Predictive Factors for Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Undergoing ¹⁷⁷Lu-PSMA-617 Radioligand Treatment

By Seray Saray¹, Hasan Bozkurt², Eyyup Cavdar³, Yakup Iriagac¹, Huseyin Kanmaz¹

Affiliations

1. Department of Medical Oncology, Balikesir Ataturk City Hospital, Balikesir, Turkiye
2. Department of Nuclear Medicine, Balikesir Ataturk City Hospital, Balikesir, Turkiye
3. Department of Medical Oncology, Faculty of Medicine, Tekirdag Namik Kemal University, Tekirdag, Turkiye

doi: 10.29271/jcpsp.2025.10.1261

ABSTRACT
Objective: To determine prognostic factors in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing ¹⁷⁷Lutetium-Prostate-specific membrane Antigen-617 radioligand therapy (¹⁷⁷Lu-PSMA RLT).
Study Design: Descriptive, analytical study.
Place and Duration of the Study: Department of Medical Oncology and Nuclear Medicine, Balikesir Ataturk City Hospital, Balikesir, Turkiye, from 2021 to 2024.
Methodology: The study retrospectively examined patients diagnosed with metastatic castration-resistant prostate cancer (mCRPC) and received ¹⁷⁷Lu-PSMA RLT. Data were collected from electronic health records of the hospital, including patient characteristics, clinical and pathological details, and blood test outcomes. Pre-treatment blood markers were documented, including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), albumin-to-alkaline phosphatase ratio (AAPR), prognostic nutritional index (PNI), haemoglobin, albumin, lymphocyte and platelet (HALP) scores, and the systemic ımmune-ınflammation index (SII). Treatment-related adverse events were recorded, and their associations with other factors were assessed using Spearman's correlation analysis. Survival analysis was conducted using the Kaplan-Meier method, and group comparisons were performed using the log-rank test. Univariate and multivariate Cox regression analyses were conducted to identify factors affecting survival.
Results: This study included 31 patients with median age of 69 (57–80) years. Twenty-three (74.2%) patients undergoing ¹⁷⁷Lu-PSMA RLT experienced at least one adverse event, while seven (22.6%) experienced serious adverse events. The presence of visceral metastasis (p = 0.023), fatigue (p = 0.032), anorexia (p = 0.048), and nephropathy (p = 0.001) were significantly associated with poor overall survival (OS). In a multivariate model, visceral metastasis (HR = 24.10; 95% CI: 1.26-461.47; p = 0.035), fatigue (HR = 6.17; 95% CI: 1.65-23.02; p = 0.007), and nephropathy (HR = 10.14; 95% CI: 2.52-40.87; p = 0.001) remained significant prognostic factors. Patients with visceral metastases (OS 20.79 months; 95% CI: 16.77-24.81; p = 0.001), anorexia (OS 15.57 months; 95% CI: 7.17-23.97; p = 0.036), fatigue (OS of 13.32 months; 95% CI: 5.39-21.25; p = 0.023), and nephropathy (OS of 14.96 months; 95% CI: 6.22-15.13; p <0.001), showed significant association with survival.
Conclusion: Adverse events during ¹⁷⁷Lu-PSMA RLT had independent prognostic factors for survival.

Key Words: Metastatic castration-resistant prostate cancer, Lutetium, Radioligand therapy.

INTRODUCTION

Prostate cancer (PCa) is the most prevalent malignancy and the second leading cause of cancer-related mortality among men in industrialised nations.¹ Although conventional hormonal therapy targeting the androgen receptor (AR) effectively suppresses PCa in its initial stage, tumour progression ultimately happens.²

Metastatic castration-resistant prostate cancer (mCRPC), the advanced and incurable form of the disease,³ poses significant therapeutic challenges. Over the past decade, several life- prolonging treatment modalities for mCRPC have been emerged.⁴ However, despite these advancements, a substantial proportion of patients continue to experience disease progression, highlighting the urgent need for novel therapeutic approaches.⁵

