The efficacy and safety comparison of radium-223 in the treatment of mCRPC patients with and without homologous recombination repair gene mutation / 中华泌尿外科杂志

Objective:To compare the efficacy and safety of radium-223 in the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients with and without homologous recombination repair (HRR) gene mutation.Methods:The clinical data of 27 patients with mCRPC bone metastases who received radium-223 therapy from April 2021 to November 2022 in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine were retrospectively analyzed. Among the 27 mCRPC patients, 18 patients carrying HRR gene mutations belonged to the HRD(+ ) group, and 9 patients without HRR gene mutation belonged to the HRD(-) group. The age of patients in HRD(+ ) group was 69.5 (63.8, 77.0) years old, alkaline phosphatase (ALP) was 243.0 (82.8, 301.3) U/L, prostate specific antigen (PSA) was 71.6 (7.3, 329.8) ng/ml, pain score was 3.0 (1.0, 5.0) points. Eastern Cooperative Oncology Group (ECOG) score ranged from 0 to 1 points in 7 cases, and 2 points in 11 cases. In the HRD(-) group, the median age was 72.0 (64.5, 76.5) years old, ALP was 88.0 (67.5, 260.6) U/L, PSA was 19.1 (1.1, 117.8) ng/ml, and pain score was 2.0 (0, 4.5) points. The ECOG score ranged from 0 to 1 in 4 cases, and 2 in 5 cases in the HRD(-) group. There was no significant difference in the above general data between the two groups ( P>0.05). All patients received radium-223 treatment every 4 weeks, no more than 6 times. The changes of ALP, PSA, pain score and hematological adverse reactions were compared between the two groups. Results:In the HRD(+ ) group, the median number of radium-223 treatment was 4.5 (3.0, 5.3) couses, 4 patients (22.2%) completed 6 courses, and 6 patients died of prostate cancer during follow-up. In the HRD(-) group, the median number of radium treatment was 4.0 (2.5, 6.0) couses, 3 patients (33.3%) completed 6 courses, and 1 patient died of prostate cancer during follow-up. There was no significant difference in the number of radium treatment courses between the two groups ( P=0.320). ALP in HRD(+ ) group was 101.8 (61.3, 147.0) U/L after radium-223 treatment, which was significantly lower than that before treatment ( P=0.002). ALP in HRD(-) group was 73.0 (64.0, 113.5) U/L after radium-223 treatment, and it was not significantly different from that before treatment ( P=0.327). The rate of ALP response (ALP decrease >10%) in HRD(+ ) group was significantly higher than that in HRD(-) group [83.3% (15/18) vs. 44.4% (4/9), P=0.037]. PSA was 105.9(5.2, 798.4) ng/ml in HRD (+ ) group after radium-223 treatment, and was 25.6(0.8, 1 031.0) ng/ml in HRD(-) group, and they were not significantly different from that before treatment ( P=0.145, P=0.386). There were no significant differences in the rate of PSA response (PSA decrease>10%) between HRD(+ ) group and HRD(-) group [38.9% (7/18) vs. 22.2% (2/9), P=0.386]. The median pain score of HRD(+ ) group was 3.0 (0, 4.0) points after treatment, which was significantly lower than that before treatment ( P=0.028). The pain score of HRD(-) group was 1.0(0, 3.0) points after treatment, and it was not significantly different from that before treatment ( P=0.129). There was no significant difference in pain relief rate between HRD(+ ) group and HRD(-) group [66.7% (12/18) vs. 44.4% (4/9), P=0.411]. The incidence of at least one hematological adverse event during radium-223 treatment in the HRD(+ ) group was higher than that in the HRD(-) group [77.8% (14/18) vs. 33.3% (3/9), P=0.039]. There was no significant difference in the incidence of grade 1-2 hematological adverse events between the two groups [72.2%(13/18) vs. 33.3%(3/9), P=0.097]. Only 1 patient in the HRD(+ ) group experienced grade 3 anemia during treatment which was recovered after blood transfusion. Conclusions:Compared to mCRPC patients without HRR gene mutation, patients with HRR gene mutations had better ALP response and bone pain relief after radium-223 treatment. The overall incidence of adverse events in the HRD(+ ) group is higher than that in HRD(-) group, and there was no significant difference in grade 1-2 hematological adverse events between the two goups. It is necessary to expand the sample size to further verify the conclusion.

