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177Lu-PSMA radioligand therapy of predominant lymph node metastatic prostate cancer.

ABSTRACT: 177Lu-PSMA radioligand therapy (LuPRLT) is mainly used for patients with metastatic castration-resistant prostate cancer who are resistant to established drugs. This study describes LuPRLT, either LuPSMA I&T or LuPSMA RLT-617, for 45 patients with predominant lymph node metastatic prostate cancer (LNM PC). Thirty-five patients had LNM and ten patients had LNM and one or two bone metastases. Before LuPRLT, the patients had prostate specific antigen (PSA) of median 18 µg/l (interquartile range (IQR): 3.3-39). LuPRLT was given with a cumulative injected 177Lu activity of median 14.5 GBq (IQR: 12.2-20.4). Maximum percentage decline of PSA was median 92% (IQR: 70-99). Thirty-five patients with only LNM had a better overall survival (OS) than ten patients with LNM and one or two bone metastases. Thirty-three docetaxel-naïve patients had a longer PSMA PET/CT progression-free survival than twelve patients who were resistant to docetaxel. Twenty-two patients who received LuPRLT with a cumulative injected 177Lu activity ? 14.8 GBq had a better PSMA PET/CT progression-free survival than 23 patients who received LuPRLT with a lower cumulative injected 177Lu activity. Seventeen patients with relapse after LuPRLT who received rechallenge LuPRLT or ActPRLT had a better OS than five patients who received other forms for relapse treatment. LuPRLT gave mild and transitory adverse effects. The findings of the present study suggest that LuPRLT of patients with LNM may be effective and safe. The promising results motivate randomized phase II trials to further quantify the impact of LuPRLT as treatment of patients with LNM.

SUBMITTER: von Eyben FE

PROVIDER: S-EPMC6497435 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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<sup>177</sup>Lu-PSMA radioligand therapy of predominant lymph node metastatic prostate cancer.

von Eyben Finn Edler FE Singh Aviral A Zhang Jingjing J Nipsch Karin K Meyrick Danielle D Lenzo Nat N Kairemo Kalevi K Joensuu Timo T Virgolini Irene I Soydal Cigdem C Kulkarni Harshad R HR Baum Richard Paul RP

Oncotarget 20190329 25

<sup>177</sup>Lu-PSMA radioligand therapy (LuPRLT) is mainly used for patients with metastatic castration-resistant prostate cancer who are resistant to established drugs. This study describes LuPRLT, either LuPSMA I&T or LuPSMA RLT-617, for 45 patients with predominant lymph node metastatic prostate cancer (LNM PC). Thirty-five patients had LNM and ten patients had LNM and one or two bone metastases. Before LuPRLT, the patients had prostate specific antigen (PSA) of median 18 µg/l (interquartil ...[more]

PMID: 31069008

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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:Clinical 177Lu-PSMA-617 radioligand therapy (RLT) is applied in advanced-stage prostate cancer. However, to the best of our knowledge murine models to study the biologic effects of various activity levels have not been established. The aim of this study was to optimize specific and total activity for 177Lu-PSMA-617 RLT in a syngeneic model of murine prostate cancer. Methods: Murine-reconstituted, oncogene-driven prostate cancer cells (0.1 × 106) (RM1), transduced to express human prostate-specific membrane antigen (PSMA), were injected into the left flank of C57Bl6 immunocompetent mice. RLT was performed by administering a single tail vein injection of 177Lu-PSMA-617 at different formulations for specific (60 MBq at high, 62 MBq/nmol; intermediate, 31 MBq/nmol; or low 15 MBq/nmol specific activity) or total activity (30, 60, or 120 MBq). Organ distribution was determined by ex vivo γ-counter measurement. DNA double-strand breaks were measured using anti-gamma-H2A.X (phospho S139) immunohistochemistry. Efficacy was assessed by serial CT tumor volumetry and 18F-FDG PET metabolic volume. Toxicity was evaluated 4 wk after the start of RLT. Results: Mean tumor-to-kidney ratios ± SEM were 19 ± 5, 10 ± 5, and 2 ± 0 for high, intermediate, and low (each n = 3) specific activity, respectively. Four of 6 (67%) mice treated with intermediate or high specific activity and none of 6 (0%) mice treated with low specific activity or formulation demonstrated significant DNA double-strand breaks (≥5% γ-H2A.X-positive cells). High when compared with intermediate or low specific activity resulted in a lower mean ± SEM tumor load by histopathology (vital tissue, 4 ± 2 vs. 8 ± 3 mm2; n = 3 vs. 6), day-4 18F-FDG PET (metabolic volume, 87 ± 23 vs. 118 ± 14 mm3; n = 6 vs. 12), and day-7 CT (volume, 323 ± 122 vs. 590 ± 46 mm3; n = 3 vs. 6; P = 0.039). 177Lu-PSMA-617 (120 MBq) with high specific activity induced superior tumor growth inhibition (P = 0.021, n = 5/group) without subacute hematologic toxicity (n = 3/group). Conclusion:177Lu-PSMA-617 (120 MBq) and high specific activity resulted in the highest efficacy in a syngeneic model of murine prostate cancer. The model will be useful for studying the effects of PSMA-directed RLT combined with potentially synergistic pharmacologic approaches.

