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Does the use of erythropoietin-stimulating agents in breast cancer patients with chemotherapy-induced anaemia impact on

Does the use of erythropoietin-stimulating agents in breast cancer patients with chemotherapy-induced anaemia impact on clinical outcomes?. Olivia Kelada. Anaemia.

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Does the use of erythropoietin-stimulating agents in breast cancer patients with chemotherapy-induced anaemia impact on

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  1. Does the use of erythropoietin-stimulating agents in breast cancer patients with chemotherapy-induced anaemia impact on clinical outcomes? Olivia Kelada

  2. Anaemia • Anaemia is “The condition of having less than the normal number of red blood cells or less than the normal quantity of haemaglobin in the blood. The oxygen-carrying capacity of the blood is, therefore, decreased.” (Medline) • Anaemia can result from the tumour itself (Anaemia of cancer) as well as from cancer treatments, especially myleosuppressive chemotherapy (chemotherapy-induced anaemia) • According to The European Cancer Anaemia survey (ECAS), anaemia affects 67% of cancer patients.

  3. Treatment of Anaemia • Blood transfusion for severe anaemia, while mild and moderate cases were not treated at all • This method remains the best way of ameliorating anaemic symptoms • However, the effect of the treatment is short-lived and there are several risks involved even with the widespread testing of donors

  4. Erythropoietin • Erythropoietin (EPO) is the glycoprotein hormone involved in controlling erythrocyte (Red blood cell) production (erythropoiesis) • In 1985, Lin et al isolated EPO and coded its gene sequence. • This discovery led to the advent of recombinant EPO (rHuEPO) and eventually a number of erythropoietin stimulating agents (ESAs) • 3 main types of ESAs used to enhance Hb production are Epoetin Alfa (EA), Epoetin Beta (EB) and Darbepoetin Alfa (DA)

  5. Impact of ESAs • In the early 1990s ESAs were shown to alleviate anemia in cancer patients receiving chemotherapy • ESAs were found to: • Increase Haemoglobin (Hb) levels • Reduce the need for red blood cell transfusions • Improve quality of life (QoL) through alleviation of anaemic symptoms e.g. fatigue • Increase overall survival However…some research suggests a decrease in overall survival and association with tumour progression, thromboembolic events, hypertension and even death.

  6. Controversy • Studies by Littlewood et al, Aapro et al and Leyland-Jones et al yielded mixed results in relation to overall survival in breast cancer patients • Why?

  7. Factors influencing efficacy • Trials differed greatly in relation to ESA and patient characterisitcs • ESA characteristics e.g. Hb baseline level upon ESA administration and target Hb level may influence the effect of ESAs on clinical outcomes in CIA patients. • Patient characteristics e.g. type of cancer, its site of origin, tumour stage and treatment administered can influence the severity of anaemia and in turn, the effect of ESAs on alleviation of anaemia

  8. Aim 1: • To investigate whether EA, EB or DA alleviate anaemia in breast cancer patients with chemotherapy-induced anaemia (BC-CIA) in respect to: • Hb response, • Need for red blood cell transfusion (RBCT) • Quality of life (QoL) • Overall survival (OS) • Tumour response (TR) • Serious adverse events e.g. thromboembolic events (TEEs) and hypertension.

  9. Patient: Age Life expectancy (LE) Stage of disease (SOD) Performance status (PS) Comorbidities Chemo type Iron supplementation ESA: Hb level at admin Target Hb level Dose of ESA Dose schedule and changes Method of admin ESA duration Aim 2: • To investigate the factors associated with patient population

  10. Method • Electronic searches in Pubmed, EMBASE, Springerlink, The Cochrane Library, ScienceDirect and Google Scholar. • Search terms: erythropoietin-stimulating agents, anaemia/anemia, and cancer • For some clinical trials only the abstracts were available.

  11. Method 1)Type of Studies: • Any that used EA, EB and DA to treat anaemia in BC-CIA. • In English • Conducted on humans • ESA versus placebo, control or no treatment

  12. Method 2) Type of participants: • Not all of the clinical trials consisted of breast cancer patients only. • All patients had to be diagnosed with a solid tumour or non-myeloid malignancy • All patients had to have CIA (those with anaemia of cancer were excluded) and receive ESA treatment or placebo. • Patients of any age, LE, SOD, PS, comorbidities and chemo type were included.

