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Results for “PSA response”

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PubMed1999

[Primary treatment for stage D2 prostate cancer: a randomized study of combined androgen blockade alone versus combined with UFT].

To evaluate the efficacy of chemoendocrine therapy for the initial treatment of stage D2 prostate cancer, we conducted a prospective randomized study which compared combined androgen blockade alone to that combined with UFT. Twenty-one patients received LH-RH agonist and flutamide (Group-A), and 23 patients received LH-RH agonist, flutamide and UFT (Group-B). The overall response rate and the PSA response rate of Group-A was 71.4% and 100% respectively, against 65.2% and 90%, respectively in Group-B. The median follow-up period was 24 months. The 2-year progression-free survival rate of Group-A was 7.4% and that of Group-B was 15.9%. The response rate and progression-free survival rate did not differ significantly between the 2 groups. Liver dysfunction due to flutamide was common in both groups, and a total of 4 patients did not continue the treatment because of this adverse effect. We conclude that in patients with stage D2 prostate cancer, treatment with combined androgen blockade and UFT is not superior to treatment with combined androgen blockade alone.

Adenocarcinoma↗

PubMed2003

[Intermittent oral hormonal chemotherapy using estramustine phosphate and etoposide for the treatment of hormone-refractory prostate cancer].

Seventeen patients were given lower dose and intermittent oral administration of estramustine phosphate (6 mg/kg/day) and etoposide (30 mg/m2/day) for 7 days. Then administration was discontinued for 7 days. This administration cycle was repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. Fifteen of the 17 patients were finally evaluated for PSA response. Overall, the pretreatment PSA levels were lowered at least 50% from baseline in 7 (47%) of the 15 patients. The median survival was 65 weeks. Five of the 17 patients complained of anorexia or nausea during the treatment, but none of them showed over grade 2 anorexia, none requiring transfusion or hospitalization. None of the patients showed edema, deep venous thrombosis, thrombocytopenia, anemia or myocardial infarction. Because of its rare and mild adverse effects, this intermittent administration of oral estramustine and oral etoposide may be a useful and secure regimen for hormone refractory prostate cancer.

Administration, Oral↗

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.

Aged↗

PubMed1978

Serological inhibition of blast transformation to purified streptococcal antigens by planned immunization in HLA (A,B) compatible unrelated individuals.

Sera obtained from planned immunizations between unrelated donors and recipients, identical or compatible at HLA-A and B, were assessed for their capacity to alter the in vitro response of a test panel of lymphocytes to PHA and a purified streptococcal antigen (PAS). In the case of PHA, no serum effects were apparent. The response to PAS, however, significantly inhibited by two sera. When tested for their complement-dependent cytotoxicity on enriched populations of T and B lymphocytes, none of the sera manifested cytotoxicity against T cells nor did serological inhibition correlate with the capacity to lyze B cells. The data suggest that inhibition of the PSA response is mediated by blocking antibodies specific for a subset of lymphocytes, possibly T cells. While the precise mechanism governing the response to PSA is not known, the data are compatible with the idea that an HLA-linked Ir gene, expressed on a subset of T lymphocytes, controls immune responsiveness to PSA.

Antibody Specificity↗

PubMed2005

Salvage radiation therapy for prostate specific antigen progression following radical prostatectomy: 10-year outcome estimates.

