SYSTEMIC THERAPY AFTER RADIATION THERAPY IN STAGE I-II FOLLICULAR LYMPHOMA: FINAL RESULTS OF AN INTERNATIONAL RANDOMIZED TRIAL TROG 99.03

Aim: The first analysis of the TROG 99.03 randomized controlled trial of curative-intent involved-field radiotherapy (IFRT) with or without systemic therapy reported improved progression–free survival (PFS) by the addition of systemic therapy, especially with rituximab. We present the final analysis of that study. Patients and Methods: Patients from Australia, New Zealand and Canada with stage I-II FL of grade 1, 2 or 3a were enrolled after CT scans and bone marrow biopsies. Patients were randomized to either; Arm A: 30Gy IFRT alone or Arm B: IFRT followed by 6 cycles of cyclophosphamide 1000 mg/m2 IV D1, vincristine 1.4 mg/m2 D1 and prednisolone 50mg/m2 D1-5 (CVP), stratified by center, stage, age and use of PET staging (which was not mandatory). A protocol amendment in 2006 added Rituximab 375 mg/m2 D1 to arm B (R-CVP). Results: Between February 2000 and July 2012, 150 patients were recruited: 75 per arm: 44 arm B patients were allocated CVP and 31 R-CVP. Median age was 57 (range 30-79) years, 52% were male, 75% had stage 1 and 48% were PET-staged. Only 8% had an extranodal site (ENS). Median potential follow-up was 11.3 years for this analysis. PFS remained significantly superior for arm B (IFRT + systemic therapy) compared to arm A [HR 0.60 (0.37-0.98); p = 0.043]. At 10 years PFS was 60% for arm B and 43% for arm A. Patients who received R-CVP had substantially superior PFS compared to those who received IFRT alone or with CVP (no rituximab) (83.1% (se = 6.9%) vs 50.4%% (se = 4.8%) at 8 years, P = 0.013). In univariable analysis, patients with ENS (p = 0.041), fewer involved nodal regions (p = 0.018) and PET staging (p = 0.086) had improved PFS. When analysis of PFS was confined to 72 PET-staged patients the difference between arms A and B increased (HR 0.38 P = 0.027), whereas analysis confined to 78 non-PET staged patients showed weak evidence of a difference between arms (HR 0.78, P = 0.42). More deaths (Figure) occurred in arm A (13 versus 6), with 10-year overall survival rates of 95.3% (se = 2.7%) and 84.4% (se = 4.9%) for arms B and A respectively (HR 0.45, p = 0.11). One possible and 5 definite transformations to aggressive lymphoma occurred in arm B versus 11 in arm A. Keywords: follicular lymphoma (FL); positron emission tomography (PET); rituximab.