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Optimizing PSMA Radioligand Therapy for Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Meta-Analysis.

ABSTRACT: The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publications and four duplicates reported 2346 patients. Nearly two-thirds of the patients had bone metastases. Median overall survival (OS) was 16 months. Asymptomatic patients and patients with only lymph node metastases lived longer than symptomatic patients and patients with more extensive metastases. Patients treated with an intensified schedule of ¹⁷⁷Lu PRLT lived longer than those treated with a conventional schedule. Half of the patients obtained a PSA decline ? 50% and these patients lived longer than those with less PSA decline. Approximately 10% of the patients developed hematologic toxicity with anemia grade 3 as the most severe adverse effect. Characteristics for patients, cancer, restaging, and PRLT predict above average overall survival following treatment with PRLT.

SUBMITTER: von Eyben FE

PROVIDER: S-EPMC7730994 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Optimizing PSMA Radioligand Therapy for Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Meta-Analysis.

von Eyben Finn Edler FE Bauman Glenn G von Eyben Rie R Rahbar Kambiz K Soydal Cigdem C Haug Alexander R AR Virgolini Irene I Kulkarni Harshad H Baum Richard R Paganelli Giovanni G

International journal of molecular sciences 20201128 23

The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publicatio ...[more]

PMID: 33260535

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Project description:AIMS:There is a controversy as to the relative efficacy of 177Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether 177Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743). METHODS:The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model. RESULTS:Twelve studies including 669 patients reported 177Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ?50% following treatment with 177Lu-PSMA RLT. The treatment with 177Lu-PSMA-617 and 177Lu-PSMA for imaging and therapy (I&T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ?50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. 177Lu-PSMA RLT gave a best PSA decline ?50% more often than third-line treatment (mean 44% versus 22%, p?=?0.0002, t test). 177Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p?=?0.004, ?2 test). Median survival was longer after 177Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p?=?0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for 177Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p?<?0.001, ?2 test). CONCLUSIONS:As for patients with mCRPC, treatment with 177Lu-PSMA-617 RTL and 177Lu-PSMA I&T gave better effects and caused fewer adverse effects than third-line treatment.

Project description:PURPOSE:The first aim of this study was to evaluate 68Ga-PSMAHBED-CC conjugate 11 positron emission tomography (PSMA PET) parameters for assessment of response to 177Lu-PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC). The second aim was to investigate factors associated with overall survival (OS). METHODS:We retrospectively assessed mean standardized uptake values (SUVmean) and total tumor volumes (TTV) on PSMA PET in 38 of 55 mCRPC patients before and after RLT. PSA testing and PSMA PET/CT(MRI) imaging were performed during the 8 weeks before and the 6 weeks after RLT. PSMA PET and CT(MRI) images were reviewed separately according to the modified PET Response Criteria in Solid Tumors (mPERCIST) and RECIST1.1. The results were compared with PSA responses. Associations between OS and the RECIST evaluation and changes in SUVmean, TTV, and PSA, CRP, LDH, hemoglobin and ALP levels were determined in a univariable survival analysis. RESULTS:The median PSA level at the time of pretherapy PSMA PET/CT(MRI) was 60.8 ng/ml (IQR 15.4, 264.2 ng/ml). After RLT the median PSA level decreased by 44%, TTV by 45.1%, SUVmean by 25.8% and RECIST by 11.3%. A PSA response was seen in 18 patients (47.4%), stable disease in 12 (31.6%) and progressive disease in 8 (21.1%). Contrary to the changes in SUVmean and the RECIST evaluation, the change in TTV was significantly associated with PSA response (p?=?0.15, p?=?0.58, and p?<?0.001, respectively). After a median follow-up of 17 months (IQR 8.0, 24.2 months), 11 patients (28.9%) had died of their prostate cancer. The changes in both TTV and PSA levels were associated with OS (HR 1.001, 95% CI 1-1.003, p?=?0.04, and HR 1.004, 95% CI 1.001-1.008, p?=?0.01, respectively), while the changes in SUVmean and the RECIST evaluation were not. The pre-therapy CRP level was also associated with OS (HR 1.07, 95% CI 1.009-1.14, p?=?0.02). CONCLUSION:TTV on PSMA PET seems to be a reliable parameter for response assessment in mCRPC patients undergoing RLT and might overcome the limitations of RECIST in prostate cancer. Furthermore, the change in TTV was significantly associated with OS in our cohort.

