Table 1. Grading of anaemia used in ECAS and that proposed by NCI (Hb in g/dL)

	ECAS	NCI
MILD	11.9-10.0	10.0-WNL
MODERATE	9.9-8.0	8.0-10.0
SEVERE	<8.0	6.5-7.9
LIFE-THREATENING	NA	<6.5

Hb= haemoglobin; NA= not applicable; WNL= within normal limits (12-16 for women, 14-16 for men); NCI= National Cancer Institute

Table 2. Prevalence of anaemia per tumour type (Ludwig et al, 2004)

Breast (n*=3123)

Lung (n=2002)

GI-CRC

(n=2402)

H&N

(n=684)

Gyn (n=1675)

Lymphoma/

Myeloma (n=2260)

Leukaemia (n=624)

U-G (n=894)

Hb<12

30.4%

37.6%

38.9%

24.9%

49.1%

52.5%

53%

29.2%

g/dL

OVERALL PREVALENCE= 39.3%

n= number of patients; Hb= haemoglobin; GI-CRC= gastro-intestinal and colorectal; H&N= head & neck; Gyn= gynaecology; U-G= uro-genital

* Evaluable population

Table 3. Correlation between Hb levels and PS in ECAS, at enrolment (Ludwig et al, 2004)

Hb (g/dL)	<8	8-9.9	10-11.9	>=12
n	187	1242	4214	8750
Mean (WHO) PS	1.7	1.4	1.0	0.8

Hb= haemoglobin; WHO= World Health Organisation; n= number of patients; PS= performance status; ECAS= European Cancer Anaemia Survey

Table 4. Changes in QOL in patients receiving interventions to correct Hb

Trial	n	Design	Population	Results
RANDOMISED TRIALS
Abels, 1993	413	r-HuEPO (100 U/kg 3xw for non-CT, 150 U/kg 3xw for CT pts) vs placebo	Anaemic (Hb<=10.5g/dL) pts on CT (n=289) or not (n=124)	EPO corrected anaemia in all groups, and seemed to improve functional capacity in responding pts
Osterborg et al, 2002	349	EPO-b (150 IU/kg 3xw) vs placebo	Transfusion-dependent pts with haematological malignancies and low serum erythropoietin concentration	Significant improvements in QOL in the EPO-b group
Witzig et al, 2004	344	EPO-a (40,000) U qw vs placebo	Anaemic (Hb<11.5 g/dL and <10.5 g/dL for males and females, respectively), after receiving CT	Changes in the average QOL scores from baseline to the end of the study were similar in the two study arms; a benefit was seen in the subgroup of Hb responders only.
Littlewood et al, 2001 Fallowfield et al, 2002	375	EPO-a (150 to 300 IU/kg 3xw) (2:1) vs placebo	Anaemic (Hb <=10.5 g/dL, or > 10.5 g/dL but <or= 12 g/dL after a Hb ¯of >or= 1.5 g/dL per cycle since starting CT) pts with solid or non-myeloid haematological malignancies receiving non-platinum CT	Improvement of all primary cancer- and anaemia-specific QOL domains was significantly greater for EPO-a. Vast majority of pts in this trial had Hb levels <10.0 g/dL. This QOL data has been later more extensively evaluated and the significant QOL gains confirmed (Fallowfield 2002)
Chang et al, 2004	354	EPO-a (40,000 U qw) vs BSC	Anaemic (Hb =12 g/dL) breast cancer pts on CT	EPO-a was effective in improving QOL
Boogaerts et al, 2003	262	EPO-b (initial dose 150 IU kg 3xw) vs BSC	Anaemic (Hb<or=11 g/dL) pts with lymphoid or solid tumour malignancies	Baseline to final visit changes in QOL scores were significantly greater with EPO-b
Savonije et al, 2004	315	EPO-a (10.000 3xw; 20.000 3xw as necessary) (2:1) vs BSC	Mildly anaemic (Hb<= 12 g/dL) pts with solid malignancies receiving platinum-based CT	EPO-aimproved QOL scores at the end of the study.
Charu et al, 2004)	170	DA (3mcg/kg q2w);(2:1) vs observation (for 12 weeks, then DA)	Anaemic (Hb<=11 g/dL) pts not on CT or RT	Improvements in QOL with DA in the first 12 weeks
Vansteenkiste et al, 2002	320	DA (2.25mcg/kg/qw, doubled as necessary) vs placebo	Anaemic (Hb<=11 g/dL) lung cancer pts receiving CT	Pts on DA had better improvements in fatigue scores
Hedenus et al, 2003	344	DA vs placebo	Anaemic lymphoma or myeloma pts receiving CT	DA improved QOL
Pronzato et al, 2002	223	EPO-a (10000-20000 3xw) vs BSC	Anaemic (Hb 10-12 g/dL) breast cancer pts receiving CT	Early treatment with EPO-a resulted in significant improvements in QOL scores
Thomas et al, 2002	130	EPO-a (10000 3xw) vs BSC	Mildly anaemic (Hb < 12.0g/dL) cancer pts undergoing CT	Early treatment with EPO-a resulted in significant improvements in QOL scores
Wilkinson et al, 2001	182	EPO-a(10000 3xw)(2:1) vs BSC	Anaemic (Hb 10-12 g/dL) ovarian cancer pts on platinum-based CT	Preliminary results from 160 pts showed significant improvements in QOL
Iconomou et al, 2003	122	rHuEPO vs placebo	Anaemic (Hb </=11.0 g/dl) pts on CT	Significant improvement in QOL with EPO
Janinis et al, 2003	372	EPO-a(10000 3xw) vs no EPO	Anaemic (Hb <11 g/dL) pts on CT		Positive impact on QOL which was independent of anti-tumour response
Dammacco et al, 2001	145	EPO-a (150 UI/kg 3xw) vs placebo	Anaemic (Hb<11 g/dL) pts with myeloma		Benefit seen only on univariate analysis
NON-RANDOMISED TRIALS						NON-RANDOMISED TRIALS
Gabrilove et al, 2001	3012	Community-based; multicentre, open-label(EPO-a 40,000 U 3xw; to 60,000 U 3xw depending on the Hb response at 4 weeks)	Anaemic (Hb <or= 10.5 g/dL, or > 10.5 g/dL but <or= 12 g/dL after a Hb ¯ of >or= 1.5 g/dL per cycle since starting CT) pts with non-myeloid malignancies on CT		Significant improvements in functional status and fatigue; improvements in QOL parameters correlated significantly with increases in Hb levels
Crawford et al, 2002	4382	Retrospective review of data from 2 open-label, community-based trials of EPO-a (given 3xw)	Anaemic (Hb 8-14 g/dL) pts undergoing chemotherapy		Non-linear relationship and significant positive correlation between high Hb levels and high QOL scores; a benefit was seen at all levels of Hb but was the largest when Hb levels of 11-13 g/dL were achieved
Shasha et al, 2003	777	Multicentre, open-label (EPO-a 40,000 U qw; to 60,000 U qw if Hb to < or = 1 g/dL after 4 weeks)	Anaemic (Hb <or=11 g/dL) pts with non-myeloid malignancies receiving RT concomitantly or sequentially with CT		In 359 pts who were evaluable for QOL assessment, EPO-a significantly improved overall QOL from baseline to the time of final evaluation.
Quirt et al, 2001	401	Prospective, open-label (EPO-a 150 IU/kg 3xw; 300 IU/kg after 4 weeks is insufficient response)	Anaemic (symptomatic or Hb<11 g/dL) pts on CT (n=218) or not (n=183)		Improvements in QOL scores, which correlated with increases in Hb levels; similar benefits were observed in the 2 cohorts
Demetri et al, 1998	2370	Community-based (EPO-a 10,000 U 3x week; to 20,000 U 3xw depending on the Hb response at 4 weeks)	Anaemic (Hb <= 11g/dL) pts with non-myeloid malignancies on CT		EPO-a increased Hb levels, which correlated with an improvement in QOL scores; this was independent of tumour response
Glaspy et al, 1997	2342	Community-based, open-label (EPO-a 150 U/kg 3xw; to 300 U/kg if insufficient response)	Anaemic (non-specified) pts receiving CT		EPO-a was effective in improving the functional status and QOL, as well as increasing Hb level and decreasing BT requirements; improvement in functional status was attributed to increases in Hb levels.
Pawlicki et al, 1997	215	Open-label, multinational (EPO-a 150 IU/kg 3xw)	Cancer pts with anaemia secondary to platinum- or non-platinum-based CT		Significant improvement in QOL and PS.
META-ANALYSES						META-ANALYSES
Jones et al, 2004	11459	Meta-analysis of 23 published and unpublished, randomised/ controlled and single-arm studies that included at least 20 pts per arm	Anaemic pts with cancer		EPO-a improved QOL in pts with cancer. Results adjusted for confounding factors remained consistent.
Seidenfeld et al, 2001	851	Meta-analysis of 22 trials (n=1927) to estimate the odds of BT Also, evaluation of 9 trials (n=581 evaluable) that have reported QOL analysis	Cancer pts undergoing anti-cancer treatment and receiving EPO		The favourable impact on QOL was significant only in studies with mean baseline Hb <10 g/dL Insufficient data to show whether initiating EPO before Hb drops to less than 10 g/dL resulted in improved QOL; these data were however considered insufficient for a meta-analysis.

