www.redjournal.

org

Critical Review

Modern Radiation Therapy for Extranodal

Nasal-Type NK/T-cell Lymphoma: Risk-Adapted
Therapy, Target Volume, and Dose Guidelines
from the International Lymphoma Radiation
Oncology Group
Shu-Nan Qi, MD,* Ye-Xiong Li, MD,* Lena Specht, MD, DMSc,y
Masahiko Oguchi, MD,z Richard Tsang, MD,x Andrea Ng, MD,k
Chang-Ok Suh, MD,{ Umberto Ricardi, MD,# Michael Mac Manus, MD,**
Bouthaina Dabaja, MD,yy and Joachim Yahalom, MDzz
*Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for
Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical
College (PUMC), Beijing, China; yDepartment of Oncology, Rigshospitalet, University of Copenhagen,
Copenhagen, Denmark; zDepartment of Radiation Oncology, Cancer Institute Hospital of the
Japanese Foundation for Cancer Research, Tokyo, Japan; xDepartment of Radiation Oncology,
Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada; kDepartment of
Radiation Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Harvard
University, Boston, Massachusetts; {Department of Radiation Oncology, CHA Bundang Medical
Center, CHA University, Gyeonggi-do, Republic of Korea; #Department of Radiation Oncology,
University of Torino, Torino, Italy; **Department of Radiation Oncology, Peter MacCallum Cancer
Centre, Melbourne, Victoria, Australia; yyDepartment of Radiation Oncology, The University of Texas
M.D. Anderson Cancer Center, Houston, Texas; zzDepartment of Radiation Oncology, Memorial Sloan-
Kettering Cancer Center, New York, New York

Received Aug 13, 2020. Accepted for publication Feb 4, 2021.

In the multidisciplinary management of early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTCL),
with curative intent, radiation therapy is the most efficacious modality and is an essential component of a combined-
modality regimen. In the past decade, utilization of upfront radiation therapy and noneanthracycline-based chemo-
therapy has improved treatment and prognosis. This guideline mainly addresses the heterogeneity of clinical features,
principles of risk-adapted therapy, and the role and appropriate design of radiation therapy. Radiation therapy methods
(including target volume definition, dose and delivery methods) are crucial for optimizing cure for patients with early-
stage ENKTCL. The application of the principles of involved site radiation therapy in this lymphoma entity often leads

Corresponding author: Ye-Xiong Li, MD; E-mail: yexiong12@163.
com or yexiong@yahoo.com
Disclosures: L.S. has received (within the last 3 years) honoraria as a
member of advisory boards for MSD, This work was supported by grants
from the Chinese Academy of Medical Science (CAMS) Innovation Fund
for Medical Sciences (CIFMS, 2016-I2M-1-001) and the National Key
Projects of Research and Development of China (2016YFC0904600).
Takeda, and Kyowa Kirin; honoraria for speaking from Takeda; and
research grants from Varian and ViewRay.
Supplementary material for this article can be found at https://doi.org/
10.1016/j.ijrobp.2021.02.011.

Int J Radiation Oncol Biol Phys, Vol. 110, No. 4, pp. 1064e1081, 2021
0360-3016/$ - see front matter Ó 2021 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ijrobp.2021.02.011
Volume 110  Number 4  2021
to a more extended clinical target volume (CTV) than in other lymphoma types because it usually presents with primary
tumor invasion, multifocal lesions, or extensive submucosal infiltration beyond the macroscopic disease. The CTV varies
across different primary sites and is classified mainly into nasal, nonnasal upper aerodigestive tract (UADT), and extra-
UADT entities. This review is a consensus of the International Lymphoma Radiation Oncology Group regarding the
approach to radiation therapy, target-volume definition, optimal dose, and dose constraints in ENKTCL treatment. Ó
2021 Elsevier Inc. All rights reserved.
Introduction
Extranodal natural killer/T-cell lymphoma, nasal type
(ENKTCL), is a distinct clinicopathologic entity with an
aggressive clinical course. Although rare globally, it is
more prevalent in East Asia and South America.1-3
ENKTCL is characterized by prior EpsteineBarr virus
(EBV) infection, is predominant in adult males, has a large
proportion of early-stage cases, is known for its clinically
extensive primary tumor invasion, and has a propensity for
extranodal failure.4-6 ENKTCL can originate from any
extranodal organ or tissue, particularly sites in the upper
aerodigestive tract (UADT), such as the nasal cavity and
Waldeyer’s ring.4-9 It also presents rarely in extra-UADT
sites, such as the skin, soft tissue, and gastrointestinal
tract.6,9,10 The wide variety of primary sites and heteroge-
neity of clinical features and prognoses create significant
challenges for treatment strategy, target definition, treat-
ment planning, and choice of radiotherapeutic method.
Important progress has been made over the last decade
for ENKTCL: better clarification of disease heterogene-
ity,2,4-10 more accurate staging with diagnostic imaging
modalities,11-13 establishment of novel prognostic models
and risk stratifications,8,14-16 utilization of upfront/early
radiation therapy,17-22 use of noneanthracycline-based
chemotherapy,23-30 and first-line risk-adapted treatment
strategies.21,22 Treatment outcomes have improved signifi-
cantly for early-stage disease according to recent reports,
with 5-year overall survival (OS) rates of 70% to 90% for
stage I disease and 50% to 70% for stage II disease, but
only 10% to 40% for stage III/IV disease. Radiation therapy
is the backbone of curative-intent combined-modality
therapy for early-stage ENKTCL, so optimized radiation
methods play an essential part in curing this disease.
This set of guideline aims to provide detailed recom-
mendations for risk-adapted therapy in early-stage
ENKTCL.21,22,30 The principles of target volume defini-
tion for lymphomas have been introduced briefly in the
International Lymphoma Radiation Oncology Group
guidelines.31 The application of the principles of involved
site radiation therapy (ISRT) in ENKTCL often leads to a
more extended clinical target volume (CTV) than in other
lymphoma types because in many patients the radiation
therapy volume must encompass sites of primary tumor
invasion, multifocal lesions, and/or extensive submucosal
infiltration beyond the macroscopic disease. The strict
Radiation therapy guideline for ENKTCL 1065
application of these principles is of paramount importance
to ensure adequate coverage of high-risk anatomic
structures.
Clinical Heterogeneity, Staging, and Risk
Stratification
Location and heterogeneity of the primary tumor
The location of the primary tumor is important because it
contributes to clinical heterogeneity that, in turn, can drive
different treatment options and target volumes in
ENKTCL.2,4-7 The definition of “nasal type” is, in general,
used for the histopathologic diagnosis for cases originating
in the nasal cavity and elsewhere.32,33 Clearly, the disease
can be classified by the anatomic site of origin, including
the nasal cavity, paranasal sinuses, nasopharynx,
oropharynx (tonsil, base of tongue, oropharyngeal wall),
hypopharynx, larynx, trachea, oral cavity (gingiva, buccal
mucosa, mouth floor), and, more rarely, skin and soft tis-
sues, stomach, small intestine, colon, lung, testis, or other
sites. Accordingly, ENKTCL can be further divided into 3
distinct clinical subgroups: (1) nasal; (2) nonnasal-UADT
(the first 2 groups combined are represented as UADT);
and (3) extra-UADT (Table 1).2,4-7 The boundaries of each
anatomic site are referenced to the American Joint Com-
mittee on Cancer classification definition.34 Figure 1 and
Table 1 show the primary locations and major clinical
characteristics of these 3 subgroups.
Presentation in the nasal cavity is prototypical; the nasal
cavity is the most commonly involved site (70% of pa-
tients). Nasal ENKTCL presents predominantly in young
adults with stage I disease, a high frequency of primary
tumor invasion, and a good Eastern Cooperative Oncology
Group (ECOG) performance status.2,4-7 Nonnasal-UADT
ENKTCL occurs mainly in Waldeyer’s ring and is associ-
ated with involvement of regional lymph nodes and a poor
ECOG performance status.4,5,7 Extra-UADT ENKTCL
(often termed “nonnasal” or “extranasal” in the litera-
ture2,10,15,35) is rare and is most commonly reported in the
cutaneous and soft tissues, gastrointestinal tract, testis,
lung, central nervous system, and orbit.2,6,9,10 Frequently,
patients with extra-UADT ENKTCL present with adverse
clinical features, such as advanced-stage disease (60%-
80%), increased levels of lactate dehydrogenase (LDH),
1066 Qi et al. International Journal of Radiation Oncology  Biology  Physics

