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Long-Term Nephrotoxicity of 177 Lu-PSMA Radioligand Therapy
Abstract
β-emitting 177Lu targeting prostate-specific membrane antigen (PSMA) is an approved treatment option for metastatic castration-resistant prostate cancer. Data on its long-term nephrotoxicity are sparse. This study aimed to retrospectively evaluate post-177Lu-PSMA estimated glomerular filtration rate (eGFR) dynamics for at least 12 mo in a cohort of metastatic castration-resistant prostate cancer patients. Methods: The institutional databases of 3 German tertiary referral centers identified 106 patients who underwent at least 4 cycles of 177Lu-PSMA and had at least 12 mo of eGFR follow-up data. eGFR (by the Chronic Kidney Disease Epidemiology Collaboration formula) at 3, 6, and 12 mo after 177Lu-PSMA radioligand therapy was estimated using monoexponentially fitted curves through available eGFR data. eGFR changes were grouped (≥15%-<30%, moderate; ≥30%-<40%, severe; and ≥40%, very severe). Associations between eGFR changes (%) and nephrotoxic risk factors, prior treatment lines, and number of 177Lu-PSMA cycles were analyzed using multivariable linear regression. Results: At least moderate eGFR decreases were present in 45% (48/106) of patients; of those, nearly half (23/48) had a severe or very severe eGFR decrease. A higher number of risk factors at baseline (-4.51, P = 0.03) was associated with a greater eGFR decrease. Limitations of the study were the retrospective design, lack of a control group, and limited number of patients with a follow-up longer than 1 y. Conclusion: A considerable proportion of patients may experience moderate or severe decreases in eGFR 1 y from initiation of 177Lu-PSMA. A higher number of risk factors at baseline seems to aggravate loss of renal function. Further prospective trials are warranted to estimate the nephrotoxic potential of 177Lu-PSMA.
... This study showed that the kidney received the highest absorbed dose; the renal absorbed dose of [ 177 Lu]Lu-LNC1011 was approximately 7 times that of [ 177 Lu]Lu-PSMA-617. Although current data indicate that no definite renal damage was caused, recent studies have shown that PSMA-RLT treatment may cause delayed radiation nephropathy [27,28]. One year after receiving 177 Lu-PSMA treatment, the majority of patients experience moderate to severe declines in EGFR, and factors such as hypertension, diabetes, and age over 65 may exacerbate the reduction in renal function [28]. ...
... Although current data indicate that no definite renal damage was caused, recent studies have shown that PSMA-RLT treatment may cause delayed radiation nephropathy [27,28]. One year after receiving 177 Lu-PSMA treatment, the majority of patients experience moderate to severe declines in EGFR, and factors such as hypertension, diabetes, and age over 65 may exacerbate the reduction in renal function [28]. Maybe it is less of a particular concern in patients with advanced stages of cancer, but as the PSMA-RLT continues to advance, it has the potential to be used for early-stage prostate cancer treatment. ...
Background
Preclinical studies have shown that the long-acting PSMA-targeting radiopharmaceutical [¹⁷⁷Lu]Lu-LNC1011 based on dansylated amino acid modification had high tumor uptake and prolonged retention. This study aimed to explore its safety and efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC).
Methods
Eight mCRPC patients who met the inclusion criteria received intravenous treatment with [¹⁷⁷Lu]Lu-LNC1011. Treatment was repeated every 6 weeks for up to a maximum of 6 cycles. Molecular imaging and hematology markers were the main evaluation indicators. The primary endpoints were biochemical (PSA) response and molecular imaging response. Toxicity grading was assessed using the Common Terminology Criteria for Adverse Events version 5.0.
Results
Hematological toxicity was the primary side effect. In all patients, adverse events (AEs) after [¹⁷⁷Lu]Lu-LNC1011 treatment were primarily characterized by decreased levels of hemoglobin, white blood cells and platelets. Grade 3 anemia was recorded in 1 patient, and grade 2 leukopenia and thrombocytopenia were recorded in 4 patients. The average systemic effective dose was 0.18 mSv/MBq, and the kidney was the organ with the highest absorbed dose (3.11 ± 0.26 mSv/MBq). Long half-life (71.30 ± 8.23 h) and high absorbed dose [5.77, (range 5.5–14 Gy/GBq)] were calculated in the lesions. All patients had a more than 50% decline of PSA during treatment, and one patient dropped to 0 ng/mL. According to assessment criteria adapted from the PERCIST v.1.0 criteria, complete response, partial response, and disease progression were observed in 2 (25%), 4 (50%), and 2 (25%) patients, respectively.
Conclusion
[¹⁷⁷Lu]Lu-LNC1011 was well tolerated and had acceptable side effects for PSMA-targeted radioligand therapy. Tumor lesions received high radiation doses and had excellent responses to the treatment. Dose escalation studies in a larger number of patients are worth pursuing and necessary to confirm these results.
URL of registry
https://clinicaltrials.gov/study/NCT06809426?term=NCT06809.
Trial registration
NCT06809426, registration date: 2025-01-23.
... The kidneys were the dose limiting organ and not all patients could receive more than 4 dose cycles. Observing these dose limits for the kidneys is important as long-term nephrotoxicity has been shown for patients with higher renal dose beyond 28 Gy although no direct dose-response relationship was investigated [44]. Red bone marrow was not investigated in this study but should not be neglected as an organ at risk in clinical dosimetry. ...
... Results of the bland-Altman analysis and RMSE comparing RM to SM1 using single timepoint imaging at 2-4, 24, 48 and 72-168 h p.i. combined for treatment cycles 2 to 4 for organs at risk (kidneys, parotid glands and submandibular glands) and tumor lesions (individual tumor lesions and the mean of tumor lesions per patient) over the long term following the initiation of treatment[44]. The mean effective half-life was with 37.6 h also in the range of effective half-lives reported for [ 177 Lu]Lu-PSMA-I&T with 33 h [29] and for [ 177 Lu]Lu-PSMA-617 with 32.1-40.0 ...
Background
Internal dosimetry in individual patients is essential for safe and effective radioligand therapy. Multiple time point imaging for accurate dosimetry is time consuming and hence can be demanding for nuclear medicine departments as well as patients. The objectives of this study were (1) to assess absorbed doses to organs at risk and tumor lesions for [¹⁷⁷Lu]Lu-PSMA-I&T using whole body SPECT imaging and (2) to investigate possible simplified dosimetry protocols.
Methods
This study included 16 patients each treated with 4 cycles of [¹⁷⁷Lu]Lu-PSMA-I&T. They underwent quantitative whole body SPECT/CT imaging (3 bed positions) at four time points (TP) comprising 2 h, 24 h, 48 h and 72–168 h post-injection (p.i.). Full 3D dosimetry (reference method) was performed for all patients and dose cycles for organs at risk (kidneys, parotid glands and submandibular glands) and up to ten tumor lesions per patient (resulting in 90 lesions overall). The simplified dosimetry methods (SM) included (1) generating time activity curves for subsequent cycles using a single TP of imaging applying the kinetics of dose cycle 1, and for organs at risk also (2) simple extrapolation from dose cycle 1 and (3) from both, dose cycle 1 and 2.
Results
Normalized absorbed doses were 0.71 ± 0.32 mGy/MBq, 0.28 ± 0.12 mGy/MBq and 0.22 ± 0.08 mGy/MBq for kidneys, parotid glands and submandibular glands, respectively. Tumor doses decreased from 3.86 ± 3.38 mGy/MBq in dose cycle 1 to 2.01 ± 2.65 mGy/MBq in dose cycle 4. Compared to the full dosimetry approach the SM 1 using single TP imaging at 48 h p.i. resulted in the most accurate and precise results for the organs at risk in terms of absorbed doses per cycle and total cumulated dose. For tumor lesions better results were achieved using the fourth TP (≥ 72 h p.i.).
