Article

Renal outcomes of radioligand therapy: experience of 177 lutetium-prostate-specific membrane antigen ligand therapy in metastatic castrate-resistant prostate cancer

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Abstract

Background Radioligand therapy (RLT) with 177lutetium (Lu)-labelled prostate-specific membrane antigen (PSMA) ligands has been increasingly used in recent years for therapy of metastatic castrate-resistant prostate cancer (mCRPC). Studies have revealed that 177Lu-PSMA ligand therapy is well tolerated and appears to cause fewer adverse effects than current standard of care third-line treatments. Notably, since 177Lu-PSMA agents are predominantly excreted by kidneys, there are concerns relating to their potential nephrotoxicity and renal outcomes. Although many recent studies have focused on mostly nephrotoxic adverse reactions at up to 3-month follow-up, assessment of renal outcomes after 177Lu-PSMA RLT in longer term follow-up is lacking. The aim of this study was to assess the influence of 177Lu-PSMA RLT on renal function in patients treated for mCRPC at >3 months post-therapy. Methods. In this retrospective cohort study, we assessed 195 men with progressive mCRPC who had received therapy with 177Lu-PSMA as second- or third-line after standard therapeutic interventions. Patients underwent investigations with 68Ga-PSMA-ligand positron emission tomography/computed tomography scan to confirm PSMA-expressing mCRPC. Eligible patients were required to have estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2, an Eastern Cooperative Oncology Group performance status score <3, no severe liver injury (as characterized by liver function tests) and no significant bone marrow dysfunction. Enrolled patients received two to five cycles of intravenous 177Lu-PSMA I&T or 177Lu-PSMA-617, at 6- to 10-week intervals. Renal outcomes were assessed according to Kidney Disease: Improving Global Outcomes guidelines as incidence of acute kidney injury (AKI), acute kidney disease (AKD) or chronic kidney disease (CKD). All assessments and tests were undertaken between therapy cycles and at follow-up of at least 3 months. Results. Of 195 assessed men with mCRPC, 110 patients aged [mean ± SD (range)] 70 ± 8 (53–92) years were recruited into this study with median follow-up of 8 (interquartile range 5–12, minimum 3, maximum 29) months and mean baseline eGFR 81 ± 13 mL/min/1.73 m2. Pre-existing CKD was identified in 12% of patients. None of the patients experienced an AKI during RLT. Two AKD and three CKD G3a cases were identified. Analysis of possible impact of prior CKD and major risk factors (hypertension, diabetes, history of AKI) on incidence of AKD or CKD demonstrated relative risk 4.2 [95% confidence interval (CI) 1.23–14.29] and 1.91 (95% CI 1.14–3.12), respectively. However, Fisher’s exact test did not reveal statistical significance of the impact of both conditions. Conclusions. Current Lu-PSMA RLT protocols appear to carry a mild nephrotoxic risk with the rate of about 4.5%. Prior CKD is potentially the most significant risk factor of post-RLT renal dysfunction.

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... 50 Hence, radiation toxicity to kidneys due to the fast clearance of radioligands through the urinary tract is of concern for their application for RLT. 6,51 However, neither acute nor long-term kidney toxicity has recently been reported to be a clinical problem in patients treated with [ 177 Lu]Lu-PSMA-617. 51 It is noteworthy that human kidneys have lower PSMA expression than mouse kidneys. ...
... 6,51 However, neither acute nor long-term kidney toxicity has recently been reported to be a clinical problem in patients treated with [ 177 Lu]Lu-PSMA-617. 51 It is noteworthy that human kidneys have lower PSMA expression than mouse kidneys. 52 8 An almost tenfold faster clearance in mice was observed with [ 177 Lu]Lu-PSMA-617. ...
Article
Prostate‐specific membrane antigen (PSMA) is the most promising target for radioligand therapy of prostate cancer. The aim of this study was to prepare a small molecular ligand p‐SCN‐Bn‐TCMC‐PSMA ligand (NG001), and compare it with the commonly used DOTA‐based PSMA‐617. The PSMA‐targeting ability of 212Pb‐labelled ligands was evaluated using PSMA‐positive C4‐2 human prostate cancer cells. Lead‐212 is an in vivo generator of alpha particles by its daughter nuclides 212Bi and 212Po. NG001 was synthesized by conjugating the isothiocyanato group of p‐SCN‐Bn‐TCMC to the amino group of a glutamate‐urea‐based PSMA binding entity. Molecular size, chelator unit and chelator linking method are different in NG001 and PSMA‐617. Both ligands were efficiently labelled with 212Pb using a 224Ra/212Pb‐solution generator in transient equilibrium with progeny. Lead‐212‐labelled NG001 was purified with a yield of 85.9±4.7% and with 0.7±0.2% of 224Ra. Compared with [212Pb]Pb‐PSMA‐617, [212Pb]Pb‐NG001 displayed a similar binding and internalization in C4‐2 cells, with comparable tumour uptake in mice bearing C4‐2 tumours, but almost a 2.5‐fold lower kidney uptake. Due to the rapid normal tissue clearance and tumour internalisation, any significant translocalization of 212Bi was not detected in mice. In conclusion, the obtained results warrant further preclinical studies to evaluate the therapeutic efficacy of [212Pb]Pb‐NG001.
... 17 Therefore, the risk for long-term renal impairment in mCRPC patients under PSMA-directed treatment has been tabulated from 4.5% to 25%. 18,19 Predictors for renal functional decline post-RLT are intensively sought and previous studies identified preexisting chronic kidney disease (CKD), diabetes mellitus, or arterial hypertension, which were all associated with higher nephrotoxicity. 18,19 According to current guidelines, a pretherapeutic PSMA-ligand positron emission tomography (PET)/computed tomography (CT) is mandatory before commencing RLT. 8 Of note, PSMA-ligands, such as Ga-68-PSMA-11, are excreted through the kidneys, 20 and the latter radiotracer may even hold potential for the determination of splitrenal function. ...
... 18,19 Predictors for renal functional decline post-RLT are intensively sought and previous studies identified preexisting chronic kidney disease (CKD), diabetes mellitus, or arterial hypertension, which were all associated with higher nephrotoxicity. 18,19 According to current guidelines, a pretherapeutic PSMA-ligand positron emission tomography (PET)/computed tomography (CT) is mandatory before commencing RLT. 8 Of note, PSMA-ligands, such as Ga-68-PSMA-11, are excreted through the kidneys, 20 and the latter radiotracer may even hold potential for the determination of splitrenal function. 21 Moreover, when scheduling patients for Lu-177-PSMA-RLT, a pretherapeutic blood-based assessment of estimated glomerular filtration rate (eGFR) and renal scintigraphy should be performed. ...
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Background Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) may be associated with renal toxicity. We aimed to identify predictive parameters for the development of chronic kidney disease (CKD) in patients with metastatic castration resistant prostate cancer (mCRPC) undergoing RLT. Methods In 46 mCRPC patients scheduled for Lu-177-PSMA-RLT, pretherapeutic estimated glomerular filtration rate (eGFR [ml/min/1.73 m²]), Tc-99m-mercaptoacetyltriglycine (Tc-99m-MAG3) clearance and baseline Ga-68-PSMA-ligand positron emission tomography (PET)-derived renal cortical uptake and PSMA-tumor volume (TV) were determined. We tested the predictive capability of these parameters and clinical risk factors for the occurrence of CKD (defined as CTCAE vers. 5.0 grade 2 or higher) during follow-up. Results After 4 ± 3 cycles of RLT average eGFR declined from 76 ± 17 to 72 ± 20 ml/min/1.73 m² (p = 0.003). Increased estimated renal radiation dose (eRRD) was significantly associated with renal functional decline (p = 0.008). During follow-up, 16/46 (30.4%) developed CKD grade 2 (no grade 3 or higher). In receiver operating characteristic (ROC) analysis, pretherapeutic eGFR was highly accurate in identifying the occurrence of CKD vs no CKD with an area under the curve (AUC) of 0.945 (p < 0.001; best threshold, 77 ml/min/1.73 m²), followed by Tc-99m-MAG3-derived tubular extraction rate (TER; AUC, 0.831, p < 0.001; best threshold, 200 ml/min/1.73 m²). Renal PET signal (p = 0.751) and PSMA-TV (p = 0.942), however, were not predictive. Kaplan–Meier analyses revealed adverse renal outcome for patients with lower eGFR (p = 0.001) and lower scintigraphy-derived TER (p = 0.009), with pretherapeutic eGFR emerging as the sole predictive parameter in multivariate analysis (p = 0.007). Conclusion Serious adverse renal events are not a frequent phenomenon after PSMA-targeted RLT. However, in patients developing moderate CKD after RLT, pretherapeutic eGFR is an independent predictor for renal impairment during follow-up.
