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Application and safety of erythropoietin in cancer management
Annals of Oncology 16 (Supplement 2): ii47 – ii52, 2005 doi:10.1093/annonc/mdi716
Application and safety of erythropoietin in cancer management R. Pirker & W. Minar Department of Internal Medicine I, Medical University Vienna, 1090 Vienna, Austria
Anemia frequently occurs in patients with cancer [1, 2]. According to the European Cancer Anemia Survey [2], prevalence of anemia increased from 39% (<10 g/dl in 10%) at enrollment to 67% (<10 g/dl in 39%) of the patients during the survey. The incidence of anemia was 54% [2]. The incidence and severity of anemia depends on cancer type, tumor stage, duration of the cancer, treatment status, patient age and bone marrow reserve [1, 2]. The incidences were 63% in patients receiving chemotherapy, 42% in those receiving concomitant chemoradiotherapy and 19.5% in those receiving radiotherapy [2]. The highest incidences of anemia are seen in patients with lung cancer, gynecological malignancies, genitourinary cancer and lymphomas [1, 2]. These high frequencies are mainly due to platinum-based chemotherapy. Anthracycline-based protocols and new anticancer drugs such as taxanes, vinorelbine or camptothecins also lead to a high frequency of anemia [1]. The etiology of cancer-related anemia includes myelosuppressive chemotherapy and/or radiotherapy, tumor infiltration of the bone marrow, relative deficiency of erythropoietin, inappropriate response of the bone marrow, functional iron deficiency, nutritional deficiencies, bleeding, hemolysis and the anemia of chronic disease [1, 3, 4]. Cancer-related anemia is a major contributor to cancerrelated fatigue [5]. Other symptoms are dizziness, vertigo, headache, pallor, dyspnea, angina pectoris, tachycardia, palpitations, depression, impaired cognitive function and loss of libido [6]. Anemia decreases overall quality of life, particularly by reducing physical, functional and emotional wellbeing [7 –10]. The severity of symptoms depends on the absolute hemoglobin (Hb) level, the rapidity of onset of anemia, compensatory mechanisms, co-morbidity and other factors [6]. Clinical assessment of anemia should focus on symptoms, impact on activities of daily living, blood cell counts, laboratory parameters (e.g. iron status, vitamin levels) and potential causes. Quality of life instruments such as the Functional Assessment of Cancer Therapy—Anemia (FACT-Anemia) scales [7 –10] are particularly useful in the context of clinical trials. Anemia is a prognostic factor for shorter survival and/or a predictive factor for worse outcome of anticancer therapy in several cancers [11]. The relative risk of death is increased by 65% overall in anemic cancer patients. The relative risks of q 2005 European Society for Medical Oncology
death increase for anemic patients by 75% in ovarian cancer, 67% in lymphoma, 47% in prostate cancer and 19% in lung cancer [11]. Anemia can reduce both acceptance and tolerance of anticancer therapy. Anemia may negatively affect the outcome of chemotherapy and radiotherapy because anemia, abnormal tumor microvasculature and reduced diffusion are the major causes in the development of tumor hypoxia, which has been linked to treatment resistance, tumor progression and poor prognosis [12]. Anemia was shown to be associated with poor tumor oxygenation in both head and neck squamous cell carcinomas and cervical cancer [13, 14]. Consistent with this association, low Hb levels before or during radiotherapy were associated with poor locoregional control and shorter survival in patients undergoing radiotherapy for locally advanced head and neck cancer [15 –17], carcinoma of the cervix [18] or other cancers. A study in cervical cancer suggested that Hb values of 12 –14 g/dl are optimal with regard to the oxygenation status [14]. Blood transfusions have been the mainstay of treatment, but recombinant human erythropoietic proteins have opened new therapeutic options. Here we review the current treatment strategies in cancer-related anemia, with emphasis on erythropoietic proteins.
Treatment of anemia Despite its detrimental effect on quality of life, anemia still goes undertreated. According to the European Cancer Anemia Survey [2], anemia was treated in only 39% of patients, either by epoetins (17%), transfusions (15%) or iron only (7%). The mean Hb level at the initiation of treatment was 9.7 g/dl. Treatment should correct the cause of anemia (Table 1). This includes treatment of infection, bleeding sources, hemolysis, iron deficiency and vitamin deficiencies. Symptomatic treatment is achieved by red blood cell (RBC) transfusions and the administration of erythropoietic proteins (Table 1).
RBC transfusions RBC transfusions are usually given only to patients with severe and/or highly symptomatic anemia. The average Hb level at the time of transfusion is 7.9 g/dl [19]. Transfusion requirements are also affected by age and co-morbidity, particularly reduced cardiovascular or pulmonary function.
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Introduction
ii48 Table 1. Management of anemia: general principles All patients
Treatment or correction of underlying cause(s)
Further management according to severity of anemia Mild
Consider erythropoietic proteins, particularly in symptomatic patients, elderly patients, patients with co-morbidities and patients with declining Hb levels
Moderate
Erythropoietic proteins
Severe or life-threatening
RBC transfusion plus erythropoietic proteins
Hb, hemoglobin; RBC, red blood cell.
