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Cancer Cell International Oct 2023Prostate cancer (PCa) is a non-cutaneous malignancy in males with wide variation in incidence rates across the globe. It is the second most reported cause of cancer... (Review)
Review
Prostate cancer (PCa) is a non-cutaneous malignancy in males with wide variation in incidence rates across the globe. It is the second most reported cause of cancer death. Its etiology may have been linked to genetic polymorphisms, which are not only dominating cause of malignancy casualties but also exerts significant effects on pharmacotherapy outcomes. Although many therapeutic options are available, but suitable candidates identified by useful biomarkers can exhibit maximum therapeutic efficacy. The single-nucleotide polymorphisms (SNPs) reported in androgen receptor signaling genes influence the effectiveness of androgen receptor pathway inhibitors and androgen deprivation therapy. Furthermore, SNPs located in genes involved in transport, drug metabolism, and efflux pumps also influence the efficacy of pharmacotherapy. Hence, SNPs biomarkers provide the basis for individualized pharmacotherapy. The pharmacotherapeutic options for PCa include hormonal therapy, chemotherapy (Docetaxel, Mitoxantrone, Cabazitaxel, and Estramustine, etc.), and radiotherapy. Here, we overview the impact of SNPs reported in various genes on the pharmacotherapy for PCa and evaluate current genetic biomarkers with an emphasis on early diagnosis and individualized treatment strategy in PCa.
PubMed: 37858151
DOI: 10.1186/s12935-023-03084-5 -
Korean Journal of Urology Nov 2011We investigated the efficacy of ketoconazole and estramustine before chemotherapy for treating patients with progressive castration-resistant prostate cancer (CRPC)...
PURPOSE
We investigated the efficacy of ketoconazole and estramustine before chemotherapy for treating patients with progressive castration-resistant prostate cancer (CRPC) after anti-androgen withdrawal syndrome.
MATERIALS AND METHODS
Eighty-four patients who were diagnosed with CRPC and were treated between 2005 and 2009 were included. Thirty-nine patients were treated with 600 mg of ketoconazole and 10 mg of prednisolone per day (group I), and 45 patients were treated with 560 mg of estramustine per day (group II). The prostate-specific antigen (PSA) response, progression-free survival, and side effects were compared.
RESULTS
The median age of the patients, PSA level, and follow-up period were 72 years, 48.5 ng/ml, and 4 months (range, 1 to 29 months), respectively. The overall PSA response rate was 35.7%, and the PSA response rates were 33.3% for group I and 37.8% for group II (p=0.672). The median progression-free survival times were 8 months (95% confidence interval [CI] 5.9-10.1) overall, 5 months (95% CI 1.6-8.3) in group I, and 8 months (95% CI 5.9-10.0) in group II (p=0.282). The most common complications in groups I and II were nausea and vomiting (51.3%) and anemia (77.8%), respectively. Nausea and vomiting and hepatotoxicity were observed more often in group I, and gynecomastia, neutropenia, and anemia were observed more often in group II. The toxicities of each adverse effect were ≤grade 2.
CONCLUSIONS
With a resultant PSA decline and mild adverse effects, both ketoconazole and estramustine are worth consideration as treatment options for progressive CRPC patients after primary hormonal therapy.
PubMed: 22195263
DOI: 10.4111/kju.2011.52.11.746 -
Annals of Oncology : Official Journal... Jul 2007Hormone-refractory prostate cancer (HRPC) is a progressive chemotherapy-resistant disease that remains a challenge to manage. Despite the recent approval of docetaxel... (Review)
Review
BACKGROUND
Hormone-refractory prostate cancer (HRPC) is a progressive chemotherapy-resistant disease that remains a challenge to manage. Despite the recent approval of docetaxel (Taxotere) for the treatment of HRPC, the need exists for additional novel agents that can further improve patient outcomes. The epothilones are potent antimicrotubule agents that have demonstrated activity in the setting of taxane resistance. They are structurally distinct compounds that appear to lack cross-resistance with the taxanes.
DESIGN
This review summarizes current preclinical and clinical data on the safety and efficacy of the epothilones ixabepilone (BMS-247550) and patupilone (EPO906) for the treatment of prostate cancer. Data were identified by searches of PubMed and the Proceedings of the American Society of Clinical Oncology annual meetings from 2000 to 2006.