... Radiolabeled PSMA ligands with 177 Lu and 225 Ac are also used to treat prostate cancer metastases with increasing success (10,11). Studies have reported no significant effect on renal function although therapeutic radiolabeled PSMA ligands show high renal uptake and excretion (12,13). ...
... As radiolabeled PSMA ligands show high renal parenchymal uptake and renal excretion, studies have assessed renal function after 177 Lu-PSMA ligand treatments in metastatic prostate cancer patients. Studies have reported low renal toxicity in castrate-resistant metastatic prostate cancer treated with 177 Lu-PSMA-617 (12,13). However, it would be interesting to study larger number of patients who underwent 177 Lu-PSMA-therapy and correlate the renal function with the renal PSMA uptake parameters as we did in the current study. ...
Article
Aim: 68Ga -PSMA ligands are used for prostate cancer but also show high renal cortical uptake. In this study, we aimed to assess if there is any correlation between renal PSMA PET parameters and renal function tests using the images of prostate cancer patients. Methods: 68Ga-PSMA-11 PET/CT images of the patients with prostate cancer were retrospectively evaluated. The following PET parameters were obtained: SUVmax, SUVmean, SULmax, SULmean, volume, TLGSUL and counts of both kidneys as well as SUVmean of liver, blood pool and spleen. Total TLGSUL, total volume, kidney to liver and kidney to blood pool ratios were calculated. Patient's creatinine values were obtained and GFR was calculated using the MDRD formula. Statistical analysis was performed to understand if there is a correlation between above parameters and renal function tests. Results: Twenty five patients were included in this study. GFR was significantly/positively correlated and creatinine was significantly/negatively correlated with renal SUV/liver SUV and renal SUV/blood pool SUV ratios. GFR was marginally positively correlated with renal SULmean and creatinine was marginally negatively correlated with total TLGSUL. Total renal parenchymal volume was significantly and directly (positively) associated with GFR and significantly and inversely (negatively) associated with creatinine. Conclusion: Renal 68Ga-PSMA uptake appears to be correlated with renal function tests. Our method of measuring approximate renal parenchymal volume on PET image appears to be reliable.
... Other classification systems, such as KDIGO GFR categories, may better reflect actual changes of renal function with RLT [17]. In addition, using this system, Gallyamov et al. reported three G3a cases in a mixed cohort treated with [ 177 Lu]Lu-PSMA I&T and -617, which is in line with our findings of two individuals worsening from G3a to G3b under RLT [18]. Even when such sophisticated approaches such as KDIGO are applied to assess current renal functional status with RLT, alterations or re-categorizations do not frequently occur. ...
Article
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(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [177Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [177Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [99mTc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman’s rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as
... This is consistent with the results of the Australian prospective phase II trial (initially n = 30) by Hofman et al. [15] and its expanded trial report with n = 50 patients [16]; their data of adverse effects were limited to a three-month follow-up. From a longer follow-up observation report by Gallyamov et al. with a median of 12 months from start of treatment, the incidence of renal impairment CTCAE grade 1 or 2 is expected to be below 5% [30]. Analogies can also be seen in studies on peptide-receptor-mediated radionuclide therapy (PRRT) in patients with neuroendocrine tumor (NET). ...
Article
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Background: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is an effective antitumor-treatment in metastatic castration-resistant prostate carcinoma (mCRPC). Concerns of potential nephrotoxicity are based on renal tubular PSMA expression and the resulting radiopharmaceutical retention during RLT, but data confirming clinically significant renal toxicity are still lacking. In this study, patients with significantly impaired baseline kidney function before initiation of therapy were investigated for treatment-associated nephrotoxicity and the potential relationship with administered activities of [177Lu]Lu-PSMA-617. Methods: Twenty-two mCRPC patients with impaired renal function (glomerular filtration rate (GFR) ≤ 60 mL/min) who received more than two cycles of [177Lu]Lu-PSMA-617 RLT (median 5 cycles and median 6-week time interval between consecutive cycles) were analyzed in this study. Patients were treated within a prospective patient registry (REALITY Study, NCT04833517). Cumulative administered activities ranged from 17.1 to 85.6 GBq with a median activity of 6.5 GBq per cycle. Renal function was closely monitored during and after PSMA-RLT. Results: Mean pre-treatment GFR was 45.0 ± 10.7 mL/min. After two (22/22 patients), four (20/22 patients), and six cycles (10/22 patients) of RLT, a significant increase of GFR was noted (each p < 0.05). End-of-treatment GFR (54.1 ± 16.7 mL/min) was significantly higher than baseline GFR (p = 0.016). Only one patient experienced deterioration of renal function (change of CTCAE grade 2 to 3). The remaining patients showed no significant reduction of GFR, including follow-up assessments (6, 9, and 12 months), and even showed improved (10/22 patients) or unchanged (11/22 patients) CTCAE-based renal impairment grades during and after the end of PSMA-RLT. No significant correlation between the change in GFR and per-cycle (p = 0.605) or cumulative (p = 0.132) administered activities were found. Conclusions: As pre-treatment chronic kidney failure did not lead to detectable RLT-induced deterioration of renal function in our study, the nephrotoxic potential of [177Lu]Lu-PSMA-617 RLT may be overestimated and not of clinical priority in the setting of palliative treatment in mCRPC. We suggest not to categorically exclude patients from enrolment to PSMA-RLT due to renal impairment.
... The article concluded that tubular extraction rate of 99m Tc-mercaptoacetyltriglycine and cystatin C were prognostic markers of nephrotoxicity. On the other hand, Gallyamov et al. [5] found only history of chronic kidney disease to be a risk factor associated with renal toxicity. The most effective approach to determine the underlying cause for renal toxicity and to develop a database regarding the category of the patient at highest risk of poor renal outcomes is to create a clinic-specific protocol for assessing risk factors and regular evaluation of kidney function parameters at different phases of the study (Fig. 1). ...
... We also believe that the rate of "attributable toxicity" for 177 Lu-PSMA is lower than what has been previously reported. In our view, the most relevant study in this context is described in a 2019 article from Australia that reported a rate of 4.5% [8]. ...
... Due to the physiological expression of PSMA in kidneys and predominantly renal excretion of 225 Ac-PSMA-617, there is concern about possible radiation toxicity to the kidneys that may cause acute and long-term effects [138,176,177]. It has been reported that the kidney function deteriorated in a patient with one functional kidney after 225 Ac-PSMA-617 [109] and that chronic kidney disease was found in two patients with mCRPC after 225 Ac-PSMA-617 therapy [114]. ...
Article
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Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months’ survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics). PSMA-targeted α therapies (PSMA-TAT) may deliver potent and local radiation more selectively to cancer cells than PSMA-targeted β- therapies. In this review, we summarize both the recent preclinical and clinical advances made in the development of PSMA-TAT, as well as the availability of therapeutic α-emitting radionuclides, the development of small molecules and antibodies targeting PSMA. Lastly, we discuss the potentials, limitations, and future perspectives of PSMA-TAT.
... The haematological adverse events contained grade 3 or 4 thrombocytopenia (10%), anaemia (10%), neutropenia (6%), and lymphopenia (32%), and the rates were similar to our data except for the incidence of neutropenia and lymphopenia. Grade 1 or 2 renal adverse effects occurred in 10% of patients, which was higher than that in the present cohort; however, this can be explained by a difference in the assessment of kidney injury [38]. ...