¹⁷⁷Lutetium-prostate-specific membrane Antigen-617 radioligand therapy (¹⁷⁷Lu-PSMA RLT) has emerged as a promising therapeutic intervention for mCRPC.⁶ This novel treatment modality offers a viable alternative for patients who are refractory to conventional therapies, demonstrating notable efficacy in advanced stages of the disease.⁷ As a new treatment option, it has recently been applied in patients with mCRPC. Given its efficacy and favourable safety profile, even in heavily pretreated patients, ¹⁷⁷Lu-PSMA RLT offers promise for the management of mCRPC and may be implemented into earlier stages of the disease in future investigations.⁴

Recent studies have suggested that ¹⁷⁷Lu-PSMA RLT is associated with prolonged overall survival (OS) in patients with advanced stages; however, a significant proportion of patients remain susceptible to treatment failure.⁸ As not all patients respond equally to ¹⁷⁷Lu-PSMA RLT, it is imperative to identify predictive factors that may help to classify patients respond to treatment.⁹ There is limited evidence to help clinicians identify patients best suited for lutetium therapy. Furthermore, biodistribution, PSMA binding affinities, and deoxyribonucleic acid (DNA)-damaging capacities of these radioactive tracers have not been compre- hensively compared.¹⁰

A primary concern with PSMA-targeted radioactive tracers is their potential adverse effects on other organs that also express PSMA, particularly the salivary glands.¹⁰ Although ¹⁷⁷Lu-PSMA RLT is tolerable and effective, some patients experience rapid progression, severe adverse events, and a significant reduced survival. Consequently, effective prognostic markers and predictors of adverse events are required.^5,11

Previous studies have examined the predictive and prognostic significance of various molecular and clinical factors and found that the presence of liver metastases, elevated levels of lactate dehydrogenase (LDH), transaminases, C-reactive protein (CRP), and alkaline phosphatase (ALP), as well as an elevated neutrophil-to-lymphocyte ratio (NLR) and reduced haemoglobin concentration, have been linked to unfavourable prognoses of the disease.¹¹ The heterogeneous nature of responses to ¹⁷⁷Lu-PSMA RLT will facilitate the identification of several prognostic factors. Currently, there is no agreement on the most suitable indicators for clinical applications. This study aimed to identify prognostic indicators that could aid oncologists in clinical practice by examining factors in patients with mCRPC who underwent ¹⁷⁷Lu-PSMA RLT.

The objectives were to ascertain which patients demonstrate superior outcomes with lutetium treatment to optimise its utilisation, to elucidate prognostic factors associated with treatment response, and to evaluate the treatment outcomes, patient characteristics, and adverse effects.

METHODOLOGY

The study adhered to the principles of the Declaration of Helsinki, and ethical approval was obtained from the Ethics Committee of Balikesir Ataturk City Hospital, Balikesir, Turkiye (Approval No. 2023/9/57; dated: 21.09.2023). The study included outpatients treated at the Department of Medical Oncology and Nuclear Medicine, Balikesir Ataturk State Hospital, Balikesir, Turkiye, from 2021 to 2024. Eligible patients had confirmed progressive mCRPC, demonstrated PSMA expression in their lesions, and underwent at least one cycle of ¹⁷⁷Lu-PSMA RLT. ¹⁷⁷Lu-PSMA RLT was administered by an interdisciplinary tumour council at the centre. Individuals with a concurrent or previous history of malignancy, active infectious diseases, use of immunosuppressants unrelated to anticancer therapy, hepatic or renal failure, and those receiving parenteral nutritional support were excluded. A power analysis was not performed for the study. Patients who met the study criteria were included.

According to the EAU guidelines mCRPC was defined as biochemical progression, considered as three consecutive rises in the prostate-specific antigen (PSA) values during metastatic hormone-sensitive prostate cancer (mHSPC) treatment, with a PSA level above 2 ng/ml and a 50% rise above the nadir. Radiographic progression in mCRPC was considered as the appearance of two new osseous or one soft-tissue metastasis, according to the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.

