Biomedical subjects

Mark Garzotto

Publications and source records attributed to Mark Garzotto.

27 records · Page 2Linked to original sources

PubMed2004

Targeting FSH in androgen-independent prostate cancer: abarelix for prostate cancer progressing after orchiectomy.

OBJECTIVES: To determine the efficacy of the gonadotropin-releasing hormone antagonist abarelix in patients with androgen-independent prostate cancer progressing after orchiectomy and to measure its effect on serum follicle-stimulating hormone (FSH). METHODS: Sixteen patients with prostate cancer progressing after orchiectomy received abarelix-depot 100 mg by intramuscular injection on days 1, 15, and 29 and then every 28 days for up to 24 weeks (52 weeks in patients who met the criteria for a prostate-specific antigen [PSA] response after 24 weeks). PSA response was the primary endpoint and was defined as a 50% reduction confirmed 4 weeks later. The time to progression and effect of therapy on serum FSH were secondary endpoints. RESULTS: No patient met the criteria for a PSA response. Five patients (31%, 95% confidence interval 11% to 58%) experienced confirmed reductions in the PSA level ranging from 9.3% to 31.8%. At the end of the six cycles of therapy, 6 patients remained stable without PSA progression or other signs of disease progression. The median time to progression was 12 weeks (95% confidence interval 6 to 18). The mean serum FSH concentration declined after 4 weeks of study treatment by nearly 90% from a baseline of 45.1 IU/L (95% confidence interval 34.0 to 56.2) and remained suppressed throughout the observation period. Treatment was well tolerated, with one grade 3 allergic reaction. CONCLUSIONS: Treatment with abarelix in patients with androgen-independent prostate cancer after orchiectomy results in marked reduction in circulating FSH. None of the patients met the PSA response criteria; nonetheless, minor reductions in serum PSA were observed in 5 of 16 patients.

Adenocarcinoma↗

PubMed2004

High-dose calcitriol and carboplatin in metastatic androgen-independent prostate cancer.

Calcitriol acts synergistically with carboplatin in preclinical models of adenocarcinoma of the prostate. The authors sought to test high-dose oral calcitriol in combination with carboplatin in patients with metastatic androgen-independent prostate cancer. Seventeen patients received oral calcitriol (0.5 microg/kg) on day 1 and intravenous carboplatin (AUC 7 or AUC 6 in patients with prior radiation) on day 2, repeated every 4 weeks. PSA response was the primary end point and was defined as a 50% reduction confirmed 4 weeks later. Palliative response (2-point reduction or normalization of pain on the present pain intensity [PPI] scale without increased analgesic consumption) was also examined. One of 17 patients (6%, 95% CI, 0-28) achieved a confirmed PSA response. Four patients (24%, 95% CI, 7-49) had PSA reductions ranging from 24 to 38%. Of the 15 patients with a PPI > or = 1 point on entry, 3 (18%, 95% CI, 4-48) met criteria for palliative response. Treatment-related toxicity was mild and generally similar to that expected with single-agent carboplatin. Despite encouraging preclinical evidence, the addition of oral calcitriol to carboplatin in this study was not associated with an increase in the response rate when compared with the reported activity of carboplatin alone.

Adenocarcinoma↗

PubMed2004

Predictors of delayed therapy after expectant management for localized prostate cancer in the era of prostate-specific antigen.

OBJECTIVE: To identify risk factors for delayed cancer-directed intervention in modern era prostate cancer patients who initially elect expectant management. MATERIALS AND METHODS: An observational, cohort study of expectantly managed patients, diagnosed with clinical T(1-4)NxM0 prostate cancer between 1993 and 2000 was carried out. Data including TNM stage, age, serum prostate-specific antigen (PSA), prostate gland volume by transrectal ultrasound, Gleason score, percent biopsies positive for cancer, imaging results, initial treatment selection, and outcome data were collected on all patients. RESULTS: 192 of 561 patients (34.3%) elected expectant management, and follow-up data were available for 187 (97.4%) patients. With a median follow-up of 3.6 years, 90 (48.1%) patients had a cancer-directed intervention. Gleason score (p = 0.0097) and percent of positive biopsy cores (p = 0.03) were independent predictors of time to intervention. As expected, PSA doubling time became the most significant predictor of intervention (p = 0.0057) when added to the model. These independent covariates are able to characterize low-, intermediate- and high-risk groups for cancer-directed intervention. CONCLUSIONS: Cancer-directed intervention is common in patients who choose expectant management in the PSA era. Gleason score and percent of positive biopsy cores predict cancer-directed interventions, thus, these patients may be least suitable for expectant management.

Adenocarcinoma↗

PubMed2004

Randomized study of high-dose pulse calcitriol or placebo prior to radical prostatectomy.

