Research

JAMA Oncology | Original Investigation

Adjuvant Capecitabine Following Concurrent Chemoradiotherapy

in Locoregionally Advanced Nasopharyngeal Carcinoma
A Randomized Clinical Trial
Jingjing Miao, MD; Lin Wang, MD; Sze Huey Tan, PhD; Jin-gao Li, MD; Junlin Yi, MD; Enya H.W. Ong, BSc; Laura L.Y. Tan, MBBS; Ye Zhang, MD;
Xiaochang Gong, MD; Qiuyan Chen, MD; Yan-qun Xiang, MD; Ming-yuan Chen, MD; Ying Guo, MS; Xing Lv, MD; Wei-xiong Xia, MD;
Linquan Tang, PhD; Xiaowu Deng, PhD; Xiang Guo, PhD; Fei Han, MD; Hai-qiang Mai, MD; Melvin L. K. Chua, PhD; Chong Zhao, PhD

Visual Abstract
IMPORTANCE Induction or adjuvant chemotherapy with concurrent chemoradiotherapy Supplemental content
(CCRT) are first-line treatment options for treatment of locoregionally advanced
nasopharyngeal carcinoma (LA-NPC). Adjuvant platinum regimens are, however, poorly
tolerated, highlighting the unmet need for an efficacious, tolerable adjuvant regimen.

OBJECTIVE To investigate the efficacy and safety of adjuvant capecitabine with CCRT for
the treatment of patients with LA-NPC.

DESIGN, SETTING, AND PARTICIPANTS This open-label randomized clinical trial recruited
patients from March 31, 2014, to July 27, 2018, at 3 institutions in China, with at least 3 years
of follow-up. The data collection cutoff date was February 9, 2022. Eligibility included stage
III-IVb nasopharyngeal carcinoma and at least 1 of the following: T3-4N2 or T1-4N3; plasma
Epstein-Barr virus DNA titer higher than 20 000 copies/mL; primary gross tumor volume
larger than 30.0 cm3; fluorodeoxyglucose F 18 positron emission tomography/computed
tomography maximum standard uptake value of the primary gross tumor volume larger
than 10.0; or multiple nodal metastases and any larger than 4.0 cm.

INTERVENTIONS Patients were randomly assigned 1:1 to receive either capecitabine

(1000 mg/m2 twice daily for 14 days every 3 weeks for 8 cycles) or observation following CCRT
(100 mg/m2 cisplatin every 3 weeks for 2 to 3 cycles, depending on duration of radiotherapy).

MAIN OUTCOMES AND MEASURES Failure-free survival in the intention-to-treat cohort was
assessed using Kaplan-Meier survival curves compared with the log-rank test. Unstratified
Cox proportional hazards regression models were used to estimate hazard ratios, with
corresponding 95% CIs based on the Wald test.

RESULTS There were 180 patients enrolled (median [IQR] age, 47 [40-55] years; 143 [79.4%]
men). Among 90 patients in the capecitabine group, 76 (84.4%) had at least 2 high-risk
factors; among 90 patients in the control group, 80 (88.9%) had at least 2 high-risk factors.
All patients completed CCRT, except 1 patient in the capecitabine group who received 1 cycle
of cisplatin. Of the 90 patients in the capecitabine group, 85 (94.4%) received capecitabine,
Author Affiliations: Author
with 71 (78.9%) completing 8 cycles. With a median (IQR) follow-up of 58.0 (49.5-80.1) affiliations are listed at the end of this
months, 18 events were recorded in the capecitabine group vs 31 events in the control group. article.
Failure-free survival was improved with adjuvant capecitabine (3 years, 83.3% vs 72.2%; Corresponding Authors: Chong
5 years, 78.5% vs 65.9%; hazard ratio, 0.53 [95% CI, 0.30-0.94]; P = .03). The incidence Zhao, PhD, Department of
of grade 3 treatment-related adverse events (TRAEs) was higher in the capecitabine group Nasopharyngeal Carcinoma,
Sun Yat-sen University Cancer Center,
than in the control group (54 of 90 patients [60.0%] vs 46 of 90 patients [51.1%]). State Key Laboratory of Oncology in
Treatment-related adverse events included xerostomia (17 [18.9%] vs 9 [10.0%] patients), South China, Collaborative Innovation
mucositis (21 [23.3%] vs 15 [16.7%] patients), and anorexia (8 [8.9%] vs 4 [4.4%] patients). Center of Cancer Medicine,
Guangdong Key Laboratory of
The incidence of grade 3 delayed treatment-related adverse events was comparable in both
Nasopharyngeal Carcinoma Diagnosis
groups (9 of 83 [10.8%] vs 7 of 81 [8.6%] patients). and Therapy, Guangzhou,
Guangdong, 510060, PR China
CONCLUSIONS AND RELEVANCE In this randomized clinical trial, adjuvant capecitabine at the (gzzhaochong@hotmail.com;
full dose following CCRT was well tolerated and improved failure-free survival among patients zhaochong@sysucc.org.cn); Melvin
with LA-NPC and high-risk factors. Further investigations assessing optimal dose and duration L. K. Chua, PhD, Department of Head
and Neck and Thoracic Cancers,
are warranted.
Division of Radiation Oncology,
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02143388 National Cancer Centre Singapore,
11 Hospital Crescent, Singapore
JAMA Oncol. 2022;8(12):1776-1785. doi:10.1001/jamaoncol.2022.4656 (melvin.chua.l.k@singhealth.com.sg;
Published online October 13, 2022. gmsclkm@nus.edu.sg).

