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Patients With Grade 3 or 4 Thrombocytopenia. Quartile Distribution of Platelet Counts Over Time Based on Platelet Counts at Screening for Patients Receiving Radium-223 (A) or Placebo (B); Time to Onset of Grade 3/4 Thrombocytopenia (C) by Number of Injections of Radium-223 or Placebo Received Before Onset, and Duration of Thrombocytopenia (D) by Time (Weeks) Since First Dose of Radium-223 or Placebo
Source publication
Background:
Myelosuppression is common in patients with progressive castration-resistant prostate cancer and bone metastases. Radium-223 prolongs overall survival in these patients but may cause myelosuppression; understanding risk factors will improve clinical decision making. We describe hematologic safety of radium-223 in ALSYMPCA and post hoc...
Contexts in source publication
Context 1
... with baseline characteristics of the ALSYMPCA safety population (Table 1), the small group of 38 radium-223 and 6 placebo patients who developed grade 3/4 thrombocytopenia had a higher percentage with prior docetaxel (31/38 [82%] radium-223 and 5/6 [83%] placebo patients) (Supplemental Table 7 Platelet counts gradually decreased, reaching grade 3/4 at median 19 weeks (range 2.4-38 weeks) relative to first radium-223 injection ( Figure 3A); 28/38 patients (74%) received ! 4, and 13/38 (34%) received all 6 radium-223 injections. In 9/38 (24%) patients, platelet counts were ! ...
Context 2
... 1/38 (3%) patient recovered to ! 150 Â 10 9 /L with no apparent relationship to screening platelet count. A similar pattern was seen for 6 placebo patients ( Figure 3B) with no recovery during follow-up. ...
Context 3
... majority of radium-223 patients with grade 3/4 thrombocytopenia (35/38 [92%]) had late onset, after at least the third injection, which may suggest a cumulative effect and mechanism different from that seen with placebo ( Figure 3C). ...
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Docetaxel-based chemotherapy, as the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC), has succeeded in helping quite a number of patients to improve quality of life and prolong survival time. However, almost half of mCRPC patients are not sensitive to docetaxel chemotherapy initially. This study aimed to establish m...
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Objective:
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Introduction
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Citations
... Given the different mechanisms of action of radium-223 and taxanes, sequential use of these agents may avoid cross-resistance to offer incremental survival benefit. Both radium-223 and taxanes, however, are associated with adverse events related to bone marrow suppression, including grade 3/4 thrombocytopenia in 6% of patients treated with radium-223 3,4 and grade 3/4 neutropenia in 32% to 58% of patients treated with taxanes. 1,2 Therefore, cumulative toxicity is a possible concern when these agents are used in sequence. ...
Background
Radium‐223 and taxane chemotherapy each improve survival of patients with metastatic castration‐resistant prostate cancer (mCRPC). Whether the radium‐223–taxane sequence could extend survival without cumulative toxicity was explored.
Methods
The global, prospective, observational REASSURE study (NCT02141438) assessed real‐world safety and effectiveness of radium‐223 in patients with mCRPC. Using data from the prespecified second interim analysis (data cutoff, March 20, 2019), hematologic events and overall survival (OS) were evaluated in patients who were chemotherapy‐naive at radium‐223 initiation and subsequently received taxane chemotherapy starting ≤90 days (“immediate”) or >90 days (“delayed”) after the last radium‐223 dose.
Results
Following radium‐223 therapy, 182 patients received docetaxel (172 [95%]) and/or cabazitaxel (44 [24%]); 34 patients (19%) received both. Seventy‐three patients (40%) received immediate chemotherapy and 109 patients (60%) received delayed chemotherapy. Median time from last radium‐223 dose to first taxane cycle was 3.6 months (range, 0.3–28.4). Median duration of first taxane was 3.7 months (range, 0–22.0). Fourteen patients (10 in the immediate and four in the delayed subgroup) had grade 3/4 hematologic events during taxane chemotherapy, including neutropenia in two patients in the delayed subgroup and thrombocytopenia in one patient in each subgroup. Median OS was 24.3 months from radium‐223 initiation and 11.8 months from start of taxane therapy.
Conclusions
In real‐world clinical practice settings, a heterogeneous population of patients who received sequential radium‐223–taxane therapy had a low incidence of hematologic events, with a median survival of 1 year from taxane initiation. Thus, taxane chemotherapy is a feasible option for those who progress after radium‐223.
