Patients Previously Transfused or Treated with Epoetin Alfa at Low Baseline Hemoglobin Are at Higher Risk for Subsequent Transfusion: An Int
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《肿瘤学家》
LEARNING OBJECTIVES
After completing this course, the reader will be able to:
Identify chemotherapy patients at risk of transfusion by carefully monitoring hemoglobin levels and prior incidence of transfusion.
Define the optimal Hb target at which epoetin alfa treatment should be initiated to minimize subsequent transfusion need.
Understand that more than 85% of units transfused occurred in patients receiving epoetin alfa with baseline Hb <10g/dl and evaluate the clinical impact of early treatment initiation.
ABSTRACT
Background. The introduction of recombinant human erythropoietin to the management of anemia in cancer patients has resulted in significant reductions in allogeneic blood transfusions, while at the same time contributing to improvements in quality of life. A recent meta-analysis of five randomized, placebo-controlled trials with patient-level data revealed that, while epoetin alfa was very effective in reducing transfusions compared with placebo, patients who were pretransfused were twice as likely to subsequently be transfused during epoetin alfa treatment.
Methods. To further assess the validity of this rather provocative concept, another integrated analysis was conducted with patient-level data from three Canadian trials, with a combined total of 665 patients receiving epoetin alfa treatments for their cancer- and chemotherapy-induced anemia.
Results. Once again, pretransfusion was the most significant baseline predictor of transfusion, with patients that were pretransfused having a significantly greater likelihood of being transfused than their transfusion-naive counterparts. Furthermore, and corroborating previous findings, baseline hemoglobin (Hb) level was again found to be a significant predictor of transfusion, with patients who were treated at a baseline Hb level < 10 g/dl having a higher chance of being transfused than patients in whom epoetin alfa was initiated at baseline Hb levels of 10–11 g/dl. In addition, when the total units transfused in patients receiving epoetin alfa at different baseline Hb levels were analyzed, >85% of the units of blood transfused were received by patients with baseline Hb levels < 10 g/dl.
Conclusion. These data strongly suggest that early treatment with epoetin alfa could significantly optimize clinical benefit in reducing the use of transfusion in cancer patients receiving chemotherapy.
INTRODUCTION
The growing recognition in the medical community that red blood cells (RBCs) are a limited, and therefore precious, resource has led to increased vigilance in establishing both the appropriate use of RBC transfusions and the pursuit of approaches to optimize their use [1]. Although the risk for transmission of blood-borne infections is very small, blood transfusion does carry other possible risks, including immunosuppression, transfusion reactions, and the potential for iron overload resulting from chronic transfusion administration. Recent years have seen the advent of improved blood screening techniques; however, newly emerging pathogens continue to infiltrate the already limited blood supply [2–4]. The primary rationale for restricting blood transfusions is to manage the limited blood resource and to avoid known and unknown transfusion-related adverse events. In this context, there exists a definitive need to implement alternative treatments that will safely and effectively treat anemia in all patients and in particular in cancer patients.
Anemia associated with cancer is a well-established phenomenon, with treatment options that include RBC transfusions, and for the past decade, the use of erythropoietic agents [5–7]. It was the development of a human recombinant erythropoietin in 1983 [8] that allowed for the first innovative and effective treatment alternative for cancer-related anemia. A consistent body of evidence has since emerged, confirmed in numerous clinical trials, that treatment with erythropoietic agents in patients with anemia related to cancer and/or cancer treatment significantly decreases RBC transfusion requirements and increases hemoglobin (Hb) levels [9–22]. More recently, improved quality of life (QOL) associated with the use of erythropoietic agents has also been confirmed in cancer patients [10–15, 23, 24]. The benefits of epoetin alfa (Procrit®; Ortho Biotech Products, L.P., Bridge-water, NJ) in the treatment of anemia in the cancer setting have been established to be independent of tumor type, treatment regimen, or whether the patients were receiving chemotherapy.
Cancer-related anemia treatment guidelines developed by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) were based on the results of a comprehensive review of the existing literature. These early guidelines have played a pivotal role in helping provide clarity to the definition of anemia in cancer patients, as well as providing direction on the use of erythropoietic agents to optimize the treatment of anemia in oncology [1]. However, as currently articulated in the guidelines, there remain several areas of uncertainty, including whether it is beneficial to initiate treatment with erythropoietic agents in cancer patients with mild anemia (Hb level of 10–11 g/dl), as opposed to waiting until moderate anemia develops (Hb level <10 g/dl) [1]. Interestingly, two other more recently established guidelines (from the National Comprehensive Cancer Network [NCCN] and European Organization for Research and Treatment of Cancer [EORTC]) have, in effect, recommended that treatment initiation occur at an Hb level 11 g/dl for cancer patients [25, 26].
Several researchers have sought to establish factors that are predictive of a future requirement for transfusion. A low baseline Hb level has consistently been identified as a prominent factor associated with the likelihood of future transfusion [18–24, 27–30]. A recent meta-analysis, which assessed the predictors of transfusion, pointed to the observation that prior RBC transfusion in cancer patients increases the risk for subsequent transfusions, with or without the use of epoetin alfa [31]. That analysis revealed previous transfusion to be the most significant predictor of subsequent transfusion (p < .0001) and found that, while epoetin alfa was similarly effective in reducing the transfusion risk in all patients, those with a previous transfusion were more than twice as likely to be subsequently transfused, when compared with those with no previous transfusion. In addition, baseline Hb level was again demonstrated to be a significant predictor of transfusion during epoetin alfa therapy.
