Anemia impact and management: focus on patient needs and the use of erythropoietic agents

Anemia Impact and Management: Focus on Patient Needs and the Use of Erythropoietic Agents Carsten Bokemeyer and Jan Foubert Anemia is a common complication associated with cancer and cancer treatment. As many as 50% to 60% of cancer patients will develop this condition. Fatigue is a major symptom of anemia and is a primary complaint in patients with cancer. Fatigue can be debilitating for patients, reducing their ability to work, decreasing physical and emotional well-being, and interfering with cognitive ability, all of which can lead to anxiety and depression. Despite the high incidence of the disease and the extent of its impact on the cancer patient, anemia remains underdiagnosed and undertreated. Erythropoietic proteins offer a valuable alternative to standard transfusion therapy, and there is increasing evidence that, in addition to raising hemoglobin levels, these therapeutic agents can lead to improvements in quality of life and patient-reported outcomes. The impact of anemia correction on survival is under investigation; a body of evidence suggests a possible benefit, although this has recently been challenged. There is a strong need for increased awareness of cancer-related anemia and the consequences of its lack of treatment. Semin Oncol 31 (suppl 8):4-11. © 2004 Elsevier Inc. All rights reserved.

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NEMIA is one of the most common conditions associated with cancer, with 50% to 60% of cancer patients experiencing anemia at some time during the course of their illness and treatment. The incidence and severity of anemia depends on the tumor type, stage of disease, patient age, and type and intensity of treatment. A growing body of evidence indicates that anemia adversely affects quality of life (QOL) and patientreported outcomes, yet both health care providers and patients with cancer remain largely unaware of the impact of anemia, and its undertreatment. Health care providers continue to underdiagnose and undertreat anemia, focusing primarily on

From the Universitatsklinikum Tuebingen, Medizinische Klinik Abteilung, Tuebingen, Germany; and Erasmushogeschool, Departement Gezondheidszorg, Brussels, Belgium. Prof Bokemeyer has received research grant support and has served as a consultant to Ortho-Biotech and Amgen. Address reprint requests to Prof C. Bokemeyer, MD, Universitatsklinikum Tuebingen, Medizinische Klinik Abteilung 11, OtfriedMueller Sr 10, D-72076 Tuebingen, Germany. © 2004 Elsevier Inc. All rights reserved. 0093-7754/04/3103-0802$30.00/0 doi:10.1053/j.seminoncol.2004.04.003 4

other symptoms (eg, pain, nausea, and vomiting). In addition, there is often no consensus on the best way to assess and treat anemia and fatigue, and these conditions are often overlooked in routine assessments.1 Successful management of anemia in cancer patients requires accurate recognition of the condition, as well as an appreciation of the burden of the disease for the patient and an understanding of the benefits and limitations of the different forms of treatment. CANCER-RELATED ANEMIA

Definition of Anemia Anemia occurs when there is an imbalance between the production and destruction, or loss, of red blood cells (RBCs), leading to decreased RBC count, hemoglobin (Hb) concentration and oxygen-carrying capacity of the blood. Anemia is defined as a reduction in Hb level, the number of RBCs or erythrocytes, or in the packed cell volume (hematocrit) per 100 mL of blood, to below normal levels. In clinical practice, anemia is defined as Hb levels ⬍13.5 g/dL in adult males (normal Hb range, 13.5 to 17.5 g/dL) and ⬍11.5 g/dL in adult females (normal Hb range, 11.5 to 15.5 g/dL). Most grading systems define severe anemia as Hb ⬍8 g/dL.2 Incidence and Etiology Cancer-related anemia falls into three distinct categories: anemia occurring as a result of the malignancy, anemia attributed to the form of cancer therapy applied, and anemia resulting from one or more contributing factors such as infections, nutritional deficiencies, and underlying chronic disorders, which are present in addition to the cancer.3 Red blood cell survival is frequently shortened in cancer anemia, possibly because of the action of immune and inflammatory cytokines activated by the presence of the tumor. As a result of the inability of the bone marrow to produce RBCs at a rate sufficient to compensate for their reduced life span, an imbalance develops between RBC production and depletion, leading to the development of anemia. Seminars in Oncology, Vol 31, No 3, Suppl 8 (June), 2004: pp 4-11