Application of radium-223 combined with new-generation hormonal agents in bone metastatic of prostate cancer / 中华泌尿外科杂志

Objective:To investigate the efficacy and safety of radium-223 in combination with new-generation hormonal agents in patients with bone metastases of prostate cancer.Methods:The clinical data of 17 patients (12 from the First Affiliated Hospital of Airforce Military Medical University and 5 from Xi'an International Medical Center Hospital) with metastatic castration-resistant prostate cancer(mCRPC) treated by radium-223 combined with new-generation hormonal agents from January 2021 to June 2022 were retrospectively analyzed. In all cases, the average age was (73.3±8.5) years old. Before treatment, the median prostate-specific antigen (PSA) was 15.7 (3.2, 36.5) ng/ml, the median alkaline phosphatase (ALP) was 131.5 (79.0, 430.7) U/L. All patients had ≥ 2 bone metastases but no visceral or lymph node metastases. The median number of bone scan lesions was 10(8, 15). Bone pain symptom was present in 16(94.1%) patients. There were 9 cases (52.9%) with Eastern Cooperative Oncology Group (ECOG) score of ≥2, 1 case (5.9%) with ECOG score of 1 and 6 cases (35.2%) with ECOG score of 0. All patients were treated with radium-223 (55 kBq/kg, injected every 4 weeks for a maximum of 6 cycles), of which 5 patients were combined with enzalutamide, 8 patients combined with apatamide and 4 patients combined with bicalutamide. PSA response (PSA decreased by ≥30% from baseline and maintained for at least 1 month), ALP response (ALP decreased by ≥30% from baseline and maintained for at least 1 month) and pain relief rates were analyzed. Imaging evaluation was performed before and after treatment to calculate the objective response rate of metastases. The incidence of treatment-related adverse effects and skeletal related event (SRE) were also recorded.Results:Eleven patients completed 6 courses, 3 patients completed 5 courses and 3 patients completed ≥4 courses. The median ALP after 1 month of last treatment was 83.2 (51.5, 126.5) U/L, which was significantly decreased than baseline. 12 patients (70.6%) showed an ALP response and the other 5 (29.4%) showed varying degrees of ALP elevation. PSA response was observed in 4 patients (23.5%), of which 2 (11.8%) had a continuous decrease and 2 (11.8%) had a late-stage increase in PSA. Pain relief was relieved in 15 cases (88.2%) during treatment, 1 case (5.9%) had worsening pain due to disease progression and 1 case (5.9%) had no change during treatment. The ECOG score decreased in 15 (88.2%) patients. The median number of bone metastases in patients decreased to 5 (4, 9). One patient (5.9%) had complete remission during treatment, 11 patients (64.7%) had a partial response, 4 patients (23.5%) were stable, and 1 (5.9%) showed imaging progression after 4 months of treatment. The overall objective remission response rate was 70.5% (12/17). Treatment-related hematologic adverse effects included anemia (1 case, 5.9%, grade 3), thrombocytopenia (1 case, 5.9%, grade 3) and leukopenia (1 case, 5.9%, grade 2). Non-hematologic adverse effects included fatigue (3 cases, 17.6%, 2 cases in grade 1, 1 case in grade 2), gastrointestinal bleeding (1 case, 5.9%, grade 3), diarrhea (1 case, 5.9%, grade 2) and fever (1 case, 5.9%, grade 1). Patients with grades 1 to 2 relieved with symptomatic management. Three cases (17.6%) were discontinued due to intolerance of grade 3 adverse reactions and 1 case (5.9%) terminated on its own. There was no SRE during treatment and follow-up.Conclusions:Radium-223 combined with New-generation hormonal agents has a high objective remission rate in patients with mCRPC, which could provide pain relief and improve quality of life. The incidence of adverse reactions was low and well tolerated.

