Clinical prostate cancer最新文献

Background

The safety, tolerability, and pharmacokinetic and preliminary efficacy of PCK3145 were determined in patients with metastatic hormone-refractory prostate cancer.

Patients and Methods

PCK3145 was administered in ascending doses of 5, 20, 40, and 80 mg/m² 3 times per week for 4 weeks to cohorts of 4 patients. Dose escalation was based on dose-limiting toxicity (DLT). Pharmacokinetic profiles, tumor burden, and tumor markers (including prostate-specific antigen [PSA] and matrix metalloproteinase-9 [MMP-9] levels) were assessed. Sixteen patients received PCK3145. The median age was 66 years, and the median PSA level was 232.5 μg/L. A total of 32 cycles of therapy were administered.

Results

The most common adverse events reported were pain and nausea. The only DLT was a grade 4 cardiac arrhythmia in a patient treated at the 80-mg/m² dose level. Pharmacokinetic analysis using a 2-compartment model indicated that the mean area under the curve values increased as the dose range increased, and the mean elimination half-life ranged from 0.35 hours to 1.45 hours. The best tumor response was stable disease in 10 patients and progressive disease in 5 patients. No PSA responses were observed, but 1 patient showed a marked reduction in PSA of 41% at cycle 2. A substantial reduction in MMP-9 levels was observed in patients with baseline levels of MMP-9 > 100 μg/L.

Conclusion

PCK3145 was safe and well tolerated at all doses. Efficacy observations were encouraging, and the biologic activity of PCK3145 in reducing MMP-9 level may suggest a potential role of this peptide in the regulation of metastatic tumor growth.

Prostate cancer and its various forms of treatment remain a source of significant controversy and morbidity despite recent advances. In response, there is an increasing trend toward the development of treatments aimed at cancer prevention and at maximizing the preservation of function without sacrificing cancer control. This article reviews the current prostate cancer literature and reports on improvements in existing surgical treatments and developing technologies aimed toward achieving these goals. Specific therapies addressed include improvements in surgical techniques, laparoscopy, robotics, cryosurgical and thermal ablation, and high-intensity focused ultrasound.

Background

We revised our prostate cancer–specific measure to better address the physiologic complications of the 3 major therapies for clinically localized prostate cancer and to assess the impact of symptoms on broader aspects of patient functioning. The study used a crosssectional design, and participants completed the measure in a clinical setting.

Patients and Methods

Participants underwent radical prostatectomy (n = 130), external beam radiation therapy (n = 120), or brachytherapy (n = 129). Their mean age was 66 years (standard deviation [SD], 8.2 years), and the median time since treatment was 12.36 months (mean, 21.7; SD, 25.4). Items were derived from previously validated instruments or developed based on the clinical experience of a multidisciplinary group of health professionals.

Results

The revised instrument included 46 items that formed 8 physiologic scales (2 urinary, 3 sexual, and 3 bowel function); 3 associated bother scales; and cancer worry, treatment regret, and treatment satisfaction scales. Correlations among scales provided evidence of convergent/divergent validity. Significant group differences were found using analysis of covariance (with time since treatment and age as covariates) on 6 of the 8 physiologic scales and on bowel bother and treatment satisfaction.

Conclusion

The instrument provides a sensitive measure of physiologic differences across the 3 primary treatment groups and indicates that there are few differences across treatment groups on broader aspects of health-related quality of life. Further development of the measure is recommended.

Differences in diet have been proposed to be at least partially responsible for the low rate of prostate cancer in Asian populations compared with men in Western countries. One of the compounds that occurs in a greater quantity in the Eastern diet is genistein, an isoflavonoid found in high concentrations in serum after ingestion of soy-rich foods. Extensive molecular studies have been performed to determine its potential health benefits. The mechanism of action of genistein is complex and includes several cellular pathways. In addition to its estrogenic and/or antiestrogenic activities, genistein has been reported to inhibit steroidogenesis and block several protein tyrosine kinases, including epidermal growth factor receptor and src tyrosine kinases. Moreover, it arrests the cell cycle, induces apoptosis, and has antiangiogenic and antimetastatic properties and antioxidant activity. Herein, we review the current literature on the molecular mechanisms of genistein in relation to its effects on prostate cancer cells.

As increasing numbers of men are living longer with prostate cancer, larger proportions will eventually present to our collective practices with increasing prostate-specific antigen (PSA) levels. Such PSA relapses, conservatively estimated to affect approximately 50,000 men each year, have become the most common form of advanced prostate cancer. Salvage radiation therapy and salvage prostatectomy have important roles in our therapeutic armamentarium and should be valid options for young, healthy men. Counseling patients regarding expectations for cancer control and treatment morbidity has become better because of reports from larger series of patients who have had salvage radiation therapy and surgery. Some patients may not be appropriate candidates for salvage local therapies. A growing body of evidence suggests early hormonal therapy improves progression-free survival (PFS) and could alter cancer-specific survival. This benefit seems to be greatest when hormonal therapy is initiated while PSA levels are low, before clinically measurable disease becomes apparent. However, there is a cost to be paid in side effects and health care dollars when androgen deprivation is administered over prolonged periods. The nonsteroidal antiandrogen agent bicalutamide could offer PFS equivalent to that seen with castration without the complications of androgen deprivation. Observational data seem to indicate that individuals at high risk could also receive benefit from therapy administered before PSA detection. The potential opportunities for novel therapeutic agents with low associated morbidity are great.