BACKGROUND: Cancer chemoprevention trials require enormous resources due to the large numbers of patients and the years of follow-up needed to achieve sufficient statistical power. Examination of candidate prevention agents using biomarkers as surrogate end points has been proposed as a method to rapidly identify promising agents for prevention trials. Treatment of patients with candidate agents prior to scheduled biopsy or surgical resection of malignancy allows for direct examination of the treatment effects on tumor tissue. In this study, we selected this approach to test several hypotheses about the effect of calcitriol (1,25-dihydroxycholecalciferol), the active form of vitamin D, on early-stage human prostate cancer. METHODS: After selection of surgical treatment for histologically confirmed adenocarcinoma of the prostate, patients were randomized to either calcitriol 0.5 mug/kg or placebo weekly for 4 weeks. The expression levels of the vitamin D receptor (VDR), proliferating cell nuclear antigen, PTEN (MMAC1/TEP1), c-Myc, transforming growth factor (TGF) beta receptor type II (TGFbeta RII), and Bcl-2 were quantified using immunohistochemistry in the patients' prostate specimens post surgery. RESULTS: Thirty-seven of 39 prostate tumors were evaluable for molecular end points. VDR expression was reduced in patients treated with calcitriol (mean, 75.3% of cells) compared with those that received placebo (mean, 98.6%; P = 0.005). Calcitriol treatment did not result in a statistically significant change in the fraction of cells expressing TGFbeta RII, PTEN, or proliferating cell nuclear antigen. Bcl-2 and c-Myc expression was at the lower limits of detection in both the calcitriol group and the placebo group; therefore, we were unable to determine whether drug treatment induced a significant change in these biomarkers. CONCLUSIONS: High-dose calcitriol down-regulates VDR expression in human prostate cancer. Further study is needed to determine the biological consequences of VDR down-regulation in prostate cancer. This study shows that the use of the preprostatectomy model is feasible and can be used to test the effect of candidate chemopreventive agents on prostate cancer.

Adenocarcinoma↗

PubMed2003

Predictive modeling for the presence of prostate carcinoma using clinical, laboratory, and ultrasound parameters in patients with prostate specific antigen levels < or = 10 ng/mL.

BACKGROUND: The objective of the current study was to develop a model for predicting the presence of prostate carcinoma using clinical, laboratory, and transrectal ultrasound (TRUS) data. METHODS: Data were collected on 1237 referred men with serum prostate specific antigen (PSA) levels < or = 10 ng/mL who underwent an initial prostate biopsy. Variables analyzed included age, race, family history, referral indication(s), prior vasectomy, digital rectal examination (DRE), PSA level, PSA density (PSAD), and TRUS findings. Twenty percent of the data were reserved randomly for study validation. Logistic regression analysis was performed to estimate the relative risk, 95% confidence interval, and P values. RESULTS: Independent predictors of a positive biopsy result included elevated PSAD, abnormal DRE, hypoechoic TRUS finding, and age 75 years or older. Based on these variables, a predictive nomogram was developed. The sensitivity and specificity of the model were 92% and 24%, respectively, in the validation study for which the predictive probability > or = 10% was used to indicate the presence of prostate carcinoma. The area under the receiver operating characteristic curve (AUC) for the model was 73%, which was significantly higher compared with the prediction based on PSA alone (AUC, 62%). If it was validated externally, then application of this model to the biopsy decision could result in a 24% reduction in unnecessary biopsy procedures, with an overall reduction of 20%. CONCLUSIONS: Incorporation of clinical, laboratory, and TRUS data into a prebiopsy nomogram significantly improved the prediction of prostate carcinoma over the use of individual factors alone. Predictive nomograms may serve as an aid to patient counseling regarding prostate biopsy outcome and to reduce the number of unnecessary biopsy procedures.

Adenocarcinoma↗

PubMed2003

A comparison of CT scan to transrectal ultrasound-measured prostate volume in untreated prostate cancer.

PURPOSE: To compare CT and transrectal ultrasound (TRUS)-measured prostate volumes in patients with untreated prostate cancer. METHODS AND MATERIALS: Between 1995 and 1999, 48 consecutive patients at the Portland Veterans Affairs Medical Center were treated with external beam radiotherapy. In 36 of these patients, TRUS and CT measurements of the prostate volume were obtained before treatment and <6 months apart. The TRUS volume was calculated using the prolate ellipsoid formula. The CT volume was calculated from the contours of the prostate drawn by one physician, who was unaware of the TRUS volume calculation, on axial CT images. RESULTS: The TRUS and CT prostate volume measurements correlated strongly (Pearson's correlation coefficient = 0.925, 95% confidence interval 0.856-0.961, p < 0.0001). The CT volume was consistently larger than the TRUS volume by a factor of approximately 1.5. In men with a TRUS prostate volume less than the median (<28 cm(3)), the CT/TRUS volume ratio was 1.7, and it was 1.4 for men whose volume was greater than the median. The CT volumes were correlated similarly with the TRUS volumes regardless of the CT slice interval. CONCLUSION: A strong correlation was found between CT scan and TRUS measurement of the prostate volume; however, CT consistently overestimated the prostate volume by approximately 50% compared with TRUS.

Adenocarcinoma↗

PubMed2003

Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer.

