This study aims to evaluate the potential value of patient characteristics in predicting overall survival （OS） in patients with metastatic castration-resistant prostate cancer （mCRPC） treated with docetaxel-based ...This study aims to evaluate the potential value of patient characteristics in predicting overall survival （OS） in patients with metastatic castration-resistant prostate cancer （mCRPC） treated with docetaxel-based thermotherapy. A total of 115 patients with mCRPC undergoing a docetaxel q3w regimen were enrolled in this study. A survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models were used to evaluate the prognostic value of all covariates for OS. OS was also analysed after stratifying patients according to the results of multivariate analysis. The median OS for the entire cohort was 17.0 months. The multivariate analysis showed that the prostate-specific antigen doubling time （PSADT）, baseline haemoglobin （Hb） concentration, alkaline phosphatase （ALP） concentration, cycles of chemotherapy and time to castration resistance were independent prognostic factors of OS. According to the presence of PSADT 〈46.3 days and baseline ALP/〉 110 IU 1-1, all patients were divided into three risk groups： low-risk group （no risk factors）, intermediate-risk group （one risk factor） and high-risk group （two risk factors）. Median OSs for patients in low-, intermediate- and high-risk groups were 28.0 months （95% Ch 23.8-32.2）, 21.0 months （95% Ch 18.9-23.1） and 11.0 months （95% Ch 7.6-14.4）, respectively （P〈O.O01）. In conclusion, PSADT, baseline Hb concentration, ALP concentration, cycles of chemotherapy and time to castration resistance were independent prognostic factors of OS in Chinese patients with mCRPC treated with docetaxel. PSADT combined with the baseline ALP concentration could be a useful risk stratification parameter for evaluating survival outcomes.展开更多
Eastern Cooperative Oncology Group(ECOG)performance status and Gleason score are commonly investigated factors for overall survival(OS)in men with castration-resistant prostate cancer(CRPC).However,there is a lack of ...Eastern Cooperative Oncology Group(ECOG)performance status and Gleason score are commonly investigated factors for overall survival(OS)in men with castration-resistant prostate cancer(CRPC).However,there is a lack of consistency regarding their prognostic or predictive value for OS.Therefore,we performed this meta-analysis to assess the associations of ECOG performance status and Gleason score with OS in CRPC patients and compare the two markers in patients under different treatment regimens or with different chemotherapy histories.A systematic literature review of monotherapy studies in CRPC patients was conducted in the PubMed database until May 2019.The data from 8247 patients in 34 studies,including clinical trials and real-world data,were included in our meta-analysis.Of these,twenty studies reported multivariate results and were included in our main analysis.CRPC patients with higher ECOG performance statuses(≥2)had a significantly increased mortality risk than those with lower ECOG performance statuses(<2),hazard ratio(HR):2.10,95%confidence interval(CI):1.68-2.62,and P<0.001.The synthesized HR of OS stratified by Gleason score was 1.01,with a 95%CI of 0.62-1.67(Gleason score≥8 vs<8).Subgroup analysis showed that there was no significant difference in pooled HRs for patients administered taxane chemotherapy(docetaxel and cabazitaxel)and androgen-targeting therapy(abiraterone acetate and enzalutamide)or for patients with different chemotherapy histories.ECOG performance status was identified as a significant prognostic factor in CRPC patients,while Gleason score showed a weak prognostic value for OS based on the available data in our meta-analysis.展开更多
Availability of novel hormonal therapies as well as docetaxel and cabazitaxel treatment for metastatic castration-resistant prostate cancer （CRPC） has changed the outlook for this group of patients with improvements...Availability of novel hormonal therapies as well as docetaxel and cabazitaxel treatment for metastatic castration-resistant prostate cancer （CRPC） has changed the outlook for this group of patients with improvements in progression-free survival and overall survival. Physicians often diagnose the progression of prostate cancer using serum prostate-specific antigen （PSA）. However, serum PSA is not always correlated with the clinical status in CRPC. To evaluate the PSA dynamics with greater precision, understanding of the control of PSA and of the mechanisms of development of CRPC is needed. Moreover, it is necessary to use new hormonal therapies with an appropriate timing to optimally improve the prognosis and the QOL of the patients. In the present review, we ascertain the PSA dynamics and the mechanisms of the development of CRPC to assist in optimal utilization of the new treatments for mCRPC.展开更多
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 t...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 models to predict sensitivity to docetaxel chemotherapy in patients with mCRPC by using serum surface-enhanced Raman spectroscopy(SERS).A total of 32 mCPRC patients who underwent docetaxel chemo-therapy at our center from July 2016 to March 2018 were included in this study.Patients were dichotomized in prostate-specific antigen(PSA)response group(n=17)versus PSA failure group(n=15)according to the response to docetaxel.In total 64 matched spectra from 32 mCRPC patients were obtained by using SERS of serum at baseline(q0)and after 1 cycle of docetaxel chemotherapy(ql).Comparing Raman peaks of serum samples at baseline(q0)be-tween two groups,significant differences revealed at the peaks of 638,810,890(p<0.05)and 1136cm^(-1)(p<0.01).The prediction models of peak 1363 cm^(-1)and principal component anal-ysis and linear discriminant analysis(PCA-LDA)based on Raman data were established,re-spectively.The sensitivity and specificity of the prediction models were 71%,80%and 69%,78%through the way of leave-one-out cross-validation.According to the results of five-cross-valida-tion,the PCA-LDA model revealed an accuracy of 0.73 and AUC of 0.83.展开更多
This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate （AA） and enzalutamide （Enz） for metastatic castration-resistant prostate cancer （mCRPC）. A lit...This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate （AA） and enzalutamide （Enz） for metastatic castration-resistant prostate cancer （mCRPC）. A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA （active comparator） and Enz （true placebo） randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings （HR. 0.90, 95% CI, 0.73-1.11; HR： 0.85, 95% CI, 0.68-1.07）. Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons： time to prostate-specific antigen （PSA） progression （HR. 0.34, 95% CI, 0.28-0.42; HR： 0.40, 95% CI, 0.30-0.53）, radiographic progression-free survival （HR： 0.37, 95% CI, 0.28-0.48; HR： 0.61, 95% CI, 0.50-0.74）, and PSA response rate （OR： 18.29, 95% CI, 11.20-29.88; OR： 10.69, 95% CI, 3.92-29.20）. With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.展开更多
