[Link].

com/scientificreports

OPEN Efficacy of Concurrent

Chemotherapy for Intermediate
Risk NPC in the Intensity-
received: 15 June 2015
accepted: 29 October 2015
Published: 27 November 2015
Modulated Radiotherapy Era: a
Propensity-Matched Analysis
Fan Zhang1,2,*, Yuan Zhang1,*, Wen-Fei Li1, Xu Liu1, Rui Guo1, Ying Sun1, Ai-Hua Lin3,
Lei Chen1 & Jun Ma1

This study is to evaluate the efficacy of additional concurrent chemotherapy for intermediate risk
(stage II and T3N0M0) NPC patients treated with intensity-modulated radiotherapy (IMRT).440
patients with intermediate risk NPC were studied retrospectively, including 128 patients treated with
IMRT alone [radiotherapy group (RT group)] and 312 paitents treated with IMRT plus concurrent
chemotherapy [chemoradiotherapy group (CRT group)]. Propensity score matching was carried out
to create RT and CRT cohorts equally matched for host and tumor factor. Significantly more severe
acute toxicities were observed in the CRT group than in the RT group. Multivariate analyses of 440
patients failed to demonstrate concurrent chemotherapy as an independent prognostic factor for
FFS, LR-FFS, and D-FFS. Between the well-matched RT cohort and the CRT cohort, no significant
difference was demonstrated in all survival endpoints (FFS: 92.8% versus 91.2%, P = 0.801; LR-FFS:
95.2% versus 94.4%, P = 0.755; D-FFS: 96.4% versus 96.3%, P = 0.803; OS: 98.2% versus 98.9%,
P = 0.276). Our results demonstrated that for patients with intermediate risk NPC treated with IMRT,
additional concurrent chemotherapy did not provide any significant survival benefit but significantly
more severe acute toxicities. However, prospective randomized trials are warranted for the ultimate
confirm of our findings.

Nasopharyngeal carcinoma (NPC) is an endemic disease in south China and a highly chemoradiosen-
sitive tumor. RT is the primary modality of treatment for nondisseminated NPC. RT alone can achieve
excellent survival in early stage (stage I) patients, while the survival of patients with stage II NPC remains
relatively unsatisfactory1,2. Currently, concurrent chemoradiotherapy with/without sequential chemo-
therapy (i.e., induction or adjuvant chemotherapy) is the standard treatment modality for stage II NPC
according to the National Comprehensive Cancer Network (NCCN) guideline. There has been one rand-
omized trial3 performed in the stage II population that demonstrated improvement in distant control and
overall survival (OS) after the addition of concurrent chemotherapy. While retrospective studies showed
no benefit in all endpoints4 or benefit in distant control and OS5 from induction chemotherapy, or only

1
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine,
Department of Radiation Oncology, Sun Yat-sen University Cancer Center, People’s Republic of China.
2
Department of Radiation Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, People’s Republic
of China. 3Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University,
No.74 Zhongshan Road, Guangzhou, People’s Republic of China. *These authors contributed equally to this work.
Correspondence and requests for materials should be addressed to L.C. (email: chenlei@[Link]) or J.M.
(email: majun2@[Link])

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improved locoregional control from concurrent chemotherapy6. Remarkably, all these studies were based
on two-dimensional conventional radiotherapy (2DCRT).
As one of the key milestones in the management of NPC, intensity-modulated radiotherapy (IMRT)
offers improved tumor target conformity, higher dose to the target, superior radiobiological effect of
accelerated fractionation, and better protection of normal organ at risk7,8; therefore it has gradually
replaced 2DCRT and changed the treatment modality of NPC. With better treatment outcomes from
IMRT than 2DCRT9–11, the differential gain in survival from additional chemotherapy was speculated
to be smaller within the framework of IMRT12,13. A previous study has showed us inspiring long-term
survival of stage II patients with IMRT alone, exceeding 90% in all endpoints14. However, for the only
two studies that investigated the efficacy of additional chemotherapy for this population treated with
IMRT, the results were conflicting and the study samples were small13,15. Thus, the sparse available
evidence addressed this issue was debatable and of limmited value for clinical reference. Additionally,
the addition of platinum-based chemotherapy obviously increased severe adverse-effects3,6,12,16,17, the
risk of treatment-related mortality18, and costs. Therefore, the possibility to omit chemotherapy in this
subgroup of patients was appealing in case of the absence of survival benefit. Moreover, better local
control of IMRT has also changed the hazard distribution for prognoses of NPC19. For example, the
stage T3N0M0 subgroup has been reported to have similar survival to stage II in the modern era19,20.
Given that, we included stage II and T3N0M0 disease as intermediate risk NPC in the era of IMRT in
our study.
Therefore, our team conducted a large-sample retrospective study to evaluate the efficacy of additional
concurrent chemotherapy for intermediate risk NPC treated with IMRT in our center in an endemic
area.

