A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer.

OBJECTIVES: To evaluate the levels of testosterone and other hormones in men with prostate cancer treated with abarelix versus leuprolide acetate. METHODS: Patients (n = 269) were randomized to receive open-label abarelix 100 mg or leuprolide acetate 7.5 mg by intramuscular injection. The results of the first 84 days of the study are reported. The primary efficacy endpoints included avoidance of testosterone surge, castration on day 8, and achievement and maintenance of castration from days 29 through 85. The secondary endpoints included castration on days 2, 4, and 15; a reduction in prostate-specific antigen level; and measurements of other hormones. Patients were monitored for clinical adverse events and laboratory abnormalities. RESULTS: No men in the abarelix group and 82% of men in the leuprolide acetate group experienced a testosterone surge (P <0.001). Abarelix caused rapid medical castration: 24% of men 1 day after treatment and 78% after 7 days compared with 0% of men treated with leuprolide acetate on either day. A comparable percentage of men achieved and maintained castration between days 29 and 85 in each group. Prostate-specific antigen had a statistically significant decrease for the first month in patients treated with abarelix. Dihydrotestosterone, luteinizing hormone, prostate-specific antigen, and follicle-stimulating hormone showed similar rapid reductions without an initial increase. The overall occurrence of adverse events was similar across the treatment groups, and most were sequelae of comorbid disorders. CONCLUSIONS: Treatment with abarelix produced a higher percentage of patients who avoided a testosterone surge and had a more rapid time to testosterone suppression with a higher rate of medical castration 1 day after treatment and greater reductions in testosterone, luteinizing hormone, follicle-stimulating hormone, and dihydrotestosterone during the first 2 weeks of treatment compared with leuprolide acetate. The achievement and maintenance of castration was comparable between the two groups.

The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer.

PURPOSE: We contrasted the endocrinological and biochemical efficacies of abarelix depot, a pure gonadotropin-releasing hormone antagonist, with a prospective concurrent control cohort receiving luteinizing hormone releasing hormone (LH-RH) agonists with or without antiandrogen for treatment of patients with prostate cancer receiving initial hormonal therapy. MATERIALS AND METHODS: In this phase 2 open label study 242 patients with prostate cancer requiring initial hormonal treatment received abarelix depot (209) or LH-RH agonists (33) with or without antiandrogen. A total of 100 mg. abarelix depot was delivered intramuscularly every 28 days with an additional injection on day 15. LH-RH agonists with or without antiandrogen were administered according to the depot formulation used. Endocrine efficacy was measured by the absence of testosterone surge and rapidity of castration onset. The rate of prostate specific antigen decrease was assessed. RESULTS: No patient treated with abarelix depot had testosterone surge during week 1 compared with 82% of those treated with LH-RH agonists. The concomitant administration of antiandrogen had no effect. During the first week of drug administration, in 75% of patients treated with abarelix depot and in 0% of those treated with LH-RH agonist medical castration was achieved. Prostate specific antigen decrease was faster, with no flare or surge in patients treated with abarelix depot. Abarelix depot was well tolerated. CONCLUSIONS: Abarelix depot represents a new class of hormonal therapy, gonadotropin releasing hormone antagonists, that has rapid medical castration and avoids the testosterone surge characteristic of LH-RH agonists.

Abarelix Depot, a GnRH antagonist, v LHRH superagonists in prostate cancer: differential effects on follicle-stimulating hormone. Abarelix Depot study group.

PURPOSE: A Phase II clinical study contrasted the endocrinologic and biochemical efficacy of Abarelix Depot, a gonadotropin-releasing hormone (GnRH) antagonist, with luteinizing hormone releasing-hormone (LHRH) superagonists, with or without additional antiandrogens, in men with prostate cancer. METHODS: This study was open-label and treated 242 men. Abarelix Depot 100 mg was administered by intramuscular injection to 209 men, and LHRH, with or without an antiandrogen, was administered to 33 men according to the formulation used. Serum concentrations of follicle-stimulating hormone (FSH) and other hormones were measured at baseline and at specified time points for the first 85 days of the study. Median serum concentrations of FSH at baseline were similar for the two treatment groups. RESULTS: Men treated with LHRH superagonists, with or without an antiandrogen, had a surge in the serum concentration of FSH on day 2 before FSH concentrations started to decline. Men in the Abarelix Depot group had an immediate and sustained decrease in the serum concentration of FSH. CONCLUSION: Recent data suggest that FSH may be an independent growth factor for prostate cancer. The Abarelix Depot-induced decreased in FSH may have a role in the treatment of men with endocrine- responsive disease or for those men whose disease has escaped from hormone sensitivity.