¹⁷⁷Lu-PSMA RLT procedures were conducted in accordance with the VISION trial protocol. Additionally, qualified radiochemists rigorously supervised the quality control measures. Under the supervision of a nuclear medicine specialist, patients received ¹⁷⁷Lu-PSMA via intravenous administration, with infusion durations ranging from one to 30 minutes. Treatment cycles were administered at 8-week intervals, during which patients received 150-200 millicuries (mCi) of ¹⁷⁷Lu-PSMA-617 per cycle. To evaluate the effectiveness and management of ¹⁷⁷Lu-PSMA-617, additional single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and full-body scintigraphy were conducted between 24–48 hours after administration.

Patient data, including demographic information, clinical characteristics, and blood test results from 1-7 days before initial treatment, were collected using the electronic medical record system. The pretreatment laboratory measurements encompassed NLR, platelet-to-lymphocyte ratio (PLR), and albumin-to- alkaline phosphatase ratio (AAPR). The Prognostic Nutritional Index (PNI) was calculated using the following equation: [serum albumin (g/dL) multiplied by 10] plus [lymphocyte count (/mm³) multiplied by 0.005]. To compute the haemoglobin, albumin, lymphocyte, and platelet (HALP) score, haemoglobin (g/L), albumin (g/L), and lymphocyte count (/L) were multiplied together, and the resultant product was subsequently divided by platelet count (/L). The systemic immune-inflammation index (SII) was calculated using the formula: SII = P × N/L (10⁹ cells/L), where P represents the preoperative peripheral blood platelet count per litre, N denotes the neutrophil count per litre, and L indicates the lymphocyte count per litre.

Data on treatment-related adverse events were collected from patient records and the hospital's digital database. Adverse reactions to treatment were documented using the common terminology criteria for adverse events (CTCAE) v4.03. Severe complications were classified as CTCAE grade 3-5, resulting in treatment cessation, hospital admission, or fatality. PSA levels were measured before each treatment cycle. The prostate cancer working group 3 (PCWG-3) criteria were used to assess bio- chemical PSA responses. Response (PR) was defined as a PSA reduction of ≥50%, while disease progression (PD) was defined as a PSA increase of ≥25%. Cases that did not meet either the PR or PD criteria were classified as stable disease (SD).¹² Radiological assessments using Gallium-68-PSMA positron emission tomography (PET)/computed tomography (CT) were conducted every two to four cycles. Regression was defined as a 30% decrease in the maximum standardised uptake value (SUVmax), while progression was indicated by either a ≥30% increase in SUVmax or the detection of a new lesion. Stable disease was determined when neither regression nor progression criteria were met. Blood tests and PSA level evaluations were performed before each treatment session.

SPSS software version 22 (IBM Corp, Armonk, NY, USA) was used for statistical analyses. Categorical variables are presented as frequencies and percentages. The Kolmogorov–Smirnov test was used to assess data normality. Due to the non-normal distribution of ¹⁷⁷Lu-PSMA cycles and administered cumulative doses, their association with adverse events was examined using the Spearman’s correlation analysis. The optimal cut-off values for the analyses were initially determined using ROC-AUC analysis. When this method proved ineffective in establishing cut-off values, the median cut-off value for laboratory parameters was employed, which was consistent with the previous research.¹³ These cut-off values were subsequently used to categorise the parameters into low and high classifications. The Kaplan-Meier method was employed for survival analysis, with differences between groups assessed using the log-rank test. To elucidate factors influencing survival, both univariate and multivariate analyses were conducted utilising the Cox regression model. Variables demonstrating statistical significance in univariate analysis were subsequently evaluated in the multivariate model, to identify independent prognostic factors for OS.

