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Effects of Epoetin Alfa on Hematologic Parameters and Quality of Life in Cancer Patients Receiving Nonplatinum Chemotherapy: Results of a Randomized, Double-Blind, Placebo-Controlled Trial

From the John Radcliffe Hospital, Oxford, United Kingdom; National Cancer Institute, Milan, Italy; Leiden University Medical Center, Leiden, the Netherlands; R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ; and The Medical Oncology Center of Rosebank, Johannesburg, South Africa.

Please visit http://www.jco.org to view the appendix for this article.Address reprint requests to Timothy J. Littlewood, MD, John Radcliffe Hospital, Headington, OX3 9DU Oxford, United Kingdom; email: tim.littlewood{at}orh.anglox.nhs.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: This randomized, double-blind, placebo-controlled clinical trial assessed the effects of epoetin alfa on transfusion requirements, hematopoietic parameters, quality of life (QOL), and safety in anemic cancer patients receiving nonplatinum chemotherapy. The study also explored a possible relationship between increased hemoglobin and survival.

PATIENTS AND METHODS: Three hundred seventy-five patients with solid or nonmyeloid hematologic malignancies and hemoglobin levels 10.5 g/dL, or greater than 10.5 g/dL but 12.0 g/dL after a hemoglobin decrease of 1.5 g/dL per cycle since starting chemotherapy, were randomized 2:1 to epoetin alfa 150 to 300 IU/kg (n = 251) or placebo (n = 124) three times per week subcutaneously for 12 to 24 weeks. The primary end point was proportion of patients transfused; secondary end points were change in hemoglobin and QOL. The protocol was amended before unblinding to prospectively collect and assess survival data 12 months after the last patient completed the study.

RESULTS: Epoetin alfa, compared with placebo, significantly decreased transfusion requirements (P = .0057) and increased hemoglobin (P < .001). Improvement of all primary cancer- and anemia-specific QOL domains, including energy level, ability to do daily activities, and fatigue, was significantly (P < .01) greater for epoetin alfa versus placebo patients. Although the study was not powered for survival as an end point, Kaplan-Meier estimates showed a trend in overall survival favoring epoetin alfa (P = .13, log-rank test), and Cox regression analysis showed an estimated hazards ratio of 1.309 (P = .052) favoring epoetin alfa. Adverse events were comparable between groups.

CONCLUSION: Epoetin alfa safely and effectively ameliorates anemia and significantly improves QOL in cancer patients receiving nonplatinum chemotherapy. Encouraging results regarding increased survival warrant another trial designed to confirm these findings.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
ANEMIA OCCURS frequently and is a common concern in cancer patients, particularly those receiving chemotherapy.^1,2 Often, anemia gives rise to symptoms such as exhaustion, fatigue, weakness, impaired concentration, respiratory distress, and chest pain, any of which can lead to diminished physical capacity and quality of life (QOL).^3-6

Epoetin alfa is recombinant human erythropoietin, the hematologic growth factor that regulates the proliferation, maturation, and differentiation of RBCs.^7-9 Epoetin alfa has been shown in clinical trials to correct or prevent anemia and to decrease the need for blood transfusions.^10-15 Recently, several large trials that included patients who received platinum or nonplatinum chemotherapy have demonstrated that the benefits of epoetin alfa extend to improvement in QOL and are directly related to the erythropoietin-stimulated increase in hemoglobin.^14-16

The study described here is an international placebo-controlled trial of epoetin alfa in patients with a broad range of malignancies for which they were receiving nonplatinum chemotherapy. This study was designed to evaluate the efficacy, safety, and QOL outcomes of epoetin alfa in patients with solid or nonmyeloid hematologic malignancies receiving nonplatinum chemotherapy, with the goal of providing additional clinical information on the role of epoetin alfa in this population.

