"Monday 13 May"

Purpose: Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to  40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble  treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitized tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided focussed ultrasound-stimulated microbubble (MRgFUS-MB) treatment, a novel radioenhancement therapy for breast cancer.

Methods/Materials: A single-arm phase 1 clinical trial included patients with stage I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was conducted. Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2-3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 KHz and 540 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary endpoint was toxicity per CTCAEv5.0 and tumour response at 3 months. Secondary endpoint was local control (LC).

Results: Eighteen patients with 20 primary breast cancers were included in this analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n=8/20), 30-35 Gy/5 fractions (35%, n=7/20), 30-40 Gy/10 fractions (15%, n=3/20), and 66 Gy/33 fractions (10%, n=2/20). The median follow-up was 9 months (range, 0.3-29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were assessed for response; 83% (n=15/18) had partial (33%, n=6/18) or complete  (50%, n=9/18) responses, with a single progression. Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94.4%, 88.5%, and 75.9%, respectively.

Conclusions: MRgFUS-MB was a safe and efficient treatment that provided durable responses.

Purpose

Approximately 10-15% of patients with renal cell carcinoma (RCC) will develop brain metastases (BM) throughout the course of their disease, which portends a median overall survival of approximately 10 months. Targeted antiangiogenic therapies such as vascular endothelial growth factor inhibitors (VEGFi) remain the preferred first-line systemic regimen for patients with RCC, while stereotactic radiosurgery (SRS) can provide excellent local control of BM. RCC BM have a known risk of intracranial hemorrhage (ICH), and it is feared that the combination of SRS and VEGFi may exacerbate that risk. We thus evaluated the incidence of ICH in a large cohort of patients with RCC BM undergoing SRS with or without concurrent VEGFi.

Methodology

90 patients with RCC and with radiographic evidence of BM that were treated at Memorial Sloan Kettering Cancer Center (MSKCC) between 2010-2020 who received LINAC-based SRS were included. Concurrent therapy was defined as receipt of a VEGFi within 60 days either before or after the start of SRS. The primary endpoint was the development of new radiographically defined intracranial hemorrhage post-SRS. Median overall survival (OS), cumulative incidence of ICH, and 95% confidence intervals (CI) were estimated using Kaplan-Meier method. Gray’s test was used to evaluate post-SRS ICH events between groups, with patient death without ICH incorporated as a competing event.

Results

The median patient age was 62 years, 66 patients (71%) were male, and 78 patients (87%) had clear cell RCC histology. Median time from RCC primary diagnosis to BM diagnosis was 30.3 months. 32 patients received SRS with concurrent VEGFi (cVEGFi). Median follow-up was 20 months, with a median OS of 23.1 months (95% CI, 14.4-33.2). 

There were 22 total ICH events across the 90-patient cohort, with 9 events occurring post-SRS. At 6-, 12-, and 24-months post-SRS, the cumulative incidence of ICH was 9.4%, 9.4%, and 9.4% (95% CI, 2.3-22.5) at each timepoint for cVEGFi patients and 0%, 1.8% (95% CI, 0.1-8.4), and 9.0% (95% CI, 3.3-18.4) for those without concurrent VEGFi, respectively (p=0.996).

Conclusion

We present the first ICH profile of patients with RCC BM treated with SRS and concurrent antiangiogenics. We could not identify a difference in cumulative incidence of ICH post-SRS between the two groups. Future work seeks to explore the mechanism of action and efficacy of SRS and concurrent VEGFi in BM.

Purpose:  While the use of 5-ALA has been used to increase the extent of surgical resection in glioblastoma (GBM), its potential to act as a radiosensitizer has not been widely studied in the CNS.  Whereas typical external beam radiotherapy (EBRT) treatments occur weeks after surgery and 5-ALA administration, intraoperative radiotherapy (IORT) delivers radiation while protoporphyrin IX is still present in residual tumor.  This current study examines the potential for radiation necrosis (RN) development following IORT and subsequent fractionated radiotherapy.           

Methods:  Interim data from the INTRAGO II study for newly diagnosed GBM (NCT02685605) were analyzed for the incidence of radiation necrosis (RN) based on 5-ALA use, IORT treatment vs SOC control (60Gy EBRT), and extent of resection. Statistical analysis was performed via univariate (ANOVA), multivariate (Cox regression), and K-M estimations with significance of p<0.005. 