Table 1 Disease heterogeneity and prognosis of ENKTCL arising at different sites

UADT ENKTCL
Nasal ENKTCL Nonnasal-UADT ENKTCL Extra-UADT ENKTCL
Other common terms in Nasal Nasal Nonnasal; extranasal
literature
Anatomy (primary site) Nasal cavity (most common), Nasopharynx (common), Skin and soft tissues,
paranasal sinuses. oropharynx (tonsil, base of gastrointestinal tract, lung,
tongue, oropharyngeal testis, other rare extra-
wall), hypopharynx, oral UADT sites.
cavity, larynx, and trachea.
Clinical features
Median age, y 40-50 40-50 >50
Sex Male predominance; Male predominance; Male predominance;
male:female Z 2-4:1 male:female Z 2.6:1 male:female Z 1.5-2.3:1
Performance status Good Good Poor
ECOG score 0-1: >80% ECOG score 0-1: >90% Usually ECOG score  2
LDH elevation 30%-50% w20% 50%-70%
Patterns of spread
Primary tumor Often extends to the Multiple lesions in 1 organ, Primary-site dependent;
ipsilateral maxillary sinus, with extension into multiple lesions in 1 organ
anterior ethmoid sinus, adjacent structures or is common.
hard palate, and organs.
nasopharynx.
Regional LN Uncommon, w30%; Level II Common, w80% Common, >80%; primary-
in the head and neck. site dependent
Distant spread 10%-30% 20%-50% Common, 60%-80%
Ann Arbor stage Usually presents with early- Usually presents with early- Usually presents with
stage disease: stage I, 50%- stage disease: stage I, advanced-stage disease:
80%; stage II, 10%-20%. <20%; stage II, 50%-60%. 60%-80%.
NRI risk stratification Low to intermediate risk Intermediate to high risk High to very high risk
predominant predominant predominant
Clinical behavior Aggressive Aggressive Highly aggressive
Prognosis Favorable Relatively favorable Extremely poor

Abbreviations: ECOG Z Eastern Cooperative Oncology Group; ENKTCL Z extranodal natural killer/T-cell lymphoma, nasal type; LDH Z lactate
dehydrogenase; LN Z lymph node; NRI Z Nomogram-revised Risk Index; UADT Z upper aerodigestive tract.

