Locoregional Treatment of Glioblastoma With Targeted α Therapy

Abstract

Background: Glioblastoma (GB) is the most malignant primary brain tumor. Therefore, introduction of new treatment options is critically important. The aim of this study was to assess local treatment with α emitters [ 213 Bi]Bi-DOTA-substance P (SP) and [ 225 Ac]Ac-DOTA-SP. Methods: Treatment was performed as salvage therapy in patients with recurrent primary and secondary GB. [ 213 Bi]Bi-DOTA-SP with injected activity 1.85 GBq per cycle was used in 20 primary (48.2 ± 11.8 years old) and in 9 secondary (38.8 ± 10.8 years old) GB patients and [ 225 Ac]Ac-DOTA-SP in 15 primary (45.1 ± 9.9 years old) and in 6 secondary (37.8 ± 6.4 years old) GB patients with a dose escalation scheme (10, 20, and 30 MBq). Results: Local treatment with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP was well tolerated with only few adverse effects. There was no statistically significant difference between [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP groups in survival parameters. For primary GB, survival parameters of patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows(in months): progression-free survival time, 2.7 versus 2.4; OS-d (overall survival from time of diagnosis to death from any cause), 23.6 versus 21.0; OS-t (overall survival from the start of treatment to death from any cause), 7.5 versus 5.0; and OS-r (overall survival from recurrence in primary tumors to death from any cause), 10.9 versus 12.0. Survival parameters of secondary GB patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows (in months): progression-free survival time, 5.8 versus 2.4; OS-d, 52.3 versus 65.0; OS-t, 16.4 versus 16.0; and OS-c (overall survival from conversion into secondary GB multiforme to death from any cause), 18.4 versus 36.0. Conclusions: The similarity results of 213 Bi or 225 Ac may suggest that the local treatment of brain tumors can be greatly simplified. The experience to date shows that local radioisotope treatment of brain tumors requires further dosimetry studies, taking into account the complexity of biological processes.

Targeted Alpha Therapy for Glioblastoma: Review on In Vitro, In Vivo and Clinical Trials

“…Bi-213, which boasts a 2.2% α-emission and 97.8% β-emission, possesses a range of 0.05–0.10 mm and a T 1/2 of 0.77 h [ 27 – 33 ]. Like Ac-225, it can be effectively complexed with DOTA, offering a straightforward and universal solution [ 26 , 30 – 32 ]. However, its short T 1/2 and gamma-energy combination make it less efficient in terms of tumour distribution before radioactive decay [ 28 ].…”

“…In the group treated with Ac-225: six patients had worsening of hemiparesis or aphasia; Only adverse effects were seen in the group treated with 20 MBq and 30 MBq - In two patients, 2 & 3 weeks after treatment with 30 MBq, severe perifocal brain edema was observed, requiring hospitalisation, without intubation; Observed haematological toxicity: thrombocytopenia grade 2 in one patient in the 20 MBq group and thrombocytopenia grade 3 in one patient in the 30 MBq group, and hepatic toxicity grade 1 was seen in one patient of the 30 MBq dose escalation group. Krolicki et al 2023 [ 30 ] Bi-213 Substance P/NK-1 29 Recurrent GB (primary and secondary) 1.85 GBq per cycle * Primary GBM: PFS: 2.7 mos OS-d: 23.6 mos OS-r: 10.9 mos OS-t: 7.5 mos Secondary GBM: PFS: 5.8 mos OS-d: 52.3 mos OS-c: 18.4 mos OS-t: 16.4 mos * Same method of delivery as described in Krolicki et al[ 31 ] SCRC surgically created resection cavity, RT residence time for At-211 in the SCRC, %ID percent of injected dose, PFS progression-free survival time is the time from the start of radioisotope treatment to clinical or imaging signs and symptoms of progression, relapse, or death, OS-d overall survival from time of initial diagnosis to death from any cause, OS-r/OS-c overall survival from recurrence or conversion in primary tumours or conversion into secondary GBM to death from any cause, OS-t overall survival from the start of treatment (first cycle of TAT) to death from any cause …”

“…The studies conducted by Krolicki et al [ 26 , 30 – 32 ] have contributed to advancing our understanding of TAT for GB. Their clinical trials began in 2018 when they investigated the use of Bi-213 conjugated with Substance P/NK-1 in nine patients with secondary GB.…”

Production of 225Ac for medical application from 232Th-metallic targets in Nb-shells irradiated with middle-energy protons

“…[6][7][8] The short-lived 213 Bi (t 1/2 = 46 min) is more preferable for the treatment of rapidly accessible types of cancer with fast pharmacokinetics. [9][10][11] Current clinical trials with 213 Bi-labeled compounds are conducted for leukemia, NHL, carcinoma, neuroendocrine tumors, glioma, etc. 12 The results of numerous studies related to both clinical and preclinical trials, the development of new chelators and medical delivery vehicles for actinium and bismuth isotopes are published annually.…”

“…Assuming the whole produced 225 Ac is used for the preparation of 225 Ac-radiopharmaceuticals, only 2000–2500 patients can be treated. 1 In many cases, 11 213 Bi-pharmaceuticals are more efficient than those with 225 Ac. However, when using 225 Ac in the form of 225 Ac/ 213 Bi generator, the number of treated patients may drop down to 100–200 annually.…”