ABSTRACT
PURPOSE: To assess whether a radiation therapy (RT) dose affects response in bulky tumors in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). METHODS AND MATERIALS: Data from patients with r/r DLBCL treated with salvage- or palliative-intent RT (2008-2020) at a single institution were examined. Index lesion size ≥7.5 cm was defined as bulky. Equivalent doses in 2-Gy fractions (EQD2) were calculated to compare doses between conventional and hypofractionated (≥2.5 Gy/fraction) schemes. Objective response rates (ORRs) were compared using nonparametric Mann-Whitney U test or Kruskal-Wallis test with Dunn's multiple comparison corrections. Freedom from local progression (FFLP) was assessed using Kaplan-Meier and Cox proportional hazard regression analyses. RESULTS: One hundred eighty-three courses of 151 unique patients were included (salvage: 37% and palliative: 63%). Nonbulky and bulky tumors were irradiated in 109 (60%) and 74 (40%) courses, respectively. Median EQD2 was 33 Gy (IQR, 23-39 Gy) with hypofractionation in 84 (46%) cases. Of those with post-RT imaging (80%), the ORR was 59%, with a trend toward worsened ORR in bulky tumors (50% vs 65%, P = .077). For bulky tumors, RT regimens with EQD2s >30 Gy were associated with better ORR (≤30 Gy vs >30 Gy: 27% vs 64%, P = .0073), whereas a lower EQD2 cutoff was sufficient for nonbulky tumors (≤20 Gy vs >20 Gy: 38% vs 75%, P = .0011). On multivariable regression analysis, bulky tumor size was associated with worsened FFLP (hazard ratio, 2.07; 95% CI, 1.16-3.68; P = .014), whereas high EQD2s >30 Gy were associated with better FFLP (hazard ratio, 0.48; 95% CI, 0.25-0.93; P = .031). Bulky tumors treated with EQD2s ≤30 Gy had the lowest median FFLP (4.0 months), whereas EQD2s >30 Gy had an unreached median FFLP (P = .0047). CONCLUSIONS: Bulky r/r DLBCL tumors were associated with less favorable tumor control outcomes in the salvage and palliative settings. RT regimens with higher EQD2s (>30 Gy) should be considered if durable local control of bulky tumors is desired.
ABSTRACT
Background and purpose: The normal tissue sparing afforded by FLASH radiotherapy (RT) is being intensely investigated for potential clinical translation. Here, we studied the effects of FLASH proton RT (F-PRT) in the reirradiation setting, with or without hypofractionation. Chronic toxicities in three murine models of normal tissue toxicity including the intestine, skin, and bone were investigated. Materials and methods: In studies of the intestine, single-dose irradiation was performed with 12 Gy of Standard proton RT (S-PRT), followed by a second dose of 12 Gy of F-PRT or S-PRT. Additionally, a hypofractionation scheme was applied in the reirradiation setting (3 x 6.4 Gy of F-PRT or S-PRT, given every 48 hrs). In studies of skin/bone of the murine leg, 15 Gy of S-PRT was followed by hypofractionated reirradiation with F-PRT or S-PRT (3 x 11 Gy). Results: Compared to reirradiation with S-PRT, F-PRT reduced intestinal fibrosis and collagen deposition in the reirradiation setting and significantly increased survival rate, demonstrating its protective effects on intestinal tissues. In previously irradiated leg tissues, reirradiation with hypofractionated F-PRT created transient dermatitis that fully resolved in contrast to reirradiation with hypofractionated S-PRT. Lymphedema was also alleviated after a second course of radiation with F-PRT, along with significant reductions in the accumulation of fibrous connective tissue in the skin compared to mice reirradiated with S-PRT. The delivery of a second course of fractionated S-PRT induced tibial fractures in 83.3% of the mice, whereas only 20% of mice reirradiated with F-PRT presented with fractures. Conclusion: These studies provide the first evidence of the sparing effects of F-PRT, in the setting of hypofractionated reirradiation. The results support FLASH as highly relevant to the reirradiation regimen where it exhibits significant potential to minimize chronic complications for patients undergoing RT.