and poor ECOG performance status, with a dismal prog-
nosis. The principles of treatment are the same as those for
the cases arising in the UADT.
Staging and risk stratification
A comprehensive evaluation before treatment is critical for
staging, risk stratification, choice of treatment modality,
and target definition. Essential procedures include
compiling a complete history and performing a physical
examination, as well as fiberoptic endoscopy, biochemistry,
imaging, and a bone marrow biopsy. Positron emission
tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose
(18F-FDG) and computed tomography (CT) is recom-
mended for locoregionally advanced or advanced-stage
disease because it is more sensitive (sensitivity >95%)
than other conventional imaging in detecting occult distant
metastasis and extranodal involvement.11,12 To accurately
determine the primary site and the extent of locoregional
involvement, contrast-enhanced magnetic resonance imag-
ing (MRI) and CT imaging of the head and neck are
preferred (Fig. 2). MRI, specifically T1 with contrast, is
most useful in assessing primary tumor extension into
surrounding normal tissues because it provides good soft-
tissue resolution in all planes.36 In some patients with
UADT ENKTCL, the primary lymphoma presents as small
superficial lesions with occult mucosal infiltration or as
extensive necrosis, which cannot be detected by diagnostic
imaging (MRI, CT, or even PET/CT) but is visible with
direct or fiberoptic examination. In addition, multiple
random biopsies of the contiguous structures to the pre-
senting or occult lesions must be carried out. Therefore,
careful physical and endoscopic examinations of UADT
sites are essential to visualize the primary site and to fully
appreciate submucosal extensions not apparent upon im-
aging (MRI, CT, or even PET/CT) when defining the target
volume. Quantitative detection of circulating EBV DNA
load is helpful in the diagnosis, for monitoring progression,
and in predicting the prognosis.37,38
Volume 110  Number 4  2021
Nasal-ENKTCL
Non-nasal-UADT-ENKTCL
gNasopharynx
gOropharynx
gHypopharynx
gOral cavity
gLarynx
gTrachea
Extra-UADT-ENKTCL
gSkin and soft tissues
gGastrointestinal tract
gLung
gTestis
gOther rare sites
Fig. 1. Distribution of 3 ENKTCL subgroups based on primary tumor location. Abbreviations: ENKTCL Z extranodal
natural killer/T-cell lymphoma, nasal type; UADT Z upper aerodigestive tract.
The Ann Arbor staging system is used widely and re-
mains the most important prognostic factor for ENKTCL.39
At the initial diagnosis, 70% to 90% of ENKTCL patients
have stage I-II disease, whereas 10% to 30% have stage III-
IV disease (Table 1). Primary tumor invasion is also a very
important factor and a surrogate of a high tumor burden in
risk stratification that helps guide treatment decision-
making and define the prognosis, especially for stage I
disease.40,41 Primary tumor invasion is defined as the
growth of the primary tumor beyond the boundary of the
original extranodal site into a neighboring structure or tis-
sue or as contiguous multisite involvement, regardless of
stage.40 Typically, primary tumor invasion in a nasal
ENKTCL case includes any involvement of the paranasal
sinuses, nasopharynx, oral cavity, orbit, or facial skin
(Fig. 2); in a nasopharynx ENKTCL case, it includes any
involvement of the nasal cavity and oropharynx. Accord-
ingly, stage IE disease using the Ann Arbor system can be
divided further into limited stage I, which is confined to a
single primary site in the absence of primary tumor inva-
sion, and extended stage I, which includes the presence of
primary tumor invasion.17 The latter was also defined as
stage II disease in a proposed new ENKTCL-specific
staging system.13
A prognostic index can be calculated as part of the initial
workup. Several prognostic models have been used for risk
stratification and treatment decision-making for ENKTCL
(Table E1).8,14-16,42 The Nomogram-Revised Risk Index
(NRI) evolved from a visual prognostic nomogram in the
era of anthracycline-based chemotherapy8 and has been
validated in the modern era of noneanthracycline-based
chemotherapy with good capability in predicting prognosis
and guiding treatment.16,21,22,43,44 Importantly, the early
stageeadjusted NRI (ES-NRI) shows good prognostic
ability for localized ENKTCL and is able to predict which
Radiation therapy guideline for ENKTCL 1067
gg
g g
g g
g g
g g
g
intermediate- and high-risk patients will receive a greater
survival benefit from additional chemotherapy in the setting
of radiation therapy.21,22,44 Other models include the In-
ternational Prognostic Index,42 the Korean Prognostic
Index,14 and the Prognostic Index of Natural Killer Cell
Lymphoma.15 However, several risk factors in the latter
models, such as advanced-stage disease (stage III or IV),
regional disease, or involvement of distant lymph nodes and
>1 extranodal sites, either overlap or are only relevant for
patients with disseminated disease and are thus incapable of
discriminating within a large population of patients with
early-stage disease. The commonly used prognostic models
in ENKTCL are summarized in Table E1.
Principles of Treatment and Risk-Adapted
Therapy
Increasing use of upfront/early modern radiation therapy
and noneanthracycline-based chemotherapy has been
associated with improved treatment outcomes over the
last decade, including 2-year progression-free survival
(PFS) of 67% to 86% in early-stage disease in single-arm
phase 2 trials23-25,28-31 and a decreased mortality risk of
w30% in the entire cohort of the China Lymphoma
Collaborative Group.30 Treatment principles differ be-
tween early-stage and advanced-stage ENKTCL. Risk-
adapted therapy is recommended for all patients with
ENKTCL (Table 2).
In early-stage disease, radiation therapy is the back-
bone of curative treatment.17-25 Chemotherapy alone,
whether with noneanthracycline-based or anthracycline-
based regimens, should not be employed
routinely.21,22,35,45-47 Radiation therapy improves locore-
gional control and long-term survival significantly48 and
1068 Qi et al. International Journal of Radiation Oncology  Biology  Physics

Fig. 2. Diagnostic images and example of positive primary tumor invasion in a nasal ENKTCL case. (A-D) MRI with T1-
weighted postcontrast sequence, (E-H) CT, and (I-L) PET demonstrate a left-sided nasal cavity primary (red shade) invading
the anterior ethmoid sinus and nasopharynx. Note that growth of the primary tumor beyond the outline of the nasal cavity
Volume 110  Number 4  2021 Radiation therapy guideline for ENKTCL 1069