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In cancer-related anemia, symptom severity is determined by the rapidity of the onset of anemia, the underlying malignancy, the intensity of cancer treatment, and the patient’s cardiovascular and pulmonary function. The type of tumor impacts on the incidence and degree of anemia.4 Patients with lymphoma, lung, ovarian, and genitourinary cancer have the highest incidence of severe anemia; as many as 50% to 60% of these patients will develop anemia requiring RBC transfusion.5 The risk of developing cancer-related anemia is also increased in those patients receiving myelosuppressive chemotherapy or radiotherapy, those with a low Hb level (10 to 12 g/dL) at the start of cytotoxic chemotherapy, and patients who are scheduled to receive platinum-containing treatment regimens. Forms of therapy involving myelosuppression of large areas of the bone marrow compromise erythropoiesis such that the production and maturation of RBCs are reduced and anemia results.5 Despite its high incidence and severity, cancerrelated anemia is frequently underdiagnosed and undertreated.6 In a survey of 284 oncologists treating 4,888 cancer patients throughout France, Germany, Italy, Spain, and the United Kingdom, 52% of patients (of 3,067 patients with Hb data available) had Hb concentrations ⬍12 g/dL. However, only 22% of patients in this group were diagnosed as anemic by their physician.6 Burden of Disease and Patient Needs Anemia is a complex condition that impacts on many body systems to produce a diverse range of symptoms. In cancer-related anemia, the primary symptoms include fatigue, exertional dyspnea, palpitations, and other cardiorespiratory complications, dizziness or vertigo, depression, impaired cognitive function, nausea, anorexia, sleeping disorders, and loss of libido.7 Fatigue is the most commonly reported clinical manifestation of anemia in cancer patients,8,9 with 78% of patients experiencing typical symptoms.8 Fatigue can manifest in patients as a number of subjective symptoms including despondency, sluggishness, apathy, faintness, and indifference. Patients suffering from fatigue have also been reported to exhibit a number of psychosocial symptoms, including anxiety, depression,10 and sleep disturbances.11 Cognitive dysfunction, memory loss, and problems with concentration can also be very disturbing for the patient and lead to more

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anxiety. An association has also been noted between fatigue and a high incidence of concomitant symptoms (eg, pain).12 Hypothyroidism and electrolyte imbalance (particularly potassium and calcium) can also occur in fatigued patients and need to be treated if present. Fatigue is not relieved by sleep or rest, and is not exacerbated by exertion. In a survey of patient, caregiver, and oncologist perceptions of cancerrelated fatigue, 32% of patients (all of whom had received chemotherapy and/or radiotherapy) reported experiencing daily fatigue; patients reported that the areas of daily life most negatively affected by fatigue included the ability to work, physical and emotional well-being, ability to enjoy life in the moment, and intimacy with partner (Fig 1).8 However, fatigue remains poorly understood and patients and oncologists differ in their perception of the importance of treating fatigue.8 When asked which factors affected their everyday life the most, 60% of patients ranked fatigue highest, followed by nausea (22%), depression (10%), and pain (6%).13 Interestingly, 41% of patients and only 6% of oncologists felt that it was more important to reduce/relieve fatigue than pain.8 Fatigue alone does not always mean that anemia is present, but it is a strong indication that is well recognized; the level of Hb has been shown to have a strong relationship with the incidence of fatigue and with QOL. In a study of patients with solid tumors or hematologic malignancies (n ⫽ 50), patients with Hb levels ⱕ12 g/dL reported significantly more fatigue, worse physical and functional well-being, and generally reduced QOL than those who had Hb levels ⱖ12 g/dL.9 The findings of another study involving 4,382 anemic cancer patients undergoing chemotherapy further emphasizes the relationship between Hb concentration and QOL improvement; patients whose Hb concentration was increased to 12 g/dL (range, 11 to 13 g/dL) exhibited the greatest QOL benefit.14 Assessment of Cancer-Related Anemia and Fatigue Accurate assessment of anemia and fatigue is important to ensure that patients are optimally managed. Assessment should be comprehensive, incorporating laboratory parameters, physical symptoms, and QOL indicators. Evaluation of anemia should be ongoing, involving assessment of changes in patient well-being over time, as well as

