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E J Small

Publications and source records attributed to E J Small.

At least 55 records · Page 3Linked to original sources
PubMed1999

Advances in prostate cancer.

The causes of prostate cancer reflect a complex interaction between environmental and genetic factors. Improvement in screening has reduced the incidence of prostate cancer, and risk assessment schemata have enhanced therapy, both for localized disease and for locally recurrent prostate cancer. The use of hormone therapy has been further evaluated, as primary therapy for locally advanced cancers, for lymph node-positive cancers, and for de novo metastatic cancer. Modest inroads have been made in the treatment and understanding of androgen-independent prostate cancer. Advances have been made in the understanding of the risk factors, genetic and environmental, associated with the development and progression of prostate cancer; in screening; and in optimizing therapy for localized, locally recurrent, and advanced disease. This article reviews the most salient observations reported between November 1, 1997 and October 31, 1998.

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PubMed1999

Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group.

PURPOSE: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. RESULT: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. CONCLUSION: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

Androgens↗
PubMed1999

Diffuse retroperitoneal amyloidosis due to renal cell carcinoma.

The case of a 61-year-old man with haematuria, in whom CT demonstrated a solid renal mass and extensive retroperitoneal infiltration, is presented. This combination of CT findings resulted in significant diagnostic uncertainty. Pathological analysis demonstrated renal cell carcinoma, with secondary amyloidosis in the retroperitoneum. Amyloidosis secondary to renal cell carcinoma has not been previously described as a cause of retroperitoneal infiltration.

Amyloidosis↗
PubMed1999

The treatment of advanced prostate cancer with ketoconazole: safety issues.

The definition of hormone refractory prostate cancer is changing. It has become clear that patients with advanced prostate cancer whose disease has progressed following treatment with luteinising hormone releasing hormone agonists and antiandrogens can respond to additional hormonal manoeuvres. Ketoconazole is an imidazole antifungal and the antiandrogen effects of this agent have been known about for over 15 years. Initial concerns about the excessive adverse effects associated with this agent appear to have been overstated. Recent studies have demonstrated that treatment with ketoconazole can produce a significant response in a majority of patients with advanced prostate cancer and that the agent has a reasonable toxicity profile. The most common adverse effect is gastrointestinal intolerance, followed by fatigue, liver function abnormalities and skin changes; the agent is also associated with a variety of rarer adverse effects. The most serious potential adverse effects of the drug can be ameliorated by simple measures.

Animals↗
PubMed1999

Therapy of advanced prostate cancer with granulocyte macrophage colony-stimulating factor.

Granulocyte macrophage colony-stimulating factor is a pleiotropic cytokine capable of inducing systemic immune responses against experimental and human tumors. To evaluate the efficacy of GM-CSF treatment in patients with hormone-refractory prostate cancer, we conducted sequential Phase II studies in 36 men with progressive disease after androgen deprivation and antiandrogen withdrawal. In a first cohort of patients (n = 23), GM-CSF was administered s.c. at a dose of 250 microg/m2 daily for 14 days of a 28-day treatment period. After we observed oscillating prostate-specific antigen (PSA) responses in several patients in this first cohort, a second trial was performed in which patients (n = 13) received maintenance GM-CSF (250 microg/m2 three times weekly) after the first 14 days of daily GM-CSF. All patients were treated until disease progression. Response was assessed by evaluation of serial changes in serum PSA and sequential imaging studies. In cohort I, 10 of 22 patients (45%) had a PSA versus time plot with a sawtooth pattern, with PSA declining during GM-CSF therapy and climbing during the off-therapy period; 5 patients had at least two consecutive declines in PSA, with a median response duration of 3.5 months. All but one patient in cohort II experienced a decline in PSA (median decline, 32%), but a PSA decline greater than 50% and sustained for more than 6 weeks was seen in only one patient, who had a >99% decline in PSA and an improvement in bone scan lasting for 14+ months. Changes in PSA levels could not be attributed to direct or indirect effects of GM-CSF on the PSA assay or down-regulation of PSA expression by GM-CSF. Toxicity was very mild, consisting primarily of transient constitutional symptoms and injection site reactions. These data suggest that GM-CSF may have antitumor activity in advanced prostate cancer, and the use of GM-CSF may be a confounding variable when PSA responses are used as an end point in clinical trials evaluating new regimens for the treatment of advanced prostate cancer.

