Received: 27 August 2017

| Revised: 25 January 2018

| Accepted: 16 March 2018
DOI: 10.1002/hed.25205

ORIGINAL ARTICLE

Survival without adjuvant chemotherapy for selected patients with

stage II and III nasopharyngeal carcinoma after concurrent
chemoradiotherapy alone

Jia-Shing Wu MD1 | Yu-Chen Tsai MD1 | James Jer-Min Jian MD1 |

Hsin-Hsuan Chen MD2 | Cheng-Fang Horng MS3 | Skye Hung-Chun Cheng MD1,2

1
Department of Radiation Oncology, Koo
Foundation Sun Yat-Sen Cancer Center,
Taipei, Taiwan
2
Department of Hematology - Oncology,
Koo Foundation Sun Yat-Sen Cancer
Center, Taipei, Taiwan
3
Clinical Protocol Office-Biostatistics
Section, Koo Foundation Sun Yat-Sen
Cancer Center, Taipei, Taiwan
Correspondence
Skye Hung-Chun Cheng, Department of
Radiation Oncology, Koo Foundation
Sun Yat-Sen Cancer Center, Taipei,
Taiwan.
Email: skye@kfsyscc.org
Abstract
Background: The role of adjuvant chemotherapy after concurrent chemoradiother-
apy (CRT) for nasopharyngeal carcinoma (NPC) is controversial. We report our
phase II prospective study of withholding adjuvant chemotherapy in a subgroup of
patients with American Joint Committee on Cancer (AJCC) stage II and III NPC with
low risk for metastasis.
Methods: Between April 1998 and December 2008, 263 patients with stage II
(AJCC 1997 T2aN0, T1-T2aN1; AJCC 2010 T1N1) NPC or stage III (AJCC 1997
T1-T2aN2; AJCC 2010 T1N2) NPC were enrolled. Patients received standard con-
current CRT with cisplatin and 5-fluorouracil (5-FU) but without adjuvant
chemotherapy.
Results: With a median follow-up of 107 months, the 5-year overall survival (OS),
disease-free survival (DFS), and distant metastasis-free survival (DMFS) were 92.4%,
84.4%, and 90.7% for all patients; 94.1%, 85.9%, and 92.9% for patients with stage II
NPC; and 90.9%, 83.2%, and 88.9% for patients with stage III NPC, respectively.
Conclusion: It is safe to withhold adjuvant chemotherapy for selected patients with
stage II and III NPC.

KEYWORDS
adjuvant chemotherapy, concurrent chemoradiotherapy, nasopharyngeal carcinoma, personalized treatment,
risk stratification

1 | INTRODUCTION
The intergroup 0099 randomized trial proved that concurrent
chemoradiotherapy (CRT) followed by adjuvant chemother-
apy is superior to radiotherapy alone in the treatment of
advanced-stage nasopharyngeal carcinoma (NPC).1 Patients
enrolled in that study had primary tumor extended beyond
the nasopharynx and/or neck lymph node metastasis. On the
basis of the American Joint Committee on Cancer (AJCC)
fifth (1997) to seventh (2010) edition staging system,
“advanced-stage” NPC included stages III, IVa, and IVb.
Concurrent CRT plus adjuvant chemotherapy has been the
standard therapy for these patients for more than a decade.
The latest guidelines also still include concurrent CRT plus
adjuvant chemotherapy as an option for patients with stage II
disease. However, 3 earlier randomized trials showed that
adding adjuvant chemotherapy to radiotherapy did not
improve survival.2–4 Significant toxicity has been observed
in patients who receive adjuvant chemotherapy after concur-
rent CRT. Several multicenter trials reported that only around
60%-70% of patients could tolerate the entire adjuvant chem-
otherapy regimen.5,6 Therefore, many have questioned the
contribution of adjuvant chemotherapy and advocated
concurrent CRT alone.

