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The=20 Oncologist, Vol. 7, No. 4, 331-341, August 2002
=A9 2002 AlphaMed= =20 Press

Managing Anemia in the Cancer Patient: Old Problems, Future = Solutions=20

Michael S. Gordon

Arizona Health Sciences Center, University of = Arizona, Phoenix,=20 Arizona, USA

Michael S. Gordon, M.D., Office of Research, Arizona Health Sciences = Center,=20 University of Arizona, 4001 North 3rd Street, Suite 415, Phoenix, = Arizona 85012,=20 USA. Telephone: 602-631-4610; Fax: 602-631-4611; e-mail: msgordon{at}u.arizona.edu


3D"    LEARNING OBJECTIVES=20
Top
3D"Learning Objectives
Abstract
Introduction
Impact of Anemia on...
Pathophysiology of Anemia in...
Managing Anemia
Future Approaches to Anemia...
Conclusions
References
 
A= fter=20 completing this course, the reader will be able to:

  1. Identify potential benefits for EPO therapy beyond those of=20 transfusions.
  2. Recognize the impact of EPO therapy on aspects of=20 health-related quality of life.
  3. Appreciate recent advances in the field of = hematopoietic=20 growth factor support as it relates to anemia=20 management.

Access and take the CME test online and receive one hour of = AMA=20 PRA category 1 credit at CME.TheOncologist.com =


3D"    ABSTRACT
Top
Learning Objectives
3D"Abstract
Introduction
Impact of Anemia on...
Pathophysiology of Anemia in...
Managing Anemia
Future Approaches to Anemia...
Conclusions
References
 
<= STRONG>Anemia=20 and associated symptoms commonly manifest in cancer patients = and may=20 have a considerable impact on outcomes. Preliminary studies = suggest=20 that overall survival and locoregional control following = radiation=20 therapy may be compromised by anemia, and recent preliminary = data=20 also suggest that anemia may be related to poorer outcomes = following=20 chemotherapy. Health-related quality of life of cancer = patients is=20 also significantly reduced by anemia. Treatment of anemia = with=20 recombinant human erythropoietin can improve these = health-related=20 quality-of-life outcomes. However, despite this knowledge, = anemia=20 remains under-recognized and under-treated in the cancer = patient=20 population. A number of issues may be determinants of this = suboptimal=20 management of anemia. These include limitations of current = therapies=20 for anemia, varying practice strategies, and the lack of = guidelines=20 on how to treat anemia. Additionally, clinicians may=20 underestimate the importance of health-related quality of = life for=20 their patients. It is vital that these issues are addressed, = which,=20 together with the development of novel erythropoietic agents, = a=20 review of the guidelines for anemia management, and = consideration=20 of further outcomes such as survival and cognitive function, = may=20 help to ensure that the cancer patient receives the best = possible=20 course of supportive care.

Key Words. Anemia =95 Cancer =95 Survival = =95 Quality of=20 life =95 Recombinant human erythropoietin =95 Darbepoetin alfa


3D"    INTRODUCTION
Top
Learning Objectives
Abstract
3D"Introduction
Impact of Anemia on...
Pathophysiology of Anemia in...
Managing Anemia
Future Approaches to Anemia...
Conclusions
References
 
T= he=20 optimal management of cancer patients is a complex and sensitive=20 issue. In recent times, emphasis has been placed on the = appropriate=20 treatment of cancer-related symptoms and the impact this can=20 have on patient quality of life and therapeutic outcomes. = Anemia=20 is a common complication of malignancy, occurring in over 50% = of patients [1].=20 It is defined as an inadequate circulating level of = hemoglobin or=20 RBCs, and may arise as a result of the underlying disease,=20 chemotherapy, or radiation therapy [2].=20 Anemia is associated with its own set of debilitating signs = and=20 symptoms and can have a significant effect on morbidity and=20 mortality, as well as on the level of care that patients = require.=20 Despite this knowledge, anemia may not be optimally managed = in the=20 cancer patient population.

The underlying issues that contribute to this suboptimal care = may=20 be related to the failure of many clinicians to recognize the = impact=20 that anemia has on the lives of their patients and the = inadequacies=20 of current treatment options. However, the continuing = development of=20 novel erythropoietic agents [3],=20 progress in defining parameters to better predict a = patient=92s=20 response to anemia treatment [4,5],=20 along with emerging data that consider the effect of anemia = on end=20 points such as survival and cognitive function [6,7],=20 may help to overcome these issues. Such initiatives suggest a = promising future for the optimal management of anemia in the = cancer=20 patient.

The impact of anemia on cancer patients, its pathophysiology = in=20 cancer, and strategies for anemia treatment are reviewed in = this=20 article, with the aim of raising awareness about current = knowledge=20 and practice. Future approaches for research and management = of anemia=20 in cancer patients are also discussed to encourage = understanding of=20 how these activities can be improved and the implications = this may=20 have for patient and clinician alike.