RESULTS
The epothilones have demonstrated potent antitumor activity in vitro and in experimental animal models of prostate cancer. In clinical studies, the epothilones have demonstrated potent activity in HRPC, including no cross-resistance with the taxanes and a manageable toxicity profile. Phase II studies of single-agent ixabepilone in patients with HRPC have reported a confirmed prostate-specific antigen (PSA) response rate of 33%. Higher PSA response rates have been reported in studies that assessed the combination of ixabepilone and estramustine in patients with HRPC.
CONCLUSIONS
The epothilones are promising new chemotherapeutic agents that have demonstrated single-agent antitumor activity in HRPC in the phase II setting. Phase III trials are needed to confirm the activity of the epothilones in tandem with docetaxel, given the experience to date.
Topics: Animals; Antineoplastic Agents; Docetaxel; Epothilones; Humans; In Vitro Techniques; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Tubulin Modulators
PubMed: 17656558
DOI: 10.1093/annonc/mdm175 -
Cancer Feb 2011The use of docetaxel prolongs survival for patients with castrate-resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with...
BACKGROUND
The use of docetaxel prolongs survival for patients with castrate-resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with bevacizumab may further enhance the antitumor effect of docetaxel and estramustine in patients with CRPC.
METHODS
This cooperative group trial enrolled men with CRPC. Patients received oral estramustine 280 mg 3 times daily on Days 1 through 5 of every cycle plus 70 mg/m² docetaxel and 15 mg/kg bevacizumab on Day 2 every 3 weeks. Prostate-specific antigen (PSA) values were monitored every cycle, and imaging studies were obtained every 3 cycles. The primary endpoint was progression-free survival (PFS), and the secondary objectives were safety, PSA decline, measurable disease response, and overall survival.
RESULTS
Seventy-nine patients were enrolled; and 77 patients received a median of 8 cycles and were evaluable. A 50% PSA decline was observed in 58 patients (75%). Twenty-three of 39 patients with measurable disease had a partial response (59%). The median PFS was 8 months, and the overall median survival was 24 months. Neutropenia without fever (69%), fatigue (25%), and thrombosis/emboli (9%) were the most common severe toxicities. Twenty-four of 77 patients were removed from protocol treatment because of disease progression, 35 of 77 patients were removed because of a physician or patient decision, and 15 patients were removed secondary to toxicity.
CONCLUSIONS
The combination of docetaxel, estramustine, and bevacizumab was tolerable but complicated by toxicity. Although the endpoint of PFS did not meet the desired level, encouraging antitumor activity and overall survival were observed. Further phase 3 evaluation of the role of bevacizumab in CRPC is ongoing.
Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Castration; Disease-Free Survival; Docetaxel; Estramustine; Humans; Male; Middle Aged; Prostatic Neoplasms; Taxoids; Vascular Endothelial Growth Factor A
PubMed: 20862750
DOI: 10.1002/cncr.25421 -
Current Drug Metabolism Jan 2007ATP-binding cassette (ABC) transporters comprise a family of critical membrane bound proteins functioning in the translocation of molecules across cellular membranes.... (Review)
Review
ATP-binding cassette (ABC) transporters comprise a family of critical membrane bound proteins functioning in the translocation of molecules across cellular membranes. Substrates for transport include lipids, cholesterol and pharmacological agents. Mutations in ABC transporter genes cause a variety of human pathologies and elicit drug resistance phenotypes in cancer cells. ABCA2, the second member the A subfamily to be identified, was highly expressed in ovarian carcinoma cells resistant to the anti-cancer agent, estramustine, and more recently, in human vestibular schwannomas. Cells expressing elevated levels of ABCA2 show resistance to variety of compounds, including estradiol, mitoxantrone and a free radical initiator, 2,2'-azobis-(2-amidinopropane). ABCA2 is expressed in a variety of tissues, with greatest abundance in the central nervous system and macrophages. This transporter, along with other proteins that have a high degree of homology to ABCA2, including ABCA1 and ABCA7, are up-regulated in human macrophages during cholesterol import. Recent studies have shown ABCA2 also plays a role in the trafficking of low-density lipoprotein (LDL)-derived free cholesterol and to be coordinately expressed with sterol-responsive genes. A single nucleotide polymorphism in exon 14 of the ABCA2 gene was shown to be linked to early onset Alzheimer disease (AD) in humans, supporting an earlier study showing ABCA2 expression influences levels of APP and beta-amyloid peptide, the primary component of senile plaques. Studies thus far implicate ABCA2 as a sterol transporter, the deregulation of which may affect a cellular phenotype conducive to the pathogenesis of a variety of human diseases including AD, atherosclerosis and cancer.