Results were presented as hazard ratios (HR) with 95% confidence intervals (CI), and statistical significance was established at p <0.05. OS was calculated from the initiation of ¹⁷⁷Lu-PSMA RLT to death from any cause. Progression-free survival (PFS) was defined as the time from treatment initiation to either disease progression or death, based on radiologic progression criteria delineated in PCWG-3.

RESULTS

This study included 31 patients who met the inclusion criteria. Participants were monitored for a mean duration of 13.8 (5.6–26.2) months. Treatment consisted of ¹⁷⁷Lu-PSMA RLT, administered in a median of three (1–6) cycles, with a median total dose of 200 (162–230) mCi. The median age of the patients was 69 (57–80) years. At diagnosis, twenty-five patients (80.6%) presented with metastatic disease, three (9.7%) had undergone prostatectomy, and eight (25.8%) had received definitive radiotherapy for the primary tumour. During ¹⁷⁷Lu-PSMA RLT, disease progression occurred in 15 patients (48.4%), and 12 (38.7%) died of cancer-related causes. The median PFS (progression-free survival) was 11.0 months (95% CI: 7.7-14.3), and the median OS was 20.8 months (95% CI: 16.7-24.8). Table I presents general characteristics of patients and laboratory data. Regarding treatment outcomes, two patients (6.5%) achieved a complete response, eleven (35.5%) exhibited a partial response, eight (25.8%) maintained stable disease, and ten (32.3%) showed disease progression.
 

Table I:   Patient   characteristics   and   blood   parameters.

Patients’ characteristics	n	%
Age (years)
<65	11	35.5
≥65	20	64.5
ECOG-PS
<2	17	54.8
≥2	14	45.2
Risk Categories-Gleason Grading
Low/very low	3	9.7
Intermediate	9	29.0
High/very high	19	61.3
De novo metastasis status
Metastatic	25	80.6
Non-metastatic	6	19.4
Visceral metastasis
Yes	3	9.7
No	28	90.3
Bone metastasis
Yes	28	90.3
No	3	9.7
Previous treatments
Radical prostatectomy
Yes	3	9.7
No	28	90.3
Prostate radiotherapy
Yes	8	25.8
No	23	74.2
Chemotherapy
Yes	17	54.8
No	14	45.2
Hormonotherapy
Enzalutamide	18	58.1
Abiraterone	13	41.9
Bone radiotherapy
Yes	21	67.7
No	10	32.3
Treatment strategy
¹⁷⁷Lu-PSMA RLT only	4	12.9
¹⁷⁷Lu-PSMA RLT + Abiraterone/       Enzalutamide	27	87.1
177Lu-PSMA RLT Treatment Lines
1	3	9.7
2	12	38.7
>2	16	51.6
Bone treatment
Bisphosphonate	5	16.1
Denosumab	20	64.5
Laboratory parameters	Low* (n/%)	High* (n/%)
Albumin (g/dL)	13 (41.9)	18 (58.1)
Haemoglobin (g/dL)	15 (48.4)	16 (51.6)
LDH (u/L)	15 (48.4)	16 (51.6)
Total PSA (ng/mL)	15 (48.4)	16 (51.6)
PLR	15 (48.4)	16 (51.6)
NLR	15 (48.4)	16 (51.6)
AAPR	15 (48.4)	16 (51.6)
PNI	14 (45.2)	17 (54.8)
SII	15 (48.4)	16 (51.6)
HALP	15 (48.4)	16 (51.6)
*Low and high values were calculated according to the optimal cut-offs. ECOG-PS: Eastern Cooperative Oncology Group Performance score; LDH: Lactate dehydro-genase; PSA: Prostate-specific antigen; PLR: Platelet-to-lymphocyte ratio; NLR: Neutrophil-to-lymphocyte ratio; AAPR: Albumin-to-alkaline phosphatase ratio; PNI: Prognostic nutritional index; SII: Systemic immune-inflammatory index; HALP score: Haemoglobin, albumin, lymphocyte, and platelet score.