PURPOSE: We evaluated men treated with salvage radiation therapy for increasing serum prostate specific antigen (PSA) following radical retropubic prostatectomy (RRP). MATERIALS AND METHODS: We retrospectively reviewed the records of 3,478 consecutive men who underwent radical retropubic prostatectomy (RRP) between 1983 and 2003, as performed by a single surgeon. A total of 307 men received salvage radiation therapy for persistently increased or increasing PSA after RRP. We compared perioperative and peri-radiotherapy clinicopathological parameters in men who achieved an undetectable PSA level after radiation therapy (responders) vs those who did not (nonresponders). We then evaluated the durability of the PSA response. RESULTS: Median time from RRP to PSA progression was 23 months (range 1 to 129). Median followup from RRP was 104 months (range 7 to 225). Median followup from salvage radiotherapy was 56 months (range 0 to 188). Of 223 men with sufficient followup information 162 (73%) subsequently had undetectable PSA (less than 0.3 ng/ml) in response to salvage radiation therapy. There was no significant difference between responders and nonresponders in the distribution of clinical and pathological tumor stages, age at RRP, surgical margin status, and the interval between RRP and salvage radiation therapy. A Gleason score of 8 to 10 was more prevalent in nonresponders than responders (28% vs 13%). Median PSA at salvage radiation therapy was 1.2 ng/ml in nonresponders vs 0.7 ng/ml in responders. Actuarial 5 and 10-year progression-free (PSA less than 0.3 ng/ml) survival probabilities in all 223 men following salvage radiation therapy were 40% (95% CI 32 to 48) and 25% (95% CI 15 to 36), respectively. Actuarial 5 and 10-year biochemical progression-free survival estimates following salvage radiation therapy in responders only were 55% (95% CI 45 to 64) and 35% (95% CI 21 to 49), respectively. Only seminal vesicle invasion was significantly associated with progression-free survival following radiation therapy on multivariate analysis. CONCLUSIONS: An undetectable PSA level following salvage radiation therapy is more frequently achieved in men with lower pre-radiation serum PSA and those without seminal vesicle or lymph node involvement. Overall approximately a fourth of men with PSA evidence of cancer progression following RRP had a durable response 10 years after the initiation of salvage radiation therapy in the protocols used in this patient cohort.

Adult↗

PubMed2005

Achieving treatment goals for hormone-refractory prostate cancer with chemotherapy.

The belief that hormone-refractory prostate cancer (HRPC) is a chemotherapy-resistant disease has been effectively refuted by the results of two recent randomized phase III trials. The TAX327 trial compared weekly docetaxel, every-3-weeks (Q3W) docetaxel, and Q3W mitoxantrone plus prednisone in 1,006 patients with HRPC, and results demonstrated that survival was significantly longer with a docetaxel-based regimen than with mitoxantrone. That trial demonstrated that only Q3W docetaxel was significantly superior to mitoxantrone with respect to overall survival. Quality of life was also superior in the docetaxel groups. In the Southwest Oncology Group (SWOG) 9916 trial, 674 men with progressive HRPC were randomized to 3-week cycles of docetaxel plus estramustine or mitoxantrone plus prednisone. Overall and disease-free survival times were significantly longer in the docetaxel arm. Collectively, the results of these trials demonstrate that survival can be significantly improved with chemotherapy in patients with HRPC to an extent that is comparable with the survival benefits seen in other cancers considered sensitive to chemotherapy such as breast cancer. Among various research tasks in HRPC is the definition of potential surrogate end points for survival, which will facilitate the conduct of pivotal trials. Prostate-specific antigen (PSA) response rate and changes in PSA constructs (i.e., PSA doubling time and PSA velocity) are promising potential surrogate end points for future trials and are being actively evaluated at the present time. Until there is clear demonstration of a surrogate role for these alternative end points, survival remains the appropriate end point for phase III trials in HRPC. There is a need for safe and effective second- and third-line regimens for patients progressing after docetaxel, and these patients should enter clinical trials designed for this population. Mitoxantrone, vinorelbine, the platinum analogue satraplatin, and epothilone are among compounds that require careful testing in this setting. The addition of targeted therapies, such as the endothelin receptor antagonist, atrasentan, and angiogenesis inhibitors, such as thalidomide and bevacizumab, to docetaxel-based therapy is being evaluated. High-dose calcitriol may also be an effective addition to docetaxel. The extensive effort devoted to the evaluation of chemotherapy and other systemic modalities of treatment of HRPC is likely to yield additional clinical benefit for patients, making HRPC a more manageable, less lethal, and less debilitating disease.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

[Induction of apoptosis in human head and neck cancer cell lines by an active component of OK-432 through p53-independent pathway via toll-like receptor (TLR) 4 signaling].

