Int. J. Radiation Oncology Biol. Phys., Vol. 46, No. 2, pp.

459 – 466, 2000

Copyright © 2000 Elsevier Science Inc.
Printed in the USA. All rights reserved
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PII S0360-3016(99)00384-3

CLINICAL INVESTIGATION Head and Neck

SEVERE ANEMIA IS ASSOCIATED WITH POOR TUMOR OXYGENATION IN

HEAD AND NECK SQUAMOUS CELL CARCINOMAS

AXEL BECKER, DR.MED.,* PETER STADLER, DR.MED.,† ROBERT S. LAVEY, M.D., M.P.H.,‡
GABRIELE HÄNSGEN, DR.MED.,* THOMAS KUHNT, DR.MED.,* CHRISTINE LAUTENSCHLÄGER, DR.RER.NAT.,§
HORST JÜRGEN FELDMANN, PD DR.MED.,† MICHAEL MOLLS, PROF.DR.MED.,†
AND JÜRGEN DUNST, PROF.DR.MED.*

*Department of Radiooncology and §Institute of Medical Biometry, Martin Luther University, Halle-Wittenberg, Germany; †Department
of Radiooncology, Technical University, Munich, Germany; and ‡Radiation Oncology Program, Children’s Hospital Los Angeles,
University of Southern California, Los Angeles, CA USA

Purpose: To investigate the relationship between tumor oxygenation and the blood hemoglobin (Hb) concentra-
tion in patients with squamous cell carcinoma of the head and neck (SCCHN).
Methods and Materials: A total of 133 patients with SCCHN underwent pretreatment polarographic pO2
measurements of their tumors. In 66 patients measurements were also made in sternocleidomastoid muscles. The
patients were divided into three groups according to their Hb concentration—severe anemia (Hb < 11.0 g/dl),
mild anemia (female: Hb 11.0 –11.9 g/dl; male: Hb 11.0 –12.9 g/dl), and normal Hb concentration (female: Hb
>12.0 g/dl; male: >13.0 g/dl).
Results: No significant difference in tumor oxygenation could be detected between mildly anemic patients and
patients with a normal Hb level. However, the tumor oxygenation in the severely anemic group was significantly
below that of each of the other two groups (p < 0.0001). There was no significant difference between the Hb
groups in oxygenation of sternocleidomastoid muscles. In a multivariate analysis including Hb group, tumor
volume, smoking habits, gender, T-stage, N-stage, and histologic grade a Hb level < 11 g/dl was found to be the
strongest predictor for a poor tumor oxygenation. Smoking also had a marginal influence on median pO2.
Conclusion: Our data suggest that a low Hb concentration and cigarette smoking contribute to inadequate
oxygenation of SCCHN and thus for increased radioresistance. Consequently, Hb correction and abstinence from
smoking may significantly improve tumor oxygenation. © 2000 Elsevier Science Inc.

Hemoglobin concentration, Anemia, Hypoxia, Smoking, Tumor oxygenation, Head and neck carcinoma.

INTRODUCTION and oxygen levels in experimental sarcomas (19, 20). A first

Hypoxia is an important factor for radioresistance. An ap-
proximately 2–3 times higher radiation dose is necessary to
kill hypoxic cells in comparison to well-oxygenated cells (1,
2). By use of polarographic electrodes, hypoxic areas have
been detected in a wide range of human tumors (3–11).
Multiple institutions have reported that tumor oxygenation
is significantly associated with tumor control and/or sur-
vival in patients with squamous cell carcinoma of the uter-
ine cervix or the head and neck after radiation therapy
(12–17). Indirect support for an oxygen effect is provided
by the results of a variety of studies showing an association
between the hemoglobin (Hb) level and efficacy of radiation
therapy (18). Hb level is presumably mediating tumor re-
sponse to radiation through delivery of oxygen to the tumor.
Animal studies have found a strong correlation between Hb
indication that severely anemic patients (Hb ⬍ 10.0 g/dl)
tend to have a lower pO2 was noted for carcinoma of the
cervix uteri by Vaupel and Höckel (21). For squamous cell
carcinoma of the head and neck, such an effect has not yet
been reported. The purpose of this study was to evaluate the
relationship between the Hb concentration and the polaro-
graphically measured pretreatment oxygenation status of
normal and malignant tissues in patients with head and neck
cancer.
METHODS AND MATERIALS
Patients
Oxygen measurements were made in 133 patients with
histologically proven squamous cell carcinoma of the head