Table 2 Risk-adapted therapy strategy for ENKTCL

Stage Risk factor* Risk group Treatment 5-y overall survival (%)
I No Low risk Radiotherapy alone; or 85-92
Radiotherapy followed by
non-anthracycline-based
chemotherapy
I/II Any Intermediate-low-/ Radiotherapy followed by 55-80
Intermediate-high-/ non-anthracycline-based
high-risk chemotherapy; or
Brief chemotherapy (3 cycles) with
non-anthracycline-based regimens
followed by radiotherapy; or
Concurrent chemoradiotherapy
followed by non-anthracycline-based
chemotherapy.
III/IV Any High-/very high-risk Clinical trial; or 10-40
Asparaginase-based chemotherapy
with or without radiotherapy
Abbreviations: NRI, Nomogram-revised Risk Index; ES-NRI, early stage-adjusted NRI; ECOG, Eastern Cooperative Oncology Group; LDH: lactate
dehydrogenase; PTI: primary-tumor invasion; ASP, asparaginase; GELOX, gemcitabine, oxaliplatin, l-asparaginase; P-GEMOX, pegaspargase, gemci-
tabine, oxaliplatin; DDGP, gemcitabine, pegaspargase, cisplatin, dexamethasone; GDP-L, gemcitabine, dexamethasone, cisplatin, l-asparaginase; SMILE,
l-asparaginase, ifosfamide, methotrexate, etoposide, dexamethasone; MESA, methotrexate, etoposide, dexamethasone, pegaspargase; AspaMetDex,
l-asparaginase, methotrexate, dexamethasone; VIDL, etoposide, ifosfamide, dexamethasone, l-asparaginase; GDP, gemcitabine, dexamethasone, cisplatin;
GEMOX, gemcitabine, oxaliplatin; GP, gemcitabine, cisplatin; VIDP, etoposide, ifosfamide, cisplatin, dexamethasone; DEVIC, dexamethasone,
etoposide, ifosfamide, carboplatin; DICE, etoposide, cyclophosphamide, cisplatin, dexamethasone; DIMG, dexamethasone, ifosfamide, methotrexate,
gemcitabine.
The most commonly used nonanthracycline-based chemotherapy included asparaginase-based or platinum-based regimens. Asparaginase-containing
regimens were usually combined with gemcitabine (GELOX, P-GEMOX, DDGP, GDP-L), methotrexate (SMILE, MESA, AspaMetDex) or platinum
(VIDL). Platinum-containing regimens were usually combined with gemcitabine (GDP, GEMOX, GP) or etoposide (VIDP, DEVIC, DICE, DIMG).
* NRI-defined risk factors (as described in Table E1): age >60 years (1 point), ECOG score 2 (1 point), increased LDH level (1 point), PTI (1 point),
stage II (1 point), and stage III/IV (2 points). Risk factors in the ES-NRI: age >60 years, ECOG score 2, increased LDH level, PTI, and stage II.

is essential even after a complete response to
asparaginase-based chemotherapy.49,50 In a large cohort
from the China Lymphoma Collaborative Group, the 5-
year OS, disease-free survival, and locoregional control
rates for early-stage patients who achieved complete
response after asparaginase-based chemotherapy were
84.9%, 76.2%, and 84.9%, respectively, for chemotherapy
and radiation therapy combined, compared with 58.9%
(P Z .006), 43.6% (P Z .001), and 62.1% (P Z .026),
respectively, for chemotherapy alone.49
Using the ES-NRI stratification, radiation therapy alone
can be used for low-risk, early-stage patients (no primary
tumor invasion, normal LDH level, stage I disease, ECOG
score 0-1, and age 60 years); additional chemotherapy
does not improve survival outcome.21,22 For intermediate-
or high-risk patients (primary tumor invasion, elevated
LDH, stage II disease, ECOG score 2, or age >60 years),
combined-modality treatment involving radiation therapy
followed by noneanthracycline-based chemotherapy, brief
chemotherapy (3 cycles) followed by radiation therapy, or
concurrent chemoradiation is recommended as an optimal
strategy.21-25,51,52
In a recent multicenter study of early-stage patients in
the modern chemotherapy era,22 radiation therapy followed
by chemotherapy or chemotherapy followed by radiation
therapy resulted in similar 5-year OS (77.7% vs. 72.4%,
respectively; P Z .290) and PFS (67.1% vs. 63.1%,
respectively; P Z .592) for intermediate- and high-risk
groups. Furthermore, for patients who achieved complete
response after induction chemotherapy, initiation of radia-
tion therapy within or beyond 3 cycles of chemotherapy
resulted in similar OS (78.2% vs. 81.7%; P Z .915) and
PFS (68.2% vs. 69.9%; P Z .519). However, for patients
who did not achieve complete response, early radiation
therapy within 3 cycles of chemotherapy resulted in better
PFS (63.4% vs. 47.6%, respectively; P Z .019) than
delayed radiation therapy after 3 cycles of chemotherapy.22
For older or frail patients, chemotherapy may need to be
reduced in intensity or omitted entirely, depending on pa-
tient tolerance.53,54
Because there are no large, randomized phase 3 trials
comparing different chemotherapy regimens in ENKTCL,
many noneanthracycline-based regimens and sequencing
combinations are acceptable. Common regimens are

