Abstract

BACKGROUND AND OBJECTIVES: Anemia in cancer patients is common, but often under-recognized and under-treated. Erythropoiesis stimulating agents (ESAs) are widely used to prevent and treat cancer and chemotherapy-related anemia, but recent studies suggest a negative impact on disease progression and survival associated with their use. This retrospective study describes the prevalence of anemia in cancer patients and recent trends in its management given the negative studies.
PATIENTS AND METHODS: All consecutive adult cancer patients (n=959) admitted to regular medical units over one year were reviewed. Patients with a hemoglobin (Hb) value <12 g/dL on admission were considered anemic. Information on the primary tumor, main reasons for admission and treatment given were collected.
RESULTS: At the time of enrollment, anemia was detected in 755 (78.7%) patients. The mean Hb value for anemic patients was 9.5 g/dL. Prevalence and severity of anemia varied according to tumor type and reason for admission. The majority (68.6%) of the anemic patients were not offered treatment. The mean Hb value at which treatment was started was 8.0 g/dL. Anemia treatment was related to its severity; treatment rates were 94.4%, 32.9%, and 5.0% in patients with severe, moderate and mild anemia, respectively (P<.0001). Blood transfusion was used the most while ESAs were rarely used. Length of hospital stay was affected by the presence of anemia (7.2 days in anemic patients vs. 4.85 days in nonanemic patients) (P<.001).
CONCLUSIONS: Blood transfusion was used the most for cancer-related anemia, while ESAs were rarely used. The majority of patients with moderate anemia were not treated, including patients on active chemotherapy. Better guidelines addressing anemia management in this subgroup of patients are highly needed.

Anemia is the most common hematological abnormality in cancer patients. Unfortunately, it is often under-recognized and under-treated. The pathogenesis of cancer-related anemia is complex and often multifactorial. While both radiotherapy and chemotherapy can be immunosuppressive and inhibit erythropoiesis, some treatments cause a greater degree of anemia than others.¹ A significant portion of cancer patients with anemia have no identifiable causes; the anemia in this situation is classified as anemia of chronic disease. The underlying mechanisms responsible for this type of anemia are unclear, but are thought to involve the activation of cytokines such as interleukin-1 and tissue necrosis factor (TNF). These cytokines may suppress endogenous erythropoietin (EPO) production, impair iron utilization and reduce erythroid precursor proliferation.²
Anemia can cause a wide range of symptoms involving almost every organ. The severity of these symptoms depends on several factors such as the degree of anemia, rapidity of onset and co-morbidities. These symptoms range from dizziness and palpitation to pulmonary edema, heart failure, depression and even cognitive impairment.³ Fatigue, a common symptom in cancer patients, is considered an important factor that adversely affects the quality of life (QOL) in such patients.^4,5 While cancer fatigue has different pathogenetic mechanisms, anemia is believed to be a significant contributing factor.⁶ Additionally, there is increasing evidence to suggest that anemia is an independent factor that can adversely affect survival in cancer patients.^7,8

Recombinant human erythropoiesis stimulating agents (ESAs) have been in use for many years to treat anemia associated with cancer and chemotherapy. Several studies have demonstrated that ESAs were effective in increasing hemoglobin levels as compared to placebo.^9-11 However, many recent studies involving patients with different kind of cancers at different stages of their disease suggest a negative impact on disease progression and survival when ESAs were used to keep hemoglobin at a higher level.^12-18 This report describes the prevalence of anemia in cancer patients and recent trends in its management at our institution following the recent confusion and uncertainties about the safety of ESAs in the treatment of anemia in cancer patients.

Patients and Methods

This was a retrospective, descriptive study, conducted at King Hussein Cancer Center (KHCC), a Joint Commission International-accredited comprehensive cancer center in Amman, Jordan. We retrospectively reviewed all consecutive adult (≥18 years) cancer patients (n=959) admitted to regular medical units between January and December 2008. Patients were eligible for inclusion regardless of their cancer type, stage, treatment or disease status. Patients admitted to leukemia, bone marrow transplantation and intensive care units were excluded. Information on demographic characteristics, reasons for admission, primary cancer diagnosis, disease stage and treatment for anemia were collected.

Based on toxicity grading criteria from the National Cancer Institute, anemia was defined as a hemoglobin level <12 g/dL. As in many clinical studies of anemia in cancer patients, age and gender variation in hemoglobin level were not considered in defining anemia. Based on this criteria, anemia was further classified as mild (Hb: 10.0-11.9 g/dL), moderate (Hb: 8.0-9.9 g/dL) and severe (Hb: <8.0 g/dL).