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 Adjuvant Capecitabine After Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma
N
asopharyngeal carcinoma (NPC) is a unique head and
neck cancer endemic in East and Southeast Asia,1,2
where it is invariably associated with Epstein-Barr
virus (EBV).3-6 Most patients with NPC present with locore-
gionally advanced disease (LA-NPC), harboring a proclivity for
metastatic recurrences to the bones, liver, and lungs.7 Induc-
tion chemotherapy or adjuvant chemotherapy in addition to
concurrent chemoradiotherapy (CCRT) is the recommended
standard of care in high-risk LA-NPC, defined as T3-4N+ or N2-3
in previous randomized clinical trials.8-11 The updated net-
work meta-analysis of chemotherapy in NPC report12 sup-
ports the efficacy of either systemic intensification strategy
for superior survival in LA-NPC.
The role of adjuvant chemotherapy in LA-NPC, using regi-
mens such as cisplatin with fluorouracil9,13-16 or gemcitabine,17
gemcitabine and paclitaxel,18 and capecitabine at metro-
nomic dosing19 has been investigated. The use of adjuvant
fluorouracil and gemcitabine in combination with cisplatin
yielded no difference in failure-free survival (FFS) and over-
all survival (OS), due in part to its inferior tolerability com-
pared with induction chemotherapy, with only 50% to 75% of
patients able to receive the full treatment dose.9,15-17 Chen et al9
did not demonstrate a survival benefit using adjuvant fluoro-
uracil with cisplatin after follow-up of approximately 5 years16
despite enriching for a high-risk subset of patients with
LA-NPC; of note, only 62.9% of participants tolerated 3 cycles
of adjuvant fluorouracil with cisplatin. Although superiority
of adjuvant fluorouracil with cisplatin was not demon-
strated, it cannot be concluded based on that trial that CCRT
alone was noninferior to CCRT and adjuvant fluorouracil
with cisplatin.
Capecitabine has proven single-agent activity in recur-
rent metastatic NPC and is efficacious when combined with cis-
platin for induction chemotherapy in patients with LA-NPC.20-25
In addition, a recent randomized clinical trial of adjuvant ca-
pecitabine given at metronomic dosing for 1 year conferred
FFS and OS benefits among patients with high-risk LA-NPC.19
Here, we report the efficacy and safety results after a median
follow-up of 58.0 months in a randomized clinical trial of
adjuvant capecitabine given at the full dose for 6 months.
Methods
Study Design and Participants
The trial was designed by investigators from 4 institutions
(Trial Protocol in Supplement 1), and patients were recruited
from 3 centers in China (eTable 1 in Supplement 2). Eligibility
criteria were (1) histologically confirmed, newly diagnosed,
nonkeratinizing NPC; (2) age 18 to 70 years; (3) Karnofsky
performance status of at least 80 points; (4) TNM stage III-
IVb based on American Joint Committee on Cancer/Union for
International Cancer Control (AJCC/UICC) 7th edition stage
classification system26; (5) no prior radiotherapy, chemo-
therapy, or surgery (except for diagnostic investigations) for
the tumor; (6) adequate organ function; and (7) presence of
1 or more of the following unfavorable prognostic factors:
T3-4N2 or T1-4N3 27 ; plasma EBV DNA titer higher than
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Original Investigation Research
Key Points
Question Is the addition of adjuvant capecitabine safe, and
does it improve failure-free survival (FFS) among patients with
locoregionally advanced nasopharyngeal carcinoma (LA-NPC)
who receive concurrent chemoradiotherapy?
Findings This multicenter, open-label randomized clinical
trial of 180 patients with LA-NPC met its primary end point
of FFS benefit in favor of the addition of adjuvant capecitabine
to concurrent chemoradiotherapy for treatment of patients
with LA-NPC. The capecitabine compliance rate was 79%;
the incidence of grade 3 or 4 treatment-related adverse
events was 61% (55 of 90) in the capecitabine group and
52% (47 of 90) in the group receiving concurrent
chemoradiotherapy alone.
Meaning These findings suggest that treatment with adjuvant
capecitabine confers an FFS benefit and is well tolerated in
patients with LA-NPC, although future trials should determine
optimal dosing and duration of adjuvant capecitabine.
20 000 copies/mL 28 ; primary gross tumor volume (GTV)
greater than 30.0 cm3,29; a maximum standard uptake value
of primary GTV higher than 10.0 on fluorodeoxyglucose F 18
positron emission tomography/computed tomography
(18F-FDG PET/CT)30; or multiple nodal metastases and at
least 1 larger than 4.0 cm. 31 Exclusion criteria included
(1) prior malignant tumors within 5 years of NPC diagnosis;
(2) concurrent pregnancy; (3) concurrent immunotherapy or
hormone therapy for other diseases; and (4) severe comor-
bidities. The protocol was reviewed and approved by the
Ethics Committee of Sun Yat-sen University Cancer Center
(SYSUCC) and by ethics committees and institutional review
boards of the other participating hospitals on March 19,
2014. The study was registered on ClinicalTrials.gov May 7,
2014,32 and was performed in accordance with the Declara-
tion of Helsinki and Good Clinical Practice guidelines. The
first patient was recruited on March 31, 2014, and the second
patient was recruited on July 23, 2014. Trial accrual was
completed on July 27, 2018. Data analyses were performed
based on a data collection cutoff date of February 9, 2022.
All patients provided written informed consent. No one
received compensation or was offered any incentive for par-
ticipating in this study. This study followed the Consolidated
Standards of Reporting Trials (CONSORT) reporting guideline.
Randomization and Masking
Patients were randomly assigned to receive in a 1:1 ratio
either capecitabine (capecitabine group) or observation (con-
trol group) following CCRT. Randomization was performed at
the Clinical Trials Center of SYSUCC on the day of study
recruitment prior to CCRT. A computer-generated sequence
was used to obtain the randomization list without stratifica-
tion. After obtaining informed consent, the investigators at
each institution contacted the study coordinators at the Clini-
cal Trials Center and received treatment assignment informa-
tion. The statistician (Y.G.) and study coordinators were unin-
volved in the treatment of patients and data monitoring.
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 Research Original Investigation Adjuvant Capecitabine After Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma
Procedures
All patients underwent CCRT and received intravenous cispl-
atin at a dosage of 100 mg/m2 every 3 weeks for 2 to 3 cycles