Results:  234 patients were enrolled in INTRAGO II between 2016 and 2022.  Of these, 185 (79%) had a surgical resection performed with the use of 5-ALA tumor fluorescence visualization.  Following surgical resection with 5-ALA, 94 (51%) received IORT (30Gy to the margin) and an additional 60Gy EBRT (ARM A).  Imaging confirmed RN occurred in 11 (12%) of ARM A patients who had 5-ALA assisted resection, compared to 3 (3.3%) of ARM B patients who received only 60Gy EBRT.  In the 49 patients not receiving 5-ALA, the imaging confirmed the RN rate in ARM A patients was 21% (5/24) compared to 12% in ARM B (3/25).  The median time to development of RN was 236 days post-IORT and 158 days post completion of EBRT.  ANOVA demonstrated a significantly (p=0.025) higher rate of RN in ARM A patients overall, but not with the addition of 5-ALA. Cox regression analysis confirmed that only significant predictor of RN on multivariate analysis was IORT plus EBRT (p=0.033) and KM estimations-Log Rank test of RN incidence were greater in Arm A/IORT patients than SOC/Arm B (p=0.029).

Conclusions:  While patients receiving IORT at the time of surgical resection had a higher rate of RN after SOC 60Gy EBRT, the use of 5-ALA in conjunction with surgical resection did not increase RN incidence.  Further analysis will need to consider local PFS rates and the impact of 5-ALA use with IORT.     

Introduction

Glioblastoma (GBM) is an aggressive, radioresistant type of cancer with a dismal prognosis. Preclinically, Sulfasalazine (SAS) has shown tumor selective radiosensitizing properties by blocking the intratumoral production of the antioxidant glutathione (GSH). We examined the safety of SAS in combination with Gamma Knife Radiosurgery (GKRS) in patients with recurrent GBM (rGBM). The trial was funded by the Norwegian Cancer Society.

Material and Methods

We conducted a phase 1 trial which used a 3+3 design with four dose cohorts (1.5, 3.0, 4.5 or 6.0 g SAS/day). Patients with rGBM underwent GKRS with 12 Gy prescription dose following 3 days of pretreatment with SAS. Primary end-point was safety. Secondary end-points were changes in GSH levels measured with GSH-magnetic resonance spectroscopy prior to and after SAS treatment, altered metabolism measured by 11-C-MET-PET, quality of life (QoL) utilizing the Functional assessment of brain cancer therapy (FACT-Br) questionnaire, freedom from local tumor progression (FFTP) using the RANO criteria, progression-free survival (PFS) and overall survival (OS).

Results

Between May 2020 and September 2022, 12 patients with recurrent GBM were included. Dose-limiting toxicity was not reached. All AE were grade 1 (n = 13) or 2 (n = 6) of which 8 (42 %) were possibly related to SAS. FACT-BR remained stable for 6 months (p= 0.056) thereafter it declined significantly. SAS led to a significant but variable reduction in intratumoral GSH levels. Best radiographic response of the treated lesion was complete control in 3 (27.2 %), partial response in 6 (54.5 %), stable disease in 1 (9.1 %) and immediate tumor progression in 1 (9.1 %) out of 11 patient with follow-up images. Six (67 %) of 9 patients with PET at baseline and follow-up had reduced signal indicative of effect. The median FFTP and PFS were 12.1 months (95 % CI 1.2 – 7.1) and 4.1 months (95% CI 1.2 – 7.1) compared to 1.6 (95 % CI 1.4 – 1.8) and 1.6 (0.9 – 2.3) for historical controls, p < 0.001 and p = 0.006, respectively. The median OS was 11.3 months (95 % CI 5.1 – 17.7).

Conclusion

Novel treatment modalities for rGBM are urgently needed. SAS in combination with GKRS was safe and well tolerated with preliminary evidence of anti-tumor response. We are planning a higher phase multicenter trial with a larger cohort of patients for efficacy testing of SAS as radiosensitizer for rGBM.

BACKGROUND

Glioblastoma (GBM) is a tumor known for its highly vascular nature and limited treatment options upon disease recurrence. While Bevacizumab which target VEGF-A has gained approval for treating recurrent glioblastoma (rGBM), the multi-target tyrosine kinase inhibitor Anlotinib has the ability to directly target Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet-Derived Growth Factor Receptor (PDGFR), and Fibroblast Growth Factor Receptor (FGFR). Theoretically, its anti-angiogenic effect may exceed that of Bevacizumab, and preliminary studies have shown its therapeutic efficacy in rGBM, indicating promising treatment potential. This study aims to present findings regarding the effectiveness and safety of combining Anlotinib with stereotactic radiosurgery (SRS) in treating patients with rGBM.