3D"    IMPACT OF ANEMIA ON THE = CANCER PATIENT=20
Top
Learning Objectives
Abstract
Introduction
3D"Impact of Anemia = on...
Pathophysiology of Anemia in...
Managing Anemia
Future Approaches to Anemia...
Conclusions
References
 
<= STRONG>Treatment=20 and Clinical Outcomes
As will be discussed later in this = article, it=20 is well established that patients with anemia may experience = reduced=20 health-related quality of life (HRQOL) as a result of the = often=20 debilitating symptoms of anemia, and that raising hemoglobin = with=20 erythropoietic proteins can improve HRQOL [8=9611].=20 However, recent studies suggest that there may be additional=20 consequences of anemia, which if proven, may necessitate = revision of=20 the way patients with cancer are managed. Results from both=20 prospective and retrospective studies in patients with head = and neck=20 cancer undergoing radiation therapy or combined modality = therapy have=20 indicated that anemia may be associated with decreased = overall=20 survival and reduced locoregional control [12=9619].=20 For example, in a large study of 451 patients with stage III = or IV=20 squamous cell carcinoma of the head and neck who were = undergoing=20 concurrent radiation therapy with or without etanidazole = treatment,=20 162 patients were considered to have a normal hemoglobin = level (=3D" src=3D"http://theoncologist.alphamedpress.org/math/ge.gif" = border=3D0>14.5=20 g/dl for men and 3D"=3D"=20 src=3D"http://theoncologist.alphamedpress.org/math/ge.gif" = border=3D0>13.0 g/dl for=20 women) and 289 patients were classified as anemic [12].=20 As shown in Figure 1, which illustrates rates of = survival and=20 locoregional failure over time in patients with normal and = low=20 hemoglobin levels, respectively, the estimated 5-year = survival rates=20 were 35.7% and 21.7%, respectively (p =3D 0.0016), and = estimated=20 5-year locoregional failure rates were 51.6% versus 67.8% = (p =3D=20 0.00028).



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  		Figure 1. = Overall=20 survival (A) and locoregional failure (B) according to = hemoglobin=20 level in a prospective study of 451 patients with advanced = head and=20 neck cancer treated with radiation therapy. = Reprinted=20 with the permission of Elsevier Science from Lee et = al. [12]. =

 = ;
It=20 has also been suggested that anemia may be an independent = prognostic=20 factor in cancer patients undergoing radiation therapy [12,14,15].=20 Dubray et al. presented data from multivariate analyses = that=20 indicated that a pretreatment hemoglobin level of <13.5 = g/dl in=20 men and <12 g/dl in women was one of several factors that = were=20 independently predictive of an increased relative risk of = 2-year=20 locoregional failure and death (relative risk of locoregional = failure=20 and death for anemic patients: 1.6 [p =3D 0.06] and = 1.7=20 [p =3D 0.04], respectively) [14].=20 Similarly, Warde et al., in a retrospective analysis, = found=20 evidence that pretreatment hemoglobin level was one of = several=20 independent prognostic factors for local failure after = radiation=20 therapy [15].=20 For example, the hazard ratio for a hemoglobin level of 12 = g/dl=20 versus a hemoglobin level of 15 g/dl was 1.8 (95% confidence=20 interval 1.2-2.5).

Although the most extensive pool of results on the effect of=20 anemia on treatment and clinical outcomes exists for patients = with head and neck cancer, data for other tumor types are = available.=20 One study in rectal cancer patients has recently indicated = that=20 anemia (hemoglobin <11 g/dl) may reduce overall survival=20 after combined therapy [20].=20 A retrospective study in ovarian cancer patients indicated = that a=20 pretreatment hemoglobin value <12 g/dl was an independent=20 prognostic factor for patients with stage I and II disease, = but the=20 association did not reach statistical significance in = patients with=20 stage III and IV disease [21].=20 A study of patients with cancer of the cervix has additionally=20 suggested that an average weekly nadir hemoglobin level of = <12=20 g/dl may be associated with inferior radiation therapy = outcomes=20 compared with a hemoglobin level 3D"=3D"=20 src=3D"http://theoncologist.alphamedpress.org/math/ge.gif" border=3D0>12 = g/dl [22].=20

The underlying mechanism by which anemia affects treatment and=20 clinical outcomes may be related to the degree of tumor = oxygenation,=20 since studies have indicated that hypoxia may have an adverse = effect on the radiosensitivity of cells [18,23].=20 However, while anemia can be an underlying cause of decreased = tumor=20 oxygenation, tumor hypoxia is a multifactorial process, and=20 compensatory mechanisms may reduce the effect of anemia. For = example,=20 in a study of 63 head and neck cancer patients, tumor hypoxia = was shown to adversely influence prognosis, and while there = was=20 a weak association between anemia and poorly oxygenated = tumors,=20 many nonanemic patients had hypoxic tumors [24].=20

Although evidence is beginning to accumulate suggesting that=20 hemoglobin level may influence local control and survival = following=20 radiotherapy, other factors that may be related to anemia and = which may affect outcomes need further investigation. Tumor=20 size, for example, is known to play a significant role in the = prognosis of cancer. A study in cervical cancer patients has=20 indicated that those with bulky hypoxic tumors had a = significantly=20 lower chance of disease-free survival (12% at 2 years) than=20 those with either bulky oxygenated or nonbulky = oxygenated/hypoxic=20 tumors (65%, p =3D 0.0001) [25].=20 Hemoglobin levels before and during treatment have been = strongly=20 correlated with tumor size, and it has been suggested that = this may=20 explain the impact of anemia on prognosis in earlier studies = that did=20 not record tumor bulk [23].=20 In addition, it is possible that, in patients who have a = worse=20 prognosis and who are less likely to respond to therapy, = anemia=20 simply occurs more often and is only a marker of poorer = outcome=20 rather than a cause. Furthermore, it is not yet clear at = which time=20 point hemoglobin level may have predictive value for = outcomes. In=20 three separate studies carried out in patients with head and = neck=20 cancer receiving radiation therapy, pretreatment and = end-of-treatment=20 hemoglobin levels have been reported to be of clinical = significance=20 [16,17,19].=20