Article
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Background Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA) radioligand therapy is emerging as a promising treatment for metastatic castration-resistant prostate cancer refractory to established therapies. While there is an increasing body of survival and other data from retrospective analyses and prospective trials, there is no clear understanding of how best to predict therapy response and survival outcomes.Objective In this retrospective cohort analysis, we aimed to identify features that are associated with response to radioligand therapy and greater survival based on analysis of real-world data.Patients and Methods191 patients aged 70 ± 8 years with metastatic castration-resistant prostate cancer treated with radioligand therapy from November 2015 to February 2019 were included for analysis. Eligible patients had PSMA-expressing metastatic castration-resistant prostate cancer (confirmed by a 68Ga-PSMA-ligand positron emission tomography (PET)/computed tomography (CT) scan), an Eastern Cooperative Oncology Group performance status score ≤ 2 and no significant kidney, liver or bone marrow dysfunction (as characterised by kidney and liver function tests and a full blood count). Patients received one to five cycles of intravenous 177Lu-PSMA-ligand therapy. Endpoints included biochemical [prostate-specific antigen (PSA)] and radiologic (PSMA PET/CT) response, progression-free survival and overall survival, defined according to the Prostate Cancer Working Group 3 guidelines. Survival analysis was conducted by Kaplan–Meier estimation.ResultsMost individuals (89.5%) previously underwent first- and second-line systematic therapy. Of the 191 men treated with 452 cycles with mean injected activity of 6.1 ± 1.0 GBq per cycle, 159 patients were assessed for a biochemical response defined as a PSA decline ≥ 50% from baseline. A ≥ 50% PSA decline was observed in 89 (56%) patients, while any PSA decline occurred in 120 (75%) men. For the entire cohort, median values (interquartile range) of overall survival [n = 191], PSA progression-free survival [n = 132] and PET/CT progression-free survival were 12 (5–18), 4 (3–8) and 6 (3–10) months, respectively. Survival analysis confirmed better outcomes in individuals who had demonstrated therapy response. Predominantly lymph node metastatic disease and chemotherapy-naïve status were significant pre-therapy factors associated with longer survival. Baseline PSA was significantly linked to survival outcomes: lower levels predicted a lower risk of death and disease progression. Treatment-related adverse events included grade 3 or 4 haematological (12%), grade 1 or 2 renal (4.5%), and grade 3 or 4 clinical events (5.7%).Conclusions Our findings suggest that 177Lu-PSMA radioligand therapy provides a significant response rate with a low toxicity profile. The evidence promotes greater efficacy of radioligand therapy in predominantly lymph node metastatic castration-resistant prostate cancer, and in individuals with chemotherapy-naïve status and lower levels of baseline PSA.
... Hence, follow-up periods might be too short to draw definitive conclusions [27]. One study increased the follow-up time of patients and reported mild nephrotoxicity in 4.5% of studied patients [39]. Salivary gland toxicity, experienced as dry mouth or xerostomia, has been reported in up to 30% of patients treated with [ 177 Lu]Lu-PSMA-617. ...
Article
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At present, prostate cancer remains the second most occurring cancer in men, in Europe. Treatment efficacy for therapy of advanced metastatic disease, and metastatic castration-resistant prostate cancer in particular is limited. Prostate-specific membrane antigen (PSMA) is a promising therapeutic target in prostate cancer, seeing the high amount of overexpression on prostate cancer cells. Clinical investigation of PSMA-targeted radionuclide therapy has shown good clinical efficacy. However, adverse effects are observed of which salivary gland hypofunction and xerostomia are among the most prominent. Salivary gland toxicity is currently the dose-limiting side effect for PSMA-targeted radionuclide therapy, and more specifically for PSMA-targeted alpha therapy. To date, mechanisms underlying the salivary gland uptake of PSMA-targeting compounds and the subsequent damage to the salivary glands remain largely unknown. Furthermore, preventive strategies for salivary gland uptake or strategies for treatment of salivary gland toxicity are needed. This review focuses on the current knowledge on uptake mechanisms of PSMA-targeting compounds in the salivary glands and the research performed to investigate different strategies to prevent or treat salivary gland toxicity.
... Although these retrospective studies showed encouraging results, it is necessary to collect additional prospective data about alpha emitters radioligand RLT. Additional studies are needed to explore the intracellular localization, retention times, and stability of 225 Ac-PSMA complexes destined for the radioligand therapy in cancer and normal tissues, especially in the renal tissues (Kratochwil et al., 2018b), because the excretion of 225 Ac-PSMA-617 through the kidney might lead to nephrotoxicity (Ristau et al., 2014;Gallyamov et al., 2019). Furthermore, the lack of 225 Ac availability is a primary obstacle that must be overcome for its use in clinical studies (Robertson et al., 2018). ...
Article
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Castration-resistant prostate cancer (CRPC) is a therapy-resistant and lethal form of prostate cancer as well as a therapeutic challenge. Prostate-specific membrane antigen (PSMA) has been proved as a promising molecular target for optimizing the theranostics for CRPC patients. When combined with PSMA radiotracers, novel molecular imaging techniques such as positron emission tomography (PET) can provide more accurate and expedient identification of metastases when compared with conventional imaging techniques. Based on the PSMA-based PET scans, the accurate visualization of local and disseminative lesions may help in metastasis-directed therapy. Moreover, the combination of 68Ga-labeled PSMA-based PET imaging and radiotherapy using PSMA radioligand therapy (RLT) becomes a novel treatment option for CRPC patients. The existing studies have demonstrated this therapeutic strategy as an effective and well-tolerated therapy among CRPC patients. PSMA-based PET imaging can accurately detect CRPC lesions and describe their molecular features with quantitative parameters, which can be used to select the best choice of treatments, monitor the response, and predict the outcome of RLT. This review discussed the current and potential role of PSMA‐based imaging and RLT in the diagnosis, treatment, and prediction of prognosis of CRPC.
... The underlying principle of AKI following TLS post radionuclide therapy is similar to that described in the setting of traditional anti-cancer therapies. Acute kidney disease (AKD) occurring within 3 months of 177 Lu-PSMA therapy has also been reported in 2/195 (1%) of patients [49]. ...
Article
Radioligand therapies have opened new treatment avenues for cancer patients. They offer precise tumor targeting with a favorable efficacy-to-toxicity profile. Specifically, the kidneys, once regarded as the critical organ for radiation toxicity, also show excellent tolerance to radiation doses as high as 50–60 Gy in selected cases. However, the number of nephrons that form the structural and functional units of the kidney is determined before birth and is fixed. Thus, loss of nephrons secondary to any injury may lead to an irreversible decline in renal function over time. Our primary understanding of radiation-induced nephropathy is derived from the effects of external beam radiation on the renal tissue. With the growing adoption of radionuclide therapies, considerable evidence has been gained with regard to the occurrence of renal toxicity and its associated risk factors. In this review, we discuss the radionuclide therapies associated with the risk of nephrotoxicity, the present understanding of the factors and mechanisms that contribute to renal injury, and the current and potential methods for preventing, identifying, and managing nephrotoxicity, specifically acute onset nephropathies.
... For example, dry mouth is a common side-effect of [ 177 Lu]Lu-PSMA ligands as they concentrate in the salivary glands [15]. In general, normal organs that are vulnerable following MRT are organs of excretion, particularly the kidneys, and the bone marrow, which may be irradiated as the radiopharmaceutical circulates freely post-injection [16,17]. ...
Article
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The emergence of effective radionuclide therapeutics, such as radium-223 dichloride, [¹⁷⁷Lu]Lu-DOTA-TATE and [¹⁷⁷Lu]Lu-PSMA ligands, over the last 10 years is driving a rapid expansion in molecular radiotherapy (MRT) research. Clinical trials that are underway will help to define optimal dosing protocols and identify groups of patients who are likely to benefit from this form of treatment. Clinical investigations are also being conducted to combine new MRT agents with other anticancer drugs, with particular emphasis on DNA repair inhibitors and immunotherapeutics. In this review, the case is presented for combining MRT with external beam radiotherapy (EBRT). The technical and dosimetric challenges of combining two radiotherapeutic modalities have impeded progress in the past. However, the need for research into the specific radiobiological effects of radionuclide therapy, which has lagged behind that for EBRT, has been recognised. This, together with innovations in imaging technology, MRT dosimetry tools and EBRT hardware, will facilitate the future use of this important combination of treatments.
