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Biomedical subjects

Matthew R Smith

Publications and source records attributed to Matthew R Smith.

At least 55 records · Page 3Linked to original sources
PubMed2003

The role of bisphosphonates in the management of metastatic prostate cancer.

Most men with advanced prostate cancer have primarily skeletal metastases, which are responsible for most of the morbidity and mortality of prostate cancer. Although bone lesions are osteoblastic in radiographic appearance, recent evidence has demonstrated that anti-osteoclast therapy with bisphosphonates reduces skeletal-related complications in hormone-refractory prostate cancer. This observation may be explained by the demonstration that osteoclast activity is greatly upregulated even in osteoblastic metastases. Furthermore, androgen deprivation therapy, the mainstay of treatment for advanced prostate cancer, leads to increased bone resorption and reduces bone mineral density. These effects can be ameliorated, and potentially completely prevented, by coadministration of bisphosphonates. These findings may point to a role for bisphosphonates in men with prostate cancer even prior to the development of skeletal metastases. Determination of whether such early therapy ultimately results in delayed time to skeletal progression or in improved survival will require large randomized studies.

Clinical Trials as Topic↗
PubMed2003

Cross-sectional study of bone turnover during bicalutamide monotherapy for prostate cancer.

OBJECTIVES: Monotherapy with bicalutamide increases serum concentrations of testosterone and estradiol. Because estrogens play an important role in male bone metabolism, bicalutamide monotherapy may have fewer adverse effects on bone than androgen-deprivation therapy with a gonadotropin-releasing hormone agonist. METHODS: In a cross-sectional study, we compared gonadal steroid levels and biochemical markers of bone turnover among three groups of men with prostate cancer: hormone-naive men, men treated with a gonadotropin-releasing hormone agonist, and men receiving bicalutamide monotherapy. Men with bone metastases or metabolic bone disease were excluded. Fifty-five eligible subjects were included in the analyses. RESULTS: Serum testosterone and estradiol concentrations were lower in men treated with a gonadotropin-releasing hormone agonist than in hormone-naive men or men receiving bicalutamide monotherapy (P <0.001 for each comparison). Serum testosterone and estradiol concentrations were higher in men receiving bicalutamide monotherapy than in the hormone-naive men (P <0.001). The mean serum urinary excretion of deoxypyridinoline, urinary excretion of N-telopeptide, and serum osteocalcin were significantly higher in men treated with a gonadotropin-releasing hormone agonist than in the other groups (P <0.05 for each comparison). In contrast, biochemical markers of bone turnover were similar for hormone-naive men and men receiving bicalutamide monotherapy (P >0.05 for each comparison). CONCLUSIONS: Biochemical markers of bone turnover are elevated in men receiving gonadotropin-releasing hormone agonist treatment but not in men receiving bicalutamide monotherapy. These observations suggest that bicalutamide monotherapy may maintain bone mineral density and prevent fractures.

Androgen Antagonists↗
PubMed2003

Finasteride and flutamide therapy in patients with advanced prostate cancer: response to subsequent castration and long-term follow-up.

OBJECTIVES: To report the efficacy of castration after progression on finasteride and flutamide. Standard androgen deprivation strategies for prostate cancer typically lead to castrate levels of testosterone. One alternative is the use of finasteride and flutamide. METHODS: A Phase II trial evaluated the combination of finasteride (5 mg/day) and flutamide (250 mg three times daily) in patients with rising prostate-specific antigen levels after local treatment for prostate cancer or with newly discovered metastatic disease. Patients were followed up for subsequent events, including castration-free, androgen-independent prostate cancer (AIPC)-free, and overall survival. RESULTS: With a median follow-up of 88 months, 5 patients (25%) continued on finasteride and flutamide, and 12 had stopped this combination and subsequently underwent medical or surgical castration. No patients experienced a flutamide withdrawal effect. All patients experienced more than a 50% decline in prostate-specific antigen after castration (mean 89%). The median protocol treatment failure-free survival was 29.9 months, the median castration-free survival was 37 months, and the median AIPC-free survival was 48.6 months. At 5 years, the overall survival rate was 65% (95% confidence interval 47% to 90%); 29% were alive and have not required castration, and 35% were alive and free of AIPC. CONCLUSIONS: Finasteride and flutamide have a durable effect in suppressing prostate-specific antigen progression in some men with advanced prostate cancer. Furthermore, castration induces secondary responses that may be of shorter duration than if started initially, although the overall period of hormonally responsive prostate cancer is more than 4 years.