Advanced prostate cancer: an update.

A number of therapeutic options are available or on the horizon for patients for whom initial treatment of localized prostate cancer has failed. Currently under study are time of therapy, maximum androgen blockade, and palliative and adjunctive therapies.

Genitourinary cancers in older adults.

Prostate and bladder carcinoma are, in large part, diseases of older adults, and they are discussed in this context. Pathology, diagnosis, and staging are reviewed. Surgical and medical approaches to these malignancies, and the limitations of these approaches, are highlighted. Renal cell carcinoma, while a relatively rare neoplasm, remains a formidable challenge: approximately 50% of patients die within 5 years of diagnosis. Advances in molecular genetics and histopathologic classification, as well as surgical management and investigational therapies, are emphasized.

Assessment of prostate cancer volume using endorectal coil magnetic resonance imaging: a new predictor of tumor response to neoadjuvant androgen suppression therapy.

OBJECTIVES: A clinical tool that can reliably assess prostate cancer response to androgen suppression is lacking. This pilot study was designed to identify the potential clinical factor(s) that correlate with tumor response after neoadjuvant therapy. METHODS: Twenty-one patients managed with definitive local therapy and neoadjuvant androgen suppression (median 3 months [range 2 to 7]) between 1995 and 1997 comprise the study population. Fisher's exact test was used to test the significance of the proportion of patients with a given clinical factor and the outcome of pathologic organ-confined disease. The clinical factors tested included preoperative prostate-specific antigen, biopsy Gleason score, clinical stage, months of total androgen suppression, the change in the endorectal magnetic resonance imaging (erMRI)-defined stage, the change in erMRI-defined tumor, and the change in the erMRI-defined prostate volume during neoadjuvant androgen suppression. RESULTS: All 21 patients had a decrease in the erMRI-determined prostate volume and prostate-specific antigen during androgen suppression, whereas only 10 of 21 (48%) had a reduction in the erMRI-determined tumor volume. There was a statistically significant increased proportion of patients with a decrease in the erMRI-determined tumor volume (P = 0.008) who had pathologic organ-confined disease. CONCLUSIONS: The results of this pilot study suggest that the changes in the erMRI-determined tumor volume occurring during androgen suppression may be predictive of the tumor response. Validation in a larger prospective study is currently underway.

Comparison of perspectives on prostate cancer: analyses of survey data.

OBJECTIVES: Prostate cancer will account for 334,500 new cases and 41,800 deaths among men in the United States in 1997. Patients and physicians are faced with many concerns related to benefits and side effects of alternative treatments, educational needs, emotional support, and costs of care. Support groups for prostate cancer patients have been established to help satisfy needs in these areas. Therefore, we addressed three issues among patients who belong to a prostate cancer support group as well as among a second group of urologists who treat prostate cancer: (1) goals for prostate cancer treatment, (2) information that is given and recalled about the disease and therapy, and (3) extent to which educational and emotional needs are being met. METHODS: Random telephone surveys were made of 1000 men with prostate cancer who belong to the prostate cancer support group US TOO, the largest prostate cancer support group in the United States, and 200 urologists who provide care to men with prostate cancer. The surveys were conducted by the Louis Harris & Associates survey research firm. RESULTS: About four fifths of patients and urologists prefer aggressive therapy for prostate cancer. Patient goals with therapy included preservation of quality of life (45%), extension of life (29%), and delaying disease progression (13%), whereas physicians overwhelmingly focused on treatment efficacy (86%), with side effects (43%) and costs (29%) being secondary considerations. Urologists and patients differed markedly in the description of the patient-physician discussion. Whereas almost 100% of physicians stated that they always discussed important considerations such as options for no therapy, life expectancy with and without therapy, patient preferences, costs, and changes in sexual function, only about one fifth of patients recalled similar discussions. Patients and physicians both believed that physicians were an excellent source of educational support, but often did not report provision of emotional support. Although support groups were viewed as good providers of educational and emotional support by 85% to 90% of patients, physicians appeared to underestimate the benefit of support groups in these areas. CONCLUSIONS: Patients who belong to US TOO have many emotional and educational needs that are not currently being fulfilled by physicians. Although the goals of therapy are viewed similarly by patients and physicians, much of the important cancer- and treatment-related information that physicians report they have provided is not recalled by patients. Policy makers would be wise to devise systematic strategies such as shared decision-making tools and better linkages to support groups to ensure that patients' needs are being met.