During the course of this study, data from other studies further established that low hemoglobin levels may be associated with a poorer prognosis in patients receiving chemotherapy, radiotherapy, or a combination of the two.^17-20 For this reason, the study protocol was amended before unblinding and prior to study completion to permit assessment of possible effects of epoetin alfa on patient survival.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Study Patients and Design
This study was a multinational, multicenter, randomized, double-blind, placebo-controlled trial. Male and female patients aged 18 years or older with a confirmed diagnosis of solid or nonmyeloid hematologic malignancy and receiving or scheduled to receive nonplatinum chemotherapy (with a minimum cycle duration of 3 weeks) were enrolled. All patients had a life expectancy of at least 6 months and had hemoglobin levels 10.5 g/dL, or levels greater than 10.5 g/dL but 12.0 g/dL after a 1.5-g/dL or greater decrease in hemoglobin level per cycle or month since beginning chemotherapy. None of the patients had received platinum-containing chemotherapy within 3 months of study enrollment. Patients with acute leukemia (acute lymphocytic leukemia or acute myelolytic leukemia) and myeloid malignancies were excluded, as were those with uncontrolled hypertension or untreated iron, folate, or vitamin B₁₂ deficiency. Also excluded were patients who had undergone myeloablative chemotherapy or who had had acute major infection or bleeding within 1 month, radiotherapy or allogeneic blood transfusion within 14 days, or severe illness or surgery within 7 days of study entry. All patients gave written informed consent before study entry, and the study protocol and amendments were reviewed by an independent ethics committee.

Enrolled patients were assigned randomly 2:1 to receive either epoetin alfa (EPREX/ERYPO; Ortho Biotech Europe/Janssen-Cilag [also marketed in the United States as PROCRIT; Ortho Biotech Products, LP]) or placebo. Randomization was prospectively stratified according to tumor stratum (solid or hematologic) and hemoglobin level ( 10.5 g/dL, or 12.0 but > 10.5 g/dL as described above; for simplicity, the latter stratification criterion will be referred to as > 10.5 g/dL). Treatment was initiated with epoetin alfa 150 IU/kg or a matching volume of placebo administered subcutaneously three times weekly for 4 weeks. If, at the end of 4 weeks, the hemoglobin level had increased by 1 g/dL above baseline or the reticulocyte count had increased by 40,000/µL, study drug was continued at the original dose. However, if the hemoglobin level had not increased by 1 g/dL and the reticulocyte count had not increased by 40,000/µL, the dose was doubled to 300 IU/kg or a matching volume of placebo three times a week. If the hemoglobin level exceeded 15 g/dL at any time, study medication was withheld until the hemoglobin level decreased to less than 12 g/dL and was then restarted at a 25% reduced dose. Dosages were also reduced by 25% if the hemoglobin level increase was 2 g/dL per month or per cycle to maintain the increase to less than 2 g/dL per cycle. Study treatment was administered for a maximum of 28 weeks, which included 12 to 24 weeks (three to six cycles) of chemotherapy and a 4-week period after the last dose of chemotherapy. Transfusion of RBCs was permitted during the study at the discretion of the physician but was to be avoided in patients with a hemoglobin level greater than 8 g/dL unless clinically indicated.

An oral daily dose of 200 mg of elemental iron was recommended to maintain appropriate iron availability and iron stores. If during the study, transferrin saturation fell to 20%, intravenous iron (preferably iron saccharate) was recommended, but use of iron dextran was not allowed.

Evaluation of Efficacy and Safety
The primary efficacy end point was the proportion of patients transfused after the first 4 weeks of treatment. Transfusions that occurred during the first 4 weeks were not included because the observed treatment effects would not be expected until after this period. Transfusion was also used as an end point in earlier trials of epoetin alfa in patients undergoing chemotherapy.^11,21,22 Secondary efficacy evaluations included the change in hemoglobin level from baseline to last value, the proportion of responders (patients with an increase in hemoglobin level 2 g/dL unrelated to transfusion, ie, no transfusion within 28 days before measurement), change in QOL scores from baseline to last value, and survival. In addition, two other transfusion-related end points were assessed: cumulative transfusion rate, calculated as the number of units transfused per patient per 3 months on study, and the time to first transfusion (or hemoglobin level < 8 g/dL) after the first 28 days. Each of these end points was specified in the original protocol. Transfusion information was recorded for the 3 months preceding study entry and then for the entire study period. Hemoglobin evaluations were performed at screening (within 7 days of first administration of study drug), 2 weeks after the start of study drug, and then every 2 weeks or after each halfway interval of each chemotherapy cycle, and at study completion or early withdrawal. QOL was measured using a patient-completed QOL battery consisting of the Functional Assessment of Cancer Therapy–Anemia (FACT-An) scale, the Cancer Linear Analog Scale (CLAS, also known as the LASA, Linear Analog Scale Assessment), and the Medical Outcomes Study Short Form-36 (SF-36). The FACT-An is a 55-item questionnaire consisting of a 34-item general questionnaire, the FACT-G, and a 21-item Anemia subscale. Thirteen of the 21 anemia items comprise a separate Fatigue subscale. The CLAS consists of three linear analog scales, each 100 mm long, that measure level of energy, the ability to do daily activities, and overall QOL related to cancer symptoms. Patients score their own perceptions of these domains (measures) by placing a mark along the line, with 0 as worst and 100 as best QOL. The FACT and CLAS scales are cancer-specific and have demonstrated sensitivity to hemoglobin^14,15,23 and therefore were considered particularly suitable for detecting any change in QOL due to administration of epoetin alfa and subsequent increase in hemoglobin. The SF-36 was included as a general measure of QOL. QOL assessments were completed before the start of the study, at weeks 4 and 16 (before the start of the second and fifth chemotherapy cycles, respectively), and again at the end of the study or at early withdrawal. A subset of seven scales and subscales from the three instruments were selected a priori for primary analysis of QOL: the FACT-G and Fatigue subscale of the FACT-An, the three CLAS scales (Energy Level, Ability To Do Daily Activities, and Overall QOL), and the Physical Component Summary and Mental Component Summary scales of the SF-36. In addition, the Anemia subscale of the FACT-An was examined as a secondary measure of QOL.

