Download Erythropoietic Agents in the Management of Cancer

R E V I E W
Erythropoietic Agents in the Management
of Cancer Patients
Part 1: Anemia, Quality of Life, and Possible Effects on Survival
Robert E. Smith, Jr., MD
rythropoietin is the major regulator of
erythropoiesis: In normal subjects, when
hemoglobin concentrations decrease to
< 12 g/dL, levels of endogenous erythropoietin increase [1]. This is primarily achieved by
recruitment of additional peritubular renal cells,
augmenting erythropoietin production by dedicated peritubular cells [2]. In patients with chronic
renal failure who have an impaired ability to produce endogenous erythropoietin, replacement
therapy with erythropoietic agents resulted in normalization of hemoglobin levels [3, 4]. The use of
erythropoietic agents to correct anemia has also
been studied extensively in patients with cancer.
Anemia (as defined by a hemoglobin concentration < 12 g/dL) is a common occurrence in oncology patients, and the endogenous erythropoietic
response to anemia is diminished in cancer-related
anemia [5, 6]. The causes of anemia in cancer patients are multifactorial and may be related to
chemotherapy (myelosuppressive chemotherapies,
as well as nephrotoxic platinum-based therapy) [7]
or neoplastic bone marrow infiltration [8]. There
is also the anemia of chronic disease (ie, inflammatory cytokines that suppress erythropoiesis and
erythropoietin production) [9–13]. This review
will briefly summarize the principal findings regarding the use of erythropoietic agents to correct anemia in oncology patients and identify several areas of continuing investigation in optimizing the
use of erythropoietic agents for that purpose, and
then review the theoretical basis and clinical data
regarding the use of erythropoietic agents in patients with cancer to impact survival or cognitive
function.
E
Correspondence to: Robert E. Smith, Jr., MD, President, South
Carolina Oncology Associates, 1301 Taylor Street, Suite 1-A,
Columbia, SC 29201; telephone: (803) 296-5721; fax: (803)
296-5741; e-mail: [email protected]
J Support Oncol 2003;1:249–259
VOLUME 1, NUMBER 4
© 2003 BioLink Communications
n
NOVEMBER/DECEMBER 2003
Abstract Erythropoietic agents have been shown to be well tolerated
and highly effective in correcting the anemia associated with cancer.
Studies aimed at optimizing their use in this regard are ongoing and are
evaluating the potential value of early dose intensification through “frontloading” schedules, the feasibility of reducing the frequency of dosing,
and the value of early initiation of erythropoietic agents to prevent anemia. The potential for erythropoietic therapy to contribute to survival in
cancer patients also is being investigated. Anemia is an independent poor
prognostic factor in several cancer settings, such as head-and-neck, lung,
and cervical cancer. In patients with B-cell chronic lymphocytic leukemia, it is possible that the period of stable disease—that is, postponement of the need for cytotoxic chemotherapy—may be prolonged when
patients are “downstaged” through correction of their anemia. In addition, anemia may affect the patient’s quality of life in ways that impact
compliance and/or the ability to tolerate therapy. Retrospective analysis
of large phase III trials designed to evaluate the effect of erythropoietic
agents on anemia in cancer patients has reported a trend toward improved survival among patients who received erythropoietic therapy.
Trials to evaluate how correction of anemia in cancer patients might
impact survival are ongoing. In this first installment of a two-part article,
the author reviews the clinical data supporting the use of erythropoietic agents for the management of the fatigue due to anemia, the effect of
anemia control on quality of life, and the evidence available so far that
control of such anemia may actually lengthen survival. In the next issue,
Dr. Smith will discuss the possible role of erythropoietic agents in neuroprotection and neurotherapy, including cognitive dysfunction in cancer
patients.
Erythropoietic Agents for Management
of Chemotherapy-Induced Anemia
RANDOMIZED PHASE III TRIALS IN ANEMIC
CANCER PATIENTS
Dr. Smith is Co-Director,
South Carolina Cancer
Center, and President,
South Carolina Oncology
Associates, Columbia,
South Carolina
Several studies have shown that, despite the
complex pathophysiology of anemia in cancer patients, erythropoietic agents can ameliorate anemia in this patient population [14–17]. Four large,
randomized, placebo-controlled phase III trials
evaluated the biologic and clinical activity of
www.SupportiveOncology.net
249
Table 1
Randomized Phase III Trials of Erythropoietic Agents for the Treatment of Anemia in Cancer Patients
STUDY
Abels
14
Littlewood
et al15
Vansteenkiste
et al16
Hedenus et al17
PATIENT POPULATION
Anemia with solid
and hematologic
malignancies
associated with
chemotherapy or
chronic anemia of
cancer
Anemic patients
with solid tumors
or hematologic
malignancy
associated with
non–platinum-based
chemotherapy
Anemic lung cancer
patients receiving
platinum-based
chemotherapy
Anemic patients
with lymphoproliferative
malignancies
PATIENT ARMS
(TOTAL PATIENTS)
TREATMENT
(EVALUABLE PATIENTS)
Non-chemotherapy
(124)
Epoetin alfa, 100 IU/kg
SC TIW for 8 wk (63)
Placebo (55)
Non–cisplatin-based
chemotherapy (157)
Epoetin alfa, 150 IU/kg
SC TIW for 12 wk (79)
Placebo (74)
Cisplatin-based
chemotherapy (132)
Epoetin alfa, 150 IU/kg
SC TIW for 12 wk (63)
Placebo (61)
Epoetin alfa, 150–300
IU/kg SC (251)
Placebo (124)
Non–platinum-based
chemotherapy (375)
CLINICAL OUTCOME
Statistically significant increase in hematocrit vs
placebo for all 3 strata (P < 0.04)
Statistically significant decrease in percentage of
patients requiring transfusions and number of units
transfused in months 2 and 3 for chemotherapytreated patients receiving rHuEPO vs placebo
(P < 0.005 and P = 0.009, respectively). No change
in percentage of patients transfused or number of
units transfused among non-chemotherapy
patients
Epoetin alfa therapy resulted in significantly
decreased transfusion requirements (P = 0.0057),
increased hemoglobin levels (P < 0.001), and
improved quality of life (P < 0.05).
Platinum-based
chemotherapy (320)
Darbepoetin alfa, 2.25–
4.5 µg/kg per week SC
for 12 wk (156)
Placebo (158)
Chemotherapy (344)
Darbepoetin alfa, 2.25–
4.5 µg/kg per week SC
for 12 wk (174)
Placebo (170)
Darbepoetin alfa therapy resulted in a statistically
significant decrease in number of transfusions
(P < 0.001), fewer units of blood transfused
(P < 0.001), and decreased incidence and severity of
fatigue (P = 0.019).
Darbepoetin alfa therapy resulted in a statistically
significant increase in patients achieving a
hemoglobin response (P < 0.001), a decrease in
number of patients receiving transfusions
(P < 0.001), and significantly decreased fatigue
(P < 0.001). The improvement in fatigue correlated
with changes in hemoglobin levels.