Even in the era of novel targeted agents, switching to a second-line nonsteroidal antiandrogen （NSAA） is still widely used in treating metastatic castration-resistant prostate cancer （mCRPC）, especially in undevel...Even in the era of novel targeted agents, switching to a second-line nonsteroidal antiandrogen （NSAA） is still widely used in treating metastatic castration-resistant prostate cancer （mCRPC）, especially in undeveloped countries. However, whether prior treatment with a second-line NSAA would impact the efficacy of abiraterone acetate （Abi） remains uncertain, in the current study, 87 mCRPC patients treated with Abi were analyzed. Among them, 21 were treated with a second-line NSAA （from bicalutamide to flutamide） before receiving abiraterone, while the remaining 66 received Abi directly. Therapeutic efficacy of Abi was compared between those with and without prior second-line NSAA using Kaplan-Meier curves, log-rank test, and Cox regression models. The therapeutic efficacy of Abi was similar between those with or without the prior switching treatment of flutamide, in terms of either prostate-specific antigen progression-free survival （PSA-PFS, 5.5 vs 5.6 months, P = 0.967）, radiographic progression-free survival （rPFS, 12.8 vs 13.4 months, P = 0.508）, overall survival （OS, not reached vs 30.6 months, P = 0.606）, or PSA-response rate （71.4% [15121] vs 60.6% [40166], P = 0.370）. This is the first time that the impact of prior switching of treatment to a second-line NSAA on the efficacy of Abi in mCRPC patients has been addressed. Our data support that, use of prior sequential bicalutamide and flutamide does not seem to preclude response to abiraterone, although larger cohort studies and, ideally, a randomized controlled trial are needed. These findings will facilitate doctors＇ decision-making in the treatment of mCRPC patients, especially for those with previous experience of switching NSAA second-line treatments in the clinic.展开更多
This study investigated the clinical activity of abiraterone plus prednisone in docetaxel-naive and docetaxel-resistant Chinese patients with metastatic castratio n-resista nt prostate can cer(mCRPC).A total of 146 pa...This study investigated the clinical activity of abiraterone plus prednisone in docetaxel-naive and docetaxel-resistant Chinese patients with metastatic castratio n-resista nt prostate can cer(mCRPC).A total of 146 patie nts with docetaxel-naive group(103 cases)and docetaxel-resista nt group(43 cases)were en rolled from the Sha nghai Cancer Center(Sha nghai,Chin a)in this retrospective cohort study.The efficacy endpoints were prostate-specific antigen response rate,prostate-specific antigen progress!on-free survival,clinical/radiographic progression-free survival,and overall survival in response to abiraterone plus prednisone.Significantly higher prostate-specific antigen response rate was found in docetaxel-naive group(54.4%,56/103)compared to docetaxel-resistant group(34.9%,15/43)(P=0.047).In addition,significantly higher median prostate-specific antigen progress!on-free survival(14.0 vs 7.7 months,P=0.005),clinical or radiographic progression-free survival(17.0 vs 12.5 months,P=0.003),and overall survival(27.0 vs 18.0 mon ths,P=0.016)were found in docetaxel-naTve group compared to docetaxel-resistant group,respectively.The univariate and multivariate analyses indicated that lower albumin and visceral metastases were independent significant predictors for shorter overall survival.To sum up,our data suggested that abiraterone plus prednisone was efficient in both docetaxel-naTve and docetaxel-resistant Chinese patients.Moreover,higher PSA response rate and longer overall survival were observed in the docetaxel-naTve group,which suggested that abiraterone was more effective for docetaxel-naive patients than for docetaxel failures.展开更多
Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate canc...Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer （CRPC）, it is possible to detect persistent activation of the androgen receptor （AR） through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17（^-hydroxylase and 17,20-1yase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival （OS） with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone （ACTH）, providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-1yase （orteronel, galeterone and VT-464） that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.展开更多
Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer （mCRPC） in China; however, the prognostic factors associated with effects in these pati...Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer （mCRPC） in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen （PSA） level 〉50% during the treatment and investigated the potential role of time to nadir （TTN） of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival （OS）. In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN 〈17 weeks （42.83 vs 21.50 weeks, P 〈 0.001）. The time to PSA progression in patients with TTN ：〉17 weeks was 11.44 weeks compared to 5.63 weeks when TTN was 〈17 weeks. We found several factors to be associated with OS, including TTN （hazard ratio [HR]. 3.937, 95% confidence interval [CI]： 1.502-10.309, P = 0.005）, PSA level at the diagnosis of cancer （HR： 4,337, 95% CI： 1.616-11.645, P= 0.004）, duration of initial androgen deprivation therapy （HR： 2.982, 95% CI： 1.104-8.045, P= 0.031）, neutrophil-to-lymphocyte ratio （HR： 3.963, 95% CI： 1.380-11.384, P = 0.011）, and total PSA response （Class 1 [〈0 response] compared to Class 2 [0-50% response], HR： 3.978, 95% CI： 1.278-12.387, P = 0.017）. In conclusion, TTN of PSA remains an important prognostic marker in predicting therapeutic outcome in Chinese population who receive chemotherapy for mCRPC and have 〉50% PSA remission.展开更多
Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer （CRPC）; however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone...Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer （CRPC）; however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival （OS）. We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 （53.6%）, 34 （30.9%）, and 17 （15.5%） in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C-index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations （〈110 g l^-1）, liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation （〈36 months） as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 （95% CI, 0.678-0.836）. In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters.展开更多
Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer(mCRPC).Here,we investigated the potential biomarkers for predicting the efficacy of cor...Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer(mCRPC).Here,we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate(AA).We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018.All cases received AA plus prednisone as first-line therapy during mCRPC.Primary end points were biochemical progression-free survival(bPFS)and overall survival(OS).The risk groups were defined based on multivariate analysis.A total of 42(41.6%)and 25(24.8%)patients achieved 30%and 50%decline in prostate-specific antigen(PSA),respectively,after corticosteroid switching.The median bPFS and median OS on AA plus dexamethasone were 4.9(95%confidence interval[CI]:3.7–6.0)months and 18.8(95%CI:16.2–30.2)months,respectively.Aldo-keto reductase family 1 member C3(AKR1C3)expression(hazard ratio[HR]:2.15,95%Cl:1.22–3.80,P=0.008)and baseline serum alkaline phosphatase(ALP;HR:4.95,95%Cl:2.40–10.19,P<0.001)were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS.Only baseline serum ALP>160 IU l−1(HR:3.41,95%Cl:1.57–7.38,P=0.002)together with PSA level at switch≥50 ng ml−1(HR:2.59,95%Cl:1.22–5.47,P=0.013)independently predicted poorer OS.Based on the predictive factors in multivariate analysis,we developed two risk stratification tools to select candidates for corticosteroid switching.Detection of serum ALP level,PSA level,and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.展开更多