Significant contributions toward erythropoietin research were made in the last decade by Canadian clinicians, researchers, and patients. Quirt et al. [24] enrolled 401 Canadian cancer patients and established the effect of erythropoietin treatment in improving QOL in cancer patients, regardless of cancer treatment regimen. Chang et al. [24] randomized 354 patients with breast cancer to standard of care (SOC) versus epoetin alfa once weekly, and the study demonstrated that patients in the epoetin alfa arm achieved a significant Hb response rate of 65.7%, in conjunction with an important relative reduction rate of 64% for transfusions. A recently completed study in hematologic cancers involving 88 Canadian patients further confirmed the benefit of epoetin alfa (40,000 IU once weekly) in patients with hematologic malignancies [32].
This integrated analysis was undertaken with the intent to validate the findings from the meta-analysis of five double-blind, controlled trials performed in the U.S. and Europe [31], using Canadian data available at the discrete patient level. The role of previous transfusion as a predictor of future transfusion during cancer treatment is further analyzed together with the predictive value of baseline Hb level. The key objective is to provide information that will help to establish a framework for cancer-related anemia management and treatment, in recognition of the need for blood conservation and optimal anemia therapy through alternative means.
METHODS
All epoetin alfa oncology trials that were carried out in Canada (defined as the Canadian Registry of epoetin alfa trials) were screened through precise criteria, defined a priori, to select the final trials for inclusion in the integrated analysis. As shown in Figure 1, criteria for selection included trial status (completed per protocol), similarity in design and end points, and the use of Canadian-only data. Three multicenter, open-label studies with similar design parameters, and with statistical power to evaluate the safety and efficacy of epoetin alfa, were ultimately selected for this integrated analysis. The studies included two open-label trials, EPO-CAN-3 [23] and EPO-INT-02, and one open-label, randomized trial, EPO-CAN-17 [24]. Patient-level data from these three studies, for patients on epoetin alfa therapy only, were integrated for the analysis evaluating factors predictive of transfusion. Although EPO-INT-02 was a global trial, only the data forthcoming from Canadian patients were integrated. Logistic regression analyses were conducted using PROC LOGISTIC of SAS statistical software [33]. Relative risk ratios (RRs) and their confidence intervals were calculated using PROC FREQ of SAS.
EPO-CAN-3 enrolled patients with multiple tumor types (solid and hematologic) with a baseline Hb level 11 g/dl who were to receive either chemotherapeutic or non-chemotherapeutic treatment for their cancer. The epoetin alfa therapy dose was based on the patient’s weight (150 IU/kg) and was administered three times a week. Dose adjustments to a maximum of 300 IU/kg were permitted if the patient’s Hb did not rise by 1 g/dl after 4 weeks on epoetin alfa therapy. EPO-INT-02 was a global multicenter trial that enrolled patients with lymphoid malignancies with a baseline Hb level 13 g/dl. Epoetin alfa was administered at a dose of 40,000 IU on a once-weekly basis, and doses could be increased to 60,000 IU once weekly if Hb did not rise by 1 g/dl in the first 4–6 weeks. EPO-CAN-17 screened and followed adjuvant or metastatic breast cancer patients with Hb levels 15 g/dl until their Hb dropped to 12 g/dl and then randomized them in a 1:1 ratio to one of two arms: epoetin alfa, 40,000 IU once weekly, or the SOC (no epoetin alfa). The strategy in that trial was to maintain Hb levels, and so the dose of epoetin alfa could be increased to 60,000 IU once weekly if the Hb dropped significantly ( 2 g/dl) after 4–6 weeks of therapy. It was not within the scope of the integrated analysis to incorporate the SOC patient data. Transfusion triggers were similar across studies; investigators were recommended to only transfuse patients whose Hb fell to <8 g/dl and/or when clinical symptoms developed. In addition, in all three studies, chemotherapy regimens were defined by the nature and stage of disease as well as by clinical practice.
The following baseline factors were considered in the logistic analysis of predictive factors for transfusion: age, gender, race, baseline Hb, previous transfusion within 28 days of baseline, cancer group (solid tumor with metastasis, solid tumor without metastasis, hematological tumor), neutrophils, reticulocytes, serum ferritin level, and transferrin saturation. An additional analysis was carried out examining transfusion during days 1–28 as a potential supplementary predictive factor, based on evidence that this factor is closely correlated with previous transfusion.
RESULTS
A review of Canadian studies investigating epoetin alfa therapy in cancer patients revealed a rather diverse array of studies, either completed or ongoing. After establishing the selection criteria a priori (multicenter, completed as specified per protocol, similar design and end points) and focusing on the review of Canadian patient data only for possible inclusion in the analysis, three multicenter studies, identified as EPO-CAN-3, EPO-CAN-17, and EPO-INT-02, with a combined total of 665 patients, were identified as meeting the required criteria for inclusion in the integrated analysis (Fig. 1).
The combined demographics of the 665 patient cohort for all three studies are presented in Table 1. Many tumor types were included in the analyses, with a proportionally higher representation of breast cancer, mainly because of the fact that EPO-CAN-17 specifically studied breast cancer patients. The range of baseline Hb level is notably wide, 4.2 g/dl–14.2 g/dl, most likely reflective of an evolution in clinical practice spanning the time period of the trials, as epoetin alfa treatment has gradually been initiated earlier and at higher baseline Hb levels. In addition, the EPO-CAN-3 and EPO-INT-02 studies were both designed to treat anemic cancer patients, whereas EPO-CAN-17 was specifically designed to test the benefits of anemia prevention through earlier epoetin alfa intervention, as opposed to treatment of anemia. As a result, patients in this latter study in particular had higher baseline Hb values.
