Darbepoetin alfa for chemotherapy-induced anemia: evolution to extended dosing intervals

Anemia is a frequent problem in cancer patients, especially in those treated with chemotherapy, and has an important negative impact on quality of life. Red blood cell transfusions provide clear but rather temporary comfort. The development of erythropoietic stimulating agents (ESAs) led to a more durable anemia treatment. Darbepoetin alpha is a unique ESA with a long plasma half life, thereby suitable for administration with different dosing intervals. Apart from administration every week, darbepoetin alpha also proved to be efficient in reducing red blood cell transfusion rates and in improving health-related quality of life when administered at a dose of 500 microg once every 3 weeks. This is a convenient therapy schedule because it can be synchronized with the chemotherapy cycle in many patients. Recently, concerns have been raised about the long-term safety of ESAs, more specifically about their effect on survival. Available data must be interpreted with caution, but at present there is no clear evidence to support a negative effect on outcome with darbepoetin alpha therapy when used according to the guidelines for treatment of chemotherapy-induced anemia. Further studies focusing on survival as the primary end point are ongoing.     

Darbepoetin alfa for chemotherapy-induced anemia: evolution to extended dosing intervals

Anemia is a frequent problem in cancer patients, especially in those treated with chemotherapy, and has an important negative impact on quality of life. Red blood cell transfusions provide clear but rather temporary comfort. The development of erythropoietic stimulating agents (ESAs) led to a more durable anemia treatment. Darbepoetin alfa is a unique ESA with a long plasma half life, thereby suitable for administration with different dosing intervals. Apart from administration every week, darbepoetin alfa also proved to be efficient in reducing red blood cell transfusion rates and in improving health-related quality of life when administered at a dose of 500 µg once every 3 weeks. This is a convenient therapy schedule because it can be synchronized with the chemotherapy cycle in many patients. Recently, concerns have been raised about the long-term safety of ESAs, more specifically about their effect on survival. Available data must be interpreted with caution, but at present there is no clear evidence to support a negative effect on outcome with darbepoetin alfa therapy when used according to the guidelines for treatment of chemotherapy-induced anemia. Further studies focusing on survival as the primary end point are ongoing.     

Darbepoetin alfa administered every three weeks is effective for the treatment of chemotherapy-induced anemia

Patients with cancer receiving chemotherapy often have chemotherapy-induced anemia (CIA) and reduced quality of life. Darbepoetin alfa can effectively treat CIA when administered at an extended dosing interval of once every 3 weeks (Q3W). Darbepoetin alfa administered Q3W may allow synchronization of darbepoetin alfa therapy with chemotherapy administered Q3W. This multicenter, open-label, 16-week study evaluated the effectiveness and safety of darbepoetin alfa administered as a fixed dose (300 mug) Q3W in patients with CIA. Eligible patients (> or =18 years) were anemic (hemoglobin <11g/dl), had a nonmyeloid malignancy, and were receiving multicycle chemotherapy. This analysis includes 1,493 patients who received at least one dose of darbepoetin alfa. The effect of baseline hemoglobin (<10 or > or =10 g/dl) on clinical outcomes was evaluated. Patients in the > or =10-g/dl stratum achieved the hemoglobin target range (11-13 g/dl)in less time than patients in the <10-g/dlstratum (3 weeks vs. 9 weeks). More patients in the > or =10-g/dl stratum achieved the hemoglobin target range (87% vs. 66%); however, similar proportions of patients in both strata maintained hemoglobin within the target range (73% vs. 71%). Fewer patients in the > or =10-g/dl stratum received RBC transfusions from week 5 to the end of the study (12% vs. 28%). Over 50% of patients in both strata reported clinically significant improvements (> or =3-point increase) in Functional Assessment of Cancer Therapy-Fatigue score. Twenty-eight percent of patients reported serious adverse events; 3% of all patients had a venous or arterial thrombotic event. This study demonstrates that darbepoetin alfa Q3W is well tolerated and effective for treating CIA.     