Survival rates were determined based on data collected during the 12-month period after study completion by the last patient. Safety was evaluated in the usual way by monitoring adverse events, which were reported by patients throughout the study either spontaneously or in response to questioning by the investigator.

Statistical Analyses
Four study populations were designated for purposes of statistical analyses: intent-to-treat (ITT): all randomized patients; efficacy (EFF): all randomized patients who were in the study more than 28 days; safety: all randomized patients who received at least one dose of study drug and for whom safety information was available; and QOL: a subset of ITT patients who had been randomized, had received study drug, and had a baseline and at least one follow-up QOL assessment. The safety and ITT populations were identical.

The primary efficacy variable (proportion of patients transfused after the first 4 weeks of treatment) was analyzed for both the ITT and EFF populations. Patients on study 28 days or less were counted as transfused for the ITT analysis. The analyses were performed using a logistic regression model that included terms correcting for the main effects of treatment group, primary tumor stratum (solid or hematologic), and hemoglobin stratum ( 10.5 g/dL or > 10.5 g/dL). Since the interaction terms for treatment by tumor stratum and treatment by hemoglobin stratum were not significant at the 10% level, they were not included in the model.

Secondary efficacy variables other than QOL domains were analyzed for the EFF population. Changes in hemoglobin level from baseline to last value were compared by t tests, and the proportions of responders were compared by the Fisher’s exact test.

Univariate analyses were performed to test within-group mean QOL change scores for differences from zero using a paired t test, and differences in mean change scores between the treatment groups were examined using independent sample t tests (two-sided). The P values for the primary QOL measures (but not for the secondary QOL measure) were adjusted for multiple comparisons using a sequentially rejective version of the Bonferroni procedure.²⁴ All hypothesis tests were performed on the adjusted P values. In a separate analysis, Pearson correlation coefficients were calculated to assess the relationship between change in hemoglobin and in QOL scores for each primary QOL measure.

The protocol, although not designed or powered for survival, was amended before unblinding and study end to permit prospective analysis of survival. Information for this analysis, including date and cause of death, was collected 12 months after study end, and survival distributions were estimated with Kaplan-Meier curves, which were compared by means of log-rank tests. In addition, to compensate for the variable survival times associated with different malignancies, Kaplan-Meier estimates of survival by tumor strata (hematologic v solid) were also performed. Further analysis with the Cox regression model was performed using a stepwise selection procedure to correct for effects of potential prognostic factors on patient survival. Eight factors were tested; four—tumor stratum, baseline hemoglobin level, age, and area under the curve for neutrophils—were found to be significant and included in the model.

For all statistical analyses, P < .05 was considered significant. Because the study was not powered for subgroups, P values were not computed for the tumor and hemoglobin strata.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
A total of 375 patients were enrolled at 73 sites in 15 countries (Table 1; ITT population). Of these patients, 251 received epoetin alfa and 124 received placebo. Sixteen patients (seven receiving epoetin alfa and nine receiving placebo) were excluded from the efficacy evaluation, 14 (six receiving epoetin alfa and eight receiving placebo) because they discontinued before completing at least 28 study days and two (one patient per treatment group) because the blind on their treatment codes was broken prematurely. The remaining 359 patients (244 receiving epoetin alfa and 115 receiving placebo) completed more than 28 study days and were assessable for efficacy (EFF population).