Clinical Trial Registration
ClinicalTrials.gov identifier NCT02141438.
Plain Language Summary
Radium‐223 and chemotherapy are treatment options for metastatic prostate cancer, which increase survival but may affect production of blood cells as a side effect.
We wanted to know what would happen if patients received chemotherapy after radium‐223.
Among the 182 men treated with radium‐223 who went on to receive chemotherapy, only two men had severe side effects affecting white blood cell production (neutropenia) during chemotherapy.
On average, the 182 men lived for 2 years after starting radium‐223 and 1 year after starting chemotherapy.
In conclusion, patients may benefit from chemotherapy after radium‐223 treatment without increasing the risk of side effects.
... Moreover, the RCT had a higher treatment completion rate (65%) and less frequent deaths (54%) than our study, despite having a longer follow-up duration (3 years). [8,19] In terms of adverse events, the occurrence of grade ≥ 3 myelosuppression was generally infrequent in the ALSYMPCA Ra-223 arm (21.5%), [18] as it was in our study (18.8%). Post-docetaxel Ra-223 patients in the RCT had a significantly increased risk for grade ≥ 2 neutropenia or thrombocytopenia and numerically higher rates of grade ≥ 3 thrombocytopenia or pancytopenia than docetaxel-naïve Ra-223 patients. ...
... Post-docetaxel Ra-223 patients in the RCT had a significantly increased risk for grade ≥ 2 neutropenia or thrombocytopenia and numerically higher rates of grade ≥ 3 thrombocytopenia or pancytopenia than docetaxel-naïve Ra-223 patients. [19] Our results illustrate an analogous numerical trend with regards to neutropenia or thrombocytopenia, but we would have possibly needed a larger sample size to reach the same statistical significance. Meanwhile, Table 2 Comparison of treatment outcomes between docetaxel-naïve and post-docetaxel patients receiving radium-223 (N = 48). ...
... the RCT also demonstrated no significant association between previous docetaxel use and risk for grade ≥ 2 anemia. [19] After high anemia rates were found in both treatment and placebo arms, the ALSYMPCA investigators surmised that the frequency and severity of anemia were influenced by disease burden rather than therapy. [19] Apart from ALSYMPCA, previous Western real-world studies on Ra-223 use in mCRPC also support our findings. ...
While radium (Ra)-223 is among the multiple, known life-prolonging treatments in bone-predominant metastatic castration-resistant prostate cancer (mCRPC), optimal treatment sequencing has not been determined, particularly in the Asia-Pacific context. Hence, we aimed to compare treatment outcomes of docetaxel-naïve and post-docetaxel mCRPC patients undergoing Ra-223 therapy in Taiwan. Using a single-center retrospective cohort design, we reviewed records of adult patients receiving Ra-223 for bone-metastatic mCRPC from 2018 to 2021. Patients were categorized into docetaxel-naïve or post-docetaxel groups based on history of docetaxel use preceding Ra-223. We compared the 2 groups in terms of all-cause death, 6-cycle treatment completion, and the following secondary outcomes: pain control, change in biochemical parameters (prostate-specific antigen, lactate dehydrogenase, alkaline phosphatase), biochemical response, and treatment-emergent adverse events. We performed total population sampling and a complete case analysis. We included 48 patients (25 docetaxel-naïve, 23 post-docetaxel) in the study. The mean follow-up duration was 12.4 months for the entire cohort. The docetaxel-naïve group exhibited a significantly lower all-cause mortality rate versus the post-docetaxel group (40.0% vs 78.3%, P = .02), as well as a significantly higher treatment completion rate (72.0% vs 26.1%, P < .01). We did not find significant differences in pain control, change in biochemical parameters, biochemical response, or hematologic treatment-emergent adverse events between the 2 groups. However, the docetaxel-naïve group had a numerically higher pain control rate, numerically greater improvements in alkaline phosphatase and prostate-specific antigen, and numerically lower rates of grade ≥ 3 neutropenia and grade ≥ 3 thrombocytopenia than the post-docetaxel group. Use of Ra-223 in docetaxel-naïve patients with mCRPC led to lower mortality and higher treatment completion than post-docetaxel use. Our study adds preliminary real-world evidence that Ra-223 may be used safely and effectively in earlier lines of treatment for bone-predominant mCRPC. Further large-scale, longer-term, and controlled studies are recommended.
