Locoregional Treatment of Glioblastoma With Targeted α Therapy: [: 213: Bi]Bi-DOTA–Substance P Versus [: 225: Ac]Ac-DOTA–Substance P—Analysis of Influence Parameters

The most common and malignant primary brain tumor is glioblastoma multiforme (GBM), lately from 2016, according to the World Health Organization Classification of Tumors, called glioblastoma (GB).1

The current standard treatment for GB involves maximal safe surgical resection, concurrent chemotherapy with radiation, and followed by adjuvant chemotherapy. Even with this extensive treatment, most patients have a recurrence of disease and die within 1.5 to 2 years of treatment. The therapeutic limitations in these malignancies are caused by the infiltrative nature of the glioma cells. The prognosis of patients with recurrent GB is not promising, with the median overall survival (OS) of less than 6 to 8 months.2,3

Therefore, introduction of new treatment options is critically important for GB patients. New therapeutic targets and schedules are evaluated. We previously described our experience with local treatment of GB with substance P (SP), which is a ligand to NK-1 receptors presented on glioma cells, labeled with 2 different α emitters, 213 Bi and 225Ac.4–7 First, 213 Bi was used for labeling of peptides, with the short T½ of 213Bi (T½ = 46 minutes) being beneficial for radiation protection, yielding quite promising results. For patients with the recurrence of secondary GB from the onset of [213Bi]Bi-DOTA-SP treatment, the median progression-free survival was 5.8 months, and the median OS (OS from the start of treatment to death from any cause [OS-t]) was 16.4 months.4 In the second group of patients with recurrent GB grade IV after standard therapy, the median survival after recurrence was 10.9 months, and the median survival time from the start of [213Bi]Bi-DOTA-SP was 7.5 months.5

These results looked promising, but it was questioned whether the short half-life of 213Bi (T½ = 46 minutes) might compromise the delivery of sufficient doses to remote tumor cells. Therefore, we considered the advantages of using an isotope with longer half-life. As a next step, we used 225Ac with a longer T½ (9.9 days), which should improve the distribution of the radiopharmaceutical within the tumor. In the group treated with [225Ac]Ac-DOTA-SP, the median progression-free survival from the start of treatment was 2.4 months, and the OS-t was 9.0 months.6

In this article, we analyze our experience of targeted α therapy with radiolabeled [213Bi]Bi-DOTA-SP and [225Ac]Ac-DOTA-SP with recurrent primary and secondary GB tumor grade IV. The aim of this study was to asses both the therapeutic potential and factors related to its success.

MATERIALS AND METHODS

Treatment was performed as salvage therapy in patients with recurrent primary and secondary glial tumors World Health Organization grade IV with [213Bi]Bi-DOTA-SP and [225Ac]Ac-DOTA-SP. The previously published data included the following: [213Bi]Bi-DOTA-SP in 20 primary GB patients (14 males and 6 females; average age, 48.2 ± 11.8 years) and in 9 GB patients (7 females and 2 males; average age, 38.8 ± 10.8 years); [225Ac]Ac-DOTA-SP in 15 primary GB patients (10 males and 5 females; average age, 45.1 ± 9.9 years) and 6 secondary GB patients (3 males and 3 females; average age, 37.8 ± 6.4 years).

The treatment was performed following standard therapy (surgery, radiotherapy, and chemotherapy) between the years 2013 and 2020. Patients were informed about the experimental character of this therapy and gave written informed consent. The study was approved by the ethical committee of the Medical University of Warsaw (KB/235/2011 and KB/172/2016).

For both radionuclide treatments, the same inclusion criteria were applied:

histopathologically confirmed recurrent GB grade IV (World Health Organization); tumor volume less than 90 mL as defined by the T1-weighed contrast-enhanced MRI; absence of obstruction of CSF circulation or decompensating intracranial pressure; Karnofsky performance status score >40; no pregnancy or lactation; age older than 18 years; and absence of psychological, familial, and sociological conditions potentially hampering compliance with the study protocol. Radionuclides and Radiolabeling

225Ac was obtained by radiochemical extraction from 229Th sources at the Directorate for Nuclear Safety and Security of the Joint Research Centre of the European Commission in Karlsruhe, Germany, and at Oak Ridge National Laboratory.8

The 225Ac/213Bi radionuclide generator was prepared as previously described.9

To control injection and biodistribution, [68Ga]Ga-DOTA-SP was coinjected together with therapeutic radiopharmaceuticals [213Bi]Bi-DOTA-SP and [225Ac]Ac-DOTA-SP.