... Among them is the recent work of Rosar et al. who demonstrated an increase in GFR determined by the MDRD formula after six cycles of PSMA-RLT with a median activity of 6.5 GBq [52]. Some studies described a dose-dependent mild renal function impairment of approximately 4.5% after 2-5 five cycles of PSMA-RLT with a mean cumulative [ 177 Lu]Lutetium dose of 18.8 ± 6.7 GBq at 6-10 week intervals [53,54]. In other earlier studies, such as the study by Yadav et al., no nephrotoxicity was detected in 31 patients after 1.11-5.55 ...
Article
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Background: [177Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT) could affect kidney and salivary gland functions in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: We retrospectively analyzed clinical, renal, and salivary scintigraphy data and salivary [68Ga]Ga-PSMA-11 ligand PET scan measures such as metabolic volume and SUVmax values of 27 mCRPC men (mean age 71 ± 7 years) before and 4 weeks after receiving three cycles of PSMA-RLT every 4 weeks. Twenty-two patients additionally obtained renal and salivary scintigraphy prior to each cycle. A one-way ANOVA, post-hoc Scheffé test and Cochran's Q test were applied to assess organ toxicity. Results: In total, 54 PSMA PET scans, 98 kidney, and 98 salivary scintigraphy results were evaluated. There were no significant differences for the ejection fraction, peak time, and residual activity after 5 min for both parotid and submandibular glands prior to each cycle and 4 weeks after the last cycle. Similarly, no significant differences in serum creatinine and renal scintigraphy parameters were observed prior to each cycle and 4 weeks after the last treatment. Despite there being no changes in the metabolic volume of both submandibular glands, SUVmax values dropped significantly (p < 0.05). Conclusion: Results evidenced no alterations in renal function and only minimal impairment of salivary function of mCRPC patients who acquired an intense PSMA-RLT regimen every 4 weeks.
Article
Purpose of the study: To report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive mCRPC after ≥1 novel androgen-axis drug, either chemotherapy naïve or post-chemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET and no visceral PSMA-negative lesions were eligible. Patients were randomized (1:1) into two activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 weeks. The primary safety endpoint was assessed by collecting and grading Adverse Events (AE) using the CTCAE. Patients were followed until disease progression, death, serious or intolerable AE, study termination by sponsor, patient withdrawal, lost to follow-up or 24 months after the first cycle. Results: The study was closed at enrollment of 71/200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least one cycle of 177Lu-PSMA-617: 28 (36%) in Arm 1 (6.0 GBq) and 41 (64%) in Arm 2 (7.4GBq). There were 10 (43.5%), 19 (46.5%) and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0 GBq arm, 7.4 GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0 GBq arm, the 7.4 GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%), nausea (52.2%; 43.9%; 46.9%), and diarrhea (13.0%; 31.7%; 25.0%). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): one subdural hematoma Grade 4, one anemia grade 3, one thrombocytopenia grade 4, one gastrointestinal hemorrhage grade 3, and one acute kidney injury grade 3. There were no clinically significant changes in vital signs in ECGs in the 2 treatment groups. No trend to creatinine increase, or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion: 177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-week intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.
Article
Lutetium-177 prostate-specific membrane antigen (¹⁷⁷Lu-PSMA) radioligand therapy is an option that is increasingly being used for treatment of metastatic castration-resistant prostate cancer. This delivers β-radiation to cells expressing PSMA and high accumulation of the radiopharmaceutical occurs in the kidneys. Here we report three cases of radiation nephropathy with severe chronic kidney disease induced by renal thrombotic microangiopathy following extensive treatment with ¹⁷⁷Lu-PSMA radioligand therapy.
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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.
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This two-part preclinical study aims to evaluate prostate specific membrane antigen (PSMA) as a valuable target for expression-based imaging applications and to determine changes in target binding in function of varying specific activities (SA) of ¹⁸ F-AlF-PSMA-11. For the evaluation of PSMA expression levels, male NOD/SCID mice bearing prostate cancer (PCa) xenografts of C4-2 (PSMA+++), 22Rv1 (PSMA+) and PC-3 (PSMA-) were administered ¹⁸ F-AlF-PSMA-11 with a medium SA (20.26 ± 3.25 MBq/µg). SUV mean and SUV max values were respectively 3.22 and 3.17 times higher for the high vs low PSMA expressing tumors (p < 0.0001). To evaluate the effect of varying SA, C4-2 and 22Rv1 xenograft bearing mice underwent additional ¹⁸ F-AlF-PSMA-11 imaging with a high (213.3 ± 39.3 MBq/µg) and/or low SA (1.94 ± 0.27 MBq/µg). SUV values showed a significantly increasing trend with higher SA. Significant changes were found for SUV mean and SUV max between the high vs low SA and medium vs low SA (both p < 0.05), but not between the high vs medium SA (p = 0.055 and 0.25, respectively). The effect of varying SA was more pronounced in low expressing tumors and PSMA expressing tissues (e.g. salivary glands and kidneys). Overall, administration of a high SA increases the detection of low expression tumors while also increasing uptake in PSMA expressing tissues, possibly leading to false positive findings. In radioligand therapy, a medium SA could reduce radiation exposure to dose-limiting organs with only limited effect on radionuclide accumulation in the tumor.
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This two-part preclinical study aims to evaluate prostate specific membrane antigen (PSMA) as a valuable target for expression-based imaging applications and to determine changes in target binding in function of varying apparent molar activities (MA app ) of [ ¹⁸ F]AlF-PSMA-11. For the evaluation of PSMA expression levels, male NOD/SCID mice bearing prostate cancer (PCa) xenografts of C4-2 (PSMA+++), 22Rv1 (PSMA+) and PC-3 (PSMA−) were administered [ ¹⁸ F]AlF-PSMA-11 with a medium MA app (20.24 ± 3.22 MBq/nmol). SUV mean and SUV max values were respectively 3.22 and 3.17 times higher for the high versus low PSMA expressing tumors ( p < 0.0001). To evaluate the effect of varying MA app , C4-2 and 22Rv1 xenograft bearing mice underwent additional [ ¹⁸ F]AlF-PSMA-11 imaging with a high (211.2 ± 38.9 MBq/nmol) and/or low MA app (1.92 ± 0.27 MBq/nmol). SUV values showed a significantly increasing trend with higher MA app . Significant changes were found for SUV mean and SUV max between the high versus low MA app and medium versus low MA app (both p < 0.05), but not between the high versus medium MA app ( p = 0.055 and 0.25, respectively). The effect of varying MA app was more pronounced in low expressing tumors and PSMA expressing tissues (e.g. salivary glands and kidneys). Overall, administration of a high MA app increases the detection of low expression tumors while also increasing uptake in PSMA expressing tissues, possibly leading to false positive findings. In radioligand therapy, a medium MA app could reduce radiation exposure to dose-limiting organs with only limited effect on radionuclide accumulation in the tumor.
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The field of nuclear imaging and therapy is rapidly progressing with the development of targeted radiopharmaceuticals that show rapid targeting and rapid clearance with minimal background. Unfortunately, they are often reabsorbed in the kidneys, leading to possible nephrotoxicity, limiting the therapeutic dose, and/or reducing imaging quality. The blocking of endocytic receptors has been extensively used as a strategy to reduce kidney radiation. Alternatively, the physicochemical properties of radiotracers can be modulated to either prevent their reuptake or promote the excretion of radiometabolites. Other interesting strategies focus on the insertion of a cleavable linker between the radiolabel and the targeting moiety or pretargeting approaches in which the targeting moiety and radiolabel are administered separately. In the context of this review, we will discuss the latest advances and insights on strategies used to reduce renal retention of low- to moderate-molecular-weight radiopharmaceuticals.
