Med Oncol (2015) 32:320
DOI 10.1007/s12032-014-0320-1
ORIGINAL PAPER
Prophylactic cervical lymph node irradiation provides no benefit
for patients of stage IE extranodal natural killer/T cell lymphoma,
nasal type
Liang Wang • Zhong-jun Xia • Yue Lu •
Yu-jing Zhang
Received: 14 October 2014 / Accepted: 2 November 2014 / Published online: 28 November 2014
Ó Springer Science+Business Media New York 2014
Abstract Radiation therapy (RT) may cure many patients
with stage IE extranodal natural killer/T cell lymphoma
(ENKTL), but the real benefit of prophylactic cervical node
irradiation (PCNI) for this patient population has not been
defined yet. We retrospectively reviewed 126 patients who
were diagnosed as stage IE ENKTL and treated with che-
moradiotherapy in Sun Yat-sen University Cancer Center.
The RT dose was 36–72 Gy (median 54 Gy), with
1.8–2.0 Gy a day and 5 fractions each week. 35 patients
(27.8 %) in this cohort received PCNI. At a median follow-
up time of 94.59 months (range 14.59–182.08 months), the
systemic failure rate and locoregional failure rate in
patients with PCNI were 76.5 and 23.5 %, respectively,
compared with 62.9 and 37.1 % in those without PCNI,
and there was no significant difference between those two
groups (P = 0.505). Whether patients received PCNI or
not did not affect the survival outcome (P [ 0.05). Also,
PCNI did not improve the survival outcome for neither
patients with primary tumor site localized to nasal cavity
nor those localized to upper aerodigestive tract beyond
nasal cavity (P [ 0.05), and PCNI did not provide survival
L. Wang
Z. Xia
Y. Lu
Y. Zhang
State Key Laboratory of Oncology in South China, Collaborative
Innovation Center for Cancer Medicine,
Guangzhou 510060, Guangdong, People’s Republic of China
L. Wang
Z. Xia
Y. Lu
Department of Hematologic Oncology, Sun Yat-sen University
Cancer Center, Guangzhou 510060, Guangdong,
People’s Republic of China
Y. Zhang (&)
Department of Radiation Oncology, Sun Yat-sen University
Cancer Center, Guangzhou 510060, Guangdong,
People’s Republic of China
e-mail: zhangyujingsysucc@126.com
benefit for neither patients with local tumor invasion nor
those without (P [ 0.05). In conclusion, in a large cohort
of 126 patients with stage IE ENKTL, we found that PCNI
provided no benefit for PFS and OS, regardless of the
primary tumor site or local tumor invasiveness.
Keywords Prophylactic cervical lymph node irradiation

Extranodal natural killer/T cell lymphoma
EPOCH

CHOP
Prognosis
Introduction
Extranodal natural killer/T cell lymphoma, nasal type
(ENKTL) is a very aggressive non-Hodgkin’s lymphoma
(NHL) featured by angiodestruction, cytotoxic phenotype
and a strong association with Epstein–Barr virus (EBV)
infection [1]. Due to the relative rarity of ENKTL in
Western countries [2], no prospective randomized clinical
trials with large cohort of patients have been conducted till
now. Thus, optimal treatment strategies have not been fully
defined yet. For early stage (IE/IIE) ENKTL, radiotherapy
alone or combined with chemotherapy can provide rapid
responses and favorable outcomes [3]. Though several
retrospective studies have shown that up-front or early
radiotherapy can improve survival for localized ENKTL in
the upper aerodigestive tract [4], whether concurrent che-
moradiotherapy or sequential strategies with up-front che-
motherapy followed by radiotherapy can further reduce the
local or distant relapse remains to be elucidated in pro-
spective trials. In our center, cyclophosphamide, doxoru-
bicin, vincristine, and prednisone (CHOP) is the most
commonly used regimen for NHL in the past two decades
[5], which did not work well in ENKTL as in B cell NHL
due to the overexpression of the multidrug-resistant (MDR)
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gene [6]. Recently, more and more L-asparaginase-based
regimens such as combined dexamethasone, methotrexate,
ifosfamide, L-asparaginase, and etoposide (SMILE) [7] and
combined gemcitabine, L-asparaginase, and oxaliplatin
(GELOX) [8] have emerged with promising results in the
treatment of patients with ENKTL. Recently, we have
demonstrated that GELOX is superior to EPOCH (contin-
uous infusion of etoposide, vincristine, and doxorubicin,
with cyclophosphamide and prednisone) or CHOP in the
treatment of patients with stage IE/IIE ENKTL [9]. How-
ever, there is still great diversity regarding the radiation
field in stage IE ENKTL, even in our single center. In
studies reported by Li et al. [10], prophylactic cervical
node irradiation was not given to patients with stage IE
nasal ENKTL, whereas it was routinely used for patients
with stage IE Waldeyer ring (nasopharynx, tonsil, base of
tongue, and oropharynx) ENKTL. However, the seldom
literatures have elucidated the real benefit of prophylactic
cervical node irradiation for stage IE ENKTL; thus, we
performed a retrospective study in a cohort of 126 patients
with stage IE ENKTL to address this issue.
