Efficacy and Haematologic Toxicity of Palliative Radioligand Therapy of Metastatic Castrate-Resistant Prostate Cancer with Lutetium-177-Labeled Prostate-Specific Membrane Antigen in Heavily Pre-Treated Patients.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains a significant contributor to the global cancer burden. lutetium-177-prostate-specific membrane antigen radioligand therapy (177Lu-PSMA RLT) is an effective salvage treatment. However, studies have highlighted haematologic toxicity as an adverse event of concern. We report our single-centre experience of compassionate access palliative 177Lu-DOTAGA-(I-y)fk(Sub-KuE) (177Lu-PSMA I&T) with respect to efficacy and haematologic safety. METHODS: Patients with mCRPC and adequate bone marrow/liver function were included. All patients included underwent baseline and response assessment by Gallium-68-PSMA-11 positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT). Prescribed activity of therapy was a median 6.24 GBq per patient per cycle (IQR1.29 GBq), administered in 8-week intervals, up to four cycles. Response was assessed by prostate specific antigen (PSA) and a week-12 PET/CT. Incidence of grade ≥ 3 haematologic toxicity, including association with risk factors (age ≥ 70 years, prior/concurrent therapy, presence of metastases, and number of cycles completed), was analysed. RESULTS: One hundred patients completed one cycle of 177Lu PSMA I&T and underwent response assessment by both PSA and PET/CT. Two patients had an uninterpretable week-12 PET/CT. Median age was 70 (50-89), median number of prior therapies was three (1-6), and median follow up was 12-months. Fifty-four percent achieved a PSA response. Disease control rate (DCR) by PET/CT was 64% (29% SD, 34% PR, and 1% CR). Disease control by PET/CT was associated with an improved one-year overall survival (OS) compared to non-responders, median OS not-reached vs 10-months (p < 0.0001; 95% CI: 0.08-0.44). Regarding haematologic toxicity, 11% experienced a grade ≥ 3 cytopenia (self-limiting). No cases of myelodysplasia/acute leukaemia (MDS/AL) have been recorded. No association with risk factors was demonstrated. CONCLUSION: 177Lu-PSMA I&T is a safe and effective palliative outpatient treatment for mCRPC. 68Ga-PSMA-11 PET/CT response is associated with an improved one-year OS and may be used to adapt therapy.

Real-World Data Analysis of Efficacy and Survival After Lutetium-177 Labelled PSMA Ligand Therapy in Metastatic Castration-Resistant Prostate Cancer.

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 METHODS: 191 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. RESULTS: Most 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.

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

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.

Gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography compared with diagnostic computed tomography in relapsed prostate cancer.

The aim of this study was to evaluate if prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has a higher detection rate compared to standard contrast CT imaging for patients with a rising prostate-specific antigen (PSA) following definitive treatment (i.e., curative radical prostatectomy, radiotherapy, and brachytherapy) for prostate cancer in a private hospital setting. A retrospective single-site clinical audit was conducted on 150 PSMA PET/CT scans done for patients with a rising PSA after definitive treatment for prostate cancer. All studies were performed using I and T Ga-68 PSMA produced on a Scintomics radiopharmaceutical unit (Munich). All scans were performed on a GE 710 PET/CT scanner. All studies were compared to standard CT and other imaging. Of the 150 patients who had a 68Gallium (Ga)-PSMA PET/CT for a rise in their PSA levels, 102/150 (68%) of patients had PSMA-avid scans compared to the conventional imaging group which had an overall detection rate of 42% (63/150). The rates of detection were 100%, 90%, 92%, 67%, and 25% at PSA levels of >10 µg/L, 5-10 µg/L, >1.5 µg/L, 0.5-1.5 µg/L, and <0.5 µg/L, respectively. PSMA PET/CT also solely picked up 39/102 (38%) of prostate cancer relapses compared to the conventional imaging group. In our study of 150 patients with biochemical recurrence of prostate cancer, 68Ga-PSMA PET/CT demonstrated a superior detection rate (P < 0.05) compared to conventional imaging, including patients with low PSA levels (<0.5 µg/L).