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Fig 1. Patient-reported areas of daily life negatively affected by fatigue. (Reprinted with permission from Elsevier.8)

long-term monitoring of anemia indicators (eg, Hb concentration and hematocrit) because anemia and fatigue can persist long after the completion of cancer therapy.15 Oncology nurses play a key role in reducing the adverse effects of cancer-related anemia by anticipating and assessing the problem during all stages of treatment. Trends over time are more useful than snapshots on day one. Nurses need to be proactive versus reactive. The need for education on anemia and fatigue is recognized and specific analyses are being conducted with patients and nurses to facilitate the development and delivery of suitable training programs across Europe. The “Training Initiative in Thrombocytopenia, Anemia and Neutropenia” (TITAN) is a result of these analyses and an example of a training program for oncology nurses to improve knowledge and skills to optimize patient care. Despite this recent move to improve patient care through training initiatives, current assessment of cancer-related anemia is often based on a single evaluation, usually a quantitative measure such as hematocrit or Hb, with considerably less emphasis placed on patient symptoms, changes in function, or QOL. As a result, the symptoms that most directly affect patients’ lives, such as fatigue, are not fully evaluated, and the full impact of anemia on the patient can often be underestimated. A variety of tools are used to assess cancerrelated anemia and fatigue. In the clinical setting, where there is limited time for detailed evaluation,

it is often only possible to perform a brief assessment composed of a few simple questions. Multidimensional questionnaires, which provide further information on the patient’s symptoms, but may be time-consuming, are more commonly used in the research setting.16 Of the many measures available, the Functional Assessment of Cancer TherapyAnemia (FACT-An) questionnaire9 has been designed specifically for anemic cancer patients and tends to be used most frequently in the clinical setting. As such, the FACT-An, and the FACT-F subscale for the assessment of fatigue, are recommended for a simple, relatively quick, and reliable assessment of anemia and fatigue in patients with cancer. In summary, an accurate assessment of anemia and fatigue in patients with cancer involves early recognition of signs and symptoms (such as despondency, difficulties sleeping, problems with concentration, exertional dyspnea, palpitations, dizziness, nausea, anorexia, and loss of libido), proactive and accurate assessment using validated tools such as the FACT-An and FACT-F subscales, communication with all members of the care team to devise and implement the appropriate interventions, and continued long-term monitoring and reassessment (of both patient symptoms and quantitative measures). TREATMENT OPTIONS

The management of anemia in patients with cancer should be based on the severity of associ-

