Microwave hyperthermia enhances radiosensitization by decreasing DNA repair efficiency and inducing oxidative stress in PC3 prostatic adenocarcinoma cells.

PURPOSE: Radiotherapy (RT) is the primary treatment for prostate cancer (PCa); however, the emergence of castration-resistant prostate cancer (CRPC) often leads to treatment failure and cancer-related deaths. In this study, we aimed to explore the use of microwave hyperthermia (MW-HT) to sensitize PCa to RT and investigate the underlying molecular mechanisms. METHODS: We developed a dedicated MW-HT heating setup, created an in vitro and in vivo MW-HT + RT treatment model for CRPC. We evaluated PC3 cell proliferation using CCK-8, colony experiments, DAPI staining, comet assay and ROS detection method. We also monitored nude mouse models of PCa during treatment, measured tumor weight, and calculated the tumor inhibition rate. Western blotting was used to detect DNA damage repair protein expression in PC3 cells and transplanted tumors. RESULTS: Compared to control, PC3 cell survival and clone formation rates decreased in RT + MW-HT group, demonstrating significant increase in apoptosis, ROS levels, and DNA damage. Lower tumor volumes and weights were observed in treatment groups. Ki-67 expression level was reduced in all treatment groups, with significant decrease in RT + MW-HT groups. The most significant apoptosis induction was confirmed in RT + MW-HT group by TUNEL staining. Protein expression levels of DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways significantly decreased in RT + MW-HT groups. CONCLUSION: MW-HT + RT treatment significantly inhibited DNA damage repair by downregulating DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways, leading to increased ROS levels, aggravate DNA damage, apoptosis, and necrosis in PC3 cells, a well-established model of CRPC.

PSMA-targeted radioligand therapy in prostate cancer: current status and future prospects.

INTRODUCTION: The prostate-specific membrane antigen (PSMA) targeted radioligand therapy (PRLT) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients has generated significant interest among the oncologic community, with several publications documenting good response rates and survival benefits with low toxicity profiles. AREAS COVERED: Indications, patient preparation, dose administration, post-treatment imaging, dosimetry, and side effect profiles of 177Lu-PSMA-617 are discussed in this article. We also discuss results from prospective studies, major retrospective studies, meta-analyses, clinical trials, and mentioned major ongoing clinical trials on PRLT. We have also portrayed our own experiences and future perspectives on PRLT. EXPERT OPINION: For PRLT, PSMA-617 and PSMA-I&T molecules have revolutionized the theranostic approach in the management of advanced prostate cancer, with solid backing from several published articles showing favorable outcomes and an excellent safety profile of 177Lu-PSMA-617. Improvement in quality of life and survival was seen in the majority of mCRPC patients after 177Lu-PSMA-617 PRLT. Patients with good performance status, asymptomatic, only lymph node metastases, high PSMA expressing lesions, and no discordant FDG avid lesions have a longer survival after 177Lu-PSMA-617 PRLT than patients with poor performance status, symptomatic, hepatic, brain, and skeletal metastases, discordant PSMA, and FDG-avid lesions. Docetaxel and cabazitaxel are approved treatments for mCRPC patients. 177Lu-PSMA-617 is approved as a third-line systemic treatment for mCRPC patients with failure to respond to androgen receptor pathway inhibitors and docetaxel therapy. PRLT is a safe and effective alternative to cabazitaxel (third-line systemic treatment), but it has a higher cost. 177Lu-PSMA-617 could be a more efficient therapeutic option for mCRPC patients as first-line or combined therapy, and it may be a useful therapeutic option for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) patients. Several clinical studies and clinical trials on PRLT are currently underway. In the future, the results of these trials will be helpful in evolving treatment strategies for prostate cancer patients.

225Ac-PSMA-617 radioligand therapy of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC): preliminary clinical findings.