Reprint requests to: Dr. Axel Becker, Department of Radiother-
apy, Martin Luther University, Halle-Wittenberg, Dryanderstrasse
4-7, 06097 Halle, Germany. E-mail: axel.becker@medizin.
uni-halle.de
Acknowledgment—The authors thank Dr. P. Vaupel, Professor and
Chairman, Institute of Physiology and Pathophysiology, Univer-
sity of Mainz, Germany, for the valuable comments and sugges-
tions.
Accepted for publication 30 August 1999.

459
460 I. J. Radiation Oncology ● Biology ● Physics Volume 46, Number 2, 2000

and neck presenting to either of two radiooncology centers Table 1. Patient characteristics
for initial treatment or planned adjuvant therapy between
Mild anemia Normal
September 1994 and June 1999. The measurements were Severe Hemoglobin Hemoglobin
done either immediately before the onset of a definitive anemia conc. female: conc. female:
radiooncological therapy or at least 1 day before the surgical Hemoglobin 11–11.9 g/dl ⱖ 12 g/dl
removal of the tumor. All tumor manifestations (primary Factor conc. male: male:
site and cervical lymph node metastases) were examined Description ⬍ 11.0 g/dl 11–12.9 g/dl ⱖ 13 g/dl
that could be reasonably reached with a polarographic elec- No. of pats.
trode without causing too much discomfort for the patient. Total n ⫽ 133 20 40 73
In one center,1 the O2 tension of the contralateral sterno- Age (median) 57 58 59
cleidomastoid muscles was also measured. We chose this Gender
female 4 5 11
muscle to obtain data from an area that is easy to identify male 16 35 62
and located in the prospective radiation field in order to T-stage
have the option for investigations of the effect of radiation T1 — — 4
therapy. The study was approved by the local ethics com- T2 — 3 8
mittee of each participating university and informed consent T3 5 3 8
T4 14 31 51
was obtained from all patients in accordance with the Dec- Tx (CUP) 1 3 1
laration of Helsinki of 1975, as revised in 1983. Patient n.a. — — 1
characteristics and the sites of measurement are outlined in N-stage
Table 1. N0 1 4 5
N1 1 7 4
N2 10 22 50
N3 8 7 14
Data collection M-stage
The oxygen tension in tumors and healthy tissues was M0 20 39 72
measured using a commercially available polarographic M1 — 1 1
needle electrode.2 Detailed description of the device has Histologic grade
G1 1 2 5
been published by others (4, 22). After localization of the
G2 8 19 29
tumors with computerized tomograpy (CT) or sonography, G3 9 18 34
a polarographic probe was inserted into the regions of G4 1 — 2
interest and moved automatically forward in steps of 0.7 Gx 1 1 3
mm. A mean of 5 electrode tracks (range 2–9) and a mean Site of primary tumor
Oropharynx 13 19 34
of 144 pO2 measurements (range 46 –327) were recorded
Hypoph./Lary. 2 8 15
per investigation. For documentation we used pO2 histo- Fl. of mouth 2 6 9
grams with classes of 2.5 mmHg (23). To estimate the Tongue 2 3 11
oxygenation status of tissue, the median pO2 from data Other* — 1 3
pooled from each patient was calculated. We used the Unknown 1 3 1
Smoking habits
proportion of pO2 values ⱕ5 mmHg as the indicator of
Smoker 2 4 10
relative hypoxia. This parameter is commonly used because Nonsmoker 18 36 62
it has been shown to closely correlate well with hypoxic Unknown — — 1
fraction as defined by classical radiobiologic assays (24, Site of pO2
25). Levels ⱕ5 mmHg probably reflect radiobiologically measurement
Primary tumor 10 20 34
relevant tissue hypoxia (1, 23).
Neck node 10 20 39
The Hb concentration was estimated by standard proce-
dure in a venous sample before each pO2 measurement. All tumors are classified according to the TNM staging system
Using the normal Hb values defined by the World Health AJC-UICC 1993.
Organization (WHO) (female: ⱖ12.0 g/dl; male: ⱖ13.0 * Nasopharynx (N ⫽ 2), maxillaris sinus (N ⫽ 1), buccal mu-
cosa (N ⫽ 1).
g/dl) the patients were divided into a normal and an anemic
group prior to analysis (26). Since diminished tumor oxy-
genation was associated only with a significantly low Hb allocated to the mild anemia group (female: Hb 11.0 –11.9
level in the sole previously published series (21), we defined g/dl; male: Hb 11.0 –12.9 g/dl). Patients with acute bleeding
in anemic patients an additional group with severe anemia were excluded. Blood transfusions or erythropoietin injec-
reflecting at least Grade 1 toxicity according to the Common tions were not given before pO2 measurements.
Toxicity Criteria (CTC) of the National Cancer Institute (Hb The tumor volume (primary tumor ⫹ all neck nodes
concentration ⬍11.0 g/dl). The remaining patients were metastases) was estimated on the basis of CT or magnetic