Material and Methods

Patient Selection. 1,811 consecutive patients with newly diagnosed nonmetastatic NPC treated with
IMRT at the Sun Yat-sen University Cancer Center (Guangzhou, People’s Republic of China) between
November 2009 and December 2012 were studied retrospectively. All clinical records and magnetic reso-
nance imaging (MRI) materials were reviewed by two radiologists with more than 10 years of experience
in head and neck cancers. All scans were evaluated independently and disagreements were resolved by
consensus. All patients were re-staged according to the 7th edition of the American Joint Committee on
Cancer (AJCC) Staging System for NPC21. Of these, 486 patients were restaged as stage II and T3N0M0.
Fourty-six (9.5%) patients who received induction or adjuvant chemotherapy alone without concurrent
chemotherapy were subsequently eliminated from the study. The resulting 440 patients were incorpo-
rated in the study, including 128 in the RT group and 312 in the chemoradiotherapy (CRT) group. This
retrospective study was approved by the Institutional Review Board of Sun Yat-sen University Cancer
Center and in accord with the institutional policy to protect the patients’ private information. The need
for informed consent was waived.

Radiotherapy. IMRT treatment details have been previously reported9. Target volumes were delin-
eated according to our institutional treatment protocol9, which is in agreement with the International
Commission on Radiation Units and Measurements Reports 50 and 62. The clinical target volumes
(CTV) were individually delineated based on the tumor invasion pattern. The prescribed radiation dose
was defined as follows: a total dose of 66–72 Gy to the planning target volume (PTV) of the gross tumor
volume of the primary (GTV-P), 64–70 Gy to the PTV of the nodal gross tumor volume (GTV-N),
60–63 Gy to the PTV of CTV-1 (i.e., high risk regions), 54–56 Gy to PTV of CTV-2 (i.e., low-risk regions)
and CTV-N (i.e., neck nodal regions). All patients were treated with one fraction daily over 5 days per
week.

Toxicity and follow-up. Acute and late toxicities were documented according to the Common
Terminology Criteria for Adverse Events version 3.0 and/or the Radiation Morbidity Scoring Criteria of
the Radiation Therapy Oncology Group. The duration of patient follow-up was measured from the first
date of treatment to either the date of death or the date of last examination. Patients were examined and
followed-up at least every 3 months during the first 2 years, and thereafter every 5 months for up to 3
years or until death.

Statistical analysis. Our primary endpoint was failure-free survival (FFS). Our secondary endpoints
were OS, locoregional failure-free survival (LR-FFS), and distant failure-free survival (D-FFS). FFS was
calculated from the first date of treatment to the date of treatment failure or death from any cause,
whichever occurred first; OS, to last examination or death; and LR–FFS and D–FFS, to first locoregional
or remote failure, respectively.
The chi-square test (or Fisher’s exact test, if indicated) was used to test the baseline balance and
toxic effect rates over two groups and/or cohorts. The estimated survival rates were calculated using
the Kaplan–Meier method and differences were compared using the log-rank test. Multivariate analyses
using the Cox proportional hazard model were used to test independent significance using backward

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Before matching After matching