  13. Method 3) Type of intervention • Trials evaluating EA, EB and DA • All dose administration methods, dosages, dose adaptations and durations were included • Hb level supplementation such as iron and RBC transfusion was allowed

  14. 4) Type of outcome measures Primary Outcomes: Hb response Need for RBCT QoL Secondary Outcomes: Overall Survival Tumour response (complete or partial response) SAEs including Thromboembolic events (TEEs) and hypertension Method

  15. 1) Intervention Construct:ESAs (epoetin alfa, epoetin beta and darbepoetin) Operations: Type ESA Hb level at of admin Target Dose ESA duration Multicenter Randomized trial Double-blinded Open-label No. of arms (ESA vs. placebo/no treatment) Data Collection Form

  16. 2) Participants Construct:Female breast cancer patients with chemotherapy-induced anaemia Operations: Breast cancer patients included in population Age Life expectancy Stage of disease Performance Status Presence of comorbidities Type of chemo: Platinum vs. non-platinum No. of participants in total and per arm Iron supplementation Data Collection form

  17. 3) Outcomes Constructs: Hb response Rate of RBC transfusion: Number of units transfused Change in QoL i.e. relief of anaemia and anemia-related symptoms Overall survival Tumour response Serious adverse events caused by treatment (TEEs, hypertension & other) Operation:ESA arm vs. non-ESA arm Data Collection Form

  18. Analysis – Primary Outcomes Improved Hb response:23/24 (95.8%) & Decrease in theRBCT rate:18/24 (75%) • Consistent with the EORTC and Bohlius et al. • Influenced by variation in trial arms • Hb level at admin (>10 g/dL) may alter significance • Trial quality • Measurement timing • No effect of target Hb level • No link for ESA type, dose, dosing schedule or chemo and outcome

  19. Analysis - Primary Outcomes Increase in QoL:15/24 (62.5%) • No linear relationship • Some trials open label • No target Hb level • Variation in QoL assessment • No link made to Hb baseline or chemo type • Use of iron supplements

  20. Analysis – Secondary Outcomes Effect on Overall Survival & Tumour response:7/24 (29.1%) • Increase, decrease and no effect • EORTC: No evidence of improved OS • Poor trial quality: LE, SOD and chemo not considered • No correlation for Hb level or dose • Link between Hb baseline and target with OS decrease • Some impact of chemo type and schedule • Influence of patient characteristics

  21. Analysis - Secondary Outcomes SAEs: in 18/24 (75%) trials. Some demonstrated an increase due to ESAs. TEEsin 13/24 (54.2%) trials and 53.8% of them showed more of these events in the ESA arm. • EORTC: 1.6 fold increased risk Hypertension: in 6/24 (25%) of studies only 33.3% recorded an increase in this side-effect in ESA group. • No link for ESA dose • Impact of chemo type & schedule • Increased risk with Hb target level outside of guidelines • Influence of patient underlying conditions on outcome

  22. Conclusions • ESAs increase haemoglobin response, decrease the need for red blood cell transfusion and increase quality of life in BC-CIA despite variation in ESA and patient characteristics between trials. • Hb level at baseline, target haemoglobin level, duration of ESA and dose changes are the ESA characteristics that impact on the effect of ESAs on primary outcomes in BC-CIA. • Patient characteristics such as age, life expectancy, stage of disease, performance status, chemotherapy type and supplementary iron also all appear to impact on the effect ESAs have on primary outcomes in BC-CIA.

  23. Conclusions • Results are not as conclusive for secondary outcomes. • Impact of ESAs on overall survival in BC-CIA is inconclusive due to the poor study design of trials used. • ESAs appear to have no effect on tumour response but data suggests an increase in serious adverse events, especially thromboembolic events but not hypertension. • It is evident that the results of secondary outcomes may be more definitive if clinical trials considered ESA and patient characteristics and adhered to current guidelines. • This review can establish that the effect of ESAs on secondary outcomes in BC-CIA patients is influenced by target haemoglobin level, ESA duration and patient characteristics including age, life expectancy, stage of disease, performance status and comorbidities.

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