Efficacy and safety of radium-223 in the treatment of metastatic castration resistant prostate cancer / 中华泌尿外科杂志

Objective:To analyze the efficacy and safety of radium-223 in the treatment of metastatic castration resistant prostate cancer (mCRPC).Methods:The clinical data of 22 patients with mCRPC treated with radium-223 in the Chongqing University Cancer Hospital from January 2021 to January 2022 were analyzed retrospectively. The average age was (70.7±1.3)years old. There were 7 cases with ECOG score of 1 and 15 cases with ECOG score of 2. There were 7 cases with grade 2 and 15 cases with grade 3 bone metastasis. For mCRPC, 1 case (4.6%) received first-line treatment, 4 cases (18.2%) received second-line treatment, 10 cases (45.5%) received third-line treatment, 4 cases (18.2%) received fourth-line treatment, and 3 cases (13.6%) received fifth-line treatment. The median time from the diagnosis of mCRPC to the start of radium-223 treatment was 29 (20, 34) months. Radium-223 (55kbq/kg) was injected intravenously every 4 weeks for up to 6 cycles. Before treatment, the median alkaline phosphatase (ALP) was 147.0 (101.8, 212.5)U/L, the median prostate specific antigen (PSA) was 44.7(20.2, 99.1)ng/ml, and 6 patients (27.3%) were complicated with grade 1-2 anemia. The median hemoglobin was 115.0 (103.8, 122.5) g/L, the average neutrophil was (3.0 ± 0.3)×10 9/L, and the average platelet was (169.8 ± 17.0)×10 9/L. The overall survival (OS), radiographic progression-free survival time (rPFS), time to PSA progression, PSA response rate, pain response rate, and time to pain progression were analyzed. Stratified analysis was carried out according to the number of treatment lines experienced before radium-223 treatment. At the same time, the main adverse reactions during radium-223 treatment were analyzed. Results:The mean number of treatment courses with radium-223 was 2.7(ranging 1 to 6), with 4 patients completing 6 courses, 12 (54.6%) completing ≥ 3 courses, and 10 (45.5%) completing < 3 courses. Thirteen patients (59.1%) were treated with radium-223 alone and 9 (40.9%) in combination with other treatments (1 of docetaxel chemotherapy, 2 of enzalutamide, 3 of olaparib, and 3 of estramustine phosphate). None of the patients in this group were treated with bisphosphonates. Ten patients (45.5%) in this group died, all due to disease progression. The median overall survival time of the 22 cases was 11.0 (2.2, 19.8) months. Three patients (13.6%), 7 patients (31.8%), 3 patients (13.6%), and 1 patient (4.5%) showed radiographic progression at 2, 3, 4, and 10 months after treatment, respectively, while the remaining 8 patients (36.4%) did not show radiographic progression during the follow-up period, and the median radiographic progression free time for the 22 patients was 4.0 (3.1, 4.9) months. There were four cases (18.2%) showed PSA response, of which three cases (13.6%) showed PSA rising again later, and one case (4.5%) showed continuous PSA decline. The median time to PSA progression for the 22 patients was 3.6 (2.2, 5.1) months. Fifteen patients (68.2%) experienced pain response at 1 month of treatment, of whom 5 (22.7%) experienced increased pain later and 10 (45.5%) experienced sustained pain relief. The median time to pain progression was 5.5 (3.5, 7.6) months in 22 patients. No patients received radiotherapy or surgery for pain, and no patients experienced fracture. In this group, 7 patients (31.8%) had a post-treatment ALP decrease ≥30% from baseline. Major adverse events during radium-223 treatment were all grade 1 to 2 events, no grade ≥3 adverse events, and no treatment discontinuers due to adverse events.Conclusions:Radium-223 resulted in high pain response rates and prolonged OS, rPFS and time to PSA progression in patients with mCRPC. Adverse effects were low during treatment. The conclusions need to be validated by further expansion of the sample size and extended follow-up.