QOL= quality of life; Hb= haemoglobin; EPO= epoetin; CT=chemotherapy; vs= versus; BT= blood transfusion; RT= radiotherapy; pts= patients; qw= once a week; = increase; ¯= decrease; WHO= World Health Organisation; PS= performance status; 3xw= three times a week; DA= darbepoetin; r-HuEPO= recombinant human epoetin; BSC= best standard of care

More recently, prospective randomised trials have compared different schedules and agents, with no major surprises. As expected, surveys have shown that patients prefer less frequent visits to clinics to receive EPO injections (Schwartzberg et al, 2004; Tauer et al, 2004).

Considering the currently available agents, the possible schedules for use in daily practice are: EPO-a (10.000 U thrice a week or 40.000 U once a week); EPO-b (10.000 U thrice a week or 30.000 U once a week) and Darbepoetin (100 mcg once a week or 200 mcg once every 2 weeks). Other schedules may also be feasible, but have been less extensively investigated and should not be recommended routinely. The optimal duration of treatment seems to be 12-16 weeks, as in most clinical trials. The optimal target Hb is currently unknown, but 12-13g/dL has been accepted as a reasonable target. The treatment should be probably interrupted if the Hb rises above 13-14 g/dL.

VII. Iron supplementation

Despite these encouraging results, approximately30% to 50% of cancer patients with CT-related anaemiafail to achieve a meaningful response to EPO. As already demonstrated in patients with anaemia of chronic renal failure (Fishbane et al, 1995; Macdougall et al, 1996; Sepandj et al, 1996), intravenous (IV) iron seems to increase HR rates in patients with CT-related anaemia. The rationale for this is the fact that, during treatment with EPO, largeamounts of iron are required to sustain the demands of accelerated erythropoiesis. In patients with chronic renal failure, oral iron supplementation has not resulted in a meaningful benefit (Fishbane et al, 1995; Macdougall et al, 1996). Of note, the risk of anaphylaxis, a feared complication of earlier IV iron preparations, seems to be a rare occurrence (<1%), at least in patients with chronic renal failure (Sepandj et al, 1996).

In a recent randomised clinical trial (Auerbach et al, 2004), 157 patients with CT-induced anaemia ((Hb <or= 105 g/L, serum ferritin <or= 450 pmol/L or <or= 675 pmol/L with transferrin saturation <or= 19%) were randomised to one of 4 arms: (1) EPO alone, (2) EPO plus iron 325 twice daily orally, (3) EPO plus iron Dextran 100 mg IV or (4) EPO plus iron Dextran total dose IV. The best HR rates were seen in both IV iron arms, though these results will need confirmation in larger randomised trials. Serious side effects were uncommon in this trial. As a note of caution, the HR rates to EPO in the “no iron supplementation” and “oral iron” arms seemed significantly lower than those reported in the pivotal trials, though this may be because of the selected population of patients with functional or absolute iron deficiency included in this trial, who may well be poor responders to EPO.

Similar results were observed in another trial (Henry et al, 2004), in which 187 anaemic (Hb <11 g/dL, with ferritin >100 ng/mL and/ or transferrin saturation >15%) cancer patients receiving CT and EPO were randomised to no iron, iron 325 mg tid orally or IV ferric gluconate. Haematological response rates were better with IV iron than with no iron supplementation or oral iron (73% vs 41%(p=.0029) vs 46%(p=.0099), respectively). The benefit seemed to be the highest among patients with transferrin saturation <20% and baseline serum ferritin >100ng/mL, the typical picture of anaemia of chronic disease.

In short, the role of IV iron supplementation as an adjunct treatment to EPO in patients with cancer-associated anaemia deserves further investigation. Preliminary evidence suggests that IV, but not oral iron, may increase HR rates in subgroups of anaemic cancer patients receiving EPO agents. It remains to be determined whether this increased activity could result in cost savings (by further reducing the need for BT and/or allowing the use of lower doses of EPO).

VIII. Prediction of response

EPO is a costly treatment, and is not exempt from toxicity. Considering that up to 30-50% of patients will not respond to this treatment, it would be important to identify those anaemic cancer patients who are most likely to respond.

