Treatment of Lung Cancer Associated Anemia 161 Transfusions

Historically, treatment options for patients with lung cancer who develop severe or symptomatic anemia were primarily limited to RBC transfusions. In fact, most physicians still do not treat, unless with RBC transfusion, in case of severe anemia (5).

Although RBC transfusion is the most rapid correction, especially useful in patients with severe or life-threatening anemia, several risks are associated with it, including acute transfusion reactions and transmission of infectious agents (71,72). Furthermore, the limited availability and the cost of transfusion products limit their use. Finally, there is the concern of decreased immunosurveillance of tumors by the recipient of allogeneic transfusion. A negative impact on outcome has been described in some but not all surgical series examining this issue in lung cancer (73) and other cancer types (74,75).

Another treatment option for the management of anemia is the administration of rHuEPO. The Food and Drug Administration (FDA) approved rHuEPO in 1989 for anemia of chronic renal failure. Early randomized trials with rHuEPO in cancer- and chemotherapy-related anemia showed that rHuEPO therapy was associated with up to 50% reduction in the number of RBC transfusions, with, however, a lag in the clinical effect, as the reduction in needed transfusions reached statistical significance only if transfusions during the first month of therapy were excluded from analysis (64,76,77). A similar effect was shown for patients with lung cancer, in whom the time to Hb response (i.e., increase in 2.0 g/dL) was a mean of 54 d (63). Later studies confirmed that rHuEPO, administered three times per week at a dose of 150 U/kg, increases Hb concentrations, decreases the number of required RBC transfusions, and improves QOL, regardless of tumor type or chemotherapy (61-63,78).

The clinical experience with rHuEPO was reviewed in a recent meta-analysis (79). rHuEPO decreased the proportion of transfused patients by 9-45% if started at a mean baseline Hb concentration of <10.0 g/dL or by 7-47% if started at 10.0-12.0 g/dL, and 7-39% if started at >12.0 g/dL. QOL data were insufficient for meta-analysis. Only studies in which rHuEPO was started at a mean baseline Hb concentration of <10.0 g/dL had statistically significant differences in QOL. In the data reviewed, insufficient QOL data were available to justify the start of rHuEPO before the Hb decreased to nearly 10.0 g/dL.

To our knowledge, only two prospective, randomized studies specifically addressed the use of rHuEPO in patients with lung cancer (80,81). The first was an open-label multicenter study designed to evaluate the efficacy and safety of rHuEPO in the prevention of the decline in Hb concentration, and in reduction of transfusion requirements, in nonanemic patients with SCLC scheduled to receive four to six cycles of platinum-based chemotherapy (Table 3) (80). Of the 130 patients, 44 had 300 U/kg rHuEPO three times a week, 42 had rHuEPO 150 U/kg three times a week, and 44 had chemotherapy only. Significantly fewer rHuEPO-treated patients developed anemia (Hb concentration <10.0 g/dL) during their chemotherapy (300 U/kg: 39%; 150 U/kg: 48%; untreated: 66%; p < 0.05; Fig. 1). The percentage of patients requiring transfusion was 20% in the 300-U/kg cohort (p < 0.001), 45% in the 150-U/kg cohort (p < 0.05), and 59% in the untreated cohort (Fig. 2). QOL was assessed by three questions (energy level, daily activity, overall QOL) answered by the patients on a 100-mm visual analog scale and by World Health Organization (WHO) performance status. No substantial differences in QOL was seen across cohorts, which was probably owing to the liberal policy toward transfusion in all groups, resulting in similar mean Hb concentrations in the three cohorts at the end of study period.

The second study was very small and dealt with 72 patients with NSCLC treated with cisplatin-based chemotherapy (81). They were randomly assigned to either 100 U/kg or

Table 3

Randomized Phase 3 Studies on the Use of Red Blood Cell Colony-Stimulating Factors in Platinum-Treated Patients with Lung Cancer

Study

Patients (No.)

Transfusions

Thatcher et al. (80)

No medication rHuEPO

3 x 150 U/kg/wk 3 x 300U/kg/wk Vansteenkiste et al. (88) Placebo

Darbepoetin alfa 1 x 2.25 pg/wk

44

34

59

6.1

16

42

52*

45*

3.8**

24*

44

61**

20***

2.1***

11

161

18

52

1.92

19

159

48***

27***

0.67***

32*

Abbreviation: rHuEPO, recombinant human erythropoietin.

a In ref. 80 expressed as % change vs. baseline on a visual analog scale for the question "How do you rate your overall quality of life (QOL)?"; in ref. 88 expressed as the proportion of patients with at least a 25% improvement from baseline on the Functional Assessment of Cancer Therapy Fatigue scale (FACT-F).