ANEMIA MANAGEMENT: ERYTHROPOIETIC AGENTS

ated symptoms and the likelihood that the anemia will worsen with continued treatment. Treatment of fatigue includes both the correction of underlying anemia if present, and additional nonpharmacologic interventions. Initially, potential underlying causes of anemia (eg, nutritional deficiencies, occult blood loss, or infections) other than cancer should be assessed, followed by a determination of the severity of the condition. The same is true for the correction of underlying causes of fatigue (other than anemia), which may include the correction of nutritional deficiencies, electrolyte imbalance, and hypothyroidism. If some specific deficiencies are identified, appropriate dietary changes and supplemental therapies should be prescribed.1 If the anemia is mild and remains asymptomatic, the appropriate response may simply be observation and regular monitoring. Nonpharmacologic Interventions In cancer patients, fatigue arising from anemia can be treated with several forms of therapy. A number of nonpharmacologic interventions can be applied to help reduce the fatigue experienced by cancer patients. The value of exercise for the management of cancer-related fatigue is being increasingly recognized10; other nonpharmacologic interventions, including restorative therapy, sleep hygiene, nutrition consultation, and education have proved successful in some patient groups.16 Red Blood Cell Transfusions When severe anemia develops in patients with cancer, RBC transfusions have historically been the main form of therapy used. Red blood cell transfusions rapidly raise the RBC count and Hb concentration and are effective in virtually all patients. However, the benefits of RBC transfusion are transient and a “roller-coaster” of unstable Hb levels results. In addition, transfusion is associated with potential risks, including transmission of infectious agents, hemolytic reactions, iron and circulatory overload, alloimmunization, and possibly an unfavorable effect on cancer outcome.5 Furthermore, treatment is not standardized; there is no trigger value (mean Hb concentration) established between clinical centers at which RBC transfusion should be implemented, leading to inconsistencies in treatment.17

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Erythropoietic Proteins With the introduction of erythropoietic proteins in the late 1980s, a valuable alternative treatment for anemia became available. Erythropoietic proteins such as epoetin alfa, epoetin beta and the longer-acting darbepoetin alfa (Aranesp; Amgen, Inc, Thousand Oaks, CA), alleviate anemia by mimicking the role of endogenous erythropoietin and stimulating the development of RBC precursor cells. Erythropoietic proteins are well-tolerated and, producing stable Hb levels, avoid the fluctuations associated with RBC transfusions. Numerous studies have shown that erythropoietic proteins increase Hb levels and reduce RBC transfusion requirements in anemic cancer patients receiving chemotherapy18-21 and in those not receiving chemotherapy.22 These studies have also shown that treatment with erythropoietic proteins improves QOL in anemic cancer patients. In a randomized, double-blind study of 375 anemic cancer patients receiving chemotherapy, significantly greater improvements in all primary cancerand anemia-specific QOL domains (P ⬍ .01) including fatigue, as measured by the FACT-F subscale (P ⬍ .01) were noted for patients receiving epoetin alfa (150 IU/kg three times per week) compared with patients receiving placebo.18 Patients receiving treatment with epoetin alfa exhibited significantly greater increases in Hb concentration (P ⬍ .001), and Hb response rate (an increase in Hb ⱖ2 g/dL in the absence of RBC transfusion; P ⬍ .001) compared with patients receiving placebo; the correlation between change in Hb level and all primary QOL parameters, including fatigue (P ⬍ .001), was also found to be statistically significant.18 In a randomized trial in 349 anemic patients receiving chemotherapy for hematologic malignancies, statistically significant differences were observed in QOL (based on total FACT-An and FACT-G [General] scores) after 12 and 16 weeks of treatment with epoetin beta (150 IU/kg three times per week) compared with placebo (P ⬍ .05).19 This correlated with a significantly higher Hb response rate in patients who received epoetin beta compared with placebo (67% v 27%; P ⬍ .0001).19 Despite these benefits, a significant number of cancer patients fail to respond to treatment with recombinant human erythropoietin (rHuEPO),