(blue dashed line) to a neighboring structure (red arrow) is defined as positive primary tumor invasion. Abbreviations:
CT Z computed tomography; ENKTCL Z extranodal natural killer/T-cell lymphoma, nasal type; MRI Z magnetic
resonance imaging; PET Z positron emission tomography.
1070 Qi et al.
asparaginase-based or platinum-based, administered
sequentially (eg, GELOX [gemcitabine, oxaliplatin, and L-
asparaginase]25 or GDP [gemcitabine, dexamethasone, and
cisplatin]28) or concurrently (eg, concurrent DeVIC
[dexamethasone, etoposide, ifosfamide, and carboplatin]
and radiation therapy followed by adjuvant DeVIC,23 or
concurrent weekly cisplatin and radiation therapy followed
by VIPD [etoposide, ifosfamide, cisplatin, and dexameth-
asone]24) with radiation therapy.51-55
In stage III or IV disease, noneanthracycline-based
chemotherapy is the primary treatment.27,30 Consolidation
radiation therapy was associated with improved local con-
trol and survival in a retrospective study.56 Asparaginase-
based regimens (eg, SMILE [dexamethasone, metho-
trexate, ifosfamide, L-asparaginase, etoposide]; GELOX;
P-GEMOX [pegaspargase, gemcitabine, oxaliplatin];
AspaMetDex [L-asparaginase, methotrexate, dexametha-
sone]) are recommended as standard treatment based on a
series of phase 1, phase 2, or retrospective studies.26-30,56
Owing to the poor prognosis (5-year OS, 10%-40%),
there is an unmet need for innovative systematic treatment
strategies for these advanced-stage, high-risk, or very
higherisk diseases. Prospective clinical trials are highly
encouraged.
Principles of Radiation Therapy and Treatment
Volume Definition
Radiation therapy methods, including target volume defi-
nition, dose, and delivery modality, are crucial for maxi-
mizing locoregional control, which is a prerequisite for the
cure of patients with early-stage ENKTCL. The optimal
radiation dose and target volume are associated with
improved locoregional control and survival,48 whereas a
lower radiation dose and a small target volume (eg, gross
tumor volume plus a small margin) result in poor outcomes,
with 5-year OS of <50%.45,48,57-59 Furthermore, there are
linear relationships between improved locoregional control
and prolonged OS or PFS in early-stage ENKTCL.48 A 5-
year OS rate of w75% can be expected if a locoregional
control rate of 90% is achieved with optimal planning and
radiation therapy method.
The basic principles of ISRT apply for all types of
lymphomas, both for nodal lymphomas and for extranodal
lymphomas, such as ENKTCL.31,60-63 The definitions of
target volume, including gross tumor volume (GTV), CTV,
internal target volume (ITV), and planning target volume
(PTV), are in accordance with the concepts in the Inter-
national Commission on Radiation Units and Measure-
ments Report 83.64 However, the CTV in ENKTCL needs
to include both initially macroscopic and microscopic dis-
ease and thus is significantly larger than that in other, more
chemosensitive lymphomas for 2 reasons. First, ENKTCL
usually presents locally with a highly destructive growth
pattern, with extensive submucosal infiltration beyond the
macroscopic disease. More than 50% of patients have
International Journal of Radiation Oncology  Biology  Physics
primary tumor invasion or continuous multisite involv-
ment.40,41 Second, the effect of chemotherapy for ENKTCL
is much less certain than in most other lymphoma
types.21,22,35,45-47 The frequent tumor regrowth observed in
complete responders with chemotherapy alone indicates
that ENKTCL exhibits secondary resistance to chemo-
therapy, and asparaginase-based chemotherapy alone is
insufficient to provide long-term disease remission in the
majority of early-stage patients.49,50 Some patients with
low-risk stage I disease will receive radiation therapy
alone.19-22
The CTV for ENKTCL includes the entire involved
primary site, adjacent high-risk anatomic sites, and regional
lymph nodes in cases with positive lymph nodes. The
philosophy of contouring is based on the destructive growth
pattern of macroscopic disease and extensive submucosal
infiltrations of microscopic disease, which pathologically
closely links to vascular invasion.
Volume Definitions
GTV
The GTV is the gross demonstrable extent and location of
the lymphoma. It is the sum of involvement found on
clinical examination, endoscopy, and imaging (MRI, CT,
and PET/CT) before treatment. As described, including the
findings of the superficial or submucosal occult lesions
from direct or fiberoptic examination and multisite random
biopsies is important in GTV delineation.
CTV
The CTV encompasses the GTV at initial diagnosis
(modified to accommodate anatomic changes during
chemotherapy) as well as potential sites of microscopic
disease at the time of radiation therapy. For patients who
receive chemotherapy or tumor resection before radiation,
the tissue volume that contained the prechemotherapy or
presurgery GTV is highly likely to still harbor microscopic
disease at the time of radiation therapy, even if an abnor-
mality cannot be found on imaging. The prechemotherapy
or presurgery GTV should therefore be transferred to the
planning CT scan, preferably using fusion of the available
images (PET/CT, CT, MRI, or a combination of these) to
ensure the inclusion of the initial GTV in its entirety in the
CTV. Volumes should be shaved off air and bones (if un-
involved) in these situations.
In ENKTCL, the definition of CTV is also highly
dependent on the pathway of primary tumor invasion and
lymph node spread (Table 3).36 Usually, ENKTCL are
multifocal, with extensive submucosal spread. Therefore,
typically any involved organ is treated in its entirety, even if
it appears initially to only be partially involved. If adjacent
tissues or structures have been involved, all of the invaded
Volume 110  Number 4  2021 Radiation therapy guideline for ENKTCL 1071

Table 3 Suggested clinical target volumes at the high-risk subclinical region of ENKTCL
Target volumes Disease involvement
Nasal ENKTCL
CTV-primary tumor
(Prechemotherapy or presurgery) GTV with a 5-mm Primary disease confined to the nasal cavity (unilateral or
margin and high-risk regions of primary tumor bilateral) without primary tumor invasion.
invasion.
Entire nasal cavity, ipsilateral medial maxillary wall
(lateral), anterior ethmoid sinuses (superior), hard palate
(inferior), posterior nasal aperture (posterior; Fig. 3).
The CTV expands further to fully cover the disease Primary disease extends into adjacent structures or organs.
extension as follows.
To include the whole nasopharynx (Fig. 4). If primary nasal disease is close to the posterior nasal
aperture or invades the nasopharynx.
To include the posterior ethmoid sinuses. If the anterior ethmoid sinuses are involved or posterior
ethmoid sinuses are involved.
To include the whole maxillary sinus (Fig. 4). If the maxillary sinus (often medial maxillary wall) is
involved.
To include the involved facial subcutaneous soft tissue If the primary tumor involves the subcutaneous soft tissue
with a bolus of 0.5-1 cm. or facial skin.
To include the (prechemotherapy or presurgery) If the orbit is involved.
orbital-GTV with a 3-mm margin. Normal structures
in the orbital cavity that were clearly uninvolved,
though previously displaced by the GTV, should be
excluded from the CTV according to clinical judgment
after induction chemotherapy.
CTV-lymph node
Prophylactic irradiation of cervical lymph nodes is not No lymph node involvement.
necessary.
First-echelon uncertain or suspicious nodes close to the
primary organ may be included (eg, retropharyngeal
nodes).
The retropharyngeal nodes and bilateral level II nodes. If the retropharyngeal nodes are positive.
The bilateral cervical lymph nodes. If the cervical nodes are positive.
Nonnasal-UADT ENKTCL
CTV-primary tumor
(Prechemotherapy or presurgery) GTV with a 5-mm
margin.
Whole Waldeyer’s ring (nasopharynx, tonsils, tongue Primary disease in the Waldeyer’s ring (single or multisite
base, and oropharyngeal wall), posterior nasal involvement).
aperture, and adjacent organs or structures involved
(Figs. 5 and 6).
The entire structure and adjacent soft tissues involved Primary disease in the oral cavity, larynx, or hypopharynx.
with at least 2-cm margin.
CTV-lymph node
Prophylactic irradiation of the neck can be considered No lymph node involvement.
(Fig. 5).
The bilateral cervical lymph nodes (Fig. 6). If the cervical nodes are positive.
Extra-UADT ENKTCL
CTV-primary tumor
Cutaneous and soft tissues with a margin of at least 2 Primary disease in cutaneous and soft tissues.
cm, and adjacent organs or structures involved.
The entire stomach and adjacent soft tissues if Primary disease in the stomach.
involved.
CTV-lymph node
Prophylactic irradiation of regional lymph nodes is not No lymph node involvement.
necessary.
The regional lymph nodes. If the regional lymph nodes are positive.