* Significance vs control cohort p < 0.05.

** Significance vs control cohort p < 0.01.

*** Significance vs control cohortp < 0.001.

100 80

1 2 3 4 5 6 Chemotherapy Cycle

A n =

44

42

41

34

24

21

Q n=

42

42

39

32

25

18

• n=

44

41

37

35

26

23

Fig. 1. Comparison of the percentage of patients becoming anemic (Hb < 10 g/dL) during platinum-based chemotherapy for small-cell lung cancer. Open triangles, untreated; open circles, rHuEPO 150 U/kg; closed circles, rHuEPO 300 U/kg. (Reprinted from ref. 80.)

Fig. 2. Transfusion-free times during platinum-based chemotherapy for small-cell lung cancer. Dotted line, rHuEPO 300 U/kg; dashed line, rHuEPO 150 U/kg; solid line, untreated. (Reprinted from ref. 80. )

200 U/kg of rHuEPO or placebo, administered three times a week for 6 wk. Based on only 53 evaluable patients, it was concluded that the Hb concentrations at the nadir after the second cycle of chemotherapy were significantly better in the rHuEPO-treated groups. Conclusions from this study are limited owing to the low number of evaluable patients per cohort and the short period of treatment.

1.6.3. Darbepoetin Alfa

Although rHuEPO has substantially improved our approach to anemic patients with lung cancer, several aspects of this type of treatment are still to be improved. The labeled use of rHuEPO is based on three subcutaneous injections every week. Hb response will be obtained in only 50-60% of the patients, and the time to response is 6-8 wk (54 d in patients with lung cancer in one large study [63]). This rather long time to response is the reason why there is a lag in the clinical effect and why the reduction in transfusion need reaches statistical significance only if transfusions during the first month of therapy are excluded from analysis (64,76,77). The limited survival prospects of patients with advanced lung cancer would make a shorter time to response particularly rewarding in this group. Some of these unmet needs in our current anemia treatment are addressed by darbepoetin alfa, which represents a new generation of ery-thropoiesis-stimulating proteins.

Human EPO is a 46-kDa glycoprotein that contains three N-glycosylation sites. Both endogenous EPO and rHuEPO have varying degrees of glycosylation, sometimes by as few as 8 or as many as 14 sialic acid groups (82). Darbepoetin alfa has 2 additional N-glycosylation sites and has up to 22 sialic acid groups.

The sialic acid content of erythropoietic proteins is directly related to their in vivo half-life and inversely proportional to their affinity to bind the EPO receptor. Preclinical research has demonstrated that the in vivo biologic activity of erythropoietic proteins depends primarily on their half-life and not on their receptor affinity (82,83). Darbepoetin alfa, with its additional sialic acid groups, has an approx threefold (25.3 h vs 8 h, intravenous [iv] administration) longer serum half-life than rHuEPO in animal models and in patients with kidney disease (84). Darbepoetin alfa also maintains Hb concentration as well as rHuEPO, even when administered less frequently (84).

Darbepoetin alfa proved to be safe and clinically effective in early clinical studies in cancer patients undergoing chemotherapy (85), when administered every 1, 2, or even 3 wk (86). In one randomized phase 2 study, involving 429 patients with solid tumors receiving chemotherapy, patients were randomly assigned to darbepoetin alfa doses of 0.5-8.0 pg/kg/wk, or to a control treatment with rHuEPO at an initial dose of 150 U/kg three times weekly (87). A dose of 1.5 pg/kg/week of darbepoetin alfa was active, and higher doses increased the proportion of patients with an Hb response and decreased the median time to response. These findings point at a clear dose-response relationship. Similar results were obtained with administration every 2 wk.