AIM: To study the efficacy and safety of abiraterone in patients with and without prior chemotherapy.METHODS: The databases including Pub Med and abstracts presented at the American Society of Clinical Oncology meetin...AIM: To study the efficacy and safety of abiraterone in patients with and without prior chemotherapy.METHODS: The databases including Pub Med and abstracts presented at the American Society of Clinical Oncology meetings up to April 2014 were systematically searched. Eligible studies included randomized controlled trials(RCTs) in which abiraterone plus prednisone was compared to placebo plus prednisone in metastatic castration-resistant prostate cancer(CRPC) patients. The summary incidence, relative risk, hazard ratio and 95%CI were calculated using random or fixed-effects models. Heterogeneity test was performed to test between-study differences in efficacy and toxicity.RESULTS: A total of two phase III RCTs were included in our analysis, with metastatic CPRC patients before(n = 1088) and after chemotherapy(n = 1195). Prior chemotherapy did not significantly alter the effect of abiraterone on overall survival(P = 0.92) and prostatespecific antigen(PSA) progression-free survival(P = 0.13), but reduced its effect on radiographic-prog-ression-free survival(P = 0.04), objective response rate(P < 0.001), and PSA response rate(P < 0.001). Prior chemotherapy significantly increased the specific risk of fluid retention and edema(P < 0.001) and hypokalemia(P < 0.001), but decreased the risk of all-grade hypertension(P < 0.001) attributable to abiraterone. There was no significant difference of cardiac disorders associated with abiraterone between the two settings(P = 0.58). CONCLUSION: Prior chemotherapy may reduce the effectiveness of abiraterone in patients with metastatic CRPC.展开更多
PROSPER is an international Phase III trial demonstrating the beneficial role of enzalutamide,an androgen receptor antagonist,in prolonging metastasisfree survival in men with nonmetastatic castration-resistant prosta...PROSPER is an international Phase III trial demonstrating the beneficial role of enzalutamide,an androgen receptor antagonist,in prolonging metastasisfree survival in men with nonmetastatic castration-resistant prostate cancer.The trial showed that the median metastasis-free survival was 21.9 months longer for those treated with enzalutamide(36.6 months)compared to those treated with placebo(14.7 months).Enzalutamide also showed prolonged time to PSA progression,PSA response,and time to initiating additional antineoplastic therapy although overall survival is not yet reached.Enzalutamide is the second antiandrogen(next to apalutamide)that has gained the United States Food and Drug Administration(US FDA)label indication for use in the setting of nonmetastatic castration-resistant prostate cancer.展开更多
Based on the results of TAX 327, a nomogram was developed to predict the overall survival of metastatic castration-resistant prostate cancer （mCRPC） after first-line chemotherapy. The nomogram, however, has not been...Based on the results of TAX 327, a nomogram was developed to predict the overall survival of metastatic castration-resistant prostate cancer （mCRPC） after first-line chemotherapy. The nomogram, however, has not been validated in an independent dataset, especially in a series out of clinical trials. Thus, the objective of the current study was to validate the TAX 327 nomogram in a community setting in China. A total of 146 patients with mCRPC who received first-line chemotherapy （docetaxel or mitoxantrone） were identified. Because clinical trials are limited in China's Mainland, those patients did not receive investigational treatment after the failure of first-line chemotherapy. The predicted overall survival rate was calculated from the TAX 327 nomogram. The validity of the model was assessed with discrimination, calibration and decision curve analysis. The median survival of the cohort was 21 months （docetaxel） and 19 months （mitoxantrone） at last follow-up. The predictive c-index of the TAX 327 nomogram was 0.66 （95% CI： 0.54-0.70）. The calibration plot demonstrated that the 2-year survival rate was underestimated by the nomogram. Decision curve analysis showed a net benefit of the nomogram at a threshold probability greater than 30%. In conclusion, the present validation study did not confirm the predictive value of the TAX 327 nomogram in a contemporary community series of men in China, and further studies with a large sample size to develop or validate nomograms for predicting survival and selecting therapies in advanced prostate cancer are necessary.展开更多
We evaluated the relationships of body composition and serum adipocytokine levels with progression-free survival(PFS)and overall survival(OS)in metastatic castration-resistant prostate cancer(mCRPC)patients receiving ...We evaluated the relationships of body composition and serum adipocytokine levels with progression-free survival(PFS)and overall survival(OS)in metastatic castration-resistant prostate cancer(mCRPC)patients receiving docetaxel.The medical records of mCRPC patients who received docetaxel between January 2011 and December 2015 at Fudan University Shanghai Cancer Center(Shanghai,China)were reviewed.The following body composition parameters were calculated using computed tomography:skeletal muscle index(SMI),visceral adipose tissue index(VATI),and subcutaneous adipose tissue index(SATI).Pretreatment serum adipocytokine levels,including interleukin 6,insulin,leptin,monocyte chemoattractant protein-1,adiponectin,and resistin,were measured using the multiplex bead-based immunoassays.Cox regression and Kaplan–Meier methods were used for survival analyses.Of the 453 mCRPC patients initially identified,105 were included in the analysis.High VATI group patients had longer PFS(median,10 months vs 7 months,P=0.008)and OS(median,24 months vs 15 months,P=0.017),compared with low VATI group patients.SMI and SATI were not significantly associated with PFS or OS.Of the six detected adipocytokines,only leptin was associated with mCRPC prognosis.High leptin group patients had shorter PFS(median,7 months vs 12 months,P=0.0018)and OS(median,17 months vs 22 months,P=0.042),compared with low leptin group patients.Multivariate analysis showed that a high VATI was an independent protective factor for PFS and OS,while a high leptin level was an independent risk factor for PFS and OS.Therefore,VATI and serum leptin levels could provide important information concerning mCRPC prognosis.展开更多
