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Chemotherapy-induced Anemia
Table 1: Guidelines for ESAs
ASH/ASCO
59
NCCN
57
EORTC
58
CMS
60
FDA
15
Hgb threshold Hgb approaching or Hgb ≤11g/dl, it can be Hgb ≤11g/dl, If Hgb <10g/dl If Hgb <10g/dl
to start ESA falls below 10g/dl started if Hgb 11.1–11.9 it can be started if
based on the clinical situation Hgb 11.1–11.9 is based
on the clinical situation
Target of Hgb Around 12g/dl Around 12g/dl Around 12g/dl 10g/dl Hgb approaches
level that is
required to
avoid transfusion
ASH = American Society of Hematology; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network; EORTC = European Organisation for Research and
Treatment of Cancer; CMS = Centers for Medicare & Medicaid Services; FDA = US Food and Drug Administration; Hgb = haemoglobin; ESA = erythropoiesis-stimulating agents.
be expressed in various cancers such as head and neck, breast, lung, time to locoregional progression (HR 1.69; p=0.007), as well as decreased
colon, gastric and uterine tumours.
40–45
Theories suggest that ESAs may OS, compared with the placebo group (HR 1.39; p=0.02).
33
contribute to stimulating tumour growth and survival through binding
EpoR and mediating a circuit of signalling pathways.
46–48
The Preoperative Epirubicin Paclitaxel Aranesp Study (PREPARE) trial
randomised 733 patients with breast cancer receiving neoadjuvant
ESAs in cancer-related anaemia not caused by chemotherapy are associated chemotherapy to placebo or darbepoetin alfa. Hgb was maintained
with an adverse effect on survival. The Epoetin Alfa in Advanced Non-Small between 12.5 and 13g/dl. Patients who received ESAs were found to have
Cell Lung Cancer (EPO-CAN-20) trial enrolled patients with metastatic non- shorter three-year OS (86 versus 90%) and relapse-free survival rate (72
small-cell lung cancer and cancer-related anaemia with Hgb <12.1g/dl. versus 78%) than those on placebo. Moreover, tumour progression was
Patients were double-blinded and randomised to either epoetin alpha or faster in the patients treated with darbepoetin alfa.
51
placebo. The targeted Hgb was 12–14g/dl. The study was suspended early
after a superior overall survival (OS) was observed in patients receiving In another randomised trial, by the National Cancer Institute (NCI)
placebo (129 versus 63 days; p=0.04).
49
Gynecologic Oncology Group (GOG), 114 patients with advanced cervical
cancer receiving concurrent cisplatin and radiotherapy were randomly
The Amgen 20010103 study is a phase III randomised, double-blinded trial assigned to receive ESAs or transfusion when the Hgb concentration was
that included 989 patients with cancer-related anaemia not undergoing ≤10mg/dl. The study was terminated early when a data analysis showed
active cancer therapy. Enrolled patients had an Hgb level of <11g/dl and the lower three-year OS (59 versus 62%) and PFS (61 versus 71%) in patients
Hgb target was 12–13g/dl. Patients were randomised to receive darbepoetin treated with epoetin alpha compared with the standard of care.
39
alpha or placebo. Unfavourable outcome was seen in the darbepoetin alpha
group compared with the placebo group, characterised by shorter OS (8 Despite the uncertain effect of ESA therapy on survival rates that were
versus 10.8 months) and failure in reducing the need for transfusion.
50
reported in earlier meta-analyses,
24
the result of a more recent large meta-
analysis, which was obtained from 51 phase III trials conducted between
There is no role for ESAs in cancer patients receiving chemotherapy with a 1985 and 2008, has established a statistically significant increased mortality
normal Hgb level, as data have shown adverse responses in terms of OS in patients receiving ESA therapy (HR 1.10, 95% CI 1.01–1.20; p=0.03).
35
when ESAs are used in non-anaemic patients.
32
The Breast Cancer
Erythropoietin Survival Trial (BEST) randomised non-anaemic patients with Iron Supplements with ESAs
metastatic breast cancer receiving chemotherapy to epoetin alpha or Iron status should be assessed and replaced in iron-deficient patients prior
placebo, targeting Hgb levels of 12–14g/dl. The study was terminated to starting ESA therapy. However, cancer patients have a functional iron
prematurely as early analysis demonstrated a trend of declining one-year deficiency as a consequence of inadequate mobilisation of iron from the
survival in the epoetin alpha group (70%) compared with the placebo group reticuloendothelial system mediated by cytokines secretion. Several
(76%) (p=0.012).
32
randomised studies have evaluated the benefits of giving iron concurrently
with ESA therapy in CIA. Studies compared ESA therapy alone versus ESAs
In the Danish Head and Neck Cancer Group (DAHANCA) 10 study, 522 plus oral or intravenous iron supplements during the course of the therapy.
patients were randomly assigned to receive radiotherapy plus darbepoetin Trials have found a favourable effect on haematological response,
alpha or radiotherapy alone in head and neck cancer. The target Hgb was transfusion requirements and QOL in patients given intravenous (IV) iron
14–15g/dl. The study was terminated early because preliminary analysis rather than oral iron supplement with ESAs compared with ESAs alone.
52–56
demonstrated a significantly decreased five-year locoregional tumour
control in the darbepoetin arm compared with the control group (RR 1.44; In a prospective, multicentre study, 157 patients with CIA were randomised
p=0.02). OS was lower in the ESAs group, but did not reach statistical to epoetin alpha alone or epoetin alpha with oral iron, iron dextran IV bolus
significance (RR 1.28; p=0.08).
38
or iron dextran total dose infusion. Mean Hgb concentration increased by
0.9, 1.5, 2.5 and 2.4g/dl, respectively. The difference in the amount of
The Erythropoietin in Head and Neck Cancer (ENHANCE) trial randomised increase of Hgb was statistically significant between patients given IV iron
non-anaemic patients with head and neck cancer receiving radiotherapy to and patients given oral iron or no iron (p<0.02), while it was statistically not
either placebo or pegzerepoetin alpha, aiming for an Hgb level of 14–15g/dl. significant between the epoetin alpha and oral iron versus epoetin alpha
The pegzerepoetin alpha group had a substantially shorter locoregional alone groups (p=0.21).
52
Parenteral iron appeared to be well
progression-free survival (PFS) (hazard ratio [HR] 1.62; p=0.0008) and shorter toleratedwithout significant toxicity.
ASIA-PACIFIC ONCOLOGY & HAEMATOLOGY 25
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