Transfusion practice patterns in patients with anemia receiving myelosuppressive chemotherapy for nonmyeloid cancer: results from a prospective observational study

Chemotherapy-induced anemia (CIA) often develops in patients with cancer who are treated with myelosuppressive chemotherapy [1‐3] and can be associated with diminished physical functioning, poor prognosis, and decreased quality of life [4, 5]. Transfusion with packed red blood cells (PRBCs) is a key supportive measure in the care of patients with CIA [3], offering the benefit of rapid correction of anemia in these patients.

In general, the uses and indications for transfusion therapy have changed over the last few years with a shift toward a more restrictive transfusion policy [6, 7]. In clinical practice, any attendant comorbidities or treatment that a patient is receiving should also be considered in the decision on whether or not to prescribe a blood transfusion, especially for cancer patients receiving chemotherapy [2, 3, 8‐10]. Additionally, the benefit of a blood transfusion has to be balanced with known risks that include the potential for transfusion-related reactions such as transfusion-associated circulatory overload, transfusion-related acute lung injury, allergic reaction, and febrile nonhemolytic transfusion reaction [7, 11‐13] and the potential for transmission of blood-borne pathogens [14]. Other factors to consider include time constraints associated with administration of transfusions [15], the inconvenience to both patients and healthcare professionals [16], and the associated costs [17, 18].

Current clinical guidelines from the National Comprehensive Cancer Network (NCCN) [3] support a restrictive transfusion policy for cancer-related anemia that limits the use of transfusions to achieve a hemoglobin (Hb) concentration of ≥ 7 g/dL but acknowledge that transfusion may be reasonable when patients exhibit anemia symptoms or when patients have comorbidities such as cardiac disease, chronic pulmonary disease, or cerebrovascular disease. While a large body of data with respect to patients with CIA has been generated from studies evaluating support with erythropoiesis-stimulating agents (ESAs) [16, 19‐25], there remains a lack of data regarding clinical factors that form the basis for making decisions on when to transfuse patients with CIA [3, 8]. As such, a study evaluating the clinical factors used in making decisions for prescribing transfusions for patients with CIA can inform practitioners on current practice patterns.

This prospective, observational study was designed to evaluate physician-assessed clinical considerations for prescribing PRBC transfusion therapy in patients with a baseline Hb concentration of ≤ 10.0 g/dL who were to receive chemotherapy without support of ESAs.

Anemia is common in patients with cancer and often occurs before patients receive treatment for the cancer [3, 26, 27]. Anemia is also one of the most frequent adverse effects of chemotherapy as shown by studies in different regions [27‐31]. An analysis of data for cancer patients receiving chemotherapy obtained from pooled placebo arms of six randomized controlled trials (RCTs) of darbepoetin alfa and from an aggregated US community oncology EMR database showed that 58% of patients in the RCTs and 46% EMR episodes had a Hb decline from < 10 to < 9 g/dL at week 9 [28]. In a multicenter observational study of patients receiving chemotherapy for nonmyeloid malignancies in Spain [29], almost half the patients (48%) had a Hb level < 12 g/dL. A multicenter survey of Japanese patients receiving chemotherapy [30] reported an average Hb level prior to treatment of 9.5 g/dL. A study of chemotherapy-associated anemia in Western Denmark reported a median Hb level before transfusion of 9.0 g/dL [31]. In data reported by the European Cancer Anemia Study, mean Hb level in cancer patients before initiation of either iron supplementation, transfusion, or use of an ESA was 9.7 g/dL [27].

Since the seminal paper by Herbert et al. evaluating transfusion requirements in critical care units in Canada [32], numerous studies and clinical guidelines have supported the use of a more restrictive transfusion policy with a target Hb concentration of 7 to 8 g/dL in patients who are not actively bleeding. These studies encompass a wide range of patient groups including patients treated in critical care units, coronary care units, and orthopedic and cardiac surgery patients, as well as patients in the setting of sickle cell disease, end stage renal disease, gastrointestinal bleeding, and sepsis [6, 7, 33‐36].

