gem cis induction chemothearpy nasopharyngeal cancer.pdf

The new engl and jour nal of medicine
n engl j med
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The authors’ full names, academic de-
grees, and affiliations are listed in the Ap-
pendix. Address reprint requests to Dr.
Ma at the Department of Radiation On-
cology, Sun Yat-sen University Cancer
Center, No. 651 Dongfeng Rd. E., Guang-
zhou 510060, China, or at
majun2@
mail
.
sysu.edu.cn.
Drs. Y. Zhang, L. Chen, G.-Q. Hu, N.
Zhang, Zhu, Yang, Jin, Shi, and Y.-P. Chen
and Drs. Chua, Xie, Ying Sun, and Ma
contributed equally to this article.
This article was published on May 31,
2019, at NEJM.org.
DOI: 10.1056/NEJMoa1905287
Copyright © 2019 Massachusetts Medical Society.
BACKGROUND
Platinum-based concurrent chemoradiotherapy is the standard of care for patients
with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and
cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials.
METHODS
In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared
gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradio-
therapy with concurrent chemoradiotherapy alone. Patients with locoregionally ad-
vanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive
gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8)
plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for
three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per
square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy)
or chemoradiotherapy alone. The primary end point was recurrence-free survival
(i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence]
or death from any cause) in the intention-to-treat population. Secondary end points
included overall survival, treatment adherence, and safety.
RESULTS
A total of 480 patients were included in the trial (242 patients in the induction
chemotherapy group and 238 in the standard-therapy group). At a median follow-
up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction
chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio
for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P
=
0.001).
Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio
for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed
three cycles of induction chemotherapy. The incidence of acute adverse events of
grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the
standard-therapy group, with a higher incidence of neutropenia, thrombocytope-
nia, anemia, nausea, and vomiting in the induction chemotherapy group. The in-
cidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy
group and 11.4% in the standard-therapy group.
CONCLUSIONS
Induction chemotherapy added to chemoradiotherapy significantly improved recur-
rence-free survival and overall survival, as compared with chemoradiotherapy alone,
among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded
by the Innovation Team Development Plan of the Ministry of Education and others;
ClinicalTrials.gov number, NCT01872962.)
ABSTR ACT
Gemcitabine and Cisplatin Induction
Chemotherapy in Nasopharyngeal Carcinoma
Y. Zhang, L. Chen, G.-Q. Hu, N. Zhang, X.-D. Zhu, K.-Y. Yang, F. Jin, M. Shi,
Y.-P. Chen, W.-H. Hu, Z.-B. Cheng, S.-Y. Wang, Y. Tian, X.-C. Wang, Yan Sun,
J.-G. Li, W.-F. Li, Y.-H. Li, L.-L. Tang, Y.-P. Mao, G.-Q. Zhou, R. Sun, X. Liu,
R. Guo, G.-X. Long, S.-Q. Liang, L. Li, J. Huang, J.-H. Long, J. Zang, Q.-D. Liu,
L. Zou, Q.-F. Su, B.-M. Zheng, Y. Xiao, Y. Guo, F. Han, H.-Y. Mo, J.-W. Lv,
X.-J. Du, C. Xu, N. Liu, Y.-Q. Li, M.L.K. Chua, F.-Y. Xie, Ying Sun, and J. Ma
Original Article
The New England Journal of Medicine
Downloaded from nejm.org on July 17, 2019. For personal use only. No other uses without permission.
Copyright © 2019 Massachusetts Medical Society. All rights reserved.

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N
asopharyngeal carcinoma is a
head and neck cancer with a specific geo-
graphic distribution. It affected an esti-
mated 130,000 patients worldwide in 2018, with
the highest rates occurring in regions in South
China, Southeastern Asia, and North Africa.1
More
than 70% of patients receive a diagnosis of lo-
coregionally advanced disease at presentation,2
and in this subgroup of patients with an unfa-
vorable prognosis, concurrent chemoradiothera-
py with a platinum-based agent constitutes the
backbone of treatment, with the chemotherapy
sensitizing the tumor to the toxic effects of the
radiotherapy. Distant metastasis predominates as
the pattern of disease relapse, and it accounts for
cancer-specific mortality among approximately
70% of patients.3,4
The addition of chemotherapy as an induction
or adjuvant regimen to chemoradiotherapy has
been investigated with mixed results.5-9
The tox-
icity of systemic therapy after chemoradiotherapy
remains a pertinent issue.6,10
The use of induction
chemotherapy is supported by the long-term re-
sults of a randomized, controlled trial in which
docetaxel, cisplatin, and fluorouracil were added
to chemoradiotherapy in patients with locoregion-
ally advanced nasopharyngeal carcinoma; patients
had prolonged overall survival with this regimen.7,9
Previous phase 2 trials have shown that gem-
citabine plus cisplatin is an effective chemothera-
py in patients with nasopharyngeal carcinoma11-13
and has been established as the first-line treat-
ment of choice over cisplatin plus fluorouracil in
patients with recurrent or metastatic disease.14
However, in the context of newly diagnosed, non-
metastatic, locoregionally advanced disease, the
efficacy and safety profile of induction therapy
with gemcitabine plus cisplatin to chemoradio-
therapy is unclear. We therefore conducted a mul-
ticenter, randomized, controlled, phase 3 clinical
trial to investigate the efficacy and safety of add-
ing gemcitabine plus cisplatin to chemoradio-
therapy in patients with locoregionally advanced
nasopharyngeal carcinoma.