View this table: [in this window] [in a new window]   Table 3. Most Frequent ( 20% overall) Chemotherapeutic Agents Used During the Study for the Three Most Common Tumor Types (ITT population)

Transfusion Requirements
In the ITT population, a significantly smaller proportion of patients in the epoetin alfa group (24.7%) than in the placebo group (39.5%) was transfused after day 28 (P = .0057, Wald’s ² test from the logistic model correcting for tumor stratum and hemoglobin stratum). Results were comparable when transfusion requirements were examined by tumor stratum (solid, 24.3% v 36.4%; hematologic, 25.2% v 43.1%) and by hemoglobin stratum ( 10.5 g/dL, 28.2% v 42.2%; > 10.5 g/dL, 7.1% v 20.0%). A similar pattern was seen in the EFF population (23.0% v 35.7%, P = .0168). These results remained significant after additional correction for between-group differences in prestudy transfusion requirements (ITT, P = .0114; EFF, P = .0232).

An advantage was also observed for epoetin alfa over placebo for two other transfusion-related end points: for all patients in the EFF population, the mean cumulative transfusion rate was lower (1.4 v 2.5 units/3 months on study, P = .03, t test) and the time to first transfusion or low hemoglobin level (< 8 g/dL) after day 28 was significantly longer (P = .0001, log-rank test) in the epoetin alfa group.

Hematopoietic Response
Figure 1 shows the mean biweekly hemoglobin levels over the 28 weeks of the study for all patients in the EFF population by treatment group. In epoetin alfa–treated patients, mean hemoglobin levels increased gradually from week 2 to reach approximately 12 g/dL by week 10 and were maintained at this level through week 28 or last value. In placebo-treated patients, mean biweekly hemoglobin levels changed little during the study period, despite a higher transfusion rate in the placebo group. The mean increase in hemoglobin level from baseline to last value was significantly greater in the epoetin alfa group than in the placebo group (2.2 g/dL v 0.5 g/dL, P < .001). Because hemoglobin was assessed irrespective of transfusions, any transfusion-related changes for this parameter were included in the calculation of mean changes in hemoglobin. Thus, the significantly greater increase in hemoglobin level seen in epoetin alfa–treated patients was achieved despite the significantly (P = .0168) lower transfusion rate in the epoetin alfa group. When change in hemoglobin was examined by tumor stratum (solid or hematologic) and hemoglobin stratum ( 10.5 g/dL or > 10.5 g/dL), a pattern similar to that of the overall efficacy population was observed (Table 4).

View larger version (14K): [in this window] [in a new window]   Fig 1. Mean biweekly hemoglobin (Hb) levels for all patients treated with epoetin alfa or placebo (EFF population). Missing values at any evaluation point are replaced by last value carried forward.

QOL
Of the 375 ITT patients, 349 (238 randomized to epoetin alfa and 111 randomized to placebo) were evaluated for changes in QOL parameters. Twenty-six patients were excluded from the QOL analysis, four because they lacked any QOL data whatsoever and 22 because they were missing either baseline or all follow-up QOL data. Fifty-four patients in the total QOL population had no FACT-An or SF-36 data because validated translations of FACT-An and SF-36 questionnaires were unavailable in the languages spoken by these individuals (ie, Czech, Greek, Hungarian, and Polish) at the start of the study. However, validated translations of the CLAS questionnaire were available for all language groups represented in the study.

Mean change scores for six cancer- and anemia-specific QOL scales (five primary end points from the FACT-An and CLAS and the Anemia subscale from the FACT-An) are shown in Figs 2 and 3. Significant differences for epoetin alfa over placebo were found for all five primary QOL scales (range, P = .0007 to P = .0048, adjusted for multiple comparisons). Also, a highly significant P value of .0007 (not adjusted for multiple comparisons) for epoetin alfa was noted for the Anemia subscale of the FACT-An. Differences in mean change scores for the two non–cancer-specific primary measures, SF-36 Physical Component Summary (epoetin alfa: 1.8 v placebo: -0.5) and Mental Component Summary (epoetin alfa, 2.1 v placebo, -0.3), demonstrated trends favoring epoetin alfa (P = .0512 and P = .0952, respectively).