... Most of our patients had grade-1 thrombocytopenia, contrary to other studies where almost 92% of patients developed grade-3 or -4 thrombocytopenia. 12,24 In particular, as anemia seems to play a crucial role in all these patients, acute monitoring may be required with acceptance for performing blood transfusions, occasional delaying, or discontinuation of the cycles. [25][26][27] Interrupted Radium-223 treatment due to hematotoxicity more often results in therapy resistance and reduced therapeutic efficacy. ...
Aim Radium-223 has been the first-approved targeted Alpha therapy agent. We retrospectively assessed different factors influencing the overall survival (OS) and patient management.
Setting and Design Thirty-two metastatic castration-resistant prostate cancer (mCRPC) patients' hematological parameters, number of cycles, performance status, and toxicities were evaluated for OS. Radium 223 dichloride (Radium-223) was administered every 4 weeks for a maximum of six cycles. Primary and secondary end points were OS, progression free survival (PFS), therapy toxicities, change in performance status, biochemical response, and skeletal-related events (SREs).
Materials and Methods Patients' median age was 77 years (range: 57–90 years) and median follow-up was 399 days (range: 5–1,761 days). A total of 163 cycles were administered in 32 patients, with 4 or less cycles in 8 patients (25%) and 5 or more cycles in 24 patients (75%). Among eight patients with 4 or less cycles, three patients died, of which two patients died due to neutropenic sepsis.
Statistical Analysis Mann–Whitney test was used to compare the cycle groups; Spearman's correlation coefficient was used to see the relation of different variables with OS. Log rank test was used for group comparison while Kaplan–Meier survivorship was used for OS.
Results Statistical correlation was seen between the number of cycles (p=0.037) and hemoglobin (p=0.028). Kaplan–Meier OS (p=0.038) was correlated with the number of cycles (≤ 4 cycles and ≥ 5 cycles). OS was 173 days in patients with one to four cycles, 226 days in five cycles, and 493 days in six cycles. Myelosuppression leading to stopping of full six cycles was seen in 7 of 32 patients (22%) and significantly correlated to inferior OS (p=0.048).
Conclusion Higher number of Radium-223 cycles was seen to be associated with better OS. Prior myelosuppression was associated with poor OS. Patients with better hematological profile were more likely to complete the maximum number of the cycles with a better OS.
... With Ra-223 therapy, radium is taken up by the osteogenic metastases of prostate cancer instead of calcium and emits alpha rays from within the bone metastasis, causing a double-strand break in the DNA. The in-vivo range of alpha particles is less than 100 µm, which in cellular size is expected to efficiently affect metastases while minimizing the effect on normal bone marrow [7,8]. The efficacy and safety of this drug in terms of overall survival (OS) and QOL were demonstrated in an international phase III study [9,10], which showed a significant prolongation of median OS (14.9 months vs. 11.3 months) and time to first SSEs (15.6 months vs. 9.8 months) compared with the placebo. ...
... These results are consistent with the subgroup analysis of the ALSYMPCA trial, in which a higher number of bone metastases was associated with a higher risk of anemia, and Ra-223 was effective even with more bone metastases [9]. It is important to note that anemia was not associated with Ra-223 use [8]. Although ALP and BSI at baseline appeared to be related biomarkers, the area under the ROC curve comparisons were 0.601 and 0.704, respectively, suggesting that BSI may be a better prognostic biomarker. ...
The optimal sequence and combination of radium-223 therapy (Ra-223) for castration-resistant prostate cancer with bone metastasis (mCRPC) remain unclear. This study aimed to explore the prognostic factors after Ra-223 administration and to determine the optimal treatment strategy. We enrolled 64 patients with mCRPC who underwent Ra-223 therapy from June 2016 to July 2022 at a single institution in Japan. Overall survival (OS) and pain progression-free survival (p-PFS), which was proposed as a measure of quality of life (QOL), were analyzed using Cox proportional hazards models and log-rank tests, and between-factor analysis was performed with the Mann–Whitney U (MWU) test. Univariable and multivariable analyses revealed prognostic factors; specifically, early treatment (≤third line), completion of six treatment cycles, low bone scan index (BSI) (<0.61), alkaline phosphatase (ALP) (<140 U/L), prostate-specific antigen (PSA; <22.9 ng/mL), lactate dehydrogenase (LDH; <240 U/L), high hemoglobin (Hb) (≥11.4 g/dL), and prior denosumab use significantly prolonged OS. Low BSI, low ALP, and early Ra-223 treatment also prolonged p-PFS in the log-rank tests. The MWU test showed that high BSI (≥0.61) was associated with high PSA and high ALP and a tendency for Hb to decrease. Late Ra-223 treatment (≥fourth line) was significantly associated with low Hb and high PSA. Early Ra-223 treatment was significantly associated with improved OS, and administering Ra-223 before novel hormonal or anticancer agents may be meaningful.