Abbreviations: SC = subcutaneously; TIW = three times per week; rHuEPO = recombinant human erythropoietin.
Erythropoietic
Agents: Anemia,
QOL, Survival
erythropoietic agents in the management of anemia in cancer patients (Table 1). The studies employed different erythropoietic agents (epoetin alfa
[Procrit] and darbepoetin alfa [Aranesp]), used
varied criteria to define anemia, included different patient populations, had nonuniform definitions for response to treatment, and had differing
study endpoints. Despite these variations, the patterns of response seen across the trials were highly
reproducible: improvements in measures of erythropoiesis from baseline (hemoglobin or hematocrit)
that translated into decreased transfusion requirements in months 2 and 3, with decreased fatigue
and improved quality of life.
OPEN-LABEL, COMMUNITY-BASED STUDIES
In addition, four large, community-based, openlabel, nonrandomized studies of erythropoietic
agents were conducted in anemic cancer patients
with nonmyeloid malignancies who were receiving
250
www.SupportiveOncology.net
chemotherapy [18–21]. The studies had similar designs and endpoints (Table 2). Despite differences
in the erythropoietic agents prescribed (epoetin
alfa and darbepoetin alfa), as well as doses and
schedules, all four studies reported very similar
improvements in mean hemoglobin change uncorrected for transfusion (Table 3). In all of the studies, quality of life (as measured by the mean change
in the linear analog score or in the FACT-Fatigue
[Functional Assessment of Cancer TherapyFatigue] scale) significantly improved during erythropoietic therapy. In three studies [19–21], improvements in quality of life correlated with
improvement in hemoglobin levels (for patients
with objective responses or stable disease following chemotherapy). Quality-of-life improvement
was most clearly seen in patients who achieved
hemoglobin concentrations ≥ 12 g/dL or an increase ≥ 2 g/dL from baseline [20]. The findings
in these community-based studies were consistent
THE JOURNAL OF SUPPORTIVE ONCOLOGY
Table 2
Community-Based Studies of Erythropoietic Agents for the Treatment of Cancer-Related Anemia:
Study Designsa
GLASPY ET AL18 (n = 2,342)
Open-label, nonrandomized
Anemic
Nonmyeloid malignancies
Chemotherapy
Epoetin alfa
Initial dose: 150 U/kg SC TIW
Increase to 300 U/kg SC TIW
if inadequate response at wk 8
Retrospective tumor response
analysis (subset)
Effect on:
• Hemoglobin
• Transfusion requirements
• Quality of life (linear analog
scale)
DEMETRI ET AL19 (n = 2,370)
GABRILOVE ET AL20 (n = 2,964)
VADHAN-RAJ ET AL21 (n = 1,173)
Open-label, nonrandomized
Anemic (Hgb ≤ 11.0 g/dL)
Nonmyeloid malignancies
Chemotherapy
Epoetin alfa
Initial dose: 10,000 U SC TIW
Increase to 20,000 U SC TIW if
Hgb rise < 1 g/dL at wk 4
Prospective tumor response
analysis
Effect on:
• Hemoglobin
• Transfusion requirements
• Quality of life (linear analog
scale, FACT-An)
Open-label, nonrandomized
Anemic (Hgb ≤ 11.0 g/dL)
Nonmyeloid malignancies
Chemotherapy
Epoetin alfa
Initial dose: 40,000 U SC QW
Increase to 60,000 U SC QW if
Hgb rise < 1 g/dL at wk 4
Prospective tumor response
analysis
Effect on:
• Hemoglobin
• Transfusion requirements
• Quality of life (linear analog
scale, FACT-An)
Open-label, nonrandomized
Anemic (Hgb ≤ 11.0 g/dL)
Nonmyeloid malignancies
Chemotherapy
Darbepoetin alfa
Initial dose: 3 µg/kg SC Q2W
Increase to 5 µg/kg SC Q2W if
Hgb rise < 1 g/dL at wk 6
N/A
Effect on:
• Hemoglobin
• Transfusion requirements
• Quality of life (FACT-Fatigue
subscale and energy numerical
grade)
Abbreviations: FACT-An = Functional Assessment of Cancer Therapy–Anemia; Hgb = hemoglobin; SC = subcutaneously; QW = every week; Q2W = every two weeks; TIW = three times per
week.; N/A= not applicable
a
Modified from Crawford22
with those reported in the randomized, placebocontrolled phase III trials and confirmed that
erythropoietic agents are effective in the management of anemia in cancer patients, independent
of tumor type or chemotherapy regimen.
clinical trials, the incidence of death and the proportion of patients withdrawing from the trial due
to an adverse effect did not differ between patients
receiving erythropoietic agents and those receiving a placebo [14–17].
ADVERSE EFFECTS OF ERY THROPOIETIC
AGENTS
EVOLVING ISSUES IN THE USE OF
ERYTHROPOIETIC AGENTS
Numerous cancer patients have received erythropoietic agents in both controlled and open-label
clinical trials and in community practice [14–21],
and they have been well tolerated. The incidence
and severity of adverse events have not differed
from those observed in patients receiving a placebo, except for shortness of breath, edema, hypertension, and injection-site reactions [23], and even
they were not clinically significant. In controlled
Dose-escalation schedules. Historically, erythropoietic agents have been administered at a fixed
dose (1 or 3 times per week for 12 weeks), and if
an adequate hematologic response was not seen
at week 4 or week 8, the dose was increased. Studies with darbepoetin alfa in cancer-associated anemia reported a correlation between the dose of
darbepoetin alfa and both the proportion of patients who met the criteria for hematologic
Smith
Table 3
Community-Based Studies of Erythropoietic Agents for the Treatment of Cancer-Related
Anemia: Effect on Hemoglobin Levelsa
GLASPY ET AL18
Baseline
Final
Mean change from baseline
a
b
9.5 g/dL
11.3 g/dL
1.8 g/dLb
DEMETRI ET AL19
9.3 g/dL
11.3 g/dL
2.0 g/dLb
GABRILOVE ET AL20
9.5 g/dL
11.3 g/dL
1.8 g/dLb
VADHAN-RAJ ET AL21
10.4 g/dL
12.4 g/dL
2.1 g/dL*
Modified from Crawford22
Significantly (P < 0.001) greater than baseline
VOLUME 1, NUMBER 4
n
NOVEMBER/DECEMBER 2003
www.SupportiveOncology.net
251
Erythropoietic
Agents: Anemia,
QOL, Survival
response and the rapidity of that response [24].
These data are consistent with the hypothesis that
higher doses of erythropoietic agents, administered
early in therapy, would result in a higher proportion of patients achieving an earlier response. This
“front-loading” hypothesis is currently being
investigated [25–29].