Efficacy and safety of radium-223 in 48 patients with bone metastatic castration resistant prostate cancer / 中华泌尿外科杂志

Objective:To observe the efficacy and safety of radium-223 in metastatic castration resistant prostate cancer (mCRPC) with bone metastasis.Methods:The clinical data of 48 patients with mCRPC treated with radium-223(55 kBq/kg, once every 4 weeks, planned to use for 6 cycles)from February 2021 to May 2022 were analyzed retrospectively. All patients had symptomatic bone metastasis without visceral metastasis, which the number of bone metastasis was more than one site.They were all classified as IVb stage. The average age was 70.5 (ranging 49-90) years. The median PSA was 44.70(ranging 0.15-1 864.00) ng/ml. The median ALP was 162 (ranging 43-1 589) U/L. The median time from mCRPC diagnosis to radium-223 use was 10 (ranging 3-47) months. 9, 18 and 11 patients had received first-line, second-line and third-line treatment for mCRPC before enrollment respectively, 10 patients had received at least fourth-line treatment. 38 (79.1%), 31 (64.5%), 30 (62.5%) and 7 (14.6%) patients had used abiraterone, enzalutamide, docetaxel and olaparib before enrollment. The probability of PSA level decrease >30%, ALP level decrease >30%, symptom improvement rate, median overall survival (OS), as well as the occurrence of treatment-related adverse reactions and the reasons for withdraw treatment were analyzed.Results:The median follow-up time was 8 (ranging 1-16) months. 11 patients completed all 6 courses of treatment. The median number of completed courses was 4 (ranging 1-6). 27 patients (56.2%) received radium-223 and bone protection drugs (Bisphosphate/ Denosumab). PSA decreased by >30% was recorded in 10 patients (20.8%) and ALP decreased by >30% was recorded in 25 patients (52.1%). 23 cases (47.9%) reported bone pain relief during treatment. Among the 9 patients who had received first-line of mCRPC previously, 6 cases (66%) had relief of bone pain symptoms, and 4 cases (44%) had a decrease of PSA >30%. Among the 18 patients who had previously received second-line mCRPC treatment, 11 cases (61%) had relief of bone pain symptoms, and 4 cases (22%) had a decrease of PSA >30%. Among the 21 patients who had received third-line or more mCRPC treatment in the past, 6 (28.5%) had symptom relief, and 2 (9.5%) had PSA decrease >30%. The median overall survival (OS) was not reached, and the OS was estimated to be 12.5 months using the Kaplan-Meier method. The most common hematological adverse effects were thrombocytopenia (15 cases, 31.2%; grade 3 in 6 cases and grade 4 in 0), followed by leucopenia (11 cases, 22.9%; grade 3 in 4 cases and grade 4 in 1 case) and anemia (8 cases, 16.7%; grade 3 in 3 cases and grade 4 in 0). Non-hematological adverse reactions included fever in 1 case (2.1%), constipation in 4 cases (8.3%), nausea and vomiting in 10 cases (20.8%), diarrhea in 7 cases (14.6%), dizziness in 1 case (2.1%) and fatigue in 11 cases (22.9%). Seven cases were discontinued due to intolerable adverse reactions (median 2 courses), 14 cases were discontinued due to disease progression or death (median 2 courses), and 5 cases were discontinued due to other reasons (median 1 course).Conclusions:Radium-223 has a good performance in symptom control for mCRPC patients who have previously received first-line or second-line therapy. Due to the high incidence of hematological adverse reactions, more attention should be paid to the changes of hemogram during the treatment, and timely treatment should be carried out to improve the drug tolerance of patients.

