Intermittent androgen deprivation therapy(IADT)is now being increasingly opted by the treating physicians and patients with prostate cancer.The most common reason driving this is the availability of an off-treatment p...Intermittent androgen deprivation therapy(IADT)is now being increasingly opted by the treating physicians and patients with prostate cancer.The most common reason driving this is the availability of an off-treatment period to the patients that provides some relief from treatment-related side-effects,and reduced treatment costs.IADT may also delay the progression to castration-resistant prostate cancer.However,the use of IADT in the setting of prostate cancer has not been strongly substantiated by data from clinical trials.Multiple factors seem to contribute towards this inadequacy of supportive data for the use of IADT in patients with prostate cancer,e.g.,population characteristics(both demographic and clinical),study design,treatment regimen,on-and off-treatment criteria,duration of active treatment,endpoints,and analysis.The present review article focuses on seven clinical trials that evaluated the efficacy of IADT vs.continuous androgen deprivation therapy for the treatment of prostate cancer.The results from these clinical trials have been discussed in light of the factors that may impact the treatment outcomes,especially the disease(tumor)burden.Based on evidence,potential candidate population for IADT has been suggested along with recommendations for the use of IADT in patients with prostate cancer.展开更多
Intermittent androgen deprivation therapy （IADT） is an alternative to continuous androgen deprivation therapy （ADT） in prostate cancer patients with nonmetastatic disease. ADT is associated with numerous side effe...Intermittent androgen deprivation therapy （IADT） is an alternative to continuous androgen deprivation therapy （ADT） in prostate cancer patients with nonmetastatic disease. ADT is associated with numerous side effects such as hot flashes, sexual dysfunction, anemia, fatigue, loss of muscle mass, osteoporosis, metabolic syndrome and premature cardiovascular disease. IADT was developed with the intention of improving the quality of life and to delay progression of prostate cancer to castration resistance. The benefits of slightly improved quality of life by IADT compared to ADT were demonstrated in multiple clinical trials. IADT was noted to be noninferior to ADT in patients with biochemical recurrence of prostate cancer but in studies performed in patients with metastatic prostate cancer, the results were inconclusive. Our recent studies suggested that the administration of 5 alpha-reductase inhibitors during the off-cycle of IADT can significantly prolong the survival of mice bearing androgen-sensitive prostate tumors when off-cycle duration was short. This review discusses the survival benefit of 5 alpha-reductase inhibition in IADT in animal models and the potential translation of this finding into clinic.展开更多
Objective The aim of the study was to evaluate the efficiency of salvage treatments for prostate specific antigen(PSA)relapse of cT3N0M0 prostatic adenocarcinoma(PCa)after radical prostatectomy(RP)combined with neoadj...Objective The aim of the study was to evaluate the efficiency of salvage treatments for prostate specific antigen(PSA)relapse of cT3N0M0 prostatic adenocarcinoma(PCa)after radical prostatectomy(RP)combined with neoadjuvant androgen deprivation(ADT).Methods A total of 332 patients with cT3N0M0 PCa were enrolled in the prospective study and received RP and pelvic lymph node dissection with neoadjuvant ADT for 3 months.All patients with PSA relapse were treated with salvage external beam radiation therapy(RT)and ADT for 6 months.Results The 5-year postoperative PSA relapse rate was 40.96%(136/332).The patients have been divided into the PSA relapse and PSA relapse-free groups in order to compare patient characteristics.The ratio of patients with Gleason score≥8 and positive surgical margin in the PSA relapse group were significantly higher than those of in the PSA relapse-free group(P=0.01).The mean duration between the start of operative treatment and PSA relapse was 31 months.Salvage treatment to all 136 PSA relapse patients led to favorable outcomes.PSA relapse was not observed after salvage treatment by the end of follow-up.The 5-year overall survival rates of the PSA relapse and PSA relapse-free groups were 94.9%and 93.9%,respectively.Conclusion In pursuit of curative treatment,our study showed that RP combined with neoadjuvant ADT is an aggressive multimodality strategy associated with lower PSA relapse and better survival outcomes for stage cT3N0M0 PCa patients.Patients with PSA relapse after RP may benefit from early aggressive salvage RT combined with short-term ADT.展开更多
Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogenei...Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.展开更多
In this review, we summarize our recently developed mathematical models that predict the effects of intermittent androgen suppression therapy on prostate cancer （PCa）. Although hormone therapy for PCa shows remarkab...In this review, we summarize our recently developed mathematical models that predict the effects of intermittent androgen suppression therapy on prostate cancer （PCa）. Although hormone therapy for PCa shows remarkable results at the beginning of treatment, cancer cells frequently acquire the ability to grow without androgens during long-term therapy, resulting in an eventual relapse. To circumvent hormone resistance, intermittent androgen suppression was investigated as an alternative treatment option. However, at the present time, it is not possible to select an optimal schedule of on- and off-treatment cycles for any given patient. In addition, clinical trials have revealed that intermittent androgen suppression is effective for some patients but not for others. To resolve these two problems, we have developed mathematical models for PCa under intermittent androgen suppression. The mathematical models not only explain the mechanisms of intermittent androgen suppression but also provide an optimal treatment schedule for the on- and off-treatment periods.展开更多
Objectives: to describe the characteristics of newly diagnosed prostate cancer (PCa) and the initial treatments offered to patients in the most important urological center of Burkina Faso. Methods: We analyzed the dat...Objectives: to describe the characteristics of newly diagnosed prostate cancer (PCa) and the initial treatments offered to patients in the most important urological center of Burkina Faso. Methods: We analyzed the data of a cohort of 168 consecutive patients with no prior history of PCa between January 2009 and December 2012. Diagnosis of PCa was based on histological analysis of transrectal prostate biopsies. Patient and disease characteristics and the initial treatment offered were taken in account. Results: The mean age at presentation was 68.59 ± 9.41 years (range 30 to 95 years). There was a 3.6-fold increase in the incidence of PCa through the four years of the study. The mean duration of symptoms prior to presentation was 11.6 ± 10.9 months. The majority of cases (86.9%) were presented as locally advanced or metastatic disease. Androgen deprivation therapy (ADT) was the first therapeutic option for 121 patients (72%) and 73 patients (43.4%) underwent ADT through bilateral orchiectomy. Only 3 patients (1.78%) underwent radical prostatectomy. Conclusion: An increase in the diagnosis of PCa in our country was observed in this study. The diagnosis of prostate cancer was usually tardive in Burkina Faso. Treatment often involves surgical ADT for socioeconomic reasons.展开更多
Prostate cancer(PC)is the most frequently diagnosed cancer and second leading cause of cancer-related deaths in men.It is heterogeneous,as is evident from the wide spectrum of therapeutic approaches.Most patients with...Prostate cancer(PC)is the most frequently diagnosed cancer and second leading cause of cancer-related deaths in men.It is heterogeneous,as is evident from the wide spectrum of therapeutic approaches.Most patients with PC are initially responsive to androgen deprivation therapy;however,themajority of cases are either hormone-sensitive PC or castration-resistant PC.Current therapeutic protocols follow the evolution of PC,a continuously progressive process involving a combination of widespread genomic alterations.These genomic alterations are either hereditary germline mutations,such as mutations in BRCA2,or specific only to tumor cells(somatic).Tumor-specific genomic spectra include genomic structural rearrangements,canonical androgen response genes,andmany other specific genes such as TMPRSS2-ERG fusion,SPOP/FOXA1,TP53/RB1/PTEN,andBRCA2.New evidence indicates the involvement of signaling pathways including PI3K,WNT/β-catenin,SRC,and IL-6/STAT,which have been shown to promote epithelial-mesenchymal transition cancer stem cell–like features/stemness,and neuroendocrine differentiation in PC.Over the last decade,our understanding of the genotype-phenotype relationships has been enhanced considerably.The genetic background of PC related to canonical genetic alterations and signaling pathway activation genes has shed more insight into the molecular subtype and disease landscape,resulting in a more flexible role of individual therapies targeting diverse genotypes and phenotypes.展开更多
基金Ferring Pharmaceuticals provided funding for editorial assistance.The author acknowledges Dr.Payal Bhardwaj of Tata Consultancy Services,who provided editorial assistance.