depending on the duration of radiotherapy. Patients random-
ized to the capecitabine group then received 8 cycles of oral
capecitabine at a dosage of 1000 mg/m2 twice daily for 14 days
every 21 days,21 commencing 4 weeks after CCRT. Chemo-
therapy dose modifications were based on the nadir blood
counts and acute toxic effects of the preceding cycle.
All patients received intensity-modulated radiotherapy
(IMRT), based on the principles of ICRU (International Com-
mission on Radiation Units and Measurements) reports 50 and
62. Details of the IMRT technique and delineation of target vol-
umes, including primary GTV, GTV of all involved lymph nodes,
high- and low-risk clinical target volumes, and the correspond-
ing planning target volumes, were as previously described.33
Prescribed doses were 68 to 72 Gy, 60 to 68 Gy, 60 to 64 Gy,
and 54 to 58 Gy in 30 to 32 fractions to the primary planning
target volume, lymph node planning target volume, high-
risk planning target volume, and low-risk planning target vol-
ume, respectively. Plan review was performed centrally by
study investigators (J.-G.L., J.Y., H.-Q.M., and C.Z.).
Patients underwent the following evaluations within
2 weeks before randomization: physical examination and
nasopharyngoscopy, Karnofsky performance status evalua-
tion, hematologic and biochemical analyses, EBV DNA titer,
magnetic resonance imaging or CT of the head and neck, and
18
F-FDG PET/CT. If 18F-FDG PET/CT was unavailable, CT of
the chest and abdomen and skeletal scintigraphy were per-
formed. Plasma EBV DNA assays were performed centrally
at SYSUCC for standardization.
Trial participants were reviewed at the following inter-
vals: weekly during IMRT, prior to each cycle of capecitabine,
every 3 months for the first 3 years, and every 6 months there-
after. All end points were assessed and validated by the phy-
sician in charge. The surveillance protocol included hemato-
logic and biochemical analyses, contrast-enhanced magnetic
resonance imaging or CT of the head and neck region, and CT
of the thorax and abdomen 3 and 6 months after CCRT and an-
nually thereafter. A plasma EBV DNA assay was performed dur-
ing the last week of CCRT, and nasopharyngoscopy was per-
formed 1 month after CCRT to evaluate tumor response. When
the presence of recurrence was indeterminate, 18F-FDG PET/CT
was performed. When feasible, fine-needle aspiration or bi-
opsy was performed for patients with suspected recurrence.
Salvage treatments for recurrent disease were at the discre-
tion of the physician in charge.
Outcomes
The primary end point was FFS, defined as time from the date
of randomization to a documented relapse or any death. Pa-
tients unavailable for follow-up or alive without disease re-
lapse were censored at the date of last follow-up. Secondary
end points included OS, defined as time from the date of ran-
domization to any death, with patients unavailable for fol-
low-up censored at the date of last follow-up; distant metas-
tasis–free survival (DMFS), defined as time from date of
randomization to documented distant metastasis or any death;
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and locoregional relapse–free survival (LRFS), defined as time
from the date of randomization to documented locoregional
relapse or any death. Patients with distant metastasis as a first
event were censored for LRFS at the date of distant metasta-
sis and vice versa; if distant metastasis and locoregional re-
lapse occurred concurrently, patients were considered as hav-
ing an event for both DMFS and LRFS. Patients unavailable for
follow-up or alive without distant metastasis or locoregional
relapse were censored at the date of last follow-up.
Treatment compliance and treatment-related adverse
events (TRAEs) during and after treatment were also re-
corded. For the capecitabine group, TRAEs were assessed at
baseline and prior to each chemotherapy cycle until ca-
pecitabine completion or at the time of treatment discontinu-
ation. For the control group, TRAEs were assessed at base-
line, prior to each concurrent cisplatin cycle and 3 and 6 months
after CCRT. Grading of TRAEs was performed using the Com-
mon Toxicity Criteria for Adverse Events, version 4.0, and the
Radiation Therapy Oncology Group radiation morbidity scor-
ing criteria. Delayed TRAEs were assessed using the latter.34
Statistical Analysis
The sample size for this study was calculated using the PS:
Power and Sample Size Calculation, version 3.1.2, software.
A 2-sided log-rank test with 54 events in both groups pro-
vided at least 80.0% power to detect a hazard ratio (HR) of 0.46
when the 3-year FFS rate in the control group was 70.0%
(estimated based on historical data35-37) at a significance level
of 5.0%. This HR would correspond to a 15.0% improvement
in 3-year FFS with the addition of adjuvant capecitabine to
CCRT.38 Considering a 4-year recruitment period and 3 years
of follow-up, 164 patients (82 per group) were needed, assum-
ing the distribution of survival times for both groups would
follow an exponential distribution. This yielded a total co-
hort size of 180 patients (90 per group), accounting for a drop-
out rate of 10.0%.
Primary efficacy analysis was performed based on the in-
tention-to-treat (ITT) principle. Safety data were summa-
rized for all patients who started the assigned treatment. Sur-
vival curves were derived using the Kaplan-Meier method and
compared using the log-rank test. Unstratified Cox propor-
tional hazards regression models were used to estimate HR.
Corresponding 95% CIs were based on the Wald test. The pro-
portional hazards assumption was tested by including time-
dependent covariates in the Cox models within the PROC
PHREG module (test for interaction), and by assessing whether
the Schoenfeld residuals were independent of time using
simple linear regression and a trend test. Graphical methods
were used to check the proportional hazards assumption using
smoothed plots of scaled Schoenfeld residuals against time.
Linear and log time scales were used for the assessment of pro-
portional hazards.39,40 Survival rates at 3 and 5 years were
reported with corresponding 95% CIs calculated using log
transformation of survival probabilities. Median follow-up time
was estimated using the reverse Kaplan-Meier method.
At the data collection cutoff date of February 9, 2022, the
prespecified number of events (54 events) for the primary end
point was not reached. The trial steering committee opted to
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 Adjuvant Capecitabine After Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma Original Investigation Research