Methods
Trial Design and Participants
This open-label, parallel-group, randomized, phase
3 trial enrolled patients from 12 hospitals in China
(Table S1 in the Supplementary Appendix, available
with the full text of this article at NEJM.org).
The institutional ethics review board at each par-
ticipating center approved the trial protocol, avail-
able at NEJM.org. The trial was performed accord-
ing to the principles of the Declaration of Helsinki
and Good Clinical Practice guidelines as defined
by the International Conference on Harmonisa-
tion. Written informed consent was obtained from
all the patients before enrollment. Patients could
withdraw consent at any time after enrollment
and could discontinue the trial if disease progres-
sion or severe coexisting conditions occurred dur-
ing treatment.
This was an investigator-initiated trial. The
last author designed, wrote, and implemented the
trial protocol and managed the trial. Lead inves-
tigators from each center gathered the data and
ensured its accuracy and completeness. One of the
authors conducted the statistical analyses. No one
who is not an author contributed to the writing of
the manuscript. The first author wrote the first
draft of manuscript, which was reviewed by all
the authors. All the authors approved the final
content of the manuscript. The trial sponsors had
no access to the data and were not involved in the
data interpretation or the manuscript preparation
or review. Qilu Pharmaceutical provided gem-
citabine and cisplatin free of charge and was not
involved in the trial design, data collection or
analysis, or manuscript preparation or review.
The last author vouches for the completeness and
accuracy of the data and for the adherence of the
trial to the protocol.
Eligibility criteria included the following: an age
between 18 and 64 years; histologic confirmation
of nonkeratinizing nasopharyngeal carcinoma; no
previous treatment for cancer; nondistant meta-
static, newly diagnosed stage III to IVB disease
(excluding subgroups of patients with low risk of
metastasis; i.e., those with bulky primary tumor
with no nodal involvement) that was staged accord-
ing to the American Joint Committee on Cancer–
Union for International Cancer Control 7th edition
stage-classification system15
; a Karnofsky perfor-
mance-status score of at least 70 (on a scale from
0 to 100, with lower scores indicating greater dis-
ability); and adequate hematologic, renal, and he-
patic function. Key exclusion criteria were the fol-
lowing: receipt of treatment with palliative intent;
a history of cancer; receipt of previous treatment
(radiotherapy, chemotherapy, or surgery [except di-
agnostic procedures]) to the nasopharynx or neck;
lactation or pregnancy; or severe coexisting illness.

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Gemcitabine and Cisplatin in Nasopharyngeal Carcinoma
For this trial, essential pretreatment evalua-
tions included the following: complete history;
physical examination; hematologic and biochemi-
cal analyses; flexible nasopharyngoscopy; histo-
pathological diagnosis; and magnetic resonance
imaging (MRI) or enhanced computed tomogra-
phy (CT) (if patients had contraindications to
MRI) of the nasopharynx and neck for primary
tumor staging. Distant metastasis staging was
completed with CT examination of the chest and
abdomen and with skeletal scintigraphy. The use
of 18
F-fluorodeoxyglucose–positron-emission to-
mography was recommended for patients with
advanced node stage or if there was a clinical
suspicion of distant metastases.16
Randomization and Masking
The randomization procedure was carried out by
telephone from the Clinical Trials Center of the
Sun Yat-sen University Cancer Center. A computer
program was used to generate the assignment list.
Randomization was stratified according to treat-
ment center and tumor–node–metastasis (TNM)
stage (III or IV), and patients were randomly as-
signed in a 1:1 ratio in blocks of four to receive
either three cycles of induction chemotherapy
plus chemoradiotherapy (induction chemothera-
py group) or chemoradiotherapy alone (standard-
therapy group). Treatment group assignment was
not masked.
Procedures
Gemcitabine at a dose of 1 g per square meter of
body-surface area on days 1 and 8 and cisplatin
at a dose of 80 mg per square meter on day 1 were
administered intravenously once every 3 weeks
for three cycles.14
Cisplatin that was concurrent
with radiotherapy was then administered intra-
venously at a dose of 100 mg per square meter
every 3 weeks on days 1, 22, and 43. Details of the
chemotherapy dose modifications and supportive
measures are provided in the Supplementary Ap-
pendix.
For radiotherapy, an intensity-modulated tech-
nique was mandatory in both groups. The guide-
lines regarding radiotherapy3,17
are provided in the
Supplementary Appendix. It was recommended
that patients in the induction chemotherapy group
commence chemoradiotherapy within 21 to 28
days after the first day of the last cycle of induc-
tion chemotherapy.
Tumors were assessed with the use of flexible
nasopharyngoscopy and MRI of the nasopharyn-
geal and neck areas at 1 week after the comple-
tion of induction chemotherapy and 16 weeks
after chemoradiotherapy. We used the Common
Terminology Criteria for Adverse Events, version
4.0, to grade acute toxic effects during treatment,
and late toxic effects that were associated with
radiotherapy were graded according to the Late
Radiation Morbidity Scoring Scheme of the Radia-
tion Therapy Oncology Group.18
In the first 3 years of follow-up, all the patients
underwent assessment every 3 months and then
every 6 months thereafter until death. All end
points were assessed or confirmed by the physi-
cian in charge. Fine-needle aspiration or biopsy of
suspected lesions was performed if deemed nec-
essary in order to confirm locoregional or distant
disease progression.
