Biomedical subjects

Tomasz M Beer

Publications and source records attributed to Tomasz M Beer.

At least 37 records · Page 2Linked to original sources

PubMed2005

Pharmacokinetics and tolerability of a single dose of DN-101, a new formulation of calcitriol, in patients with cancer.

BACKGROUND: Intermittent administration allows substantial dose escalation of calcitriol but limited bioavailability of the commercially available formulations at high doses is limiting. In this dose escalation study, we sought to evaluate the tolerability and pharmacokinetics of a single oral dose of DN-101, a high-dose calcitriol formulation. METHODS: DN-101 doses were escalated in sequential groups of three to six patients with advanced solid tumors. Dose-limiting toxicity was defined as grade > or =2 hypercalcemia or grade > or =3 persistent treatment-related toxicities. Single-dose administration of 15, 30, 60, 75, 90, 105, 135, and 165 mug was tested. RESULTS: Thirty-eight patients were enrolled in 2002 and 2003. The median age was 70 years (range, 44-91 years). Dose escalation was stopped at the 165 microg level when the number of capsules required at one time reached 11. No dose-limiting toxicities occurred. Transient and self-limited grade 3 toxicities were hyponatremia (2) and proteinuria (1). A dose-proportional increase in peak concentration (C(max)) and area under the concentration curve (AUC) was seen across the full range of DN-101 doses tested. At the 165 microg dose, C(max) was 6.21 +/- 1.99 ng/mL, AUC(0-24) was 41.3 +/- 9.77 ng h/mL, AUC(0-infinity) was 55.4 +/- 8.44, and half-life (T(1/2)) was 16.2 hours. CONCLUSIONS: At doses between 15 and 165 microg, DN-101 exhibits linear pharmacokinetics. At 165 microg, DN-101 achieves systemic exposure that is 5- to 8-fold higher than that achieved with commercial formulations of calcitriol, which makes DN-101 comparable to that required for antitumor activity in vivo in a murine squamous cell carcinoma model.

Administration, Oral↗

PubMed2005

Statins and prostate cancer risk: a case-control study.

Observational studies have shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) use may be associated with reduced cancer risk. The purpose of this case-control study was to elucidate the association between statin use and prostate cancer risk. Prostate cancer cases (n = 100), recruited upon referral for prostate biopsy, and frequency age-matched, prostate-specific antigen-normal clinic controls (n = 202) were recruited from the Portland, Oregon, Veterans Affairs Medical Center. Information on any use of statins from May 1997 through August 2004 was obtained from an electronic pharmacy database. Days of use, type of statin, dose, and prescription changes were recorded. Duration and intensity were calculated for each statin type on the basis of days of use and prescribed dose. Thirty-six percent of cases and 49 percent of controls had a record of any statin use. Following adjustment for other potential risk factors, statin use was associated with a significant reduction in prostate cancer risk (odds ratio = 0.38, 95% confidence interval: 0.21, 0.69). Furthermore, in analyses stratified by Gleason score, the inverse association with statin use was maintained only among men with Gleason scores of > or =7 (odds ratio = 0.24, 95% confidence interval: 0.11, 0.53). The results of this case-control study suggest that statins may reduce the risk of total prostate cancer and, specifically, more aggressive prostate cancer.

Aged↗

PubMed2005

Resistance of prostate cancer cell lines to COX-2 inhibitor treatment.

Targeting of cyclooxygenase-2 (COX-2) for cancer chemoprevention is well supported for several tumor types, most notably colon cancer. In contrast, the data for its role in prostate cancer carcinogenesis are correlative only. Thus, we compared the COX-2 expression, activity, and effects of inhibition in prostate cancer cells on COX-2-dependent colon cancer cells. COX-2 levels in benign and malignant human prostate tissue were determined by immunohistochemistry. Compared to colon cancer cells, prostate cancer cells expressed lower levels of COX-2, produced less PGE2, and were resistant to selective COX-2 inhibition. Examination of benign prostatic epithelium from prostatectomy samples demonstrated rare foci of COX-2. Whereas, human prostate cancer sections were uniformly negative for COX-2. In conclusion, these studies indicate the lack of a putative role for COX-2 in prostate cancer development. Direct evidence for the involvement of COX-2 in prostate cancer carcinogenesis is desperately needed.

