Once-weekly epoetin beta (30,000IU) in anemic patients with lung cancer receiving chemotherapy

1. Introduction 

Anemia frequently occurs in patients with lung cancer undergoing chemotherapy. In the recently published European Cancer Anaemia Survey, which included an evaluation of nearly 2000 patients with lung cancer over a 6-month period, 83.3% of patients receiving chemotherapy were found to have anemia (hemoglobin [Hb]<12g/dL) at some point during the follow-up period [1]. This survey also highlighted that the incidence of anemia (determined in patients not anemic at enrolment and who received their first anticancer therapy during the survey) was 70.9% in patients with lung cancer, higher than in patients with any other cancer type [1]. The negative impact of anemia on quality of life (QoL) is well known, with symptoms including fatigue, dizziness, headache, shortness of breath and depression [2]. Interestingly, patients with cancer consider fatigue to be more debilitating than pain or nausea and vomiting [3], [4], [5], suggesting that fatigue is less well managed than other cancer-related complications.

The widespread use of platinum-based chemotherapy regimens is a major contributing factor to the high incidence of anemia in patients with lung cancer [6], [7]. Platinum compounds cause both direct myelosuppressive effects and damage to the renal tubule, resulting in reduced erythropoietin (EPO) production [8]. Moreover, in patients with lung cancer, comorbid conditions, such as chronic obstructive pulmonary disease, heart disease and other smoking-related disorders, exacerbate the symptoms of anemia and, therefore, the impact of fatigue is often more severe in these patients than in those with other tumor types [9].

The introduction of recombinant human EPO (rHuEPO) has revolutionized the management of anemia. Epoetin beta (NeoRecormon®), a rHuEPO with the same structure and function as the endogenous hormone, is effective in anemic patients with a range of solid or hematologic malignancies. In these patients, epoetin beta increases Hb levels, reduces transfusion requirements and improves QoL [10], [11], [12], [13], [14].

rHuEPO has traditionally been administered three times weekly [15], a schedule that had already proved to be effective in patients with chronic kidney disease on dialysis [16]. However, three times weekly administration of epoetin is perceived as inconvenient and cumbersome by patients and physicians. A less frequent dosing schedule, for example once weekly, simplifies the administration regimen, allowing the treatment to be given on the same day each week. This may improve compliance in patients who self-administer. Once-weekly administration is also more convenient and will reduce administration costs for those patients who attend the clinic for injection.

A previous study in patients with lymphoid malignancies showed epoetin beta to be equally effective at the same overall weekly dose (30,000IU), whether administered once weekly or three times weekly [17]. Rapid Hb increases of >2g/dL from baseline were seen within 8 weeks of therapy in both groups, and Hb response rates were similar with once-weekly (72%) and three times weekly (75%) administration. Once-weekly epoetin beta 30,000IU has subsequently proved to be effective in patients with breast cancer receiving anthracycline- or taxane-based chemotherapy [18].

In this study, we assessed the efficacy and safety of epoetin beta 30,000IU subcutaneously (SC) once weekly in a real-life, clinical setting in patients with lung cancer who developed anemia during palliative chemotherapy. Anemia is a frequent finding in patients with lung cancer, which in our experience occurs early during the course of chemotherapy. Consequently, we used an early intervention strategy with epoetin beta (threshold Hb level for treatment was <12g/dL) to determine whether this could lead to improved patient outcomes, with regard to anemia correction and avoidance of transfusions.

2. Methods 

This was a prospective, observational study performed under real-life, clinical-practice conditions. Patients were enrolled in a sequential manner over a 7-month period in 2004 in the Oncology Department of the Vienna General Hospital.

Patients with small-cell lung cancer (SCLC) or non-SCLC (NSCLC) were eligible for inclusion. All patients were to be treated with chemotherapy during the study. The type of chemotherapy was based on the treating physician's decision according to the individual patient history and no particular regimens were specified.

3. Results 

3.1. Patients 

Forty-two patients were included in the study; however, data on two patients were excluded from the analyses because they did not fulfill the eligibility criteria (one of these was diagnosed with pleuromesothelioma and the other received radiotherapy only). Of the 40 evaluable patients, 72.5% had NSCLC and 27.5% had SCLC (Table 1). Nine patients (24%) had received previous erythropoietic protein therapy; however, none of the patients receiving chemotherapy first-line had received previous erythropoietic protein therapy. The mean baseline Hb level (as measured immediately before epoetin beta initiation) was 10.4±1.2g/dL.

Table 1. Baseline characteristics and demographics of the 40 evaluable patients

	Characteristic	Value
	Gender, n (%)
	Male	18 (45)
	Female	22 (55)
	Age (year)
	Median	60
	Range	37–68
	Mean (S.D.) Hb level (g/dL)	10.4 (1.2)
	Tumor type, n (%)
	SCLC	11 (27.5)
	NSCLC	29 (72.5)
	Prior chemotherapy, n (%)
	No	27 (67.5)
	Yes	13 (32.5)
	Prior erythropoietic protein therapya (%)	9 (24)

SCLC: small-cell lung cancer; NSCLC: non-small-cell lung cancer.

a Data on prior erythropoietic protein therapy is available for 37 patients only.

