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Biomedical subjects

T Curley

Publications and source records attributed to T Curley.

17 recordsLinked to original sources
PubMed2000

The development of biologic end points in patients treated with differentiation agents: an experience of retinoids in prostate cancer.

The evaluation of new therapies in prostate cancer requires unique end points for agents with diverse mechanisms of action. Because retinoic acid may have a confounding effect on prostate-specific antigen, we incorporated a pathological end point into the outcome assessment of two sequential clinical trials using all-trans-retinoic acid (ATRA) and the combination of 13-cis-retinoic acid and IFN-2a (cRA¿IFN). Pre- and posttherapy tumor biopsy specimens were studied for histological changes, apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling assay), and proliferation index (Ki67). Prostate-specific membrane antigen (PSMA) expression was also evaluated using two different monoclonal antibodies to its intracellular domain (Cytogen 7E11 and Hybritech PM2). Fourteen patients with androgen-independent disease were treated with ATRA (50 mg/m2 p.o. every 8 h daily) and 16 androgen-independent and 4 androgen-dependent patients were treated with cRA¿IFN (10 mg/kg/day cRA plus 3, 6, or 9 million units daily IFN). Both therapies were well tolerated, with fatigue and cheilitis being the most common adverse events. Clinical activity, assessed by radiographs and serum prostate-specific antigen, was minimal, and the majority of patients progressed within 3 months. One patient with androgen-dependent disease had prolonged stabilization for >1 year. The majority of cases (95%) showed no gross histological changes and no difference in apoptotic or proliferative indices. Increased PSMA immunoreactivity was seen in seven of nine (78%) cases using PM2 antibody and in two of nine (22%) cases using the 7E11 antibody. Although antitumor effects were modest, the results suggest a role for retinoids in modulating the expression of PSMA on prostate cancer cells.

Aged↗
PubMed1999

Rhenium-186-labeled hydroxyethylidene diphosphonate dosimetry and dosing guidelines for the palliation of skeletal metastases from androgen-independent prostate cancer.

Rhenium-186 (tin)-labeled hydroxyethylidene diphosphonate (186Re-labeled HEDP) was evaluated in 27 men with progressive androgen-independent prostate cancer and bone metastases. Administered activities ranged from 1251 to 4336 MBq (33.8-117.2 mCi). The primary objectives were to assess tumor targeting, normal organ dosimetry, and safety. Antitumor effects were assessed by posttherapy changes in prostate-specific antigen and, when present, palliation of pain. Whole-body kinetics, blood and kidney clearance, skeletal dose, marrow dose, and urinary excretion of the isotope were assessed. Targeting of skeletal disease was observed over the period of quantification (4-168 h). Radiation doses to whole body, bladder, and kidney were well tolerated. The dose-limiting toxicity was myelosuppression (grade III) at 4107 MBq (111 mCi) and grade II at 296 MBq (80 mCi). Probe clearance (whole body) and urinary excretion measurements were highly correlated. Of the six patients treated at the highest dosage schedules (three at 1510 MBq/m2 and three at 1665 MBq/m2), three showed a posttherapy decline in prostate-specific antigen of 50% or more. The declines were not sustained. The determination of total activity retained at 24 h, as well as an estimate of marrow dose, correlated with the amount of myelosuppression observed. These results suggest that a single 24-h measurement of retained activity would allow individualized dosing and an improved therapeutic index relative to fixed dosing schema. Repetitive dosing is required to increase palliation.

Androgens↗
PubMed1995

Detection of circulating tumor cells in patients with localized and metastatic prostatic carcinoma: clinical implications.