Head & Neck. 2018;1–8. wileyonlinelibrary.com/journal/hed V

C 2018 Wiley Periodicals, Inc. | 1
2 |
In our previous report of patients with stage II NPC
treated with concurrent CRT and adjuvant chemotherapy,7
only 2 of 44 patients developed distant relapses; both had
T2b disease. Our previous analysis of NPC prognostic fac-
tors showed that some stage III (T1-2aN2) disease had an
excellent outcome with an extremely low risk of distant
metastasis (0/23). We found that some patients with stages II
and III NPC had a low risk of distant metastasis if there was
no tumor involvement of the parapharyngeal venous plexus,
prevertebral muscle, or skull base.8 Because, in theory, adju-
vant chemotherapy is mostly for microscopic disseminated
disease, we hypothesized that for selected patients with stage
II (AJCC 1997 T2aN0, T1-2aN1) and stage III (AJCC 1997
T1-2aN2) NPC, adjuvant chemotherapy may be omitted and
the treatment outcome would not be compromised.
In this phase II prospective study, we tested the hypothe-
sis that these selected patients could be treated with concur-
rent CRT only and still achieved >90% of 5-year distant
metastasis-free survival (DMFS).
2 | MATERIALS AND METHODS
Between April 1998 and December 2008, patients were
enrolled in this prospective protocol at the Koo Foundation
Sun Yat-Sen Cancer Center, Taipei, Taiwan. This study was
under the guidance of the Institutional Review Board of the
Koo Foundation Sun Yat-Sen Cancer Center. The study was
conceived early in 1998 and, therefore, not registered before
patient enrollment. We registered post hoc with Clinical-
Trials.gov, number NCT03175939. Eligible criteria included:
(1) biopsy-proven carcinoma of the nasopharynx; (2) AJCC
1997 stage II (T2aN0, T1-T2aN1) or stage III (T1-T2aN2)
disease; (3) normal renal function (Cr <1.6 mg/dL); and (4)
informed consent. Patients who underwent excisional biopsy
of a cervical lymph node, had previous chemotherapy or
radiotherapy to the head and neck region, or who had distant
metastasis or other malignant diseases except skin cancer
were excluded. Pretreatment evaluation included a complete
medical history, physical examination, fiber-optic endoscopic
examination (nasopharynx, oropharynx, and larynx), MRI of
the head and neck, chest radiography, bone scintigraphy,
ultrasonography of the liver, complete blood counts, and
serum chemical evaluation.
All patients received concurrent CRT. There was no
blinding of treatment to patients or caregivers. Radiation
technique before 2003 was 3D conformal radiotherapy (3D
conformal RT) and was gradually shifted to intensity-
modulated radiotherapy (IMRT) in the middle of 2003. The
details of 3D conformal RT have been reported before.3 The
IMRT protocol included the following. (1) The gross tumor
volume (GTV) included the gross primary tumor and neck
lymph nodes identified in the treatment planning CT and
WU ET AL.
MRI of the head and neck. (2) The high-risk clinical target
volume (CTV1) included all gross tumor volume with a
1 cm margin and the nasopharyngeal cavity, retropharyngeal
nodes, pterygoid fossae, parapharyngeal space, sphenoid
sinus, posterior third of the nasal cavity, and involved neck
lymph node levels. (3) The low-risk clinical target volume
(CTV2) included uninvolved neck lymph node levels. (4)
High-risk planning target volume (GPTV) was defined as
gross tumor volume plus a 0.4-cm margin in all directions
and a 0.1-cm margin in the clivus area if the brain stem
was intersected. (5) Moderate-risk planning target volume
(CPTV1) was defined as CTV1 plus a 0.4-cm margin in the
sphenoid, pterygoid, and oral areas, and a 0.1-cm margin in
the clivus area if brain stem or spinal cord were intersected.
(6) Low-risk planning target volume (CPTV2) was defined as
CTV2 plus a 0.4-cm margin. (7) The radiation dose to the
GPTV was 2 Gy per fractions, 5 fractions per week, to a total
dose of 70 Gy in 35 fractions; the radiation dose to the
CPTV1 was 1.8 Gy per fractions to a total dose of 63 Gy in
35 fractions; and the CPTV2 was 1.8 Gy per fractions to a
total dose of 50.4 Gy in 28 fractions.
Chemotherapy consisted of cis-diamine-dichloroplatinum
(CDDP, cisplatin) and 5-fluorouracil (5-FU). The CDDP 60
mg/m2 infusion was delivered on day 1 and 5-FU 600 mg/m2
was administered by 24-hour continuous infusion daily, day 1
through day 5 for 5 days in weeks 1 and 5 of CRT for patients
who were treated with 3D conformal RT. Because we observed
more toxicity, such as mucositis after switching from 3D con-
formal RT to IMRT, this regimen was modified for patients
who were treated with IMRT: to CDDP 60 mg/m2 infusion on
day 1 and 5-FU 600 mg/m2 on day 1 through day 3 for 3 days
in week 1, week 4, and week 7 of radiation treatment. No adju-
vant chemotherapy was delivered after radiotherapy.
All clinical information of the enrolled patients was entered
in a comprehensive Nasopharyngeal Carcinoma Database pro-
spectively. Information collected in this database consisted of
(1) the General Data Form, which included patient demo-
graphic information, general medical and family history, as
well as specific, clinical, and treatment history; (2) the Imaging
Review Form, which recorded imaging information of the
head and neck areas; (3) the Chemotherapy Form, which con-
tained chemotherapy information and related complications;
(4) the Radiotherapy Form, which contained radiotherapy
information and related complications; (5) the Follow-up
Form, which was submitted every 3 to 6 months after the com-
pletion of all treatments or when tumor relapse was observed;
and (6) the Late Complication Form, which was submitted
when any late complication was observed.
2.1 | Follow-up
All patients were evaluated by a multidisciplinary team for
disease control, complications, and survival at a 3-month
WU ET AL.
| 3

