Anna Yordanova

Therapeutic response and side effects of repeated radioligand therapy with 177 Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer

Prostate-specific membrane antigen (PSMA) is highly expressed on prostate epithelial cells and strongly up-regulated in prostate cancer (PC), making it an optimal target for the treatment of metastasized PC. Radioligand therapy (RLT) with 177Lu-PSMA-DKFZ-617 (Lu-PSMA) is a targeted therapy for metastatic PC. In this study, we retrospectively analyzed the side effects and the response rate of 24 hormone and/or chemorefractory PC patients with a mean age of 75.2 years (range: 64–82) with distant metastases and progressive disease according to the PSA level, who were treated with Lu-PSMA. Median PSA was 522 ng/ml (range: 17–2360). Forty-six cycles of Lu-PSMA were performed. Of the 24 patients, 22 received two cycles. Eight weeks after the first cycle of Lu-PSMA therapy 79.1% experienced a decline in PSA level. Eight weeks after the second cycle of Lu-PSMA therapy 68.2% experienced a decline in PSA relative to the baseline value. Apart from two cases of grade 3 anemia, there was no relevant hemato- or nephrotoxicity (grade 3 or 4). These results confirmed that Lu-PSMA is a safe treatment option for metastatic PC patients and has a low toxicity profile. A positive response to therapy in terms of decline in PSA occurs in about 70% of patients.

Response and Tolerability of a Single Dose of 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: A Multicenter Retrospective Analysis

Radiolabeled prostate-specific membrane antigen (PSMA) ligands represent a true theranostic concept for diagnosis and therapy in patients with relapsed or metastatic prostate cancer. The aim of this study was to evaluate the response to and tolerability of a single dose of 177Lu-PSMA-617 in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: The data of 82 consecutive patients (median age, 73 y; range, 43–87 y) with mCRPC who received a single dose of 177Lu-PSMA-617 (mean, 5.9 ± 0.5 GBq) were retrospectively analyzed. Data were collected at baseline and 8 wk after therapy. 68Ga-PSMA-11 PET/CT was performed on all patients to verify sufficient PSMA expression. Bone, lymph node, liver, and lung metastases were present in 99%, 65%, 17%, and 11% of the patients, respectively. Tolerability and response were evaluated using hematologic parameters, renal scintigraphy, clinical data, and the prostate-specific antigen (PSA) level at baseline and 8 wk after therapy application. Results: Six patients died, and 2 patients dropped out because they were not willing to continue therapy and follow-up. The complete dataset of 74 patients was available for analysis. Forty-seven patients (64%) showed a PSA decline, including 23 (31%) with a decline by more than 50%. Thirty-five patients (47%) had stable disease: the change in their PSA level ranged from less than a 50% decline to less than a 25% rise. Seventeen patients (23%) had progressive disease: their PSA level rose by more than 25%. There were no significant changes in hemoglobin, white blood cells, creatinine, or tubular extraction rates indicative of toxicity. There was a significant but mild decrease in platelets, but the median value was still within the reference range. Conclusion: This retrospective multicenter analysis suggests that radioligand therapy with 177Lu-PSMA-617 is safe and well tolerated and has a considerable effect on PSA level. Therefore, it offers an additional therapeutic option for patients with mCRPC. These data may justify further prospective randomized studies to evaluate and prove the clinical benefit in terms of survival and quality of life.

68Ga-PSMA-11 PET as a gate-keeper for the treatment of metastatic prostate cancer with radium-223: proof of concept.

We retrospectively evaluated the utility of 68Ga-PSMA-11 PET for planning 223RaCl2 therapy of patients with metastatic prostate cancer and its impact on the therapeutic response as determined by prostate-specific antigen (PSA) and alkaline phosphatase (ALP), as well as the correlation of PSA changes with the results of prostate-specific membrane antigen (PSMA) PET follow-up scans. Methods: Sixty-three patients with a median age of 73 y who underwent 307 cycles of therapy with 223RaCl2 were analyzed. In 31 patients, bone scanning and radiologic imaging were performed for pretherapeutic imaging (group 1). In 32 patients, bone scanning and PSMA PET were performed before therapy (group 2). Patients with small lymph node metastases and local recurrence were not excluded from treatment, consistent with current guidelines. PSA and ALP were measured before each treatment cycle and 4 wk after the final cycle. Thirteen patients from group 2, who underwent a second PSMA PET scan as a follow-up, were evaluated to determine the significance of PSA changes as a follow-up marker. Results: In group 1, 4 patients (12.9%) showed a PSA decline, of whom 2 patients and 1 patient showed a PSA decline of more than 30% and more than 50%, respectively. In contrast, in group 2, 14 patients (43.8%) showed a PSA decline, of whom 10 and 8 patients showed a decline of more than 30% and more than 50%, respectively (P = 0.007). Thirty-seven patients had a high ALP level (19 from group 1 and 18 from group 2). Twelve (63.2%) and 16 (88.9%) patients in groups 1 and 2, respectively, showed an ALP decline. This difference was not significant; however, 7 (36%) and 13 (72.2%) patients in groups 1 and 2, respectively, showed an ALP decline of more than 30% (P = 0.04). Considering any ALP decline as a response, no patient with increasing ALP showed a PSA response (P = 0.036). There was a significant correlation between the PSA changes and the therapeutic response according to follow-up PSMA PET. Conclusion: When PSMA PET is used as the gatekeeper in addition to bone scanning, radionuclide therapy with 223Ra may be more effective and have more success regarding changes in the PSA. An increase in PSA during therapy cycles occurs because of disease progression.