Few treatment options are available for patients with metastatic hormone- refractory prostate cancer (HRPC) that is not responsive to or continues to progress after taxane-based chemotherapy. Although single-agent carboplatin has modest activity in HRPC, carboplatin chemotherapy could induce a synergistic effect when combined with taxanes in patients with disease resistant to taxane-based chemotherapy. We report a case series of 4 consecutive patients treated with docetaxel (60-70 mg/m²) plus carboplatin (area under the curve of 4/5) following progression after taxane-based chemotherapy. Prostate-specific antigen levels decreased by > 50% in all 4 patients and were associated with improvement in symptoms in 3 of 4 patients. Treatment was well tolerated, with fatigue as the most common reported side effect. Patients received 4-11 cycles of treatment and, after initiation of docetaxel/carboplatin chemotherapy, survival ranged from 4.5 months to 12 months. In this small series, there is a suggestion of a greater than expected response with carboplatin and docetaxel for patients who exhibit disease progression despite taxane-based chemotherapy or do not respond to therapy. A clinical trial to evaluate this effect has been initiated.

Prostate cancer treatments have positive and negative outcomes that must be taken into account when deciding how to proceed with a patient's care. One way to quickly determine a patient's preferences in this situation is to ascertain their health utilities for various health states. Health utilities are underutilized but powerful tools in aiding shared decision making between patients and physicians. This review is intended to inform physicians about the different techniques available, help the physician choose among them, and aid initial development of utilities for use in the clinic by way of the tables' references. A brief history, summary of applications and current directions of health utilities, and collection of references are provided to increase the reader's overall knowledge of health utilities and encourage their use in the clinic. Ultimately, the use and choice of one of these direct preference-based measures depends on the needs of the physician.

Men with prostate cancer are at high risk of developing bone metastases that can lead to clinically significant skeletal morbidity. Recently, a randomized, placebo-controlled, phase III trial in 422 men with hormone- refractory prostate cancer and bone metastases demonstrated that zoledronic acid (4 mg every 3 weeks) significantly reduced the incidence and onset of skeletal complications and provided significant long-term reductions in bone pain compared with placebo. Patients received zoledronic acid for a 15-month core phase, with the option to continue therapy for 9 more months on the extension phase. To evaluate the continuing benefit of long-term zoledronic acid therapy, retrospective exploratory analyses were conducted based on the incidence of skeletal-related events (SREs; defined as pathologic bone fracture, spinal cord compression, surgery or radiation therapy to bone, or change in antineoplastic therapy for bone pain) occurring only during the extension phase of this trial. Quality of life parameters included assessment with the Brief Pain Inventory. Similar to results reported for the 15-month core phase and the entire 24-month study, the 9-month extension phase demonstrated that zoledronic acid significantly reduced the percentage of patients with an SRE (P = 0.017), prolonged the median time to first SRE (P = 0.036), reduced the annual incidence of SREs by 52% (P = 0.016), and reduced the risk of SREs by 53% (P = 0.022) compared with placebo. Furthermore, zoledronic acid was safe and well tolerated. Therefore, zoledronic acid provides long-term continuing clinical benefit for men with prostate cancer and bone metastases and represents a new therapeutic option for this population.

Purpose

Prostate needle biopsy (PNB) is the definitive method for the diagnosis of prostate cancer. Our objective was to evaluate prebiopsy parameters, including lower urinary tract symptoms, that may be predictive of positive biopsy.

Patients and Methods

We performed a prospective review of 569 consecutive men who underwent transrectal ultrasound (TRUS)–guided PNB. The prebiopsy variables recorded included age, prostate-specific antigen (PSA) levels, prostate volume (PV), percent free PSA levels, suspicious digital rectal examination (DRE) findings, TRUS-detected lesions, race, and American Urologic Association Symptom Score (AUASS).

Results

Low AUASS, PV, patient age, and abnormal TRUS findings were independent predictors of positive PNB results (P < 0.05). In patients with PSA levels between 4 and 10 ng/mL, the positive predictive value of a low AUASS (< 8) in predicting a positive PNB result is 68.7%. When race was considered (black vs. white), univariate analysis (UVA) indicated that race was a significant predictor (P = 0.034) of positive PNB. A subgroup analysis was performed for black men undergoing PNB (n = 256). Multivariate analysis (MVA) indicates that abnormal TRUS findings; low AUASS, PV, and PSA levels; and absence of prior biopsy are all independent predictors of PNB in the black patient group. A final subgroup analysis (UVA and MVA) was performed for white men (n = 310). Only patient age and PV demonstrated significance as independent predictors of PNBs in this group.

Conclusion

This prospective analysis of 569 men demonstrates that traditional indicators for PNB (abnormal DRE findings and PSA levels) are not significant predictors of prostate cancer. Independent predictors for prostate included age, low AUASS, low PV, and abnormal TRUS findings. A low AUASS (indicative of the absence of benign disease) is an important predictor of prostate cancer.

Patients diagnosed with clinically localized prostate cancer face a daunting variety of management choices, including conservative management, brachytherapy, external-beam irradiation therapy with or without neoadjuvant hormonal therapy, as well as surgery. As we have learned to characterize the nature of each cancer, we can now “riskadjust” treatment decisions. Physicians have long sought to guide patients through these choices based on their best judgment about the threat posed by the cancer, the effectiveness of treatment, the side effects of therapy, and the life expectancy of the patient. Today, many patients wish to participate more actively in decisions about their care, weighing the risks of treatment-related complications and the anxiety of living with an untreated or uncontrolled cancer. Patient utilities measure the value patients place on a health state, such as living with cancer or becoming incontinent, allowing quantitative assessments of risks and benefits of different therapeutic options specific for each patient's own preferences and the nature of his cancer and life expectancy. As early detection programs for prostate cancer expand, men are being diagnosed with prostate cancer earlier in its natural history. Some of these cancers may not require immediate treatment but rather a period of active surveillance with definitive curative therapy being administered only if there are signs of cancer progression. This review summarizes our current understanding of active surveillance with selective delayed definitive therapy.