Dataset Information

¹⁷⁷ Lu-PSMA radioligand therapy effectiveness in metastatic castration-resistant prostate cancer: An updated systematic review and meta-analysis.

ABSTRACT:

Background

An updated systematic review and meta-analysis of relevant studies to evaluate the effectiveness of prostate-specific membrane antigen (PSMA)-targeted endoradiotherapy/radioligand therapy (PRLT) in castration resistant prostate cancer (CRPC).

Methods

A systematic search was performed in July 2020 using PubMed/Medline database to update our prior systematic review. The search was limited to papers published from 2019 to June 2020. A total of 472 papers were reviewed. The studied parameters included pooled proportion of patients showing any or ≥50% prostate-specific antigen (PSA) decline after PRLT. Survival effects of PRLT were assessed based on pooled hazard ratios (HRs) of the overall survival (OS) according to any PSA as well as ≥50% PSA decline after PRLT. Response to therapy based on ≥50% PSA decrease after PRLT versus controls was evaluated using Mantel-Haenszel random effect meta-analysis. All p values < 0.05 were considered as statistically significant.

Results

A total of 45 publications were added to the prior 24 studies. 69 papers with total of 4157 patients were included for meta-analysis. Meta-analysis of the two recent randomized controlled trials showed that patients treated with ¹⁷⁷ Lu-PSMA 617 had a significantly higher response to therapy compared to controls based on ≥50% PSA decrease. Meta-analysis of the HRs of OS according to any PSA decline and ≥50% PSA decline showed survival prolongation after PRLT.

Conclusions

PRLT results in higher proportion of patients responding to therapy based on ≥50% PSA decline compared to controls. Any PSA decline and ≥50% PSA decline showed survival prolongation after PRLT.

Advances in knowledge

This is the first meta-analysis to aggregate the recent randomized controlled trials of PRLT which shows CRPC patients had a higher response to therapy after PRLT compared to controls.

SUBMITTER: Sadaghiani MS

PROVIDER: S-EPMC9311733 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

<sup>177</sup> Lu-PSMA radioligand therapy effectiveness in metastatic castration-resistant prostate cancer: An updated systematic review and meta-analysis.

Sadaghiani Mohammad S MS Sheikhbahaei Sara S Werner Rudolf A RA Pienta Kenneth J KJ Pomper Martin G MG Gorin Michael A MA Solnes Lilja B LB Rowe Steven P SP

The Prostate 20220314 7

<h4>Background</h4>An updated systematic review and meta-analysis of relevant studies to evaluate the effectiveness of prostate-specific membrane antigen (PSMA)-targeted endoradiotherapy/radioligand therapy (PRLT) in castration resistant prostate cancer (CRPC).<h4>Methods</h4>A systematic search was performed in July 2020 using PubMed/Medline database to update our prior systematic review. The search was limited to papers published from 2019 to June 2020. A total of 472 papers were reviewed. The ...[more]

PMID: 35286735

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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:AimsThere 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).MethodsThe 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.ResultsTwelve 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, χ2 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, χ2 test).ConclusionsAs 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:PurposeThe 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).MethodsWe 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.ResultsThe 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).ConclusionTTV 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:PurposeThere is increasing evidence for convincing efficacy and safety of 177Lu-labled prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) for metastatic castration-resistant prostate cancer (mCRPC). However, data are not available regarding the feasibility of 177Lu-labled PSMA-targeted RLT in East Asians. The present study summarized the first experience with 177Lu-PSMA-I&T therapy for mCRPC in China.MethodsForty consecutive patients with mCRPC were enrolled from December 2019 to September 2021. Eligible patients received 177Lu-PSMA-I&T RLT at intervals of 8-12 weeks. Toxicity was assessed based on standardized physicians' reports and the Common Toxicity Criteria for Adverse Events criteria. Response to PRLT was evaluated according to the changes of prostate specific antigen (PSA) response and imaging response. Quality of life (QOL), Karnofsky performance status (KPS) and pain (visual analogue scale, VAS) were also evaluated. The impacts of baseline parameters on the therapeutic effects were explored by univariate and multivariate logistic regression analyses.ResultsAll patients underwent a total of 86 cycles of 177Lu-PSMA-I&T (range: 1-5 cycles) with dosages of 3.70-14.43GBq per cycle, with a median of 8 months followed up. Six patients (15%) developed mild reversible xerostomia during follow-up, and 28 patients (70%) experienced grade 1-4 bone marrow dysfunction. Changes in PSA were assessed after therapy, accompanied by the partial response (PR) in 25 patients (62.5%), the stable disease (SD) in 5 patients (12.5%), and the progressive disease (PD) in 10 patients (25%), respectively. QOL, KPS (%) and VAS scores were improved significantly due to treatment (P<0.05). Overweight and elevated AST, ALP, and LDH were associated with poor outcomes.Conclusions177Lu-PSMA-I&T achieves the favourable response and well tolerance in mCRPC, which associates with not only PSA decline but also with tumor remission including lymphadenopathy and bone metastasis. We also find that patients with overweight and high AST, ALP, and LDH should be cautious to undergo the PRLT. Large-cohort studies are warranted to confirm the initial findings and elucidate the survival benefit of the treatment.