Conclusion
Simplification of safety dosimetry protocols is possible for [¹⁷⁷Lu]Lu-PSMA-I&T therapy. If tumor dosimetry is of interest a later imaging TP (≥ 72 h p.i.) should be used/added to account for the slower kinetics of tumors compared to organs at risk.
... Emerging data with 177 Lu-PSMA-617 suggest that providing a greater radiation dose to the tumour may improve outcomes for patients, and this is further supported by data with other RLT agents such as 177 Lu-dotatate [10,11,12,13]. However, there remains clinical uncertainty regarding the safe limits of dose to the kidneys which are a key at-risk organ with PSMA-targeted RLT, with decline in renal function and histopathologically-confirmed nephropathy having been documented in patients undergoing 177 Lu-labelled PSMA RLT [14,15,16]. While the risk of delayed radiation nephropathy from RLT is unlikely to impact clinical decision-making for patients with very end stage mCRPC and limited life expectancy, the potential also exists for use of 177 Lu-labelled PSMA RLT earlier in prostate cancer care (see ongoing trials such as NCT04720157 and NCT06066437). ...
Purpose
To evaluate tumour and normal organ dosimetry of PSMA-targeted RLT ¹⁷⁷Lu-rhPSMA-10.1.
Methods
PSMA-positive mCRPC patients experiencing disease progression following standard-of-care treatment were enrolled and underwent ≤ 3 cycles of 5.55 or 7.40 GBq ¹⁷⁷Lu-rhPSMA-10.1 at 6-week intervals. Multi-bed SPECT/CT was conducted 3-, 24-, 48-, and 168-hours post-administration to calculate tumour and organ absorbed doses. Two methods (activity- and anatomy-based) were used for selecting and delineating tumours for dosimetry. Venous blood was collected for radioactivity measurement 30 min before ¹⁷⁷Lu-rhPSMA-10.1 administration, and 0.5-, 1.5-, 4-, 24-, and 48-hours post-administration.
Results
Thirteen patients were enrolled; three received 5.55 GBq/cycle and 10 received 7.40 GBq/cycle. Mean absorbed doses were 0.266, 0.130 and 8.87 Gy/GBq in kidneys, salivary glands, and tumours (activity-method), respectively, giving mean tumour-to-kidney and tumour-to-salivary ratios of 32.1 and 73.2, respectively. Tumour dose estimates were consistently higher with the activity-method vs. anatomy-method. Tumour absorbed doses decreased each cycle; Cycle 2 and 3 doses were ~ 37% and ~ 56% lower than Cycle 1 estimates, respectively. ¹⁷⁷Lu-rhPSMA-10.1 was rapidly cleared from the blood (effective half-life, 2.2 h). Imaging data showed mean effective half-lives to be 91.4, 33.7 and 45.4 h in tumours, kidneys, and salivary glands, respectively.
Conclusion
¹⁷⁷Lu-rhPSMA-10.1 delivers high radiation doses to tumours vs. normal organs, facilitated by its favourable pharmacokinetics. Cumulative doses to normal organs were well within established tolerable limits, suggesting higher cumulative radioactivity could be administered in clinical trials. The observation of decreasing tumour absorbed dose with subsequent cycles also supports the exploration of front-loading radioactivity in Phase II.
... Long-term effects of 177Lu-PSMA-617 in patients with prostate cancer have not been readily characterized in most completed studies due to the limited median overall survival (13-16 mo) of patients with advanced mCRPC. A recent retrospective analysis of kidney function in patients with mCRPC exposed to 177Lu-PSMA-617 found at least 15-30% decrease in eGFR at 12 months in 48 of 106 patients (45%) who had received at least 4 cycles of 177Lu-PSMA-617 [10]. The risk of second primary malignancies and MDS/AML will need to be characterized. ...
Opinion Statement
Prostate-specific membrane antigen targeted radionuclide therapies (PSMA-TRT) such as 177Lu-PSMA-617 hold great promise in improving clinical outcomes at various stages of prostate cancer. The FDA approval of 177Lu-PSMA-617 represents a significant advancement in the treatment of metastatic castration-resistant prostate cancer (mCRPC). The VISION trial demonstrated improved radiographic progression-free survival (rPFS) and overall survival (OS) with 177Lu-PSMA-617 in patients with mCRPC who had already receive androgen receptor pathway inhibitor (ARPI) and taxane chemotherapy. Exploration of 177Lu-PSMA-617 in earlier stages of prostate cancer, such as in the PSMAfore trial for patients who have not received chemotherapy, holds great promise for improving long-term outcomes and delaying exposure to chemotherapy. Combining 177Lu-PSMA-617 with other therapies, including chemotherapy, PARP inhibitors, and immunotherapy, is an area of active investigation. This review will also discuss alternative radionuclides (such as actininum-225 and terbium-161) and delivery vehicles (such as PSMA-I&T), which we find promising. Predictive biomarkers and dosimetry will be crucial for identifying patients most likely to benefit from PSMA-TRT. Continued research and refinement of these therapies will lead to PSMA-targeted treatments becoming an integral part of prostate cancer management.
... In a longterm follow-up study on renal toxicity after 177 Lu-PSMA treatment, it was found that in most mCRPC patients who received at least 4 cycles of 177 Lu-PSMA treatment, nearly a quarter of patients experienced a severe decrease in GFR 12 months after the treatment. In the following 2-3 years, some patients experienced further deterioration of renal function (30). However, due to the small number of patients, the practicality of these data is limited. ...
Background
We aimed to report our clinical experience with the use of ²²⁵Ac-PSMA-617 in the treatment of mCRPC patients.
Methods
A retrospective analysis was conducted on 29 metastatic castration-resistant prostate cancer (mCRPC) patients treated with ²²⁵Ac-PSMA-617. Patients underwent treatment at 8-week intervals and discontinued treatment upon disease progression or the occurrence of intolerable adverse effects. We acquired ⁶⁸Ga-PSMA-11 PET/CT images and laboratory test outcomes of patients at baseline and 8 weeks following each treatment. Short-term efficacy was evaluated through the biochemical response of serum prostate-specific antigen (PSA) and molecular tumor response criteria. A follow-up was conducted to assess the long-term effectiveness by examining the patient’s overall survival (OS) and progression-free survival (PFS). The numerical rating scale (NRS) assessed the patient’s pain. The side effects after treatment were evaluated based on common terminal criteria for adverse events version 5.0 (CTCAE v5.0).
Results
29 patients with mCRPC underwent a total of 50 treatment cycles. The median age of the patients was 67 years (55-84years). Out of these patients, 11 had previously underwent ¹⁷⁷ Lu-PSMA-617 radioligand therapy (RLT). After treatment, any PSA decline was observed in 75.9% of patients, and a PSA decline≥50% was observed in 62.1%. 61.1% of patients had disease control according to molecular response. The estimated OS and PFS were 18 months (95% CI: 15-21 months) and 8 months (95% CI: 6-10 months). Univariate analysis showed that any PSA decline was positively correlated with PFS (p<0.001). The most common side effect was xerostomia, observed in 79.3% of patients. Grade III blood toxicity was observed in 7/29 patients. After treatment, the pain disappeared in 4 patients and was relieved in 13 individuals.
Conclusions
In mCRPC, the results indicated that ²²⁵Ac-PSMA-617 demonstrated a favorable disease control rate and relatively minimal side effects. However, additional high-quality randomized controlled trials are required for future validation.
... These 6 patients cRD ranged between 17.7 and 42.2 Gy. This is consistent with the findings of Steinhelfer et al. [33], where patients with a ≥ 3% decrease in eGFR during the early period (3 months) showed continuous decline without stabilization or recovery throughout follow-up. These results highlight the potential long-term renal risks for patients experiencing early declines in eGFR, suggesting the need for further monitoring and risk assessment in similar treatment protocols. ...