Project description:Rationale: Lu-177-PSMA-617 radioligand therapy (RLT) is currently under approval for treatment of metastatic castration resistant prostate cancer (mCRPC) patients with late stage disease. However, previous studies demonstrated both heterogeneity of prostate specific membrane antigen (PSMA) expression, as well as response to PSMA treatment among mCRPC patients. Thus, there is an unmet need for identifying predictive parametres prior or under PSMA-RLT treatment. We therefore aimed to correlate several clinical and molecular parameters with response to PSMA treatment in a cohort of mCRPC patients undergoing PSMA RLT followed by a detailed analysis of promising candidates. Methods: Nineteen patients, median age 68.8 years (range: 56.9 - 83.3) with mCRPC were included in this study. We performed baseline analysis of clinical parameters based on PSMA PET/CT, (metabolic tumor volume (MTV), total tumor volume (TTV)), serum PSA, ALP, LDH and gene expression analysis of circulating tumor cells (expression of AR full length (AR-FL), AR splice variant 7 (AR-V7), PSA and PSMA) as well as common markers for neuroendocrine differentiation (NED). Results: Patients presented with bone, lymph node, and visceral metastases (89%, 68%, and 21%, respectively). All patients were pretreated with docetaxel, either abiraterone or enzalutamide, or both. Biochemical response in terms of PSA decline ?50 or ?30% was observed in 42% and 63%, respectively. There were significant correlations between PSA and PSMA mRNA expression, as well as tumor volumes (both MTV and TTV), AR-FL and AR-V7 mRNA expression. However, there was no correlation with response to PSMA treatment. Furthermore, none of these parameters was significantly correlated with baseline serum PSA values. Common NED markers were shown to be specifically high expressed and revealed impact on OS independent from AR-V7 gene expression. Conclusion: We demonstrate that AR-FL and its splice variant AR-V7 might serve as prognostic biomarkers displaying high tumor burden in mCRPC patient prior to PSMA-RLT. Contrary, PSMA, which has been discussed as a biomarker for PSMA targeted treatment, does not display strong prognostic ability - at least on the mRNA level. Surprisingly, none of these parameters correlates to response to PSMA treatment. In contrast, commom NED markers such as SYP and ENO2 as well as FOXA1 expression level seem to predict OS, but not PFS, more reliably. We admit that a limitation of our study is the focus on mRNA expression of potential biomarkers only. Further investigations analyzing the potential role of protein expression of these markers are therefore warranted.

Project description:ObjectiveInvestigators have extensively explored the short-term safety and efficacy data on 177Lu-PSMA-617 radioligand therapy (RLT) in mCRPC patients. However, scarce literature is reported on the long-term outcome of these patients. The current goal of this study is focused on the long-term outcome of mCRPC patients treated with 177Lu-PSMA-617 RLT.MethodsAmong 135 patients, 121 mCRPC patients fulfilled the eligibility criteria and were included in the final analysis. Patients received a median of 3 cycles of 177Lu-PSMA-617 RLT at 6 to 12-week intervals. Primary endpoint included overall survival (OS) and secondary endpoints involved progression-free survival (PFS), predictive factors of OS and PFS, PSA response rate, molecular response, clinical response, and toxicity assessment.ResultsThe median administered cumulative activity was 20 GBq (3.7-37 GBq). The median follow-up duration was 36 months (6-72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3-13 mo) and 16 mo (95% CI: 13-17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with ≥2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining 177Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post 177Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%).ConclusionThe current study supports the short-term safety and efficacy results of high response rates, prolonged PFS and OS, improved quality of life, and low treatment-related toxicities in patients treated with 177Lu-PSMA-617 radioligand therapy.

Project description:BackgroundMyelosuppression is a potential dose-limiting factor in radioligand therapy (RLT). This study aims to investigate occurrence, severity and reversibility of hematotoxic adverse events in patients undergoing RLT with 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). The contribution of pretreatment risk factors and cumulative treatment activity is taken into account specifically.MethodsRLT was performed in 140 patients receiving a total of 497 cycles. A mean activity of 6.9 [Formula: see text] 1.3 GBq 177Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6 [Formula: see text] 15.9 GBq. Hematological parameters were measured at baseline, prior to each treatment course, 2 to 4 weeks thereafter and throughout follow-up. Toxicity was graded based on Common Terminology Criteria for Adverse Events v5.0.ResultsSignificant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT. Myelosuppression was significantly more frequent in patients with pre-existing grade 2 cytopenia (OR: 3.50, 95%CI 1.08-11.32, p = 0.04) or high bone tumor burden (disseminated or diffuse based on PROMISE miTNM, OR: 5.08, 95%CI 1.08-23.86, p = 0.04). Previous taxane-based chemotherapy was associated with an increased incidence of significant hematotoxicity (OR: 4.62, 95%CI 1.23-17.28, p = 0.02), while treatment with 223Ra-dichloride, cumulative RLT treatment activity and activity per cycle were not significantly correlated (p = 0.93, 0.33, 0.29).ConclusionHematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates.