The labeling procedure of [213Bi]Bi-DOTA-SP, [225Ac]Ac-DOTA-SP, and [68Ga]Ga-DOTA-SP was described previously.4

Study Protocol and Injection of the Radiopharmaceutical

One or 2 catheters connected to a subcutaneous port (Medtronic, USA) were implemented stereotactically into the postsurgical cavity 2 to 4 weeks before treatment. The proper catheter position excluding connection to the ventricles or subarachnoid space was confirmed in MRI as previously described.4,5

Therapy with [213Bi]Bi-DOTA-SP or [225Ac]Ac-DOTA-SP was performed in 2-month intervals, administering 1 to 6 cycles. The injection procedure of [213Bi]Bi-DOTA-SP or [225Ac]Ac-DOTA-SP and PET/CT after coinjection of [68Ga]Ga-DOTA-SP with therapeutic doses were performed as a previously described protocol for [213Bi]Bi-DOTA-SP.4,5

Toxicity and Follow-up

Laboratory tests performed included blood cell count, hemoglobin, creatinine, blood-urea-nitrogen, liver enzymes, and clinical status. Patient history was reassessed every 4 to 6 weeks after each treatment cycle, classifying toxicity grades using the Common Terminology Criteria for Adverse Events v3.0. Follow-up MRI imaging was performed every 4 to 6 weeks following injection and thereafter every 3 months.

Statistical Methods

Parameters were characterized by mean ± SD. Progression-free survival time was defined as the time from the start of radioisotope treatment to clinical or imaging signs and symptoms of progression, relapse, or death.

Overall survival from time of diagnosis was defined as the time from initial tumor diagnosis to death from any cause (OS-d); OS from recurrence or conversion was defined as the time from the diagnosis of recurrence in primary tumors or conversion into secondary GBM to death from any cause (OS-r, OS-c). Overall survival from the start of treatment was defined as the time from the first cycle of [213Bi]Bi-DOTA-SP or [225Ac]Ac-DOTA-SP treatment to death from any cause (OS-t). Survival parameters were calculated using the Kaplan-Meier estimator and compared using the log-rank test. Calculations were performed on GraphPad PRISM 5 (GraphPad Software Inc) and Excel for MAC (version 16.28, 2019 Microsoft).

RESULTS Patient Characteristics and Functional Status

Patients with histologically confirmed recurrent or conversion GB grade IV following a standard therapy have been included in the treatment. Twenty-nine patients (age of 45.3 ± 12.5 years) received [213Bi]Bi-DOTA-SP and 21 patients (age of 43.0 ± 9.5 years) received treatment with [225Ac]Ac-DOTA-SP. The outcome of therapy was analyzed separately for recurrence of primary and secondary patients in both treatment groups (Fig. 1).

F1FIGURE 1:

MRI scans of a 32-year-old woman suffering from an astrocytoma World Health Organization grade II, conversion into a secondary GB grade IV manifested 10.6 months after initial diagnosis. The patient was treated with 4 cycles of [223Bi]Bi-DOTA-SP with a total activity of 8 GBq. A and B, The T1-weighed enhanced and T2-weighted MRI scans before local treatment of recurrent tumor. C and D, Eight years after the treatment. Lack of neurological symptoms and shrinkage of the tumor in MRI scans are observed.

In all patients, MRI of the brain demonstrated recurrence of disease in the form of diffuse T2 and FLAIR changes and irregular ring-shaped contrast enhancement part in T1 around the postoperative cavity.

The functional status of patients before the treatment and during the follow-up was assessed using the Karnofsky performance status and Barthel Index.

For the groups treated with [213Bi]Bi-DOTA-SP versus [225Ac]Ac-DOTA-SP, the median pretherapeutic Karnofsky performance status was 70 (range, 50–100) versus 70 (range, 40–100), and Barthel Index was 90 (range, 35–100) versus 90 (range, 25–100).

