Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer

BACKGROUND:

The natural history of castration‐resistant nonmetastatic prostate cancer is poorly defined.

METHODS:

The authors used data from 331 subjects in the placebo group of a randomized controlled trial to evaluate the relations of disease and host characteristics with time to first bone metastases in men with prostate cancer, rising prostate‐specific antigen (PSA) despite androgen deprivation therapy, and no radiographic evidence of metastases. Relations between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were age, body mass index, prior prostatectomy, prior orchiectomy, Gleason score, performance status, PSA, urinary N‐telopeptide, bone alkaline phosphatase, albumin, lactate dehydrogenase, and hemoglobin.

RESULTS:

At 2 years, 46% of subjects had developed bone metastases, and 20% had died. Median bone metastasis‐free survival was 25 months. In multivariate analyses, baseline PSA ≥13.1 ng/mL was associated with shorter overall survival (relative risk [RR], 2.34; 95% confidence interval [CI], 1.71–3.21; P < .0001), time to first bone metastasis (RR, 1.98; 95% CI, 1.43‐2.74; P < .0001), and bone metastasis‐free survival (RR, 1.98; 95% CI, 1.45–2.70; P < .0001). PSA velocity was significantly associated with overall and bone metastasis‐free survival. Other covariates were not consistently associated with clinical outcomes.

CONCLUSIONS:

In men with progressive castration‐resistant prostate cancer and no detectable metastases, baseline PSA was significantly associated with time to first bone metastasis, bone metastasis‐free survival, and overall survival. Other disease and host characteristics, including body mass index and bone turnover markers, were not consistently associated with clinical outcomes. Cancer 2011. © 2010 American Cancer Society.     

Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer.

PURPOSE: To identify predictors of biochemical outcome following radiotherapy in patients with a rising prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer. PATIENTS AND METHODS: One hundred fifteen patients with a rising PSA after radical prostatectomy received salvage three-dimensional conformal radiotherapy (3D-CRT) alone or with neoadjuvant androgen deprivation. Tumor-related and treatment-related factors were evaluated to identify predictors of subsequent PSA failure. RESULTS: The median follow-up time after 3D-CRT was 42 months. The 4-year actuarial PSA relapse-free survival, distant metastasis-free survival, and overall survival rates were 46%, 83%, and 95%, respectively. Multivariate analysis, which was limited to 70 patients receiving radiation without androgen deprivation therapy, showed that negative/close margins (P =.03), absence of extracapsular extension (P <.01), and presence of seminal vesicle invasion (P <.01) were independent predictors of PSA relapse after radiotherapy. Neoadjuvant androgen deprivation did not improve the 4-year PSA relapse-free survival in patients with positive margins, extracapsular extension, and no seminal vesicle invasion (P =.24). However, neoadjuvant androgen deprivation did improve PSA relapse-free survival when one or more of these variables were absent (P =.03). CONCLUSIONS: Salvage 3D-CRT can provide biochemical control in selected patients with a rising PSA after radical prostatectomy. Among patients with positive margins and no poor prognostic features, 77% achieved PSA control after salvage 3D-CRT. Salvage neoadjuvant androgen deprivation therapy may improve short-term biochemical control, but it requires further study.     

Natural history of disease progression in patients who fail to achieve an undetectable prostate-specific antigen level after undergoing radical prostatectomy

BACKGROUND: To the authors' knowledge, the natural history of disease progression to distant metastasis is unknown in men who fail to achieve an undetectable prostate-specific antigen (PSA) level after radical retropubic prostatectomy (RRP),. The authors assessed the clinical outcome of men with a persistently detectable PSA level after RRP for clinically localized prostate carcinoma. METHODS: Between 1989 and 2002, 160 men failed to achieve an undetectable PSA level (>/= 0.1 ng/mL) after undergoing RRP for clinically localized prostate carcinoma. No patient received adjuvant therapy before documented metastasis. The Kaplan-Meier method was used to estimate distant metastasis-free survival. Univariate and multivariate Cox proportional hazards regression was used to assess the ability of clinical and pathologic variables to predict distant metastasis-free survival. RESULTS: The probability of distant metastasis-free survival at 3 years, 5 years, and 10 years was reported to be 68%, 49%, and 22%, respectively. Seventy-five men (47%) developed distant metastases after RRP (median time to metastases of 5.0 years; range, 0.5-13 years). The combination of RRP Gleason score, seminal vesicle status, and lymph node status resulted in 3 risk groups for the prediction of distant metastasis-free survival (hazards ratio [HR] = 1.6; P < 0.01). The slope of PSA changes approximately 3-12 months after RRP at a cutoff value >/= 0.05 was found to be even more predictive of distant metastasis-free survival (HR = 2.9; P < 0.01). CONCLUSIONS: Many patients remained free of metastatic disease for an extended period despite failing to achieve an undetectable PSA level after undergoing RRP for clinically localized prostate carcinoma. However, other patients experienced rapid disease progression to distant metastasis. The authors defined clinical (PSA slope) and pathologic (Gleason score) prognostic variables to help identify those patients with a higher risk of developing distant metastasis after undergoing RRP.     

