Radiotherapy and Oncology 98 (2011) 28–33

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Radiotherapy and Oncology

journal homepage: www.thegreenjournal.com

Phase III randomised trial

The importance of haemoglobin level and effect of transfusion in HNSCC

patients treated with radiotherapy – Results from the randomized DAHANCA 5
study
Camilla Molich Hoff a,⇑, Hanne Sand Hansen b, Marie Overgaard c, Cai Grau c, Jørgen Johansen d,
Jens Bentzen e, Jens Overgaard a
a
Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark; b Department of Oncology, The Finsen Centre, Rigshospitalet, Copenhagen, Denmark;
c
Department of Oncology, Aarhus University Hospital, Denmark; d Department of Oncology, Odense University Hospital, Denmark; e Department of Oncology, Herlev Hospital,
Denmark

a r t i c l e i n f o a b s t r a c t

Article history: Background and purpose: Patients with head and neck squamous cell carcinoma (HNSCC) and a low level
Received 15 July 2010 of haemoglobin (Hb) often have a poor response to radiation which may be related to hypoxia induced
Received in revised form 23 September radioresistance. The aim of the study was to evaluate the prognostic significance of low Hb level and
2010
its modification by transfusion in HNSCC patients treated with radiotherapy. The study was performed
Accepted 24 September 2010
Available online 20 October 2010
as a subrandomization in the DAHANCA 5 trial.
Material and methods: Patients were randomized to treatment with the hypoxic radiosensitizer nimoraz-
ole or placebo, and in addition, patients with ‘‘low” pre-irradiation Hb values (females < 13 g/dL; mal-
Keywords:
Transfusion
es < 14.5 g/dL) were subrandomized to plus or minus transfusion. Transfusion was given with packed
Radiotherapy red blood cells with the aim to achieve a Hb level in the ‘‘high” value range.
Randomized trial Results: A total of 414 patients were included, 243 patients had high Hb levels and 171 patients had low
Head and neck squamous cell cancer Hb levels. Of the low Hb patients, 82 were randomized to receive transfusion and 89 not to receive trans-
Haemoglobin fusion. The treatment arms were well balanced. In the majority of patients, transfusion resulted in
Hypoxia increased Hb levels although this tended to decline throughout treatment. Patients with high Hb levels
had a significantly better probability of locoregional control, disease-specific survival and overall survival
compared to ‘low Hb no transfusion’ patients. In the low Hb group, transfusion did not improve the out-
come in locoregional control, disease-specific survival or overall survival. In multivariate analyses, T and
N classifications were significant for all outcome measures, whereas there was no significant influence of
transfusion or Hb level on endpoints.
Conclusion: The univariate prognostic significance of high Hb level was demonstrated in patients with
HNSCC treated with radiotherapy; however, transfusion prior to and during treatment did not improve
the outcome in patients with low Hb values.
Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 98 (2011) 28–33

Patients with squamous cell carcinomas of the head and neck
(HNSCC) and a low level of haemoglobin (Hb) often have a poor re-
sponse to radiotherapy (RT) [1–4]. Tumours are heterogenic and
hypoxic radioresistant cells are often present [5,6]. A correlation
between hypoxia and haemoglobin level has been shown, but the
precise relationship remains uncertain [4,7,8]. The recent use of
erythropoietin stimulating agents (ESA) and the uncertainty in
safety when using these agents [9–13] have again opened the dis-
cussion on how to raise haemoglobin levels before and during
treatment.
⇑ Corresponding author. Address: Department of Experimental Clinical Oncology,
Aarhus University Hospital, Noerrebrogade 44, bld 5 2nd floor, DK-8000 Århus C,
Denmark.
E-mail address: camilla@oncology.dk (C.M. Hof.
Several studies, both experimental and clinical, have shown that
low haemoglobin levels and hypoxia are related [14,15]. Transfu-
sions to tumour bearing anaemic mice have suggested that tumours,
otherwise radioresistant, could regain radiosensitivity [16–19]. Cor-
rection of anaemia in clinical studies has resulted in improvement in
tumour oxygenation and a subsequent increase in the therapeutic
efficacy of irradiation [2,20–28].
As part of the randomized trial DAHANCA 5, evaluating the
role of nimorazole as a hypoxic radiosensitizer, the role of trans-
fusion to low haemoglobin patients was evaluated [29,30]. The
hypothesis being that in HNSCC patients with low haemoglobin
levels, an increase in haemoglobin level by transfusion may im-
prove the effect of radiotherapy irrespective of hypoxic modifica-
tion [29].

