1 South West Wales Cancer Institute, Singleton Hospital, Swansea, UK; 2 Ludwig Maximilians Universität München, Department of Obstetrics and Gynecology, München, Germany
* Correspondence to: Professor R. C. Leonard, South West Wales Cancer Institute, Singleton Hospital, Swansea, UK. Tel: +44-1792-285299; Fax: +44-1792-285201; Email: r.c.f.leonard{at}swansea.ac.uk
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Abstract |
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Key words: anaemia, anaemia prevention, breast cancer, dose-dense chemotherapy, erythropoietin
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Introduction |
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The consequences of anaemia in patients with cancer are often underappreciated. Anaemia results in a variety of manifestations, with fatigue being the most debilitating. Patients consider that fatigue affects their daily life more than other cancer-associated complications, including nausea and pain [35
]. Other manifestations of anaemia include dyspnoea, cardiovascular complications, dizziness, headache, chest pain, decreased motivation, depression and anorexia [6
]. Consequently, anaemia affects patients' quality of life (QoL), and it has been shown that health-related QoL correlates directly with the severity of anaemia [7
]. Anaemia is also associated with reduced tumour control and overall survival of patients with cancer [8
]. Therefore, the ability to identify the patients most at risk of developing anaemia early in treatment would allow early intervention to prevent or reduce the incidence of anaemia.
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Anaemia in patients with breast cancer |
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Adjuvant endocrine and/or combination chemotherapy remain the mainstay of systemic treatment for patients with early-stage breast cancer; [9]. Anaemia is a common occurrence in patients with breast cancer; its prevalence depending on the extent of the disease and type and duration of anticancer therapy [10
, 11
]. The most commonly used chemotherapy regimens in the adjuvant setting, FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and CMF (cyclophosphamide, methotrexate, 5-fluorouracil), induce similar rates of anaemia (Hb <12 g/dl) of 4347% [12
]. Moreover, severe anaemia (grade 34: Hb level
7.9 g/dl) has been observed in 11% of patients treated with FAC [13
]. The taxanes also induce high rates of anaemia, with grade 12 anaemia (Hb level <10.98 g/dl) occurring in 6797% of previously untreated patients receiving taxanes as single agents [1
, 12
]. Anaemia is also common in patients receiving radiotherapy [14
]. However, anaemia occurs less frequently with the newer agents found to be effective in metastatic breast cancer, such as capecitabine and trastuzumab [15
17
].
The incidence of anaemia was determined in a prospective survey of 247 Austrian patients with primary non-metastatic breast cancer receiving four cycles of adjuvant, non-platinum-based chemotherapy [18]. At baseline (after surgery), 29% of patients were found to have anaemia (Hb <12 g/dl), and another 42% of the patients developed anaemia during adjuvant chemotherapy. On multivariate analysis, the only significant predictive factor for developing anaemia during chemotherapy was the Hb level at baseline. Of particular note, only 27 of the 145 patients (19%) found to have anaemia at some point during the survey received any treatment for this condition. The findings of this study were remarkably similar to a Europe-wide survey, which included over 3000 patients with breast cancer [19
]. Overall, 62% of breast cancer patients were found to have anaemia at some point during the survey, but only 26% of these received any treatment for anaemia [19
]. These findings highlight the high incidence of anaemia in patients with breast cancer receiving adjuvant therapy. However, the small proportion of patients receiving treatment suggests that anaemia is frequently unrecognised and/or its importance underappreciated.
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Impact of anaemia on survival in patients with breast cancer |
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Finally, pretreatment Hb level (12 g/dl) was an important prognostic factor for overall survival in a study of patients with metastatic breast cancer receiving first-line paclitaxel chemotherapy (relative risk of death in patients with Hb levels <12 g/dl was 2.26 compared with patients with higher Hb) [25
].
There are several possibilities to explain why low Hb levels are associated with impaired survival. First, the presence of anaemia may merely reflect the state of advancement of the cancer, with its impact on the general health of the patient reflected in anaemia and probably other co-morbid markers such as hypoalbuminaemia. Secondly, the development of anaemia may delay administration of potentially curative anticancer treatment and, therefore, affect treatment outcome. Thirdly, an indirect effect of anaemia on patient QoL and well-being may influence survival. Perhaps most importantly, however, many anticancer agents, including those commonly used in breast cancer such as radiotherapy, doxorubicin and 5-fluorouracil, require adequate tissue oxygenation in order to be effective [26]. This suggests that poorly oxygenated or hypoxic tumours will respond less well to treatment than those with better oxygen delivery.
Anaemia is a causative factor in the development of tumour hypoxia, and almost 60% of patients with locally advanced breast cancer have hypoxic tumours [27]. As well as potentially reducing response to chemotherapy, hypoxia gives rise to a more aggressive tumour phenotype and increased likelihood of distant metastases [28
]. A study of patients with head and neck cancer undergoing radiotherapy has confirmed that patients with hypoxic tumours have decreased locoregional control, disease-free and overall survival rates than patients with well-oxygenated tumours [29
].