Materials and methods
Patients
One hundred and twenty-six patients diagnosed as stage IE
ENKTL were treated with up-front chemotherapy followed
by radiotherapy in Sun Yat-sen University Cancer Center
between January 1995 and January 2010. Approval to
review, analyze, and publish the data in this study was
given by the Sun Yat-sen University Cancer Center
Research Ethics Board. Informed consent for the collection
of medical information was obtained from all patients at
their first visit.
All pathology tissues were reviewed and confirmed as
ENKTL according to the 2008 World Health Organization
(WHO) classification of Tumours of Haematopoietic and
Lymphoid Tissues [11]. Using computed tomography (CT)
scan of the chest, abdomen, and pelvis, magnetic resonance
imaging (MRI) of the head and neck, and bilateral bone
marrow aspiration or biopsy, patients were staged as IE
based on the Ann Arbor staging system. Positron emission
tomography (PET)-CT, bone marrow EBER stain, or EBV-
DNA blood levels were not routine staging investigations
in the study. Follow-up information was obtained from
patients’ medical records or by telephone.
Treatments
Almost all patients of ENKTL were given up-front che-
motherapy in our center, and for this cohort of stage IE
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Med Oncol (2015) 32:320
patients, CHOP or EPOCH were given one–six cycles
(median four cycles). The dosage of CHOP and EPOCH
was as previously reported [9]. In brief, CHOP regimen
was cyclophosphamide 750 mg/m2 on day 1, tetra-
hydropyranyl-adriamycin (THP) 50 mg/m2 on day 1, vin-
cristine 1.4 mg/m2 and maximal dose 2.0 mg on day 1, and
prednisolone 60 mg/m2 daily p.o. on days 1–5, which was
repeated at 21-day intervals. EPOCH regimen was 24 h of
continuous infusion of etoposide 50 mg/m2/day, vincristine
0.4 mg/m2/day and THP 10 mg/m2/day administered on
days 1–4, followed by cyclophosphamide 750 mg/m2/day
over 15 min intravenously on day 5 and prednisone 60 mg/
m2/day on days 1–5 orally, which was repeated at 21-day
intervals.
If patients got progressive disease after one cycle of
chemotherapy, stable disease (SD) after two cycles, or
partial response (PR) after four cycles, they would be
referred to radiation therapy (RT) immediately. If they
had achieved complete response (CR) after four cycles of
chemotherapy, then a maximum of six cycles can be
given before RT. RT was delivered using 6-MV linear
accelerator and conventional planning RT. The RT dose
was 36–72 Gy (median 54 Gy), with 1.8–2.0 Gy a day
and 5 fractions each week. We defined the clinical target
volume (CTV) of limited stage IE disease as the bilateral
nasal cavity, bilateral ethmoid sinuses, and ipsilateral
maxillary sinus, and the CTV extended to involved tis-
sues for patients with extensive stage IE disease. Two
coplanar opposed lateral wedged fields were used, with
or without an anterior nasal photon field and an anterior
inter-orbital ethmoid electron field. Prophylactic cervical
lymph node irradiation was not routinely given to all
patients, which depended on the treating physician. But
in patients with Waldeyer ring involvement, the facio-
cervical RT fields included part of the upper neck lym-
phatic system.
Response and toxicity criteria
The treatment response was assessed after every two
cycles of chemotherapy or before and after radiotherapy
in accordance with standard response criteria for NHL.
After completion of treatment, patients were followed up
by their oncologist in the outpatient department. Each
follow-up visit consisted of a physical examination,
complete blood count, serum biochemistry, and either a
CT scan, MRI of the involved regions, or PET-CT scan.
Follow-up visits were conducted every 3 months for the
first 2 years, every 6 months for the next 3 years, and
annually after the initial 5 years. All adverse events fol-
lowing treatment were graded based on the National
Cancer Institute Common Terminology Criteria of
Adverse Events v3.0.