report the results on the following grounds: there was (1) a

Figure 1. Trial Profile
lower than expected number of events despite enriching for
a high-risk study population, (2) there was a substantial de-
206 Assessed for eligibility
crease in events beyond the third year of follow-up (9 vs 40
events in the first 3 years), and (3) the study period had reached
26 Excluded
8 years with a median follow-up of nearly 5 years and a mini- 21 Did not meet inclusion
mum follow-up of 42.5 months for the last patient enrolled. criteria
5 Declined to participate
A 2-sided P < .05 was considered statistically significant.
Statistical analyses were performed using SAS, version 9.4
(SAS Institute Inc); STATA, version 16 (StataCorp LLC); and 180 Randomized
R, version 4.0.2 (R Foundation for Statistical Computing).
Figures were drawn using GraphPad Prism, version 9.0.0
(GraphPad Software). 90 Capecitabine group 90 Control group

90 Completed IMRT 90 Completed IMRT

90 Received concurrent cisplatin 90 Received concurrent cisplatin
Results 3 Completed 3 cycles 90 Completed 2 cycles
86 Completed 2 cycles
Patient and Treatment Characteristics 1 Completed 1 cycle (due to AEs)

Between March 31, 2014, and July 27, 2018, 206 patients were
screened, of whom 180 patients (median [IQR] age, 47 [40- 5 Received no capecitabine
2 Patients withdrawn
55] years; 143 [79.4%] men; 37 [20.6%] women; and 156 [86.7%]
2 AEs
with ≥2 unfavorable risk factors) were enrolled and randomly 1 PD
assigned to the capecitabine group (median [IQR] age, 46 [39-
55] years; 73 [81.1%] men and 17 [18.9%] women) or the con- 85 Received capecitabine
trol group (median [IQR] age, 48 [41-55] years; 70 [77.8%] men 1 Completed 13 cyclesa
70 Completed 8 cycles
and 20 [22.2%] women) (Figure 1). Pretreatment clinical char-
2 Completed 6-7 cycles
acteristics were comparable between groups (Table 1). Of 90 1 Treatment noncompliant
patients in the capecitabine group, 14 (15.6%) had 1 unfavor- 1 PD
4 Completed 4-5 cycles
able risk factor, 31 (34.4%) had 2 risk factors, and 45 (50.0%) 3 Treatment noncompliant
had 3 or more risk factors. Of 90 patients in the control group, 1 AE
8 Completed 1-3 cycles
10 (11.1%) had 1 unfavorable risk factor, 42 (46.7%) had 2 risk 2 Treatment noncompliant
factors, and 38 (42.2%) had 3 or more risk factors (Table 1; 4 AEs
2 PD
eTable 2 and eFigure 1 in Supplement 2).
All patients completed the prescribed course of IMRT, with
comparable dosimetric outcomes (eTable 3 in Supplement 2). 4 Had local or regional relapse 14 Had local or regional relapse
14 Had distant metastasis 18 Had distant metastasis
In the capecitabine group, 89 of 90 patients (98.9%) com- 11 Died 17 Died
pleted at least 2 cycles of concurrent cisplatin (1 patient re- 79 Survived 73 Survived
ceived only 1 cycle due to grade 2 hepatotoxicity). All patients
in the control group completed 2 cycles of concurrent cispl- 90 ITT set 90 ITT set
atin (Figure 1). The median (IQR) cumulative dose intensity for 90 Safety analysis set 90 Safety analysis set

cisplatin in both groups was 200.0 (200.0-200.0) mg/m2

(Table 1).
Of 90 patients in the capecitabine group, 85 (94.4%) re-
ceived capecitabine, with 71 (78.9%) completing all 8 cycles;
5 patients did not initiate treatment, 8 patients completed
1 to 3 cycles, 4 patients completed 4 to 5 cycles, and 2 patients
completed 6 to 7 cycles. The median (IQR) relative dose inten-
sity of capecitabine was 100% (84.7%-100%) (eTable 4 in
Supplement 2). The capecitabine dose was reduced for 19
of 90 patients (21.1%): 11 because of hand-foot syndrome,
4 because of gastrointestinal adverse events, 2 because of
recurrent myelosuppression, 1 because of fatigue, and 1 be-
cause of treatment noncompliance.
Outcomes
At 1 month after CCRT, endoscopic examination indicated that
for 90 patients in the capecitabine group, 78 (86.7%) showed
complete response and 12 (13.3%) showed partial response; and
All patients randomly assigned to either adjuvant capecitabine (capecitabine
group) or observation (control group) following concurrent chemoradiotherapy
were included in the intention-to-treat (ITT) analysis according to their
allocated treatments. All patients who received at least 1 dose of chemotherapy
were included in the safety analysis. AEs represent adverse events;
IMRT, intensity-modulated radiotherapy; PD, progressive disease.
a
Patient purchased adjuvant capecitabine off protocol from another hospital.
for 90 patients in the control group, 79 (87.8%) showed com-
plete response and 10 (11.1%) showed partial response (Table 1).
The median (IQR) follow-up duration was 58.0 (49.5-80.1)
months. The last patient enrolled in the trial was followed up
for 42.5 months. We recorded 49 disease relapse or death
events: 18 in the capecitabine group and 31 in the control group.
Details regarding the patterns of relapse and salvage thera-
pies are shown in eTables 5 and 6 in Supplement 2. Of note,
7 patients in the capecitabine group and 5 patients in the con-
trol group received anti–programmed cell death 1 antibodies.

