Darbepoetin Alfa for the Treatment of Chemotherapy-Induced Anemia: Disease Progression and Survival Analysis From Four Randomized, Double-Bl
http://www.100md.com
《临床肿瘤学》
the Sundsvall Hospital, Sundsvall, Sweden
University Hospital Gasthuisberg, Leuven, Belgium
Ashford Cancer Centre, Ashford, Australia
Amgen Inc, Thousand Oaks, CA
ABSTRACT
PURPOSE: To determine the effect of darbepoetin alfa (DA) on progression-free survival (PFS) and overall survival (OS) in patients with chemotherapy-induced anemia (CIA).
PATIENTS AND METHODS: Two 16-week randomized, double-blind, placebo-controlled phase III studies of weekly DA in anemic patients with lung cancer (n = 314) or lymphoproliferative malignancies (LPMs; n = 344) undergoing chemotherapy were analyzed with prospectively defined long-term PFS and OS end points. Short-term effects of DA on PFS and OS were analyzed by including two additional 16-week dose-finding, double-blind, placebo-controlled studies in anemic patients with multiple tumor types (n = 405) and LPMs (n = 66).
RESULTS: Median follow-up is 15.8 months (lung cancer) and 32.6 months (LPM). Median duration of PFS was comparable between DA and placebo: 5.1 months (95% CI, 4.1 to 6.9 months) versus 4.4 months (95% CI, 3.7 to 5.3 months) for lung cancer and 14.2 months (95% CI, 12.2 to 17.5 months) versus 15.9 months (95% CI, 13.1 to 19.0 months) for LPMs. The estimated hazard ratio (HR) of death related to DA use for lung cancer was 0.77 (95% CI, 0.59 to 1.01) and 1.26 (95% CI, 0.92 to 1.71) for LPMs. In the pooled analyses of all four studies (n = 1,129), no differences in PFS or OS were observed between DA and placebo (HR = 0.92; 95% CI, 0.78 to 1.07; and HR = 0.95; 95% CI, 0.78 to 1.16, respectively).
CONCLUSION: Treatment with DA does not seem to influence PFS or OS in patients with CIA. Prospective, randomized clinical trials will provide additional insights into the effects of DA on PFS and OS in specific tumor types.
INTRODUCTION
Anemia, a common comorbidity of patients with cancer, has been associated with poor prognosis in multiple cancer settings.1-8 A recent meta-analysis of 60 published studies suggested that hemoglobin level may be an independent prognostic factor for survival.1 One possible mechanism by which anemia could potentially affect clinical outcomes in anemic cancer patients may relate to the known association between low hemoglobin levels and decreased tumor oxygenation.9 Multiple preclinical and clinical studies hypothesize that tumor hypoxia contributes to the malignant phenotype.10-17 Tumor hypoxia correlates with increased tumor aggressiveness, resistance to radiotherapy and chemotherapy, and decreased patient survival.8,18,19 Many studies have also reported that inadequate tumor oxygenation in anemic patients is associated with poor treatment outcomes after curative radiotherapy.3,4,20-24 Several studies, including randomized clinical trials and retrospective analyses, have reported an association between anemia correction, tumor oxygenation, and improved outcomes in head and neck cancer,2 cervical cancer,3 non–small-cell lung cancer,25 and mixed tumors.26 A recently presented meta-analysis examining the effect of erythropoietic agents on overall survival in eight randomized controlled trials in chemotherapy-induced anemia (CIA) involving 1,624 patients showed a benefit trend for patients receiving erythropoietic treatment (hazard ratio [HR], 0.80; 95% CI, 0.65 to 1.00).27
In contrast to these results, two randomized, placebo-controlled studies conducted in metastatic breast cancer (INT-76)28 and head and neck cancer (MF4449)29 in patients with epoetin alfa and epoetin beta, respectively, have suggested increased tumor progression and decreased survival associated with epoetin treatment. These studies, which used baseline and target hemoglobin levels beyond those approved by regulatory agencies and recommended in evidence-based guidelines,30-32 have been criticized because of limitations related to trial design and execution.33-36 More recent studies in breast cancer, head and neck cancer, and lymphoproliferative malignancies (LPMs) have not shown a negative effect of epoetin treatment on survival.37-39
Darbepoetin alfa is a unique erythropoietic protein with greater sialic acid content, a longer terminal half-life, and greater biologic activity than epoetin alfa,40,41 allowing less-frequent administration with a similar efficacy and safety profile.42,43 We performed an analysis of the darbepoetin alfa clinical trial experience to ascertain whether administration of darbepoetin alfa influences tumor progression and overall survival (OS) in patients with cancer. We report here on analyses including four double-blind, randomized studies to evaluate the impact of darbepoetin alfa on progression-free survival (PFS) and OS.