from the first day of treatment until the day of disease recur-
rence, metastasis, or death. Survival estimates were calcu-
lated using the Kaplan-Meier method. In subgroup analysis,
survival was compared using the log-rank test, and hazard
ratio was estimated by Cox regression. SAS for Windows
was used for all analyses.
With historical data of DMFS of 90% and equivalence
limit of 10%, 195 patients are required to be 90% sure that
the limits of a 2-sided 95% confidence interval will exclude a

TA B L E 1 Patient characteristics

No. of patients

All Stage II Stage III

Characteristics patients T1-2aN0-1 T1-2aN2

263 119 144

Age, year
Median 42 44 42
Range 24-74 26-74 24-65

Sex
Male 186 85 101
Female 77 34 43

Histology, WHO type

I 4 3 1
FIGURE 1 Flowchart showing the process of patient enrollment and IIA 24 7 17
reasons for exclusion. The staging classifications are by the American IIIB 232 107 125
Joint Committee on Cancer 1997 fifth edition. CCRT, concurrent chemo- Unknown 3 2 1
radiotherapy; LN, lymph node; NPC, nasopharyngeal carcinoma; RT,
AJCC stage (1997)a
radiotherapy
T2aN0 22 22 0
interval for the first 2 years, a 6-month interval between the T1N1 83 83 0
T2aN1 14 14 0
third and fifth years, and at 1-year intervals thereafter.
T1N2 108 0 108
Follow-up examination of the head and neck regions
T2aN2 36 0 36
included fiber-optic endoscopy and MRI 3 months after com-
pletion of radiotherapy. Fiber-optic endoscopy was then per- Radiotherapy technique
formed at every follow-up visit subsequently. All patients 3D 104 45 59
had MRI, blood chemical evaluation, chest X-ray, and IMRT 159 74 85
sonography of the liver every 6 months for the first 2 years
Radiotherapy dose, cGy
and annually between the third and fifth years. Whole body
Median 7000 7000 7000
bone scan was performed for continuous bone pain. For Range 6600-8000 6600-7800 6800-8000
patients with recurrence, a biopsy is required if possible. The
restaging evaluation was the same as the initial evaluation. Total cisplatin dose, mg
December 31, 2014, was selected as the cutoff point for data Median 220 220 220
collection and statistical analysis. Range 80-590 85-360 80-590

Size of largest lymph node

4 cm 63 22 41
2.2 | Statistic consideration <4 cm 200 97 103
The primary end point of the study was 5-year DMFS. The Abbreviations: AJCC, American Joint Committee on Cancer; IMRT, intensity-
secondary end points were 5-year overall survival (OS) and modulated radiotherapy; WHO, World Health Organization
a
disease-free survival (DFS). The duration was calculated Staging according to the AJCC fifth edition in 1997.
4 | WU ET AL.