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and dosing schedules can be inconvenient both for the patient and health care provider. Darbepoetin alfa, an erythropoietic protein with an extended half-life23 and increased biological activity compared with rHuEPO (epoetin alfa and epoetin beta), has also been shown to improve QOL and increase hematologic response rates relative to placebo in several studies following administration at more convenient dosing schedules. Once weekly administration of darbepoetin alfa was associated with decreased patient-reported fatigue that correlated with increases in Hb concentration in anemic cancer patients receiving chemotherapy for nonmyeloid malignancies in two large phase III, double-blind, randomized, controlled trials, one in 314 patients with lung cancer,20 and the other in 344 patients with lymphoproliferative malignancies.21 Compared with placebo, 2.25 ␮g/kg once weekly darbepoetin alfa resulted in a ⱖ25% improvement in fatigue in 32% of patients with lung cancer (compared with 19% who received placebo; P ⫽ .019).20 Similarly, patients with lymphoproliferative malignancies who received darbepoetin alfa at this dosage experienced a statistically significant increase in FACT-F score (P ⫽ .032) compared with placebo.21 In this study, a relationship was also observed between change in Hb concentration and FACT-F score; for every 1 g/dL increase in Hb there was a mean estimated increase in FACT-F score of 1.39 (95% confidence interval: 0.83 to 1.94). The long half-life (⬎70 hours)23 of darbepoetin alfa offers even more convenient dosing possibilities, which are discussed in ¨ sterborg elsewhere greater detail in the article by O in this supplement. In this study, darbepoetin alfa produced a mean Hb increase of 1 g/dL after 6 weeks of treatment and a Hb increase of approximately 2 g/dL during the first 10 weeks of therapy.23 Practice Guidelines Clinical use of erythropoietic proteins for the treatment of cancer-related anemia varies widely, particularly between the United States and Europe. In the United States, treatment with rHuEPO is well established,24 while European patients are still very likely to suffer from anemiarelated problems caused by differences in standard practice and a general lack of awareness of the condition. Clinical practice guidelines can facilitate and standardize the assessment and manage-

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ment of cancer-related anemia and fatigue by providing recommendations based on the best currently available scientific evidence. Several organizations have already developed clinical practice guidelines for the management of cancer-related anemia. The American Society of Clinical Oncology and American Society of Hematology have previously published US guidelines for the use of erythropoietic agents in the treatment of cancer anemia.25 The guidelines recommend the use of erythropoietic agents in cancer patients with chemotherapy-related anemia and a Hb level ⬍10 g/dL. In patients with less severe anemia (Hb ⬍12 g/dL but never below 10 g/dL) the use of erythropoietic proteins should be determined by clinical circumstances. The dose of erythropoietic protein should be titrated once a target Hb level of 12 g/dL is reached. The National Comprehensive Cancer Network has created similar guidelines for the assessment and treatment of cancer anemia.26 These guidelines state that erythropoietic therapy should be strongly considered in patients with symptomatic anemia and Hb levels ⬍10 g/dL, and considered in patients with Hb levels 10 to 11 g/dL. Dosage should be titrated to maintain an optimal Hb concentration of 12 g/dL. In Europe, evidence-based guidelines for the use of erythropoietic agents in the management of cancer-related anemia are being developed by a panel of oncologists, hematologists, and nurses endorsed by the European Organisation for Research and Treatment of Cancer. These guidelines, which should provide a basis for the standardization of care of anemic cancer patients in Europe, are due to be published shortly. Nurses can also benefit from access to evidence-based guidelines. Nursingspecific guidelines for managing anemia and neutropenia have been developed by the US Oncology Nursing Society.27 The National Comprehensive Cancer Network has also created guidelines for the evaluation and management of fatigue in patients with cancer. In the UK, guidelines with a similar focus are available from the Mersey Palliative Care Audit Group.28 ANEMIA, ERYTHROPOIETINS, AND SURVIVAL IN PATIENTS WITH CANCER

There is a growing body of evidence suggesting that anemia can adversely affect survival in patients with cancer.29 When Caro et al29 conducted a systematic review of 60 articles reporting the

ANEMIA MANAGEMENT: ERYTHROPOIETIC AGENTS

Table 1. Impact of Anemia on Relative Risk of Death

Type of Tumor

Increase of RRD, % (95% Confidence Interval)

Lung Head and neck Prostate Lymphoma Overall

19 (10 to 29) 75 (37 to 123) 47 (21 to 78) 67 (30 to 113) 65 (54 to 77)