Abbreviations: CTV Z clinical target volume; ENKTCL Z extranodal nasal-type natural killer/T-cell lymphoma; GTV Z gross tumor volume;
UADT Z upper aerodigestive tract.
1072 Qi et al. International Journal of Radiation Oncology  Biology  Physics

Fig. 3. Representative slices of target delineation of the GTV (red line) and CTV (blue line) in a patient with localized
stage I nasal ENKTCL (disease confined to the left nasal cavity without primary tumor invasion). Abbreviations: CTV Z
clinical target volume; ENKTCL Z extranodal natural killer/T-cell lymphoma, nasal type; GTV Z gross tumor volume.
(A color version of this figure is available at https://doi.org/10.1016/j.ijrobp.2021.02.011.)
Volume 110  Number 4  2021 Radiation therapy guideline for ENKTCL 1073

Fig. 4. Representative slices of target delineation of the GTV (red line) and CTV (blue line) in a patient with extended
stage I nasal ENKTCL. Abbreviations: CTV Z clinical target volume; ENKTCL Z extranodal natural killer/T-cell lym-
phoma, nasal type; GTV Z gross tumor volume. (A color version of this figure is available at https://doi.org/10.1016/j.ijrobp.
2021.02.011.)
1074 Qi et al. International Journal of Radiation Oncology  Biology  Physics

Fig. 5. Representative slices of target delineation of the GTV (red line) and CTV (blue line) in a patient with localized
nasopharyngeal ENKTCL. Notice a separate CTV (light blue line) with a lower dose (40-45 Gy) to the prophylactic cervical
lymph nodes radiation could be considered. Abbreviations: CTV Z clinical target volume; ENKTCL Z extranodal natural
killer/T-cell lymphoma, nasal type; GTV Z gross tumor volume. (A color version of this figure is available at https://doi.org/
10.1016/j.ijrobp.2021.02.011.)
Volume 110  Number 4  2021 Radiation therapy guideline for ENKTCL 1075