Adenocarcinoma↗
PubMed2003

Management of treatment-related osteoporosis in men with prostate cancer.

Osteoporosis is an important and preventable adverse effect of androgen deprivation therapy for prostate cancer. Androgen deprivation therapy by either bilateral orchiectomies or administration of a gonadotropin-releasing hormone agonist decreases bone mineral density and increases fracture risk. Treatment-related osteoporosis can be prevented by intermittent administration of either intravenous pamidronate or zoledronic acid. Pamidronate (60 mg intravenously every 3 months) prevents bone loss during androgen deprivation therapy. Zoledronic acid (4 mg intravenously every 3 months) not only prevents bone loss but also increases bone mineral density. Alendronate and other oral bisphosphonates may be effective but have not been evaluated in men with castrate testosterone levels. Oestrogen replacement therapy and treatment with selective ooestrogen receptor modulators may prevent bone loss during androgen deprivation therapy. Bicalutamide (150 mg daily) monotherapy increases serum ooestrogen levels and maintains bone mineral density.

Androgen Antagonists↗
PubMed2003

Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer.

PURPOSE: A multicenter double-blind, randomized, placebo controlled clinical trial was performed to assess the effect of zoledronic acid, a potent new bisphosphonate, on bone mineral density during androgen deprivation therapy for nonmetastatic prostate cancer. MATERIALS AND METHODS: Men with M0 (no distant metastases) prostate cancer beginning androgen deprivation therapy were randomly assigned to receive 4 mg. zoledronic acid or placebo intravenously every 3 months for 1 year. The primary efficacy variable was the percent change from baseline to 1 year in bone mineral density of the lumbar spine as measured by dual energy x-ray absorptiometry. RESULTS: A total of 106 men were enrolled in the trial. Mean bone mineral density in the lumbar spine increased by 5.6% in men receiving zoledronic acid and decreased by 2.2% in those given placebo (mean difference 7.8%, 95% confidence interval 5.6%-10.0%, p <0.001). Mean bone mineral density of the femoral neck, trochanter and total hip also increased in the zoledronic acid group and decreased in the placebo group. Zoledronic acid was well tolerated. CONCLUSIONS: Zoledronic acid increases bone mineral density in the hip and spine during androgen deprivation therapy for nonmetastatic prostate cancer.

Aged↗
PubMed2003

Bisphosphonates to prevent skeletal complications in men with metastatic prostate cancer.

PURPOSE: The literature on clinical trials of bisphosphonates in men with metastatic prostate cancer is reviewed to familiarize the reader with biology of bone metastases and rationale for use of bisphosphonates. MATERIALS AND METHODS: A MEDLINE review of the literature on prostate cancer and bisphosphonates was performed. RESULTS: In uncontrolled clinical trials bisphosphonates improved pain and analgesic scores in men with symptomatic bone metastases. In a randomized controlled trial of men with bone metastases and progressive disease after first line hormonal therapy zoledronic acid decreased the skeletal related events, a composite end point defined as fracture, surgery or radiation therapy to bone, or change in antineoplastic therapy for bone pain. Randomized controlled trials with other bisphosphonates reported no significant benefit in men with bone metastases. Problems with the study populations, drug bioavailability and potency, statistical power and end point definition may have contributed to the negative results of these other studies. CONCLUSIONS: Zoledronic acid decreases the risk of skeletal related events in men with bone metastases and disease progression after first line hormonal therapy. Additional clinical research is needed to evaluate the optimal timing, schedule and duration of bisphosphonate treatment in men with metastatic prostate cancer. Additional research is also necessary to determine whether bisphosphonates can prevent bone metastases in men with high risk nonmetastatic prostate cancer.

Analgesics, Non-Narcotic↗
PubMed2003

Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer.

