CONTRAST-ENHANCED ULTRASOUND MONITORING OF PERFUSION CHANGES IN HEPATIC NEUROENDOCRINE METASTASES AFTER SYSTEMIC VERSUS SELECTIVE ARTERIAL 177LU/90Y-DOTATOC AND 213BI-DOTATOC RADIOPEPTIDE THERAPY

Radiopeptide therapy with beta emitter labeled 177Lu/90Y- DOTA(0)-Phe(1)-Tyr(3)-octreotide (DOTATOC) and more recently also alpha emitting 213Bi-DOTATOC are promising new treatments for neuroendocrine tumors. No early predictors for treatment response have been recognized and tumor-shrinkage after radiation therapy appears slowly. In some solid tumors a decline in tumor perfusion was found predictive of final treatment response but the gold standard multiphase computed tomography (CT) has a high radiation burden. Therefore we evaluated the ability of contrast-enhanced ultrasound (CEUS) to evaluate tumor perfusion as a response criteria. Materials and Methods: 14 patients with hepatic neuroendocrine tumor (NET) metastases were enrolled in the retrospective study. Eleven patients were treated with beta-emitting 177Lu/90Y-DOTATOC, either intravenous (i.v.) (n = 5) or intra-arterial (i.a.) (n = 6) and three patients received alpha-emitting 213Bi-DOTATOC (i.a.). CEUS and contrast-enhanced CT (CE-CT) were performed before and 3 months after treatment. Results: CE-CT and CEUS presented comparable results in the baseline study and in the assessment of perfusion changes due to the different treatment regimes. A therapy related decrease in tumor perfusion is an early predictor of longterm morphologic response. Conclusion: CEUS is a cheap, ubiquitary available and radiation free technique which showed comparable results for perfusion and diameter of liver metastases compared to CE-CT. Intensity reduction in an arterial phase CEUS can be seen as a positive sign indicating long term tumor response to treatment. Therefore CEUS may be considered as an imaging modality for monitoring early treatment after focal alpha and beta targeted therapy.JRC.E.5-Nuclear chemistr

Ac-225-Dotatoc – Empirische Dosisfindung für die Alphastrahler-basierte Radionuklidtherapie neuroendokriner Tumore

Bisher gibt es keine etablierten, bildgebungsgestützten Dosimetrie-Konzepte um die Toxizität einer „targeted alpha-therapy“ (TAT) präzise vorhersagen zu können. Im Rahmen der klinischen Anwendung des Alphastrahlers Ac-225-Dotatoc wurden daher die maximal tolerable Dosis (MTD) und auch ein tolerables Fraktionierungskonzept empirisch ermittelt.JRC.E.5-Nuclear chemistr

225Ac-PSMA617: PSMA targeting alpha-radiation therapy of patients with mCRPC

To evaluate the potential of PSMA targeting 225Ac-PSMA617 as a promising new treatment option for poor prognosis advanced stage mCRPC (metastatic castration-resistant prostate cancer) patients. An appropriate starting activity for clinical application of 225Ac-PSMA617 was defined by preliminary dosimetry modeling. The treatment protocol was further refined by an empirical dose escalation during “compassionate use” in a first group of advanced stage patients. The derived “standard operation procedure” was used to treat a larger group of patients, which now has >6 months of follow up. Here we report our clinical observations in regard to anti-tumor activity as well as acute and mid-term toxicities experienced with this new concept of mCRPC therapy.JRC.G.I.5-Advanced Nuclear Knowledg