Hormonal therapy in the management of prostate cancer: from Huggins to the present.

Hormonal therapy has been the mainstay of treatment for advanced forms of prostate cancer. Although early clinical studies suggested that major improvements and even cure could occur, later randomized prospective investigations showed that hormonal treatments were palliative rather than curative. Subsequent studies have suggested, but not conclusively proven, that earlier initiation of hormonal therapy for patients with early forms of metastatic disease may prolong disease-free and overall survival. The choice of hormonal agents, either alone as monotherapy or in combination with agents of differing mechanisms of action, suggests that further improvements in survival can be achieved with combinations of hormonal agents. Many studies have suggested that the use of hormonal therapy with localized forms of prostate cancer may provide pathologic benefit in decreasing the amount of tumor found at the time of radical prostatectomy or treated during radiation therapy. Although short-term outcomes looking at tumor "downstaging" have been positive, longer follow-up will be necessary before definitive conclusions can be made regarding the ultimate utility of preoperative or preradiation therapy hormonal treatments (neoadjuvant hormonal therapy).

Leydig cell hyperplasia mimicking testicular neoplasm.

Patients with extragonadal seminoma are at high risk of developing a primary testicular neoplasm many years after the initial diagnosis and therapy. Therefore, long-term follow-up is critical in the proper management of these patients. We present the first case of Leydig cell hyperplasia, mimicking a testicular neoplasm, 21 years after diagnosis and treatment of extragonadal seminoma.

Prostate cancer: emerging concepts. Part II.

OBJECTIVE: To review important topics related to prostate cancer that have arisen since this subject was last covered in Annals in 1993. The review consists of two parts. Part II describes neoadjuvant hormonal therapy, new local treatment options (including three-dimensional conformal radiation therapy, brachytherapy, and cryosurgery), antiandrogen therapy management of erectile dysfunction, funding and legislation for research, and areas for future research, especially in genetics investigations. STUDY SELECTION: Randomized studies identified through a MEDLINE search (1992 to 1996); large, single-institutional conferences and consortiums; and studies presented at regional, national, and international symposia. DATA SYNTHESIS: Qualitative and quantitative data are reported. Part II describes results of completed randomized trials that used neoadjuvant hormonal therapy. Studies have shown that nearly 50% more patients with cT2 disease will have pathologically confined (pT2) prostate cancer as a result of preoperative neoadjuvant hormonal therapy. Time to development of progressive disease and disease-free survival are improved in patients receiving neoadjuvant hormonal therapy before radiation therapy, but the long-term overall effects on survival of neoadjuvant therapy before surgery or radiation are unknown. Other methods for treating localized prostate cancer (three-dimensional conformal radiation therapy, brachytherapy, and cryotherapy) are gaining popularity, despite the lack of long-term efficacy results. Advances in the understanding of the optimal use of antiandrogens and managing treatment-induced erectile dysfunction continue to benefit patients with prostate cancer. CONCLUSIONS: Prostate cancer is being detected with increasing frequency, and many patients are receiving such treatments as radical prostatectomy and radiation therapy. Although refinements in prostate-specific antigen (PSA)-based testing have contributed substantially to the increased rate of detection of prostate cancer, the incidence of disease was increasing dramatically even before PSA detection was possible. Despite earlier detection, the optimal therapy for the early form of the disease is still enigmatic. Further studies and longer follow-up of patients who participated in completed studies are needed to better define the outcomes and importance of prostate cancer therapies. More research is needed to help elucidate the reasons for the increased incidence of the disease; such efforts should help define strategies to ultimately prevent prostate cancer.

Prostate cancer: emerging concepts. Part I.