Patients with bone metastatic castration-resistant prostate cancer (mCRPC) might benefit from radium-223 (^(223)Ra) combined withnew-generation hormonal agents (NHAs) in terms of survival and quality of life (QoL). Ho...Patients with bone metastatic castration-resistant prostate cancer (mCRPC) might benefit from radium-223 (^(223)Ra) combined withnew-generation hormonal agents (NHAs) in terms of survival and quality of life (QoL). However, the safety of combination therapiesremains unclear. Therefore, we aimed to perform a network meta-analysis by reviewing the literature about the combination of^(223)Ra with abiraterone acetate plus prednisone (AAP) or enzalutamide and to evaluate the safety of combination therapy in bonemCRPC patients. Ultimately, ten studies (2835 patients) were selected, including four randomized controlled trials (RCTs), fiveretrospective cohort studies, and one single-arm study. Overall, there was no difference in the incidence of fracture between the^(223)Ra+NHA combination group and the ^(223)Ra monotherapy group (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 0.91–2.34,P = 0.66), but the incidences in both the ^(223)Ra+NHA combination group (OR: 3.22, 95% CI: 2.24–4.63, P < 0.01) and the ^(223)Ramonotherapy group (OR: 2.24, 95% CI: 1.23–4.08, P < 0.01) were higher than that in the NHA monotherapy group. However, inthe meta-analysis involving only RCTs, there was no difference between the ^(223)Ra monotherapy group and the NHA monotherapygroup (OR: 1.14, 95% CI: 0.22–5.95, P = 0.88), while the difference between the ^(223)Ra+NHA combination group and the NHAmonotherapy group remained significant (OR: 3.22, 95% CI: 2.24–4.63, P < 0.01). Symptomatic skeletal events (SSEs), SSE-freesurvival (SSE-FS), all grades of common adverse events (AEs), and ≥grade 3 AEs among all groups did not show any significantdifference. Our results indicate that the combination of ^(223)Ra with NHAs was well tolerated in bone mCRPC patients compared to ^(223)Ra monotherapy, even though the incidence of fracture was higher in patients who received ^(223)Ra than that among those whoreceived NHA monotherapy. More evidence is needed to explore the safety and efficiency of ^(223)Ra combination therapies.展开更多
We investigated the prognostic value of some variables of effective ketoconazole treatment for metastatic castration-resistant prostate cancer （mCRPC）. In total, 163 patients with mCRPC were eligible, receiving keto...We investigated the prognostic value of some variables of effective ketoconazole treatment for metastatic castration-resistant prostate cancer （mCRPC）. In total, 163 patients with mCRPC were eligible, receiving ketoconazole 200-400 mg three times daily with replacement doses of prednisone. Progression-free survival （PFS） was calculated from the beginning of the ketoconazole therapy to the onset of disease progression. The prognostic value of different variables for PFS was assessed by Cox regression analysis. The median PFS was 2.6 months （0.5-8.6 months） for these patients. The serum testosterone level changed during therapy, which decreased when the prostate-specific antigen （PSA） declined; the serum testosterone level increased as the levels of PSA relapsed. The median PFS values for patients associated with different factors were the following： 1.4 and 3.5 months for a nadir PSA of ≥ 0.2 and 〈0.2 ng ml- 1, respectively （hazard rate （HR）=4.767, P〈0.001）; 3.1 and 1.6 months for a baseline testosterone of ≥0.1 and 〈0.1 ng m1-1, respectively （HR=2.865, P=0.012）; 2.8 and 1.9 months for a baseline haemoglobin of ≥ 120 and 〈120 g 1-1, respectively （HR= 1.605, P〈0.001）; and 3.0 and 1.9 months for a PSA doubling time （PSADT） of ≥ 2.0 and 〈2.0 months, respectively （HR= 1.454, P=-0.017）. A risk model was constructed according to the four factors that divided patients into three subgroups of low risk （0-1 factors）, moderate risk （2 factors） and high risk （3-4 factors） with PFS values of 3.6, 3.0 and 1.4 months, respectively （HR=1.619, P〈0.001）. A nadir PSA of ≥0.2 ng m1-1, a baseline testosterone of 〈0.1 ng m1-1, a baseline haemoglobin of 〈 120 g I- 1 and a PSADT of 〈2 months were associated with a poor PFS. This risk model could provide evidence to predict the survival benefit of ketoconazole therapy.展开更多
Objective:To review follow-up imaging after equivocal bone scans in men with castration resistant prostate cancer(CRPC)and examine the characteristics of equivocal bone scans that are associated with positive follow-u...Objective:To review follow-up imaging after equivocal bone scans in men with castration resistant prostate cancer(CRPC)and examine the characteristics of equivocal bone scans that are associated with positive follow-up imaging.Methods:We identified 639 men from five Veterans Affairs Hospitals with a technetium-99m bone scan after CRPC diagnosis,of whom 99(15%)had equivocal scans.Men with equivocal scans were segregated into“high-risk”and“low-risk”subcategories based upon wording in the bone scan report.All follow-up imaging(bone scans,computed tomography[CT],magnetic resonance imaging[MRI],and X-rays)in the 3 months after the equivocal scan were reviewed.Variables were compared between patients with a positive vs.negative follow-up imaging after an equivocal bone scan.Results:Of 99 men with an equivocal bone scan,43(43%)received at least one follow-up imaging test,including 32/82(39%)with low-risk scans and 11/17(65%)with high-risk scans(p=0.052).Of follow-up tests,67%were negative,14%were equivocal,and 19%were positive.Among those who underwent follow-up imaging,3/32(9%)low-risk men had metastases vs.5/11(45%)high-risk men(p=0.015).Conclusion:While 19%of all men who received follow-up imaging had positive follow-up imaging,only 9%of those with a low-risk equivocal bone scan had metastases versus 45%of those with high-risk.These preliminary findings,if confirmed in larger studies,suggest follow-up imaging tests for low-risk equivocal scans can be delayed while high-risk equivocal scans should receive follow-up imaging.展开更多
Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(...Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(computed tomography or bone scan)-has been defined as a lethal disease by the Prostate Cancer Work Group.One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC,with death occurring an average of 2.5 years after diagnosis of castration resistance.Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment.In patients with short PSA doubling times(<10 mo)and high baseline PSA levels,there is a high risk of bone metastases followed by prostate cancer-related mortality.These patients also present significant morbidity that negatively impacts quality of life(QoL).Recently,the results of three randomized trials(PROSPER,SPARTAN,and ARAMIS)were published.Those trials evaluated the efficacy of three different androgen receptor inhibitors-enzalutamide,apalutamide,and darolutamide-in patients with nmCRPC.In all three trials,the study drugs improved both metastasis-free survival and overall survival compared to placebo,plus on-going androgen deprivation therapy without a negative impact on QoL.In patients with nmCRPC,the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval.For patients with nmCRPC,these novel drugs offer new hope for better QoL and survival outcomes.展开更多
AIM： To review the defnition and performance of the commonly used end points in trials of systemic thera-pies in metastatic castration-resistant prostate cancer patients. METHODS： A literature search was undertaken...AIM： To review the defnition and performance of the commonly used end points in trials of systemic thera-pies in metastatic castration-resistant prostate cancer patients. METHODS： A literature search was undertaken on PubMed database to identify studies meeting estab-lished criteria, with the aim of selecting randomized clinical trials and study definition and performance of their end points. The end points were grouped into three categories： overall survival （OS）, time-to-event end points, and response end points. A special analysis was performed for secondary end points of the studies which documented a beneft in OS in the experimental arm. Finally, publishes analyses for surrogacy of the in-cluded end points were also reported. RESULTS： OS, time-to-event and response end points in 31 selected trials were analyzed. OS was the pri-mary end point in 14 trials, and the secondary end point in 17. A time-to-event end point was the primaryend point in 8 studies, and the secondary end point in 22; the most reported time-to-event end points were composite end points, and the events changed among trials. A response end point was the primary end point in 9 studies, in 3 it was prostate-specifc antigen （PSA）-related, in 3 pain-related and in 3 mixed. A response end point was the secondary end point in 19 studies： PSA response and radiologic response were the most frequently used secondary end points in 19 and 11 tri-als, respectively, while pain response was used in 5 studies.CONCLUSION： A homogeneous defnition of progres-sion in future trials is mandatory. Among response end points, pain-response and PSA-response appear to be the most reliable.展开更多