A total of 27 patients (67.5%) were receiving first-line chemotherapy and 13 (32.5%) were receiving second-line chemotherapy. In two patients, the type of chemotherapy was not recorded; in the remaining 38 patients, 23 (60.5%) received platinum-based chemotherapy and 15 (39.5%) received non-platinum-based chemotherapy. During the study, patients received one to six (median four) chemotherapy cycles. The number of cycles administered after initiation of epoetin beta treatment ranged from 0 to 5.

3.2. Epoetin beta treatment 

Most patients (72.5%) had initiated treatment with epoetin beta for their anemia by the time of completion of the second chemotherapy cycle (Fig. 1). Patients received epoetin beta for a median duration of 4 weeks (range: 1 to >9).

View Large Image Download to PowerPoint

Fig. 1. Chemotherapy cycle after which treatment with epoetin beta 30,000IU once weekly was initiated in patients with lung cancer and anemia (n=40).

All patients initially received epoetin beta 30,000IU once weekly delivered by a single pre-filled syringe. The schedule for increasing the dose of epoetin beta in the event of a suboptimal response was at the investigator's discretion, based on the clinical situation of the patient. Only two patients received an increase in dose of epoetin beta.

3.3. Efficacy evaluations 

Epoetin beta 30,000IU once weekly was associated with a rapid increase in Hb levels. Mean Hb levels at weeks 2, 4 and 6 were 10.6, 11.7 and 12.0g/dL, respectively, indicating a mean increase by week 4 of 1.3g/dL (Fig. 2). In addition, no patient developed severe anemia (Hb≤7.9g/dL) during epoetin beta therapy despite the concomitant chemotherapy; in 19 patients, Hb levels increased above the baseline level and, in the other patients, Hb levels were maintained at about 10g/dL or above.

View Large Image Download to PowerPoint

Fig. 2. Mean hemoglobin levels during treatment with epoetin beta 30,000IU once weekly in patients with lung cancer and anemia.

A Hb response (Hb increase of ≥1g/dL from baseline) was observed in 17 patients (42.5%) over the course of the study; in 16 of these patients (94%), the increase was observed within 4 weeks of initiation of therapy. In addition, 19 patients (47.5%) had a hematopoietic response (Hb increase≥1g/dL and/or Hb level≥12g/dL), 16 (84%) of whom responded within 4 weeks.

4. Discussion 

Anemia is a frequent complication in patients with lung cancer who are receiving chemotherapy. Anemia has a profound impact on QoL, with fatigue being one of its most debilitating symptoms [2]. Furthermore, the widespread use of platinum-based chemotherapy contributes further to the development of anemia in patients with lung cancer [6].

This is the first study to examine the effects of epoetin beta 30,000IU once weekly in patients with lung cancer and anemia in a real-life, clinical-practice setting. The results confirm that epoetin beta 30,000IU once weekly is an effective treatment of anemia under real-life conditions. Responding patients showed a rapid improvement in Hb levels when receiving this therapy, with a mean Hb increase of 1.3g/dL after only 4 weeks of treatment. The need for blood transfusions was very low during the study and epoetin beta was well tolerated. In addition, severe anemia (Hb≤7.9g/dL) was avoided in all patients during epoetin beta therapy.

In patients with lung cancer, anemia is predominantly chemotherapy-related and patients usually receive approximately four chemotherapy cycles. Although epoetin beta treatment duration was relatively short in this study (median of 4 weeks), almost half of the patients demonstrated a hematopoietic response (Hb increase≥1g/dL or Hb level of ≥12g/dL). Therefore, the present study suggests that only a short duration of epoetin beta treatment may be sufficient to control anemia during chemotherapy in many patients with lung cancer. This would have implications for minimizing treatment costs, and this important issue should be proven in further studies. Furthermore, it is possible that a longer duration of treatment with epoetin beta might have resulted in even more patients demonstrating a hematopoietic response.

Coiffier et al. [19] showed that low baseline Hb levels and a decrease in Hb levels during the first 2 months of chemotherapy were factors associated with the development of severe anemia. Similar findings were observed in other studies [1], [20], [21]. Consequently, recent evidence-based guidelines published by the European Organisation for Research and Treatment of Cancer (EORTC) advocate the early initiation of erythropoietic protein therapy at Hb levels of 9–11g/dL, with the aim of improving QoL and reducing transfusion requirements in patients with cancer receiving chemotherapy [22]. Similarly, the American Society of Clinical Oncology/American Society of Hematology clinical-practice guidelines found good evidence to recommend use of epoetin in patients with chemotherapy associated anemia and a Hb <10g/dL; while it was suggested that use of epoetin in patients with less severe anemia (Hb levels between 10 and <12g/dL) should be determined by clinical circumstances [23].