End Points
The primary end point was recurrence-free sur-
vival, which was defined as the time from ran-
domization to documented disease recurrence
(either distant metastasis or locoregional disease
recurrence) or death from any cause, whichever
occurred first. Secondary end points included over-
all survival, distant recurrence–free survival (free-
dom from documented distant metastasis or death
from any cause), locoregional recurrence–free sur-
vival (freedom from documented locoregional
recurrence or death from any cause), treatment
response, treatment adherence, and safety. (Def-
initions of the end points are provided in the
Supplementary Appendix.) Patients who were lost
to follow-up or were still alive without distant
metastasis or locoregional recurrence at the end
of the trial had their data censored at the date of
last follow-up.
Statistical Analysis
This trial aimed to evaluate whether the addition
of induction chemotherapy to chemoradiotherapy
improved recurrence-free survival as compared
with chemoradiotherapy alone. We estimated that
approximately 452 patients would need to un-
dergo randomization in a 1:1 ratio (226 patients
per group) in order for 77 events to be observed
for the primary analysis of recurrence-free survival.
We estimated that the trial would have 80% power
to detect a hazard ratio for disease recurrence or
death of 0.52 using a log-rank test with a two-sided
significance level of 0.05. We further assumed

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that 5% of the patients would be lost to follow-
up or would prematurely discontinue the trial.
This yielded a final sample size of 476 (238 pa-
tients per group).19
Efficacy analyses were performed in both the
intention-to-treat and per-protocol trial popula-
tions (see the Supplementary Appendix). The
safety population comprised patients who start-
ed treatment in each group. Kaplan–Meier curves
were used to present time-to-event data, and the
two treatment groups were compared by means
of log-rank tests that were stratified according to
trial center and disease stage (primary analysis).20
The stratified Cox proportional-hazards model,
with treatment as a single covariate, was used to
calculate the hazard ratios and 95% confidence
intervals, and the proportional-hazards assump-
tion was tested with Schoenfeld residuals.21
We further performed an interaction analysis
to explore whether the effect of the experimental
treatment varied in the subgroups defined accord-
ing to sex, age, Karnofsky performance-status
score, tumor category, node category, and TNM
stage (see the Supplementary Appendix). The in-
teraction analysis was conducted by means of a
test of treatment-by-covariate interaction on the
basis of the Cox proportional-hazards model.22
For each chemotherapy drug, we calculated the
relative dose intensity as the total dose actually
received during treatment, divided by the dose
defined by the protocol. Dose intensity in the two
groups was compared with the use of the Wil-
coxon rank-sum test.
An independent data monitoring committee
monitored the trial and made decisions regarding
possible early trial stoppage. An interim analysis
was performed on October 30, 2016, when the
trial reached approximately half the expected
number of disease recurrences or deaths (i.e., 38
events). To preserve an overall type I error rate of
0.05 for the entire trial, the O’Brien–Fleming type
boundary (alpha of 0.003) was used for early
trial stoppage. The data monitoring committee
reviewed the analyses and approved the continu-
ation of the trial. Separately, we implemented a
central safety monitoring committee to monitor
unexpected adverse events and treatment-related
death. The database was locked on April 15, 2019,
and here we report the survival and toxicity
analyses. Analyses were conducted with the use of
SPSS software, version 22.0 (IBM), and Stata soft-
ware, version 14.2 (StataCorp). The type I error
rate was set to 0.05 for the primary end point, and
all tests were two-sided.
Results
Patients and Treatment
From December 2013 through September 2016,
we enrolled 480 patients across 12 sites. The in-
duction chemotherapy group comprised 242 pa-
tients, and the standard-therapy group comprised
238 patients (Fig. 1). The characteristics of the
patients at baseline were well balanced between
the two groups (Table 1).
Of the 242 patients who had been randomly
assigned to undergo induction chemotherapy plus
chemoradiotherapy, 239 (98.8%) started protocol-
defined induction chemotherapy and were in-
cluded in the safety population (Fig. 1). A total of
3 patients withdrew from the trial before the
initiation of trial treatment (1 patient received
chemoradiotherapy alone, and 2 received differ-
ent induction chemotherapy plus chemoradiother-
apy). A total of 231 of the 239 patients (96.7%)
completed three cycles of induction chemotherapy;
8 patients (3.3%) did not complete all three cy-
cles of induction chemotherapy (3 patients re-
ceived two cycles and 5 received one cycle; the
reasons included a case of the patient declining
the treatment, a case of disease progression, and
discontinuation due to adverse events in the re-
maining six cases) (Table S2 in the Supplemen-
tary Appendix). A total of 31 of the 239 patients
(13.0%) had dose reductions of gemcitabine or
cisplatin, mainly because of hematologic toxic
effects (in 21 patients). Overall, the median rela-
tive dose intensity was 100% (interquartile range,
100 to 100) for gemcitabine and 100% (interquar-
tile range, 100 to 100) for cisplatin.
In the induction chemotherapy group, 234 of
239 patients (97.9%) received concurrent chemo-
radiotherapy after induction chemotherapy, and
5 patients (2.1%) did not (Fig. 1). A total of 93 pa-
tients (38.9%) completed three cycles of concurrent
cisplatin, 127 (53.1%) received two cycles, and 14
(5.9%) received one cycle.
In the standard-therapy group, of the 238
patients who had undergone randomization, 237
received the protocol-defined concurrent chemo-
radiotherapy and were included in the safety popu-
lation; 1 patient who deviated from the protocol

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Figure 1. Enrollment, Randomization, and Follow-up.
The induction chemotherapy group received gemcitabine and cisplatin plus concurrent chemoradiotherapy, and the standard-therapy
group received chemoradiotherapy alone. Other induction chemotherapy regimens included docetaxel, cisplatin plus fluorouracil, and
docetaxel plus cisplatin.
