Aim: Involved field radiation therapy (IFRT) alone is potentially curative in stage I-II low-grade follicular lymphoma (FL) but relapse occurs in >50% of cases, predominantly outside RT fields. We hypothesized that systemic therapy given after IFRT would improve disease control, as assessed by progression-free survival (PFS).
Patients and Methods: This randomized controlled trial enrolled patients (pts) from Australia, New Zealand and Canada. Eligible patients had stage I-II low-grade FL (grade 1,2 or 3a). Staging included CT scans and marrow biopsy. FDG-PET staging was permitted but not mandated. Pts were randomized to either; A: IFRT alone or 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). A 2006 protocol amendment added Rituximab 375 mg/m2 D1 to arm B (R-CVP). Randomization was stratified by center, stage, age (<60/≥60) and whether PET-staged.
Results: From Feb 2000 to July 2012, 150 patients were recruited: 75 per arm. In Arm B, 44 patients were allocated CVP and 31 R-CVP. At randomization 75% had stage I, median age was 57 years, 52% were male, 48% were PET staged and 8% had an extranodal site (ENS). Median potential follow-up time was 9.6 years (range, 3.1-15.8). Major protocol deviations occurred in 2%. PFS was significantly superior in the (R-)CVP arm, Arm B, HR 0.57 (95% CI 0.34-0.95) p=0.033. Those Arm B patients randomized to R-CVP had markedly superior PFS compared with those randomized to IFRT alone after the trial amendment, HR0.26 (95% CI 0.07-0.97) p=0.045. Other factors associated with superior PFS were ENS (p=0.02), fewer involved nodal regions (p=0.047) and PET staging (p=0.056). Fewer patients had transformation to high-grade lymphoma in Arm B(4 vs 10). Ten deaths were observed in Arm A vs 5 in Arm B but overall survival (OS) is not currently significantly different (p=0.4); 10 yr rates 95 vs 87%.
Conclusion: Systemic therapy with CVP or R-CVP after IFRT significantly improved PFS compared to IFRT alone, potentially defining a new standard of care.