Standard therapy for metastatic, hormone-sensitive prostate cancer is androgen-deprivation therapy, usually with docetaxel. A large, multinational, phase 3 trial assessed the addition of the ...androgen-receptor blocker darolutamide to standard therapy. At 4 years, survival was higher with darolutamide than with placebo (62.7% vs. 50.4%), with no major differences in the frequency of adverse events.
Prostate cancer accounts for about 25% of all the newly diagnosed cancers in American men and was projected to cause >28 000 deaths in 2008. Black men are disproportionately affected; their incidence ...rate is about 1.6 times greater than the rate for white men. As the population ages, the number of new cases per year is expected to increase by >60% and reach 300 000 by 2015. This high incidence, coupled with the protracted onset of the disease, makes PCa a particularly appropriate candidate for prevention and early intervention strategies. Potential disease precursors, particularly high-grade prostatic intraepithelial neoplasia, might help identify men at high risk of developing PCa. Dihydrotestosterone, a product converted from testosterone by 5α-reductases, plays an important role in normal prostate growth and in the development of PCa. The 5α-reductase levels, particularly type 1, appear to increase during the disease course of prostatic intraepithelial neoplasia and PCa, with greater expression occurring as the disease progresses. Therefore, the inhibition of 5α-reductase could potentially reduce the risk of PCa development, slow or prevent disease progression, and/or treat existing disease. A substantial research effort has recently focused on understanding the pathways involved in the disease's emergence and progression, particularly the 5α-reductase pathway.
Abstract Prostate cancer is the most common cause of cancer in men, with 137.9 new cases per 100,000 men per year. The overall 5-year survival rate for prostate cancer is very high. Up to 20% of men ...who undergo state-of-the art treatment for prostate cancer will develop castration-resistant prostate cancer (CRPC) within 5 years, with median survival for those with metastatic CRPC ranging from approximately 15 to 36 months in recent studies. With the advent of several new drugs in the past 5 years to treat CRPC, the challenge facing clinicians is how to best sequence or combine therapies or both to optimize outcomes. A better understanding of the disease process and the role of the androgen receptor as a target for both therapy and resistance have led to the consideration of biomarkers as an approach to aid in selecting the appropriate agent for a given patient as patients respond to or tolerate different drugs differently. Research to identify new prognostic biomarkers, which are associated with outcome measures, as well as predictive biomarkers, which predict response or resistance to therapy is ongoing. The treatment of advanced prostate cancer and the research related to biomarkers are discussed.
To evaluate the survival outcomes for patients with lymph node-positive, nonmetastatic prostate cancer undergoing definitive local therapy (radical prostatectomy RP, external beam radiation therapy ...EBRT, or both) versus no local therapy (NLT) in the US population in the modern prostate specific antigen (PSA) era.
The Surveillance, Epidemiology, and End Results database was queried for patients with T1-4N1M0 prostate cancer diagnosed from 1995 through 2005. To allow comparisons of equivalent datasets, patients were analyzed in separate clinical (cN+) and pathologically confirmed (pN+) lymph node-positive cohorts. Kaplan-Meier overall survival (OS) and prostate cancer-specific survival (PCSS) estimates were generated, with accompanying univariate log-rank and multivariate Cox proportional hazards comparisons.
A total of 796 cN+ and 2991 pN+ patients were evaluable. Among cN+ patients, 43% underwent EBRT and 57% had NLT. Outcomes for cN+ patients favored EBRT, with 10-year OS rates of 45% versus 29% (P<.001) and PCSS rates of 67% versus 53% (P<.001). Among pN+ patients, 78% underwent local therapy (RP 57%, EBRT 10%, or both 11%) and 22% had NLT. Outcomes for pN+ also favored local therapy, with 10-year OS rates of 65% versus 42% (P<.001) and PCSS rates of 78% versus 56% (P<.001). On multivariate analysis, local therapy in both the cN+ and pN+ cohorts remained independently associated with improved OS and PCSS (all P<.001). Local therapy was associated with favorable hazard ratios across subgroups, including patients aged ≥70 years and those with multiple positive lymph nodes. Among pN+ patients, no significant differences in survival were observed between RP versus EBRT and RP with or without adjuvant EBRT.