Topics: ATP-Binding Cassette Transporters; Alzheimer Disease; Amino Acid Sequence; Cholesterol, LDL; Drug Resistance, Multiple; Molecular Sequence Data; Mutation; Neoplasms; Protein Transport; Sterols
PubMed: 17266523
DOI: 10.2174/138920007779315044 -
Journal of Clinical Oncology : Official... Oct 2014To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). (Review)
Review
PURPOSE
To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC).
METHODS
The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature.
RESULTS
When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib.
RECOMMENDATIONS
Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or combinations of therapies. Palliative care should be offered to all patients.
Topics: Abiraterone Acetate; Androstadienes; Benzamides; Docetaxel; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Practice Guidelines as Topic; Prednisone; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Randomized Controlled Trials as Topic; Taxoids
PubMed: 25199761
DOI: 10.1200/JCO.2013.54.8404 -
Molecular and Clinical Oncology Jan 2018It has previously been demonstrated that the intratumoral generation of the potent androgen dihydrotestosterone (DHT), contributes critically to the progression of...
It has previously been demonstrated that the intratumoral generation of the potent androgen dihydrotestosterone (DHT), contributes critically to the progression of prostate cancer and its castration-resistant form, castration-resistant prostate cancer (CRPC). Circulating testosterone is converted into DHT by 5α-reductase (SRD5A). Dutasteride is a dual inhibitor of type I and II SRD5A. The present study assessed the effectiveness of dutasteride in the treatment of CRPC. Between 2010 and 2013, CRPC was diagnosed in 41 patients at the Tokyo Metropolitan Tama Medical Center. Following diagnosis, the patients received 0.5 mg dutasteride daily. The patients' median age was 77.3 years (range, 63-90). Bone metastases were recognized in 12 patients. All the patients received dexamethasone. Twenty-four (59%) patients had previously undergone chemotherapy, while 11 (27%) received docetaxel, and 24 (59%) estramustine. The prostatic-specific antigen (PSA) level declined in 17 (41%) patients from the baseline value, following dutasteride treatment. The median value for the PSA decrease was 23% (range, 4.3-89.8%), and the median duration of the response was 4 months (range, 1-10). The PSA response rate (defined as >50% decline in PSA from the baseline value) was recognized in 7 (17%) patients. The median duration of the response was 3 months (range, 2-10). Dutasteride was efficacious against CRPC in certain patients and may be a promising option in CRPC treatment. A prospective randomized trial is necessary to verify the efficacy of dutasteride.
PubMed: 29387405
DOI: 10.3892/mco.2017.1480 -
Asian Journal of Andrology 2016In this paper, we reviewed the long-term survival outcomes, safety, and quality-of-life of androgen-deprivation therapy (ADT) alone versus combined with radiation... (Meta-Analysis)
Meta-Analysis Review
In this paper, we reviewed the long-term survival outcomes, safety, and quality-of-life of androgen-deprivation therapy (ADT) alone versus combined with radiation therapy (RT) or chemotherapy for locally advanced and metastatic prostate cancer (PCa). A literature search was performed using OvidSP. Randomized controlled trials (RCTs) that met the following criteria were included: including locally advanced or metastatic PCa, comparing ADT alone versus combined with any treatment method and reporting quantitative data of disease control or survival outcomes. Finally, eight RCTs met the inclusion criteria. Among these, three compared ADT versus ADT plus RT (n = 2344) and one compared ADT versus ADT plus docetaxel-estramustine (n = 413) in locally advanced PCa; two compared ADT versus ADT plus docetaxel (n = 1175) and two compared ADT versus ADT plus estramustine (n = 114) in metastatic PCa. For locally advanced PCa, the addition of RT to long-term ADT can improve the outcomes of survival and tumor control with fully acceptable adverse effects. Specially, the pooled odds ratio (OR) of overall survival (OS) was 1.43 (95% confidence interval 1.20-1.71) when compared ADT plus RT with ADT alone (P < 0.0001). For metastatic hormonally sensitive PCa, the concurrent use of docetaxel plus ADT was effective and safe (pooled OR of OS: 1.29 [1.01-1.65]: P = 0.04). In all, long-term ADT plus RT and long-term ADT plus docetaxel should be considered as proper treatment option in locally advanced and metastatic hormonally sensitive PCa, respectively. The major limitation for the paper was that only eight RCTs were available.