... The current clinical practice shows that the application of 223 Radium in later stages, when 20 or more bone lesions are present, is not that effective and associated with higher frequency of myelosuppression. The significant baseline predictors for grade 2-4 hematologic toxicities related to radium-223 treatment are the extent of disease (6-20 vs.< 6 bone metastases), elevated prostate-specific antigen for anaemia and prior docetaxel, decreased haemoglobin, decreased platelets for thrombocytopenia, respectively [32]. This is also in line with the results in our third patient, whom initial bone marrow involvement was extremely extensive, with documented radiological and biochemical progression right after the fourth course and subsequent survival less than 11 months. ...
The incidence of prostate cancer in Bulgaria is steadily increasing over the last few decades [1,2]. While the therapeutic strategy for hormone sensitive prostate cancer is well established, Metastatic Castration-Resistant Prostate Cancer (mCRPC) is still a challenge with an average life span of not more than two years [3]. Nevertheless, treatment options in this setting have emerged considerably during past ten years and showed significant improvement in survival rates compared to the preexisting palliative regimens [4-6].
... The extent of disease with involvement of six or more sites and elevated PSA at baseline were predictors for grade 2-4 anemia; baseline hemoglobin and platelet levels and prior treatment with docetaxel were predictors for thrombocytopenia. The number of injections of 223 RaCl 2 was not found to be significantly associated with cumulative hematologic toxicity [133]. ...
... Follow-up studies on patients excluded long-term emergence of secondary malignancies associated with 223 Ra treatment (such as other primary bone cancers or acute myelogenous leukemia) for up to 3 y (13,14). Hematologic safety analyses instead showed an impact by 223 Ra on bone marrow function (15). Accordingly, median absolute neutrophil counts and platelet number, which remained constant for placebo-treated patients, significantly decreased in 223 Ra-treated men, with a rebound after the end of the treatment. ...
... Neutropenia and thrombocytopenia currently represent the most common adverse reactions and hint at significant levels of bone marrow toxicity (15). Therefore, understanding the biologic determinants of 223 Ra-mediated myelosuppression and the medium-to long-term consequences on bone marrow function is critical to support a more meaningful and rational application of this agent in current and future patients. ...
... The absence of splenomegaly for up to day 40 after treatment suggests that no extramedullary hematopoiesis emerged to compensate the bone marrow functional damage (Fig. 3B). Analysis of peripheral blood at different time points after 223 Ra treatment showed a significant decrease in white blood cells until up to day 28 after treatment, as well as a significant decrease in platelets until up to day 16 after treatment, and no significant reduction in red blood cells, hemoglobin, or hematocrit (Fig. 3C), in agreement with the outcome observed in patients (15). ...
Radium 223 (Ra223) is a bone-seeking, alpha-particle-emitting radionuclide approved for the treatment of patients with metastatic prostate cancer and is currently being tested in a variety of clinical trials for primary and metastatic cancers to bone. Clinical evaluation of Ra223 hematologic safety showed a significantly increased rate of neutropenia and thrombocytopenia in patients, hinting at myelosuppression as a side effect. In this study we investigate the consequences of Ra223 treatment on bone marrow biology. Ra223 accumulated in bones and induced zonal radiation damage confined at the bone interface, followed by replacement of the impaired areas with adipocyte infiltration, as monitored by three-dimensional multiphoton microscopy, ex vivo. Flow cytometry and single cell transcriptomic analyses on bone marrow hematopoietic populations revealed transient, non-specific Ra223-mediated cytotoxicity on resident populations, including stem, progenitor and mature leukocytes. This was paralleled by a significant decrease of white blood cells and platelets in peripheral blood, which was overcome within 40 days post-treatment. Ra223 exposure did not impair full hematopoietic reconstitution, suggesting that the bone marrow function is not permanently hampered. Our results provide a comprehensive explanation of Ra223 reversible effects on bone marrow cells and exclude long-term myelotoxicity, supporting its safety for patients.