It is apparent that a complex relationship exists among anemia,=20 hypoxia, and treatment/clinical outcomes, however, we are = still=20 a long way from understanding this relationship [23].=20 Further investigation of anemia as an independent prognostic=20 factor is required, along with randomized trials to determine = the=20 effect of anemia correction on clinical outcomes. These = studies=20 will help to conclusively determine whether there is an=20 association among inadequate hemoglobin level, locoregional = control,=20 and survival.

Whether anemia may have an impact on cancer patients receiving=20 chemotherapy alone is another largely unaddressed issue. A=20 retrospective analysis conducted as part of a recently = reported=20 multicenter study has presented preliminary evidence that = treatment=20 of anemia may improve survival, although the results must be=20 interpreted with caution, as the trial was not designed or = powered to=20 measure this end point [6].=20 Three hundred seventy-five patients with solid tumors or = nonmyeloid=20 hematologic malignancies receiving nonplatinum-based = chemotherapy=20 were assessed. Median survival time for patients who received = three-times-weekly recombinant human erythropoietin (rHuEPO) = was 17=20 months compared with 11 months for those who received = placebo.=20 Kaplan-Meier 12-month estimates of survival were 60% for = patients=20 receiving rHuEPO and 49% for those on placebo, suggesting a = possible=20 favorable trend in overall survival for rHuEPO, although the=20 difference was not statistically significant (p =3D = 0.13). Cox=20 regression analysis, to control for factors such as age, = tumor type,=20 and baseline hemoglobin and neutrophil levels, also favored=20 survival in the rHuEPO-treated group, although the difference = was=20 again not statistically significant (p =3D 0.052). = While these=20 results may appear promising, it should be noted that this = study=20 was not powered with respect to survival and, therefore, did = not=20 measure or stratify by variables that can influence survival, = such as disease stage, bone marrow involvement, intensity of=20 chemotherapy, and disease progression. Nevertheless, the = possibility=20 that correction of anemia can convey a survival benefit in = cancer=20 patients receiving chemotherapy deserves further = investigation.=20

HRQOL Outcomes
Quality of life is a subjective = and=20 multidimensional concept that includes functional ability and = emotional and social well-being, as influenced by disease, = its=20 symptoms, and treatment side effects [8].=20 Cancer-related anemia is associated with a whole host of = symptoms=20 that include dyspnea, tachycardia, fatigue, dizziness, = depressive=20 moods, menstrual problems, loss of libido, anorexia, nausea, = and=20 sleeping disorders [1,26].=20 The occurrence and severity of symptoms in individual = patients can=20 vary considerably and may be influenced by the degree of = anemia and=20 how rapidly it develops, the underlying malignancy, pulmonary = and=20 cardiovascular function, as well as nutritional status. =

The negative impact of anemia and related manifestations on = the=20 HRQOL of cancer patients is now well documented, and a number = of=20 studies have highlighted the potential benefit of treating = anemia on=20 HRQOL [6,9=9611,27].=20 The development of specialized tools to measure the effect of = anemia=20 and associated symptoms on HRQOL has also greatly aided this=20 research.

The Functional Assessment of Cancer Therapy-Anemia (FACT-An) = and=20 FACT-Fatigue (FACT-F) tools were designed and validated to = assess the=20 impact of anemia, fatigue, and other associated symptoms on = the=20 cancer patient [8,28].=20 These patient questionnaires were developed from the = FACT-General=20 scale but contain additional assessment items. Table 1 shows the FACT-An subscale items, = with the=20 separate fatigue and nonfatigue components of the questionnaire.=20 Analysis of scores for physical and functional well-being, as = well as for the fatigue and nonfatigue components of the = FACT-An=20 subscale, has clearly differentiated between patients with = low=20 and high hemoglobin levels [8,29].=20 Those with lower hemoglobin levels (3D"<=3D"=2012 = g/dl) had=20 lower scores and, therefore, reduced HRQOL compared with = patients who=20 had hemoglobin levels >12 g/dl, which is shown in Figure = 2 for the physical and functional = well-being=20 subscales and the fatigue and nonfatigue items. The ability = to=20 work has also been correlated with hemoglobin levels; in a = survey of=20 50 patients, one in four with hemoglobin levels 3D"<=3D"=2012 = g/dl=20 reported that they could not work at all [29].=20


View = this=20 table:
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  		Table 1. The FACT-An = subscale items=20 =
 


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  		Figure 2. = FACT-An=20 subscale physical and functional well-being scores (A) and = FACT-An=20 subscale fatigue and nonfatigue scores (B) according to low = (12 g/dl) and high (3D"=3D"=20 src=3D"http://theoncologist.alphamedpress.org/math/ge.gif" = border=3D0>12=20 g/dl) hemoglobin levels in cancer patients. A = higher=20 score represents higher well-being in A and lower levels of = fatigue=20 in B. Reprinted with the permission of W.B. Saunders & = Company=20 from Cella et al. [8]. =