Apoptosis↗

PubMed2005

In vivo bioavailability and pharmacokinetics of a c-MYC antisense phosphorodiamidate morpholino oligomer, AVI-4126, in solid tumors.

Phosphorodiamidate morpholino oligomers (PMO) inhibit targeted gene expression by preventing ribosomal assembly, thereby preventing mRNA translation. AVI-4126, a PMO targeted against c-MYC, has been extensively characterized in multiple cancer and other disease models and is currently in human clinical trials. A phase I clinical study was conducted to address the issue of PMO bioavailability in malignant tumors surgically excised from patients with adenocarcinoma of prostate and breast 1 day after i.v. administration of a single dose of 90 mg AVI-4126 PMO. The study objectives were to evaluate safety, to determine AVI-4126 concentration in tissue samples of the tumors, and to examine the distribution of AVI-4126 (margin versus tumor core). Significant concentrations of intact PMO similar to the animal models were detected in both human prostate and breast tumor tissues with increased distribution in the tumor core for the vascular breast tumors. No serious adverse events (graded according to National Cancer Institute Common Toxicity Criteria) were reported. Another phase I study was conducted in normal human volunteers to assess AVI-4126 plasma pharmacokinetics following single i.v. administration of 90 mg AVI-4126. Data from both human studies indicated similar plasma concentration-time profile. These studies show PMO bioavailability in tumor tissue and establish the feasibility of using PMO targeting specific genes in human cancer clinical trials.

Animals↗

PubMed2005

Improved detection of prostate cancer using classification and regression tree analysis.

PURPOSE: To build a decision tree for patients suspected of having prostate cancer using classification and regression tree (CART) analysis. PATIENTS AND METHODS: Data were uniformly collected on 1,433 referred men with a serum prostate-specific antigen (PSA) levels of < or = 10 ng/mL who underwent a prostate biopsy. Factors analyzed included demographic, laboratory, and ultrasound data (ie, hypoechoic lesions and PSA density [PSAD]). Twenty percent of the data was randomly selected and reserved for study validation. CART analysis was performed in two steps, initially using PSA and digital rectal examination (DRE) alone and subsequently using the remaining variables. RESULTS: CART analysis selected a PSA cutoff of more than 1.55 ng/mL for further work-up, regardless of DRE findings. CART then selected the following subgroups at risk for a positive biopsy: (1) PSAD more than 0.165 ng/mL/cc; (2) PSAD < or = 0.165 ng/mL/cc and a hypoechoic lesion; (3) PSAD < or = 0.165 ng/mL/cc, no hypoechoic lesions, age older than 55.5 years, and prostate volume < or = 44.0 cc; and (4) PSAD < or = 0.165 ng/mL/cc, no hypoechoic lesions, age older than 55.5 years, and 50.25 cc less than prostate volume < or = 80.8 cc. In the validation data set, specificity and sensitivity were 31.3% and 96.6%, respectively. Cancers that were missed by the CART were Gleason score 6 or less in 93.4% of cases. Receiver operator characteristic curve analysis showed that CART and logistic regression models had similar accuracy (area under the curve = 0.74 v 0.72, respectively). CONCLUSION: Application of CART analysis to the prostate biopsy decision results in a significant reduction in unnecessary biopsies while retaining a high degree of sensitivity when compared with the standard of performing a biopsy of all patients with an abnormal PSA or DRE.

Adult↗

PubMed2005

Phase II study of transdermal estradiol in androgen-independent prostate carcinoma.