PURPOSE: 225Ac-PSMA-617 has demonstrated good anti-tumor effect as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients. No study has previously assessed treatment outcome and survival following 225Ac-PSMA-617 treatment of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC) patients. Based on the potential side effects that are known and explained to the patients by the oncologist, some of the patients refused the standard treatment and are seeking alternative therapies. Thus, we report our preliminary findings in a retrospective series of 21 mHSPC patients that refused standard treatment options and were treated with 225Ac-PSMA-617. METHODS: We retrospectively reviewed patients with histologically confirmed de novo treatment-naïve bone ± visceral mHSPC that were treated with 225Ac-PSMA-617 radioligand therapy (RLT). Inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, treatment-naive bone ± visceral mHSPC, and patients refusal for ADT ± docetaxel, abiraterone acetate, or enzalutamide. We evaluated the response to treatment using prostate-specific antigen (PSA) response and the progression-free survival (PFS) and overall survival (OS) as well as the toxicities. RESULTS: Twenty-one mHSPC patients were included in this preliminary work. Following treatment, twenty patients (95%) had any decline in PSA and eighteen patients (86%) presented with a PSA decline of ≥ 50% including 4 patients in whom PSA became undetectable. A lower percentage decrease in PSA following treatment was associated with increased mortality and shorter progression-free survival. Overall, administration of 225Ac-PSMA-617 was well tolerated. The commonest toxicity seen was grade I/II dry mouth observed in 94% of patients. CONCLUSIONS: Given these favorable results, randomized prospective multicenter trials assessing the clinical value of 225Ac-PSMA-617 as a therapeutic agent for mHSPC administered either as monotherapy or administered concomitant with ADT are of interest.

Redox-responsive nanoparticles enhance radiation therapy by altering multifaceted radio-resistance mechanisms in human castration-resistant prostate cancer cells and xenografts.

INTRODUCTION: Radiation therapy (RT) is a major modality for the treatment of prostate cancer (PCa), especially castration-resistant PCa (CRPC). However, hypoxia, often seen in PCa tumors, leads to radiation-resistance. This work investigates the effect of a novel oxygen-generating polymer-lipid manganese dioxide nanoparticle (PLMDs) on improving RT outcomes in CRPC xenograft models by modulating the tumor microenvironment (TME) both before and after RT. MATERIALS AND METHODS: Human PC3 and DU145 PCa cells were used to investigate clonogenic inhibition and DNA repair pathways in vitro. Tumor hypoxia and post-RT angiogenesis were evaluated in a PC3-bearing SCID mouse model. PC3 and DU145 xenografts were used to study the efficacy of PLMD in combination with single or fractionated RT. RESULTS: PLMD plus RT significantly inhibited clonogenic potential, increased DNA double-strand breaks, and reduced DNA damage repair in hypoxic PC3 and DU145 cells as compared to RT alone. PLMD significantly reduced hypoxia-positive areas, hypoxia induced factor 1α (HIF-1α) expression, and protein carbonyl levels (a measure of oxidative stress). Application of PLMD with RT decreased RT-induced angiogenic biomarkers by up to 3-fold. Treatment of the human CRPC xenografts with PLMD plus RT (single or fractionated doses) significantly prolonged median survival of the host compared to RT alone resulting in up to a 40% curative rate. CONCLUSION: PLMD treatment modulated TME and sensitized hypoxic human CRPC cells to RT thus enhancing the efficacy of RT. These results confirmed the potential of PLMD as an adjuvant to RT for the treatment of hypoxic CRPC.

Phase I Trial of Weekly Cabazitaxel with Concurrent Intensity Modulated Radiation and Androgen Deprivation Therapy for the Treatment of High-Risk Prostate Cancer.

PURPOSE: Cabazitaxel has been demonstrated to improve the overall survival for men with metastatic castrate-resistant prostate cancer. The purpose of this study was to determine the maximum tolerated dose for concurrent cabazitaxel with androgen deprivation and intensity modulated radiation therapy in men with high-risk prostate cancer. METHODS AND MATERIALS: Twenty men were enrolled in this institutuional review board-approved phase I clinical trial using a 3 + 3 design. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition. RESULTS: With a median follow-up time of 56 months, the maximum tolerated dose of concurrent cabazitaxel was 6 mg/m2. The 5-year biochemical disease-free survival was 73%, despite 75% of patients having very high risk prostate cancer per the National Comprehensive Cancer Network guidelines. Four patients were unable to complete chemotherapy owing to dose-limiting toxicities (eg, rectal bleeding, diarrhea, and elevated transaminase). There was no significant minimally important difference in Expanded Prostate Index Composite patient-reported outcomes for either the urinary or bowel domains; however, there was a significant decrease in the sexual domain. CONCLUSIONS: This is the first clinical trial of prostate cancer to report on the combination of cabazitaxel and radiation therapy. The maximum tolerated dose of concurrent cabazitaxel with radiation and androgen deprivation therapy was determined to be 6 mg/m2. Despite the aggressive nature of the disease, robust biochemical control was observed.

