Efficacy
Evidence supporting a survival benefit from radical radiation therapy (RT) for early-stage indolent NHL comes from National Cancer Data Base.r Vargo et al. reported on 35961 patients with early-stage follicular lymphoma diagnosed between 1998 and 2012. Patients treated with RT had 5-year and 10-year OS rates of 86% and 68%, compared with 74% and 54% for patients treated without RT (p<0.0001). On multivariate analyses, including with propensity score adjustment, upfront RT was independently associated with improved OS (HR death 0.54, p<0.0001).
Further data supporting this protocol comes from a phase III multicentre randomised control trial of reduced dose RT in both indolent and aggressive non-Hodgkin lymphoma.r The study included patients receiving RT for local disease control with radical, consolidative or palliative treatment intent. Between April 1997 and January 2005, 1001 sites (361 indolent NHL and 640 aggressive NHL) were randomised to either conventional dose radiation therapy of 40-45 Gy/20-23 # (n=502) or low dose RT 24 Gy/12 # (indolent NHL) or 30 Gy/15 # (aggressive NHL) (n=499). In the indolent group, 149 patients were receiving radiation therapy with a radical intent (119 low dose arm and 130 conventional arm). After a median follow up of 5.6 years there was no significant difference in local progression; indolent group HR 1.09 (95%CI: 0.76-1.56; p=0.64) and aggressive group HR 0.98 (95%CI: 0.68-1.4; p=0.89). There was no significant difference in progression free and overall survival (OS). The overall response rate (ORR) was 93% in the standard indolent arm, 92% in the lower dose indolent arm (p=0.72). In the indolent group there was no significant difference in 5 year OS between the two arms, 73% versus 74% in the high and low dose arms respectively (95%CI: -9% to 8%).
Figure 1: Freedom from local progression, progression-free survival and overall survival for indolent group, by treatment arm.
Freedom from local progression - patients with no progression/relapse within field were censored at the date of last follow-up or date of death. Progression-free survival (PFS) – duration from date of randomisation to date of any progression/relapse or date of death, whatever occurs first. Overall survival (PFS) – date of randomisation to date of death from any cause. PFS and OS calculated on an intention-to-treat basis, using the first randomisation for patients with more than one site randomised.
© Radiother Oncol 2011r
Further supporting evidence comes from the Brady et.al paper, a retrospective multicentre review under the direction of the International Lymphoma Radiation Oncology Group (ILROG).r Patients treated with definitive RT (dose of at least 24 Gy) for FDG PET-CT staged 1 or 2 follicular lymphoma had improved outcomes at 5 years compared to historical controls. 5-year freedom from progression (FFP) and OS were 68.9% and 95.7% respectively.
Figure 2: Outcomes from definitive RT
© Blood 2019r
Evidence for addition of chemotherapy
Evidence for addition of sequential chemotherapy comes from the TROG 99.03 trial, a randomised, international, multicentre phase 3 trial.r A total of 150 patients with stage I-II low grade FL were randomized to either arm A (30 Gy of involved field RT alone) or arm B (30 Gy of involved field RT plus sequential systemic therapy: six cycles of cyclophosphamide, vincristine, and prednisolone [R-CVP]). At 10 years there was superior progression free survival (PFS) with the addition of R-CVP (hazard ratio, 0.57; 95% CI, 0.34 to 0.95; P = 0.33), ten-year PFS was 41% with RT alone and 59% with RT plus R-CVP. There was no significant improvement in OS at 10 years.
Figure 3: Progression free survival
© J Clin Oncol 2018r
Evidence for extremely low dose
Evidence for extremely low dose comes from the FORT trial, a prospective, randomised, unblinded phase III non-inferiority trial.r The trial compared 4 Gy in 2 fractions to 24 Gy in 12 fractions in patients with follicular or marginal zone lymphoma receiving RT with a palliative intent or curative intent (for those with early stage disease). The primary outcome was time to local progression. Secondary outcomes were OS, response, toxic effects and quality of life. After a median follow up of 26 months there were 21 local progressions in the 24 Gy group and 70 in the 4 Gy group. Local progression-free survival in the 4 Gy group was inferior to a higher dose of 24 Gy in 12 fractions with a time to local progression HR(95%CI: 2.09-5.55; p<0.0001). OS was 226 patients in the 24 Gy group and 282 in the 4 Gy group (HR -.84; 95%CI: 0.52-1.36; p=0.47). At a median follow-up of 73.8 months, there were 27 local progressions in the 24 Gy group and 90 in the 4 Gy group. The 5 year local progression-free rate 89.9% (85.5-93.1) after 24 Gy and 70.4% (64.7-75.4) after 4 Gy (HR 3·46, 95% CI 2.25-5.33; p<0.0001).r
Figure 4: Progression free survival for all sites (A) and OS for one site per patient (B)
© Lancet Oncol 2014r