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PubMed1999

Hormone-refractory prostate cancer: an evolving standard of care.

The treatment of advanced prostate cancer has evolved rapidly in the last several years. Therapeutic options for patients with advanced disease, once limited to the use of androgen deprivation, have expanded to include a number of interventions, including secondary hormonal manipulations, chemotherapy, and a variety of investigational approaches.

Antineoplastic Agents, Hormonal↗
PubMed1998

Intermittent androgen deprivation for clinically localized prostate cancer: initial experience.

OBJECTIVES: To evaluate the use of intermittent androgen deprivation (IAD) in the treatment of selected patients with clinically localized prostate cancer. METHODS: We report our initial experience with 47 patients (aged 50 to 92 years) treated with IAD for clinically localized prostate cancer (Stage T1c in 3 patients, T2 in 21, T3 in 21, T4 in 1, and unknown in 1). No patient was found to have systemic disease prior to the initiation of therapy. Twenty-seven patients with localized cancers refused local therapy and have been treated with IAD only. Seven patients developed recurrent disease following radiotherapy, 2 following cryotherapy, 8 following radical prostatectomy, and 3 following radical prostatectomy with adjuvant radiotherapy. Mean and median serum prostate-specific antigen (PSA) prior to the start of treatment were 20.5 and 8.4 ng/mL, respectively (range 0.6 to 190). Androgen deprivation was continued 1 to 2 months after serum PSA became undetectable or a nadir level was reached. Therapy was then reinstituted after serum PSA reached a predetermined level. Thirty-three patients have been treated with total androgen blockade and 14 have been treated with a luteinizing hormone-releasing hormone agonist only. RESULTS: Follow-up ranges from 5 to 52 months from the start of treatment (mean 24 months). Patients have received from 1 to 5 treatment cycles (median 2 cycles), with the mean and median cycle lengths being 15 and 14 months, respectively. Eighteen patients are currently on cycle 1, 15 on cycle 2, 11 on cycle 3, 1 on cycle 5, and 1 patient has discontinued treatment after undergoing salvage radical prostatectomy. The mean and median nadir serum PSA on androgen deprivation have been 0.2 and 0.0 ng/mL, respectively. Nadir PSA was reached within an average of 4 months (range 1 to 11) after initiating treatment. The mean serum PSA at the start of cycle 2 was 7.0 ng/mL (range 0.6 to 19.1). Only 1 patient has failed to respond to reinstitution of treatment; this patient was found to have metastatic disease during his second cycle of treatment (time to progression 25 months from the start of IAD). No other patient has demonstrated disease progression during the follow-up period. Patients have spent an average of 47% of the time off of therapy. CONCLUSIONS: IAD appears to be a viable treatment option in selected patients with clinically localized prostate cancer. However, the durability and advantage of IAD, if any, over continuous therapy is unknown at present. Consequently, at the present time IAD should be considered an investigative form of treatment for patients with prostate cancer.

Adenocarcinoma↗
PubMed1998

Stage II nonseminomatous testis cancer: the roles of primary and adjuvant chemotherapy.

Historically, a retroperitoneal lymph node dissection (RPLND) has been the primary treatment of stage II nonseminomatous germ cell tumor (NSGCT) patients, whereas chemotherapy has been used in the adjuvant setting. Increasing evidence of the efficacy of chemotherapy has led to additional treatment possibilities for stage II patients. Both chemotherapy and RPLND have a role in the primary therapy of stage II NSGCT, and both modalities can be used as secondary adjunctive therapy. Management of these patients now requires a renewed emphasis on risk stratification and on the integration of patient preferences into the management algorithm.

Antineoplastic Agents↗
PubMed1998

Long-term side effects of treatment for testis cancer.

