Biomedical subjects

Eric J Small

Publications and source records attributed to Eric J Small.

87 records · Page 5Linked to original sources

PubMed2002

Randomized study of three different doses of suramin administered with a fixed dosing schedule in patients with advanced prostate cancer: results of intergroup 0159, cancer and leukemia group B 9480.

PURPOSE: To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent. PATIENTS AND METHODS: Patients were randomized with equal probability to receive low-, intermediate-, or high-dose suramin (total doses 3.192, 5.320, and 7.661 g/m(2), respectively). Overall survival, time to progression, and response rate (prostate-specific antigen [PSA] and objective) for each treatment arm were compared. Relationships between plasma suramin concentrations and response, toxicity, and survival were also evaluated. RESULTS: Three hundred ninety patients were randomized. For the low-, intermediate-, and high-dose arms, the median survival time was 16, 14, and 13 months, respectively (P =.49). The objective response rate was 9%, 7%, and 15%, respectively (P =.10). PSA response rates were 24%, 28%, and 34%, respectively (P =.082). Landmark analyses of a 50% decline in PSA at 20 weeks showed a significant correlation with survival. There was a dose-response relationship between dose and toxicity. After adjusting for treatment arm, the measured suramin concentration was not associated with clinical response, PSA response, survival, or toxicity. CONCLUSION: Although high-dose suramin was associated with higher objective and PSA response rates, these were not statistically significant. Overall, no dose-response relationship was observed for survival or progression-free survival, but toxicity was increased with the higher dose. Patients treated with the low-dose level experienced modest toxicity, making it the preferred arm on this study. The lack of a dose-response relationship and the toxicity profile observed raise questions regarding the utility of suramin, particularly high-dose suramin, as administered on this schedule.

Aged↗

PubMed2002

Hormone-refractory Prostate Cancer.

For more than five decades, the preferred treatment for advanced prostate cancer has been suppression of androgen production by medical or surgical castration. However, all patients treated with androgen deprivation eventually develop resistant disease as manifested by increasing prostate-specific antigen levels, progressive disease on imaging studies, and ultimately worsening symptoms. The treatment of patients with hormone-refractory prostate cancer (HRPC), once thought to represent a relatively futile endeavor, has changed significantly in the past several years with the development of new therapeutics. One of the most important new treatment strategies involves secondary hormonal manipulation after the failure of primary androgen deprivation; this approach is predicated on the recognition that HRPC is a heterogenous disease. Some patients may respond to alternative hormonal interventions despite the presence of castrate levels of testosterone. Furthermore, the application of chemotherapeutic regimens has provided viable treatment options for patients with HRPC.

Androgens↗

PubMed2002

PC-SPES and prostate cancer.

PC-SPES (Botanic Lab, Brea, CA) is a combination of eight herbal therapies with activity against prostate cancer, both in vitro and in vivo. Studies in human prostate cancer cell lines demonstrate significant dose-dependent decreases in cellular viability after exposure to extracts of PC-SPES. Clinical studies suggest that PC-SPES can reduce specific antigen levels in both androgen-dependent and androgen-independent prostate cancer patients. Toxicity is mild, thought there is an approximately 5% risk of thromboembolic events with treatment. Although PC-SPES has apparent estrogenic activity, controversy exists over the exact mechanism of its effects.

Antineoplastic Agents, Phytogenic↗

PubMed2002

Bloodborne biomolecular markers in prostate cancer development and progression.

Prostate cancer is notoriously difficult to treat, which makes its early detection a priority. Biomarkers have been used to diagnose and monitor prostate cancer for more than 50 years, and the discovery of the serum marker prostate-specific antigen (PSA) significantly altered the detection and management of prostate cancer. But imperfect correlation with cancer hinders the usefulness of PSA. The elucidation and validation of new biological markers of prostate cancer should aid detection, and improve the application of the available therapeutics.

Biomarkers, Tumor↗

PubMed2002

Prostate-specific antigen in prostate cancer: a case study in the development of a tumor marker to monitor recurrence and assess response.