T A BL E 2 Failure pattern more patients with stage III had a distant failure than stage II
but still just about 10%.
No. of patients (%)
The patients had excellent survival. The 5-year and 8-
Stage II Stage III year OS, DFS, and DMFS for all (263) patients were 92.4%,
T1-2aN0-1 T1-2aN2 Total 84.4%, and 90.7% and 88.1%, 83.5%, and 90.7%, respec-
All patients 119 144 263 tively (Figure 2).
Two hundred and fifty-eight patients were treated strictly
Any recurrence 18 (15.1)a 26 (18.0) 44 (16.7) per protocol. Their outcome was like that of the intent-to-
Local failure 7 (5.9) 8 (5.6) 15 (5.7) treat group. The 5-year OS, DFS, and DMFS were 93%,
85%, and 90.6%, respectively.
Nodal failure 4 (3.3) 9 (6.3) 13 (4.9)
When we analyzed survival by the AJCC staging system,
Distant failure 8 (6.7) 15 (10.4) 23 (8.7) there was no statistically significant difference between stage
a
Percentage is relative to the total patients in each stage. II (N0-1) and stage III (N2) groups (Figure 3). The 5-year
OS, DFS, and DMFS were 94.1%, 85.9%, and 92.9% for
stage II and 90.9%, 83.2%, and 88.9% for stage III,
difference between the standard (with adjuvant chemother- respectively.
apy) and the experimental group (without adjuvant chemo-
therapy) of >10% (a 0.025, power 0.9).
3.3 | Prognostic factors
3 | RESULTS On univariate analysis (Table 3) and multivariate analysis
(Table 4) of subgroups, the outcome did not differ by age,
3.1 | Baseline characteristics sex, treatment year, histology, radiotherapy technique, or
lymph node size. For the 63 patients with lymph nodes 4
Between April 1998 and December 2008, 322 patients with
cm, the 5-year OS and DMFS were 93.6% and 86.7%,
selected stage II and stage III NPC were treated in our hospi-
tal; 263 of them were enrolled in this prospective protocol
(Figure 1). Figure 1 shows the reasons for exclusion and
unenrollment. Of the enrolled patients, 4 did not complete
radiotherapy and 1 patient received adjuvant chemotherapy
because of the persistent palpable lymph node by the end of
radiotherapy. These patients were all included in the intent-
to-treat analysis. Patient characteristics are shown in Table 1.
The man-to-woman ratio was 2.3:1. The median age was 42
years. The majority (90%) of patients had the World Health
Organization (WHO) type IIB histology. Based on the AJCC
1997 fifth edition staging system, 119 patients (45.2%) were
in stage II and 144 patients (54.8%) in stage III. The patients
had relatively lower-volume neck disease; 200 of 263 had
the largest lymph node <4 cm.
The compliance to treatment protocol was good. Of 263
patients, 241 (91.6%) received a radiation dose of 7000 cGy
or more. Of 152 patients, 137 (90.1%) during 1998-2004 and
95 of 110 (86.4%) during 2005-2008 received all the sched-
uled chemotherapy.