 = ;
Fatigue,=20 often described by patients as a feeling of tiredness, = weakness, or=20 lack of energy, has been suggested to be one of the most = common=20 symptoms of cancer and cancer therapy. It can be a = distressing=20 condition and can have serious adverse effects on HRQOL [30].=20 Curt et al. have reported that, in a survey of 379 = cancer=20 patients, 91% of subjects stated that fatigue prevented them = from=20 having a "normal life" [31].=20 Anemia often contributes to fatigue; in a group of patients = split by=20 hemoglobin level, those with hemoglobin >12 g/dl reported=20 significantly less fatigue [8].=20 However, it should be noted that a recent study by Cella = et=20 al. indicated that a significantly lower percentage of = patients=20 (17%) may have experienced cancer-related fatigue, as opposed = to=20 general fatigue due to overexertion or lack of sleep, than = previously=20 estimated (60%-90%) [32].=20 It is worth noting, however, that in the group of patients = reporting=20 cancer-related fatigue (17%), the majority had completed = treatment=20 more than a year previously, and fatigue in this group was = assessed=20 using a set of stringent, formal diagnostic criteria. This is = in=20 contrast to the studies estimating a 60%-90% prevalence, = which were=20 not necessarily based on formal diagnostic criteria and = usually=20 estimated the prevalence of any fatigue at any time, usually=20 during treatment.

As anemia, fatigue, and other related symptoms can have such = a=20 profound effect on patients=92 HRQOL, numerous studies have = been=20 conducted to address how treatment of anemia with rHuEPO = impacts on=20 HRQOL [6,10,11,27].=20 Evidence from three large community-based trials has provided = data=20 indicating that patients=92 HRQOL can significantly improve = following=20 treatment of anemia [10,11,27].=20

Glaspy et al. and Demetri et al., in their respective=20 studies, analyzed over 4,000 patients with malignancies = undergoing=20 chemotherapy and receiving rHuEPO three times per week [10,11].=20 As measured by the Linear Analog Scale Assessment (LASA), a=20 significant correlation was demonstrated between improvements = in=20 HRQOL and increases in hemoglobin levels from baseline. = Energy,=20 activity level, and overall quality of life scores all = improved,=20 and transfusion use was shown to decrease. Importantly, it = was=20 shown that HRQOL improved regardless of whether patients=20 exhibited a complete or partial tumor response or had stable=20 disease. Glaspy et al. even reported a significant = improvement=20 in energy levels in patients who had progressive = disease.

In the study by Demetri et al., HRQOL assessment using the=20 FACT-An subscale was also performed [11].=20 Similar to results using the LASA, their findings showed that = HRQOL=20 improved in correlation with hemoglobin and that those who = achieved a=20 mean increase in hemoglobin of 2 g/dl or greater had the = largest=20 increase in HRQOL. Interestingly, patients who experienced a=20 hemoglobin change of <2 g/dl also had a significant = increase in=20 FACT-An total score when tumor response was complete, = partial, or=20 stable, as shown in Figure 3. A separate analysis of the data from the = Glaspy et al. [10]=20 and Demetri et al. [11]=20 studies noted that the largest incremental gains in HRQOL = occurred=20 when hemoglobin increased from 11 to 12 g/dl [33],=20 which highlights the potential importance of detecting and = treating=20 even mild anemia.



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  		Figure 3. = Analysis of=20 HRQOL parameters (assessed by FACT-An) based on changes in=20 hemoglobin levels and tumor response from baseline to final=20 assessment, in a study of 2,289 patients with nonmyeloid=20 malignancies receiving chemotherapy and rHuEPO = treatment.=20 *Significantly different from baseline (p < = 0.01); significantly different from adjacent hemoglobin = change=20 group (p < 0.01); 3D{ddagger}=20significantly different from adjacent hemoglobin = change=20 group (p < 0.05). Reprinted with the permission of = Lippincott, Williams & Wilkins from Demetri et = al. [11]. =

 = ;
In=20 the third, large, community-based study, Gabrilove et al.=20 prospectively evaluated the effectiveness and clinical = benefits=20 of once-weekly rHuEPO [27].=20 Improvements in HRQOL were shown to correlate significantly = (p=20 < 0.001) with increased hemoglobin levels, and transfusion = requirements were decreased with this less frequent dosing = regimen.=20 Littlewood et al. have additionally studied HRQOL and=20 hemoglobin levels in a placebo-controlled trial of patients = with=20 solid or nonmyeloid hematologic malignancies undergoing = chemotherapy=20 and receiving rHuEPO three times per week [6].=20 Changes in energy level, ability to do daily activities, and = fatigue=20 were all associated with an elevation in hemoglobin level. In = a=20 recent analysis of data from two clinical trials of patients = with=20 solid tumors undergoing chemotherapy and receiving a novel=20 erythropoiesis-stimulating protein, darbepoetin alfa, a = positive,=20 although small, correlation was demonstrated between fatigue = score on=20 the FACT-F subscale and change in hemoglobin (r =3D = 0.19;=20 p =3D 0.002) [34].=20 An increase in hemoglobin of 3D"=3D"=20 src=3D"http://theoncologist.alphamedpress.org/math/ge.gif" border=3D0>2 = g/dl=20 resulted in a mean improvement in FACT-F score of 4.0 points. = While these latter results suggest that increased hemoglobin=20 level may correlate with improvement in patient-reported = fatigue,=20 other factors may also cause changes in fatigue levels, such = as=20 the disease itself, anticancer therapy, depression, anxiety, = or even=20 sleep deprivation [31].=20