The characteristics of the patients are summarized in Table 1 and Table 2.

TABLE 1 - Detailed Patients' Data Treated With [213Bi]Bi-DOTA-SP Age at Start of Bi Therapy Grade 4 Total, GBq Cycles Barthel Karnofsky Before Treatment Viable Tumor Volume, mL 1 51 Primary GB NOS 3.1 2 70 70 27.3 2 38 Primary GB NOS 1.7 1 50 50 23.1 3 58 Primary GB NOS 11.2 6 95 80 64.3 4 53 Primary GB NOS 2.1 1 70 60 20.4 5 37 Primary GB NOS 7.8 4 100 70 4.5 6 40 Primary GB NOD 1.7 1 80 70 53.2 7 54 Primary GB NOS 7.6 4 100 70 72.8 8 47 Primary GB NOS 2.0 1 50 60 29.2 9 68 Primary GB NOS 1.9 1 35 50 83.0 10 41 Primary GB NOS 5.0 3 100 90 42.7 11 45 Primary GB NOS 1.7 1 60 40 42.7 12 57 Primary GB NOS 1.8 1 90 90 26.6 13 27 Primary GB NOS 10.8 7 100 100 57.6 14 53 Primary GB NOS 1.6 1 85 60 42.1 15 43 Primary GB NOS 3.4 2 100 90 23.0 16 48 Primary GB NOS 7.4 4 100 90 62.4 17 66 Primary GB NOS 6.3 4 100 100 10.3 18 22 Primary GB NOS 6.2 4 85 60 24.8 19 51 Primary GB NOS 4.3 4 90 90 17.7 20 65 Primary GB NOS 3.1 3 95 70 6.5 21 42 Secondary GB NOS 5.5 4 60 80 3.9 22 38 Secondary GB NOS 4.2 3 100 80 15.6 23 59 Secondary GB NOS 3.1 2 70 60 60.9 24 35 Secondary GB NOS 2.3 2 50 40 81.5 25 29 Secondary GB NOS 6.9 6 100 90 57.5 26 42 Secondary GB NOS 4.9 4 70 60 17.3 27 32 Secondary GB NOS 5.4 4 100 100 42.3 28 51 Secondary GB NOS 1.0 1 45 50 64.3 29 21 Secondary GB NOS 1.1 1 100 90 18.7

GB, glioblastoma; NOS, not otherwise specified; SP, substance P.


TABLE 2 - [225Ac]Ac-DOTA-SP Patient Characteristics Age at Start of ac Therapy Grade 4 Total, MBq Cycles Barthel Karnofsky Before Treatment Viable Tumor Volume, mL 1 41 Primary GB NOS 53.4 5 100 80 27.3 2 42 Primary GB NOS 44.8 4 100 90 23.1 3 64 Primary GB NOS 22.8 2 100 80 64.3 4 48 Primary GB NOS 11.6 1 60 60 20.4 5 46 Primary GB NOS 54.9 2 80 60 17.7 6 43 Primary GB IDH wild type 149.5 6 90 70 53.2 7 47 Primary GB NOS 28.4 1 100 90 77.3 8 35 Primary GB NOS 53.2 2 100 80 24.8 9 32 Primary GB NOS 17.6 1 90 60 83.0 10 48 Primary GB NOS 57.6 3 70 70 42.7 11 63 Primary GB NOS 18.1 1 25 50 42.7 12 53 Primary GB NOS 19.1 1 80 100 26.6 13 28 Primary GB NOS 20.6 1 85 70 57.6 14 45 Primary GB NOS 75.0 3 100 90 42.1 15 42 Primary GB IDH mutant 105.0 3 95 80 23.0 16 26 Secondary GB NOS 56.5 2 75 60 6.5 17 43 Secondary GB NOS 101.5 5 100 100 4.5 18 39 Secondary GB IDH wild type 98.7 5 45 40 72.8 19 38 Secondary GB NOS 97.0 4 90 70 29.2 20 37 Secondary GB IDH mutant 54.6 2 100 80 62.4 21 44 Secondary GB IDH mutant 26.8 1 65 60 10.3

GB, glioblastoma; IDH, isocitrate dehydrogenase; NOS, not otherwise specified; SP, substance P.


