CTNI-31. RESECTION AND SURGICALLY TARGETED RADIATION THERAPY FOR TREATMENT OF LOCALLY RECURRENT GBM IN 28 PROSPECTIVELY TREATED PATIENTS

INTRODUCTION Recurrent GBM is a diffuse disease and resection (R) alone does not routinely provide durable local control (LC) or prolonged overall survival (OS). We hypothesized R plus immediate radiation (RT) utilizing a novel brachytherapy device might achieve more durable LC and thereby secondarily improve OS. METHODS From 2/2013-2/2018, locally recurrent GBM were treated in a single arm trial (ClinicalTrials.gov, NCT#03088579) of R plus immediate implantation of a surgically targeted radiation therapy (STaRT) device utilizing Cs-131 in bioresorbable collagen tiles (GammaTile, GT Medical Technologies, Tempe AZ USA). RESULTS 28 patients (pts) were treated, 20 at first recurrence (range 1-3). Median age 58 (range 21-80), KPS 80 (60-100), female:male ratio 10:18. Median OS was 10.7 mo., radiographic LC 8.8 mo., and no first failure was local. MGMT, KPS, and sex were non-predictive. Post hoc analysis disclosed after R+STaRT, 17 pts (54%) received > 1 cycle of Sys (“Sys+”) and 13 (46%) did not (“Sys- “). Sys was given as adjuvant, salvage, or both, either alone or in combination. 15 pts received bevacizumab (BEV), 12 temozolomide (TMZ) and 8 lomustine (CCNU). Median OS (mo.) for Sys+ vs. Sys- was 15.1/6.5 (hazard ratio (HR) .38, p=.017); OS for BEV+ vs. BEV- was 16.7/4.5 (HR .38, p=.017), TMZ+ vs. TMZ- 17.5/6.7 (HR .40, p=.025) and for CCNU+ vs. CCNU- 17.5/7.9 (HR .61, p=.25), respectively. LC was 11.4 mo. for Sys+ vs. 2.1 mo. for Sys- (HR .44; p=.16). Three attributed AE occurred, 1 wound infection requiring surgery and 2 radiation brain effects, managed medically. CONCLUSION Post hoc analysis suggests R+STaRT+Sys may have the potential to impact OS in locally recurrent GBM, possibly by allowing sufficient time for effective but biologically slower treatments to have an impact. FDA clearance was received in 2018 for recurrent intracranial neoplasms and in 2020 for newly-diagnosed malignant brain tumors.

RTID-01. PHASE III MULTICENTER RCT OF POST-SURGICAL STEREOTACTIC RADIOTHERAPY VERSUS SURGICALLY TARGETED RADIATION THERAPY FOR THE TREATMENT OF LARGE NEWLY DIAGNOSED BRAIN METASTASES – TRIAL IN PROGRESS

BACKGROUND Resection (R) followed by single- or multi-fraction stereotactic radiosurgery (SRT) of brain metastases (BMs) lowers resection bed recurrence compared to R alone. Nevertheless, for larger BMs, 12-month recurrence rates after R+SRT can exceed 20–30%. Aiming to improve outcomes, a permanently implanted collagen tile brachytherapy device (GammaTile, GT Medical Technologies, Tempe, AZ) utilizing Cs-131 seeds embedded within a bioresorbable collagen tile was developed and is described as Surgically Targeted Radiation Therapy (STaRT) to distinguish it from external beam radiotherapy. STaRT allows rapid, intense localized radiation dose delivery directly to the tumor bed with predictable dosimetry immediately at the time of R, which may confer reduced risk for radiation necrosis compared to other therapies. It is hypothesized that R+ STaRT will increase surgical bed recurrence-free survival (SB-RFS), while reducing impact on functional and neurocognitive status compared to R+SRT. METHODS Multicenter, randomized, comparison trial of patients with resectable, previously untreated “index” BMs (≥ 2.5–5cm), and 0–3 other tumors, will be preoperatively randomized 1:1 to undergo R+SRT or R+STaRT to the index lesion; unresected tumors in both groups will receive SRT. Planned sample size is 180 from 14 sites. Enrollment opened 03/31/2021. First subject was enrolled 04/07/2021. Primary endpoint is SB-RFS. Secondary endpoints include overall survival, quality of life, neurocognition, functional status, imaging findings and adverse events. Follow-up will be through 24 months. This will be the first randomized trial comparing R+SRT versus R+STaRT delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. Primary and secondary outcome measures captured will elucidate the potential risks and benefits of these two RT delivery methods in the setting of newly diagnosed BMs. We will present trial accrual progress, available data, experience and lessons learned.