Abbreviation: RRD, relative risk of death. Reprinted from Cancer, vol 91, 2001, pp 2214-2221. Copyright © 2001 American Cancer Society. Reprinted by permission of Wiley-Liss Inc., a subsidiary of John Wiley & Sons Inc.29

survival of cancer patients in relation to anemia and Hb concentration, they found a 65% increase in the relative risk of death for anemic patients compared with non-anemic patients (Table 1). In hematologic tumors, the prognostic impact of anemia has been suggested in patients with nonHodgkin’s lymphoma, Hodgkin’s disease, plasmacytoma, and chronic lymphocytic leukemia.30 Similar data are also available from solid tumor patients, and evidence for a negative impact of anemia exists for patients with lung, ovarian, renal, urothelial, prostate, colorectal, head and neck, cervical, testicular, and breast cancer.30 These data provide evidence that anemia is an adverse prognostic factor in patients receiving treatment for cancer. Increased Hb concentration has been linked to improved survival in a number of studies of cancer patients.14,18,29,31 Over a decade ago, Ludwig et al32 observed a statistically significant difference in patients responding to treatment with rHuEPO (epoetin alfa; Cilag, Vienna, Austria) versus patients whose disease did not respond.32 A retrospective review of patients (n ⫽ 191) with oral cavity and oropharyngeal squamous cell carcinoma receiving neoadjuvant chemoradiotherapy and undergoing surgery suggested that increased Hb concentrations following treatment with rHuEPO (epoetin alfa; Janssen-Cilag) were associated with significant improvements in both locoregional control and survival.33 More recently a Cochrane metaanalysis including 27 randomized, controlled trials (n ⫽ 3,284) evaluated the outcomes of patients treated with rHuEPO.34 The meta-analysis of these trials found that, in addition to significantly

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reduced transfusion and increased hematologic response, there was a trend toward increased survival in patients receiving rHuEPO (relative risk of death 0.8; 95% confidence interval, 0.65 to 1.0).34 Although it seems logical to try to improve response to therapy and thereby patient outcome by increasing Hb levels through treatment with erythropoietic proteins, the results achieved in randomized trials to date have not provided a conclusive answer. The body of evidence suggesting a possible benefit34 has been recently challenged by the publication of two negative studies. In October 2003, the Lancet published a letter from Leyland-Jones et al35 reporting that a randomized, placebo-controlled study in patients receiving chemotherapy for metastatic breast cancer (n ⫽ 939) was terminated early because of a higher mortality in the prophylactic epoetin alfa treatment arm compared with the placebo arm at 12 months. These findings were primarily attributed to the observation of an increased incidence of breast cancer progression in rHuEPO-treated patients compared with placebo recipients (6% v 3%), and to an increase in fatal thrombotic and vascular events in the rHuEPO arm (1% v 0.2%). Most of these deaths occurred in the first 4 months of the trial and the authors stated that they were unlikely to be the result of rHuEPO administration. The authors also reported limitations of the study with regard to design, conduct, and post-trial analysis. Importantly, a retrospective chart review suggested a greater probability of adverse risk factors in the rHuEPO group (advanced age, lower performance status, more severe disease at enrollment, and a greater risk of thrombotic and vascular events). It should also be noted that patients were not anemic at study entry (Hb ⬎13 g/dL); rHuEPO was administered prophylactically to nonanemic patients in an attempt to prevent the development of anemia from concomitant chemotherapy. Because the study population was not anemic, the impact on survival of correcting Hb levels could not be assessed. Further negative results were reported in another study of 351 patients with head and neck cancer receiving radiotherapy and treatment with epoetin beta 300 IU/kg three times per week. This study reported that administration of epoetin beta resulted in significantly worse outcomes than placebo.36 The study also reported that, compared with placebo, treatment with epoetin beta was