PATIENTS AND METHODS
Study Design
Four double-blind, randomized, placebo-controlled CIA studies were included in these analyses. The design of the studies has been published previously 44-47 and these studies are summarized in Table 1. Two of these were 16-week phase III studies of darbepoetin alfa administered weekly and conducted in anemic patients with lung cancer (study A)44 or LPMs (study B)45 receiving chemotherapy. For safety reasons, both studies included prospectively defined collection of long-term, open-label survival and disease progression information. Because of the observation of an early effect on mortality seen with epoetin alfa in the INT-76 study, two 16-week, phase II dose-finding studies that did not include long-term follow-up were combined with study A and study B. These studies were conducted in patients with mixed tumor types (study C)46 and LPMs (study D).47
Survival and disease status data were collected at 3-month intervals for a median duration of 15.8 months for study A. For study B, data were collected at 3-month intervals for the first year and then every 6 months for a median duration of 32.6 months. Patients who withdrew from the study due to withdrawal of consent were censored at the time of withdrawal.
PFS was measured from first investigational product administration until progression or death as a result of any cause. The investigator reported tumor status as either progressed or not progressed relative to the disease stage recorded at baseline according to the WHO definition of tumor response. OS was measured from the date of first investigational product administration until death as a result of any cause. Patients were censored at the date of last contact. Fifteen patients in study B had imputed values for PFS and 10 patients had imputed values for OS. All OS imputed values and 13 of the 15 PFS imputed values were because only the month and year were recorded; the 15th of the month was used as the value for the day when this occurred. Two patients had imputed dates for PFS; we used the midpoint between the date the patient was last known not to have progressed and the earliest date the patient was known to have progressed. Two patients in study A had imputed values for PFS and six patients had imputed values for OS. All PFS and OS imputed dates were because only the month and year were recorded, with a maximum error of 16 days. A sensitivity analysis was performed by removing the patients with imputed dates; these analyses were consistent with the findings and conclusions stated in this article.
Statistical Analysis
The effect of darbepoetin alfa on PFS and OS was evaluated with Kaplan-Meier estimates and Cox regression models. Patients included in the analysis received at least one dose of darbepoetin alfa. Patients were censored at the date of last contact.
Cox regression models, stratified by study protocol, examined the relationship between treatment (darbepoetin alfa compared with placebo) and baseline hemoglobin, maximum hemoglobin achieved, and rate of hemoglobin increase. This stratified Cox model (an extension of the proportional hazards model) allows for each stratum (study) to have a distinct baseline hazard function. In this manner, common coefficients of interest between the studies can be estimated.
Time-dependent, hemoglobin-related covariates were used to assess the effect of changes in hemoglobin concentrations and their association with PFS and OS. The minimum hemoglobin value among all values in the specified interval was compared with the current value to determine increases in hemoglobin concentration. Hemoglobin measurements on the day of a transfusion and for the next 28 days thereafter were excluded from the analysis to eliminate transfusion as the cause of hemoglobin increases.
All analyses were performed using SAS software, version 8.2 (SAS Institute Inc, Cary, NC) and S-PLUS software, version 6.2 (Insightful Corp, Seattle, WA).
RESULTS
Patient Demographics and Disposition
Long-term follow-up: studies A and B. Recruitment for study A and study B began in September 1999 and October 2000, respectively; long-term follow-up analysis includes final data as of February 2002 for study A and April 2004 for study B. Three hundred twenty lung cancer patients and 349 patients with LPM were randomly assigned to receive either darbepoetin alfa (159 and 176 patients) or placebo (161 and 173 patients). Six lung cancer patients and five patients with LPM withdrew from the study before receiving study drug; thus, 314 patients (98%) with lung cancer (155 darbepoetin alfa, 159 placebo) and 344 patients (99%) with LPM (175 darbepoetin alfa, 169 placebo) who received at least one dose of darbepoetin alfa were included in the analysis. In both studies, patient baseline demographics and tumor type distribution were well balanced between groups. However, some imbalances for prognostic factors within individual tumor types were observed in study B.45 A higher proportion of patients with high/intermediate-risk and high-risk non-Hodgkin's lymphoma, as defined by International Prognostic Index, were included in the darbepoetin alfa group than in the placebo group (44% v 33%, respectively). In addition, the darbepoetin alfa group had a higher proportion of patients with stage C chronic lymphocytic leukemia (59% v 42%).
Dose finding: studies C and D. Patient demographics and disposition for study C and study D have been reported previously.46,47 Briefly, 405 patients with mixed solid tumors and 66 patients with LPM were randomly assigned to receive either darbepoetin alfa or placebo. In both studies, baseline demographics and disease characteristics were similar between the darbepoetin alfa and placebo groups, except for a higher proportion of women in the placebo group in study D.
Analysis of PFS and OS: Long-Term Follow-Up Studies
Study A. Disease progression or death for lung cancer patients in the darbepoetin alfa group was similar to that of patients in the placebo group (Fig 1). The median duration of PFS was 5.1 months (95% CI, 4.1 to 6.9 months) and 4.4 months (95% CI, 3.7 to 5.3 months) for darbepoetin alfa and placebo (HR, 0.79; 95% CI, 0.62 to 1.00; P = .051; Fig 1, upper panel). The median OS time was 10.4 months (95% CI, 8.8 to 12.0 months) and 7.8 months (95% CI, 6.6 to 9.0 months; HR, 0.77; 95% CI, 0.59 to 1.01; P = .060; Fig 1, lower panel). Progression and survival end points analyzed by histology (non–small-cell lung cancer or small cell lung cancer) also revealed no significant differences between patients receiving darbepoetin alfa and placebo (data not shown).
