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\begin{document}

\title{NK/T}


\author[ ]{Accord Tsai}

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\section{Abstract}
Radiotherapy with or without chemotherapy is the standard approach to early stage extranodal NK/T-cell lymphoma, while chemotherapy remains the mainstay of treatment for advanced stage disease. In this study, we retrospectively review all patients with NK/T-cell lymphoma treated from 2000-2014 at our institution. A total of 21 patients were included, of which 12 (57) were early stage (I-II), and the other 9 (43) was advanced stage (III-IV). Median overall survival for all patients was 2 years; 2-year and 5-year overall survival was 47% and 31%, respectively. Disease-free survival was ?????. In univariate analysis, stage, IPI, and KPI, B symptoms, extensive disease were associated with poor overall survival. ??? remained an independent prognostic factor for overall survival on multivariate analysis. 

\section{Introduction}
Natural killer (NK)/T-cell lymphomas are rare but aggressive malignancies compared to other common histologic subtypes[@tse_how_2013]. Although they occur worldwide, it is known that the prevelance in Asia and South America is much higher than that of other continents. The overlap with Epstein-Barr Virus (EBV) endemic area, and the ubiquitous prescence of EBV-encoded RNA (EBER) demonstrated by in situ hybridization (ISH) highly suggests a central role of EBV in the pathogenesis of this disease. Researchers have suggested that "nasal" or "nasal-type", or upper aerodigestive tract NK/T cell lymphoma (UKNTL), should be classified apart from extra-upper aerodigestive tract NK/T cell lymphoma (EUNKTL), as the latter warrants aggressive treatment due to its poor prognosis[@lee_extranodal_2005]. Radiotherapy with or without chemotherapy is the standard approach to early stage disease[@tse_how_2013], while chemotherapy remains the mainstay of treatment for advanced stage disease. 

Traditionally, lymphomas were staged according to the Ann Arbor system, and risk stratification with the International Prognostic Index[@_predictive_1993] proposed in 1993. However, individual prognostic indexes have been proposed for each specific histological type, including F-LIPI \cite{12525518}etc. This approach was pioneered by Korean researchers Lee et al., and later termed the Korean Prognostic Index (KPI)[@lee_extranodal_2006]. This was an improvement over the IPI with more balanced distribution between groups. 

Other additional factors potentially contributing to outcome includes local invasion[@hanakawa_novel_2014][@bi_extent_2015], pretreatment platelet lymphocyte ratio (PLR)[@wang_prognostic_2014], and EBV viral load[@hsieh_ebv_2007][@suzuki_prospective_2011]. Especially, the role of EBV virus in the pathogenesis of NK/T cell is strongly implicated, as virtually all extranodal NK/T-cell lymphoma were positive for EBV in situ hybridization[@jhuang_extranodal_2015]. Previous research indicated that EBV related expression in bone marrow is associated with a poor prognosis[@huang_bone_2005]. The importance of plasma EBV viral load as a prognostic factor was reported independently in Taiwan[@hsieh_ebv_2007] and Japan[@suzuki_prospective_2011]. Complete remission following treatment is an important prognosticator for long-term survival[@chauchet_complete_2012], but plasma EBV DNA was able to contribute to improved risk stratification when combined with PET-CT in a retrospective study[@kim_risk_2015]. 

Previous studies have shown treatment with radiotherapy has a high systemic failure rate, while treatment with chemotherapy alone results in high local failure rate; Combination therapy is suggested to improved local and systemic cure rate[@kwong_management_2009]. Experimental approaches, such as early radiotherapy[@zang_early_2015] or concurrent chemoradiotherapy[@yamaguchi_phase_2009] had been investigated in clinical trials. Concurrent chemoradiotherapy (CCRT) was investested in a phase II trial, and showed that upfront CCRT plus consolidation chemotherapy is feasible and effective for treating localized nasal NK/T cell lymphoma[@tsai_long-term_2015].

In this study, we aim to review our institutional experience on treatment of this rare disease. 


