Lutetium-177 Prostate-Specific Membrane Antigen-617 Treatment in Metastatic Castration-Resistant Prostate Adenocarcinoma: Results of Single-Center Experience

Objective: Lutetium-177 prostate-specific membrane antigen-617 is a novel alternative therapeutic option in metastatic castration-resistant prostate cancer, especially useful for patients who do not respond to standard therapy methods. The aim of this study was to define the efficacy and safety profile of lutetium-177 prostate-specific membrane antigen-617 treatment in a group of patients with metastatic castration-resistant prostate cancer. Materials and Methods: Study group included 34 men with metastatic castration-resistant prostate cancer (median, 69.6 ± 7.7 years) who were treated with lutetium-177 prostate-specific membrane antigen-617 therapy (22/34; 4 courses, 12/34; 2 courses). Patients were evaluated by physical examination, Eastern cooperative oncology group performance status, gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography, brief pain inventory-short form questionnaire, biochemical tests, and complete blood counts. Treatment response and adverse effects were examined by brief pain inventory scores, SUVmax values, biochemical tests, and complete blood counts. Independent variables were analyzed statistically (significance; P < .05). Results: The Eastern cooperative oncology group performance was grade 0 in 5/34 (14.7%), grade 1 in 25/34 (73.5%), and grade 2 in 4/34 (11.8%) patients. Distribution of patient numbers according to brief pain inventory scores (score: <1, scores: 1-4, and scores: 5-10) was 2, 10 and 22 at the beginning, 6, 16 and 12 after the second course, and 10, 10 and 2 after the fourth course of treatment, respectively. Serum prostate-specific antigen decreased in 15 of 22 patients (68%) (P < .05). Before and after the treatment, we found a substantial decrease in SUVmax values (22.3 vs. 11.8, P < .001) and brief pain inventory scores (score ≥ 5; 22/34 pts vs. 0/22 pts). The counts of white blood cells (P < .05), hemoglobin (P < .05), and thrombocytes (P = .001) were all significantly lower at the conclusion of the therapy. The most important adverse events were severe leukopenia (1/34 pts; 2.29 × 103/µL) and thrombocytopenia (3/34 pts; 32 000, 36 000, 32 000 × 106/L). Conclusion: We found that lutetium-177 prostate-specific membrane antigen-617 therapy is a promising treatment method for metastatic castration-resistant prostate cancer patients who are unresponsive to conventional therapy, according to our biochemical, positron emission tomography/computed tomography, and pain score outcomes.


Introduction
Prostate adenocarcinoma is the second commonest cancer worldwide and one of the leading causes of cancer death. It still has significant morbidity and mortality despite diagnostic and therapeutic advances. 1,2 Androgen deprivation therapy (ADT) is the gold standard method for patients with prostate cancer. In spite of the high initial response rates, cancer treatment with ADT is of limited duration; many men eventually develop progressive disease, so-called metastatic castration-resistant prostate cancer (mCRPC) following ADT. 3 Since the approval of docetaxel as the first-line chemotherapy in 2004, several new life-prolonging systemic therapies such as abiraterone, enzalutamide, cabazitaxel, and 223r adium have become available for mCRPC patients. Despite these treatments, many patients have progressed to advanced cancer stages despite new treatment modalities. Today, effective therapeutic alternatives are needed to control disease-related symptoms and to improve quality of life.
Lutetium-177 prostate-specific membrane antigen ( 177 Lu-PSMA-617) has become a potent treatment agent thanks to the increased expression of PSMA in most men with mCRPC. 4,5 It has been reported that 177 Lu-PSMA-617 treatment is valuable in providing biochemical and symptomatic pain control and improving quality of life in mCRPC patients. 5 Prostate-specific membrane antigen, also called folate hydrolase I or glutamate carboxypeptidase II, is expressed at high levels in prostatic adenocarcinoma cells. It has been reported that there is a significant increase in PSMA levels of patients who have either high-grade or castration-resistant cancers. Prostate-specific membrane antigen represents an excellent biomarker for both imaging and treatment of prostate cancer and so this topic has become the focus of extensive research. Some tissues have varying degrees of PSMA expression, including prostate epithelium, small intestine, renal tubules, and salivary glands. 6 Prostate-specific membrane antigen is a type II transmembrane protein with 2 monomers and corresponding intracellular transmembrane and extracellular domains that are enzymatically active proteins in homodimeric form. 7 In ligand binding, PSMA undergoes clathrin-mediated endocytosis. 8 Identification of the substrate and binding site has spurred the development of urea-based high-affinity PSMA inhibitors with favorable biodistribution and high tumorto-background uptake rates. 6 Lutetium-177 prostate-specific membrane antigen-617 synthesis was originally developed by the German Cancer Research Center (DKFZ, Deuts chesK rebsf orsch ungsz entru m) in collaboration with University Hospital Heidelberg. It is a small molecule inhibitor that binds to PSMA with high affinity. The short-range 1 mm path length of the beta particle emitted by 177 Lu ensures effective delivery of radiation to tumoral tissue while minimizing damage to surrounding normal tissues. 9 The aim of this retrospective study was to report our results and confirm the efficacy and side effect profile of 177 Lu-PSMA-617 treatment in mCRPC patients.