Overall survival prediction in metastatic castration-resistant prostate cancer treated with radium-223

ABSTRACT Objective Radium-223(223Ra) is indicated for patients (p) with metastatic castration resistant prostate cancer (mCRCP). Objectives The aim of this study was to evaluate the role of baseline clinical variables associated with overall survival (OS) and toxicity of 223Ra. Its purpose was to identify the factors that can predict a better response to treatment and provide information regarding the most appropriate time for the application of 223Ra. Materials and Methods Prospective study in 40p with mCRPC treated with 223Ra. End points were OS, progression-free survival and time to progression. The follow-up parameters were: doses received, hemoglobin (Hb), absolute neutrophil count (ANC), platelet count (PC), prostate specific antigen (PSA), alkaline phosphatase (ALP), Visual Analogue Scale for pain, Eastern Cooperative Oncology Group (ECOG) and WHO's Cancer Pain Ladder. The use of other treatments was also evaluated. Results Median OS was 17.1 months(mo) (CI95%6.5-27.7); 26/40p received complete treatment of 223Ra, without reaching a median OS and 14p received incomplete treatment with a median OS 13.6mo(CI95%1.6-25.6). Median follow-up was 11.2mo (range:1.3-45.2). The univariate analysis showed that factors as VAS, ECOG, Hb and ALP values were independently associated with OS. First line treatment with 223Ra was started in 11/40p, while 19p had been heavily pre-treated and 13p received concomitant treatment. Conclusions 223Ra therapy require an adequate selection of patients to obtain the greatest clinical benefit. Low basal Hb, hight basal ALP, bone marrow involvement and an altered ECOG were the main factors that decreased OS in our patients. 223Ra should be considered relatively early in the course of treatment.

Is interim 18F-fluoride PET/CT a predictor of outcomes after radium-223 therapy? / O PET/CT interim com fluoreto-18F é capaz de predizer desfechos após a terapia com rádio-223?

Abstract Objective: To determine whether an interim 18F-fluoride positron-emission tomography/computed tomography (PET/CT) study performed after the third cycle of radium-223 dichloride (223RaCl2) therapy is able to identify patients that will not respond to treatment. Materials and Methods: We retrospectively reviewed 34 histologically confirmed cases of hormone-refractory prostate cancer with bone metastasis in patients submitted to 223RaCl2 therapy. All of the patients underwent baseline and interim 18F-fluoride PET/CT studies. The interim study was performed immediately prior to the fourth cycle of 223RaCl2. The skeletal tumor burden-expressed as the total lesion fluoride uptake above a maximum standardized uptake value of 10 (TLF10)-was calculated for the baseline and the interim studies. The percent change in TLF10 between the baseline and interim studies (%TFL10) was calculated as follows: %TFL10 = interim TLF10 - baseline TLF10 / baseline TLF10. End points were overall survival, progression-free survival, and skeletal-related events. Results: The mean age of the patients was 72.4 ± 10.2 years (range, 43.3-88.8 years). The %TLF10 was not able to predict overall survival (p = 0.6320; hazard ratio [HR] = 0.753; 95% confidence interval [CI]: 0.236-2.401), progression-free survival (p = 0.5908; HR = 1.248; 95% CI: 0.557-2.797) nor time to a bone event (p = 0.5114; HR = 1.588; 95% CI: 0.399-6.312). Conclusion: The skeletal tumor burden on an interim 18F-fluoride PET/CT, performed after three cycles of 223RaCl2, is not able to predict overall survival, progression-free survival, or time to bone event, and should not be performed to monitor response at this time.

