotherapy cycles during which the children received rhEPO was compared with other cycles when they did not receive rhEPO, so each case acted as its own control. During cycles in which they received rhEPO, the children’s’ red cell transfusion requirements decreased markedly (mean of 5 vs. 15 units) and 8/15 children (53%) achieved a Hb increase to at least the 10th percentile for their age and sex. There was no difference in response between children with haematological and solid tumours and no adverse effects were reported.

Table 1 Overview of the studies in methodologies

Leon compared 25 children receiving chemotherapy for solid tumours with 25 historical controls14. The patients’ mean age was 12.6 years, with a range from 6 to 17 years and all had Hb concentrations below 10.5 g/dL. All received 150 IU/kg rhEPO, five times per week for 12 weeks. They also received oral iron if their serum ferritin concentration was < lOOng/mL. Red cell transfusions were given if the Hb fell below 9 g/dL. A response to rhEPO was defined as an increase in Hb concentration of at least 2 g/dL. Compared with the historical controls, the children who received rhEPO required significantly fewer transfusions (16% vs. 96%) and received significantly fewer units of blood (0.35 vs. 3.56/ patient). Of the 25 children, 18 achieved a response of Hb > +2 g/ dL.

Locatelli et al. studied 20 children undergoing bone marrow transplants (BMT: 10 autologous, 10 allogeneic) for acute leukaemia who were all given rhEPO intravenously at a dose of 75 IU/kg for 30 days following transplantation15. Their response was compared to that of 25 controls (15 allogeneic, 10 autologous BMT cases) who did not receive rhEPO. Erythroid marrow activity was estimated by measuring serum transferrin receptor (TfR) concentration. Children who had received rhEPO and an allogeneic transplant showed greater and more rapid increases in TfR than controls over the 30 days following transplantation (mean TfR rose from 3100 to 8300 mg/L in the rhEPO group and from 2400 to 4500 mg/L in controls) but there was no significant difference in TfR levels in the autologous transplant group (mean TfR rising from 1900 to 2400 mg/L in the rhEPO group and from 2300 to 2900mg/L in the control group). Use of rhEPO in the allogeneic transplant group was also associated with a higher mean reticulocyte count (187 +-51 x 10^sup 9^/L vs. 107 +- 63 x 10^sup 9^/L) and fewer blood transfusions than controls (mean number of units 1.7 +- 1.3 x 10^sup 9^/L vs. 5.1 +- 3.0 x 10^sup 9^/L). However, once again, there was no difference in the autologous transplant group. The authors concluded that use of rhEPO in children who have received an allogeneic BMT can enhance erythroid repopulation but, following mafosfamidepurged autologous BMT, addition of rhEPO does not increase erythropoiesis, since this is largely controlled by the marrow proliferative capacity. Tenenbaum et al. reported their experience over 16 years with 14 Jehovah’s Witness (JW) children matched with similar non-Jehovah’s Witness cases16. The JW children received subcutaneous epoetin 50- 150 IU/kg, three times per week or 150-900 IU/kg once a week. One case received darbepoietin 50 [mu]g/ week. All the children also received iron, G-CSF and interleukin. The JW children received 39% fewer transfusions than the matched controls and 4/14 children required no transfusions compared with 2/14 of the controls.

Table 2. Mean baseline and post-treatment haemoglobin (Hb) concentrations and number of patients requiring red cell transfusions for all studies reporting these parameters

Yilmaz et al. studied children with haematological malignancies (N = 27) or solid tumours (N = 14) aged 0.5-17 years17. They received rhEPO 150 or 250 IU/kg, three times per week for 12 weeks. Additional iron was given if ferritin concentrations fell below < 400[mu]g/dL. They were compared with a control group of 30 patients undergoing similar treatments. Use of rhEPO was associated with a significant increase in Hb by the 2nd and 3rd month of treatment. After 3 months, mean Hb levels had risen from 9.62 g/dL to 10.85 g/ dL in the rhEPO group compared with a decrease from 9.46 g/dL to 8.77 g/dL in the controls. By the third month of rhEPO treatment, the children in the rhEPO group also received fewer transfusions than the control group.

Zoubek studied 37 children with solid tumours and a mean age of 11 (range 1-18) years18. They received subcutaneous rhEPO 150 or 300 IU/kg, three times per week plus iron for 28 weeks and were compared with a historical control group. The rhEPO group required significandy fewer red cell transfusions than the controls (62% vs. 89%) and the mean time to first transfusion was significantly longer in rhEPO group. However, there was no statistically significant difference in Hb concentration in the rhEPO group from baseline to the end of treatment (mean Hb concentration fell from 10.8 g/dL to 10.1 g/dL) compared with the control group (in which Hb concentration fell from 11.1 g/dL to 9.3 g/dL).

Uncontrolled studies

Beck and Beck report a phase I/II dose escalation study in which 15 children receiving cytotoxic agents for cancer received 25-100 IU/ kg rhEPO for 14 days19. The mean age of the children was 8 (range 0.5-18) years and all had severe anaemia (Hb < 7.5 g/dL). The mean Hb concentration at baseline was 6.9 (range 6.2-7.5) g/dL. It is not clear whether supplementary iron was given. No significant improvement in haematological parameters was observed, but the authors noted that the use of rhEPO was safe. Most studies have used longer treatment periods and higher doses of rhEPO, so this study probably represents sub-optimal dosing.

Discussion

The rhEPO studies that have been performed in paediatric cancer patients are, sadly, often small and rarely randomized. Only one, reasonably large, randomized trial has been published. Nevertheless, a clear pattern emerges, suggesting that rhEPO is safe and effective in this population.

