Health-related quality of life, psychological distress, and fatigue in metastatic castration-resistant prostate cancer patients treated with radium-223 therapy

The study addresses whether mCRPC patients treated with radium-223 experience distinct trajectories of HR-QoL, psychological distress, and fatigue in real-world practice, particularly comparing those who complete the planned six injections versus those who discontinue early. The context is that while radium-223 has shown survival and pain benefits in clinical trials, there is a noted discrepancy between HR-QoL observed in tightly controlled trials and real-world patients, and prior trials often used instruments not tailored to mCRPC. The purpose was to evaluate cancer-specific and bone metastases-related HR-QoL, psychological distress, and fatigue before, during, and after radium-223, and to identify baseline predictors of HR-QoL deterioration to guide follow-up care.

Prior phase 3 and earlier-phase studies (e.g., ALSYMPCA) demonstrated survival and pain relief benefits with radium-223 and a higher rate of meaningful HR-QoL improvement versus placebo, but often used HR-QoL tools not specific to mCRPC. Real-world studies have reported pain reduction during therapy, yet comprehensive evaluations of HR-QoL, psychological distress, and fatigue in routine practice have been lacking. Given differences between selected trial cohorts and real-world populations, and the advent of newer life-prolonging agents (abiraterone, enzalutamide, cabazitaxel) since ALSYMPCA, updated real-world assessments using disease-relevant instruments were needed.

Design: Multicenter, prospective, observational cohort study of mCRPC patients receiving radium-223 in daily practice. Assessments occurred before, during, and after therapy (three time points approximately 12 weeks apart). Primary endpoint: Cancer-specific and bone metastases-related HR-QoL via EORTC QLQ-C30 (functional domains: physical, role, emotional, cognitive, social; symptom scales; global health status) and EORTC BM-22 (physical sites, pain characteristics, functional interference, psychosocial aspects). Scores were linearly transformed to 0–100 per EORTC manuals; clinically relevant changes (CRC) defined as small 5–10, moderate 10–20, large ≥20 points. Secondary endpoints: Bone pain (BPI-SF worst and average pain items), psychological distress (HADS; anxiety and depression subscales; total score ≥11 indicates distress), and fatigue (CIS-Fatigue fatigue severity). Subgroup comparisons: Number of radium-223 injections (1–3 vs 4–5 vs 6). Trajectory analysis: EORTC QLQ-C30 summary score computed and categorized as ≤60 (low), 60–80 (intermediate), >80 (high). Trajectories classified as deteriorated, stable intermediate, stable high, improved, or fluctuating. Candidate baseline predictors of trajectory class: age, marital/partnership status, ECOG PS, opioid use, number of prior therapies, hemoglobin (Hb), alkaline phosphatase (ALP), and PSA. Prognostic validation: Overall survival (OS) compared across baseline summary score classes and trajectory classes. Statistics: Between-group comparisons with Chi-square or Fisher’s Exact tests (categorical) and Mann-Whitney or Kruskal-Wallis tests (nonparametric continuous). Paired t-tests for within-patient changes over time. OS by Kaplan–Meier with log-rank tests. Univariate multinomial logistic regression for trajectory class membership. ALP and PSA were log-transformed due to skewness. Two-sided P<0.05 considered significant. Analyses performed in SPSS 25.0. Registration: NCT04995614.

- Enrollment and compliance: 122/124 enrolled patients completed baseline HR-QoL and were analyzed; 327 EORTC QLQ-C30+BM-22 questionnaires completed. Ninety-one patients (75%) completed all HR-QoL questionnaires; 23 (19%) completed two; 8 (7%) completed only baseline. Decreases in compliance over time were mainly due to treatment discontinuation (14%), refusal (3%), non-response (3%), or death (6%). - Baseline characteristics: Median age 73 years; 85% ECOG 0–1; 80% prior abiraterone or enzalutamide; high disease burden common. - Baseline patient-reported outcomes (total cohort): EORTC QLQ-C30 means: global health status 62.5, physical functioning 71.5, role functioning 64.3; most burdensome symptoms were pain, fatigue, and insomnia. Psychological distress present in 47% (HADS total mean 11.0). Severe fatigue reported by ~52% (CIS-Fatigue mean 33.5). - Subgroup baseline differences: Patients receiving only 1–3 injections had clinically relevant lower global health status and physical functioning and higher pain and dyspnea at baseline versus those completing therapy. - Longitudinal outcomes: Patients completing six injections showed stabilization of cancer-specific HR-QoL with only small changes in global health status, physical and role functioning by end of treatment, and no increase in psychological distress; moderate CRCs were noted in fatigue, nausea/vomiting, and appetite loss. In contrast, patients who discontinued radium-223 experienced clinically meaningful deterioration across all EORTC QLQ-C30 functioning scales and increases in multiple symptoms; HADS and CIS-Fatigue showed clinically relevant and statistically significant increases in psychological distress and fatigue over time. - Trajectory analysis: Considerable heterogeneity in HR-QoL patterns; approximately 40% remained stable, while 44% deteriorated over time. Baseline opioid use, low hemoglobin, and high ALP were associated with HR-QoL deterioration. - Survival association: Higher baseline EORTC QLQ-C30 summary scores were associated with longer OS (median 14.2 months for high baseline scores; 95% CI not fully reported in excerpt).

The study demonstrates that real-world mCRPC patients who complete the planned course of radium-223 generally maintain stable HR-QoL, psychological distress, and fatigue, addressing the research question by showing divergent HR-QoL trajectories between completers and discontinuers. Patients who discontinue have worse baseline HR-QoL and show progressive deterioration across functioning domains and symptoms, along with rising psychological distress and fatigue. Identification of baseline opioid use, low hemoglobin, and high ALP as predictors of HR-QoL deterioration provides clinically relevant markers for risk stratification and follow-up planning. These findings support integrating systematic HR-QoL assessments into routine care to inform treatment selection and monitoring, acknowledging differences between trial settings and real-world populations.

In this multicenter prospective cohort, patients completing six injections of radium-223 exhibited stabilization of HR-QoL, psychological distress, and fatigue, whereas those discontinuing therapy had poorer baseline HR-QoL and showed clinically meaningful deterioration over time. Baseline opioid use, low hemoglobin, and high ALP identified patients at higher risk for HR-QoL decline, warranting targeted attention during follow-up. Incorporating HR-QoL evaluation into routine practice may aid clinical decision-making and assessment of treatment effects. Future research should validate these predictors and trajectory classes in larger cohorts and explore interventions to mitigate HR-QoL deterioration in high-risk patients.

- Observational design with treatment decisions made by local physicians without uniform criteria for evaluation or discontinuation, introducing potential selection and confounding biases. - HR-QoL assessed at three time points approximately 12 weeks apart, which may miss interim fluctuations; more frequent assessments could increase patient burden and reduce compliance. - Decreasing questionnaire compliance over time due to discontinuation, refusal, non-response, or death may bias longitudinal estimates. - Small sizes within some trajectory classes limit power and generalizability of trajectory analyses; validation in larger cohorts is needed.