480 Patients underwent randomization
242 Were assigned to receive induction
chemotherapy with gemcitabine and cisplatin
plus concurrent chemoradiotherapy
(intention-to-treat population)
238 Were assigned to receive concurrent
chemoradiotherapy alone
(intention-to-treat population)
3 Withdrew consent and did not receive
induction chemotherapy with gem-
citabine and cisplatin
2 Received other induction chemo-
therapy and concurrent chemo-
radiotherapy
1 Received concurrent chemoradio-
therapy alone
1 Did not receive protocol-defined
concurrent cisplatin (withdrew
consent and received radiotherapy
and weekly cisplatin)
218 Were included in the per-protocol
population (completed 3 cycles of induction
chemotherapy with gemcitabine and cisplatin
and 2 to 3 cycles of concurrent cisplatin and
radiotherapy)
177 Were included in the per-protocol
population (completed 3 cycles of concurrent
cisplatin and radiotherapy)
239 Started induction chemotherapy with
gemcitabine and cisplatin (safety
population)
8 Discontinued induction chemotherapy
5 Received 1 cycle
5 Had adverse event
3 Received 2 cycles
1 Had adverse event
1 Had disease progression
1 Declined to participate
5 Did not receive concurrent cisplatin
4 Received radiotherapy alone
2 Had adverse event
1 Had disease progression
1 Withdrew consent
1 Received radiotherapy and carboplatin
1 Had adverse event
234 Started concurrent chemoradiotherapy
141 Discontinued concurrent cisplatin
14 Completed 1 cycle
7 Had adverse event
127 Completed 2 cycles
13 Had adverse event
23 Had other reason
237 Started concurrent chemoradiotherapy
(safety population)
2 Discontinued radiotherapy
60 Discontinued concurrent cisplatin
4 Completed 1 cycle
1 Had adverse event
56 Completed 2 cycles
6 Had adverse event
6 Had other reason

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received weekly cisplatin (Table S3 in the Supple-
mentary Appendix). A total of 177 of 237 patients
(74.7%) completed three cycles of concurrent cis-
platin, 56 (23.6%) received two cycles, and 4 (1.7%)
received one cycle.
Overall, 191 of 239 patients (79.9%) in the in-
duction chemotherapy group and 227 of 237 pa-
tients (95.8%) in the standard-therapy group
received at least 200 mg per square meter of
concurrent cisplatin. The median dose intensity
for concurrent cisplatin, which had been admin-
istered every 3 weeks, was 200 mg per square
meter (interquartile range, 200 to 300) in the
induction chemotherapy group and 300 mg per
square meter (interquartile range, 200 to 300) in
the standard-therapy group (P<0.001). The medi-
an cumulative dose of cisplatin was 440 mg per
square meter (interquartile range, 440 to 540) in
the induction chemotherapy group; only 63 of
239 patients (26.4%) received the full cumulative
dose of 540 mg per square meter.
Regarding radiotherapy, all 239 patients in the
induction chemotherapy group completed proto-
col-defined intensity-modulated radiotherapy. The
median time from the start of the last induction
chemotherapy cycle to the commencement of
chemoradiotherapy was 25 days (interquartile
range, 22 to 28). In the standard-therapy group,
radiotherapy was discontinued in 2 of 237 pa-
tients (0.8%) because the patients declined the
treatment. The time to the completion of radio-
therapy and the radiotherapy doses received were
similar in the two groups (Table S3 in the Sup-
plementary Appendix).
Efficacy
Overall, 94.6% of the patients (226 of 239) had a
response after induction chemotherapy before the
start of chemoradiotherapy; 24 patients (10.0%)
had a complete response, and 202 (84.5%) had a
partial response. At 16 weeks after radiotherapy,
97.1% of the patients (235 of 242) in the induc-
tion chemotherapy group had a complete response,
as did 96.6% of the patients (230 of 238) in the
standard-therapy group (Table 2).
At the last follow-up on April 15, 2019, the
median follow-up was 42.7 months (range, 3.5 to
65.0). A total of 296 of the 427 patients who were
alive (69.3%) as of this date had follow-up re-
cords of at least 36 months, and the last patient
who had enrolled in the trial had a follow-up of
31.2 months. We recorded a total of 100 events
of recurrence or death (20.8% of the patients in
the overall trial population), including events in
37 of 242 patients (15.3%) in the induction che-
motherapy group and in 63 of 238 (26.5%) in the
standard-therapy group. Details regarding the
patterns of relapse and subsequent therapies
after relapse are provided in Tables S5 and S6 in
the Supplementary Appendix. The 3-year recur-
rence-free survival was 85.3% (95% confidence
interval [CI], 80.0 to 89.3) in the induction che-
motherapy group, as compared with 76.5% (95%
Characteristic
Induction Chemotherapy
(N = 242)
Standard Therapy
(N = 238)
Median age (range) — yr 46 (18–64) 45 (20–64)
Sex — no. (%)
Male 182 (75.2) 164 (68.9)
Female 60 (24.8) 74 (31.1)
Karnofsky performance-
status score†
100 10 (4.1) 10 (4.2)
90 189 (78.1) 198 (83.2)
80 36 (14.9) 21 (8.8)
70 7 (2.9) 9 (3.8)
Tumor category — no. (%)‡
T1 2 (0.8) 3 (1.3)
T2 16 (6.6) 16 (6.7)
T3 115 (47.5) 116 (48.7)
T4 109 (45.0) 103 (43.3)
Node category — no. (%)‡
N1 114 (47.1) 106 (44.5)
N2 101 (41.7) 108 (45.4)
N3A 12 (5.0) 8 (3.4)
N3B 15 (6.2) 16 (6.7)
Disease stage — no. (%)‡
III 111 (45.9) 120 (50.4)
IVA 104 (43.0) 94 (39.5)
IVB 27 (11.2) 24 (10.1)
*
Patients in the induction chemotherapy group received gemcitabine plus cis-
platin as well as concurrent chemoradiotherapy, and patients in the standard-
therapy group received concurrent chemoradiotherapy alone. There were no
significant differences between the treatment groups in the characteristics at
baseline. Percentages may not total 100 because of rounding.