Purpose
This study aimed to evaluate the personalized dosimetric approach by calculating the cumulative renal absorbed dose (cRD) and assessing its impact on renal functions in patients diagnosed with metastatic castration-resistant prostate cancer who underwent four or more cycles of [¹⁷⁷Lu] Lu-PSMA − 617 therapy.
Methods
The study included 110 patients who received ≥ 4 cycles of [¹⁷⁷Lu] Lu-PSMA − 617 therapy. Whole-body static and abdominal SPECT-CT imaging was performed at 4, 24, and 96 h post-administration. Kidney function was assessed using dynamic renal scintigraphy and biochemical tests conducted prior to treatment. Estimated glomerular filtration rate (eGFR) levels were calculated using the CKD-EPI formula before each treatment cycle and at the 6th week post-treatment.
Results
Pearson correlation analysis reveal no significant relationship between cRD and CKD-EPI values (p >.05). No significant differences were observed between pre-treatment CKD-EPI levels and those measured after the 4th, 5th, 6th, 7th, and 8th cycles (p >.05). Among patients reaching a cRD of 23 Gy, a statistically significant difference was observed between pre- and post-treatment CKD-EPI values (p <.05). Of the 13 patients exceeding cRD of 28 Gy, five maintained CKD-EPI levels above 90 mL/min/1.73 m² post-treatment.
Conclusion
Despite treatment-related declines in eGFR levels, our findings indicate that a personalized dosimetric approach may enable extended cycles of [¹⁷⁷Lu] Lu-PSMA-617 therapy with manageable nephrotoxicity. Considering the significant inter-patient variability, establishing universal absorbed dose-response relationships remains challenging. Prospective multicenter studies are crucial to refining toxicity thresholds and advancing tailored treatment strategies to optimize safety and efficacy.
... Lu-PSMA therapy (18,19 (20). ...
Introduction
SPLASH (NCT04647526) is a multicenter phase III trial evaluating the efficacy and safety of [¹⁷⁷Lu]Lu-PNT2002 radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC). This study leveraged a lead-in phase to assess tissue dosimetry and evaluate preliminary safety and efficacy, prior to expansion into a randomized phase. Here we report those results.
Methods
Enrolled participants had mCRPC that progressed on one prior androgen receptor pathway inhibitor (ARPI), were prostate-specific membrane antigen (PSMA) PET–positive as determined by a central reader, were chemotherapy-naïve for mCRPC, and had adequate bone marrow and end-organ reserve. Participants received up to 4 cycles of [¹⁷⁷Lu]Lu-PNT2002 at 6.8 GBq (± 10%) intravenously per cycle every 8 weeks. Dosimetry (planar + SPECT/CT [n=7]; planar only [n=20]), safety, prostate-specific antigen (PSA) response, objective response rate (ORR), and radiographic progression-free survival (rPFS) per blinded independent central review were assessed.
Results
Of 34 individuals screened, 32 underwent PSMA-PET/CT; 27 met all eligibility criteria. Median (range) age was 72 (57-86) years; all participants were enrolled in North America; 40.7% initiated prior ARPI treatment without distant metastases (M0) and 25.9% while hormone sensitive. Nineteen of 27 (70.4%) participants completed all 4 planned cycles. Organs receiving the largest mean (median, range) specific absorbed doses were lacrimal glands at 1.2 (0.9, 0.4-6.7) Gy/GBq (planar only [n=27]), followed by kidneys at 0.73 (0.63, 0.22-1.8) Gy/GBq (planar + SPECT/CT [n=7]; planar only [n=20]). Mean (median, range) tumor specific absorbed dose was 4.3 (2.1, 0.3-33.4) Gy/GBq (approximately 29 Gy/cycle) based on planar + SPECT/CT of 21 lesions in seven participants. [¹⁷⁷Lu]Lu-PNT2002 was associated with no treatment-related deaths, few treatment-related grade ≥3 treatment-emergent adverse events (TEAEs), and no discontinuations for unacceptable toxicity. Treatment-related TEAEs occurring in ≥10% of participants included dry mouth (22.2%; all grade 1), fatigue (18.5%; grades 1-2), nausea (18.5%; grades 1-2), and anemia (14.8%; grades 1-3). Median (95% CI) rPFS was 11.5 (9.2-19.1) months, a PSA decline of ≥50% occurred in 42.3% (11/26) of participants, and confirmed ORR for evaluable disease was 50% (5/10).
Conclusion
[¹⁷⁷Lu]Lu-PNT2002, administered at 6.8 GBq/cycle for 4 cycles, demonstrated a favorable dosimetry and safety profile, as well as promising preliminary efficacy.
Clinical trial registration
https://clinicaltrials.gov/, identifier NCT04647526.
... Many studies have investigated the potential nephrotoxicity of [ 177 Lu]Lu-PSMA therapy because of the expected high retention of radioactivity in kidneys (2,28,38). The model was used to determine the cumulative absorbed doses in organs at risk corresponding to a total injected activity of 44.4 GBq during [ 177 Lu]Lu-PSMA therapy. ...
The treatment regimen for [177Lu]Lu-prostate-specific membrane antigen (PSMA) 617 therapy follows that of chemotherapy: 6 administrations of a fixed activity, each separated by 6 wk. Mathematic modeling can be used to test the hypothesis that the current treatment regimen for a radiopharmaceutical modality is suboptimal. Methods: A mathematic model was developed to describe tumor growth during [177Lu]Lu-PSMA therapy. The model examined alternative treatment schedules to maximize tumor mass reduction while still maintaining an acceptable biologically effective dose to kidneys. Median patients' pharmacokinetics from literature reports were used to obtain the dose rate over time. The model incorporates the Gompertz tumor growth and linear quadratic models to describe the effect of radiation-induced cell kill on tumor growth. For a fixed total activity of 44.4 GBq of [177Lu]Lu-PSMA-617 and a 6-wk interval between cycles, the efficacy of the standard fractionation (6-cycle) treatment schedule was compared with different treatment regimens for a distribution of published tumor masses. A treatment schedule whereby 7.4 GBq are administered in the first cycle, and the remaining activity (37 GBq) in the second cycle (1-2-cycle treatment), was examined. Results: When tumor mass nadir was used as the optimization metric, a lower tumor burden (e.g., <4 g) was insensitive to the number of cycles; the 6-cycle treatment was equivalent to the 1-2-cycle treatment. For larger masses, fewer cycles yielded better results. For a 7-g tumor, the 5-cycle, 4-cycle, 3-cycle and 1-2-cycle schedules were 24%, 50%, 76%, and 84% more efficacious, respectively, than the 6-cycle schedule. The absorbed doses to kidneys, parotid glands, lacrimal glands, and red marrow were 23, 16, 70, and 1 Gy, respectively. In all fractionated schedules, the biologically effective dose to kidneys was within tolerance (<40 Gy). Conclusion: On the basis of model-derived simulations, treatment delivered in a 1-2-cycle schedule is recommended to achieve better outcomes for patients undergoing [177Lu]Lu-PSMA therapy.
... Consequently, a CXCR4-directed ERT approach in earlier therapy lines may not only enhance objective outcomes but also improve the quality of life for high-risk AML patients, as it counteracts the decline associated with multiple treatment lines and their long-term toxicities [45]. However, long-term experience with other ERT approaches, such as PSMA-and SSTR-directed ERT, suggests that these therapies rarely can lead to hematological toxicities, including myelodysplastic syndromes, or organ dysfunctions such as renal insufficiency [46,47]. Although no such side effects have been observed in the studied cohort, the small number of patients and brief follow-up period preclude any definitive conclusions regarding long-term toxicity and efficacy following CXCR4-directed ERT. ...
