Int J Gynecol Cancer 2003, 13, 633639

Anemia before and during concurrent

chemoradiotherapy in patients with cervical
carcinoma: Effect on progression-free survival
A. OBERMAIR*,, R. CHEUK, K. HORWOOD, M. NEUDORFER, M. JANDA, G. GIANNIS,
J.L. NICKLIN*, L.C. PERRIN* & A.J. CRANDON*
*Queensland Center for Gynaecological Cancer, Royal Womens Hospital; Queensland Radium Institute; and Division of
Oncology, Royal Brisbane Hospital; Queensland University of Technology, School of Public Health, Brisbane, Australia;
and University Hospital Vienna, Department of Gynecology and Obstetrics, Vienna, Austria

Abstract. Obermair A, Cheuk R, Horwood K, Neudorfer M, Janda M,

Nicklin JL, Perrin LC, Crandon AJ. Anemia before and during
concurrent chemoradiotherapy in patients with cervical carcinoma: Effect
on progression-free survival. Int J Gynecol Cancer 2003;13:633639.

To determine the impact of anemia before and during chemoradiation in

patients with cervical cancer, we collected data on hemoglobin (Hb)
levels before and during treatment from 60 unselected patients with
cervical carcinoma. All patients had FIGO stage IB to IVA disease and
were treated with concurrent chemoradiation for the aim of cure.
Patients with an Hb value below or equal to the lower 25th quartile
were considered anemic. Progression-free survival (PFS) was evaluated
by univariate and multivariate analyses. After a median follow-up of
26.3 months, 20 patients developed disease progression. The lowest Hb
during chemoradiation (nadir Hb), the stage of disease, and parametrial
involvement were correlated significantly with PFS. On multivariate
analysis, the nadir Hb (relative risk [RR] 0.29) and tumor stage (RR
3.4) remained the only prognostically relevant factors predicting PFS.
At 60 months the PFS was 39.1% for anemic patients and 48.0% for
nonanemic patients (P < 0.0002). In patients undergoing chemoradiation
for cervical carcinoma, a low nadir Hb is highly predictive of shortened
PFS, whereas the Hb before treatment is prognostically not significant.

KEYWORDS: anemia, chemoradiotherapy, cervical cancer, prognostic factors,

treatment.

Tumour-associated anemia is a common finding in cer-
vical cancer patients in the US(1). More than one-third of
the patients have a hemoglobin level of
120 g/l at pre-
sentation(1). The causes for tumor-associated anemia are
not fully understood(2,3). A number of studies suggest an
Address correspondence and reprint requests to: Andreas
Obermair, MD, Queensland Center for Gynaecological
Cancer, Royal Womens Hospital, Brisbane, Australia. Email:
andreas_obermair@health.qld.gov.au
impaired prognosis for anemic compared to nonanemic
cervical cancer patients who undergo radiotherapy. It has
been argued that anemia might be a surrogate marker for
tissue hypoxia and thus mediate resistance to radiother-
apy rather than anemia representing a biologically more
aggressive tumor(1,46).
Until 1999, radiotherapy was the standard of care
for patients with locally advanced cervical cancer.
Therefore, studies which examined the impact of anemia
were based on patients who were treated with
radiotherapy as a single modality treatment. Recently,