OK-PSA, an active component of OK-432, induces anti-tumor immunity via Toll-like receptor (TLR) 4/MD-2 complex. In the current study, we evaluated the effect of the OK-PSA on human head and neck cancer cell lines. Twelve cancer cell lines including 7 squamous cell carcinoma (SCC) cell lines and 5 salivary gland cancer (SGC) cell lines were examined. The quantitative real-time PCR analysis revealed that TLR4 mRNA was expressed in all 12 cell lines, and that MD-2 mRNA was expressed in 5 cell lines. OK-PSA stimulation resulted in the activation of NF-kappaB in the 4 SCC cell lines which express both TLR4 and MD-2 genes, and in 5 SGC cell lines which express at least TLR4 gene independently of MD-2 expression. In these OK-PSA-responsive cell lines, OK-PSA activated caspase-1, caspase-3 and caspase-8, and induced apoptosis. OK-PSA-induced apoptosis were observed even in a SGC cell line in which p53 is mutated and its function is impaired. These findings strongly suggest that OK-PSA induces apoptosis by the activation of caspases through p53-independent pathway via TLR4 signaling in head and neck cancer cells.

Apoptosis↗

PubMed1999

Early castration-induced upregulation of transforming growth factor beta1 and its receptors is associated with tumor cell apoptosis and a major decline in serum prostate-specific antigen in prostate cancer patients.

BACKGROUND: The mechanism behind castration-induced apoptosis in prostate cells is unknown, but data from other species suggest that transforming growth factor beta1 (TGF-beta1) may be involved. METHODS: By using quantitative RT-PCR and immunohistochemistry, expression of TGF-beta1 and its receptors type I and II (RI and RII) was studied in normal and tumor areas of core biopsies taken before and 2-11 days after castration therapy. The TGF-beta responses were related to changes in apoptotic index and to changes in serum prostate-specific antigen (PSA). RESULTS: In normal prostate tissue, apoptosis was generally increased by castration, and apoptosis was accompanied by an increase in TGF-beta1 and RII mRNA levels (P < 0.05). In tumors, apoptosis was seen only in 44% of the cases and in these, but not in the others, TGF-beta1, RI, and RII mRNA levels were increased (P < 0.05). In the patients showing a prognostically favorable PSA response (nadir PSA <5 ng/ml), but not in the others, RI and RII mRNA levels were significantly upregulated (P < 0.05). CONCLUSIONS: Short-term upregulation of TGF-beta1 and its receptors is associated with apoptosis in human prostate and prostate cancer, and possibly with a favorable clinical outcome after castration therapy.

Apoptosis↗

PubMed1999

Prostate cancer: molecular biology of early progression to androgen independence.

To improve the therapy for prostate cancer, it will be necessary to address the problems of progression to androgen independence and the process of metastatic spread of tumour. The complexity of the latter condition is likely to mitigate against the immediate development of relevant therapeutic approaches. However, the basis of androgen independence appears to be a problem of simpler dimensions and more amenable to treatment with current therapeutic technology. Since early tumour progression can be detected by an incomplete prostate-specific antigen (PSA) response to androgen withdrawal therapy, a study of the molecular biology of PSA gene regulation may well provide insight into new methods for preventing or delaying this problem. Mounting evidence suggests that ligand-independent activation of the androgen receptor may be one underlying mechanism of androgen independence. In the absence of androgen, a compensatory increase in the activity of cAMP-dependent protein kinase (PKA) enhances the ability of the androgen receptor to bind to the response elements regulating PSA gene expression. The activation of the androgen receptor through up-regulation of the PKA signal transduction pathway involves the amino-terminus of the androgen receptor, the function of which may be altered either by modifications such as phosphorylation, or through interactions with co-regulators or other proteins. Of therapeutic interest is the fact that this effect can be counteracted experimentally by the anti-androgen, bicalutamide, and clinically by several other similar agents. We speculate that the inhibition of PKA-activated androgen receptor might also be accomplished by decoy molecules that can bind to the relevant activated site on the amino-terminus or competitively interact with proteins recruited by the PKA pathway that are responsible for activating the receptor in the absence of androgen. Such molecules might include small mimetic substances or agents that can gain access to the nucleus of the cell.