Med Oncol (2015) 32:320 Page 3 of 8 320

Statistical analysis Table 1 Patients’ characteristics

Variables Prophylactic cervical P value
Overall survival (OS) was calculated from the time of lymph node
diagnosis until death from any cause or until the time of the irradiation
last follow-up visit for the surviving patients. Progression- Yes No
free survival (PFS) was defined as the interval from the time (N = 35) (N = 91)
of diagnosis to the time of first documented disease pro-
Age (years old)
gression or relapse or to the time of the last follow-up visit.
[60 4 22 0.181
The Chi-square test was used to calculate statistical group
B60 31 69
comparisons of categorical variables. Survival analysis was
performed using the Kaplan–Meier method, and compari- Gender
sons were calculated using the log-rank test. Multivariate Male 29 62 0.152
analysis was used to estimate the prognostic impact of dif- Female 6 29
ferent variables in OS and PFS using the Cox regression B symptoms
model. P \ 0.05 was considered statistically significant, and Yes 18 37 0.373
all P values correspond to two-sided significance tests. Sta- No 17 54
tistical analyses were performed using SPSS 19.0 software. LDH
Elevated 14 22 0.123
Normal 21 69
Results Induction CT
CHOP 28 65 0.451
Patient characteristics EPOCH 7 26
ECOG performance status
Patients’ characteristics were shown in Table 1. The pri- C2 4 5 0.262
mary lesion of all patients was in the upper aerodigestive \2 31 86
tract, among which 73 patients (57.9 %) had lesions Extensive local invasion
localized to nasal cavity and the other patients had lesions Yes 24 60 0.944
beyond nasal cavity (including Waldeyer ring). Eighty-four No 11 31
patients (66.7 %) presented with local invasiveness, and IPI
the most frequently affected regions included paranasal B1 34 85 0.672
sinus, skull base, and facial skin. [1 1 6
In this cohort of stage IE patients, 35 patients (27.8 %) Primary tumor site
received prophylactic cervical lymph node irradiation, of Localized to nasal cavity 14 59 0.020
whom 21 patients (60 %) had primary tumor lesions in the Upper aerodigestive tract beyond 21 32
upper aerodigestive tract beyond nasal cavity (including nasal cavity
Waldeyer ring). In contrast, 64.8 % (59/91) patients had Bold value indicates there is significant difference between those two
primary lesions localized only to the nasal cavity in those groups
without prophylactic cervical node irradiation. Ninety- LDH, lactate dehydrogenase; CT, chemotherapy; ECOG, Eastern
three patients (73.8 %) received CHOP as induction che- Cooperative Oncology Group; IPI, international prognostic index;
motherapy, and the others were given EPOCH regimen. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone;
EPOCH, continuous infusion of etoposide, vincristine, and doxoru-
There were no significant differences between patients with bicin, with cyclophosphamide and prednisone
prophylactic cervical node irradiation and those without it
in regard to age, gender, B symptoms, LDH level, induc- all patients, and the CR rate at the end of RT was 74.4 %. For
tion regimen, performance status, local invasiveness, and those who received prophylactic cervical lymph node irradi-
IPI score (P [ 0.05). ation, a median of 40 Gy (32–60 Gy) RT was given.
This strategy of sequential chemoradiotherapy was tol-
Treatment outcomes erable in most patients. The most common toxicity devel-
oped during the period of induction chemotherapy was
Patients received a median of four cycles of CHOP or EPOCH neutropenia, especially in patients who received EPOCH
before RT. After induction chemotherapy, the complete regimen. The most common adverse events for RT were
response (CR) rate was 37.8 % in CHOP group, and 29.0 % in grade 1/2 skin toxicity, grade 1–3 mucositis, grade 1/2
EPOCH group, and no significant difference existed pharyngitis, grade 1/2 esophagitis, and grade 1/2 salivary
(P [ 0.05). A median of 54 Gy RT (36–72 Gy) was given to gland toxicity. In patients with prophylactic cervical

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irradiation, toxicity in the neck was generally cutaneous
pricking, itching, and mild pigmentation with slight dry
desquamation. No patients’ complaint obvious late RT-
related cervical toxicity.
Survival analysis and relapse patterns
By the end of April 2014, 64 patients died of tumor and
four patients died of unknown reasons. For patients who
were still alive, the median follow-up time was
94.59 months (range 14.59–182.08 months). The 64 deaths
of tumor progression occurred within a median of
16.36 months (range 0.62–146.40 months) after diagnosis
of ENKTL. Five-year and ten-year OS rates were 50 and
43 %, respectively. Relapsed disease or disease progres-
sion was documented with detailed information in 52
patients (including 17 patients with prophylactic cervical
irradiation and 35 patients without it). Among those 52
patients, 35 patients (67.3 %) had systemic failure that was
the primary pattern of failure, including gastrointestinal
tract invasion, liver invasion, bone marrow invasion, he-
mophagocytic syndrome, and skin invasion in order. Sev-
enteen patients (32.7 %) had locoregional relapse,
including only 2 patients with cervical lymph node relapse.