RT group CRT group CRT cohort
Characteristics, n (%) n = 128 n = 312 P value RT cohortn = 112 n = 193 P value
Age 0.095 0.629
< 50y 82 (64.1) 225 (72.1) 73 (65.2) 131 (67.9)
≥ 50y 46 (35.9) 87 (27.6) 39 (34.8) 62 (32.1)
Sex 0.652 0.898
Male 93 (72.7) 220 (70.5) 82 (73.2) 140 (72.5)
Female 35 (27.3) 92 (29.5) 30 (26.8) 53 (27.5)
KPS 0.238 0.305
100–90 124 (96.9) 308 (98.7) 124 (97.6) 192 (99.5)
70–80 4 (3.1) 4 (1.3) 3 (2.4) 1 (0.5)
Histology 0.198 0.417
WHO type I 1 (0.8) 1 (0.3) 1 (0.9) 0 (0)
WHO type II 10 (7.9) 13 (4.2) 7 (6.2) 10 (5.2)
WHO type III 117 (91.4) 298 (95.5) 104 (92.9) 183 (94.8)
Staging a
0.060 0.777
II 108 (84.4) 238 (76.3) 92 (82.1) 156 (80.8)
III 20 (15.6) 74 (23.7) 20 (17.9) 37 (19.2)
T classification
a
0.108 0.900
T1 45 (35.2) 112 (35.9) 45 (40.2) 80 (41.5)
T2 63 (49.2) 126 (40.4) 47 (42.0) 76 (39.4)
T3 20 (15.6) 74 (23.7) 20 (17.9) 37 (19.2)
N classificationa 0.011 0.355
N0 56 (43.8) 97 (31.1) 40 (35.7) 59 (30.6)
N1 72 (56.2) 215 (68.9) 72 (64.3) 134 (69.4)
GTV-P level < 0.001 0.768
Stage II, < 19 ml 82 (64.1) 142 (45.5) 66 (58.9) 114 (59.1)
Stage II, ≥ 19 ml 26 (20.3) 96 (30.8) 26 (23.2) 42 (21.8)
Stage III, < 19 ml 12 (9.4) 21 (6.7) 12 (10.7) 17 (8.8)
StageIII, ≥ 19 ml 8 (6.2) 53 (17.0) 8 (7.1) 20 (10.4)
Pretreatment pEBV DNA level 0.001 0.569
< 4000 copy/ml 110 (85.9) 223 (71.5) 94 (83.9) 157 (81.3)
≥ 4000 copy/ml 18 (14.1) 89 (28.5) 18 (16.1) 36 (18.7)
Combined chemoradiotherapy regimen (n = 312 before matching; n = 193 after matching)
CCRT 213 (68.3) 137 (71.0)
ICT +  CCRT 95 (30.4) 53 (27.5)
CCRT +  ACT 3 (1.0) 2 (1.0)
ICT +  CCRT +  ACT 1 (0.3) 1 (0.5)
Concurrent chemotherapy regimen (n = 312 before matching; n = 193 after matching)
Weekly Cisplatin 110 (35.2) 73 (37.8)
3-weekly Cisplatin Cisplatin 138 (44.2) 83 (43.0)
Nedaplatin or Carboplatin 37 (11.8) 21 (10.8)
Docetaxel 14 (4.5) 8 (4.1)
Others 13 (4.2) 8 (4.1)

Table 1. Baseline characteristics and treatment details before and after matching. Abbreviations:
WHO, World Health Organization; KPS, Karnofsky scale; RT, radiotherapy; CRT, chemoradiotherapy; NP,
nasopharynx; LN, lymph node; GTV-P, gross tumor volume of the primary; pEBV DNA, plasma Epstein–
Barr Virus DNA; CCRT, concurrent chemoradiotherapy; ICT, induction chemotherapy; ACT, adjuvant
chemotherapy. aStaging, T classification, N classification were based on the 7th edition of the American Joint
Commission on Cancer staging system.

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Concurrent Administered dose Total Median

regimen n (%) per cycle (mg/m2) dose (mg/m2)
Weekly regimen (n =  140)
Cisplatin 110 (35.2) 30–50 180
Nedaplatin 14 (4.5) 20–30 150
Carboplatin 2 (0.6) 100 400
Docetaxel 14 (4.5) 15–35 85
3-Weekly regimen (n =  172)
Cisplatin 138 (44.2) 80–100 160
Nedaplatin 21 (6.7) 80–100 160
Others a
13 (4.2) — —

Table 2. Details of concurrent chemotherapy (n = 312). aOthers included nedaplatin, 5-Fu regimen
in 7 patients; Cisplatin, 5-Fu regimen in 2 patients; docetaxel, cisplatin regimen in 3 patient; docetaxel,
nedaplatin in 1 patient.