Osteoporosis is an important complication of androgen deprivation therapy for prostate cancer. Androgen deprivation therapy either by bilateral orchiectomies or treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density (BMD) and increases the risk of fracture. Dietary factors and lifestyle may contribute to bone loss. There are limited prospective data about treatment or prevention of osteoporosis in men with prostate cancer and many recommendations are based on studies of postmenopausal osteoporosis. Lifestyle modification including smoking cessation, moderation of alcohol consumption, and regular weight bearing exercise should be encouraged. Supplemental calcium and vitamin D are recommended. Additional treatment may be warranted for men with osteoporosis, fractures, or high rates of bone loss during androgen deprivation therapy. Recent studies have evaluated the efficacy of bisphosphonates to prevent bone loss during androgen deprivation therapy. Pamidronate (pamidronic acid), a second-generation bisphosphonate, prevents bone loss in the hip and spine during androgen deprivation therapy. Zoledronic acid, a more potent third-generation bisphosphonate, not only prevents bone loss but also increases BMD in the hip and spine. Alendronate (alendronic acid) is approved for the treatment of osteoporosis in men although its efficacy and that of other oral bisphosphonates has not been evaluated in men receiving androgen deprivation therapy. Additional prospective studies are needed to evaluate the long-term effects of bisphosphonates on fracture risk and disease-related outcomes.

Androgen Antagonists↗
PubMed2003

Changes in body composition during hormonal therapy for prostate cancer.

Androgens are important determinants of body composition in men. Androgen-deprivation therapy, the mainstay of treatment for advanced prostate cancer, increases fat mass and decreases lean body mass. These adverse changes in body composition may contribute to treatment-related fatigue, fracture risk, insulin resistance, and increased cardiovascular disease risk. Potential strategies to treat or prevent these adverse body composition changes include exercise training, alternative forms of hormonal therapy, and insulin-sensitizing agents.

Aged↗
PubMed2002

Selective aromatase inhibition for patients with androgen-independent prostate carcinoma.

BACKGROUND: First and second-generation aromatase inhibitors have shown activity in patients with androgen-independent prostate carcinoma. These early-generation aromatase inhibitors are nonselective, however, and inhibition of other steroidogenic enzymes may contribute to their reported clinical activity. The authors conducted a Phase II clinical study of letrozole to determine the safety and efficacy of a potent and selective third-generation aromatase inhibitor in men with androgen-independent prostate carcinoma. METHODS: Forty-three men with androgen-independent prostate carcinoma were treated with oral letrozole (2.5 mg daily). Treatment was continued until progressive disease or Grade 3 toxicity developed. Response and progressive disease were defined according to recommendations of the Prostate Specific Antigen Working Group. RESULTS: In total, 380 weeks of treatment were administered to the 43 study patients. The median duration of treatment was 8 weeks. Forty men discontinued treatment due to progressive disease. Only one patient responded to treatment with a sustained decrease > 50% in serum prostate specific antigen (PSA) levels. Three other patients experienced transient minor decreases (< 50%) in serum PSA levels. There were no serious treatment-related adverse events. CONCLUSIONS: Selective aromatase inhibition with letrozole is not active in men with androgen-independent prostate carcinoma.

Aged↗
PubMed2002

Peroxisome proliferator-activated receptor gamma (PPargamma) as a novel target for prostate cancer.

Peroxisome proliferator activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARgamma is expressed at high levels in adipose tissue and plays a central role in adipocyte differentiation. Recent studies have implicated PPARgamma in the pathogenesis of several human malignancies. Here we review the evidence that PPARgamma contributes to prostate carcinogenesis and the potential for PPARgamma as a novel therapeutic target for prostate cancer.

Antineoplastic Agents↗
PubMed2002

Osteoporosis and other adverse body composition changes during androgen deprivation therapy for prostate cancer.

Osteoporosis and other body composition changes are important complications of androgen deprivation therapy (ADT) for prostate cancer. Bilateral orchiectomy and gonadotropin-releasing hormone agonist treatment decrease bone mineral density and increase fracture risk. Other factors including diet and lifestyle may contribute tobone loss in men with prostate cancer. Estrogens play an important role in male bone metabolism. Androgen deprivation therapy with estrogens probably causes less bone loss than bilateral orchiectomy or gonadotropin-releasing hormone agonist treatment. Bicalutamide monotherapy increases serum estrogen levels and may also spare bone. Lifestyle modification including smoking cessation, moderation of alcohol use, and regular weight bearing exercise are recommended to decrease treatment-related bone loss. Supplemental calcium and vitamin D are also recommended. Pamidronate (Aredia), an intravenous bisphosphonate, prevents bone loss during ADT. Other bisphosphonates are probably effective but have not been studied in hypogonadal men. Androgen deprivation therapy increases fat mass and decreases muscle mass. These body composition changes may contribute to treatment-related decreases in physical capacity and quality of life.