†
Karnofsky performance-status scores are assessed on a scale from 0 to 100,
with lower scores indicating greater disability.
‡
Tumor and node categories and disease stage were assessed according to the
7th edition of American Joint Committee on Cancer–Union for International
Cancer Control stage classification system.15
Table 1. Characteristics of the Patients at Baseline.*

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CI, 70.4 to 81.5) in the standard-therapy group
(stratified hazard ratio for recurrence or death,
0.51; 95% CI, 0.34 to 0.77; P = 0.001) (Table 2 and
Fig. 2A).
At the time of analysis, 18 of 242 patients
(7.4%) in the induction chemotherapy group and
35 of 238 patients (14.7%) in the standard-therapy
group had died. Details regarding the cause of
death are provided in Table S5 in the Supplemen-
tary Appendix. Patients in the induction chemo-
therapy group had better 3-year overall survival
than those in the standard-therapy group (94.6%
[95% CI, 90.6 to 96.9] vs. 90.3% [95% CI, 85.6
to 93.5]; stratified hazard ratio for death, 0.43;
95% CI, 0.24 to 0.77) (Table 2 and Fig. 2B). The
3-year distant recurrence–free survival was bet-
ter in the induction chemotherapy group than in
the standard-therapy group (91.1% [95% CI, 86.4
to 94.2] vs. 84.4% [95% CI, 79.1 to 88.5]; strati-
fied hazard ratio for distant recurrence or death,
0.43; 95% CI, 0.25 to 0.73) (Table 2 and Fig. 2C).
However, the 3-year locoregional recurrence–free
survival was similar in the induction chemother-
apy group and the standard-therapy group
(91.8% [95% CI, 87.3 to 94.7] and 91.0% [95%
CI, 86.2 to 94.0], respectively; stratified hazard
ratio for locoregional recurrence or death, 0.77;
95% CI, 0.42 to 1.41) (Table 3 and Fig. 2D).
Adverse Events
During induction chemotherapy, 93 of 239 pa-
tients (38.9%) had acute adverse events of grade
3 or 4 (Table S4 in the Supplementary Appendix).
Neutropenia was the most common event (in 49
Variable
(N = 242)
Standard Therapy
(N = 238)
Hazard Ratio
(95% CI)
Recurrence-free survival
Recurrence or death — no. (%) 37 (15.3) 63 (26.5)
Percentage of patients alive and without recurrence
at 3 yr (95% CI)
85.3 (80.0–89.3) 76.5 (70.4–81.5) 0.51 (0.34–0.77)
Overall survival
Death — no. (%) 18 (7.4) 35 (14.7)
Percentage of patients alive at 3 yr (95% CI) 94.6 (90.6–96.9) 90.3 (85.6–93.5) 0.43 (0.24–0.77)
Distant recurrence–free survival
Distant metastasis or death — no. (%) 23 (9.5) 40 (16.8)
Percentage of patients alive and without distant
metastasis at 3 yr (95% CI)
91.1 (86.4–94.2) 84.4 (79.1–88.5) 0.43 (0.25–0.73)
Locoregional recurrence–free survival
Locoregional recurrence or death — no. (%) 17 (7.0) 22 (9.2)
Percentage of patients alive and without locoregional
recurrence at 3 yr (95% CI)
91.8 (87.3–94.7) 91.0 (86.2–94.0) 0.77 (0.42–1.41)
Response to induction chemotherapy†
Complete response — no./total no. (%) 24/239 (10.0) —
Partial response — no./total no. (%) 202/239 (84.5) —
Stable disease — no./total no. (%) 10/239 (4.2) —
Progressive disease — no./total no. (%) 3/239 (1.3) —
Response to whole treatment — no. (%)
Complete response 235 (97.1) 230 (96.6)
Partial response 2 (0.8) 5 (2.1)
Progressive disease 1 (0.4) 1 (0.4)
Could not be assessed 4 (1.7) 2 (0.8)
*
Hazard ratios were calculated by a stratified Cox proportional-hazards model. CI denotes confidence interval.
†
Response to induction chemotherapy was assessed only in the 239 patients who began receiving induction chemotherapy.
Table 2. Survival and Response to Treatment.*

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8
patients [20.5%]), followed by leukopenia (in 26
[10.9%]) and vomiting (in 26 [10.9%]). Over the
entire treatment course, 181 patients (75.7%) in
the induction chemotherapy group and 132 (55.7%)
in the standard-therapy group reported adverse
events of grade 3 or 4 (Table 3). Mucositis was
the most common adverse event of grade 3 or 4
(in 69 patients [28.9%] in the induction chemo-
therapy group and in 76 [32.1%] in the standard-
therapy group). The induction chemotherapy group
had a higher incidence than the standard-therapy
group of grade 3 or 4 neutropenia (67 patients
[28.0%] vs. 25 [10.5%]), thrombocytopenia (27
[11.3%] vs. 3 [1.3%]), anemia (23 [9.6%] vs. 2
[0.8%]), nausea (55 [23.0%] vs. 33 [13.9%]), and
vomiting (54 [22.6%] vs. 33 [13.9%]). The induc-
tion chemotherapy group also had a higher inci-
dence than the standard-therapy group of grade
1 or 2 nephrotoxic effects (46 patients [19.2%] vs.