1 2
Department of Radiooncology Martin Luther University, Eppendorf KIMOC 6650, Hamburg, Germany.
Halle-Wittenberg.
 Severe anemia and poor tumor oxygenation ● A. BECKER et al. 461

resonance imaging (MRI) scan or using sonography data.

The volume calculation was made by the formula: V⫽ 1/6
␲ ⫻ height ⫻ breadth ⫻ depth.

Statistical considerations
For evaluation of the relationship between oxygenation of
primary tumors and neck node metastases as well as Hb
concentration and tumor oxygenation, we performed a re-
gression analysis. To compare the pO2 status between dif-
ferent groups, the Mann-Whitney U-test for independent
samples was applied. Since the analysis was based on a
multiple testing of parameters and groups, the Bonferroni
method was performed for an adjustment of the significance
level (basic level p ⬍ 0.05). To control for influences of
other factors on tumor oxygenation, a logistic regression
was performed. This analysis included Hb group, gender,
tumor volume, smoking habits, T-stage, N-stage, and his-
tologic grade. Based on their unequal distribution T-stage,
N-stage, and histologic grade were allocated to T1/2 vs.
T3/4, N0 vs. N⫹, and G1/2 vs. G3/4. Depending on smok-
ing habits the patients were classified as smoker or non-
smoker. All nonsmokers had a negative smoking history for
at least 5 years. Because a logistic regression requires a
dichotomous variable, the median value of the median pO2
and the percent of measures ⱕ 5 mmHg were independently
used to divide patients into a well-oxygenated and a poorly
oxygenated group. All calculations were done with a com-
mercially available software package.3

RESULTS
Pretreatment tumor pO2 levels were obtained in 133
patients. Both the primary tumor and a neck node metastasis
were measured in 30 patients, only the primary tumor was
measured in 34 patients, and only a neck node metastasis
was measured in 69 patients. Measurements in the contralat-
eral sternocleidomastoid muscle were made in 66 patients.
The average pretreatment median pO2 in primary tumors
was 12 mmHg (range: 0 –58 mmHg; 95% confidence inter-
val of mean [95% CI]: 9 –15 mmHg) and in metastases was
13 mmHg (range: 0 –50 mmHg; 95% CI: 11–16 mmHg).
The mean proportion of values ⱕ 5 mmHg in primary
tumors was 30% (range: 0 –90%; 95% CI: 23–36%) and in
metastases was 36% (range: 0 –96%; 95% CI: 31– 41%). No
statistically significant difference was seen between the
oxygenation status of primary tumors and neck node me-
tastases (median pO2: p ⫽ 0.9; proportion of values ⱕ5
mmHg: p ⫽ 0.15). In consensus with our previously pub-
lished data (11), we found a strong correlation between
primary tumor and neck node metastasis measured by either
the median pO2 (r ⫽ 0.89) or the proportion of values ⱕ5
mmHg (r ⫽ 0.87, Fig. 1). Therefore, for all patients in
whom both the primary tumor and a neck node metastasis
Fig. 1. Scatter graph showing the correlation between polarograph-
ically measured oxygenation in primary tumors and neck node
metastases (n ⫽ 30) with regard to median pO2 (p ⫽ 0.0001, r ⫽
0.89, Spearman) (A) and proportion of values ⱕ 5 mmHg (p ⫽
0.0001, r ⫽0.82, Spearman) (B).
were measured, only the values of the primary tumors were
included in further analyses.
In the sternocleidomastoid muscles, the average median
pO2 was 38 mmHg (range: 21– 68 mmHg; 95% CI: 35– 40
mmHg) and the proportion of values ⱕ5 mmHg was 1%
(range: 0 – 8%; 95% CI: 0.6 –1.6%). Measurements ⱕ5
mmHg in healthy muscles are probably caused by short-
time localization of the probe in fascias and tendons (see
also Ref. 11). Of the 66 patients in whom measurements
were made of both sternocleidomastoid muscle and tumor,
the median pO2 was higher and the proportion of values ⱕ5
mmHg was lower in the sternocleidomastoid muscle in each
patient. The differences in median pO2 and proportion ⱕ5
mmHg were both highly significant (p ⬍ 0.0001).
The mean Hb concentration among the 133 patients was
12.8 g/dl (range: 8.8 –17.0 g/dl; 95% CI: 12.6 –13.2 g/d). As
expected, females had a lower mean Hb level than males,