Study B. Disease progression or death was similar for LPM patients in the darbepoetin alfa and placebo groups (Fig 2). The median duration of PFS was 14.2 months (95% CI, 12.2 to 17.5 months) and 15.9 months (95% CI, 13.1 to 19.0 months) for darbepoetin alfa and placebo (HR, 1.03; 95% CI, 0.80 to 1.32; P = .803; Fig 2, upper panel). The median OS time was 30.4 months (95% CI, 22.7 months to not assessable) for darbepoetin alfa and 36.6 months (95% CI, 30.2 months to not assessable) for placebo (HR, 1.26; 95% CI, 0.92 to 1.71; P = .152; Fig 2, lower panel). Progression and survival end points analyzed by histology (aggressive and indolent lymphomas, chronic lymphocytic leukemia, and multiple myeloma) or disease stage also revealed no significant differences between patients receiving darbepoetin alfa and placebo (data not shown).
Pooled Analysis of PFS and OS
Because the detrimental effect on survival reported in the INT-76 study seemed to be due to an increase in mortality in the epoetin alfa arm during the first 16 weeks of the study,28 we performed a pooled analysis of the two studies described above combined with two additional double-blind, randomized, placebo-controlled studies with short-term (16 week) follow-up, and analyzed PFS and OS over 16 weeks, concomitant with darbepoetin alfa and placebo administration. This pooled analysis of PFS and OS, combining data from all four studies (n = 1,129), revealed an estimated HR related to darbepoetin alfa use of 0.92 (95% CI, 0.78 to 1.07; P = .280) for PFS and 0.95 (95% CI, 0.78 to 1.16; P = .619) for OS (Fig 3). The median duration of PFS was 8.0 months (95% CI, 7.2 to 9.3 months) for darbepoetin alfa and 6.8 months (95% CI, 5.9 to 8.0 months) for placebo. The median OS time was 19.0 months (95% CI, 14.6 to 22.3 months) for darbepoetin alfa and 16.4 months (95% CI, 14.6 to 22.6 months) for placebo.
PFS and OS: Subset Analyses
Analysis by baseline hemoglobin category. One atypical design feature shared by the INT-76 and MF4449 studies, relative to most studies of erythropoietic-stimulating proteins, was that epoetin therapy was initiated in patients with mild anemia (mean hemoglobin, 12 g/dL in the MF4449 study) or in nonanemic patients (INT-76). To determine whether hemoglobin concentration at baseline influenced PFS and OS in studies with darbepoetin alfa, we performed a pooled analysis of the four placebo-controlled oncology trials evaluating progression and survival end points in three different patient subsets: patients with baseline hemoglobin concentrations less than 9.0, 9.0 to 10.5, and more than 10.5 g/dL. These categories were selected to allow for groups of sufficient size. Analyses on mildly anemic or nonanemic patients (ie, hemoglobin > 11.0 g/dL) could not be conducted because the inclusion criteria for all darbepoetin alfa studies specified baseline hemoglobin less than 11.0 g/dL.
The numbers of patients included in each baseline hemoglobin category, length of follow-up, and number of mortality events observed for darbepoetin alfa and placebo groups are listed in Table 2. Studies C and D randomly assigned more patients to the darbepoetin alfa treatment arm than placebo and did not contain a long-term follow-up component. As a result, when combined with studies A and B, which had 1:1 randomization and a long-term follow-up component, the median time of follow-up for the placebo-treated group is longer than for those patients treated with darbepoetin alfa. Relative to patients receiving placebo with hemoglobin concentrations of 9 to 10.5 g/dL, the estimated HRs for PFS for patients with a baseline hemoglobin concentration less than 9 g/dL was 2.05 (95% CI, 1.49 to 2.82) for patients receiving placebo and 1.51 (95% CI, 1.09 to 2.10) for patients receiving darbepoetin alfa. Similarly, an association between anemia and adverse effects on OS was observed for patients receiving placebo (HR, 2.08; 95% CI, 1.38 to 3.14) and darbepoetin alfa (HR, 1.86; 95% CI, 1.20 to 2.89). These results (summarized in Table 3) are consistent with multiple previous reports indicating an association between anemia and adverse tumor and survival outcomes.1
Comparisons of PFS and OS between patients receiving darbepoetin alfa and placebo were analyzed for each of the baseline hemoglobin categories. These analyses suggest a benefit of darbepoetin alfa administration relative to placebo in terms of OS for patients with moderate or severe anemia (baseline hemoglobin < 9 g/dL), with an estimated HR of 0.66 (95% CI, 0.45 to 0.98; P = .037; Fig 4). Similar results were observed for PFS (HR, 0.62; 95% CI, 0.45 to 0.86; P = .004). No significant differences between darbepoetin alfa and placebo patient groups were observed for either end point for the other baseline hemoglobin categories.