\section{Material and Methods}

We retrospectively included all patients with pathologically confirmed NK/T cell lymphoma, who were treated at our hospital from January 2000 to December 2014. A total of 27 patients were identified from the institutional database. Six patients were excluded from this study because they did not receive further treatment. Patient baseline and follow-up data were extracted through chart review. This study is approved by the institutional review board of National Cheng Kung University Hospital.

\subsection{Treatment}
In accordance with institutional and international guidelines, early stage patients received radiotherapy-based treatment, while advanced stage patients received chemotherapy as first line treatment. Radiotherapy was given with or without concurrent chemotherapy at the discretion of the treating physician. Radiotherapy was given in 1.8-2.0 Gy fractions for five consecutive days each week. Treatment plans were designed with Eclipse (Varian, Palo Alto) were delivered with Clinac iX linear accelerator (Varian, Palo Alto).

\subsection{Endpoints}

The investigated endpoints in this study were loco-regional control (LRC), progression-free survival (PFS), and overall survival (OS). Loco-regional recurrence was defined as recurrence of persistence of tumor at the original site or nodal drainage sites. Any recurrence, either loco-regional or distant, was considered an event in calculation of progression-free survival. Overall survival was defined as death from any cause. All durations were calculated from the date of diagnosis to the date of event. For early stage patients, objective response rate was determined by post-treatment imaging using the RECIST criteria.

\subsection{Statistical Analysis}
Survival curves were estimated with the Kaplan--Meier method. Patients without events were censored at the last follow-up date. We employed the Cox proportional hazards model in comparing survival curves. All statistical tests were performed using SPSS (version 17.0, IBM, New York). We defined a two-tailed significance level of 0.05 as significant. 

\section{Results}
A total of 21 patients were included in this study. The median follow-up time for patients who were still alive was 9.4 years. The baseline characteristics is shown in Table 1. Sixteen patients (76%) were male, and five (24%) were female. When staged with the Ann Arbor staging system, 12 patients (57%) had early stage (stage I-II) disease, while 9 patients (43%) presented with advanced (stage IV) disease. At the time of diagnosis, 6 patients (29%) had B symptoms, and 9 patients (43%) had LDH elevation. 

Median overall survival for the entire cohort was ?? years. Overall survival was significantly longer for early stage (median, 3.8 years) than advanced stage (median, 2.5 months)(P=0.0008). Patients presenting with advanced stage disease generally received chemotherapy, but prognosis was dismal regardless of the therapeutic agents used. 


= Treatment outcome of advanced stage patients =
6 COP (+H, +E), 2 SMILE, 1 hyperCVAD followed by PBSCT. Only the patient with hyperCVAD survived over 1 year.


= Early stage =
Twelve patients were diagnosed as early stage (Ann Arbor stage I-II) in this study, and all received radiotherapy (RT)-based treatment. 3 received RT alone, while the other 9 received concurrent chemoradiotherapy (CCRT). Early stage patients demonstrated a high response to radiotherapy-based treatment: 11 (92%) patients had a clinical complete response, while 1 (8%) had a partial response. The 2-year and 5-year overall survival in early stage patients are 74% and 46%, respectively. We investigated the known prognostic factors on the impact of overall survival (Table 2), and found the NK/T-cell lymphoma prognostic index (NKPI) predicted overall survival (Group 1 vs. Group 2-3, HR=33.31 95% CI 1.68-662, P=0.022); all other factors did not have significant associations with overall survival.

However, local and distal failures were also common in these patients, with a median progression-free survival (PFS) of 2.0 years. Two-year and 5-year PFS of early stage patients were 52% and 25%, respectively. Sites of failure were local recurrence in 2, distant metastasis in 3, and concomitant local and distant failure in 2 patients. None of the prognostic factors investigated correlated with PFS.

Local invasiveness ???. 

Ten early-stage patients had baseline EBV DNA data available; five (50%) were found with elevated plasma EBV DNA at diagnosis. Four patients eventually had disease relapse, of which 2 (50%) had elevated plasma EBV DNA elevation preceding clinical recurrence.

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