RT group CRT group

n = 128 n = 312 HR (95% CI)* P value†
Failure-free survival
Events 10 (7.8%) 39 (12.5%) — —
Rate at 3 years 92.9% 86.7% 1.68 (0.83 –3.36) 0.140
Locoregional Failure-free survival
Events 6 (4.7%) 21 (6.7%) — —
Rate at 3 years 95.0% 92.6% 1.51 (0.61 –3.73) 0.374
Distant Failure-free survival
Events 4 (3.1%) 21 (6.7%) — —
Rate at 3 years 96.9% 93.0% 2.24 (0.77–6.53) 0.128
Overall survival
Events 3 (2.3%) 8 (2.6%) — —
Rate at 3 years 98.4% 97.7% 1.08 (0.29 –4.07) 0.910

Table 3. Patterns of failure and survival between the RT and CRT groups. Abbreviations: CRT,
chemoradiotherapy; RT, radiotherapy; HR, hazards ratio; 95% CI, 95% confidence interval. *Hazard ratios
were calculated with the unadjusted Cox proportional hazards model. †P values were calculated with the
unadjusted log-rank test.

elimination of insignificant explanatory variables. Covariates included host factors (i.e., sex, age), tumor
factors (i.e., T and N classification), and chemotherapy intervention (i.e., CRT group).
Since patient selection bias might be one of the explanations for the equally excellent survival results
in both groups, propensity score (PS) matching, an effective technique for adjusting bias, was used create
two cohorts equally matched for host and tumor factors22. The PS was developed using sex, age, T stage,
N stage, GTV-P level, and pretreatment plasma Epstein–Barr Virus DNA (pEBV DNA) level23,24. We
carried out a two-to-one propensity matching using the caliper match algorithm, with sampling without
replacement and caliper width set to 0.2 to yield sufficient power and similarity between the CRT and
RT cohorts22,25.
The criterion for statistical significance was set at α  =  0.05. P-values were determined from two-sided
tests. All analyses were carried out with the Stata Statistical Computer Package (STATA 10; StataCorp
LP, College Station, Texas, USA).

Results
Patient and chemotherapy characteristics. Table 1 shows the not perfectly well balanced baseline
characteristics between the two groups, as well as chemotherapy regimen in the CRT group. With respect
to concurrent chemotherapy, 172/312 patients (55.4%) received a 3-weekly platinum-based regimen and
94.8% of them received at least two cycles of chemotherapy. Furthermore, 126/312 (39.4%) received a

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Subgroup Analysis
Endpoints (RT group v T2N0 T1N1 T2N1 T3N0
CRT group) (n = 59) (n = 157) (n = 130) (n = 94)
FFS
3-year estimated rate*, % 88.9 v 86.7 95.6 v 87.5 92.6 v 83.0 95.0 v 91.1
P value† 0.854 0.160 0.267 0.913
LR-FFS
3-year estimated rate*, % 94.4 v 91.3 95.1 v 94.0 100 v 94.8 95.0 v 95.0
P value† 0.675 0.726 0.211 0.962
D-FFS
3-year estimated rate*, % 94.4 v 90.9 97.8 v 93.5 96.3 v 91.3 100 v 95.8
P value† 0.631 0.296 0.413 0.356
OS
3-year estimated rate*, % 94.4 v 90.9 100 v 100 100 v 97.1 100 v 97.3
P value† 0.645 — 0.328 0.108

Table 4. Comparison of survival in different subgroups according to stage (n = 440). Abbreviations: RT,
radiotherapy; CRT, chemoradiotherapy; FFS, failure-free survival; LR-FFS, locoregional failure-free survival;
D-FFS, distant failure-free survival; OS, overall survival. *The estimated survival rates were calculated using
the Kaplan–Meier method. †P values were calculated with the unadjusted log-rank test.

weekly platinum-based regimen and 72.2% of them received at least five cycles, respectively. Further
chemotherapy details were available in Table 2