Optimizing the frequency of dosing. In early studies, erythropoietic agents were dosed 3 times per
week (TIW) for 12 weeks. Gabrilove [20] and others [30–32] reported that a dose of 40,000 IU of
epoetin alfa administered once weekly (with escalation to 60,000 IU at week 4 if the hemoglobin
rise was < 1 g/dL) appeared to produce an acceptable clinical response. Chemotherapy-induced
anemia also has been treated successfully utilizing
darbepoetin alfa in a once-every-2-week (Q2W)
regimen [21, 28–30] or once-every-3-week
(Q3W) regimen [33, 34]. Currently, 200 µg Q2W
has been adopted as the most common dose and
schedule for darbepoetin alfa. Further exploration
of schedules that would minimize the frequency
of administration without sacrificing efficacy is
ongoing.
Prevention of anemia. A number of studies have
looked at the use of erythropoietic agents prophylactically in patients at risk for anemia [35–40].
In these randomized trials, early treatment with
erythropoietic agents consistently resulted in statistically significant decreases in the mean hemoglobin fall, which translated into decreases in the
number of patients receiving red blood cell (RBC)
transfusions and the units of RBCs transfused per
patient. These findings were consistent whether
the patient population was receiving platinumbased chemotherapy or non–platinum-based therapy and whether the patient population was one
in which baseline anemia is common (small-cell
lung cancer [SCLC]) or relatively uncommon
(patients receiving adjuvant therapy for breast
cancer) (Table 4). Further evaluation of the clinical and economic impact of early treatment with
erythropoietic agents in patient populations at risk
for anemia is warranted.
Erythropoietic Therapy:
Impact on Survival
THEORETICAL BASIS FOR AN IMPACT ON
SURVIVAL IN CANCER PATIENTS
Hypoxia and cancer survival. Approximately
25%–50% of patients with certain major non-
252
www.SupportiveOncology.net
myeloid tumors (namely, breast, lung, and gynecologic cancers and lymphoma) treated with a single agent or a standard chemotherapy regimen experience severe (≥ grade 3) anemia [41].
Hemoglobin levels < 13 g/dL have been associated
with tumor hypoxia [42], and more pronounced
anemia (hemoglobin < 10 g/dL) has been associated with impaired local control and decreased
survival in specific cancers treated with
radiotherapy-based regimens [43–46]. A comprehensive meta-analysis found that median survival
times were longer for non-anemic cancer patients
in all of the studies evaluated [47]. Overall, the
estimated increased risk of death was 65% in patients with cancer and anemia, compared with
cancer patients without anemia, suggesting that,
at least in some cases, anemia may be an independent predictor of survival in patients with cancer.
The theoretical basis for the clinical impact of
low hemoglobin levels relates to the cellular regulation of oxygen delivery. Hypoxia results in an
increased expression of hypoxia-inducible factor-1
alpha (HIF-1 alpha) within hours of hypoxic stress.
HIF-1 alpha dimerizes with constitutively expressed HIF-1 beta to form a transcription factor
that regulates increased expression of a number of
genes, including erythropoietin (EPO), vascular
endothelial growth factor (VEGF), glucose transporters, glycolytic enzymes, transferrin, and the
transferrin receptor [48]. Under well-oxygenated
conditions, HIF-1 alpha is ubiquitinated and degraded after being bound by the product of the
von Hippel-Lindau tumor suppressor gene (VHL).
Congenital deficiency of or mutation in VHL leads
to an increased incidence of cancer, suggesting that
chronic and/or inappropriate activation of the
HIF-1 alpha response may be central to the initiation or progression of some tumors [49].
Mechanism(s) of hypoxia impact on cancer
survival. The up-regulation of HIF-1 alpha in response to hypoxia may affect the survival of cancer patients in one or more ways:
1. HIF-1 alpha expression results in upregulation of proangiogenic factors that support
tumor growth, metastasis, and resistance to
chemotherapy [50].
2. Hypoxia results in resistance to free radicals
formed subsequent to ionizing radiation therapy
and/or chemotherapy [51, 52].
3. Hypoxia increases resistance to apoptosis [49].
4. Hypoxia impacts survival by impacting the
host, resulting in reduced tolerance to therapy,
THE JOURNAL OF SUPPORTIVE ONCOLOGY
Table 4
Erythropoietic Agent Prophylaxis of Chemotherapy-Induced Anemia
STUDY
ERYTHROPOIETIC AGENT
DOSE AND SCHEDULE
PATIENTS (n)
CHEMOTHERAPY
DESIGN
ten Bokkel Huinink
et al37
Ovarian cancer
(118)
6 cycles of platinumbased combination
therapy
Randomized, openlabel, controlled trial
vs standard management
150 or 300 U/kg 3 ×
week up to Hgb =
15 g/dL
de Campos et al36
SCLC (36)
6 cycles of VICE
Randomized, openlabel, controlled trial
vs standard management
150 or 300 U/kg 3 ×
week up to Hgb =
15 g/dL
Del Mastro et al38
Breast cancer
(62)
6 cycles of CEF
150 or 300 U/kg 3 ×
week up to Hgb =
15 g/dL
Dunphy et al39
Head and neck
or lung cancer
(29)
Carboplatin and
paclitaxel
Randomized, openlabel, controlled trial
vs standard management
Randomized, openlabel, controlled trial
vs standard management
Thatcher et al40
SCLC (130)
6 cycles of platinumbased combination
therapy
Randomized, openlabel, controlled trial
vs standard management
150 or 300 U/kg 3 ×
week up to Hgb =
15 g/dL
150 or 300 U/kg 3 ×
week up to Hgb =
15 g/dL
RESULTS
EPO arms had a statistically significant prolongation in time to first
transfusion and a decrease in the
percentage of patients receiving
transfusions.
EPO arms had a statistically significant decrease in number of patients receiving transfusions, number of RBC units/transfusion episode, and total number of RBC
units transfused.
EPO arms had a statistically significant decrease in clinically significant anemia and mean Hgb
decrease.
EPO arms had a statistically significant decrease in mean Hgb fall by
the end of 2 cycles of therapy and
a decrease in the proportion of
transfused patients at study end.
EPO arms had a statistically significant decrease in the number of
patients experiencing anemia, as
well as the number of patients
transfused.
Abbreviations: SCLC = small-cell lung cancer; VICE = vincristine, ifosfamide, carboplatin, and etoposide; CEF = cyclophosphamide, epirubicin, and fluorouracil; EPO = epoetin alfa; Hgb =
hemoglobin
reduced immune function, and reduced quality of
life [49].
In preclinical murine models, hypoxic tumor
cells were two- to six-fold more chemoresistant
than normoxic tumor cells [53]. Hemoglobin levels < 10 g/dL have been reported to be associated
with impaired local control rates and survival rates
in head-and-neck as well as cervical cancer patients receiving radiotherapy-based treatment regimens [43–44, 54]. Furthermore, retrospective
analyses of head-and-neck cancer patients treated with radiotherapy demonstrated that hemoglobin levels are an independent prognostic factor
for survival [55]. Similar data have been reported
for cervical cancer patients and non–small-cell
lung cancer (NSCLC) patients treated with
chemoradiotherapy [47, 54, 56].