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177 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 (interquartile range (IQR): 3.3-39). LuPRLT was given with a cumulative injected 177 Lu 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 177 Lu activity ≥ 14.8 GBq had a better PSMA PET/CT progression-free survival than 23 patients who received LuPRLT with a lower cumulative injected 177 Lu 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.
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Background: Prostate-specific membrane antigen (PSMA)-based radiopeptide/radioligand therapy represents a rapidly expanding field in the management of metastatic castrate-resistant prostate cancer (mCRPC). However, there remains concern for the development of significant toxicities in heavily pretreated patients. In this study, the authors present their local experience, with respect to efficacy and toxicity, of 22 consecutive patients treated with lutetium-177-DOTAGA-(I-y)fk(Sub-KuE) or 177Lu-PSMA I&T radioimmunotherapy for progressive mCRPC, followed up over 1 year. Materials and methods: All patients had progressive mCRPC, an European Cooperative Oncology Group (ECOG) ≤2 with adequate bone marrow and liver function. 177Lu-PSMA I&T therapy was administered at 8-week intervals with a mean prescribed activity of 5.5 GBq (gigabecquerel) per patient. Results: Twenty patients had evaluable results, median age of 71 years, and median duration of follow-up of 17 months. Three patients (15%) experienced a G1/2 myelotoxicity and four (20%) G3/4. No incidences of myelodysplasia/acute leukemia have been identified. All toxicities were self-limiting. Baseline cytopenia was predictive of the development of subsequent G3/4 myelotoxicity (p = 0.0035). Eight patients (40%) experienced an objective PSA response, with a median time to response of 15 weeks. The median time to PSA progression was not reached. Patients receiving three cycles of therapy were statistically more likely to experience a disease response when compared to those treated with one, two, or four cycles (p < 0.0001). Conclusions: 177Lu-PSMA I&T radioimmunotherapy of progressive mCRPC is safe and effective with three cycles being the potential optimal number for determining long-term disease response.
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Prostate Cancer is the forth most common type of cancer. Prostate-specific membrane antigen (PSMA) is anchored in the cell membrane of prostate epithelial cells. PSMA is highly expressed on prostate epithelial cells and strongly up-regulated in prostate cancer. Therefore it is an appropriate target for diagnostic and therapy of prostate cancer and its metastases. This article discusses several articles on radionuclide treatments in prostate cancer and the results on PSMA therapy with either beta or alpha emitters as a salvage therapy.
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Background: Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new effective therapeutic agents that improve patient outcomes are urgently needed. Lutetium-177 [177Lu]-PSMA-617, a radiolabelled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA) enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer. We aimed to investigate the safety, efficacy, and effect on quality of life of [177Lu]-PSMA-617 in men with metastatic castration-resistant prostate cancer who progressed after standard treatments. Methods: In this single-arm, single-centre, phase 2 trial, we recruited men (aged 18 years and older) with metastatic castration-resistant prostate cancer and progressive disease after standard treatments, including taxane-based chemotherapy and second-generation anti-androgens, from the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Patients underwent a screening PSMA and FDG-PET/CT to confirm high PSMA-expression. Eligible patients had progressive disease defined by imaging (according to Response Evaluation Criteria In Solid Tumours [RECIST] or bone scan) or new pain in an area of radiographically evident disease, and were required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or lower. Eligible patients received up to four cycles of intravenous [177Lu]-PSMA-617, at six weekly intervals. The primary endpoint was PSA response according to Prostate Cancer Clinical Trial Working Group criteria defined as a greater than 50% PSA decline from baseline and toxicity according to CTCAE. Additional primary endpoints were imaging responses (as measured by bone scan, CT, PSMA, and FDG PET/CT) and quality of life (assessed with the EORTC-Q30 and Brief Pain Inventory-Short Form questionnaires), all measured up to 3 months post completion of treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number 12615000912583. Findings: Between Aug 26, 2015, and Dec 8, 2016, 43 men were screened to identify 30 patients eligible for treatment. 26 (87%) had received at least one line of previous chemotherapy (80% docetaxel and 47% cabazitaxel) and 25 (83%) received prior abiraterone acetate, enzalutamide, or both. The mean administered radioactivity was 7·5 GBq per cycle. 17 (57%) of 30 patients (95% CI 37-75) achieved a PSA decline of 50% or more. There were no treatment-related deaths. The most common toxic effects related to [177Lu]-PSMA-617 were grade 1 dry mouth recorded in 26 (87%) patients, grade 1 and 2 transient nausea in 15 (50%), and G1-2 fatigue in 15 (50%). Grade 3 or 4 thrombocytopenia possibly attributed to [177Lu]-PSMA-617 occurred in four (13%) patients. Objective response in nodal or visceral disease was reported in 14 (82%) of 17 patients with measurable disease. Clinically meaningful improvements in pain severity and interference scores were recorded at all timepoints. 11 (37%) patients experienced a ten point or more improvement in global health score by the second cycle of treatment. Interpretation: Our findings show that radionuclide treatment with [177Lu]-PSMA-617 has high response rates, low toxic effects, and reduction of pain in men with metastatic castration-resistant prostate cancer who have progressed after conventional treatments. This evidence supports the need for randomised controlled trials to further assess efficacy compared with current standards of care. Funding: None.
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Acute kidney injury (AKI) consists of a rapid renal function decline which usually increases serum urea and creatinine levels. Since kidney injury begins by inducing biological and molecular changes which evolve to cellular damage, biomarkers could be used as tools for monitoring early AKI appearance, and predicting its recovery. Among the main AKI biomarkers the neutrophil gelatinase-associated lipocalin, cystatin C, kidney injury molecule-1, monocyte chemotactic peptide-1, N-acetyl-β-D-glucosaminidase, interleukin-18, liver-type fatty acid-binding protein, netrin-1, cycle arrest markers, endogenous ouabain, selenium-binding protein 1, and BPIFA2 marker, have been described. Even though novel biomarkers seem to be more helpful to early detect AKI and/or predict the need for renal replacement, and mortality compared to serum creatinine, more comprehensive studies are still required to determine their clinical utility.
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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). 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. 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). 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.
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Purpose: Radioligand therapies targeting prostate-specific membrane antigen (PSMA) have been established for the treatment of metastasized castration-resistant prostate cancer (mCRPC) in the last decade and show promising response rates and a favourable toxicity profile. The aim of this study was to evaluate the overall survival (OS) and to identify parameters predicting outcome in mCRPC patients treated with (177)Lu-PSMA-617. Methods: Between December 2014 and January 2017, 59 consecutive patients (median age 72 years; interquartile range, (IQR, 66-76 years) with mCRPC, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy, were included in this study. Biochemical response was evaluated using Prostate Cancer Working Group 3 (PCWG3) criteria. Survival was evaluated using Kaplan-Meier estimates and Cox regression proportional hazards model. Toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE). The study was approved by the local ethics committee. Results: The 59 patients were treated with a total of 159 cycles (median 3 cycles, range 1-7) of (177)Lu-PSMA-617 (median dose 6.11 GBq, IQR 5.9-6.3 GBq). The median follow-up was 24 weeks (IQR 15-36 weeks). Follow-up data for at least 12 weeks (PCWG3) were available in 76% (45) of the patients. For outcome results data from all patients treated with at least one cycle were analysed. A decline in prostate-specific antigen (PSA) of ≥50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. An initial alkaline phosphatase (ALP) level <220 U/L and a PSA decline after the first cycle were associated with a longer OS (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). The median estimated PSA progression-free survival (PPFS) was 18 weeks. Only ALP level <220 U/L was significantly associated with a longer PPFS (41 vs. 18 weeks, p < 0.01). Conclusions: A PSA decline after the first cycle of (177)Lu-PSMA-617 and an initial ALP level <220 U/L were predictors of a longer OS in patients with end-stage mCRPC. An ALP level <220 U/L was additionally associated with a longer PPFS.