Darbepoetin alfa for the treatment of cancer-related anemia: an update

Anemia is a common and potentially debilitating complication of cancer. Darbepoetin alfa (Aranesp, Amgen) has been in routine clinical use for the treatment of chemotherapy-induced anemia since 2002. The extended half-life of darbepoetin alfa permits less frequent and consequently more flexible dosing than other erythropoietic therapies. Data suggest that hemoglobin levels can be effectively and safely increased with darbepoetin alfa in cancer patients who are receiving chemotherapy (patients with treatment-induced anemia), and in those who are not receiving chemotherapy (patients with tumor-induced anemia). This review provides an overview of clinical trial results, particularly those exploring flexible, extended dosing schedules.     

Darbepoetin alfa for the treatment of cancer-related anemia: an update

Anemia is a common and potentially debilitating complication of cancer. Darbepoetin alfa (Aranesp^®, Amgen) has been in routine clinical use for the treatment of chemotherapy-induced anemia since 2002. The extended half-life of darbepoetin alfa permits less frequent and consequently more flexible dosing than other erythropoietic therapies. Data suggest that hemoglobin levels can be effectively and safely increased with darbepoetin alfa in cancer patients who are receiving chemotherapy (patients with treatment-induced anemia), and in those who are not receiving chemotherapy (patients with tumor-induced anemia). This review provides an overview of clinical trial results, particularly those exploring flexible, extended dosing schedules.     

A randomized, multicenter study of subcutaneous and intravenous darbepoetin alfa for the treatment of chemotherapy-induced anemia.

BACKGROUND: This randomized, open-label study evaluated the efficacy, safety and pharmacokinetics of darbepoetin alfa administered intravenously (i.v.) or subcutaneously (s.c.) in chemotherapy-induced anemia. PATIENTS AND METHODS: Patients received darbepoetin alfa i.v. (n=59) or s.c. (n=59) at a dose of 4.5 mug/kg once weekly for 6 weeks (correction phase) followed by 4.5 mug/kg once every 3 weeks for the remainder of the 18-week treatment period (maintenance phase). RESULTS: During the correction phase, the mean [95% confidence interval (CI)] change in hemoglobin (intention-to-treat) was 1.1 (0.6-1.5) g/dl in the i.v. group and 1.3 (0.9-1.7) g/dl in the s.c. group; using available data, the mean change was 1.4 (1-1.9) g/dl and 1.6 (1.2-2) g/dl, respectively. The percentage (95% CI) of patients maintaining hemoglobin (i.e. average decrease < or =0.5 g/dl) during the maintenance phase was similar between the i.v. (82%; 95% CI 66% to 92%) and s.c. (80%; 95% CI 66% to 90%) groups. Thirty-five per cent (95% CI 20% to 50%) of patients in the i.v. group and 32% of patients in the s.c. group (95% CI 18% to 45%) received red blood cell transfusions during week 5 to the end of the treatment period. Darbepoetin alfa was well tolerated in both groups. No significant difference (P=0.36) in weekly darbepoetin alfa serum concentrations was observed between groups. CONCLUSIONS: Darbepoetin alfa can be administered i.v. or s.c. at equal doses for the treatment of anemia in this setting.     

Darbepoetin alfa in the treatment of anemia in cancer patients undergoing chemotherapy

For years, the treatment of chemotherapy-induced anemia (CIA) consisted of red blood cell transfusions. Major disadvantages of transfusions are their temporary effect and limitation to treatment of severe anemia. In an extensive clinical trial program in patients with CIA, darbepoetin alfa (DA) – a long-acting recombinant human erythropoietin – was proven to be very effective in reducing transfusion needs in patients developing CIA. The administration is suitable with most chemotherapy schemes. Caution is needed in patients with a history of thrombo-embolic events, as a slightly higher incidence of these events is noted in patients treated with darbepoetin alfa or erythropoietin substitution agents (ESAs) in general. In recent years, concerns have been raised about a potential negative influence of these agents on survival. In this respect, it is important to make the distinction between studies on the treatment of existing CIA versus treatment with ESAs outside this indication. On the other hand, it has always been assumed that transfusions were a completely safe treatment, but concerns about a potential negative effect on survival have been raised for transfusions as well. The safety concerns with DA and ESAs in general led to a pharmacovigilance program and an adaptation of the guidelines for treatment of CIA, focusing on treatment of moderate CIA but no longer on mild CIA. Now that the most recent safety data of the pharmacovigilance program of ESAs is almost completed, the clinical impact of the shift to the treatment of only moderate anemia is discussed in this review, which provides a critical view on the indications of DA and the benefit–risk assessment, in order to provide good supportive care without harm to the patient.     

Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial.

PURPOSE: This randomized, double-blind, placebo-controlled trial (N93-004) evaluated the effects of epoetin alfa on tumor response to chemotherapy and survival in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Adult patients with hemoglobin < or = 14.5 g/dL starting chemotherapy received epoetin alfa 150 U/kg or placebo subcutaneously 3 times weekly until 3 weeks after completion of chemotherapy. Survival was assessed for 3 years. The primary end point was the proportion of patients with complete or partial response after three chemotherapy cycles. RESULTS: The trial was terminated prematurely after 224 of a projected 400 patients were accrued. Baseline characteristics were similar between groups. Epoetin alfa and placebo patients (n = 109 and n = 115, respectively) had mean baseline hemoglobin of 12.8 g/dL and 13.0 g/dL, respectively. Overall tumor response was similar between the epoetin alfa and placebo groups after three chemotherapy cycles (72% and 67%, respectively; 95% CI of difference, -6% to 18%) and after completion of chemotherapy (60% and 56%, respectively; 95% CI of difference, -9% to 17%). Epoetin alfa and placebo groups had similar median overall survival (10.5 and 10.4 months, respectively) and overall mortality (91.7% and 87.8%, respectively; hazard ratio, 1.172; 95% CI, 0.887 to 1.549; P = .264). Hemoglobin was maintained in the prechemotherapy range in epoetin alfa patients, but decreased substantially in placebo patients. Fewer epoetin alfa patients than placebo patients required transfusion. CONCLUSION: These results suggest that in newly diagnosed patients with SCLC epoetin alfa does not affect tumor response to chemotherapy or survival. However, the early trial closure makes these conclusions preliminary.     

Treating anemia of cancer with every-4-week darbepoetin alfa: final efficacy and safety results from a phase II, randomized, double-blind, placebo-controlled study

Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia. This phase II, double-blind, placebo-controlled study examined the efficacy of darbepoetin alfa for treating anemia of cancer (AoC) in patients not receiving chemotherapy or radiotherapy. Patients were randomized 3:1 to receive darbepoetin alfa (6.75 microg/kg) or placebo every 4 weeks; the end of the study was at week 17. The primary endpoint was the percentage of patients with a hematopoietic response. Secondary endpoints included transfusion incidence and safety parameters. Efficacy analyses were performed on 162 patients in the darbepoetin alfa group and 56 patients in the placebo group. The Kaplan-Meier percentages of patients who achieved a hematopoietic response (darbepoetin alfa, 69%; placebo, 24%) or achieved the target hemoglobin (darbepoetin alfa, 85%; placebo, 50%) differed significantly between treatment groups. The transfusion incidence did not differ between treatment groups probably because of the low baseline transfusion rates in AoC patients. The incidence of adverse events (including on-study deaths) was similar in both groups. In conclusion, darbepoetin alfa appeared to be well tolerated and significantly increased hemoglobin levels in these AoC study patients.     

Sucralfate in the treatment of chemotherapy-induced stomatitis: a double-blind, placebo-controlled pilot study

BACKGROUND: The study was a double-blind, placebo-controlled, randomised pilot study to assess the efficacy of sucralfate gel in the treatment of chemotherapy-induced mucositis. PATIENTS AND METHODS: At the onset of stomatitis, forty patients received sucralfate gel (1 gr.) or placebo and were instructed to apply the gel over oral mucosas, 3 times daily. RESULTS: Objective response was observed in 14 patients (11 complete response+3 partial response) and in 15 patients (10 CR+5 PR), in the sucralfate and placebo arms, respectively; (p = NS). Analysis of VAS (visual analogue scale) scoring of pain did not detect any statistical difference between the two groups. No important side-effects were observed. Twelve out 21 patients who obtained a complete resolution of stomatitis (5 out of 11 and 7 out of 10 in the sucralfate and in placebo arms, respectively) received further treatment at the subsequent course of chemotherapy; prevention of mucositis was observed in 4 patients in the sucralfate arm and in 6 patients in the placebo arm, respectively. CONCLUSION: In the present pilot study, sucralfate did not demonstrate a significant advantage in comparison to the placebo in the treatment of chemotherapy-induced stomatitis.     