PURPOSE: To determine the safety and efficacy of weekly high-dose oral calcitriol (Rocaltrol, Roche Pharmaceuticals, Basel, Switzerland) and docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ) in patients with metastatic androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS: Thirty-seven patients were treated with oral calcitriol (0.5 micro g/kg) on day 1 followed by docetaxel (36 mg/m(2)) on day 2, repeated weekly for 6 weeks of an 8-week cycle. Patients maintained a reduced calcium diet and increased oral hydration. Prostate-specific antigen (PSA) response was the primary end point, which was defined as a 50% reduction in PSA level confirmed 4 weeks later. RESULTS: Thirty of 37 patients (81%; 95% confidence interval [CI], 68% to 94%) achieved a PSA response. Twenty-two patients (59%; 95% CI, 43% to 75%) had a confirmed > 75% reduction in PSA. Eight of the 15 patients with measurable disease (53%; 95% CI, 27% to 79%) had a confirmed partial response. Median time to progression was 11.4 months (95% CI, 8.7 to 14 months), and median survival was 19.5 months (95% CI, 15.3 months to incalculable). Overall survival at 1 year was 89% (95% CI, 74% to 95%). Treatment-related toxicity was generally similar to that expected with single-agent docetaxel. Pharmacokinetics of either calcitriol or docetaxel were not affected by the presence of its companion drug in an exploratory substudy. CONCLUSION: The combination of weekly oral high-dose calcitriol and weekly docetaxel is a well-tolerated regimen for AIPC. PSA and measurable disease response rates as well as time to progression and survival are promising when compared with contemporary phase II studies of single-agent docetaxel in AIPC. Further study of this regimen is warranted.

Aged↗

PubMed2003

Phase II study of abarelix depot for androgen independent prostate cancer progression during gonadotropin-releasing hormone agonist therapy.

PURPOSE: We determine the clinical efficacy of the gonadotropin-releasing hormone (Gn-RH) antagonist abarelix in patients with androgen independent prostate cancer, and measure its effect on serum follicle-stimulating hormone (FSH) and testosterone. MATERIALS AND METHODS: A total of 20 patients with prostate cancer progression during Gn-RH agonist therapy received 100 mg. abarelix depot by intramuscular injection on days 1, 15 and 29, and then every 28 days for up to 24 weeks. Gn-RH agonist therapy was not continued. Patients who met criteria for prostate specific antigen (PSA) response after 24 weeks of therapy could receive treatment for up to 52 weeks. PSA response was the primary end point and was defined as a 50% decrease confirmed 4 weeks later. Secondary end points of this study were the effect of therapy on serum FSH and testosterone. RESULTS: No patient met the criteria for PSA response. At the end of the 6 cycles of therapy 2 patients remained stable without PSA progression or other signs of disease progression. Median time to progression was 8 weeks (95% CI 5.7-10.3). Mean serum FSH decreased by more than 50% from a baseline of 5.7 IU/l. (95% CI 4.2-7.1) and remained suppressed throughout the observation period. Mean serum testosterone did not change after 4 and 8 weeks of therapy and remained in the anorchid range. Treatment was well tolerated with no grade 3 or higher toxicity. CONCLUSIONS: Treatment of androgen independent prostate cancer with abarelix decreases circulating FSH and maintains anorchid testosterone but does not result in clinical responses.

Aged↗

PubMedDate not supplied

Neoadjuvant mitoxantrone and docetaxel for high-risk localized prostate cancer.

PURPOSE: Currently available treatment modalities for high-risk clinically localized prostate cancer have limited chances of achieving complete tumor elimination because of either inadequate local or metastatic tumor eradication. The goal of this phase I/II study is to evaluate the safety and efficacy of neoadjuvant docetaxel and mitoxantrone before prostatectomy. MATERIALS AND METHODS: A total of 22 men with high-risk clinically localized prostate cancer underwent weekly treatment with docetaxel (35 mg/m(2)), with increasing doses of mitoxantrone (2-5 mg/m(2)) for a 12 of 16-week treatment cycle before prostatectomy. Testosterone and prostate-specific antigen (PSA) measurements were made before and after chemotherapy. RESULTS: The maximally tolerated dose for mitoxantrone was 4 mg/m(2), and the primary toxicity was neutropenia. Testosterone levels were maintained throughout treatment. PSA reductions were observed in 95% of patients, with a median reduction of 41%. The surgery was well tolerated after chemotherapy, without any major complications. Negative surgical margins were attained in 76% of patients. CONCLUSIONS: Administration of multi-agent chemotherapy before prostatectomy was safe in this population. This regimen appeared to have antineoplastic activity as evidenced by PSA reductions in the absence of significant testosterone changes. The benefit of chemotherapy for improving surgical margin rates could not be determined outside of a phase III trial because the effect of patient or surgeon factors could not be dissected from the potential effect of neoadjuvant therapy. Continued study of novel agents in the neoadjuvant setting is warranted because this approach allows for the rapid identification of active agents and for molecular investigation into the mechanism of drug activity.

Aged↗