As discussed in the previous section, patients with functional or absolute iron deficiency may be less likely to respond to treatment with EPO, but the HR rate may be significantly improved by the administration of IV iron supplementation. In a small study, the presence of <5% of hypochromic erythrocytes at baseline and an increase in reticulocytes of >= 50% after 2 weeks of treatment were strongly predictive of response to EPO, whilst the presence of >5% hypochromic erythrocytes at baseline indicated functional iron deficiency, requiring the use of IV iron (Katodritou et al, 2004).

There is also good evidence that low levels of endogenous erythropoietin may be predictive of response to EPO (Cazzola et al, 1995; Osterborg et al, 2002; Boogaerts et al, 2003; Bamias et al, 2003; Hedenus et al, 2003). Since the majority of the patients included in these studies had haematological malignancies, the evidence is currently considered less robust for solid malignancies (Bokemeyer et al, 2004). Furthermore, not all studies have confirmed the predictive value of low levels of endogenous erythropoietin (Littlewood et al, 2003; Chang et al, 2004).

There is also general agreement that HR in the first 4 weeks is predictive of response to EPO (Gonzalez-Baron et al, 2002), though it is also known that a further 10-15% of patients may still respond to EPO after the starting dose is doubled. There is also some data suggesting that baseline Hb levels (>=90 g/dL) (Bokemeyer et al, 2004; Chang et al, 2004) and age (<60 years) (Bokemeyer et al, 2004) may also be predictive factors of response to EPO in patients with CT-induced anaemia.

In short, apart perhaps from erythropoietin endogenous concentration in patients with haematological malignancies and the presence of functional or absolute iron deficiency, for the time being the variables above cannot be routinely used for prediction of response to EPO in daily practice.

IX. Effect on cognitive impairment

Several studies have linked the administration of CT to a degree of cognitive impairment (van Dam et al, 1998; Schagen et al, 1999; Brezden et al, 2000; Wefel et al, 2004). Interestingly, EPO receptors are known to be expressed throughout the central nervous system (Marti et al, 1997; Juul et al, 1999; Nagai et al, 2001), and at least one small randomised trial has suggested that EPO may have a “neuroprotectant” effect in patients receiving cytotoxic CT for early breast cancer (O'Shaughnessy et al, 2002).

Although this potential “neuroprotectant” effect of EPO in patients with CT-induced cognitive dysfunction (and other neurological diseases/brain injury) has been an area of intense research, for the time being this should not be considered an indication for the use of EPO in daily practice.

X. Safety profile

Epoetin proteins have been generally considered safe agents. There is a larger experience in patients with chronic renal failure, and data is starting to accumulate in cancer patients. The most feared toxicities with these compounds are thromboembolic events and hypertension, both having been shown to be slightly increased in patients with CT induced anaemia receiving EPO (level I evidence) (Bokemeyer et al, 2004).

In the BEST study (Leyland-Jones, 2003), a prospective randomised trial closed early because of an increased mortality associated with the use of EPO, some of the early deaths were attributed to thromboembolic events, though it is important to point out that this trial was investigating the role of EPO in patients with normal baseline Hb levels. Another prospective randomised trial investigating the role of EPO in patients with breast cancer has also been prematurely closed due to an increased incidence of thromboembolism (Rosenzweig et al, 2004). In the ENHANCE trial, a prospective randomised trial investigating the role of EPO in patients with head and neck cancer, an increased incidence of vascular events was noted in the EPO arm (11% vs 5%) (Henke et al, 2003). As in the BEST trial, very high levels of Hb were achieved in this study, suggesting that this may be a risk factor for thromboembolic events in this population.

In the Cochrane meta-analysis (Bohlius et al, 2004), which included 1738 patients from 12 clinical trials, thromboembolic events occurred in 43/1019 and 14/719 patients in the EPO and control groups respectively (absolute risk difference of 0.02 (95% CI 0.00 to 0.04)). In this review, neither thromboembolism nor hypertension could be definitively linked to the administration of EPO, but under-reporting was a concern with the former. In this same meta-analysis, there was no definite evidence that EPO increased the risk of other adverse events such as rash, irritation, pruritus, haemorrhage and thrombocytopenia.

So far, pure red-cell aplasia, a rare but grave complication of treatment with EPO, has been seen only in patients with chronic renal failure (Casadevall et al, 2002; Locatelli and Del Vecchio, 2003), possibly because of the deficient immunity typically present in cancer patients.

XI. Cost-utility analysis

There is very limited data on the cost-effectiveness of EPO in anaemic cancer patients. Furthermore, costs probably need to be assessed taking into account local realities, so that results of studies are not automatically applicable in different countries or services.

In a retrospective study of patients receiving CT for breast cancer, EPO-a given prophylactically was significantly more costly than BTs, though one confusing factor was the absence of guidelines for the indication of BT (Meadowcroft et al, 1998). In another American retrospective study performed in 1997, conventional treatment (with BT as necessary) resulted in cost savings of more than US$ 8,000 per patient, compared to EPO (Sheffield et al, 2003).

In a more recent study of 55 metastatic breast cancer patients receiving non-platinum-based CT, a high probability of favourable cost-utility outcomes with EPO-a was suggested by the authors (Martin et al, 2003). Stage IV breast cancer therapy costs were collected by surveying UK oncologists, and utilities for associated health states were from published sources.

In short, though such estimations are usually difficult, the use of EPO in anaemic patients with cancer is likely to result in increased costs. This should be weighed against the benefits, i.e. improved QOL and saving of blood stocks/risks associated with BT and, in countries like the UK, the risk of variant Creutzfeldt-Jacob disease transmission. Interestingly, in health services that rely totally on BT for the treatment of cancer-associated anaemia, an interesting dilemma has been observed: despite compelling evidence that QOL is improved by the correction of anaemia, there is considerable reluctance to offer early BT to patients, mainly because of potentially unknown risks.

XII. Conclusion

Although EPO has been considered the preferred treatment for CT-induced anaemia (after exclusion of other causes), there is a surprising variation in its use in different countries. In addition, there is emerging evidence that EPO should also be considered the treatment of choice for cancer-related anaemia. However, the impact of EPO on survival is currently unknown. The disappointing results of some recent prospective randomised trials, which showed a possible negative impact of EPO on outcome, must be balanced against evidence from other trials showing just minor or no increased incidence of thromboembolism and no negative impact on outcome, particularly when a lower Hb target is used (such as 12-13 g/dL). All currently available agents and schedules seem to have similar efficacy. Serious complications are unusual with these agents, the most feared in cancer patients being the risk of thromboembolic events. The use of EPO for cancer and/or CT-induced anaemia significantly reduces the need for BT and spares stocks of blood, but is likely to result in increased costs. Therefore, its cost-effectiveness should be determined on a local basis, and in light of the resources available. It is still too early to routinely use predictive factors of response to EPO in the clinical practice, though serum baseline erythropoietin levels in patients with haematological malignancies and the presence of functional or absolute iron deficiency may be occasionally useful. The role of IV iron supplementation as an adjunct to EPO in subgroups of patients with cancer-associated anaemia should be further investigated.

