Efficacy
There is a paucity of evidence and randomised studies to guide the use of consolidative radiation therapy (RT) for advantaged stage EBRT following systemic therapy. Current recommendations are largely based on retrospective and cohort series, with limited randomised data published. In the modern era of accessible FDG PET/CT there is a trend towards PET adapted treatment recommendations and less weight given to bulky disease at diagnosis to identify patients who will most likely benefit from the addition of RT. Individual patient and disease characteristics are considered, namely whether a patient is suitable for salvage therapy with transplant or not. The reference committee supported publication of the protocol on the basis of the information summarised below, most strongly influenced by the Freeman et al 2021 retrospective analysis.r
Freeman et al. 2021 published a retrospective analysis of standard of care in British Columbia of 723 patients, reporting outcomes of a FDG PET/CT guided approach to selectively administer involved site RT following 6-8 cycles of R-CHOP chemotherapy, omitting radiation in PET-NEG (FDG PET/CT negative) patients.r Median follow-up was 3.4 years. This group had an excellent prognosis without RT. PET-NEG patients who did not receive RT had an 83% Time to progression (TTP) and overall survival of 87% at 3 years. PET-positive patients with non-progressing disease given radiotherapy at EOT had outcomes similar to PET-NEG EOT with 3 year estimates of 76% TTP and 80% OS. This better than expected outcome suggests a rationale for this PET guided approach. PET-NEG patients with Bulk (>10cm) at diagnosis had outcomes equivalent to those without bulk suggesting that EOT PET/CT can reliably guide selective administration of consolidative RT even in patients with initially bulky disease.
Phan et al. 2010 in a retrospective study compared consolidative IFRT (30-39.6 Gy) with R-CHOP chemotherapy in 469 patients with Stage 1-IV DLBCL (190 stage I-II, 279 stage III-IV).r Patients were staged with PET/CT. The study demonstrated overall that consolidation RT significantly improved OS and PFS after R-CHOP chemotherapy. In the patients with stage III-IV disease 5yr OS was 89% for RT and 66% without. PFS was 76% with RT vs 55% with R-CHOP only. On secondary matched pair analysis in advanced stage disease there was a suggestion of improved OS/PFS in those that had RT (HR=0.29/0.24). This was based on 59% of the cohort (N=279) who had advanced disease and only 39 of 279 patients (14%) of advanced stage patients had RT.
A non-randomised comparison of the OPTIMAL>60 trial in bulky disease patients which omitted RT (39.6 Gy) if PET negative post R-CHOP to the RICOVER-60 was non inferior (2 year PFS 79% vs 75%; 2 year OS 89% vs 78%).r These results are also currently only in abstract form.
The “UNFOLDER” trial randomised patients to R-CHOP-21 versus R-CHOP-14, as well as a randomisation to bulky and extralymphatic disease irradiation or observation alone.r Although the only relevant randomised study, UNFOLDER was not FDG PET/CT guided and remains unpublished, reported only as a planned interim analysis in abstract form. Nevertheless they reported significant differences (16% increase in event free survival (P=.0001) and 8% higher PFS (P=.221) in patients treated with RT, favouring the addition of involved site RT.
Held et al. 2014 conducted a trial to investigate the benefit of adding RT for elderly patients with bulky or extra lymphatic disease.r They compared patients receiving the best arm of the RICOVER-60 trial (6xR-CHOP-14+2R plus IFRT: 36 Gy to sites of initial bulky disease) with patients receiving the same immunochemotherapy without RT (RICOVER noRTh). The intention to treat analysis on patients with bulky disease showed fewer relapses in the group receiving RT. Trends towards worse outcomes in overall survival (OS) were seen at three years in RICOVER-noRTh (63% vs 78%).
Lowry et al. 2011 randomised 460 patients with aggressive NHL (predominantly DLBCL) to receive either 40-45 Gy in 20-23 fractions or 30 Gy in 15 fractions.r Overall response rate (ORR) was 91% in both arms of the trial, there was also no significant difference detected in the rate of within radiation-field progression, progression free survival (PFS) or OS. There was a trend towards less toxicity in lower dose arm however only the difference in reported erythema was significant.
The MINT Trial showed rituximab decreased, but did not eliminate, the adverse prognostic effect of maximum tumour diameter (MTD) in young patients with good-prognosis DLBCL.r The study provides indirect support for the use of consolidative RT for the bulky sites.