Overall, 33% of cancer patients require at least one transfusion and 16% require multiple transfusions [20]. High transfusion rates are seen in patients with lung cancer, ovarian cancer or genitourinary cancer and in patients receiving platinum-based chemotherapy [1, 2, 19, 20]. A low baseline Hb level predicts the likelihood of future transfusion. Other potentially predictive factors are advanced age, advanced disease, reduced performance status, weight loss, platinum- or anthracycline-based chemotherapy, duration of chemotherapy, and a marked Hb decrease after the first cycle of chemotherapy. RBC transfusions result in rapid improvement in all transfused patients. However, transfusions often do not result in sustained effects and also have the risks of transfusion reactions, immunosuppression and transmission of infectious agents. Concerns about these risks and in several countries an additional shortage in blood supply have a negative impact on current transfusion policies.
Erythropoietic proteins Administration of erythropoietic proteins (epoetin alfa, epoetin beta, darbepoetin alfa) increases Hb levels and decreases RBC transfusions in patients either receiving chemotherapy [21– 33] or not receiving chemotherapy [33]. The efficacy of epoetins was also demonstrated in patients receiving radiotherapy [34, 35] or chemoradiotherapy [17]. Treatment with erythropoietic proteins improves anemiarelated symptoms and significantly increases energy level, daily activity and overall quality of life [9, 21–33, 36]. The improvements in quality of life correlate with Hb increases in patients across the Hb range of 8–14 g/dl, with a maximal incremental gain in the range of 11 –13 g/dl [36]. Thus the benefit appears to be greater in patients with mild anemia than in those with moderate to severe anemia. These findings suggest that therapeutic intervention should aim to maintain Hb levels of 11 –12 g/dl, particularly in patients with fatigue and/or co-morbidities. Epoetins decrease the relative odds of receiving a RBC transfusion by an average of 62%, and four to five patients
Practice guidelines Practice guidelines on the use of erythropoietic proteins have been published by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) [37], the National Comprehensive Cancer Network [40] and the European Organization for Research and Treatment of Cancer (EORTC) [41]. A flow chart considering these guidelines is shown in Figure 1. The guidelines also stress the importance of regular monitoring of iron status, particularly in non-responders, and, if indicated, iron repletion.
ASCO/ASH guidelines Epoetins are recommended for patients with chemotherapy_ 10 g/dl, but RBC transassociated anemia and a Hb level < fusions are also a treatment option, depending on the severity of anemia or clinical circumstances. For patients with declining Hb levels but less severe anemia (those with Hb <12 g/dl but who have never fallen below 10 g/dl), epoetins might be used either immediately or after Hb levels fall closer to 10 g/dl, dependent on clinical circumstances. RBC transfusions are also a therapeutic option when warranted by severe clinical conditions.
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RBC transfusion dependent on clinical circumstance
have to be treated in order to benefit one patient [37]. The time to response depends on the dose and schedule of erythropoietic proteins. Non-responders after 4 weeks should be considered for a dose escalation for an additional 4–6 weeks, and should also be investigated for iron deficiency or tumor progression [37]. Epoetin alfa is usually administered at a dose of either 150 U/kg (or 10 000 U) three times per week or 40 000– 60 000 U once weekly. The two schedules show similar efficacy [23]. Epoetin beta is commonly given at 150 U/kg three times per week or 30 000 U once weekly. Darbepoetin alfa is usually administered at 150 mg once weekly or at higher doses with extended dosing intervals [28–31]. Response to erythropoietic proteins is affected by dose, frequency as well as route of administration, duration of therapy, presence of other or additional causes of anemia, functional iron deficiency, presence of infection and by other factors [37]. Response is usually independent of age, sex, type of cancer, type of chemotherapy (platinum versus non-platinum) and chemotherapy response [21, 22]. Early intervention was shown to be effective in breast cancer patients receiving chemotherapy [25]. In patients who developed Hb <12 g/dl, once weekly epoetin alfa maintained Hb levels, improved quality of life and reduced transfusions in comparison with standard of care. Similarly, darbepoetin alfa was shown to have a beneficial effect in both patients with baseline Hb levels >10 g/dl and those with levels <10 g/dl [30]. Few studies have demonstrated the potential of epoetins for the prevention of anemia in patients receiving myelosuppressive therapy [38, 39], but confirmatory trials are warranted.
ii49
Epoetins should be given until the Hb level reaches 12 g/dl and then the epoetin dose should be titrated to maintain Hb levels. Dose escalation is recommended for patients who do not respond to the initial dose. In the absence of response, treatment should not be continued beyond 6 –8 weeks.
EORTC guidelines Initiation of treatment with erythropoietic proteins is recommended at a Hb level of 9–11 g/dl based on anemia-related
symptoms in patients with or without chemotherapy. The erythropoietic proteins may also be considered according to individual factors in asymptomatic patients with Hb levels of 9–11 g/dl in order to prevent a further decline. A target Hb level of 12–13 g/dl is recommended. Neither the prophylactic use nor the use in patients undergoing autologous blood stem cell transplantation are recommended, but the use in patients undergoing allogeneic blood stem cell transplantation can be considered on an individual basis.