Preparation of starch-based porous carbon electrode and biopolymer electrolyte for all solid-state electric double layer capacitor.

An ever-increasing demand for energy coupled with environmental pollution associated with conventional energy production continues to drive the search for alternative renewable energy storage solutions. In this regard, a high surface area (1841 m2 g-1), hierarchically porous (∼1.18 cm3 g-1) and self-inherited nitrogen (2.1 at.wt%) based activated carbon are obtained from Artocarpus heterophyllus seed derived starch as a result of ZnCl2 chemical activation. A flexible, conductive, thermally stable and bio-degradable biopolymer electrolyte film is prepared from Manihot esculenta starch powder. These eco-friendly hierarchically porous architectured carbon electrode and flexible biopolymer electrolytes are employed as significant components in a coin cell-based all-solid-state supercapacitor. The resulting device delivers a high specific capacitance of 240 Fg-1 at 0.5 mA with 97% coulombic efficiency over 2000 cycles. In addition, the device provided excellent specific energy (17 Wh kg-1) and specific power (3823 W kg-1). Interestingly, the starch derived biopolymer electrolyte film, when buried under soil, shows a favourable natural rate of degradation. Therefore, this fabricated electric double layer capacitor can be used as a promising device with little to no potential environmental harm.

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

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

Salvage Radiopeptide Therapy of Advanced Castrate-Resistant Prostate Cancer with Lutetium-177-Labeled Prostate-Specific Membrane Antigen: Efficacy and Safety in Routine Practice.

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.

Review of Gallium-68 PSMA PET/CT Imaging in the Management of Prostate Cancer.

Over 90% of prostate cancers over-express prostate specific membrane antigen (PSMA) and these tumor cells may be accurately targeted for diagnosis by 68Ga-PSMA-positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) imaging. This novel molecular imaging modality appears clinically to have superseded CT, and appears superior to MR imaging, for the detection of metastatic disease. 68Ga-PSMA PET/CT has the ability to reliably stage prostate cancer at presentation and can help inform an optimal treatment approach. Novel diagnostic applications of 68Ga-PSMA PET/CT include guiding biopsy to improve sampling accuracy, and guiding surgery and radiotherapy. In addition to facilitating the management of metastatic castrate resistant prostate cancer (mCRPC), 68Ga-PSMA can select patients who may benefit from targeted systemic radionuclide therapy. 68Ga-PSMA is the diagnostic positron-emitting theranostic pair with the beta emitter Lutetium-177 PSMA (177Lu-PSMA) and alpha-emitter Actinium-225 PSMA (225Ac-PSMA) which can both be used to treat PSMA-avid metastases of prostate cancer in the molecular tumor-targeted approach of theranostic nuclear oncology.

The role of 68Ga-PSMA-I&T PET/CT in the pretreatment staging of primary prostate cancer.

OBJECTIVES: This retrospective study aimed to evaluate the role of Ga-PSMA-I&T PET/CT in the primary staging of newly diagnosed prostate cancer (PCa), with a focus on the detection of metastatic nodal disease. Correlation of the rate of detection of metastatic disease by Ga-PSMA-I&T PET/CT with the Gleason score (GS) and serum prostate-specific antigen (PSA) was performed to determine the GS and PSA criteria defining patients who would benefit from Ga-PSMA-I&T PET/CT imaging for staging, risk stratification and therapy optimization. PATIENTS AND METHODS: Patient data and images from 70 patients with a recent diagnosis of prostate cancer who had undergone Ga-PSMA-I&T PET/CT were analysed retrospectively. Data and images were analysed for the rate of detection of primary and metastatic PCa, and correlation with PSA and GS. RESULTS: The rate of detection of primary tumour by Ga-PSMA-I&T for patients with serum PSA less than 5 ng/ml was 73%. The corresponding rate was 90% for patients with PSA 5-10 ng/ml and 97% for patients with PSA more than 10 ng/ml. Metastatic PCa and/or infiltrative disease was detected in 24/70 study patients in total: 1/11 patients with PSA less than 5 ng/ml and 23/59 patients with serum PSA at least 5 ng/ml. The rate of detection of metastatic PCa was greater in patients with GS 9 or more (48%) relative to those with GS 8 (32%) or GS ≤7 (18%). CONCLUSION: A role for Ga-PSMA-I&T PET/CT in primary PCa staging of high-grade disease (GS 8 or more and PSA >10 ng/ml) has been shown. There was a low rate of detection of PSMA-avid metastases in low-grade disease (GS 7 or less and PSA <5 ng/ml), suggesting that there is a limited role for this modality in such cases.