# 2003 IGCS
634 A. Obermair et al.
five prospective randomized trials reported a reduc-
tion of 24% to 51% for the risk of death for patients
treated with concurrent chemoradiation when com-
pared with conventional radical radiotherapy(711).
As a consequence, chemoradiation has replaced
radiotherapy as the current standard of treatment
for locally advanced cervical carcinoma(12).
Until recently, no data were available about the
significance of anemia in patients undergoing concur-
rent chemoradiation for cervical carcinoma. In our
previous study the nadir hemoglobin rather than the
hemoglobin at presentation was highly predictive of
the response to treatment in patients with carcinoma
of the cervix who received radical chemoradiation(13).
Because of the short follow-up, no data regarding the
prognostic effect of anemia could be provided. There-
fore, in the present study we aimed to describe a possible
relationship between hemoglobin levels before and
during treatment and the prognosis in patients under-
going chemoradiation for cervical cancer.
Patients and methods
Patients
Sixty two patients with histologically proven cervical
carcinoma underwent definitive concurrent chemoradia-
tion at the Queensland Radium Institute in Brisbane,
Australia between January 1996 and March 2001. We
excluded two patients because they underwent a comple-
tion hysterectomy after radiotherapy. For the aim of this
analysis, patients had to have: histologically proven
cervical carcinoma, stage IB to IVA disease; radical radio-
therapy with concurrent chemotherapy; and no previous
radical or standard hysterectomy. Patients with stage IVB
disease were not included into this series because the aim
of treatment was palliation rather than cure in those
patients. Histologic grading was based on the proportion
of the tumor that was undergoing keratinization with the
formation of squamous pearls and the number of mito-
sis(14). Tumors were graded as well differentiated (grade
1), moderately differentiated (grade 2), or poorly differ-
entiated (grade 3). The stage of disease was determined
clinically according to the 1995 FIGO staging system(15).
Treatment
Before commencement of chemoradiotherapy, all
patients underwent a CT scan of the pelvis and the abdo-
men and an X-ray of the chest. Patients with bulky pelvic
lymph nodes had a extraperitoneal lymph node debulk-
ing prior to chemoradiation. All patients received radical
radiotherapy to the pelvis and concurrent chemother-
# 2003 IGCS, International Journal of Gynecological Cancer 13, 633639
apy. Fourteen patients (23.3%) had a pelvic/aortic
lymph node debulking prior to chemoradiation. Radical
pelvic radiotherapy was given with the aim of cure in all
patients. The pelvis was treated by external beam radio-
therapy with a linear accelerator using minimum
photon-beam energy of 4 MV within a standard four-
field box. Patients with stage IB, IIA, and IIB cervical
carcinoma received a dose of 4045 Gy at the ICRU
(International Commission of Radiation Units) reference
point external beam radiotherapy given in 2528
fractions over 55 weeks. Patients with stage III and
IVA cervical carcinoma received a dose of 52.5 Gy as
external beam radiotherapy given in 30 fractions over 6
weeks. External beam radiotherapy was followed by
intracavitary low-dose rate brachytherapy up to 2
weeks after completion of external beam radiotherapy.
Patients with stage IB, IIA, and IIB cervical carcinoma
received 50 Gy to point A in one or two insertions.
Patients with stage III and IVA cervical carcinoma
received 25 Gy to point A in one insertion. Due to poor
compliance with treatment, one patient did not receive
brachytherapy.
Chemotherapy consisted of cisplatin alone (n 54),
cisplatin combined with vinblastine (n 1), cisplatin
combined with 5-fluorouracil (n 3), or 5-fluorouracil
as single agent (n 2). Chemotherapy started at the
commencement of radiotherapy (day 1) and was
given every 7 days thereafter. One liter of normal
saline was given both before and after cisplatin. Pre-
medication included ondansetron and dexametha-
sone. The median dose of cisplatin was 40 mg per
square meter of body-surface area per week (range,
3050 mg/m2). Generally the total dose of cisplatin
did not to exceed 70 mg per week. Two patients had
single agent 5-fluorouracil at a dose of 800 mg/m2 per
day intravenously (iv) continuous for 96 h and in
another two patients 5-fluorouracil was given at a
dose of 800 mg/m2 per day i.v. continuous for 96 h
combined with 80 mg/m2 of cisplatin on day 1. This
schedule was repeated after 4 weeks. One patient had
cisplatin 40 mg/m2 combined with vinblastine at a
dose of 4 mg/m2. The median number of cycles was
five (range, four to six). Treatment with cisplatin was
withheld if neutrophil count was less than 1.0109
per liter or if the platelet count was less than 80109
per liter. During treatment patients were seen weekly
and a full blood count and serum electrolytes, liver
function tests, and renal function tests were taken.
Determination of anemia
A full blood count was determined by venous punc-
ture before commencing radiotherapy and then every
 Anemia before and during concurrent chemotherapy in cervical cancer patients 635