Ac-225-DOTATOC – dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors

Objectives: There are no established dosimetry tools to predict toxicity of “targeted alpha-therapy” (TAT) yet. We conducted an dose escalation study to find the maximum tolerable dose (MTD) of single cycle and fractionation concepts for Ac-225-DOTATOC radionuclide therapy. Methods: According to Declaration of Helsinki’s “Unproven interventions in Clinical Practice” we performed 46 treatment cycles in 34 patients with progressive neuroendocrine tumors (NET). After each cycle acute toxicity was documented according to CTCAE criteria. First observations are also available for chronic kidney toxicity as the follow up for the first 17 patients has now reached 2 years. Results: The MTD of a single cycle Ac-225-DOTATOC was considered to be 40 MBq. Multiple fractions were tolerated with 25 MBq every 4 months or 18.5 MBq every 2 months. Cumulative activities of 75 MBq were found tolerable in regard to delayed toxicity. The radiologic treatment response that was observed in some patients is without clear preference of a particular fractionation concept until now. Conclusions: We present a well tolerable treatment protocol for TAT with Ac-225-DOTATOC in NET patients that also demonstrated promising treatment efficacy in various patients. Whether TAT provides general advantages in comparison to beta emitter based radionuclide therapy cannot be derived from the available data yet. Comparative trials are needed in the future.JRC.E.5-Nuclear chemistr

Targeted Alpha Therapy of mCRPC with 225Actinium-PSMA617: Dosimetry, toxicity and duration of tumor-control

Objectives: To evaluate 225Ac-PSMA617 for PSMA-targeting alpha-therapy of advanced-stage mCRPC patients. Methods: A protocol for synthesis and quality control of 225Ac-PSMA617 was developed and an appropriate starting activity for clinical application of 225Ac-PSMA617 was defined by preliminary dosimetry modeling. The treatment protocol was refined by an empirical dose escalation with n=14 patients and consecutively an additional group of n=40 was treated following this protocol. PSA and radiological response were assessed. Duration of response was compared to the duration of tumor control of preceding treatment lines. Lab tests and clinical exam was done to assess toxicity. Results: 225Ac-PSMA617 was routinely synthesized with a radiochemical purity exceeding 98%. Assuming a RBE of 5, a mean dose of 2.3 Sv for salivary glands, 0.7 Sv for kidneys and 0.05 Sv for red marrow were estimated for 1 MBq of 225Ac-PSMA617; comparable to an activity of 1 GB of 177Lu-PSMA617. In dose-escalation phase, severe xerostomia became dose-limiting and defined the MTD even before relevant hematological toxicity was observed. 100 kBq/kg BW 225Ac-PSMA617 administered every 2 months was chosen as treatment protocol. From 40 patients intended to treat, 31 patients were treated “per-protocol”, while 5 patients discontinued due to non-response and 4 patients due to xerostomia. In patients surviving at least eight weeks, a PSA decline >50% was observed in 24/38 (63%) and any PSA response in 33/38 (87%) of patients. Median duration of tumor control under 225Ac-PSMA-617 last-line therapy was 9.0 months; 5 patients presented with enduring responses of > 2 years. No grade-3/4 hematological toxicity was observed for patients with grade-0/1 values at baseline, regardless of the extent of bone involvement. PFS under PSMA-TAT was longer than the mean duration of tumor control under preceding treatment lines. Conclusion: First clinical results imply that PSMA-targeting alpha-radiation therapy with 225Ac-PSMA617 benefits from favorable low hematological toxicity even in “superscan”-pattern patients and also presents remarkable anti-tumor activity in regard to objective response and PFS. Swimmer-plot analysis indicates promising duration of tumor-control, especially taking into account the unfavorable prognostic profile of the selected advanced-stage patients.JRC.G.I.5-Advanced Nuclear Knowledg

Ac-225-DOTATOC – an empiric dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors

There are no established dosimetry tools to predict toxicity of “targeted alpha-therapy” (TAT), yet. We conducted an empiric dose escalation to find the maximum tolerable dose (MTD) of single cycle and fractionation concepts for Ac-225-DOTATOC radionuclide therapy.JRC.E.5-Nuclear chemistr

PSMA-targeting alpha-Radiation therapy with 225Actinium-PSMA-617: Dosimetry, toxicity and duration of tumor-control

To evaluate the potential of 225Ac-PSMA617 for PSMA-targeting alpha-therapy of poor-prognosis advanced-stage mCRPC patients.JRC.G.I.5-Advanced Nuclear Knowledg

Optimizing the treatment regimen for targeted alpha therapy of mCRPC with Ac-PSMA-617