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Background[177Lu]Lu-PSMA-617 is a well-tolerated therapy for the treatment of metastatic prostate cancer. However, because of the mainly renal excretion of the tracer, the kidneys are one of the most limiting organs. The purpose of this study was to examine the post-therapeutic changes in renal function over time and to identify risk factors for developing renal toxicity. We also tested the reliability of markers for renal function monitoring. Methods Fifty-five patients with castrate-resistant metastatic prostate cancer treated with at least three cycles of [177Lu]Lu-PSMA-617 were investigated. Renal function was assessed through laboratory tests (creatinine, GFR, cystatin C) and Tc-99 m-MAG3 measurements. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. To identify risk factors for renal toxicity, we used Pearson’s correlation coefficient and the corresponding p values. ResultsNone of the 55 patients experienced severe nephrotoxicity (grade 3/4). In 14 patients (25%), we observed increased creatinine levels of CTC 1° or 2°. There were 16 cases of increased GFR (grade 1/2). At the baseline, only 14 patients had elevated cystatin C. However, post-therapeutic cystatin C was elevated in 32 patients (58%). A significant effect on renal function was found for age (p = 0.049), hypertension (p = 0.001) and pre-existing kidney disease (p = 0.001). The most reliable predictive markers of nephrotoxicity were TER-MAG3 and cystatin C. Conclusion Renal toxicity in patients treated with [177Lu]Lu-PSMA-617 was low. There was no (sub)acute grade 3 or 4 nephrotoxicity.
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Prostate-specific membrane antigen (PSMA) is a receptor on the surface of prostate cancer cells that is revolutionising the way we image and treat men with prostate cancer. New small molecule peptides with high-binding affinity for the PSMA receptor have allowed high quality, highly specific PET imaging, in addition to the development of targeted radionuclide therapy for men with prostate cancer. This targeted therapy for prostate cancer has, to date, predominately used Lutetium 177 (Lu) labelled PSMA peptides. Early clinical studies evaluating the safety and efficacy of Lu PSMA therapy have demonstrated promising results with a significant proportion of men with metastatic prostate cancer, who have already failed other therapies, responding clinically to Lu PSMA. This review discusses the practical issues of administering Lu PSMA, and gives an overview of the findings from currently published trials in regards to treatment response rates, expected toxicities and safety.
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Introduction: A targeted theragnostic approach based on increased expression of prostate-specific membrane antigen (PSMA) on PC cells is an attractive treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Ten consecutive mCRPC patients were selected for (177)Lu-PSMA617 therapy on the basis of PSMA-targeted (68)Ga-PSMA-HBED-CC PET/CT diagnosis showing extensive and progressive tumour load. Following dosimetry along with the first therapy cycle restaging ((68)Ga-PSMA-HBED-CC and (18)F-NaF PET/CT) was performed after 2 and 3 therapy cycles (each 6.1 ± 0.3 GBq, range 5.4-6.5 GBq) given intravenously over 30 minutes, 9 ± 1 weeks apart. PET/CT scans were compared to (177)Lu-PSMA617 24-hour whole-body scans and contrast-enhanced dual-phase CT. Detailed comparison of SUVmax values and absorbed tumour doses was performed. Results: (177)Lu-PSMA617 dosimetry indicated high tumour doses for skeletal (3.4 ± 1.9 Gy/GBq; range 1.1-7.2 Gy/GBq), lymph node (2.6 ± 0.4 Gy/GBq; range 2.3-2.9 Gy/GBq) as well as liver (2.4 ± 0.8 Gy/GBq; range 1.7-3.3 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 18 ± 0.3 GBq. Three patients showed partial remission, three mixed response, one stable and three progressive disease. Decreased (177)Lu-PSMA617 and (68)Ga-PSMA-HBED-CC uptake (mean SUVmax values 20.2 before and 15.0 after 2 cycles and 11.5 after 3 cycles, p < 0.05) was found in 41/54 skeletal lesions, 12/13 lymph node metastases, 3/5 visceral metastases and 4/4 primary PC lesions. Conclusion: Due to substantial individual variance, dosimetry is mandatory for a patient-specific approach following (177)Lu-PSMA617 therapy. Higher activities and/or shorter treatment intervals should be applied in a larger prospective study.
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A potential milestone in personalized nuclear medicine is theranostics of metastatic castration-resistant prostate cancer (mCRPC) based on molecular imaging using PET/CT with 68 Ga-labeled prostate-specific membrane antigen (PSMA) ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with 177 Lu-PSMA ligands. 68 Ga-PSMA PET/CT enables accurate detection of mCRPC lesions with high diagnostic sensitivity and specificity and provides quantitative and reproducible data that can be used to select patients for PRLT and therapeutic monitoring. Our comprehensive experience over the last 3 years using different radioligands indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved.
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Prostate cancer can be targeted by ligands to the prostate-specific membrane antigen (PSMA). We aimed to evaluate dosimetry, safety and efficacy of ¹⁷⁷Lu-PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC). Fifteen patients each received two cycles of 3.7 GBq (n = 5) or 6.0 GBq (n = 10) ¹⁷⁷Lu-PSMA-617 at an eight to ten weeks interval. For safety monitoring, each treatment was followed by dosimetry with serial quantitative SPECT as well as inpatient and outpatient recording of adverse events. Response to RLT was primarily determined by baseline to follow-up change in ⁶⁸Ga-PSMA PET/CT (RECIST1.1), as well as change in prostate-specific antigen (PSA), quality of life (QoL, FACT-P scale), and pain (Brief Pain Inventory) as secondary endpoints. Radiation dose delivered to the tumor (6.1 Gy/GBq) was six to twelve-fold higher than to critical organs (kidney left/right 0.5/0.6 Gy/GBq each, salivary glands 1.0 Gy/GBq). Total radiation dose per kidney did not exceed 23 Gy in any patient. Three patients had sub-acute and latent grade 3 events, i.e. anemia, leukocytopenia, and nausea. No acute events, grade ≥4 events or high grade events for salivary gland or kidney function were observed. After two RLT cycles, 4 (27%) patients had partial response, 6 (40%) had stable disease, and 5 (33%) had progressive disease according to RECIST. Any PSA decline was observed in 12/15 (80%) patients during RLT. Significant pain relief was documented in 7/10 (70%) symptomatic patients and QoL improved in 9/15 (60%) patients. ¹⁷⁷Lu-PSMA-617 therapy proved safe and indicated promising response rates for both objective and patient-reported outcomes in our small group of mCRPC patients.
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Objective: To present a summary of the 2016 version of the European Association of Urology (EAU) - European Society for Radiotherapy & Oncology (ESTRO) - International Society of Geriatric Oncology (SIOG) Guidelines on the treatment of relapsing, metastatic, and castration-resistant prostate cancer (CRPC). Evidence acquisition: The working panel performed a literature review of the new data (2013-2015). The guidelines were updated, and the levels of evidence and/or grades of recommendation were added based on a systematic review of the literature. Evidence synthesis: Relapse after local therapy is defined by a rising prostate-specific antigen (PSA) level >0.2ng/ml following radical prostatectomy (RP) and >2ng/ml above the nadir after radiation therapy (RT). 11C-choline positron emission tomography/computed tomography is of limited importance if PSA is <1.0ng/ml; bone scans and computed tomography can be omitted unless PSA is >10ng/ml. Multiparametric magnetic resonance imaging and biopsy are important to assess biochemical failure following RT. Therapy for PSA relapse after RP includes salvage RT at PSA levels <0.5ng/ml and salvage RP, high-intensity focused ultrasound, cryosurgical ablation or salvage brachytherapy of the prostate in radiation failures. Androgen deprivation therapy (ADT) remains the basis for treatment of men with metastatic prostate cancer (PCa). However, docetaxel combined with ADT should be considered the standard of care for men with metastases at first presentation, provided they are fit enough to receive the drug. Follow-up of ADT should include analysis of PSA, testosterone levels, and screening for cardiovascular disease and metabolic syndrome. Level 1 evidence for the treatment of metastatic CRPC (mCRPC) includes, abiraterone acetate plus prednisone (AA/P), enzalutamide, radium 223 (Ra 223), docetaxel at 75 mg/m2 every 3 wk and sipuleucel-T. Cabazitaxel, AA/P, enzalutamide, and radium are approved for second-line treatment of CRPC following docetaxel. Zoledronic acid and denosumab can be used in men with mCRPC and osseous metastases to prevent skeletal-related complications. Conclusions: The knowledge in the field of advanced and metastatic PCa and CRPC is changing rapidly. The 2016 EAU-ESTRO-SIOG Guidelines on PCa summarise the most recent findings and advice for use in clinical practice. These PCa guidelines are the first endorsed by the European Society for Therapeutic Radiology and Oncology and the International Society of Geriatric Oncology and reflect the multidisciplinary nature of PCa management. A full version is available from the EAU office or online (http://uroweb.org/guideline/prostate-cancer/). Patient summary: In men with a rise in their PSA levels after prior local treatment for prostate cancer only, it is important to balance overtreatment against further progression of the disease since survival and quality of life may never be affected in many of these patients. For patients diagnosed with metastatic castrate-resistant prostate cancer, several new drugs have become available which may provide a clear survival benefit but the optimal choice will have to be made on an individual basis.