The systemic failure rate and locoregional failure rate in
patients with prophylactic irradiation were 76.5 and
23.5 %, respectively, compared with 62.9 and 37.1 % in
those without prophylactic irradiation, and there was no
significant difference between those two groups
(P = 0.505). In overall, five-year and ten-year PFS rates
were 37 and 21 %, respectively.
As shown in Fig. 1, whether patients received prophy-
lactic cervical lymph node irradiation or not did not affect
the survival outcome (P [ 0.05). Patients with local tumor
invasion had significantly inferior OS (P = 0.034) and a
trend for inferior PFS (P = 0.085). For this cohort of stage
IE patients, the primary tumor site (i.e., localized to nasal
cavity or localized to upper aerodigestive tract beyond
nasal cavity) had no influence on OS and PFS (P [ 0.05).
In subgroup analysis (Figs. 2, 3), prophylactic cervical
lymph node irradiation did not improve the survival out-
come for neither patients with primary tumor site localized
to nasal cavity nor those localized to upper aerodigestive
tract beyond nasal cavity (P [ 0.05). Furthermore, pro-
phylactic cervical lymph node irradiation did not provide
survival benefit for neither patients with local tumor
invasion nor those without (P [ 0.05).
Discussion
Although ENKTL is relatively rare in Western countries, it
makes up 5–10 % of all lymphomas in the Chinese
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Med Oncol (2015) 32:320
population [2]. ENKTL can present with either nasal or
extranasal involvement, and the upper aerodigestive tract is
the most frequently involved site. RT is a widely recog-
nized treatment modality for early stage ENKTL, which
can provide rapid locoregional control of the disease [12].
However, there are some issues still remained to be elu-
cidated. Firstly, for patients with stage IE disease, which
localized to upper aerodigestive tract without cervical
lymph node involvement, whether prophylactic cervical
lymph node irradiation should be given to all patients or
not remains unanswered. Secondly, approximately 50 % of
patients who receive RT alone experience local relapse,
and systemic failure reportedly occurs in approximately
25 % of patients [13]; thus, the addition of chemotherapy is
emphasized to reduce the risk of recurrence. However, in
clinical practice, the mode and time of chemotherapy vary
among different centers and different physicians. Both
issues need to be addressed in future clinical trials.
In this retrospective study, we tried to address the first
issue in a large cohort of stage IE ENKTL patients. All
patients received up-front anthracycline-based chemother-
apy and followed by RT. The complete response rate was
very low after chemotherapy, which was 37.8 and 29.0 %
for CHOP and EPOCH groups, respectively. Nowadays,
anthracycline-based chemotherapy regimens have been
confirmed to be unsuitable for ENKTL due to the over-
expression of the multidrug-resistant (MDR) gene [6],
which confers primary resistance to anthracycline-based
regimens. Recently, we used asparaginase-based chemo-
therapy (GELOX regimen) for all patients of ENKTL, CR
rate increases to more than 55.0 % after two cycles [8], and
few primary resistant cases have been found. Consolidative
RT can significantly improve the disease control rate in this
cohort of patients, and the CR rate after RT was 74.4 %. Li
et al. [10] reported the outcome of patients with stage IE
ENKTL of upper aerodigestive tract treated with radio-
therapy alone, and the overall response rate was 97.7 %,
with a CR rate of 95.4 %, much higher than our results.
However, there were more patients with local tumor
invasion, non-nasal cavity lesions, and B symptoms, which
may partially contribute to the lower CR rate in our cohort.
Moreover, the use of up-front chemotherapy with anthra-
cycline-based regimens delayed the deliver of RT and may
increase the probability of RT-resistant cases. Thus, for
stage IE ENKTL patients, we recommend up-front RT
followed by chemotherapy or concurrent chemoradiother-
apy in future prospective clinical trials.
In this study, 35 patients (27.8 %) received prophylactic
cervical lymph node irradiation, of whom 60.0 % patients
had primary tumor site localized to upper aerodigestive
tract beyond nasal cavity. As reported by Li et al. [10],
prophylactic cervical node irradiation was not given to
patients with Stage I nasal ENKTL, but it was routinely
Med Oncol (2015) 32:320 Page 5 of 8 320

Fig. 1 Survival curves for the whole group of patients. No significant (P [ 0.05); local tumor invasion correlated with significantly poor
differences in OS (a) and PFS (b) existed between patients with OS (c) (P = 0.034) and a trend for poor PFS (d) (P = 0.085);
prophylactic cervical lymph node radiation and those without it primary tumor site did not affect OS (e) and PFS (f) (P [ 0.05)

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Fig. 2 Subgroup survival analysis. For patients with primary tumor
lesions localized to upper aerodigestive tract beyond nasal cavity,
prophylactic cervical lymph node radiation did not improve OS
used for patients with Stage I Waldeyer ring ENKTL.