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:Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands allow for labeling with 18F and radiometals for endoradiotherapy. rhPSMA-7.3 has been designated as a lead compound with promising preclinical data for 177Lu-rhPSMA-7.3, which has shown higher tumor uptake than 177Lu-PSMA I&T. In this retrospective analysis, we compared pretherapeutic clinical dosimetry data of both PSMA ligands. Methods: Six patients with metastatic castration-resistant prostate cancer underwent both 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T pretherapeutic dosimetry. Whole-body scintigraphy was performed at 1 h, 4 h, 24 h, 48 h, and 7 d after injection. Regions of interest covering the whole body, organs, bone marrow, and tumor lesions were drawn for each patient. Absorbed doses for individual patients and pretherapeutic applications were calculated using OLINDA/EXM. To facilitate the comparison of both ligands, we introduced the therapeutic index (TI), defined as the ratio of mean pretherapeutic doses to tumor lesions over relevant organs at risk. Results: Mean whole-body pretherapeutic effective doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were 0.12 ± 0.07 and 0.05 ± 0.03 Sv/GBq, respectively. Mean absorbed organ doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were, for example, 1.65 ± 0.28 and 0.73 ± 0.18 Gy/GBq for the kidneys, 0.19 ± 0.09 and 0.07 ± 0.03 Gy/GBq for the liver, 2.35 ± 0.78 and 0.80 ± 0.41 Gy/GBq for the parotid gland, and 0.67 ± 0.62 and 0.30 ± 0.27 Gy/GBq for the bone marrow, respectively. Tumor lesions received mean absorbed doses of 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T of 6.44 ± 6.44 and 2.64 ± 2.24 Gy/GBq, respectively. The mean TIs for the kidneys were 3.7 ± 2.2 and 3.6 ± 2.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively, and those for the bone marrow were 15.2 ± 10.2 and 15.1 ± 10.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively. Conclusion: Pretherapeutic clinical dosimetry confirmed preclinical results of mean absorbed doses for tumors that were 2-3 times higher for 177Lu-rhPSMA-7.3 than for 177Lu-PSMA I&T. Absorbed doses to normal organs also tended to be higher for 177Lu-rhPSMA-7.3, resulting overall in similar average TIs for both radiopharmaceuticals with considerable interpatient variability. 177Lu-rhPSMA-7.3 has promise for a therapeutic efficacy similar to that of 177Lu-PSMA I&T at smaller amounts of injected activity, simplifying radiation safety measurements (especially for large patient numbers or dose escalation regimens).

Project description:Baseline uptake on prostate-specific membrane antigen (PSMA)-targeted imaging is a prerequisite for radioligand therapy (RLT) with [177Lu]Lu-PSMA-617. This study aims to quantify lesion-based response to RLT in relation to pretreatment standard molecular imaging metrics derived from [68Ga]Ga-PSMA-11 PET/CT. Sixty-one patients with mCRPC underwent [68Ga]Ga-PSMA-11 PET/CT imaging before and after a median of 4 (IQR 2−6) RLT cycles. Maximum and mean standardized uptake values (SUVmax, SUVmean), as well as tumor-to-liver ratio (TLR), were assessed. A median of 12 (IQR 7−17) lesions was analyzed per patient, resulting in a total of 718 lesions. Lesions with ≥30% SUVmax decline or falling below the blood pool uptake were considered responsive; ≥30% SUVmax increase marked lesion progression. Additionally, 4-point visual scoring was performed according to E-PSMA consensus. In total, 550/718 (76.6%) lesions responded to RLT, including 389/507 (76.7%) bone metastases and 143/181 (79.0%) lymph node metastases. Baseline SUVmax, SUVmean, and TLR values were associated with lesion response by a moderate but significant correlation (rs = 0.33, p < 0.001, rs = 0.32, p < 0.001, and rs = 0.31, p < 0.001, respectively). For the classification of lesion progression based on baseline PSMA uptake, receiver operating characteristics (ROC) found SUVmax, SUVmean, and TLR to have comparable discriminatory value (AUC 0.85, 0.87, and 0.83). Of 42 tumor sites with baseline uptake below the liver (V-score < 2), 19/42 (45.2%) were responsive, 9/42 (21.4%) were stable, and 14/42 (33.3%) showed progression, leaving liver uptake a threshold with low prognostic value for the identification of RLT-refractory lesions (PPV 33%). This was observed accordingly for various liver uptake-based thresholds, including TLR < 1.5, <2.0 with a PPV at 24%, 20%, respectively. Standard uptake parameters quantified by routine baseline [68Ga]Ga-PSMA-11 PET/CT are moderately associated with post-treatment lesion response to [177Lu]Lu-PSMA-617. Commonly applied liver-based uptake thresholds have limited value in predicting refractory lesions at individual tumor sites.

Dataset Information

177Lu-PSMA radioligand therapy of predominant lymph node metastatic prostate cancer.

Publications

<sup>177</sup>Lu-PSMA radioligand therapy of predominant lymph node metastatic prostate cancer.

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