Since anaemia is associated with poor outcome in patients with breast cancer, effective treatment of anaemia should be considered within the management strategy of these patients.
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Treatment of chemotherapy-induced anaemia |
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Blood transfusions are inconvenient, produce only a temporary rise in Hb and are associated with several risks, including transfusion-mediated immunomodulation, haemolytic reactions, iron overload and the possibility of infection transmission [31]. Transfusions have also been associated with an increase in cancer recurrence rates [32
] and a reduction in overall survival time [33
]. Blood supplies are becoming a limited resource in many countries [34
]. For these reasons, blood transfusion is often delayed until a patient becomes severely anaemic (Hb levels of 78 g/dl) [2
]. Thus, patients with less severe anaemia remained untreated despite the presence of anaemia-related symptoms and their detrimental effect on QoL.
The introduction of recombinant human erythropoietin (epoetin) has provided an effective and convenient treatment of anaemia without the risks of blood transfusion. A number of studies have confirmed that epoetin results in increased Hb levels, reducing transfusion requirements and improving QoL in patients with chemotherapy-associated anaemia and solid or haematological malignancies [3540
].
The benefits of epoetin therapy have been shown both in patients with early-stage and with metastatic breast cancer. A study by Olsson et al. [41] investigated the effect of epoetin beta on the QoL of 180 patients with stage IV metastatic breast cancer and Hb levels <11 g/dl. The majority of patients were receiving second- or third-line chemotherapy. Epoetin beta significantly improved Hb levels and 83% of patients had a clinically significant response to treatment (defined in this study as an increase in Hb of at least 2 g/dl). Global QoL (Figure 1A) and the associated factors of fatigue (Figure 1B) and tiredness all improved over the course of this study, and these improvements became apparent within 4 weeks of treatment initiation. The rapid improvements in QoL represent a particularly beneficial effect of epoetin beta for the chronically ill patients included in this study, who had short expected survival times.
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Prevention of chemotherapy-induced anaemia |
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Until recently, epoetin therapy was not initiated until Hb levels fell to 10 g/dl, or even lower in some circumstances. However, because patients with anaemia often show a poor tolerance to chemotherapy and reduced overall survival, it is possible that prevention of anaemia may result in better patient outcomes. Therefore, use of epoetin to prevent anaemia may represent an important role for this agent in the treatment of patients with breast cancer. In addition, as reported by Crawford et al. [49], Hb levels <12 g/dl are associated with reduced QoL, encouraging earlier use of epoetin to maintain Hb levels of at least 12 g/dl. Indeed, recent guidelines suggest initiating epoetin at Hb levels of 911 g/dl based on anaemia-related symptoms, with a target Hb level of 1213 g/dl [50
].
Studies evaluating the ability of epoetin to prevent the development of clinically significant anaemia during chemotherapy treatment of solid tumours have confirmed the feasibility of this approach. An early controlled study of 227 patients (25% of whom had breast cancer) showed that epoetin beta increased Hb levels and reduced transfusion needs of patients receiving concomitant chemotherapy [51]. In an open-label, community-based study by Hudis and Williams [52
], 1632 patients with stage IIII breast cancer and Hb levels of 1014 g/dl received epoetin alpha concurrently with anthracycline-based adjuvant chemotherapy. Hb levels improved significantly in patients with baseline Hb levels <13 g/dl, and were maintained in patients with Hb levels >13 g/dl. The improvements in Hb levels correlated with improvements in QoL.
Studies have also confirmed that epoetin is effective in preventing anaemia in patients receiving dose-intensified chemotherapy. One of the first studies to investigate the benefits of epoetin in supporting the administration of accelerated adjuvant chemotherapy was reported by Del Mastro et al. [53]. In this controlled study of 62 patients with early-stage breast cancer treated with six cycles of cyclophosphamide, epirubicin and 5-fluorouracil given every 2 weeks, concomitant epoetin administration maintained stable Hb levels >12 g/dl throughout the study (Figure 3). In contrast, control patients developed a progressive anaemia (Figure 3). In addition, during the accelerated chemotherapy, 52% of control patients developed clinically significant anaemia (Hb level
10 g/dl), whereas no epoetin-treated patients developed this level of anaemia. Other studies reported in preliminary form also suggest that concurrent epoetin can maintain Hb levels and reduce the incidence of anaemia in node-positive breast cancer patients receiving dose-intensified chemotherapy [48
, 54
].
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Effect of epoetin on cognitive function |
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Impact of epoetin treatment on survival of breast cancer patients |
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Erythropoietin receptors have been observed on some cancer cells [63, 64
], although their functionality and clinical relevance is currently unknown. Preclinical studies have suggested that epoetin does not induce proliferation of neoplastic cells [65
]. In addition, preculture of various cancer cell lines with epoetin did not cause a significant change in the sensitivity to subsequent exposure to cisplatin [64
].
