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Page 4 of 14 Fujimoto et al. J Cancer Metastasis Treat 2021;7:66 https://dx.doi.org/10.20517/2394-4722.2021.157

evaluating the prognosis by the site of disease origin. In fact, another study reported that prognosis does not
[20]
significantly differ between the two groups in subgroup analyses by disease stage .
There are no prognostic models for ANKL. In general, the prognosis of this disease is extremely poor, with a
[21]
median OS of 2-3 months [5,11,12] , except for that of the subacute-type ANKL . Allogeneic stem cell
transplantation is the only curative treatment and could be the most important factor for survival. Patients
with subacute ANKL have symptoms of infectious mononucleosis for more than 90 days prior to the
fulminant onset, and the prognosis is significantly better than that of typical ANKL, with a median OS of
[21]
214 days . ANKL originating from EBV-associated NK/T cell lymphoproliferative diseases such as chronic
active EBV infection has been reported , but its clinical course and prognosis are not well known.
[13]
TREATMENT OF NK-CELL LYMPHOMA
The recommended algorithm of treatments for ENKL patients is shown in Figure 1. The scheme is divided
based on the extent of disease (limited vs. advanced). The history of treatment development is further
shown in Table 1.

Limited-stage ENKL
For limited-stage ENKL, concurrent chemoradiotherapy (CCRT) is recommended as a first-line therapy.
[22]
Radiotherapy (RT) has been used as an effective treatment for limited-stage ENKL since the 1980s .
[23]
Although RT-containing treatment provides significantly better outcomes for limited-stage ENKL , RT
alone frequently induces local or systemic treatment failure in more than 50% of patients [24-26] . Several
studies have shown that the recommended dose of RT that is necessary for local control of limited-stage
ENKL is 50 Gy or more [23,27,28] . A combination of CHOP (cyclophosphamide, doxorubicin, vincristine, and
prednisone) and RT is an established treatment for localized non-Hodgkin lymphoma, and it is also used to
treat ENKL patients . However, because normal and abnormal NK cells express multidrug resistant
[29]
(MDR)-associated P-glycoprotein [30,31] , anthracycline-containing regimens such as CHOP are not
satisfactory for treating ENKL patients, with a five-year OS of less than 50%, even combined with RT [6,24,32,33] .
In addition, chemotherapy followed by RT was shown to yield a worse response rate than RT followed by
chemotherapy for limited-stage ENKL in a few studies [22,34,35] . Based on these experiences, several CCRT
regimens have been developed as novel anti-MDR treatments for limited-stage ENKL patients since the
early 2000s [36-38] . These regimens consist of non-MDR-associated anti-cancer agents, such as platinum
derivatives, and ifosfamide (IFM), L-asp which has in vitro sensitivity against an NK cell tumor cell line ,
[39]
or etoposide (ETP) which is known to be effective against EBV-associated hemophagocytic syndrome [40,41] .
One of the most popular CCRT regimens is RT-2/3DeVIC (dexamethasone, ETP, IFM, and carboplatin) ,
[36]
which includes concurrent RT of 50-50.4 Gy in 25-28 fractions with three cycles of a two-third dose of
DeVIC. The efficacy of RT-2/3DeVIC therapy for newly diagnosed stage IE or contiguous IIE ENKL
patients is better with a two-year OS of 78% and an overall response rate (ORR) of 81%, relative to the
historical data. The adverse events (AEs) of RT-2/3DeVIC are acceptable. There have been no treatment-
related deaths and only neutropenia was reported as a Grade 4 AE, developing in more than 20% of the
patients. Other CCRT regimens used in Korea, such as CCRT-VIPD [ETP, IFM, cisplatin (CDDP), and
dexamethasone (DEX)] and CCRT-VIDL (ETP, IFM, DEX, and L-asp) [37,38] , have common characteristics
such as RT with a median of 40 Gy conducted with weekly CDDP monotherapy, and then combination
chemotherapy is conducted after RT completion. VIPD is given every three weeks for three cycles after 3-5
[37]
weeks from the time of CCRT completion . VIDL is similar to VIPD, but L-asp is used instead of CDDP
every other day from Day 8 to Day 20, as in the SMILE regimen [38,42] . VIDL is given every three weeks for
two cycles after 3-4 weeks from the time of CCRT completion . Compared to the RT-2/3DeVIC regimen,
[38]
these regimens include a lower dose of RT and take a longer time to complete the treatment, but both