Potential consequences of erythropoietic agents on
cancer cell growth. Theoretically, if tumor cells have
active erythropoietin receptors (EPO-R), erythropoietic agents might stimulate neoplastic cell
growth. Several authors have demonstrated in vitro
stimulation of erythroleukemic cell lines expressVOLUME 1, NUMBER 4
n
NOVEMBER/DECEMBER 2003
ing EPO-R [57–59] and stimulation of myeloma
cells expressing EPO-R [60, 61]. However, exposure to an erythropoietic agent did not affect in
vitro colony formation or the percentage of S-phase
cells in panels of tumor cells [62, 63], and had no
additive effect on the cell lines’ response to granulocyte-macrophage colony stimulating factor (GMCSF) or interleukin-3 (IL-3). To date, there are
no data supporting the hypothesis that erythropoietic agents can accelerate nonmyeloid cancer progression in animal models or humans. When progression of disease has been reported in patients
with myeloma or acute myelogenous leukemia
(AML), there has been no indication of a causal
relationship [23].
Smith
Clinical Data on the Impact of
Erythropoietic Agents on Survival of
Cancer Patients
Pilot studies have reported that the correction
of anemia (via RBC transfusions or erythropoietic
agents) in patients receiving potentially curative
radiotherapy for cervical and/or head-and-neck
www.SupportiveOncology.net
253
Erythropoietic
Agents: Anemia,
QOL, Survival
cancer resulted in improved survival [64–66]. In
two large, randomized phase III trials where survival was a secondary endpoint, the treatment arm
receiving erythropoietic agents showed trends toward longer overall and progression-free survival
[15, 67].
The Littlewood study. Littlewood et al [15] randomized 375 patients with solid or nonmyeloid
hematologic malignancies and a hemoglobin level
< 10.5 g/dL (or ≥ 10.5 g/dL but < 12.0 g/dL after
a hemoglobin decrease of ≥ 1.5 g/dL per cycle since
the start of chemotherapy) in a double-blind,
placebo-controlled trial. The randomization was
2:1. Patients received epoetin alfa starting at 150
IU/kg TIW for up to 28 weeks (n = 251) or placebo (n = 124) and were eligible for a dose increase
at week 4 if there was an inadequate initial response. Patient demographics were generally comparable between the two arms. The three most
common malignancies (breast, non-Hodgkin’s lymphoma, and myeloma) were present in similar percentages in the two arms, and the overall distribution of chemotherapy regimens within specific
malignancy types was generally balanced between
the epoetin alfa and placebo groups (Table 5) [15].
Although not a primary endpoint and added as
a secondary endpoint after the start of the study,
survival was assessed 12 months after the last patient enrolled had completed the study. At a median follow-up of 26 months, the median overall
survival was 17 months among the patients treat-
Table 5
Most Frequent (≥ 20% Overall) Chemotherapeutic Agents Used
for the Three Most Common Tumor Types in the Study Reported
by Littlewood et al15
EPOETIN ALFA (n = 251)
TUMOR TYPE/CHEMOTHERAPEUTIC AGENT
NUMBER
Breast Cancer
Cyclophosphamide
Fluorouracil
Epirubicin
Methotrexate
Non-Hodgkin’s lymphoma
Cyclophosphamide
Vincristine
Doxorubicin
Myeloma
Melphalan
Vincristine
Doxorubicin
254
PLACEBO (n = 124)
PERCENT
NUMBER
44.9
39.7
26.9
18.0
13
16
8
9
63.4
58.5
53.7
11
9
5
n = 78
35
31
21
14
n = 36
n = 41
26
24
22
36.1
44.4
22.2
25.0
n = 21
n = 37
21
11
12
PERCENT
52.3
42.9
23.8
n = 25
56.8
29.7
32.4
www.SupportiveOncology.net
13
5
4
52.0
20.0
16.0
Table 6
Secondary Endpoint Survival Assessment
Reported by Littlewood et al15
EPOETIN ALFA, n (%)
Alive at follow-upa
Died
Lost to follow-upa
a
94 (37%)
155 (62%)
2 (1%)
PLACEBO, n (%)
41 (33%)
82 (66%)
1 (1%)
Median follow-up of 26 months
ed with epoetin alfa and 11 months among the placebo-treated patients (Table 6). The Kaplan-Meier 12-month estimate of survival was 60% for the
epoetin alfa group and 49% for the placebo group,
with a log-rank test showing a trend in overall survival favoring epoetin alfa (P = 0.13). A similar
trend in favor of the patients given epoetin alfa
was seen in both those with hematologic
malignancies and those with solid tumors.
The Vansteenkiste study. Retrospective data regarding a possible survival impact were also reported by Vansteenkiste et al [67]. They reported on a
double-blind, phase III trial that randomized anemic patients (hemoglobin ≤ 11 g/dL) with lung
cancer receiving platinum-containing chemo therapy to receive darbepoetin alfa or placebo.
Randomization was stratified to balance the treatment groups by tumor type (NSCLC vs SCLC) and
geographic region. Although they were secondary
endpoints, data on tumor progression and survival status were collected quarterly for 1 year after
the last patient enrolled had completed treatment.
The median overall survival was 46 weeks (range,
39–53 weeks) among darbepoetin alfa patients and
34 weeks (range, 29–40 weeks) among placebo
patients. The median time to disease progression
or death was 23 weeks (range, 19–31 weeks) for
patients treated with darbepoetin alfa and 20
weeks (range, 17–23 weeks) for those receiving a
placebo. Analysis of the tumor strata showed a
more pronounced effect of darbepoetin alfa on time
to treatment failure or death among SCLC patients, with an 11-week time to disease progression prolongation in the darbepoetin alfa arm
compared with the placebo arm (Table 7).
A CAVEAT
Neither of the phase III trials discussed above
was designed or powered to evaluate survival endpoints. The variables that have a known influence
on survival (stage of disease, marrow involvement,
THE JOURNAL OF SUPPORTIVE ONCOLOGY
intensity of chemotherapy, and use of radio therapy) were not controlled for or stratified in the
studies. These retrospective analyses of survival
endpoints do, however, serve to generate hypotheses concerning the benefit of correcting hemoglobin levels in cancer patients undergoing chemotherapy. Randomized phase III trials testing these
hypotheses are currently ongoing.
Table 7
TREATMENT ARM
Darbepoetin alfa
Median, wk
Range, wk
Placebo
Median, wk
Range, wk
WHEN ANEMIA MAY AFFECT CHOICE OF
TREATMENT
Erythropoietic therapy also may affect survival
in diseases where the presence of anemia may be a
factor in therapeutic strategies. For instance, anemia is common in patients with chronic lymphocytic leukemia (CLL) and may be due to one or
more of several factors: extensive bone marrow
infiltration, hypersplenism, blood loss, auto immune hemolysis, deficiency of hematopoietic
cofactors, and/or the anemia of chronic disease.
Both the Rai and Binet staging systems identify
anemia as an indicator of disease progression [68,
69]. Consistent with the finding that increased severity of anemia indicates disease progression in
B-cell chronic lymphocytic leukemia (B-CLL),
National Cancer Institute guidelines state that patients with hemoglobin levels < 10 g/dL are
candidates for chemotherapy [70].