27 [11.4%]) but not of ototoxic effects such as
deafness or otitis (172 [72.0%] and 178 [75.1%],
respectively).
The incidence of all late toxic effects of grade
1 or 2 was 84.9% (203 of 239 patients) in the
induction chemotherapy group and 87.8% (208
of 237) in the standard-therapy group. A total of
9.2% of the patients (22 of 239) in the induction
chemotherapy group and 11.4% of the patients
(27 of 237) in the standard-therapy group had
one or more late toxic effects of grade 3 or 4
(Table 3). The incidence of late toxic effects was
similar in the treatment groups, with the excep-
Figure 2. Kaplan–Meier Analysis of Recurrence-free Survival, Overall Survival, Distant Recurrence–free Survival, and Locoregional
Recurrence–free Survival (Intention-to-Treat Population).
Hazard ratios and 95% confidence intervals were calculated by a stratified Cox proportional-hazards model. The primary end point was
recurrence-free survival, defined as the time from randomization to documented disease recurrence (either distant metastasis or locore-
gional disease recurrence) or death from any cause, whichever occurred first. Secondary end points included overall survival, distant re-
currence–free survival, and locoregional recurrence–free survival. Tick marks indicate censored data.
Percentage
of
Patients
100
80
60
40
20
0
90
70
50
30
10
0 12 24 36 48 60
Months since Randomization
A Recurrence-free Survival
3-Yr recurrence-free survival:
Induction chemotherapy, 85.3%
vs. standard therapy, 76.5%
Hazard ratio for recurrence or death, 0.51
(95% CI, 0.34–0.77)
P=0.002
No. at Risk
Induction chemotherapy
Standard therapy
242
238
234
217
215
194
146
130
93
73
35
26
Standard therapy
Percentage
of
Patients
100
80
60
40
20
0
90
70
50
30
10
0 12 24 36 48 60
B Overall Survival
3-Yr overall survival:
Hazard ratio for death, 0.43
(95% CI, 0.24–0.77)
No. at Risk
Standard therapy
242
238
241
232
236
219
162
152
100
87
36
29
Standard therapy
Percentage
of
Patients
100
80
60
40
20
0
90
70
50
30
10
0 12 24 36 48 60
C Distant Recurrence–free Survival
3-Yr distant recurrence–free survival:
(95% CI, 0.25–0.73)
No. at Risk
Standard therapy
242
238
238
217
226
204
154
140
96
80
35
28
Standard therapy
Percentage
of
Patients
100
80
60
40
20
0
90
70
50
30
10
0 12 24 36 48 60
D Locoregional Recurrence–free Survival
3-Yr locoregional recurrence–free survival:
(95% CI, 0.42–1.41)
No. at Risk
Standard therapy
242
238
237
230
225
206
152
141
97
81
36
27
Standard therapy

n engl j med
nejm.org 9
tion of grade 1 or 2 peripheral neuropathy, the
incidence of which was higher in the induction
chemotherapy group than in the standard-thera-
py group (8.8% vs. 1.7%).
Discussion
We report the results of a randomized, controlled,
phase 3 trial that showed the superior tumor
control and survival with the addition of induc-
tion chemotherapy to chemoradiotherapy in a se-
lected cohort of patients with high-risk locore-
gionally advanced nasopharyngeal carcinoma. The
majority of patients had unfavorable prognostic
features of N2 or N3 disease or bulky primary
tumors (T3 or T4), all of which are surrogates
for occult metastasis.23
The efficacy of induction
chemotherapy was due to the lower incidence of
Event
(N = 239)
Standard Therapy
(N = 237)
Grade 1 or 2 Grade 3 or 4 Grade 1 or 2 Grade 3 or 4
number of patients with event (percent)
Any acute adverse event 58 (24.3) 181 (75.7) 105 (44.3) 132 (55.7)
Leukopenia 168 (70.3) 63 (26.4) 178 (75.1) 48 (20.3)
Neutropenia 135 (56.5) 67 (28.0) 147 (62.0) 25 (10.5)
Febrile neutropenia 0 1 (0.4) 0 0
Neutropenic infection 0 0 0 0
Anemia 178 (74.5) 23 (9.6) 157 (66.2) 2 (0.8)
Thrombocytopenia 91 (38.1) 27 (11.3) 54 (22.8) 3 (1.3)
Mucositis 139 (58.2) 69 (28.9) 154 (65.0) 76 (32.1)
Vomiting 85 (35.6) 54 (22.6) 52 (21.9) 33 (13.9)
Nausea 176 (73.6) 55 (23.0) 188 (79.3) 33 (13.9)
Dry mouth 168 (70.3) 12 (5.0) 166 (70.0) 6 (2.5)
Diarrhea 18 (7.5) 6 (2.5) 15 (6.3) 4 (1.7)
Dermatitis 141 (59.0) 5 (2.1) 152 (64.1) 9 (3.8)
Weight loss 148 (61.9) 5 (2.1) 145 (61.2) 4 (1.7)
Deafness or otitis 172 (72.0) 0 178 (75.1) 0
Nephrotoxic event 46 (19.2) 6 (2.5) 27 (11.4) 1 (0.4)
Hepatotoxic event 68 (28.5) 6 (2.5) 53 (22.4) 0
Any late adverse event 203 (84.9) 22 (9.2) 208 (87.8) 27 (11.4)
Symptomatic temporal-lobe necrosis 14 (5.9) 0 19 (8.0) 2 (0.8)
Cranial neuropathy 6 (2.5) 2 (0.8) 8 (3.4) 2 (0.8)
Peripheral neuropathy 21 (8.8) 3 (1.3) 4 (1.7) 0
Eye damage 3 (1.3) 0 2 (0.8) 0
Deafness or otitis 60 (25.1) 13 (5.4) 65 (27.4) 16 (6.8)
Dry mouth 179 (74.9) 7 (2.9) 190 (80.2) 5 (2.1)
Neck tissue damage 62 (25.9) 1 (0.4) 74 (31.2) 3 (1.3)
Bone necrosis 4 (1.7) 0 6 (2.5) 2 (0.8)
Trismus 7 (2.9) 0 9 (3.8) 0
Nephrotoxic event 7 (2.9) 0 5 (2.1) 0
*
This analysis was conducted in the safety population, which included only patients who began receiving the trial treat-
ment.