0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.radonc.2010.09.024
 C.M. Hoff et al. / Radiotherapy and Oncology 98 (2011) 28–33
Methods
Patients and treatment
The Danish Head and Neck Cancer Study, DAHANCA protocol 5–
85 was activated in January 1986 as a multicenter randomized and
balanced double-blind trial with the purpose of assessing (1) the
efficacy of nimorazole in conjunction with radiotherapy, (2) the
tolerance and toxicity of nimorazole and (3) the influence of hae-
moglobin concentration on tumour response to irradiation. De-
tailed study design has been published previously [29–31].
In brief, patients were prior to randomization stratified accord-
ing to gender, institution, tumour site, tumour stage and haemo-
globin concentration. In the main study the patients were
randomized to radiotherapy with nimorazole or placebo. In addi-
tion to the randomization to nimorazole, patients with ‘‘low”
pre-irradiation haemoglobin (females < 13.0 g/dL; males < 14.5 g/
dL) were offered subrandomization to receive or not to receive
transfusion prior to and during radiotherapy. Transfusions were gi-
ven with packed red blood cells (one unit approximately
equivalent to 500 mL full blood) to achieve a haemoglobin concen-
tration in the ‘‘high” value range. Transfusion was given before
radiotherapy and if during radiation the haemoglobin level fell be-
low the values indicated above, the transfusion was repeated. The
haemoglobin level was measured at least every 2 weeks [29].
Radiotherapy was given according to DAHANCA guidelines
(www.dahanca.dk). Primary target was given a total of 66–68 Gy,
2 Gy/Fx, 5 Fx/week over a period of 6.5 weeks, including a boost
to the primary tumour, maximum 18 Gy while elective regions re-
ceived 46–50 Gy. Nimorazole was given according to protocol
guidelines. No elective neck dissection was performed [29].
The study was done in accordance with the Helsinki declaration
and approved by relevant ethical committees. All patients gave
written informed consent [29].
Follow up
Patients were followed at the oncological centres for at least
5 years or until death. They were evaluated with clinical examina-
tion weekly during treatment, 2 months after treatment, 3 month
intervals for the first year, 4 month intervals for the second year,
and then twice annually for up to 5 years after randomization [29].
Endpoints
The primary endpoint was locoregional control after radiother-
apy. The definition of this endpoint was complete and persistent
disappearance of the disease in the primary tumour (T-site) and re-
gional lymph nodes (N-site) after radiotherapy. Failure was re-
corded in case of recurrent tumour, or if the primary tumour
never completely disappeared. In the latter situation, the tumour
was assumed to have failed at the time of randomization. The pri-
mary endpoint did not include the effect of successful procedure
with salvage surgery. Secondary endpoints include disease-specific
survival and overall survival. The endpoint used for disease-
specific survival was death from or with the actual cancer. The
endpoint for overall survival was any death, irrespective of cause.
All time estimates were done using the date of randomization as
the initial value.
The treatment effect was evaluated using the ‘intention to treat’
principle and patients were included in their randomization group
irrespective of whether or not they had completed the planned
treatment. Time for evaluation of locoregional control, disease-
specific survival and overall survival was 5 years after randomiza-
tion since patients were followed regularly only for that period.
29
Statistical analyses
First patients with high haemoglobin and patients with low
haemoglobin without transfusion (high, low t) were compared
to determine the effect of haemoglobin level. The effect of transfu-
sion was evaluated by comparing the two low groups, with and
without transfusion (low+t, low t), respectively. Statistical analy-
ses were done using the STATA 10 software package. Patient char-
acteristics were compared with chi2-test and significance level was
chosen to be 5%. The actuarial values of endpoints were evaluated
by the Kaplan–Meier plots and compared with log-rank test for
equality of survivor functions. The p-values estimated are those
for a two tailed test and the significance level was chosen to be
5%. A multivariate Cox proportional hazards analysis was used to
evaluate prognostic factors and treatment with respect to the risk
of locoregional failure, disease-specific survival and overall sur-
vival. Parameters were included when statistically significant in
univariate analysis. Data are presented as 5-year actuarial hazard
ratios (HR) with 95% confidence intervals, unless otherwise
mentioned.
The study was not dimensioned with regard to the present anal-
ysis of transfusion effect, but with approximately 50 events in each
of the low groups and an expected locoregional control rate of 50%,
a difference of approximately 27% with alpha 0.05 and a power of
0.8 can be detected.
Results
Study flow chart and patient characteristics are shown in Fig. 1
and Table 1. The analysis included 414 eligible and evaluable pa-
tients, 243/414 (59%) in the high haemoglobin and 171/414
(41%) in the low haemoglobin group. No patients were excluded
from the analysis.
The high haemoglobin group contained relatively more male
patients and more supraglottic cancers, beside from this, the pa-
tient and tumour characteristics in three groups were in general
similar. There were no differences between the transfused and
the non-transfused low Hb groups (Table 1).
Pre-treatment measurements showed that 171 patients had
low haemoglobin levels, 25/110 (23%) of females and 146/304
(48%) of males. These patients were subsequently randomized to
transfusion 82/171 (48%) or no transfusion 89/171 (52%). The
group given transfusion consisted of 11/25 (44%) females and 71/
146 (49%) males. There was no difference in the distribution of
haemoglobin levels in the transfused and non-transfused group be-
fore treatment.
Compliance to radiotherapy was good and overall 97% com-
pleted the planned radiotherapy treatment, irrespective of treat-
ment group.
Transfusion
In the majority of the cases, transfusion was able to raise hae-
moglobin values. The haemoglobin level during radiotherapy
decreased throughout the course of radiotherapy, despite an obvi-
ous effect of transfusion at the beginning of treatment (Fig. 2,
Appendices 1 and 2).
The number of packed red blood cells received per patient ran-
ged between 0–6 units (median 2). A total of 55/82 (67%) patients
received transfusion at one occasion, 20/82 (24%) received more
than one transfusion and 7/82 (9%) never received any transfusions
despite their randomization group. Most patients received their
first transfusion immediately prior to start of radiotherapy (med-
ian 1 day, range: 13 to 43 days).
30 DAHANCA 5 - Effect of transfusion in HNSCC