文摘This study aims to evaluate the potential value of patient characteristics in predicting overall survival （OS） in patients with metastatic castration-resistant prostate cancer （mCRPC） treated with docetaxel-based thermotherapy. A total of 115 patients with mCRPC undergoing a docetaxel q3w regimen were enrolled in this study. A survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models were used to evaluate the prognostic value of all covariates for OS. OS was also analysed after stratifying patients according to the results of multivariate analysis. The median OS for the entire cohort was 17.0 months. The multivariate analysis showed that the prostate-specific antigen doubling time （PSADT）, baseline haemoglobin （Hb） concentration, alkaline phosphatase （ALP） concentration, cycles of chemotherapy and time to castration resistance were independent prognostic factors of OS. According to the presence of PSADT 〈46.3 days and baseline ALP/〉 110 IU 1-1, all patients were divided into three risk groups： low-risk group （no risk factors）, intermediate-risk group （one risk factor） and high-risk group （two risk factors）. Median OSs for patients in low-, intermediate- and high-risk groups were 28.0 months （95% Ch 23.8-32.2）, 21.0 months （95% Ch 18.9-23.1） and 11.0 months （95% Ch 7.6-14.4）, respectively （P〈O.O01）. In conclusion, PSADT, baseline Hb concentration, ALP concentration, cycles of chemotherapy and time to castration resistance were independent prognostic factors of OS in Chinese patients with mCRPC treated with docetaxel. PSADT combined with the baseline ALP concentration could be a useful risk stratification parameter for evaluating survival outcomes.
文摘Eastern Cooperative Oncology Group(ECOG)performance status and Gleason score are commonly investigated factors for overall survival(OS)in men with castration-resistant prostate cancer(CRPC).However,there is a lack of consistency regarding their prognostic or predictive value for OS.Therefore,we performed this meta-analysis to assess the associations of ECOG performance status and Gleason score with OS in CRPC patients and compare the two markers in patients under different treatment regimens or with different chemotherapy histories.A systematic literature review of monotherapy studies in CRPC patients was conducted in the PubMed database until May 2019.The data from 8247 patients in 34 studies,including clinical trials and real-world data,were included in our meta-analysis.Of these,twenty studies reported multivariate results and were included in our main analysis.CRPC patients with higher ECOG performance statuses(≥2)had a significantly increased mortality risk than those with lower ECOG performance statuses(<2),hazard ratio(HR):2.10,95%confidence interval(CI):1.68-2.62,and P<0.001.The synthesized HR of OS stratified by Gleason score was 1.01,with a 95%CI of 0.62-1.67(Gleason score≥8 vs<8).Subgroup analysis showed that there was no significant difference in pooled HRs for patients administered taxane chemotherapy(docetaxel and cabazitaxel)and androgen-targeting therapy(abiraterone acetate and enzalutamide)or for patients with different chemotherapy histories.ECOG performance status was identified as a significant prognostic factor in CRPC patients,while Gleason score showed a weak prognostic value for OS based on the available data in our meta-analysis.
文摘Availability of novel hormonal therapies as well as docetaxel and cabazitaxel treatment for metastatic castration-resistant prostate cancer （CRPC） has changed the outlook for this group of patients with improvements in progression-free survival and overall survival. Physicians often diagnose the progression of prostate cancer using serum prostate-specific antigen （PSA）. However, serum PSA is not always correlated with the clinical status in CRPC. To evaluate the PSA dynamics with greater precision, understanding of the control of PSA and of the mechanisms of development of CRPC is needed. Moreover, it is necessary to use new hormonal therapies with an appropriate timing to optimally improve the prognosis and the QOL of the patients. In the present review, we ascertain the PSA dynamics and the mechanisms of the development of CRPC to assist in optimal utilization of the new treatments for mCRPC.
基金The study was supported by Clinical Research Plan of SHDC(No.SHDC2020CR3014A)National Natural Science Foundation of China(Grant No.82003148).
文摘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 models to predict sensitivity to docetaxel chemotherapy in patients with mCRPC by using serum surface-enhanced Raman spectroscopy(SERS).A total of 32 mCPRC patients who underwent docetaxel chemo-therapy at our center from July 2016 to March 2018 were included in this study.Patients were dichotomized in prostate-specific antigen(PSA)response group(n=17)versus PSA failure group(n=15)according to the response to docetaxel.In total 64 matched spectra from 32 mCRPC patients were obtained by using SERS of serum at baseline(q0)and after 1 cycle of docetaxel chemotherapy(ql).Comparing Raman peaks of serum samples at baseline(q0)be-tween two groups,significant differences revealed at the peaks of 638,810,890(p<0.05)and 1136cm^(-1)(p<0.01).The prediction models of peak 1363 cm^(-1)and principal component anal-ysis and linear discriminant analysis(PCA-LDA)based on Raman data were established,re-spectively.The sensitivity and specificity of the prediction models were 71%,80%and 69%,78%through the way of leave-one-out cross-validation.According to the results of five-cross-valida-tion,the PCA-LDA model revealed an accuracy of 0.73 and AUC of 0.83.
文摘This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate （AA） and enzalutamide （Enz） for metastatic castration-resistant prostate cancer （mCRPC）. A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA （active comparator） and Enz （true placebo） randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings （HR. 0.90, 95% CI, 0.73-1.11; HR： 0.85, 95% CI, 0.68-1.07）. Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons： time to prostate-specific antigen （PSA） progression （HR. 0.34, 95% CI, 0.28-0.42; HR： 0.40, 95% CI, 0.30-0.53）, radiographic progression-free survival （HR： 0.37, 95% CI, 0.28-0.48; HR： 0.61, 95% CI, 0.50-0.74）, and PSA response rate （OR： 18.29, 95% CI, 11.20-29.88; OR： 10.69, 95% CI, 3.92-29.20）. With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.
基金This work was supported by the National Natural Science Foundation of China （NSFC 81672547, 81402110, and 81272820） Science and Technology Support Program of Sichuan Province （2015SZ0142） and the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University.