Rationale: Despite recent advances in the targeted therapy of AML, the disease continues to have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloSCT) remains to be the curative therapy option for fit patients with high-risk disease. Especially patients with relapsed or refractory (r/r) AML continue to have poor outcomes. Myeloablative total body irradiation (TBI) based conditioning can be used in AML patients refractory to multiple lines of standard therapy, but the optimal conditioning regimen remains unclear for patients considered to be chemotherapy- refractory. Feasibility of C-X-C-motif chemokine receptor 4 (CXCR4)-directed endoradiotherapy (ERT) has previously been demonstrated in AML patients with CXCR4 expression on leukemic blasts. Methods: Here, we report on a small cohort of seven AML patients refractory to multiple lines (range 3-7) of therapy, who received CXCR4-directed ERT with [177Lu]Pentixather in combination with TBI and chemotherapy prior to alloSCT. We report outcomes with a focus on toxicity, engraftment, the impact on the bone marrow (BM) niche and efficacy. Results: In this intensively pre-treated group of patients, promising response (6 out of 7 patients) and engraftment (6 out of 7 patients) rates were observed. Histopathological analysis showed that niche compartments are spared and allow for engraftment to occur despite the combined ERT and TBI conditioning. Conclusion: To the best of our knowledge, we report on the first seven patients who received CXCR4-directed ERT in sequential combination with TBI and chemotherapy, providing an effective, individualized conditioning regimen for intensively pre-treated r/r AML patients.
... Unsurprisingly then, for TRT, the kidneys are the dose-limiting organ, although there are efforts to push the acceptable absorbed dose estimates higher. 11,12 High renal uptake is often dismissed as important for imaging agents; however, this phenomenon can create a high background, potentially masking lesions near or in the kidneys including lesions in abdominal or pelvic regions. 9 Several strategies have been reported to reduce the kidney uptake of nanobodies, peptides, and other antibody fragments. ...
... The traditional irradiation threshold of 23 Gy to limit nephrotoxicity is based on homogeneous external irradiation of the kidney, which differs substantially from low-dose-rate RPT-induced irradiation (16). Nevertheless, there is potential for cumulated radiationinduced nephrotoxicity from 177 Lu-PSMA-617 RPT, particularly in patients with baseline acutely impaired renal function, such as in obstructive uropathy. ...
... Nephrotoxicity after [ 177 Lu]Lu-PSMA-617 was evaluated at 3, 6, and 12 mo by estimated glomerular filtration rate (eGFR), using the Chronic Kidney Disease Epidemiology Collaboration creatinine formula, which is based on age and sex and is independent of race (10). Renal failure stages were subsequently defined according to Chronic Kidney Disease Epidemiology Collaboration criteria at baseline and at the 12-mo follow-up (11). ...
[177Lu]Lu-PSMA-617 was approved by the U.S. Food and Drug Administration for patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC). Since the time of regulatory approval, however, real-world data have been lacking. This study investigated the efficacy, safety, and outcome predictors of [177Lu]Lu-PSMA-617 at a major U.S. academic center. Methods: Patients with mCRPC who received [177Lu]Lu-PSMA-617 at the Johns Hopkins Hospital outside clinical trials were screened for inclusion. Patients who underwent [177Lu]Lu-PSMA-617 and had available outcome data were included in this study. Outcome data included prostate-specific antigen (PSA) response (≥50% decline), PSA progression-free survival (PFS), and overall survival (OS). Toxicity data were evaluated according to the Common Terminology Criteria for Adverse Events version 5.03. The study tested the association of baseline circulating tumor DNA mutational status in homologous recombination repair, PI3K alteration pathway, and aggressive-variant prostate cancer-associated genes with treatment outcome. Baseline PSMA PET/CT images were analyzed using SelectPSMA, an artificial intelligence algorithm, to predict treatment outcome. Associations with the observed treatment outcome were evaluated. Results: All 76 patients with PSMA-positive mCRPC who received [177Lu]Lu-PSMA-617 met the inclusion criteria. A PSA response was achieved in 30 of 74 (41%) patients. The median PSA PFS was 4.1 mo (95% CI, 2.0-6.2 mo), and the median OS was 13.7 mo (95% CI, 11.3-16.1 mo). Anemia of grade 3 or greater, thrombocytopenia, and neutropenia were observed in 9 (12%), 3 (4%), and 1 (1%), respectively, of 76 patients. Transient xerostomia was observed in 23 (28%) patients. The presence of aggressive-variant prostate cancer-associated genes was associated with a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P = 0.040). No other associations were observed between circulating tumor DNA mutational status and treatment outcomes. Eighteen of 71 (25%) patients classified by SelectPSMA as nonresponders had significantly lower rates of PSA response than patients classified as likely responders (6% vs. 51%; P < 0.001), a shorter PSA PFS (median, 1.3 vs. 6.3 mo; P < 0.001), and a shorter OS (median, 6.3 vs. 14.5 mo; P = 0.046). Conclusion: [177Lu]Lu-PSMA-617 offered in a real-world setting after regulatory approval in the United States demonstrated antitumor activity and a favorable toxicity profile. Artificial-intelligence-based analysis of baseline PSMA PET/CT images may improve patient selection. Validation of these findings on larger cohorts is warranted.
... Through a meticulous retrospective analysis of the estimated glomerular filtration rate (eGFR) over a year post PSMA-TRNT, they revealed that a considerable segment of patients faced moderate to severe reductions in eGFR 12 months after beginning their therapy. Alarmingly, 45% of the patients experienced at least moderate eGFR decreases, with nearly half of this group witnessing severe or very severe downturns [193]. The study revealed that a greater number of initial risk factors was associated with a greater decrease in the eGFR, raising concerns about the renal implications of such treatments. ...
In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by the eminent Londoner surgeon John Adams. Rapidly forward to 2018, the landscape dramatically altered. Currently, men face a one-in-nine lifetime risk of PCa, accentuated by improved diagnostic methods and an ageing population. With more than three million men in the United States alone grappling with this disease, the overall risk of succumbing to stands at one in 39. The intricate clinical and biological diversity of PCa poses serious challenges in terms of imaging, ongoing monitoring, and disease management. In the field of theranostics, diagnostic and therapeutic approaches that harmoniously merge targeted imaging with treatments are integrated. A pivotal player in this arena is radiotheranostics, employing radionuclides for both imaging and therapy, with prostate-specific membrane antigen (PSMA) at the forefront. Clinical milestones have been reached, including FDA- and/or EMA-approved PSMA-targeted radiodiagnostic agents, such as [18F]DCFPyL (PYLARIFY®, Lantheus Holdings), [18F]rhPSMA-7.3 (POSLUMA®, Blue Earth Diagnostics) and [68Ga]Ga-PSMA-11 (Locametz®, Novartis/ ILLUCCIX®, Telix Pharmaceuticals), as well as PSMA-targeted radiotherapeutic agents, such as [177Lu]Lu-PSMA-617 (Pluvicto®, Novartis). Concurrently, ligand-drug and immune therapies designed to target PSMA are being advanced through rigorous preclinical research and clinical trials. This review delves into the annals of PSMA-targeted radiotheranostics, exploring its historical evolution as a signature molecule in PCa management. We scrutinise its clinical ramifications, acknowledge its limitations, and peer into the avenues that need further exploration. In the crucible of scientific inquiry, we aim to illuminate the path toward a future where the enigma of PCa is deciphered and where its menace is met with precise and effective countermeasures. In the following sections, we discuss the intriguing terrain of PCa radiotheranostics through the lens of PSMA, with the fervent hope of advancing our understanding and enhancing clinical practice.