Table II: Univariate Cox regression analysis for PFS and OS for ¹⁷⁷Lu-PSMA RLT.

Variables	Categories	PFS		OS
		HR (95% CI)	p-values	HR (95% CI)	p-values
Age (years)	<65 vs. ≥65	1.42 (0.46-4.33)	0.541	1.12 (0.35-3.58)	0.851
ECOG PS	<2 vs. ≥2	0.55 (0.19-1.57)	0.265	3.28 (0.84-12.14)	0.075
Risk categories	A/B*	0.69 (0.25-1.95)	0.487	0.70 (0.22-2.19)	0.539
Metastasis status	Yes vs. No	1.20 (0.77-1.89)	0.422	0.88 (0.59-1.32)	0.546
Visceral metastasis	Yes vs. No	4.06 (0.79-21.0)	0.094	24.98(1.56-399.59)	0.023
Bone metastasis	Yes vs. No	0.80 (0.59-1.08)	0.137	1.05 (0.67-1.64)	0.839
Previous Treatments
Prostatectomy	Yes vs. No	1.53 (0.33-7.07)	0.584	1.48 (0.31-6.93)	0.622
Prostate radiotherapy	Yes vs. No	2.14 (0.72-6.36)	0.173	1.31 (0.39-4.38)	0.660
Chemotherapy	Yes vs. No	1.30 (0.44-3.83)	0.634	1.38 (0.43-4.40)	0.584
Hormonotherapy	Enzalutamid vs. abirateron	0.90 (0.30-2.65)	0.844	0.39 (0.12-1.27)	0.119
Bone radiotherapy	Yes vs. No	1.29 (0.41-4.09)	0.665	0.77 (0.23-2.58)	0.669
Treatment strategy	With HRT vs. without HRT	0.39 (0.08-1.80)	0.224	0.94 (0.12-7.67)	0.953
Treatment lines	≤2 vs. >2	0.99 (0.35-2.80)	0.983	0.85 (0.30-2.44)	0.763
Bone treatment	Denosumab vs. bisphosphonate	1.26 (0.35-4.52)	0.719	0.28 (0.04-2.15)	0.219
Laboratory parameters
Albumin (g/dL)	<4.2 vs. ≥4.2	0.44 (0.16-1.24)	0.120	1.21 (0.36-4.02)	0.758
Haemoglobin (g/dl)	<12.2 vs. ≥12.2	0.62 (0.22-1.71)	0.351	1.09 (0.35-3.46)	0.878
LDH (u/L)	<248 vs. ≥248	1.87 (0.66-5.32)	0.240	0.79 (0.25-2.51)	0.694
Total PSA (ng/Ml)	<20.7 vs. ≥20.7	1.01 (0.36-2.81)	0.982	1.62 (0.51-5.17)	0.413
PLR	<179.7 vs. ≥179.7	0.73 (0.26-2.02)	0.543	1.58 (0.47-5.27)	0.461
NLR	<3.46 vs. ≥3.46	0.63 (0.23-1.75)	0.373	0.76 (0.24-2.35)	0.628
AAPR	<0.56 vs. ≥0.56	0.87 (0.32-2.42)	0.796	1.39 (0.44-4.43)	0.574
PNI	<50.5 vs. ≥50.5	0.72 (0.26-1.98)	0.519	1.07 (0.34-3.39)	0.904
SII	<824.6 vs. ≥824.6	1.25 (0.45-3.47)	0.674	1.0 (0.32-3.11)	0.994
HALP	<30.65 vs. ≥30.65	0.91 (0.33-2.51)	0.848	0.41 (0.12-1.37)	0.149
Adverse effects**	Yes vs. No	3.52 (0.74-16.66)	0.113	3.84 (0.49-29.90)	0.198
Anaemia	Yes vs. No	3.34 (0.92-12.13)	0.067	6.51 (0.84-50.59)	0.073
Leucopenia	Yes vs. No	2.09 (0.74-5.92)	0.164	2.46 (0.78-7.78)	0.126
Lymphopenia	Yes vs. No	2.05 (0.72-5.82)	0.176	1.44 (0.46-4.49)	0.527
Fatigue	Yes vs. No	1.80 (0.60-5.42)	0.298	3.58 (1.11-11.48)	0.032
Xerostomia	Yes vs. No	1.11 (0.25-4.97)	0.894	3.30 (0.82-13.35)	0.094
Anorexia	Yes vs. No	1.03 (0.28-3.70)	0.970	3.40 (1.01-11.42)	0.048
Nephropathy	Yes vs. No	1.65 (0.58-4.70)	0.345	8.35 (2.35-29.74)	0.001
Univariate and multivariate Cox regression model was used to determine the p-values. A: Elevated/substantially elevated; B: Additional categories. ****Prevalent adverse reactions were included in the evaluation. ECOG-PS: Eastern Cooperative Oncology Group Performance score; HRT: Hormone therapy (enzalutamide or abiraterone), LDH: Lactate dehydrogenase; PSA: Prostate-specific antigen; PLR: Platelet-to-lymphocyte ratio; NLR: Neutrophil-to-lymphocyte ratio; AAPR: Albumin-to-alkaline phosphatase ratio; PNI: Prognostic nutritional index; SII: Systemic immune-inflammatory index; HALP score: Haemoglobin, albumin, lymphocyte, and platelet score; PFS: Progression-free survival; OS: Overall survival.