Couture et al. [31] previously reported, in a meta-analysis of five double-blind, placebo-controlled trials, that prior transfusion before epoetin alfa therapy was one of the most significant predictors of transfusion after day 28 during epoetin alfa therapy. When a similar analysis was applied to the Canadian data, the trend was identical, with the patients that were previously transfused having a >240% chance of being subsequently transfused during epoetin alfa therapy (RR, 3.43; 95% confidence interval [CI], 2.54–4.63), compared with nontransfused patients. In addition, results modeling the probability of not being transfused, as a function of baseline Hb level for both pretransfused and non–pre-transfused patients (Fig. 2), were almost identical to those reported previously by Couture et al. [31].
To further understand the significant predictors of transfusion during epoetin alfa therapy, baseline patient characteristics relevant to transfusion were analyzed in a multivariate regression model. Similar to the results reported previously, prior transfusion (odds ratio [OR], 3.62; 95% CI, 1.94–6.74) and baseline Hb level (OR, 0.57; 95% CI, 0.46–0.72) were confirmed as the only significant (p < .0001) predictors for transfusion from day 29 to the end of study during epoetin alfa treatment (Table 2). However, an unexpected predictor that was identified in additional exploratory analyses was transfusion during the first 28 days of epoetin alfa therapy. Historically, percent transfusion has been consistently defined by most erythropoietin studies and has been measured from day 29 (after initiation of erythropoietin therapy) to the end of study. This was based on the understanding that it takes approximately 4 weeks for erythropoietin therapy to adequately raise Hb to the desired levels. However, in this analysis, transfusion during the first 28 days of epoetin alfa therapy and its impact on subsequent transfusions from day 29 to the end of study was also investigated. Although transfusion during days 1–28 is not a baseline predictor, it was found to have such a profound impact on subsequent transfusions from day 29 to the end of study, with an OR of 4.09 (95% CI, 2.13–7.85), that it was included in subsequent select analyses.
When considering the impact of prognostic factors on transfusions from day 1 to the end of study, providing a more accurate clinical picture of transfusion incidence, both baseline Hb and pretransfusion status were also seen to be highly statistically significant (data not shown).
Since baseline Hb level was a significant predictor of subsequent transfusion, the RR of patients receiving epoetin alfa therapy at different baseline Hb strata were calculated and are shown in Figure 3A and Figure 3B. Patients in whom therapy was initiated at Hb levels >11 g/dl had relatively fewer transfusions, thus allowing the calculation of RR by baseline Hb strata relative to this higher Hb level. As anticipated, patients with baseline Hb levels <10 g/dl had a significantly higher risk for subsequent transfusion than patients with baseline Hb levels of 10–11 g/dl. When directly comparing Hb level strata at which epoetin alfa treatment was initiated, patients were found to have a 165% higher risk for transfusion from day 29 to the end of study (RR, 2.65; 95% CI, 1.54–4.56) at a baseline Hb level <10 g/dl compared with a baseline Hb level of 10–11 g/dl. When all transfusions from day 1 to the end of study were considered, a very similar RR was observed. Baseline Hb level, not surprisingly, was also predictive of early transfusion during days 1–28, with an RR of 23.23 (95% CI, 5.79–93.14) for patients with baseline Hb levels <10g/dl, compared with an RR of 7.73 (95% CI, 1.74–34.26) for patients with baseline Hb levels of 10–11 g/dl.
The rather striking difference in RR for subsequent transfusion for patients in whom epoetin alfa therapy was initiated at different baseline Hb levels prompted further analyses to delineate the number of units of blood received by patients during epoetin alfa treatment according to baseline Hb level. Figure 4 depicts the mean number of RBC units transfused per patient from day 1 to the end of study plotted as a linear function of baseline Hb level for all patients and for the subset of pretransfused patients. The plot clearly illustrates the inverse relationship between units transfused and baseline Hb level. Not surprisingly, the subgroup of patients that were previously transfused showed a higher level of units transfused.
A more detailed depiction of the distribution of transfusions is outlined in Table 3A and Table 3B, illustrating that the majority of patients transfused were those with baseline Hb levels <10 g/dl. Greater than 85% of the total RBC units transfused were administered to patients in whom epoetin alfa therapy was initiated with baseline Hb levels <10 g/dl. These findings were consistent for both transfusions from day 29 to the end of study (86% of total RBC units) and those from day 1 to the end of study (87% of total RBC units). Even more striking was the finding that over 40% of the total number of units transfused to patients over the course of epoetin alfa treatment occurred in the first 4 weeks (comparing Table 3B with Table 3A).
CONCLUSION
The clinical benefit of erythropoietin in the treatment of both chemotherapy- and cancer-related anemia has been well recognized by the oncology community, with an impressive and growing collection of literature demonstrating the effectiveness of the recombinant molecule in significantly increasing Hb level, reducing RBC transfusion need, and improving QOL. A recently published meta-analysis revealed that patients who were transfused before the initiation of epoetin alfa therapy could have a higher risk for receiving subsequent transfusions during epoetin alfa therapy, and the observed occurrence of this risk was correlated with baseline Hb level, independent of tumor stage/type, chemotherapy regimen, or baseline performance status [31].
Analysis of data from this current review indicates that the same transfusion risk profile was observed as that seen in the previous meta-analysis. Patients who were previously transfused had a >240% higher risk of being subsequently transfused during therapy (RR, 3.43; 95% CI, 2.54–4.63). As previously reported, an evaluation of the baseline predictors showed that Hb level at epoetin alfa therapy initiation was highly significant in predicting subsequent transfusion. Patients who received epoetin alfa at baseline Hb levels <10g/dl were found to have a 165% higher chance of receiving additional RBC transfusions after day 28 of treatment than patients with baseline Hb levels of 10–11 g/dl. Interestingly, the recent meta-analysis published by Bohlius et al. [34] mentions a lack of statistical significance in the association between transfusion risk and baseline Hb level. However, this may possibly be reflective of a lower sensitivity in analyses using aggregate data sets compared with the discrete individual patient-level data used in the present analysis.