References

Abels R (1993) Erythropoietin for anaemia in cancer patients. Eur J Cancer 29A (Suppl 2), S2-8.

Acs G, Acs P, Beckwith SM, Pitts RL, Clements E, Wong K, Verma A (2001) Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res. 61, 3561-5.

Albain KS, Crowley JJ, LeBlanc M, Livingston RB (1991) Survival determinants in extensive-stage non-small-cell lung cancer, the Southwest Oncology Group experience. J Clin Oncol 9, 1618-26.

Antonadou D, Cardamakis E, Puglisi M, Malamos N, Throuvalas N (2001) Erythropoietin enhances radiation treatment efficacy in patients with pelvic malignancies. Final results of a randomised phase III study. Eur J Cancer 37 (Suppl 6), 144.

Arcasoy MO, Amin K, Karayal AF, Chou SC, Raleigh JA, Varia MA, Haroon ZA (2002) Functional significance of erythropoietin receptor expression in breast cancer. Lab Invest 82, 911-8.

Armour A, et al (2003) The prognostic importance of haemoglobin in lung cancer patients. 10th World Conference on the Lung Cancer, Vancouver, Canada

Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman A, Bahrain H, Balan S, Barker L, Rana J (2004) Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia, a multicenter, open-label, randomized trial. J Clin Oncol 22, 1301-7.

Bamias A, Aravantinos G, Kalofonos C, Timotheadou N, Siafaka V, Vlahou I, Janinis D, Pectasides D, Pavlidis N, Fountzilas G; Hellenic Cooperative Oncology Group (2003) Prevention of anemia in patients with solid tumors receiving platinum-based chemotherapy by recombinant human Erythropoietin (rHuEpo, a prospective, open label, randomized trial by the Hellenic Cooperative Oncology Group. Oncology 64, 102-10.

Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennet C, Engert A (2004) Erythropoietin for patients with malignant disease. The Cochrane Database of Systematic Reviews, Issue 3.

Bokemeyer C, Aapro MS, Courdi A, Foubert J, Link H, Osterborg A, Repetto L, Soubeyran P (2004) EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 40, 2201-16.

Bokemeyer C, Oechsle K, Hartmann JT, Schoffski P, Schleucher N, Metzner B, Schleicher J, Kanz L (2002) Treatment-induced anaemia and its potential clinical impact in patients receiving sequential high dose chemotherapy for metastatic testicular cancer. Br J Cancer 87, 1066-71.

Boogaerts M, Coiffier B, Kainz C; Epoetin beta QOL Working Group (2003) Impact of epoetin b on quality of life in patients with malignant disease. Br J Cancer 88, 988-95.

Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF (2000) Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 18, 2695-701

Bryne M, Eide GE, Lilleng R, Langmark F, Thrane PS, Dabelsteen E (1991) A multivariate study of the prognosis of oral squamous cell carcinomas. Are blood group and hemoglobin new prognostic factors? Cancer 68, 1994-8

Caro JJ, Salas M, Ward A, Goss G (2001) Anemia as an independent prognostic factor for survival in patients with cancer, a systemic, quantitative review. Cancer 91, 2214-21.

Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V, Teyssandier I, Varet B, Mayeux P (2002) Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 346, 469-75.

Cazzola M, Beguin Y, Kloczko J, Spicka I, Coiffier B (2003) Once-weekly epoetin b is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production. Br J Haematol 122, 386-9

Cazzola M, Messinger D, Battistel V, Bron D, Cimino R, Enller-Ziegler L, Essers U, Greil R, Grossi A, Jager G, et al (1995) Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma, dose finding and identification of predictors of response. Blood 86, 4446-53.

Chang J, Couture F, Young S, McWatters KL, Lau CY (2004) Once Weekly Epoetin a Maintains Hemoglobin, Improves Quality of Life, and Reduces Transfusion in Breast Cancer Patients Receiving Chemotherapy. J Clin Oncol, in press

Charu V, Belani C. P, Gill A. N, Bhatt M, Ben-Jacob A, Tomita D, Katz D (2004) A controlled, randomized, open-label study to evaluate the effect of every-2-week darbepoetin a for anemia of cancer. J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 8084

Chua DT, Ma J, Sham JS, Mai HQ, Choy DT, Hong MH, Lu TX, Min HQ (2004) Prognostic impact of hemoglobin levels on treatment outcome in patients with nasopharyngeal carcinoma treated with sequential chemoradiotherapy or radiotherapy alone. Cancer 101, 307-16

Crawford J, Cella D, Cleeland CS, Cremieux PY, Demetri GD, Sarokhan BJ, Slavin MB, Glaspy JA (2002) Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin a therapy. Cancer 95, 888-95.

Cremieux PY, Fastenau JM, Kosicki G, Piech CT, Fendrick AM (2004) Cost-minimization analysis of once-weekly versus thrice-weekly epoetin a for chemotherapy-related anemia. J Manag Care Pharm. 10, 531-7.

Dammacco F, Castoldi G, Rodjer S (2001) Efficacy of epoetin a in the treatment of anaemia of multiple myeloma. Br J Haematol 113, 172-9.

Demetri GD (2001) Anaemia and its functional consequences in cancer patients, current challenges in management and prospects for improving therapy. Br J Cancer 84 (Suppl 1), 31-7.

Demetri GD, Kris M, Wade J, Degos L, Cella D (1998) Quality-of-life benefit in chemotherapy patients treated with epoetin a is independent of disease response or tumor type, results from a prospective community oncology study. Procrit Study Group. J Clin Oncol 16, 3412-25.

Dubray B, Mosseri V, Brunin F, Jaulerry C, Poncet P, Rodriguez J, Brugere J, Point D, Giraud P, Cosset JM (1996) Anemia is associated with lower local-regional control and survival after radiation therapy for head and neck cancer, a prospective study. Radiology 201, 553-8.

Dunst J, Kuhnt T, Strauss HG, Krause U, Pelz T, Koelbl H, Haensgen G (2003) Anemia in cervical cancers, impact on survival, patterns of relapse, and association with hypoxia and angiogenesis. Int J Radiat Oncol Biol Phys. 56, 778-87.

Fallowfield L, Gagnon D, Zagari M, Cella D, Bresnahan B, Littlewood TJ, McNulty P, Gorzegno G, Freund M; Epoetin Alfa Study Group (2002) Multivariate regression analyses of data from a randomised, double-blind, placebo-controlled study confirm quality of life benefit of epoetin a in patients receiving non-platinum chemotherapy. Br J Cancer 87, 1341-53.

Fein DA, Lee WR, Hanlon AL, Ridge JA, Langer CJ, Curran WJ Jr, Coia LR (1995) Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol 13, 2077-83.