Resumo Objetivo: Avaliar se o PET/CT interim com fluoreto-18F após a terceira dose da terapia com dicloreto de rádio-223 (223Ra) é capaz de identificar pacientes que não responderão ao tratamento. Materiais e Métodos: Revisamos, retrospectivamente, 34 pacientes com diagnóstico histológico de câncer de próstata refratários a hormonioterapia e com metástases ósseas que foram submetidos a 223Ra. Todos os pacientes foram submetidos a PET/CT com fluoreto-18F antes de iniciar o tratamento (basal) e imediatamente antes da quarta dose de 223Ra (interim). A carga tumoral esquelética (TLF10) foi calculada em ambos os exames da PET/CT com fluoreto-18F de cada paciente e foi determinada a alteração percentual na TLF10 entre eles (%TFL10 = TLF10 interim - TLF10 basal / TLF10 basal). Foram avaliados a sobrevida global, a sobrevida livre de progressão e o tempo para um evento ósseo. Resultados: A idade média dos pacientes foi 72,4 ± 10,2 anos (variação: 43,3-88,8 anos). A %TLF10 não foi capaz de predizer a sobrevida global (p = 0,6320; HR = 0,753; intervalo de confiança [IC] 95%: 0,236-2,101), a sobrevida livre de progressão (p = 0,5908; HR = 1,248; IC 95%: 0,557-2,797) nem o tempo para um evento ósseo (p = 0,5114; HR = 1,588; IC 95%: 0,399-6,312). Conclusão: A carga tumoral esquelética da PET/CT com fluoreto-18F realizada após três doses de 223Ra não é capaz de predizer sobrevida global, sobrevida livre de progressão ou tempo até um evento ósseo, e não deve ser realizada para monitorar a resposta ao tratamento desses pacientes, nesse momento.

Current concepts and trends in the treatment of bone metastases in patients with advanced prostate cancer / 亚洲男科学杂志(英文版)

Bone metastases have a major impact on quality of life and survival of patients with advanced prostate cancer. In the last decade, the development and approval of substances inhibiting the vicious cycle of bone metastases have enabled the reduction of complications caused by bone metastases in patients with castration-resistant prostate cancer. These drugs have raised awareness of the importance of skeletal-related events which in the meantime represent an important end point also in trials using agents not specifically designed for bone lesions. Second-generation antihormonal drugs such as enzalutamide or abiraterone have been shown to have a positive impact on the incidence of skeletal complications and therefore provide an important tool in the armamentarium used for treating bone metastases. Radiopharmaceuticals such as radium-223 dichloride ([223Ra]) have been demonstrated not only to reduce skeletal-related events and bone-related pain, but also to prolong overall survival, thereby being the first bone-Targeting agent showing a survival benefit. As previous studies have not provided an obvious benefit of bone-Targeted lesions in castration-sensitive disease, the use of these agents is not recommended. In oligometastatic prostate cancer, the role of local treatment of metastases using stereotactic radiation or radiosurgery is a matter of intense debates and may play an increasing role in the future.

Metastatic castration-resistant prostate cancer and the challenge of a patient with chronic kidney disease in hemodialysis

At a time when the population shows increasing longevity, entities such as cancer and chronic kidney disease (CKD) are more frequently connected. In the United States, approximately 6% of the patients on hemodialysis have cancer. The challenge to manage oncologic patients with CKD in a hemodialytic program represents a great shortage of available information on the choice of the best drug, timing, dosage adjustments, dialysis method, and treatment safety. We present the case of a patient with prostate cancer and terminal CKD in hemodialysis, and the treatment sequence after the development of resistance to hormonal blockade therapy, which included docetaxel, enzalutamide, and radium-223.

Radium-223 for the treatment of bone metastasis of prostate cancer / 中华男科学杂志

Over 80% of the patients with prostate cancer (PCa) develop bone metastasis, which seriously affects the patients' quality of life and remains a major cause of morbidity. Radium-223 (Ra-223), a newly approved agent targeting bone metastasis of PCa, can improve the quality of life and prolong the overall survival of the PCa patients with bone metastasis. This article presents an overview of the clinical trials recently published on the management of bone metastasis of PCa with Ra-223.