Cyclic AMP-Dependent Protein Kinases↗

PubMed2005

Randomized phase II study of two doses of gefitinib in hormone-refractory prostate cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group.

PURPOSE: Overexpression of the epidermal growth factor receptor has been demonstrated in advanced prostate cancer and is associated with a poor outcome. A multi-institutional, randomized, phase II study was undertaken by the National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of two doses of oral gefitinib in patients with minimally symptomatic, hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Between July and November 2001, 40 patients with HRPC and increasing prostate-specific antigen (PSA) or progression in measurable disease who had not received prior chemotherapy were randomly assigned to 250 mg (n = 19) or 500 mg (n = 21) oral gefitinib daily continuously. The primary end points were PSA response rate and objective measurable response. Functional Assessment of Cancer Therapy Prostate Cancer Subscale (FACT-P) quality-of-life questionnaires were completed at baseline and during treatment. RESULTS: None of the patients demonstrated a PSA or objective measurable response. Five (14.3%) of 35 assessable patients had stable PSA (one patient at 250 mg and four patients at 500 mg), and five patients (14.3%) had a best response of stable disease (duration, 2.5 to 16.8 months). No significant effect on the rate of increase in PSA was seen. The most common drug-related nonhematologic toxicities observed were grade 1 to 2 diarrhea (250 mg, 65%; 500 mg, 56%), fatigue (250 mg, 29%; 500 mg, 33%), and grade 1 to 2 skin rash (250 mg, 24%; 500 mg, 39%). FACT-P scores decreased during treatment, indicating worsening of symptoms compared with baseline. CONCLUSION: Gefitinib did not result in any responses in PSA or objective measurable disease at either dose level. Gefitinib has minimal single-agent activity in HRPC.

Adenocarcinoma↗

PubMed2004

Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): a trial of the Eastern Cooperative Oncology Group.

PURPOSE: A phase II clinical trial was conducted to evaluate the feasibility and tolerability of a prime/boost vaccine strategy using vaccinia virus and fowlpox virus expressing human prostate-specific antigen (PSA) in patients with biochemical progression after local therapy for prostate cancer. The induction of PSA-specific immunity was also evaluated. PATIENTS AND METHODS: A randomized clinical trial was conducted by the Eastern Cooperative Oncology group and 64 eligible patients were randomly assigned to receive four vaccinations with fowlpox-PSA (rF-PSA), three rF-PSA vaccines followed by one vaccinia-PSA (rV-PSA) vaccine, or one rV-PSA vaccine followed by three rF-PSA vaccines. The major end point was PSA response at 6 months, and immune monitoring included measurements of anti-PSA and anti-vaccinia antibody titers and PSA-specific T-cell responses. RESULTS: The prime/boost schedule was well tolerated with few adverse events. Of the eligible patients, 45.3% of men remained free of PSA progression at 19.1 months and 78.1% demonstrated clinical progression-free survival. There was a trend favoring the treatment group that received a priming dose of rV-PSA. Although no significant increases in anti-PSA antibody titers were detected, 46% of patients demonstrated an increase in PSA-reactive T-cells. CONCLUSION: Therapy with poxviruses expressing PSA and delivered in a prime/boost regimen was feasible and associated with minimal toxicity in the cooperative group setting. A significant proportion of men remained free of PSA and clinical progression after 19 months follow-up, and nearly half demonstrated an increase in PSA-specific T-cell responses. Phase III studies are needed to define the role of vaccination in men with prostate cancer or those who are at risk for the disease.

Aged↗

PubMed1999

Diminished regional cerebral blood flow response to vibration in patients with blepharospasm.

