Abstract
Background/Aim: Radium-223 (Ra-223) therapy provides a survival benefit for castration-resistant prostate cancer (CRPC) patients with bone metastasis. The optimal timing of using Ra-223 has not been determined. We evaluated the efficacy and safety of Ra-223 before and after docetaxel (DOC) therapy. Patients and Methods: We retrospectively reviewed 36 CRPC patients with bone metastasis who were treated with Ra-223 in our institution and satellite hospitals. Ra-223 was used before DOC (pre-DOC group) in 17 patients (47%) and after DOC (post-DOC group) in 19 patients (53%). The treatment completion rate of 6 cycles, progression-free survival (PFS), cause-specific survival (CSS) and occurrence rate of adverse events were compared between the groups. Results: The median follow-up duration was 45 months. In the pre-DOC compared with the post-DOC group, treatment completion rate was significantly higher (94% vs. 52%, p<0.01), PFS was significantly longer (median: 8 vs. 5 months, p=0.024) and CSS was significantly longer (median: 32 vs. 15 months, p=0.028). The difference in CSS was significant in multivariate analysis. In the pre-DOC compared with the post-DOC group, the occurrence rate of grade ≥3 adverse events tended to be lower (6% vs. 36%, p=0.322), and the CSS tended to be longer (median: not reached vs. 45 months, p=0.208). Conclusion: Ra-223 could be used more safely and more effectively for CRPC patients with bone metastasis before than after DOC therapy.
The treatment of castration-resistant prostate cancer (CRPC) has improved in the past few decades. Radium-223 (Ra-223) is an alpha-emitting radionuclide that selectively targets bone metastases. In the ALSYMPCA trial (1), Ra-223 treatment led to an improvement in the survival and quality of life of CRPC patients with bone metastasis (1-3). On the basis of these findings, Ra-223 was established as a standard treatment modality for CRPC patients with predominant bone metastasis and no visceral metastasis (4).
Various clinical factors associated with poor prognosis after Ra-223 have been reported, including poor performance status, high prostate-specific antigen (PSA) levels, short PSA doubling time (PSA-DT), high lactate dehydrogenase, high alkaline phosphatase (ALP), low number of treatment cycles, and progressive new bone lesions (5-10). These results indicated that earlier use of Ra-223 before severe progression of metastasis might be associated with better efficacy. For CRPC patients with resistance to androgen receptor axis targeted drugs (ARATs), chemotherapy using docetaxel (DOC) is standard (11). Ra-223 is another treatment for patients with bone metastasis but it has not been determined whether Ra-223 should be used before or after DOC treatment. Therefore, Ra-223 has been used at various times depending on institutions and physicians. To explore the optimal timing for the use of Ra-223, we performed a multi-institutional retrospective investigation of patients with CRPC treated with Ra-223.
Patients and Methods
Study design and patients. We retrospectively reviewed 36 CRPC patients with bone metastasis who were treated with Ra-223 between November 2016 and December 2020 at the University of Miyazaki and satellite hospitals. We compared the patients who received Ra-223 before DOC (pre-DOC group) and after DOC (post-DOC group) therapy.
In the total cohort, 33 patients were pathologically diagnosed and 3 were clinically diagnosed with prostate cancer. Patients were administered Ra-223 at 55 kBq/kg intravenously every 4 weeks for up to six cycles. Surgical castration was performed, or luteinizing hormone-releasing hormone agonist or antagonist was administered to all patients. Castration-resistant disease was defined as progression of serum PSA levels, radiographic findings, and clinical symptoms after initial hormonal therapy. Progression of PSA levels was defined as increase in PSA levels >25% relative to the nadir after initial hormonal therapy. Bone metastasis was detected by bone scintigraphy or computed tomography, and no visceral or extra-pelvic lymph node metastases were found before Ra-223 administration. Laboratory data were collected from medical records, including PSA, ALP, lactate dehydrogenase, hemoglobin, extent of disease grade (12), PSA-DT, presence of symptoms, and treatment with ARATs and bone-modifying agents (BMAs). PSA-DT was calculated by log(2) divided by the slope of the linear regression of log (PSA) over time in months (13, 14). ARATs were abiraterone acetate and enzalutamide and BMAs were zoledronic acid and denosumab.