Fig. 6. Representative slices of target delineation of the GTV (red line) and CTV (blue line) in a patient with stage II
oropharyngeal ENKTCL. Notice a separate CTV (light blue line) with a lower dose (40-45 Gy) to the prophylactic cervical
lymph nodes radiation could be considered. Abbreviations: CTV Z clinical target volume; ENKTCL Z extranodal natural
killer/T-cell lymphoma, nasal type; GTV Z gross tumor volume. (A color version of this figure is available at https://doi.org/
10.1016/j.ijrobp.2021.02.011.)
1076 Qi et al.
structure/organ should be included in the CTV. An even
wider safety margin is recommended along the airway.
There are no data supporting a smaller CTV for patients
in complete response after efficacious chemotherapy (eg,
asparaginase-based regimens).48,49 However, an adaptive
target volume could be considered after the tumor shrinks
with brief chemotherapy if the primary tumor is close to
critical organs, such as the optic nerves and corneas, with a
careful balance between tumor control and late toxicities.
The CTV varies between different primary sites, and the
delineations for each site are presented below.
Nasal ENKTCL
 The major pattern of spread is primary disease invasion
into the adjacent structures; regional lymph node
involvement is uncommon and usually follows an orderly
pattern.36
 The (prechemotherapy or presurgery) GTVs of the pri-
mary tumor and lymph nodes should be fully covered in
the CTV.
 For limited stage I nasal ENKTCL (confined to the nasal
cavity without primary tumor invasion), the CTV en-
compasses the high-risk structures based on the fre-
quency of involvement and risk of relapse: whole nasal
cavity, ipsilateral medial maxillary wall, anterior ethmoid
sinuses, hard palate, posterior nasal aperture (Fig. 3). For
a case of extended stage I disease, the CTV expands
further to fully cover the disease extension (Fig. 4).
 The target delineations of nasal ENKTCL are described
in Table 3. Examples of GTV (red line) and CTV (blue
line) in limited stage I disease and extended stage I nasal
ENKTCL are illustrated in Figures 3 and 4.
 Prophylactic irradiation of cervical lymph nodes is not
necessary for stage I nasal ENKTCL, even with extension
into the nasopharynx. Without prophylactic irradiation,
the prevalence of failure in cervical lymph nodes in stage
I nasal ENKTCL is <6%.20,59,65,66 However, first-
echelon uncertain or suspicious nodes close to the pri-
mary organ may be included (eg, retropharyngeal nodes).
 For cases with only involvement of retropharyngeal
nodes, the CTV should include retropharyngeal nodes
and bilateral level II nodes. For stage II nasal ENTKCL
with positive cervical lymph nodes, the CTV encom-
passes the bilateral cervical lymph nodes.
Nonnasal-UADT ENKTCL
 Patients with nonnasal-UADT ENKTCL tend to have
multisite involvement or primary tumor invasion (59%)
and involvement of regional lymph nodes (60%-80%).4-7
The most commonly involved sites are in Waldeyer’s
International Journal of Radiation Oncology  Biology  Physics
ring. The propensity for involvement of regional lymph
nodes at presentation and the primary patterns of failure in
lymph nodes after treatment may reflect the drainage
pattern of Waldeyer’s ring in the UADT as a lymphatic
structure.4,5
 The target delineations of nonnasal-UADT ENKTCL are
summarized in Table 3. Examples of GTV (red line) and
CTV (blue line) in stage I and stage II Waldeyer’s ring
ENKTCL are illustrated in Figures 5 and 6.
 If single or multisite Waldeyer’s ring organs are involved,
the CTV should include the whole Waldeyer’s ring
(nasopharynx, tonsils, tongue base, and oropharyngeal
wall), the posterior nasal aperture, and adjacent organs or
structures if they are involved (Figs. 5 and 6).61
 Controversy exists regarding the value of prophylactic
cervical lymph node irradiation because no study has
shown a survival benefit for UADT ENKTCL.65 Pro-
phylactic irradiation of the neck can be considered for
Waldeyer’s ring ENKTCL (Fig. 5).61 In a single institu-
tional retrospective study (in Chinese), patients with
stage I Waldeyer’s ring ENKTCL who did not receive
prophylactic neck irradiation experienced a high recur-
rence rate in the cervical lymph nodes (27.3%).66
 If cervical lymph nodes are involved, the CTV extends to
encompass all of them (Fig. 6).
Extra-UADT ENKTCL
Radiation therapy is given according to the ISRT principles
in the International Lymphoma Radiation Oncology Group
guidelines for extranodal lymphomas.31 Cutaneous and soft
tissue are the most commonly involved sites of extra-
UADT ENKTCL. The CTV should include the involved
cutaneous and soft tissues, with a margin of 2 cm
(Table 3). Usually, gastric ENKTCL is multifocal; the CTV
should include the entire stomach and any suspicious per-
igastric lymph nodes. After complete resection of extra-
UADT ENKTCL lesions (eg, stomach and intestine), ra-
diation therapy may not be necessary, whereas post-
operative chemotherapy is the first-line treatment.67
However, even with very aggressive treatment, the prog-
nosis of extra-UADT ENKTCL is dismal.
ITV
The ITV is defined by the International Commission on
Radiation Units and Measurements as the CTV plus a
margin, taking into account uncertainties in size, shape, and
position of the CTV within the patient. ITV use is depen-
dent on the location; for patients with UADT ENKTCL, it
is not required because movements and changes in the size
and shape of the CTV are minor and are unlikely to have a
clinical impact. Some primary sites (eg, lung, stomach)
Volume 110  Number 4  2021
may move and change their volume or shape dramatically
during treatment. Motion management strategies and
incorporation of ITV in the planning process must be done
in these settings. Treating in deep-inspiration breath hold
may reduce the motion of CTVs in the chest and upper
abdomen, and use of a 4-dimensional CT is recommended
to determine the ITV.
PTV
The PTV is an expansion of the CTV or ITV that accounts
for setup uncertainties in patient positioning and beam
alignment during planning and through treatment sessions.
Although the CTV-to-PTV margin varies in different in-
stitutions, it is dependent mainly on the use of immobili-
zation devices, the image guidance protocol, and the
primary location for ENKTCL. The expansion from CTV
to PTV is usually 0.3 to 0.5 cm for UADT sites and 0.5 to 1
cm for other sites, but it should be determined by each
institution, and may be even smaller if daily imaging-
guided radiation therapy is used.
Radiation Dose
ENKTCL is relatively chemoresistant but is radiosensitive.
However, it is less radiosensitive than B-cell lymphomas. A
dose-response effect of radiation therapy affects locore-
gional control in the dose range from 0 Gy (chemotherapy
alone) to 50 Gy, which has a meaningful impact on PFS and
OS.48 The radical radiation dose required to maximize
tumor control is 50 Gy in 25 fractions over 5 weeks (con-
ventional fractionation). Patients are recommended to have
a comprehensive evaluation for the tumor response at
approximately 50 Gy, typically with fiberoptic examination
and MRI of the UADT. A boost of 5 to 10 Gy (2 Gy per
fraction) is recommended for suspicious residual disease
after clinical evaluation. A maximum tumor dose of 60
Gy is recommended.
A dose of 50 Gy is appropriate for patients who achieve
a complete response after initial chemotherapy. For patients
who achieve a complete response after chemotherapy,
doses <50 Gy have been associated with high rates of
locoregional failure (35.5%).48,49 For patients who have
local residual, relapsed, or progressive disease after
chemotherapy, a dose of 50 Gy is required to provide
optimal locoregional control (90%).48
If a concurrent chemoradiotherapy regimen is chosen,
owing to radiosensitization of tumor and normal tissues, a
slightly lower dose of 45 Gy may be prescribed.23,24 Pro-