3D"    PATHOPHYSIOLOGY OF ANEMIA = IN CANCER
Top
Learning Objectives
Abstract
Introduction
Impact of Anemia on...
3D"Pathophysiology of Anemia = in...
Managing Anemia
Future Approaches to Anemia...
Conclusions
References
 
I= t is=20 clear from the presented evidence that anemia is a common = occurrence=20 in cancer patients and has a significant impact on clinical = and HRQOL=20 outcomes. It is, therefore, important to understand the = underlying=20 etiology of anemia in cancer in order to provide the correct = and most=20 effective treatment for individual patients.

Factors including the type and stage of malignancy, duration = of=20 tumor growth, regimen and intensity of chemotherapy or radiation=20 therapy, and complications of treatment, such as infection or = sepsis, may contribute to the development of anemia [1,35].=20 A high incidence of anemia (50%-60%) occurs in patients with=20 lymphomas, multiple myeloma, lung tumors, and gynecologic or=20 genitourinary tumors, and while the occurrence of anemia in=20 patients with solid tumors is less than that observed for=20 hematological malignancies, incidence of mild-to-moderate = anemia can=20 be high [1,26,35].=20 Platinum-based therapies are also known to be associated with = a high=20 incidence of anemia, which may help to explain the frequency = of=20 anemia in lung and ovarian cancer patients who regularly = receive such=20 treatment.

Multiple underlying mechanisms can contribute to the development = of anemia in the cancer patient. Bone marrow replacement may = be=20 a direct effect of cancer. Metastases within the bone marrow = can lead=20 to displacement and destruction of progenitor cells, = disrupting the=20 microenvironment as well as the production of mature=20 erythroid-lineage cells [1,36].=20 Anemia associated with chronic disease is also an extremely = common=20 manifestation in cancer patients [1].=20 Current thinking suggests this is a largely cytokine-mediated = disorder, and that tumor interaction with the immune system = leads to=20 overproduction of inflammatory cytokines such as = interleukin-1 and=20 tumor necrosis factor-3D{alpha}=20. These=20 cytokines can impair erythroid colony formation in response = to=20 erythropoietin (EPO), decrease the life span of erythrocytes, = impede=20 EPO production, and prevent the normal utilization of iron = [37,38].=20

Chemotherapy can cause or exacerbate anemia in cancer patients = by=20 reducing EPO production or sensitivity to this hormone and = damaging=20 or destroying progenitor and mature hematopoietic cells, = while=20 radiation therapy causes bone marrow damage. Blood loss and=20 nutritional deficiencies may additionally contribute to = anemia in=20 cancer patients [1].=20


3D"    MANAGING ANEMIA=20
Top
Learning Objectives
Abstract
Introduction
Impact of Anemia on...
Pathophysiology of Anemia in...
3D"Managing = Anemia
Future Approaches to Anemia...
Conclusions
References
 
A= lthough=20 there is a large body of data describing the negative = outcomes of=20 anemia in cancer patients, and information on the etiology of = anemia=20 is accumulating, the question remains as to how to optimally = treat=20 anemia, and management of this condition remains a = controversial=20 subject. For example, at a debate on the use of rHuEPO held = at the=20 annual meeting of the European Society for Medical Oncology = in=20 October 2000, 40% of the audience, comprising largely = Europeans,=20 indicated that they did not use rHuEPO to treat anemia at all = [39].=20 In a U.S. community practice study, Lawless et al. = have also=20 reported that 52%-70% of cancer patients, with a range of = tumor=20 types, were not administered rHuEPO therapy despite being = anemic [40].=20

As discussed, limitations in current therapies for anemia, which = include RBC transfusions, iron supplementation, and rHuEPO,=20 lack of global guidelines for treatment, and an = underappreciation=20 of the impact of anemia may contribute to this situation. It = is=20 critical that these factors be addressed and that emerging = and future=20 approaches are incorporated into clinical practice to = maximize the=20 future treatment of anemia in the cancer patient.

RBC Transfusions
RBC transfusions provide = immediate=20 correction of anemia, which is of particular value in = patients with=20 life-threatening anemia. However, transfusions have been = associated=20 with a number of risks, and although the introduction of = stringent=20 screening programs has greatly increased their safety, some = hazards=20 still remain. These include immunosuppression, which may = enhance=20 tumor growth, adverse hemolytic reactions, infection, and=20 alloimmunization [2,26].=20 Additionally, some patients may be reluctant to undergo = transfusions=20 on personal, religious, or logistical grounds.

Despite these drawbacks, RBC transfusions will still find = application=20 for cancer patients who are anemic due to bone marrow = infiltration=20 or damage to hematopoietic precursor cells, or who are = unresponsive=20 to rHuEPO therapy. Definitive studies investigating any = potential=20 benefits of transfusions on HRQOL are also required.