Nonmetastatic castration-resistant prostate cancer: Novel agents to treat a lethal disease

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.     

Isolated Peritoneal Metastasis of Prostate Cancer Presenting with Massive Ascites: A Case Report

The peritoneal carcinomatosis of prostate cancer without bone or other visceral organ involvement is extremely rare. We report a case of an isolated peritoneal metastasis of prostate cancer in a patient without other metastatic sites and a history of prostate surgery. A 63-year-old male with locally advanced prostate cancer without known distant metastasis on androgen deprivation therapy presented with abdominal distension that had persisted for a month. Abdominopelvic computed tomography (CT) showed gastric wall thickening and a moderate amount of ascites. The gastroscopy showed hyperemic mucosal patches on the antrum body. A cytological examination of the ascites fluid was negative for malignant cells. Diagnostic laparoscopy showed multiple nodules in the peritoneum. A biopsy was performed. Histological findings were compatible with metastatic carcinoma of the prostate, which was immunohistochemically positive for pan-cytokeratin, the androgen receptor, and prostate-specific antigen (PSA). The patient was then treated with abiraterone acetate. After 1 month of treatment, both ascites and the PSA value decreased. We describe an extremely rare case of isolated peritoneal carcinomatosis from prostate cancer without any organ metastasis or history of surgery. Clinicians should be aware of these very rare metastases of prostate cancer. Hormonal therapy may be helpful for such cases.     

The clinical merit of anti-RANKL antibody denosumab in prostate cancer

Prostate cancer has been reported to have a high bone metastatic rate and longer survival duration by current therapies, accordingly, the treatment for bone metastasis is important to maintain a good quality of life. The standard medication for advanced prostate cancer, androgen deprivation therapy(ADT)has been associated with bone loss, consequently, the management of controlling the risk of fracture is required. A new drug denosumab is a fully human monoclonal antibody that binds to RANKL, a cytokine essential for the differentiation, function, and survival of osteoclasts which mainly regulate bone metabolic turnover. In a phase 3 clinical study in patients with bone metastasis of castrate-resistant prostate cancer, 120 mg denosumabsub cutaneously every 4 weeks statistically significantly delayed the time to first skeletal-related events(SRE)by 18% and also the time to first and subsequent on-study SRE by 18%when compared with that of the standard of care, 4 mg zoledronic acid by iv infusion every 4 weeks. In another phase 3 clinical study in patients with castrate-resistant prostate cancer without bone metastases, 120 mg once in 4-week subcutaneous injection of denosumab has been indicated to delay the onset of the bone metastasis significantly when compared with placebo. In another phase 3 clinical study in patients with hormone-sensitive nonmetastatic prostate cancer, 60 mg denosumab subcutaneously every 6 months significantly reversed bone loss due to ADT and demonstrated statistically significant prevention of vertebral fractures compared with placebo. Based on these evidences, it has been proved that denosumab is effective in many different stages across the disease continuum of advanced prostate cancer. In US, denosumab has been approved for the indication of prevention of SRE caused by bone metastasis of solid tumor since 2010. Denosumab is useful for treatment of bone metastases from prostate cancer, because the administration route is an every 4-week subcutaneous injection and, dose adjustment by renal impairment is not required. The use of denosumab will be expected to largely contribute to prostate cancer treatment in the future.     