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Figure 1. Proposal for the clinical use of erythropoietic proteins in anemic patients with cancer undergoing chemotherapy (modified after references [37] and [41]). Hb, hemoglobin; s.c., subcutaneously.
ii50
Safety of erythropoietic proteins
Erythropoietic proteins and survival Because anemia contributes to tumor hypoxia, erythropoietic protein-mediated control of anemia could improve tumor hypoxia and, thereby, increase response to chemotherapy or radiotherapy, which then could translate into improved survival. A retrospective analysis in patients with head and neck cancer undergoing chemoradiotherapy indicated that patients with baseline Hb levels >14.5 g/dl showed improved local tumor control and longer survival than those with Hb levels <14.5 g/dl [17]. When patients with Hb levels <14.5 g/dl received prophylactic epoetin alfa, however, outcome was similar to the outcome of patients with Hb levels >14.5 g/dl. Epoetin alfa treatment was associated with a trend towards improved survival in cancer patients undergoing non-platinum chemotherapy [24]. Darbepoetin alfa treatment was associated with a prolonged progression-free survival in patients with small-cell lung cancer [29]. Both trials were not designed to study the association between treatment with erythropoietic proteins and survival. A recent meta-analysis of controlled trials also suggested that epoetin treatment might result in a survival benefit [42]. Ongoing trials with adequate design and sufficient statistical power should more clearly define the relationship between treatment with erythropoietic proteins and survival. Recently, two trials raised the possibility of a potentially negative impact of epoetin treatment on survival [45, 46]. In the breast cancer trial [45], patients with metastatic breast cancer were included if their Hb levels were 13 g/dl or below, and the goal was to maintain Hb levels of 12 –14 g/dl. The 1-year survival rate was 70% in the epoetin alfa group but 76% in the placebo group. The imbalance in mortality occurred within the first 4 months and was mainly due to disease progression. Whether this survival difference was related to epoetin treatment or just reflected imbalances in prognostic factors between the two groups remains unclear.
Open issues More research is warranted on the relationship between Hb levels and symptom relief or quality of life. With regard to quality of life outcomes, proper handling of missing data and the definition of minimum clinically meaningful differences are important [9]. Studies on the impact of erythropoietic proteins on the improvement of respiratory or cognitive functions might further support their clinical use [37]. Open issues are optimal time of treatment initiation, starting Hb threshold, optimal dose and scheduling (e.g. front-loading concept, extended dosing intervals) with regard to both rate and rapidity of response, target Hb level, characterization of responders or non-responders, proper role of iron supplementation and the economic impact of costs.
References 1. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999; 91: 1616–1634. 2. Ludwig H, Van Belle S, Barrett-Lee P et al. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 2004; 40: 2293– 2306.
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Treatment with erythropoietic proteins is usually well tolerated. Side-effects related to erythropoietic proteins include hypertension and thromboembolic events. According to a meta-analysis of controlled clinical trials, erythropoietic proteins increase the risk of hypertension by 1.25-fold and the risk of thromboembolic events by 1.55-fold [42]. However, each of these side-effects occurs in <10% of the patients. Other occasional side-effects are skin reactions, cephalea and influenza-like symptoms. The development of anti-erythropoietic antibodies or pure red cell aplasia has not been observed in patients with cancer. Recently, the demonstration of erythropoietin receptors on the surface of tumor cells [43, 44] has raised concerns that erythropoietic proteins might stimulate tumor growth. This possibility may not be of relevance in patients undergoing palliative treatment but should be considered in patients undergoing curative treatment.
The head and neck cancer trial included patients with Hb levels <12 g/dl (women) or <13 g/dl (men) [46]. The percentage of patients achieving Hb levels >14 g/dl (women) or >15 g/dl (men) was much higher in the epoetin beta group than in the placebo group (82% versus 15%). Survival was shorter in the epoetin group in the intention-to-treat analysis, but no survival difference was seen in the per protocol analysis. The authors concluded that epoetin corrects anemia but does not improve cancer control or survival in patients with head and neck cancer undergoing curative radiotherapy. Criticisms of the study were a heterogeneous patient population, imbalances between the groups (e.g. higher proportion of both smokers and relapsed patients in the epoetin arm), inappropriate treatment (radiotherapy instead of radiochemotherapy), protocol violations and poor overall outcome. In particular, the high target Hb level achieved in most epoetin-treated patients might have impaired oxygen delivery to the tumor, thereby having decreased the efficacy of radiotherapy in these patients. Based on the currently available data, several precautions should be taken. First, the use of erythropoietic proteins in non-anemic cancer patients outside clinical trials is not recommended. Secondly, treatment with erythropoietic proteins should be discontinued before Hb levels reach the high normal range in order to avoid both thromboembolic events and impairment of tumor oxygenation. Thirdly, the potential of erythropoietic protein-mediated tumor growth has to be considered and needs further studies. Finally, the impact of erythropoietic proteins on disease outcome has to determined in properly designed and closely monitored clinical trials, several of which are already ongoing.
ii51
23.