Materials and Methods
Study Group A total of 42 consecutive patients, between February 2017 and November 2021, were referred to the Department of Nuclear Medicine of Atatürk University Medical Faculty Hospital. All patients were discussed by an interdisciplinary tumor board for 177 Lu-PSMA-617 therapy recommendation due to mCRPC. The study protocol conforms to the Declaration of Helsinki and was approved by the local ethics committee (decision date: November 25, 2021; decision number: 08-26). Since this study was a retrospective study, informed consent form could not be obtained from the patients. After evaluation according to exclusion criteria, the final study group consisted of 34 mCRPC patients (age range; 69.6 ± 7.7 years) who underwent 177 Lu-PSMA-617 therapy.

Pre-Evaluation and Exclusion Criteria of Patients
At the time of hospitalization, all patients with mCRPC who were candidates for 177 Lu-PSMA-617 therapy were subjected to a physical examination by an experienced medical doctor, and necessary tests were performed for preliminary evaluation. Patients were graded by the Eastern cooperative oncology group (ECOG) performance status and Brief Pain Inventory (BPI) score according to previously published criteria. 10 Routinely measured laboratory parameters in each patient included complete blood counts and biochemistry tests [liver function enzymes, serum creatinine, and prostate-specific antigen (PSA) levels]. Each patient underwent a gallium-68 prostate-specific membrane antigen positron emission tomography/ computed tomography ( 68 Ga-PSMA-11 PET/ CT) prior to treatment to demonstrate the presence of PSMA over-expression in their lesions.
We used some exclusion criteria and 8 patients were excluded from this study. The criteria for blood picture are as follows: liver enzymes more than 5 times the upper limit, total white blood cell (WBC) count less than 3 × 10 9 /L, platelet count less than 75×10 9 /L, and hemoglobin less than 8 g/dL. We excluded 4 patients (n = 4) due to low platelet counts. The other 4 excluded patients (n = 4) had metastases on CT but no PSMA expression on 68 Ga-PSMA-11 PET/CT. Lutetium-177 prostate-specific membrane antigen-617 therapy We followed a previously published 177 Lu-PSMA-617 treatment protocol for all patients. 6 We applied 4 courses of treatment to 22 of 34 (64.7%) patients. We had to apply 2 courses of treatment in 12 of 34 patients due to the following reasons; six patients refused to continue the next courses of the treatmente clinicians decided to terminate the treatment in four patients, two patients died due to another concomitant disease before the third course of the treatment. The interval between each course of treatment was 6-8 weeks. During each administration, patients received an infusion of 1 L of normal saline at 300 mL/h, 30 min before 177 Lu-PSMA-617 administration with an average dose of 7315 ± 573 MBq. We did not use a special protection method for the salivary glands.