View larger version (21K): [in this window] [in a new window]   Fig 2. Comparison of QOL (FACT-An, comprising FACT-G, Fatigue Subscale, and Anemia Subscale) mean change scores by treatment group (QOL population). Asterisk (*) indicates that the P value for the Anemia subscale (secondary measure) is unadjusted. All other P values, which correspond to primary measures, are adjusted for multiple comparisons (sequentially rejective Bonferroni procedure).

View larger version (22K): [in this window] [in a new window]   Fig 3. Comparison of QOL (CLAS, comprising Energy Level, Ability To Do Daily Activities, and Overall QOL) mean change scores by treatment group (QOL population). All P values, which correspond to primary measures, are adjusted for multiple comparisons (sequentially rejective Bonferroni procedure).

View larger version (23K): [in this window] [in a new window]   Fig 4. Kaplan-Meier estimate of survival at 26-month median follow-up (safety population), which was 12 months after completion of study by last patient; slashes represent the end of the observation period for surviving patients. Differences in estimated survival rates, P = .13 by log-rank test.

View larger version (33K): [in this window] [in a new window]   Fig 5. Kaplan-Meier estimate of survival at 26-month median follow-up by tumor stratum (solid v hematologic) (safety population), which was 12 months after completion of study by last patient; slashes represent the end of the observation period for surviving patients.

Safety
Epoetin alfa was well tolerated. The overall incidence of adverse events and the incidence of individual adverse events were generally similar between the two treatment groups (Table 6). The most common adverse events were fever, disease progression, granulocytopenia, and nausea. Hypertension was reported in nine (4%) of the 251 patients in the epoetin alfa group and one (1%) of the 124 patients in the placebo group. A total of 25 patients, 17 (7%) in the epoetin alfa group and eight (6%) in the placebo group, experienced a thrombotic or possible thrombotic event during the course of the study. The incidence of deep vein thrombosis was identical in the two groups. A somewhat larger proportion of patients in the placebo group (n = 22; 18%) than in the epoetin alfa group (n = 34; 14%) died during the study. Of the patients who died, the majority in both the epoetin alfa group (25 of 34; 74%) and the placebo group (18 of 22; 82%) either showed no response to chemotherapy or experienced disease progression while receiving chemotherapy. All adverse events associated with death were judged by the investigators as unlikely to be related to study treatment, with the possible exception of a stroke in one epoetin alfa patient who was elderly with a history of dyspnea and paresthesia.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Over the last decade, the results of numerous placebo-controlled and open-label clinical studies have demonstrated the efficacy and safety of epoetin alfa for the treatment of anemia in patients undergoing platinum- or nonplatinum-based chemotherapy.^{10,11,13-16,25} Results were consistent across studies: epoetin alfa significantly increased hemoglobin levels and decreased the incidence of blood transfusions. In studies that assessed QOL, the increase in hemoglobin level was associated with improved energy level, ability to do daily activities, and overall QOL.^14,15 In addition, one study¹⁵ prospectively demonstrated direct and significant correlations between change in hemoglobin level and change in overall QOL independent of response to chemotherapy; ie, correlations were seen in patients who had a complete response (r = .242, P < .001), partial response (r = .275, P < .001), or stable disease (r = .253, P < .001) but not in those who had progressive disease (r = .084, P = .072).

Three of the published studies cited above were large, open-label, nonrandomized, community-based studies comprising a combined population of over 7,000 patients.^14-16 All patients had solid or nonmyeloid hematologic malignancies for which they were receiving chemotherapy. In all three studies, patients who received epoetin alfa, either three times weekly^14,15 or once weekly,¹⁶ had significant (P < .01) decreases in transfusion requirements and significant (P < .01) increases of 1.8 g/dL to 2.0 g/dL in hemoglobin level.

In the present study, administration of epoetin alfa to anemic cancer patients receiving nonplatinum-containing chemotherapy resulted in a significantly smaller proportion of patients requiring transfusions after the first 4 weeks of treatment (24.7% v 39.5%, respectively; P = .0057) and a significantly greater increase in hemoglobin level (mean, 2.2 g/dL v 0.5 g/dL, respectively; P < .001) in the epoetin alfa group than in the placebo group. Similar increases in hemoglobin levels were seen for epoetin alfa–treated patients in all tumor and hemoglobin strata. In contrast, placebo-treated patients in the greater than 10.5-g/dL hemoglobin stratum had a decrease from baseline in hemoglobin level, whereas those in the 10.5-g/dL stratum had a minor increase. This difference was probably related to the larger number of transfusions given to placebo patients in the 10.5-g/dL hemoglobin stratum compared with those in the greater than 10.5-g/dL stratum. Thus, these findings, which were obtained under randomized, placebo-controlled conditions, are consistent with the body of previously described work.^{10,11,13-16,25}

Epoetin alfa was safe and well tolerated in this study, and the incidence and type of adverse events were generally comparable between groups. Although granulocytopenia was reported more often in epoetin alfa–treated patients (20%) than in placebo-treated patients (13%), the mean weekly granulocyte counts and the minimal absolute neutrophil counts (a marker for intensity of chemotherapy) were similar between the treatment groups.