... However, Sch€ afer et al. reported 3 cases in which patients who received more than 6 cycles of [ 177 Lu]Lu-PSMA therapy showed nephropathy with severe chronic kidney disease that was likely induced by diffuse subacute renal thrombotic microangiopathy as well as acute tubular injury (11). In addition, most recently, Steinhelfer et al. reported that a considerable proportion (45%) of patients may experience moderate to severe decreases in estimated GFR 1 y from initiation of [ 177 Lu]Lu-PSMA, but without association with the number of treatment cycles (12). Follow-up after the last cycle of treatment in our study was short, precluding definitive statements on possibly delayed renal toxicity. ...
Prospective results have demonstrated favorable safety and efficacy of [177Lu]Lu-PSMA radiopharmaceutical therapy for up to 6 cycles in men with metastatic castration-resistant prostate cancer. However, no systematic data are available outlining the feasibility of extended therapy beyond 6 cycles. We aim to evaluate the safety and efficacy of extended [177Lu]Lu-PSMA radiopharmaceutical therapy in patients who have received more than 6 cycles. Methods: In total, 111 patients were included in this multicenter retrospective analysis. Based on individual decisions, patients underwent uninterrupted continuation of therapy (continuous treatment) or reexposure after a therapy break (rechallenge treatment) between 2014 and 2023. Overall survival, 50% prostate-specific antigen (PSA) decline (measured 8-12 wk after treatment initiation or rechallenge), PSMA PET response, and grades per Common Terminology Criteria for Adverse Events were assessed. χ2 tests, multivariable Cox regression analysis, and log-rank tests were applied for statistical analyses. Results: Patients received extended treatment with [177Lu]Lu-PSMA, either as a continuous treatment (43/111, 38.7%) or as a rechallenge (68/111, 61.3%) treatment, with median cumulative doses of 57.4 or 60.8 GBq, respectively. Overall survival from the initiation of [177Lu]Lu-PSMA was 31.3, 23.2, and 40.2 mo for the entire cohort, the continuous treatment group, and the rechallenge treatment group, respectively. The initial 50% PSA decline was significantly higher in the retreated group than in the continuous group (57/63 [90.4%] vs. 26/42 [61.9%]; P = 0.006). A 50% PSA decline was observed in 23 of 62 patients (37.1%) after the first rechallenge. The rate of grades 3-4 toxicity was comparable between continuous and rechallenge treatments (anemia, 7/43 [16.3%] vs. 13/68 [19.1%)], P = 0.6; leukocytopenia, 1/43 [2.3%] vs. 2/67 [3.0%], P = 0.3; thrombocytopenia, 3/43 [7.0%] vs. 3/68 [4.4%], P = 0.3; renal, 2/43 [4.7%] vs. 5/68 [7.4%], P = 0.2). Conclusion: Extended therapy with [177Lu]Lu-PSMA is safe and has not been associated with increased grades 3-4 toxicity. Patient candidates for extended treatment experienced a favorable median survival of 31.3 mo from the first administration. Response under [177Lu]Lu-PSMA rechallenge demonstrated preserved efficacy of [177Lu]Lu-PSMA after a treatment break.
... On the other hand, no- with about 2-fold, 4-fold and 84-fold differences observed at 1, 4 and 24 h post-injection, respectively. Renal radiation toxicity after treatment with radiolabeled small molecule PSMA inhibitors can be problematic [40]. Thus, NB7 sdAbs labeled with these guanidino-substituted residualizing prosthetic agents could provide an attractive treatment option, either alone or in tandem with a small molecule PSMA, for achieving tumor control while delivering less radiation dose to the kidneys. ...
... Given the specific binding of PSMA ligands to the kidneys, long-term nephrotoxicity is a major concern. A recent retrospective study by Steinhelfer et al. 57 analyzed data from 106 patients who were treated with at least four cycles of Lu-PSMA and had glomerular filtration rate (GFR) data available at least 12 months after starting the therapy. A moderate decrease in estimated GFR (eGFR) was reported in 45% of the patients. ...
This review paper highlights the transformative role of PSMA-targeted diagnostics and therapy in prostate cancer management, particularly focusing on 177Lu-PSMA-617, approved by the FDA and EMA for metastatic castration-resistant prostate cancer (mCRPC) patients post-chemotherapy and ARPI treatment. Originating from the VISION trial's success, this paper navigates the current radioligand therapy (RLT) indications, emphasizing practical patient selection, planning, and treatment execution. It critically examines Lu-PSMA's comparative effectiveness against cabazitaxel and Ra-223, addressing decision-making dilemmas for mCRPC treatments. Furthermore, the paper discusses Lu-PSMA in chemotherapy-naïve patients and its application in hormone-sensitive prostate cancer, underlined by ongoing global studies. A significant concern is Lu-PSMA's long-term safety profile, particularly nephrotoxicity risks, necessitating further investigation. The possibility of Lu-PSMA rechallenge in responsive patients is explored, stressing the need for comprehensive analyses and real-world data to refine treatment protocols. Conclusively, PSMA-targeted therapy marks a significant advance in prostate cancer therapy, advocating for its integration into a multimodal, patient-centric treatment approach. The review underscores the imperative for additional comparative studies to optimize treatment sequences and outcomes, ultimately enhancing long-term prognosis and disease control in prostate cancer management.
... 2,3,5,28,29 In addition, for 177 Lu-PSMA therapy, studies suggest a higher threshold also may be safe, especially for patients without renal risk factors, but Steinhelfer et al 32 confirm the importance of long-term follow-up for renal toxicity (see Data Supplement discussion). 14,15,22,[30][31][32][33] For patients in phase I trials and those in last line treatment options, the benefits of enhanced treatment efficacy may outweigh the risk of late renal toxicity because of short life expectancy. ...
... As theranostics matures and clinical applications emerge in patients with longer life expectancies, questions around longer-term toxicities become relevant. In this context, we congratulate Steinhelfer et al. (4) for their attempt to characterize the longer-term nephrotoxicity of [ 177 Lu]Lu-PSMA therapy. ...
A decrease in total kidney volume after lutetium 177 prostate-specific membrane antigen radioligand therapy predicted renal function decline at 12 months in patients with metastatic castration-resistant prostate cancer.
Theranostics in nuclear oncology combines diagnostic and therapeutic procedures using radiotracers to target tumor cells. Prostate-specific membrane antigen (PSMA) is a key target in metastatic prostate cancer, and the radioligand [177Lu]Lu-PSMA-617, which binds to PSMA, has shown promising results in treating metastatic castration-resistant prostate cancer (mCRPC), leading to its approval by the European Medicines Agency in 2022.
In this narrative review, the current evidence of [177Lu]Lu-PSMA-617 in mCRPC was discussed in the context of selected studies and the joint EANM/SNMMI guidelines for Lutetium-177-labeled PSMA-targeted radioligand therapy.
The use of [177Lu]Lu-PSMA-617 for post-chemotherapy mCRPC is supported by substantial evidence from the phase II TheraP and the phase III VISION trials, demonstrating its safety and efficacy. The theranostic approach identifies patients likely to benefit from [177Lu]Lu-PSMA-617, which is effective only in tumors with sufficient PSMA expression, as detected by PSMA-ligand PET/CT, which is also used for response assessment.
The success of [177Lu]Lu-PSMA-617 in post-chemotherapy mCRPC patients has led to further ongoing studies evaluating its use earlier in the treatment sequence, prior to chemotherapy. To ensure beneficial treatment outcome, adequate patient selection and evaluation of imaging-based response through PSMA-ligand PET/CT is necessary.
Purpose
This study aims to evaluate the outcome and renal safety of prostate-specific membrane antigen (PSMA)–radioligand therapy (RLT) in patients with metastatic castration-resistant prostate carcinoma (mCRPC) and preexisting renal impairment.