Fishbane S, Frei GL, Maesaka J (1995) Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 26, 41-46

Fishbane S, Ungureanu VD, Maesaka JK, Kaupke CJ, Lim V, Wish J (1996) The safety of intravenous iron dextran in hemodialysis patients. Am J Kidney Dis 28, 529-534

Gabrilove JL, Cleeland CS, Livingston RB, Sarokhan B, Winer E, Einhorn LH (2001) Clinical evaluation of once-weekly dosing of epoetin a in chemotherapy patients, improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. Oncol 19, 2875-82.

Girinski T, Pejovic-Lenfant MH, Bourhis J, Campana F, Cosset JM, Petit C, Malaise EP, Haie C, Gerbaulet A, Chassagne D (1989) Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of the cervix treated by radiation therapy, results of a retrospective study of 386 patients. Int J Radiat Oncol Biol Phys. 16, 37-42.

Glaser CM, Millesi W, Kornek GV, Lang S, Schull B, Watzinger F, Selzer E, Lavey RS (2001) 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, 705-15.

Glaspy J (2001) Anemia and fatigue in cancer patients. Cancer 92 (Suppl 6), 1719-24.

Glaspy J, Bukowski R, Steinberg D, Taylor C, Tchekmedyian S, Vadhan-Raj S (1997) Impact of therapy with epoetin a on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol 15, 1218-34.

Gonzalez-Baron M, Ordonez A, Franquesa R, Constenla M, Montalar J, Gili F, Camps C, Sancho JF, Perez-Cachot P (2002) Response predicting factors to recombinant human erythropoietin in cancer patients undergoing platinum-based chemotherapy. Cancer 95, 2408-13.

Granetto C, Ricci S, Martoni A, Pezzella G, Testore F, Mattioli R, Lampignano M, Tacconi F, Porrozzi S, Gasparini G, Mantovani G; EPO-ITA3 Study Group (2003) Comparing the efficacy and safety of fixed versus weight-based dosing of epoetin a in anemic cancer patients receiving platinum-based chemotherapy. Oncol Rep 10, 1289-96.

Grogan M, Thomas GM, Melamed I, Wong FL, Pearcey RG, Joseph PK, Portelance L, Crook J, Jones KD (1999) The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 86, 1528-36.

Groopman JE, Itri LM (1999) Chemotherapy-induced anemia in adults, incidence and treatment. J Natl Cancer Inst 91, 1616-34.

Haugen H, Magnusson B, Svensson M, Mercke C (2004) Preradiotherapy Hemoglobin Level but not Microvessel Density Predicts Locoregional Control and Survival in Laryngeal Cancer Treated with Primary Radical Radiotherapy. Clin Cancer Res 10, 7941-9.

Hedenus M, Adriansson M, San Miguel J, Kramer MH, Schipperus MR, Juvonen E, Taylor K, Belch A, Altes A, Martinelli G, Watson D, Matcham J, Rossi G, Littlewood TJ; Darbepoetin Alfa 20000161 Study Group (2003) Efficacy and safety of darbepoetin a in anaemic patients with lymphoproliferative malignancies, a randomized, double-blind, placebo-controlled study. Br J Haematol 122, 394-403.

Henke M, Laszig R, Rube C, Schafer U, Haase KD, Schilcher B, Mose S, Beer KT, Burger U, Dougherty C, Frommhold H (2003) Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy, randomised, double-blind, placebo-controlled trial. Lancet 362, 1255-60.

Henry DH, et al (2004) Intravenous Ferric Gluconate (FG) for Increasing Response to Epoetin (EPO) in Patients with Anemia of Cancer Chemotherapy - Results of a Multicenter, Randomized Trial (abstract 3696). Blood, 104, 11

Hesketh PJ, Arena F, Patel D, Austin M, D'Avirro P, Rossi G, Colowick A, Schwartzberg L, Bertoli LF, Cole JT, Demetri G, Dessypris E, Dobbs T, Eisenberg P, Fleischman R, Hall J, Hoffman PC, Laber DA, Leonard J, Lester EP, McCachren S, McMeekin S, Meza L, Miller DS, Nand S, Oliff I, Paroly W, Pawl L, Perez A, Raftopoulos H, Rigas J, Rowland K, Scullin DC Jr, Tezcan H, Waples J, Ward J, Yee LK (2004) A randomized controlled trial of darbepoetin a administered as a fixed or weight-based dose using a front-loading schedule in patients with anemia who have nonmyeloid malignancies. Cancer 10, 859-68.

Iconomou G, Koutras A, Rigopoulos A, Vagenakis AG, Kalofonos HP (2003) Effect of recombinant human erythropoietin on quality of life in cancer patients receiving chemotherapy, results of a randomized, controlled trial. J Pain Symptom Manage 25, 512-8.

Janinis J, Dafni U, Aravantinos G, Kalofonos H. P, Papakostas P, Tsavdaridis D, Koutras A, Samelis G, Tsolakidis D, Fountzilas G (2003) Quality of life (QoL) outcome of epoietin-a (EPO-A) in anemic cancer patients undergoing platinum or non-platinum-based chemotherapy, A randomized study conducted by the Hellenic Cooperative Oncology Group (abstract 3172). Proc Am Soc Clin Oncol 22, 789

Jones M, Schenkel B, Just J, Fallowfield L (2004) Epoetin a improves quality of life in patients with cancer, results of metaanalysis. Cancer 101, 1720-32.

Juul SE, Yachnis AT, Rojiani AM, Christensen RD (1999) Immunohistochemical localization of erythropoietin and its receptor in the developing human brain. Pediatr Dev Pathol 2, 148-58.

Katodritou E, et al (2004) Evaluation of Traditional and Novel Predictive Markers of Anemia Response to Recombinant Human Erythropoietin (rh-EPO) in Patients with Multiple Myeloma and Lymphoma, Emerging Role of Functional Iron Deficiency (abstract 3690). Blood, 104, 11

Kumar P, Wan J, Viera F (1997) Analysis of survival outcome and prognostic factors (PF) in the treatment of unresectable head and neck (H/N) squamous cell carcinoma (SCCa) using supradose intra-arterial targeted cisplatin (SIT-P) and concurrent radiation therapy (RT) (abstract 1394). Proc Am Soc Clin Oncol 16, 390a

Landers DF, Hill GE, Wong KC, Fox IJ (1996) Blood transfusion-induced immunomodulation. Anesth Analg 82, 187-204.

Langendijk H, de Jong J, Wanders R, Lambin P, Slotman B (2003) The importance of pre-treatment haemoglobin level in inoperable non-small cell lung carcinoma treated with radical radiotherapy. Radiother Oncol 6, 321-5.

Lavey RS, Liu PY, Greer BE, Robinson WR 3rd, Chang PC, Wynn RB, Conrad ME, Jiang C, Markman M, Alberts DS (2004) Recombinant human erythropoietin as an adjunct to radiation therapy and cisplatin for stage IIB-IVA carcinoma of the cervix, a Southwest Oncology Group study. Gynecol Oncol 95, 145-51.