In addition to the efficacy of epoetin alfa with respect to transfusion requirements and hematopoietic parameters, the present study demonstrated a strong positive effect of epoetin alfa on QOL measures. Results showed significant (P .0048) differences for epoetin alfa over placebo for all five cancer- and anemia-specific primary QOL measures that were reported (FACT-G, Fatigue subscale of the FACT-An, CLAS: Energy Level, CLAS: Ability To Do Daily Activities, and CLAS: Overall QOL), as well as a highly favorable result for the secondary cancer- and anemia-specific QOL measure reported (Anemia subscale of the FACT-An). Trends favoring epoetin alfa for the two non–cancer-specific (SF-36) primary QOL measures were also seen (P .0952). Again, these results, which were obtained under double-blind, placebo-controlled conditions and evaluated by rigorous statistical analyses, confirmed those of previously published QOL studies,^10,11,13-16 including one study that also used both the Linear Analog Scale Assessment (CLAS) and FACT-An scales as measures of change in QOL.¹⁵

As in previous studies,^14-16 results of the present study further confirm that improvement in QOL is associated with increases in hemoglobin level. In the present study, a significantly greater proportion of placebo-treated than epoetin alfa–treated patients were transfused. However, the mean hemoglobin level of the placebo patients did not change (mean, 10.8 g/dL at week 28; Fig 2). Likewise, the QOL of the placebo patients did not improve; in fact, their QOL decreased. Patients in the epoetin alfa group, in contrast, demonstrated a significant increase in hemoglobin level (mean, 12.5 g/dL at week 28) and significant improvement in QOL domains. Overall, QOL domains were positively and strongly correlated with increased hemoglobin levels, driving the differences in QOL improvement seen between the two treatment groups.

Another study prospectively designed to explore the relationship between hemoglobin level and QOL found that increased hemoglobin level is an independent contributory factor for improved QOL in patients with disease responses to chemotherapy classified as stable, partial, or complete.¹⁵ Thus, the improvement in QOL related to hemoglobin levels noted in epoetin alfa–treated patients in the present randomized placebo-controlled study supports the result of the previous study. Further, the present study demonstrated that increased hemoglobin levels can exert a significant positive effect on QOL and that stabilization of the baseline hemoglobin level in the placebo group (mean, 10.8 g/dL at week 28) by transfusion is not sufficient to maintain QOL in anemic cancer patients. In an effort to identify the optimal hemoglobin level at which patients have significant improvement in QOL, data from two of the previously mentioned QOL studies^14,15 were examined using an incremental analysis technique.²⁶ The results of these analyses showed that epoetin alfa–related increases in hemoglobin level were associated with QOL improvements for the hemoglobin range of 8 to 14 g/dL, with the greatest improvement in QOL for each 1-g/dL change in hemoglobin occurring when the hemoglobin level increased from 11 to 12 g/dL (range, 11 to 13 g/dL). In the present study, the correction of hemoglobin levels in the epoetin alfa group to approximately 12 g/dL by study end suggests that the greatest QOL benefits were achieved with epoetin alfa treatment.

In addition to the established relationship between hemoglobin levels and QOL, there seems to be a possible relationship between hemoglobin levels and patient survival. Over the course of the present study, a growing body of evidence from other studies suggested an association between low hemoglobin levels and poorer prognosis in cancer patients who receive radiotherapy, chemotherapy, or a combination of these treatment modalities.^17-20 To obtain further information on hemoglobin levels and prognosis in cancer patients receiving chemotherapy, the protocol was amended to include survival as an additional secondary end point.

