Optimizing treatment for nasal NK T-cell lymphoma

Nasal natural killer (NK) T-cell lymphoma (NKTCL) is an aggressive form of non-Hodgkin lymphoma characterized by extensive tumor involvement of the nasal cavity and contiguous structures, associated with necrosis and inflammation. It is much more common in Asia and Latin America than in the USA and Europe, and it exhibits unique clinical and biological features that present challenges for both hematologists and radiation oncologists. [1] Unlike aggressive B-cell lymphomas, NKTCL has been characterized by high rates of treatment failure after standard anthracycline-based chemotherapy; and unlike peripheral T-cell lymphomas, locoregional failure is a dominant pattern of failure. Importantly, in contrast to Hodgkin lymphoma, for which a ‘minimalist’ approach to the use of radiotherapy is predicated on the both the effectiveness of modern chemotherapy and concern for late radiation effects, localized NKTCL is the hematological malignancy ‘par excellence’ for which radiotherapy remains the primary therapy, with systemic therapy still considered adjuvant. For these reasons, and because NKTCL often presents with early-stage disease, there has been a strong focus in the literature on defining optimal radiotherapy fields and doses. It has become well established that for optimal local disease control, ‘conventional’ lymphoma radiation doses (30–36Gy) and fields (‘involved-site’ fields) are inadequate. The key radiotherapy literature is largely based on the Asian clinical experience and indicates that the outcome of NKTCL is highly dose dependent, with doses of 50–56Gy required for optimal local control. [2,3] It is also evident that generous radiotherapy fields are mandatory as NKTCL has a propensity to infiltrate extensively along tissue planes and within cavities adjacent to clinically evident disease sites. These uncertainties are reflected in recent guidelines on optimal radiotherapy fields for NKTCL. [4] For patients with locoregional disease, optimal radiotherapy has played a critical role in achieving 5-year overall survival that can range from 50% to 90%, and for selected patients with localized presentations, it appears that radiotherapy alone may be adequate therapy. [5–7] Regarding systemic therapy, as it became evident that CHOP chemotherapy was relatively ineffective for NKTCL, efforts were directed at exploring both novel chemotherapy regimens, incorporating drugs such as asparaginase (that were less affected by the p-glycoprotein-related multidrug resistance) and high dose therapy with stem cell support. [8,9] Several intensive asparaginase-based regimens have now been developed, with published outcomes suggesting higher rates of response than with CHOP, as well as potentially improved survival in both early-stage and advanced disease. Regimens currently used concurrently or sequentially with locoregional radiotherapy for localized disease include DeVIC (dexamethasone, etoposide, ifosfamide, caboplatin); VIDP (etoposide, ifosfamide, cisplatin, dexamethasone); GDP (gemcitabine, dexamethasone and cisplatin); and SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide). The SMILE regimen appears to play an important role in stage-III/stage-IV disease and in locally advanced disease in combination with radiotherapy. [10–13] While combined modality therapy incorporating asparaginase-based chemotherapy and radiotherapy has become standard of care, many important questions remain to be addressed in the management of early stage NKTCL. What is the optimal staging system and prognostic index; what is the significance of