Survival outcome. The median follow-up was 37.3 months (range 8.0–58.8 months). 432 participants
(98.2%) were followed up for more than 2 years. We observed 49 events and 46 treatment failures. A
summary of failure patterns is displayed in Table 3.
No statistically significant difference was observed in the estimated 3-year FFS, LR-FFS, D-FFS, and
OS rates between the RT group and the CRT group (FFS: 92.9% versus 86.7%, P =  0.140; LR-FFS: 95.0%
versus 92.6%, P =  0.374; D-FFS: 96.9% versus 93.0%, P =  0.128; OS: 98.4% versus 97.7%, P =  0.910,
Table 3). Additionally, we performed subgroup analyses according to TNM classification (T2N0M0,
T1N1M0, T2N1M0, and T3N0M0). We found that additional concurrent chemotherapy failed to result
in significant differences in the four subgroups for all endpoints examined (Table 4). For those with
pretreatment pEBV DNA level ≥ 4000 copy/ml, our analyses failed to examed out any survival benefit
from concurrent chemotherapy.
CRT group was not an independent prognostic factor for FFS, LR-FFS, or D-FFS using multivariate
analyses. However, we did observe that pretreatment pEBV DNA levels ≥ 4000 copy/ml was an inde-
pendent prognostic factor FFS and D-FFS; Detectable post-treatment pEBV DNA was also an independ-
ent prognostic factor FFS, LR-FFS and D-FFS (Table 5).

Toxicity. No treatment-related death was observed in our study. Patients in the CRT group experi-
enced significantly higher rate of severe acute toxicities (grade 3–4) than the RT group during RT (42.3%
versus 21.1%, P <  0.001) and this difference was mainly attributed to mucositis, leucopenia, neutropenia,
and gastrointestinal reactions (Table 6). In addition, we noted that more patients in the CRT group
had over 5% weight loss (grade 1–4) compared with the RT group (57.4% versus 22.7%, P <  0.001). No
significant difference in severe late toxicities was observed between the two groups [CRT group (3.2%)
versus RT group (2.3%), P =  0.628, Table 6].

Role of concurrent chemotherapy. As shown in Table 1 and Table 3, with more patients with N1
disease than the RT group, the CRT group experienced slightly lower, though not statistically significant,
survival than the RT group despite the additional concurrent chemotherapy these patients received.
We then carried out PS matching and the resulting two well-balanced cohorts were shown in Table 1.
As displayed in Fig. 1, no difference was observed in the estimated 3-year FFS, LR-FFS, D-FFS, or OS
between the RT cohort and the CRT cohort (FFS: 92.8% versus 91.2%, P =  0.801, Fig. 1A; LR-FFS: 95.2%
versus 94.4%, P =  0.755, Fig. 1B; D-FFS: 96.4% versus 96.3%, P =  0.803, Fig. 1C; OS: 98.2% versus 98.9%,
P =  0.276, Fig. 1D).

Discussion
To our knowledge this is the first large-sample comparison study between IMRT alone and IMRT
plus concurrent chemotherapy in intermediate risk NPC. By conducting multivariate analyses and PS

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Figure 1. Kaplan–Meier survival curves for the matched RT and CRT cohorts. Failure–free survival
(A), locoregional failure–free survival (B), distant failure–free survival (C), and overall survival (D). Hazard
ratios (HRs) were calculated with the unadjusted Cox proportional hazards model; P-values were calculated
by the unadjusted log–rank test. RT =  radiotherapy; CRT =  chemoradiotherapy.