Methods
Ninety-four patients with preexisting renal impairment were included in this retrospective analysis. Inclusion criterion was a glomerular filtration rate (GFR) of ≤60 mL/min (equivalent to Common Terminology Criteria of Adverse Events [CTCAE] ≥2). Patients underwent either [ ¹⁷⁷ Lu]Lu-PSMA-617 RLT exclusively (n = 63) or additionally in augmented manner with [ ²²⁵ Ac]Ac-PSMA-617 (n = 31). The median number of administered cycles was 4 (range, 1–16 cycles) with a mean cumulative activity of 29.9 ± 16.3 GBq (range, 6.9–87.2 GBq) [ ¹⁷⁷ Lu]Lu-PSMA-617. Main blood parameters of interest were creatinine, cystatin C, and the respective GFR values. Changes in GFR were categorized according to CTCAE v5.0.
Results
In the entire cohort, mean best PSA response was −56.73% ± 45.71%, with 63 of 94 patients (67%) experiencing partial remission. The median progression-free survival and overall survival were 6.7 and 14.1 months, respectively. Under PSMA-RLT, 5 of 94 patients (5.3%) improved to CTCAE grade 0, and 23 of 94 (24.5%) improved to CTCAE grade 1. Three of 94 patients (3.2%) improved from CTCAE grade 3 to grade 2, and only 5 of 94 (5.3%) decreased. The majority (58/94 [61.7%]) of patients stayed stable in terms of CTCAE grading.
Conclusion
PSMA-RLT is an effective and safe treatment in mCRPC patients with preexisting impaired renal function (CTCAE ≥2). In daily clinical practice, patients should not be categorically excluded from enrolment to PSMA-RLT due to renal impairment.
Background
The optimal regimen for ¹⁷⁷Lu-labeled prostate-specific membrane antigen-targeted radioligand therapy, including treatment intervals, remains under study, with evidence suggesting shorter intervals could benefit patients with high disease volume and rapid progression. This retrospective analysis evaluated treatment toxicity, PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) in matched cohorts of mCRPC patients receiving 177Lu-PSMA-RLT at 4-week versus 6-week intervals.
Results
A PSA response (PSA decline ≥ 50%) was achieved in 47.8% and 21.7% of patients in the 4-week and 6-week treatment interval groups, respectively (p = 0.12). There was a trend towards longer PSA-PFS in the 4-week group compared to the 6-week group (median PSA-PFS, 26.0 weeks vs. 18.0 weeks; HR 0.6; p = 0.2). Although not statistically significant, there was a trend towards shorter OS in the 4-week group compared to the 6-week group (median OS, 15.1 months vs. 18.4 months; HR 1.3; p = 0.5). The 4-week group had a significantly greater decrease in leucocyte and platelet counts compared to the 6-week group (38.5% vs. 18.2% and 26.7% vs. 10.7%; p = 0.047 and p = 0.02). Severe adverse events were modest in both groups.
Conclusions
Intensifying treatment intervals from 6 weeks to 4 weeks showed some improvements in PSA response and PSA-PFS for mCRPC patients, but did not significantly affect OS. Additionally, bone marrow reserve was significantly reduced with the intensified regimen. Therefore, the overall benefit remains uncertain, and further prospective studies are needed to compare 4-week and 6-week intervals regarding toxicity, treatment response, and outcome.
Radiopharmaceuticals are drugs used in treatment or diagnosis that contain a radioactive part, usually a pharmaceutical part in their structure. Adverse drug reactions are harmful and unexpected responses that occur when administered at normal doses. Although radiopharmaceuticals are regarded as safe medical products, adverse reactions should not be ignored. More serious adverse reactions such as myelosuppression, pleural effusion, and death may develop in therapeutic radiopharmaceuticals due to their use at higher doses than those used in diagnosis. Therefore, monitoring adverse reactions and reporting them to health authorities is important. This review aims to provide information about adverse reactions that may be related to radiopharmaceuticals used in treatment.
documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}\end{document} radiopharmaceutical therapy is a standardized systemic treatment, with a typical dose of 7.4 GBq per injection, but its response varies from patient to patient. Dosimetry provides the opportunity to personalize treatment, but it requires multiple post-injection images to monitor the radiopharmaceutical’s biodistribution over time. This imposes an additional imaging burden on centers with limited resources. This review explores methods to lessen this burden by optimizing acquisition types and minimizing the number and duration of imaging sessions. After summarizing the different steps of dosimetry and providing examples of dosimetric workflows for -DOTATATE and -PSMA, we examine dosimetric workflows based on a reduced number of acquisitions, or even just one. We provide a non-exhaustive description of simplified methods and their assumptions, as well as their limitations. Next, we detail the specificities of each normal tissue and tumors, before reviewing dose-response relationships in the literature. In conclusion, we will discuss the current limitations of dosimetric workflows and propose avenues for improvement.
Glomerular filtration rate (GFR) declines with age by approx. 1 ml/min/m ² per year beginning in the third decade of life. At 70 years of age > 40 ml/min/m ² of GFR will be lost. Thus, factors affecting loss of GFR have significant public health implications. Furthermore, the definition of chronic kidney disease based on GFR may not be appropriate for the elderly. We analyzed factors affecting absolute and relative change of eGFR over a 5 year period in 12,381 participants of the Gutenberg Health Study. We estimated GFR at baseline and after 5 years of follow-up by two different equations. Association with the decline of estimated GFR (eGFR) was assessed by multivariable regression analysis. We confirmed a median loss of eGFR per year of approx. 1 ml/min/m ² . Aside from albuminuria systolic blood pressure was most strongly associated with faster decline of eGFR followed by echocardiographic evidence of left ventricular diastolic dysfunction and reduced ejection fraction. White blood cell count showed a moderate association with eGFR loss. Diastolic blood pressure, serum uric acid and serum albumin were associated with slower GFR decline in multivariable analysis. Sensitivity analysis with exclusion of individuals taking diuretics, antihypertensive, antidiabetic, or lipid lowering drugs confirmed these associations.
Objective
To assess the activity and safety of sequential lutetium‐177 (¹⁷⁷Lu)‐PSMA‐617 and docetaxel vs docetaxel on a background of androgen deprivation therapy (ADT) in men with de novo metastatic hormone‐naïve prostate cancer (mHNPC).
Patients and Methods
UpFrontPSMA (NCT04343885) is an open‐label, randomized, multicentre, phase 2 trial, recruiting 140 patients at 12 Australian centres. Key eligibility criteria include: prostate cancer with a histological diagnosis within 12 weeks of screening commencement; prostate‐specific antigen (PSA) >10 ng/mL at diagnosis; ≤4 weeks on ADT; evidence of metastatic disease on computed tomography (CT) and/or bone scan; high‐volume prostate‐specific membrane antigen (PSMA)‐avid disease with a maximum standardized uptake value >15; and absence of extensive discordant fluorodeoxyglcuose (FDG)‐positive, PSMA‐negative disease. ⁶⁸Ga‐PSMA‐11 and ¹⁸F‐FDG positron‐emission tomography (PET)/CT undergo central review to determine eligibility. Patients are randomized 1:1 to experimental treatment, Arm A (¹⁷⁷Lu‐PSMA‐617 7.5GBq q6w × 2 cycles followed by docetaxel 75 mg/m² q3w × 6 cycles), or standard‐of‐care treatment, Arm B (docetaxel 75 mg/m² q3w × 6 cycles). All patients receive continuous ADT. Patients are stratified based on disease volume on conventional imaging and duration of ADT at time of registration. The primary endpoint is the proportion of patients with undetectable PSA (≤0.2 ng/L) at 12 months after study treatment commencement. Secondary endpoints include safety, time to castration resistance, overall survival, PSA and radiographic progression‐free survival, objective tumour response rate, early PSMA PET response, health‐related quality of life, and frequency and severity of adverse events. Enrolment commenced in April 2020.