Patients newly diagnosed with testis cancer can now expect excellent results with respect to long-term, disease-free survival after treatment. Given the young age of presentation for many of these patients, the long-term consequences of curing testis cancer have become a major concern. Surgery, radiation, and chemotherapy for testis cancer have all been associated with potential long-term side-effects. Consequently, new treatment regimens have been directed toward minimizing these possible side-effects while at the same time maintaining high cure rates (i.e., limiting the size of radiation fields, decreasing the number of chemotherapy cycles, eliminating bleomycin). Patients and physicians must be made aware of the potential adverse side effects of treatment for testis cancer. At the present time, however, it appears that the beneficial effects of such treatment, with respect to overall and disease-free survival, far outweigh the limited probability of persistent treatment-related side effects in patients newly diagnosed with testis cancer.

Antineoplastic Agents↗
PubMed1998

Update on the diagnosis and treatment of prostate cancer.

Our understanding of the causes of prostate cancer and improvements in screening methodologies and risk assessment prior to definitive local therapy continue to be refined. The utility of hormone therapy has been further evaluated, both as adjuvant and neoadjuvant therapy with radiation therapy or radical prostatectomy, as well as for patients with more advanced disease. Finally, modest inroads continue to be made in the treatment and understanding of hormone-refractory prostate cancer.

Adult↗
PubMed1998

Prostate cancer, Incidence, management and outcomes.

The incidence of prostate carcinoma in the US now appears to be declining slightly, as a consequence of removal of prevalent cases from the population by screening. Screening for serum prostate-specific antigen (PSA) levels has been improved by the use of PSA transformations including PSA density, PSA velocity and age-specific PSA reference ranges. The ratio of free to total PSA may increase the specificity of single serum PSA evaluations without decreasing its sensitivity for the diagnosis of prostate cancer. Despite the proliferation of risk assessment tools and nomograms, the optimal therapy for localised disease remains controversial, and the usefulness of radical prostatectomy or radiation therapy (either external beam or brachytherapy) has not been tested prospectively against watchful waiting. However, watchful waiting is probably more appropriate for men whose life expectancy is less than 10 to 15 years and/or who have low grade tumours. In patients with metastatic disease, androgen deprivation remains the mainstay of treatment. Whether or not the addition of an antiandrogen prolongs survival remains controversial. Intermittent androgen deprivation appears to be one means of avoiding continuous androgen deprivation and possibly decreasing adverse effects, although its efficacy remains to be proven. For patients whose disease progresses after combined androgen blockade, withdrawal of antiandrogen is now considered mandatory. Tremendous heterogeneity exists among patients who progress after antiandrogen withdrawal, so that patients previously considered resistant to hormones may in fact retain some hormonal sensitivity to second- or third-line hormone therapy. For patients with hormone-refractory prostate cancer, a variety of options exist, including the use of estramustine combinations, suramin, mitoxantrone and doxorubicin combinations. Despite these options, there is presently no standard of care, and clinical trials should receive priority. Palliative interventions, including the use of corticosteroids, radiopharmaceuticals and external beam radiation therapy, should not be overlooked.

Adult↗
PubMed1998

Pyrazoloacridine for the treatment of hormone-refractory prostate cancer.

There is a pressing need for new agents for the treatment of hormone-resistant prostate cancer (HRPC). Pyrazoloacridine (PZA) has antitumor activity in several in vitro and in vivo tumor systems, and was selected for testing in clinical trials by the National Cancer Institute (NCI). We conducted a phase II trial of PZA for the treatment of HRPC. Seventeen male patients with HRPC were treated with PZA at 750 mg/m2 i.v. given over a period of 3 hr every 3 weeks. Response to therapy was assessed with serial measurements of serum prostate-specific antigen (PSA) and sequential imaging studies. The 17 patients were treated and fully evaluable. One patient experienced a significant decrease in PSA, from over 10,000 ng/ml to 423 ng/ml, along with an improvement in bone scan findings. However, no other patient obtained an objective or PSA response (overall PSA response rate = 5.9%). Median survival duration was 15.3 months. Toxicity was moderate. If PSA is used as a marker of response, single-agent PZA appears to lack efficacy in the treatment of HRPC. However, the one unambiguous response, and the favorable toxicity profile observed, may warrant further evaluation of this agent.