Twenty-three (74.2%) patients undergoing ¹⁷⁷Lu-PSMA RLT experienced at least one adverse event, while seven (22.6%) experienced serious adverse events. The proportions of patients experiencing any CTCAE grade adverse events and serious adverse events were as follows: 64.5%/13% for anaemia; 6.4%/3.2% for thrombocytopenia; 22.6%/0.0% for leucopenia; 35.5%/6.4% for lymphopenia; 6.5%/0.0% for emesis; 32.3%/3.2% for fatigue; 16.1%/0.0% for dry mouth; 22.6%/0.0% for anorexia; 25.9%/0.0% for nephropathy; and 9.7%/0.0% for hepatotoxicity. No significant correlation was observed between either the cumulative administer dose of lutetium dosage or the number of treatment cycle  and the incidence of adverse events (r = -0.005, p = 0.980; r = -0.034, p = 0.856).

The median values were used in the PFS and OS analyses. Cut-off values were 20.7 for total PSA (ng/mL), 12.2 for haemoglobin (g/dL), 4.2 for albumin (g/dL), 248 for LDH (u/L), 3.46 for NLR, 179.66 for PLR, 824.57 x 10⁹ cells/L for SII, 50.5 for PNI, 30.65 for HALP, and 0.56 for AAPR.

The univariate Cox regression analysis revealed no prognostic factor for PFS. In the OS model, the presence of visceral metastasis (p = 0.023), fatigue (p = 0.032), anorexia (p = 0.048), and nephropathy (p = 0.001) were significantly associated with poor OS (Table II). For accurate evaluation of prognostic factors for OS, factors found to be significant in the univariate analysis were evaluated in a multivariate model. In this model, visceral metastasis (HR = 24.10; 95% CI: 1.26-461.47, p = 0.035), fatigue (HR = 6.17; 95% CI: 1.65-23.02, p = 0.007), and nephropathy (HR = 10.14; 95% CI: 2.52-40.87; p = 0.001) remained prognostic.

Survival curves were constructed using the Kaplan-Meier analysis of prognostic factors for OS. Patients with visceral metastases exhibited an OS of 20.79 months (95% CI: 16.77-24.81; p = 0.001), those experiencing anorexia as an adverse event demonstrated an OS of 15.57 months (95% CI: 7.17-23.97; p = 0.036), those with fatigue as an adverse event presented an OS of 13.32 months (95% CI: 5.39-21.25; p = 0.023), and those who developed nephropathy displayed an OS of 14.96 months (95% CI: 6.22-15.13; p <0.001), as shown in Figure 1. In contrast, the corresponding groups without these factors had not yet reached the median OS.