PURPOSE: To determine the frequency with which prostate-specific antigen (PSA)-positive cells can be detected in the peripheral blood of patients with prostatic cancer in different stages and with different sensitivities to hormonal therapy. PATIENTS AND METHODS: Peripheral blood from 107 men with prostatic cancer and 27 non-prostate cancer controls was analyzed for PSA mRNA using reverse-transcriptase polymerase chain reaction (RT-PCR) and Southern blotting. RESULTS: The lower limit of detection was one PSA-producing cell diluted into 1 x 10(6) blood mononuclear cells. The test detected PSA mRNA in four of 25 patients (16%) with clinically organ-confined (T1-2) disease, three of 10 (30%) with T3-4 or N+ tumors, and 25 of 72 (35%) with distant metastases. None of the control samples were positive. An increase in positivity was observed with increasing PSA levels. Within the subgroup of patients with distant metastases, positivity was observed in six of 16 patients (38%) with normal or undetectable PSA levels after hormonal therapy and, overall, in 37% of patients (21 of 57) with androgen-independent disease. CONCLUSION: An RT-PCR-based assay for PSA mRNA can detect circulating cells in the peripheral blood of patients with prostatic cancer. The frequency of positivity increases with tumor stage. A unique observation was the detection of cells in patients with no measurable PSA on hormonal therapy. This suggests that continued seeding of distant sites may still be occurring in these patients, despite seemingly successful therapy. The relationship between continued seeding, disease progression, and survival will require further study.

Base Sequence↗
PubMed1995

Prospective evaluation of hydrocortisone and suramin in patients with androgen-independent prostate cancer.

PURPOSE: To assess efficacy of intermittent infusion of suramin in patients with androgen-independent prostate cancer who have had disease progression on hydrocortisone. PATIENTS AND METHODS: Chemotherapy-naive patients with progressive androgen-independent prostate cancer were given hydrocortisone 40 mg/d and monitored for treatment effect. At the time of disease progression, suramin was administered on a pharmacokinetically derived, 2-week dosing schedule. RESULTS: Thirty patients with a median Karnofsky performance status (KPS) of 90% were treated with hydrocortisone. No responses were seen in 12 patients with measurable disease or 29 patients with abnormal bone scans. Thirty patients had an increasing prostate-specific antigen (PSA) level before treatment and six (20%) had a more than 50% decline in PSA from the baseline value for a median of 16 weeks (range, 12 to 52+). Twenty-eight patients had disease progression after a median of 7 weeks (range, 3 to 23), and two patients have continued to receive hydrocortisone for 44 and 52 weeks. Twenty-eight patients received hydrocortisone and suramin, with median suramin concentrations of 97 to 170 micrograms/mL for 4 weeks. No responses in measurable disease and no improvements in bone scans were seen. Five patients (18%) showed a more than 50% decline in PSA levels from baseline, of whom three had previously responded to hydrocortisone. Only two of 24 patients who did not show a posttherapy decline in PSA levels after hydrocortisone had a reduction in PSA levels with the addition of suramin. Toxicity profiles were acceptable with each agent, although a higher proportion of subjects showed hematologic, cardiac, and neurologic events when suramin was added. CONCLUSION: Suramin has limited efficacy in patients with androgen-independent prostate cancer who have had disease progression after hydrocortisone.

Aged↗
PubMed1995

Suramin and hydrocortisone: determining drug efficacy in androgen-independent prostate cancer.

PURPOSE: The combination of suramin and hydrocortisone has shown clinical benefit in patients with androgen-independent prostate cancer. Widespread use was limited by the complex dose schedules and the need for pharmacologic monitoring. This study reports three sequential pharmacokinetically derived treatment regimens that simplified the administration of suramin and hydrocortisone with reduced toxicity. PATIENTS AND METHODS: Three cohorts of patients with advanced prostate cancer that progressed despite castrate levels of testosterone received oral hydrocortisone plus suramin administered in the following manners: (1) a loading dose of suramin followed by a continuous infusion using an adaptive control program (cohort A); (2) an intermittent schedule using a simplified adaptive control schedule (cohort B); and (3) an empiric dosing regimen (cohort C). Drug concentrations were monitored along with the toxicities associated with each regimen. Efficacy was assessed using measurable-disease criteria, radionuclide scans, and posttherapy changes in prostate-specific antigen (PSA) levels. RESULTS: Fifty-six patients were treated and plasma suramin concentrations were similar for each regimen. A partial response was observed in 4% (one of 28; 95% confidence interval, 0% to 18.4%) of patients with measurable disease, while 12% (six of 50; 95% confidence interval, 4.5% to 24.3%) had a greater than 80% decline in the baseline PSA level. The median duration of response was 12 months. No responses on radionuclide scans were seen. Anemia and lymphocytopenia were the most common toxicities, while 7% of patients developed a sensory or motor neurotoxicity. In the sequential regimens, the frequency of renal insufficiency (P = .04) and coagulopathy (P < .0001) decreased, while transaminase elevations (P = .05) were more common using intermittent infusions (cohorts B and C) versus continuous infusion schedules (cohort A). CONCLUSION: The administration of suramin was simplified and the drug concentrations were maintained. In this cohort of patients with advanced prostate cancer, the clinical activity of suramin using these dosing schedules was limited. Pharmacodynamic issues, patients selection, and criteria to assess efficacy could have effected the clinical outcome.