METHODS

HSCK-002 is a prospective single-arm, single center, phase II study (ClinicalTrials.gov Identifier: NCT04197492). Patients who underwent surgery, standard radiotherapy, and temozolomide chemotherapy and were diagnosed with recurrence based on Response Assessment in Neuro-Oncology (RANO) criteria and/or biopsy were eligible for inclusion. Each patient underwent CyberKnife SRS (25Gy/5fx) in combination with oral administration of Anlotinib (12 mg, daily, days 1–14/3 weeks) until encountering disease progression or experiencing intolerable adverse effects. The primary objective was the investigator-assessed median overall survival (OS) using the RANO criteria.

RESULTS

Between December 2019 and July 2023, 22 patients (median age: 55 years; range: 28–70 years) were included. According to RANO criteria, 21 patients exhibited tumor response, with 6 achieving complete response, resulting in an objective response rate of 95.5%. Additionally, one patient maintained stable disease without progression. Median progression-free survival (PFS) was 9.1 months (95% CI, 7.5–24.7), with a 6-month PFS rate of 85.7% (95% CI, 71.9–100.0). Median overall survival was 19.5 months (95% CI, 10.6–46.8). Common adverse events included hand-foot skin reactions (40.9%), hypercholesterolemia (27.3%), and hypertension (22.7%). Four patients experienced grade 3 adverse events, accounting for an 18.2% incidence rate. Therapy discontinuation due to ischemic stroke (grade 3) occurred in one patient. No grade 4 events or treatment-related deaths were reported.

CONCLUSIONS

The combination of salvage SRS with Anlotinib demonstrated promising outcomes and manageable toxicity in managing recurrent GBM. Currently, a phase II randomized controlled trial, supported by the Shanghai Municipal Commission of Health, is underway. This trial aims to compare the efficacy of Anlotinib combined with radiosurgery against Bevacizumab combined with radiosurgery for the treatment of rGBM patients, further exploring this therapeutic regimen.

Objectives

A number of studies have demonstrated that variations in the overall treatment time of an SRS treatment affects the Biological Equivalent Dose (BED) delivered for a given prescription dose and hence the potential outcome of an SRS treatment. We investigate the feasibility of using an LGP lightning optimization system that fixes the overall treatment time and hence the BED for a given prescription dose.

Materials and methods

A series of 20 consecutive clinical AVM treatment plans, with a volume range of 0.23-8.0cc, were selected for replanning using a modified version of Lightning running on MATLAB. For each of the targets, a hard constraint of beam-on-time was enforced in the optimization algorithm producing plans of 30, 45 and 60 minutes duration. To accommodate cobalt decay, reference dose rates of 1.5Gy/min, 2.5Gy/min and 3.5Gy/min were simulated, resulting in nine plans for each target.

For each case the Paddick (PCI) and Gradient Indices (GI) were calculated. The BED, for the dose prescription iso-surface (mean and associated minimum and maximum values) was calculated using the bi-exponential repair equation described by Millar and Hopewell.  

Results

For fixed 30 min treatments, and varying the dose-rate between 1.5 Gy/min and 3.5Gy/min, the average PCI increased from 0.63 to 0.81 and the average GI decreased from 3.6 to 2.8.

Increasing the beam on time from 30 to 60 minutes increased the average PCI from 0.79 to 0.85 and decreased the average GI from 2.9 to 2.6. Increasing either dose-rate or treatment time will improve the quality of the plan, but this is an exponential effect with diminishing returns. 

Reanalysis of the original manual plans showed a significant variation in BED (between 69% and 84%) relative to the basic LQ derived value assuming no repair. This was significantly reduced by fixing treatment times (range 79-84%, 74-80% and 70-75% for 30-, 45- and 60-minutes respectively).

Conclusion

Results indicate that quality plans can be created for 45- and 60-minute treatment times even for low reference dose-rates. This gives clinicians the opportunity to deliver the same BED to every target prescribed to the same dose. This work also demonstrates that BED depends mainly on the overall treatment time (inclusive of any gaps in treatment) and the physical prescription dose and not on isocentre number or the reference dose rate.