Figure 1: Kaplan-Meier survival curves for overall survival according to visceral metastasis (A), anorexia (B), fatigue (C), and nephropathy (D).

DISCUSSION

This study examined prognostic indicators and patient characteristics influencing treatment response duration and OS among individuals with mCRPC undergoing ¹⁷⁷Lu-PSMA RLT. In the presented study, visceral metastasis status and adverse events, such as nephropathy, fatigue, and anorexia, were found to be prognostic factors. In the multivariate model, visceral metastasis, fatigue, and nephropathy were found to be strong prognostic factors for survival.

According to a meta-analysis by Satapathy et al., patients with mCRPC who exhibited visceral metastases demonstrated inferior response and survival outcomes when subjected to ¹⁷⁷Lu-PSMA RLT.¹⁴ Similarly, Rahbar et al. demonstrated that visceral metastases were correlated with reduced biochemical response rates in patients receiving ¹⁷⁷Lu-PSMA RLT. The authors emphasised the importance of closely monitoring visceral metastases in making treatment decisions, particularly in cases of disease progression.¹⁵ Furthermore, Heck et al. observed that patients with organ metastases exhibited poorer outcomes than those with ¹⁷⁷Lu-PSMA RLT.¹⁶ The findings of the present study are consistent with previously published results. The conclusion drawn was that the presence of visceral metastases may serve as an indicator of poor prognosis when selecting patients for ¹⁷⁷Lu-PSMA RLT. The presence of visceral metastasis at progression may guide clinicians toward other treatments options during decision-making and treatment selection.

In the VISION study, 92.6% of patients had an ECOG-PS of 0–1, while only 54.8% of patients showed an ECOG-PS of 0–1 in the present study.¹⁷ Despite this, adverse events were reported in 98.1% of patients in the VISION study, with serious adverse events occurring in 52.7%. In contrast, in the present study, 74.2% of patients experienced at least one adverse event, while 22.6% experienced serious adverse events.¹⁷ The lower incidence of adverse events, despite the inclusion of patients with worse PS, may reflect incomplete records owing to the retrospective study design.

There is limited literature regarding long-term nephrotoxicity associated with ¹⁷⁷Lu-PSMA RLT. Steinhelfer et al. reported that a substantial proportion of patients may experience significant or moderate decreases in renal function, as measured by glomerular filtration rate, one year after the initiation of ¹⁷⁷Lu-PSMA RLT treatment.¹⁸ They reported that approximately 25% of patients experienced severe estimated glomerular filtration rate reductions within 12 months of treatment initiation.¹⁸ Schafer et al. documented three cases of radiation-induced nephropathy that resulted in severe chronic renal dysfunction.¹⁹ This condition was attributed to thrombotic microangiopathy in the kidneys, following substantial renal accumulation of radioactive agents in patients undergoing ¹⁷⁷Lu-PSMA RLT treatment.¹⁹ Nephrotoxicity may have developed through a mechanism similar to that used in the present study. Steinhelfer et al. stated that the nephrotoxicity observed in their cohort could be partly attributed to the higher number of cycles per patient (and consequently dose administered) compared to other reports, with a median of six cycles of ¹⁷⁷Lu-PSMA RLT.¹⁸ In the present study, although patients received a median of three cycles, nephrotoxicity was observed at a similar rate (25.9%), suggesting that this side effect should be considered. This potential adverse effect should be considered when initiating or continuing treatment, as responses may be worse in patients who develop nephrotoxicity. Further prospective studies are required to better estimate the nephrotoxic risk associated with ¹⁷⁷Lu-PSMA RLT.