In this large, population-based cohort, definitive local therapy was associated with significantly improved survival in patients with lymph node-positive prostate cancer.
Despite theoretical benefits of intermittent as compared with continuous androgen-deprivation therapy in patients with metastatic prostate cancer, intermittent therapy did not result in longer ...survival or long-term improvement in quality of life.
Prostate cancer is an androgen-dependent disease, and continuous androgen deprivation has been the standard therapy for metastatic hormone-sensitive disease. Despite a high response rate, resistance to androgen-deprivation therapy occurs in most patients, resulting in a median survival of 2.5 to 3 years.
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There is evidence suggesting that progression to castration resistance is adaptive in part, and pathways involving the androgen receptor, as well as cell-survival pathways independent of the androgen receptor, have been implicated.
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Data from an androgen-dependent tumor model have suggested that androgen withdrawal alters the ratio of putative stem cells in the tumor-cell population.
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Initially, differentiated . . .
After nearly 12 years of follow-up, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial has shown that screening with flexible sigmoidoscopy reduces colorectal-cancer incidence by 21% ...and mortality by 26%.
Colorectal cancer is the second leading cause of cancer-related deaths in the United States.
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Colorectal-cancer mortality
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and incidence
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are reduced with screening by means of fecal occult-blood testing. Endoscopic screening with flexible sigmoidoscopy or colonoscopy is more sensitive than fecal testing for the detection of adenomatous polyps, the precursor lesions of colorectal cancer.
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Three European randomized trials of flexible sigmoidoscopy have been performed.
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In the United Kingdom, one-time screening with flexible sigmoidoscopy significantly reduced the incidence of colorectal cancer (by 23%) and associated mortality (by 31%).
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In Italy, an 18% reduction in incidence and a nonsignificant 22% . . .
The advanced prostate cancer therapeutic landscape has changed dramatically over the last several years, resulting in improved overall survival for patients with both castration-naive and ...castration-resistant disease. The evolution and development of novel next generation imaging (NGI) techniques will affect diagnostic and therapeutic decision-making. Clinicians must navigate when and which NGI techniques to use and how to adjust treatment strategies based upon their results, oftentimes in the absence of correlative therapeutic data. Therefore, guidance is needed based on best available information and current clinical experience.
The RADAR III Group convened to offer guidance on the use of NGI to stage prostate cancer based on available data and clinical experience. The group also discussed the potential impact of NGIs on treatment options based on earlier detection of disease.
The group unanimously agreed that progression to metastatic disease is a seminal event for patient management. NGI techniques are able to detect previously undetectable metastases, which could redefine the phases of prostate cancer progression. Hence, earlier treatment, either systemic or locally directed, may positively alter patient outcomes.
The RADAR III Group recommends NGI techniques for select patients suspected of disease progression based on laboratory (biomarker) values, comorbidities, and symptoms. Currently, 18F-fluciclovine and 68Gallium (Ga) PSMA PET/CT are the NGI agents with a favorable combination of availability, specificity, and sensitivity. There is ongoing research for additional NGI technologies, which may offer improved diagnostic accuracy and therapeutic options. As NGI techniques evolve and presumably result in improved global accessibility, a clinician’s ability to detect micrometastases may be enhanced for both decision-making and patient outcomes.
