The change of PSA doubling time and its association with disease progression in patients with biochemically relapsed prostate cancer treated with intermittent androgen deprivation.

BACKGROUND: We sought to determine the change of PSA doubling time (PSADT) and its association with disease progression during intermittent androgen deprivation (IAD) therapy for prostate cancer. METHODS: Data were retrospectively analyzed in 96 patients with biochemically relapsed prostate cancer (BRPC) treated with IAD since 1995. IAD consisted of LHRH-agonists ± antiandrogen given usually at PSA threshold (ng/ml) of 10-20, for 6-9 months. Cycles were repeated until the development of castration resistance. Mixed effects model was used to study PSADT change over cycles. Multivariate cox regression model was used to identify outcome-associated variables. RESULTS: Patients received a mean of 2.8 treatment cycles over a mean follow-up time of 71 months. Fifty-seven (59%) remain on treatment and 39 (41%) developed PSA refractoriness (n = 8) or positive scans (n = 31). First off treatment interval PSADT (median 2.3 months) was significantly shorter than the baseline (median 7.34) but remained stable in subsequent cycles. Off treatment interval PSADT adjusted for testosterone recovery (median 3.7) was significantly longer than that based on all PSA determinations (median 2). Factors associated with disease progression were pre-treatment PSADT (≥6 vs. <6), first off treatment interval PSADT (≥3 vs. <3), and PSA nadir during the first treatment interval (<0.1 vs. ≥0.1). CONCLUSIONS: During IAD for BRPC, PSADT becomes shorter, and is associated with testosterone recovery. PSADT before treatment and during the first off treatment interval is associated with disease progression. If prospectively validated these data may guide treatment with IAD and clinical trial design.

Prostate cancer: a practical approach to current management of recurrent disease.

Prostate cancer is the leading cause of cancer in men in the United States, with 234,460 men expected to be diagnosed as having the disease in 2006 (33% of cancers in men), and the third leading cause of cancer deaths in men, with 27,350 men expected to die of the disease (9% of cancer deaths). Through early detection and improved local therapies, including surgery or radiation therapy, a large number of men will be cured, but unfortunately, a significant number of men will still experience relapse of disease and require continued surveillance and ongoing therapy. This article discusses approaches to treatment of men who have recurrent disease, including active surveillance, androgen ablation therapy, secondary hormone therapy, chemotherapy, bisphosphonates, radiation therapy, and future directions.

A phase II trial of temozolomide and IFN-alpha in patients with advanced renal cell carcinoma.

The combination of temozolomide (TEM) and interferon-alpha (IFN-alpha) previously demonstrated a 30% response rate in metastatic melanoma. A single institution, phase II trial evaluating the efficacy of TEM/IFN in patients with advanced renal cell carcinoma (RCC) was conducted. Safety and tumor response were the main outcomes. Eligible patients received 200 mg/m(2)/day TEM orally on days 1-5 every 28 days, with IFN 2.5 million U/m(2)/day subcutaneously (s.c.) three alternate days/week for days 1-15 first cycle, then 5 million U/m(2)/day s.c. 3 alternate days/week throughout each 28-day cycle. Efficacy was evaluated every 8 weeks, and dose-limiting toxicities (DLTs) were treated with dose reductions of the culprit drug. Sixteen patients (ages 37-67) were initially enrolled. Of the 14 evaluable patients, there was one minor response. Best response was stable disease, with 7 patients remaining on study for > or =6 months. Five were alive for more than 2 years, and 2 remain alive at 45 and 50 months after enrollment. DLTs included TEM-induced myelosuppression and IFN-induced fever/chills. Other toxicities were mild to moderate (grades 1-3). The combination of TEM/IFN proved quite tolerable. This regimen appears inactive in terms of response in this population with poor prognosis, but the patients with stable disease > or =6 months remain of interest.

Pharmacological treatments for prostate cancer.