Current management of castrate-resistant prostate cancer

Prostate cancer (PCa) is the most frequently diagnosed cancer in North America. Castrate-resistant PCa presents a spectrum of disease ranging from rising PSA levels in the absence of metastases or symptoms and despite androgen-deprivation therapy, to metastases and significant debilitation from cancer symptoms. Castrate-resistant PCa is usually suspected in patients with new symptoms on androgen deprivation therapy, with a rising PSA, or with new evidence of disease on bone scans or computed tomography scans. Institution of treatment and the choice of systemic or local therapy depend on a number of factors. This review discusses the various currently available treatments for patients with castrate-resistant PCa, from secondary hormonal manipulations to options for post-docetaxel systemic therapy.     

Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) for determining prognosis in advanced stage hormone relapsing prostate cancer

Prostate cancer frequently progresses despite early diagnosis and appropriate treatment with radical prostatectomy and/or radiotherapy. The clinical utility of SELDI-TOF MS to identify serum biomarker patterns associated with prostate cancer progression was examined by analysis of the serum proteome of advanced prostate cancer patients receiving standard androgen deprivation therapy. Serum from advanced-stage patients receiving androgen deprivation therapy was profiled by SELDI-TOF MS. Group 1 patients (n=15) had stable prostate specific antigen (PSA) responses to treatment; Group 2 (n=16) had rising PSA levels. Spectra were subjected to peak identification following total ion current (TIC) normalization. Peak intensities with m/z between 2,000 and 20,000 were tested for group differences via Kruskal-Wallis tests, and assessed individually for PSA-independent associations with overall survival via covariate-adjusted Cox regressions. TIC normalization yielded 53 useable spectra; 119 peaks with m/z between 2,000 and 20,000 were identified. Seven peaks showed statistically significant (p<0.05) differences between PSA groups, and several other peaks showed significant associations with overall survival independent of PSA status. In summary, SELDI-TOF MS captured a specific biomarker profile associated with biochemical relapse and provided additional prognostic information regarding long-term survival, independent of clinical PSA status.     

Pattern of prostate-specific antigen (PSA) failure dictates the probability of a positive bone scan in patients with an increasing PSA after radical prostatectomy.

PURPOSE: Physicians often order periodic bone scans (BS) to check for metastases in patients with an increasing prostate-specific antigen (PSA; biochemical recurrence [BCR]) after radical prostatectomy (RP), but most scans are negative. We studied patient characteristics to build a predictive model for a positive scan. PATIENTS AND METHODS: From our prostate cancer database we identified all patients with detectable PSA after RP. We analyzed the following features at the time of each bone scan for association with a positive BS: preoperative PSA, time to BCR, pathologic findings of the RP, PSA before the BS (trigger PSA), PSA kinetics (PSA doubling time, PSA slope, and PSA velocity), and time from BCR to BS. The results were incorporated into a predictive model. RESULTS: There were 414 BS performed in 239 patients with BCR and no history of androgen deprivation therapy. Only 60 (14.5%) were positive for metastases. In univariate analysis, preoperative PSA (P = .04), seminal vesicle invasion (P = .02), PSA velocity (P < .001), and trigger PSA (P < .001) predicted a positive BS. In multivariate analysis, only PSA slope (odds ratio [OR], 2.71; P = .03), PSA velocity (OR, 0.93; P = .003), and trigger PSA (OR, 1.022; P < .001) predicted a positive BS. A nomogram for predicting the bone scan result was constructed with an overfit-corrected concordance index of 0.93. CONCLUSION: Trigger PSA, PSA velocity, and slope were associated with a positive BS. A highly discriminating nomogram can be used to select patients according to their risk for a positive scan. Omitting scans in low-risk patients could reduce substantially the number of scans ordered.     

Therapy of Advanced Prostate Cancer: Targeting the Androgen Receptor Axis in Earlier Lines of Treatment

