A Phase II Study of Ifosfamide, Methotrexate, Etoposide, and Prednisolone for Previously Untreated Stage I/II Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Multicenter Trial of the Korean Cancer Study Group

Abstract

Background.

Combination chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) was active as first-line and second-line treatment for extranodal natural killer/T-cell lymphoma (NTCL).

Methods.

Forty-four patients with chemo-naïve stage I/II NTCL were enrolled in a prospective, multicenter, phase II study and received six cycles of IMEP (ifosfamide 1.5 g/m² on days 1–3; methotrextate 30 mg/m² on days 3 and 10; etoposide 100 mg/m² on days 1–3; and prednisolone 60 mg/m² per day on days 1–5) followed by involved field radiotherapy (IFRT).

Results.

Overall response rates were 73% (complete remission [CR] in 11 of 41 evaluable patients [27%]) after IMEP chemotherapy and 78% (CR 18 of 27 evaluable patients [67%]) after IMEP followed by IFRT. Neutropenia and thrombocytopenia were documented in 33 patients (75%) and 7 patients (16%), respectively. Only 8 patients (18%) experienced febrile neutropenia. Three-year progression-free survival (PFS) and overall survival (OS) were 66% and 56%, respectively. High Ki-67 (≥70%) and Ann Arbor stage II independently reduced PFS (p = .004) and OS (p = .001), respectively.

Conclusion.

Due to the high rate of progression during IMEP chemotherapy, IFRT needs to be introduced earlier. Moreover, active chemotherapy including an l-asparaginase-based regimen should be use to reduce systemic treatment failure in stage I/II NTCL.

Discussion

Our trial was based on the scheme of chemotherapy followed by radiotherapy (sequential). However, other trials used concurrent chemoradiation followed by ifosfamide plus etoposide-based combination chemotherapy [4, 5]. Although the designs of two concurrent chemoradiation trials [4, 5] were very similar, large differences were observed regarding survival data. We chose the JCOG0211 study [4] for comparison with our data because the other study provided limited information on patterns of failure due to short-term follow-up [5]. Our study showed a relatively higher locoregional failure rate (18% vs. 4%) but lower rates of systemic failure than in the JCOG0211 study (14% vs. 33%). These data suggest that upfront chemoradiation is favorable for locoregional control, but it is unfavorable for systemic failure in stage I/II natural killer/T-cell lymphoma (NTCL). Extended chemotherapy of up to six cycles in our study might be a factor for the high incidence of locoregional failure. Better coordination of the sequence between chemotherapy and radiotherapy might reduce both locoregional and systemic failures. A reduced number of cycles of chemotherapy, for example, followed by involved field radiotherapy (IFRT), concurrent chemoradiation, or sandwich radiotherapy during chemotherapy may be more efficacious for untreated stage I/II NTCL. Considering that the planned doses were reduced for 11 patients (25%) in 35 of 229 cycles (15%) in our study, the ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) regimen was safe and relatively well tolerated.

Recently, regimens based on l-asparaginase (l-asp) have shown promising efficacy in patients with refractory/relapsed or newly diagnosed advanced NTCL (overall response rate of 78%–81% and complete response [CR] of 45%–66%) [6–8] and with untreated stage I/II NTCL (CR of 90%, 2-year overall survival [OS] of 88%, and 2-year progress-free survival [PFS] of 90%) [10]. Furthermore, gemcitabine, which is active against NTCL [11], plus oxaliplatin and l-asp followed by IFRT resulted in a CR rate of 74% and 2-year PFS of 86% in stage I/II upper aerodigestive tract NTCL [12]. Furthermore, sandwich l-asp, vincristine, and prednisolone chemotherapy with IFRT showed a promising outcome (2-year OS of 88.5% and 2-year PFS of 80.6%) [13]. Consequently, more active l-asp-based regimens should be introduced in patients with stage I/II NTCL.

The IMEP regimen is effective and safe in patients with stage I/II NTCL before the introduction of l-asp, and IMEP followed by IFRT resulted in improved treatment outcomes in localized NTCL (Table 1). However, a short-course of the l-asp-based regimen followed by IFRT or concurrent or sandwich radiation with an l-asp-based regimen should be introduced in patients with untreated stage I/II NTCL.

Table 1.

Treatment outcomes after completion of each treatment

Author disclosures and references available online.