Evaluation of Treatment Response
A rate of change in BPI score, serum PSA, and lesion SUV max values obtained before and after administration of 177 Lu-PSMA-617 was examined to evaluate the treatment response. Follow-up BPI score assessments were repeated 2 times; 45 days after the fourth course of the treatment in 34 patients and 1 month after the fourth course of the treatment in 22 patients. Serum PSA measurements and 68 Ga-PSMA-11 PET/CT were routinely performed in each patient 1 month after the last course of 177 Lu-PSMA-617 administration.

Evaluation of Side Effects
All patients were evaluated in order to define treatment-related side effects. They were questioned for the presence of newly developed symptoms after each course administration. They were examined by complete blood counts and biochemistry tests 1 month after the last course of treatment and test results were analyzed for change before and after 177 Lu-PSMA-617 therapy. Toxicity-attributed side effects and hematologic changes were documented according to version 4.0 of the Common Toxicity Criteria for Adverse Events.

Statistical Analysis
Statistical analyses were performed using the International Business Machines' Statistical Package for the Social Sciences Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA). The variables were investigated using visual (histograms, probability plots) and analytic methods (Kolm ogoro v-Smi rnov/ Shapi ro-Wi lks test) to determine whether or not they are normally distributed. Data with normal distribution

Main Points
• Lutetium-177 prostate-specific membrane antigen-617 ( 177 Lu-PSMA-617) therapy is an important treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients who do not respond to conventional treatment protocols.
• 177 Lu-PSMA-617 treatment significantly reduces the pain that negatively affects the quality of life in patients with metastatic prostate cancer.
• 177 Lu-PSMA-617 treatment appears to be safe in patients with mCRPC with a low side effect profile.
are given as mean ± standard deviation (SD), and the data whose distribution was not normal are given as median (interquartile range). After checking the normality distribution of scale variables, independent samples were compared with appropriate significance tests (e.g., the Mann-Whitney U test, Kruskal-Wallis H test).
The results with P < .05 were considered statistically significant.

Results
The characteristics of the patients included in the study are given in The BPI score values of 34 mCRPC patients before and after treatment are given in Table 2.
The distribution of patient numbers according to BPI scores (score:<1, score:1-4 and score:5-10) were 2, 10 and 22 at the beginning, 6, 16 and 12 after the second course, and 10, 10 and  Ga-PSMA-11 PET/CT-derived semiquantitative SUV max values of the patients and the comparisons of pre-and post-treatment values to assess treatment response and side effects. When we compared pre-and post-treatment PSA levels of the patients, we found a statistically significant difference between these 2 data sets (P < .05, 115 vs. 24 ng/mL, Figure 1). After the fourth course of 177 Lu-PSMA-617 therapy, a PSA decline was detected in 15 of 22 patients (68.1%). Thirteen of these 22 patients (59%) had a decrease of more than 50%, and there was more than 80% reduction in 9 of them (40.9%). In agreement with the decreasing PSA values, we found a statistically significant difference between pre-and post-treatment bone SUV max values (P < .001) and a distinct decrease in median SUV max values (22.2 vs. 11.8). Gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography images of a patient before and after 4 sessions of 177 Lu-PSMA-617 treatment are given in Figure 1.