文摘Even in the era of novel targeted agents, switching to a second-line nonsteroidal antiandrogen （NSAA） is still widely used in treating metastatic castration-resistant prostate cancer （mCRPC）, especially in undeveloped countries. However, whether prior treatment with a second-line NSAA would impact the efficacy of abiraterone acetate （Abi） remains uncertain, in the current study, 87 mCRPC patients treated with Abi were analyzed. Among them, 21 were treated with a second-line NSAA （from bicalutamide to flutamide） before receiving abiraterone, while the remaining 66 received Abi directly. Therapeutic efficacy of Abi was compared between those with and without prior second-line NSAA using Kaplan-Meier curves, log-rank test, and Cox regression models. The therapeutic efficacy of Abi was similar between those with or without the prior switching treatment of flutamide, in terms of either prostate-specific antigen progression-free survival （PSA-PFS, 5.5 vs 5.6 months, P = 0.967）, radiographic progression-free survival （rPFS, 12.8 vs 13.4 months, P = 0.508）, overall survival （OS, not reached vs 30.6 months, P = 0.606）, or PSA-response rate （71.4% [15121] vs 60.6% [40166], P = 0.370）. This is the first time that the impact of prior switching of treatment to a second-line NSAA on the efficacy of Abi in mCRPC patients has been addressed. Our data support that, use of prior sequential bicalutamide and flutamide does not seem to preclude response to abiraterone, although larger cohort studies and, ideally, a randomized controlled trial are needed. These findings will facilitate doctors＇ decision-making in the treatment of mCRPC patients, especially for those with previous experience of switching NSAA second-line treatments in the clinic.
基金the National Natural Science Foundation(No.81702535,81572531)Natural Science Foundation of Shanghai Municipality(No.16ZR1406500)Outstanding Young Talent Training Plan of Shanghai Municipal Commission of Health and Family Planning(No.XYQ2013102).
文摘This study investigated the clinical activity of abiraterone plus prednisone in docetaxel-naive and docetaxel-resistant Chinese patients with metastatic castratio n-resista nt prostate can cer(mCRPC).A total of 146 patie nts with docetaxel-naive group(103 cases)and docetaxel-resista nt group(43 cases)were en rolled from the Sha nghai Cancer Center(Sha nghai,Chin a)in this retrospective cohort study.The efficacy endpoints were prostate-specific antigen response rate,prostate-specific antigen progress!on-free survival,clinical/radiographic progression-free survival,and overall survival in response to abiraterone plus prednisone.Significantly higher prostate-specific antigen response rate was found in docetaxel-naive group(54.4%,56/103)compared to docetaxel-resistant group(34.9%,15/43)(P=0.047).In addition,significantly higher median prostate-specific antigen progress!on-free survival(14.0 vs 7.7 months,P=0.005),clinical or radiographic progression-free survival(17.0 vs 12.5 months,P=0.003),and overall survival(27.0 vs 18.0 mon ths,P=0.016)were found in docetaxel-naTve group compared to docetaxel-resistant group,respectively.The univariate and multivariate analyses indicated that lower albumin and visceral metastases were independent significant predictors for shorter overall survival.To sum up,our data suggested that abiraterone plus prednisone was efficient in both docetaxel-naTve and docetaxel-resistant Chinese patients.Moreover,higher PSA response rate and longer overall survival were observed in the docetaxel-naTve group,which suggested that abiraterone was more effective for docetaxel-naive patients than for docetaxel failures.
文摘Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer （CRPC）, it is possible to detect persistent activation of the androgen receptor （AR） through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17（^-hydroxylase and 17,20-1yase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival （OS） with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone （ACTH）, providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-1yase （orteronel, galeterone and VT-464） that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.
基金This study was partially supported by the National Natural Science Foundation of China （NSFC 81202014 to KJW, NSFC 81130041 to DLH） and the Fundamental Research Funds for the Central Universities （to KIW）.
文摘Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer （mCRPC） in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen （PSA） level 〉50% during the treatment and investigated the potential role of time to nadir （TTN） of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival （OS）. In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN 〈17 weeks （42.83 vs 21.50 weeks, P 〈 0.001）. The time to PSA progression in patients with TTN ：〉17 weeks was 11.44 weeks compared to 5.63 weeks when TTN was 〈17 weeks. We found several factors to be associated with OS, including TTN （hazard ratio [HR]. 3.937, 95% confidence interval [CI]： 1.502-10.309, P = 0.005）, PSA level at the diagnosis of cancer （HR： 4,337, 95% CI： 1.616-11.645, P= 0.004）, duration of initial androgen deprivation therapy （HR： 2.982, 95% CI： 1.104-8.045, P= 0.031）, neutrophil-to-lymphocyte ratio （HR： 3.963, 95% CI： 1.380-11.384, P = 0.011）, and total PSA response （Class 1 [〈0 response] compared to Class 2 [0-50% response], HR： 3.978, 95% CI： 1.278-12.387, P = 0.017）. In conclusion, TTN of PSA remains an important prognostic marker in predicting therapeutic outcome in Chinese population who receive chemotherapy for mCRPC and have 〉50% PSA remission.
文摘Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer （CRPC）; however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival （OS）. We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 （53.6%）, 34 （30.9%）, and 17 （15.5%） in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C-index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations （〈110 g l^-1）, liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation （〈36 months） as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 （95% CI, 0.678-0.836）. In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters.
基金This work was supported by the Natural Science Foundation of China(NSFC,No.81672547,81872107,81872108,81972502,81902577,and 81902577)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(No.0040205301E21)+1 种基金the Research Foundation for the Postdoctoral Program of Sichuan University(2021SCU12014)Postdoctoral Research Project,West China Hospital,Sichuan University(20HXBH026).
文摘Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer(mCRPC).Here,we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate(AA).We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018.All cases received AA plus prednisone as first-line therapy during mCRPC.Primary end points were biochemical progression-free survival(bPFS)and overall survival(OS).The risk groups were defined based on multivariate analysis.A total of 42(41.6%)and 25(24.8%)patients achieved 30%and 50%decline in prostate-specific antigen(PSA),respectively,after corticosteroid switching.The median bPFS and median OS on AA plus dexamethasone were 4.9(95%confidence interval[CI]:3.7–6.0)months and 18.8(95%CI:16.2–30.2)months,respectively.Aldo-keto reductase family 1 member C3(AKR1C3)expression(hazard ratio[HR]:2.15,95%Cl:1.22–3.80,P=0.008)and baseline serum alkaline phosphatase(ALP;HR:4.95,95%Cl:2.40–10.19,P<0.001)were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS.Only baseline serum ALP>160 IU l−1(HR:3.41,95%Cl:1.57–7.38,P=0.002)together with PSA level at switch≥50 ng ml−1(HR:2.59,95%Cl:1.22–5.47,P=0.013)independently predicted poorer OS.Based on the predictive factors in multivariate analysis,we developed two risk stratification tools to select candidates for corticosteroid switching.Detection of serum ALP level,PSA level,and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.