24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 1998; 16: 3412–3425. Gabrilove JL, Cleeland CS, Livingston RB et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to threetimes-weekly dosing. J Clin Oncol 2001; 19: 2875–2882. Littlewood TJ, Bajetta E, Nortier JW et al. Epoetin Alfa Study Group. 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 2001; 19: 2865–2874. Chang J, Couture F, Young S et al. Once weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol 2004; Sep 27: Epub ahead of print. Osterborg A, Brandberg Y, Molostova V et al. Randomized, doubleblind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol 2002; 20: 2486–2494. Boogaerts M, Coiffier B, Kainz C. Impact of epoetin beta on quality of life in patients with malignant disease. Br J Cancer 2003; 88: 988–995. Pirker R, Smith R. Darbepoetin alfa: potential role in managing anemia in cancer patients. Expert Rev Anticancer Ther 2002; 2: 377–384. Vansteenkiste J, Pirker R, Massuti B et al. Double-blind, placebocontrolled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002; 94: 1211–1220. Pirker R, Vansteenkiste J, Gateley J et al Exploratory analysis of the effect of baseline hemoglobin in a double-blind study in lung cancer patients. Ann Oncol 2002; 13 (Suppl 5): 177 (Abstr 651). Hedenus M, Adriansson M, San Miguel J et al. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol 2003; 122: 394–403. Seidenfeld J, Piper M, Flamm C et al. Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials. J Natl Cancer Inst 2001; 93: 1204–1214. Quirt I, Robeson C, Lau CY et al. Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy. J Clin Oncol 2001; 19: 4126–4134. Lavey RS, Dempsey WH. Erythropoietin increases hemoglobin in cancer patients during radiation therapy. Int J Radiat Oncol Biol Phys 1993; 27: 1147–1152. Sweeney PJ, Nicolae D, Ignacio L et al. Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial. Br J Cancer 1998; 77: 1996– 2002. 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 2002; 95: 888–895. Rizzo JD, Lichtin AE, Woolf SH et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002; 20: 4083–4107. Crawford J, Demetri GD, Gabrilove JL et al. Clinical benefits of epoetin alpha therapy in patients with lung cancer. Clin Lung Cancer 2002; 3: 180–190.
Downloaded from http://annonc.oxfordjournals.org/ at Juridische Bibliotheek Der UU/University Library Utrecht on March 12, 2015
3. Krantz SB. Pathogenesis and treatment of the anemia of chronic disease. Am J Med Sci 1994; 307: 353 –359. 4. Harrison LB, Shasha D, White C et al. Radiotherapy-associated anemia: the scope of the problem. Oncologist 2000; 5 (Suppl 2): 1–7. 5. Portenoy RK, Itri LM. Cancer-related fatigue: guidelines for evaluation and management. Oncologist 1999; 4: 1–10. 6. Ludwig H, Strasser K. Symptomatology of anemia. Semin Oncol 2001; 28 (Suppl 8): 7–14. 7. Cella D. The Functional Assessment of Cancer Therapy—Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 1997; 34 (Suppl 2): 13 –19. 8. Yellen SB, Cella DF, Webster K et al. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997; 13: 63–74. 9. Cella D, Zagari MJ, Vandoros C et al. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol 2003; 21: 366 –373. 10. Cella D, Eton DJ, Fairclough DL et al. What is a clinically meaningful change on the Functional Assessment of Cancer Therapy—Lung (FACT-L) Questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592. J Clin Epidemiol 2002; 55: 285 –295. 11. Caro JJ, Salas M, Ward A et al. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 2001; 91: 2214–2221. 12. Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol 2001; 18: 243 –259. 13. Becker A, Stadler P, Lavey RS et al. Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 2000; 46: 459 –466. 14. Vaupel P, Thews O, Mayer A et al. Oxygenation status of gynecologic tumors: what is the optimal hemoglobin level? Strahlenther Onkol 2002; 178: 727–731. 15. Fein DA, Lee WR, Hanlon AL et al. Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol 1995; 13: 2077–2083. 16. Lee WR, Berkey B, Marcial V et al. Anemia is associated with decreased survival and increased locoregional failure in patients with locally advanced head and neck carcinoma: a secondary analysis of RTOG 85-27. Int J Radiat Oncol Biol Phys 1998; 42: 1069–1075. 17. 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 2001; 50: 705–715. 18. Grogan M, Thomas GM, Melamed I et al. The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 1999; 86: 1528– 1536. 19. Estrin JT, Schocket L, Kregenow R et al. A retrospective review of blood transfusions in cancer patients with anemia. Oncologist 1999; 4: 318–324. 20. 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 2000; 82: 93 –97. 21. Glaspy J, Bukowski R, Steinberg D et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 1997; 15: 1218–1234. 22. Demetri GD, Kris M, Wade J et al. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of
ii52
43. 44. 45.
46.
diseases? Results of a comprehensive meta-analysis. Blood 2003; 102: 203a (Abstr 709). Acs G, Acs P, Beckwith SM et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 2001; 61: 3561–3565. Yasuda Y, Fujita Y, Matsuo T et al. Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 2003; 24: 1021– 1029. Leyland-Jones B, on behalf of the BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 2003; 4: 459– 460. Henke M, Laszig R, Ru¨be C et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomized, double-blind, placebo-controlled trial. Lancet 2003; 362: 1255–1260.