A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer

An important clinical question is the relative efficacy of the most common dosages of darbepoetin alfa (Aranesp; Amgen Inc.; Thousand Oaks, CA) 200 microg every 2 weeks (Q2W) and epoetin alfa (Procrit; Ortho Biotech Products, LP; Raritan, NJ) 40,000 U weekly (QW) for the treatment of chemotherapy-induced anemia. We designed three concurrent randomized, open-label, multicenter, identical trials (with the exception of tumor type criteria of breast, gynecologic, or lung cancer) of darbepoetin alfa and epoetin alfa in patients with chemotherapy-induced anemia to validate the Patient Satisfaction Questionnaire for Anemia (PSQ-An) treatment tool and to compare the efficacies and safety profiles of these two agents. In each trial, patients were randomized 1:1 to receive either darbepoetin alfa at a dose of 200 microg Q2W or epoetin alfa at a dose of 40,000 U QW for up to 16 weeks. The PSQ-An was assessed for validity, feasibility, and reliability. Secondary clinical endpoints were analyzed using the primary analysis set. Both individual trial analyses and a protocol-specified combined analysis of data from all three trials were conducted. Overall, 312 patients (157 darbepoetin alfa; 155 epoetin alfa) were randomized and received study drug. Baseline characteristics were similar in both treatment groups in each trial and overall. The PSQ-An was valid, feasible, and reliable. In general, no difference between treatment groups was observed for hemoglobin- and transfusion-based endpoints in each individual trial or in the combined analysis. From exploratory analyses, achievement and maintenance of a hemoglobin target range (11-13 g/dl) were similar in both groups. No differences in safety were observed. With the PSQ-An, formal comparisons of the impact of anemia therapies on patients and caregivers can be made in future prospective studies. Further, darbepoetin alfa (200 microg Q2W) and epoetin alfa (40,000 U QW) appear to achieve comparable clinical and hematologic outcomes.     

A randomized, open-label, multicenter trial of immediate versus delayed intervention with darbepoetin alfa for chemotherapy-induced anemia

The optimal hemoglobin concentration at which to initiate erythropoietic therapy for chemotherapy-induced anemia (CIA) is not well defined. This randomized, open-label, multicenter study evaluated the ability of darbepoetin alfa (300 microg every 3 weeks) to maintain hemoglobin levels > or =10 g/dl in patients with CIA (hemoglobin > or =10.5 g/dl and < or =12.0 g/dl) randomized 1:1 to an immediate-intervention group (received darbepoetin alfa immediately) or observation group (received darbepoetin alfa if hemoglobin fell to <10 g/dl). In 201 evaluable patients, there was a significant difference between the two groups in the Kaplan-Meier proportion of patients with a hemoglobin decrease to <10 g/dl during weeks 1-13 (test period) (primary endpoint): 29% for immediate-intervention patients versus 65% for observation patients. Sixty-four patients in the observation group received darbepoetin alfa (delayed-intervention subgroup). The Kaplan-Meier proportion of patients who received transfusions was lower in the immediate-intervention group than in the delayed-intervention subgroup (14% versus 31% for the test period; 17% versus 36% over the whole study). The target hemoglobin level (> or =11 g/dl) was achieved by a higher percentage of patients (crude percentage) in less time in the immediate-intervention group (94% in 2 weeks) than in the delayed-intervention subgroup (73% in 6 weeks); hemoglobin endpoints for the delayed-intervention subgroup were calculated from recalibrated study week 1 (the date patients first received darbepoetin alfa). For both groups, a higher mean change in hemoglobin from baseline led to a greater improvement in Functional Assessment of Cancer Therapy-Fatigue scores. In conclusion, immediate intervention resulted in a significantly lower proportion of patients who experienced a decline in hemoglobin, lower requirement for transfusions, and greater proportion of patients achieving and maintaining the target hemoglobin level.     

Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial.

BACKGROUND: We report the first results of a randomized trial assessing a new oral aminobisphosphonate, ibandronate, in patients with bone metastases from breast cancer. PATIENTS AND METHODS: Patients (n = 435) received placebo, or oral ibandronate 20 mg or 50 mg once-daily for 96 weeks. The primary efficacy measure was the number of 12-week periods with new bone complications [skeletal morbidity period rate (SMPR)]. Multivariate Poisson regression analysis assessed the relative risk reduction of skeletal-related events. Secondary efficacy analyses included bone pain and analgesic use. Adverse events were monitored. RESULTS: SMPR was significantly reduced with oral ibandronate [placebo 1.2, 20 mg group 0.97 (P = 0.024), 50 mg group 0.98 (P = 0.037)]. Ibandronate 50 mg significantly reduced the need for radiotherapy (P = 0.005 versus placebo). The relative risk of skeletal events was reduced by 38% (20 mg dose) and 39% (50 mg dose) versus placebo (P = 0.009 and P = 0.005). The tolerability profile of ibandronate was similar to placebo. CONCLUSIONS: Oral ibandronate is an effective and well-tolerated treatment for metastatic bone disease. The 50 mg dose is being further evaluated in clinical trials, and this dose was recently approved in the European Union for the prevention of skeletal events in patients with breast cancer and bone metastases.     

The effect of zinc sulfate in the prevention of high-dose chemotherapy-induced mucositis: a double-blind, randomized, placebo-controlled study

The purpose of this study was to evaluate the effect of oral zinc sulfate in the prevention of chemotherapy-induced mucositis in patients undergoing hematopoietic stem-cell transplantation (HSCT). This study was a double-blind, randomized, placebo-controlled design, with 60 patients undergoing HSCT, divided proportionally in experimental group who received zinc sulfate, and in placebo group. They all had received high-dose chemotherapy conditioning regimen for allogenic transplantation. Oral mucositis assessed was based on World Health Organization (WHO) oral mucositis scale. There were no significant differences in the development of mucositis between the two groups. Severity of mucositis was not significantly different between the two groups either. The same result was obtained regarding the duration of mucositis. Zinc sulfate did not show any significant adverse effects in experimental group. In conclusion, Zinc sulfate did not have any clinical benefits in prevention or reduction of severity, and duration of high-dose chemotherapy-induced mucositis in patients undergoing HSCT.     

A double-blind placebo-controlled randomized study of Chinese herbal medicine as complementary therapy for reduction of chemotherapy-induced toxicity.

BACKGROUND: Chinese herbal medicine (CHM) is a common complementary therapy used by patients with cancer for reduction of chemotherapy-induced toxic effects. This study applied the highest standard of clinical trial methodology to examine the role of CHM in reducing chemotherapy-induced toxicity, while maintaining a tailored approach to therapy. PATIENTS AND METHODS: Patients with early-stage breast or colon cancer who required postoperative adjuvant chemotherapy were eligible for the study. Enrolled patients were randomly assigned to one of three Chinese herbalists who evaluated and prescribed a combination of single-item packaged herbal extract granules. Patients received either CHM or placebo packages with a corresponding serial number. The placebo package contained nontherapeutic herbs with an artificial smell and taste similar to a typical herbal tea. The primary end points were hematologic and non-hematologic toxicity according to the National Cancer Institute Common Toxicity Criteria Version 2. RESULTS: One hundred and twenty patients were accrued at the time of premature study termination. Patient characteristics of the two groups were similar. The incidence of grade 3/4 anemia, leukopenia, neutropenia, and thrombocytopenia for the CHM and placebo groups were 5.4%, 47.3%, 52.7%, and 1.8% and 1.8%, 32.2%, 44.7%, and 3.6%, respectively (P = 0.27, 0.37, 0.63, and 0.13, respectively). Incidence of grade 2 nausea was the only non-hematologic toxicity that was significantly reduced in the CHM group (14.6% versus 35.7%, P = 0.04). CONCLUSIONS: Traditional CHM does not reduce the hematologic toxicity associated with chemotherapy. CHM, however, does have a significant impact on control of nausea.     