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associated with poorer locoregional progressionfree survival (adjusted relative risk 1.62; P ⫽ .0008), locoregional progression (relative risk 1.69; P ⫽ .007), and survival (relative risk 1.39; P ⫽ .02). However, more than 30% of patients did not receive radiotherapy per protocol and a further 8% had major protocol violations. In addition, no statistically significant differences in disease progression or survival endpoints were seen when the data were analyzed for the group of patients who did receive radiotherapy per protocol. Furthermore, the investigators noted that in a subgroup of patients with cancer of the hypopharynx, more rHuEPO-treated patients than placebo had certain unfavorable characteristics, including male gender, smoker, relapse at baseline, and stage IV disease. It is important to point out that anemia in this trial was also treated aggressively, with double the recommended dose of epoetin beta administered both before and during the course of radiotherapy. As a result, 82% of patients in the epoetin beta arm of the study exceeded Hb levels recommended in the prescribing information, with Hb levels ⬎14 g/dL (women) or ⬎15 g/dL (men). Despite these two negative reports, the majority of available data strongly suggest that studies looking at a possible impact on patient survival should be continued. Only well-designed clinical studies addressing specific and well-defined treatment situations in specific tumor types with defined treatment approaches may help to answer the question of whether improving anemia through erythropoietic protein therapy may improve the overall poor prognosis associated with anemia in cancer patients. In particular, conventional correction of anemia (treatment started at Hb ⬍11 g/dL, target Hb of 12 g/dL) should be clearly distinguished from studies that involve prophylactic treatment of nonanemic patients, or the use of higher than recommended Hb targets. Furthermore, the established benefits of anemia correction for cancer patients need to be taken into consideration. SUMMARY

Despite the well-documented incidence and impact of anemia and fatigue in patients receiving chemotherapy and/or radiotherapy, patient needs remain underappreciated, underrecognized, and undertreated. It is the responsibility of both physicians and nurses to recognize early symptoms of cancer-related anemia, including fatigue, and to

take steps to proactively treat the condition before it becomes debilitating for the patient. Fatigue and cancer-related anemia have a significant impact on many aspects of cancer patients’ lives, and a full evaluation of the development and degree of cancer-related anemia is needed for appropriate management of the condition. Erythropoietic proteins have a well-documented positive impact on QOL and patient-reported outcomes when used as the prescribing information recommends and should be part of any cancer anemia management program. REFERENCES 1. Gillespie TW: Effects of cancer-related anemia on clinical and quality-of-life outcomes. Clin J Oncol Nurs 6:206-211, 2002 2. Gillespie TW: Anemia in cancer. Cancer Nurs 26:119128, 2003 3. Nowrousian MR: Recombinant human erythropoietin in the treatment of cancer-related or chemotherapy-induced anaemia in patients with solid tumours. Med Oncol 15:S19S28, 1998 (suppl 1) 4. Skillings JR, Rogers-Melamed I, Nabholtz J-M: An epidemiological review of anaemia in cancer chemotherapy in Canada. Eur J Cancer 31A:S5, 1995 (suppl 5) 5. Groopman JE, Itri LM: Chemotherapy-induced anemia in adults: Incidence and treatment. J Natl Cancer Inst 91:16161634, 1999 6. ISIS Research Ltd. The treatment of cancer in Europe. London, UK, ISIS, 2000 7. Ludwig H, Fritz E: Anemia in cancer patients. Semin Oncol 3:2-6, 1998 (suppl 7) 8. Vogelzang NJ, Breitbart W, Cella D: Patient, caregiver, and oncologists perceptions of cancer-related fatigue: Results of a tripart assessment survey. Semin Hematol 34:4-12, 1997 (suppl 2) 9. Cella D: The Functional Assessment of Cancer TherapyAnemia (FACT-An) Scale: A new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 34: 13-19, 1997 (suppl 2) 10. Mock V, Dow KH, Meares CJ, et al: Effects of exercise on fatigue, physical functioning, and emotional distress during radiation therapy for breast cancer. Oncol Nurs Forum 24:9911000, 1997 11. Berger AM, Farr L: The influence of daytime inactivity and nighttime restlessness on cancer-related fatigue. Oncol Nurs Forum 26:1663-1671, 1999 12. Blesch K, Paice J, Wickham R, et al: Correlates of fatigue in people with breast or lung cancer. Oncol Nurs Forum 18:81-87, 1991 13. Curt GA, Breitbart W, Cella D, et al: Impact of cancerrelated fatigue on the lives of patients: New findings from the Fatigue Coalition. Oncologist 5:353-360, 2000 14. Crawford J, Cella D, Cleeland CS, et al: Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 95:888-895, 2002