Downloaded from http://annonc.oxfordjournals.org/ at Juridische Bibliotheek Der UU/University Library Utrecht on March 12, 2015
39. Thatcher N, De Campos ES, Bell DR et al. Epoetin alpha prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br J Cancer 1999; 80: 396 –402. 40. Sabbattini P. On behalf of the NCCN anemia panel. NCCN clinical practice guidelines in oncology: cancer and treatment-related anemia, version 1.2005. Available online at http://www.nccn.org/ physician_gls/f_guidelines.html (23 March 2005, date last accessed). 41. Bokemeyer C, Aapro MS, Courdi A et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004; 40: 2201– 2216. 42. Bohlius JF, Langensiepen S, Schwarzer G et al Does erythropoietin improve overall survival in the treatment of patients with malignant
Application and safety of erythropoietin in cancer management R. Pirker & W. Minar Department of Internal Medicine I, Medical University Vienna, 1090 Vienna, Austria
Anemia frequently occurs in patients with cancer [1, 2]. According to the European Cancer Anemia Survey [2], prevalence of anemia increased from 39% (<10 g/dl in 10%) at enrollment to 67% (<10 g/dl in 39%) of the patients during the survey. The incidence of anemia was 54% [2]. The incidence and severity of anemia depends on cancer type, tumor stage, duration of the cancer, treatment status, patient age and bone marrow reserve [1, 2]. The incidences were 63% in patients receiving chemotherapy, 42% in those receiving concomitant chemoradiotherapy and 19.5% in those receiving radiotherapy [2]. The highest incidences of anemia are seen in patients with lung cancer, gynecological malignancies, genitourinary cancer and lymphomas [1, 2]. These high frequencies are mainly due to platinum-based chemotherapy. Anthracycline-based protocols and new anticancer drugs such as taxanes, vinorelbine or camptothecins also lead to a high frequency of anemia [1]. The etiology of cancer-related anemia includes myelosuppressive chemotherapy and/or radiotherapy, tumor infiltration of the bone marrow, relative deficiency of erythropoietin, inappropriate response of the bone marrow, functional iron deficiency, nutritional deficiencies, bleeding, hemolysis and the anemia of chronic disease [1, 3, 4]. Cancer-related anemia is a major contributor to cancerrelated fatigue [5]. Other symptoms are dizziness, vertigo, headache, pallor, dyspnea, angina pectoris, tachycardia, palpitations, depression, impaired cognitive function and loss of libido [6]. Anemia decreases overall quality of life, particularly by reducing physical, functional and emotional wellbeing [7 –10]. The severity of symptoms depends on the absolute hemoglobin (Hb) level, the rapidity of onset of anemia, compensatory mechanisms, co-morbidity and other factors [6]. Clinical assessment of anemia should focus on symptoms, impact on activities of daily living, blood cell counts, laboratory parameters (e.g. iron status, vitamin levels) and potential causes. Quality of life instruments such as the Functional Assessment of Cancer Therapy—Anemia (FACT-Anemia) scales [7 –10] are particularly useful in the context of clinical trials. Anemia is a prognostic factor for shorter survival and/or a predictive factor for worse outcome of anticancer therapy in several cancers [11]. The relative risk of death is increased by 65% overall in anemic cancer patients. The relative risks of q 2005 European Society for Medical Oncology
death increase for anemic patients by 75% in ovarian cancer, 67% in lymphoma, 47% in prostate cancer and 19% in lung cancer [11]. Anemia can reduce both acceptance and tolerance of anticancer therapy. Anemia may negatively affect the outcome of chemotherapy and radiotherapy because anemia, abnormal tumor microvasculature and reduced diffusion are the major causes in the development of tumor hypoxia, which has been linked to treatment resistance, tumor progression and poor prognosis [12]. Anemia was shown to be associated with poor tumor oxygenation in both head and neck squamous cell carcinomas and cervical cancer [13, 14]. Consistent with this association, low Hb levels before or during radiotherapy were associated with poor locoregional control and shorter survival in patients undergoing radiotherapy for locally advanced head and neck cancer [15 –17], carcinoma of the cervix [18] or other cancers. A study in cervical cancer suggested that Hb values of 12 –14 g/dl are optimal with regard to the oxygenation status [14]. Blood transfusions have been the mainstay of treatment, but recombinant human erythropoietic proteins have opened new therapeutic options. Here we review the current treatment strategies in cancer-related anemia, with emphasis on erythropoietic proteins.
Treatment of anemia Despite its detrimental effect on quality of life, anemia still goes undertreated. According to the European Cancer Anemia Survey [2], anemia was treated in only 39% of patients, either by epoetins (17%), transfusions (15%) or iron only (7%). The mean Hb level at the initiation of treatment was 9.7 g/dl. Treatment should correct the cause of anemia (Table 1). This includes treatment of infection, bleeding sources, hemolysis, iron deficiency and vitamin deficiencies. Symptomatic treatment is achieved by red blood cell (RBC) transfusions and the administration of erythropoietic proteins (Table 1).
RBC transfusions RBC transfusions are usually given only to patients with severe and/or highly symptomatic anemia. The average Hb level at the time of transfusion is 7.9 g/dl [19]. Transfusion requirements are also affected by age and co-morbidity, particularly reduced cardiovascular or pulmonary function.
Downloaded from http://annonc.oxfordjournals.org/ at Juridische Bibliotheek Der UU/University Library Utrecht on March 12, 2015
Introduction
ii48 Table 1. Management of anemia: general principles All patients
Treatment or correction of underlying cause(s)
Further management according to severity of anemia Mild
Consider erythropoietic proteins, particularly in symptomatic patients, elderly patients, patients with co-morbidities and patients with declining Hb levels
Moderate
Erythropoietic proteins
Severe or life-threatening
RBC transfusion plus erythropoietic proteins
Hb, hemoglobin; RBC, red blood cell.