Lentz SS, Shelton BJ, Toy NJ (1998) Effects of perioperative blood transfusion on prognosis in early-stage cervical cancer. Ann Surg Oncol 5, 216-9.

Leyland-Jones B (2003) BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4, 459-60.

Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B; Epoetin Alfa Study Group (2001) Epoetin a Study Group. Effects of epoetin a 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, 2865-74.

Littlewood TJ, Nortier J, Rapoport B, Pawlicki M, de Wasch G, Vercammen E, Schuette W, Wils J, Freund M; Epoetin Alfa Study Group (2003) Epoetin a corrects anemia and improves quality of life in patients with hematologic malignancies receiving non-platinum chemotherapy. Hematol Oncol 21, 169-80.

Littlewood TJ, Zagari M, Pallister C, Perkins A (2003) Baseline and early treatment factors are not clinically useful for predicting individual response to erythropoietin in anemic cancer patients. Oncologist 8, 99-107.

Locatelli F, Del Vecchio L (2003) Pure red cell aplasia secondary to treatment with erythropoietin. J Nephrol 16, 461-6.

Ludwig H, Strasser K (2001) Symptomatology of anemia. Semin Oncol 28 (2 Suppl 8), 7-14.

Ludwig H, Van Belle S, Barrett-Lee P, Birgegard G, Bokemeyer C, Gascon P, Kosmidis P, Krzakowski M, Nortier J, Olmi P, Schneider M, Schrijvers D (2004) 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 40, 2293-306

Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE (1996) A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int 50, 1694-1699

Marti HH, Gassmann M, Wenger RH, Kvietikova I, Morganti-Kossmann MC, Kossmann T, Trentz O, Bauer C (1997) Detection of erythropoietin in human liquor, intrinsic erythropoietin production in the brain. Kidney Int 51, 416-8.

Martin SC, Gagnon DD, Zhang L, Bokemeyer C, Van Marwijk Kooy M, van Hout B (2003) Cost-utility analysis of survival with epoetin-a versus placebo in stage IV breast cancer. Pharmacoeconomics 21, 1153-69.

McKenzie SR, Heifetz LJ, Duh MS, et al (2002) Effectiveness of Epoetin a beyond Once-Weekly Dosing Schedules in the Oncology Community Practice Setting (abstract 5591). Blood 100, 501b-502b.

Meadowcroft AM, Gilbert CJ, Maravich-May D, Hayward SL (1998) Cost of managing anemia with and without prophylactic epoetin a therapy in breast cancer patients receiving combination chemotherapy. Am J Health Syst Pharm 55, 1898-902.

Miller CB, Platanias LC, Mills SR, Zahurak ML, Ratain MJ, Ettinger DS, Jones RJ (1992) Phase I-II trial of erythropoietin in the treatment of cisplatin-associated anemia. J Natl Cancer Inst 84, 98-103

Mirtsching B, Charu V, Vadhan-Raj S, Colowick AB, Rossi G, Tomita D, McGuire WP (2002) Every-2-week darbepoetin a is comparable to rHuEPO in treating chemotherapy-induced anemia. Results of a combined analysis. Oncology (Huntingt). 16(10 Suppl 11), 31-6.

Mittelman M, Neumann D, Peled A, Kanter P, Haran-Ghera N (2001) Erythropoietin induces tumor regression and anti-tumor immune responses in murine myeloma models. Proc Natl Acad Sci USA 98, 5181-86.

Möbus VJ, Untch M, du Bois A, Lueck HJ, Thomssen C, Kuhn W, Kurbacher C, Nitz U, Kreienberg R, Jackisch C (2004) Dose-dense sequential chemotherapy with epirubicin (E), paclitaxel (T) and cyclophosphamide (C) (ETC) is superior to conventional dosed chemotherapy in high-risk breast cancer patients (≥ 4 +LN). First results of an AGO-trial (abstract 513). J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (Suppl 15).

Munstedt K, Johnson P, Von Georgi R, Vahrson H, (2004) Adjuvant radiotherapy in carcinomas of the uterine cervix – The prognostic role of hemoglobin levels (abstract 5113). Proc Am Soc Clin Oncol 476s.

Nagai A, Nakagawa E, Choi HB, Hatori K, Kobayashi S, Kim SU (2001) Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. J Neuropathol Exp Neurol 60, 386-92.

Ng T, Marx G, Littlewood T, Macdougall I (2003) Recombinant Erythropoetin in Clinical Practice. Postgrad Med J 79, 367-376

Obermair A, Cheuk R, Horwood K, Janda M, Bachtiary B, Schwanzelberger B, Stoiber A, Nicklin JL, Perrin LC, Crandon AJ (2001) Impact of hemoglobin levels before and during concurrent chemoradiotherapy on the response of treatment in patients with cervical carcinoma, preliminary results. Cancer 92, 903-8.

Obermair A, Cheuk R, Horwood K, Neudorfer M, Janda M, Giannis G, Nicklin JL, Perrin LC, Crandon AJ (2003) Anemia before and during concurrent chemoradiotherapy in patients with cervical carcinoma, Effect on progression-free survival. Int J Gynecol Cancer 13, 633-9.

Obermair A, Handisurya A, Kaider A, Sevelda P, Kolbl H, Gitsch G (1998) The relationship of pretreatment serum hemoglobin level to the survival of epithelial ovarian carcinoma patients, a prospective review. Cancer 83, 726-31.

Okuno Y, Takahashi T, Suzuki A, Ichiba S, Nakamura K, Hitomi K, Sasaki R, Imura H (1990) Expression of the erythropoietin receptor on a human myeloma cell line. Biochem Biophys Res Commun 170, 1128-34.

O'Shaughnessy J, Vukelja S, Savin M, et al (2002) Impact of epoetin a on cognitive function, asthenia, and quality of life in women with breast cancer receiving adjuvant or neoadjuvant chemotherapy, analysis of 6-month follow-up data (abstract 550). Breast Cancer Res Treat 76 (suppl 1): S138.

Osterborg A, Brandberg Y, Molostova V, Iosava G, Abdulkadyrov K, Hedenus M, Messinger D; Epoetin Beta Hematology Study Group (2002) Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin b, in hematologic malignancies. J Clin Oncol 20, 2486-94.

Patton J, Reeves J, Walla J (2004) Effectiveness of darbepoetin a versus epoetin a in patients with chemotherapy-induced anemia treated in clinical practice. Oncologist 9, 451-8.

Pawlicki M, Jassem J, Bosze P, Lotan C, Kurteva GP, Siddiqui M, Kosmidis PA, Rigatos GA, Kansu E, Durkovic P, Aziz Z, Al Idrissi H, Roth A, Cozma G (1997) A multicenter study of recombinant human erythropoietin (epoetin a) in the management of anemia in cancer patients receiving chemotherapy. Anticancer Drugs. 8, 949-57.

