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The Oncologist, Vol. 10, No. 1, 63-71, January 2005; doi:10.1634/theoncologist.10-1-63
© 2005 AlphaMed Press

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Prior Red Blood Cell Transfusions in Cancer Patients Increase the Risk of Subsequent Transfusions With or Without Recombinant Human Erythropoietin Management

F. Couturea, A.R. Turnerb, B. Meloskyc, L. Xiud, R.K. Plantee, C.Y. Laue, I. Quirtf

a Hôtel-Dieu de Lévis, Lévis, Québec and Hôtel-Dieu de Québec, Québec City, Québec, Canada; b Cross Cancer Institute, Edmonton, Alberta, Canada; c British Columbia Cancer Agency, Vancouver, British Columbia, Canada; d Johnson & Johnson Pharmaceutical Research and Development, Raritan, New Jersey, USA; e Ortho Biotech, Division of Janssen-Ortho, Inc., Toronto, Ontario, Canada; f Princess Margaret Hospital, Toronto, Ontario, Canada

Correspondence: Ian Quirt, M.D., Princess Margaret Hospital, 610 University Avenue, 5th Floor, Room 209, Toronto, Ontario, Canada M5G 2M9. Telephone: 416-946-2252; Fax: 416-946-6546; e-mail: ian.quirt{at}uhn.on.ca


   ABSTRACT
Top
 Abstract
Introduction
 Methods
 Results
 Conclusions
 References
 
Cancer patients often receive transfusions when their hemoglobin concentration falls to dangerously low levels due to chemotherapy or due to the disease itself. The availability of recombinant human erythropoietin (rHuEPO) has significantly reduced transfusion frequencies in cancer patients. However, the predictability of transfusions prior to the use of rHuEPO for future transfusions has not been evaluated. Data from five randomized, double-blind, placebo-controlled trials in cancer patients receiving chemotherapy and epoetin alfa were utilized to calculate the relative risk of subsequent transfusions in patients who were pretransfused. A meta-analysis with patient-level data was used to assess predictors of transfusion. Baseline data from an open-label study were used to compare quality-of-life (QOL) parameters between previously transfused and transfusion-naïve patients. The mean relative risks (RR) of exposure to additional transfusion for pretransfused patients on placebo or epoetin alfa were 2.14 (95% confidence interval [CI]: 1.73, 2.65) and 2.51 (95% CI: 1.92, 3.27), respectively, compared with nontransfused patients. Data from the meta-analysis of patients on epoetin alfa showed that pretransfusion was the most significant predictor for subsequent transfusions (parameter estimate = –1.2628, p < 0.0001 from Logistic Regression Analysis). While epoetin alfa was similarly effective in reducing transfusion risks for patients with or without pretransfusions (compared with placebo), those who were pretransfused were more than twice as likely to be subsequently transfused, compared with those not pretransfused. QOL was significantly worse for pretransfused patients than for nontransfused patients, as measured by the Functional Assessment of Cancer Therapy –Anemia and the Linear Analogue Scale Assessment QOL instruments. The results suggest that transfusions prior to epoetin alfa therapy increase the risk of future transfusions, and early treatment with epoetin alfa might reduce the risk of subsequent transfusions.

Key Words. Epoetin alfa • Transfusion reduction • Anemia • Quality of life


   INTRODUCTION
Top
 Abstract
 Introduction
Methods
 Results
 Conclusions
 References
 
Cancer patients often experience significant anemia due to the disease itself or due to myelosuppressive therapy received. In prospective trials and surveys, up to 75% of cancer patients have been shown to have mild to moderate anemia [1–3]. Although the degree of anemia experienced by cancer patients may vary, the impact of symptomatic anemia on a patient’s quality of life (QOL) is of considerable concern [4]. The major complaints associated with this anemia are patient fatigue, low energy levels, dyspnea, dizziness, and an associated decrease in functionality [5, 6].

Management of anemia is multifaceted, including erythrocyte transfusional support or treatment with recombinant human erythropoietin (rHuEPO). Intervention through transfusional support has traditionally been reserved for patients with severe anemia necessitating immediate and direct relief (usually triggered by a threshold hemoglobin [Hb] level <8 g/dl and/or appearance of clinically significant symptoms) [7]. While there are well-defined risks associated with transfusion (i.e., acute immunologic effects and risk of infection), the long-term effects of cell-mediated and humoral immunity in transfused patients is certainly less well understood, as these effects have a complex etiology [8, 9]. Although retrospective analyses have suggested that cancer patients (colorectal, cervical, laryngeal tumors, lung) receiving blood transfusions during antineoplastic treatment may have higher rates of recurrence and decreased survival [10–12], no definitive or conclusive prospective data relating to this question are available. While it is difficult to explain the observed impact on patient outcome by transfusion-associated risks, a recent meta-analysis suggests that leukoreduction may minimize risk and decrease infection rates following transfusion [13].