Recombinant Human Erythropoietin
The introduction = of=20 rHuEPO as a treatment option represented a significant = advance in the=20 treatment of anemia. rHuEPO can increase erythrocyte and = hemoglobin=20 levels, and therefore, alleviate the symptoms of anemia while = reducing patients=92 requirements for blood transfusions [10,11,41=9643].=20 It also has been shown to be safe and well tolerated and is=20 associated with very few side effects in cancer patients with = a range=20 of tumor types receiving varying chemotherapy/radiation = therapy=20 regimens.

A study by Abels analyzed 413 patients receiving either no=20 chemotherapy (n =3D 124), cyclic noncisplatin = chemotherapy=20 (n =3D 157), or cyclic cisplatin-containing = chemotherapy=20 (n =3D 132) [42].=20 Those in the =91no chemotherapy=92 group received 100 U/kg = rHuEPO=20 three times per week for 8 weeks, while those in the latter = two=20 groups received 150 U/kg rHuEPO three times per week for 12 = weeks. In=20 all three groups, mean weekly hematocrit levels remained = stable among=20 the placebo-treated patients but increased progressively in = those=20 receiving rHuEPO, as shown in Figure 4. The mean proportion of patients transfused = and mean=20 number of RBC units transfused decreased for all three rHuEPO = treatment groups compared with placebo.



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  		Figure 4. = Change in=20 hematocrit levels from baseline to last value in a study of = cancer=20 patients receiving rHuEPO with or without = chemotherapy.=20 *Significantly (p < 0.004) greater than = placebo.=20 Adapted from [42]. =

 = ;
However,=20 rHuEPO therapy has been associated with moderate response = rates=20 (50%-60%) and slow time to response. In addition, it is = difficult to=20 predict which patients will respond. It has been shown, in = one cohort=20 of patients, that median time to response was approximately 4 = weeks,=20 but it can take up to 12 weeks to determine responsiveness = [44].=20 Such long-term treatment and monitoring of patients can be = expensive=20 and represents a burden, especially if the patient ultimately = fails=20 to respond to treatment, as happens in 40%-50% of cases. The=20 inconvenience of three-times-weekly dosing schedules may also = be a=20 consideration for some patients and clinicians [44],=20 although the study by Gabrilove et al. in the U.S. = recently=20 has shown that once-weekly dosing of rHuEPO is safe and = effective [27].=20

Data on useful predictive parameters for response are emerging.=20 For example, studies have indicated that patients with = relatively=20 high levels of EPO before treatment are less likely to = respond=20 to rHuEPO [45,46].=20 The combination of baseline EPO level and the increase in = hemoglobin=20 or transferrin receptor after 2 weeks of therapy with rHuEPO = has also=20 been suggested as a good predictor of response [4].=20 Ultimately, whichever parameters prove to be the most = accurate and=20 useful, it is extremely important that predictive algorithms = are=20 developed that utilize easily measurable factors [47].=20

Darbepoetin alfa
Darbepoetin alfa=20 (ARANESPTM; Amgen Inc.; Thousand Oaks, CA) = is a=20 novel erythropoiesis-stimulating protein that is currently = undergoing=20 trials in cancer patients and may confer benefits in the = treatment of=20 anemia. Darbepoetin alfa was developed to contain two = additional=20 sialic acid-containing carbohydrate side chains compared with = rHuEPO=20 [3].=20 It binds to the EPO receptor, stimulates erythropoiesis, and, = in=20 preclinical studies and trials involving patients with = chronic kidney=20 disease, it has been shown to have a two to three times = longer serum=20 half-life than rHuEPO [3,48].=20 Darbepoetin alfa has undergone extensive testing in the renal = disease=20 setting and has recently been approved for use in chronic = kidney=20 disease in both the U.S. and Europe.

The half-life of subcutaneously administered darbepoetin alfa = in=20 cancer patients receiving chemotherapy is over 40 hours [49].=20 In phase I, II, and III clinical studies to date, over 1,000=20 cancer patients have received darbepoetin alfa, and it was = effective=20 and well tolerated, with an adverse event profile consistent=20 with that for cancer patients and comparable with that = observed=20 for rHuEPO [50=9653].=20 Administration of darbepoetin alfa at intervals of once every = 1, 2,=20 or 3 weeks increased hemoglobin levels and reduced the = requirement=20 for RBC transfusions in patients with lymphoproliferative=20 malignancies or solid tumors undergoing multicycle = chemotherapy [50=9654].=20 Additionally, in patients with chronic anemia of cancer not = receiving=20 chemotherapy, once-weekly darbepoetin alfa at doses of 1.0, = 2.25, and=20 4.5 =B5g/kg demonstrated efficacy in eliciting a hemoglobin = response=20 (increase 3D"=3D"=20 src=3D"http://theoncologist.alphamedpress.org/math/ge.gif" border=3D0>2 = g/dl) in=20 68%, 66%, and 92% of patients, respectively [55].=20

