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Fujimoto et al. J Cancer Metastasis Treat 2021;7:66 https://dx.doi.org/10.20517/2394-4722.2021.157 Page 5 of 14

Figure 1. Treatment flowchart of ENKL patients. *CCRT-VIPD and CCRT-VIDL regimens are included. AspaMetDex regimen is included
‡
only in relapsed or refractory ENKL patients. The definition of limited stage in this flowchart is a little different from that in the
conventional Lugano/Ann Arbor classification. UAT: Upper aerodigestive tract; LN: lymph node; RT: radiotherapy; DeVIC:
dexamethasone, etoposide, ifosfamide, carboplatin; CR: complete response; PR: partial response; PD: progressive disease; SMILE:
steroid, methotrexate, ifosfamide, L-asparaginase, etoposide; L-asp: L-asparaginase; HSCT: hematopoietic stem cell transplantation.
results are good and comparable to those of RT-2/3DeVIC. VIDL shows less hematologic toxicity than
VIPD, but there are no trials comparing these regimens. RT-2/3DeVIC is the most commonly used regimen
in Japan. Recently, its durable response was reported with a five-year OS of 70% . Although there are
[7]
several sequential chemoradiotherapies, no significant difference in OS has been observed compared to that
[43]
with CCRT , and no studies comparing an efficacy of each regimen have been reported.
Advanced-stage ENKL
For advanced stage ENKL, SMILE [steroid (DEX), methotrexate (MTX), IFM, L-asp, and ETP]
chemotherapy is the most recommended regimen as a first-line therapy. Compared to that with peripheral
T-cell lymphoma, because of the MDR-associated P-glycoprotein described previously herein, CHOP is
much less effective for advanced-stage ENKL patients, with a five-year OS of only 8%-12% [5,24,44] . The durable
efficacy of L-asp monotherapy for CHOP-resistant ENKL patients was reported in several cases [45,46] , and L-
asp-containing combination chemotherapy has been developed [47-49] . The SMILE regimen, which is a non-
anthracycline-containing and non-MDR-associated agent-containing combination chemotherapy, is the