Pre-clinical evaluation of 2,3-dimercaptosuccinic acid as a radiation nephrotoxicity protective agent during radiopeptide therapy of neuroendocrine malignancy.

AIM: To determine if dimercaptosuccinic acid (DMSA), an agent originally developed as a safe non-toxic antidote for heavy metal poisoning, would be useful as a kidney radiation dose reduction agent in patients undergoing radiopeptide therapy for cancer. METHODS: Thirty-six adult male Wistar rats were injected via the penile vein with 10 MBq of 177Lu-DOTA-tyr(3)-octreotate. At 30 min after the radiopeptide injection, 18 of the animals (intervention group) were injected with 0.15 mg x g(-1) of DMSA (i.p.). Samples were collected for gamma counting at 24 (n=12), 48 (n=12) and 72 h (n=12) after administration of the radiopeptide. At each time point, the percentage injected dose per gram of tissue in each sample of the six control animals was compared with that of the six animals from the DMSA injection regimen. RESULTS: The i.p. injection of 0.15 mg x g(-1) of DMSA 30 min following the administration of the 177Lu-DOTATATE reduced the mean (95% CI) kidney retention of radiopeptide by 15.6% (2.6-24.6) at 72 h while not significantly affecting uptake in other organs. Statistical testing of the difference between the two groups of animals (DMSA versus controls) at 72 h post-administration of the radiopeptide indicated only a 3% chance that the magnitude of the reduction in kidney radiopeptide retention observed would be expected due to natural variation (i.e., if there was no difference between the groups). CONCLUSION: This study has indicated that DMSA has the potential to selectively reduce radiopeptide kidney retention. Further work is necessary to determine the most effective dose of DMSA and the most effective timing regimen, and to examine the clinical efficacy of several other chelating agents.

Effect of multipurpose solutions for contact lens care on the in vitro drug-induced spoliation of poly(2-hydroxyethyl methacrylate) in simulated aqueous humour.

Drug-induced spoliation of hydrogels as contact lenses or as implants in the anterior eye is a frequent occurrence in clinical practice. This study explores the capacity of three commercial multipurpose solutions for contact lens care to reduce the spoliation of poly(2-hydroxyethyl methacrylate) (PHEMA) specimens exposed to a simulated aqueous humour formulation and to three topical drugs commonly administered after insertion of artificial corneas (Predsol, Optimol and Depo-Ralovera). ReNu MultiPlus (Bausch & Lomb), Complete Blink-N-Cleantrade mark Lens Drops (Allergan) and Complete Protein Remover Tablets dissolved in Complete ComfortPLUS (both from Allergan) were evaluated. All multipurpose solutions were able to dislodge passively the deposits formed on hydrogels in the simulated aqueous and in the presence of Predsol and Optimol, but none were effective against the deposits induced by Depo-Ralovera. A reduction of the calcium content in deposits caused by Predsol and Optimol was confirmed after treatment with the protein remover preparation, while the other multipurpose solutions caused the complete removal of the deposits. In experiments designed to evaluate the preventive action of the multipurpose solutions, no such effects were observed regardless of the drug involved. The prospect of using multipurpose solutions as eye drops following implantation of a hydrogel artificial cornea is a valid alternative for reducing device spoliation, however it appears to depend on the nature of the postoperative medication.