The pivotal randomized, double-blind, placebo controlled, phase 3 study was done in platinum-treated patients with lung cancer (Table 3) (88). In the active cohort, patients received 2.25 pg/kg of darbepoetin alfa per week. This dose was based on pre-clinical and chronic kidney disease data (84), which showed that it had similar effects as rHuEPO 150 U/kg administered three times a week, and on separate studies, in which this dose proved to be clinically effective, in patients receiving chemotherapy for both solid tumors or lymphoproliferative malignancies (87,89). The dose of the study drug could be doubled at wk 7, if the Hb concentration at the beginning of wk 6 had not increased by 1.0 g/dL over the baseline.

Patients with lung cancer, who were expected to receive at least 12 additional weeks of platinum-containing chemotherapy, could be entered in the study if they were anemic (i.e., Hb concentration < 11.0 g/dL), primarily because of their cancer or chemotherapy, with adequate serum folate, vitamin B12, ferritin, and saturated transferrin concentrations. A total of 314 patients could be assessed for RBC transfusions and Hb response (increase of 2.0 g/dL over baseline), adverse events, antibody formation to darbepoetin alfa, hospitalizations, FACT-F score, and disease outcome.

A statistically significant and clinically meaningful reduction > 50% was observed in both the incidence of transfusions and the number of units transfused. The proportion of patients that needed transfusion was significantly lower in the darbepoetin alfa group than in the placebo group (27% vs 52%, p < 0.001), and this proportion was the case for the period of wk 5 until end of study, but also wk 1 until end of study (Fig. 3). They also needed fewer RBC units (mean: 0.67 vs 1.92, p < 0.001). The fact that the effect on the reduction of the number of required RBC transfusions was apparent even when data from the first 4 wk of therapy were included suggests that the 1-mo lag in

Fig. 3. Comparison of the Kaplan-Meier percentage of patients in the placebo or darbepoetin alfa groups who received a red blood cell (RBC) transfusion from wk 5 until end of study. Bars, 95%, CI, p value < 0.001. (Adapted from ref. 88.)

the clinical effect of rHuEPO (64,76,77) may be surpassed with this new agent. This lag probably reflects the influence of pharmacologic doses of rHuEPO on the kinetics of erythropoiesis; such doses do not act rapidly enough to impact on the need for transfusions within the first month of treatment. The results from this study suggested that darbepoetin alfa may improve anemia management not only by less frequent administration but also by a faster onset of action. Darbepoetin alfa appeared to be safe; adverse events were similar across treatment groups, and specific items such as thrombosis or hypertension were also similar. No anti-darbepoetin alfa antibodies were detected. The patients treated with darbepoetin alfa also had better improvement in QOL. Thirty-two percent of patients in the darbepoetin alfa group showed a > 25% improvement in FACT-F, vs only 19% in the placebo group (p = 0.019).

An additional interesting observation was that patients in the darbepoetin alfa group were hospitalized for 10.3±13.7 (mean±SD) d, whereas this figure was 13.0±17.7 d for the placebo group (p = 0.13). Although this study was not designed to identify a causal relationship between hospitalization and the use of darbepoetin alfa, it is possible that patients with higher Hb concentrations may benefit by an overall improvement in performance status that may allow for overall decreased resource utilization. The cost of drug could then be offset by a potential reduction in the duration of hospitalization and reduction in RBC transfusion.

As part of the safety evaluation, all patients who received study drug were included in an analysis of progression-free survival and overall survival. Darbepoetin alfa did

CD O

• Placebo n= 159 149 137 123 104 87 75 66 55 51 45 36 28 21 14 6 4 2 0 0 ADarb. alfa 2.25 n = 155 149 139 125 99 92 85 78 71 60 51 39 25 19 12 8 4 3 1 0 -1-1-1-1-1-1-1-1-T-1-1-1-1-1-1-1-1-1-1-T

1 6 11 16 21 26 31 36 41 46 51 56 61 66 71 76 81 86 91 96 Study Week

Fig. 4. Kaplan-Meier survival for placebo (closed circles) versus darbepoetin alfa patients (open triangles). The median survival time was 34 wk vs. 46 wk for patients receiving darbepoetin alfa. The number of patients at risk is shown above in the x-axis. (Reprinted from ref. 88.)

not have any negative influence on survival; in contrast, the median survival time was 34 wk in the placebo group and 46 wk in the darbepoetin alfa group (Fig. 4). Although no conclusions can be drawn from this ancillary observation, these data, together with the findings in an other study (61), warrant further investigation of the role of anemia correction on overall treatment outcome in prospectively designed studies.

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