Overall, 33% of cancer patients require at least one transfusion and 16% require multiple transfusions [20]. High transfusion rates are seen in patients with lung cancer, ovarian cancer or genitourinary cancer and in patients receiving platinum-based chemotherapy [1, 2, 19, 20]. A low baseline Hb level predicts the likelihood of future transfusion. Other potentially predictive factors are advanced age, advanced disease, reduced performance status, weight loss, platinum- or anthracycline-based chemotherapy, duration of chemotherapy, and a marked Hb decrease after the first cycle of chemotherapy. RBC transfusions result in rapid improvement in all transfused patients. However, transfusions often do not result in sustained effects and also have the risks of transfusion reactions, immunosuppression and transmission of infectious agents. Concerns about these risks and in several countries an additional shortage in blood supply have a negative impact on current transfusion policies.
Erythropoietic proteins Administration of erythropoietic proteins (epoetin alfa, epoetin beta, darbepoetin alfa) increases Hb levels and decreases RBC transfusions in patients either receiving chemotherapy [21– 33] or not receiving chemotherapy [33]. The efficacy of epoetins was also demonstrated in patients receiving radiotherapy [34, 35] or chemoradiotherapy [17]. Treatment with erythropoietic proteins improves anemiarelated symptoms and significantly increases energy level, daily activity and overall quality of life [9, 21–33, 36]. The improvements in quality of life correlate with Hb increases in patients across the Hb range of 8–14 g/dl, with a maximal incremental gain in the range of 11 –13 g/dl [36]. Thus the benefit appears to be greater in patients with mild anemia than in those with moderate to severe anemia. These findings suggest that therapeutic intervention should aim to maintain Hb levels of 11 –12 g/dl, particularly in patients with fatigue and/or co-morbidities. Epoetins decrease the relative odds of receiving a RBC transfusion by an average of 62%, and four to five patients
Practice guidelines Practice guidelines on the use of erythropoietic proteins have been published by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) [37], the National Comprehensive Cancer Network [40] and the European Organization for Research and Treatment of Cancer (EORTC) [41]. A flow chart considering these guidelines is shown in Figure 1. The guidelines also stress the importance of regular monitoring of iron status, particularly in non-responders, and, if indicated, iron repletion.
ASCO/ASH guidelines Epoetins are recommended for patients with chemotherapy_ 10 g/dl, but RBC transassociated anemia and a Hb level < fusions are also a treatment option, depending on the severity of anemia or clinical circumstances. For patients with declining Hb levels but less severe anemia (those with Hb <12 g/dl but who have never fallen below 10 g/dl), epoetins might be used either immediately or after Hb levels fall closer to 10 g/dl, dependent on clinical circumstances. RBC transfusions are also a therapeutic option when warranted by severe clinical conditions.
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RBC transfusion dependent on clinical circumstance
have to be treated in order to benefit one patient [37]. The time to response depends on the dose and schedule of erythropoietic proteins. Non-responders after 4 weeks should be considered for a dose escalation for an additional 4–6 weeks, and should also be investigated for iron deficiency or tumor progression [37]. Epoetin alfa is usually administered at a dose of either 150 U/kg (or 10 000 U) three times per week or 40 000– 60 000 U once weekly. The two schedules show similar efficacy [23]. Epoetin beta is commonly given at 150 U/kg three times per week or 30 000 U once weekly. Darbepoetin alfa is usually administered at 150 mg once weekly or at higher doses with extended dosing intervals [28–31]. Response to erythropoietic proteins is affected by dose, frequency as well as route of administration, duration of therapy, presence of other or additional causes of anemia, functional iron deficiency, presence of infection and by other factors [37]. Response is usually independent of age, sex, type of cancer, type of chemotherapy (platinum versus non-platinum) and chemotherapy response [21, 22]. Early intervention was shown to be effective in breast cancer patients receiving chemotherapy [25]. In patients who developed Hb <12 g/dl, once weekly epoetin alfa maintained Hb levels, improved quality of life and reduced transfusions in comparison with standard of care. Similarly, darbepoetin alfa was shown to have a beneficial effect in both patients with baseline Hb levels >10 g/dl and those with levels <10 g/dl [30]. Few studies have demonstrated the potential of epoetins for the prevention of anemia in patients receiving myelosuppressive therapy [38, 39], but confirmatory trials are warranted.
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Epoetins should be given until the Hb level reaches 12 g/dl and then the epoetin dose should be titrated to maintain Hb levels. Dose escalation is recommended for patients who do not respond to the initial dose. In the absence of response, treatment should not be continued beyond 6 –8 weeks.
EORTC guidelines Initiation of treatment with erythropoietic proteins is recommended at a Hb level of 9–11 g/dl based on anemia-related
symptoms in patients with or without chemotherapy. The erythropoietic proteins may also be considered according to individual factors in asymptomatic patients with Hb levels of 9–11 g/dl in order to prevent a further decline. A target Hb level of 12–13 g/dl is recommended. Neither the prophylactic use nor the use in patients undergoing autologous blood stem cell transplantation are recommended, but the use in patients undergoing allogeneic blood stem cell transplantation can be considered on an individual basis.
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Figure 1. Proposal for the clinical use of erythropoietic proteins in anemic patients with cancer undergoing chemotherapy (modified after references [37] and [41]). Hb, hemoglobin; s.c., subcutaneously.