Pedersen D, Sogaard H, Overgaard J, Bentzen SM (1995) Prognostic value of pretreatment factors in patients with locally advanced carcinoma of the uterine cervix treated by radiotherapy alone. Acta Oncol 34, 787-95.

Pronzato P, Cortesi E, van der Rijt C, et al (2002) Early intervention with epoetin a in breast cancer (BC) patients (pts) undergoing chemotherapy (CT, Results of a randomized, multicenter, phase IIIb study (EPO-INT-47 Study Group). Ann Oncol 13 (Suppl 5), 168

Quirt I, Robeson C, Lau CY, Kovacs M, Burdette-Radoux S, Dolan S, Tang SC, McKenzie M, Couture F; Canadian Eprex Oncology Study Group (2001) Epoetin a 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 19, 4126-34.

Rearden TP, Charu V, Saidman B, Ben-Jacob A, Justice GR, Manaim A. S, Tomita D, Rossi G (2004) Results of a randomized study of every three-week dosing (Q3W) of darbepoetin a for chemotherapy-induced anemia (CIA). J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (Suppl 15), 8064

Reichel O, Panzer M, Wimmer C, Duhmke E, Kastenbauer E, Suckfull M (2003) Prognostic implications of hemoglobin levels before and after surgery as well as before and after radiochemotherapy for head and neck tumors. Eur Arch Otorhinolaryngol 260, 248-53.

Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, Djulbegovic B, Goode MJ, Jakubowski AA, Lee SJ, Miller CB, Rarick MU, Regan DH, Browman GP, Gordon MS; American Society of Clinical Oncology. American Society of Hematology (2002) 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 20, 4083-107.

Rosenzweig MQ, Bender CM, Lucke JP, Yasko JM, Brufsky AM (2004) The decision to prematurely terminate a trial of R-HuEPO due to thrombotic events. J Pain Symptom Manage 27, 185-90

Savonije J, Van Groeningen C, Van Bochove A, Pinedo H, Giaccone G (2004) Early intervention with epoetin-a during platinum-based chemotherapy. J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S, 8111

Schagen SB, van Dam FS, Muller MJ, Boogerd W, Lindeboom J, Bruning PF (1999) Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 85, 640-50.

Schwartzberg L, Shiffman R, Tomita D, Stolshek B, Rossi G, Adamson R (2003) A multicenter retrospective cohort study of practice patterns and clinical outcomes of the use of darbepoetin aand epoetin afor chemotherapy-induced anemia. Clin Ther 25, 2781-96.

Schwartzberg L, Yee L, Senecal F, Charu V, Tomita D, Rossi G (2004) Darbepoetin a (DA) 200 mcg every 2 weeks (Q2W) vs epoetin a (Epo) 40,000 U weekly (QW) in anemic patients (pts) receiving chemotherapy (ctx) (abstract 8063). J Clin Oncol; Proc Am Soc Clin Oncol (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement)

Seidenfeld J, Piper M, Flamm C, Hasselblad V, Armitage JO, Bennett CL, Gordon MS, Lichtin AE, Wade JL 3rd, Woolf S, Aronson N (2001) Epoetin treatment of anemia associated with cancer therapy, a systematic review and meta-analysis of controlled clinical trials. J Natl Cancer Inst 93, 1204-14

Sepandj F, Jindal K, West M, Hirsch D (1996) Economic appraisal of maintenance parenteral iron administration in treatment of anaemia in chronic haemodialysis patients. Nephrol Dial Transplant 11, 319-322

Shasha D, George MJ, Harrison LB (2003) Once-weekly dosing of epoetin-a increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy. Cancer 98, 1072-9.

Sheffield R, Sullivan SD, Saltiel E, Nishimura L (2003) Cost comparison of recombinant human erythropoietin and blood transfusion in cancer chemotherapy-induced anemia. Ann Pharmacother 31, 15-22.

Silver DF, Piver MS (1999) Effects of recombinant human erythropoietin on the antitumor effect of cisplatin in SCID mice bearing human ovarian cancer, A possible oxygen effect. Gynecol Oncol 73, 280-4.

Sloan JA, Witzig T, Silberstein P (2002) Quality of Life, Blood Transfusions, and Toxicity, in Anemic Patients with Advanced Cancer Receiving Weekly Erythropoietin While on Chemotherapy, Results from a Phase III Randomized Double-Blind Placebo-Controlled Study (abstract 1103). Blood 100, 287a–287b.

Straus DJ (2002) Epoetin a as a supportive measure in hematologic malignancies. Semin Hematol 39 (Suppl 3), 25-31.

Tauer KW, Zhu L, Fortner BV (2004) The impact of anemia treatment visits on the patient and their caregiver (abstract 8114). J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S.

Thames WA, Smith SL, Scheifele AC, Yao B, Giffin SA, Alley JL (2004) Evaluation of the US Oncology Network's recommended guidelines for therapeutic substitution with darbepoetin a 200 microg every 2 weeks in both naïve patients and patients switched from epoetin a. Pharmacotherapy 24, 313-23.

Thatcher N, De Campos ES, Bell DR, Steward WP, Varghese G, Morant R, Vansteenkiste JF, Rosso R, Ewers SB, Sundal E, Schatzmann E, Stocker H (1999) Epoetin a prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer. Br J Cancer 80, 396-402.

Thews O, Koenig R, Kelleher DK, Kutzner J, Vaupel P (1998) Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br J Cancer 78, 752-6.

Thomas H, et al (2002) Early intervention with Epoetin a for treatment of anaemia and improvement of quality of life in cancer patients undergoing myelotoxic chemotherapy. Ann Oncol 13 (Suppl 5), 177

van Acht MJ, Hermans J, Boks DE, Leer JW (1992) The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal carcinoma. Radiother Oncol 23, 229-35.

van Dam FS, Schagen SB, Muller MJ, Boogerd W, vd Wall E, Droogleever Fortuyn ME, Rodenhuis S (1998) Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer, high-dose versus standard-dose chemotherapy (abstract. J Natl Cancer Inst 210-218.

Vansteenkiste J, Pirker R, Massuti B, Barata F, Font A, Fiegl M, Siena S, Gateley J, Tomita D, Colowick AB, Musil J; Aranesp 980297 Study Group (2002) Double-blind, placebo-controlled, randomized phase III trial of darbepoetin a in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 94, 1211-20.

Waltzman RJ, Fesen M, Justice GR, Croot C, Williams D (2004) Epoetin a 40,000 U QW vs darbepoetin a 200 mcg Q2W in anemic cancer patients receiving chemotherapy, Preliminary results of a comparative trial (abstract 8153). J Clin Oncol, ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement).

Wefel JS, Lenzi R, Theriault RL, Davis RN, Meyers CA (2004) The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma, results of a prospective, randomized, longitudinal trial. Cancer 100, 2292-9.