With the decrease in PSA screening based on the 2011 United States Preventive Services Task Force guidelines and the potential approval of highly sensitive imaging techniques over the next few years, we are likely to see an increasing trend of metastatic prostate cancer diagnosis. Traditional therapy for nonmetastatic prostate cancer (nmPC) has consisted of androgen deprivation therapy (ADT) followed by other hormonal therapy maneuvers, such as anti-androgen withdrawal, herbal preparations, low dose steroids, or ketoconazole. Androgen receptor-axis-targeted therapies (ARAT) were previously only approved for patients with metastatic castration resistant prostate cancer (mCRPC). This has recently changed after reporting of results from the SPARTAN and PROSPER trials, which were conducted in nonmetastatic CRPC (nmCRPC) patients. These studies demonstrated improved metastasis-free survival with apalutamide and enzalutamide, each compared to placebo in a double blind randomized setting. In 2017, the LATITUDE and STAMPEDE studies demonstrated marked survival benefit with early abiraterone and prednisone in patients with metastatic hormone sensitive prostate cancer (mHSPC) in addition to ADT. Other second-generation AR antagonists are currently in phase 3 trials in mHSPC and nmCRPC. This article summarizes the key clinical trials that led to FDA approval of ARAT in the mHSPC and nmCRPC settings and highlights potential limitations, future directions, and treatment-algorithms when selecting patients for early therapy in mHSPC and NMPC.     

Intermittent androgen deprivation for patients with recurrent/metastatic prostate cancer

This study was designed to assess the duration of response to intermittent androgen deprivation therapy (IAD) in patients with recurrent and/or metastatic prostate cancer. Between January 1993 and March 2000, 74 patients with recurrent and/or metastatic prostate cancer had IAD with either luteinizing hormone-releasing hormone agonist (LHRH) or an LHRH with an oral antiandrogen. Forty-one patients were treated for an increasing prostate-specific antigen (PSA) level after primary local treatment. Of the remaining 33 patients, 17 patients were treated for metastases (9 for bone metastases, 8 for lymph nodes metastases, and 16 for local recurrence). Patients who had undergone IAD completed between 1 and 6 cycles. A cycle was defined as the period during which the patient was actively taking the hormone medication. Seventy-four patients completed the first cycle, 49 completed the second cycle, and 23 completed the third cycle. The pattern of PSA changes with each cycle, the length of each cycle, and the time interval between successive cycles were studied. The time to progression (defined as an increasing PSA level on two consecutive measurements or radiologic evidence of progression of disease while the patient was on androgen deprivation) was also studied. The median PSA before the IAD was 11.4 ng/mL (range 0.12-378). The median PSA nadir at the end of each cycle increased progressively (0.1 ng/mL after the first cycle to 3.3 ng/mL after the fifth cycle). The time interval between the cycles progressively decreased from 9.5 months between the first and second cycles to 6 months between the third and fourth cycles. The 4-year actuarial androgen-independent free survival was 71%. For the subgroups of patients treated for biochemical failure, locoregional recurrence, and bone metastases, the 4-year actuarial progression-free survival rates were 80%, 67%, and 45% respectively (P = 0.018). The median time of 18 months to progression in patients with bone metastases is similar to that reported with continuous hormonal therapy. In patients with biochemical failure, the median time to progression (more than 5 years) suggests that the IAD approach may be a viable option for this group of patients.     

Early versus delayed androgen deprivation for prostate cancer: new fuel for an old debate.

The purpose of this review is to discuss the recent increase in data supporting the use of androgen ablation early in the clinical course for patients with nonmetastatic prostate cancer. We systematically reviewed recent publications that report on the use of androgen deprivation (AD) in nonmetastatic prostate cancer patients from the 2003 and 2004 proceedings of the American Society of Clinical Oncology, the 2003 and 2004 proceedings of the American Urological Association as well as published literature from 2003 to 2005. Five recently published mature randomized trials of AD plus local therapy were evaluated plus two large data sets on the use of AD for patients with serologic relapse after local therapy. Four mature randomized studies demonstrate an overall survival benefit to the use of AD in conjunction with definitive local therapy (three with radiation and one with surgery). One retrospective analysis suggests that AD administered early after serologic progression improves overall survival, and one retrospective analysis shows a reduction in metastasis-free survival but has not yet shown an overall survival benefit. For patients with nonmetastatic prostate cancer with high-risk features, as well as those for serologic relapse, the use of AD before the development of metastatic disease is supported by long-term outcomes from a series of clinical trials. Consideration of AD is therefore warranted early in the clinical course of high-risk patients.     

