Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 4, pp.

1471–1478, 2012
Copyright Ó 2012 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/$ - see front matter

doi:10.1016/j.ijrobp.2011.05.009

CLINICAL INVESTIGATION Head and Neck Cancer

INVOLVEMENT OF DIFFERENCE IN DECREASE OF HEMOGLOBIN LEVEL IN POOR

PROGNOSIS OF STAGE I AND II NASOPHARYNGEAL CARCINOMA:
IMPLICATION IN OUTCOME OF RADIOTHERAPY

JIN GAO, M.D.,*yz YA-LAN TAO, M.D.,*y GUO LI, M.D.,*y WEI YI, M.D., PH.D.,*y
y
AND YUN-FEI XIA, M.D.*

*Department of Radiation Oncology, Cancer Center, yState Key Laboratory of Oncology in Southern China, Sun Yat-Sen University,
Guangzhou, People’s Republic of China; and zDepartment of Radiation Oncology, Anhui provincial hospital, Hefei,
People’s Republic of China

Purpose: To investigate the effect of hemoglobin (Hb) concentration and the difference in its decrease during
treatment on outcome of radiotherapy (RT) alone for patients with Stage I and II nasopharyngeal carcinoma.
Methods and Materials: A total of 572 patients with Stage I-II nasopharyngeal carcinoma with RT alone between
January 2001 and December 2004 were retrospectively analyzed. Patient characteristics, tumor variables, and Hb
level, including pre-RT Hb, mid-RT Hb, and dynamic change of Hb between pre- and post- RT and its difference in
decrease (6Hb) were subjected to univariate and multivariable analysis to identify factors that predict disease-
specific survival (DSS), local regional recurrence-free survival (LRFS), and metastases-free survival (MFS).
Results: The 5-year DSS was poorer in the Hb continuous decrease group than in the Hb noncontinuous decrease
group (84% vs. 89%; p = 0.008). There was poorer 5-year DSS in patients with 6Hb of >11.5 g/L than in those with
6Hb of #11.5 g/L (82% vs. 89%; p = 0.001), and poorer LRFS (79% vs. 83%; p = 0.035). Univariate and multi-
variate analysis showed that Hb decrease difference with greater than 11.5 g/L was an independent prognostic
factor for DSS and LRFS.
Conclusions: The difference in decrease of Hb level during the course of radiation treatment appeared as a poor
prognostic factor in Stage I and II nasopharyngeal carcinoma patients. Ó 2012 Elsevier Inc.

Hemoglobin, Radiotherapy, Nasopharyngeal carcinoma, Prognostic factor.

INTRODUCTION neck. How is it in NPC? There were only a few papers on

the prognostic value of Hb levels in NPC. Chua et al. (7)
Nasopharyngeal carcinoma (NPC) has a distinct epidemiol-
found that the Hb concentration during RT was an important
ogy, etiology, and clinical biological behavior. Up to now, ra-
prognostic factor affecting treatment outcomes, but the Hb
diotherapy (RT) is still the main treatment of choice for all
concentration before RT did not affect the local control
stages of NPC. Local recurrence is one of the most important
and survival. However, their study did not consider the effect
reasons of treatment failure. As a common feature of solid
of dynamic changes of Hb during treatment on the progno-
malignancies, tumor hypoxia plays the important role in
sis. We had analyzed 520 patients with NPC and obtained
the reasons of recurrence. Tumor hypoxia can lead to in-
results similar to those reported by Chua et al., especially
creased chemoresistance and radioresistance by lowering
for the advanced-stage patients (8). Furthermore, we also
oxygen levels in the tumor microenvironment, consequently
found that patients with continuously decreased Hb during
leading to poorer local regional control (1).
RT had lower local recurrence-free survival rate and overall
Decreased hemoglobin (Hb) could cause a decline of
survival rate. As we know, the advanced-stage NPC often
blood oxygen leading to tumor hypoxia, which may result
require chemotherapy, which could inhibit marrow function,
in the development of treatment resistance (2). Previous
causing decrease of Hb level. In addition, patients with
studies (3–6) have shown that low pretreatment Hb levels
advanced stages of NPC have relatively poor performance
appeared as an independent prognostic factor for survival
status and easily suffer from anemia. To reduce the effect
and predictive factor for local recurrence in patients
of previously mentioned factors, we selected patients with
receiving RT for squamous cell carcinoma of the head and