3.2 | Failure pattern and outcome

By the end of 2014, the median follow-up interval was 108
months (ranging from 10.8-174.8 months); 44 of 263
patients developed recurrent disease, 23 at distant sites, 15
locally, and 13 in regional lymph nodes (Table 2). The rates
of local or nodal failure were all very low (<10%). Slightly
F I G U R E 2 Kaplan-Meier survival curves showing A, overall sur-
vival (OS) and B, distant metastasis-free survival (DMFS) of all patients.
CI, confidence interval [Color figure can be viewed at wileyonlinelibrary.
com]
WU ET AL.
| 5

T1N0 with choana invasion with the 2010 AJCC seventh

edition staging system, which merged T2a disease into T1.
These patients had such a low risk for distant metastasis that
they should not be classified as “advanced-stage.” The
patients with stage III disease (T1-T2aN2) concurred with
our previous retrospective observation, which showed a simi-
lar outcome for patients with stage II disease (T1-T2aN0-1).

TA B L E 3 Univariate analysis of prognostic factors by log-rank

test

No. of 5-y P value by

patients metastasis-free log-rank
Prognostic factor N 5 263 survival, % test

Age, years
<50 196 90.2 .6489
50 67 92.1

Sex
Male 186 90.8 .9182
Female 77 90.5

Treatment year
1998-2003 113 92.3 .4623
2004-2008 150 89.7

FIGURE 3 Kaplan-Meier survival curves comparing A, overall sur- Histology, WHO type
vival and B, distant metastasis-free survival of the American Joint Com- Type I 4 100 .5566
mittee on Cancer (AJCC) 1997 of patients with stage II (T2aN0, T1-2aN1) Type IIA 24 90.9
and stage III (T1-2aN2) nasopharyngeal carcinoma [Color figure can be Type IIB 232 90.9
viewed at wileyonlinelibrary.com] Unknown 3 66.7

AJCC stagea
respectively. Within this group, 41 patients had stage III and
T2aN0 22 95 .3995
had OS and DMFS of 92.7% and 85%, respectively.
T1N1 83 93.7
T2aN1 14 85.1
3.4 | Toxicity of radiotherapy and T1N2 108 87.1
chemotherapy T2aN2 36 94.3

The concurrent CRT was well tolerated by all 255 patients Radiotherapy technique
except 1 patient, who developed cardiac arrhythmia after 3D 104 92.7 .3795
receiving cisplatin and 5-FU. The most severe side effects IMRT 159 89.5
(stage 3 or more) during concurrent CRT were stomatitis/ Radiotherapy dose
mucositis (54.4%), pharyngitis (14.7%), nausea (10.3%), and <7000 cGy 22 84.2 .2833
vomiting (7.4%). 7000 cGy 241 91.3

Total cisplatin dose

4 | DISCUSSION 120 mg/m2 168 91.0 .7935
>120 mg/m2 95 90.4
Our study confirms our hypothesis that a selected group of
patients with 1997 AJCC fifth edition stage II and III NPC Largest lymph node
(T1-T2a N0-2 except T1N0) can be managed with concur- 4 cm 63 86.7 .1921
rent CRT without adjuvant chemotherapy. The 8-year OS, <4 cm 200 92.0
DFS, and DMFS were 88.1%, 83.5%, and 90.7%, respec- Abbreviations: AJCC, American Joint Committee on Cancer; IMRT, intensity-
tively. The risk of distant metastasis at 8 years was only modulated radiotherapy; WHO, World Health Organization.
a
9.3%. These patients would be classified as T1N1-2 and Stage based on the AJCC fifth edition, 1997.
6 | WU ET AL.