In previously reported erythropoietin studies, transfusions have traditionally been assessed after week 4, based on the rationale that erythropoietin requires a few weeks to stimulate the bone marrow to make fresh RBCs. The current analyses demonstrate that a considerable number of transfusions (40%) occur within the first 4 weeks of epoetin alfa treatment, especially for those patients in whom treatment was initiated at lower baseline Hb levels. In addition, patients who were transfused during the first 28 days of therapy were more likely to receive additional transfusions from day 29 to the end of treatment (OR, 4.09; 95% CI, 2.13–7.85).
When the total number of units of RBCs transfused was assessed according to baseline Hb strata, 86% of the units transfused were administered to patients treated with epoetin alfa at baseline Hb levels <10 g/dl (day 29 to end of study), and 87% of the units were administered if the entire study period (day 1 to end of study) was included in the analysis. The current analysis further demonstrates that a 50% lower probability of a subsequent transfusion can be expected for every 1 g/dl higher baseline Hb level at which epoetin alfa is initiated.
Both in this integrated analysis and in the previously published meta-analysis [31], baseline prognostic factors that could possibly be responsible for transfusions during epoetin alfa therapy were analyzed. Prior transfusion and low baseline Hb level were the only two significant predictors of transfusion, whereas other potential predictors, such as performance status, tumor stage/type, chemotherapy administered, and bone marrow involvement, did not turn out to be significant. The true physiological reason for this observation remains unclear. It could be postulated that patients entered into these studies were possibly already experiencing a fast downward spiraling of their Hb levels as a result of advanced disease state or in response to the chemotherapy they were receiving, and early management of anemia with epoetin alfa might have prevented the fall and avoided transfusions. However, one cannot undermine the possibility that at least some of the transfused patients might have been experiencing severe anemia as a result of the disease itself or the chemotherapy given, and even early treatment with epoetin alfa might not have been effective in preventing subsequent transfusions. From this, it would appear that an effective strategy to reduce or eliminate transfusion need during the treatment period would be to initiate therapy earlier, when a patient’s Hb level is 10–11 g/dl rather than <10 g/dl. More recent treatment guidelines, such as those published by the NCCN and EORTC, have shifted somewhat, now recommending the initiation of treatment at an Hb level 11 g/dl. In contrast, ASH/ASCO and the Canadian treatment guidelines still recommend 10 g/dl as the initiating Hb level, in the absence of clinical circumstances that warrant earlier intervention. Since treatment guidelines are likely to influence physician behavior and also impact reimbursement criteria, it is essential that these guidelines be updated to reflect findings from recent peer-reviewed publications. The ideal approach might also involve the incorporation of an anemia predictor tool and the monitoring of patients who appear to have a high potential for developing anemia, thus allowing intervention in a timely manner where possible to prevent avoidable transfusions.
Another potentially interesting prognostic factor not previously examined that could impact both the need for transfusion and the response to erythropoietin therapy is the rate of change in Hb level. When this was added to the list of predictive factors presented in Table 2, in addition to prior transfusion and baseline Hb level, Hb change within the first 2 weeks of epoetin alfa therapy was found to be a very significant predictive factor for transfusion (p<.0001), with the risk for transfusion increasing with a decrease in Hb level. This result suggests that the rate of Hb drop prior to entry into the study might also be a very significant factor in determining future transfusions. Regrettably, in the absence of available prestudy Hb data, the rate of Hb drop prior to epoetin alfa therapy as a predictor of subsequent transfusion could not be determined and remains an issue requiring further research.
The limitations of this integrated analysis include the retrospective nature of the review itself, differences in the designs of the studies included, and also the evolving physician approach to anemia management over the time frame spanning the review. The generalizability of this review could also be challenged by the fact that only Canadian data were included in the analyses. However, the fact that the main findings from this review were identical to those of the meta-analysis performed by Couture et al. [31], using data from five U.S./European double-blind, placebo-controlled trials, suggests that the current analysis was robust and that the main observations were not affected by the limitations mentioned above. The key observations of this review, including prior transfusion, transfusion in the first 4 weeks of epoetin alfa therapy, and low baseline Hb level as constituting major drivers of transfusions during epoetin alfa therapy, were recently confirmed in two community-based observational studies [35, 36]
The introduction of erythropoietic agents in the last decade has revolutionized the treatment of anemia in cancer patients. Evidence collected from the systematic review of clinical trial data and published results has provided a framework for the use of these agents in anemic cancer patients, although optimized guidelines remain outstanding. The results obtained from this Canadian integrated analysis confirm the observation made by Couture et al. [31] that early treatment with epoetin alfa could potentially decrease RBC transfusion needs, thus preserving a precious resource.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Dr. Kovacs is an employee of London Regional Cancer Center. Dr. Couture is an employee of Hôtel-Dieu de Québec and Lévis. Dr. Turner is an employee of the Cross Cancer Institute. Dr. Noble is an employee of Royal Columbian Hospital. Dr. Burkes is an employee of Mount Sinai Hospital. Dr. Dolan is an employee of Saint John Regoinal Hospital. Dr. Quirt is an employee of Princess Margaret Hospital. Dr. Chang has acted as a consultant and received support from the R.S. McLaughlin Durham Regional Cancer Center. Dr. Lau and Dr. Plante own stock in Johnson & Johnson and are employed by Ortho Biotech.
