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A Retrospective Review of Blood Transfusions in Cancer Patients with Anemia

^a MCP-Hahnemann University School of Medicine, Philadelphia, Pennsylvania; ^b University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ^c Temple University School of Medicine, Philadelphia, Pennsylvania, USA

Correspondence: David H. Henry, M.D., Pennsylvania Oncology Hematology Associates, 700 Spruce Street, Suite 305, Philadelphia, Pennsylvania 19107, USA. Telephone: 215-829-6088; Fax: 215-829-6104; e-mail: dhhenry{at}juno.com

	Abstract

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Background: The factors contributing to blood transfusions in patients with anemia of chronic disease are not well documented in the literature. We analyzed all blood transfusion events within a single oncology practice to determine if certain chemotherapy drugs, cancer types, or other factors necessitated more frequent transfusions.

Patients and Methods: Out of 331 patients receiving chemotherapy, 103 (31%) patients received a blood transfusion in 1995. Each of these charts was reviewed and sorted by diagnosis, treatment medications, and past transfusion and/or treatment history. Hemoglobin levels were obtained for each transfusion received in 1995.

Results: The average hemoglobin at time of transfusion was 7.9 g/dl. Higher hemoglobin levels at transfusion were observed for patients over the age of 60 and patients who received prior chemotherapy. Lower hemoglobin levels at transfusion were observed for patients receiving Epoetin Alfa and sarcoma patients. The average number of red blood cell (RBC) units transfused in 1995 was 5.1 per patient. More units were given to patients receiving etoposide, while fewer units were given to those receiving ifosfamide. We created a transfusion severity index (TSI) to jointly measure these two variables.

Conclusion: The results of this study identify transfusion needs associated with certain groups of cancer patients and with certain types of chemotherapy drugs.

Key Words. Transfusion • Anemia • Epoetin Alfa • Chemotherapy

	Introduction

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Anemia of chronic disease (ACD) is common in patients with cancer [1]. It is characterized by erythroid hypoplasia, inadequate serum erythropoietin (EPO) levels in response to the anemia, and poor iron reutilization by the bone marrow [2, 3]. Anemia in cancer patients is often exacerbated by myelosuppressive chemotherapy and may also be aggravated by radiation therapy. Cancer patients may experience such severe anemia that red blood cell (RBC) transfusions are required for symptomatic palliation.

Relying on blood transfusion to support chemotherapy patients is not the optimal strategy. Risks associated with blood transfusion include infectious disease transmission (cytomegalovirus [CMV], hepatitis, HIV), allergic responses, noncardiogenic pulmonary edema, alloimmunization, and hypervolemia, which can lead to cardiac failure [4-6]. Over the last decade, the observation that ACD is often associated with inadequate EPO levels and increased awareness of the risks associated with transfusion have led to the treatment of the anemia of cancer with recombinant EPO (epoetin). This treatment can elevate hemoglobin levels in over 50% of anemic cancer patients and, thus, reduce the need for blood transfusions. Patients who respond to treatment with epoetin experience an elevated overall performance status, an improvement in their symptoms of anemia, and an enhanced quality of life, independent of their response to cancer treatment [6-10].

Epoetin might also play a role in the prevention of anemia in patients starting chemotherapy. While data indicate that this strategy is effective, an improvement in quality of life by this approach has not yet been demonstrated [11]. Recognizing this limitation, it is important to predict which cancer patients will have the most severe need for a blood transfusion during their course of treatment. While there is one retrospective cohort study in the literature that addresses the frequency of blood transfusion by primary tumor site, there are no studies analyzing which chemotherapy drugs are most commonly associated with severe anemia [1].

In the United States, more than 12 million units of blood are collected each year and some one million RBC units are given to anemic cancer patients [12]. While data are available to document the frequency of anemia associated with many of the commercially available chemotherapy drugs, very little information is available to document the actual need for RBC transfusions in their patients. In a study of 381 patients in the London (Ontario) Regional Cancer Center treated in 1989, Skillings described the diagnosis and treatment regimens of 75 patients who received RBC transfusions in this patient cohort [1].

The purpose of our study was to review all transfusion episodes in a single oncology practice population during the year 1995. Patients were analyzed by type of cancer diagnosis and type of cancer treatment, if any. Each of these patients and their transfusion episodes were examined to find which risk factors produced the most severe need for a blood transfusion as measured by the drop in hemoglobin from baseline and the total number of RBCs received. This retrospective study attempts to identify the categories of patients who are most likely to receive a blood transfusion during the course of their cancer treatment. This information, currently not readily available in the literature, may help physicians select patients who can benefit from prophylactic administration of epoetin.