Darbepoetin alfa administered every 2 weeks also appears to = be as=20 effective as darbepoetin alfa administered weekly, according = to=20 results from a study in anemic (hemoglobin 3D"<=3D"=2011 = g/dl)=20 patients with solid tumors receiving multicycle chemotherapy = [50].=20 The percentages of patients achieving a hematopoietic = response=20 (hemoglobin level 3D"=3D"=20 src=3D"http://theoncologist.alphamedpress.org/math/ge.gif" border=3D0>12 = g/dl or a=20 hemoglobin increase 3D"=3D"=20 src=3D"http://theoncologist.alphamedpress.org/math/ge.gif" border=3D0>2 = g/dl) in the=20 cohorts receiving darbepoetin alfa once weekly at 1.5 =B5g/kg = or=20 4.5 =B5g/kg were 53% and 84%, respectively. Similarly, = respective=20 response rates of 66% and 84% were observed with darbepoetin=20 alfa given once every 2 weeks at 3.0 =B5g/kg or 9.0 =B5g/kg. = Blood=20 transfusion rates were also comparable between patients = assigned=20 once-weekly and once-every-2-weeks treatment. Additionally, = in this=20 and in separate trials, efficacy and rapidity of response = appears to=20 increase with higher doses of darbepoetin alfa [50=9652].=20

Importantly, these data indicate that darbepoetin alfa has the=20 potential to be dosed less frequently, which could simplify=20 anemia management for patients and physicians alike and = reduce=20 the burden on health care resources. Furthermore, results = from=20 a phase III trial involving lung cancer patients receiving=20 chemotherapy and once-weekly darbepoetin alfa suggest that = median=20 time to disease progression may be increased for small-cell = lung=20 cancer patients receiving darbepoetin alfa compared with = placebo=20 (33 weeks versus 23 weeks, respectively) [54];=20 however, this relationship was not observed in non-small cell = lung=20 cancer patients. Darbepoetin alfa impacted positively on RBC=20 transfusion requirements, with 26% of the darbepoetin alfa = cohort and=20 60% of the placebo cohort receiving transfusions over the = course of=20 the study. Data from this study also suggested patients = administered=20 darbepoetin alfa spent fewer days in hospital compared with = placebo=20 (mean number of days hospitalized [standard deviation]: 10.3=20 [13.5] days versus 13.0 [17.7] days, respectively) and that=20 significantly more darbepoetin alfa recipients had a 3D"=3D"=20 src=3D"http://theoncologist.alphamedpress.org/math/ge.gif" = border=3D0>10% increase=20 in FACT-F scale score relative to placebo recipients (42% = versus=20 28%, respectively, p =3D 0.023). Studies of = darbepoetin alfa in=20 the oncology setting are ongoing and should provide = additional=20 data on the potential advantages of this novel agent in the=20 cancer patient population.

Complicating Factors
Potentially, a number of = factors may=20 complicate the treatment of anemia and outline the need for = further=20 research and the development of treatment guidelines. For = example,=20 functional iron deficiency, a suboptimal mobilization of iron = despite=20 the presence of adequate iron stores, is the most common = cause=20 of inadequate response to rHuEPO in chronic renal failure=20 patients [56].=20 There is a real possibility that this underutilization of = iron may=20 also inhibit the response to rHuEPO therapy in cancer = patients.=20 Parameters that appropriately measure iron deficiency or = predict the=20 development of iron deficiency are not clearly defined, and = the most=20 appropriate method for iron supplementation is uncertain [47,56].=20 However, increasing recognition of this problem and debate = and=20 further research into iron metabolism will aid in the = definition of=20 the best way to approach functional iron deficiency in cancer = patients with anemia [57].=20 While iron may be delivered orally or intravenously, recent = research=20 suggests that the latter route provides a better source of = iron in=20 deficiency, as it can meet the required rate of iron delivery = in=20 rHuEPO-stimulated erythropoiesis [56].=20 Aggressive iron supplementation has led to substantial = reductions in=20 rHuEPO doses in hemodialysis patients [47],=20 and this fact may have important cost implications if it = holds true=20 in the oncology setting.

The question of when to treat anemia also deserves = consideration.=20 Currently there are no universally accepted guidelines for = managing=20 anemia, and treatment practices may differ among hospitals,=20 regions, and countries, adding to the confusion and = ultimately=20 leading to the suboptimal treatment of anemia. The = appropriate=20 hemoglobin levels at which to initiate therapy, stop = treatment,=20 or increase dose are also controversial, and gender = differences=20 are often ignored [1,58].=20 Additionally, questions remain as to whether = anemia-associated=20 symptoms and their severity should be considered in the = diagnosis of=20 the condition, whether patients are sufficiently monitored = for=20 anemia, and whether patients are considered on an individual = basis=20 [59].=20 Guideline development and specification of treatment criteria = and end=20 points are ongoing and should provide support for the future=20 optimization of anemia management.


3D"    FUTURE APPROACHES TO ANEMIA MANAGEMENT=20
Top
Learning Objectives
Abstract
Introduction
Impact of Anemia on...
Pathophysiology of Anemia in...
Managing Anemia
3D"Future Approaches to = Anemia...
Conclusions
References
 
W= hile many=20 clinicians may be aware to some degree that anemia is = associated with=20 reduced HRQOL and possibly poorer treatment outcomes = following=20 radiation therapy, knowledge and understanding of recent and = emerging=20 data are also vital. Further end points and outcomes of = anemia in=20 cancer patients are currently being explored and, although = data are=20 currently only preliminary, these end points may prove to be=20 significant in the management of anemia.