T A BL E 4 Multivariate analysis of prognostic factors by Cox enrollment criteria to the US intergroup 0099 study showed
proportional hazards model that the addition of chemotherapy to radiotherapy improved
survival for advanced NPC10–14 (Table 5). Two of these
No. of Hazard
Prognostic factor patients ratio P value studies had concurrent chemotherapy without adjuvant chem-
otherapy and showed an OS benefit. Their results concurred
Age, years with our finding that in selected patients there was an
<50 196 1.1 (0.4-3.0) .8872 improvement in survival without adjuvant chemotherapy. In
50 67 1.0 these randomized trials, the 5-year OS and DFS of the CRT
Sex arm were in the range of 60% to 70%. Our patients with stage
Male 186 1.0 .8029 III NPC (AJCC 1997 T1-2aN2; AJCC 2010 T1N2) had
Female 77 1.1 (0.5-2.8) much better survival: around 90% as for patients with stage
II NPC (AJCC 1997 T1-T2aN1, T2aN0; AJCC 2010 T1N1).
Treatment year Therefore, we think these patients with stage III may be
1998-2003 113 1.0 .556 reclassified to stage II.
2004-2008 150 1.9 (0.2-14.9) Our findings can be explained by tumor biology and
Histology
anatomy. Nasopharyngeal carcinoma usually has an orderly
lymphatic spread from the upper to the lower neck. Concur-
WHO type 2b 232 1.0 .9444
Others 31 1.1 (0.2-4.6) rent CRT can effectively control the disease unless there is
an extension of the tumor to the lower neck or bulky disease,
AJCC stage, 1997 regardless of unilateral or bilateral cervical lymphadenopathy
II 119 1.0 .555 (N1 or N2). On the other hand, if the tumor locally invades
III 144 1.3 (0.5-3.2) highly vascular regions, such as the parapharyngeal space or
prevertebral fascia, there will be a greater chance for cancer
Radiotherapy technique
cells to spread to distant sites via the bloodstream. Therefore,
3D 104 1.0 .9098
patients with N2 disease but without parapharyngeal space or
IMRT 159 1.1 (0.2-7.7)
prevertebral fascia invasion have a good prognosis with con-
Radiotherapy dose current CRT alone.
<7000 cGy 22 1.9 (0.5-7.3) .3402 One potential bias in this study is the use of MRI rou-
7000 cGy 241 1.0 tinely for stage. An MRI detects smaller lymph nodes and is
more sensitive than palpation or CT. This may potentially
Cisplatin dose
cause a stage migration from N1 to N2. Indeed, the AJCC
120 mg/m2 168 1.0 .578
staging system does not specifically require MRI for staging.
>120 mg/m2 95 1.4 (0.5-4.0)
However, we believe that MRI is essential for better target
Largest lymph node delineation during IMRT planning. More and more hospitals
<4 cm 200 1.0 .1919 also have adopted MRI as the primary evaluation tool.
4 cm 63 1.8 (0.7-4.5) Therefore, our findings will be applicable.
A limitation of the study is the extremely favorable char-
Abbreviations: AJCC, American Joint Committee on Cancer; IMRT, intensity-
modulated radiotherapy; WHO, World Health Organization.
acteristics of the population (T1 without parapharyngeal
extension, low-volume neck disease, 232/263 WHO type
IIB). Some patients who had a neck lymph node 4 cm or
Postradiation chemotherapy could be safely omitted in these underwent excisional biopsy of neck nodes before concurrent
low-risk patients. The strength of our single-center study is CRT received adjuvant chemotherapy. They were not
uniform staging, treatment, and long follow-up (>9 years). enrolled in the study. Fortunately, 63 of 263 patients in our
The study spanned a long period and involved changes in study had the largest lymph nodes 4 cm. Their 5-year
radiotherapy and chemotherapy protocol. However, subgroup DMFS was 86.7% and was not statistically different from
analysis (Tables 3 and 4) shows that the high DMFS rates that of those with lymph node <4 cm (Table 3). We will
were not influenced by changes in radiation technique or need more data to see whether adjuvant chemotherapy bene-
chemotherapy dose intensity. fits those with larger cervical lymph nodes.
Nasopharyngeal carcinoma with primary tumor extended A multicenter phase III randomized controlled trial from
beyond the nasopharynx and neck lymph node enlargement China compared concurrent CRT (weekly cisplatin 40 mg/
has long been considered as “advanced”-stage for its poor m2) plus adjuvant chemotherapy (cisplatin 80 mg/m2 day 1
prognosis after radiotherapy alone.9 Five randomized studies and fluorouracil 800 mg/m2 day 1 to 5) versus concurrent
from an NPC endemic Asia-Pacific region using similar CRT alone in patients with AJCC stages III-IV (excluding
WU ET AL.
| 7