phylactic radiation (40-45 Gy) to cervical lymph nodes is
recommended for patients with stage I Waldeyer’s ring
ENKTCL or nonnasal-UADT ENKTCL.
Radiation therapy guideline for ENKTCL 1077
Organs at Risk and Dose Constraints
The relevant organs at risk (OARs) are determined mainly
by the location of the primary site. For UADT ENKTCL,
the most relevant OARs mainly include the parotid glands,
brain stem, spinal cord, retina, optic nerves, chiasm,
cornea, and lens. For most critical OARs in UADT
ENKTCL, the recommended maximum dose constraints
are68 50 Gy for the brain stem, 40 Gy for the spinal
cord, 50 Gy for the optic nerve and chiasm, 45 Gy for
the retina, 50 Gy for the cornea, and 10 Gy for the
lens. There is a linear relationship between the mean dose
to the parotid glands and grade 2 xerostomia,69 so the
dose constraint to the parotid glands should be kept as low
as possible. The mean dose to the parotid glands can
usually be kept at 18 Gy for nasal ENKTCL and 26 Gy
for Waldeyer’s ring ENKTCL.60,61 The primary tumor in
UADT ENKTCL is relatively far from many important
OARs, and the prescribed dose in ENKTCL is typically
lower than that used for head and neck cancers; hence,
dose constraints to OARs should be kept “as low as
reasonably achievable” (ALARA principle) to achieve a
better quality of life among cured cases (75% in UADT
ENKTCL). For extra-UADT ENKTCL, the dose con-
straints to the normal organs should follow the Quantita-
tive Analyses of Normal Tissue Effects in the Clinic
recommendations.70
Radiation Therapy Method
Patients with UADT ENKTCL are set up in the supine
position, with the neck extended when irradiating the cer-
vical lymph nodes. The patient should be immobilized as in
head and neck cancer treatment, usually with a thermo-
plastic mask. A bite block is recommended to push the
tongue away from the high-dose region in patients with
nasal ENKTCL. Image registration and fusion applications
with MRI and PET scans should be used. Daily image
guided setup with cone beam CT or KV images allows for
reduced margins near critical structures.
Advances in imaging and conformal radiation therapy
methods have improved the outcome and reduced the side
effects of radiation therapy.43,50 Intensity modulated radi-
ation therapy (IMRT), often in the form of volumetric arc
therapy, achieves excellent target coverage, dose confor-
mity and sparing of normal tissues in ENKTCL.71-74 A
risk-adapted survival benefit of IMRT over 3-dimensional
conformal radiation therapy or 2-dimensional radiation
therapy has been observed in early-stage ENKTCL.43
Evidence for proton and other particle therapies is scarce
for ENKTCL. However, based on experiences in head and
neck cancer and mediastinal lymphoma,75 proton therapy
may benefit patients by reducing toxicity and potentially
further improving tumor control. The same target defini-
tions are applied regardless of the type of radiation used,
except that adaptive replanning may be necessary during
1078 Qi et al.
particle therapy given the location and radiosensitivity of
the disease and the sensitivity of particle therapy to changes
in tissue density.
Treatment Toxicities and Supportive Care
Radiation-related acute toxicities are transient, dose-
dependent, and confined to the irradiated volume; late
toxicities and secondary malignancies are rarely reported.
The common radiation-related acute toxicities for UADT
ENTKCL include grade 1/2 skin reaction (>95%), grade 1/
2 xerostomia (>80%), grade 1/2 mucositis (>80%), and
grade 1/2 dysphagia (>70%); grade 3 acute toxicities
include mucositis (15%-35%) and dysphagia (5%-
25%).60,61 With modern IMRT techniques and strict dose
constraints, mild xerostomia (grade 2 in 7%-27%) is
observed as the only late toxicity, whereas grade 3/4 late
toxicities have not been reported.60,61
When applying the recommended concurrent chemo-
radiotherapy, the majority of systemic toxicities are
chemotherapy related, including grade 3/4 hematologic
toxicities (>90%) and accompanying grade 3/4 infections
(w20%); common grade 3/4 nonhematologic toxicities are
radiation-related mucositis (30%-40%) and other
chemotherapy-related gastrointestinal disorders
(<6%).23,24,51 For local toxicity, supportive care measures,
such as placement of a feeding tube or percutaneous
placement of an endoscopic gastrostomy tube, are impor-
tant to prevent severe weight loss and delay/interrupt ra-
diation therapy, especially for cases receiving extensive
irradiation to the mucosa and/or cervical lymph nodes.
When applying sequential or “sandwich” chemo-
radiation therapy, most toxicities are related to chemo-
therapy. Asparaginase is the fundamental drug for current
chemotherapy regimens. Other important components in
the combination include methotrexate (SMILE and Aspa-
MetDex) and gemcitabine/platinum (P-GEMOX, GELOX,
and DDGP [gemcitabine, pegaspargase, cisplatin, dexa-
methasone]).23-27,51,52 Hematologic toxicities are common
and severe. The most common grade 3/4 nonhematologic
complication is infection, and other complications include
liver failure, renal failure, and decreased levels of
fibrinogen.
Salvage Reirradiation for Locoregionally
Relapsed Disease
Salvage treatment significantly improves the survival of
patients with locoregionally refractory/relapsed
ENKTCL.76,77 For patients who develop in-field or mar-
ginal recurrence after initial radiation therapy, salvage
chemotherapy should be considered first. Reirradiation
after chemotherapy could be implemented in carefully
selected patients if doses to OARs will not be exceeded. For
cases where dose constraints will be exceeded, toxicity
International Journal of Radiation Oncology  Biology  Physics
risks and potential benefits should be discussed with the
patient in the multidisciplinary setting. Compared with
salvage chemotherapy alone, radiation therapy improves
survival significantly.77 To avoid the potential for severe
toxicity induced by reirradiation, the CTV should be
reduced to cover the prechemotherapy GTV with narrow
margins, where appropriate. Proton and particle therapies
may be recommended for UADT reirradiation to reduce
long-term severe toxicities, depending on comparative
planning of photons and protons.
Conclusions and Future Directions
Risk-based and response-adapted therapy, involving
radiation therapy with or without chemotherapy for
low-risk patients and upfront/early radiation therapy com-
bined with chemotherapy (radiation therapy followed by
noneanthracycline-based chemotherapy or 3 cycles of
noneanthracycline-based chemotherapy followed by radi-
ation therapy) for intermediate-low to high-risk patients
should be considered the optimal strategy for early-stage
ENKTCL (Table 2).21,22 ISRT (50 Gy) should be
considered as a standard therapeutic option.43,48
Asparaginase-based chemotherapy with or without
consolidation radiation therapy is the standard of care for
advanced-stage ENKTCL.30
Further studies are needed to consider deescalated
treatment and surveillance for low-risk early-stage patients
and to identify the small subgroups at high risk of failure
who might benefit from additional chemotherapy. More
effective, lower-toxicity systemic therapies with optimal
radiation therapy warrant further investigation for inter-
mediate- and high-risk early-stage patients. The poor
prognosis in patients with advanced-stage or high-risk/very
high-risk disease indicates the need for innovative systemic
therapy or novel agents in future trials.78 Prospective
comparative evidence should be gathered to determine the
value of proton and other particle therapy, especially for
reirradiation. Patients who achieve PFS at 24 months have a
clinically similar subsequent survival compared with the
general population, and PFS at 24 months could be used as
an endpoint for study design and risk stratification in
ENKTCL.79
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