BACKGROUND: Oral estrogen therapy has activity in patients with hormone-naive and androgen-independent prostate carcinoma (AIPC), but its utility is limited by the associated risk of thromboembolic toxicity. Parenteral administration may be safer as it avoids "first pass" liver exposure to estrogen. The authors tested the safety and efficacy of transdermal estradiol (TDE), as well as the effect of therapy on hot flashes, sex hormones, the procoagulant cascade, and bone turnover in patients with AIPC. METHODS: Patients with prostate carcinoma progressing after primary hormonal therapy received TDE 0.6 mg per 24 hours (administered as six 0.1 mg per 24-hour patches replaced every 7 days). Serum prostate-specific antigen (PSA) and hormone levels, coagulation factors, markers of bone turnover, bone density measurements, and a hot flash diary were collected at regular intervals. RESULTS: Three of 24 patients (12.5%; 95% confidence interval [CI], 0-26%) had a confirmed PSA reduction >50%. The Kaplan-Meier estimate of median time to disease progression was 12 weeks (95% CI, 4.6-19.4 weeks). Toxicity was modest and no thromboembolic complications occurred. The mean (+/-95% CI) serum estradiol level increased from 17.2 pg.mL (range, 14.8-19.6 pg/mL) to 460.7 pg/mL (range, 334.6-586.7 pg/mL). The total testosterone level remained stable in the anorchid range during treatment, but the free testosterone level decreased as a result of increased sex hormone binding globulin. No change in factor VIII activity, F 1.2, or resistance to activated protein C was observed, whereas a modest decrease in the protein S level was observed. CONCLUSIONS: In patients with APIC, TDE was well tolerated and produced a modest response rate, but was not associated with thromboembolic complications or clinically important changes in several coagulation factors.

Administration, Cutaneous↗

PubMed2005

Rationale for the development and current status of calcitriol in androgen-independent prostate cancer.

Calcitriol, the principal active metabolite of vitamin D, has significant antineoplastic activity in pre-clinical models of prostate cancer and many other tumor types. Reported mechanisms of activity include inhibition of proliferation and cell cycle arrest, induction of apoptosis, and reduction of invasiveness and angiogenesis. Different mechanisms may be responsible in different tumor types and under different experimental conditions. Importantly, preclinical data suggest that calcitriol acts in a synergistic and/or additive manner when combined with antineoplastic agents that are relevant to prostate cancer, including dexamethasone and several classes of cytotoxic agents. The antineoplastic effects of calcitriol occur at concentrations that substantially exceed the normal physiologic range and cannot be safely achieved with conventional daily dosing. Intermittent administration of calcitriol has allowed significant dose escalation. In combination with weekly docetaxel, the agent produced encouraging results in a single-institution phase II study. An international placebo-controlled randomized trial that is currently under way will provide more robust information about the safety and efficacy of this combination.

Androgens↗

PubMed2005

Novel cytotoxic and biological agents for prostate cancer: where will the money be in 2005?

In 2004, docetaxel-based chemotherapy became the first treatment capable of extending life in androgen-independent prostate cancer. The era of therapeutic nihilism in this disease has thus been put to rest and a broad range of agents is being tested with the goal of improving on the successes of 2004. Lessons learned from other tumour types will need to be applied to prostate cancer in order to harness the bounty of available ideas. Target amplification or activating mutations and not merely the presence of a target are likely to be important to the success of targeted agents. Thus, the promise of the current crop of targeted agents is most likely to be realised when pursued in the context of well-credentialed targets and tested in highly translational clinical trials that are capable not only of assessing tumour response, but also of evaluating the status of the targeted pathway. The most promising agents in clinical development are reviewed.

Angiogenesis Inhibitors↗

PubMed2005

Prostate-specific antigen decline after gonadotropin-releasing hormone antagonist withdrawal in androgen-independent prostate cancer.

A 66-year-old man with androgen-independent prostate cancer was treated with abarelix, a gonadotropin-releasing hormone antagonist, for 20 weeks in an experimental protocol. He did not respond to therapy, but his serum prostate-specific antigen level dropped from 15.8 ng/mL to a confirmed 0.8 ng/mL after abarelix was stopped. His prostate-specific antigen level did not return to greater than 15.8 ng/mL for 14 months. This is the first report of a withdrawal response after therapy with a gonadotropin-releasing hormone antagonist, a new class of agents for prostate cancer. Additional observations are needed to determine whether this is an isolated case or a harbinger of a more common phenomenon.

Aged↗

PubMed2005

Androgen deprivation impairs memory in older men.