matching to adjust the bias, our data still fail to prove any significant survival improvement from con-
current chemotherapy in addition to IMRT in all endpoints. Moreover, significantly more severe acute
toxicities were observed in the CRT group.
There are three possible explanations for our negative findings. Firstly, the stronger benefit of con-
current chemotherapy in locoregional control and overall survival by enhancing the local effect of radi-
otherapy has been proven and established by numerous trials12,16,17 and meta-analyses26,27 in the 2DCRT
era. However, a substantial improvement in treatment outcomes with IMRT compared with 2DCRT
has been shown primarily in LR-FFS9–11 in NPC patients. This might have narrowed any potential ther-
apeutic gain in locoregional control offered by concurrent chemotherapy. Additionally, the improved
locoregional control from concurrent chemotherapy in 2DCRT era may have a favorable influence on
the distant control, which might has been likely substituted by IMRT. Moreover, there have been some
studies4,6,12,13,17 and meta-analysis26 that demonstrated the ineffectiveness of concurrent platinum-based
chemotherapy for the eradication of micro metastases. The above reasons might contribute together to
the absence of improved distant control.
Secondly, it is possible that the extra severe acute hematologic and nonhematologic toxicities from
concurrent chemotherapy were harmful to patient’s prognosis. There has been evidence that severe treat-
ment related lymphopenia was associated with poor progression free survival in patients with squamous
cell head and neck cancer28. Moreover, notably 30% more patients in the CRT group experienced over
a 5% weight loss during RT, which was found to be the only independent factor associated with poor
survival in a retrospective study of NPC and the possible reason might be the unfavorable impact of
weight loss on treatment including compliance29,30 and less accuracy in patient position for IMRT31,32.
Therefore, despite tolerable these toxicities may seem to be, them might have further compromised the
therapeutic ratio of concurrent chemotherapy in this population.
Finally, as the main criteria for prediction patient’s prognosis, the present NPC AJCC staging system
has been widely used in clinic practice for reseanable treatment stratification and in clinical trials for tar-
get patient selection, as well as in our study. We should aware that the AJCC staging system is restricted
in its diagnostic reach to the anatomical extent of the tumors, and not accurate enough to categorize
patients at intermediate risk of disease recurrence. An increasing number of promising indictors have
been studied to improve the TMN staging system, such as biological, genetic, and molecular prognosis
factors29,30. Researchers might consider testing combinations of both anatomical and non-anatomical

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Variable Hazards ratio (95% CI) P value†

Failure-free survival
Sex, women v men 1.29 (0.68–2.45) 0.44
Age, ≥ 50 years v < 50 years 1.14 (0.63–2.07) 0.66
T classification, T2–3 v T1 1.32 (0.72–2.43) 0.37
N classification, N1 v N0 0.89 (0.42–1.86) 0.75
 Pretreatment pEBV DNA level, ≥ 4000 copy/ml v
2.22 (1.26–3.94) < 0.01
< 4000copy/ml
Post-treatment pEBV DNA, Detectable v Undetectable 7.26 (4.13–12.7) < 0.01
GTV-P level, ≥ 19 ml v < 19 ml 1.04 (0.57–1.90) 0.89
Treatment group, CRT group v RT group 1.40 (0.69–2.83) 0.36
Locoregional failure-free survival
Sex, women v men 2.24 (1.03–4.91) 0.43
Age, ≥ 50 years v < 50 years 1.05 (0.46–2.37) 0.91
T classification, T2–3 v T1 1.50 (0.66–3.50) 0.32
N classification, N1 v N0 1.16 (0.44–3.07) 0.77
 Pretreatment pEBV DNA level, ≥ 4000 copy/ml v
1.31 (0.58–3.00) 0.52
< 4000copy/ml
Post-treatment pEBV DNA, Detectable v Undetectable 6.26 (2.89–13.55) < 0.01
GTV-P level, ≥ 19 ml v < 19 ml 1.19 (0.53–2.67) 0.68
Treatment group, CRT group v RT group 1.46 (0.59–3.62) 0.41
Distant failure-free survival
Sex, women v men 0.49 (0.17–1.45) 0.20
Age, ≥ 50 years v < 50 years 0.75 (0.31–1.81) 0.52
T classification, T2–3 v T1 1.07 (0.40–2.88) 0.89
N classification, N1 v N0 0.67 (0.25–1.77) 0.42
 Pretreatment pEBV DNA level, ≥ 4000 copy/ml v
3.88 (1.76–8.57) 0.01
< 4000 copy/ml
Post-treatment pEBV DNA, Detectable v Undetectable 8.48 (3.84–18.73) < 0.01
GTV-P level, ≥ 19 ml v < 19 ml 0.84 (0.36–1.95) 0.68
Treatment group, CRT group v RT group 1.54 (0.52–4.57) 0.44