Given the large number of cancer patients with anemia requiring treatment or developing anemia as a result of their cancer therapy, the integral role of red cell transfusions in this and other clinical settings has begun to stress the already delicate balance of limited supply and demand [14, 15]. The realization that donated red cells are a rare and precious resource has been instrumental in the exploration of strategies to optimize use of red cells, and limit their transfusion to situations where alternatives do not exist.

Numerous randomized, controlled clinical trials have demonstrated that intervention with rHuEPO therapy is effective in significantly increasing Hb levels, reducing transfusion requirements, and improving QOL. This benefit of rHuEPO has been observed to be independent of tumor type and response, treatment regimen (either platinum- or nonplatinum-based chemotherapy), or whether or not patients were receiving chemotherapy [16–20]. The positive impact of rHuEPO therapy has been further substantiated in four large trials carried out in the community setting [21–24]. Subsequently, the results of a comprehensive review of existing literature guided the development of joint recommendations for the treatment of cancer-related anemia by the American Society of Clinical Oncology and the American Society of Hematology. These clinical guidelines have helped define and optimize the treatment of anemia in cancer patients with the use of rHuEPO [25].

More recent research with rHuEPO has focused on the identification of variables that are predictive of future response to therapy. These include baseline variables such as serum ferritin, serum erythropoietin levels, and baseline Hb levels, as well as early response variables [26–29]. However, results have yet to demonstrate clinical sensitivity and specificity in prognosticating response to rHuEPO [30]. Although recent studies have shown that early treatment of mildly anemic patients (baseline Hb 10–12 g/dl) results in better hematological response compared with those patients whose Hb is allowed to drift down [20, 31], there still remains a compelling need to increase awareness of cancer-related anemia as well as to understand the consequences of its suboptimal treatment. Surprisingly, the direct impact of previous transfusion (possibly attributed to delayed epoetin alfa treatment) on hematological response in cancer patients, as measured by successive transfusional needs, has not been previously evaluated. Data from the efficacy populations of five cancer studies, in concert with a meta-analysis of the integrated efficacy population data from only the epoetin-alfa-treated patients, was thus used to assess the impact of baseline transfusion on the future incidence of transfusion during the course of cancer and anemia management.


   METHODS
Top
 Abstract
 Introduction
 Methods
Results
 Conclusions
 References
 
Five multicenter, double-blind, placebo-controlled studies with similar design parameters and with statistical power to evaluate the safety and efficacy of epoetin alfa were selected for this review. The five studies included two U.S.-based studies (Chemotherapy and Cisplatin [16, 32–35]), and three international studies (EPO-INT-2 [17], EPO-INT-3 [data on file], and EPO-INT-10 [18]). Study designs, dose regimens, and patient numbers are shown in Table 1Go. Patient level data from these five studies for patients on epoetin alfa therapy only (efficacy population) were integrated for a meta-analysis to evaluate factors that might predict positive responses to epoetin alfa [36]. Logistic regression analysis was conducted using PROC LOGISTIC of SAS statistical software [37], with a cross-validation procedure to confirm model performance and fit, thus permitting clinical interpretation [38, 39].


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  		Table 1. Overview of double-blind, placebo-controlled, clinical trials included in meta-analyses
 
In the two US studies (Chemotherapy and Cisplatin), when the patient’s hematocrit reached 38%–40% (12.7–13.3 g/dl), the dose of study drug was titrated to maintain the hematocrit within this target range. Patients had to have a diagnosis of cancer being treated with an aggressive, cyclic, cytotoxic, either non-cisplatin-containing regimen for the Chemotherapy trial or cisplatin-containing regimen for the Cisplatin trial. For both studies, patients were randomized in a 1:1 ratio to epoetin alfa or placebo and the entry Hb levels were <10.5 g/dl.

In the three international studies, chemotherapy regimens were defined by the nature and the stage of their disease as well as by clinical practice. For EPO-INT-3 and 10, patients were randomized in a 2:1 ratio (epoetin alfa: placebo), whereas for EPO-INT-2, randomization was in a 1:1 ratio (epoetin alfa:placebo). EPO-INT-2 was conducted in multiple myeloma patients with a baseline Hb level of <11 g/dl. EPO-INT-3 enrolled patients with a baseline Hb level ≤12 g/dl or a drop of ≥1.5 g/dl per cycle since the initiation of chemotherapy. EPO-INT-10 enrolled patients receiving nonplatinum chemotherapy, with a baseline Hb level ≤10.5 g/dl or Hb ≤12 g/dl with a drop of 1.5 g/dl per chemotherapy cycle.