Androgen Antagonists↗
PubMed2002

A phase II trial of interferon-alpha and toremifene in advanced renal cell cancer patients.

Treatment options for patients with metastatic renal cell carcinoma are limited. Interferon-alpha has an overall response rate of 10-15% in phase II and III clinical trials and is considered a standard option for patients. Though the anti-estrogen toremifene has shown only modest single agent activity in renal cell carcinoma, evidence for synergy of anti-estrogens with interferon-alpha exists in renal cell and other cancers. Therefore, a phase II trial was undertaken to test the combination of interferon-alpha and toremifene in advanced renal cell carcinoma. Thirteen patients with measurable metastatic or unresectable local disease were treated with interferon-alpha at a dose of 5 million units/m2 three times a week and daily oral toremifene at 300 mg daily in divided doses. Patients were treated for 12 weeks and then restaged. Clinical response was the primary endpoint of the trial. Four patients (31%) had evidence of stable disease at 12 weeks, while the remaining nine patients (69%) progressed on treatment. Toxicity was moderate, with grade 2 or 3 fatigue, nausea and anorexia each noted in 31% of patients. We conclude that the combination of interferon-alpha plus toremifene demonstrates no significant activity in advanced renal cell carcinoma.

Adult↗
PubMed2002

Changes in body composition during androgen deprivation therapy for prostate cancer.

The aim of this study was to determine the effects of initial treatment with a GnRH agonist on body composition in asymptomatic men with nonmetastatic prostate cancer. Forty men with locally advanced, node-positive or biochemically recurrent prostate cancer, no radiographic evidence of metastases, and no prior androgen deprivation therapy were treated with leuprolide 3-month depot 22.5 mg im every 12 wk for 48 wk. The main outcome measures were percentage changes in weight, percentage fat body mass, percentage lean body mass, fat distribution, and muscle size after 48 wk. Thirty-two subjects were evaluable. Serum T concentrations decreased by 96.3% plus or minus 0.4% (P < 0.001). Weight increased by 2.4% plus or minus 0.8% (P = 0.005). Percentage fat body mass increased by 9.4% plus or minus 1.7% (P < 0.001), and percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001). Cross-sectional areas of the abdomen and abdominal sc fat increased by 3.9% plus or minus 1.2% (P = 0.003) and 11.1% plus or minus 3.4% (P = 0.003), respectively. In contrast, the cross-sectional area of intraabdominal fat did not change significantly (P = 0.94). Cross-sectional paraspinal muscle area decreased by 3.2% plus or minus 1.3% (P = 0.02). GnRH agonists increase weight and percentage fat body mass and decrease percentage lean body mass and muscle size in men with nonmetastatic prostate cancer. Increased fatness resulted primarily from accumulation of sc rather than intraabdominal adipose tissue.

Aged↗
PubMed2002

Osteoporosis during androgen deprivation therapy for prostate cancer.

Osteoporosis is an important complication of androgen deprivation therapy (ADT). ADT by either orchiectomy or treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density and increases fracture risk. Other factors, including diet and lifestyle, may contribute to bone loss in men with prostate cancer. Routine osteoporosis screening in men with prostate cancer is appropriate based on the high prevalence of osteoporosis. There is limited information about the best strategy to treat or prevent bone loss during ADT. Lifestyle modification, including smoking cessation, moderate alcohol consumption, and regular weight-bearing exercise should be encouraged. Supplemental calcium and vitamin D are also recommended. Additional treatment is warranted for men with osteoporosis, fractures, or high rates of bone loss during ADT. Pamidronate, an intravenous bisphosphonate, prevents bone loss during ADT. Other bisphosphonates are probably effective, although they have not been evaluated in this clinical setting. Alternative forms of hormonal therapy, including bicalutamide monotherapy, may cause less bone loss than ADT.

Aged↗