Cause-specific survival (CSS) was calculated from the first administration of Ra-223 to the last follow-up time point or the date of cancer-related death. We also analyzed CSS as the time from diagnosis of CRPC to the last follow-up time point or the date of cancer-death. Progression-free survival (PFS) was calculated from the first administration of Ra-223 to the time of cancer progression. Progression was defined as exacerbation of radiographic findings or clinical symptoms, but not increased PSA level alone. Adverse Events (AEs) were graded according to the Common Terminology Criteria for Adverse Events, version 4.0.
Statistical analysis. Statistical analysis was performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Differences in patient characteristics, clinical effects and AEs between the Pre-DOC and Post-DOC groups were compared using Mann–Whitney U-test and Fisher’s exact test. PFS and CSS were calculated using the Kaplan–Meier method. Log-rank tests were used to analyze differences in CSS and PFS between the two groups. Univariate Cox proportional hazard analyses were performed for predicting short PFS and CSS. The multivariate analyses were performed using the parameters significantly associated in the univariate analyses. All tests were considered statistically significant when the p-value was <0.05.
Results
Patient characteristics of pre-DOC and post-DOC groups. The median follow-up time was 46 months for the overall cohort. There were 17 patients in the pre-DOC group and 19 in the post-DOC group. There were no significant differences in patient characteristics including age, and levels of PSA, ALP, and hemoglobin. Extent of disease grade >2, presence of symptoms, and treatment with ARATs and BMAs were not significantly different between the groups (Table I).
Comparison of baseline characteristics and disease history in pre- docetaxel (pre-DOC) and post-DOC populations.
Efficacy and AEs under Ra-223 therapy. Nineteen patients (53%) had a decrease in PSA and 32 patients (89%) had a decrease in ALP. Symptomatic and radiological improvements were found in 11 (31%) and 8 (22%) patients, respectively. Decreases in PSA and ALP were found in 19 (53%) and 32 (89%) patients, respectively. Completion of 6 cycles of Ra-223 was achieved in 26 (72%) patients. The six cycle-completion rate was significantly higher in the pre-DOC than in the post-DOC group (94% vs. 53%, p<0.01) (Table II).
Comparison of baseline characteristics and clinical effects of Radium-223 in pre-docetaxel (pre-DOC) and post-DOC populations.
One or more AEs of any grade occurred in 14 (39%) patients. There were eight grade 1/2 and 6 grade ≥3 AEs. The number of each type of AE was evaluated in the two groups (Table III). The rate of grade ≥3 AEs tended to be lower in the pre-DOC than in the post-DOC group, although the difference was not significant (6% vs. 26%, p=0.322).
Comparison of adverse events of Radium-223 in the overall cohort, pre-docetaxel (pre-DOC) and post-DOC groups.
Parameters associated with the efficacy of Ra-223. Median PFS was six months, and median CSS was 28 months in the overall cohort. PFS was significantly longer in the pre-DOC than in the post-DOC group (median: 5 vs. 8 months, p=0.028) (Figure 1A). CSS was significantly longer in the pre-DOC than in the post-DOC group (median: 15 vs. 32 months, p=0.024) (Figure 1B). The factors associated with PFS were examined by Cox proportional hazard analyses. In univariate analyses, PSA-DT <3 months and post-DOC Ra-223 were associated with shorter PFS. However, they were not significant in multivariate analyses (Table IV). The factors associated with CSS were also examined. ALP >322 U/l, PSA-DT <3 months and post-DOC Ra-223 were significantly associated with shorter CSS. They were also significant in multivariate analyses (Table V).
Kaplan–Meier curves of (A) progression-free survival (PFS) and (B) cause-specific survival (CSS) from initiation of Radium-223 in the overall cohort.
Univariate and multivariate analyses of significant predictors of progression-free survival (PFS) from initiation of Radium223.
Univariate and multivariate analyses of significant predictors of cause-specific survival (CSS) from initiation of Radium223.
Ra-223 therapy before DOC meant that it was started earlier in disease progression. CSS from the initiation of Ra-223 seemed to be longer when Ra-223 was started earlier. To resolve bias, CSS from the time of diagnosis of CRPC was examined. CSS tended to be longer in the pre-DOC than in the post-DOC group, although the difference was not significant (median: 45 months vs. not reached, p=0.208) (Figure 2).
Comparison of cause-specific survival (CSS) from castration-resistant prostate cancer diagnosis (CSS from CRPC) between pre-docetaxel (pre-DOC) and post-DOC populations.