T A BL E 5 Randomized trials of radiotherapy alone versus chemoradiotherapy with or without adjuvant chemotherapy for nasopharyngeal
carcinoma

Country
Author Inclusion Concurrent Adjuvant Patient
Year period Stage CRT chemotherapy no. OSa DFSa

United States 1989-1995 III-IV Cisplatin Cisplatin, 5-FU 193 78% vs 47% 69% vs 24%
Al-Sarraf1 1998 (3 y) (3 y)

Singapore 1997-2003 T3-4Nx or TxN2-3 Cisplatin Cisplatin, 5-FU 221 80% vs 65%
Wee et al14 2005 (3 y)

Hong Kong 1999-2004 T1-4N2-3M0 Cisplatin Cisplatin, 5-FU 348 68% vs 64% 62% vs 53%
Lee et al12 2010 (5 y) (5 y)

China 2002-2005 T3-4NxM0 or Cisplatin Cisplatin, 5-FU 316 90% vs 80% 84.6% vs 72.5%
Chen et al11 2008 TxN-3M0 (2 y) (2 y)

Hong Kong 1994-1999 Ho’s stage N2-3 or Cisplatin None 350 70% vs 59% 60% vs 52%
Chan et al10 2005 N1 with lymph (5 y) (5 y)
node 4 cm

Taiwan 1993-1999 AJCC 1992 Cisplatin, None 284 72% vs 54% 72% vs 53%
Lin et al13 2003 stage III-IV 5-FU (5 y) (5 y)

Abbreviations: 5-FU, 5-fluorouracil; AJCC, American Joint Committee on Cancer; CRT, chemoradiotherapy; DFS, disease-free survival; OS, overall survival.
a
The survival comparison is in the order of the experimental arm (with chemotherapy) vs the control arm (no chemotherapy).

T3-4N0) NPC.6 At a median follow-up of 37.8 months, esti- AC K NO WLE DG M E NTS

mated 2-year failure-free survival, OS, distant failure-free
survival, or locoregional failure-free survival did not differ
significantly between the 2 groups. In this trial, 65%-67% of
patients in both arms were stage III. We suppose that some
of them, namely the T1-2aN2 group (T1N2 in the AJCC
2010 stage), had a good prognosis without adjuvant chemo-
therapy. Therefore, the true benefit of adjuvant chemotherapy
might be masked by the inclusion of patients who actually
had a low risk of distant metastasis. This observation also
could partially explain the marginal benefit of adjuvant
chemotherapy in a previous meta-analysis.15 Our finding
may help future clinical trials to stratify patients better.
In summary, some low-risk patients with AJCC 1997
stage II and III (AJCC 2010 T1N1-2) NPC have a very low
risk of distant metastasis and excellent survival with concur-
rent CRT alone. We can avoid giving adjuvant chemotherapy
and exposing these patients to unnecessary side effects and
risks.
5 | CONCLUSIONS
It is safe to withhold adjuvant chemotherapy for selected
patients with AJCC 1997 stage II and III (AJCC 2010 T1N1-
2) NPC. We propose to reclassify patients with T1-2aN2 dis-
ease (T1N2 in AJCC 2010 staging) to stage II because of
their excellent prognosis without adjuvant chemotherapy.
The study could not have been completed without the
diligent work of members of the Head and Neck Cancer
Multidisciplinary Functional Group, and data managers and
biostatisticians in the Clinical Research Office in Koo
Foundation Sun Yat-Sen Cancer Center. We thank Dr
Cheng-Ming Guo for reviewing and correcting grammar
and spelling of the manuscript.
O RC ID
Jia-Shing Wu MD http://orcid.org/0000-0001-8531-0187
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How to cite this article: Wu J-S, Tsai Y-C, Jian JJ-M,
Chen H-H, Horng C-F, Cheng SH-C. Survival without
adjuvant chemotherapy for selected patients with stage
II and III nasopharyngeal carcinoma after concurrent
chemoradiotherapy alone. Head & Neck. 2018;00:1–8.
https://doi.org/10.1002/hed.25205