Biologically Targeted Radiation Therapy: Incorporating Patient-Specific Hypoxia Data Derived from Quantitative Magnetic Resonance Imaging

Purpose: Hypoxia has been linked to radioresistance. Strategies to safely dose escalate dominant intraprostatic lesions have shown promising results, but further dose escalation to overcome the effects of hypoxia require a novel approach to constrain the dose in normal tissue.to safe levels. In this study, we demonstrate a biologically targeted radiotherapy (BiRT) approach that can utilise multiparametric magnetic resonance imaging (mpMRI) to target hypoxia for favourable treatment outcomes. Methods: mpMRI-derived tumour biology maps, developed via a radiogenomics study, were used to generate individualised, hypoxia-targeting prostate IMRT plans using an ultra- hypofractionation schedule. The spatial distribution of mpMRI textural features associated with hypoxia-related genetic profiles was used as a surrogate of tumour hypoxia. The effectiveness of the proposed approach was assessed by quantifying the potential benefit of a general focal boost approach on tumour control probability, and also by comparing the dose to organs at risk (OARs) with hypoxia-guided focal dose escalation (DE) plans generated for five patients. Results: Applying an appropriately guided focal boost can greatly mitigate the impact of hypoxia. Statistically significant reductions in rectal and bladder dose were observed for hypoxia-targeting, biologically optimised plans compared to isoeffective focal DE plans. Conclusion: Results of this study suggest the use of mpMRI for voxel-level targeting of hypoxia, along with biological optimisation, can provide a mechanism for guiding focal DE that is considerably more efficient than application of a general, dose-based optimisation, focal boost.

Clinical Trials in Progress: ROADS Trial

Phase 3 Randomized Controlled Trial of Post-Surgical Stereotactic Radiotherapy (SRT) versus Surgically Targeted Radiation Therapy (STaRT) with GammaTile for Treatment of Newly Diagnosed Metastatic Brain Tumors (ROADS; NCT04365374).

Resection and surgically targeted radiation therapy for locally recurrent GBM.

2054 Background: Recurrent GBM (rGBM) is a diffuse disease, and resection (R) alone does not provide durable local control (LC) or prolong overall survival (OS). Hypothesizing R plus immediate radiation (RT) may achieve durable LC and secondarily improve OS by permitting time for subsequent potentially effective but biologically slower treatments to have an impact, we prospectively evaluated R combined with a novel surgically targeted radiation therapy (STaRT) device utilizing Cs-131 embedded in bioresorbable collagen tiles. Methods: From 2/13-2/18 patients (pts) with locally recurrent GBM were treated on a prospective single arm trial (ClinicalTrials.gov, NCT#03088579) of maximum safe resection and immediate RT (GammaTile, GT Medical Technologies, Tempe AZ). Upon resection the at-risk areas of the surgical bed were lined with the GammaTile (GT) device, delivering 60-80 Gy at 5 mm. Follow up treatments were not specified but captured; no pt. underwent additional local therapy without progression, and no pt. was lost to follow up. We present study specified endpoints of local control (LC), overall survival (OS), and adverse events (AE), and a post hoc, hypothesis-generating analysis of outcomes by receipt of systemic (Sys) therapy. Results: 28 locally recurrent GBM were treated, 20 at first progression (range 1-3). Median age was 58 years (yrs.) (range 21-80), KPS 80 (60-100), female: male ratio 10:18 (36/64%). MGMT was methylated in 11%, unmethylated in 18%, and unknown in 71%. For all pts., median OS was 10.7 months (mo.) (range.1-42.3), and radiographic LC was 8.8 mo. (range.01-34.5). LC (defined as < 15 mm from surgical bed) was maintained in 50% of pts., and no first failure was local. 12 mo. OS was 75% for pts. < 50 yrs. vs. 43% for > 50 yrs. (HR.46, p =.009). MGMT, KPS, and sex were non-predictive. After R+GT, 17 pts. received > 1 cycle of systemic therapy (Sys), either as adjuvant or salvage, alone or in combination . Sys was bevacizumab (BEV) in 15 pts., temozolomide (TMZ) in 12, and lomustine (CCNU) in 8 (N > 17 as some pts. received > 1 Sys). Post hoc analysis disclosed a 15.1 mo. OS for pts. receiving > 1 cycle of Sys (Sys+, N = 17) vs. 6.5 mo. for no Sys (Sys-, N = 11) (hazard ratio (HR).38, p =.017)). LC was 11.4 mo. for Sys+ and 2.1 mo. for Sys- (HR.44; p =.16)). Median OS (mo.) for BEV+ vs. BEV- was 16.7/4.5 (HR.38, p =.017), for TMZ+ vs. TMZ- 17.5/6.7 (HR.40, p =.025) and for CCNU+ vs. CCNU- 17.5/7.9 (HR.61, p =.25), respectively. Three attributed AE occurred, 1 dehiscence requiring surgery and 2 radiation brain effects, medically treated. 4 unrelated deaths occurred < 60 days post-op, all in the Sys- cohort, impacting their opportunity for subsequent treatment. Conclusions: In this study local treatment alone was insufficient to achieve prolonged OS. Post hoc analysis suggests R+GT coupled with Sys may have potential to impact OS in rGBM patients. GT was FDA cleared in 2020 for use in newly diagnosed malignant and all recurrent intracranial neoplasms. Clinical trial information: NCT#03088579.