7 days thereafter. We recorded the hemoglobin before
treatment and the lowest hemoglobin level which was
observed throughout chemoradiation (nadir Hb).
Hemoglobin values are given in gram per liter102
(g/dl). Seventeen patients (28.3%) received at least
one blood transfusion during chemoradiation and
the median number of blood transfusions was four
(range, two to nine) with a median trigger Hb of
8.6 g/dL (range, 6.3 g/dl to 10.6 g/dl). Two, four,
eight, and three patients received their first blood
transfusion at chemotherapy cycle numbers 1, 2, 3,
or 4, respectively. There was no uniform policy on
blood transfusion and no patient received erythropoietin
prior or during chemoradiation. Patients were considered
smokers if they regularly smoked more than five
cigarettes per day at the time of diagnosis.
(25th) quartile was used as the cut-of level for both
the initial and the nadir hemoglobin levels. Patients
with values below or equal this value were considered
anemic. Univariate and multivariate Cox models
were calculated in order to identify independent
prognostic factors for PFS. We did not include the
histologic type as a covariate in the Cox model
because only five of 62 patients had a histologic type
other than squamous cell carcinoma (SCC). Univariate
analysis of PFS was performed as outlined by Kaplan
and Meier(22) and survival curves were compared using
the log-rank test(23). P-values are the result of two-sided
tests and a P-value <0.05 was considered to indicate a
statistically significant difference. Statistical analysis
was done using SPSS (Version 9.0, SPSS, INC, Chicago,
IL).

Statistical methods Results

The primary statistical endpoint was progression-free
survival (PFS), which was defined as the period from
the commencement of chemoradiation until the date
of first recurrence. Data on patients who were tumor-
free were censored at the last follow-up visit. By using
the ANOVA test, mean hemoglobin levels were
compared among various clinical and histopathologic
parameters (patients characteristics). Hemoglobin
values were entered in the ANOVA test as a continuous
variable. Hemoglobin values were dichotomized. In
the absence of an established cut-off level the lower
Analysis is based on the data of 60 patients with a
mean age of 48.3 years (range, 2977 years). The
distribution of patients to stages IB, IIA, IIB, III, and
IVA was 13, 3, 24, 18, and 2 patients, respectively. The
median tumor size (25th quartile, 75th quartile) was
5 cm (4 cm, 6 cm). Data on the grade of differentiation
were available in 53 patients but not available in
seven patients. Further patients characteristics are
given in Table 1.
Forty-seven patients (75.3%) had a complete clinical
response to chemoradiation, 10 patients (16.7%) had

Table 1. Patients characteristics

Hb presentation Nadir Hb
n (mean  SD) P-value (mean  SD) P-value
Stage
IB, IIA 16 13.5  1.5 10.8  1.9
IIB 24 12.8  1.2 10.9  1.2
III, IVA 20 12.1  1.2 0.007 10.6  1.8 0.287
Histologic type
SCC 56 12.7  1.4 10.6  1.6
Adenocarcinoma, adenosquamous carcinoma 4 13.2  0.9 0.479 10.7  2.3 0.895
Grading
Well/moderately 28 12.3  1.5 10.8  1.8
Poorly 25 12.8  1.1 0.183 10.4  1.3 0.437
Parametrial involvement
None 14 13.4  1.6 10.7  1.8
Unilateral 27 12.6  1.3 10.7  1.4
Bilateral 19 12.3  1.2 0.068 10.3  1.7 0.695
Lymph nodes
Negative 46 12.7  1.3 10.4  1.7
Positive 14 12.7  1.8 0.919 11.1  1.2 0.221
Tumor size