Androgen deprivation leads to a profound loss of synaptic density in the hippocampus and changes in learning and memory in animal models. The authors examined group differences in verbal memory between men on androgen deprivation therapy (ADT), a commonly used treatment for prostate cancer, and healthy men. The authors found that men on ADT have a specific impairment of retention but normal encoding and retrieval processes on a word list-learning task. Speed and accuracy for both perceptual and semantic encoding, as well as retrieval at a very short retention interval, were not affected; however, recognition fell to chance after a 2-min retention interval in men on ADT. Healthy men showed only moderate forgetting, and performance was still above chance at 12 min. This pattern of preserved encoding and retrieval but impaired retention suggests that androgens play a role in hippocampally mediated memory processes, possibly having a specific affect on consolidation.

Aged↗

PubMed2005

Treatment of erectile dysfunction following therapy for clinically localized prostate cancer: patient reported use and outcomes from the Surveillance, Epidemiology, and End Results Prostate Cancer Outcomes Study.

PURPOSE: Erectile dysfunction (ED) persists for years following curative therapies for clinically localized prostate cancer. We report use and treatment outcomes in a 5-year interval in a population based cohort from the Surveillance, Epidemiology, and End Results Prostate Cancer Outcomes Study. MATERIALS AND METHODS: A sample of 1,977 men with localized prostate cancer who received external beam radiation therapy or radical prostatectomy in 1994 to 1995 were surveyed for 5 outcome measures of ED treatment, namely treatment, perceived helpfulness, erectile sufficiency, sexual activity frequency and erection maintenance. Subjects were surveyed 6, 12, 24 and 60 months after prostate cancer diagnosis. RESULTS: Overall 50.5% of men ever used ED treatment. The use of ED treatments increased during the study course. Subject age, regular sexual partner and baseline sexual activity were factors positively associated with ED treatments. While it was used uncommonly (1.9%), a penile prosthesis was perceived as the most helpful ED treatment (helped a lot in 52% of respondents). Sildenafil helped a lot in 12% of respondents. Erectile fullness, erection maintenance and sexual activity frequency were modestly improved in men using ED treatment compared with those in men not using ED treatment. CONCLUSIONS: Approximately half of the patients in this population based cohort of men used ED treatment during the 5 years following prostate cancer diagnosis. Men using ED treatments had modest improvement in sexual function compared with men that in who did not receive ED treatment at 60 months. More effective treatments for ED following local therapy for prostate cancer are needed.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2005

High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer: a phase I/II study.

PURPOSE: We determined the safety and preliminary efficacy of the combination of high dose pulse calcitriol (1,25-dihydroxycholecalciferol) with a standard regimen of docetaxel plus estramustine in patients with metastatic androgen independent prostate cancer. MATERIALS AND METHODS: Patients were treated with 60 microg calcitriol orally on day 1, 280 mg estramustine orally 3 times daily on days 1 to 5 and 60 mg/m docetaxel on day 2 (70 mg/m after cycle 1) every 21 days for up to 12 cycles. Patients also received 325 mg aspirin and 1 or 2 mg warfarin orally daily. Regimen safety was assessed in the first 6 patients and a dose de-escalation scheme for calcitriol was planned if dose limiting toxicities were noted during treatment cycle 1 in greater than a third of patients. RESULTS: A total of 24 patients, including 11 who were chemotherapy naïve and 13 who had previously been treated with docetaxel, were evaluable for toxicity and 22 for prostate specific antigen decrease data. The regimen was generally well tolerated. Treatment related grades 3 or greater toxicity seen in more than 1 patient included hypophosphatemia in 16.7% and neutropenia in 12.5%. Four patients had thromboembolic complications. Asymptomatic hypercalcemia was seen in 4 patients, including grades 2 and 1 in 1 and 3, respectively. Six of 11 evaluable, chemotherapy naïve patients (55%) met prostate specific antigen response criteria. One of 11 patients (9%) treated with prior docetaxel met these criteria. CONCLUSIONS: High dose calcitriol may be safely added to docetaxel and estramustine administered on a 21-day schedule.

Administration, Oral↗

PubMed2005

Clinical outcomes of androgen deprivation as the sole therapy for localized and locally advanced prostate cancer.