Topics: Androgen Antagonists; Combined Modality Therapy; Humans; Male; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 25851657
DOI: 10.4103/1008-682X.150840 -
The Oncologist 2001In the Karnell Cancer Center Grand Rounds, we present a patient who underwent radical prostatectomy with bilateral pelvic lymphadenectomy, but had positive margins and...
In the Karnell Cancer Center Grand Rounds, we present a patient who underwent radical prostatectomy with bilateral pelvic lymphadenectomy, but had positive margins and subsequently developed local recurrence and then systemic disease. Pathologic and radiologic aspects of his disease are discussed. Therapeutic options at different stages of the disease are examined from the point of view of the urologist, radiation oncologist, and medical oncologist. The surgical portion of the discussion focuses on the selection of initial therapy. Both the selection of surgical candidates and choice of pre- or post-operative therapy in patients can be aided by prognostic tools looking at several variables, including prostate-specific antigen (PSA) level, Gleason score of the tumor, seminal vesicle invasion, extracapsular invasion, and lymph node involvement. Low-risk patients can be treated with monotherapy, such as radical prostatectomy, external beam radiation therapy, prostate brachytherapy, or cryosurgical ablation of the prostate. Higher risk patients may require adjuvant and possibly neoadjuvant therapy in addition. The radiation portion of the discussion focuses on the use of radiation therapy as salvage for relapsing disease. Of particular importance is the point that treating high-risk patients whose PSA levels have started to rise but are less than 1 ng/ml results in a long-term PSA control rate as high as 75%, but that limiting the use of salvage radiation therapy to patients with high PSA levels or biopsy confirmation of local recurrence in the face of a negative bone scan results in biochemical long-term control of less than 40%. In the medical oncology part of the discussion, the major focus is on the use of chemotherapy to treat patients whose disease has become resistant to hormonal therapy. Mitoxantrone plus a corticosteroid has been found to offer significant palliation for such patients. Combination therapy with estramustine plus taxanes, other microtubule inhibitors, or other agents such as topoisomerase II inhibitors, has been found to cause shrinkage of measurable soft tissue disease and diminution of serum PSA levels. The development of effective hormonal and chemotherapeutic drugs for treatment of metastatic disease has led to new interest in adjuvant and neoadjuvant therapy of high-risk patients.
Topics: Adenocarcinoma; Aged; Follow-Up Studies; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Neoplasm Recurrence, Local; Prognosis; Prostate-Specific Antigen; Prostatectomy; Prostatic Hyperplasia; Prostatic Neoplasms; Radiotherapy, Conformal; Survival Rate
PubMed: 11306730
DOI: 10.1634/theoncologist.6-2-183 -
Scientific Reports Jun 2022We aimed to determine the survival and staging benefit of limited pelvic lymph node dissection (PLND) during radical prostatectomy (RP) in high-risk prostate cancer (PC)...
We aimed to determine the survival and staging benefit of limited pelvic lymph node dissection (PLND) during radical prostatectomy (RP) in high-risk prostate cancer (PC) patients treated with neoadjuvant chemohormonal therapy. We retrospectively analyzed 516 patients with high-risk localized PC (< cT4N0M0) who received neoadjuvant androgen-deprivation therapy plus estramustine phosphate followed by RP between January 2010 and March 2020. Since we stopped limited PLND for such patients in October 2015, we compared the surgical outcomes and biochemical recurrence-free survival (BCR-FS) between the limited-PLND group (before October 2015, n = 283) and the non-PLND group (after November 2015, n = 233). The rate of node metastases in the limited-PLND group were 0.8% (2/283). Operation time was significantly longer (176 vs. 162 min) and the rate of surgical complications were much higher (all grades; 19 vs. 6%, grade ≥ 3; 3 vs. 0%) in the limited-PLND group. The inverse probability of treatment weighting-Cox analysis revealed limited PLND had no significant impact on BCR-FS (hazard ratio, 1.44; P = 0.469). Limited PLND during RP after neoadjuvant chemohormonal therapy showed quite low rate of positive nodes, higher rate of complications, and no significant impact on BCR-FS.
Topics: Androgen Antagonists; Humans; Lymph Node Excision; Lymph Nodes; Male; Neoadjuvant Therapy; Prostatectomy; Prostatic Neoplasms; Retrospective Studies
PubMed: 35690635
DOI: 10.1038/s41598-022-13651-x