Randomized, controlled studies have reported
that erythropoietic agents can ameliorate the anemia seen in CLL patients, as measured by increased
hemoglobin levels and decreased transfusion
requirements [71–74].
Correction of anemia also may result in “downstaging” of CLL patients. Pangalis et al [75] evaluated whether the “downstaging” of B-CLL patients by correction of disease-related anemia could
prolong the time to cytotoxic therapy and potentially offer a survival advantage. The study enrolled
32 Rai stage III or IV B-CLL patients who had
had no treatment for CLL at least 1 month prior
to study entry, an ECOG performance status ≤ 2,
a life expectancy of at least 6 months, and were
clinically stable for at least 1 month prior to study
entry. Anemia was defined as a hematocrit < 32%
on two occasions 2 weeks apart.
Of the 32 patients enrolled, 11 were anemic at
baseline and 14 developed anemia while on the
study (median of 53.5 months after being enrolled
in the study; range 17–120 months). The baseline
(at the time anemia was diagnosed) hemoglobin
level among the 25 patients who experienced aneVOLUME 1, NUMBER 4
n
NOVEMBER/DECEMBER 2003
Smith
Median Time to Disease Progression or
Death Reported by Vansteenkiste et al67
SCLC
NSCLC
33
26–41
18
16–26
21
16–26
19
16–23
Abbreviations: SCLC = small-cell lung cancer; NSCLC = non–small-cell lung
cancer
mia was a median of 9.4 g/dL (range, 5.9–9.9 g/dL).
Treatment with epoetin alfa included both an
induction phase (150 IU/kg TIW for a maximum
of 12 weeks, with dose escalation permitted to 300
IU/kg TIW) and a maintenance phase (150 IU/kg
weekly). A complete response to epoetin alfa was
defined as a hematocrit level ≥ 38%, whereas a
partial response was defined as an increase > 6%
from baseline with a hematocrit < 38%. Of the
25 evaluable patients, 18 (72%) achieved a complete response and 2 (8%) had a partial response.
Among the 20 responders, 18 experienced prolonged responses (median of 30.8+ months; range
27.5–64+ months) and 2 died of infection while
still maintaining their hematocrit levels.
At the completion of the induction period, 19
of 20 patients were “downstaged”: 6 to Rai stage
0; 9 to Rai stage 1; and 4 to Rai stage II. During a
median of 31+ months follow-up (range, 25 to
65+ months), antileukemic therapy was required
in 4 of the 20 responding patients, and corticosteroid therapy for autoimmune hemolysis in a fifth
Table 8
Rai Stage Prior to and After Completion of
the Induction Phase of Erythropoietic
Agent Administrationa
ERYTHROPOIETIC AGENT ADMINISTRATION
RAI STAGE
0
I
II
III
IV
a
b
PRIOR, n (%)
AFTER 3 MONTHS, n (%)
0
0
0
24 (96%)
1 (4%)
6 (24%)
9 (36%)
4 (16%)
5 (20%)
1 (4%)b
From Pangalis et al75
Without anemia
www.SupportiveOncology.net
255
Erythropoietic
Agents: Anemia,
QOL, Survival
patient was needed (Table 8). The median overall
survival of the 25 evaluable patients had not been
reached as of publication of the Pangalis paper, and
the 2- and 3-year survival rates were 96% and 78%.
The reported median overall survival of Rai stage
III patients is approximately 3 years, although the
B-CLL population is heterogeneous and longer
survival times have been reported [68, 69, 76].
These data are consistent with the hypothesis
that “downstaging” B-CLL by correction of disease-related anemia may prolong the time to cytotoxic therapy and offer a survival advantage; however, these results also could be due to a subset
selection of patients with less aggressive disease.
Given the low toxicity, high response rate, and
prolonged response duration and time to chemotherapy reported with erythropoietic therapy in this
trial, a randomized prospective study specifically
designed to evaluate the impact of erythropoietic
agents on survival in B-CLL patients would seem
to be warranted.
Summary
Erythropoietic agents have been shown to be
well tolerated and highly effective in correcting
the anemia associated with cancer. Studies
aimed at optimizing their use in this regard are
ongoing and are evaluating the potential value
of early dose intensification through “frontloading” schedules, the feasibility of reducing the
frequency of dosing, and the value of the early
initiation of erythropoietic therapy in patients
at risk for anemia.
The potential for erythropoietic agents to contribute to survival in cancer patients is being investigated. Anemia is an independent poor prognostic factor in several cancer settings. Preclinical
and clinical data have shown improved local control and survival in head-and-neck and cervical
cancer patients who are managed with erythropoietic agents or RBC transfusions to correct their
anemia while they are undergoing potentially curative chemoradiotherapy. In patients with B-CLL,
it is possible that the time to cytotoxic chemotherapy may be prolonged when patients are
“downstaged” through correction of their anemia.
Hypoxia may contribute to improved cancer cell
survival, proliferation, metastases, and resistance
to therapy. In addition, anemia may affect the quality of life of the patient in ways that impact compliance and/or the ability to tolerate therapy. Retrospective analysis of large phase III trials designed
to evaluate the effect of erythropoietic agents on
anemia in cancer patients has reported a trend
toward improved survival among patients managed
with erythropoietic agents. Prospective, randomized trials to evaluate a possible survival impact of
correcting anemia in cancer patients by means of
erythropoietic agent therapy are ongoing.
Editor’s note: Part 2 of this review—the possible
role of erythropoietic agents as neuroprotectants/neurotherapeutics—will appear in the next issue of The
Journal of Supportive Oncology.
References
1. Finch CA. Erythropoiesis, erythropoietin and
iron. Blood 1982;60:1241–1246.
2. Koury ST, Koury MJ, Bondurant MC, et al.
Quantitation of erythropoietin-producing cells in
kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA,
and serum erythropoietin concentration. Blood
1989;74:645–651.
3. Admanson JW. Epoetin alfa: into the new millennium. Semin Oncol 1998;25(suppl 7):76–79.
4. Macdougall IC. Novel erythropoiesis stimulating protein. Semin Nephrol 2000;20:375–381.
5. Groopman JE, Itri LM. Chemotherapy induced anemia in adults: incidence and treatment.
J Natl Cancer Inst 1999;91:1616–1634.
6. Miller CB, Jones RJ, Piantadosi S, et al. Decreased erythropoietin response in patients with
the anemia of cancer. N Engl J Med 1990;322:1689–
1692.
7. Kazur ME, Greco FA. Cisplatin-induced ane-
256
mia. N Engl J Med 1980;303:110–111.
8. Oster W, Herrmann F, Gamm H, et al. Erythropoietin for the treatment of anemia of malignancy associated with neoplastic bone marrow
infiltration. J Clin Oncol 1990;8:956–962.
9. Means Jr RT, Krantz SB. Progress in understanding the pathogenesis of the anemia of
chronic disease. Blood 1992;80:1639–1647.
10. Sears DA. Anemia of chronic disease. Med
Clin North Am 1992;76:567–579.
11. Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hypoxiainduced erythropoietin production. Blood
1992;79:1987–1994.
12. Hulkkonen J, Vilpo J, Vilpo L, Koski T, Hurme M. Interleukin-1 beta, interleukin-1 receptor
antagonist and interleukin-6 plasma levels and
cytokine gene polymorphisms in chronic lymphocytic leukemia: correlation with prognostic
parameters. Haematologica 2000;85:600–606.
www.SupportiveOncology.net
13. Beguin Y, Lampertz S, Bron D, Fillet G.
Serum erythropoietin in chronic lymphocytic
leukaemia. Br J Haematol 1996;93:154–156.
14. Abels RI. Recombinant human erythropoietin in the treatment of the anaemia of cancer.
Acta Haematol 1992;87(suppl 1):4–11.
15. Littlewood TJ, Bajetta E, Nortier JW, et al.
Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial.
J Clin Oncol 2001;19:2865–2874.
16. Vansteenkiste J, Pirker R, Massuti B, et al.
Double blind placebo controlled randomized
phase III trial of darbepoetin alfa in lung cancer
patients receiving chemotherapy. J Natl Cancer
Inst 2002;94:1211–1220.
17. Hedenus, M, Adriansson M, San Miguel T,
Continued on page 258
THE JOURNAL OF SUPPORTIVE ONCOLOGY
P E E R
V I E W P O I N T
Commentary by Matti S. Aapro, MD
D
r. Smith’s paper reviews most of the existing evidence of a relationship between sustained correction of anemia
in cancer patients by various erythropoietic
agents available today and the quality-of-life improvement experienced by these patients. He
also could have mentioned the positive data for
epoetin beta [1]. Clearly, the majority of practicing hematologists and oncologists agree with
the existing evidence and are convinced that
epoetins will not only decrease the need for
transfusions (the official cancer-related indication) but also help patients cope with the disease and its treatment.
There are, however, discordant voices, sometimes because the data have evolved too quickly between evaluation of studies and guideline
publication. For some other experts the data require scrutiny, as much of the old data come from
studies with methodological problems [2]. Nevertheless, anyone who has had the opportunity
to observe patients who respond to epoetin therapy and transform themselves from “zombies” to
almost normal, active adults knows that at least
a proportion of cancer patients derive considerable benefit from the administration of epoetins.
PHARMACOECONOMIC AND OTHER
ISSUES IN EUROPE
The pharmacoeconomic issues in regard to
the use of these agents and their reimbursement
are widely debated in Europe, at least, and the
complexities of these calculations go beyond the
scope of this commentary. But to quote, with a
slight change, a prominent colleague:“Given the
negative impact of anemia in cancer patients and
the benefits derived from rhEPO treatment, it can
no longer be justified that so few European patients are given the chance to receive this therapy, especially as more convenient and cost-effective epoetin regimens are now available” [3].
The adverse event related seemingly to the
European market version of epoetin alfa (Eprex)
needs a mention. This product has been implicated in the development of pure red blood cell
aplasia (PRCA ) in patients with chronic renal failure, although recently the number of reported
cases has decreased dramatically [4]. Subjected
to considerable scrutiny from health authorities,
Eprex, which is similar but not exactly the same
VOLUME 1, NUMBER 4
n
NOVEMBER/DECEMBER 2003
Smith
as its US counterparts Epogen and Procrit, now
carries a warning against its subcutaneous use
in patients with chronic renal failure. Epogen and
Procrit, as well as epoetin beta (NeoRecormon),
have been implicated in a very small number of
cases compared with Eprex. With the accumulated evidence available up to July 2003, darbepoetin alfa (Aranesp) has not been associated
with any increase of PRCA [5]. Should the number of cases associated with Eprex continue to
decrease, it will be reassuring for all, but the explanation of the phenomenon might continue
to escape us.
PROSPECTIVE DATA ARE NEEDED
Smith discusses one of the most fascinating
developments for the practitioner and the patient, namely, the simplification of the treatment
schedule, which could soon mean that epoetin
will be administered once every 3 weeks, along
with chemotherapy. Of course, in a review article, one has to make choices as to what data to
include, but I believe the evidence that has led
the National Comprehensive Cancer Network to
advocate the maintenance of hemoglobin levels above 12 g/dL in elderly patients, as well as
issues surrounding quality of life and anemia in
the elderly, who represent the majority of our
patients—should have been mentioned [6].
Smith’s excellent paper does discuss the laboratory and indirect clinical evidence that leads
one to believe that there should be not only a
direct correlation between hemoglobin level and
local tumor-control rate by radiation therapy but
also between hemoglobin level and patient survival after chemotherapy, or even without chemotherapy, as in some intriguing data on B-cell
chronic lymphocytic leukemia. Although there is
a body of highly suggestive retrospective data,
one of the first studies designed to evaluate
these hypotheses ended earlier than it should
have as, very surprisingly, the independent data
monitoring committee realized that more early
deaths occurred in the epoetin alfa arm of the
study than in the placebo arm [7]. Another negative study has also been reported in patients
with head and neck cancer [8]. However, many
other studies are ongoing, with probably better
designs, and their results are eagerly awaited.
Meanwhile, existing guidelines governing the
use of epoetins in cancer patients urgently need
to be revisited [9]. The European Organization for
www.SupportiveOncology.net
257
Erythropoietic
Agents: Anemia,
QOL, Survival
Research and Treatment of Cancer has a guidelines committee working on this, and hopefully
its conclusions will be ready soon. The American
Society of Clinical Oncologists also has reconvened its committee.
Matti S. Aapro, MD
Dean
Institut Multidisciplinaire d’Oncologie
Genolier, Switzerland
REFERENCES
1. Boogaerts M, Coiffier B, Kainz C: Epoetin beta QOL
Working Group. Impact of epoetin beta on quality of
life in patients with malignant disease. Br J Cancer
2003;88:988–995.
2. Bottomley A, Thomas R, van Steen K, Flechtner H,
Djulbegovic B. Human recombinant erythropoietin and
quality of life: a wonder drug or something to wonder
about? Lancet Oncol 2002;3:145–153.
3. Coiffier B. Advocating recombinant human eryth-
References
Continued from page 256
et al. Efficacy and safety of darbepoetin alfa in
anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebocontrolled study. Br J Haematol, in press.
18. Glaspy J, Bukowski R, Steinberg D, et al.
Impact of therapy with epoetin alfa on clinical
outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin
Oncol 1997;15:1218–1234.
19. Demetri GD, Kris M, Wade J, et al. Qualityof-life benefit in chemotherapy patients treated
with epoetin alfa is independent of disease response or tumor type: results from a prospective
community oncology study. Procrit Study Group.
J Clin Oncol 1998;16:3412–3425.
20. Gabrilove JL, Cleeland CS, Livingston RB, et
al. Clinical evaluation of once-weekly dosing of
epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol
2001;19:2875–2882.
21. Vadhan-Raj S, Mirtsching B, Charu V, et al.
Assessment of hematologic effects and fatigue
in cancer patients with chemotherapy-induced
anemia given darbepoetin alfa every two weeks.