Fig. 1. Study flow chart.

Table 1
Patient and tumour characteristics.

Parameter Low Hb transf Low Hb + transf High Hb All patients p-Value* p-Value#
Age <60 years 42 47% 32 39% 127 52% 201 0.3 0.4
>60 years 47 53% 50 61% 116 48% 213
Gender Female 14 16% 11 13% 85 35% 110 0.7 0.001
Male 75 84% 71 87% 158 65% 304
Site Supraglottis 20 22% 21 26% 84 35% 125 0.6 0.04
Pharynx 69 78% 61 74% 159 65% 289
T-classification T1 + T2 37 42% 35 43% 125 51% 197 0.9 0.1
T3 + T4 52 58% 47 57% 118 49% 217
N-classification N0 37 42% 28 34% 122 50% 187 0.3 0.2
N+ 52 58% 54 66% 121 50% 227
Stage I + II 15 17% 17 21% 59 24% 91 0.5 0.2
III + IV 74 83% 65 79% 184 76% 323
Treatment Nimorazole 44 49% 48 59% 127 52% 219 0.2 0.6
Placebo 45 51% 34 41% 116 48% 195
Total 89 82 243 414
*
Comparing difference between the two low Hb groups (low t vs low+t).
#
Comparing difference between the two non-transfused Hb groups (low t vs high).