OBJECTIVE: To characterize the clinical outcomes of androgen deprivation therapy (ADT) as the sole therapy for localized prostate cancer, and to determine independent predictors of disease progression, as recent studies indicate an increasing use of ADT. PATIENTS AND METHODS: The records of all patients with cT1-4NXM0 adenocarcinoma of the prostate treated with ADT as the primary initial therapy at the Portland Veterans Affairs Medical Center between 1993 and 2000 were reviewed. Age, race, Charlson Health Index, family history, prostate-specific antigen (PSA) level, PSA density, digital rectal examination (DRE) findings, Gleason score, and percentage of positive biopsy cores at diagnosis were recorded for 81 patients. Patients had a median (SD, range) age of 73 (5.6, 58-84) years, a PSA level of 14.3 (34.6, 1.4-252) ng/mL and tumours were classified as Gleason score < or = 5 in 9% of patients, 6 in 31%, 7 in 31% and 8-10 in 30%. Outcomes extracted were PSA progression, PSA nadir, bone fractures, local progression, distant progression and overall survival. RESULTS: With a median (range) follow-up of 54 (6-115) months, the incidence of local progression, distant progression, bone fractures, PSA progression, and death were 10%, 7%, 25%, 21% and 41% respectively. The percentage of positive biopsy cores > or = 83%, age < 70 years, Gleason score > or = 7, abnormal DRE, and PSA nadir > or = 0.2 ng/mL were significantly associated with PSA progression by univariate analysis. The multivariate analysis identified age < 70 years (hazard ratio 6.52, 95% confidence interval 2.29-18.55) and Gleason score > or = 6 (4.0, 2.0-12.0) as independent risk factors for PSA progression. CONCLUSIONS: ADT resulted in modest control of localized prostate cancer, but younger patients and those with Gleason > or = 6 cancers were at higher risk of treatment failure. Toxicity, principally in the form of bone fractures, was high.

Adenocarcinoma↗

PubMed2005

ASCENT: the androgen-independent prostate cancer study of calcitriol enhancing taxotere.

ASCENT, the Androgen-Independent Prostate Cancer (AIPC) Study of Calcitriol Enhancing Taxotere, is a double-blind, placebo-controlled randomized clinical trial designed to determine if DN-101, a high-dose oral formulation of calcitriol designed for cancer therapy, significantly increases the proportion of patients who have > 50% reduction in serum prostate-specific antigen (PSA) levels in response to docetaxel. The secondary goals of ASCENT are to evaluate the effect of DN-101 combined with docetaxel on PSA progression-free survival, tumour response rate in measurable disease, tumour progression-free survival, skeletal morbidity-free survival, clinical progression-free survival, and overall survival, and to examine the safety and tolerability of DN-101 combined with docetaxel. ASCENT builds on phase I work showing that weekly dosing allows substantial dose-escalation of calcitriol, the natural ligand for the vitamin D receptor, and on phase II work that suggested that adding weekly high-dose 'pulse' calcitriol may enhance the activity of weekly docetaxel in patients with AIPC. The preclinical rationale for calcitriol and its combination with docetaxel for prostate cancer therapy is reviewed, as are the key clinical trials that led to the development of ASCENT. The ASCENT design and its strengths and limitations are presented.

Aged↗

PubMed2004

How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30.

PURPOSE: Adverse events in chemotherapy clinical trials are assessed and reported by clinicians, yet clinician accuracy in assessing symptoms has been questioned. We compared patient reporting of eight symptoms using a validated instrument, the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (QLQ-C30 or QLQ) with physicians' reporting of the same symptoms in the study's adverse events log. PATIENTS AND METHODS: Thirty-seven men with metastatic, androgen-independent prostate cancer enrolled onto a phase II trial of weekly calcitriol and docetaxel completed the QLQ every 4 weeks for up to 28 weeks. A patient-reported symptom was defined as an increase in a QLQ symptom score by at least 10 points (0 to 100 scale), sustained for at least 4 weeks. A physician-reported symptom was considered present if it was ever documented in the adverse event log. RESULTS: Forty-nine (new or worsened) symptoms were detected by both physician and QLQ, 48 symptoms were detected by the physician alone, and 55 symptoms were detected by the QLQ alone. They agreed on the absence of a symptom in 102 instances of 254 possible opportunities. Their uncorrected agreement was 59.4%, but Cohen's kappa, a coefficient of agreement that corrects for chance, was 0.15, indicating only slight agreement. Using the QLQ as the standard, overall physician sensitivity and specificity was 47% and 68%, respectively, although it varied considerably among symptoms. CONCLUSION: Even in a tightly controlled clinical trial, physician reporting was neither sensitive nor specific in detecting common chemotherapy adverse effects. Tools for collecting patient-reported adverse event data in chemotherapy clinical trials should be developed.