Analysis of the collected survival data in the present study revealed median survival times of 17 months with epoetin alfa and 11 months with placebo. Kaplan-Meier estimates showed a trend in survival favoring epoetin alfa (P = .13). This trend continued when examined by tumor stratum to compensate for longer survival associated with hematologic malignancies and after further analysis with the Cox regression model controlling for potential prognostic factors (age, tumor stratum, baseline hemoglobin level, and area under the curve for neutrophils). It must be emphasized that the present study was not powered with respect to survival. Moreover, the interpretive value of the data regarding survival is further limited because variables that have an influence on survival, such as stage of disease, bone marrow involvement, intensity of chemotherapy, and disease progression, were not controlled for or stratified in the study or collected during the follow-up period. Thus, these findings must be interpreted with caution. However, from the perspective of the patient with advanced cancer, such an increase in survival time, if confirmed, combined with a significant improvement in QOL, would be meaningful.

In summary, the results of the present study show that epoetin alfa is effective in significantly reducing the proportion of patients transfused and increasing hemoglobin levels in anemic cancer patients receiving nonplatinum chemotherapy. Epoetin alfa therapy also significantly improved cancer- and anemia-related QOL domains, including energy level and ability to do daily activities, and significantly reduced fatigue. Importantly, the study results demonstrated that stabilizing baseline hemoglobin levels (placebo group, mean level 10.8 g/dL) by blood transfusion is inadequate for improving QOL; achievement of this QOL benefit seems to depend on increasing and maintaining the hemoglobin levels (epoetin alfa group, mean level 12.5 g/dL). The encouraging results with regard to increased survival time support the need for another trial to confirm these findings.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following investigators participated in this study: Belgium: Yves Beguin, MD, CHU Sart-Tilman, Liege; Rene Brys, MD, H. Hart Klinick, Ecklo; H. De Wasch, MD, Henri Serruys Hospital, Oostende; Mario Antonio Dicato, MD, Centre Hospitalier de Luxembourg, Luxembourg; Raymond Mathijs, MD, A.Z. Middelheim, Antwerpen; M. Symann, MD, Oncologie Médicale, Cliniques St Luc, Brussels; Achiel Van Hoof, MD, Algemeen Ziekenhuis St Jan, Brugge; and Ignace Vergote, MD, U.Z. Gasthuisberg, Leuven. Czech Republic: Otakar Bednarik, MD, Masaryk Memorial Cancer Institute, Brno; Michael Frank, MD, Department of Radiotherapy, Faculty Hospital, Plzen; and Milada Zemanova, MD, Veobecná Fakultní Nemocnice United Kingdom, Praha 2. France: Pierre-Etienne Cailleux, MD, Service de Radiotherapie/Chimiotherapie, Tours; Herve Cure, MD, Centre Regional de Lutte, Contre le Cancer Jean Perrin, Clermont-Ferrand; Marine Divine, MD, Hospital Henri Mondor, Creteil; Jean-Paul Guastalla, MD, Centre Regional de Lutte, Contre le Cancer Leon Berard, Lyon; M. Faress Husseini, MD, Hospital Pasteur, Hospitaux Civils Colmar, Colmar; and Hervé Lacroix, MD, CHU-Hospital Laennec, Service D’Oncologie Generale, Nantes. Great Britain: Peter Jeffrey Barrett-Lee, MD, Department of Oncology, Velindre Hospital, Cardiff; David Fairlamb, MD, New Cross Hospital, Ceansly Center, Wolverhampton; Riaz Janmohamed, MD, Hillingdon Hospital, Uxbridge; Timothy James Littlewood, MD, John Radcliffe Hospital, Oxford; John Rory O’Donnell, MD, Beaumont Hospital, Dublin; Graham Smith, MD, Royal United Hospital, Bath; and John Sweetenham, MD, Southampton General Hospital, CRC Oncology Unit, Southampton. Germany: Gerhard Adam, MD, Asklepios Klinik Triberg, Triberg; Konstantin Akrivakis, MD, Universitätsklinikum Charité, Berlin; Carsten Bokemeyer, MD, Medizinische