Radioligand therapy of metastatic prostate cancer using 177 Lu-PSMA-617 after radiation exposure to 223 Ra-dichloride

Radioligand therapy with 177Lu-PSMA-617 is an innovative and effective therapy for castrate-resistant metastatic prostate cancer patients. For patients with symptomatic bone metastases without visceral metastases, the guidelines recommend radionuclide therapy with 223Ra-dichloride as a single therapeutic agent or in combination with hormone therapy. The aim of this study was to evaluate the safety of repeated cycles of 177Lu-PSMA-617 after exposure to more cycles of 223Ra. Forty-nine patients were treated with three cycles of Lu-PSMA-617 divided into two groups subjected to a history of therapy with 223Ra. Group 1 included 20 patients, who had received therapy with 223Ra prior to Lu-PSMA-617 therapy. Group 2, which was the control group regarding hematotoxicity, comprised 29 patients without any history of a bone-targeted radionuclide therapy. No CTC 4° hematotoxicity was observed in the entire study population. There was no CTC 3° or CTC 4° leucopenia in either group. One and three patients from group 1 and 2, respectively, showed CTC 3° anemia. In group 1 there was significantly more CTC 2° anemia (50% vs. 6.9%) (p=0.008). One patient from group 1 (5%) showed a CTC 3° thrombocytopenia without any concurrent anemia, and two patients from group 2 (7%) showed a CTC 3° thrombocytopenia, one with CTC 3° anemia and one without any anemia. There were no significant differences between the two groups regarding leucopenia and thrombocytopenia. These results confirmed that performing repeated cycles of Lu-PSMA-617 after 223Ra seems to be safe with a very small probability of hematotoxicity.Radioligand therapy with 177Lu-PSMA-617 is an innovative and effective therapy for castrate-resistant metastatic prostate cancer patients. For patients with symptomatic bone metastases without visceral metastases, the guidelines recommend radionuclide therapy with 223Ra-dichloride as a single therapeutic agent or in combination with hormone therapy. The aim of this study was to evaluate the safety of repeated cycles of 177Lu-PSMA-617 after exposure to more cycles of 223Ra. Forty-nine patients were treated with three cycles of Lu-PSMA-617 divided into two groups subjected to a history of therapy with 223Ra. Group 1 included 20 patients, who had received therapy with 223Ra prior to Lu-PSMA-617 therapy. Group 2, which was the control group regarding hematotoxicity, comprised 29 patients without any history of a bone-targeted radionuclide therapy. No CTC 4° hematotoxicity was observed in the entire study population. There was no CTC 3° or CTC 4° leucopenia in either group. One and three patients from group 1 and 2, respectively, showed CTC 3° anemia. In group 1 there was significantly more CTC 2° anemia (50% vs. 6.9%) (p=0.008). One patient from group 1 (5%) showed a CTC 3° thrombocytopenia without any concurrent anemia, and two patients from group 2 (7%) showed a CTC 3° thrombocytopenia, one with CTC 3° anemia and one without any anemia. There were no significant differences between the two groups regarding leucopenia and thrombocytopenia. These results confirmed that performing repeated cycles of Lu-PSMA-617 after 223Ra seems to be safe with a very small probability of hematotoxicity.

Predictors of response to radioligand therapy of metastatic castrate-resistant prostate cancer with 177Lu-PSMA-617.

Radioligand therapy (RLT) with 177Lu-PSMA-617 (PSMA is prostate-specific membrane antigen) is a novel targeted therapy for metastatic prostate cancer. In this study, we evaluated the effect of different pretherapeutic parameters on the therapeutic response measured by prostate-specific antigen (PSA) 2 mo after RLT. Methods: RLT was performed in 40 hormone-refractory patients with distant metastases and progressive disease (mean age, 71.4 y). 68Ga-PSMA-11 PET/CT was performed in all patients 1–2 wk before RLT. All patients were treated with a mean of 6 GBq. The SUVmax of tumor lesions was determined using region-of-interest analysis. Complete blood counts, renal and liver function assessments, previous therapies, pain medication, and SUVs were included in the analysis. PSA was assessed 2 mo after RLT. Results: In the univariate analysis, younger age, higher levels of γ-glutamyl transferase, lower pretherapeutic hemoglobin, a higher Gleason score, a higher number of platelets, higher C-reactive protein, regular need for pain medication, and higher lactate dehydrogenase had a negative impact on the therapeutic response; however, the multivariate analysis revealed that the most significant independent factors were the number of platelets and regular need for pain medication. The response was independent of the amount of PSMA uptake as well as previous therapies and other measured factors. Conclusion: A PSA decline of more than 50% was observed significantly more in patients without a regular need for analgesics.