Results and Conclusions
The results of this trial will generate data on the activity and safety of ¹⁷⁷Lu‐PSMA‐617 in men with de novo mHNPC in a randomized phase 2 design.
Radiation nephropathy (RN) is a kidney injury induced by ionizing radiation. In a clinical setting, ionizing radiation is used in radiotherapy (RT). The use and the intensity of radiation therapy is limited by normal-tissue damage including kidney toxicity. Different thresholds for kidney toxicity exist for different entities of RT. Histopathologic features of RN include vascular, glomerular and tubulointerstitial damage. The different molecular and cellular pathomechanisms involved in RN are not fully understood. Ionizing radiation causes double-stranded breaks in the DNA, followed by cell death including apoptosis and necrosis of renal endothelial, tubular and glomerular cells. Especially in the latent phase of RN oxidative stress and inflammation have been proposed as putative pathomechanisms, but so far no clear evidence was found. Cellular senescence, activation of the renin–angiotensin–aldosterone-system and vascular dysfunction might contribute to RN, but only limited data is available. Several signalling pathways have been identified in animal models of RN and different approaches to mitigate RN have been investigated. Drugs that attenuate cell death and inflammation or reduce oxidative stress and renal fibrosis were tested. Renin–angiotensin–aldosterone-system blockade, anti-apoptotic drugs, statins, and antioxidants have been shown to reduce the severity of RN. These results provide a rationale for the development of new strategies to prevent or reduce radiation-induced kidney toxicity.
Background
Lutetium-177 [ ¹⁷⁷Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [ ¹⁷⁷Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer.
Methods
We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0–2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [ ⁶⁸Ga]Ga-PSMA-11 and 2-flourine-18[ ¹⁸F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [ ¹⁷⁷Lu]Lu-PSMA-617 (6·0–8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m ² intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428.
Findings
Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [ ¹⁷⁷Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [ ¹⁷⁷Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9–37]; p=0·0016). Grade 3–4 adverse events occurred in 32 (33%) of 98 men in the [ ¹⁷⁷Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [ ¹⁷⁷Lu]Lu-PSMA-617.
Interpretation
[ ¹⁷⁷Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [ ¹⁷⁷Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel.
Funding
Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.
Objectives: Lutetium-177 (177Lu)-PSMA-617 (LuPSMA) is a radioligand with high affinity for prostate specific membrane antigen (PSMA) enabling targeted beta-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castrate-resistant prostate cancer (mCRPC). We now report their longer-term outcomes including a 20 patient extension cohort and outcomes of subsequent systemic treatments following completion of trial therapy. Methods: 50 patients with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. Endpoints included PSA response (PCWG2), toxicity (CTCAE v4.03), imaging response, patient-reported health-related quality of life (QoL), progression-free and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including LuPSMA. Results: 75 men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 months) and extensive prior treatment including prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline ≥ 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with ≥ 80% decrease. Of 27 patients with measurable soft tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to LuPSMA were self-limiting G1-2 dry mouth (66%), transient G1-2 nausea (48%), G3-4 thrombocytopenia (10%) and G3 anemia (10%). Brief pain inventory severity and interference scores decreased at all time points including at the 3 month follow-up with a decrease of -1.2 (95% CI -0.5 to -1.9, P = 0.001) and 1.0 (95% CI -0.2 to -0.18, P = 0.013), respectively. At a median follow-up of 31.4 months, median OS was 13.3 months (95% CI 10.5-18.7) with a significantly longer survival of 18.4 months (95% CI 13.8-23.8) in patients achieving a PSA decline ≥ 50%. At progression following prior response, further LuPSMA was administered to 15 (30%) patients (median 2 cycles commencing 359 days from enrolment) with PSA decline ≥ 50% in 11 patients (73%). 4 of 21 patients (19%) receiving other systemic therapies upon progression experienced PSA decline ≥ 50%. There were no unexpected adverse events with LuPSMA re-treatment. Conclusion: This expanded 50 patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity and improved QoL with LuPSMA radioligand therapy. Upon progression, re-challenge LuPSMA demonstrated higher response rates than other systemic therapies.
Prostate-specific membrane antigen (PSMA) is expressed in most prostate cancers and can be identified by PSMA-ligand imaging, which has already become clinically accepted in several countries in- and outside Europe. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (¹⁷⁷Lu-PSMA) is currently undergoing clinical validation. Retrospective observational data have documented favourable safety and striking clinical responses. Recent results from a prospective clinical trial (phase II) have been published confirming high response rates, low toxicity and reduction of pain in metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed after conventional treatments. Such patients typically survive for periods less than 1.5 years. This has led some facilities to adopt compassionate or unproven use of this therapy, even in the absence of validation within a randomised-controlled trial. As a result, a consistent body of evidence exists to support efficacy and safety data of this treatment. The purpose of this guideline is to assist nuclear medicine specialists to deliver PSMA-RLT as an “unproven intervention in clinical practice”, in accordance with the best currently available knowledge.
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.
PurposeTo present data from an interim analysis of a Phase II trial designed to determine the feasibility, safety, and efficacy of individualising treatment based on renal dosimetry, by giving as many cycles as possible within a maximum renal biologically effective dose (BED). Method
Treatment was given with repeated cycles of 7.4 GBq 177Lu-DOTATATE at 8-12-week intervals. Detailed dosimetry was performed in all patients after each cycle using a hybrid method (SPECT + planar imaging). All patients received treatment up to a renal BED of 27 ± 2 Gy (α/β = 2.6 Gy) (Step 1). Selected patients were offered further treatment up to a renal BED of 40 ± 2 Gy (Step 2). Renal function was followed by estimation and measurement of the glomerular filtration rate (GFR). ResultsFifty-one patients were included in the present analysis. Among the patients who received treatment as planned, the median number of cycles in Step 1 was 5 (range 3-7), and for those who completed Step 2 it was 7 (range 5-8); 73% were able to receive >4 cycles. Although GFR decreased in most patients after the completion of treatment, no grade 3-4 toxicity was observed. Patients with a reduced baseline GFR seemed to have an increased risk of GFR decline. Five patients received treatment in Step 2, none of whom exhibited a significant reduction in renal function. Conclusions
Individualising PRRT using renal dosimetry seems feasible and safe and leads to an increased number of cycles in the majority of patients. The trial will continue as planned.
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.
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.
BACKGROUND
Metastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (177Lu)–PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.
METHODS
We conducted an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor–pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)–labeled PSMA-11 positron-emission tomographic–computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment.
RESULTS
From June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. 177Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001). All the key secondary end points significantly favored 177Lu-PSMA-617. The incidence of adverse events of grade 3 or above was higher with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected.
CONCLUSIONS
Radioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer. (Funded by Endocyte, a Novartis company; VISION ClinicalTrials.gov number, NCT03511664. opens in new tab.)
The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR>30mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0mL/min/1.73m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.
OBJECTIVE. Several clinical studies have shown the efficacy of 177Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) for metastatic castration-resistant prostate cancer (mCRPC). The purpose of this article is to present results of a systematic review and meta-analysis aimed at compiling and outlining efficacy and safety data on 177Lu-PSMA RLT for mCRPC across all studies published to date. CONCLUSION. The results of the systematic review and meta-analysis suggest that 177Lu-PSMA RLT is an effective treatment of advanced-stage mCRPC that is refractory to standard therapeutic options and that it has a low toxicity profile. High-level evidence from randomized control trials is crucial for confirming the effectiveness of 177Lu-PSMA RLT and for instituting this therapy in the routine clinical care of patients with mCRPC.
Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly being used in metastatic castration-resistant prostate cancer (mCRPC). The objective of this study is to report our clinical experience with RLT using 177-lutetium–labeled PSMA-I&T. A total of 100 patients were treated under a compassionate use protocol with a total number of 319 cycles (median two cycles, range 1–6). Eligibility criteria included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy or chemoineligibility, and positive PSMA-ligand uptake at positron-emission tomography scan. The ¹⁷⁷Lu-PSMA-I&T was given 6–8 weekly with an activity of 7.4 GBq up to six cycles. The median number of previous mCRPC regimens was 3 (range 1–6), and 35 patients had visceral metastases. Prostate-specific antigen decline of ≥50% was achieved in 38 patients, median clinical progression-free survival (cPFS) was 4.1 mo, and median overall survival (OS) was 12.9 mo. Subgroup analyses identified an association of visceral metastases with a poor prostate-specific antigen (PSA) response and shorter cPFS and OS, and an association of rising lactate dehydrogenase (LDH) with shorter cPFS and OS. Patients achieving PSA decline of ≥50% within 12 wk of treatment showed longer cPFS and OS. Treatment-emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%). Grade 3/4 nonhematologic toxicities were not observed. RLT with ¹⁷⁷Lu-PSMA-I&T showed good activity in more than one-third of patients with late-stage mCRPC at low toxicity. Presence of visceral metastases and rising LDH were associated with worse treatment outcome. Patient summary: We analyzed the treatment outcome and toxicity of prostate-specific membrane antigen–targeted radioligand therapy in patients with metastatic castration-resistant prostate cancer. We found that a good treatment response could be achieved in a subgroup of patients with few side effects. We also observed that treatment outcome was worse in patients with organ metastases and elevated lactate dehydrogenase in blood tests. Radioligand therapy with ¹⁷⁷Lu-PSMA-I&T showed good activity in more than one-third of patients with late-stage metastatic castration-resistant prostate cancer at low toxicity. Presence of visceral metastases and rising lactate dehydrogenase were associated with worse treatment outcome.
Background
Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher levels.
The US Food and Drug Administration currently accepts halving of glomerular filtration rate (GFR), assessed as doubling of serum creatinine level, as a surrogate end point for the development of kidney failure in clinical trials of kidney disease progression. A doubling of serum creatinine level generally is a late event in chronic kidney disease (CKD); thus, there is great interest in considering alternative end points for clinical trials to shorten their duration, reduce sample size, and extend their conduct to patients with earlier stages of CKD. However, the relationship between lesser declines in GFR and the subsequent development of kidney failure has not been well characterized. The National Kidney Foundation and Food and Drug Administration sponsored a scientific workshop to critically examine available data to determine whether alternative GFR-based end points have sufficiently strong relationships with important clinical outcomes of CKD to be used in clinical trials. Based on a series of meta-analyses of cohorts and clinical trials and simulations of trial designs and analytic methods, the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40% may be more broadly acceptable than a 30% decline across a wider range of baseline GFRs and patterns of treatment effects on GFR. However, there are other circumstances in which these end points could lead to a reduction in statistical power or erroneous conclusions regarding benefits or harms of interventions. We encourage careful consideration of these alternative end points in the design of future clinical trials.
Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values.
To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates.
Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006.
8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES.
GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age.
In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%).
The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR.
The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use.
National Institute of Diabetes and Digestive and Kidney Diseases.
The importance of knowledge on tolerance of normal tissue organs to irradiation by radiation oncologists cannot be overemphasized. Unfortunately, current knowledge is less than adequate. With the increasing use of 3-D treatment planning and dose delivery, this issue, particularly volumetric information, will become even more critical. As a part of the NCI contract N01 CM-47316, a task force, chaired by the primary author, was formed and an extensive literature search was carried out to address this issue. In this issue. In this manuscript we present the updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, with a special emphasis on partial volume effects. Due to a lack of precise and comprehensive data base, opinions and experience of the clinicians from four universities involved in the contract have also been contributory. Obviously, this is not and cannot be a comprehensive work, which is beyond the scope of this contract.
During the past 10 years, a variety of radiolabeled monoclonal antibodies, antibody fragments, and low-molecular- weight oncophilic peptides have been used to deliver radioactivity to target cells for therapeutic purposes. The high and persistent localization of several of these radiolabeled molecules in the kidneys raised concern about potential renal radiation toxicity compromising therapeutic effectiveness. In particular, radiolabeled peptides, such as yttrium-90-labeled synthetic somatostatin analogues, have initiated a discussion on the safety profiles of the various somatostatin derivatives in recent clinical trials. In general, the toxicity risk seems to depend on the characteristics of the oncophilic molecule, such as the molecular weight, electric charges and clearance pathways as well as the chemical and physical characteristics of the applied radionuclide. Encouraging results for the prevention of radiation-induced renal damage by radiolabeled peptides have been obtained by co-infusion of positively charged amino acids. The available literature on nephrotoxicity after radiolabeled peptide therapy is reviewed, and therapeutic options that have become available as a result of greater insights into putative pathogenic mechanisms are discussed.
The kidneys are critical organs in peptide receptor radiation therapy (PRRT). Renal function loss may become apparent many years after PRRT. We analyzed the time course of decline in creatinine clearance (CLR) in patients during a follow-up of at least 18 mo after the start of PRRT with (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA),Tyr(3)-octreotide ((90)Y-DOTATOC) or (177)Lu-DOTA(0),Tyr(3)-octreotate ((177)Lu-DOTATATE).
Twenty-eight patients with metastasized neuroendocrine tumors received 1-5 cycles of (90)Y-DOTATOC, leading to renal radiation doses of 5.9-26.9 Gy per cycle and a total of 18.3-38.7 Gy. Median follow-up was 2.9 y (range, 1.5-5.4 y), with a median of 16 measurements (range, 5-53) per patient. Thirty-seven patients with metastasized neuroendocrine tumors received 3-7 cycles of (177)Lu-DOTATATE, leading to renal radiation doses of 1.8-7.8 Gy per cycle and a total of 7.3-26.7 Gy. Median follow-up was 2.4 y (range, 1.7-4.0 y), with a median of 10 (range, 6-27) measurements per patient. All renal dose estimates were calculated with the MIRDOSE3 model. All patients were infused with renoprotective amino acids during the administration of the radioactive peptides. The time trend of CLR was determined by fitting a monoexponential function through the data of individual patients, yielding the decline in CLR in terms of percentage change per year.
The median decline in CLR was 7.3% per y in patients treated with (90)Y-DOTATOC and 3.8% per y in patients treated with (177)Lu-DOTATATE (P = 0.06). The time trend of decline in CLR was sustained during the follow-up period. Eleven patients had a >15% per y decline in CLR. Cumulative renal radiation dose, per-cycle renal radiation dose, age, hypertension, and diabetes are probable contributing factors to the rate of decline in CLR after PRRT.
This study showed that the time course of CLR after PRRT was compatible with the pattern of sustained CLR loss in progressive chronic kidney disease.
Clinical trial protocol for LuTectomy: a single-arm study of the dosimetry, safety, and potential benefit of 177Lu-PSMA-617 prior to prostatectomy
- Dhiantravan
Clinical trial protocol for LuTectomy: a single-arm study of the dosimetry, safety, and potential benefit of 177 Lu-PSMA-617 prior to prostatectomy
- N Dhiantravan
- J Violet
- R Eapen
Dhiantravan N, Violet J, Eapen R, et al. Clinical trial protocol for LuTectomy: a
single-arm study of the dosimetry, safety, and potential benefit of 177 Lu-PSMA-617 prior to prostatectomy. Eur Urol Focus. 2021;7:234-237.