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Purpose: The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, (177)Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). Methods: Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic(68)Ga-PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly (177)Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and ttoxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. Results: The mean age of patients was 65.93 ± 9.77 years (range: 38-81 years). The mean activity administered in the 31 patients was 5069 ± 1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity. Conclusion: (177)Lu-DKFZ-PSMA-617 radionuclide therapy is a safe and effective approach in the treatment of mCRPC patients.
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Prostate cancer (PCa) is the most common malignancy in men worldwide, leading to substantial morbidity and mortality. At present, imaging of PCa has become increasingly important for staging, restaging, and treatment selection. Until recently, choline-based positron emission tomography/computed tomography (PET/CT) represented the state-of-the-art radionuclide imaging technique for these purposes. However, its application is limited to patients with high PSA levels and Gleason scores. Prostate-specific membrane antigen (PSMA) is a promising new target for specific imaging of PCa, because it is upregulated in the majority of PCa. Moreover, PSMA can serve as a target for therapeutic applications. Currently, several small-molecule PSMA ligands with excellent in vivo tumor targeting characteristics are being investigated for their potential in theranostic applications in PCa. Here, a review of the recent developments in PSMA-based diagnostic imaging and therapy in patients with PCa with radiolabeled PSMA ligands is provided.
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Radioligand therapy (RLT) with (177)Lu-DKFZ-617 PSMA (Lu-PSMA) (prostate-specific membrane antigen) is a novel targeted therapy of metastatic prostate cancer. We analysed retrospectively the early side effects and the response rate in the first patients, who received a therapy with Lu-PSMA in our departments. RLT was performed in ten hormone- and/or chemo-refractory patients with distant metastases and progressive disease (mean age 73.5 years). (68)Ga-PSMA HBED-CC PET/CT was performed in all patients prior to RLT. The median PSA level prior to the therapy was 298.5 ng/ml (range 5-853 ng/ml). All patients received CBC, renal and liver function tests the day before and 2 days after application (mean administered activity 5.6 GBq, range 4.1-6.1 GBq), followed by further tests every 2 weeks. All patients were contacted by telephone every week regarding side effects or any positive and negative changes. Eight weeks after the therapy, seven patients (70 %) experienced a PSA decline, of whom six experienced more than 30 % and five more than 50 %. Three patients showed a progressive disease according to the PSA increase. No patient experienced any side effects immediately after injection of Lu-PSMA. Relevant hematotoxicity (grade 3 or 4) occurred 7 weeks after the administration in just one patient. The same patient showed a leucopenia grade 2. Two patients showed a disturbance of only 1 hematologic cell line, whereas one patient showed a reduction of grades 1 and 2 in leucocytes and thrombocytes, respectively. Six patients did not show any hematotoxicity during the 8 weeks after therapy. There was no relevant nephrotoxicity (grade 3 or 4). Our initial results indicate that RLT with Lu-PSMA is safe and seems to have low early side-effect profile. A relevant PSA decline was detected in 70 % of patients.
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Purpose Peptide receptor radionuclide therapy (PRRT) with 90Y and 177Lu provides objective responses in neuroendocrine tumours, and is well tolerated with moderate toxicity. We aimed to identify clinical parameters predictive of long-term renal and haematological toxicity (myelodysplastic syndrome and acute leukaemia). Methods Of 807 patients studied at IEO-Milan (1997–2013), 793 (98 %) received 177Lu (278, 34.4 %), 90Y (358, 44.4 %) or 177Lu and 90Y combined (157. 19.5 %), and 14 (2 %) received combinations of PRRT and other agents. Follow-up was 30 months (1–180 months). The parameters evaluated included renal risk factors, bone marrow toxicity and PRRT features. Data analysis included multiple regression, random forest feature selection, and recursive partitioning and regression trees. Results Treatment with 90Y and 90Y + 177Lu was more likely to result in nephrotoxicity than treatment with 177Lu alone (33.6 %, 25.5 % and 13.4 % of patients, respectively; p
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Peptide Receptor Radionuclide Therapy (PRRT) is a promising new treatment modality for inoperable or metastasized GastroEnteroPancreatic NeuroEndocrine Tumors (GEPNET) patients. Most studies report objective response rates in 15-35% of patients. Also, outcome in terms of PFS and OS compares very favourably with that for somatostatin analogues, chemotherapy, or new, "targeted" therapies. They also compare favourably to PFS data for liver-directed therapies. Two decades after the introduction of PRRT there is a growing need for randomised controlled trials comparing PRRT to "standard" treatment, that is treatment with agents that have proven benefit when tested in randomised trials. Combining PRRT with liver-directed therapies, or with targeted therapies could improve treatment results. The question to be answered, however, is whether a combination of therapies performed within a limited time-span from one another, results in a better PFS than a strategy in which other therapies are reserved until after (renewed) tumor progression. Randomized clinical trials comparing PRRT with other treatment modalities should be undertaken to determine the best treatment options and treatment sequelae for patients with GEPNETs.
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Objective: PSMA-617 is reported to exhibit very high binding affinity towards PSMA receptors, over-expressed on prostate cancer cells and therefore, (177)Lu-labeled PSMA-617 is expected to play a pivotal role in the clinical management of patients suffering from ca prostate. The objective of the present study is to formulate the patient dose of (177)Lu-labeled PSMA-617, pre-clinical studies in animal model and clinical investigation in limited number of prostate cancer patients as well evaluating its potential for theranostic application. Experimental: Patient dose of 7.4 GBq (200 mCi) of (177)Lu-labeled PSMA-617 was prepared by incubating 100 μg of PSMA-617 with (177)LuCl3 at 95 °C for 15 minutes. Radiochemical purity as well as in-vitro stability of the preparation was determined by PC and HPLC methods. The pharmacokinetic behavior and in-vivo distribution of the agent were studied by carrying out biodistribution studies in normal male Wistar rats. Preliminary clinical investigation was performed in 7 patients suffering from prostate cancer. Results: The complex was prepared with >98% radiochemical purity under the optimized reaction protocols and the preparation exhibited adequate in-vitro stability. Biodistribution studies revealed no significant uptake in any of the major organ/tissue along with major clearance through renal pathway. Clinical studies showed similar distribution in lesions and physiologic areas of uptake as seen in diagnostic (68)Ga-PSMA-11 PET scans performed earlier. Conclusion: Preliminary clinical studies indicated the promising potential of the agent for theranostic applications. However, further investigations in large pool of patients are warranted to establish the theranostic potential of the agent.
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Key issues for prostate cancer patients are the detection of recurrent disease and the treatment of metastasized cancer. Early detection is a major challenge for all conventional imaging modalities. Furthermore, therapy of patients with hormone-resistant tumor lesions presents a major clinical challenge. Because the prostate-specific membrane antigen (PSMA) is frequently overexpressed in prostate cancer, several PSMA-targeting molecules are under development to detect and treat metastatic castration-resistant prostate cancer (mCRPC). mCRPC represents a situation where cure is no longer achievable and novel therapeutic approaches for palliation and increase of survival are needed. In this article, we discuss the recent development for noninvasive detection of recurrent disease and therapy of mCRPC with corresponding PSMA-targeted radioligands. (C)2016 AACR.
