Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with 213Bi-substance P analogue

Abstract

Background: Glioblastoma multiforme (GBM), the most common malignant brain tumor, mainly manifests as a primary de novo and less frequently as a secondary glial neoplasm. GBM has been demonstrated to overexpress the NK-1 receptor and substance P can be used as a ligand for targeted therapy. Alpha emitters, e.g. ²¹³Bi, that deposit their high energy within a short range allow the selective irradiation of tumor cells while sparing adjacent neuronal structures.

Material and methods: Among 50 glioma patients of different subtypes that have to date been treated with targeted alpha therapy at the Medical University Warsaw, we report here the data on nine patients with secondary GBM. Following surgery, chemo- and radiotherapy, recurrent GBM was treated by intracavitary injection of 1-6 doses of 0.9-2.3 GBq ²¹³Bi- DOTA-[Thi⁸,Met(O₂)¹¹]-substance P (²¹³Bi-DOTA-SP) in 2-month intervals. ⁶⁸Ga-DOTA-[Thi⁸,Met(O₂)¹¹]-substance P (⁶⁸Ga-DOTA-SP) was co-injected with the therapeutic doses to assess biodistribution using PET/CT. Therapeutic response was monitored with MRI.

Results: Treatment with activities ranging from 1.4 to 9.7 (median 5.8) GBq ²¹³Bi- DOTA-SP was well tolerated with only mild transient adverse reactions, mainly headaches due to a transient perfocal edema reaction. The median progression free survival and overall survival time following the initiation of alpha therapy was 5.8 and 16.4 months, respectively. The median overall survival time from the first diagnosis was 52.3 months. Two out of nine patients are still alive 39 and 51 months, respectively, after the initiation of the therapy.

Conclusions: Targeted alpha therapy of secondary GBM with ²¹³Bi-DOTA-SP is safe and well tolerated and may evolve as a promising novel therapeutic option for secondary GBM.

Keywords: 213Bi-DOTA-SP; 68Ga-DOTA-SP; GBM; Glioblastoma; Substance P; Targeted alpha therapy.

Fig. 1

Implementation of catheters into the postsurgical cavity. A cavity of 1.5 cm diameter is drilled into the external tabula of the skull with a central opening. A port capsule connected with a catheter is then stereotactically inserted into the tumor or resection cavity. The wound is then closed. Injections into the capsule were performed some 10 days later

Fig. 2

PET/CT after local co-injection of 10 MBq ⁶⁸Ga-DOTA-SP with a therapeutic dose of ²¹³Bi-DOTA-SP into the resection cavity of a glioblastoma in patient 2. Most of the activity is concentrated within the lesion, with little activity remaining in the capsule and within the catheter

Fig. 3

Whole body PET/CT scan shows biodistribution 30 min after intralesional injection of 10 MBq ⁶⁸Ga-DOTA-SP analogue: the signal detected in the body outside the brain is very faint or negligible in liver, kidney, spleen and bone marrow. The cleaved linear peptidic vector is excreted into the bladder and can show a weak signal corresponding to <5% of injected activity

Fig. 4

The Kaplan-Meier estimator displays the progression free survival (PFS), overall survival following initial diagnosis (OS-D), overall survival following conversion (OS-C) and overall survival after initiation of therapy with ²¹³Bi-DOTA-SP analogue (OS-T)

Fig. 5

In a 32-year-old woman suffering from an astrocytoma WHO grade II, conversion into a secondary GBM manifested 10.6 months after initial diagnosis. Following standard treatment consisting of surgery, radio- and chemotherapy with TMZ, four cycles of ²¹³Bi-DOTA-SP were applied. The total activity injected amounted to 8.0 GBq of the therapeutic isotope. The T1-weighted enhanced MRI examination revealed shrinkage of the tumor by 32%