A phase III multicenter randomized controlled trial of postsurgical stereotactic radiotherapy versus surgically targeted radiation therapy (STaRT) for the treatment of large (>2.5cm) newly diagnosed brain metastases: Trial in progress.

TPS2067 Background: Resection (R) followed by single or multi-fraction stereotactic radiosurgery (SRT) of brain metastases lowers resection bed recurrence compared to R alone. Nevertheless, for larger (>2.5cm) brain metastasis, 12-month recurrence rates after R+SRT can exceed 20–30%. Aiming to improve outcomes, a permanently implanted collagen tile brachytherapy device (GammaTile or GT, GT Medical Technologies, Tempe, AZ) utilizing Cs-131 seeds embedded within a bioresorbable collagen tile was developed and is described as Surgically Targeted Radiation Therapy (STaRT) to distinguish it from external beam radiation therapy. It is hypothesized that immediate adjuvant radiotherapy (RT) and/or RT dose intensification could improve outcomes. The device is FDA-cleared for this indication and early commercial use is demonstrating favorable safety and efficacy outcomes. STaRT allows rapid dose delivery of radiation therapy directly to the tumor bed with predictable dosimetry immediately at the time of resection, and an intense but localized radiation treatment, which may confer a reduced risk for radiation necrosis compared to other therapies. The device is easily placed with minimal additional operative time and limited staff radiation exposure. It is hypothesized that R+ STaRT will increase the surgical bed recurrence-free survival, while reducing the impact on functional and neurocognitive status compared to R+SRT. Methods: Multicenter, randomized, comparison trial of patients with resectable, previously untreated “index” brain metastases measuring ≥2.5–5 cm, and 0–3 other tumors, will be preoperatively randomized 1:1 to undergo either R+ SRT or R+STaRT to the index lesion; unresected tumors in both groups will receive SRT. Planned sample size is 180 from 13 sites. Enrollment will open in Q1. Primary endpoint is surgical bed-recurrence free survival. Secondary endpoints include overall survival, quality of life (Functional Assessment of Cancer Therapy-Brain, Linear Analog Self-Assessment), neurocognition (Hopkins Verbal Learning Test, Trail Making Tests, Controlled Oral Word Association), functional status (Karnofsky Performance Scale, Barthel-ADL), and adverse events. Follow-up will be at 1,3,6,9, and 12 months, then every 6 months through 24 months. This will be the first randomized trial comparing R+SRT versus R+STaRT delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. Primary and secondary outcome measures will be captured to elucidate the potential risks and benefits of these two differing post-operative RT delivery methods in the setting of newly diagnosed metastatic brain tumors. Clinical trial information: NCT04365374.

RADT-47. A MULTICENTER OBSERVATIONAL STUDY OF SURGICALLY TARGETED RADIATION THERAPY (START) USING IMPLANTED CS-131 SEEDS IN A COLLAGEN-BASED CARRIER TILE IN INTRACRANIAL BRAIN NEOPLASMS - PROTOCOL IN PROGRESS

INTRODUCTION Post-resection radiotherapy (RT) is the most effective adjuvant treatment for brain tumors. However, there is no current consensus as to the “best” type of post-resection RT, either at diagnosis or recurrence. The use of internally placed radiation (brachytherapy) allows immediate initiation of RT when residual tumor burden is minimal, which theoretically should lessen the risk of recurrence. Brachytherapy placement intraoperatively allows more precise identification of the tumor margins than by postoperative imaging. Traditional brachytherapy methods have several drawbacks, including uneven dose distribution, long operating room times, a need for expensive equipment, and/or frequent adverse events (AE). To address these issues, a device with Cs-131 radiation seeds in a resorbable collagen-based carrier tile (GammaTile, GT Medical Technologies, Tempe AZ) was developed and is described as Surgically Targeted Radiation Therapy or STaRT. The device has demonstrated excellent safety and local control in early commercial use. OBJECTIVE The objectives of this registry study are to evaluate real-world clinical outcomes and patient reported outcomes that measure the effectiveness and safety of STaRT. METHOD Patients (N=600) with surgically resected (R) brain tumors of any pathology who have undergone STaRT are eligible. Accrual to start at 20+ sites in Q3 2020. Data collected includes local control, overall survival, QOL, neurocognition, functional decline, and surgical and radiation associated AE’s. Data will be collected at 1, 3, 6, 9, and 12 months, then every 6 months through 5 years. RESULT Data will be used to benchmark clinical outcomes of STaRT therapy and allow for comparisons to existing standard-of-care treatments. CONCLUSION This will be the first observational registry study of R+STaRT, delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. The outcome measures captured will allow for evaluation of the potential risks and benefits of this treatment approach for patients in a real-world setting.