Reduction of Radiotherapy Intensity after Achieving Complete Remission with Induction Chemotherapy in Newly Diagnosed Stage I/II Extranodal NK/T-Cell Lymphoma: A Prospective Study

Background: Prior to the era of asparaginase treatment, achieving optimal therapeutic outcomes in early-stage extranodal NK/T-cell lymphoma (ENKTL) required a radiation dose of 50 Gy or higher, as doses below 50 Gy were associated with poorer prognosis. With the widespread use of asparaginase in ENKTL, higher complete remission (CR) rates have been achieved with induction chemotherapy. Additionally, higher radiation doses may be accompanied by increased adverse reactions (AEs). Therefore, it is worth exploring whether the radiation dose intensity can be safely reduced in patients with early-stage ENKTL who achieve CR after induction chemotherapy.

Methods: This prospective study included newly diagnosed ENKTL patients with Lugano stage I-II who achieved CR after induction therapy with L-asparaginase or pegaspargase-containing multidrug chemotherapy regimens. The efficacy was evaluated by PET/CT or PET/MRI. Patients were randomly divided into reduced-dose radiotherapy group or conventional-dose radiotherapy group. After completing radiotherapy, patients continued to receive consolidation chemotherapy with the original regimen. The study compared the impact of reduced radiation doses with traditional radiation doses on local control rates, survival, and radiotherapy side effects.

Results: From March 2020 to December 2023, 37 patients who achieved CR after 2-3 cycles of L-asparaginase or pegaspargase-containing induction chemotherapy were enrolled. Of these, 14 (37.8%) received VDLP (L-asparaginase, etoposide, cisplatin, and dexamethasone) and 23 (62.2%) received P-Gemox (pegaspargase, gemcitabine, and oxaliplatin). Among them, 19 patients were in the reduced-dose radiotherapy group, and 18 patients were in the conventional-dose radiotherapy group. All cases originated in the upper aerodigestive tract, with a median age of 46 years (range 20-67), and 24 (64.9%) being male. 28 (75.7%) patients were Lugano stage I, and 9 (24.3%) patients were Lugano stage II. 32 (86.5%) had a PINK-E score of 0-1, and 5 (13.5%) had a score of 2. Radiotherapy was administered using volumetric modulated arc therapy with image guidance (VMAT-IGRT). The reduced-dose group received 45 Gy total, with 1.8 Gy per fraction. The conventional-dose group had a median dose of 56 Gy (range 50-56), medium dose per fraction was 2 Gy (range 1.8-2). Radiotherapy completion was 100%. After radiotherapy, patients continued to receive 1-3 cycles of consolidation chemotherapy, with a total median number of chemotherapy cycles of 3 (range 3-6). After the completion of all treatments, efficacy was re-evaluated using PET/CT or PET/MRI, and all patients maintained continuous CR. The median follow-up to date was 27 months (range 7-52). During follow-up, two patients in the conventional-dose group relapsed and died, while only one patient in the reduced-dose group relapsed and no deaths was reported. All of the relapses occurred outside of the radiation field. Neither group achieved median progression-free survival (PFS) nor median overall survival (OS). According to Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) grading criteria, the most common acute AEs were nasal and oral mucositis, dermatitis, and salivary gland dysfunction, characterized by dry mouth and/or altered taste. The incidence was 68.4% vs 83.3% (p=0.291), 57.9% vs 83.3% (p=0.091), and 73.7% vs 66.7% (p=0.641) in the reduced-dose and the conventional-dose groups, respectively. The most common late radiotherapy AE was dry mouth, with incidence rates of 26.3% vs 27.8% (p=0.920) in the reduced-dose and standard-dose groups, respectively, both of which were grade 1.

Conclusions: For newly diagnosed I/II ENKTL patients who achieve CR with asparaginase-containing induction chemotherapy regimens, appropriately reducing the radiation dose did not decrease the local control rate and had no significant impact on PFS or OS. It also reduces the incidence of radiotherapy AEs to a certain extent, which is worthy of further exploration.