Discussion
Prostate cancer is one of the most common types of human urogenital system malignancies. It still has serious morbidity and mortality   despite the use of new treatment protocols and advanced diagnostic imaging methods. Androgen deprivation therapy is positioned as the first-line application in the treatment algorithm of prostate cancer. A combination of chemotherapy, radiotherapy, and a second-generation antiandrogen drug is often preferred in patients with advanced prostate cancer. In recent years, 177 Lu-PSMA-617 has been used more frequently as an alternative or complementary treatment option in advanced disease, especially for mCRPC patients. 1,2 Prostate-specific antigen is a useful biomarker approved by US Food and Drug Administration for diagnosing and monitoring prostate cancer.
It is especially useful in the follow-up of patients with advanced disease and it correlates well with their clinical status. According to the results of a pooled meta-analysis studied on 10 different studies which are investigating the efficacy of 177 Lu-PSMA-617 therapy, there was a decrease in PSA level in 165 of 238 patients (69.3%). 11 This meta-analysis also confirmed our results (68%). Extreme low and high efficacy values were also observed. However, some studies have reported lower and higher rates. In the study by Ahmadzadehfar et al. 12 a decrease in PSA level after 177 Lu-PSMA-617 therapy was found to be 79.1%, while Kratochwil 9 found it to be 72%. Rahbar et al 13 , on the other hand, measured the decrease in PSA as 59.7%.
According to meta-analysis by Emmett et al. 14 hematological side effects are common and significant, especially for bone metastasis. In their analysis, hemoglobin levels ranged from 10% to 32%, platelet counts ranged from 0% to 25%, and WBC counts ranged from 3% to 15%. Our study is compatible with the metaanalysis of Emmett in terms of hematological side effects. In our study, hemoglobin level, platelet, and WBC count decreased by 8.94%, 29%, and 18%, respectively. This side effect is mostly observed either in grade 1 or grade 2. However, severe side effects could be reported in patients who take chemotherapy before the 177 Lu PSMA.
The significant decrease in PSA value, which is accepted as the most important biomarker of prostate cancer, can predict that patients respond positively to 177 Lu-PSMA-617 treatment. In our study, 177 Lu-PSMA-617 treatment was administered to patients who progressed despite chemotherapy and second-generation anti-androgen therapy and to patients who were unsuitable or did not accept this treatment. In our series, when we evaluate PSA and bone SUV max values of patients, a significant decrease was found in the PSA levels (P < .05), and a significant decrease was observed in the SUV max values of the patients (P < .001) according to the 68 Ga-PSMA-11 PET/CT scores obtained before and after the treatment. This significant decrease in SUV max values is another good indicator of response to the treatment. When these 2 parameters were integrated, it was seen that the patients have a positive response to this alternative treatment. According to our survey on pain scores, it was reported that patients felt severe bone pain before and after the therapy. A remarkable decrease was observed in many patients even after the administration of the first dose. Significant pain reduction was observed in 27 (79.41%) of 34 patients; although there was  no decrease in PSA level in 3 patients, a decline in pain score was also observed.
In all patients, WBC, calcium, hemoglobin, platelet, and creatinine levels were followed; even if some of those values decreased during therapy, the values were within normal limits. It was reported that only 1 patient developed severe leukopenia and 3 patients developed severe thrombocytopenia. Taking into account all mentioned findings and the severity of present side effects, we emphasized that the 177 Lu-PSMA-617 treatment does not have a serious side effect profile, as well as it has promising results and remarkable improvements in the patient's quality of life.
This study has some limitations as it was carried out with a limited number of patients in a small group. For more precise results, the patient group should be enlarged. Another limitation of the study is that we could not complete the standard 4 courses treatment regimen in all patients. This expectation is difficult to meet due to patient compliance, other treatment options, co-morbidities, and social reasons. Nevertheless, we think that our findings still remain reliable since most of the patients in the study group (22/34; 64.7%) met this requirement.
In conclusion, 177 Lu-PSMA-617 therapy is an important treatment option for mCRPC patients who do not respond to conventional treatment protocols. It has a low side effect profile and can improve patients' quality of life thanks to its therapeutic effect on metastatic lesions. Ethics Committee Approval: Ethical committee approval was received from the Ethics Committee of Atatürk University (Date: November 25, 2021, Approval No: 26).
Informed Consent: Written informed consent was obtained from all participants who participated in this study.
Peer-review: Externally peer-reviewed. Funding: The author declared that this study has received no financial support.