Adaptation, Physiological↗
PubMed1993

Effect of relative cumulative dose-intensity on survival of patients with urothelial cancer treated with M-VAC.

PURPOSE: To evaluate the received dose-intensity in a mature data set of patients with advanced urothelial cancer who received at least one cycle of the methotrexate (M), vinblastine (V), Adriamycin ([A], doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (C) regimen (M-VAC). PATIENTS AND METHODS: Received dose-intensity was evaluated over time by summing doses over cycles for each patient, cumulating treatment times, and assuming four cycles of chemotherapy were planned. Relative cumulative dose-intensity was then calculated for individual patients at the end of each cycle. To assess a relationship with survival, relative cumulative dose-intensity was then used as a time-dependent covariate in Cox regression. RESULTS: The median follow-up was 6 years and median survival 13.3 months, with 20 patients alive at the time of analysis. Out of a maximum of 1.0, the median relative dose-intensity for the M-VAC combination decreased from .69 to .59 from cycle 1 to cycle 4. Similarly, a decrease from .68 to .62 and from .80 to .72 was observed for A and C, respectively. The median received dose-intensity for A was 6.0 mg/m2/wk, and for C 14 mg/m2/wk. Neither the four-cycle relative cumulative dose-intensity for the M-VAC combination, nor the relative cumulative dose-intensities for A or C were found to be significant prognostic factors. CONCLUSION: The absence of an effect for received dose-intensity on survival may reflect the low dose-intensities of the components of the regimen actually delivered in this study. The results question whether the individual agents can be escalated sufficiently, with growth factor support, to improve significantly complete response proportions, a prerequisite for increasing the proportion of long-term survivors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Dose-intensification of MVAC with recombinant granulocyte colony-stimulating factor as initial therapy in advanced urothelial cancer.

PURPOSE: This study was undertaken to define an escalated dose schedule of methotrexate, vinblastine, doxorubicin, and cisplatin (E-MVAC) with hematopoietic growth-factor support, to define the ability to deliver E-MVAC with recombinant human granulocyte colony-stimulating factor (rhG-CSF) on 21- and 14-day schedules, and to assess the ability of rhG-CSF to maintain dose-intensity over four cycles of chemotherapy. PATIENTS AND METHODS: Twenty-three patients with transitional-cell carcinoma of the urothelium received E-MVAC in a phase I investigation. Patients were treated on an every-21-day (n = 19) or every-14-day schedule of administration (n = 4), with rhG-CSF support. Delivered dose-intensity was calculated at the completion of four cycles of therapy relative to the planned administration of conventional MVAC (relative dose-intensity [RDI]). Peripheral-blood progenitor cell kinetics in these patients were studied prospectively. RESULTS: Overall, the delivered RDI was 33% higher than the previously reported delivered dose-intensity of MVAC without hematopoietic support (140% for doxorubicin, 51% for cisplatin). Dose-intensity was well maintained through three cycles of therapy, after which leukopenia and thrombocytopenia became dose-limiting. Sixty-nine percent of patients with measurable disease responded, four (25%) with complete remissions. In five patients treated beyond the maximally tolerated dose (MTD), a 50- to 200-fold increase in G-CSF, granulocyte-macrophage CSF (GM-CSF), and interleukin-3 (IL-3)-responsive peripheral-blood progenitor cells over baseline was observed after 9 days of rhG-CSF administration. CONCLUSION: These findings demonstrate the feasibility and limitations of dose intensification of M-VAC with rhG-CSF. While the overall impact of the increased drug administration can only be assessed in randomized comparisons, the results of the present trial suggest that escalations of the components of the four-drug regimen are unlikely to improve significantly the outcome for patients with advanced urothelial tract tumors.