文摘Intermittent androgen deprivation therapy(IADT)is now being increasingly opted by the treating physicians and patients with prostate cancer.The most common reason driving this is the availability of an off-treatment period to the patients that provides some relief from treatment-related side-effects,and reduced treatment costs.IADT may also delay the progression to castration-resistant prostate cancer.However,the use of IADT in the setting of prostate cancer has not been strongly substantiated by data from clinical trials.Multiple factors seem to contribute towards this inadequacy of supportive data for the use of IADT in patients with prostate cancer,e.g.,population characteristics(both demographic and clinical),study design,treatment regimen,on-and off-treatment criteria,duration of active treatment,endpoints,and analysis.The present review article focuses on seven clinical trials that evaluated the efficacy of IADT vs.continuous androgen deprivation therapy for the treatment of prostate cancer.The results from these clinical trials have been discussed in light of the factors that may impact the treatment outcomes,especially the disease(tumor)burden.Based on evidence,potential candidate population for IADT has been suggested along with recommendations for the use of IADT in patients with prostate cancer.
文摘Intermittent androgen deprivation therapy （IADT） is an alternative to continuous androgen deprivation therapy （ADT） in prostate cancer patients with nonmetastatic disease. ADT is associated with numerous side effects such as hot flashes, sexual dysfunction, anemia, fatigue, loss of muscle mass, osteoporosis, metabolic syndrome and premature cardiovascular disease. IADT was developed with the intention of improving the quality of life and to delay progression of prostate cancer to castration resistance. The benefits of slightly improved quality of life by IADT compared to ADT were demonstrated in multiple clinical trials. IADT was noted to be noninferior to ADT in patients with biochemical recurrence of prostate cancer but in studies performed in patients with metastatic prostate cancer, the results were inconclusive. Our recent studies suggested that the administration of 5 alpha-reductase inhibitors during the off-cycle of IADT can significantly prolong the survival of mice bearing androgen-sensitive prostate tumors when off-cycle duration was short. This review discusses the survival benefit of 5 alpha-reductase inhibition in IADT in animal models and the potential translation of this finding into clinic.
文摘Objective The aim of the study was to evaluate the efficiency of salvage treatments for prostate specific antigen(PSA)relapse of cT3N0M0 prostatic adenocarcinoma(PCa)after radical prostatectomy(RP)combined with neoadjuvant androgen deprivation(ADT).Methods A total of 332 patients with cT3N0M0 PCa were enrolled in the prospective study and received RP and pelvic lymph node dissection with neoadjuvant ADT for 3 months.All patients with PSA relapse were treated with salvage external beam radiation therapy(RT)and ADT for 6 months.Results The 5-year postoperative PSA relapse rate was 40.96%(136/332).The patients have been divided into the PSA relapse and PSA relapse-free groups in order to compare patient characteristics.The ratio of patients with Gleason score≥8 and positive surgical margin in the PSA relapse group were significantly higher than those of in the PSA relapse-free group(P=0.01).The mean duration between the start of operative treatment and PSA relapse was 31 months.Salvage treatment to all 136 PSA relapse patients led to favorable outcomes.PSA relapse was not observed after salvage treatment by the end of follow-up.The 5-year overall survival rates of the PSA relapse and PSA relapse-free groups were 94.9%and 93.9%,respectively.Conclusion In pursuit of curative treatment,our study showed that RP combined with neoadjuvant ADT is an aggressive multimodality strategy associated with lower PSA relapse and better survival outcomes for stage cT3N0M0 PCa patients.Patients with PSA relapse after RP may benefit from early aggressive salvage RT combined with short-term ADT.