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 Research Original Investigation Adjuvant Capecitabine After Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma

Table 1. Patient Pretreatment Clinical and Demographic Characteristics, Table 1. Patient Pretreatment Clinical and Demographic Characteristics,
and Treatment Summary and Response Rates and Treatment Summary and Response Rates
Before Starting Capecitabine Before Starting Capecitabine (continued)

Group, No. (%) Group, No. (%)

Capecitabine Control Capecitabine Control
(n = 90) (n = 90) (n = 90) (n = 90)
Pretreatment characteristica Treatment
Age, median (IQR), y 46 (39-55) 48 (41-55) Receipt of radiotherapy 90 (100) 90 (100)
Sex With radiotherapy delay 36 (40.0) 29 (32.2)
Female 17 (18.9) 20 (22.2) Radiotherapy delay, d 1 (1-4) 1 (1-2)
Male 73 (81.1) 70 (77.8) No. of cisplatin cycles completed
KPS score, points 1 1 (1.1)c 0
80 2 (2.2) 3 (3.3) 2 86 (95.6) 90 (100)
≥90 88 (97.8) 87 (96.7) 3 3 (3.3) 0
WHO category Cumulative cisplatin dose 200.0 200.0
intensity, median (IQR), mg/m2 (200.0-200.0) (200.0-200.0)
II 10 (11.1) 5 (5.6)
<200.0 10 (11.1) 4 (4.4)
III 80 (88.9) 85 (94.4)
≥200.0 80 (88.9) 86 (95.6)
T stageb
Patients with cisplatin 30 (33.3)c 33 (36.7)
T1 3 (3.3) 2 (2.2) administration delay
T2 7 (7.8) 5 (5.6) Time until start capecitabine, d 28 (27-31) NA
T3 53 (58.9) 56 (62.2) Response
T4 27 (30.0) 27 (30.0) Objective response rate after CCRTd
b
N stage Complete response 78 (86.7) 79 (87.8)
N0 3 (3.3) 2 (2.2) Partial response 12 (13.3) 10 (11.1)
N1 27 (30.0) 26 (28.9) Could not be assessed 0 1 (1.1)e
N2 38 (42.2) 45 (50.0) EBV DNA titer after CCRT,
copies/mL
N3 22 (24.4) 17 (18.9)
0 79 (87.7) 76 (84.4)
TNM stageb
>0 7 (7.8) 9 (10.0)
III 45 (50.0) 49 (54.4)
Not performed 4 (4.4) 5 (5.6)
IVa 23 (25.6) 24 (26.7)
IVb 22 (24.4) 17 (18.9) Abbreviations: CCRT, concurrent chemoradiotherapy; EBV, Epstein-Barr virus;
GTV, gross tumor volume; KPS, Karnofsky performance status; Max LN,
No. of high-risk factors maximum lymph node; NA, not applicable; SUVmax, maximum standard uptake
1 14 (15.6) 10 (11.1) value; WHO, World Health Organization.
a
2 31 (34.4) 42 (46.7) Distribution of eligibility criteria well balanced between groups (details in
eFigure 1 and eTable 2 in Supplement 2).
≥3 45 (50.0) 38 (42.2)
b
American Joint Committee on Cancer/Union for International Cancer Control,
TNM stage classificationb 7th edition.
T3-4N2M0 35 (38.9) 42 (46.7) c
One patient had grade 2 hepatotoxicity after receiving 1 cycle of cisplatin.
T1-4N3M0 22 (24.4) 17 (18.9) d
Objective response rate by nasopharyngoscopy at 1 month after CCRT, prior to
All others 33 (36.7) 31 (34.4) commencement of capecitabine.
e
SUVmax One patient committed suicide 1 week after CCRT.

≤10.0 13 (14.4) 16 (17.8)

For the primary end point in the ITT set, treatment with
>10.0 67 (74.4) 66 (73.3) CCRT and capecitabine resulted in FFS superior to treatment
Not performed 10 (11.1) 8 (8.9) with CCRT only (3 years, 83.3% vs 72.2%; 5 years, 78.5% vs
Primary GTV, cm3 65.9%; HR, 0.53 [95% CI, 0.30-0.94]; P = .03) (Figure 2A;
≤30.0 20 (22.2) 21 (23.3) Table 2; eFigure 2 in Supplement 2). The rates for 3-year OS
>30.0 70 (77.8) 69 (76.7) were 93.3% for the capecitabine group vs 87.8% for the con-
Max LN diameter, cm trol group (HR, 0.62; 95% CI, 0.29-1.32); rates for 3-year DMFS
≤4.0 83 (92.2) 81 (90.0) were 85.5% for the capecitabine group vs 80.4% for the con-
>4.0 7 (7.8) 9 (10.0) trol group (HR, 0.69; 95% CI, 0.35-1.35); and rates for 3-year
LRFS were 97.5% for the capecitabine group vs 84.1% for the
EBV DNA titer, copies/mL
control group (HR, 0.28; 95% CI, 0.10-0.76) (Figure 2B-D;
≤20 000 74 (82.2) 73 (81.1)
Table 2; eFigure 2 in Supplement 2).
>20 000 15 (16.7) 16 (17.8)
Treatment effects by high-risk factors for FFS in the ITT set
Not performed 1 (1.1) 1 (1.1)
are shown in eFigure 3 in Supplement 2. No interaction be-
(continued) tween the high risk factors and treatment was observed, al-

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 Adjuvant Capecitabine After Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma Original Investigation Research

Figure 2. Survival Curves in the Intention-to-Treat Set

A Failure-free survival B Overall survival

100 100 Capecitabine group (n = 90)

Capecitabine group (n = 90)
80 80
Control group (n = 90)
60 60
FFS, %

OS, %
Control group (n = 90)

40 40

20 20
HR, 0.53 (95% CI, 0.30-0.94)
Log-rank P = .03 HR, 0.62 (95% CI, 0.29-1.32)
0 0
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
Time, mo Time, mo
No. at risk (censored) No. at risk (censored)
Capecitabine group 90/0 83/0 82/0 75/0 53/21 33/39 23/49 13/59 Capecitabine group 90/0 90/0 87/6 84/0 59/22 37/43 25/54 14/65
Control group 90/0 80/0 68/0 65/0 52/11 26/35 21/39 6/54 Control group 90/0 87/0 84/0 79/0 64/13 32/43 24/49 7/66

C Distant metastasis–free survival D Locoregional relapse–free survival

Capecitabine group (n = 90)
100 100
Capecitabine group (n = 90)

80 80
Control group (n = 90)
Control group (n = 90)
60 60
DMFS, %

LRFS, %
40 40

20 20

HR, 0.69 (95% CI, 0.35-1.35) HR, 0.28 (95% CI, 0.10-0.76)
0 0
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
Time, mo Time, mo
No. at risk (censored) No. at risk (censored)
Capecitabine group 90/0 83/0 82/0 75/2 53/24 33/42 23/52 13/62 Capecitabine group 90/0 83/7 82/8 75/13 53/34 33/51 23/62 13/72
Control group 90/0 80/2 68/8 65/8 52/20 26/44 21/49 6/64 Control group 90/0 80/6 68/10 65/2 52/24 26/50 21/54 6/69

DMFS represents distant metastasis–free survival; FFS, failure-free survival; HR, hazard ratio; LRFS, locoregional relapse–free survival; and OS, overall survival.