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After completing this course, the reader will be able to:
Identify chemotherapy patients at risk of transfusion by carefully monitoring hemoglobin levels and prior incidence of transfusion.
Define the optimal Hb target at which epoetin alfa treatment should be initiated to minimize subsequent transfusion need.
Understand that more than 85% of units transfused occurred in patients receiving epoetin alfa with baseline Hb <10g/dl and evaluate the clinical impact of early treatment initiation.
ABSTRACT
Background. The introduction of recombinant human erythropoietin to the management of anemia in cancer patients has resulted in significant reductions in allogeneic blood transfusions, while at the same time contributing to improvements in quality of life. A recent meta-analysis of five randomized, placebo-controlled trials with patient-level data revealed that, while epoetin alfa was very effective in reducing transfusions compared with placebo, patients who were pretransfused were twice as likely to subsequently be transfused during epoetin alfa treatment.
Methods. To further assess the validity of this rather provocative concept, another integrated analysis was conducted with patient-level data from three Canadian trials, with a combined total of 665 patients receiving epoetin alfa treatments for their cancer- and chemotherapy-induced anemia.
Results. Once again, pretransfusion was the most significant baseline predictor of transfusion, with patients that were pretransfused having a significantly greater likelihood of being transfused than their transfusion-naive counterparts. Furthermore, and corroborating previous findings, baseline hemoglobin (Hb) level was again found to be a significant predictor of transfusion, with patients who were treated at a baseline Hb level < 10 g/dl having a higher chance of being transfused than patients in whom epoetin alfa was initiated at baseline Hb levels of 10–11 g/dl. In addition, when the total units transfused in patients receiving epoetin alfa at different baseline Hb levels were analyzed, >85% of the units of blood transfused were received by patients with baseline Hb levels < 10 g/dl.
Conclusion. These data strongly suggest that early treatment with epoetin alfa could significantly optimize clinical benefit in reducing the use of transfusion in cancer patients receiving chemotherapy.
INTRODUCTION
The growing recognition in the medical community that red blood cells (RBCs) are a limited, and therefore precious, resource has led to increased vigilance in establishing both the appropriate use of RBC transfusions and the pursuit of approaches to optimize their use [1]. Although the risk for transmission of blood-borne infections is very small, blood transfusion does carry other possible risks, including immunosuppression, transfusion reactions, and the potential for iron overload resulting from chronic transfusion administration. Recent years have seen the advent of improved blood screening techniques; however, newly emerging pathogens continue to infiltrate the already limited blood supply [2–4]. The primary rationale for restricting blood transfusions is to manage the limited blood resource and to avoid known and unknown transfusion-related adverse events. In this context, there exists a definitive need to implement alternative treatments that will safely and effectively treat anemia in all patients and in particular in cancer patients.
Anemia associated with cancer is a well-established phenomenon, with treatment options that include RBC transfusions, and for the past decade, the use of erythropoietic agents [5–7]. It was the development of a human recombinant erythropoietin in 1983 [8] that allowed for the first innovative and effective treatment alternative for cancer-related anemia. A consistent body of evidence has since emerged, confirmed in numerous clinical trials, that treatment with erythropoietic agents in patients with anemia related to cancer and/or cancer treatment significantly decreases RBC transfusion requirements and increases hemoglobin (Hb) levels [9–22]. More recently, improved quality of life (QOL) associated with the use of erythropoietic agents has also been confirmed in cancer patients [10–15, 23, 24]. The benefits of epoetin alfa (Procrit®; Ortho Biotech Products, L.P., Bridge-water, NJ) in the treatment of anemia in the cancer setting have been established to be independent of tumor type, treatment regimen, or whether the patients were receiving chemotherapy.
Cancer-related anemia treatment guidelines developed by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) were based on the results of a comprehensive review of the existing literature. These early guidelines have played a pivotal role in helping provide clarity to the definition of anemia in cancer patients, as well as providing direction on the use of erythropoietic agents to optimize the treatment of anemia in oncology [1]. However, as currently articulated in the guidelines, there remain several areas of uncertainty, including whether it is beneficial to initiate treatment with erythropoietic agents in cancer patients with mild anemia (Hb level of 10–11 g/dl), as opposed to waiting until moderate anemia develops (Hb level <10 g/dl) [1]. Interestingly, two other more recently established guidelines (from the National Comprehensive Cancer Network [NCCN] and European Organization for Research and Treatment of Cancer [EORTC]) have, in effect, recommended that treatment initiation occur at an Hb level 11 g/dl for cancer patients [25, 26].
Several researchers have sought to establish factors that are predictive of a future requirement for transfusion. A low baseline Hb level has consistently been identified as a prominent factor associated with the likelihood of future transfusion [18–24, 27–30]. A recent meta-analysis, which assessed the predictors of transfusion, pointed to the observation that prior RBC transfusion in cancer patients increases the risk for subsequent transfusions, with or without the use of epoetin alfa [31]. That analysis revealed previous transfusion to be the most significant predictor of subsequent transfusion (p < .0001) and found that, while epoetin alfa was similarly effective in reducing the transfusion risk in all patients, those with a previous transfusion were more than twice as likely to be subsequently transfused, when compared with those with no previous transfusion. In addition, baseline Hb level was again demonstrated to be a significant predictor of transfusion during epoetin alfa therapy.