J Supp Oncol 2003:1:131–138.
22. Crawford J. Recombinant human erythropoietin in cancer-related anemia: review of clinical evidence. Oncology 2002;16(suppl 10);41–53.
23. Beguin Y. A risk-benefit assessment of epoetin in the management of anaemia associated
with cancer. Drug Saf 1998;19:269–282.
258
ropoietin as standard practice in Europe for treatment
of cancer-related anaemia. Ann Oncol 2003;14:804.
4. Johnson & Johnson. Summary of PRCA case reports: update on our Company’s effort to reduce case
reports of pure red cell aplasia. Johnson & Johnson Web
site. Available at http://www.jnj.com/news/jnj_news/
1021024_095632.htm. Accessed October 15, 2003.
5. Amgen. Information for healthcare providers: pure
red cell aplasia (PRCA). Amgen Web site. Available at
http://www.amgen.com/clinicians/prca.html. Accessed October 15, 2003.
6. Aapro MS, Cella D, Zagari M. Age, anemia, and fatigue. Semin Oncol 2002;29(suppl 8):55–59.
7. Lleyland-Jones B; BEST Investigators and Study
Group. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 2003;4:459–460.
8. Henke M, Laszig R, Rube C, et al. Erythropoietin to
treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003;362:1255–1260.
9. Henry DH. Guidelines for the use of epoetin in cancer patients: a much-needed step forward in standardizing anemia treatment. Blood 2003;102:2697–2698.
24. Glaspy J, Jadeja JS, Justice G, et al. A randomized active-control, pilot trial of front-loaded dosing regimens of darbepoetin alfa for the
treatment of patients with anemia during chemotherapy for malignant disease. Cancer
2003;97:1312–1320.
25. Hesketh PJ, Arena F, Patel D, et al. Frontloaded darbepoetin alfa with Q3W maintenance
administered as a fixed or weight-based dose in
anemic cancer patients results in similar efficacy
profiles. In: Program/Proceedings of the 39th
Annual Meeting of the American Society of Clinical Oncology; May 31–June 3, 2003; Chicago, Ill.
Abstract 2941.
26. Schwartzberg L, Hesketh P, Rossi G, et al.
Optimizing management of chemotherapy-induced anemia: a combined analysis of data using a darbepoetin alfa frontloading/maintenance
approach. In: Program/Proceedings of the 39th
Annual Meeting of the American Society of Clinical Oncology; May 31–June 3, 2003; Chicago, Ill.
Abstract 2945.
27. Glaspy J, Tchekmedyian NS, Erder MH, et
al. Early and sustained improvement in healthrelated quality of life (HRQOL) was observed with
frontloaded darbepoetin alfa compared to conventional therapy. In: Program/Proceedings of
the 39th Annual Meeting of the American Society of Clinical Oncology; May 31–June 3, 2003;
Chicago, Ill. Abstract 3063.
28. Jumbe NL, Heatherington AC. Darbepoetin
alfa rational dose/schedule evaluation based on
quantitative understanding of erythropoiesis for
early and sustained alleviation of anemia. In: Program/Proceedings of the 39th Annual Meeting of
the American Society of Clinical Oncology; May 31–
June 3, 2003; Chicago, Ill. Abstract 3077.
www.SupportiveOncology.net
29. Beguin Y, Glaspy JA, Henry DH, et al. Prediction of hemoglobin non-response in studies of
darbepoetin alfa compared with epoetin alfa to
treat chemotherapy-induced anemia. In: Program/Proceedings of the 39th Annual Meeting
of the American Society of Clinical Oncology; May
31–June 3, 2003; Chicago, Ill. Abstract 3605.
30. Mirtsching BC, Beck JT, Charu V, et al. Darbepoetin alfa administered every two weeks
(Q2W) reduces chemotherapy-induced anemia
(CIA) to the same extent as recombinant human
erythropoietin (rHuEPO) but with less-frequent
dosing. In: Program/Proceedings of the 39th Annual Meeting of the American Society of Clinical
Oncology; May 31–June 3, 2003; Chicago, Ill. Abstract 2944.
31. Thames W, Yao B, Scheifele A, et al. Drug use
evaluation (DUE) of darbepoetin alfa in anemic
patients undergoing chemotherapy supports a
fixed dose of 200 mcg Q2W given every 2 weeks
(Q2W). In: Program/Proceedings of the 39th Annual Meeting of the American Society of Clinical
Oncology; May 31–June 3, 2003; Chicago, Ill. Abstract 2196.
32. Blayney DW, Spiridonidis H, Fesen MR, et
al. Darbepoetin alfa every 2 weeks to treat chemotherapy-induced anemia: experience in a randomized, open-label study. In: Program/Proceedings of the 39th Annual Meeting of the American
Society of Clinical Oncology; May 31–June 3,
2003; Chicago, Ill. Abstract 3003.
33. Kotasek D, Steger G, Faught W, et al. Darbepoetin alfa administered every 3 weeks alleviates
anaemia in patients with solid tumours receiving chemotherapy: results of a double-blind, placebo-controlled, randomised study. Eur J Cancer,
in press.
THE JOURNAL OF SUPPORTIVE ONCOLOGY
34. Henry D, Patel R, Tchekmedyian S, et al. A
phase 2 randomized study evaluating the timing of darbepoetin alfa administration relative to
chemotherapy. In: Program/Proceedings of the
39th Annual Meeting of the American Society of
Clinical Oncology; May 31–June 3, 2003; Chicago, Ill. Abstract 3162.
35. Welch RS, James RD, Wilkenson PM, et al.
Recombinant human erythropoietin and platinum based chemotherapy in advanced ovarian
cancer. Cancer J Sci Am 1995;1:261–266.
36. de Campos E, Radford J, Steward W, et al.
Clinical and in vitro effects of recombinant human erythropoietin in patients receiving intensive chemotherapy for small-cell lung cancer. J
Clin Oncol 1995;13:1623–1631.
37. ten Bokkel Huinink WW, de Swart CA, van
Toorn DW, et al. Controlled multicentre study of
the influence of subcutaneous recombinant human erythropoietin on anaemia and transfusion
dependency in patients with ovarian carcinoma
treated with platinum-based chemotherapy. Med
Oncol 1998;15:174–182.
38. Del Mastro L, Venturini M, Lionetto R, et al.
Randomized phase III trial evaluating the role of
erythropoietin in the prevention of chemotherapy-induced anemia. J Clin Oncol 1997;15:2715–
2721.
39. Dunphy FR, Harrison BR, Dunleavy TL. Erythropoietin reduces anemia and transfusions: a randomized trial with or without erythropoietin during chemotherapy. Cancer 1999;86:1362–1367.
40. Thatcher N, De Campos ES, Bell DR, et al.
Epoetin alpha prevents anaemia and reduces
transfusion requirements in patients undergoing
primarily platinum-based chemotherapy for
small cell lung cancer. Br J Cancer 1999;80:396–
402.