Adequate QOL data to compare QOL between pretransfused and nontransfused cancer patients were not available for all five trials used in the meta-analysis. Therefore, data from an open-label Canadian study, assessing the effect of epoetin alfa on cancer patients with or without chemotherapy, was utilized for the QOL analysis [24]. One of the study’s endpoints was the change in QOL from baseline to week 12. QOL was measured using the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Linear Analogue Scale Assessment (LASA). Patients were enrolled in the study when their baseline Hb level was <10.5 g/dl and the regimen of epoetin alfa used was similar to the five double-blind, placebo-controlled trials. Baseline QOL data and Hb levels between patients with or without pretransfusions were compared using a standard t-test for the comparison of two independent samples.

Relative risk ratios (RR) and their confidence intervals were calculated using SAS. Tests of heterogeneity were based on the Breslow-Day test for heterogeneity of odds ratios. The comparison of RR was based on a t-test derived from the asymptotic distribution of the logarithm of the RR. In the current study, the RR of transfusion was calculated based on data from both reports and published literature using data from both the efficacy populations and the intent-to-treat (ITT) populations. Due to the fact that the meta-analysis of the five studies was performed using the efficacy populations as shown in Table 2Go, most analyses were carried out using only the efficacy population data. Data from ITT populations are mentioned where appropriate. The ITT population was defined as patients who were enrolled and had at least one dose of study drug. The efficacy population was defined as patients who stayed in the trial for more than 28 days (EPO-INT-2, 3, and 10) or more than 1 month (Chemotherapy and Cisplatin). The primary end point for all five studies was transfusion requirements after 28 days or 1 month on study drug.


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  		Table 2. Baseline transfusion status for efficacy population
 

   RESULTS
Top
 Abstract
 Introduction
 Methods
 Results
Conclusions
 References
 
Table 1Go describes the study design, dose regimens, and patient numbers (ITT and efficacy populations) in the five double-blind, placebo-controlled studies. The total number of patients in the ITT and efficacy populations (as defined in Methods) was 1,010 and 934, respectively.

Table 2Go shows the baseline transfusion status of patients (efficacy population) for all five studies. The percent of patients who were pretransfused ranged from 16% to over 50%. The high baseline transfusion rates in the two U.S. trials that were conducted in the late 1980s reflect both the medical practice at that time, when transfusion was used more liberally, and the fact that rHuEPO was not yet available as an alternative for cancer patients. Data were similar for the ITT population (legend to Table 2Go).

Figure 1Go compares the RR of transfusion requirements in patients with or without prior transfusions in the placebo arm. As indicated, the RR for subsequent transfusion in patients who were pretransfused was similar among the studies, and the overall pooled RR is 2.14 (95% CI: 1.73, 2.65). Consequently, patients who received transfusions before entering the study were subjected to significantly higher risk of additional transfusions during the study period. The mean RR for pretransfused patients receiving subsequent transfusions while receiving epoetin alfa treatment is 2.51 (95% CI: 1.92, 3.27), indicating that even while on epoetin alfa treatment, pretransfused patients were twice as likely to receive subsequent transfusions as compared with transfusion-naïve patients (Fig. 2Go). For the purposes of the regression analysis within the meta-analysis database, baseline transfusion was simply entered as yes or no, and as such the predictability of one or more transfusions could not be ascertained on subsequent transfusion outcome.



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  		Figure 1. Relative risk of transfusion in patients who were pretransfused. Relative risk of subsequent transfusion was calculated from the number of patients transfused after 1 month or 4 weeks on trial. Data used from the placebo patient efficacy population from the five double-blind, placebo-controlled trials.

 


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  		Figure 2. Pretransfused patients have lower response to rHuEPO as measured by subsequent transfusions. Relative risk of subsequent transfusion was calculated from the number of patients transfused after 1 month or 4 weeks of epoetin alfa treatment. Data used from the epoetin alfa patient efficacy population from the five double-blind, placebo-controlled trials.

 
For the patient population receiving epoetin alfa, a meta-analysis of the five double-blind studies was performed with patient level data to assess positive predictor factors for hematological responses (defined as a >2 g/dl rise in Hb) and for transfusion responses (defined as zero transfusion after 28 days or 1 month on study drug). Only the analysis relating to transfusion responses are presented here. Table 3Go shows pooled demographics and baseline characteristics of the efficacy population for all five studies combined.