Analysis by rate of increase and maximum hemoglobin. Because the adverse outcomes observed in the INT-76 and MF4449 studies may have been attributable to aggressive dosing and design rules leading to rapid hemoglobin in-creases and high hemoglobin concentrations, we next examined the potential effects of these factors on PFS and OS in studies of darbepoetin alfa. Analyses using achievement of high hemoglobin values were limited by the small number of patients (particularly in the placebo group) meeting this criterion; therefore, we selected hemoglobin parameters that were represented sufficiently in our studies. Because long-term mortality potentially attributable to these pharmacodynamic effects is unlikely to be influenced by short-term exposure to treatment, we limited these analyses to the first 12 months of follow-up. Table 4 lists sample size, median follow-up, and mortality for patients achieving a hemoglobin concentration of 13 g/dL and for those experiencing a hemoglobin increase 1 g/dL in any 14-day period. As listed in Table 5, achievement of these hemoglobin parameters was associated with significant improvements in PFS and OS. The estimated HR of PFS or OS for those experiencing a hemoglobin increase more than 1 g/dL in any 14-day period was 0.51 (95% CI, 0.42 to 0.62) and 0.43 (95% CI, 0.34 to 0.56; P < .001). In those patients achieving a hemoglobin concentration of 13 g/dL, the estimated HR of PFS was 0.66 (95% CI, 0.51 to 0.84) and OS was 0.56 (95% CI, 0.40 to 0.79; P = .001).
DISCUSSION
Subsequent to the emergence of literature reports describing a potential role of epoetin alfa and epoetin beta in tumor progression,28,29 we undertook an analysis of the darbepoetin alfa clinical trial experience to ascertain whether similar observations were associated with darbepoetin alfa therapy in CIA. We described here individual and pooled analyses of four studies showing nearly identical PFS and OS for patients receiving darbepoetin alfa and placebo, both after short- and long-term follow-up. These analyses include double blind, randomized, placebo-controlled studies designed to assess efficacy and safety end points in CIA. Consequently, these studies are heterogeneous for factors that are important in assessing the benefits of oncology therapeutics, including tumor histology, disease stage, chemotherapy treatment, method and timing of tumor assessment, and length of follow-up. Nevertheless, the size of the resulting patient sample (n = 1,129) and estimated HRs corresponding to decreases in PFS and OS provide more than 80% power to detect an effect on survival of the magnitude seen in previous reports (HR, 1.36 for INT-76; HR, 1.39 for MF4449).28,29,48
The results published in the INT-76 and MF4449 trials contrast with the lack of an apparent adverse effect on tumor progression and OS seen previously in the oncology setting in patients receiving erythropoietic agents.2,25-27,37-39,44,45 We considered that the negative results reported in the INT-76 and MF4449 trials may have been the result of unique design features of those studies, such as the inclusion of patients with higher baseline hemoglobin levels and the use of aggressive dosing in a nonmyelosuppressive setting resulting in rapid hemoglobin increases.29 In our combined analyses, we explored whether these factors were associated with an adverse outcome for patients treated with darbepoetin alfa relative to placebo. These analyses first confirmed that hemoglobin concentration at baseline is a strong and highly significant marker of risk. This relationship does not necessarily establish a causal effect, given that it may represent an association between anemia severity and disease burden.
We also observed that increasing hemoglobin concentration during the study represents a highly significant marker of reduced risk. This effect was apparent in the patients treated with darbepoetin alfa but not in the patients treated with placebo (data not shown). Consistent with these results, we further observed that an increase in hemoglobin concentrations to values of 13 or 14 g/dL might represent a marker of reduced risk. However, these analyses do not address causality; a possible interpretation of these observations is that patients with more advanced cancer are less responsive to darbepoetin alfa treatment. Although these observations do not support the concept that the findings of the INT-76 and MF4449 trials were the result of an exaggerated pharmacodynamic effect of erythropoietic therapy in nonanemic patients, firm conclusions regarding the effects of aggressive erythropoietic therapy on PFS and OS in nonanemic patients cannot be drawn from these results; high hemoglobin targets and fast rates of hemoglobin increases could not be studied given the more conservative titration rules used in these darbepoetin alfa trials.
In summary, although the primary end points of these studies were not PFS and OS, both individual trial analyses and pooled analyses indicate that darbepoetin alfa does not significantly alter PFS or OS in cancer patients with CIA. These studies confirm that baseline hemoglobin is a highly significant marker of risk and that increasing hemoglobin is associated with reduced risk. Prospective, randomized clinical trials will provide additional insights into the effects of darbepoetin alfa on PFS and OS in specific tumor types.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank the patients and study coordinators for their dedication to these trials. We thank Steve Dahlberg for his assistance with statistical analysis, and Janis Schaap for editorial support.
NOTES
Supported by Amgen Inc, Thousand Oaks, CA.