OBJECTIVE: To determine whether patients with blepharospasm have abnormal sensorimotor processing similar to patients with writer's cramp. BACKGROUND: Blepharospasm is a focal dystonia manifest by involuntary, excessive blinking and squeezing of the eyes. Altered sensorimotor processing may contribute to the development of dystonic movements. Previously the authors demonstrated decreased vibration-induced cortical blood flow responses in hand primary sensorimotor area (PSA) in patients with hand dystonia. METHODS: In this prospective, case-control study, seven patients with blepharospasm were compared with seven normal subjects. PET measurements of regional blood flow were obtained using bolus administration of H(2)15O at rest or during sequential vibration of either the left or the right hand or side of the mouth. RESULTS: PSA activation decreased significantly in the patients with blepharospasm both ipsilateral (-68%; p = 0.0004) and contralateral to the side of facial stimulation (-56%; p = 0.0009). Patients had a 31% lower mean contralateral PSA response to hand vibration and a 51% smaller right supplementary motor area response to left-hand vibration than normal subjects, but these differences did not reach statistical significance. CONCLUSIONS: Patients with blepharospasm have abnormal sensorimotor processing in response to lower face vibration. They may also have abnormal brain responses to stimulation of clinically uninvolved parts of the body, but this requires confirmation.

Aged↗

PubMed1996

Characterization of a novel androgen-sensitive, prostate-specific antigen-producing prostatic carcinoma xenograft: LuCaP 23.

Prostatic carcinoma has proven extremely difficult to establish as cell lines or xenografts. In this article, we describe a new series of prostate cancer xenografts propagated in athymic mice, designated LuCaP 23, developed from prostate metastases harvested at autopsy shortly after death. Tumor from three separate metastatic deposits was developed into three xenograft sublines: two from lymph node metastases (LuCaP 23.1 and 23.8) and one from a liver metastasis (LuCaP 23.12). Fluorescence in situ hybridization analysis confirms the xenografts are human. Histologically, the xenografts are comprised of columnar epithelial cells arranged in a glandular pattern. Tumor doubling times range from 11 to 21 days for the three sublines. The cells secrete large amounts of prostate-specific antigen (PSA) with PSA indices of 1.27, 1.63, and 5.21 ng/ml/mm3 for the mice bearing the LuCaP 23.1, 23.8, and 23.12 sublines, respectively. Following androgen deprivation a temporary decrease in PSA secretion and a decrease in tumor size are noted in most tumors. Eventually, the tumors become androgen independent and resume growth in castrate hosts. The degree of PSA response to castration and time to PSA nadir correlate with time to progression. Thus, unlike most existing models of prostatic carcinoma, this novel xenograft exhibits many phenotypic characteristics of clinical prostatic carcinoma, including androgen sensitivity. These properties make this xenograft an excellent model for future study.

Acid Phosphatase↗

PubMed1999

Limited suppression of prostate-specific antigen after salvage radiotherapy for its isolated elevation after radical prostatectomy.

OBJECTIVES: To investigate the clinical outcome and degree of prostate-specific antigen (PSA) suppression after salvage radiotherapy performed because of isolated PSA elevation after radical prostatectomy. METHODS: We examined the outcomes of 32 patients who underwent radiotherapy after radical prostatectomy. Hypersensitive, as well as conventional, PSA assays were used to measure PSA levels after irradiation. RESULTS: Of 125 patients who underwent radical prostatectomy for clinically resectable prostate cancer, 42 (33.6%) developed detectable PSA an average of 13.5 months postoperatively. Thirty-two patients underwent salvage radiotherapy. In 13 patients (40.6%), PSA became undetectable (less than 0.1 ng/mL) at a mean of 1.2 months. Two of these patients later developed detectable PSA within 1 2 months. Of 22 patients who had at least 12 months of follow-up, 8 had a durable PSA response. Of 13 patients who attained an undetectable PSA postoperatively and then showed a delayed progressive increase, 7 exhibited a durable response lasting for more than the 12 months after irradiation. By contrast, only 1 of 9 patients with persistently elevated postoperative PSA showed undetectable levels after irradiation. Frozen sera from the 8 patients with a durable response to irradiation were available to measure levels less than 0.1 ng/mL by hypersensitive assay. The mean value was 0.035 ng/mL at an average of 26.9 months after irradiation. Only 3 patients had levels less than 0.01 ng/mL. CONCLUSIONS: Although radiotherapy may be beneficial in a small number of patients, many patients continue to have measurable levels of PSA (more than 0.01 ng/mL) after irradiation. Our results suggest that this treatment in its current form is inadequate to eradicate residual carcinoma.