Discussion
Currently, there are many choices of treatment in the clinical guidelines for metastatic CRPC (mCRPC) that include Ra-223 (11, 14). The ALSYMPCA trial demonstrated that Ra-223 significantly improved prognosis, the time to skeletal events, and quality of life in patients with bone mCRPC (1, 15). Additionally, Ra-223 has been proven safe to use in Asian and Japanese populations (4, 16).
However, there are no reliable predictors for Ra-223 treatment efficacy in mCRPC patients. Various predictive factors and optimal timing have been reported (5-10, 17) but they remain inconclusive. Hashimoto et al. evaluated 127 mCRPC patients and reported the correlation between dynamic changes in bone metastases and Ra-223 response (10). In this study, the types of the new progressive lesions in bone metastases and short PSA-DT just before Ra-223 therapy were poor prognostic factors (HR=1.45, p=0.003 and HR=1.53, p=0.007, respectively). Yamamoto et al. reported that PSA-DT, greater volume of bone metastases and Ra-223 in a later line of therapy were poor prognostic factors (HR= 4.35, p=0.003, HR= 2.86, p=0.02, and HR= 4.87, p=0.001, respectively) for mCRPC patients (18). Vidal et al. insisted that Ra-223 should be used in an early line of CRPC treatment (19). Shim et al. reported that taxane-based chemotherapy induced androgen receptor splice variant 7 in patients with CRPC (20). Based on these reports, we hypothesized that Ra-223 therapy prior to DOC would lead to better response against mCRPC. PFS and CSS in the pre-DOC group were significantly longer than in the post-DOC group. Moreover, the occurrence of AEs tended to be lower in the pre-DOC than in the post-DOC group. Our study is believed to be the first to compare the efficacy and safety of Ra-223 before and after DOC treatment. In the Cox proportional hazard analyses, short PSA-DT was associated with short PFS and CSS. These results indicate that Ra-223 is not effective and DOC or other cytotoxic therapies should be administered to patients with short PSA-DT.
In our study, 89% of patients used ARATs at the time of Ra-223 therapy. Of them, 47% received previous ARAT therapy before the start of Ra-223, and 42% started concomitant ARAT therapy at the same time as Ra-223. Previous or concomitant ARAT therapy was not associated with the PFS and CSS of patients treated with Ra-223 (data not shown). Previous retrospective studies have indicated that combination therapies of Ra-223 and ARATs or vintage drug might be effective for bone mCRPC patients (6, 21-25). However, a randomized controlled trial of combination therapy with Ra-223 and abiraterone acetate (ERA223) showed no improvement in survival and resulted in an increased frequency of bone fractures compared with abiraterone acetate alone (21). The ongoing randomized controlled trial of enzalutamide with or without Ra-223 (NCT0219482) is expected to confirm the benefit and safety of the combination therapy.
This study has some limitations. This was a retrospective study with a small number of patients and short follow-up period. The indication and timing of Ra-223 therapy were not determined and differed among physicians. It is possible that the differences in baseline variables between the groups influenced the results. Moreover, the entire data were confounded by lead time bias. To start Ra-223 before DOC therapy means that the tumor is smaller and the time to death is longer. To resolve the bias, the overall survival from the time of diagnosis of CRPC was evaluated. These results could not completely resolve the bias. However, we believe that they might help to build our arguments more valid to some extent. Further prospective studies are needed to determine the optimal timing of starting Ra-223 therapy in patients with bone mCRPC.
Conclusion
We performed a multi-institutional retrospective study to evaluate the efficacy and safety of Ra-223 in patients with CRPC with bone metastasis. The efficacy of Ra-223 was associated with short PSA-DT and previous DOC therapy. Our study suggested that using Ra-223 prior to DOC therapy might be safe and potentially have survival benefit for patients with CRPC with bone metastasis.
Footnotes
Authors’ Contributions
Ko Okabe: study outline, data collection or management, data analysis, literature research, article writing and editing, preparation of tables. Naoki Terada: study conception and outline, article editing. Tatsuya Shirakawa, Chie Onizuka, Tomoya Kimura, Yasuhiro Yamashita, Isamu Otuka, Takashi Ueno and Masafumi Nagano: data collection. Hiroki Takamori, Shoichiro Mukai and Toshiyuki Kamoto: revision of article. All Authors read and agreed to publication of the article.
Conflicts of Interest
The Authors report no conflicts of interest in relation to this study.
- Received July 29, 2022.
- Revision received August 23, 2022.
- Accepted August 25, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