The serum marker known as prostate-specific antigen (PSA) has established itself as the most important tool for the early detection of prostate cancer. However, more recent data indicate that (post-treatment) PSA and PSA kinetics can be used to predict the outcome of a variety of therapeutic interventions including radical prostatectomy, radiation therapy, androgen deprivation, and treatment of hormone-refractory prostate cancer. PSA recurrence after radiation therapy is now accepted as a harbinger of developing metastatic disease. The American Society for Therapeutic Radiation Oncology (ASTRO) consensus definition is the most widely accepted definition of failure after radiation therapy. Rather than using a specific PSA cutoff, three consecutive PSA rises was felt to be a more reliable indicator of biochemical failure. The PSA nadir (the lowest PSA level achieved after therapeutic intervention) also appears to correlate with the likelihood of remaining disease-free. Similarly, a rapid doubling time is a significant predictor of developing distant metastases. The most appropriate definition for biochemical (PSA) failure following radical prostatectomy is usually considered to be a non-zero value. As is the case after radiotherapy, there appears to be a relationship between the rate of rise of the PSA and the risk of distant failure following radical prostatectomy. In patients with metastatic disease, multiple studies appear to indicate that a fall in PSA, however measured, appears to be predictive of improved outcome in prostate cancer patients treated with androgen deprivation. Multiple reports of trials in the treatment of hormone-refractory prostate cancer (HRPC) appear to substantiate the observation that patients who have a greater than 50% decline in PSA have an improved survival. Correlation of PSA declines with other markers of clinical benefit, including clinically significant "subjective" end points such as pain control, have strengthened the argument that a PSA decline can serve as an intermediate endpoint in clinical trials involving HRPC patients.

Humans↗

PubMed2002

Complementary and alternative therapies in prostate cancer.

Complementary and alternative therapies are used with increasing frequency in men with prostate cancer. However, little is known about the efficacy of such therapies for this cancer. While epidemiological data support the association between intake of certain micronutrients with development of prostate cancer, there exist limited prospective data that support the chemopreventative or therapeutic value of such nutritional agents in prostate cancer. To date, one of the most studied treatments has been PC-SPES, a combination of eight herbal therapies with activity against prostate cancer. Studies in cell lines of human prostate cancer demonstrate significant dose-dependent decreases in cellular viability after exposure to extracts of this agent. Clinical studies suggested that PC-SPES could reduce prostate specific antigen levels in patients with either androgen-dependent or androgen-independent prostate cancer. Toxicity was mild, although there was a low risk of thromboembolic events with such treatment. Manufacture of PC-SPES was recently halted, after revelations that the herbal combination was contaminated with warfarin, which led to a recall by the manufacturer. Subsequent analyses also revealed the presence of diethylstilbestrol (DES) and indomethacin in some lots of PC-SPES. Available data regarding other alternative therapies are reviewed as well.

Acupuncture Therapy↗

PubMed2002

Secondary hormonal manipulation of prostate cancer.

Prostate cancer is the second leading cause of cancer mortality among men in Western countries. The initial treatment of advanced prostate cancer is suppression of testicular androgen production by medical or surgical castration, but nearly all men with metastases will develop disease progression. Patients with hormone-resistant prostate cancer (HRPC) have a median survival of approximately 18 months, and no therapy has yet demonstrated a definitive survival advantage. However, in the past several years, a number of promising new treatment strategies have emerged. One of the most important new treatment strategies involves secondary hormonal manipulation after the failure of primary androgen deprivation. This approach is predicated on the recognition that HRPC is a heterogeneous disease, and some patients may respond to alternative hormonal interventions despite the presence of castrate levels of testosterone.

Androgen Antagonists↗

PubMed2002

Neoadjuvant strategies for prostate cancer prior to radical prostatectomy.

Although definitive therapy with either radical prostatectomy or radiation therapy can be effective, the optimal treatment for prostatic adenocarcinoma remains controversial. Patients may be at significant risk for primary treatment failure even with apparent clinically localized disease. Thus, there has been increased interest in initial multimodal therapy in order to maximize the potential for cure. Neoadjuvant hormonal therapy prior to radical prostatectomy has been used for several decades and a large body of literature discusses its use; nevertheless, the current data suggest that it only decreases rates of positive surgical margins without improving prostate-specific antigen (PSA)-free or disease-free survival. Novel neoadjuvant hormonal and chemotherapeutic regimens are under investigation and may improve outcomes for patients undergoing radical prostatectomy.

Adenocarcinoma↗

PubMed2002

Prostate cancer update.

Recent advances in prostate cancer have focused on treatment strategies in patients with biochemical relapse and novel methods of androgen deprivation therapy such as intermittent therapy, the role of bisphosphonates, and immunotherapeutic approaches. Continued investigation into the mechanism of androgen independence and effective treatments for hormone-refractory disease are described. This article reviews the major advances in prostate cancer published between November 1, 2000, and October 31, 2001.

Androgen Antagonists↗

PubMed2002

Liposomal doxorubicin for the treatment of hormone-refractory prostate cancer.