3
SPSS for Windows.
462 I. J. Radiation Oncology ● Biology ● Physics
Fig. 2. Scatter graph showing the relationship between polaro-
graphically measured tumor oxygenation and Hb concentration
with regard to median pO2 (A) and proportion of values ⱕ 5
mmHg (B) (n ⫽ 133). The vertical dotted line indicates the cutoff
point to separate severe anemia and mild anemia as well as normal
Hb concentration.
however, this difference was not significant (p ⫽ 0.23) (12.5
g/dl vs. 12.9 g/dl). Forty-five percent of the patients were
anemic according to the WHO definition. Severe anemia
(Hb ⬍11.0 g/dl) was found in 15%.
Analyzed as a continuous variable, Hb concentration was
found to be significantly related with both median pO2 (p ⫽
0.011, r ⫽ 0.25 by quadratic regression) and the relative
proportion of hypoxic values (p ⫽ 0.001, r ⫽ 0.33 by
quadratic regression) in tumors but the predictive value of
Hb concentration for tumor oxygenation was weak (Fig. 2).
Although the scatter graph for Hb concentration and
tumor oxygenation (Fig. 2) suggests a decrease of tumor
pO2 not only at low Hb levels but also at the upper end of
the Hb scale, we abstained to define a fourth group with a
very high Hb level since the number of patients was not
large enough for this purpose. For analysis of tumor oxy-
genation by Hb category, we used only the three groups
defined prior to pO2 measurements (Fig. 3). There were 73
patients in the normal Hb category, 40 patients in the mild
anemia category, and 20 patients in the severe anemia
Volume 46, Number 2, 2000
Fig. 3. Comparison of tumor oxygenation in patients with severe
anemia, mild anemia, and normal Hb concentration. Median pO2
(A): severe anemia vs. mild anemia, p ⫽ 0.0001; severe anemia vs.
normal Hb, p ⫽ 0.0001; mild anemia vs. normal Hb, p ⫽ 0.3.
Proportion of values ⱕ5 mmHg (B): severe anemia vs. mild
anemia, p ⫽ 0.002; severe anemia vs. normal Hb, p ⫽ 0.0001;
mild anemia vs. normal Hb, p ⫽ 0.7. Bars indicate 95% confidence
interval of the mean.
category. The trend toward higher median pO2 and lower
proportion of measures ⱕ 5 mmHg in the normal Hb group
than in the mild anemia group did not reach statistical
significance (median pO2: p ⫽ 0.3; values ⱕ 5 mmHg: p ⫽
0.7). However, the median pO2 in the severe anemia group
(5 mmHg, range 0 –19 mmHg, 95% CI: 2–7 mmHg) was
statistically significantly below that of both the mild anemia
group (13 mmHg, range 0 – 47 mmHg, 95% CI: 9 –16
mmHg) and the normal Hb group (15 mmHg, range 0 –58
mmHg, 95% CI: 12–18 mmHg) (both p ⫽ 0.0001). The
severe anemia group also had a significantly higher mean
proportion of measures ⱕ 5 mmHg (55%, range 1– 86%,
95% CI: 44 – 66%) compared to the mild anemia (32%,
range 0 –96%, 95% CI: 24 – 41%) and normal Hb groups
(30%, range 0 –96%, 95% CI: 24 –36%) (p ⫽ 0.002 and p ⫽
0.0001).
A weak inverse correlation could be detected between
 Severe anemia and poor tumor oxygenation ● A. BECKER et al. 463