In addition to presenting information on diagnosis, severity and treatment of anemia by counts and percentages, we compared different variables between anemic versus nonanemic patients and patients treated for anemia versus those not treated. Comparisons of categorical variables were performed using the chi-square test. Length of stay was compared between anemic and non-anemic groups using the Wilcoxon rank test. The impact of anemic status, age, stage, primary diagnosis and reason for admission on length of stay was tested using ANCOVA. ANCOVA assumptions were verified and the log transformation was applied to the length of stay to satisfy the normality assumption.

Results

The 959 patients had a mean age (SD) of 53 (16) years and 492 (51%) patients were males. Main reasons for admission at time of enrollment were chemotherapy in 217 (22.6%), infections including neutropenic fever in 190 (19.8%), and palliative and supportive care in 145 (15.1%). Other reasons for admission were pulmonary, neurological, renal and electrolyte imbalances. Primary cancer diagnoses were gastrointestinal in 203 (21.2%), breast in 154 (16.1%), lymphoma and multiple myeloma in 151 (15.7%), and lung in 106 (11.1%). At time of enrollment, 54.7% of patients had advanced-stage disease. Demographic data and patient characteristics at enrollment are presented in Table 1.

Anemia at time of first admission was detected in 755 (78.7%) patients. The mean hemoglobin value for anemic patients was 9.5 g/dL (range 3.5-11.9, median 9.6). Severe anemia was detected in 126 (16.7%), moderate in 319 (42.3%) and mild in 310 (41.1%) patients. Prevalence and severity of anemia varied according to tumor type (Table 2); thyroid cancers and unknown primary tumors had the lowest prevalence of severe anemia with rates of 0% and 7.7% respectively, while lymphoma/multiple myeloma and genitourinary tumors were associated with the highest rate of severe anemia with rates of 22.1% and 19.7%, respectively. Anemia prevalence also varied in relation to reason for admission; except for bleeding, severe anemia was observed most often among patients admitted with infections (24.4%) and lowest among patients admitted for initial staging and workup (4.8%) (Table 3).

Of the 755 patients who were anemic at enrollment, more than two-thirds (518, 68.6%) were not offered anemia treatment. However, most (60%) had hemoglobin levels between 10.0 and 11.9 g/dL. The mean hemoglobin value at which treatment was started was 8.0 g/dL, while the mean hemoglobin for the patients who were not treated was 10.2 g/dL. Anemia treatment was related to severity; 119 (94.4%) patients with severe anemia were treated compared to a treatment rate of 32.9% in the group with moderate anemia, and 5.0% in patients with mild anemia (P<.0001). Treatment offered for patients with anemia varied; blood transfusion was given to 188 (79.3%), supplements (including iron, folate and/or vitamin B12) were used in 25 (10.5%) while ESAs were offered for only 8 (3.4%) of the treated patients. Combination therapy was given to 16 (6.7%) patients (Table 4).

We also looked at the rate and type of treatment in relation to primary tumor site and reason for admission. Except for thyroid and unknown primary site tumors, which were the least primary tumor sites to be treated (6.7% and 7.7%, respectively), no difference was observed in anemia treatment across different primary sites (P=.1831). Treatment rate also varied according to reason for admission; only 29 (21.6%) anemic patients admitted for chemotherapy were offered any treatment compared to a rate of 33.4% for the rest of the cancer patients (P=.0075).

Nearly half of the patients (427, 44.5%) were admitted more than once. The median number of admissions was 1 with a range of 2 to 14 admissions. Among the other 532 (55.5%) patients who were admitted only once, anemia was found in 409 (76.8%) patients, compared to a prevalence of 81% among the 427 patients who had multiple admissions (P=.138). Length of hospital stay was affected by the presence of anemia; the mean hospital stay was 7.27 days (95% CI: 6.95-7.59) in anemic patients compared to 4.85 days (95% CI: 4.59-5.11) among the nonanemics (P<.001). In addition to anemia status, age, reason for admission, primary tumor site and stage were studied for impact on length of hospital stay. It was shown that anemia status (P<.0001) and primary disease (P<.0001) followed by reason for admission (P=.053) were the factors associated with significant impact on length of stay.