Evaluation of postradiotherapy PSA patterns and correlation with 10-year disease free survival outcomes for prostate cancer

PURPOSE: To describe the prostate-specific antigen (PSA) pattern profiles observed after external beam radiotherapy with and without short-term neoadjuvant androgen deprivation therapy (ST-ADT) and to report the association of established posttreatment PSA patterns with long-term disease-free survival outcomes. METHODS AND MATERIALS: A total of 1,665 patients were treated with conformal external beam radiotherapy for clinically localized prostate cancer. Of 570 patients who had the requisite>10 consecutive PSA measurements for statistical analysis, 194 patients received a median of 3 months of ADT before radiotherapy and 376 were treated with radiotherapy alone. The median follow up was 103 months. RESULTS: In the group treated with ST-ADT, three distinct postradiotherapy PSA patterns were identified: a stable trend (44%), an increasing trend followed by stabilization of the PSA (25%), and an increasing trend (31%). Among the subgroup that demonstrated a rising and subsequent stabilizing patterns, PSA levels had gradually risen to a median value of 0.9 ng/mL after therapy, stabilized, and remained durably suppressed. The only identified trends among patients treated with external beam radiotherapy without ST-ADT were declining PSA levels followed by stable PSA trends or declining patterns followed by rising levels. Patients whose PSA levels stabilized after an initial rise or those with slowly rising PSA profiles had a lower incidence of distant metastasis compared to those with accelerated rises after therapy. CONCLUSIONS: For those treated with external beam radiotherapy in conjunction with ST-ADT, a significant percentage who develop a rising PSA after treatment are expected to manifest subsequent stabilization at plateaued levels of approximately 1.0 ng/mL, which can remain durably suppressed. The likelihood of distant metastasis in these patients is low despite the PSA stabilization at levels 1.0 ng/mL or higher and comparable to outcomes observed for those with lower nonrising PSA values.     

PSA Doubling Time and Absolute PSA Predict Metastasis-free Survival in Men With Biochemically Recurrent Prostate Cancer After Radical Prostatectomy

IntroductionThe aim of this study was to investigate the association of prostate-specific antigen (PSA) values on metastasis-free survival (MFS) in men with biochemically recurrent prostate cancer (BRPC) and PSA doubling time (PSADT) < 12 months. This dataset also reflects an update with longer follow-up of our prior publications on the natural history of BRPC in the absence of treatment.Materials and MethodsIn this report, we combined databases from the Center for Prostate Disease Research and Johns Hopkins University (CPDR/JHU). In the CPDR/JHU radical prostatectomy database (30,936 total patients), 656 men with BRPC (> 0.2 ng/mL) after prostatectomy and PSADT < 12 months, who received no adjuvant/salvage androgen deprivation and/or radiation therapy, were prospectively followed until radiologic evidence of metastasis and are included in this analysis.ResultsMetastasis occurred in 250 of 656 patients with BRPC (median follow-up, 5 years). PSADT < 7.5 months and Gleason score were independent risk factors for distant metastasis in multivariable analysis. Risk of metastasis increased for PSADT 6.01 to 7.50, 4.51 to 6.0, 3.01 to 4.50, and ≤ 3.0 months, after adjusting for Gleason score. A PSA value ≥ 0.5 ng/mL significantly and independently increased risk of metastasis in patients with PSADT < 12 months (hazard ratio, 2.79; 95% confidence interval, 1.47-5.29; P = .001).ConclusionsIn men with PSADT < 12 months, PSADT ≤ 7.5 months, PSA ≥ 0.5 ng/mL, and Gleason score are independent predictors of MFS on multivariable analysis.     

The AKT inhibitor perifosine in biochemically recurrent prostate cancer: a phase II California/Pittsburgh cancer consortium trial

BACKGROUND: Perifosine is an oral alkylphospholipid that inhibits cancer cell growth through decreased Akt phosphorylation. We conducted a phase II trial of perifosine in patients with biochemically recurrent, hormone-sensitive prostate cancer. PATIENTS AND METHODS: Eligible patients had histologically confirmed prostate cancer, previous prostatectomy and/or radiation therapy, and rising prostate-specific antigen (PSA) without radiographic evidence of metastasis. Previous androgen deprivation therapy < 9 months in duration (completed >or= 1 year before registration) was allowed. The primary endpoint was PSA response, defined as a decrease by >or= 50% from the pretreatment value. Treatment was composed of a loading dose of perifosine 900 mg orally on day 1, then 100 mg daily starting 24 hours later. RESULTS: Of 25 patients, 24 were evaluable for response. After a median follow-up of 8 months, 5 patients (20%) had a reduction in serum PSA levels, but none met criteria for PSA response. Three patients immediately progressed with no response to therapy. Median progression-free survival was 6.64 months (range, 4.53-12.81 months). No change in the PSA doubling time (7 months) was observed before and after treatment initiation. Dose-limiting toxicities (all grade 3) included hyponatremia, arthritis, hyperuricemia, and photophobia. CONCLUSION: Although well tolerated, perifosine did not meet prespecified PSA criteria for response as a single agent in biochemically recurrent prostate cancer. However, 20% of patients had evidence of PSA reduction, suggesting modest single-agent clinical activity. The role of perifosine in combination with androgen deprivation or chemotherapy is currently under investigation.     