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Prostate-specific membrane antigen (PSMA) is an integral, non-shed membrane glycoprotein that is highly expressed on prostate epithelial cells and strongly upregulated in prostate cancer (PCa). Prostatic neoplastic transformation results in the transfer of PSMA from the apical membrane to the luminal surface of the ducts. However, the role of PSMA in tumor angiogenesis and carcinogenesis is poorly understood. PSMA is characterized by folate hydrolase and carboxypeptidase activity and internalization function, and its levels are directly correlated to androgen independence, metastasis and PCa progression. As largely substantiated by preclinical and clinical findings, PSMA could represent a promising target for Positron Emission Tomography (PET) radiopharmaceuticals for PCa imaging. Furthermore, PSMA could prove an important target for the development of new therapeutic approaches, including PSMA-based aptamers, peptides, antibody-drug conjugated therapy, as well as radiotherapy and immunotherapy. This review will summarize the role of PSMA in PCa development and progression and its potential role in the diagnosis and treatment of patients with initial and advanced PCa.
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Prostate-specific membrane antigen (PSMA) is an integral, non-shed membrane glycoprotein that is highly expressed on prostate epithelial cells and strongly upregulated in prostate cancer (PCa). Prostatic neoplastic transformation results in the transfer of PSMA from the apical membrane to the luminal surface of the ducts. However, the role of PSMA in tumor angiogenesis and carcinogenesis is poorly understood. PSMA is characterized by folate hydrolase and carboxypeptidase activity and internalization function, and its levels are directly correlated to androgen independence, metastasis and PCa progression. As largely substantiated by preclinical and clinical findings, PSMA could represent a promising target for Positron Emission Tomography (PET) radiopharmaceuticals for PCa imaging. Furthermore, PSMA could prove an important target for the development of new therapeutic approaches, including PSMA-based aptamers, peptides, antibody-drug conjugated therapy, as well as radiotherapy and immunotherapy. This review will summarize the role of PSMA in PCa development and progression and its potential role in the diagnosis and treatment of patients with initial and advanced PCa.
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Radioimmunotherapy (RIT) has been developed for more than 30 years. Two products targeting the CD20 antigen are approved in the treatment of non-Hodgkin's B-cell lymphoma (NHBL): 131I-tositumomab (Bexxar®) and 90Y-ibritumomab tiuxetan (Zevalin®). RIT can be integrated in clinical practice for the treatment of patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy. High-dose treatment, RIT in first-line treatment, fractionated RIT and use of new humanized MAbs, in particular targeting CD22, showed promising results in NHBL. In other hemopathies, such as multiple myeloma, efficacy has been demonstrated in preclinical studies. In solid tumors, more resistant to radiations and less accessible to large molecules such as MAbs, clinical efficacy remains limited. However, pretargeting methods have shown clinical efficacy. Finally, new beta emitters such as lutetium-177, with better physical properties will further improve the safety of RIT and alpha emitters such as bismuth-213 or astatine-211 offer the theoretical possibility to eradicate the last microscopic clusters of tumor cells, in the consolidation setting. Personalized treatments, based on quantitative Positron Emission Tomography (PET) pre-therapeutic imaging and dosimetry procedures, could also be applied to adapt injected activity to each patient.
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BACKGROUND Prostate specific membrane antigen (PSM) is a membrane-bound antigen that is highly specific for benign and malignant prostate epithelial cells. Its expression in high grade prostatic intraepithelial neoplasia (PIN) has not been compared with that in prostate carcinoma.METHODS The authors performed an immunohistochemical study of representative sections from 184 radical prostatectomies from previously untreated patients with pathologic stage T2N0M0 adenocarcinoma treated at the Mayo Clinic between 1987 and 1991. Affinity-purified monoclonal antibody 7E11-5.3 directed against PSM was employed at a concentration of 20 μg/mL overnight. For comparison, serial sections in each case were stained with prostate specific antigen (PSA). Staining for all antibodies was performed using the streptavidin-biotin method. For each case, the percentage of immunoreactive cells in benign epithelium, PIN, and adenocarcinoma was estimated in increments of 10%. Cox proportional hazards models were used to identify the risk of carcinoma recurrence according to the number of immunoreactive PIN or cancer cells for PSM and PSA; the date of radical prostatectomy was used as the starting time, and serum PSA (biochemical) failure or clinical failure was the event. PSA biochemical failure was defined as serum PSA > 0.2 ng/mL at least 30 days after surgery.RESULTSIntense cytoplasmic immunoreactivity for PSM was observed in benign and neoplastic epithelial cells in all cases (100% of cases staining). The number of cells staining was lower in benign epithelium and PIN than in adenocarcinoma (69.5 ± 17.3% [range, 20-90%] vs. 77.9 ± 13.2% [range, 30-100%] vs. 80.2 ± 13.7% [range, 30-100%], respectively). With rare exceptions, basal cells were negative, and there was no immunoreactivity of the prostate stroma, urothelium, or vasculature. Adenocarcinoma gave the most intense and extensive staining, and the highest grades of adenocarcinoma (Gleason primary patterns 4 and 5) showed staining in virtually every cell; there was greater heterogeneity of staining in lower grades of adenocarcinoma. By contrast, PSA immunoreactivity was more intense and extensive in benign epithelium than in PIN and adenocarcinoma. The number of immunoreactive PIN or cancer cells for PSM and PSA was not predictive of PSA biochemical or clinical failure as defined in this study.CONCLUSIONSPSM was expressed in all cases of prostate adenocarcinoma, with the greatest extent and intensity observed in the highest grades. The expression increased incrementally from benign epithelium to high grade PIN or adenocarcinoma. Conversely, PSA showed the greatest staining in benign epithelium, with decreased expression incrementally from benign epithelium to high grade PIN or adenocarcinoma. Expression of PSM is clinically useful for the identification of prostate epithelium, particularly PIN or adenocarcinoma, and its expression is regulated independent of PSA. The number of PSM immunoreactive cells was not predictive of recurrence, most likely because of the presence of abundant immunoreactivity in most cases, or because of differential expression in primary and metastatic disease. Cancer 1998;82:2256-2261. © 1998 American Cancer Society.
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Prostate-specific membrane antigen is a type II membrane protein with folate hydrolase activity produced by prostatic epithelium. The expression of this molecule has also been documented in extraprostatic tissues, including small bowel and brain. In the present study, an extensive immunohistochemical analysis was performed on a panel of well-characterized normal and malignant human tissues to further define the pattern of prostate-specific membrane antigen (PSMA) expression. Detectable PSMA levels were identified in prostatic epithelium, duodenal mucosa, and a subset of proximal renal tubules. A subpopulation of neuroendocrine cells in the colonic crypts also exhibited PSMA immunoreactivity. All other normal tissues, including cerebral cortex and cerebellum, had undetectable levels of PSMA. Thirty-three of 35 primary prostate adenocarcinomas and 7 of 8 lymph node metastases displayed tumor cell PSMA immunostaining. Eight of 18 prostate tumors metastatic to bone expressed PSMA. All of the other nonprostatic primary tumors studied had undetectable PSMA levels. However, intense staining was observed in endothelial cells of capillary vessels in peritumoral and endotumoral areas of certain malignancies, including 8 of 17 renal cell carcinomas, 7 of 13 transitional cell carcinomas, and 3 of 19 colon carcinomas. Extraprostatic PSMA expression appears to be highly restricted. Nevertheless, its diverse anatomical distribution implies a broader functional significance than previously suspected. The decrease in PSMA immunoreactivity noted in advanced prostate cancer suggests that expression of this molecule may be linked to the degree of tumor differentiation. The neoexpression of PSMA in endothelial cells of capillary beds in certain tumors may be related to tumor angiogenesis and suggests a potential mechanism for specific targeting of tumor neovasculature.
radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review
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Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review. Eur J Nucl Med Mol Imaging 2018; 45: 496-508
The 2015 CUA-CUOG guidelines for the management of castration-resistant prostate cancer (CRPC)
  • Saad
Prostate-specific membrane antigen expression in normal and malignant human tissues
  • Silver