Adolescent↗
PubMed1992

Use of adaptive control with feedback to individualize suramin dosing.

Suramin is the first putative growth factor inhibitor in clinical trial that has demonstrated antitumor activity. Administration of suramin is complicated by a narrow therapeutic index and significant interpatient variability of measured pharmacokinetic parameters. Because both antitumor response and dose-limiting toxicities are related to plasma suramin concentration profiles, individualized dose schedules are required for optimal administration of the compound. In this report, the use of optimal sampling theory to derive sparse data monitoring and control strategies for use with suramin is described. A fixed rate continuous infusion schedule was used in seven patients, and the time to peak concentration (280-300 micrograms/ml) ranged from 7.7-21 days (mean, 13.2 days) with a decline to 150 micrograms/ml in 3-22 days (mean, 11 days). An initial population pharmacokinetic model was fit using a maximum likelihood algorithm. The mean volume of the central compartment was 4.5 +/- 6.7 liters/m2, volume of the peripheral compartment 10.6 +/- 1.4 liters/m2, distributional half-life 25 +/- 5.4 h, and elimination half-life 29.7 +/- 6.9 h. The terminal half-life was shorter than previously reported. These parameters were used as the initial population model for an iterative 2-stage analysis. The resulting distributional half-life of 22.3 +/- 2.7 h and elimination half-life of 28.2 +/- 5.0 h were similar, reflecting the intensive sampling. The iterative 2-stage analysis model was then used to determine the optimal sampling times and to simulate 20 data sets for a protocol designed to maintain plasma concentrations in a defined concentration range. This strategy is currently under investigation in phase I clinical trials.

Adenocarcinoma↗
PubMed1992

Estramustine and vinblastine: use of prostate specific antigen as a clinical trial end point for hormone refractory prostatic cancer.

The combination of estramustine phosphate and vinblastine sulfate, 2 agents with separate and unique antimicrotubular effects, has demonstrated additive cytotoxicity against the DU145 human prostate derived cell line in vitro. We evaluated this combination in 25 patients with progressive hormone refractory prostate cancer. Of 24 patients with an elevated prostate specific antigen (PSA) level at the start of treatment 13 (54%, 95% confidence limits 34 to 74%) had a greater than 50% decrease in PSA levels on at least 3 consecutive biweekly determinations. The median decrease in PSA in responding patients was 64% (mean 71.7%) and the median duration of response was 7 months. In 5 patients with bidimensionally measurable disease 2 partial responses were observed. Treatment was well tolerated, with mild and manageable toxicity. This is a well tolerated outpatient treatment regimen for patients with hormone-refractory prostatic cancer which deserves further investigation.

Aged↗
PubMed1992

Therapeutic alternatives for hormone-refractory prostatic cancer.

The currently available prognostic factors allow the identification of patients who are destined to do poorly with primary hormone therapy. Standardization of these factors is required so that they become incorporated into routine practice. For patients who relapse in osseous sites radiolabeled diphosphonates are one therapeutic alternative that can provide palliation. Future use will be directed to optimize treatment schedules, and use earlier in the course of the disease so that more durable palliation of bony metastases can be achieved. Evolving data on the use of PSA show that elevations antedate clinical relapse for most patients. In these cases, sequential changes can be used to assess therapeutic effects, which in turn can allow novel therapies to be screened more rapidly in the clinic. Criteria for the degree of change that is indicative of response must be standardized. Preliminary data suggest a 50% decline be the minimum that is used. The results with agents such as suramin, which interrupts autocrine and paracrine growth factor loops, are a therapeutic strategy that need further study. Future efforts will focus on defining which patients are best suited for specific therapeutic approaches.

Antigens, Neoplasm↗
PubMed1990

Trimetrexate in prostatic cancer: preliminary observations on the use of prostate-specific antigen and acid phosphatase as a marker in measurable hormone-refractory disease.