Wilkinson PM, et al (2001) Early intervention with epoetin a treats anaemia and improves quality of life in ovarian cancer patients undergoing chemotherapy (abstract 980). Eur J Cancer 37 (Suppl 6), S144.

Witzig TE, Silberstein PT, Loprinzi CL, Sloan JA, Novotny PJ, Mailliard JA, Rowland KM, Alberts SR, Krook JE, Levitt R, Morton RF (2004) Phase III, Randomized, Double-Blind Study of Epoetin a Versus Placebo in Anemic Patients With Cancer Undergoing Chemotherapy. J Clin Oncol, in press

Yasuda Y, Fujita Y, Matsuo T, Koinuma S, Hara S, Tazaki A, Onozaki M, Hashimoto M, Musha T, Ogawa K, Fujita H, Nakamura Y, Shiozaki H, Utsumi H (2003) Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 24, 1021-29

Trial	n	Design	Population	Results
RETROSPECTIVE
Glaser et al, 2001	191	Retrospective. Pts with a low Hb before or during CH-RT received r-HuEPO 10,000 IU/kg s.c. 3-6x week until surgery	Pts with SCC of the oral cavity or oropharynx treated with neoadjuvant CH-RT and surgery	On multivariate analysis, Hb level and use of r-HuEPO were independent prognostic factors for response to CH-RT and locoregional control (p < 0.01).
Littlewood et al, 2001 Littlewood et al, 2003	375	Placebo-controlled, double-blind, randomised (EPO-a vs placebo; 2:1). EPO-a 150 to 300 IU/kg 3xw (retrospective analysis)	Anaemic (<or= 10.5 g/dL, or > 10.5 g/dL but <or= 12 g/dL after a Hb ¯ of >or= 1.5 g/dL per cycle since starting CT) pts with solid or non-myeloid haematological malignancies receiving non-platinum CT	Kaplan-Meier estimates showed a trend in OS favouring EPO-a (P =.13, log-rank test), and Cox regression analysis showed an estimated hazards ratio of 1.309 (P =.052) favouring EPO-a
Sloan et al, 2002	344	Double-blind, placebo-controlled, randomised (EPO-a vs placebo). EPO-a 40,000 U qw	Pts with advanced cancer and with anaemia (Hb<11.5 g/dL and 10.5 g/dL for males and females, respectively) after receiving myelosuppressive CT	Tumour response and survival between the two groups were virtually identical (17% vs 20% response for EPO and placebo respectively, p=0.57; 7% vs 6% death rate at study completion respectively, p=0.65)
PROSPECTIVE, RANDOMISED, MULTICENTRE
Antonadou et al, 2001	385	RT ± r-HuEPO 10.000 U daily 5x/week	Pts with pelvic malignancies receiving RT	The addition of r-HuEPO to the treatment course of RT significantly improved 4-year DFS and local control
Henke et al, 2003	351	RT ± EPO-b	Anaemic (Hb <12g/dL for women and <13 g/dL for men) pts receiving radical RT for locally-advanced head and neck cancer	Significantly worse loco-regional control and survival in EPO-b arm; however, the design has been criticized
Leyland-Jones, 2003	939	CT ± EPO-a	Non-anaemic metastatic breast cancer pts receiving CT	Significantly worse one-year OS in EPO-a arm; however, the design has been criticized
Möbus et al, 2004	1284	CT ± EPO-a (2^nd randomisation)	Non-anaemic early breast cancer pts receiving adjuvant CT	No impact on DFS or survival
META-ANALYSES
Bohlius et al, 2004	2865	Meta-analysis of 19 randomised clinical trials (none designed to investigate survival as primary endpoint)	Anaemic pts receiving anti-cancer treatment (in 14 baseline Hb <10g/dL; in 2 between 10-12 g/dL,; in 3 Hb > 12 g/dL) In 9 studies the CT was platin-based, in 7 non-platin-based	Inconclusive effect of EPO on survival, but a trend for improved survival with the use of EPO was observed (HR 0.81;95% CI 0.67-0.99)

Trial	n	Design	Results
RANDOMISED TRIALS
Cazzola et al, 2003	241	Pts with lymphoproliferative disorders Randomised (EPO-b 10.000 U 3xw vs 30.000 U qw)	Comparable efficacy
Waltzman et al, 2004	First 123	Randomised (1:1), open-label, multicentre EPO-a 40000 U qw vs DA 200 mcg q2w; pts on CT	Preliminary results suggested that EPO-a may be slightly more active
Mirtsching et al, 2002	375	Pooled analysis of 3 DA trials	rHuEPO and DA were equality effective, but DA seemed to result in less BT requirements
Schwartzberg et al, 2004	312	Pooled analysis of 3 identical multicentre, prospective, randomised 1:1 (DA 200 mcg q2w or EPO-a 40000 U qw	No differences in efficacy and safety
Rearden et al, 2004	204	Randomised, prospective Early (immediate treatment) vs late intervention (when Hb dropped below 10 g/dL) Agent: DA 300 mcg q3w	Early intervention resulted in reductions in BTs and improved QOL
Thatcher et al, 1999	130	Multicentre, randomised (no additional treatment [n = 44], EPO-a 150 IU kg 3xw [n = 42] or 300 IU kg 3xw [n = 44]) Pts on CT	Significantly fewer (P < 0.05) EPO-a pts experienced anaemia (Hb <10 g/dL) during the course of CT (300 IU kg= 39%; 150 IU kg= 48%; untreated= 66%);
Hesketh et al, 2004	242	Randomised phase II (fixed or weight-based dose after a front-loading schedule)	Comparable efficacy
Granetto et al, 2003	546	Multicentre, open-label, randomised (EPO-a fixed vs weight-based dose)	Similar efficacy
RETROSPECTIVE AND PROSPECTIVE/NON-RANDOMISED STUDIES
McKenzie et al, 2002	1238	Retrospective, community-based analysis of pts receiving EPO-a 40000 U qw(50%), q2w(32%), or q3w or less frequently(17%)	Comparable efficacy
Schwartzberg et al, 2003	1391	Multicentre, retrospective cohort study (practice patterns of the use of DA-a and EPO-a for CT-induced anaemia)	Both agents seemed equally effective. Darbepoetin-a (q2w) has reduced frequency of dosing as compared to EPO-a (qw)
Patton et al, 2004	408	Retrospective, observational (practice patterns of the use of DA-a and EPO-a)	Comparable efficacy
Thames et al, 2004	330	Retrospective, multicentre chart review	DA-a is effective in treating CT-induced anaemia in both EPO-a-naïve pts and those switched from EPO-a
Gabrilove et al, 2001	3012	Community-based; multicentre, open-label, non-randomised. EPO-a 40,000 U 3xw; to 60,000 U 3x week depending on the Hb response at 4 weeks	Comparable efficacy (with that of a historical control arm)

Review Article

Received: 20 January 2005; Accepted: 28 January 2005; electronically published: February 2005

I. Introduction

References