Table 2. Multivariate analysis of factors with potential influence Table 3. Multivariate analysis of factors with potential influence
on tumor oxygenation using median pO2 as parameter for on tumor oxygenation using proportion of values ⱕ 5 mmHg as
differentiation of well-oxygenated and poorly oxygenated tumors parameter for differentiation of well-oxygenated and poorly
(cutoff point: 9.5 mmHg) oxygenated tumors (cutoff point: 33.3%)

Odds ratio Better Odds ratio Better

Parameter p-value (CI 95%) oxygenation Parameter p-value (CI 95%) oxygenation

Hb group Hb group
Severe anemic vs. 0.01 7.2 (1.6–33.8) Mild anemic Severe anemic vs. 0.02 5.8 (1.3–24.8) Mild anemic
mild anemic mild anemic
Severe anemic vs. 0.002 10.6 (2.4–47.8) Normal Hb Severe anemic vs. 0.009 6.5 (1.6–26.3) Normal Hb
normal Hb normal Hb
Smoking Smoking
Smoker vs. nonsmoker 0.07 3.5 (0.9–13.8) Nonsmoker smoker vs. nonsmoker 0.15 — —
Gender Gender
Females vs. males 0.9 — — females vs. males 0.64 — —
T-stage T-stage
T1⫹2 vs. T3⫹4 0.96 — — T1⫹2 vs. T3⫹4 0.9 — —
N-stage N-stage
N0 vs. N⫹ 0.6 — — N0 vs. N⫹ 0.73 — —
Grading Grading
G1⫹2 vs. G3⫹4 0.75 — — G1⫹2 vs. G3⫹4 0.72 — —
Volume 0.26 — — Volume 0.31 — —

