CVP OR R‐CVP GIVEN AFTER INVOLVED‐FIELD RADIOTHERAPY IMPROVES PROGRESSION FREE SURVIVAL IN STAGE I‐II FOLLICULAR LYMPHOMA: RESULTS OF AN INTERNATIONAL RANDOMIZED TRIAL

Abstract

Aim: Curative-intent involved field radiation therapy (IFRT) is a standard treatment for stage I-II follicular lymphoma (FL). It achieves durable local disease control and can produce life-long remissions. However >=50% of patients relapse, generally outside irradiated volumes. We conducted a randomized controlled trial (RCT) to determine if systemic therapy could improve progression free survival (PFS). Patients and Methods: Patients from Australia, New Zealand and Canada with stage I-II FL of grade 1, 2 or 3a were enrolled after mandatory CT scans and marrow biopsies. PET staging was permitted. 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 50 mg/m2 D1-5 (CVP), stratified by center, stage, age and PET. A protocol amendment in 2006 added Rituximab 375 mg/m2 D1 to arm B (R-CVP). Result(s): 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 9.6 years (range, 3.1-15.8). PFS was significantly superior for arm B (IFRT + systemic therapy) compared to arm A HR 0.57 (0.34-0.95); p = 0.033]. At 10 years PFS was 58% (95% CI 46-74%) for arm B and 41% (95% CI 30-57%) for arm A. Patients randomized to R-CVP had a substantially superior PFS to those contemporaneously randomized to IFRT alone, HR 0.26 (0.07-0.97); p = 0.045]. In univariate analysis, patients who had ENS (p = 0.02), fewer involved regions (p = 0.047) and PET staging (p = 0.056) also had improved PFS. Transformation to high-grade lymphoma occurred in 4 patients in arm B compared to 10 in arm A (p = 0.1). Overall survival (OS) is not currently significantly different between arms (HR 0.62, p = 0.4); 10 year rates 95 vs 87% for arms B and A respectively. Only 2 patients had isolated infield relapses, therefore systemic therapy primarily prevented progression outside RT fields. Only 3 cases with grade 3-4 acute and 1 case with grade 3 late radiation toxicities were observed. Systemic therapy was associated with 29 cases of grade 3 toxicity and one of grade 4 (neuropathy). One treatment-associated death occurred per arm. Conclusion(s): Treatment with 6 cycles of CVP or R-CVP after IFRT significantly improved PFS compared to IFRT alone. Further follow up is required to detect any potential effect of systemic therapy on OS.