文摘AIM: To study the efficacy and safety of abiraterone in patients with and without prior chemotherapy.METHODS: The databases including Pub Med and abstracts presented at the American Society of Clinical Oncology meetings up to April 2014 were systematically searched. Eligible studies included randomized controlled trials(RCTs) in which abiraterone plus prednisone was compared to placebo plus prednisone in metastatic castration-resistant prostate cancer(CRPC) patients. The summary incidence, relative risk, hazard ratio and 95%CI were calculated using random or fixed-effects models. Heterogeneity test was performed to test between-study differences in efficacy and toxicity.RESULTS: A total of two phase III RCTs were included in our analysis, with metastatic CPRC patients before(n = 1088) and after chemotherapy(n = 1195). Prior chemotherapy did not significantly alter the effect of abiraterone on overall survival(P = 0.92) and prostatespecific antigen(PSA) progression-free survival(P = 0.13), but reduced its effect on radiographic-prog-ression-free survival(P = 0.04), objective response rate(P < 0.001), and PSA response rate(P < 0.001). Prior chemotherapy significantly increased the specific risk of fluid retention and edema(P < 0.001) and hypokalemia(P < 0.001), but decreased the risk of all-grade hypertension(P < 0.001) attributable to abiraterone. There was no significant difference of cardiac disorders associated with abiraterone between the two settings(P = 0.58). CONCLUSION: Prior chemotherapy may reduce the effectiveness of abiraterone in patients with metastatic CRPC.
文摘PROSPER is an international Phase III trial demonstrating the beneficial role of enzalutamide,an androgen receptor antagonist,in prolonging metastasisfree survival in men with nonmetastatic castration-resistant prostate cancer.The trial showed that the median metastasis-free survival was 21.9 months longer for those treated with enzalutamide(36.6 months)compared to those treated with placebo(14.7 months).Enzalutamide also showed prolonged time to PSA progression,PSA response,and time to initiating additional antineoplastic therapy although overall survival is not yet reached.Enzalutamide is the second antiandrogen(next to apalutamide)that has gained the United States Food and Drug Administration(US FDA)label indication for use in the setting of nonmetastatic castration-resistant prostate cancer.
文摘Based on the results of TAX 327, a nomogram was developed to predict the overall survival of metastatic castration-resistant prostate cancer （mCRPC） after first-line chemotherapy. The nomogram, however, has not been validated in an independent dataset, especially in a series out of clinical trials. Thus, the objective of the current study was to validate the TAX 327 nomogram in a community setting in China. A total of 146 patients with mCRPC who received first-line chemotherapy （docetaxel or mitoxantrone） were identified. Because clinical trials are limited in China's Mainland, those patients did not receive investigational treatment after the failure of first-line chemotherapy. The predicted overall survival rate was calculated from the TAX 327 nomogram. The validity of the model was assessed with discrimination, calibration and decision curve analysis. The median survival of the cohort was 21 months （docetaxel） and 19 months （mitoxantrone） at last follow-up. The predictive c-index of the TAX 327 nomogram was 0.66 （95% CI： 0.54-0.70）. The calibration plot demonstrated that the 2-year survival rate was underestimated by the nomogram. Decision curve analysis showed a net benefit of the nomogram at a threshold probability greater than 30%. In conclusion, the present validation study did not confirm the predictive value of the TAX 327 nomogram in a contemporary community series of men in China, and further studies with a large sample size to develop or validate nomograms for predicting survival and selecting therapies in advanced prostate cancer are necessary.
基金supported financially by the Medical Innovation Research Project of the Science and Technology Commission of Shanghai Municipality(20Y11905000)Natural Science Foundation of Science and Technology Commission of Shanghai Municipality(20ZR1412300)AoXiang Project of the Shanghai Anti-Cancer Association(SACA-AX202005).
文摘We evaluated the relationships of body composition and serum adipocytokine levels with progression-free survival(PFS)and overall survival(OS)in metastatic castration-resistant prostate cancer(mCRPC)patients receiving docetaxel.The medical records of mCRPC patients who received docetaxel between January 2011 and December 2015 at Fudan University Shanghai Cancer Center(Shanghai,China)were reviewed.The following body composition parameters were calculated using computed tomography:skeletal muscle index(SMI),visceral adipose tissue index(VATI),and subcutaneous adipose tissue index(SATI).Pretreatment serum adipocytokine levels,including interleukin 6,insulin,leptin,monocyte chemoattractant protein-1,adiponectin,and resistin,were measured using the multiplex bead-based immunoassays.Cox regression and Kaplan–Meier methods were used for survival analyses.Of the 453 mCRPC patients initially identified,105 were included in the analysis.High VATI group patients had longer PFS(median,10 months vs 7 months,P=0.008)and OS(median,24 months vs 15 months,P=0.017),compared with low VATI group patients.SMI and SATI were not significantly associated with PFS or OS.Of the six detected adipocytokines,only leptin was associated with mCRPC prognosis.High leptin group patients had shorter PFS(median,7 months vs 12 months,P=0.0018)and OS(median,17 months vs 22 months,P=0.042),compared with low leptin group patients.Multivariate analysis showed that a high VATI was an independent protective factor for PFS and OS,while a high leptin level was an independent risk factor for PFS and OS.Therefore,VATI and serum leptin levels could provide important information concerning mCRPC prognosis.
基金supported by the Science and Technology Support Program of Sichuan Province(2021YFS0119)the Natural Science Foundation of China(No.82172785,81902577,81974398,and 81872107)+1 种基金Research Foundation for the Postdoctoral Program of Sichuan University(2021SCU12014)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC21020).
文摘Patients with bone metastatic castration-resistant prostate cancer (mCRPC) might benefit from radium-223 (^(223)Ra) combined withnew-generation hormonal agents (NHAs) in terms of survival and quality of life (QoL). However, the safety of combination therapiesremains unclear. Therefore, we aimed to perform a network meta-analysis by reviewing the literature about the combination of^(223)Ra with abiraterone acetate plus prednisone (AAP) or enzalutamide and to evaluate the safety of combination therapy in bonemCRPC patients. Ultimately, ten studies (2835 patients) were selected, including four randomized controlled trials (RCTs), fiveretrospective cohort studies, and one single-arm study. Overall, there was no difference in the incidence of fracture between the^(223)Ra+NHA combination group and the ^(223)Ra monotherapy group (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 0.91–2.34,P = 0.66), but the incidences in both the ^(223)Ra+NHA combination group (OR: 3.22, 95% CI: 2.24–4.63, P < 0.01) and the ^(223)Ramonotherapy group (OR: 2.24, 95% CI: 1.23–4.08, P < 0.01) were higher than that in the NHA monotherapy group. However, inthe meta-analysis involving only RCTs, there was no difference between the ^(223)Ra monotherapy group and the NHA monotherapygroup (OR: 1.14, 95% CI: 0.22–5.95, P = 0.88), while the difference between the ^(223)Ra+NHA combination group and the NHAmonotherapy group remained significant (OR: 3.22, 95% CI: 2.24–4.63, P < 0.01). Symptomatic skeletal events (SSEs), SSE-freesurvival (SSE-FS), all grades of common adverse events (AEs), and ≥grade 3 AEs among all groups did not show any significantdifference. Our results indicate that the combination of ^(223)Ra with NHAs was well tolerated in bone mCRPC patients compared to ^(223)Ra monotherapy, even though the incidence of fracture was higher in patients who received ^(223)Ra than that among those whoreceived NHA monotherapy. More evidence is needed to explore the safety and efficiency of ^(223)Ra combination therapies.