Treatment outcome Univariate analysis showed statistical significance of age at

inclusion, gender, site, T- and N-classifications, stage, nimorazole
At the time of clinical assessment, 225/414 (54%) patients had
treatment and haemoglobin level at inclusion (Table 2).
experienced locoregional failure. A total of 204/414 (49%) had died
The high haemoglobin group had a better outcome regarding
of disease and 272/414 (66%) had died overall (Fig. 1). The fre-
locoregional control probability compared to low non-transfused
quency of patients with distant metastases in the three groups
patients (HR 0.71; CI 0.51–0.97; p = 0.03). However, no difference
low t, low+t and high were 11% (10/89), 15% (12/82) and 9%
between transfusion and no transfusion in the low haemoglobin
(22/243), respectively. Only 9 patients experienced an isolated dis-
group was observed (HR 0.99; CI 0.67–1.47; p = 0.9) (Fig. 3a and
tant recurrence, distributed in the groups as one, three and five pa-
Table 2). Similar results were found using the endpoint of dis-
tients, respectively.
 C.M. Hoff et al. / Radiotherapy and Oncology 98 (2011) 28–33 31

cance however did not appear in the multivariate analysis. This fi-

Fig. 2. Haemoglobin level during RT treatment as a function of gender.
ease-specific survival probability between high and low t (HR
0.66; CI 0.47–0.92; p = 0.01), and a lack of effect of transfusion
(HR 1.07; CI 0.71–1.60; p = 0.8) (Fig. 3b and Table 2). Finally the
same pattern was found for overall survival probability in high
haemoglobin and low non-transfused patients (HR 0.69; CI 0.51–
0.92; p = 0.01), and again no benefit from transfusion (HR 1.10;
CI 0.78–1.57; p = 0.6) (Fig. 3c and Table 2). The importance of hae-
moglobin level and lack of effect of transfusion were found irre-
spective of whether the patients had received nimorazole
treatment or not (Appendix 3).
Multivariate analysis confirmed the importance of T- and N-
classifications and gender for all endpoints whereas neither hae-
moglobin value nor transfusion could be identified as independent
factors of outcome. Age at inclusion was significant for overall and
disease-specific survival and nimorazole treatment for locore-
gional control (Table 2).
Discussion
The study confirmed the prognostic importance of haemoglobin
level in HNSCC patients receiving radiotherapy. In patients with a
low haemoglobin level transfusion was able to raise the haemoglo-
bin level during radiotherapy, however, this increase in haemoglo-
bin level did not improve the effect of radiotherapy. The
haemoglobin level was found to be a significant prognostic factor
in univariate analysis for all outcome measurements, this signifi-
nal conclusion is therefore in accordance with the initial
haemoglobin results of the DAHANCA 5 study, which also demon-
strated univariate prognostic importance of haemoglobin level and
no benefit of transfusion [29].
The use of transfusion to improve hypoxic radioresistance has
only been investigated in one small randomized trial in patients
with cancer of the uterine cervix. Bush et al. concluded that pa-
tients with a haemoglobin level during treatment below 12 g/dL
had a significantly higher recurrence rate and lower cure rate
and that a correction of anaemia by transfusion could decrease
the recurrence and increase the cure rate, this being consistent
with tumour hypoxia being greater in anaemic patients [26]. How-
ever, a reanalysis of this trial by Fyles et al. using the intention-to-
treat principle could not confirm the convincing evidence of the
original report [27]. Other non-randomized uterine cervix studies
showing an importance of haemoglobin level and effect of transfu-
sion have been published [12,28,32,33], but cancers of the uterine
cervix differ from head and neck cancers since they often suffer
from bleeding from the tumour and bleeding could also be a sign
of more advanced disease, poorer performance status, etc.
There are several potential reasons to explain the lack of effect
of transfusion, but they are not examined by the present analysis
and still subject to discussion.
Hirst et al. has in several preclinical studies investigated the
importance of anaemia in radiation resistance [16,34]. Using ro-
dent tumours they not only described a clear benefit of blood
transfusion to improve outcome in radiotherapy [19], but also that
the timing between transfusion and irradiation was of outmost
importance, since increased haemoglobin concentration may in-
duce tumour cell proliferation. Although head and neck tumour
volume doubling time is relatively slow [35], tumour cells around
a small blood vessel may show a very fast cellular proliferation
[36]. We cannot exclude that some patients in our study may have
had a too long interval between transfusion and irradiation, in such
a way that the tumours may have adapted to the increased blood
supply by growth [37,38].
It can also be argued that the aim for haemoglobin level was set
too high since it has been suggested that the optimal range in hae-
moglobin levels for achieving maximum oxygenation status in so-
lid tumours are 12–14 g/dL for women and 13–15 g/dL for men
[15]. We attempted to keep females above 13.0 g/dL and males