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Safety of erythropoietic proteins
Erythropoietic proteins and survival Because anemia contributes to tumor hypoxia, erythropoietic protein-mediated control of anemia could improve tumor hypoxia and, thereby, increase response to chemotherapy or radiotherapy, which then could translate into improved survival. A retrospective analysis in patients with head and neck cancer undergoing chemoradiotherapy indicated that patients with baseline Hb levels >14.5 g/dl showed improved local tumor control and longer survival than those with Hb levels <14.5 g/dl [17]. When patients with Hb levels <14.5 g/dl received prophylactic epoetin alfa, however, outcome was similar to the outcome of patients with Hb levels >14.5 g/dl. Epoetin alfa treatment was associated with a trend towards improved survival in cancer patients undergoing non-platinum chemotherapy [24]. Darbepoetin alfa treatment was associated with a prolonged progression-free survival in patients with small-cell lung cancer [29]. Both trials were not designed to study the association between treatment with erythropoietic proteins and survival. A recent meta-analysis of controlled trials also suggested that epoetin treatment might result in a survival benefit [42]. Ongoing trials with adequate design and sufficient statistical power should more clearly define the relationship between treatment with erythropoietic proteins and survival. Recently, two trials raised the possibility of a potentially negative impact of epoetin treatment on survival [45, 46]. In the breast cancer trial [45], patients with metastatic breast cancer were included if their Hb levels were 13 g/dl or below, and the goal was to maintain Hb levels of 12 –14 g/dl. The 1-year survival rate was 70% in the epoetin alfa group but 76% in the placebo group. The imbalance in mortality occurred within the first 4 months and was mainly due to disease progression. Whether this survival difference was related to epoetin treatment or just reflected imbalances in prognostic factors between the two groups remains unclear.
Open issues More research is warranted on the relationship between Hb levels and symptom relief or quality of life. With regard to quality of life outcomes, proper handling of missing data and the definition of minimum clinically meaningful differences are important [9]. Studies on the impact of erythropoietic proteins on the improvement of respiratory or cognitive functions might further support their clinical use [37]. Open issues are optimal time of treatment initiation, starting Hb threshold, optimal dose and scheduling (e.g. front-loading concept, extended dosing intervals) with regard to both rate and rapidity of response, target Hb level, characterization of responders or non-responders, proper role of iron supplementation and the economic impact of costs.
References 1. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999; 91: 1616–1634. 2. Ludwig H, Van Belle S, Barrett-Lee P et al. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 2004; 40: 2293– 2306.
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Treatment with erythropoietic proteins is usually well tolerated. Side-effects related to erythropoietic proteins include hypertension and thromboembolic events. According to a meta-analysis of controlled clinical trials, erythropoietic proteins increase the risk of hypertension by 1.25-fold and the risk of thromboembolic events by 1.55-fold [42]. However, each of these side-effects occurs in <10% of the patients. Other occasional side-effects are skin reactions, cephalea and influenza-like symptoms. The development of anti-erythropoietic antibodies or pure red cell aplasia has not been observed in patients with cancer. Recently, the demonstration of erythropoietin receptors on the surface of tumor cells [43, 44] has raised concerns that erythropoietic proteins might stimulate tumor growth. This possibility may not be of relevance in patients undergoing palliative treatment but should be considered in patients undergoing curative treatment.
The head and neck cancer trial included patients with Hb levels <12 g/dl (women) or <13 g/dl (men) [46]. The percentage of patients achieving Hb levels >14 g/dl (women) or >15 g/dl (men) was much higher in the epoetin beta group than in the placebo group (82% versus 15%). Survival was shorter in the epoetin group in the intention-to-treat analysis, but no survival difference was seen in the per protocol analysis. The authors concluded that epoetin corrects anemia but does not improve cancer control or survival in patients with head and neck cancer undergoing curative radiotherapy. Criticisms of the study were a heterogeneous patient population, imbalances between the groups (e.g. higher proportion of both smokers and relapsed patients in the epoetin arm), inappropriate treatment (radiotherapy instead of radiochemotherapy), protocol violations and poor overall outcome. In particular, the high target Hb level achieved in most epoetin-treated patients might have impaired oxygen delivery to the tumor, thereby having decreased the efficacy of radiotherapy in these patients. Based on the currently available data, several precautions should be taken. First, the use of erythropoietic proteins in non-anemic cancer patients outside clinical trials is not recommended. Secondly, treatment with erythropoietic proteins should be discontinued before Hb levels reach the high normal range in order to avoid both thromboembolic events and impairment of tumor oxygenation. Thirdly, the potential of erythropoietic protein-mediated tumor growth has to be considered and needs further studies. Finally, the impact of erythropoietic proteins on disease outcome has to determined in properly designed and closely monitored clinical trials, several of which are already ongoing.
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23.