median pO2 and tumor volume (p ⫽ 0.03, r ⫽ ⫺0.19). No
correlation was found for the proportion of values ⱕ 5
mmHg and volume of tumor (p ⫽ 0.24).
Of the 133 patients measured, 116 were smokers, 16 were
nonsmokers, and one could not be classified due to lack of
information on smoking habits. The median pO2 in tumors
tended to be lower in smokers than in nonsmokers (12
mmHg, range 0 –58 mmHg, 95% CI: 10 –14 mmHg vs. 17
mmHg, range 1– 45 mmHg, 95% CI: 10 –24 mmHg; p ⫽
0.06). There was also a trend toward a higher proportion of
values ⱕ 5 mmHg in smokers than in nonsmokers (36%,
range 0 –96%, 95% CI: 31– 41% vs. 25%, range 0 – 80%,
95% CI: 12–38%) that did not reach statistical significance
(p ⫽ 0.13).
As expected our study included more men than women
(Table 1). The median pO2 in women (12 mmHg, range
0 –38 mmHg, 95% CI: 7–18 mmHg) was similar to men (13
mmHg, range 0 –58 mmHg, 95% CI: 11–15 mmHg). The
proportion of measures ⱕ 5 mmHg tended to be higher in
females (43%, range 2–96%, 95% CI: 29 –57%) than in
males (33%, range 0 –92%, 95% CI: 28 –38%) but the
difference did not reach statistical significance (p ⫽ 0.13).
There was no significant difference in the median pO2 or
proportion of measures ⱕ 5 mmHg by tumor size (T1/2 vs.
T3/4), lymph node involvement (N0 vs. N1-3), or tumor
grade (G1/2 vs. G3/4), with all p-values ⱖ0.16.
By logistic regression a Hb concentration ⬍ 11 g/dl was
found to be the strongest predictor for poor tumor oxygen-
ation. The smoking habits had only a marginal influence on
median pO2 in our study. For all other parameters an impact
on tumor oxygenation could not be detected. The detailed
results are given in Tables 2 and 3.
The relationship between normal tissue oxygenation and
Hb concentration was investigated in 66 patients for whom
polarographic measurements of their sternocleidomastoid
muscles were taken. Analyzed as continuous variable by
linear regression, the Hb concentration was not significantly
related with either median pO2 (p ⫽ 0.9) or proportion of
measures ⱕ 5 mmHg in the sternocleidomastoid muscle
(p ⫽ 0.2). There were 35 patients with a normal Hb, 22
patients with mild anemia, and 9 patients with severe ane-
mia. The severe anemia group showed a trend toward a
lower median pO2 (32 mmHg, range 21– 46 mmHg, 95%
CI: 26 –38 mmHg) as compared to the mild anemia (40
mmHg, range 28 – 68 mmHg, 95% CI: 36 – 45 mmHg; p ⫽
0.09) or the normal Hb group (38 mmHg, range 24 – 68
mmHg, 95% CI: 34 – 41 mmHg; p ⫽ 0.2). However, the
differences did not reach statistical significance.
DISCUSSION
Hb concentration was found in this study to be associated
with the oxygen level in primary tumors and neck node
metastases from squamous cell carcinoma of the head and
neck. A Hb concentration below 11 g/dl was associated with
a highly significantly lower median pO2 as well as with a
highly significantly higher proportion of values ⱕ 5 mmHg.
This effect was confirmed by a multivariate analysis includ-
ing Hb group, tumor volume, smoking habits, gender, and
the tumor parameters T-category, N-category, and histo-
logic grade. Our findings support the results of several
previous studies (12, 13–18, 27–32). A low Hb concentra-
tion is a predictor for a decreased local control and a
diminished survival following radiation therapy for cancer
of the uterine cervix, bladder, lung, and head and neck (18,
27–32). Low polarographically measured tumor oxygen
levels are also associated with diminished local control and
survival in squamous cell carcinoma of the uterine cervix
and head and neck (12, 13–17). Our data demonstrate a link
between Hb level and tumor oxygenation and provide evi-
464 I. J. Radiation Oncology ● Biology
dence that the association between Hb concentration and the
outcome is mediated through tumor hypoxia. However, this
fact does not necessarily mean that tumors of patients with
a normal Hb or only a mild anemia are always well-oxy-
genated. In our study, a considerable variance of the median
pO2 and similarly of the hypoxic values was seen— espe-
cially at Hb concentrations above 11.0 g/dl (Fig. 2). This
spread of values clearly indicates that a given Hb level is
only one of the factors that are influencing the pO2 status of
tumors. Tumor hypoxia is a direct consequence of structural
abnormalities of the microvasculature and functional im-
pairments of the microcirculation and results from either
limited pO2 diffusion (chronic hypoxia) or limited perfusion
(acute hypoxia). Unfortunately, the Eppendorf technique is
not able to distinguish between these different causes of
hypoxia. The polarographically measured pO2 is a relatively
crude parameter that is influenced by a variety of factors
(e.g., blood flow, pH, temperature, irregular vascularization,
reduced deformability of erythrocytes, interstitial pressure)
(33–36). Under clinical conditions it is impossible to hold
all these factors constant and therefore a large number of
patients is needed to prove the impact of a single parameter
(e.g., Hb level) on the tumor oxygenation. Possibly other
authors did not observe any relationship between Hb values
and the polarographically measured pO2 status because the
number of their patients was not large enough for this
purpose or they did not compare patients with severe ane-