Table 2. Survival Analyses for the Intention-to-Treat Set

Events, No. (%)a Survival at 3 years, % (95% CI) Survival at 5 years, % (95% CI)
Capecitabine Control Capecitabine Control Capecitabine Control
Survival (n = 90) (n = 90) (n = 90) (n = 90) (n = 90) (n = 90)
Failure-free 18 (20.0) 31 (34.4) 83.3 (73.9-89.6) 72.2 (61.7-80.3) 78.5 (67.7-86.0) 65.9 (54.3-75.2)
Overall 11 (12.2) 17 (18.9) 93.3 (85.8-96.9) 87.8 (79.0-93.0) 87.8 (78.0-93.3) 82.1 (71.7-89.0)
Distant 15 (16.7) 20 (22.2) 85.5 (76.3-91.3) 80.4 (70.3-87.3) 81.6 (70.9-88.7) 74.5 (62.5-83.2)
metastasis–free
Locoregional 5 (5.6) 16 (17.8) 97.5 (90.4-99.4) 84.1 (74.2-90.5) 91.8 (80.8-96.6) 82.9 (72.7-89.5)
relapse–free
a
Events include the survival measure plus any death.

though the addition of adjuvant capecitabine favored the sub-
group of patients having risk factors with a maximum standard
uptake value higher than 10.0, a primary GTV larger than 30.0
cm3, and an EBV DNA titer higher than 20 000 copies/mL. An
exploratory analysis for FFS performed for patients with or with-
out a detectable EBV DNA titer after CCRT suggested an infe-
rior FFS for the former, although statistical significance was not
reached (eFigure 4 in Supplement 2).
TRAEs
Incidences of grade 3 TRAEs during treatment (up to 7 months
after CCRT) were higher in the capecitabine group (54 of 90
patients [60.0%]) than for the control group (46 of 90 pa-
tients [51.1%]) (Table 3), whereas the incidence of grade 4
TRAEs was 1 patient (1.1%) in each group. Grade 3 TRAEs were
mainly xerostomia (17 patients [18.9%] vs 9 patients [10.0%]),
mucositis (21 patients [23.3%] vs 15 patients [16.7%]), and an-
orexia (8 patients [8.9%] vs 4 patients [4.4%]). Among 85 pa-
tients, there were 65 occurrences of grade 1 or 2 hand-foot syn-
drome (76.5%) associated with capecitabine and 3 occurrences
of grade 3 (3.5%).
The incidence of grade 3 or 4 delayed TRAEs was 9 of 83
(10.8%) in the capecitabine group and 7 of 81 (8.6%) in the con-
trol group (eTable 7 in Supplement 2). The incidences of de-

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 Research Original Investigation Adjuvant Capecitabine After Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma

Table 3. Incidence of Treatment-Related Adverse Events During Treatment Duration up to 7 Months

After Concurrent Chemoradiotherapy

Participants, No. (%)

TRAE Any grade TRAE Grade 1 or 2 TRAE Grade 3 TRAE Grade 4 TRAE
Capecitabine group (n = 90)a
Any TRAEs 90 (100) 35 (38.9) 54 (60.0) 1 (1.1)
Nonhematologic AEs
Hand-foot syndromeb 68 (80.0) 65 (76.5) 3 (3.5) 0
Xerostomia 90 (100) 73 (81.1) 17 (18.9) 0
Mucositis 87 (96.7) 66 (73.3) 21 (23.3) 0
Radiodermatitis 86 (95.6) 84 (93.3) 2 (2.2) 0
Dysgeusia 84 (93.3) 84 (93.3) 0 0
Dysphagia 3 (3.3) 3 (3.3) 0 0
Anorexia 89 (98.9) 81 (90.0) 8 (8.9) 0
Nausea 87 (96.7) 84 (93.3) 3 (3.3) 0
Vomiting 70 (77.8) 67 (74.4) 3 (3.3) 0
Constipation 44 (48.9) 44 (48.9) 0 0
Diarrhea 9 (10.0) 9 (10.0) 0 0
Fatigue 85 (94.4) 85 (94.4) 0 0
Insomnia 16 (17.8) 16 (17.8) 0 0
Allergy 3 (3.3) 3 (3.3) 0 0
Cardiotoxicity 2 (2.2) 2 (2.2) 0 0
Hematologic AEs
Leukopenia 88 (97.8) 62 (68.9) 26 (28.9) 0
Neutropenia 70 (77.8) 58 (64.4) 11 (12.2) 1 (1.1)
Anemia 69 (76.7) 64 (71.1) 5 (5.6) 0
Thrombocytopenia 23 (25.6) 23 (25.6) 0 0
Hypoalbuminemia 23 (25.6) 23 (25.6) 0 0
Hepatotoxicity 47 (52.2) 46 (51.1) 1 (1.1) 0
Nephrotoxicity 27 (30.0) 27 (30.0) 0 0
Control group (n = 90)c
Any TRAEs 90 (100) 43 (47.8) 46 (51.1) 1 (1.1)
Nonhematologic AEs
Hand-foot syndrome NA NA NA NA
Xerostomia 90 (100) 81 (90.0) 9 (10.0) 0
Mucositis 88 (97.8) 73 (81.1) 15 (16.7) 0
Radiodermatitis 86 (95.6) 85 (94.4) 1 (1.1) 0
Dysgeusia 90 (100) 90 (100) 0 0
Dysphagia 1 (1.1) 1 (1.1) 0 0
Anorexia 90 (100) 86 (95.6) 4 (4.4) 0
Nausea 86 (95.6) 83 (92.2) 3 (3.3) 0
Vomiting 68 (75.6) 66 (73.3) 2 (2.2) 0
Constipation 38 (42.2) 38 (42.2) 0 0
Abbreviations: AEs, adverse events;
Diarrhea 6 (6.7) 6 (6.7) 0 0 NA, not applicable; TRAEs,
Fatigue 85 (94.4) 85 (94.4) 0 0 treatment-related adverse events.
a
Insomnia 15 (16.7) 15 (16.7) 0 0 For the capecitabine group, TRAEs
Allergy 2 (2.2) 2 (2.2) 0 0 were assessed at baseline and prior
to each chemotherapy cycle until
Cardiotoxicity 1 (1.1) 1 (1.1) 0 0
capecitabine completion, or at the
Hematologic AEs time of treatment discontinuation.
Leukopenia 87 (96.7) 57 (63.3) 30 (33.3) 0 b
Of 85 patients who received at least
Neutropenia 67 (74.4) 49 (54.4) 17 (18.9) 1 (1.1) 1 cycle of adjuvant capecitabine
evaluated for hand-foot syndrome.
Anemia 63 (70.0) 61 (67.8) 2 (2.2) 0
c
For the control group, TRAEs were
Thrombocytopenia 27 (30.0) 24 (26.7) 3 (3.3) 0
assessed at baseline, prior to each
Hypoalbuminemia 17 (18.9) 17 (18.9) 0 0 concurrent cisplatin cycle, and at
Hepatotoxicity 40 (44.4) 40 (44.4) 0 0 3 and 6 months after concurrent
chemoradiotherapy, or at the time
Nephrotoxicity 29 (32.2) 28 (31.1) 1 (1.1) 0
of treatment discontinuation.