文摘We investigated the prognostic value of some variables of effective ketoconazole treatment for metastatic castration-resistant prostate cancer （mCRPC）. In total, 163 patients with mCRPC were eligible, receiving ketoconazole 200-400 mg three times daily with replacement doses of prednisone. Progression-free survival （PFS） was calculated from the beginning of the ketoconazole therapy to the onset of disease progression. The prognostic value of different variables for PFS was assessed by Cox regression analysis. The median PFS was 2.6 months （0.5-8.6 months） for these patients. The serum testosterone level changed during therapy, which decreased when the prostate-specific antigen （PSA） declined; the serum testosterone level increased as the levels of PSA relapsed. The median PFS values for patients associated with different factors were the following： 1.4 and 3.5 months for a nadir PSA of ≥ 0.2 and 〈0.2 ng ml- 1, respectively （hazard rate （HR）=4.767, P〈0.001）; 3.1 and 1.6 months for a baseline testosterone of ≥0.1 and 〈0.1 ng m1-1, respectively （HR=2.865, P=0.012）; 2.8 and 1.9 months for a baseline haemoglobin of ≥ 120 and 〈120 g 1-1, respectively （HR= 1.605, P〈0.001）; and 3.0 and 1.9 months for a PSA doubling time （PSADT） of ≥ 2.0 and 〈2.0 months, respectively （HR= 1.454, P=-0.017）. A risk model was constructed according to the four factors that divided patients into three subgroups of low risk （0-1 factors）, moderate risk （2 factors） and high risk （3-4 factors） with PFS values of 3.6, 3.0 and 1.4 months, respectively （HR=1.619, P〈0.001）. A nadir PSA of ≥0.2 ng m1-1, a baseline testosterone of 〈0.1 ng m1-1, a baseline haemoglobin of 〈 120 g I- 1 and a PSADT of 〈2 months were associated with a poor PFS. This risk model could provide evidence to predict the survival benefit of ketoconazole therapy.
基金The study was supported by the NIH/NCI under Award Number P50CA09231(WJA)and NIH K24 CA160653(SJF).
文摘Objective:To review follow-up imaging after equivocal bone scans in men with castration resistant prostate cancer(CRPC)and examine the characteristics of equivocal bone scans that are associated with positive follow-up imaging.Methods:We identified 639 men from five Veterans Affairs Hospitals with a technetium-99m bone scan after CRPC diagnosis,of whom 99(15%)had equivocal scans.Men with equivocal scans were segregated into“high-risk”and“low-risk”subcategories based upon wording in the bone scan report.All follow-up imaging(bone scans,computed tomography[CT],magnetic resonance imaging[MRI],and X-rays)in the 3 months after the equivocal scan were reviewed.Variables were compared between patients with a positive vs.negative follow-up imaging after an equivocal bone scan.Results:Of 99 men with an equivocal bone scan,43(43%)received at least one follow-up imaging test,including 32/82(39%)with low-risk scans and 11/17(65%)with high-risk scans(p=0.052).Of follow-up tests,67%were negative,14%were equivocal,and 19%were positive.Among those who underwent follow-up imaging,3/32(9%)low-risk men had metastases vs.5/11(45%)high-risk men(p=0.015).Conclusion:While 19%of all men who received follow-up imaging had positive follow-up imaging,only 9%of those with a low-risk equivocal bone scan had metastases versus 45%of those with high-risk.These preliminary findings,if confirmed in larger studies,suggest follow-up imaging tests for low-risk equivocal scans can be delayed while high-risk equivocal scans should receive follow-up imaging.
文摘Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(computed tomography or bone scan)-has been defined as a lethal disease by the Prostate Cancer Work Group.One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC,with death occurring an average of 2.5 years after diagnosis of castration resistance.Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment.In patients with short PSA doubling times(<10 mo)and high baseline PSA levels,there is a high risk of bone metastases followed by prostate cancer-related mortality.These patients also present significant morbidity that negatively impacts quality of life(QoL).Recently,the results of three randomized trials(PROSPER,SPARTAN,and ARAMIS)were published.Those trials evaluated the efficacy of three different androgen receptor inhibitors-enzalutamide,apalutamide,and darolutamide-in patients with nmCRPC.In all three trials,the study drugs improved both metastasis-free survival and overall survival compared to placebo,plus on-going androgen deprivation therapy without a negative impact on QoL.In patients with nmCRPC,the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval.For patients with nmCRPC,these novel drugs offer new hope for better QoL and survival outcomes.
文摘AIM： To review the defnition and performance of the commonly used end points in trials of systemic thera-pies in metastatic castration-resistant prostate cancer patients. METHODS： A literature search was undertaken on PubMed database to identify studies meeting estab-lished criteria, with the aim of selecting randomized clinical trials and study definition and performance of their end points. The end points were grouped into three categories： overall survival （OS）, time-to-event end points, and response end points. A special analysis was performed for secondary end points of the studies which documented a beneft in OS in the experimental arm. Finally, publishes analyses for surrogacy of the in-cluded end points were also reported. RESULTS： OS, time-to-event and response end points in 31 selected trials were analyzed. OS was the pri-mary end point in 14 trials, and the secondary end point in 17. A time-to-event end point was the primaryend point in 8 studies, and the secondary end point in 22; the most reported time-to-event end points were composite end points, and the events changed among trials. A response end point was the primary end point in 9 studies, in 3 it was prostate-specifc antigen （PSA）-related, in 3 pain-related and in 3 mixed. A response end point was the secondary end point in 19 studies： PSA response and radiologic response were the most frequently used secondary end points in 19 and 11 tri-als, respectively, while pain response was used in 5 studies.CONCLUSION： A homogeneous defnition of progres-sion in future trials is mandatory. Among response end points, pain-response and PSA-response appear to be the most reliable.