文摘Neuroendocrine prostate cancer(NEPC)shows an aggressive behavior compared to prostate cancer(PCa),also known as prostate adenocarcinoma.Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer.NEPC may arise de novo or develop following androgen deprivation therapy(ADT).NEPC that arise following ADT has the nomenclature“treatmentemerging/induced NEPC(t-NEPC)”.t-NEPC would be anticipated in castration resistant prostate cancer(CRPC)and metastatic PCa.t-NEPC is characterized by low or absent androgen receptor(AR)expression,independence of AR signaling,and gain of neuroendocrine phenotype.t-NEPC is an aggressive metastatic tumor,develops from PCa in response to drug induced ADT,and shows very short response to conventional therapy.t-NEPC occurs in 10%-17%of patients with CRPC.De novo NEPC is rare and is accounting for less than 2%of all PCa.The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated.Sphingosine kinase 1 plays a significant role in t-NEPC development.Although neuroendocrine markers:Synaptophysin,chromogranin A,and insulinoma associated protein 1(INSM1)are expressed in t-NEPC,they are non-specific for diagnosis,prognosis,and follow-up of therapy.t-NEPC shows enriched genomic alteration in tumor protein P53(TP53)and retinoblastoma 1(RB1).There are evidences suggest that t-NEPC might develop through epigenetic evolution.There are genomic,epigenetic,and transcriptional alterations that are reported to be involved in development of t-NEPC.Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC.PCa is resistant to immunotherapy,and at present there are running trials to approach immunotherapy for PCa,CRPC,and t-NEPC.
文摘In this review, we summarize our recently developed mathematical models that predict the effects of intermittent androgen suppression therapy on prostate cancer （PCa）. Although hormone therapy for PCa shows remarkable results at the beginning of treatment, cancer cells frequently acquire the ability to grow without androgens during long-term therapy, resulting in an eventual relapse. To circumvent hormone resistance, intermittent androgen suppression was investigated as an alternative treatment option. However, at the present time, it is not possible to select an optimal schedule of on- and off-treatment cycles for any given patient. In addition, clinical trials have revealed that intermittent androgen suppression is effective for some patients but not for others. To resolve these two problems, we have developed mathematical models for PCa under intermittent androgen suppression. The mathematical models not only explain the mechanisms of intermittent androgen suppression but also provide an optimal treatment schedule for the on- and off-treatment periods.
文摘Objectives: to describe the characteristics of newly diagnosed prostate cancer (PCa) and the initial treatments offered to patients in the most important urological center of Burkina Faso. Methods: We analyzed the data of a cohort of 168 consecutive patients with no prior history of PCa between January 2009 and December 2012. Diagnosis of PCa was based on histological analysis of transrectal prostate biopsies. Patient and disease characteristics and the initial treatment offered were taken in account. Results: The mean age at presentation was 68.59 ± 9.41 years (range 30 to 95 years). There was a 3.6-fold increase in the incidence of PCa through the four years of the study. The mean duration of symptoms prior to presentation was 11.6 ± 10.9 months. The majority of cases (86.9%) were presented as locally advanced or metastatic disease. Androgen deprivation therapy (ADT) was the first therapeutic option for 121 patients (72%) and 73 patients (43.4%) underwent ADT through bilateral orchiectomy. Only 3 patients (1.78%) underwent radical prostatectomy. Conclusion: An increase in the diagnosis of PCa in our country was observed in this study. The diagnosis of prostate cancer was usually tardive in Burkina Faso. Treatment often involves surgical ADT for socioeconomic reasons.
文摘Prostate cancer(PC)is the most frequently diagnosed cancer and second leading cause of cancer-related deaths in men.It is heterogeneous,as is evident from the wide spectrum of therapeutic approaches.Most patients with PC are initially responsive to androgen deprivation therapy;however,themajority of cases are either hormone-sensitive PC or castration-resistant PC.Current therapeutic protocols follow the evolution of PC,a continuously progressive process involving a combination of widespread genomic alterations.These genomic alterations are either hereditary germline mutations,such as mutations in BRCA2,or specific only to tumor cells(somatic).Tumor-specific genomic spectra include genomic structural rearrangements,canonical androgen response genes,andmany other specific genes such as TMPRSS2-ERG fusion,SPOP/FOXA1,TP53/RB1/PTEN,andBRCA2.New evidence indicates the involvement of signaling pathways including PI3K,WNT/β-catenin,SRC,and IL-6/STAT,which have been shown to promote epithelial-mesenchymal transition cancer stem cell–like features/stemness,and neuroendocrine differentiation in PC.Over the last decade,our understanding of the genotype-phenotype relationships has been enhanced considerably.The genetic background of PC related to canonical genetic alterations and signaling pathway activation genes has shed more insight into the molecular subtype and disease landscape,resulting in a more flexible role of individual therapies targeting diverse genotypes and phenotypes.
