Pain Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with 223Ra: PARABO, a Prospective, Noninterventional Study.

223Ra, a targeted α-therapy, is approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have bone metastases. In the phase 3 ALSYMPCA study, 223Ra prolonged survival and improved quality of life versus placebo. Our real-world study, PARABO, investigated pain and bone pain-related quality of life in patients with mCRPC and symptomatic bone metastases receiving 223Ra in clinical practice. Methods: PARABO was a prospective, observational, noninterventional single-arm study conducted in nuclear medicine centers across Germany (NCT02398526). The primary endpoint was a clinically meaningful pain response (≥2-point improvement from baseline for the worst-pain item score in the Brief Pain Inventory-Short Form). Results: The analysis included 354 patients, who received a median of 6 223Ra injections (range, 1-6). Sixty-seven percent (236/354) received 5-6 injections, and 33% (118/354) received 1-4 injections. Of 216 patients with a baseline worst-pain score of more than 1, 59% (128) had a clinically meaningful pain response during treatment. Corresponding rates were 67% (range, 98/146) with 5-6 223Ra injections versus 43% (range, 30/70) with 1-4 injections, 60% (range, 60/100) in patients with no more than 20 lesions versus 59% (range, 65/111) in those with more than 20 lesions, and 65% (range, 69/106) in patients without prior or concomitant opioid use versus 54% (range, 59/110) in those with prior or concomitant opioid use. Mean subscale scores (pain severity and pain interference) on the Brief Pain Inventory-Short Form improved during treatment. Conclusion: 223Ra reduced pain in patients with mCRPC and symptomatic bone metastases, particularly in patients who received 5-6 injections. The extent of metastatic disease did not impact pain response.

227Th-Labeled Anti-CD22 Antibody (BAY 1862864) in Relapsed/Refractory CD22-Positive Non-Hodgkin Lymphoma: A First-in-Human, Phase I Study.

Background: BAY 1862864 is an α-particle emitting 227Th-labeled CD22-targeting antibody. This first-in-human dose-escalation phase I study evaluated BAY 1862864 in patients with CD22-positive relapsed/refractory B cell non-Hodgkin lymphoma (R/R-NHL). Materials and Methods: BAY 1862864 intravenous injections were administered at the starting 227Th radioactivity dose of 1.5 MBq (2 or 10 mg antibody), and the radioactivity dose escalated in ∼1.5 MBq increments (10 mg antibody) until the maximum tolerated dose (MTD) was reported. The primary objective was to determine the safety, tolerability, and MTD. Results: Twenty-one patients received BAY 1862864. Two dose-limiting toxicities (grade 3 febrile neutropenia and grade 4 thrombocytopenia) were reported in one patient in the 4.6 MBq (10 mg antibody) cohort. The MTD was not reached. Ten (48%) patients reported grade ≥3 treatment-emergent adverse events, with the most common being neutropenia, thrombocytopenia, and leukopenia, each occurring in 3 (14%) patients. Pharmacokinetics demonstrated the dose proportionality and stability of BAY 1862864 in the blood. The objective response rate (ORR) was 25% (5/21 patients) according to the LUGANO 2014 criteria, including 1 complete and 4 partial responses. The ORR was 11% (1/9) and 30% (3/10) in patients with relapsed high- and low-grade lymphomas, respectively. Conclusions: BAY 1862864 was safe and tolerated in patients with R/R-NHL. Clinical Trial Registration numbers: NCT02581878 and EudraCT 2014-004140-36.

Assessment of the radiation exposure of relatives and caregivers of patients treated with Ra-223 - Results of a German multicenter study.

A multicenter study was conducted to assess the radiation exposure of relatives and caregivers of patients suffering from castration resistant prostate cancer with bone metastases and treated with Ra-223 dichloride in an outpatient setting. As Ra-223 and most of its progeny emit alpha particles, especially the internal exposure of persons in the patient's vicinity had to be evaluated. METHODS: The external radiation was measured in distances of 1 m and 2 m. Wipe-tests were taken in the patients' homes to identify significant contaminations and evaluated by liquid scintillation counting. Samples of saliva and sweat were taken and measured using gamma spectrometry. RESULTS: The external exposure from the patients measured 10-20min post injection (p. i.) was<0.080µSv/h in median in 1 m distance (range: below decision threshold (

Radiopharmaceutical tracking of particles injected into tumors: a model to study clearance kinetics.