Possible Survival Benefit of Treating Anemia in Patients With = Cancer
As previously described, preliminary evidence = suggests=20 that anemia may impact on radiation therapy outcomes. = However,=20 Littlewood et al. have very recently reported a = possible=20 survival benefit in patients treated with rHuEPO and = chemotherapy,=20 although as previously mentioned, these data are preliminary = and=20 require confirmation [6].=20 Similarly, preliminary data from trials of darbepoetin alfa = in=20 small-cell lung cancer patients receiving platinum-based = chemotherapy=20 suggest that median time to disease progression may be = decreased with=20 improvement of anemia [54].=20 However, further research into the survival benefit of = treating=20 anemia in cancer patients is required to support these data. =

It has also been suggested that anemia may stimulate = tumor-associated=20 angiogenesis via hypoxia, as increased levels of vascular = endothelial=20 growth factor (VEGF), a factor contributing to increased = angiogenesis=20 and, thus, tumor growth, have been detected in the serum of=20 anemic cancer patients [60].=20 Twenty-six patients with low hemoglobin levels (<13 g/dl) = had=20 raised serum VEGF compared with 28 patients with hemoglobin = levels=20 >13 g/dl (805 =B1 656 pg/ml versus 438 =B1 360 pg/ml, = respectively;=20 p =3D 0.016). Several other factors, including total = tumor=20 volume and platelet counts, were also found to correlate with = elevated serum VEGF levels, suggesting that lowered = hemoglobin levels=20 may only partially explain the upregulation of VEGF = expression=20 detected in these anemic patients. Nevertheless, hemoglobin = is a=20 variable that can be corrected, suggesting that treating = anemia in=20 all cancer patients may be an important part of their = care.=20

HRQOL and Cognitive Function Outcomes
The = debilitating=20 effects that anemia can have on HRQOL outcomes have been = reviewed,=20 and management of these issues should be of high priority, as = even=20 small incremental increases in hemoglobin level can = significantly=20 improve a patient=92s HRQOL [10,11].=20 While factors such as energy level, ability to work, and = fatigue=20 have been assessed, closer evaluation of other HRQOL end = points,=20 such as social interaction and depression, may also further=20 delineate the impact of anemia on cancer patients.

Whether treating anemia can improve cognitive function in cancer = patients may also deserve investigation. It has been = suggested=20 that increases in hematocrit levels following rHuEPO therapy=20 may improve cognitive function in hemodialysis patients, as=20 assessed by improved memory and ability to sustain attention=20 [7,61].=20 Additionally, in rat models, rHuEPO has recently been shown = to cross=20 the blood-brain barrier via specific capillary receptors and = protect=20 against hypoxia-induced neuronal death by preventing = apoptosis [62,63].=20 Potentially, rHuEPO could have a direct effect in the brain = by=20 binding to specific receptors, preventing brain injury and,=20 therefore, sustaining cognitive function. However, whether = the=20 findings in animals and in hemodialysis patients translate to = patients with cancer needs to be further investigated. =

Hospitalization
It has been suggested that rHuEPO = and=20 darbepoetin alfa may decrease the number of days cancer = patients with=20 anemia spend in hospital [64,65].=20 Hospitalization represents a significant burden on health = care=20 resources, as well as an inconvenience to the patient. = Consideration=20 of treatments that lighten this load is, therefore, = important.=20


3D"    CONCLUSIONS
Top
Learning Objectives
Abstract
Introduction
Impact of Anemia on...
Pathophysiology of Anemia in...
Managing Anemia
Future Approaches to Anemia...
3D"Conclusions
References
 
A= ccumulating=20 evidence suggests anemia is a common complication in cancer = patients=20 and may impact on HRQOL, radiation therapy and chemotherapy = efficacy,=20 and survival. Management of anemia can improve these = outcomes, but it=20 is apparent that anemia may not be optimally managed in = cancer=20 patients at this time. However, new approaches and novel = therapies=20 that may shift the balance to a more promising future for = cancer=20 patients with anemia are on the horizon.

Furthermore, end points such as survival and cognitive function=20 are beginning to be explored, and improved predictive = algorithms=20 developed. Continued research into anemia and discussion and=20 understanding of the impact that even mild-to-moderate anemia = can have on patient outcomes will ultimately contribute to = the=20 optimization of anemia management.


3D"    ACKNOWLEDGMENT
Top
Learning Objectives
Abstract
Introduction
Impact of Anemia on...
Pathophysiology of Anemia in...
Managing Anemia
Future Approaches to Anemia...
Conclusions
References
 
<= I>M.S.G.=20 is a consultant for Amgen.


3D"    REFERENCES
Top
Learning Objectives
Abstract
Introduction
Impact of Anemia on...
Pathophysiology of Anemia in...
Managing Anemia
Future Approaches to Anemia...
Conclusions
3D"References
&nb= sp;

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Received=20 January 7, 2002; accepted for publication May 10, 2002.




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THE = ONCOLOGIST STEM=20 CELLS CME ALPHAMED=20 PRESS JOURNALS
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Opera = requires=0A= the Sun Java Runtime Environment .=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_0019_01C87196.664DB1A0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://theoncologist.alphamedpress.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else 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quoted-printable Content-Location: http://theoncologist.alphamedpress.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. 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