In the VISION study, decreased appetite was observed in 21.2% of patients of all grades and in 1.9% of patients with grade 3 or above.¹⁷ In the present study, anorexia was observed in 22.6% of patients, and grade 3 and above anorexia was not observed. Results similar to those reported in the literature were obtained in terms of frequency. In the VISION study, fatigue was observed in 43.1% of patients, and grade 3 or higher fatigue was observed in 5.9% of patients.¹⁷ In the present study, fatigue was observed in 32.3% of patients, and 3.2% experienced grade 3 or higher fatigue. These adverse effects may reduce adherence to treatment and negatively impact prognosis. The identification of nephropathy, anorexia, and fatigue as prognostic factors in the present study indicates that adverse effects should be closely monitored during the treatment process and considered when determining treatment continuation, as they may have prognostic significance. To the best of the authors’ knowledge, no studies have investigated the prognostic role of nephrotoxicity, fatigue, and anorexia in PCa, and the present study may provide a foundation for future prospective studies evaluating the effect of adverse events on prognosis.

The prognostic role of NLR, PLR, SII, PNI, HALP, and AAPR—markers known to have prognostic value in various cancers and to reflect tumour-associated inflammation—could not be demonstrated in the patient cohort of the present study. A study by Aydin et al. evaluated NLR, SII, and PLR in patients with PCa and observed no impact of these inflammatory parameters on OS.²⁰ PCa is known to exhibit heterogeneity, a cold tumour microenvironment, and limited neoantigen load.²¹ Compared to many other cancers, the limited response of PCa to treatment with immune checkpoint blockade has been attributed to its cold tumour microenvironment,²¹ which is characterised by a low density of immune cells infiltrating within the tumour.²² The lack of prognostic value for inflammatory parameters in the present study may be related to the cold tumour microenvironment. The fact that the laboratory results of patients who continued abiraterone and steroid treatment during lutetium treatment were affected by steroid use may have influenced the results of the present study. Studies have also reported that inflammatory markers have a prognostic role in PCa, which is inconsistent with the findings of the present study.^23,24 Prospective studies with larger patient populations are necessary to elucidate the prognostic value of these indices.

In a study by Celen et al., favourable outcomes regarding OS and PFS were observed with second-line ¹⁷⁷Lu-PSMA RLT, particularly in cases where chemotherapy and new-generation androgen deprivation therapies (ADTs) were not viable options for castration-resistant disease.²⁵ Consistent with the results of the present study, no significant difference was observed in OS and PFS between patients who received first- and second-line treatments and those who received treatment after second- line treatment.

The limitations of this study include the absence of evaluations for homologous recombination deficiency mutations, specifically breast cancer genes BRCA1 and BRCA2, and molecular investigations such as AR gene amplification detection, as well as its retrospective design and limited sample size. The inclusion of adverse events in the prognostic analysis and the examination of multiple laboratory indices within the same patient cohort are notable strengths of this research.

CONCLUSION

Adverse events occurring during ¹⁷⁷Lu-PSMA RLT treatment have independent prognostic significance for survival. These findings suggest that the early recognition of adverse events and timely treatment strategy modifications may improve patient outcomes. Further studies are required to generalise the results.

ETHICAL APPROVAL:
Ethical approval was obtained from the Ethics Committee of Balikesir Ataturk City Hospital, Balikesir, Turkiye (Approval No. 2023/9/57; dated: 21.09.2023). The research was conducted in accordance with the principles of the Declaration of Helsinki.

PATIENTS’ CONSENT:
Written informed consent was obtained from the study patients for the publication of this paper.

COMPETING INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
SS: Conceptualisation, data curation, formal analysis, funding, acquisition, investigation, methodology, project administration, resources supervision, validation, visualisation, writing of the original draft, review, and editing.
HB: Conceptualisation, data curation, methodology.
EC: Formal analysis, methodology, software supervision, validation, visualisation, writing of the original draft, review, and editing.
YI: Conceptualisation, data curation, and supervision.
HK: Data curation.
All authors approved the final version of the manuscript to be published.

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