Response assessment using [68 Ga]Ga-PSMA ligand PET in patients undergoing systemic therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: To assess which parameters of [68 Ga]Ga-PSMA-11 positron emission tomography (PSMA-PET) predict response to systemic therapies in metastatic (m) castration-resistant prostate cancer (CRPC). In addition, to investigate which of these factors are associated with overall survival (OS). METHODS: We retrospectively assessed the following PSMA-PET parameters in 43 patients before and after systemic therapies for mCRPC: PSMA total tumor volume (TTV), mean standardized uptake value (SUVmean), SUVmax, and SUVpeak. prostate-specific antigen (PSA) levels and PSMA-PET/CT(magnetic resonance imaging [MRI]) imaging were both performed within 8 weeks before and 6 weeks after systemic therapy. PSMA-PET and CT (MRI) images were reviewed according to the modified PET Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results were compared to PSA response. Univariable survival analyses were performed. RESULTS: Overall, 43 patients undergoing 67 systemic therapies were included (9 patients radium-223, 12 cabazitaxel, 22 docetaxel, 6 abiraterone, and 18 enzalutamide). Median serum PSA level before any therapy was 11.3 ng/mL (interquartile range [IQR] = 3.3, 30.1). Delta (d) PSA after systemic therapies was -41%, dTTV 10.5%, dSUVmean -7.5%, dSUVmax -13.3%, dSUVpeak -12%, and dRECIST -13.3%. Overall, 31 patients had dPSA response (46.3%), 12 stable disease (17.9%), and 24 progressive disease (35.8%). All observed PET parameters, as well as the RECIST evaluation, were significantly associated with PSA response (dTTV P = .003, dSUVmean P = .003, dSUVmax P = .011, dSUVpeak P < 0001, dRECIST P = .012), while RECIST assessment was applicable in 37 out of 67 patients (55.2%). Within a median follow-up of 33 months (IQR = 26, 38), 10 patients (23.3%) died of PC. On univariable survival analyses, neither the investigated PET parameters nor PSA level or RECIST criteria were associated with OS. CONCLUSION: PSMA-PET provides reliable parameters for prediction of response to systemic therapies for mCRPC. These parameters, if confirmed, could enhance RECIST criteria, specifically concerning its limitations for sclerotic bone lesions.

Efficacy and Safety of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer Patients.

PURPOSE: The aim of this study was to evaluate the efficacy and safety of Lu-PSMA-617 radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC). METHODS: In this prospective, single-arm, single-institutional study, 90 mCRPC patients with progressive disease (PD) on second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic Ga-PSMA-HBED-CC PET/CT, prior to inclusion for therapy. Included patients underwent Lu-PSMA-617 therapy at 8- to 12-weekly intervals. The primary end point was to assess the overall survival. The secondary and cosecondary end points included biochemical response assessment as per the Prostate Cancer Working Group 3 criteria, progression-free survival, radiological and molecular response criteria, clinical response, safety profile, and disease control rates. All the outcome parameters were evaluated in 90 patients except for the radiographic and molecular response, which was evaluated in 69 patients. RESULTS: The median age of patients was 66.5 years (range, 30-88 years). The median activity administered per cycle was 3.7 to 8 GBq ranging from 1 to 7 cycles, and patients were followed up over a median duration of 28 months. At 2- to 3-month interval after the first therapy and the end of the assessment, greater than 50% decline in prostate-specific antigen was observed in 32.2% and 45.5%, respectively. Univariate analysis did not reveal any variables such as prior therapies, laboratory parameters, concomitant hormonal therapy, and SUV patient parameters associated with prostate-specific antigen decline. Radiographic response by diagnostic CT revealed partial remission in 23% (16/69), stable disease in 54% (37/69), and PD in 23% (16/69) of patients. Molecular tumor response by PET Response Criteria in Solid Tumor 1 criteria revealed 19 (27.5%) of 69 patients with partial remission, 30 (43.5%) of 69 with stable disease, and 20 (29%) of 69 with PD. The disease control rates according to the radiographic and molecular response were 77% and 71%, respectively. The median overall survival and median progression-free survivals were 14 and 11.8 months, respectively. Toxicities related to radioligand therapy were low and transient with no serious adverse effects. CONCLUSIONS: Lu-PSMA-617 radionuclide therapy is a safe and effective approach to the treatment of mCRPC patients.