Recently, chemotherapy for prostate cancer has been primarily reserved for the palliation of symptoms secondary to prostate cancer. Chemotherapy regimens and new approaches are being developed that offer new hope of response and improved survival to men with prostate cancer. This paper discusses pharmacological strategies that are under investigation: cytotoxic agents and biological or targeted therapies, including the microtubule inhibitors (taxane/taxoids, vinorelbine) alone and in novel combinations with other experimental agents such calcitriol, thalidomide or flavopiridol (cell-cycle inhibitor) and treatment with epothilone analogues; endothelin receptor antagonists; other novel strategies such as vaccine therapy (GVAX; Cell Genesys) and prostate-specific membrane antibodies; and bisphosphonates.

Phase II, randomized, placebo-controlled trial of neoadjuvant celecoxib in men with clinically localized prostate cancer: evaluation of drug-specific biomarkers.

PURPOSE: Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy. PATIENTS AND METHODS: Patients with localized prostate cancer and Gleason sum > or = 7, prostate-specific antigen (PSA) > or = 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance. RESULTS: Seventy-three patients consented, and 64 were randomly assigned and included in the intention-to-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P < .0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities. CONCLUSION: Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint.

PURPOSE: CEP-701 is a potent inhibitor of trk receptors that causes cell death in prostate cancer (PC) models. CEP-701 binds to serum proteins and a preprostatectomy study was performed to assess prostate tissue penetration and clinical response to CEP-701. METHODS: Growth assays and Western blot analyses were performed to evaluate CEP-701 kinase inhibition. In a preprostatectomy study, patients received CEP-701 for five days prior to prostatectomy and prostate tissue analyzed for CEP-701 levels. A phase II dose escalation study was performed in patients with hormone refractory PC with rising PSA and no metastases. Endpoints included PSA response and safety. RESULTS: CEP-701 binds to serum proteins limiting tissue penetration. An oral dose of 40 mg bid of CEP-701 for five days produced levels of 219 +/- 38 nM in prostate at time of prostatectomy. No patients in the Phase II study met the primary response criteria of >50% PSA decline. 7/9 patients had increase in PSA slope on CEP-701 compared to PSA slope prestudy. 5/9 patients had a decrease in PSA levels after stopping CEP-701. Laboratory studies showed increased PSA production by CEP-701 growth arrested human PC cells in vitro and in vivo. CONCLUSIONS: Evaluation of PSA response is an inadequate indicator of response in CEP-701 treated PC patients. Therefore, the effectiveness of CEP-701 as treatment for prostate cancer has not been adequately tested. Based on a strong preclinical rationale, further clinical studies with CEP-701 using alternative endpoints are indicated.

Phase II evaluation of docetaxel plus exisulind in patients with androgen independent prostate carcinoma.

OBJECTIVES: In this phase II study, the combination of docetaxel and exisulind (a GMP phosphodiesterase inhibitor) was given to patients with metastatic androgen independent prostate cancer (AIPC) to establish efficacy, assess toxicity, and determine pharmacokinetics of docetaxel administered alone and in combination with exisulind. METHODS: Fourteen patients with metastatic AIPC were registered to receive weekly docetaxel for 4 weeks, followed by 2 weeks of rest; repeated up to a maximum of 6 cycles. Exisulind 250 mg was given orally twice a day starting on day 8 of the study and taken continuously. RESULTS: All patients were evaluable for toxicity, response and survival. Grade 3 reversible toxicities included: fatigue, nausea, diarrhea, abdominal pain, rash, syncope, pulmonary edema, deep vein thrombosis, congestive heart failure, and elevations in transaminases, requiring therapy delays and/or dose reductions, or removal from therapy. Only 3 out of 14 patients (21.4%) had a 50% decline in prostate specific antigen (PSA) level that lasted > or =4 weeks; 1 out of 14 patients (7%) had a lymph node response. Median survival was 17.28 months. Docetaxel pharmacokinetics for 11 patients demonstrated mean +/- SD clearance values that were similar during week 1 and week 3 when exisulind had been added. CONCLUSIONS: : Overall, our trial indicated that the toxicity profile and efficacy of this regimen is unlikely to be substantially better than single agent docetaxel.