Aged↗

PubMed2001

Docetaxel, estramustine, plus trastuzumab in patients with metastatic androgen-independent prostate cancer.

The incidence of human epidermal growth factor receptor 2 (HER2) protein overexpression and its prognostic value are not well characterized in patients with prostate cancer. A phase I study was designed to evaluate docetaxel/estramustine plus trastuzumab, a humanized monoclonal antibody that binds to the HER2 receptor, in patients with metastatic androgen-independent prostate cancer (AIPC). HER2 positivity was not required because safety was the primary endpoint. Patients received oral estramustine 280 mg three times daily (days 1 to 5); docetaxel, 70 mg/m(2) intravenously (day 2); and trastuzumab, 2 mg/kg intravenously (days 2, 9, and 19), every 21 days until the disease progressed or toxicity became unacceptable. This regimen was well tolerated among the first 13 treated patients. Grade 4 neutropenia was seen in 10% of administered cycles. There were two episodes of febrile neutropenia and two thrombembolic events. Of the 13 patients evaluable for prostate-specific antigen (PSA) response, nine (69%) experienced a decrease in PSA level of >50%. Two (33%) of six patients with measurable disease had objective responses, and one complete response was seen on bone scan. Docetaxel/estramustine/trastuzumab appears to be a safe combination when used in the treatment of metastatic AIPC. The response data are too preliminary for speculation about the relative benefits of this 3-drug regimen compared with the combination of only docetaxel and estramustine in this clinical setting.

Adenocarcinoma↗

PubMed2002

A randomized phase II and pharmacokinetic study of the antisense oligonucleotides ISIS 3521 and ISIS 5132 in patients with hormone-refractory prostate cancer.

PURPOSE: Protein kinase C (PKC)-alpha and Raf-1 are important elements of proliferative signal transduction pathways in both normal and malignant cells. Abrogation of either Raf-1 or PKC-alpha function can both inhibit cellular proliferation and induce apoptosis in several experimental cancer models including prostate cancer cell lines. ISIS 3521 and ISIS 5132 are antisense phosphorothioate oligonucleotides that inhibit PKC-alpha and Raf-1 expression, respectively, and induce a broad spectrum of antiproliferative and antitumor effects in several human tumor cell lines. In Phase I evaluation both ISIS 3521 and ISIS 5132 could be safely administered on 21-day i.v. infusion schedules and demonstrated preliminary evidence of antitumor activity. On the basis of these findings, a randomized Phase II study of ISIS 3521 and ISIS 5132 was performed in two comparable cohorts of patients who had chemotherapy-naïve, hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Patients with documented evidence of metastatic HRPC and a prostate-specific antigen (PSA) value > or =20 ng/ml were randomized to receive treatment with either ISIS 3521 or ISIS 5132 as a continuous i.v. infusion for 21 days repeated every 4 weeks. Patients were stratified according to the presence or absence of bidimensionally measurable disease at the time of randomization. The principal endpoints included PSA response, objective response in patients with bidimensionally measurable disease, and treatment failure defined as new or worsening symptoms; a fall in performance status of 2 levels; new or objective progression of disease; or a rise in PSA for 12 weeks without symptom improvement. Plasma samples were collected to assess individual steady-state concentrations and to relate this pharmacokinetic parameter to observed toxicities and responses. RESULTS: Thirty-one patients were randomized in this study; 15 patients received 43 courses of ISIS 3521 and 16 patients received 48 courses of ISIS 5132. The most common toxicities observed were mild to moderate (grade 1 or 2) fatigue and lethargy in 21% and 56% of patients treated with ISIS 3521 and ISIS 5132, respectively. Although no objective or PSA responses were observed in any patient treated with ISIS 3521 or ISIS 5132, persistent stable disease was observed in 3 patients for 5 or more months, and in 5 patients the PSA values did not rise >25% for 120 days or longer. CONCLUSIONS: The antisense oligonucleotides ISIS 3521 and ISIS 5132, at these doses and on this schedule, do not possess clinically significant single-agent antitumor activity in HRPC. Protracted stable disease in some patients may indicate a cytostatic effect. Additional work is required to define the optimal role of PKC-alpha or Raf-1 inhibition in the treatment of HRPC.