Should the Denosumab Metastasis Prevention Trial Change Practice for Men with Nonmetastatic Prostate Cancer?

Presentation of the Case

A 68-year-old man presents for management of prostate-specific antigen (PSA)-recurrent prostate cancer. His PSA level had become undetectable after prostatectomy for a high-risk localized tumor but began to rise 8 months later. This later led to the initiation of androgen deprivation therapy (ADT), which he has received for the last 3.5 years. After initially falling in response to ADT, his PSA level again trended steadily upward and is now 13.2. Restaging with an abdominal and pelvic computed tomography scan and a bone scan reveals no evidence of metastases. Is this man likely to benefit from denosumab?Bone is the most common site of metastasis for advanced prostate cancer. Bone metastases can cause considerable morbidity in the form of pain, pathologic fractures, and even spinal cord compression. Two bone-targeted therapies (zoledronic acid and denosumab) have been shown to reduce the risk for skeletal events (SREs) among men with bone metastases and a rising PSA level despite a testosterone level <50 ng/dL (castration-resistant prostate cancer [CRPC]). Until recently, no therapy had been shown to reduce the risk for developing bone metastases for the first time. Denosumab 147 was a randomized, placebo-controlled, phase III trial that enrolled 1,432 men with CRPC, no bone metastases, and at least one feature consistent with a high risk for the development of bone metastases (PSA ≥8 ng/mL or PSA doubling time ≤10 months). Participants were treated every 4 weeks with s.c. denosumab (120 mg) or placebo.The trial was positive because denosumab led to a 4.2-month significantly longer bone-metastasis-free survival time relative to placebo (median, 29.5 months versus 25.2 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73–0.98; p = .028) [1]. The time to first bone metastasis and risk for symptomatic bone metastasis were also significantly better with denosumab treatment. Dror Michaelson and Philip Saylor discuss the potential implications of this trial.

• Oncologist. 2012 Feb; 17(2): 288–290.
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2012 Feb; 17(2): 288–290. Published online 2012 Jan 20. doi: 10.1634/theoncologist.2011-0433