Reprint requests to: Yun-Fei Xia, M.D., 651 Dongfeng Road
East, Guangzhou 510060, People’s Republic of China. Tel: 86-
20-87343169; Fax: 86-20-87343392; E-mail: xiayf@sysucc.org.cn
Supported by grants from the Hi-Tech Research and Develop-
ment Program of China (no. 2006AA02Z4B4).
1471
Conflict of interest: none.
Acknowledgments—We would like to thank Mr. Charles Chen for
critically reading and editing this revised manuscript.
Received Oct 15, 2010, and in revised form April 24, 2011.
Accepted for publication May 10, 2011.
1472 I. J. Radiation Oncology d Biology d Physics
Fig 1. Flow diagram of the patient grouping.
Stage I and II NPC treated with RT alone to study the effect
of Hb level on the treatment outcome. Up to now, in patients
with Stage I and II NPC treated with RT alone, no published
studies had addressed the prognostic value of Hb level, espe-
cially for the difference in its decrease. The aim of our study
is to test the hypothesis of whether the difference in the de-
crease of Hb level could be a prognostic factor for patients
with Stage I and II NPC.
METHODS AND MATERIALS
Population
A total of 572 patients with Stage I and II NPC were selected
from the hospitalized patients at the Cancer Center of Sun Yat-
Sen University between 2001 and 2004 who were treated by RT
alone. The patients who met the following criteria were enrolled:
1) pathologically proved NPC; 2) Stage I-II; 3) first receiving rad-
ical RT; and 4) complete Hb level recorded. Computed tomography
scanning or magnetic resonance imaging was essential for disease
staging before treatment, and the disease of all patients was staged
prospectively according to the 2002 American Joint Committee on
Cancer staging classifications (9). No patients received epoetin alfa
therapy.
Definition of anemia and Hb group
Anemia was diagnosed for men if the Hb concentration was <130
g/L and for women if the Hb concentration was <120 g/L according
to the World Health Organization definition of anemia.
Hb baseline level (pre-RT Hb level) was measured 1week before
the start of RT for all patients. During the course of RT, Hb level
was examined once per week. If the result was abnormal, Hb
needed to be examined twice or three times per week. Mid-RT
Volume 82, Number 4, 2012
Hb level was defined as the average of all Hb values during RT.
Post-RT Hb level was defined as the Hb value or average Hb value
at the last week of RT. Hb continuous decrease was defined as pre-
RT Hb > mid-RT Hb > post-RT Hb. All situations other than Hb
continuous decrease were considered Hb noncontinuous decrease.
Individual difference value (6Hb) of Hb level from pre-RT to
post-RT was equal to (pre-RT Hb value) – (post-RT Hb value).
Figure 1 shows the patients were grouped according to their
different Hb levels.
Treatment
All patients were treated with definitive-intent RT with high en-
ergy 6–8 MV X-ray by linear accelerator, with 506 (88.5%) patients
treated with two-dimensional conformal radiotherapy (2D-CRT),
27 (4.7%) patients treated with three-dimensional conformal radio-
therapy (3D-CRT) and 39 (6.8%) patients treated with intensity-
modulated radiotherapy (IMRT). Opposing lateral facial-cervical
fields were used in the 2D-CRT to cover the nasopharynx and upper
cervical lymphatic drainage region, with one lower anterior cervi-
cal field to cover the lower cervical region. After 36–40 Gy, oppos-
ing lateral preauricular fields were used for the primary region, and
anterior split neck fields were used for the cervical region. The
primary tumor was irradiated to a dose of 60–78 Gy. The dose of
prophylactic irradiation for patients with 2D-CRT was 50–54 Gy
to the prophylactic areas. For 3D-CRT, the total prescribed dose
was 66–72 Gy to the gross tumor volume of nasopharynx (GTVnx),
60–70 Gy to the region involved by the metastatic lymph nodes
(GTVnd), 60 Gy to CTV-1 (the GTVnx and an additional 5- to
10-mm margin), and 50–54 Gy to the prophylactic irradiating
region (CTV-2). For IMRT, the target definition and delineation
were the same as described previously for 3D-CRT. The prescrip-
tion dose was 68 Gy to the GTVnx, 60–64 Gy to the GTVnd of
neck, 60 Gy to the CTV-1, and 54 Gy to CTV-2.
 Hemoglobin and outcome of radiotherapy for nasopharyngeal carcinoma d J. GAO et al. 1473