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15. Payne JK: The trajectory of fatigue in adult patients with breast and ovarian cancer receiving chemotherapy. Oncol Nurs Forum 29:1334-1340, 2002 16. Portenoy RK, Itri LM: Cancer-related fatigue: Guidelines for evaluation and management. Oncologist 4:1-10, 1999 17. Barrett-Lee PJ, Bailey NP, O’Brien ME, et al: Large-scale UK audit of blood transfusion requirements and anaemia in patients receiving cytotoxic chemotherapy. Br J Cancer 82:9397, 2000 18. Littlewood TJ, Bajetta E, Nortier JW, et al: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: Results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19:2865-2874, 2001 ¨ sterborg A, Brandberg Y, Molostova V, et al: Epoetin 19. O Beta Hematology Study Group. Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol 20: 2486-2494, 2002 20. Vansteenkiste J, Pirker R, Massuti B, et al: Aranesp 980297 Study Group. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 94:12111220, 2002 21. Hedenus M, Adriansson M, San Miguel J, et al: Darbepoetin Alfa 20000161 Study Group. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: A randomized, double-blind, placebo-controlled study. Br J Haematol 122:394-403, 2003 22. Smith RE, Tchekmedyian NS, Chan D, et al: A doseand schedule-finding study of darbepoetin alpha for the treatment of chronic anaemia of cancer. Br J Cancer 88:1851-1858, 2003 23. Glaspy J, Henry D, Patel R: Effects of darbepoetin alfa (Aranesp) timing with chemotherapy administration: A randomized study. Presented at the 8th International Conference on Geriatric Oncology: Cancer in the Elderly; November 2122, 2003 (abstr 29 and poster) 24. Coiffier B: Advocating recombinant human erythropoietin as standard practice in Europe for treatment of cancerrelated anaemia. Ann Oncol 14:804, 2003 25. Rizzo JD, Lichtin AE, Woolf SH, et al: Use of epoetin in

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patients with cancer: Evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20:4083-4107, 2002 26. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Cancer and treatmentrelated anaemia. Version 2. Available at: www.nccn.org/ physician_gls/f_guidelines.html 27. Brown KA, Esper P, Kelleher LO, et al: Chemotherapy and biotherapy: Guidelines and recommendations for practice. Pittsburg, PA, Oncology Nursing Society; 2001 28. Coackley A, Hutchinson T, Saltmarsh P, et al: Assessment and management of fatigue in patients with advanced cancer: Developing guidelines. Int J Palliat Nurs 8:381-388, 2002 29. Caro JJ, Salas M, Ward A, et al: Anemia as an independent prognostic factor for survival in patients with cancer: A systematic, quantitative review. Cancer 91:2214-2221, 2001 30. Van Belle SJF, Cocquyt V: Impact of haemoglobin levels on the outcome of cancers treated with chemotherapy. Crit Rev Oncol Haematol 47:1-11, 2003 31. Frommhold H, Guttenberger R, Henke M: The impact of blood hemoglobin content on the outcome of radiotherapy. Strahlenther Onkol 17:31-34, 1998 (suppl 4) 32. Ludwig H, Fritz E, Leitgeb C, et al: Erythropoietin treatment for chronic anemia of selected hematological malignancies and solid tumors. Ann Oncol 4:161-167, 1993 33. Glaser CM, Millesi W, Kornek GV, et al: Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 50:705-715, 2001 34. Bohlius JF, Langenspiepen S, Schwarzer G, et al: Does erythropoietin improve overall survival in the treatment of patients with malignant diseases? Results of a comprehensive meta-analysis. Blood 102:203a, 2003 (abstr 709) 35. Leyland-Jones B: Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncology 4:459-460, 2003 36. Henke M, Laszig R, Rube C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 362:1255-1260, 2003