Determination of whole-body tumour burden on [68Ga]PSMA-11 PET/CT for response assessment of [177Lu]PSMA-617 radioligand therapy: a retrospective analysis of serum PSA level and imaging derived parameters before and after two cycles of therapy.

AIM: In patients with metastasized castration-resistant prostate cancer a reliable imaging-based therapy response assessment in addition to PSA kinetics is desirable. Recently, measurements of whole-body tumour burden by [68Ga]PSMA-11 PET/CT have been reported for response assessment in oligometastasic patients. The present study investigated the association of PSMA PET derived parameters and serum PSA level before and after [177Lu]PSMA-617 radioligand therapy (RLT). METHODS: This retrospective study assessed whole-body PSMA tumour volume (PSMA-TV) in 10 patients with multifocal to diffuse metastases before and after 2 cycles of RLT using volume of interest (VOI) analysis. A standardized uptake value (SUV) threshold-based approach was used to semi-automatically delineate all voxels with a SUV ≥ 2.0 g/ml using the software ROVER® (ABX Radeberg, Germany). Voxels with physiological tracer uptake (e. g. kidneys) were excluded manually. Correlations between PSMA-TV and serum PSA level before and after two cycles of RLT as well as changes thereof (ΔPSMA-TV and ΔPSA, respectively) were calculated. RESULTS: Changes of ΔPSMA-TV and ΔPSA were concordant in 7 of 10 patients. Whereas a good correlation was found between PSMA-TV and PSA before RLT (ρ = 0.81, p = 0.0049), this correlation was attenuated after RLT (ρ = 0.64, p = 0.0479). Consequently, no association was found between ΔPSMA-TV and ΔPSA (ρ = 0.39, p = 0.26). CONCLUSION: The attenuation of the correlation of PSA and PSMA-TV after RLT suggests that in patients with advanced disease the comparison of imaging based parameters such as PSMA-TV and PSA level might be useful for an adequate monitoring of treatment response.

Can Local Ablative Radiotherapy Revert Castration-resistant Prostate Cancer to an Earlier Stage of Disease?

In prostate cancer, disease progression after primary treatment and subsequent androgen deprivation therapy is common. Intensification of systemic treatment is the standard of care. Recently, 68Ga prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging was introduced to identify oligometastatic prostate cancer patients. In this retrospective, exploratory study, we report on the efficacy of PSMA-PET-guided local ablative radiotherapy (aRT) in 15 oligometastatic castration-resistant prostate cancer (CRPC) patients, selected from our prospective institutional database and treated between 2013 and 2016. After multidisciplinary discussion, aRT was delivered with two different schedules. Androgen deprivation therapy remained unchanged. Prostate-specific antigen (PSA) response and time to PSA progression were analysed. For comparison, individual time to PSA progression without aRT was estimated by individual PSA doubling time (PSADT). PSA response was observed in 11 patients (73%). Mean time to PSA progression or last follow-up was 17.9mo, as opposed to 2.9mo estimated from the PSADT without aRT (p<0.001). A relevant subset of CRPC patients had a PSA response with aRT to PET-positive lead metastases. A prospective trial is in preparation. PATIENT SUMMARY: In selected patients with prostate-specific antigen (PSA) increase during androgen deprivation, metastases were detected with prostate-specific membrane antigen positron emission tomography imaging. Fifteen patients with three or fewer metastases were treated with high-dose radiotherapy. Subsequently, PSA values dropped in 11 patients and in six patients no PSA progression was detected for >12mo.

225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study.