Table 2
Univariate and multivariate analyses.

Locoregional control Disease-specific survival Overall survival

HR CI p-Value HR CI p-Value HR CI p-Value
Univariate parameter
Age >60 vs < 60 1.15 (0.89–1.50) 0.3 1.32 (1.00–1.74) 0.05 1.39 (1.09–1.77) 0.007
Gender Female vs male 0.67 (0.49–0.92) 0.01 0.63 (0.46–0.89) 0.007 0.63 (0.47–0.84) 0.002
Site Pharynx vs supragl 1.24 (0.93–1.66) 0.1 1.66 (1.20–2.28) 0.002 1.44 (1.10–1.89) 0.007
T-classification T1 + T2 vs T3 + T4 0.66 (0.51–0.86) 0.002 0.67 (0.51–0.89) 0.005 0.73 (0.57–0.92) 0.009
N-classification N0 vs N+ 0.52 (0.40–0.82) <0.001 0.45 (0.33–0.60) <0.001 0.60 (0.47–0.76) <0.001
Stage I + II vs III + IV 0.58 (0.40–0.68) 0.002 0.55 (0.38–0.81) 0.002 0.72 (0.53–0.97) 0.03
Treatment Nimo vs placebo 0.70 (0.54–0.91) 0.007 0.76 (0.58–1.00) 0.05 0.96 (0.76–1.22) 0.7
Differentiation Moderate + well vs UK + poor 1.19 (0.91–1.55) 0.2 1.10 (0.83–1.45) 0.5 1.09 (0.85–1.39) 0.5
Haemoglobin level Low + t vs low t 0.99 (0.67–1.47) 0.9 1.07 (0.71–1.60) 0.8 1.10 (0.78–1.57) 0.6
High vs low t 0.71 (0.51–0.97) 0.03 0.66 (0.47–0.92) 0.01 0.69 (0.51–0.92) 0.01
Multivariate analysis
Age >60 vs < 60 1.17 (0.89–1.52) 0.3 1.33 (1.00–1.76) 0.05 1.38 (1.08–1.77) 0.009
Gender Female vs male 0.73 (0.53–1.01) 0.06 0.68 (0.48–0.96) 0.03 0.67 (0.50–0.90) 0.008
Site Pharynx vs supragl 1.04 (0.75–1.43) 0.8 1.31 (0.92–1.86) 0.1 1.26 (0.94–1.69) 0.1
T-classification T1 + T2 vs T3 + T4 0.64 (0.49–0.84) 0.001 0.65 (0.49–0.87) 0.004 0.73 (0.57–0.93) 0.01
N-classification N0 vs N+ 0.53 (0.39–0.71) <0.001 0.48 (0.35–0.67) <0.001 0.63 (0.48–0.82) 0.001
Treatment Nimo vs placebo 0.72 (0.55–0.94) 0.02 0.79 (0.60–1.04) 0.09 0.98 (0.77–1.25) 0.9
Haemoglobin level Low + t vs low t 0.93 (0.62–1.37) 0.7 0.98 (0.65–1.47) 0.9 1.02 (0.72–1.46) 0.9
High vs low t 0.81 (0.58–1.12) 0.2 0.79 (0.56–1.12) 0.2 0.81 (0.60–1.09) 0.2
32 DAHANCA 5 - Effect of transfusion in HNSCC
Fig. 3. Locoregional control (a), disease-specific (b) and overall survival (c)
probability curves (Kaplan–Meier method) according to haemoglobin group.
above 14.5 g/dL based on previous observations of the relationship
between haemoglobin level and locoregional control [1,39,40].
Only few patients reached such high haemoglobin levels, and the
present study did not have enough patients to make a proper sub-
analysis of different haemoglobin levels.
The benefit of high haemoglobin concentration relates to the
assumption that the oxygen carrying capacity of the blood is asso-
ciated with tumour cell oxygenation. Disturbing this oxygen carry-
ing capacity by binding carbon monoxide to the haemoglobin may
strongly alter this mechanism as it may happen in smokers [41,42].
Animal studies have shown that the oxygen availability is de-
creased to 30–40% of the normal air-breathing controls [43]. There-