	Methods

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In a retrospective review, we analyzed all cancer patients receiving treatment during 1995 in a single oncology practice at the Graduate Hospital in Philadelphia. Only patients who also received a blood transfusion in 1995 were included. The patient charts were reviewed and information about their diagnosis, course of treatment, and outcome was obtained. The following information was extracted from their charts: diagnosis date, diagnosis location, diagnosis type, past or present chemotherapy (dates and type), radiation therapy (date), Epoetin Alfa (Procrit, Ortho Biotech; Raritan, NJ) therapy (dates), transfusions prior to 1995, and baseline hemoglobin level. The baseline hemoglobin level was defined as the earliest recorded hemoglobin level following diagnosis, usually just prior to the initiation of cycle one of chemotherapy. These patients were then cross-referenced with the blood bank database at the Graduate Hospital to determine when these patients received transfusions, how much they were transfused, and the type of transfusion. These dates were cross-referenced back to the charts and to computerized inpatient lab records to determine the hemoglobin level at the time of transfusion.

A statistical analysis was performed to determine the effects of different patient variables, diagnosis type, and therapies involved on the need for transfusions. Transfusion-free days were defined as the time between chemotherapy treatment and first transfusion. The drop in hemoglobin was defined as the baseline hemoglobin level minus the hemoglobin level at first transfusion. A Kaplan-Meier analysis was used to evaluate these variables. The Kruskal-Wallis chi-squared test was used to evaluate baseline hemoglobin and the effects on transfusion requirements.

For each diagnosis type, Kaplan-Meier analysis for median transfusion-free days was done, and the diagnoses with significant frequency were compared. A Kruskal-Wallis chi-squared test was used with multiple comparisons between diagnoses to look at both transfusion variables as well as the drop in hemoglobin. The Mann-Whitney test was used to compare each diagnosis versus all others while evaluating the transfusion variables. The Kaplan-Meier test was used to compare each diagnosis versus all others while evaluating the median transfusion-free days.

The Mann-Whitney test was used to evaluate the effects of prior chemotherapy, radiation therapy, and Epoetin Alfa therapy on the transfusion variables. The Kruskal-Wallis chi-squared test involved a four-way comparison among patients who were newly diagnosed, previously treated, previously transfused, and lacking any history of transfusion. Kaplan-Meier analysis was used to determine if prior chemotherapy or Epoetin Alfa therapy had any effect on the median transfusion-free days. The Mann-Whitney test was used to examine prior chemotherapy, Epoetin Alfa therapy, or radiation therapy and their effects on the drop in hemoglobin. This test also compared the effect of the various drugs on the number of transfusions, the amount transfused, and the drop in hemoglobin. Differences in the median transfusion-free days for each drug were evaluated using Kaplan-Meier analysis.

	Results

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Three hundred thirty-one patients received chemotherapy in 1995. This retrospective study includes 103 patients, 53 females and 50 males, who had a blood transfusion during this calendar year. Fifty-one of these patients were Caucasian and 45 African-American. Three patients required only platelet transfusions and are thus not included in the analysis of RBC transfusions. Nine additional patients required platelet transfusions in combination with RBCs. The average number of RBC units given for a transfusion event was 5.1. However, since 46 units were given to one patient, a median of three units per transfusion event is a more accurate reflection of the data. Thirty-eight patients received two units, typical for transfusion events. The average number of transfusion events per patient was 2.3, with a median of slightly more than one event. Forty-six patients had only one transfusion event.

The average hemoglobin level at time of transfusion was 7.9 g/dl. These figures were identical when first 1995 transfusion events were averaged separately. The lowest hemoglobin level at first transfusion was 4.3 g/dl while the highest was 15.0 g/dl. The highest number of patients, nine, were transfused at 7.4 g/dl. The median drop in hemoglobin level from baseline to first transfusion was 3.3 g/dl (range 0.1 to 8.5 g/dl; eight patients experienced a rise in hemoglobin before transfusion). The median drop for females was 3.4 g/dl versus 3.1 g/dl for males. There were 56 patients over the age of 60. Their average hemoglobin at transfusion was 8.1 g/dl compared to patients younger than 60 years who had a mean hemoglobin at transfusion of 7.6 g/dl (p < 0.01).

Sixty-five patients had their first transfusion in 1995 following the initiation of a chemotherapy regimen. Twenty-two patients had a transfusion in 1995 prior to beginning chemotherapy and 16 patients received radiation therapy instead of chemotherapy. Three patients received both chemotherapy and radiation. There was no significant difference in hemoglobin levels at transfusion attributed to radiation therapy. For the 65 patients with a transfusion following chemotherapy, 73 (± 22) days was the median time period from the beginning of cycle one to the first transfusion. Four patients were transfused during the first week of cycle one while the longest a patient went without a transfusion was slightly more than a year at 371 days. Also, the most severe drops in hemoglobin occurred sooner, as drops larger than the median occurred over a median of 70 days compared to drops below this average, which happened over a median of 105 days. Overall, the rate of the hemoglobin drop was 0.045 g/dl per day.