Acridines↗
PubMed1997

Simultaneous antiandrogen withdrawal and treatment with ketoconazole and hydrocortisone in patients with advanced prostate carcinoma.

BACKGROUND: Although antiandrogen withdrawal has moderate efficacy in patients with hormone refractory prostate carcinoma (HRPC), the effect of the simultaneous suppression of adrenal androgens with ketoconazole at the time of antiandrogen withdrawal is not known. METHODS: Twenty consecutive patients with HRPC who had developed progressive disease despite combined androgen blockade were treated with antiandrogen withdrawal and simultaneous ketoconazole as a means of inhibiting adrenal steroid production. Prostate specific antigen (PSA) response was defined as a > 50% fall in PSA from baseline that was maintained for at least 8 weeks. RESULTS: Ten patients had established metastatic disease, 2 had high PSAs and no imaging studies (PSA of 70 and 160 ng/mL, respectively), 3 had microscopically positive lymph nodes and serologic progression, and 5 had serologic progression alone. Overall, of 20 evaluable patients, 11 (55%) had a > 50% fall in PSA (95% confidence interval [CI], 31.5-76.9%). The median PSA response duration was 8.5 months (95% CI, 7-17 months). The median survival was 19 months. Toxicity was mild, with Grade 1 and 2 nausea and emesis in 15% of patients, Grade 1 fatigue in 10% of patients, and reversible Grade 1 or 2 hepatotoxicity in 10% of patients. Mild skin toxicity was observed in 20% of patients. CONCLUSIONS: The addition of ketoconazole and hydrocortisone to antiandrogen withdrawal appears to increase the PSA response proportion observed with antiandrogen withdrawal alone. Toxicity is mild.

Adrenal Cortex Hormones↗
PubMed1997

Prostate cancer.

Prostate cancer accounted for over 41,000 deaths in the United States in 1996. Prostate-specific antigen (PSA) screening is capable of detecting prostate cancer and appears to detect cancers that are both clinically significant as well as organ-confined, and therefore potentially curable. The positive predictive value of PSA value has been increased by the use of the free-to-total PSA ratio. The early detection of a large number of nonpalpable tumors has mandated the development of new risk assessment schemas, which include nomograms and equations in which Gleason score, PSA, and clinical stage play a prominent role. Definitive answers to the question of watchful waiting versus intervention await conclusion of the prostate cancer intervention-versus-observation trial. For both radical prostatectomy and radiation therapy, one means of potentially reducing the risk of relapse is the use of androgen deprivation. Neoadjuvant androgen deprivation prior to surgery results in a lower incidence of positive surgical margins, but impact on survival is unknown. By contrast, the use of concurrent androgen deprivation appears to be associated with enhanced survival in patients treated with definitive radiotherapy. For good risk tumors, modem brachytherapy results in freedom from biochemical relapse rates similar to those observed with surgery and external beam radiation therapy. The best therapy for patients with positive margins or serologic progression, including radiation therapy, remains to be identified. The widespread availability of PSA testing has led to an empirically driven redefinition of advanced disease and includes patients with earlier stage disease in which primary treatment has failed. In these patients, debate remains as to whether combined androgen deprivation is superior to monotherapy. A comparison of flutamide with bicalutamide awaits maturation of survival data. The utility of antiandrogen withdrawal in patients with progressive disease despite androgen deprivation has been confirmed. Thereafter, second-line hormonal maneuvers may be appropriate. In patients with truly hormone refractory prostate cancer, a variety of nonhormonal agents, including estramustine-based therapy, suramin, mitoxantrone, and doxorubicin-based regimens have demonstrated activity and remain as options.

Antineoplastic Agents↗
PubMed1997

Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm.