Table 1. Patient characteristics Follow-up

After completion of RT, patients were followed up every 3
Characteristic Patients (n) %
months for the first 3 years, the intervals gradually increased to 6
Age (y) months to 1 year after 3 years.
#47 299 52
>47 273 48
Gender Statistical analysis
Male 436 76 All analyses were performed using SPSS software, version 13.0
Female 136 24 (SPSS, Chicago, IL). Disease-specific survival (DSS) was calcu-
02AJCC T Stage lated as time from start of RT to death, only deaths from disease
T1 199 35 progression or treatment-related complications were counted. Lo-
T2 373 65 cal regional recurrence-free survival (LRFS) and metastases-free
02AJCC N Stage survival (MFS) were calculated as time from start of RT to locore-
N0 280 49
gional or distant failure, respectively. The survival was assessed ac-
N1 292 51
02AJCC overall stage cording to the Kaplan-Meier method. Log–rank test was used to
I 103 18 compare the survival curves. Multivariate analyses with the Cox
II 469 82 proportional hazards model were used to test the independent sig-
Hb dynamic change nificance of different variables. p value of less than 0.05 was con-
Continuous decrease 301 53 sidered statistically significant.
Noncontinuous decrease 271 47 The receiver operating characteristic (ROC) curve was used to
6Hb value determine the best threshold difference value from pre-RT to
#11.5 g/L 315 55 post-RT (6Hb), which would be predictive of mortality. The best
>11.5 g/L 257 45 threshold was the minimal distance to the ideal point (sensitivity =
Abbreviations: AJCC = American Joint Committee on Cancer; specificity = 100%) on the ROC curve. It provides a criterion for
Hb = hemoglobin; 6Hb = individual differences between hemo- choosing the ‘‘optimal’’ threshold value, the threshold value for
globin concentrations at the beginning and end of radiotherapy. which Se(c)+Sp(c)-1 is maximized (10). The whole study popula-
tion was then stratified according to this optimum cutoff point.

Table 2. The treatment outcome of the different groups

5-y DSS (%) p 5-y LRFS (%) p 5-y MFS (%) p

Pre-RT Hb levels
Anemia 86 73 93
No anemia 87 0.51 82 0.16 94 0.65
Mid-RT Hb levels
Anemia 85 74 92
No anemia 87 0.23 82 0.099 93 0.93
Hb dynamic change
Continuous decrease 84 78 92
Noncontinuous decrease 89 0.008 82 0.062 94 0.55
Pre-RT anemia
Continuous decrease 71 56 92
Noncontinuous decrease 93 0.019 80 0.063 93 0.90
Pre-RT no anemia
Continuous decrease 85 78 92
Noncontinuous decrease 89 0.032 82 0.12 94 0.49
6Hb value
6Hb # 11.5 g/L 89 83 94
6Hb > 11.5 g/L 82 0.001 79 0.035 93 0.67
Pre-RT anemia
6Hb # 11.5 g/L 90 76 93
6Hb > 11.5 g/L 70 0.16 56 0.33 92 0.38
Pre-RT no anemia
6Hb # 11.5g/l 89 85 94
6Hb > 11.5 g/L 83 0.002 76 0.028 92 0.56
Continuous decrease
6Hb # 11.5 g/L 89 82 95
6Hb > 11.5 g/L 81 0.036 74 0.065 94 0.53
Noncontinuous decrease
6Hb # 11.5 g/L 90 82 93
6Hb > 11.5 g/L 87 0.46 81 0.83 90 0.59

Abbreviations: DSS = disease-specific survival; Hb = hemoglobin; 6Hb = individual differences between hemoglobin concentrations at
the beginning and end of radiotherapy; LRFS = local regional recurrence-free survival; MFS = metastases-free survival; RT = radiotherapy.
1474 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 4, 2012