Project description:BackgroundThe purpose of this study was to evaluate the safety and outcome of rechallenge [177Lu]Lu-PSMA-I&T in newly progressed mCRPC patients after response to initial [177Lu]Lu-PSMA radioligand therapy (PRLT).MethodsWe retrospectively included 18 patients who underwent rechallenge with [177Lu]Lu-PSMA-I&T. All patients presented with (i) newly progressed disease after response to initial PRLT; (ii) a [68Ga]Ga-PSMA-11 PET/CT confirming the presence of PSMA-positive metastases; iii) ECOG performance status 0-1. Adverse events were graded according to CTCAE v5.0. Response was assessed by PSA and classified according to PCWG3 recommendations. For patients who underwent restaging with [68Ga]Ga-PSMA-11 PET/CT, imaging response was categorised according to adapted PERCIST v1.0. In patients with discordant [68Ga]Ga-PSMA-11 PET/CT and PSA, other available imaging modalities were evaluated to confirm disease status. Overall survival (OS) was calculated from the first cycle of initial PRLT and rechallenge PRLT, respectively, until last patient contact or death.ResultsPatients were initially treated with a median of 5 cycles (range 4-7) and were rechallenged after a median of 9 months (range 3-13). Each patient received a median of 4 (range 2-7) rechallenge cycles (median cumulative activity 26.1 GBq). None of the patients experienced life-threatening G4 adverse events during either treatment period. Grade 3 adverse events included one case of anaemia, one case of thrombocytopenia, and one case of renal failure. In 8/18 patients long-term toxicities were evaluated. Serious toxicities (≥ Grade 3) occurred in 3/8 patients (n = 1 G4 thrombocytopenia, n = 1 G4 renal failure and n = 1 pancytopenia and G4 renal failure). Best PSA50%-response was observed in 44% of patients and PSA-disease control was confirmed in 56% of patients at the last cycle. Of the 12/18 patients restaged by imaging, 6/12 (50%) patients had disease control (partial response/stable disease), 1/12 had a mixed response, and 5/12 had progression. After a median follow-up time of 25 months (range 14-44), 10 patients had died, 7 were still alive, and one patient was lost at follow-up. The median OS was 29 months (95%CI, 14.3-43.7 months) for the initial treatment and 11 months (95%CI, 8.1-13.8 months) for the first rechallenge course.ConclusionMore than half of patients benefit from rechallenge PRLT. Our analysis suggests that rechallenge may prolong survival in selected patients, with an acceptable safety profile.

Dataset Information

¹⁷⁷ Lu-PSMA radioligand therapy effectiveness in metastatic castration-resistant prostate cancer: An updated systematic review and meta-analysis.

Background

Methods

Results

Conclusions

Advances in knowledge

Publications

<sup>177</sup> Lu-PSMA radioligand therapy effectiveness in metastatic castration-resistant prostate cancer: An updated systematic review and meta-analysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

177 Lu-PSMA radioligand therapy effectiveness in metastatic castration-resistant prostate cancer: An updated systematic review and meta-analysis.

Background

Methods

Results

Conclusions

Advances in knowledge

Publications

<sup>177</sup> Lu-PSMA radioligand therapy effectiveness in metastatic castration-resistant prostate cancer: An updated systematic review and meta-analysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

¹⁷⁷ Lu-PSMA radioligand therapy effectiveness in metastatic castration-resistant prostate cancer: An updated systematic review and meta-analysis.