There is a pressing need for new agents to treat hormone-refractory prostate cancer (HRPC). Doxorubicin has shown modest activity in this setting, but its use is limited by its toxicities. Liposomal encapsulation of doxorubicin appears to promote enhanced tumor accumulation in some tumor types, and toxicity appears to be reduced. A phase II trial of liposomal doxorubicin was therefore conducted in patients with HRPC. Fourteen patients with progressive HRPC were treated. For the first dose only, patients were randomized to receive either doxorubicin 50 mg/m2 or liposomal doxorubicin 50 mg/m2 in order to evaluate exploratory pharmacokinetics. For all subsequent cycles, all patients received liposomal doxorubicin 50 mg/m2. Response to therapy was assessed with serial measurements of serum prostate-specific antigen (PSA) and sequential imaging studies. All 14 patients were evaluable for response and toxicity. Two patients (14%) had declines in serum PSA of > or = 50%. The first patient had a baseline PSA of 34.7 ng/mL and a nadir of 17.0 ng/mL. The second patient had a baseline PSA of 5580.0 ng/mL and a nadir of 200.7 ng/mL. The latter of these 2 patients had an unambiguous improvement in bone scan and a reduction in pain. Treatment was well tolerated overall. One patient was removed from treatment after the development of a grade 3 infusion reaction with the first cycle of liposomal doxorubicin. Neutropenia was the most common toxicity; in only 1 case was it grade 3, and no cases of grade 4 were seen. Doxorubicin plasma concentrations were best fit by a linear, two-compartment model. Liposomal doxorubicin plasma concentrations were best fit by a linear, one-compartment model. Treatment with liposomal doxorubicin was well tolerated overall. While monotherapy with liposomal doxorubicin has only modest activity in the treatment of HRPC, it may be of interest to study this agent as part of combination chemotherapy.

Adenocarcinoma↗

PubMed2002

Osteoporosis in men treated with androgen deprivation therapy for prostate cancer.

PURPOSE: We surveyed the growing literature on osteoporosis secondary to androgen deprivation therapy and provide suggestions regarding its identification and treatment. MATERIALS AND METHODS: We reviewed pertinent studies of male osteoporosis, osteoporotic fracture incidence or bone mineral density loss as a possible side effect of prostate cancer treatment and potential therapies for this side effect. RESULTS: Hypogonadism is a well-known cause of secondary osteoporosis in men. There is evidence of decreased bone mineral density with all types of androgen deprivation therapy, presumably due to its anti-testosterone effect. Bone mineral density loss is 3% to 5% yearly in the first few years of androgen deprivation therapy with an increase in osteoporotic fracture incidence. There are little data on potential treatments, although bisphosphonates and intermittent androgen deprivation therapy may have salutary effects. CONCLUSIONS: Osteoporosis is an important and debilitating side effect of androgen deprivation therapy, although precise estimates of its incidence, degree and cost are not completely elucidated. Until more data are available, it is prudent for all men beginning androgen deprivation therapy to receive calcium and vitamin D, and maintain a moderate exercise regimen. Baseline and at least 1 followup bone density measurement seem appropriate with bisphosphonate treatment a possibility in those in whom osteoporosis develops. More research is needed to explore the effect of bisphosphonates, calcium and vitamin D supplementation, exercise, calcitonin, selective estrogen re-uptake inhibitors, estrogens and intermittent androgen deprivation therapy on the course of androgen deprivation therapy induced osteoporosis. The osteoporotic fracture incidence and bone mineral density should be regularly incorporated into studies involving the hormonal treatment of prostate cancer.

Androgen Antagonists↗

PubMed2002

Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer.