Adverse Drug Reaction Reporting Systems↗

PubMed2004

Quality of life and pain relief during treatment with calcitriol and docetaxel in symptomatic metastatic androgen-independent prostate carcinoma.

BACKGROUND: The current study evaluated the analgesic activity and impact on quality of life (QOL) of a new chemotherapy regimen of calcitriol and docetaxel in men with androgen-independent prostate carcinoma. METHODS: Analgesic response was defined as a 2-point reduction on the Present Pain Intensity (PPI) scale (or compete relief if baseline PPI was 1) without an increase in analgesic use or a 50% decrease in analgesic medication use without an increase in pain, maintained for > or = 4 weeks. Pain, pain medication consumption, and QOL (measured by the European Organization for Research and Treatment of Cancer QLQ-C30) were evaluated every 4 weeks. RESULTS: Treatment resulted in an analgesic response in 14 of 29 evaluable patients (48%; 95% confidence interval [95% CI], 30-67%). The median time to symptomatic progression in the 14 patients who met criteria for analgesic response was 41 weeks (95% CI, 26-56 weeks). Worsening in physical and role functioning, fatigue, appetite, and global health status and improvement in constipation were detected using the QLQ-C30 QOL questionnaire. CONCLUSIONS: Significant analgesic activity was demonstrated, although worsening in several QOL domains was observed in a patient population with relatively low pain intensity (median PPI, 2).

Adenocarcinoma↗

PubMed2004

Phase I study of weekly mitoxantrone and docetaxel before prostatectomy in patients with high-risk localized prostate cancer.

PURPOSE: The purpose is to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of mitoxantrone and docetaxel administered weekly before prostatectomy in men with localized prostate cancer at high risk for recurrence. EXPERIMENTAL DESIGN: Twenty-two patients were treated with four cycles of docetaxel 35 mg/m(2) and increasing doses of mitoxantrone starting at 2 mg/m(2) repeated weekly for 3 weeks of a 4-week cycle before prostatectomy. The MTD was defined as that dose at which fewer than one-third of patients experienced a DLT (>or=grade 4 hematological or >or=>grade 3 nonhematological toxicity). Changes in serum prostate-specific antigen and serum testosterone, and pathological outcome with surgery were secondary endpoints. RESULTS: The MTD for mitoxantrone in combination with this dose of docetaxel was 4 mg/m(2). Neutropenia was the DLT for the combination. Ten of 12 patients treated at the MTD completed the planned 16 weeks of chemotherapy, whereas 2 discontinued therapy early because of toxicity. The median reduction in PSA was 41% (range, 4-88%). Serum testosterone levels remained constant postchemotherapy. CONCLUSIONS: In this patient population, the planned Phase II regimen is 4 mg/m(2) mitoxantrone and 35 mg/m(2) docetaxel weekly for 3 of every 4 weeks. Delivery of this regimen before prostatectomy is feasible with acceptable toxicity. Additional studies are needed to determine whether this combined modality approach will reduce cancer recurrence rates in this high-risk population. Because extent of disease and exposure to prior therapy may impact treatment tolerance these safety data may not be applicable to patients with advanced prostate cancer.

Aged↗

PubMed2004

Fine-needle aspiration diagnosis of plasmacytoma presenting as breast masses in a patient on estrogen therapy for prostate cancer.

We describe a 79-yr-old man with a history of androgen-independent metastatic prostate cancer treated with exogenous estrogens presenting with bilateral breast masses associated with bilateral axillary lymphadenopathy. Although the findings on physical examination with the concomitant history of estrogen therapy for metastatic prostate cancer raised the clinical suspicion of breast cancer, fine-needle aspiration (FNA) cytology identified the lesions as multiple myeloma.

Aged↗