Thirty-one patients with bidimensionally measurable hormone-refractory prostatic cancer received trimetrexate (TMTX). Serial values of prostate-specific antigen (PSA) and acid phosphatase (SAP) were correlated with response. Five patients (17%; 95% confidence interval, 3% to 30%) achieved a partial remission for a median of 3 months (range, 3 to 7.5 months). Marker levels showed large variations with no discernible patterns. Serial PSA and SAP in 19 patients with abnormal baseline values showed a correlation with measurable disease response in only 68% (13 of 19) and 47% (nine of 19) of patients, respectively. Values were then smoothed using an exploratory data analysis technique of running medians and averages. Trends in marker changes were much more apparent. Several "decision rules" were evaluated for use of markers as indices of disease progression. A 50% increase from the patient's minimum value in either PSA or SAP on two successive determinations correlated with progression in 90% of cases in this trial. TMTX has modest activity in prostatic cancer, and further trials are not warranted. Biochemical markers do not uniformly reflect disease activity in hormone-refractory disease, and changes in biochemical markers must be interpreted cautiously when used as the sole end point to assess efficacy in clinical trials.

Acid Phosphatase↗
PubMed1989

Phase I clinical trial of doxorubicin and iproplatin combination chemotherapy in patients with breast cancer.

Forty-eight patients with advanced breast cancer were treated in a disease-specific phase I trial of doxorubicin and iproplatin combination chemotherapy. The doses of doxorubicin ranged between 30 and 50 mg/m2, and the doses of iproplatin ranged between 150 and 250 mg/m2. Myelosuppression was observed at all levels, but was dose-limiting at the highest level. In addition, nausea, diarrhea and malaise were prominent toxicities. Neither cardiac nor renal toxicity was encountered. Nine of 26 (35%) of previously untreated patients, and 5 of 22 (23%) previously treated patients demonstrated partial or complete responses. Although this combination possesses therapeutic activity, given its toxicities, further evaluation of doxorubicin in combination with iproplatin is not recommended.

Adenocarcinoma↗
PubMed1989

Palliative hemiskeletal irradiation for widespread metastatic prostate cancer: a comparison of single dose and fractionated regimens.

Between 1986 and 1987 patients with hormone refractory metastatic adenocarcinoma of the prostate were treated with hemiskeletal irradiation. One group of 15 patients was treated with a fractionated regimen of 2500-3000 cGy in 9 to 10 fractions. A second group of 14 patients received a single dose of 600 cGy or 800 cGy depending upon whether the upper or lower hemiskeleton was irradiated. Both groups were similar with respect to their initial Karnofsky performance status and extent of disease. With the exception of one patient in the single dose group, all patients treated achieved complete or partial relief shortly after completion of their respective courses of therapy. Of the patients treated with single dose therapy, 10 of 14 (71%) ultimately needed retreatment in the region initially irradiated because of recurrent bone pain or spinal cord compression. In contrast, only 2 of 15 (13%) of the patients receiving the fractionated treatment course needed retreatment (p = .001). Although the median survival of both groups from the time of initial treatments was similar (10 and 11 months), the median duration for palliation was greater for those patients receiving the fractionated regimen as compared with single dose therapy (8.5 months vs 2.8 months). The incidence of treatment related toxicity was similar for both groups. We conclude that fractionated hemiskeletal radiation is a more effective means of palliation when compared to single dose therapy.

Adenocarcinoma↗
PubMed1987

Gallium nitrate in prostatic cancer: evaluation of antitumor activity and effects on bone turnover.

Gallium nitrate, an agent known to inhibit bone resorption, was evaluated in patients with bidimensionally measurable hormone-refractory prostatic cancer. The starting dose was 200 mg/m2 iv by continuous infusion over 7 days. Two patients (10%; 95% confidence limits, 0%-22%) achieved short partial remissions of 1 and 6+ months, while seven of 23 (30%; 95% confidence limits, 14%-52%) showed a diminution of bone pain. Serial indices of bone turnover including serum calcium, phosphorus, and urinary hydroxyproline excretion showed a significant decrease at the completion of the infusion which returned to baseline prior to the next cycle. The data suggest the effect on bone was too short to produce consistent improvement. Reasons for the dissociation of pain relief and antitumor activity are discussed.

Adenocarcinoma↗