68Ga-PSMA-11 PET Represents the Tumoricidal Effect of 223Ra in a Patient With Castrate-Resistant Metastatic Prostate Cancer.

A 64-year-old man with prostate cancer and an increasing prostate-specific antigen (PSA) level under therapy with abiraterone acetate underwent a therapy with Ra. Before the first therapy and 4 weeks after the last cycle, the patient underwent Ga-PSMA PET, which showed a clear response of bone metastases.

Theranostics in Nuclear Medicine Practice

The importance of personalized medicine has been growing, mainly due to a more urgent need to avoid unnecessary and expensive treatments. In nuclear medicine, the theranostic approach is an established tool for specific molecular targeting, both for diagnostics and therapy. The visualization of potential targets can help predict if a patient will benefit from a particular treatment. Thanks to the quick development of radiopharmaceuticals and diagnostic techniques, the use of theranostic agents has been continually increasing. In this article, important milestones of nuclear therapies and diagnostics in the context of theranostics are highlighted. It begins with a well-known radioiodine therapy in patients with thyroid cancer and then progresses through various approaches for the treatment of advanced cancer with targeted therapies. The aim of this review was to provide a summary of background knowledge and current applications, and to identify the advantages of targeted therapies and imaging in nuclear medicine practices.

Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [ 177 Lu]Lu-PSMA-617 radioligand therapy

Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis of and therapy for metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to measure overall-survival (OS) in mCRPC patients who received either abiraterone or enzalutamide prior to PSMA therapy. The second aim of this study was to analyse the predictors of OS according to different pre-therapeutic parameters and also the responses to the first cycle of radioligand therapy (RLT) base on PSA level. Patients with mCRPC and a history of therapy with either abiraterone or enzalutamide or both, were included in this study. Different laboratory tests and pre-therapeutic parameters have been included into the analysis. One-hundred patients received a total of 347 cycles of Lu-PSMA (median: three cycles). 69 patients showed a decline in PSA two months after the first cycle, and 38 of those patients showed a PSA decline of = > 50%. The median OS was 60 weeks. In the multivariate analysis, the level of albumin, AST and haemoglobin, existence of liver metastases and a decline of > 14% in PSA level had a significant impact on overall-survival. The median OS is significantly longer in patients without hepatic involvement, with high levels of albumin and Hb and low levels of AST. A decline in PSA levels of more than 14% was the most important response parameter with regard to overall survival.

A Step-by-Step Clinical Approach for the Management of Neuroendocrine Tumours

Neuroendocrine tumours (NET) are rare neoplasms, but the incidence is permanently increasing. Most of the NETs are slow proliferating and clinically silent, and for that reason, they are often diagnosed at a stage with advanced disease. The complexity and diversity of the NET-biology require the treatment of patients in specialised centres to guarantee a qualified, multidisciplinary treatment planning. At our institution, we developed an interdisciplinary model for the assessment and treatment of NET. The aim was to adapt the guidelines to the clinical practice, exchange of current knowledge, and a tailored approach to the individual patient. In our team are included medical professionals from pathology, radiology, oncology, gastroenterology, oncological surgery, and nuclear medicine. In this paper, we describe step-by-step a procedural algorithm for the management of patients with neuroendocrine tumours, focusing on midgut-NETs in terms of therapy.

The Role of Adding Somatostatin Analogues to Peptide Receptor Radionuclide Therapy as a Combination and Maintenance Therapy

Purpose: Although somatostatin analogues (SSA) and peptide receptor radionuclide therapy (PRRT) are validated therapies in patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET), it remains unclear whether SSA combined with PRRT or as maintenance therapy can provide prolonged survival compared with patients treated with PRRT alone. In this retrospective study, we aimed to investigate whether there is a survival benefit to adding SSA to PRRT as a combination therapy and/or maintenance therapy. Patients and Methods: The investigation included 168 patients with unresectable GEP-NETs treated at the University Hospital Bonn, Bonn, Germany. The patients were divided into two main groups: PRRT monotherapy (N = 81, group 1) and PRRT plus SSA (N = 87, group 2) as combined therapy with PRRT and/or as maintenance therapy after PRRT. Results: Data for overall survival (OS) were available from 168 patients, of whom 160 had data for progression-free survival (PFS). The median PFS was 27 months in group 1 versus 48 months in group 2 (P = 0.012). The median OS rates were 47 months in group 1 and 91 months in group 2 (P < 0.001). The death-event rates were lower in group 2 (26%) than in group 1 (63%). SSA as a combination therapy with PRRT and/or as a maintenance therapy showed a clinical benefit rate (objective response or stable disease) of 95%, which was significantly higher than group 1 (79%). Conclusions: SSA as a combination therapy and/or maintenance therapy may play a significant role in tumor control in patients with GEP-NET who underwent a PRRT. Clin Cancer Res; 24(19); 4672–9. ©2018 AACR.