Presented in part at the 29th Congress of the European Society for Medical Oncology, October 29-November 2, 2004, Vienna, Austria; 16th International Symposium of the Multinational Association of Supportive Care in Cancer, June 24–27, 2004, Miami, FL; and 9th Congress of the European Hematology Association, June 10-13, 2004, Geneva, Switzerland.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Briefing Package for the FDA Oncologic Drugs Advisory Committee Meeting, May 2004. http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037b2.htm(Michael Hedenus, Johan Va)
University Hospital Gasthuisberg, Leuven, Belgium
Ashford Cancer Centre, Ashford, Australia
Amgen Inc, Thousand Oaks, CA
ABSTRACT
PURPOSE: To determine the effect of darbepoetin alfa (DA) on progression-free survival (PFS) and overall survival (OS) in patients with chemotherapy-induced anemia (CIA).
PATIENTS AND METHODS: Two 16-week randomized, double-blind, placebo-controlled phase III studies of weekly DA in anemic patients with lung cancer (n = 314) or lymphoproliferative malignancies (LPMs; n = 344) undergoing chemotherapy were analyzed with prospectively defined long-term PFS and OS end points. Short-term effects of DA on PFS and OS were analyzed by including two additional 16-week dose-finding, double-blind, placebo-controlled studies in anemic patients with multiple tumor types (n = 405) and LPMs (n = 66).
RESULTS: Median follow-up is 15.8 months (lung cancer) and 32.6 months (LPM). Median duration of PFS was comparable between DA and placebo: 5.1 months (95% CI, 4.1 to 6.9 months) versus 4.4 months (95% CI, 3.7 to 5.3 months) for lung cancer and 14.2 months (95% CI, 12.2 to 17.5 months) versus 15.9 months (95% CI, 13.1 to 19.0 months) for LPMs. The estimated hazard ratio (HR) of death related to DA use for lung cancer was 0.77 (95% CI, 0.59 to 1.01) and 1.26 (95% CI, 0.92 to 1.71) for LPMs. In the pooled analyses of all four studies (n = 1,129), no differences in PFS or OS were observed between DA and placebo (HR = 0.92; 95% CI, 0.78 to 1.07; and HR = 0.95; 95% CI, 0.78 to 1.16, respectively).
CONCLUSION: Treatment with DA does not seem to influence PFS or OS in patients with CIA. Prospective, randomized clinical trials will provide additional insights into the effects of DA on PFS and OS in specific tumor types.
INTRODUCTION
Anemia, a common comorbidity of patients with cancer, has been associated with poor prognosis in multiple cancer settings.1-8 A recent meta-analysis of 60 published studies suggested that hemoglobin level may be an independent prognostic factor for survival.1 One possible mechanism by which anemia could potentially affect clinical outcomes in anemic cancer patients may relate to the known association between low hemoglobin levels and decreased tumor oxygenation.9 Multiple preclinical and clinical studies hypothesize that tumor hypoxia contributes to the malignant phenotype.10-17 Tumor hypoxia correlates with increased tumor aggressiveness, resistance to radiotherapy and chemotherapy, and decreased patient survival.8,18,19 Many studies have also reported that inadequate tumor oxygenation in anemic patients is associated with poor treatment outcomes after curative radiotherapy.3,4,20-24 Several studies, including randomized clinical trials and retrospective analyses, have reported an association between anemia correction, tumor oxygenation, and improved outcomes in head and neck cancer,2 cervical cancer,3 non–small-cell lung cancer,25 and mixed tumors.26 A recently presented meta-analysis examining the effect of erythropoietic agents on overall survival in eight randomized controlled trials in chemotherapy-induced anemia (CIA) involving 1,624 patients showed a benefit trend for patients receiving erythropoietic treatment (hazard ratio [HR], 0.80; 95% CI, 0.65 to 1.00).27
In contrast to these results, two randomized, placebo-controlled studies conducted in metastatic breast cancer (INT-76)28 and head and neck cancer (MF4449)29 in patients with epoetin alfa and epoetin beta, respectively, have suggested increased tumor progression and decreased survival associated with epoetin treatment. These studies, which used baseline and target hemoglobin levels beyond those approved by regulatory agencies and recommended in evidence-based guidelines,30-32 have been criticized because of limitations related to trial design and execution.33-36 More recent studies in breast cancer, head and neck cancer, and lymphoproliferative malignancies (LPMs) have not shown a negative effect of epoetin treatment on survival.37-39
Darbepoetin alfa is a unique erythropoietic protein with greater sialic acid content, a longer terminal half-life, and greater biologic activity than epoetin alfa,40,41 allowing less-frequent administration with a similar efficacy and safety profile.42,43 We performed an analysis of the darbepoetin alfa clinical trial experience to ascertain whether administration of darbepoetin alfa influences tumor progression and overall survival (OS) in patients with cancer. We report here on analyses including four double-blind, randomized studies to evaluate the impact of darbepoetin alfa on progression-free survival (PFS) and OS.