Project description:PurposePreliminary data from retrospective analyses and recent data from large randomized controlled trials suggest safety and efficacy of radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC). Limited data on this modality have been published regarding large samples treated in everyday practice.MethodsWe analyzed prospectively collected registry data regarding lutetium-177 (177Lu)-PSMA-617 RLT of 254 consecutive men with mCRPC seen in everyday academic practice. Since 177Lu-PSMA-617 was experimental salvage treatment following failure of individually appropriate conventional therapies, patients were generally elderly and heavily pretreated (median age 70 years; prior taxanes 74.0%, 188/254), with late-end-stage disease (visceral metastasis in 32.7%, 83/254). Primary endpoints were response to RLT, defined by changes from baseline serum prostate-specific antigen (PSA) concentration, PSA progression-free survival (PSA-PFS), and overall survival (OS), estimated with Kaplan-Meier statistics, and caregiver-reported and patient-reported safety. Unless noted, median (minimum-maximum) values are given.ResultsPatients received 3 (1-13) 177Lu-PSMA-617 activities (6.5 [2.5-11.6] GBq/cycle) every 5.7 (3.0-11.0) weeks. Best response was ≥ 50% PSA reduction in 52.0% of patients (132/254). PSA-PFS was 5.5 (95% confidence interval [95%CI] 4.4-6.6) months and OS, 14.5 (95%CI 11.5-17.5) months. In multivariable Cox proportional-hazards modeling, response to the initial ≤ 2 RLT administrations was the strongest significant prognosticator related to OS (hazard ratio 3.7 [95%CI 2.5-5.5], p < 0.001). No RLT-related deaths or treatment discontinuations occurred; the most frequent RLT-related Grade 3/4 adverse events were anemia (18/254 patients, 7.1%), thrombocytopenia (11/254, 4.3%), and lymphopenia (7/254, 2.8%). RLT-related xerostomia, all grade 1/2, was noted in 53/254 (20.9%).ConclusionsIn a large, prospectively observed "real-world" cohort with late-stage/end-stage mCRPC and conventional treatment failure, 177Lu-PSMA-617 RLT was effective, safe, and well-tolerated. Early biochemical disease control by such therapy was associated with better OS. Prospective study earlier in the disease course may be warranted.

Project description:ContextCastration-resistant prostate cancer (CRPC) treatment is an evolving challenge. Prostate-specific membrane antigen (PSMA)-targeted endoradiotherapy/radioligand therapy (PRLT) with small-molecule, urea-based agents labeled with the β-particle-emitting radionuclide lutetium-177 (177Lu) is a promising new approach.ObjectiveIn this systematic review and meta-analysis, we evaluated the efficacy and toxicity of PRLT.Evidence acquisitionA systematic search was performed in PubMed/Medline (last updated February 18, 2019). A total of 250 studies were reviewed, and 24 studies with 1192 patients were included in the analysis. Proportions of patients with ≥50% serum prostate-specific antigen (PSA) decrease, any PSA decrease, and any PSA increase were extracted. Proportions of patients showing any grade toxicity and those with grade 3/4 toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) grading were extracted from manuscripts. Overall survival and progression-free survival were evaluated. A meta-analysis of single proportions was carried out. Furthermore, we compared the two most common PRLT agents, 177Lu-PSMA with 177Lu-PSMA-I&T, for effectiveness and toxicity.Evidence synthesisAmong the 24 included studies, 20 included data on 177Lu-PSMA-617, three included data on 177Lu-PSMA-I&T, and one study had aggregated data for 177Lu-PSMA-617 and 177Lu-PSMA-I&T. The estimated proportion of 177Lu-PSMA-617-treated patients who showed a serum PSA decrease of ≥50% with at least an 8-wk interval between therapy and PSA measurement was 0.44 (0.39; 0.50). Therapy with 177Lu-PSMA-I&T demonstrated an estimated proportion of patients with ≥50% PSA reduction to be 0.36 (0.26; 0.47). The aggregate results for men treated with more than one cycle of any kind of PRLT showed an estimated proportion of 0.46 (0.41; 0.51) for PSA response ≥50%. Regarding aggregate data from all of the PRLT agents, we found that grade 3 and 4 toxicities were uncommon, with estimated proportions from 0.01 (0.00;0.04) for nausea, fatigue, diarrhea, and elevated aspartate transaminase up to 0.08 (0.05; 0.12) for anemia. There was considerable heterogeneity among the studies in the "any-grade toxicity" groups. Meta-regression showed that more than one cycle of PRLT is associated with a greater proportion of patients with ≥50% PSA reduction. Overall survival according to pooled hazard ratios (HRs) for any PSA decline was 0.29 (0.18; 0.46), and for >50% PSA reduction was 0.67 (0.43; 1.07). Progression-free survival according to a pooled HR of >50% PSA reduction was 0.53 (0.32; 0.86).ConclusionsThe relatively high number of PSA responders alongside the low rate of severe toxicity reflects the potentially promising role of PRLT in treating CRPC. The ultimate utility of this treatment modality will become clearer as multiple prospective studies continue to accrue. In the interim, this systematic review and meta-analysis can serve as a compendium of effectiveness and adverse events associated with PRLT for treating clinicians.Patient summaryProstate-specific membrane antigen-targeted endoradiotherapy/radioligand therapy (PRLT) is associated with ≥50% reduction in prostate-specific antigen level in a large number of patients and a low rate of toxicity, reflecting its potential in treating castration-resistant prostate cancer. This systematic review and meta-analysis presents as a compendium of the effectiveness and adverse events related to PRLT for treating clinicians.

Dataset Information

Optimizing PSMA Radioligand Therapy for Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Meta-Analysis.

Publications

Optimizing PSMA Radioligand Therapy for Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Meta-Analysis.

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