BACKGROUND: A remarkable therapeutic efficacy has been demonstrated with 225Ac-prostate-specific membrane antigen (PSMA)-617 in heavily pre-treated metastatic castration-resistant prostate cancer (mCRPC) patients. We report our experience with 225Ac-PSMA-617 therapy in chemotherapy-naïve patients with advanced metastatic prostate carcinoma. METHODS: Seventeen patients with advanced prostate cancer were selected for treatment with 225Ac-PSMA-617 in 2-month intervals, with initial activity of 8 MBq, then de-escalation to 7 MBq, 6 MBq or 4 MBq in cases of good response. In one patient, activity was escalated to 13 MBq in the third cycle. Fourteen patients had three treatment cycles administered, while in three patients treatment was discontinued after two cycles due to good response. Six out of 17 patients received additional treatments after the third cycle. Prostate-specific antigen (PSA) was measured every 4 weeks for PSA response assessment. 68Ga-PSMA-PET/CT was used for functional response assessment before each subsequent treatment cycle. Serial full blood count, renal function test, and liver function were obtained to determine treatment-related side effects. RESULTS: Good antitumor activity assessed by serum PSA level and 68Ga-PSMA-PET/CT was seen in 16/17 patients. In 14/17 patients, PSA decline ≥90% was seen after treatment, including seven patients with undetectable serum PSA following two (2/7) or three cycles (5/7) cycles of 225Ac-PSMA-617. Fifteen of 17 patients had a > 50% decline in lesions avidity for tracer on 68Ga-PSMA-PET/CT including 11 patients with complete resolution (PET-negative and either stable sclerosis on CT for bone or resolution of lymph node metastases) of all metastatic lesions. Grade 1/2 xerostomia was seen in all patients, and none was severe enough to lead to discontinuation of treatment. One patient had with extensive bone marrow metastases and a background anemia developed a grade 3 anemia while another patient with solitary kidney and pre-treatment grade 3 renal failure developed grade 4 renal toxicity following treatment. The group presented with significant palliation of bone pain and reduced toxicity to salivary glands due to de-escalation. CONCLUSIONS: 225Ac-PSMA-617 RLT of chemotherapy-naïve patients with advanced metastatic prostate carcinoma led to a ≥ 90% decline in serum PSA in 82% of patients including 41% of patients with undetectable serum PSA who remained in remission 12 months after therapy. The remarkable therapeutic efficacy reported in this study could be achieved with reduced toxicity to salivary glands due to de-escalation of administered activities in subsequent treatment cycles. This necessitates further exploration for informing clinical practice and clinical trial design.

The 68Ga/177Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUVmax values and absorbed dose estimates.

INTRODUCTION: A targeted theragnostic approach based on increased expression of prostate-specific membrane antigen (PSMA) on PC cells is an attractive treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Ten consecutive mCRPC patients were selected for 177Lu-PSMA617 therapy on the basis of PSMA-targeted 68Ga-PSMA-HBED-CC PET/CT diagnosis showing extensive and progressive tumour load. Following dosimetry along with the first therapy cycle restaging (68Ga-PSMA-HBED-CC and 18F-NaF PET/CT) was performed after 2 and 3 therapy cycles (each 6.1 ± 0.3 GBq, range 5.4-6.5 GBq) given intravenously over 30 minutes, 9 ± 1 weeks apart. PET/CT scans were compared to 177Lu-PSMA617 24-hour whole-body scans and contrast-enhanced dual-phase CT. Detailed comparison of SUVmax values and absorbed tumour doses was performed. RESULTS: 177Lu-PSMA617 dosimetry indicated high tumour doses for skeletal (3.4 ± 1.9 Gy/GBq; range 1.1-7.2 Gy/GBq), lymph node (2.6 ± 0.4 Gy/GBq; range 2.3-2.9 Gy/GBq) as well as liver (2.4 ± 0.8 Gy/GBq; range 1.7-3.3 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 18 ± 0.3 GBq. Three patients showed partial remission, three mixed response, one stable and three progressive disease. Decreased 177Lu-PSMA617 and 68Ga-PSMA-HBED-CC uptake (mean SUVmax values 20.2 before and 15.0 after 2 cycles and 11.5 after 3 cycles, p < 0.05) was found in 41/54 skeletal lesions, 12/13 lymph node metastases, 3/5 visceral metastases and 4/4 primary PC lesions. CONCLUSION: Due to substantial individual variance, dosimetry is mandatory for a patient-specific approach following 177Lu-PSMA617 therapy. Higher activities and/or shorter treatment intervals should be applied in a larger prospective study.

Excellent Response to 177Lu-PSMA-617 Radioligand Therapy in a Patient With Advanced Metastatic Castration Resistant Prostate Cancer Evaluated by 68Ga-PSMA PET/CT.

Recently radiolabeled ligands targeting prostate specific membrane antigen (PSMA) have been introduced for diagnostics and treatment of prostate cancer. Labeled with Lutetium, PSMA radioligand therapy (RLT) is one of the most promising new treatments of metastatic castration refractory prostate cancer. We present images of Ga-PSMA PET/CT and parameters of response of a 75-year-old heavily pretreated metastatic castration refractory prostate cancer patient with extended bone metastases, showing an extraordinary biochemical response in PSA-levels concordant to SUV decline in bone metastases. Furthermore, this case shows that CT is of no use in assessing response in bone metastases of prostate cancer.