Aim: PSMA-targeting alpha-therapy (PSMA-TAT) of mCRPC with 225Ac-PSMA-617 (8 MBq, 3 cycles, 8 week intervals) already demonstrated promising anti-tumor activity, but also induced severe and often irreversible xerostomia (1,2). Our objective was to optimize the treatment protocol to improve tolerability. Methods: Patients with PSMA-positive mCRPC that were resistant against or ineligible for approved options and presented with progressive disease were treated with 225Ac-PSMA-617 under the conditions of the updated declaration of Helsinki, § 37 (Unproven interventions in clinical practice) and in accordance to the German Pharmaceuticals Law §13(2b) as a salvage therapy. In n=20 patients (concept A) only the first cycle was performed with a fixed dose of 8 MBq and in case of a >50% PSA-response at week-8, the treatment activity was reduced by 2 MBq for the next cycle, respectively. In n=20 patients (concept B), already at cycle-1 the treatment activity was reduced from 8 MBq to 6 MBq. Depending on PSA-response at week-8, treatment activity was escalated, de-escalated or kept constant. In n=5 patients (concept C, ongoing) 4 MBq 225Ac-PSMA-617 and 4 GBq 177Lu-PSMA-617, i.e. 50% of the respective single dose, were administered as a cocktail-regimen. Results: For concept A treatments were conducted with 8/8/6 MBq in 4 patients, 8/6/6 MBq in 13 patients, 8/6/4 MBq in 3 patients. PSA response rate was comparable to the already published (2) protocol because only favorable responders de-escalated dose; de-escalated patients did not discontinue due to dry mouth but this might include some psychological bias in awareness of the favorable response. For concept B 10 patients completed with 6/6/6 or further de-escalation, 5 had to escalate and 5 left therapy due to non-response. Tolerability of non-escalating patients was improved, but counteracted by the decreased anti-tumor activity. For concept C no patient discontinued due to dry mouth, yet. Until now 60% (3/5) demonstrated positive PSA-response. The observations for this group are currently ongoing. Conclusion: Dose de-escalation protocols or radionuclide combinations of low-dose 225Ac amended by beta-therapy, seem promising approaches to improve the tolerability of PSMA-TAT without losing too much anti-tumor activity.JRC.G.I.5-Advanced Nuclear Knowledg

Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control

The aim of this evaluation was to identify the first indicators of efficacy for 225Ac-labeled prostate-specific membrane antigen (PSMA)–617 therapy in a retrospectively analyzed group of patients. Methods: Forty patients with metastatic castration-resistant prostate cancer were selected for treatment with three 100 kBq/kg cycles of 225Ac-PSMA-617 at 2-mo intervals. Prostate-specific antigen (PSA) and blood cell count were measured every 4 wk. PSMA PET/CT or PSMA SPECT/CT were used for baseline staging and imaging follow-up at month 6. Follow-up included the duration of PSA response and radiologic progression-free survival at month 6. Patient histories were reviewed for the duration of previous treatment lines, and a swimmer plot was used to intraindividually compare the duration of tumor control by PSMA therapy versus prior treatment modalities. Results: Thirty-one of 40 patients were treated per protocol. Five patients discontinued treatment because of nonresponse, and 4 because of xerostomia. Of the 38 patients surviving at least 8 wk, 24 (63%) had a PSA decline of more than 50%, and 33 (87%) had a PSA response of any degree. The median duration of tumor control under 225Ac-PSMA-617 last-line therapy was 9.0 mo; 5 patients had an enduring response of more than 2 y. Because all patients had advanced disease, this result compares favorably with the tumor control rates associated with earlier-phase disease; the most common preceding first-, second-, third-, and fourth-line therapies were abiraterone (median duration 10.0 mo), docetaxel (6.5 mo), enzalutamide (6.5 mo), and cabazitaxel (6.0 mo), respectively. Conclusion: A positive response for surrogate parameters demonstrates remarkable antitumor activity for 225Ac-PSMA-617. Swimmer-plot analysis indicates a promising duration of tumor control, especially considering the unfavorable prognostic profile of the selected advanced-stage patients. Xerostomia was the main reason patients discontinued therapy or refused additional administrations and was in the same dimension as nonresponse; this finding indicates that further modifications of the treatment regimen with regard to side effects might be necessary to further enhance the therapeutic range.JRC.G.I.5-Advanced Nuclear Knowledg