24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 1998; 16: 3412–3425. Gabrilove JL, Cleeland CS, Livingston RB et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to threetimes-weekly dosing. J Clin Oncol 2001; 19: 2875–2882. Littlewood TJ, Bajetta E, Nortier JW et al. Epoetin Alfa Study Group. 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 2001; 19: 2865–2874. Chang J, Couture F, Young S et al. Once weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol 2004; Sep 27: Epub ahead of print. Osterborg A, Brandberg Y, Molostova V et al. Randomized, doubleblind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol 2002; 20: 2486–2494. Boogaerts M, Coiffier B, Kainz C. Impact of epoetin beta on quality of life in patients with malignant disease. Br J Cancer 2003; 88: 988–995. Pirker R, Smith R. Darbepoetin alfa: potential role in managing anemia in cancer patients. Expert Rev Anticancer Ther 2002; 2: 377–384. Vansteenkiste J, Pirker R, Massuti B et al. Double-blind, placebocontrolled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002; 94: 1211–1220. Pirker R, Vansteenkiste J, Gateley J et al Exploratory analysis of the effect of baseline hemoglobin in a double-blind study in lung cancer patients. Ann Oncol 2002; 13 (Suppl 5): 177 (Abstr 651). Hedenus M, Adriansson M, San Miguel J et al. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol 2003; 122: 394–403. Seidenfeld J, Piper M, Flamm C et al. Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials. J Natl Cancer Inst 2001; 93: 1204–1214. Quirt I, Robeson C, Lau CY et al. Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy. J Clin Oncol 2001; 19: 4126–4134. Lavey RS, Dempsey WH. Erythropoietin increases hemoglobin in cancer patients during radiation therapy. Int J Radiat Oncol Biol Phys 1993; 27: 1147–1152. Sweeney PJ, Nicolae D, Ignacio L et al. Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial. Br J Cancer 1998; 77: 1996– 2002. 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 2002; 95: 888–895. Rizzo JD, Lichtin AE, Woolf SH et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002; 20: 4083–4107. Crawford J, Demetri GD, Gabrilove JL et al. Clinical benefits of epoetin alpha therapy in patients with lung cancer. Clin Lung Cancer 2002; 3: 180–190.
Downloaded from http://annonc.oxfordjournals.org/ at Juridische Bibliotheek Der UU/University Library Utrecht on March 12, 2015
3. Krantz SB. Pathogenesis and treatment of the anemia of chronic disease. Am J Med Sci 1994; 307: 353 –359. 4. Harrison LB, Shasha D, White C et al. Radiotherapy-associated anemia: the scope of the problem. Oncologist 2000; 5 (Suppl 2): 1–7. 5. Portenoy RK, Itri LM. Cancer-related fatigue: guidelines for evaluation and management. Oncologist 1999; 4: 1–10. 6. Ludwig H, Strasser K. Symptomatology of anemia. Semin Oncol 2001; 28 (Suppl 8): 7–14. 7. Cella D. The Functional Assessment of Cancer Therapy—Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 1997; 34 (Suppl 2): 13 –19. 8. Yellen SB, Cella DF, Webster K et al. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997; 13: 63–74. 9. Cella D, Zagari MJ, Vandoros C et al. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol 2003; 21: 366 –373. 10. Cella D, Eton DJ, Fairclough DL et al. What is a clinically meaningful change on the Functional Assessment of Cancer Therapy—Lung (FACT-L) Questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592. J Clin Epidemiol 2002; 55: 285 –295. 11. Caro JJ, Salas M, Ward A et al. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 2001; 91: 2214–2221. 12. Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol 2001; 18: 243 –259. 13. Becker A, Stadler P, Lavey RS et al. Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 2000; 46: 459 –466. 14. Vaupel P, Thews O, Mayer A et al. Oxygenation status of gynecologic tumors: what is the optimal hemoglobin level? Strahlenther Onkol 2002; 178: 727–731. 15. Fein DA, Lee WR, Hanlon AL et al. Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol 1995; 13: 2077–2083. 16. Lee WR, Berkey B, Marcial V et al. Anemia is associated with decreased survival and increased locoregional failure in patients with locally advanced head and neck carcinoma: a secondary analysis of RTOG 85-27. Int J Radiat Oncol Biol Phys 1998; 42: 1069–1075. 17. 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 2001; 50: 705–715. 18. Grogan M, Thomas GM, Melamed I et al. The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 1999; 86: 1528– 1536. 19. Estrin JT, Schocket L, Kregenow R et al. A retrospective review of blood transfusions in cancer patients with anemia. Oncologist 1999; 4: 318–324. 20. 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 2000; 82: 93 –97. 21. Glaspy J, Bukowski R, Steinberg D et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 1997; 15: 1218–1234. 22. Demetri GD, Kris M, Wade J et al. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of
ii52
43. 44. 45.
46.
diseases? Results of a comprehensive meta-analysis. Blood 2003; 102: 203a (Abstr 709). Acs G, Acs P, Beckwith SM et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 2001; 61: 3561–3565. Yasuda Y, Fujita Y, Matsuo T et al. Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 2003; 24: 1021– 1029. Leyland-Jones B, on behalf of the BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 2003; 4: 459– 460. Henke M, Laszig R, Ru¨be C et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomized, double-blind, placebo-controlled trial. Lancet 2003; 362: 1255–1260.
Downloaded from http://annonc.oxfordjournals.org/ at Juridische Bibliotheek Der UU/University Library Utrecht on March 12, 2015
39. Thatcher N, De Campos ES, Bell DR et al. Epoetin alpha prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br J Cancer 1999; 80: 396 –402. 40. Sabbattini P. On behalf of the NCCN anemia panel. NCCN clinical practice guidelines in oncology: cancer and treatment-related anemia, version 1.2005. Available online at http://www.nccn.org/ physician_gls/f_guidelines.html (23 March 2005, date last accessed). 41. Bokemeyer C, Aapro MS, Courdi A et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004; 40: 2201– 2216. 42. Bohlius JF, Langensiepen S, Schwarzer G et al Does erythropoietin improve overall survival in the treatment of patients with malignant