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  		Table 3. Demographic and baseline characteristics of efficacy population included in meta-analyses
 
The majority of patients (64%) enrolled in the five double-blind studies and receiving epoetin alfa (EPREX) were female, and the overall mean age was 59.3 years. The baseline Hb level was 9.8 g/dl, and 34% of the patients had been pretransfused. Forty-one percent of patients had overall bone marrow involvement, and 78% of patients had received prior chemotherapy.

All baseline characteristics shown in Table 3Go were used in a PROC LOGISTIC model to identify predictors of subsequent transfusion. Of all baseline parameters evaluated, only baseline transfusion status and baseline Hb levels were found to be significant predictors of subsequent transfusions. The parameter estimates for prestudy transfusions and baseline Hb levels were –1.26 (SD = 0.20; p = 0.0001) and 0.33 (SD = 0.34; p = 0.0001), respectively.

To further compare the pretransfused population from the nontransfused population, the probability of transfusion response, as a function of baseline Hb levels and baseline transfusion status, are presented in Figure 3Go. As can be observed, the two lines delineating the two populations of patients, one defined by no baseline transfusion compared with the other defined by the presence of baseline transfusions, never meet even at high baseline Hb levels. This is particularly important, as it suggests that pretransfused patients were always responding less to epoetin alfa, regardless of the baseline Hb level. Separation between the two lines is greater at lower Hb levels and narrows at high Hb levels. The diversion of the two lines narrows around 10.5 g/dl and subsequently becomes parallel, suggesting that patients who were pretransfused, with a baseline Hb level <10.5 g/dl, were at highest risk of receiving transfusion on epoetin alfa treatment compared with transfusion-naïve patients.



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  		Figure 3. Probability of transfusion response as a function of baseline transfusion status and baseline Hb level. Predicted probability of subsequent transfusion and its point-wise 95% confidence region (dotted lines) are shown for the pretransfused and non-pretransfused patient populations. Data used from the epoetin alfa patient efficacy population from the five double-blind, placebo-controlled trials.

 
Although patients with baseline transfusions were at higher risk of receiving additional transfusions in both placebo and EPO arms in the five studies, the regimen of 150 IU/kg epoetin alfa s.c. three times weekly used in the five studies effectively reduced the risk of subsequent transfusion to the same extent (RR reduction, 0.55–0.64, p = 0.4481) and increased Hb levels (data not shown) compared with placebo for all patients studied (Fig. 4Go).



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  		Figure 4. Effect of epoetin alfa treatment on subsequent transfusions in previously transfused patients, nontransfused patients, and in all patients. *Pooled risk reduction of transfusion in the pretransfused, nontransfused, and entire patient population, in the presence of epoetin alfa treatment compared with placebo. Data used from the efficacy population from the five double-blind, placebo-controlled trials.

 
The use of epoetin alfa in cancer patients not only reduced transfusion but significantly improved QOL. However, patients who were previously transfused before receiving epoetin alfa therapy experienced a poorer QOL compared with those patients who were transfusion naïve, even with similar baseline Hb levels. Figure 5Go illustrates the results from an open-label study [20] showing the differences in scores between previously transfused and transfusion-naïve patients. Except for "Energy" in the LASA instrument, all other scores in the LASA (Daily Activity and Overall QOL) and FACT-An (Fatigue sub-scale, Anemia sub-scale, and General QOL) instruments were significantly better for patients who had not received a previous transfusion, despite the comparable Hb levels between the two groups (p = 0.1918).



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  		Figure 5. Quality of life in patients pretransfused compared with those patients without pretransfusion. Difference in baseline quality-of-life values was calculated between pretransfused and non-pretransfused patients using the FACT-An and LASA questionnaires scores. Data used from the open-label QOL trial.

 
The fact that transfusions might not improve QOL as well as rHuEPO is not surprising, as reported in studies by Ludwig et al. [40] and Österborg [41] comparing the ability of epoetin alfa or transfusions to maintain Hb levels. It is quite clear that red cell transfusions only provide transient relief and fail to maintain Hb levels, compared with the sustained Hb level effectuated by epoetin alfa (Fig. 6Go). This transient relief by transfusion alone has been repeatedly observed in patients not receiving epoetin alfa, while sustained Hb levels have been confirmed in thousands of patients treated with epoetin alfa in large community-based studies [21, 22].