PURPOSE: High-dose (400 mg.) oral ketoconazole 3 times daily with replacement doses of hydrocortisone has become a standard treatment option for patients with advanced prostate cancer which progresses after androgen deprivation. However, toxicity can hinder the ability to deliver treatment and the cost of the regimen can be substantial. Therefore, a prospective phase II study was conducted to assess the efficacy and safety of a regimen of low dose (200 mg.) oral ketoconazole 3 times daily with replacement doses of hydrocortisone in men with androgen independent prostate cancer. MATERIALS AND METHODS: The study included 28 patients with progressive prostate cancer despite anorchid levels of testosterone and ongoing testicular androgen suppression. Treatment consisted of low dose ketoconazole and replacement doses of oral hydrocortisone (20 mg. every morning and 10 mg. at bedtime). At the time of disease progression patients were treated with high dose ketoconazole and continued on the same dose of hydrocortisone. Adrenal androgen levels were measured, and baseline and followup levels correlated with clinical outcome. RESULTS: Overall, 13 (46%) of 28 patients had a prostate specific antigen decrease of more than 50% (95% confidence interval 27.5% to 66.1%). Median duration of prostate specific antigen decrease for all responders was 30+ weeks and 5 patients continue to exhibit a response, ranging from 36+ to 53+ weeks. In general, therapy was well tolerated. There were no grade 4 toxicities. Grade 3 toxicities included hepatotoxicity in 1 patient and depression in 2. The most common toxicities were nausea (29% grades 1 and 2), dry skin (18% grade 1) and fatigue (14% grade 1). Four (14%) patients discontinued low dose ketoconazole due to toxicities. Of the 16 patients who received high dose ketoconazole after disease progression with low dose ketoconazole, 3 were removed from treatment due to toxicity and no patient responded to high dose ketoconazole. There was no difference in the distribution of pretreatment endocrine values between responders and nonresponders, and the magnitude of change in adrenal androgen levels was not associated with response to therapy, although a potential association could easily have been missed due to small sample size. CONCLUSIONS: The regimen of low dose ketoconazole with replacement doses of hydrocortisone is well tolerated and has moderate activity in patients with progressive androgen independent prostate cancer.

Adenocarcinoma↗

PubMedDate not supplied

Immunotherapy for prostate cancer using prostatic acid phosphatase loaded antigen presenting cells.

Dendritic cells from patients with cancer are deficient in number and functional activity, leading to inadequate tumor immunosurveillance as a result of poor induction of T-cell antitumor responses. Loaded dendritic cell therapy is a vaccination strategy aimed at eliciting tumor antigen-specific, T-cell immune responses. Loaded dendritic cell therapy using prostatic acid phosphatase (APC8015; Provenge, Dendreon Corp., Seattle, WA) as an immunogen has shown a survival benefit in patients with metastatic hormone-refractory prostate cancer in a randomized phase III trial. This review will summarize the prostate cancer clinical trials using APC8015 and discuss the potential future role of APC8015 in prostate cancer treatment.

Acid Phosphatase↗

PubMedDate not supplied

Reduced incidence of bony metastasis at initial prostate cancer diagnosis: data from CaPSURE.

PURPOSE: Despite stage migration as a result of screening, many individuals are diagnosed each year with metastatic (M+), as opposed to localized (M0), prostate cancer. This study describes features that characterize patients with M+ compared to those diagnosed with M0 disease. MATERIALS AND METHODS: Patients enrolled in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a national, longitudinal registry of men with prostate cancer, formed the basis of this study. The prevalence, and changes with time, of patients with M+ and M0 cancer by clinical and sociodemographic characteristics were examined. RESULTS: Of 10,113 patients diagnosed between 1990 and 2003, 266 (2.6%) had M+ disease at diagnosis. From 1990 to 1997, 4.2% of 4020 total patients had M+ versus 1.6% of 6093 total patients diagnosed between 1998 and 2003 (odds ratio 0.34; 95% confidence interval 0.24-0.48; P < 0.0001). In univariate analysis, advanced age, higher prostate-specific antigen, Gleason grade, black race, lower income, and lower educational level were associated with M+ versus M0 disease (P < 0.01). However, in multivariate analysis, only higher serum prostate-specific antigen and higher Gleason grade, and not the sociodemographic variables, remained associated with M+ disease (P < 0.01). Patients with M+ diagnosed between 1998 and 2003 are more likely to harbor high-grade (Gleason > or =8) primary tumors (62% vs. 45%, P = 0.02) than those diagnosed between 1990 and 1997. No changes in age, race, education, insurance status, or income were observed in the early versus late era. CONCLUSIONS: These findings show a reduction in the incidence of metastatic disease at initial prostate cancer diagnosis. Furthermore, biologic, rather than socioeconomic, factors are associated with this type of disease presentation.

Aged↗

PubMedDate not supplied

Angiogenesis inhibition plus chemotherapy for metastatic hormone refractory prostate cancer: history and rationale.

Angiogenesis inhibition with bevacizumab and other agents of this class are showing significant activity in a variety of cancers. In prostate cancer, the single agent activity has been low, but the addition of these agents to chemotherapy may be the area in which they provide their greatest clinical benefit. An ongoing study conducted by the Cancer and Leukemia Group B will test this approach in men with metastatic hormone refractory prostate cancer. Future studies may test the efficacy of anti-angiogenic strategies in earlier stage disease as well as in combination with other approaches. This review will highlight the clinical experience to date with angiogenesis inhibitors in prostate cancer and the ongoing studies.

Angiogenesis Inhibitors↗