H. Lee Moffitt Cancer Center and Research Institute Tampa, FL, United States
A. O. Naghavi1, J. Costello2, Y. Kim3, D. Joyce4, K. A. Ahmed5, G. Redler1, G. Q. Yang1, S. A. Rosenberg1, J. M. Bryant1, M. M. Bui6, E. B. Henderson-Jackson6, R. J. Gonzalez4, O. Binitie4, A. Lazarides4, J. Mullinax4, V. Feygelman1, A. F. Ahmed2, N. Parikh2, J. F. Torres-Roca1, and K. Latifi1; 1H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL, 2H. Lee Moffitt Cancer Center and Research Institute, Department of Radiology, Tampa, FL, 3H. Lee Moffitt Cancer Center and Research Institute, Department of Bioinformatics and Biostatistics, Tampa, FL, 4H. Lee Moffitt Cancer Center and Research Institute, Department of Sarcoma, Tampa, FL, 5Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 6H. Lee Moffitt Cancer Center and Research Institute, Department of Pathology, Tampa, FL
Purpose/Objective(s): Soft tissue sarcomas (STS) have significant inter- and intra-tumoral heterogeneity with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR=95%) from RT is associated with improved patient outcomes. Genomic adjusted radiation dose (GARD), a radiation-specific genomic metric that quantifies the expected RT treatment effect as a function of tumor dose, proposed that STS is considerably underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel phase II clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and target them with predetermined GARD doses, to improve FPR in high-grade STS. Materials/
Methods: The study is a phase 2 non-randomized single-arm clinical trial (NCT05301283) that includes adults with resectable non-metastatic deep high-grade STS. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient maps (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that neoadjuvant RT with a simultaneous integrated boost of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50Gy, would lead to a >3-fold FPR increase to 24%. An mpMRI taken between week 2-3 of treatment will be used for biological plan adaptation to account for tumor response. Surgery was planned 3-12 weeks after RT completion, evaluating FPR and margin status. Patients were assessed for acute toxicity up to 4 months post-surgery. With a Fleming’s three-stage optimal design, a total of 5 FPRs among the first 13 patients enrolled, or 7 in the first 36 patients, would be a statistically significant success. Results: A total of 14 patients were screened with 13 enrolled. The median patient age was 61 (21-85 years) with a tumor size of 15.6 cm (7.5-29cm). All patients had grade 3 lower extremity STS, with the most common histology being undifferentiated pleomorphic sarcoma (81%). All patients completed protocol specified RT and 11 proceeded to surgery, all of whom were resected with clear margins, with primary closure in 91%. The trial was deemed an early success with a total of 7 (64%; 95%CI 0.308-0.891) achieving an FPR, along with 72% and 91% achieving =90% and =80% response, respectively. Most common acute toxicities were grade 3 wound complications (45%) and grade 2 RT dermatitis (31%). Conclusion: The integration of a genomic-based RT dose optimization (GARD) and radiomic habitat directed dose escalation has led to the highest reported pathologic response rates in STS. This novel approach ushers in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and future trial designs, personalizing treatment for STS.