41. Demetri GD. NCCN: new applications for
erythropoietin. Cancer Control 2001;8(suppl
2):72–76.
42. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment.
J Natl Cancer Inst 1999;91:1616–1634.
43. Fein DA, Lee WR, Hanlon AL, et al. Pretreatment hemoglobin level influences local control
and survival of T1-T2 squamous cell carcinomas
of the glottic larynx. J Clin Oncol 1995;13:2077–
2083.
44. Lee WR, Berkey B, Marcial V, et al. Anemia is
associated with decreased survival and increased
locoregional failure in patients with locally advanced head and neck carcinoma: a secondary
analysis of RTOG 85-27. Int J Radiat Oncol Biol
Phys 1998;42:1069–1075.
45. Brizel DM, Sibley GS, Prosnitz LR, et al. Tumor hypoxia adversely affects the prognosis of
carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997;38:285–289.
46. Becker A, Stadler P, Lavey RS, et al. Severe
anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 2000;46:459–
466.
47. Caro JJ, Salas M, Ward A, et al. Anemia as an
independent prognostic factor for survival in pa-
VOLUME 1, NUMBER 4
n
tients with cancer: a systematic, quantitative review. Cancer 2001;91:2214–2221.
48. Richard DE, Berra E, Pouyssegur J. Angiogenesis: how a tumor adapts to hypoxia. Biochem
Biophys Res Commun 1999;266:718–722.
49. Glaspy J. The potential for anemia treatment to improve survival in cancer patients. Oncology 2002;16(suppl 10):35–40.
50. Laughner E, Taghavi P, Chiles K, et al. HER2
(neu) signaling increases the rate of hypoxia inducible factor 1 alpha (HIF-1-alpha) synthesis:
novel mechanism for HIF-1-alpha mediated vascular endothelial growth factor expression. Mol
Cell Biol 2001;21:3995–4004.
51. Kumar P. Impact of anemia in patients with
head and neck cancer. Oncologist 2000;5:13–18.
52. Brizel DM, Dodge RK, Clough RW, et al. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 1999;53:113–117.
53. Teicher BA, Holden SA, al-Achi A, et al. Classification of antineoplastic treatments by their
differential toxicity toward putative oxygenated
and hypoxic tumor subpopulations in vivo in the
FSaIIC murine fibrosarcoma. Cancer Res
1990;50:3339–3344.
54. Grogan M, Thomas GM, Melamed I, et al.
The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer
1999;86:1528–1536.
55. Frommhold H, Guttenberger R, Henke M. The
impact of blood hemoglobin content on the outcome of radiotherapy: the Freiburg experience.
Strahlenther Onkol 1998;174(suppl 4):31–34.
56. MacRae R, Choy H, Shyr Y, Johnson D. Significance of hemoglobin changes during chemoradiotherapy in non-small cell lung cancer (NSCLC): an
analysis of three sequential trials. In: Program/Proceedings of the 37th Annual Meeting of the American Society of Clinical Oncology; May 12–15, 2001;
San Francisco, Calif. Abstract 1336.
57. Tomonaga M, Jinnai I, Tagawa M, et al. Leukemic blast cell colony formation in semisolid
culture with erythropoietin: a case report of acute
poorly differentiated erythroid leukemia. Blood
1987;69:546–552.
58. Hitomi K, Fujita K, Sasaki R, et al. Erythropoietin receptor of a human leukemic cell line
with erythroid characteristics. Biochem Biophys
Res Commun 1988;154:902–909.
59. Mitjavila MT, Villeval JL, Cramer P, et al. Effects of granulocyte-macrophage colony-stimulating factor and erythropoietin on leukemic
erythroid colony formation in human early erythroblastic leukemias. Blood 1987;70:965–973.
60. Kimata, H, Yoshida A, Ishioka C, et al. Erythropoietin enhances immunoglobulin production
and proliferation by human plasma cells in a serum-free medium. Clin Immunol Immunopathol
1991;59:495–501.
61. Okuno Y, Takahashi T, Suzuki A, et al. Expression of the erythropoietin receptor on a human
myeloma cell line. Biochem Biophys Res Commun
1990;170:1128–1134.
62. Rosti V, Pedrazzoli P, Ponchio L, et al. Effect of
recombinant human erythropoietin on hematopoi-
NOVEMBER/DECEMBER 2003
etic and non-hematopoietic malignant cell growth
in vitro. Haematologica 1993;78:208–212.
63. Berdel WE, Oberberg D, Reufi B, et al. Studies
on the role of recombinant human erythropoietin
in the growth regulation of human nonhematopoietic tumor cells in vitro. Ann Hematol 1991;63:5–8.
64. Grogan M, Thomas GM, Melamed I, et al.
The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer
1999;86:1528–1536.
65. Antonadou D, Cardamekis E, Sarris V, et al.
Effect of the administration of recombinant human erythropoietin in patients with pelvic malignancies during radiotherapy. Radiother Oncol
1998;S48:483.
66. Glaser CM, Millesi W, and Kornek GV, et al. Impact of hemoglobin level and use of recombinant
erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of
the oral cavity and oropharynx. Int J Radiat Oncol
Biol Phys 2001;50:705–715.
67. Vansteenkiste J, Pirker R, Massuti B, et al.
Double-blind, placebo-controlled, randomized
phase III trial of darbepoetin alfa in lung cancer
patients receiving chemotherapy. J Natl Cancer
Inst . 2002;94:1211–1220.
68. Rai KP, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia.
Blood 1975;46:219–234.
69. Binet JG, Catovsky D, Chandra P, et al. Chronic lymphocytic leukemia: proposals for revised
prognostic staging system. Br J Haematol
1981;48:365–367.
70. Cheson, BD, Bennett JM, Greves M, et al.
National Cancer Institute sponsored working
group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996;87:4990–4997.
71. P Õsterborg A, Brandberg Y, Molostova V,
et al. Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin beta, in hematologic malignancies.
J Clin Oncol 2002;20:2486–2494.
72. Rose E, Rai K, Revicki D, et al. Clinical and
health status assessment in anemic chronic lymphocytic leukemia (CCL) patients treated with
epoetin alfa (EPO). Blood 1994;84(suppl 1):526.
Abstract 2091.
73. Hedenus M, Hansen S, Taylor K, et al. Randomized dose-finding study of darbepoetin alfa
in anemic patients with lymphoproliferative malignancies. Br J Haematol 2002:119:79–86.
74. Pangalis GA, Poziopolous C, Angelopoulou
M, et al. Effective treatment of disease-related
anemia in B-chronic lymphocytic leukemia patients with recombinant human erythropoietin.
Br J Haematol 1995;89:627–629.
75. Pangalis GA, Siakantaris MP, Angelopoulou
MK, et al. Downstaging Rai stage III B-chronic lymphocytic leukemia patients with the administration of recombinant human erythropoietin. Haematologica 2002;87:500–506.
76. Keating MJ. Improving the complete remission rate in chronic lymph leukemia. In: American Society of Hematology Education Program
Bench 1999;262–269.
www.SupportiveOncology.net
259