Significant contributions toward erythropoietin research were made in the last decade by Canadian clinicians, researchers, and patients. Quirt et al. [24] enrolled 401 Canadian cancer patients and established the effect of erythropoietin treatment in improving QOL in cancer patients, regardless of cancer treatment regimen. Chang et al. [24] randomized 354 patients with breast cancer to standard of care (SOC) versus epoetin alfa once weekly, and the study demonstrated that patients in the epoetin alfa arm achieved a significant Hb response rate of 65.7%, in conjunction with an important relative reduction rate of 64% for transfusions. A recently completed study in hematologic cancers involving 88 Canadian patients further confirmed the benefit of epoetin alfa (40,000 IU once weekly) in patients with hematologic malignancies [32].
This integrated analysis was undertaken with the intent to validate the findings from the meta-analysis of five double-blind, controlled trials performed in the U.S. and Europe [31], using Canadian data available at the discrete patient level. The role of previous transfusion as a predictor of future transfusion during cancer treatment is further analyzed together with the predictive value of baseline Hb level. The key objective is to provide information that will help to establish a framework for cancer-related anemia management and treatment, in recognition of the need for blood conservation and optimal anemia therapy through alternative means.
METHODS
All epoetin alfa oncology trials that were carried out in Canada (defined as the Canadian Registry of epoetin alfa trials) were screened through precise criteria, defined a priori, to select the final trials for inclusion in the integrated analysis. As shown in Figure 1, criteria for selection included trial status (completed per protocol), similarity in design and end points, and the use of Canadian-only data. Three multicenter, open-label studies with similar design parameters, and with statistical power to evaluate the safety and efficacy of epoetin alfa, were ultimately selected for this integrated analysis. The studies included two open-label trials, EPO-CAN-3 [23] and EPO-INT-02, and one open-label, randomized trial, EPO-CAN-17 [24]. Patient-level data from these three studies, for patients on epoetin alfa therapy only, were integrated for the analysis evaluating factors predictive of transfusion. Although EPO-INT-02 was a global trial, only the data forthcoming from Canadian patients were integrated. Logistic regression analyses were conducted using PROC LOGISTIC of SAS statistical software [33]. Relative risk ratios (RRs) and their confidence intervals were calculated using PROC FREQ of SAS.
EPO-CAN-3 enrolled patients with multiple tumor types (solid and hematologic) with a baseline Hb level 11 g/dl who were to receive either chemotherapeutic or non-chemotherapeutic treatment for their cancer. The epoetin alfa therapy dose was based on the patient’s weight (150 IU/kg) and was administered three times a week. Dose adjustments to a maximum of 300 IU/kg were permitted if the patient’s Hb did not rise by 1 g/dl after 4 weeks on epoetin alfa therapy. EPO-INT-02 was a global multicenter trial that enrolled patients with lymphoid malignancies with a baseline Hb level 13 g/dl. Epoetin alfa was administered at a dose of 40,000 IU on a once-weekly basis, and doses could be increased to 60,000 IU once weekly if Hb did not rise by 1 g/dl in the first 4–6 weeks. EPO-CAN-17 screened and followed adjuvant or metastatic breast cancer patients with Hb levels 15 g/dl until their Hb dropped to 12 g/dl and then randomized them in a 1:1 ratio to one of two arms: epoetin alfa, 40,000 IU once weekly, or the SOC (no epoetin alfa). The strategy in that trial was to maintain Hb levels, and so the dose of epoetin alfa could be increased to 60,000 IU once weekly if the Hb dropped significantly ( 2 g/dl) after 4–6 weeks of therapy. It was not within the scope of the integrated analysis to incorporate the SOC patient data. Transfusion triggers were similar across studies; investigators were recommended to only transfuse patients whose Hb fell to <8 g/dl and/or when clinical symptoms developed. In addition, in all three studies, chemotherapy regimens were defined by the nature and stage of disease as well as by clinical practice.
The following baseline factors were considered in the logistic analysis of predictive factors for transfusion: age, gender, race, baseline Hb, previous transfusion within 28 days of baseline, cancer group (solid tumor with metastasis, solid tumor without metastasis, hematological tumor), neutrophils, reticulocytes, serum ferritin level, and transferrin saturation. An additional analysis was carried out examining transfusion during days 1–28 as a potential supplementary predictive factor, based on evidence that this factor is closely correlated with previous transfusion.
RESULTS
A review of Canadian studies investigating epoetin alfa therapy in cancer patients revealed a rather diverse array of studies, either completed or ongoing. After establishing the selection criteria a priori (multicenter, completed as specified per protocol, similar design and end points) and focusing on the review of Canadian patient data only for possible inclusion in the analysis, three multicenter studies, identified as EPO-CAN-3, EPO-CAN-17, and EPO-INT-02, with a combined total of 665 patients, were identified as meeting the required criteria for inclusion in the integrated analysis (Fig. 1).
The combined demographics of the 665 patient cohort for all three studies are presented in Table 1. Many tumor types were included in the analyses, with a proportionally higher representation of breast cancer, mainly because of the fact that EPO-CAN-17 specifically studied breast cancer patients. The range of baseline Hb level is notably wide, 4.2 g/dl–14.2 g/dl, most likely reflective of an evolution in clinical practice spanning the time period of the trials, as epoetin alfa treatment has gradually been initiated earlier and at higher baseline Hb levels. In addition, the EPO-CAN-3 and EPO-INT-02 studies were both designed to treat anemic cancer patients, whereas EPO-CAN-17 was specifically designed to test the benefits of anemia prevention through earlier epoetin alfa intervention, as opposed to treatment of anemia. As a result, patients in this latter study in particular had higher baseline Hb values.