Purpose The availability of newly approved treatment options for metastatic castration resistant prostate cancer is not matched with conclusive data on optimal sequencing strategies and resistance ...patterns. A comprehensive review of efficacy and safety data for new agents and current knowledge regarding treatment sequencing would enable treating physicians to make rational drug selections in patients with metastatic castration resistant prostate cancer. Materials and Methods We searched MEDLINE® and relevant congresses for data on cabazitaxel, docetaxel,223 radium dichloride, abiraterone, enzalutamide and sipuleucel-T, focusing on sequencing strategies, resistance mechanisms and biomarkers of response. Results Abiraterone and enzalutamide target the androgen axis with different mechanisms of action. Abiraterone blocks cytochrome P450 17, inhibiting androgen synthesis, whereas enzalutamide inhibits androgen receptor, reducing nuclear translocation of the androgen receptor complex and subsequent DNA binding. Both agents provide improved overall survival in patients with metastatic castration resistant prostate cancer who received prior docetaxel treatment and in those who are chemotherapy naïve. Cabazitaxel provides improved overall survival in patients with metastatic castration resistant prostate cancer with prior docetaxel therapy. Sipuleucel-T provides improved overall survival in asymptomatic patients and223 radium provides improved overall survival in chemotherapy naïve and chemotherapy treated patients with symptomatic bone metastases. Selecting the correct treatment with metastatic castration resistant prostate cancer is complex as no head-to-head trials have been done and comparison between existing trials is difficult due to differences in study populations and a lack of validated biomarkers. Factors to consider include prior therapy, symptom burden, metastasis type, performance status, comorbidities, adverse event profiles and patient preference. Another consideration is treatment sequence since some agents affect responses to subsequent choices. For example, resistance to abiraterone or enzalutamide may result in limited responses to subsequent androgen targeted agents. Identifying factors predictive of resistance is an area of ongoing research with androgen receptor variants representing a good candidate. Prognostic factors for survival are also likely to be useful and are currently being studied. Conclusions New therapies for metastatic castration resistant prostate cancer have brought new challenges with regard to treatment selection and sequencing. While hormonal agents provide good therapeutic responses, resistance may be intrinsic without prior drug exposure. Identifying predictors of response and relevant biomarkers will allow therapies to be more precisely tailored to individual patient profiles.
Objective
To examine prostate cancer (PCa) incidence and mortality by arm in the randomized Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial.
Patients and Methods
Patients aged ...55–74 years at 10 screening centres were randomized between 1993 and 2001 to an intervention or usual care arm. Patients in the intervention arm received six annual prostate‐specific antigen (PSA) tests and four annual digital rectal examinations. The patients were followed for PCa incidence and for mortality via active follow‐up processes and by linkage to state cancer registries and the National Death Index. For cancers identified through active follow‐up, trial ors recorded the mode of diagnosis (screen‐detected, symptomatic, other).
Results
A total of 38 340 patients were randomized to the intervention arm and 38 343 to a usual care arm. The median follow‐up for mortality was 16.9 (intervention) and 16.7 years (usual care). There were 333 (intervention) and 352 (usual care) PCa cancer deaths, giving rates (per 10 000 person‐years) of 5.5 and 5.9, respectively, and a rate ratio (RR) of 0.93 (95% confidence interval CI 0.81–1.08; P = 0.38). The RR for overall PCa incidence was 1.05 (95% CI 1.01–1.09). The RRs by Gleason category were 1.17 (95% CI 1.11–1.23) for Gleason 2–6, 1.00 (95% CI 0.93–1.07) for Gleason 7 and 0.89 (95% CI 0.80–0.99) for Gleason 8–10 disease. By mode of detection, during the trial's screening phase, 13% of intervention arm vs 27% of usual care arm cases were symptomatic; post‐screening, these percentages were 18% in each arm.
Conclusion
After almost 17 years of median follow‐up, there was no significant reduction in PCa mortality in the intervention compared with the usual care arm. There was a significant increase in Gleason 2–6 disease and a significant reduction in Gleason 8–10 disease in the intervention compared with the usual care arm.
Purpose Extraprostatic disease will be manifest in a third of men after radical prostatectomy. We present the long-term followup of a randomized clinical trial of radiotherapy to reduce the risk of ...subsequent metastatic disease and death. Materials and Methods A total of 431 men with pT3N0M0 prostate cancer were randomized to 60 to 64 Gy adjuvant radiotherapy or observation. The primary study end point was metastasis-free survival. Results Of 425 eligible men 211 were randomized to observation and 214 to adjuvant radiation. Of those men under observation 70 ultimately received radiotherapy. Metastasis-free survival was significantly greater with radiotherapy (93 of 214 events on the radiotherapy arm vs 114 of 211 events on observation; HR 0.71; 95% CI 0.54, 0.94; p = 0.016). Survival improved significantly with adjuvant radiation (88 deaths of 214 on the radiotherapy arm vs 110 deaths of 211 on observation; HR 0.72; 95% CI 0.55, 0.96; p = 0.023). Conclusions Adjuvant radiotherapy after radical prostatectomy for a man with pT3N0M0 prostate cancer significantly reduces the risk of metastasis and increases survival.
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