Universitätsklinik Abt. II, Eberhard-Karls Universität, Tübingen; Lothar Böning, MD, Onkologische Praxisgemeinschaft, München; Mathias Freund, MD, Abteilung Hämatologic/Onkologic, Klinik und Poliklinik für Innere Medizin, Rostock; Hans-Jürgen Hurtz, MD, Onkologische Gemeinschaftspraxis, Halle; Hartmut Kirchner, MD, Siloa Hospital, Clinic for Hematology and Oncology, Hannover; Erhard Kurschel, MD, Gemeinschaftspraxis, Oberhausen; Wolf-Dieter Ludwig, MD, Virchow-Klinikum, Robert-Rössle-Klinik, Berlin; Norbert Marschner, MD, Praxis in der Klinik für Tumorbiologie, Freiburg; Karl Ulrich Petry, MD, Frauenklinik der MHH, Hannover; Uwe Reinhardt, MD, Klinikum Bayreuth, Abteilung Onkologie, Bayreuth; Peter Reitzig, MD, Humaine Klinik, Dresden; and Wolfgang Schütte, MD, Städtisches Krankenhaus Martha-Maria Halle-Dölau, Hämatologie, Halle. Greece: Vassilis Georgoulias, MD, University Hospital of Heraklion, Department of Clinical Oncology, Heraklion, Crete; Gerasimos Pangalis, MD, Laikon General Hospital, Athens; Nicholas Pavlidis, MD, University Hospital of Ioannina, Ioannina; and Dimostenis-Vasilios Skarlos, MD, Agii Anargiri Cancer Hospital, Athens. Hungary: Tamás Pintér, MD, Petz Aladár County Hospital, Gyõr, Department Oncoradiology, Gyõr; Gyula Szegedi, MD, Debrecen University Medical School, Third Department for Internal Medicine, Debrecen; and Gyula Varga, MD, Albert Szent-Gyocrgyi Med. University Szeged, Second Department of Internal Medicine, Szeged. Italy: Emilio Bajetta, MD, Instituto Nazionale Per Lo Studio E La Cura dei Tumori, Milan; Agostino Cortelezzi, MD, Università Degli Studi di Milano, Ospedale Policlinico, Cattedra Di Ematologia, Milan; and Gabriella Gorzegno, MD, Osperdale S. Luigi, Istituto di Clinica Medica Generale, Orbassano (Torino). The Netherlands: Franciscus L.G. Erdkamp, MD, Maaslandziekenhuis, Sittard; H.J. Keizer, MD, Academisch Ziekenhuis Leiden, Leiden; J.J. Mol, MD, Ziekenenhuis Rijnstate, Arnhem; J.W.R. Nortier, MD, Diakonessenhuis, Utrecht; Ron C. Rietbrock, MD, Academisch Medisch Centrum, Amsterdam; C.J. Rodenburg, MD, Algemeen Christelijk Ziekenhuis Eemland, Lokatie De Lichtenberg, Amersfoort; M.R. Schaafsma, MD, Medisch Spectrum Twente, Enschede; L.H. Siegenbeek van Heukclom, MD, Medisch Centrum Alkmaar, Alkmaar; C. Van der Heul, MD, Sint Elisabeth Ziekenhuis, Tilburg; Marinus Van Marwijk Kooy, MD, St Sophia Ziekenhuis, Zwolle; Gerard Vreugdenhil, MD, Sint Joseph Ziekenhuis, Veldhoven; and Jacques A.M.J. Wils, MD, Sint Laurentius Ziekenhuis, Roermond. Poland: Jerzy Holowiecki, MD, Department of Haematology, Silesian School of Medicine, Katowice; Marek Pawlicki, MD, Maria Skiodowska-Curie Memorial Cancer Center, Division in Cracow, Kraków; and Piotr Siedlecki, MD, Maria Skiodowska-Curie Memorial Cancer Center, Warsaw, Warszawa. Portugal: Cândida Azevedo, MD, Instituto Português de Oncologia, Porto; Ricardo Marques da Costa, MD, Hospital Dristrital de Leiria, Leiria; and Joaquim Gouveia, MD, Hospital de Santo António dos Capuchos, Lisboa. South Africa: Dayle Hacking, MD, Durban Oncology Center, Westridge, Durban; Johann Raats, MD, 110 Delmar Medical Center, Capetown; and Bernardo Rapoport, MD, The Medical Oncology Center of Rosebank, Johannesburg. Switzerland: Matti S. Aapro, MD, Centre Anticancéreux, Genolier; Richard Herrmann, MD, Kantonspital Basel, Basel; J.M. Lüthi, MD, Regionalspital Thun, Thun; and Kaspar Rhyner, MD, Kantonspital Glarus, Glarus.

	ACKNOWLEDGMENTS

 
Supported by a research grant from R. W. Johnson Pharmaceutical Research Institute and Ortho Biotech Europe/Janssen-Cilag.

We thank Ernst Schatzmann, PhD, Biostatistician, of R.W. Johnson Pharmaceutical Research Institute, for his active and extensive participation in the design and analysis of this study.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted October 11, 2000; accepted March 12, 2001.

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