Couture et al. [31] previously reported, in a meta-analysis of five double-blind, placebo-controlled trials, that prior transfusion before epoetin alfa therapy was one of the most significant predictors of transfusion after day 28 during epoetin alfa therapy. When a similar analysis was applied to the Canadian data, the trend was identical, with the patients that were previously transfused having a >240% chance of being subsequently transfused during epoetin alfa therapy (RR, 3.43; 95% confidence interval [CI], 2.54–4.63), compared with nontransfused patients. In addition, results modeling the probability of not being transfused, as a function of baseline Hb level for both pretransfused and non–pre-transfused patients (Fig. 2), were almost identical to those reported previously by Couture et al. [31].
To further understand the significant predictors of transfusion during epoetin alfa therapy, baseline patient characteristics relevant to transfusion were analyzed in a multivariate regression model. Similar to the results reported previously, prior transfusion (odds ratio [OR], 3.62; 95% CI, 1.94–6.74) and baseline Hb level (OR, 0.57; 95% CI, 0.46–0.72) were confirmed as the only significant (p < .0001) predictors for transfusion from day 29 to the end of study during epoetin alfa treatment (Table 2). However, an unexpected predictor that was identified in additional exploratory analyses was transfusion during the first 28 days of epoetin alfa therapy. Historically, percent transfusion has been consistently defined by most erythropoietin studies and has been measured from day 29 (after initiation of erythropoietin therapy) to the end of study. This was based on the understanding that it takes approximately 4 weeks for erythropoietin therapy to adequately raise Hb to the desired levels. However, in this analysis, transfusion during the first 28 days of epoetin alfa therapy and its impact on subsequent transfusions from day 29 to the end of study was also investigated. Although transfusion during days 1–28 is not a baseline predictor, it was found to have such a profound impact on subsequent transfusions from day 29 to the end of study, with an OR of 4.09 (95% CI, 2.13–7.85), that it was included in subsequent select analyses.
When considering the impact of prognostic factors on transfusions from day 1 to the end of study, providing a more accurate clinical picture of transfusion incidence, both baseline Hb and pretransfusion status were also seen to be highly statistically significant (data not shown).
Since baseline Hb level was a significant predictor of subsequent transfusion, the RR of patients receiving epoetin alfa therapy at different baseline Hb strata were calculated and are shown in Figure 3A and Figure 3B. Patients in whom therapy was initiated at Hb levels >11 g/dl had relatively fewer transfusions, thus allowing the calculation of RR by baseline Hb strata relative to this higher Hb level. As anticipated, patients with baseline Hb levels <10 g/dl had a significantly higher risk for subsequent transfusion than patients with baseline Hb levels of 10–11 g/dl. When directly comparing Hb level strata at which epoetin alfa treatment was initiated, patients were found to have a 165% higher risk for transfusion from day 29 to the end of study (RR, 2.65; 95% CI, 1.54–4.56) at a baseline Hb level <10 g/dl compared with a baseline Hb level of 10–11 g/dl. When all transfusions from day 1 to the end of study were considered, a very similar RR was observed. Baseline Hb level, not surprisingly, was also predictive of early transfusion during days 1–28, with an RR of 23.23 (95% CI, 5.79–93.14) for patients with baseline Hb levels <10g/dl, compared with an RR of 7.73 (95% CI, 1.74–34.26) for patients with baseline Hb levels of 10–11 g/dl.
The rather striking difference in RR for subsequent transfusion for patients in whom epoetin alfa therapy was initiated at different baseline Hb levels prompted further analyses to delineate the number of units of blood received by patients during epoetin alfa treatment according to baseline Hb level. Figure 4 depicts the mean number of RBC units transfused per patient from day 1 to the end of study plotted as a linear function of baseline Hb level for all patients and for the subset of pretransfused patients. The plot clearly illustrates the inverse relationship between units transfused and baseline Hb level. Not surprisingly, the subgroup of patients that were previously transfused showed a higher level of units transfused.
A more detailed depiction of the distribution of transfusions is outlined in Table 3A and Table 3B, illustrating that the majority of patients transfused were those with baseline Hb levels <10 g/dl. Greater than 85% of the total RBC units transfused were administered to patients in whom epoetin alfa therapy was initiated with baseline Hb levels <10 g/dl. These findings were consistent for both transfusions from day 29 to the end of study (86% of total RBC units) and those from day 1 to the end of study (87% of total RBC units). Even more striking was the finding that over 40% of the total number of units transfused to patients over the course of epoetin alfa treatment occurred in the first 4 weeks (comparing Table 3B with Table 3A).
CONCLUSION
The clinical benefit of erythropoietin in the treatment of both chemotherapy- and cancer-related anemia has been well recognized by the oncology community, with an impressive and growing collection of literature demonstrating the effectiveness of the recombinant molecule in significantly increasing Hb level, reducing RBC transfusion need, and improving QOL. A recently published meta-analysis revealed that patients who were transfused before the initiation of epoetin alfa therapy could have a higher risk for receiving subsequent transfusions during epoetin alfa therapy, and the observed occurrence of this risk was correlated with baseline Hb level, independent of tumor stage/type, chemotherapy regimen, or baseline performance status [31].
Analysis of data from this current review indicates that the same transfusion risk profile was observed as that seen in the previous meta-analysis. Patients who were previously transfused had a >240% higher risk of being subsequently transfused during therapy (RR, 3.43; 95% CI, 2.54–4.63). As previously reported, an evaluation of the baseline predictors showed that Hb level at epoetin alfa therapy initiation was highly significant in predicting subsequent transfusion. Patients who received epoetin alfa at baseline Hb levels <10g/dl were found to have a 165% higher chance of receiving additional RBC transfusions after day 28 of treatment than patients with baseline Hb levels of 10–11 g/dl. Interestingly, the recent meta-analysis published by Bohlius et al. [34] mentions a lack of statistical significance in the association between transfusion risk and baseline Hb level. However, this may possibly be reflective of a lower sensitivity in analyses using aggregate data sets compared with the discrete individual patient-level data used in the present analysis.