PURPOSE: To discuss the evolution of new concepts in the Use of second-line hormonal therapy for patients with progressive prostate cancer despite androgen deprivation. DESIGN: Pertinent contemporary prostate-specific antigen (PSA)-based reports of the utility of secondary hormonal maneuvers after treatment with combined androgen blockade (CAB) were reviewed. RESULTS: The use of PSA as an end point in hormonerefractory prostate cancer (HRPC) trials is more widely accepted, but still remains somewhat controversial. Using PSA as an end point, it is clear that a variety of secondary hormonal maneuvers can result in responses. Antiandrogen withdrawal is efficacious in approximately 20% of patients and can be observed with a variety of antiandrogens, including flutamide, bicalutamide, and megestrol acetate. A variety of regimens, including megestrol, bicalutamide, glucocorticoids, aminoglutethimide, and ketoconazole, retain activity (14% to 75% PSA response proportion) even in patients who have failed to respond to CAB and flutamide withdrawal. CONCLUSION: Once CAB (suppression of gonadal and adrenal androgen) is undertaken, further hormonal maneuvers remain efficacious in some patients with progressive prostate cancer. Antiandrogen withdrawal is now a mandatory maneuver before proceeding to other regimens. It is clear that certain patients will continue to respond to hormonal maneuvers even after antiandrogen withdrawal. An understanding of the molecular basis of these responses may result in the development of a more targeted therapy in the future.

Androgen Antagonists↗
PubMed1997

Prostate specific antigen decreases after withdrawal of antiandrogen therapy with bicalutamide or flutamide in patients receiving combined androgen blockade.

PURPOSE: We determined whether decreases in prostate specific antigen (PSA) would occur after withdrawal of double-blinded antiandrogen therapy with flutamide or bicalutamide for clinical progression or increasing PSA concentration in patients receiving combined androgen blockade for advanced prostate cancer. MATERIALS AND METHODS: PSA concentrations were determined weekly for at least 6 weeks and then every other week for 6 weeks in 22 patients with stage D2 prostate cancer. All patients were withdrawn from antiandrogen therapy (8 flutamide and 14 bicalutamide) due to progression or an increasing PSA concentration. Objective response was evaluated before antiandrogen withdrawal and at week 12. RESULTS: In 4 of 8 patients (50%) withdrawn from flutamide and 4 of 14 (29%) withdrawn from bicalutamide serum PSA concentrations decreased by 50% or more. PSA responses after withdrawal of flutamide therapy occurred within the first few days, whereas those after withdrawal of bicalutamide therapy occurred within 4 to 8 weeks. Of 4 patients assessed for objective response 2 had stable disease and 2 had progression. A PSA response was observed in the 2 patients with stable disease but not the 2 with progression. CONCLUSIONS: For patients with stage D2 prostate cancer and disease progression or an increasing PSA concentration, withdrawal of antiandrogen therapy with bicalutamide or flutamide may result in a PSA response. The time to PSA response is longer with bicalutamide than with flutamide. The clinical significance of the antiandrogen withdrawal phenomenon is unknown.

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PubMed1997

Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal.

PURPOSE: We tested the hypothesis that certain patients with hormone refractory prostate cancer retain hormonal sensitivity even after progression following antiandrogen withdrawal. The efficacy of ketoconazole and hydrocortisone in this patient population was evaluated. MATERIALS AND METHODS: A total of 50 consecutive patients with advanced prostate cancer received ketoconazole and hydrocortisone at progression after antiandrogen withdrawal. Prostate specific antigen (PSA) response was defined as greater than a 50% decrease in PSA from baseline that was maintained for at least 8 weeks. RESULTS: Overall, of 48 evaluable patients 30 (62.5%, 95% confidence interval 47.3 to 76.1%) had greater than a 50% decrease in PSA, while 23 (48%) had greater than an 80% decrease. The median duration of response was 3.5 months but 23 of 48 patients continue to exhibit a response, ranging from 3.25 to 12.75 or more months. The ketoconazole response rate in patients with no response to prior antiandrogen withdrawal was not different from that in patients with such a response (65 versus 40%, p = 0.35). Toxicity was mild. Grade 1 or 2 nausea, fatigue, edema, hepatotoxicity and rash occurred in 10.4 (5 of 48), 6.25, 6.25, 4.2 and 4.2% of patients, respectively, and anorexia occurred in 2%. CONCLUSIONS: Failure to respond to antiandrogen withdrawal does not identify patients with truly hormone refractory disease. Ketoconazole retains significant activity in this setting and is extremely well tolerated.

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