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Copyright and License information DisclaimerCopyright notice By M. Dror MichaelsonMassachusetts General HospitalOpen in a separate windowM. Dror MichaelsonThe pivotal trial of denosumab in men with nonmetastatic CRPC reported a significant benefit in preventing the development of metastasis [1]. Bone-targeted therapy in prostate cancer has a well established role, because the majority of morbidity and mortality attributable to prostate cancer is a function of the skeletal metastases that characterize this disease. In contrast to hormone therapy and cytotoxic chemotherapy, which focus on antineoplastic effects, bone-targeted therapies such as denosumab and zoledronic acid focus on impacting the bone milieu to produce benefit [2].A randomized, phase III study of zoledronic acid in men with metastatic CRPC demonstrated a significant benefit in preventing SREs, a composite outcome that combines symptomatic and asymptomatic pathologic fractures, the need for radiation therapy or surgery to treat bone metastases, spinal cord compression, and change in antineoplastic therapy to treat bone pain [3]. On the basis of this study, zoledronic acid became the accepted standard of care for bone-targeted therapy in men with metastatic CRPC.More recently, a double-blind, multicenter trial treated 734 men receiving androgen ablative therapy for nonmetastatic prostate cancer with either denosumab or placebo [4]. Significant improvements in bone mineral density were seen in the denosumab-treated men, along with a lower incidence of vertebral fractures (1.5% at 36 months, versus 3.9% in the placebo group; relative risk, 0.38; p = .006). Another important trial, published in 2011, compared denosumab with zoledronic acid among 1,900 men with metastatic CRPC [5]. The investigators found that the time to first SRE was 3.6 months longer in men treated with denosumab than in those treated with zoledronic acid (HR, 0.82; p = .008.). There was greater suppression of bone turnover markers in men treated with denosumab, whereas the overall adverse event rates were comparable in the two treatment arms. These studies further established a role for bone-targeted therapy, and in particular for denosumab, in men with advanced prostate cancer.The current landmark trial in men with nonmetastatic CRPC extended these findings by demonstrating that bone metastases can be prevented or delayed with bone-targeted therapy. In men with high-risk features for the development of bone metastases, the median time to initial metastasis was 25.2 months in the placebo group and 29.5 months in the denosumab group. Considering the clinical impact of bone metastases on men with prostate cancer, a median delay of 4.2 months in their development is a meaningful observation with immediate treatment implications. Moreover, treatment with bone-targeted therapy should continue for men with advanced prostate cancer even after the development of bone metastases, because both zoledronic acid and denosumab have shown benefit in preventing SREs after the development of metastases.Though the majority of bone metastases detected in the Denosumab 147 study were not symptomatic, the study design required that men be immediately withdrawn from the investigational study drug upon detection of initial metastasis. One implication of this design was that the ability to establish when metastases became symptomatic was limited. A second implication was that bone-targeted treatment was discontinued sooner than would be done in standard practice. The impact of denosumab on the development of symptomatic metastases is therefore not yet established, and conceivably the true benefit of ongoing bone-targeted therapy would be greater than represented in this study.In balancing the risk–benefit ratio of treatment, the main toxicity to consider is the development of osteonecrosis of the jaw (ONJ), a difficult but fortunately rare complication with denosumab [5–7]. The incidence of ONJ was 5% in this study and it resolved in 39% of observed cases with conservative management. It is important to emphasize to all practitioners the critical role for universal dental examinations as bone-targeted therapies are used in more patients and for longer durations. The more widespread recognition of ONJ risk, and adoption of preventative measures, will hopefully result in a diminished incidence in the future.At the current time, because skeletal-related complications are the main source of morbidity in men with prostate cancer, the significantly longer time before the appearance of skeletal metastases is an important benefit that establishes denosumab as the standard of care for men with CRPC and a high risk for development of bone metastases.     

Real-world use of enzalutamide in men with nonmetastatic castration-resistant prostate cancer in Japan

Background

The purpose of the study is to evaluate real-world effectiveness and safety of enzalutamide in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) in Japan.

Methods

This was a retrospective evaluation of medical records from men in Japan who started enzalutamide treatment from November 1, 2014, to March 31, 2018, and received androgen deprivation therapy throughout. The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included PSA response rate, time to first use of new antineoplastic therapy, time to first use of cytotoxic chemotherapy, and enzalutamide treatment duration. An exploratory analysis of metastasis-free survival (MFS) was also performed. Adverse events (AEs) were analyzed to assess safety.

Results

Based on data from medical records of 205 men in Japan, median time to PSA progression was 27 months (95% confidence interval [CI] 19–not reached [NR]), with 82.5% and 52.0% of men achieving PSA response rates of ≥ 50% and ≥ 90%, respectively. Median time to first use of new antineoplastic therapy was 36 months (95% CI 27−NR) and median enzalutamide treatment duration was 13 months (interquartile range: 7–24). Median time to first use of cytotoxic chemotherapy was NR (95% CI 41−NR). Median MFS was 29 months (95% CI 23−35). In total, 51.7% of men experienced AEs, with malaise (18.5%), decreased appetite (10.7%), and nausea (4.9%) the most frequently reported.

Conclusions

This is the first study to demonstrate the real-world effectiveness and safety of enzalutamide in men with nmCRPC in Japan, further informing healthcare providers about available treatment options for this patient population.

     

Immunocytochemical monitoring of micrometastatic disease: Reduction of prostate cancer cells in bone marrow by androgen deprivation