OBJECTIVE: To review important topics related to prostate cancer that have arisen since this subject was last covered in Annals in 1993. The review consists of two parts, Part I describes advances in prostate-specific antigen (PSA) interpretation (including PSA density and velocity, age-specific reference ranges, "free" and "bound" PSA ratios, the utility of PSA in defining the pathologic extent of prostate cancer, and the use of these concepts in helping define appropriate treatment strategies), the management of patients with organ-confined prostate cancer, and pathologic interpretation of prostatectomy specimens. STUDY SELECTION: Randomized studies identified through a MEDLINE search (1992 to 1996); large, single-institution conferences and consortiums; and studies presented at regional, national, and international symposia. DATA SYNTHESIS: Both qualitative and quantitative data are reported. Most of the data presented in part I concern advances in the interpretation of PSA results and characterization of the pathologic findings of prostatectomy specimens. Studies show that almost 50% of patients with clinically organ-confined prostate cancer have disease that is beyond the confines of the prostatic capsule. The chances of developing clinical (radiographic) and biochemical failure (that is, elevation of PSA levels) are 3% and 6%, respectively, for pathologically organ-confined cancer and 10% and 26%, respectively, for non-specimen-confined prostate cancer. Actual progression-free survival rates 10 years after radical prostatectomy are 70% for patients with organ-confined cancer and 39% for patients with cancer that has spread through the capsule. CONCLUSIONS: Prostate cancer is being detected with increasing frequency, and many patients with this condition are receiving such treatments as radical prostatectomy and radiation therapy. Although refinements in PSA-based testing have contributed substantially to the increased detection rate of prostate cancer, the incidence of disease was increasing dramatically even before the detection of PSA was possible. Yet, despite earlier detection, the optimal therapy for the early form of the disease remains enigmatic. Further studies and longer follow-up of patients who participated in completed studies are needed to better define the outcomes of prostate cancer therapies and to help determine the importance of the therapies. Increased research efforts are necessary to help elucidate the reasons for the great increase in the incidence of the disease; such efforts should help define strategies to ultimately prevent prostate cancer.

A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy.

Thrombocytopenia is a complication of cancer treatment that can limit dose intensity. Interleukin-11 (IL-11) is a growth factor that increases platelet production. We conducted a multicenter, randomized, placebo-controlled trial of recombinant human IL-11 (rhIL-11) in 93 patients with cancer who had already been transfused platelets for severe thrombocytopenia resulting from chemotherapy. The patients had received platelet transfusions for nadir platelet counts of < or = 20,000/microL during the chemotherapy cycle immediately preceding study entry. Chemotherapy was continued during the study without dose reduction. Patients were randomized to receive placebo or rhIL-11 at 50 or 25 micrograms/kg subcutaneously once daily for 14 to 21 days beginning 1 day after chemotherapy. Eight of 27 (30%) evaluable patients treated with rhIL-11 at a dose of 50 micrograms/kg did not require platelet transfusions versus 1 of 27 (4%) patients who received placebo (P < .05). Five of 23 (18%) patients treated with rhIL-11 at 25 micrograms/kg avoided platelet transfusions (P = .23). Side effects were fatigue and cardiovascular symptoms, including a low incidence of atrial arrhythmias and syncope. There were no differences among treatment groups in the incidence of neutropenic fever, days of hospitalization, or number of red blood cell transfusions. This study shows that rhIL-11 treatment of a dose of 50 micrograms/kg significantly increases the likelihood that patients who have already been transfused platelets for severe chemotherapy-induced thrombocytopenia will not require platelet transfusions during a subsequent chemotherapy cycle.

Phase I study of continuous-infusion recombinant macrophage colony-stimulating factor in patients with metastatic melanoma.

Macrophage colony-stimulating factor (M-CSF) is a lineage-specific, homodimeric growth factor that supports the proliferation and maturation of bone marrow progenitors and the survival and function of mononuclear/macrophage cells. In vitro studies have demonstrated antitumor activity of macrophage colony-stimulating factor-treated monocytes against melanoma target cells. A Phase I study was conducted by administering the glycosylated form of the protein to patients with metastatic melanoma as two 7-day continuous i.v. infusions separated by a 2-week rest. Cohorts of three patients per dose level received escalating doses of 10-160 microgram/kg/day. Safety, clinical, and biological effects were evaluated. The infusions were well tolerated with occasional maximum grade 2 nonhematological toxicity. Rapidly reversible thrombocytopenia was the major hematological adverse effect. Its etiology may in part be explained by proliferation and activation of monocyte/macrophage cells in bone marrow samples. Evidence for a biological effect on tumors was suggested by the delayed, complete disappearance of multiple lesions in one patient and a decrease in the size of one marker lesion in a second patient with a mixed response. Fasting serum cholesterol levels decreased during the infusions and may represent an additional therapeutic application for this growth factor.