Fig 2. Kaplan-Meier curves showing disease-specific survival (DSS) in continuously decreased and noncontinuously
decreased group. (a) The 5-year DSS rates in hemoglobin (Hb) continuously decreased group and noncontinuously
decreased group were 84% and 89% (p = 0.008). (b) The 5-year Local regional recurrence-free survival (LRFS) rates
in Hb continuously decreased group and noncontinuously decreased group were 78% and 82% (p = 0.062). (c) The 5-
year DSS rates in pre-radiation therapy (RT) no anemia patients in the Hb continuously decreased and noncontinuously
decreased group were 85% and 89% (p = 0.032). (d) The 5-year LRFS rates in pre-RT no anemia patients in the Hb
continuously decreased and noncontinuously decreased group were 78% and 82% (p = 0.12).

RESULTS the Hb continuously decreased group (pre-RT Hb > mid-RT

Patients characteristics and follow-up
There were data of 572 hospitalized patients with AJCC
Stage I and II NPC to be respectively reviewed. Patients
and disease characteristics were listed in Table 1. Histolog-
ical examination showed that 99.6% of the patients had
World Health Organization type II or III disease, and 0.4%
of patients had adenocarcinoma. Hb concentration before
RT ranged from 76 to 184 g/L, with a mean value of 145
g/L and a median value of 148 g/L, Hb concentration during
RT from 65 to 173 g/L with a mean value of 137 g/L and
a median value of 138 g/L, and Hb concentration after RT
from 64 to 178 g/L with a mean value of 135 g/L and a me-
dian value of 137 g/L. Of 572 patients, 517 (90.4%) had nor-
mal Hb and 55 (9.6%) had anemia before RT. During
radiation treatment, 82.5% had normal Hb, and 17.5% had
anemia (as seen in Fig. 1). According to the Hb level before,
during, and after RT, 301 patients (52.6%) were divided into
Hb > post-RT Hb) and 271 patients (47.4%) into the nonde-
creased group (Fig. 1).
The median time of follow-up was 75.7 months (range, 3–
112 months).
The cutoff value of 6Hb
The area under the ROC curve was 0.60 (95% CI 0.54–
0.66; p = 0.002). The cutoff value of 6Hb was 11.5 g/L
(the sensitivity was 60%, the specificity was 59%). Accord-
ing to the cutoff value of 6Hb, 315 patients (55.1%) were
classified into 6Hb #11.5 g/L group, and 257 patients
(44.9%) into 6Hb > 11.5 g/L group (Fig. 1).
Treatment outcomes
Survival comparison of the different groups. Table 2
listed the 5-year DSS, LRFS, and MFS rates of the different
groups including pre-RT anemia vs. pre-RT no anemia,
 Hemoglobin and outcome of radiotherapy for nasopharyngeal carcinoma d J. GAO et al. 1475

Fig 3. Kaplan-Meier curves showing disease-specific survival (DSS) and local regional recurrence-free survival (LRFS)
in 6 hemoglobin (Hb) # 11.5 g/L and 6Hb > 11.5 g/L group. (a) The 5-year DSS rates in the 6Hb # 11.5 g/L group and
the 6Hb > 11.5 g/L group were 89% and 82% (p = 0.001). (b) The 5-year LRFS rates in the 6Hb # 11.5 g/L group and
the 6Hb > 11.5 g/L group were 83% and 79% (p = 0.035). (c) The 5-year DSS rates in pre-RT no anemia patients with
6Hb # 11.5 g/L and those with 6Hb > 11.5 g/L were 89% and 83% (p = 0.002). (d) The 5-year LRFS rates in pre-RT no
anemia patients with 6Hb # 11.5 g/L and those with 6Hb > 11.5 g/L were 85% and 76% (p = 0.028). (e) The 5-year DSS
rates in the Hb continuously decreased patients with 6Hb # 11.5 g/L and those with 6Hb > 11.5 g/L were 89% and 81%
(p = 0.036). (f) The 5-year LRFS rates in the Hb continuously decreased patients with 6Hb # 11.5 g/L and those with
6Hb > 11.5 g/L were 82% and 74% (p = 0.065).
1476 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 4, 2012