Occult dissemination of tumor cells mainly determines the prognosis of patients with primary prostate cancer. The effect of androgen deprivation on micrometastatic tumor cells in these patients is currently unknown. We therefore used an immunocytochemical assay with monoclonal antibodies (MAbs) directed against epithelial cytoskeleton proteins (i.e., cytokeratins) to monitor the concentration of isolated tumor cells in the bone marrow of 36 prostate cancer patients (stage C), who underwent hormonal androgen deprivation with Flutamide and Leuproreline acetate. Tumor cells in cytologic bone marrow preparations were detected using an assay that employed the MAb CK2 directed against cytokeratin (CK) 18 and the alkaline anti-alkaline phosphatase staining method. Prior to therapy, we detected between 1 and 38 CK-positive cells per sample of 2 × 10⁴ nucleated cells in 21 patients, while the remaining 15 patients displayed tumor-free marrow samples. There was no significant correlation between the concentration of CK-positive cells and the volume of hypo-echogenic lesions as an indicator of the primary tumor volume or the serum level of prostate-specific antigen (PSA). After androgen deprivation, 20 of the 21 initially positive patients either became negative (n = 16) or showed at least a reduction in the concentration of CK-positive cells (n = 4). Moreover, only 2 of the 15 patients with negative pre-treatment findings became positive. All of the 7 patients with remaining tumor cells in the bone marrow after therapy showed no detectable amounts of PSA in their serum. Our findings suggest that serum PSA concentration is no indicator of micrometastatic disease in bone marrow. Neoadjuvant androgen deprivation appears to eliminate disseminated CK-positive tumor cells present in bone marrow, a preferred site of overt metastasis in prostate cancer patients. Int. J. Cancer 71:521-525, 1997. © 1997 Wiley-Liss, Inc.     

Familial prostate cancer: outcome following radiation therapy with or without adjuvant androgen ablation

PURPOSE: To compare the outcome of familial versus sporadic prostate carcinoma after definitive external radiation. METHODS AND MATERIALS: Between 1987 and 1996, 1214 men with clinically localized prostate cancer (T1-T4, N0/NX, M0) received definitive radiation therapy in our department. By retrospective review of charts and questioning of patients, a record on the presence or absence of prostate cancer in a first degree relative was obtained in 1164 men. Univariate and multivariate analysis was performed on these cases with relapse or rising prostate-specific antigen (PSA), local recurrence, metastasis, and survival as endpoints. RESULTS: Familiar prostate cancer was present in 148 of 1164 men (13%). Men with familial disease were slightly but significantly younger (mean 66 years) at diagnosis than those with sporadic disease (mean 68 years) (p = 0.02). Apart from this there were no significant differences between the two groups in T-stage, Gleason score, pretreatment PSA levels, DNA ploidy, or serum testosterone levels. There were no significant differences in treatment parameters including radiation dose and the use of adjuvant androgen ablation. With a median follow-up of 42 months, there was no difference in freedom from relapse or rising PSA at 6 years between those with a family history (54%) and those without a family history (58%) (p = 0.171). Likewise there was no difference between the two groups when local recurrence or metastasis was the endpoint. Multiple subgroup analyses (younger and older; T1/T2 and T3; low Gleason and high Gleason; no androgen ablation and androgen ablation; race) failed to reveal any differences in outcome in any category between familial and sporadic disease. Among patients with a rising post-treatment PSA profile, PSA doubling times were similar in those with sporadic and familial disease. CONCLUSIONS: This study provides no evidence for any substantial difference between familial and sporadic prostate cancer either in clinicopathological features, in response to treatment, or in ultimate outcome.     

Testicular Metastasis of Prostate Cancer: A Case Report

The incidence of secondary neoplasms of the testis during autopsies is approximately 2.5%. Although most secondary testicular metastases are due to prostate cancer, only a few patients with prostate cancer have clinically manifested testicular metastasis. We report the case of a prostate cancer patient with testicular metastasis who was diagnosed after the presence of a palpable mass in the right testis. A 56-year-old Japanese male presented to our hospital with an elevated serum prostate-specific antigen (PSA) level of 137 ng/ml. He was diagnosed with stage IV (T3N1M1b) prostate cancer and received androgen deprivation therapy, followed by various hormonal manipulations. His serum PSA level was undetectable for 1 year. No distant metastases were detected during imaging examinations. He received radiation therapy; however, his serum PSA level increased gradually. Four months later, he presented with right testicular swelling. Computed tomography revealed a heterogenous mass in the right testis and a right high inguinal orchiectomy was performed. Histopathological analysis showed that the right testis was infiltrated with metastatic adenocarcinoma with a Gleason score of 8. This is a rare case of right testicular metastasis in a patient with prostate cancer. Testicular metastasis of prostate cancer can be aggressive and metastasize.Key Words: Prostate cancer, Testicular metastasis, Orchiectomy