However, the real benefit of prophylactic cervical node
irradiation for both nasal disease and Waldeyer ring disease
has not been demonstrated till now. As shown in Fig. 1a, b,
cervical prophylactic radiation did not improve the OS and
PFS in the whole group of stage IE patients. Then, we
performed subgroup analysis to elucidate the role of pro-
phylactic cervical radiation in patients with both nasal dis-
ease and extranasal disease. As shown in Fig. 2a, b, for
patients with primary tumor localized to upper aerodigestive
tract beyond nasal cavity (N = 53, including 29 patients
with tumor localized to Waldeyer ring, which was defined as
nasopharynx, tonsil, base of tongue, and oropharynx [14],
and 24 patients with both nasal cavity and Waldeyer
ring involvement), no improvement of PFS and OS was
attained through addition of prophylactic cervical nodes
irradiation. Moreover, as expected, no survival benefits were
achieved through cervical prophylactic radiation in patients
with only nasal cavity disease. As shown in Fig. 1c, d, local
tumor invasion correlated with significantly poor survival
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Med Oncol (2015) 32:320
(a) and PFS (b) (P [ 0.05); for patients with primary tumor lesions
localized to nasal cavity, prophylactic cervical lymph node radiation
did not provide benefits for OS (c) and PFS (d) (P [ 0.05)
outcomes, which was consistent with previous reports [15].
Then, we evaluated the role of prophylactic cervical node
irradiation in patients with local tumor invasion (N = 84,
which was defined as bony invasion or perforation or
invasion of the overlying skin [15], and adjacent paranasal
sinus invasion). As demonstrated in Fig. 3c, d, no benefit for
PFS and OS was attained by prophylactic cervical irradia-
tion. The patterns of failure in our cohort were consistent
with results reported by Li et al. [10], in which 65.2 % of
relapsed cases were systemic extranodal dissemination, and
34.8 % were locoregional relapses. Furthermore, there were
no significant differences in failure patterns in regard to
prophylactic cervical lymph node irradiation. Thus, consid-
ering the potential toxicity of cervical nodes irradiation, we
do not recommend to give prophylactic cervical lymph node
irradiation to patients with stage IE ENKTL unless there is
confirmed survival benefit in well-designed prospective
clinical trials.
However, there were some limitations in our study,
which should be taken into account when applying these
Med Oncol (2015) 32:320
Fig. 3 Subgroup survival analysis. For patients without local tumor
invasion, prophylactic cervical lymph node radiation did not improve
OS (a) and PFS (b) (P [ 0.05); for patients with local tumor invasion,
results. Firstly, the nature of retrospective study indicated
that some bias may be introduced and that some important
data may be missing. Secondly, as mentioned above, more
and more asparaginase-based regimens are used in clinical
practice, and whether these regimens could improve the
tumor sensitivity to RT or not remained to be demon-
strated. Thirdly, patients with Waldeyer ring involvement
were treated with faciocervical RT fields, which cannot
avoid irradiation to part of upper cervical lymph node
region. Finally, this study covered a period of 15 years,
during which the RT technique developed tremendously
from conventional planning techniques to newer generation
of precise RT, including 3D conformal RT and intensity-
modulated techniques (IMRT). Thus, prospective clinical
trials are needed to validate our results.
In conclusion, in a large cohort of 126 patients with
stage IE ENKTL, we found that prophylactic cervical
lymph node irradiation provided no benefit for PFS and
OS, regardless of the primary tumor site or local tumor
invasiveness.
Page 7 of 8 320
prophylactic cervical lymph node radiation did not provide benefits
for OS (c) and PFS (d) (P [ 0.05)
Acknowledgments We would like to thank all of the doctors of Sun
Yat-sen University Cancer Center for allowing us to include their
patients. In addition, we appreciate the cooperation of all the
pathologists of Sun Yat-sen University Cancer Center for their sup-
port. This work received grant support from Young Teachers’ Cul-
tivation Project of Sun Yat-sen University (No. 12ykpy54) and
Outstanding Young Talents’ Project of Sun Yat-sen University Can-
cer Center (No. 04190101#).
Conflict of interest The authors declare that they have no conflict
of interest.
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