In previously reported erythropoietin studies, transfusions have traditionally been assessed after week 4, based on the rationale that erythropoietin requires a few weeks to stimulate the bone marrow to make fresh RBCs. The current analyses demonstrate that a considerable number of transfusions (40%) occur within the first 4 weeks of epoetin alfa treatment, especially for those patients in whom treatment was initiated at lower baseline Hb levels. In addition, patients who were transfused during the first 28 days of therapy were more likely to receive additional transfusions from day 29 to the end of treatment (OR, 4.09; 95% CI, 2.13–7.85).
When the total number of units of RBCs transfused was assessed according to baseline Hb strata, 86% of the units transfused were administered to patients treated with epoetin alfa at baseline Hb levels <10 g/dl (day 29 to end of study), and 87% of the units were administered if the entire study period (day 1 to end of study) was included in the analysis. The current analysis further demonstrates that a 50% lower probability of a subsequent transfusion can be expected for every 1 g/dl higher baseline Hb level at which epoetin alfa is initiated.
Both in this integrated analysis and in the previously published meta-analysis [31], baseline prognostic factors that could possibly be responsible for transfusions during epoetin alfa therapy were analyzed. Prior transfusion and low baseline Hb level were the only two significant predictors of transfusion, whereas other potential predictors, such as performance status, tumor stage/type, chemotherapy administered, and bone marrow involvement, did not turn out to be significant. The true physiological reason for this observation remains unclear. It could be postulated that patients entered into these studies were possibly already experiencing a fast downward spiraling of their Hb levels as a result of advanced disease state or in response to the chemotherapy they were receiving, and early management of anemia with epoetin alfa might have prevented the fall and avoided transfusions. However, one cannot undermine the possibility that at least some of the transfused patients might have been experiencing severe anemia as a result of the disease itself or the chemotherapy given, and even early treatment with epoetin alfa might not have been effective in preventing subsequent transfusions. From this, it would appear that an effective strategy to reduce or eliminate transfusion need during the treatment period would be to initiate therapy earlier, when a patient’s Hb level is 10–11 g/dl rather than <10 g/dl. More recent treatment guidelines, such as those published by the NCCN and EORTC, have shifted somewhat, now recommending the initiation of treatment at an Hb level 11 g/dl. In contrast, ASH/ASCO and the Canadian treatment guidelines still recommend 10 g/dl as the initiating Hb level, in the absence of clinical circumstances that warrant earlier intervention. Since treatment guidelines are likely to influence physician behavior and also impact reimbursement criteria, it is essential that these guidelines be updated to reflect findings from recent peer-reviewed publications. The ideal approach might also involve the incorporation of an anemia predictor tool and the monitoring of patients who appear to have a high potential for developing anemia, thus allowing intervention in a timely manner where possible to prevent avoidable transfusions.
Another potentially interesting prognostic factor not previously examined that could impact both the need for transfusion and the response to erythropoietin therapy is the rate of change in Hb level. When this was added to the list of predictive factors presented in Table 2, in addition to prior transfusion and baseline Hb level, Hb change within the first 2 weeks of epoetin alfa therapy was found to be a very significant predictive factor for transfusion (p<.0001), with the risk for transfusion increasing with a decrease in Hb level. This result suggests that the rate of Hb drop prior to entry into the study might also be a very significant factor in determining future transfusions. Regrettably, in the absence of available prestudy Hb data, the rate of Hb drop prior to epoetin alfa therapy as a predictor of subsequent transfusion could not be determined and remains an issue requiring further research.
The limitations of this integrated analysis include the retrospective nature of the review itself, differences in the designs of the studies included, and also the evolving physician approach to anemia management over the time frame spanning the review. The generalizability of this review could also be challenged by the fact that only Canadian data were included in the analyses. However, the fact that the main findings from this review were identical to those of the meta-analysis performed by Couture et al. [31], using data from five U.S./European double-blind, placebo-controlled trials, suggests that the current analysis was robust and that the main observations were not affected by the limitations mentioned above. The key observations of this review, including prior transfusion, transfusion in the first 4 weeks of epoetin alfa therapy, and low baseline Hb level as constituting major drivers of transfusions during epoetin alfa therapy, were recently confirmed in two community-based observational studies [35, 36]
The introduction of erythropoietic agents in the last decade has revolutionized the treatment of anemia in cancer patients. Evidence collected from the systematic review of clinical trial data and published results has provided a framework for the use of these agents in anemic cancer patients, although optimized guidelines remain outstanding. The results obtained from this Canadian integrated analysis confirm the observation made by Couture et al. [31] that early treatment with epoetin alfa could potentially decrease RBC transfusion needs, thus preserving a precious resource.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Dr. Kovacs is an employee of London Regional Cancer Center. Dr. Couture is an employee of Hôtel-Dieu de Québec and Lévis. Dr. Turner is an employee of the Cross Cancer Institute. Dr. Noble is an employee of Royal Columbian Hospital. Dr. Burkes is an employee of Mount Sinai Hospital. Dr. Dolan is an employee of Saint John Regoinal Hospital. Dr. Quirt is an employee of Princess Margaret Hospital. Dr. Chang has acted as a consultant and received support from the R.S. McLaughlin Durham Regional Cancer Center. Dr. Lau and Dr. Plante own stock in Johnson & Johnson and are employed by Ortho Biotech.
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