5 cm 34 13.0  1.5 11.0  1.4
>5 cm 26 12.3  1.1 0.064 10.0  1.6 0.008

# 2003 IGCS, International Journal of Gynecological Cancer 13, 633639

636 A. Obermair et al.
a partial response, and two patients (3.3%) did not
respond to treatment. In one patient we were
unable to determine the response to chemoradiation.
The mean PFS for patients who recurred was 15.0
months (25% to 75%, 6.022.6). After a median
follow-up of 26.3 months (25% to 75%, 18.326.3
months), 20 patients developed recurrent disease.
The site of the first recurrence was the pelvis in 13
patients, six patients developed metastases at distant
sites (supraclavicular lymph nodes, n 1; lung, n 2;
umbilicus, n 1), and one patient developed a central
local recurrence. At the time of statistical analysis, 34
patients were alive without any evidence of disease,
nine patients were alive with disease, 12 patients had
died of disease, and three patients had died of causes
other than cervical cancer (biliary sepsis due to a
calculus in the biliary duct, n 1; small bowel
obstruction due to radiation changes, n 1). Two
patients were lost for follow-up after 10 and 21
months, respectively. The overall survival probability
was 78.7% at 5 years for all patients.
Association of hemoglobin levels with clinical and
histopathologic features
For all patients the mean Hb (SD) at presentation
and the mean nadir Hb (SD) were 12.8 g/dl (1.4 g/
dl) and 10.6 g/dl (1.6 g/dl), respectively. Patients
with lower tumor stage presented with higher Hb
values before chemoradiation (P 0.007) compared
to patients with higher tumor stages. Patients with
tumors measuring larger than 5 cm had lower nadir
Hb values throughout treatment (P 0.013) than
patients with smaller tumors. No other statistically
significant association of the initial Hb or nadir Hb
with stage, tumor size, parametrial or lymph node
involvement, histologic grading, or histologic type
was found (Table 1).
Table 2. Univariate Cox models with regard to disease-free survival in 60 patients with concurrent chemoradiation for cervical
carcinomaa
Covariates
Stage (IB, IIA vs. IIIB vs. III, IVA)
Hb nadir
Size (
5 cm vs. >5 cm)
Parametrial involvement (nil vs. unilateral vs. bilateral)
Hb at presentation (continuous)
Grading (g1,g2 vs. g3)
Lymph nodes (negative vs. positive)
Cigarette smoking (yes vs. no)
a
Abbreviations: OR, odds ratio; 95% CI, 95% Confidence interval;
# 2003 IGCS, International Journal of Gynecological Cancer 13, 633639
Nine of 14 patients who were anemic before the
commencement of treatment experienced anemia dur-
ing treatment, whereas five patients remained non-
anemic. Forty-five patients were considered not
anemic before treatment and only seven of those
patients developed anemia during chemoradiotherapy
(Chi-square 12.82, P 0.001).
Association of hemoglobin levels with PFS
Univariate Cox models revealed that stage, nadir Hb,
and parametrial involvement were determinants of
PFS, whereas the Hb at presentation, tumor size, histo-
logic grade, lymph node involvement, and cigarette
smoking were not (Table 2). A multivariate Cox model
including the covariates stage, nadir Hb, and parame-
trial involvement demonstrated an independent prog-
nostic effect on PFS for stage and nadir Hb but not for
parametrial involvement (Table 3).
At 60 months the PFS was zero and 66.6% for
patients who started chemotherapy with an initial Hb
of
11.6 and who were therefore considered anemic
and for nonanemic patients, respectively (log-rank
P 0.147) (Fig. 1A). At 60 months the PFS was 39.1%
and 48.0% for patients who had a nadir Hb of 9.4 g/dl
or less during chemoradiation compared to patients
with a lowest recordable Hb of >9.4 g/dl throughout
chemoradiation (Log-rank P 0.005) (Fig. 1B).
Within the follow-up period, local control could be
maintained in 45 patients (75.0%). The probability of
local control at 60 months was 41.9% and 81.3% for
patients who had a nadir Hb of 9.4 g/dl or less during
chemoradiation compared to patients with a lowest
recordable Hb of >9.4 g/dl throughout chemoradia-
tion (Log-rank P 0.002).
Discussion
Disease progression was significantly more likely in
patients who became anemic during chemoradiation
OR 95% CI P-value
3.4 1.67.0 0.001
0.3 0.10.7 0.009
1.6 0.63.9 0.299
1.9 1.03.7 0.037
0.5 0.21.3 0.155
0.9 0.81.0 0.323
0.7 0.22.4 0.637
1.01 0.42.5 0.967
 Anemia before and during concurrent chemotherapy in cervical cancer patients
Table 3. Multivariate Cox model (nonstepwise) with regard to disease-free survival in 60 patients with concurrent chemoradiation
for cervical carcinomaa
Covariates
Stage (IB, IIA vs. IIB vs. III, IVA)
Hb nadir (continuous)
Parametrial involvement (none vs. unilateral vs. bilateral)
a
Abbreviations: OR, odds ratio; CI, confidence interval
compared to patients who maintained normal Hb