Meta‐analysis of epoetin beta and darbepoetin alfa treatment for chemotherapy‐induced anemia and mortality: Individual patient data from Japanese randomized,placebo‐controlled trials

Erythropoiesis‐stimulating agents (ESA) reduce the need for transfusions and improve the quality of life in patients receiving chemotherapy, but several clinical trials have suggested that ESA might have a negative impact on survival. To evaluate the efficacy and safety of ESA, epoetin beta and darbepoetin alfa, including their impact on overall survival and thromboembolic events, we conducted an individual data‐based meta‐analysis of three randomized, placebo‐controlled trials studying Japanese patients with chemotherapy‐induced anemia. All trials were conducted in compliance with Good Clinical Practice. A total of 511 patients with solid tumor or lymphoma (epoetin beta or darbepoetin alfa, n = 273; placebo, n = 238) were included. The ESA significantly reduced the risk of transfusion (relative risk, 0.47; 95% confidence interval, 0.29–0.76). No significant effect of the ESA on overall survival was observed (unadjusted hazard ratio, 1.00; 95% confidence interval, 0.75–1.34). A prespecified subgroup analysis showed no strong interaction between the baseline hemoglobin concentration and the effect of ESA on overall survival. Among the ESA‐treated patients, the highest hemoglobin achieved during the treatment period in each patient had no impact on mortality. No increase in thromboembolic events was observed in the ESA‐treated patients (0.7% vs 1.7% placebo). The ESA reduced the risk of transfusion without a negative impact on the survival of patients with chemotherapy‐induced anemia.     

Once-weekly epoetin-beta improves hemoglobin levels in cancer patients with chemotherapy-induced anemia: A randomized, double-blind, dose-finding study

OBJECTIVE: To determine a recommended dose of once-weekly epoetin-beta administration for anemic cancer patients receiving myelosuppressive chemotherapy, we conducted a multicenter, randomized, double-blind trial. METHODS: A total of 86 patients with malignant lymphoma or lung cancer who received chemotherapy containing platinum, taxanes or anthracyclines were enrolled in the study. Patients were randomly assigned into groups that received three dose levels of epoetin-beta (9000, 18,000 or 36,000 IU) administered subcutaneously once a week for 12 weeks. The primary endpoint was change in hemoglobin, while the secondary endpoints were quality of life (QOL) assessed by Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and transfusion requirements. RESULTS: Among the 69 patients (per protocol set population) assessable for efficacy, hemoglobin level change in the 36,000 IU group was significantly greater than that in the 9000 IU group (1.75 +/- 2.15 versus 0.04 +/- 1.98 g/dl; P = 0.009), and a significant dose-response relationship was observed for the change in hemoglobin level (P = 0.003). Although changes in FACT-An Total Fatigue subscale (Fatigue subscale) scores were similar for the three dosage groups, there was a statistically significant correlation (r = 0.435, P < 0.001) between the change in hemoglobin levels and the change in Fatigue subscale scores. The proportion of transfused patients was significantly smaller in the 36 000 IU group compared with that in the 9000 IU group (P = 0.022, not adjusted for pre-study transfusions). The incidence of adverse events was similar in the three dosage groups. CONCLUSIONS: Once-weekly epoetin-beta 36,000 IU for 12 weeks was well tolerated and significantly increased hemoglobin levels in anemic cancer patients receiving chemotherapy.     

Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind,placebo-controlled,randomised study

This dose-finding, placebo-controlled study evaluated the safety and efficacy of darbepoetin alfa administered every 3 weeks (Q3W) to anaemic patients receiving chemotherapy. In part A, patients (haemoglobin 50% of patients achieving a haematopoietic response. Administration of darbepoetin alfa Q3W has a tolerable safety profile and effectively ameliorates anaemia due to chemotherapy.