A Prospective, Randomized, Open-label, Multi-center Study of Efficacy of Palliative Low-Dose Involved-Field Radiation Therapy for Recurrent Advanced Follicular Lymphoma: Wuhan University Cancer Center -NHL02 Trial

Introduction: Follicular lymphoma（FL) often involves lymph nodes and the bone marrow and is widely regarded as a systemic and advanced-stage disease when it is diagnosed in more than two-thirds of patients at initial presentation. Follicular lymphoma Grade 1 or 2 with indolent histologic characteristics is presently not considered curable in the majority of patients though it is very sensitive to both chemotherapy and radiotherapy. The policy treated for patients with stage III and IV FL, which recommended by NCCN, is suggested regimens, clinical trial or local RT (palliation) based on the previous results that similar efficacy was obtained after management by chlorambucil single-agent therapy, polychemotherapy, immunochemotherapy, RT or CMT(RT and Chemotherapy). Patients with advanced-stage disease tend to have frequent relapses and the interval between subsequent relapses tends to shorten over time. However, they usually have a relatively long life expectancy, with a median survival ranging from 6 to 10 years. Try to change the natural history of FL and have a long term PFS are the goals of treatment for advanced stage FL.

Since the treatment strategy, watch and wait, was managed in Standford in the 1980s, several prospective randomized trials have failed to demonstrate a survival advantage with immediate treatment versus a "watch and wait" approach in patients with advanced stage, low tumor burden FL. Though many systemic therapy options are available for patients with stage III and IV FL, there is no consensus as to which first-line treatment should be provided to those patients. "Watch and wait" as a approach is still recommended to the patients even in the rituximab era. GELA provided the indications for treatment, when the treatment a patient should be initiated.

The role of traditional RT with or without chemotherapy in advanced stage FL is not definite. FL is considered to be one of the most radiosensitive tumors. However, a significant proportion of patients relapse with systemic disease outside of radiation fields and no difference in OS were observed in advanced patients between RT alone and CMT. The complications related to traditional RT, including cardiovascular disease and disorders of blood cell production, were needed to emphasize for those indolent advanced patients who need frequent palliative management and can long-term survive with NHL. In order to decrease the late complications after Large-field RT, reduction of irradiation field and smaller therapeutic doses of radiation were commonly managed.

Many trials that patients with advanced or recurrent FL managed with very low-dose (4Gy) limited-field RT have shown that high response rates and durable remission can be achieved. The response rates (either a complete or partial response) reported in previous study that low-dose involved-field RT (LD-IFRT) is given in 2 daily fractions (2×2 Gy) is 81% to 92%. The median time to first recurrence was 14 to 15 months. The median overall survival for patients with a positive response was 41 months. The median time to in-field progression was 21months, and the median time to out-field progression was 8 months. The predominant mode of tumor cell death after low-dose RT may be by apoptosis.

Two phase III trials have been designed to assess the further role of LD-IFRT. However, the results have failed to demonstrate the lasting response rate (RR) with LD-IFRT versus in other approaches. The HOVON 47/EORTC 20013 Intergroup study (www.hovon.nl) which compares LD-IFRT to chlorambucil chemotherapy in previously untreated FL patients, the main end points including progression-free survival and quality of life are evaluating. However, the trial was closed in 2005 after 21 cases included because of the clinical adoption of rituximab. The age of most eligible patients was older than 65 years. Another trial, Follicular Radiotherapy Trial (CRUK- FORT), launched recently in the United Kingdom is randomizing patients with FL needing RT to 24 Gy in 12 fractions versus 4 Gy in 2 fractions as either definitive or palliative treatment for FL. A significantly lower overall response rate (81% vs 74%) and 2-year local progression-free rate (94% vs 80%) were found in the 4Gy group. Over half of the patients in the clinic trial were on stage I and stage II. Moreover, the histologies included many other pathologic subtypes of indolent lymphoma besides follicular Grade 1 or 2.