Table 3. Adverse Events, According to Trial Group and Grade.*

n engl j med
nejm.org
10
distant metastatic recurrences in the induction
chemotherapy group than in the standard-therapy
group, which probably explained the early over-
all survival advantage in the patients treated in
the induction chemotherapy group. The 3-year
recurrence-free survival was 85.3% in the induc-
tion chemotherapy group and 76.5% in the stan-
dard-therapy group, which corresponded to over-
all survival at 3 years that was 4.3 percentage
points higher with induction chemotherapy than
with standard therapy. This clinical advantage
was evident when the outcomes of the two treat-
ment groups were analyzed in patients who com-
pleted the planned course of treatment (three cy-
cles of chemotherapy plus two or three cycles of
concurrent cisplatin and radiotherapy vs. three
cycles of concurrent cisplatin and radiotherapy
alone) (see the Supplementary Appendix).
Among patients with recurrent or metastatic
disease, objective response rates of 64% and 91%
(including complete and partial responses) have
been observed with gemcitabine plus cisplatin
alone and together with camrelizumab (an anti–
programmed death 1 antibody), respectively.24
Likewise, in patients with locoregionally advanced
disease, Yau and colleagues found that three
cycles of induction therapy with gemcitabine plus
cisplatin yielded high percentages (90%) of pa-
tients with a clinical response.12
Our results con-
trast with those from a similar trial conducted by
Tan et al., in which a combination of gemcitabine,
carboplatin, and paclitaxel did not prolong pro-
gression-free survival or overall survival.25
Sev-
eral explanations may be offered for the con-
flicting results, including a cohort with more
favorable characteristics in the trial conducted
by Tan et al. (fewer patients with N2 or N3 dis-
ease than in the present trial) and the use of
low-dose carboplatin (area under the curve, 2.0)
that could have compromised the synergy with
gemcitabine. The improvements in recurrence-
free survival at 3 years are similar among patients
who received induction therapy with gemcitabine
plus cisplatin (difference vs. standard therapy,
8.8 percentage points) and those who received
docetaxel plus cisplatin and fluorouracil (differ-
ence vs. standard therapy, 8.0 percentage points).7
It remains unclear whether these regimens differ
significantly with regard to efficacy or toxicity.
We noted a higher overall incidence of acute
adverse events among patients treated with in-
duction chemotherapy than among those treated
with chemoradiotherapy alone; in particular, the
incidence of severe neutropenia, thrombocytope-
nia, anemia, nausea, and vomiting was higher in
the induction chemotherapy group. The incidence
of acute grade 1 or 2 nephrotoxic effects was also
greater with the higher cumulative dose of cispla-
tin in the induction chemotherapy group, al-
though the frequencies of late nephrotoxic effects
and ototoxic effects were similar in the treatment
groups, with the exception of grade 1 or 2 periph-
eral neuropathy. The incidence of severe late com-
plications was low in both groups, and we did
not find any treatment-related deaths. In our
previous chemotherapy trial (which investigated
docetaxel plus cisplatin plus fluorouracil),7
a high
incidence of grade 3 or 4 acute adverse events
such as neutropenia (35.5%), leukopenia (27.2%),
and diarrhea (8.0%) was observed despite the
modified doses (a 20% reduction of each drug as
compared with the other trials26,27
); in that trial,
four patients (2%) had leukopenic fever, and one
patient died from neutropenic sepsis (Table S7
in the Supplementary Appendix). Given the pau-
city of comparative data, the choice of either a
gemcitabine-based or taxane-based induction che-
motherapy regimen could be made on the basis of
the expected toxic effects matched against the pa-
tient’s status with regard to coexisting conditions.
In conclusion, the addition of induction thera-
py with gemcitabine plus cisplatin to a backbone
of chemoradiotherapy with cisplatin, adminis-
tered every 3 weeks, improved recurrence-free
survival among patients with high-risk locoregion-
ally advanced nasopharyngeal cancer. This result
translated into a 4.3-percentage-point advantage
in survival over standard therapy at 3 years, at the
cost of a higher incidence of acute adverse events.
Supported by grants from the Innovation Team Development
Plan of the Ministry of Education (IRT_17R110), the Natural Sci-
ence Foundation of Guangdong Province (2017A030312003), the
Planned Science and Technology Project of Guangdong Province
(2019B020230002), the Health and Medical Collaborative Inno-
vation Project of Guangzhou City, China (201803040003), the
Sun Yat-Sen University Clinical Research 5010 Program
(2014009), and the Overseas Expertise Introduction Project for
Discipline Innovation (111 Project, B14035) and by a National
Medical Research Council Singapore Clinician-Scientist Award
(NMRC/CSA/0027/2018) and the Duke–NUS Oncology Academic
Program Proton Research Program (EX/42-A92) (both to Dr.