fore, smoking status should also be known when considering the
haemoglobin level and the oxygen carrying capacity of haemoglo-
bin. Unfortunately, such data are not available in the present study,
but a prospective recording has subsequently been initiated. The
influence of other tobacco related health factors may indirectly
be seen when looking at the survival curves in the present study.
The largest influence of haemoglobin concentration is found in
overall survival. This might be an indication of other factors (e.g.
tobacco related diseases, secondary cancers) than the cancer in
question may influence the outcome.
The study confirmed that LRC was significantly improved by
nimorazole irrespective of haemoglobin concentration. However,
in some cases these differences did not reach statistical signifi-
cance, probably due to a small number of patients in each group,
and the haemoglobin level was therefore important despite hyp-
oxic modification.
The present study has been performed as a subrandomization in
the DAHANCA 5 trial, with a risk that the study does not have the
necessary power to detect clinical relevant differences. The subran-
domization was therefore continued in the DAHANCA 7 protocol
and will be reported later. This will also allow a more detailed anal-
ysis of the haemoglobin levels during treatment.
Despite efforts to maintain high haemoglobin level following
transfusion there was a general trend of reduction of the peak le-
vel. This may account for the lack of response in the transfused pa-
tients, since a continuous increased gradient in the haemoglobin
concentration is a part of the theoretical mechanism behind im-
proved tumour oxygenation. Such decrease may be avoided by
using treatment with erythropoietin stimulating agents, and sev-
eral clinical trials (including DAHANCA 10) have been initiated to
investigate this hypothesis, without showing any significant bene-
fit [9–13].
Conclusion
The study confirmed the univariate prognostic importance of
haemoglobin level in HNSCC patients receiving radiotherapy.
Transfusion was able to raise the haemoglobin level during radio-
therapy, however, this increase in haemoglobin level by transfu-
sion was not maintained during the entire treatment period, and
did not result in improved effect of radiotherapy. The study was
however too small to ultimately determine the role of transfusion,
and the randomization has consequently been continued in the
DAHANCA 7 protocol.
Conflicts of interest statement
No conflicts of interest declared by the authors.
Acknowledgements
Supported by CIRRO – The Lundbeck Foundation Center for
Interventional Research in Radiation Oncology and the Danish
Council for Strategic Research.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.radonc.2010.09.024.
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