mia (e.g., Hb ⬍ 11.0 g/dl) to the remainder of the study
population (14, 15). Vaupel and Höckel investigated using
the same method in 65 patients with carcinoma of the
uterine cervix and found that severely anemic patients (⬍
10 g/dl) tend to have a lower pO2 compared to that of
patients with a normal Hb concentration (21). These data are
in accordance with our results.
In contrast to tumors, the median pO2 in sternocleido-
mastoid muscles in the severe anemia group in our study
was not significantly lower than in the mild anemia or
normal Hb group. These data suggest that tumors respond
more sensitively to a lower Hb concentration than resting
muscles. A possible explanation for this phenomenon could
be that the inadequate vascular structure in malignant tissue
is not able to compensate for the deficiency of oxygen
carriers with a decreased vascular resistance and an en-
hanced blood flow.
A disadvantage of the Eppendorf technique is that the
oxygen-sensitive electrode is not able to distinguish be-
tween measurements made in viable tumor parts and those
made in necrotic areas. Based on the assumption that ne-
crosis is more prominent in large tumors, one can argue that
the polarographically measured oxygenation could be more
influenced by tumor volume than the Hb concentration.
However, in our study we did not find a support for this
hypothesis. The correlation between median pO2 and vol-
ume was extremely weak and not verifiable for the propor-
tion of values ⱕ5 mmHg. Furthermore, a significant effect
of tumor volume could not be detected in the multivariate
analysis (Tables 2 and 3). Our results indicate that even
● Physics Volume 46, Number 2, 2000
large tumors can be well-oxygenated provided neovascular-
ization increases proportional to tumor growth and that
small tumors can be hypoxic in case of insufficient tumor
angiogenesis.
A further aspect of our study was the influence of the
smoking habits on tumor oxygenation. Smokers inhale
small amounts carbon monoxide which reacts with Hb to
form carboxyhemoglobin (CO-Hb). Overgaard et al.
showed for head and neck cancer patients that in the range
of 0 –12% CO-Hb the oxygen utilization decreased from
70% to 52% (37). This means a relative reduction of 25% of
the amount of oxygen available to the tumor. However, in
our trial smokers presented only a trend toward a poorer
tumor oxygenation compared to nonsmokers. Moreover, in
the multivariate analysis smoking was found to have only a
marginal effect on tumor oxygenation—in contrast to the
Hb concentration. Unfortunately, we were not able to esti-
mate CO-Hb in our patients. It is not unreasonable to
postulate that the influence of smoking habits on tumor
oxygenation could be better regarded using this parameter.
We are therefore seeking to include CO-Hb levels in our
future studies.
Some clinical trials have shown that women had a better
prognosis than men (30, 38). Our data indicate that this
difference could not be explained by differences in tumor
oxygenation.
Previous studies revealed that poor tumor oxygenation
worsens the initial treatment response and the survival of
head and neck cancer patients after radiotherapy (14, 15).
On the one hand, this fact could be explained by hypoxia-
mediated radioresistance of tumor cells. On the other hand,
hypoxia was recently shown to enhance the genetic insta-
bility of tumor cells and result in cell clones with a dimin-
ished apoptotic potential and more aggressive behavior (39,
40). It remains currently unclear what is the dominating
feature in malignant tissue. An enhanced tumor aggressivity
is probably irreversible and limits the beneficial effects of
an increased tumor oxygenation. Postulated, however, that
the prognosis of cancer patients is mainly influenced by
radiobiological hypoxia, the pretreatment correction of a
low Hb concentration as well as the maintenance of a
sufficient Hb level during radiation therapy could be a
meaningful way to improve the outcome. The effect of an
Hb correction should be supported by smoking abstinence
although the detrimental influence of smoking was not
unambiguously demonstrated in our study. Clinically, in-
creased tumor oxygenation was demonstrated by pO2 mea-
surements in cervical cancers after blood transfusion (41–
43). However, the impact of transfusion on response to
tumor treatment is controversial. Some authors describe an
adverse effect of allogeneic transfusions on tumor control,
possibly due to an immunosuppressive effect caused by the
transfused blood (44, 45). Other investigators did not find
any association between blood transfusion and locoregional
control or survival (46).
A good alternative to avoid the risks of a transfusion
seems to be the application of erythropoietin. Several clin-
 Severe anemia and poor tumor oxygenation
ical trials have shown that this cytokine is able to increase
the Hb level within 2 weeks and that the Hb concentration
continues to rise until the end of erythropoietin treatment
(47). In laboratory animals Kelleher et al. found that the
improvement of an anemia-induced oxygenation deficit in
small tumors is as good after the administration of erythro-
poietin as after blood transfusions (48). However, there
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