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 Adjuvant Capecitabine After Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma Original Investigation Research

layed TRAEs for any grade were comparable between the
groups, apart from a higher incidence in the capecitabine group
than in the control group of ototoxicity (58 of 83 [69.9%] vs
47 of 81 [58.0%]) and grade 1 xerostomia (49 of 83 [59.0%]
vs 40 of 81 [49.4%]).
Discussion
This randomized clinical trial addressed the unmet clinical
need for a tolerable adjuvant regimen after CCRT by showing
the efficacy and safety of single-agent adjuvant capecitabine
in 180 patients with LA-NPC. With a median follow-up of
58.0 months, we recorded FFS rates in favor of CCRT with
adjuvant capecitabine at 3 years (83.3% vs 72.2%) and 5 years
(78.5% vs 65.9%; HR, 0.53 [95% CI, 0.30-0.94]; P = .03). Of
90 patients, 71 (78.9%) completed the full course of ca-
pecitabine, to our knowledge the highest compliance rate re-
ported thus far among adjuvant chemotherapy trials.9,13-17,19
Our results support the use of capecitabine as an effective
and tolerable adjuvant regimen for treating patients with
LA-NPC.
Nevertheless, we acknowledge the relevance of our trial
may be questionable with the recent shift toward induction
chemotherapy in LA-NPC.8,41 At the time of trial design in
March 2014, the role of induction chemotherapy was not yet
established. Thus, our goal was to find a well-tolerated and ef-
fective regimen to add to a CCRT treatment backbone. Chen
et al19 found that metronomic capecitabine at a dose of 650
mg/m2 twice daily for 1 year conferred a 9.6% FFS benefit de-
spite 316 of 406 patients (77.8%) having received induction che-
motherapy. That trial, but not ours, showed improved OS, al-
though the cumulative dose intensities of capecitabine in both
trials were comparable. The discordance in results thus sug-
gests a need to further investigate the optimal duration and
dosing of adjuvant capecitabine in LA-NPC because there could
be antiangiogenic and immune modulation properties with
metronomic dosing.42,43 Patients’ preferences and likelihood
of compliance for a 6-month vs a 1-year course of treatment
also need to be considered.
Although OS was not significantly different in the ITT
population, the 3-year OS difference was 5.5% in favor of
adjuvant capecitabine. The lack of statistical significance for
OS is a consequence of the low number of death events even
though we had enriched for high-risk factors in our study popu-
lation (156 of 180 patients [86.7%] had ≥2 risk factors). The low
number of deaths in our study could be due to the efficacious
salvage therapies used at the time of recurrence, which in-
cluded anti–programmed cell death 1 antibody treatment and
local metastasis–directed therapies (eTable 6 in Supple-
ment 2). A meta-analysis of 19 trials investigating the role of
CCRT in LA-NPC suggested that progression-free survival may
be a justifiable surrogate for OS in this patient population.42
This suggestion is further supported by recent trials for
patients with NPC that reported FFS and corresponding OS
benefits after 3 to 4 years of follow-up. 44-47 An updated
meta-analysis will provide insights regarding whether
progression-free survival remains a valid surrogate for OS
among patients with LA-NPC given the emergence of effec-
tive salvage therapies.
Limitations
This study has several limitations. First, this trial did not
meet the expected number of FFS events. The trial steering
committee opted to report the study results at this juncture
because longer follow-up may not have yielded the required
number of events given the acute decrease in event rates
beyond the third year of follow-up. Second, the high risk fac-
tors included in the eligibility criteria were chosen based on
retrospective series.27-29,31 In addition, EBV DNA assay and
18
F-FDG PET/CT are not widely available in the community,
which may limit the applicability of our results. Third, a pla-
cebo control and masking of the physicians and patients to
the treatments were not used in our trial. Fourth, most trial
participants in both groups received only 2 cycles of 100
mg/m2 of cisplatin with IMRT. Thus, there is a question of
whether adjuvant capecitabine may only be beneficial for
patients with high-risk LA-NPC (by the study criteria) who
received this deintensified treatment.48,49 To clarify, the pre-
dominant use of 2 cycles of cisplatin was due to the IMRT
fractionation schema, as treatment was completed within
6 to 6.5 weeks. Several studies have reported that cumulative
dosing of 160 to 200 mg/m2 of cisplatin with radiotherapy is
adequate to yield a survival advantage over radiotherapy
alone among patients with LA-NPC.50-52
Conclusions
The results of this randomized clinical trial indicated that
treatment with adjuvant capecitabine following CCRT was
well tolerated and had a high compliance rate. Long-term
follow-up of nearly 5 years confirmed an FFS benefit with
this treatment regimen. These results suggest that single-
agent capecitabine may be considered an adjuvant regimen
when treating patients with high-risk LA-NPC.