... Skeletal metastases are most frequently observed in multiple myeloma (up to 95%), breast and prostate cancer patients (65-80%), while lower rates are observed in patients with lung, kidney, thyroid or other cancers [4][5][6]. In pediatric cancers, bone metastasis is frequent in children suffering from neuroblastoma [7], osteosarcoma [8] and Ewing sarcoma [9]. ...
... Therefore, they preferentially accumulate in osteoblastic bone metastases, and have been shown to improve both the survival and quality of life of prostate and breast cancer patients [218]. Unfortunately, their application for treatment of osteolytic bone metastasis is limited because of myelosuppression [9]. ...
... Despite antimetastatic benefits for patients, hormone therapy shows several adverse side effects, including osteoporosis [9]. For large-scale antimetastatic drug-screening purposes, the use of xenograft models is limited. ...
Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients’ quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies.
... Several studies are investigating the effectiveness of a combination therapy on patients with mCRPC and its potential cumulative effect on hematologic toxicity. Even though the biological damages of Radium-223 on the bone marrow have been minimized (6,7), defining the hematologic profile of patients with mCRPC is a key step to limit the chance of hematologic AEs. Although rare, the potential AEs of Radium-223 on bone marrow functionality must be considered (8). ...
There have been several studies on the clinical outcomes of Radium-223 treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) who may have an increased risk of hematologic comorbidities. To the best of our knowledge, this is the first study to explore the potential bone marrow adverse effects (AEs) of Radium-223 administered with specific drugs used for hematologic conditions, such as polycythemia vera (PV). We report the case of a patient with mCRPC who was administered a combined treatment of Radium-223 and hydroxyurea for PV, aiming to support clinicians in predicting eventual AEs.
... To approximate the natural course of mCRPC in patients with bone-dominant tumor load, the placebo arm of the ALSYMPCA trial may provide a useful comparison [6]. In this group of 301 mCRPC patients with bone-dominant disease, new onset grade ≥ 3 anemia, neutropenia and thrombocytopenia occurred in 13%, 1% and 3% of patients [45]. ...
Advanced stage metastatic prostate cancer with extensive bone marrow involvement is associated with a high risk of therapy-induced myelotoxicity and unfavorable outcomes. The role of salvage radioligand therapy (RLT) with 177Lu-PSMA-617 in this subset of patients remains to be further elucidated. Forty-five patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and diffuse bone marrow involvement were treated with repeated cycles of RLT after having exhausted standard treatment options. A mean treatment activity of 7.4 ± 1.4 GBq 177Lu-PSMA-617 was administered in a median of four treatment cycles (IQR 2-6) and the mean cumulative activity was 32.6 ± 20.1 GBq. After two RLT cycles, ≥50% PSA decline was observed in 25/45 (56%) patients and imaging-based partial remission (PR) was observed in 18/45 (40%) patients. Median imaging-based progression-free survival (PFS) was 6.4 mo (95% CI, 3.0–9.8) and the median overall survival (OS) was 10.2 months (95% CI, 7.2–12.8). The biochemical response translated into a significantly prolonged PFS (12.9 vs. 2.8 mo, p < 0.001) and OS (13.5 vs. 6.7 mo, p < 0.001). Patients with PR on interim imaging after two cycles had a longer median OS compared to patients with stable or progressive disease (15.5 vs. 7.1 mo, p < 0.001). Previous taxane-based chemotherapy (HR 3.21, 95%CI 1.18–8.70, p = 0.02) and baseline LDH levels (HR 1.001, 95%CI 1.000–1.001, p = 0.04) were inversely associated with OS on a Cox-regression analysis. Grade ≥ 3 hematological decline was observed after 22/201 (11%) cycles with anemia, leukopenia and thrombocytopenia in 15/45 (33%), 6/45 (13%) and 8/45 (18%) patients, respectively. Cumulative treatment activity and absorbed whole-body dose were not correlated with new onset grade ≥ 3 hematotoxicity (p = 0.91, p = 0.69). No event of grade ≥ 3 chronic kidney disease was observed during RLT or the follow-up. Last line RLT with 177Lu-PSMA-617 in mCRPC patients with diffuse bone marrow involvement may thus contribute to prolonged disease control at an acceptable safety profile.
