Main Session
Sep
27
PQA 02 - Pediatric Cancer, Sarcoma and Cutaneous Tumors, Medical Education & Professional Development, and Health Services Research
2309 - Evaluating the Effect of Tumor-Draining Nodal Irradiation By Flash vs. Conventional Dose-Rate Radiotherapy of a Clinically Relevant Melanoma Mouse Model
Presenter(s)
Patrick Carriere, MD, PhD - MD Anderson Cancer Center, Houston, TX
P. P. Carriere1, E. Konradsson2, L. Connell2, T. Waldrop2, D. Neill2, E. Aguilar2, M. Davies3, J. Wargo4, R. J. H. Park5, E. Schueler2, and D. Mitra1; 1Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 2Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 3Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 4Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 5Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s):
There is growing appreciation that radiotherapy (RT) targeting tumor-draining lymph nodes (TDLN) may alter tumor-immune biology and therapeutic efficacy, particularly in the era of immune modulating systemic treatments. Using a clinically relevant mouse model of subcutaneous melanoma metastasis, we sought to evaluate how ultra-high dose-rate FLASH RT (FLASH-RT) vs. conventional dose-rate RT (CONV-RT) affected melanoma tumor growth kinetics and survival with and without irradiation of TDLN.Materials/Methods:
C57BL/6 mice bearing subcutaneous syngeneic D4M BRAFV600E/PTEN-/- melanoma tumors (70–150 mm³) underwent sham irradiation or 30 Gy single-fraction CONV-RT or FLASH-RT. Tumors were implanted on the flank (FL; tumor-draining nodal field included) or hindlimb (HL; nodal field excluded). Endpoints included tumor doubling time (TDT), recurrence-free survival (RFS), cure rate, and overall survival (OS). RFS was defined as =40 mm³ regrowth above nadir; mice without regrowth were censored. Time-to-event outcomes were analyzed by Kaplan-Meier with log-rank comparison, and cure rates by Fisher’s exact test.Results:
Tumors were implanted in the FL (Sham n=4, CONV-RT n=3, FLASH-RT n=4) or HL (Sham n=18, CONV-RT n=18, FLASH-RT n=18). In FL tumors, median TDT was 41 days (23–NR) for CONV-RT and 28 days (16–NR) for FLASH-RT. In HL tumors, median TDT was not reached for either CONV-RT or FLASH-RT. Thus, TDT was significantly prolonged in HL vs FL tumors for both CONV-RT (p=0.012) and FLASH-RT (p=0.0002). Similarly, median RFS in FL tumors was 28 days (21–NR) for CONV-RT and 22 days (14–NR) for FLASH-RT, compared with 144 days (32–NR) and 101 days (37–NR), respectively, in HL tumors. Thus, RFS was significantly longer in HL vs FL tumors for FLASH-RT (p<0.0001), though not significantly different for CONV-RT (p=0.27). Cure rates numerically favored HL vs FL tumors for both FLASH-RT (50% vs 0%, p=0.12) and CONV-RT (44% vs 33%, p=1.0) but were not statistically significant. Median OS was prolonged in HL vs FL tumors for both CONV-RT (88 [60–NR] vs 49 [41–NR] days; p=0.012) and FLASH-RT (81 [53–NR] vs 61.5 [51–NR] days; p=0.0002). Ongoing immune profiling studies suggest differences between FLASH-RT and CONV-RT that depend on inclusion of the TDLN. These results are currently being validated.Conclusion:
In a clinically relevant model of cutaneous melanoma metastasis, FLASH-RT and CONV-RT achieve equivalent tumor control. However, irradiation of the TDLN significantly alters tumor control across modalities. Ongoing immune profiling studies suggest TDLN irradiation has RT modality specific effects on local and systemic immune biology. We anticipate these studies will inform the optimal approach for rational immunomodulatory combination therapies.