Transfusion requirements in cancer patients receiving myelosuppressive chemotherapy have not been prospectively studied [37, 38]. Data on transfusion practices generated in Europe show a wide variation in transfusion practices as it relates to cancer patients with anemia who are receiving chemotherapy [38‐41]. These data may not be directly applicable to the US population in view of variations in treatment guidelines, approved supportive agents such as ESAs, and differences in reimbursement policies. In addition, since the US Food and Drug Administration placed restrictions on ESA use in 2007, a number of studies have shown a change in patterns of transfusion practice with a documented increase in transfusion frequency seen in most studies [9, 40, 42‐44].

In our prospective, multicenter, observational study, we sought to understand current transfusion practice patterns and the factors that contribute to a decision to transfuse patients with anemia who were receiving myelosuppressive chemotherapy for nonmyeloid malignancies, in an era of restricted ESA use. The most common reason to prescribe a transfusion in our patient population was anemia symptoms in 72.1% of patients, with fatigue being the predominant symptom in 69.2% of patients. Absolute Hb value was only a secondary consideration, being cited as the reason to prescribe a transfusion in 25.2% of patients (Fig. 1 and Table 3). Even though comorbidities were reported in 27.9% of patients, physicians considered them relevant to prescribing a transfusion only 2.7% of the time.

While patients in our study were treated according to current clinical guidelines for transfusion of cancer-related anemia [3], 47.9% received a transfusion at a Hb level ≥ 8.0 g/dL (Table 1). This pattern was consistent across multiple covariates including sex, cancer type, and chemotherapy type (platinum versus non-platinum) (Online Resources 4 to 7). There was a trend to prioritize Hb value over anemia symptoms in patients ≥ 65 years of age (Online Resource 4).

Anemia symptoms appear to have been an important clinical consideration in the decision to transfuse in our study. In general, fatigue has not been a major indication for transfusion outside of the cancer setting [45, 46]. There may be a number of factors that distinguish patients with cancer from other non-cancer patient groups. Cancer-related fatigue is common and typically multifactorial. As noted above, many patients with cancer may already be anemic prior to starting treatment for their cancer. The physical and psychological effects of the cancer itself, treatment effects (which may or may not include myelosuppression), the effect of repetitive cycles of chemotherapy, and the recovery interval between treatments impact on the decision making for management of patients with cancer.

Although we did not attempt to quantify the degree of fatigue in our patient group, fatigue was the most frequently recorded clinical consideration for prescribing a PRBC transfusion over the absolute Hb value or medical history/comorbidities. Additional factors that may have influenced the decision for PRBC transfusion at a higher Hb value as observed in our study may relate to the fact that ESA use was excluded in this study, and thus treating physicians may have anticipated a further fall in Hb levels due to planned chemotherapy treatment.

The major strength of our study is the prospective design with predefined measures and endpoints that enabled the evaluation of PRBC transfusion patterns in cancer patients with anemia who were receiving chemotherapy in a real-world setting. However, the findings from this study should be considered in the context of a number of limitations. The assessments of iron stores or iron treatments were not recorded. Also, any attendant complications associated with transfusion therapy were not recorded. Our study relied on questionnaires completed by the physicians; patients did not fill out comparable questionnaires. Patient-reported symptoms were abstracted from the subject’s EMR or reported to the oncology nurse and then recorded. Physicians were not asked to comment on how they might have integrated ESAs in their transfusion algorithm or whether their decision to transfuse was correlated with the number of chemotherapy cycles anticipated. Anemia signs and symptoms were only assessed on a 10-point prespecified list without using a commonly accepted, validated instrument and without severity grading. Likewise, validated instruments were not used to assess quality of life measures for patients in our study.

In conclusion, in this prospective, multicenter, observational study of transfusion practices in patients with CIA, the primary clinical consideration for prescribing a PRBC transfusion was anemia symptoms in 72.1% of patients. The absolute Hb value was the second clinical consideration for the decision to transfuse in 25.2% of patients. Overall, 47.9% of patients received a transfusion at a Hb level ≥ 8 g/dL. The decision to transfuse was independent of sex, medical comorbidities, cancer type, or chemotherapy type (platinum or non-platinum), with a trend to rely more on Hb value when transfusing patients ≥ 65 years of age. Clinical judgment based on individual patient signs and symptoms of anemia, in particular fatigue, and not only the absolute Hb value, were used in the decision to prescribe a PRBC transfusion.