levels. In a multivariate analysis, the nadir Hb and
the stage of the disease were the only prognostic
factors predictive of tumor progression. A quarter of
A cant (Fig. 1A).
B
Fig. 1. Kaplan-Meier estimates of progression-free survival (PFS) in
60 patients who underwent chemoradiation for cervical carcinoma.
The bold lines represent anemic patients and the dotted lines
represent nonanemic patients. Patients who had an Hb below the
25th quartile were considered anemic. A) Patients were
dichotomized according to the Hb at the time of commencing
treatment (
11.6 g/dl vs. >11.6 g/dl, Log-rank P 0.147). B)
Patients were dichotomized according to the lowest Hb during
chemoradiation (
9.4 g/dl vs. >9.4 g/dl, Log-rank P 0.0057).
637
OR 95% CI P-value
3.1 1.37.2 0.007
0.4 0.151.0 0.05
0.9 0.44.9 0.556
the patients had a nadir Hb of
9.4 g/dl and experi-
enced a PFS of only 39% at 5 years. In contrast,
patients who maintained a Hb of >9.4 g/dl had a
48% chance of being disease-free at the same time
(Fig. 1B). Interestingly, as with previous studies,
anemia at presentation was not prognostically signifi-
Recently, the impact of anemia and blood transfu-
sion on the survival of 605 patients with cervical
cancer has been investigated at seven centers in
Canada(1). A low average weekly nadir Hb had a
negative effect on disease-free and overall survival.
The 5-year survival was 74% for patients who main-
tained a normal Hb (120 g/l) throughout radiother-
apy and only 45% for patients who dropped their Hb
below 110 g/l. In contrast, the Hb at presentation and
blood transfusion were prognostically irrelevant(1).
Similar findings were reported in another study of
386 patients treated with radiation therapy for locally
advanced cervical carcinoma(6). Multivariate analysis
demonstrated that a Hb <10 g/dl before radiation
therapy was not prognostically relevant. In contrast,
patients with at least one Hb value below 10 g/dl
during therapy had an 80% increased risk of local
regional failure compared with patients with all
their values above 10 g/dl(6).
Three possible explanations exist why anemia
appears to be associated with a worse outcome: 1)
The presence of anemia might indicate tumors
which are biologically more aggressive. However,
previous findings(1,6,13) and the findings from this
study indicate that the Hb values recorded before
treatment are prognostically irrelevant, whereas the
Hb values which were recorded during or even at
the end of radiotherapy are prognostically important;
2) Anemia might be a surrogate marker of tumor
hypoxia. This is known to mediate resistance to radio-
therapy(1821); 3) A mechanism different from anemia
might not only mediate resistance to therapy but also
induce anemia as a consequence.
In contrast to histopathologic factors, anemia is
potentially reversible. Various approaches have been
evaluated to overcome the effects of hypoxia. Carbo-
gen, a mixture of carbon dioxide and oxygen, reduces
# 2003 IGCS, International Journal of Gynecological Cancer 13, 633639
638 A. Obermair et al.
the hypoxic cell fraction and increases tumor oxygen-
ation(22,23). Blood transfusions and human recombin-
ant Erythropoietin (rh-EPO) are the most frequently
used methods to correct anemia. For the correction of
chronic anemia, blood transfusions are not optimal
because the effect is only short lasting. Therefore,
multiple transfusions may be required throughout a
treatment program that lasts 5 to 6 weeks. In addition,
there are small but definitive risks of transfusion
reactions and viral infection and the availability of
blood products is limited(24,25). As an alternative,
research has concentrated on rh-EPO as its effect is
long-lasting and it is synthesized recombinantly.
In summary, we have demonstrated that anemia dur-
ing treatment identifies a group of patients who are at an
unacceptably high risk for treatment failure. The likeli-
hood of patients with a nadir HB
9.4 g/dl during
chemoradiation being tumor-free at 30 months is only
39%. This is similar to the results for patients receiving
palliative radiotherapy for stage IV disease(26).
As with every retrospective study, the authors
acknowledge the limitations of this analysis. While
an association of a low Hb during chemoradiotherapy
with treatment outcome is likely, a treatment recom-
mendation cannot be drawn. In the absence of
explanations as to why some patients become anemic
and others maintain normal Hb values throughout
chemoradiation, future research should investigate
causes and pathogenetic mechanisms of anemia.
Clinical trials currently evaluate whether rh-EPO not
only increases the blood Hb level but also increases
the response to chemoradiation in cervical carcinoma
patients.
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# 2003 IGCS, International Journal of Gynecological Cancer 13, 633639