Chua).
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank the patients who participated in this study, their
families, and the medical, nursing, and research staff at the
study centers; Xiao-Qing Hu, Xiao-Dan Jiang, Xiao-Fen Xiao,

n engl j med
nejm.org 11
Qiu-Hui Zheng, and Hui-Xia Feng (Department of Radiation On-
cology, Sun Yat-sen University Cancer Center) for assistance with
data management and logistic support; the staff of the National
Clinical Study Center for Anticancer Drugs, Sun Yat-sen Univer-
sity Cancer Center, for trial monitoring, data management, and
statistical analysis; and Tan Sze Huey (Division of Clinical Trials
and Epidemiologic Sciences, National Cancer Center Singapore)
for assistance with statistics.
Appendix
The authors’ full names and academic degrees are as follows: Yuan Zhang, M.D., Ph.D., Lei Chen, M.D., Ph.D., Guo‑Qing Hu, M.D.,
Ning Zhang, M.D., Xiao‑Dong Zhu, M.D., Ph.D., Kun‑Yu Yang, M.D., Feng Jin, M.D., Mei Shi, M.D., Ph.D., Yu‑Pei Chen, M.D.,
Wei‑Han Hu, M.D., Zhi‑Bin Cheng, M.D., Si‑Yang Wang, M.D., Ye Tian, M.D., Xi‑Cheng Wang, M.D., Yan Sun, M.D., Ph.D., Jin‑Gao
Li, M.D., Wen‑Fei Li, M.D., Ph.D., Yu‑Hong Li, M.D., Ling‑Long Tang, M.D., Ph.D., Yan‑Ping Mao, M.D., Ph.D., Guan‑Qun Zhou,
M.D., Ph.D., Rui Sun, M.D., Xu Liu, M.D., Ph.D., Rui Guo, M.D., Ph.D., Guo‑Xian Long, M.D., Ph.D., Shao‑Qiang Liang, M.D., Ling
Li, M.D., Ph.D., Jing Huang, M.D., Ph.D., Jin‑Hua Long, M.D., Jian Zang, M.D., Qiao‑Dan Liu, M.D., Ph.D., Li Zou, M.D., Ph.D.,
Qiong‑Fei Su, M.D., Bao‑Min Zheng, M.D., Ph.D., Yun Xiao, M.D., Ying Guo, Ph.D., Fei Han, M.D., Ph.D., Hao‑Yuan Mo, M.D., Jia‑Wei
Lv, M.D., Xiao‑Jing Du, M.D., Ph.D., Cheng Xu, M.D., Ph.D., Na Liu, M.D., Ph.D., Ying‑Qin Li, M.D., Ph.D., Melvin L. K. Chua, M.D.,
Ph.D., Fang‑Yun Xie, M.D., Ying Sun, M.D., Ph.D., and Jun Ma, M.D.
The authors’ affiliations are as follows: the Departments of Radiation Oncology (Y.Z., L.C., Y.-P.C., W.-H.H., W.-F.L., L.-L.T., Y.-
P.M., G.-Q.Z., R.S., X.L., R.G., F.H., J.-W.L., X.-J.D., C.X., N.L., Y.-Q.L., F.-Y.X., Ying Sun, J.M.), Medical Oncology (Y.-H.L.), and
Nasopharyngeal Carcinoma (H.-Y.M.) and the Clinical Trials Center (Y.G.), Sun Yat-sen University Cancer Center, the State Key Labora-
tory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal
Carcinoma Diagnosis and Therapy (Y.Z., L.C., Y.-P.C., W.-H.H., W.-F.L., L.-L.T., Y.-P.M., G.-Q.Z., R.S., X.L., R.G., F.H., J.-W.L., X.-
J.D., C.X., N.L., Y.-Q.L., F.-Y.X., Ying Sun, J.M.), and the Department of Radiation Oncology, First Affiliated Hospital of Guangdong
Pharmaceutical University (X.-C.W., Q.-F.S.), Guangzhou, the Cancer Center, Tongji Hospital Affiliated to Tongji Medical College
(G.-Q.H., G.-X.L.), and the Cancer Center, Union Hospital, Tongji Medical College (K.-Y.Y., J.H.), Huazhong University of Science and
Technology, Wuhan, the Department of Radiation Oncology, First People’s Hospital of Foshan, Foshan (N.Z., S.-Q.L.), the Department
of Radiation Oncology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning (X.-D.Z., L.L.), the Department of Head and
Neck Oncology, Affiliated Hospital of Guizhou Medical University, Guizhou Cancer Hospital, Guiyang (F.J., J.-H.L.), the Department of
Radiation Oncology, XiJing Hospital of Fourth Military Medical University, Xi’an (M.S., J.Z.), the Cancer Center (Z.-B.C.), and the De-
partment of Head and Neck Oncology (S.-Y.W., Q.-D.L.), Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, the Department of
Radiation Oncology, Second Affiliated Hospital of Soochow University, Suzhou (Y.T., L.Z.), the Department of Radiation Oncology,
Peking University Cancer Hospital, Beijing (Yan Sun, B.-M.Z.), and the Department of Radiation Oncology, Jiangxi Cancer Hospital,
Nanchang (J.-G.L., Y.X.) — all in China; and the Divisions of Radiation Oncology and Medical Sciences, National Cancer Center Singa-
pore, and the Oncology Academic Program, Duke–National University of Singapore Medical School — both in Singapore (M.L.K.C.).
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