Discussion

To our knowledge, this is the first study to address the impact on clinical practice of recently published negative studies of ESA when used to prevent or to treat anemia in cancer patients. The prevalence of anemia in our cancer patients was high: at enrollment, 78.7% of patients had hemoglobin levels <12.0 g/dL. The prevalence of anemia was even higher (83.0%) when considering all patients in whom low hemoglobin levels were recorded at least once during the survey. These rates are higher than what previous studies had reported. In a large, multinational, prospective survey defining the prevalence, incidence and treatment of anemia in cancer patients, the European Cancer Anemia Survey (ECAS), the prevalence of anemia at enrollment was 39.3%; the majority were mild and moderate, while severe anemia was reported in only 10% of their patients compared to a rate of 16.7% among our study group.¹⁹

Though most of patients in our study had mild (41.1%) or moderate anemia (42.3%), even at these levels of hemoglobin, anemia has a significant impact on quality of life and performance status. Although we did not compare the symptoms and performance status of patients in relation to severity of anemia, many previous studies have addressed this issue and showed a direct relationship between low hemoglobin level, fatigue and poor performance status.^20-22

The rate of anemia treatment in our group was low (21.6%), specifically in the in the group of patients undergoing active treatment with chemotherapy, in whom a higher treatment rate is expected. Several reasons might have contributed to our findings of high prevalence and low treatment rates among hospitalized cancer patients. ESAs were the standard treatment for anemic patients with cancer on active treatment or even on supportive care.²³ However, many recent reports and randomized studies raised many concerns about the safety of such an approach. Many of studies were terminated early because of higher early mortality in the ESA-treated group. Following these findings, the United States Food and Drug Administration announced revisions and a warning to restrict ESA indications.²⁴ In response to these concerns and warnings, many physicians and medical centers refrained from using ESA. This was very evident in our study where ESA was used in only 8 of 237 (3.4%) treated patients. Additionally, the concerns about safety of transfusion as a treatment modality had kept 68% of the patients in the moderate anemia group (Hb: 8.0-9.9 g/dL) without treatment. Luckily, this concern was not an issue in the severe anemia group (n=126) where 94% were treated, mostly with blood transfusion (87%).

Given these concerns in offering ESA or even blood transfusion, every effort should be made to identify the etiology of anemia. Treatment should be directed to the underlying cause. Unfortunately, only in a minority of such patients can a specific causative factor be identified and directed therapeutic intervention offered. Thus, blood transfusion will continue to be the mainstay of treatment especially for patients with symptomatic anemia, severe hemolysis or bleeding who require rapid correction of their hemoglobin and an increase in blood volume. However, one should remember that the effect of transfusion is short-lived and may be associated, on rare occasions, with potentially serious complications.

The American Society of Hematology and the American Society of Clinical Oncology responded positively to these concerns and recently issued common guidelines addressing when and how to treat cancer and chemotherapy-related anemia.^25,26 In these guidelines, the use of ESA was restricted to patients with cancer on active treatment without curative intent. The routine use of ESA in cancer patients in whom cure is the primary objective was strongly discouraged. Additionally, both societies recommended against the use of these products in cancer patients not on active cancer therapy. Blood transfusion was suggested to be the treatment modality for cancer patients with a hemoglobin level below 8.0 g/dL. Until further data becomes available, these guidelines should be strictly followed.

More recently, safety concerns regarding ESA were evaluated in a meta-analysis of controlled ESA oncology trials.²⁷ The 60 studies analyzed included 15 323 patients and were conducted in the settings of chemotherapy, radiotherapy or combined therapy and anemia of cancer. The authors concluded that ESA use did not significantly affect mortality (60 studies: OR=1.06; 95% CI: 0.97-1.15) or disease progression (26 studies: OR=1.01; 95% CI: 0.90-1.14), but increased the risk for venous-thromoboembolic events (44 studies: OR=1.48; 95% CI: 1.28-1.72). However, prospectively designed, randomized clinical trials are needed to examine ESA safety when used according to the revised labeling information.

Our study is not without limitations. The data presented represent the practice at a single institution during a time when the use of ESA was questioned, and such practice may not be the same at other institutions at a different time interval. Large multi-institutional studies are needed to further address these issues.

Given the recent negative ESA studies and FDA warnings, anemia is under-recognized and under-treated. Only severe anemia was adequately treated, mostly with blood transfusion while ESA were rarely used. The majority of patients with moderate anemia were not treated, including patients on active chemotherapy. Better guidelines addressing anemia management in this subgroup of patients are highly needed.

Acknowledgments
The authors would like to thank Dr. Luna Zaru and Dalia Al-Rimawi for the valuable contributions in preparing this manuscript.

Author contribution:
Concept and design, Hikmat Abdel-Razeq; collection and assembly of data: Shadi Hijjawi, Hazem Abdulelah, Rula Amarin, Majid Asawaeer, Haitham Shaheen; data analysis and interpretation: Hikmat Abdel-Razeq, Shadi Hijjawi; anuscript writing: Hikmat Abdel-Razeq; final approval of manuscript: all authors

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