Aged↗

PubMed2005

Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily x 5 in hormone refractory prostate cancer (HRPC).

JM-216 is an orally bioavailable platinum compound with activity against many tumor models. The objective of this study was to determine the safety profile and anti-tumor activity of JM-216 in patients with hormone refractory prostate cancer (HRPC) when given orally daily x 5 days. In this open label phase II study JM-216 was administered orally at the dose of 120 mg/m2/d for 5 days every 4 weeks. Patients continued on the therapy until evidence of disease progression or intolerable toxicity developed. Dose escalation and de-escalation were allowed according to patient's tolerance. Thirty-nine patients were enrolled onto the study and received a total of 155 courses (median 2, range 1-16) of JM-216. Dose delays (77% of courses) and dose reductions (31% of courses) were common and were mainly due to myelosupression. Treatment was discontinued in 5 patients due to treatment related toxicities. One patient developed myelodysplastic syndrome 11 months after the start of treatment. The most frequent grade III or higher adverse events included thrombocytopenia (54%), neutropenia (52%), anemia (24%) nausea (13%), vomiting (16%) and diarrhea (28%). PSA response was assessed in 32 patients, 10 (26%) had partial response, 14 (36%) had stable disease while PSA progression was seen in 8 (21%) patients. Of 20 (54%) patients with measurable disease two patients had a documented partial response. Although JM-216 had moderate activity in HRPC when given on daily basis for 5 days, it is associated with significant treatment related toxicities in this patient population.

Administration, Oral↗

PubMed2006

Dose escalation of oral vinorelbine in combination with estramustine in hormone-refractory adenocarcinoma of the prostate.

BACKGROUND: The primary objective of the current study was to identify the tolerable dose level of oral vinorelbine when given in combination with estramustine to men with hormone-refractory prostate cancer (HRPC). The secondary objectives were to describe the toxicities of the combined regimen in patients with HRPC and to estimate the efficacy of oral vinorelbine in combination with estramustine based on the prostate-specific antigen (PSA) response. METHODS: Thirty-three patients with HRPC were treated on a 28-day cycle with estramustine at a dose of 140 mg orally 3 times a day on Days 1-3 and 8-10. Vinorelbine was given orally on Days 2 and 9. The initial dose of vinorelbine was 50 mg/m2 and was escalated to 70 mg/m2 using the time-to-event continual reassessment method. RESULTS: Three of 17 patients experienced dose-limiting toxicity at the 70 mg/m2 dose level of oral vinorelbine. One patient experienced dose-limiting toxicity at a dose of 60 mg/m2 and no dose-limitig toxicities were reported at the 50 mg/m2 dose. The overall response rate by > or = 50% reduction in PSA was 17.2%, (95% confidence interval, 5.9-35.8%). CONCLUSIONS: Oral vinorelbine at doses of 70 mg/m2 may be safely combined with estramustine. The combination appears to have modest activity in men with advanced prostate cancer. The trial design employed the time-to-event continual reassessment method, which potentially allows for rapid accrual, a more complete assessment of toxicities, and a larger fraction of patients to be treated at an effective dose. More active regimens are needed to further evaluate the utility of this clinical trial design in patients with prostate cancer.

Adenocarcinoma↗