In three out of five randomized, controlled trials in children with solid tumours, rhEPO significantly reduced transfusion requirements and in the other, small study (of only 15 patients) there was a nonsignificant trend towards reduction. In the randomized trials which reported haemoglobin concentration, this increased significantly with rhEPO treatment. One study of patients with high-risk neuroblastoma showed no significant difference when rhEPO was added to G-CSF therapy.

The non-randomized studies accord with the randomized trials although, once again, the populations studied tend to be small. rhEPO has been used successfully in children with both haematological and solid tumours. In all studies using a reasonable dose and treatment period, patients who received rhEPO had significantly reduced transfusion requirements and significantly improved haematological parameters. The only study that noted no effect gave low doses (25-100 IU/kg) for only 2 weeks19. The most common dose used was 150 IU/kg, three times per week, given subcutaneously, but one study used daily 75 IU/kg intravenous rhEPO and the largest study used weekly doses of 600-900 IU/kg intravenous rhEPO and doses in some studies could be increased if there was an inadequate response.

The range of malignancies and of chemotherapy included in these studies, despite their small size, is large, as is the age range of the children. Most studies included patients up to the age of 18 years, aldiough, clinically speaking one might expect an 18-year- old to respond more like an adult than a much younger child. Several studies included infants (< 2 years of age). Despite the heterogeneity of the populations, use of a dose based on body weight appeared generally to be appropriate and few treatment-related adverse effects were reported. The only population that appeared not to benefit from treatment was children who had received an autologous bone marrow transplant for acute leukaemia who did not respond, although those who had received an allogeneic transplant did benefit from rhEPO.

It is unfortunate that nearly all the published trials of the use of ESAs in children are small. However, this may reflect the difficulty of obtaining consent and, therefore, recruiting children with cancer into randomized trials. We cannot rule out the possibility of publication bias (i.e. unfavourable findings being less likely to be published than favourable ones) especially as four of the five randomized trials were funded, at least in part, by manufacturers of ESAs, while two of the six non-randomized case- control studies were funded by pharmaceutical companies and the others did not state their funding source. However, much larger studies have been performed in adults, so it is constructive to consider some of these.

Comparison with studies in adults

The paediatric studies of ESAs, although generally smaller, are otherwise very much in line with adult trials. Several, large- scale, randomized trials have demonstrated that use of an ESA can reduce transfusion requirements, increase haemoglobin levels and improve quality of life in anaemic cancer patients.

For example, Cascinu et al. studied 99 patients with cisplatin- induced anaemia (Hb < 9 g/dL) randomized to receive either rhEPO (100 IU/kg three times per week) or placebo20. The rhEPO group showed significant increases in Hb while those receiving placebo showed no increase. Only 20% of the rhEPO group required transfusions compared with 56% of the placebo group.

Case et al. reported on 153 anaemic cancer patients randomized to rhEPO (150 IU/kg three times per week) or placebo21. The rhEPO group showed significantly greater increases in haematocrit and also significant improvements in energy levels and ability to perform daily activities than the placebo group.

Littlewood et al. randomized 375 anaemic patients with solid or non-myeloid haematological malignancies to rhEPO (n = 251) or placebo (n = 124)22. The rhEPO group had significantly fewer transfusions, increased haemoglobin and improvements in all domains of the cancer and anaemia-specific quality of life instrument.

Del Mastro et al. showed that rhEPO may also be used to prevent chemotherapy-induced anaemia in 62 patients with breast cancer23. Those who received rhEPO maintained stable Hb concentrations, while those in the control group developed progressive anaemia.

Thus, several, large scale, well-controlled studies in adults have demonstrated the efficacy and safety of ESAs. Most of the placebo-controlled studies found no important differences in adverse events between rhEPO and placebo. Some adult studies have also shown improvements in health-related quality of life which may be harder to measure in young children, or difficult to detect in small studies.

In recent years, concerns have been raised about the possibility that ESAs might enhance tumour growth after two studies in adult cancer patients suggested that the use of an ESA might be associated with worse survival24, and on the basis of preclinical studies suggesting a theoretical link between tumour growth and ESA receptors25. However, more recent reviews of both the preclinical and clinical literature have concluded that such concerns are unwarranted since many of the preclinical studies have methodological limitations and, therefore, according to Osterborg et al. ‘must not be over-translated in terms of their clinical relevance to patients with cancer’25. None of the paediatric studies investigated this concern specifically, and most would probably have been underpowered to detect such effects.

Conclusions

While it would be helpful to have more, well controlled, homogeneous studies, the overall pattern is that rhEPO can benefit children with cancer who become anaemic. Use of rhEPO appears to reduce the need for blood transfusions in this vulnerable population and also improves haematological recovery after chemotherapy and may prevent or treat anaemia. Acknowledgements

Declaration of interest: Assistance in performing the literature search and preparing this manuscript were funded by Janssen-Cilag.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-4106_2, Accepted for publication: 20 September 2007

Published Online: 01 October 2007

doi: 10.1185/030079907X242601

Kyriaki Mystakidou(a), Anna Potamianou(b) and Eleni Tsilika(a)

a Department of Radiology, School of Medicine, Areteion Hospital, University of Athens, Athens 115 26, Greece

b Memorial Cancer Hospital Metaxa, Athens 17563, Greece

Address for correspondence: Kyriaki Mystakidou, MD, PhD, Pain Relief and Palliative Care Unit, Department of Radiology, Areteion Hospital, School of Medicine, University of Athens, 27 Korinthias Street, Ampelokipi, Athens 115 26, Greece, mistakidou@yahoo.com

Copyright Librapharm Nov 2007

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