We analyzed past experiences with chemotherapy and blood transfusions. Forty patients received transfusions prior to 1995, 18 of which were associated with a prior course of chemotherapy. In all, 34 patients had a previous cycle of chemotherapy ending prior to the beginning of 1995. Past chemotherapy led to a seemingly more liberal transfusion practice as those with previous chemotherapy were transfused at 8.3 g/dl compared to 7.7 g/dl for those who were chemotherapy naïve (p = 0.08). There was no difference observed in the drop in hemoglobin levels based on past chemotherapy regimens. In addition, transfusion history was only relevant for the 34 patients with prior chemotherapy, although the numbers, 8.6 g/dl for a positive transfusion history versus 7.9 g/dl for a negative transfusion history, did not reach significance. Out of the 66 chemotherapy-naïve patients, both transfusion-naïve and transfusion-experienced patients had their first transfusion at 7.9 g/dl. These demographic data are summarized in Table 1.

The relative differences in hemoglobin levels by specific primary site of diagnosis were also analyzed. Only breast cancer (n = 14, 13.6%), gastrointestinal (GI) tract cancer (n = 27, 26.2%), and lung cancer (n = 21, 20.4%) had a sufficient number of patients to be considered sufficient for analysis. Other cancers not considered were genitourinary (n = 7, 6.8%), gynecologic (n = 7, 6.8%), and sarcoma (n = 7, 6.8%). For breast cancer, 57.1% had prior chemotherapy, 21.4% received radiation therapy, 35.7% received Epoetin Alfa, and only 14.3% had prior transfusions. For GI cancer, 22.2% had prior chemotherapy, 14.8% received radiation therapy, 14.8% received Epoetin Alfa, and 29.6% received previous transfusions. For lung cancer, 28.6% received previous chemotherapy, 28.6% received radiation therapy, none received Epoetin Alfa, but 52.4% received previous transfusions. Finally, median transfusion-free days were evaluated for patients who were not transfused on the same day as they started their first cycle of chemotherapy. These data are compared in Table 2.

We also analyzed the results by chemotherapy agent. Of the 103 patients in this study, all but 18 received chemotherapy either prior to or during 1995. Four patients received carboplatin (Paraplatin, Bristol-Myers Squibb; Princeton, NJ), 14 patients doxorubicin (Adriamycin, Pharmacia UpJohn; Kalamazoo, MI), 29 cisplatin (Platinol, Bristol-Myers Squibb), 8 cyclophosphamide (Cytoxan, Bristol-Myers Squibb), 11 etoposide (VePesid, Bristol-Myers Squibb), 18 5-FU (Fluorouracil, American Pharmaceuticals; Nutley, NJ), 7 ifosfamide (Ifex, Bristol-Myers Squibb), 6 mitomycin (Mutamycin, SuperGen; Princeton, NJ), 15 paclitaxel (Taxol, Bristol-Myers Squibb), and 2 vincristine (Oncovin, Faulding; Indianapolis, IN). For each agent, the average hemoglobin at transfusion, baseline hemoglobin, drop in hemoglobin after chemotherapy, total RBCs transfused, and the number of transfusions were calculated and compared to the cohort of 18 patients who received no chemotherapy. Only patients treated with doxorubicin had a lower average hemoglobin at transfusion, 7.2 g/dl, than those not exposed to any chemotherapy (p = 0.05).

Patients receiving each chemotherapy agent were also compared to those patients not receiving that particular agent. These analyses showed that the patients treated with cisplatin and etoposide experienced a significantly higher rate of transfusion (p = 0.04 for both). In addition, patients treated with ifosfamide were transfused with an overall larger number of units of RBCs (p = 0.05). These variables for each chemotherapy agent are provided in Table 3. Comparing the TSIs for each category with the standard of 16.8 reveals that patients treated with etoposide 23.1 and 5-fluorouracil (5-FU) 24.8 had a significantly more pressing need for a transfusion during the course of their therapy.