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  		Figure 6. Hb Levels over time in patients treated with either epoetin alfa or blood transfusion. Hb levels during 6 months of therapy in multiple myeloma patients. The epoetin alfa line represents the median Hb value of 11 patients receiving 150 IU/kg epoetin alfa tiw. The without epoetin alfa line represents a patient not receiving epoetin alfa who is repeatedly dependent on allogeneic red blood cell transfusions (arrows indicate transfusions of 500 ml).

 

   CONCLUSIONS
Top
 Abstract
 Introduction
 Methods
 Results
 Conclusions
References
 
An impressive collection of literature, including several meta-analyses, have shown that epoetin alfa significantly reduces transfusions, increases Hb levels, and improves QOL in anemic cancer patients with solid tumors and hematologic malignancies [42, 43]. Analysis of predictors of response showed baseline Hb levels, baseline serum erythropoietin, baseline serum ferritin levels, and an early response variable defined as a >1 g/dl increase in Hb level from baseline to week 4 to be important predictors of hematopoietic response [44]. Interestingly, there has been little or no critical appraisal of the impact of baseline transfusions on the response to rHuEPO. In this study, using data from five double-blind, placebo-controlled trials, we demonstrate for the first time that cancer patients on chemotherapy who were pretransfused were at significantly higher risk of additional transfusions compared with transfusion-naïve patients, regardless of whether they received epoetin alfa or placebo during the study. While epoetin alfa was similarly effective in reducing transfusions in both groups, patients who were pretransfused were still more than twice as likely to receive subsequent transfusions as those who were not previously transfused. Regression analysis using all clinically relevant baseline characteristics demonstrated that baseline Hb level and baseline transfusion status were the only significant predictors of subsequent transfusion in epoetin-alfa-treated patients. In addition, data from an open-label study also showed that the QOL of patients who were previously transfused was significantly lower than patients who were not transfused, even when Hb levels between the two groups were similar.

Despite the strong evidence from the meta-analysis showing that pretransfused patients were at higher risk of subsequent transfusions, the clinical reasons for this observation require further investigation. It could be hypothesized that transfused patients were older, had more severe disease, or had a longer duration of illness. However, predictor analysis did not reveal any of those baseline characteristics (age, sex, bone marrow involvement, duration of illness, tumor type, or prior chemotherapy) to be significant predictors of additional transfusion. In these same analyses, baseline serum erythropoietin level was also found to not be a significant predictor. The most significant baseline predictors for subsequent transfusions were baseline Hb levels and prior transfusion exposure, with pretransfusion being the most significant predictor of subsequent transfusion.

One possible reason for the inferior response experienced by the pretransfused patients could be attributed to the delay in the treatment of mild anemia. When Hb levels drop to transfusion threshold levels (usually around 8–9 g/dl), clinicians often transfuse regardless of symptomology. However, these transfused red cells will increase Hb levels only transiently, as shown in Figure 6Go. Even in patients treated with epoetin alfa, if treatment is delayed and Hb levels are permitted to drop to subthreshold levels, transfusions, which correct anemia almost instantly, may be required to allow epoetin alfa to have sufficient time to stimulate hematopoiesis (approximately 2–4 weeks).

The QOL of previously transfused patients was compared with transfusion-naïve patients with comparable Hb levels. QOL assessed by both the FACT-An and LASA was worse for the transfused patients, suggesting that raising Hb levels by transfusion may not provide the same functional capacity for patients as their own de novo Hb increase (through rHuEPO). This observation is not surprising given that transfused red blood cells might be aged and possibly deteriorated, and as a consequence could result in a compromised oxygen carrying capacity. In addition, it has been shown that transfusion only provides transient relief of anemia and might not effectively correct anemia symptoms.

The post hoc nature of the analyses must be acknowledged as a possible limitation to the conclusions reached in this current study. In addition, prebaseline transfusions could artificially inflate baseline Hb levels of patients in the pretransfused group. As a result, analysis of the probability of transfusion as a function of baseline Hb levels could be rendered less significant. However, the total units of blood received by pretransfused patients in the 3 months prior to study entry were approximately 3–4 units per patient (data not shown), and as such, the Hb increase as a result is unlikely to affect the separation of the two populations, as shown in Figure 3Go.

Data in this report were extracted from five rigorously designed and executed studies including almost 1,000 patients. Evidence indicating that cancer patients who were pretransfused were at higher risk of additional transfusions, even with rHuEPO treatment, is strong. Early administration of epoetin alfa to prevent a drop in Hb level can thus significantly reduce the risk of future transfusions.


   REFERENCES
Top
 Abstract
 Introduction
 Methods
 Results
 Conclusions
 References
 

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Received July 26, 2004; accepted for publication October 11, 2004.




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