Table 5. Multivariate analyses of prognostic factors in intermediate risk NPC (n = 440)*. Abbreviations:
95% CI, 95% confidence interval; GTV-P, gross tumor volume of the primary; pEBV DNA, plasma Epstein–
Barr Virus DNA; RT, radiotherapy; CRT, chemoradiotherapy. *Multivariate analyses were not carried out
for OS because the total numbers of failures were too low to obtain a non-overfit model. †P values were
calculated with an adjusted Cox proportional-hazards model.

prognosis factors to achieve optimal selection for concurrent chemotherapy in this population in the
future. Similarly, the NPC-0502 study (NCT00370890), a promising clinical trial, was designed to use
pEBV DNA level as a selection for chemotherapy regimen.
Interestingly, both pretreatment pEBV DNA level ≥ 4000 copy/ml and detectable pEBV DNA after
treatment are the independent prognostic factor for FFS, D-FFS. These results were cosistent with previos
studies24,33,34. However, for those with pretreatment pEBV DNA level ≥ 4000 copy/ml, our analyses failed
to examed out any survival benefit from the current chemotherapy. We prefer to attribute this negec-
tive finding to the unadjustable bias and the small sample size of our data: the overwhelming majority
of this cohort (89/107, 83.2%) received chemotherapy. We expect the benefit of chemotherapy for this
special cohort may be proved in the retrospective or prospective study series with adjustable bias or
no bias in the furture. Moreover, detectable post-treatment pEBV DNA was found to be a more strong
prognostic factor than pretreatment pEBV DNA level ≥ 4000 copy/ml in our study, which may be very
meaningful for selecting patients at high risk of disease recurrence after radiotherapy for more aggressive
treatment. Further investigation was warrant for best treatment for patients with detectable pEBV DNA
after treatment.
There were two small-sample retrospective studies performed in the IMRT era. Luo et al.15 focused
on 69 patients with stage I-II NPC and demonstrated an improvement of survival in all endpoints from

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CRT group
RT group (n = 128) (n = 312)
Grade 3 or 4 Grade 3 or 4 P value
Acute toxicity during RT, n (%)
Hematologic 2 (1.6) 46 (14.7) < 0.001
  Leukopenia 1 (0.8) 36 (11.5) < 0.001
  Granulocytopenia 1 (0.8) 24 (7.7) 0.004
  Thrombocytopenia 0 (0) 7 (2.2) 0.113
  Anemia 1 (0.8) 2 (0.6) 1.000
Nonhematologic 25 (19.5) 100 (32.1) 0.008
  Mucositis 23 (18.0) 90 (28.8) 0.018
  Dermatitis 1 (0.8) 4 (1.3) 1.000
  Gastrointestinal reactions 0 (0) 15 (4.8) 0.008
  Liver dysfunction 1 (0.8) 1 (0.3) 0.498
  Renal impairment 0 (0) 0 (0) —
  Wight loss 0 (0) 1 (0.3) 1.000
Total any 27 (21.1) 132 (42.3) < 0.001
Late toxicity, n (%)
Xerostomia 0 (0) 0 (0) —
Neck tissue damage 0 (0) 0 (0) —
Deafness or otitis 3 (2.3) 9 (2.9) 1.000
Neuro damage 0 (0) 1 (0.3) *
1.000
Total any 3 (2.3) 10 (3.2) 0.764

Table 6. Major severe acute and late toxicities (n = 440). Abbreviations: RT, Radiotherapy; CRT,
chemoradiotherapy. *One patient who developed a seizure due to radiation-induced brain damage.