Analysis of Adverse Effects [213Bi]Bi-DOTA-SP Versus [225Ac]Ac-DOTA-SP Group

Generally, local treatment with [213Bi]Bi-DOTA-SP and [225Ac]Ac-DOTA-SP was well tolerated. In the group treated with [213Bi]Bi-DOTA-SP, no signs of hematological, liver, and kidney toxicity were observed. In that group, in 4 of 29 patients, some flush of face was observed as systemic SP effects following absorption of small amounts of tracer into the bloodstream. In 2 patients, transient worsening of paresis and aphasia were observed for 5 days. Epileptic seizures were observed in 10 patients within 2 to 5 days after injection; however, in all these cases, seizures were noted sporadically also before radioisotope treatment, despite treatment with antiepileptic drugs. Only 1 patient had leakage to the ventricle with ventricular enhancement was seen in MRI, but without clinical symptoms, successfully treated with high doses of corticosteroids. No other severe adverse events in group treated with [213Bi]Bi-DOTA-SP occurred.

In the group treated with [225Ac]Ac-DOTA-SP, epileptic seizures were observed 2 to 5 days after injection in 4 patients; in all these cases, seizures were noted also before radioisotope treatment. Six patients revealed worsening of hemiparesis or aphasia; in the majority, transient, and in one of them, local symptoms were progressive. In another patient, transient worsening of the general clinical condition was observed. One patient had leakage to the ventricle because of partial connection to the ventricles, successfully treated with high doses of corticosteroids.

In 2 patients, 2 and 3 weeks after treatment with 30 MBq of [225Ac]Ac-DOTA-SP, severe perifocal brain edema was observed, requiring hospitalization and intensive intravenous treatment, without intubation. In that group, additional hematological, liver, and kidney toxicity was measured. Only adverse effects were seen in the group treated with 20 MBq and 30 MBq of [225Ac]Ac-DOTA-SP: observed hematological toxicity: thrombocytopenia grade 2 in 1 patient in the 20 MBq group and thrombocytopenia grade 3 in 1 patient in the 30 MBq group, and hepatic toxicity grade 1 was seen in 1 patient of the 30 MBq dose escalation group.

There was no other toxicity observed related to [225Ac]Ac-DOTA-SP.

Analysis of Survival Parameters [213Bi]Bi-DOTA-SP Versus [225Ac]Ac-DOTA-SP Group

We analyzed our previously published data for patients treated with [213Bi]Bi-DOTA-SP and with [225Ac]Ac-DOTA-SP for primary and secondary GB.4–6

Patients were treated with [213Bi]Bi-DOTA-SP with injected activity approximately 1.85 GBq per cycle and [225Ac]Ac-DOTA-SP in a dose escalation scheme and activity of 10 MBq followed by 20 MBq and 30 MBq. There was no statistically significant difference between the patient group treated with [213Bi]Bi-DOTA-SP and that treated with [225Ac]Ac-DOTA-SP for both primary and secondary GB. Data are presented in Tables 3 and 4.

TABLE 3 - Survival Parameters of Primary Glioblastoma Patients Treated With [213Bi]Bi-DOTA-SP and [225Ac]Ac-DOTA-SP [213Bi]Bi-DOTA-SP (n = 20) [225Ac]Ac-DOTA-SP (n = 15) P PFS, mo 2.7 2.4 ns OS-d, mo 23.6 21.0 ns OS-t, mo 7.5 5.0 ns OS-r, mo 10.9 12.0 ns

ns, not significant; OS-d, overall survival from time of diagnosis to death from any cause; OS-r, overall survival from recurrence in primary tumors to death from any cause; OS-t, overall survival from the start of treatment to death from any cause; PFS, progression-free survival; SP, substance P.


TABLE 4 - Survival Parameters of Secondary Glioblastoma Patients Treated With [213Bi]Bi-DOTA-SP and [225Ac]Ac-DOTA-SP [213Bi]Bi-DOTA-SP (n = 9) [225Ac]Ac-DOTA-SP (n = 6) P

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