PATIENTS AND METHODS
Study Design
Four double-blind, randomized, placebo-controlled CIA studies were included in these analyses. The design of the studies has been published previously 44-47 and these studies are summarized in Table 1. Two of these were 16-week phase III studies of darbepoetin alfa administered weekly and conducted in anemic patients with lung cancer (study A)44 or LPMs (study B)45 receiving chemotherapy. For safety reasons, both studies included prospectively defined collection of long-term, open-label survival and disease progression information. Because of the observation of an early effect on mortality seen with epoetin alfa in the INT-76 study, two 16-week, phase II dose-finding studies that did not include long-term follow-up were combined with study A and study B. These studies were conducted in patients with mixed tumor types (study C)46 and LPMs (study D).47
Survival and disease status data were collected at 3-month intervals for a median duration of 15.8 months for study A. For study B, data were collected at 3-month intervals for the first year and then every 6 months for a median duration of 32.6 months. Patients who withdrew from the study due to withdrawal of consent were censored at the time of withdrawal.
PFS was measured from first investigational product administration until progression or death as a result of any cause. The investigator reported tumor status as either progressed or not progressed relative to the disease stage recorded at baseline according to the WHO definition of tumor response. OS was measured from the date of first investigational product administration until death as a result of any cause. Patients were censored at the date of last contact. Fifteen patients in study B had imputed values for PFS and 10 patients had imputed values for OS. All OS imputed values and 13 of the 15 PFS imputed values were because only the month and year were recorded; the 15th of the month was used as the value for the day when this occurred. Two patients had imputed dates for PFS; we used the midpoint between the date the patient was last known not to have progressed and the earliest date the patient was known to have progressed. Two patients in study A had imputed values for PFS and six patients had imputed values for OS. All PFS and OS imputed dates were because only the month and year were recorded, with a maximum error of 16 days. A sensitivity analysis was performed by removing the patients with imputed dates; these analyses were consistent with the findings and conclusions stated in this article.
Statistical Analysis
The effect of darbepoetin alfa on PFS and OS was evaluated with Kaplan-Meier estimates and Cox regression models. Patients included in the analysis received at least one dose of darbepoetin alfa. Patients were censored at the date of last contact.
Cox regression models, stratified by study protocol, examined the relationship between treatment (darbepoetin alfa compared with placebo) and baseline hemoglobin, maximum hemoglobin achieved, and rate of hemoglobin increase. This stratified Cox model (an extension of the proportional hazards model) allows for each stratum (study) to have a distinct baseline hazard function. In this manner, common coefficients of interest between the studies can be estimated.
Time-dependent, hemoglobin-related covariates were used to assess the effect of changes in hemoglobin concentrations and their association with PFS and OS. The minimum hemoglobin value among all values in the specified interval was compared with the current value to determine increases in hemoglobin concentration. Hemoglobin measurements on the day of a transfusion and for the next 28 days thereafter were excluded from the analysis to eliminate transfusion as the cause of hemoglobin increases.
All analyses were performed using SAS software, version 8.2 (SAS Institute Inc, Cary, NC) and S-PLUS software, version 6.2 (Insightful Corp, Seattle, WA).
RESULTS
Patient Demographics and Disposition
Long-term follow-up: studies A and B. Recruitment for study A and study B began in September 1999 and October 2000, respectively; long-term follow-up analysis includes final data as of February 2002 for study A and April 2004 for study B. Three hundred twenty lung cancer patients and 349 patients with LPM were randomly assigned to receive either darbepoetin alfa (159 and 176 patients) or placebo (161 and 173 patients). Six lung cancer patients and five patients with LPM withdrew from the study before receiving study drug; thus, 314 patients (98%) with lung cancer (155 darbepoetin alfa, 159 placebo) and 344 patients (99%) with LPM (175 darbepoetin alfa, 169 placebo) who received at least one dose of darbepoetin alfa were included in the analysis. In both studies, patient baseline demographics and tumor type distribution were well balanced between groups. However, some imbalances for prognostic factors within individual tumor types were observed in study B.45 A higher proportion of patients with high/intermediate-risk and high-risk non-Hodgkin's lymphoma, as defined by International Prognostic Index, were included in the darbepoetin alfa group than in the placebo group (44% v 33%, respectively). In addition, the darbepoetin alfa group had a higher proportion of patients with stage C chronic lymphocytic leukemia (59% v 42%).
Dose finding: studies C and D. Patient demographics and disposition for study C and study D have been reported previously.46,47 Briefly, 405 patients with mixed solid tumors and 66 patients with LPM were randomly assigned to receive either darbepoetin alfa or placebo. In both studies, baseline demographics and disease characteristics were similar between the darbepoetin alfa and placebo groups, except for a higher proportion of women in the placebo group in study D.
Analysis of PFS and OS: Long-Term Follow-Up Studies
Study A. Disease progression or death for lung cancer patients in the darbepoetin alfa group was similar to that of patients in the placebo group (Fig 1). The median duration of PFS was 5.1 months (95% CI, 4.1 to 6.9 months) and 4.4 months (95% CI, 3.7 to 5.3 months) for darbepoetin alfa and placebo (HR, 0.79; 95% CI, 0.62 to 1.00; P = .051; Fig 1, upper panel). The median OS time was 10.4 months (95% CI, 8.8 to 12.0 months) and 7.8 months (95% CI, 6.6 to 9.0 months; HR, 0.77; 95% CI, 0.59 to 1.01; P = .060; Fig 1, lower panel). Progression and survival end points analyzed by histology (non–small-cell lung cancer or small cell lung cancer) also revealed no significant differences between patients receiving darbepoetin alfa and placebo (data not shown).