Table 3. Factors associated with outcome by univariate and multivariate analysis in 572 patients

Multivariate
Univariate
Outcomes and variable p value RR 95%CI p value

Locoregional recurrence-free survival

T1 vs. T2 0.012 – – 0.80
T2N1 vs. non-T2N1 <0.001 2.036 1.460–2.841 <0.001
Stage I vs. II 0.033 – – 0.25
6Hb # 11.5 g/L vs. >11.5 g/L 0.035 1.416 1.006–1.992 0.046
Metastases-free survival
N0 vs. N1 0.003 – – 0.31
T2N1 vs. non-T2N1 <0.001 2.895 1.546–5.421 0.001
Disease-specific survival
Age #47 vs. >47 0.042 1.506 1.003–2.260 0.048
T1 vs. T2 0.022 – – 0.16
N0 vs. N1 <0.001 – – 0.059
T2N1 vs. non-T2N1 <0.001 2.789 1.853–4.199 <0.001
Stage I vs. II 0.040 – – 0.82
6Hb # 11.5 g/L vs. >11.5 g/L 0.001 1.774 1.174–2.678 0.006

Abbreviations: RR = relative risk; CI = confidence interval; 6Hb = individual differences between pre-RT hemoglobin (Hb) and post-RT
Hb; RT = radiotherapy.

