Phase I/II Study of Concurrent Chemoradiotherapy for Newly-Diagnosed, Localized Nasal NK/T-Cell Lymphoma: Results of a Phase I Portion of JCOG0211-DI.

Abstract

Nasal NK/T-cell lymphoma is a rare lymphoid neoplasm, and its standard therapy has not been established. It is one of the Epstein-Barr virus (EBV) - associated lymphoid malignancies, and lymphoma cells express P-glycoprotein concerning multi-drug resistance (MDR) of the disease. Anthracycline-containing chemotherapy followed by radiotherapy (RT) has been established as the standard care for localized aggressive NHL; however this strategy is not effective for localized nasal NK/T-cell lymphoma. The 5-year overall survival rates of RT alone are only 30–40%. To explore a more effective treatment for newly-diagnosed localized nasal NK/T-cell lymphoma, we conducted a multicenter phase I/II study of concurrent chemoradiotherapy consisted of 50 Gy of RT and 3 courses of DeVIC chemotherapy [carboplatin (CBDCA) 300mg/m2 d1 IV, etoposide (ETP) 100mg/m2 d1-3 IV, ifosfamide (IFM) 1.5g/m2 d1-3 IV, dexamethasone (DMS) 40mg/body d1-3 IV; every 21 days]. DeVIC comprised of MDR-non-related agents and ETP that shows both in vitro and in vivo efficacy for NK-cell neoplasms, and is well-known to be effective for EBV-associated hemophagocytic syndrome. Pts with newlydiagnosed, localized (IE and contiguous IIE with cervical node involvement) diseases, 20–69 years of age and PS 0–2 were eligible. The protocol requests the CT based 2 or 3 dimensional RT planning that the volume with appropriate margin (2 cm) to gross tumor, entire nasal cavities and nasopharynx should be irradiated. In the phase I portion, a standard 3+3 design was used to evaluate dose-limiting toxicities (DLTs). The doses of RT and DMS were fixed. Two dose levels of CBDCA/ETP/IFM were evaluated: Level 1 (2/3-dose DeVIC) CBDCA 200mg/m2, ETP 67mg/m2, IFM 1.0g/m2 and Level 2 (100%-dose DeVIC). Enrolled 10 pts showed the following features: age 30–61 yrs (median 44.5), M:F=5:5, stage IE 6, stage IIE 4, B symptom(+) 4, elevated serum LDH 2, PS0 6, PS1 4. No treatment-related death occurred, and no grade 4 non-hematologic toxicities other than transient hypokalemia were observed. Grade 4 neutropenia and grade 3 mucositis due to RT were common. At Level 2, grade 4 leukopenia/anemia/thrombocytopenia and grade 3 infection were more frequent than Level 1. In summary, at Level 1, 1 pt developed PD before evaluation of DLT. Remaining 3 pts did not develop DLT. At Level 2, 4 out of 6 pts developed DLT. Thus, we decided to select the Level 1 for the subsequent phase II portion. Of all 10 enrolled pts, 7 achieved CR, 2 PD, and 1 not evaluable. Of note, all 10 pts achieved local control. Our results suggest that concurrent chemoradiotherapy using MDR-non-related agents and ETP is a promising treatment strategy for localized nasal NK/T-cell lymphoma. Feasibility and efficacy of Level 1 will be evaluated further in the phase II portion.