Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma

Abstract

Background: 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 outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS.

Methods: Phase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies.

Discussion: This is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS.

Trial registration: NCT05301283.

Trial status: The trial started recruitment on March 17, 2022.

Keywords: Adaptive therapy; Clinical trial; Genomic; Neoadjuvant; Pathology; Radiomic; Radiotherapy; Sarcoma; Soft tissue sarcomas.

Fig. 1

Trial schema. Radiation therapy begins between visit 1 and visit 2. All patients will be seen during weekly treatment visits throughout radiation therapy. Radiation therapy ends between visit 2 and visit 3. Surgical resection occurs between visit 3 and visit 4

Fig. 2

Distribution curve of the cumulative incidence of GARD from 231 STS samples. GARD pathologic response prediction based on historic (8%) and institutional (18%) FPR rates to standard neoadjuvant radiotherapy (50 Gy in 25 fractions), with GARD thresholds of 31.37 and 22.96, respectively. Note the effect that dose escalation with 60 Gy (red) and 70 Gy (green) in 25 fractions has on the percent of patients that are predicted beyond the thresholds. Since both GARD targets are after the linear region in the curve, a uniform dose increase quickly impacts the number of patients that achieve each of the GARD target values. Since habitats are dichotomized based on the gross tumor volumes median value, then 50% of the volume will receive standard dose and the other half will receive dose escalation of either 60 or 70 Gy. Therefore, the probability of achieving a FPR is 8 to 18% for the standard half and an average of 15.2–60.2% to the escalated half of the GTV, would predict for a > 24.3% estimated FPR for the cohort. A tripled FPR rate (8–24%) is a modest estimate that assumes complete dose conformality, with neighboring habitats adjacent to one another, this would be a conservative minimum FPR increase we expect to see clinically. The estimated FPR is assuming the same probability of response for each habitat, but knowing that radioresistant hypoxic regions often require > 30% higher dose for response [40], the radiomic habitat directed approach may better identify the regions that would most benefit from dose escalation, therefore improving overall response

Fig. 3

Example of the custom MRI compatible immobilization for a left thigh STS. BB marks on the left anterior thigh will then be tattooed to serve as a guide for setup (e.g., imaging, daily treatment) and habitat directed biopsy that will be used for exploratory genomic studies

Fig. 4

MRL planning shows the GTV on a TRUFI image (A and C), is rigidly mapped onto an ADC (B) and DCE (D) sequence to determine the low and high ADC/DCE regions. The regions of high and low overlaps based on median value (E: axial view; F: sagittal view; G: coronal view) are then used to determine habitats 1, 2, and 3

Fig. 5

Adaptation at fraction 1 (B) to account for tumor growth from the time of simulation (A). Solid green line represents GTV at time of simulation and dotted green line represents GTV at time of fraction 1

Fig. 6

Specimen radiograph displaying markers for each habitat and to help orient with preoperative imaging (A). At time of pathological evaluation, the specimen is mapped to a grid to determine percentage of pathological response throughout the specimen (B)

Fig. 7

Example of stereotactic biopsy within a habitat of the posterior thigh. (A) MRI identification of Habitat 1 (blue) target. To account for sofit tissue rotation, needle insertion is designated at the proximal tattoo (BB#1) and a depth of 7 cm towards the center of the femur is measured, with a medial tangential 5.5 cm line (90 degrees), creating the final biopsy track 9 cm from the surface. (B) CT measurements, biopsy, and clip placement are illustrated. Each site is defined by a different marker (e.g., one visicoil proximal biopsy, two visicoils at midpoint habitat, and one visicoil plus one helical mammotome for the distal habitat sampled). In addition to helping with daily set up, these markers will also be used at the time of pathological evaluation to orient the specimen and determine treatment response within each habitat