Study B. Disease progression or death was similar for LPM patients in the darbepoetin alfa and placebo groups (Fig 2). The median duration of PFS was 14.2 months (95% CI, 12.2 to 17.5 months) and 15.9 months (95% CI, 13.1 to 19.0 months) for darbepoetin alfa and placebo (HR, 1.03; 95% CI, 0.80 to 1.32; P = .803; Fig 2, upper panel). The median OS time was 30.4 months (95% CI, 22.7 months to not assessable) for darbepoetin alfa and 36.6 months (95% CI, 30.2 months to not assessable) for placebo (HR, 1.26; 95% CI, 0.92 to 1.71; P = .152; Fig 2, lower panel). Progression and survival end points analyzed by histology (aggressive and indolent lymphomas, chronic lymphocytic leukemia, and multiple myeloma) or disease stage also revealed no significant differences between patients receiving darbepoetin alfa and placebo (data not shown).
Pooled Analysis of PFS and OS
Because the detrimental effect on survival reported in the INT-76 study seemed to be due to an increase in mortality in the epoetin alfa arm during the first 16 weeks of the study,28 we performed a pooled analysis of the two studies described above combined with two additional double-blind, randomized, placebo-controlled studies with short-term (16 week) follow-up, and analyzed PFS and OS over 16 weeks, concomitant with darbepoetin alfa and placebo administration. This pooled analysis of PFS and OS, combining data from all four studies (n = 1,129), revealed an estimated HR related to darbepoetin alfa use of 0.92 (95% CI, 0.78 to 1.07; P = .280) for PFS and 0.95 (95% CI, 0.78 to 1.16; P = .619) for OS (Fig 3). The median duration of PFS was 8.0 months (95% CI, 7.2 to 9.3 months) for darbepoetin alfa and 6.8 months (95% CI, 5.9 to 8.0 months) for placebo. The median OS time was 19.0 months (95% CI, 14.6 to 22.3 months) for darbepoetin alfa and 16.4 months (95% CI, 14.6 to 22.6 months) for placebo.
PFS and OS: Subset Analyses
Analysis by baseline hemoglobin category. One atypical design feature shared by the INT-76 and MF4449 studies, relative to most studies of erythropoietic-stimulating proteins, was that epoetin therapy was initiated in patients with mild anemia (mean hemoglobin, 12 g/dL in the MF4449 study) or in nonanemic patients (INT-76). To determine whether hemoglobin concentration at baseline influenced PFS and OS in studies with darbepoetin alfa, we performed a pooled analysis of the four placebo-controlled oncology trials evaluating progression and survival end points in three different patient subsets: patients with baseline hemoglobin concentrations less than 9.0, 9.0 to 10.5, and more than 10.5 g/dL. These categories were selected to allow for groups of sufficient size. Analyses on mildly anemic or nonanemic patients (ie, hemoglobin > 11.0 g/dL) could not be conducted because the inclusion criteria for all darbepoetin alfa studies specified baseline hemoglobin less than 11.0 g/dL.
The numbers of patients included in each baseline hemoglobin category, length of follow-up, and number of mortality events observed for darbepoetin alfa and placebo groups are listed in Table 2. Studies C and D randomly assigned more patients to the darbepoetin alfa treatment arm than placebo and did not contain a long-term follow-up component. As a result, when combined with studies A and B, which had 1:1 randomization and a long-term follow-up component, the median time of follow-up for the placebo-treated group is longer than for those patients treated with darbepoetin alfa. Relative to patients receiving placebo with hemoglobin concentrations of 9 to 10.5 g/dL, the estimated HRs for PFS for patients with a baseline hemoglobin concentration less than 9 g/dL was 2.05 (95% CI, 1.49 to 2.82) for patients receiving placebo and 1.51 (95% CI, 1.09 to 2.10) for patients receiving darbepoetin alfa. Similarly, an association between anemia and adverse effects on OS was observed for patients receiving placebo (HR, 2.08; 95% CI, 1.38 to 3.14) and darbepoetin alfa (HR, 1.86; 95% CI, 1.20 to 2.89). These results (summarized in Table 3) are consistent with multiple previous reports indicating an association between anemia and adverse tumor and survival outcomes.1
Comparisons of PFS and OS between patients receiving darbepoetin alfa and placebo were analyzed for each of the baseline hemoglobin categories. These analyses suggest a benefit of darbepoetin alfa administration relative to placebo in terms of OS for patients with moderate or severe anemia (baseline hemoglobin < 9 g/dL), with an estimated HR of 0.66 (95% CI, 0.45 to 0.98; P = .037; Fig 4). Similar results were observed for PFS (HR, 0.62; 95% CI, 0.45 to 0.86; P = .004). No significant differences between darbepoetin alfa and placebo patient groups were observed for either end point for the other baseline hemoglobin categories.