mid-RT anemia vs. mid-RT no anemia, continuous decrease
vs. noncontinuous decrease, and 6Hb # 11.5 g/L vs. 6Hb
> 11.5 g/L.
No significant difference in DSS, LRFS, and MFS rate
was found between anemia group and nonanemia group
when patients were stratified according to pre-RT and mid-
RT Hb levels, respectively (Table 2).
Patients with Hb continuous decrease had significantly
poorer DSS than those with non-continuous decrease (84%
vs. 89% for 5-year DSS rate, p = 0.008) (Table 2, Fig. 2),
but their LRFS and MFS didn’t show significant difference.
The subgroups were further analyzed. The 5-year DSS
rates in pre-RT anemic patients in the Hb continuously de-
creased and noncontinuously decreased groups were71%
and 93% (p = 0.019, Table 2), respectively. The 5-year
DSS rates in pre-RT no anemia patients in the Hb continu-
ously decreased and noncontinuously decreased group
were 85% and 89% (p = 0.032; Table 2, Fig. 2).
Treatment outcomes according to 6Hb
The patients with 6Hb # 11.5 g/L had significantly bet-
ter DSS (p = 0.001) and LRFS (p = 0.035) compared with
those with 6Hb > 11.5 g/L (Table 2, Fig. 3). The 5-year
MFS rates in the 6Hb # 11.5 g/L group and the 6Hb >
11.5 g/L group were 94% and 93% (p = 0.67), respectively.
On subgroups analyses, the 5-year DSS, LRFS, and MFS
rates did not show significant difference between pre-RT
anemic patients with 6Hb # 11.5 g/L and those with
6Hb > 11.5 g/L. In contrast, when these comparisons
were made between pre-RT no anemic patients with 6Hb
# 11.5 g/L and those with 6Hb > 11.5 g/L, significant dif-
ferences were found. The 5-year DSS rates in pre-RT no ane-
mic patients with 6Hb # 11.5 g/L and those with 6Hb >
11.5 g/L were 89% and 83% (p = 0.002) (Table 2, Fig. 3).
The 5-year LRFS rates were 85% and 76% (p = 0.028;
Table 2, Fig. 3), respectively.
The 5-year DSS rates in the Hb continuously decreased
patients with 6Hb # 11.5 g/L and those with 6Hb >
11.5 g/L were 89% and 81% (p = 0.036, Fig. 3). The 5-
year LRFS and MFS rates of the two groups didn’t show sig-
nificant difference (p = 0.065, p = 0.53).
In patients with Hb non-continuous decrease, no signifi-
cant differences in DSS, LRFS, and DMF rates were found
between the 6Hb # 11.5 g/L and the 6Hb > 11.5 g/L
groups.
Univariate and multivariate analyses
Table 3 summarizes the univariate analysis of other rele-
vant prognostic factors. T status, clinical stage, the different
combining T and N subgroup (T2N1 vs. non-T2N1), and
6Hb status were significant factors that predicted local re-
gional recurrence. Age status, 6Hb status, T status, N sta-
tus, clinical stage, and the different combining T and N
subgroup (T2N1 vs. non-T2N1) were significant factors
that predicted death. N status and the different combining
T and N subgroup (T2N1 vs. non-T2N1) were significant
predictors of distant metastasis.
The following parameters were included in multivariate
analysis using a Cox proportional hazards model: gender,
age (#47 years vs. >47 years), T status (T1 vs. T2), clinical
stage (Stage I vs. II), the different combining T and N sub-
group (T2N1 vs. non T2N1), pre-RT Hb (anemia vs. nonane-
mia), mid-RT Hb (anemia vs. nonanemia), Hb dynamic
change (continuous decrease vs. noncontinuous decrease),
and 6Hb (#11.5 g/L vs. >11.5 g/L). Results were summa-
rized in Table 3. 6Hb was found to be independently predic-
tive of both DSS and LRFS rates.
DISCUSSION
In this study, we evaluated the relationship between Hb
concentration, particularly for its difference in decrease,
 Hemoglobin and outcome of radiotherapy for nasopharyngeal carcinoma d J. GAO et al.
and prognosis in patients with Stage I and II NPC treated
with RT alone. We found that there was no apparent effect
of pre-RT or mid-RT anemia on treatment outcomes in the
univariate and multivariable analyses. But the decrease
6Hb with >11.5 g/L for Stage I and II NPC appeared signif-
icantly and independently related to DSS and LRFS in the
analyzed data set. To our knowledge, this is the first study
to address the prognostic value of Hb concentration in
patients with Stage I and II NPC treated with RT alone.
However, this prognostic significance of decrease 6Hb
was also found in the laryngeal carcinoma reported by Rut-
kowski et al. (11). They found that individual change in Hb
concentration during the course of RT appeared as an inde-
pendent prognostic factor for LRFS in the laryngeal cancer
patients, the patients with decrease 6Hb with greater than
0 had significantly poorer 5-year LRFS compared with other
patients (72% vs. 80%, p = 0.01). The reason may be that
continuous decreased Hb during radiotherapy could lead to
the reduced oxygen carrier capacity in blood and could indi-
rectly cause tumor tissue hypoxia that can result in radiore-
sistance, consequently leading to poorer local control (7).
However, the result was related to the extent of difference
in Hb decrease. Our study showed 5-year LRFS was lower
in the group with DHb of >11.5 g/L, supporting this hypoth-
esis. In addition, in our study on body mass index and NPC
prognostics, we found underweight (poor nutritional status)
patients had a significant decrease in the overall survival
rate (12). So, we surmise that when difference in Hb de-
crease reaches certain value, it is associated with malnutri-
tion. Malnutrition could increase toxicity and decrease
response to treatment. This notion was also supported by
the study results reported by Nitenberg et al. (13) and Isenr-
ing et al. (14). The patients with pre-RT anemia (11/572)
and mid-RT anemia (51/572) in this study seldom showed
continuous decrease DHb of >11.5 g/L, so continuous de-
crease in Hb is significant but pre-RT Hb and mid-RT Hb
are not. Nordsmark (15) studied the relationship between
pretreatment tumor oxygenation status and prognosis of ad-
vanced head-and-neck squamous cell carcinoma. In their
studies, the majority of tumors were classified as hypoxic
with a 45% locoregional tumor control probability as com-
pared with 90% among well-oxygenated tumors (p = 0.04).
Tumor hypoxia not only impairs locoregional tumor control
probability but also impairs overall survival probability. Bri-
zel (16) reported that among 63 patients with head and neck
cancer receiving RT, median pO2 was 3.8 mm Hg in the
residual tumor patients and 12.2 mm Hg in the no residual
disease patients (p = 0.002). Tumor median pO2 of <10 mm
Hg adversely affected 2-year locoregional control (30% vs.
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