ARTICLE INFORMATION
Accepted for Publication: July 31, 2022.
Published Online: October 13, 2022.
doi:10.1001/jamaoncol.2022.4656
Open Access: This is an open access article
distributed under the terms of the CC-BY License.
© 2022 Miao J et al. JAMA Oncology.
Author Affiliations: Department of
Nasopharyngeal Carcinoma, Sun Yat-sen University
Cancer Center, State Key Laboratory of Oncology
in South China, Collaborative Innovation Center for
Cancer Medicine, Guangdong Key Laboratory of
Nasopharyngeal Carcinoma Diagnosis and Therapy,
Guangzhou, Guangdong, PR China (Miao, Wang,
Q. Chen, Xiang, M.-y. Chen, Lv, Xia, Tang, X. Guo,
Mai, Zhao); Division of Clinical Trials &
Epidemiological Sciences, National Cancer Centre
Singapore, Singapore (S. H. Tan); Oncology
Academic Programme, Duke-NUS Medical School,
Singapore (S. H. Tan, Chua); Department of
Radiation Oncology, Jiangxi Cancer Hospital of
Nanchang University, Nanchang, China (Li, Gong);
National Health Commission Key Laboratory of
Personalized Diagnosis and Treatment of
Nasopharyngeal Carcinoma, Jiangxi Cancer
Hospital of Nanchang University, Nanchang, China
(Li, Gong); Department of Radiation Oncology,
National Cancer Center/National Clinical Research
Center for Cancer/Cancer Hospital, Chinese

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 Research Original Investigation
Academy of Medical Sciences and Peking Union
Medical College, Beijing, 100021, PR China (Yi,
Zhang); Division of Medical Sciences, National
Cancer Centre Singapore, Singapore (Ong, Chua);
Department of Head and Neck and Thoracic
Cancers, Division of Radiation Oncology, National
Cancer Centre Singapore, Singapore (L. L. Tan,
Chua); Ministry of Health Holdings, Singapore
(L. L. Tan); Department of Clinical Trials Center,
Sun Yat-sen University Cancer Center, State Key
Laboratory of Oncology in South China,
Collaborative Innovation Center for Cancer
Medicine, Guangdong Key Laboratory of
Nasopharyngeal Carcinoma Diagnosis and Therapy,
Guangzhou, Guangdong, PR China (Y. Guo);
Department of Radiation Oncology, Sun Yat-sen
University Cancer Center, State Key Laboratory of
Oncology in South China, Collaborative Innovation
Center for Cancer Medicine, Guangdong Key
Laboratory of Nasopharyngeal Carcinoma Diagnosis
and Therapy, Guangzhou, Guangdong, PR China
(Deng, Han).
Author Contributions: Dr Zhao had full access
to all the data in the study and takes responsibility
for the integrity of the data and the accuracy of
the data analysis. Drs Miao, Wang, Tan, Li, and Yi
contributed to this work equally. Drs Han, Mai,
Chua, and Zhao served as co–senior authors.
Concept and design: Han, Mai, Chua, Zhao.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Miao, Wang, S. Tan, Li,
Yi, Ong, Chua, Zhao.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Miao, Y. Guo.
Obtained funding: Zhao.
Administrative, technical, or material support:
S. Tan, Han, Mai, Chua, Zhao.
Supervision: S. Tan, Han, Mai, Chua, Zhao.
Conflict of Interest Disclosures: Dr Chua reported
receiving personal fees from Astellas, Janssen,
Bayer, Pfizer, Merck Sharp & Dohme, Varian, IQVIA,
Telix Pharmaceuticals; receiving personal fees and
nonfinancial support from AstraZeneca,
nonfinancial support from Decipher Biosciences
and MedLever; being a consultant for
immunoSCAPE; being a coinventor of and patent
holder in Singapore for a high-sensitivity lateral
flow immunoassay for detection of analyte in
sample; and serving on the board of directors of
Digital Life Line Pte Ltd, which owns the licensing
agreement of the patent, all outside the submitted
work. No other disclosures were reported.
Funding/Support: This study was funded by grants
81872469 and 82073330 from the National
Natural Science Foundation of China and award
308-2016-04-01 from the Sun Yat-sen University
Cancer Center 308 Program to Dr Zhao; and
Clinician Scientist Awards from the National Medical
Research Council Singapore, and grants from the
Duke-NUS Oncology Academic Programme, the
Goh Foundation Proton Research Programme, the
National Cancer Centre Singapore Cancer Fund, and
the Kua Hong Pak Head and Neck Cancer Research
Programme to Dr Chua.
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review,
or approval of the manuscript; and decision to
submit the manuscript for publication.
1784 JAMA Oncology December 2022 Volume 8, Number 12 (Reprinted)
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Adjuvant Capecitabine After Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma
Meeting Presentation: Preliminary results of this
study were presented at the virtual annual meeting
of the American Society of Clinical Oncology, June 7,
2021.
Data Sharing Statement: See Supplement 3.
Additional Contributions: The authors thank
the patients and their families for their participation
in this study.
Additional Information: The authenticity of this
study has been validated by uploading the key
raw data to the Research Data Deposit
(RDDA2022723721).
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