Benefit of 68Ga-PSMA-PET/CT in Patients Considered for 223Ra-Dichloride Therapy.

A 66-year-old man with castration-resistant prostate carcinoma and multiple symptomatic bone mestastases was considered for Ra-dichloride (Xofigo) therapy. Staging with Ga-PSMA-PET/CT revealed additional extensive tumor involvement of the spine without relevant uptake in bone scintigraphy. Based on this imaging result, the patient was rescheduled for a PSMA-targeted therapy. Additional Ga-PSMA-PET/CT may have a considerable benefit for patients considered for Xofigo.

177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy.

UNLABELLED: The objective of this study was to analyze the safety and efficacy of the (177)Lu-labeled DOTAGA-based prostate-specific membrane antigen (PSMA) ligand (177)Lu-DOTAGA-(I-y)fk(Sub-KuE) ((177)Lu-PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Fifty-six mCRPC patients underwent PSMA radioligand therapy (RLT) with (177)Lu-PSMA. (68)Ga-PSMA-(N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) ((68)Ga-PSMA) PET/CT was used for patient selection and follow-up after PSMA RLT. Hematologic status, renal function, and serum prostate-specific antigen levels were documented before and after therapy. Dosimetry was performed in 30 patients. RESULTS: (177)Lu-PSMA demonstrated high absorbed tumor doses (median, 3.3 mGy/MBq) compared with the levels in normal organs. Parotid glands received higher doses (1.3 mGy/MBq) than kidneys (0.8 mGy/MBq). All patients tolerated the therapy without any acute adverse effects. Except for mild reversible xerostomia in 2 patients, no long-term side effects were observed. There was a small but statistically significant reduction in erythrocyte and leukocyte counts; only the reduction in erythrocyte counts decreased slightly below the reference range. No thrombocytopenia occurred. The severity of pain was significantly reduced in 2 of 6 patients (33.3%). A decrease in prostate-specific antigen levels was noted in 45 of 56 patients (80.4%). Of 25 patients monitored for at least 6 mo after 2 or more PSMA RLT cycles, a molecular response evaluation ((68)Ga-PSMA PET/CT) revealed partial remission in 14, stable disease in 2, and progressive disease in 9 patients. Contrast-enhanced CT revealed partial remission in 5, stable disease in 13, and progressive disease in 7 patients. The median progression-free survival was 13.7 mo, and the median overall survival was not reached during follow-up for 28 mo. CONCLUSION: PSMA RLT with (177)Lu-PSMA is feasible, safe, and effective in end-stage progressive mCRPC with appropriate selection and follow-up of patients by (68)Ga-PSMA PET/CT through application of the concept of theranostics.

Radiation safety considerations for the use of ²²³RaCl2 DE in men with castration-resistant prostate cancer.

The majority of patients with late stage castration-resistant prostate cancer (CRPC) develop bone metastases that often result in significant bone pain. Therapeutic palliation strategies can delay or prevent skeletal complications and may prolong survival. An alpha-particle based therapy, radium-223 dichloride (²²³RaCl2), has been developed that delivers highly localized effects in target areas and likely reduces toxicity to adjacent healthy tissue, particularly bone marrow. Radiation safety aspects were evaluated for a single comprehensive cancer center clinical phase 1, open-label, single ascending-dose study for three cohorts at 50, 100, or 200 kBq kg⁻¹ body weight. Ten patients received administrations, and six patients completed the study with 1 y follow-up. Dose rates from patients administered ²²³Ra dichloride were typically less than 2 µSv h⁻¹ MBq⁻¹ on contact and averaged 0.02 µSv h⁻¹ MBq⁻¹ at 1 m immediately following administration. Removal was primarily by fecal excretion, and whole body effective half-lives were highly dependent upon fecal compartment transfer, ranging from 2.5-11.4 d. Radium-223 is safe and straightforward to administer using conventional nuclear medicine equipment. For this clinical study, few radiation protection limitations were recommended post-therapy based on facility evaluations. Specific precautions are dependent on local regulatory authority guidance. Subsequent studies have demonstrated significantly improved overall survival and very low toxicity, suggesting that ²²³Ra may provide a new standard of care for patients with CRPC and bone metastases.