additional concurrent chemotherapy. Notably, although patients with stage I was included, the locore-
gional and distant control rate for the patients with IMRT alone remained 81.4–84.0%, far lower than
that reported in a previous large-sample study14 and in our study. The main reason for this difference
may be that (1) Luo and colleagues’ study was from a non-endemic area of China, (2) 71% of patients
involved were with World Health Organization (WHO) II histology and (3) the study sample was small.
Thus, it should be cautious to apply their findings to endemic area with predominantly WHO III histol-
ogy, which was found to confer better prognosis35. On the contrary, Tham et al.13 reported no significant
improvement in all survival endpoints from chemotherapy of any schedule in 107 patients with stage II
NPC. However, they did not focus on concurrent chemotherapy because most patients were treated with
induction chemotherapy alone and only 8 patients received concurrent chemotherapy13, which is proved
to be the most effective chemotherapy regimen to NPC26,27 and most widely-used in clinical practice to
attempt better survival according to the influential NCCN guideline. Therefore, their findings may not be
representative evidence for the efficacy of CRT and of limited persuasion for treatment reconsideration
from oncologists.
Oncologists should notice that current NCCN guideline recommendations of chemotherapy for inter-
mediate risk NPC is based on evidence from studies in the 2DCRT era. However our data demostrated
that the additional concurrent chemotherapy did not provide any further survival benefit to intermediate
risk NPC patients within the framwork of IMRT. Therefore our results might provide important infor-
mation in clinical decision-making, avoiding overtreatment as well as unnecessary toxicities and costs
without hazarding patients’ survival. Our study has some limitations. This is a retrospective study with
inevitable selection bias. However, we managed to use PS matching to adjust the bias effectively and the
final matched cohort was well balanced on the both host and tumor factors, including known important
prognostic factors such as GTV-P level and pretreatment EBV DNA level. Therefore our results should
be of credible references to clinical practise and future confirm of optimal treatment modality for inter-
mediate risk NPC. However, it should be awared that PS matching was limitted to unknown prognostic
factors; some factors such as economic status, living conditions may affect patients’ treatment choice.
However, the collection of these factors was not in the protocal of our centre, which may be the potential
hidden bias though PS matching was used in this series. Therefore, we are looking forward to trials to
confirm our findings and two prospective phase II randomized trials are underway (NCT00817258 and
NCT01187238).

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Conclusion
Our results demonstrated that for patients with intermediate risk NPC treated with IMRT, additional
concurrent chemotherapy did not provide any significant survival benefit but significantly more severe
acute toxicities, therefore might not be recommended as routine use. However, prospective randomized
trials are warranted for the ultimate confirm of our findings.

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Acknowledgements
This work was supported by grants from the Health & Medical Collaborative Innovation Project of
Guangzhou City, China (201400000001), the National Science & Technology Pillar Program during
the Twelfth Five-year Plan Period (No. 2014BAI09B10), the Innovation Team Development Plan of the
Ministry of Education (No. IRT1297), the National Natural Science Foundation of China (No. 81302366),
and the Medical Science and Technology Research Foundationof Guangdong Province (No. B2013148).

Author Contributions
Conception and design of the study: F.Z., Y.Z., L.C. and J.M. Acquisition of data: F.Z., Y.Z., W.F.L. and
R.G. Analysis and interpretation of the data: F.Z., Y.Z. and A.H.L. Contributed reagents/materials/
analysis tools: All authors. Writing and revision of the manuscript: All authors. All authors reviewed
the manuscript.

Additional Information
Competing financial interests: The authors declare no competing financial interests.
How to cite this article: Zhang, F. et al. Efficacy of Concurrent Chemotherapy for Intermediate Risk
NPC in the Intensity-Modulated Radiotherapy Era: a Propensity-Matched Analysis. Sci. Rep. 5, 17378;
doi: 10.1038/srep17378 (2015).
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the material. To view a copy of this license, visit [Link]

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OPEN Corrigendum: Efficacy of

Concurrent Chemotherapy for
Intermediate Risk NPC in the
Intensity-Modulated Radiotherapy
Era: a Propensity-Matched Analysis
Fan Zhang, Yuan Zhang, Wen-Fei Li, Xu Liu, Rui Guo, Ying Sun, Ai-Hua Lin, Lei Chen & Jun Ma
Scientific Reports 5:17378; doi: 10.1038/srep17378; published online 27 November 2015; updated on 08 February
2016

This Article contains a typographical error in Affiliation 2. The correct affiliation is listed below:

Department of Radiation Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, People’s Republic of
China

This work is licensed under a Creative Commons Attribution 4.0 International License. The images
or other third party material in this article are included in the article’s Creative Commons license,
unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material. To view a copy of this
license, visit [Link]

Scientific Reports | 6:20748 | DOI: 10.1038/srep20748 1