Phase 3 randomized trial evaluating second-line hormonal therapy versus docetaxel-estramustine combination chemotherapy on progression-free survival in asymptomatic patients with a rising prostate-specific antigen level after hormonal therapy for prostate cancer: an Eastern Cooperative Oncology Group (E1899), Intergroup/Clinical Trials Support Unit study.

Despite improvements in early detection of prostate cancer when it is clinically localized--and therefore most amenable to curative local therapies-- approximately 33% of men with early prostate cancer will develop biochemical failure with a rising prostate-specific antigen (PSA) during follow-up. The early use of androgen suppression in this group of men has changed the clinical picture of androgen-independent disease. Now, there are men on androgen suppression who will develop biochemical failure and remain free of clinical or radiographic evidence of metastatic disease for a period of time. There is no standard approach to this group of men, who have a rising PSA on androgen deprivation, because there are little or no data about strategies that may improve survival, delay time to progression, or improve quality of life. Therefore, current management of this population remains controversial. In an effort to determine which of these 2 approaches--second-line hormone therapy or chemotherapy--is optimal in delaying the time to progression, the Eastern Cooperative Oncology Group (ECOG) developed protocol E1899. Although both approaches offer the potential for response (reduction in PSA and prolonging the time to clinical progression), they have very different toxicity profiles, making impact on quality of life another important end point. This randomized trial evaluating second-line hormonal therapy using ketoconazole and hydrocortisone versus docetaxel and estramustine combination chemotherapy on progression-free survival in asymptomatic men with a rising PSA on androgen ablation for prostate cancer is the subject of this article.

Psychometric evaluation of two scales assessing functional status and peripheral neuropathy associated with chemotherapy for ovarian cancer: a gynecologic oncology group study.

PURPOSE/OBJECTIVES: To evaluate the psychometric properties of two adapted scales, one for functional status and one for peripheral neuropathy secondary to neurotoxic chemotherapy. DESIGN: Repeated measures methodologic design conducted within a Gynecologic Oncology Group (GOG) phase III clinical trial that randomly assigned patients with advanced epithelial ovarian cancer to cisplatin and cyclophosphamide or cisplatin and paclitaxel. SETTING: 8 GOG institutions participating in the GOG clinical trial. SAMPLE: 88 evaluable outpatients enrolled in the GOG clinical trial. Sample size at time 1 (T1) was 88 patients and at time 2 (T2) was 67 patients. METHODS: All scales were administered at T1 (prior to initiation of chemotherapy) and T2 (after six cycles of chemotherapy but prior to second-look laparotomy). Internal consistency reliability, criterion validity, and construct validity were evaluated, and clinical application was explored. MAIN RESEARCH VARIABLES: Self-reported peripheral neuropathy and functional status (comprised of physical function and role function subscales), the GOG performance status scale, and the GOG toxicity criteria. FINDINGS: Reliability coefficients at T1 were physical function = 0.83, role function = 0.96, and peripheral neuropathy = 0.91; at T2, they were physical function = 0.83, role function = 0.92, and peripheral neuropathy = 0.89. At T1, physical function and role function correlated positively with performance status. Peripheral neuropathy correlated positively with GOG toxicity criteria used at T2. Principal component factor analysis suggested that the functional status scale had a two-factor structure with factors representing general and specific mobility and that the peripheral neuropathy scale also had a two-factor structure with factors representing foot and hand neuropathy. CONCLUSIONS: The physical function, role function, and peripheral neuropathy scales have internal consistency, reliability, criterion validity, and construct validity. However, revision of the scales should address modification of specific questions and consider increasing the Likert scale from a four-point to a five- or seven-point scale to enhance clinical sensitivity and application. IMPLICATIONS FOR NURSING: With minor modifications, these scales should be useful in assessing physical function, role function, and peripheral neuropathy in patients who receive agents that may cause peripheral neuropathy.