To date, two studies have reported survival rates following epoetin treatment in patients with breast cancer [39, 62
]. Littlewood et al. [39
] performed a placebo-controlled trial of epoetin alpha in 375 anaemic patients with non-myeloid malignancies (30% of whom had breast cancer) and treated with non-platinum-based chemotherapy. Although the trial was not powered to evaluate survival as an end point, there was a trend towards improved survival with epoetin treatment. Median survival times were 17 months for patients treated with epoetin and 11 months for patients treated with placebo [39
].
In contrast, a recent epoetin alpha trial failed to show a survival benefit in patients with metastatic breast cancer receiving epoetin alpha to prevent anaemia during first-line chemotherapy [62]. At 12 months, there was a higher rate of survival in the placebo group (76%) than the epoetin alpha group (70%) (P=0.012). This difference resulted mainly from an increase in disease progression during the first 4 months of the study in the epoetin group. Because this adverse event occurred after such a brief exposure time, it seems unlikely that it was related to epoetin administration [62
]. Methodological issues have complicated interpretation of this study, with a retrospective chart review suggesting more adverse prognostic factors in patients randomised to epoetin. These differences may have yielded a survival advantage for patients receiving placebo. It should be pointed out that this study was investigational in nature, using epoetin outside of its approved labelling. Also complicating interpretation of the data, a high proportion of patients in the placebo group did not become anaemic during treatment.
One other publication (although not in patients with breast cancer), also using epoetin outside of approved indications, suggests that epoetin may have a negative effect on survival when used to prevent anaemia in patients with head and neck cancer undergoing radiotherapy [61]. In contrast, a number of studies have suggested that epoetins have a beneficial effect on survival in patients with various malignancies [60
, 66
68
]. An independent comprehensive review including all randomised studies evaluating epoetin to prevent or treat anaemia in patients with cancer up to the end of 2001 identified 19 studies including 2865 patients that evaluated survival as an end point [69
]. Meta-analysis of these studies suggested a possible trend towards improved survival in patients receiving epoetin [hazards ratio 0.81; 95% confidence interval (CI) 0.670.99].
Another meta-analysis was performed using pooled data from nine randomised, controlled studies of epoetin beta only in patients with solid and haematological malignancies [70]. A total of 1409 patients (800 receiving epoetin beta and 609 receiving placebo or standard care control treatment) were included. The meta-analysis showed that no positive or negative association exists between the risk of mortality and treatment with epoetin beta (relative risk 0.97; 95% CI 0.691.36; log-rank, P=0.86). The analysis showed a trend to reduced risk of tumour progression in patients treated with epoetin beta compared with control (relative risk 0.79; 95% CI 0.621.00; log-rank, P <0.05). This meta-analysis confirms that epoetin beta can be safely administered to anaemic patients with solid or haematological malignancies: epoetin beta had no negative impact on overall survival and was associated with a trend towards delayed tumour progression.
Further prospective, controlled clinical trials are required to determine whether epoetin has a beneficial effect on survival of patients with cancer. A currently ongoing study, BReast CancerAnaemia and the Value of Erythropoietin (BRAVE), is designed to investigate the impact of epoetin beta on treatment outcome in patients with metastatic breast cancer receiving anthracycline- and/or taxane-based chemotherapy [45]. Recruitment of this study is now complete and its results are expected after an 18-month post-treatment follow-up.
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Impact of epoetin treatment on thromboembolic events |
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The incidence of thrombosis was examined in the meta-analysis of pooled data from nine randomised, controlled trials of epoetin beta in patients with solid and haematological malignancies [73]. The incidence of thromboembolic events was 6% in the 800 patients treated with epoetin beta and 4% in the 609 patients treated with placebo or standard care, a difference that was not statistically significant. Importantly, the proportion of patients who died as a result of a thromboembolic event was identical for the two treatment groups (1.1% of each group). These findings are consistent with the information already contained in the product labelling for the epoetins. It is nevertheless important to avoid overtreatment as the risks of thrombosis rise with levels of Hb above the normal range.
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Conclusions |
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Epoetin is an effective and convenient treatment for chemotherapy-associated anaemia. Several studies have shown than epoetin administered concurrently with chemotherapy can maintain Hb levels and prevent anaemia in breast cancer patients. The European Regulatory Authorities have recently recognised the benefits of the early intervention strategy and approved use of epoetin beta in patients with solid tumours receiving platinum-based chemotherapy that has a high likelihood of inducing anaemia. With the increased use of dose-intensified chemotherapy in an attempt to improve response rates, administration of epoetin to prevent anaemia could potentially benefit many patients with breast cancer.
In patients with breast cancer and anaemia, epoetin increases Hb levels; thus reducing the need for emergency blood transfusions and improving QoL. A recent study in patients with lymphoproliferative malignancies confirms that epoetin beta is equally effective when given once weekly or three times weekly. This once weekly regimen has also proved effective in patients with breast cancer.
Received for publication September 6, 2004. Revision received November 29, 2004. Accepted for publication December 27, 2004.
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