OBJECTIVES: Success of selective drug therapies depends on the drug's depot time in the target to treat. Depot time is currently being prolonged, using drug-eluting beads or microspheres for selective internal radiation therapy. The purpose of this study was to establish a model for investigating the depot time of particles injected into tumors in relation to tumor vascularization and particle size. MATERIALS AND METHODS: An animal model with two different vascularized tumors (Walker Carcinoma 256 (hypervascularized) and Yoshida Sarcoma (hypovascularized)) was used. The tumors were implanted into the hind leg of Wistar rats. When the tumors reached 10-15mm, rhenium radiolabeled particles of 25microm and 0.3microm were percutaneously injected into the tumors: large particles (Re-188 microspheres) in 10 hypo- and 10 hypervascularized tumors and small particles (Re-186 sulfid colloid) in 4 hypo- and 16 hypervascularized tumors with the co-injection of the vasoconstrictor, adrenalin (0.01 mg), into 8 hypervascularized tumors. Tumor activity was measured with a gamma camera at 10 min, 1h, 3h, 6h, 14h and 48h p.i. In addition, activity in the lung, liver, spleen, kidneys, and lymph nodes was measured at 48 h p.i. Measurements were adjusted for decay times and then compared. RESULTS: Drainage of the injected particles is bi-phasic, characterized by a fast wash-out. At 10 min p.i., intratumoral activity decreases to 70% of the initially injected activity. This is followed by a slow decline at 48 h p.i in which intratumoral activity decreases to at least 60% of the initially injected activity. Slow decline is independent of particle size and vascularization, whereas fast leakage depends on both. Co-injecting adrenalin significantly reduced the wash-out of the small particles. Radiolabeled microspheres accumulated mainly in the lungs, smaller colloids in the liver. CONCLUSIONS: Particle stay time, biodistribution, and stability can be easily monitored as shown in this animal model. The hematogeneous wash-out can be reduced, using larger particles and vasoconstrictors. Prolonged retention is independent of vascularization and particle size and appears to be sufficient for therapy.

Feasibility of high activity rhenium-188-microsphere in hepatic radioembolization.

BACKGROUND: This paper describes the feasibility of intra-arterial high-activity administration of (188)Re-microspheres. METHODS: Patients with unresectable colorectal liver metastases or hepatocellular cancer (HCC) received single treatments with (188)Re-microspheres. The administered activity was calculated to give a liver dose of 100 Gy. From post-therapeutic scans and urine sampling, the dose to the liver, metastases and bladder was calculated. Toxicity was assessed up to 3 months after administration by means of the Common Terminology Criteria for Adverse Events v3.0 (Trotti et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13(3):176-81). Response was evaluated on CT. RESULTS: 13.6 +/- 4.7 GBq (188)Re-microspheres was administered selective in the feeding artery of the tumour to 10 patients (3 x HCC and 7 x colorectal liver metastases). There was a low urinary excretion rate of 8.9 +/- 3.8% of administered activity within 96 h. The absorbed dose to the tumour, normal liver (excluding the tumour) and bladder was 10.24 +/- 5.02 Gy/GBq (128 +/- 47 Gy), 3.94 +/- 2.52 Gy/GBq (50 +/- 33 Gy) and 0.27 +/- 0.20 Gy/GBq (2.4 +/- 1.9 Gy), respectively. There was an acceptable rate of toxicity in 30% of grades I and II, respectively, and 10% with grade III. There was reversible in the most patients within 14 days after treatment. The response was assessed on CT: two patients had a partial response (PR), five patients had stable disease and three patients had disease progression. CONCLUSION: Treatment of colorectal liver metastases or HCC using high activities of (188)Re-microspheres was well tolerated and a PR was seen in 2 of 10 patients. The treatment represents a therapeutic option in these patients.