	Discussion

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Typical of blood transfusion in most of oncology today, the average hemoglobin at transfusion in our patients was 7.9 g/dl. However, patients over 60 years of age were transfused sooner (8.1 g/dl) than those under 60 years old (7.6 g/dl). Patients without previous bone marrow suppression from cancer treatment and no history of blood transfusion were generally not transfused until a lower hemoglobin (7.1 g/dl) versus those who had previously been transfused who were transfused at a higher hemoglobin (8.1 g/dl). Within this sample the most common primary site of diagnosis was gastrointestinal cancer, and the chemotherapy drug most often associated with a transfusion was cisplatin. The lowest average hemoglobin at the time of transfusion was in breast cancer patients, and the greatest number of units transfused was in gastrointestinal cancer patients, but these differences did not reach statistical significance. The lowest hemoglobin at transfusion over all patients was found in the sarcoma patients at 7.1 g/dl. This was probably because these patients were younger and their chemotherapy regimens were more myelosuppressive.

To better describe the tendency to avoid blood transfusion in some patients and/or regimens, we developed a TSI. The TSI is obtained by multiplying the drop in hemoglobin from baseline to first transfusion by the number of RBC units transfused. A low TSI indicated a population that is more likely to tolerate low hemoglobin levels. Conversely, a high TSI is indicative of a population that was more likely to require a blood transfusion. Thus, patients with higher TSIs were deemed more likely to require a blood transfusion to maintain a tolerable quality of life. Sarcoma patients had the lowest TSI while GI cancer patients had the highest TSI.

Of the chemotherapy drugs employed in this study, doxorubicin was associated with the lowest hemoglobin at transfusion. The highest transfusion rate occurred with cisplatin, etoposide, and 5-FU therapy. The largest number of units transfused occurred with either etoposide or 5-FU; and ifosfamide-treated patients had the largest drop in hemoglobin, probably because of the high-dose ifosfamide used (12 g/m²). In spite of the large drop in hemoglobin, the ifosfamide patients had the lowest TSIs because of their clinician's reluctance to transfuse these relatively younger sarcoma patients. Patients receiving etoposide and 5-FU had the highest TSI.

Twenty-two of our 103 patients received Epoetin Alfa therapy for their anemia. Breast cancer patients had the greatest percentage of Epoetin Alfa use and they also had the largest transfusion-free interval, but this observation was not significantly different when compared with all the other cancer patients. We speculate that the greater Epoetin Alfa use in breast cancer delayed the need for the first transfusion in these patients.

In the only other published observational study of this type, 381 cancer patients were treated at the London (Ontario) Regional Cancer Centre in 1989; and 75 (19%) received a blood transfusion [1]. Leukemic patients were the most often transfused (78%) followed by lung cancer patients (34%). In the large phase III, double-blind, placebo-controlled American trial of Epoetin Alfa in 413 anemic cancer patients, 200 received placebo. These 200 placebo patients comprise a prospectively followed cohort with a well-documented transfusion history. Out of these 200 patients, 135 received chemotherapy and 56 (41%) received a blood transfusion. The most common diagnoses were lung cancer (62%), myeloma/chronic lymphocytic leukemia/lymphoma (59%), gynecologic cancer (58%), and breast cancer (50%) [6]. By comparison, a similar Italian trial of 100 cancer patients receiving Epoetin Alfa or placebo, 58% of the placebo patients were transfused [11].

Why is anemia important when managing cancer patients and why are anemic cancer patients transfused? Certainly, the answer is that anemia can cause symptoms of fatigue and malaise. Relief of anemia palliates these symptoms and improves the patient's quality of life. The American epoetin trial of anemic cancer patients demonstrated a significant improvement in quality of life in those Epoetin Alfa-treated patients whose hematocrits increased six percentage points versus controls [6]. In two follow-up phase IV open label studies of epoetin in more than 4,000 anemic cancer patients on chemotherapy, there was a significant improvement in quality of life in those patients whose hemoglobin levels increased, independent of whether or not they responded to the chemotherapy employed [9, 10]. Fatigue may be even more important to cancer patients than pain [13].

In summary, we report here our observations over one year of a retrospective cohort of general oncology patients who required at least one blood transfusion. While breast, GI, and lung cancer patients were the most often transfused, this probably simply represents their greater frequency in oncology overall. We have shown that higher blood transfusion rates are seen with breast, GI, and lung cancer and that cisplatin, etoposide, and 5-FU are the chemotherapy drugs most often associated with anemia severe enough to require blood transfusion. Certainly an increasing body of evidence now supports that increasing hemoglobins in anemic cancer patients is associated with improved quality of life. Blood transfusions are safer now then ever, but will always carry some inherent risks. As patients live longer with cancer and receive chemotherapy longer and with greater dose intensity, it may be more important to devise strategies to intervene sooner with agents like epoetin to blunt the anemia associated with cancer therapy.

	Acknowledgments

 
We would like to acknowledge the contributions of Rosemarie Mick, Ph.D., at the University of Pennsylvania School of Medicine, who performed the statistical analysis of the database, Maryellen Meyer for handling many of the logistics between the authors, and Ortho Biotech, Inc., for providing funding for this project.

	References

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