Although we set a higher threshold Hb level (<12g/dL) for treatment than that recommended in the EORTC guidelines, we feel such an early intervention strategy was justified. All patients in the study had experienced a decrease in Hb during the initial stages of chemotherapy and were scheduled to receive further chemotherapy cycles, during which a further decrease in Hb level was anticipated. Moreover, the study confirms the rapid development of anemia in patients with lung cancer receiving chemotherapy. Despite the fact that most patients included in the study were receiving first-line chemotherapy, 72.5% received treatment for anemia early in the course of treatment after the first or second chemotherapy cycle. In addition, the Hb level at the time of epoetin beta initiation was 10.4±1.2g/dL, which is consistent with many trials evaluating epoetin therapy in patients with cancer [10], [11], [17].

The current study suggests that once-weekly epoetin beta 30,000IU is effective in patients with lung cancer and anemia, but the results need to be verified in a prospective, randomized trial. Nevertheless, the results are similar to a previous study in which we evaluated the efficacy and safety of epoetin beta 10,000IU three times weekly in a separate cohort of patients with similar baseline characteristics [24], [25]. In this study of 69 patients with lung cancer and anemia (Hb≤11g/dL) receiving chemotherapy or chemoradiotherapy, 81% achieved a Hb response (Hb increase of ≥1g/dL) and 57% achieved a hematopoietic response (Hb increase≥2g/dL and/or Hb level≥12g/dL). Similar to the current study, the mean Hb increase was approximately 1g/dL after just 4 weeks of epoetin beta therapy.

Other studies with epoetin alfa, epoetin beta or darbepoetin alfa, given at various dosing intervals, have also shown beneficial effects of treatment on Hb levels and transfusion requirements in patients with lung cancer [26], [27], [28], [29], [30], [31], [32], [33]. Although the transfusion rate in the present study was lower than in most previous studies of erythropoietic therapy in patients with lung cancer, it is difficult to make comparisons since the studies vary in their designs. However, the low rate of transfusions (5%) in our study could possibly be explained by the early intervention strategy used. Of particular note, a study in 255 patients with various solid tumors (102 of whom had lung cancer) and scheduled to receive platinum-based chemotherapy also suggested that early intervention with epoetin could prevent severe anemia [32], [33]. In this study, patients received epoetin beta 10,000IU three times weekly if Hb levels decreased to ≤12g/dL in women or ≤13g/dL in men. Overall, 62.4% of patients had an increase in Hb level of at least 1g/dL above baseline and a further 29.4% maintained their Hb level at ±1g/dL of baseline despite the platinum-based chemotherapy [32]. Furthermore, similar results were observed in the subset of patients with lung cancer [33].

Transfusion avoidance through use of an early intervention strategy is an important finding. Transfusions are common in patients with lung cancer [34] and are especially common in those receiving platinum-based chemotherapy, occurring in up to 50% of patients during cisplatin therapy without epoetin support [27], [35]. Avoidance of transfusions has become an important goal of epoetin therapy [22], because blood supplies are limited, transfusions are inconvenient and they are associated with several risks.

Surveys have highlighted that anemia is undertreated in the oncology setting, with only 48% of anemic patients with lung cancer receiving any anti-anemia therapy [1]. Recent research aims to improve the convenience and ease of use of epoetins in the hope that this will allow more patients to receive the benefits of epoetin therapy. Indeed, epoetin beta 30,000IU once weekly has been shown to be equally effective as the traditional 10,000IU three times weekly regimen in the management of anemia in patients with various hematologic cancers [17]. The current study suggests that this regimen is also effective in patients with lung cancer and other studies suggest its feasibility in patients with breast cancer receiving chemotherapy [18], as well as other solid tumor types [36].

There has been some concern lately that erythropoietic therapy may be associated with an increase in the risk of thromboembolic events [37], especially if the target Hb level is above the 12–13g/dL recommended by the EORTC. Consequently, care should be taken to ensure that patients’ Hb levels do not increase beyond this target range, particularly in patients who are at high risk of these complications. There may also be concerns that intervention at higher threshold Hb levels may be associated with an increased risk of complications. In this regard, Bohlius et al. found no evidence of a statistically significant association between the relative risk for thromboembolic events and Hb level at baseline in their meta-analysis of 35 trials including 6769 patients [37]. In addition, epoetin beta was well tolerated in our study and there were no reports of thromboembolic events. However, there is a need for further study in this area.

In conclusion, anemia is a common complication in patients with lung cancer and develops early during the course of chemotherapy. The current study suggests that an early intervention strategy with epoetin beta 30,000IU once weekly given at Hb levels<12g/dL in patients with lung cancer is effective and well tolerated. Mean Hb levels increased under this therapy and all patients avoided severe anemia, despite the concomitant chemotherapy. In addition, most patients avoided transfusions, which is a major goal of erythropoietic therapy. The benefits of epoetin beta were observed with a relatively short duration of therapy (median 4 weeks), a finding that should be verified in a larger controlled trial; however, if proven this would have implications for the cost-effectiveness of treatment.