Analysis by rate of increase and maximum hemoglobin. Because the adverse outcomes observed in the INT-76 and MF4449 studies may have been attributable to aggressive dosing and design rules leading to rapid hemoglobin in-creases and high hemoglobin concentrations, we next examined the potential effects of these factors on PFS and OS in studies of darbepoetin alfa. Analyses using achievement of high hemoglobin values were limited by the small number of patients (particularly in the placebo group) meeting this criterion; therefore, we selected hemoglobin parameters that were represented sufficiently in our studies. Because long-term mortality potentially attributable to these pharmacodynamic effects is unlikely to be influenced by short-term exposure to treatment, we limited these analyses to the first 12 months of follow-up. Table 4 lists sample size, median follow-up, and mortality for patients achieving a hemoglobin concentration of 13 g/dL and for those experiencing a hemoglobin increase 1 g/dL in any 14-day period. As listed in Table 5, achievement of these hemoglobin parameters was associated with significant improvements in PFS and OS. The estimated HR of PFS or OS for those experiencing a hemoglobin increase more than 1 g/dL in any 14-day period was 0.51 (95% CI, 0.42 to 0.62) and 0.43 (95% CI, 0.34 to 0.56; P < .001). In those patients achieving a hemoglobin concentration of 13 g/dL, the estimated HR of PFS was 0.66 (95% CI, 0.51 to 0.84) and OS was 0.56 (95% CI, 0.40 to 0.79; P = .001).
DISCUSSION
Subsequent to the emergence of literature reports describing a potential role of epoetin alfa and epoetin beta in tumor progression,28,29 we undertook an analysis of the darbepoetin alfa clinical trial experience to ascertain whether similar observations were associated with darbepoetin alfa therapy in CIA. We described here individual and pooled analyses of four studies showing nearly identical PFS and OS for patients receiving darbepoetin alfa and placebo, both after short- and long-term follow-up. These analyses include double blind, randomized, placebo-controlled studies designed to assess efficacy and safety end points in CIA. Consequently, these studies are heterogeneous for factors that are important in assessing the benefits of oncology therapeutics, including tumor histology, disease stage, chemotherapy treatment, method and timing of tumor assessment, and length of follow-up. Nevertheless, the size of the resulting patient sample (n = 1,129) and estimated HRs corresponding to decreases in PFS and OS provide more than 80% power to detect an effect on survival of the magnitude seen in previous reports (HR, 1.36 for INT-76; HR, 1.39 for MF4449).28,29,48
The results published in the INT-76 and MF4449 trials contrast with the lack of an apparent adverse effect on tumor progression and OS seen previously in the oncology setting in patients receiving erythropoietic agents.2,25-27,37-39,44,45 We considered that the negative results reported in the INT-76 and MF4449 trials may have been the result of unique design features of those studies, such as the inclusion of patients with higher baseline hemoglobin levels and the use of aggressive dosing in a nonmyelosuppressive setting resulting in rapid hemoglobin increases.29 In our combined analyses, we explored whether these factors were associated with an adverse outcome for patients treated with darbepoetin alfa relative to placebo. These analyses first confirmed that hemoglobin concentration at baseline is a strong and highly significant marker of risk. This relationship does not necessarily establish a causal effect, given that it may represent an association between anemia severity and disease burden.
We also observed that increasing hemoglobin concentration during the study represents a highly significant marker of reduced risk. This effect was apparent in the patients treated with darbepoetin alfa but not in the patients treated with placebo (data not shown). Consistent with these results, we further observed that an increase in hemoglobin concentrations to values of 13 or 14 g/dL might represent a marker of reduced risk. However, these analyses do not address causality; a possible interpretation of these observations is that patients with more advanced cancer are less responsive to darbepoetin alfa treatment. Although these observations do not support the concept that the findings of the INT-76 and MF4449 trials were the result of an exaggerated pharmacodynamic effect of erythropoietic therapy in nonanemic patients, firm conclusions regarding the effects of aggressive erythropoietic therapy on PFS and OS in nonanemic patients cannot be drawn from these results; high hemoglobin targets and fast rates of hemoglobin increases could not be studied given the more conservative titration rules used in these darbepoetin alfa trials.
In summary, although the primary end points of these studies were not PFS and OS, both individual trial analyses and pooled analyses indicate that darbepoetin alfa does not significantly alter PFS or OS in cancer patients with CIA. These studies confirm that baseline hemoglobin is a highly significant marker of risk and that increasing hemoglobin is associated with reduced risk. Prospective, randomized clinical trials will provide additional insights into the effects of darbepoetin alfa on PFS and OS in specific tumor types.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank the patients and study coordinators for their dedication to these trials. We thank Steve Dahlberg for his assistance with statistical analysis, and Janis Schaap for editorial support.
NOTES
Supported by Amgen Inc, Thousand Oaks, CA.
Presented in part at the 29th Congress of the European Society for Medical Oncology, October 29-November 2, 2004, Vienna, Austria; 16th International Symposium of the Multinational Association of Supportive Care in Cancer, June 24–27, 2004, Miami, FL; and 9th Congress of the European Hematology Association, June 10-13, 2004, Geneva, Switzerland.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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