Balancing the Therapeutic Ratio in DLBCL Requires Appropriate, Individualized Patient Selection Rather Than Broad Elimination of Radiation Therapy

The potential additional benefit of consolidation radiation therapy (RT) for diffuse large B-cell lymphoma (DLBCL) has been hotly debated for decades. The addition of consolidation RT unequivocally reduces the risk of local failure; however, the more challenging question has been whether this local control benefit ultimately translates into an overall survival advantage. Now firmly within the rituximab and positron emission tomography (PET) era, this question has become even more contentious and at times divisive. Recent studies have focused on strategizing management approaches to enable the selective omission of consolidation RT, citing the desire to avoid the risk of RT-induced toxicities as the primary driver for these strategies. However, this localized toxicity profile must be considered and counterbalanced against the risks of disease relapse, in particular the greater morbidity and higher economic costs associated with current and emerging salvage options for those patients with relapsed disease. Herein, we review a selection of the most impactful papers from the recent published literature of consolidation RT for DLBCL in the rituximab and PET eras (Table 1), discuss our perspective on the roles of consolidation RT in current clinical practice, and focus on the importance of patient selection to identify those in whom improved local control has the potential to achieve optimal patient outcomes. TABLE 1Summary of the three recently published and impactful studies of consolidation RT for DLBCL in the era of PET and rituximab Study Eligibility Study design Treatment groups Primary endpoint Other notable findings LYSA/GOELAMS trial 02-03(1) PET-staged stage I or limited Stage II, and non-bulky (<7cm) DLBCL, age 18-75 years Prospective, Phase 3, randomized, non-inferiority study (upper limit of 8%) All patients received 4 cycles of R-CHOP-14 followed by a PET scan.Randomized to: (a) RT: 40Gy/20# consolidation IFRT,(b) No RT.For patients who did not achieve CMR after cycle 4: 2 additional cycles of R-CHOP+RT were delivered (both study arms). 5-year EFS: R-CHOP alone was not inferior to R-CHOP + RT (89% vs 92%, HR 0.61 CI, 0.3-1.2; P = 0.18). 5-year OS: not statistically different for R-CHOP alone vs R-CHOP + RT (92% vs 96%, HR 0.62; 95% CI, 0.3-1.5; P = 0.28). No local failures after RT.Severe acute toxicities were less common from RT than R-CHOP. National Clinical Trials Network study S1001(13) PET-staged stage I or II non-bulky (<10cm) high grade B-cell lymphoma. Prospective, Phase 2, non-randomized study All patients received 3 cycles of R-CHOP followed by iPET:(a) iPET-negative: 1 additional cycle of R-CHOP,(b) iPET-positive: IFRT plus ibritumomab tiuxetan and rituximab. 5-year PFS: similar for iPET-negative and iPET-positive (89% vs 86%). 5-year OS: similar outcomes for iPET-negative and iPET positive (91% vs 85%).No local failures after RT.No severe RT toxicities reported. BC Cancer retrospective study(16) Non-PET staged, advanced DLBCL: stage III/IV or stages I/II with B symptoms and/or bulky disease (≥10cm). Retrospective analysis of a protocol-driven, population-based treatment strategy. All patients received ≥6 cycles of R-CHOP, and EOT PET:(a) PET-negative: no further treatment,(b) PET-positive: considered. for consolidation ISRT (received by 53%) 3-year TTP: favored the PET-negative group, 83% vs 56% for PET-positive (p<0.001). 3-year OS: favored the PET-negative group, 87% vs 64% for PET-positive (p<0.001).PET-positive patients who received RT had similar outcomes to PET-negative patients, but poorer outcomes were observed for PET-positive patients who did not receive RT (3-year OS, 80% vs 87% vs 44%, respectively).No toxicity data reported. Abbreviations: CI = confidence interval; CMR = complete metabolic response; DLBCL = diffuse large B-cell lymphoma; EFS = event-free survival; EOT PET = end of treatment PET; HR = hazard ratio; IFRT = involved field RT; iPET = interim PET; ISRT = involved site RT; LYSA/GOELAMS = Lymphoma Study Association/Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang; OS = overall survival; PET = positron emission tomography; PFS = progression-free survival; RT = radiation therapy; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; TTP = time to progression. Open table in a new tab Abbreviations: CI = confidence interval; CMR = complete metabolic response; DLBCL = diffuse large B-cell lymphoma; EFS = event-free survival; EOT PET = end of treatment PET; HR = hazard ratio; IFRT = involved field RT; iPET = interim PET; ISRT = involved site RT; LYSA/GOELAMS = Lymphoma Study Association/Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang; OS = overall survival; PET = positron emission tomography; PFS = progression-free survival; RT = radiation therapy; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; TTP = time to progression.