Induction of complete remission in metastatic hormone-refractory prostate cancer: A combined anti-inflammatory therapy approach

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15636-15636 ◽  
Author(s):  
A. Reichle ◽  
B. Walter ◽  
A. Berand ◽  
M. Vogelhuber ◽  
K. Bross ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Complete Remission ◽  
Objective Response ◽  
Hormone Refractory Prostate Cancer ◽  
Who Grade ◽  
Therapy Approach ◽  
Psa Response ◽  
Anti Inflammatory ◽  
Hormone Refractory ◽  
Negative Predictor

15636 Background: The present multi-centre phase II study was designed to support the hypothesis that networking agents binding to ubiquitous accessible targets in metastatic hormone-refractory prostate cancer (HRPC) may counteract neoplasia-specific aberrant cellular functions, thereby mediating objective response (primary endpoint). Method: Patients with metastatic HRPC, received both an anti- inflammatory and angiostatic therapy consisting of low-dose chemotherapy with capecitabine 1 g twice daily for 14 days every 3 weeks, day 15+, COX-2 blockade with etoricoxib 60 mg daily, day 1+, combined with two transcription modulators, pioglitazone 60 mg daily, day 1+, plus dexamethason 1 mg daily for 14 days, every 3 weeks, day 15+, until disease progression. The study was planned using the Simon optimal design. Results: Thirty-six consecutive patients (N= 22 (61%) chemo-naive, n= 14 (39%) with preceding chemotherapies, mean 2.1 regimen) with metastatic HRPC, confirmed PSA increase, assessable response, and ECOG 0–2 were enrolled between 1/03 to 5/06. Objective response occurred in 10 of 13 cases (N/n: 41%/7%) with PSA (and C-reactive protein) response >50% (N/n: 45%/21%). Median time to PSA response was 2.4 months (range 1.0 to 7.3 months). Two of three patients responding with PSA <4 ng/ml achieved complete remission after 9 and 16 months, 16 patients stable disease (N/n: 41%/64%), and 5 patients experienced progressive disease (N/n: 14%/14%). Median progression-free survival (PFS) was 3.6 months (range 0.5 to 28.5) and median overall survival (OS) 14.4 months (range 0.6 to 37.2). Multivariate analysis recognized pre-treatment with chemotherapy as negative predictor for both OS (hazard ratio 2.26 (CI 95%: 0.970; 5.277), p=0.05) and PFS (HR 2.47 (CI 95%: 1.146; 5.348), p= 0.02), and <50% PSA response as negative predictor for PFS (HR 0.38 (CI 95%: 0.171; 0.857), p= 0.01). Toxicities > WHO grade II were reported: Hand-foot syndrome (n=1), anemia (n=6), edema (n=1), cushing syndrome (n=1), hydronephrosis (n=1). Conclusions: This is the first study reporting continuous complete remissions in HRPC with a biomodulatory therapy approach. Further, the study may clinically support the upper mentioned hypothesis. No significant financial relationships to disclose.

PSA flare-up in patients with hormone-refractory prostate cancer (HRPCA) receiving docetaxel-based chemotherapy: Incidence and differentiation from progressive disease

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14523-14523
Author(s):  
D. Sahi ◽  
C. H. Ohlmann ◽  
I. Cordia ◽  
U. Engelmann ◽  
A. Heidenreich
Keyword(s):  
Prostate Cancer ◽  
Progressive Disease ◽  
Initial Increase ◽  
Hormone Refractory Prostate Cancer ◽  
Common Phenomenon ◽  
Maximum Increase ◽  
Psa Response ◽  
Hormone Refractory ◽  
Initiation Of Therapy ◽  
Doubling Times

14523 Background: Docetaxel-based chemotherapy displays the standard therapy for patients with hormone-refractory prostate cancer. A subset of patients will experience an initial PSA increase after initiation of therapy followed by a subsequent PSA decrease. The aim of our study was to investigate the incidence of this phenomenon and to identify factors that differentiate the flare-up from progressive disease. Methods: We retrospectively analyzed the patient records of 46 patients who received docetaxel as monotherapy or in combination with either mitoxantron or estramustine for hormone-refractory prostate cancer. PSA flare-up was defined as an initial PSA increase of more than 25% after initiation of therapy over baseline followed by a PSA decrease of at least 75% compared to the maximum increase over baseline. Progressive disease was defined as a PSA increase of at least 25% over baseline in patients with no PSA response which had to be confirmed four weeks later. Results: Of 46 patients who received docetaxel-based chemotherapy 16 (34.8%) showed a PSA decrease of at least 50%, 6 (13.0%) between 30–50%, 17 (37.0%) had stable disease and 7 (15.2%) patients experienced progressive disease. An initial PSA increase followed by a subsequent PSA decrease was seen in 6 (13.0%) of the patients. Median PSA increase compared to baseline was 81.0% (25–239). The median following PSA decrease was 110.5% (77–160) compared to the initial increase. Median PSA doubling times of patients with PSA flare up or progressive disease were 113.3 and 100.7 days (p = 0.7941), respectively. Conclusions: PSA flare-up seems to be a common phenomenon in patients being treated with docetaxel-based chemotherapy for hormone-refractory prostate cancer. In order not to prevent those patients from a subsequent PSA decrease by early cessation of therapy it would be useful to discriminate them from patients with progressive disease. According to the results of our study PSADT does not differ between patients with flare-up or progressive disease and can therefore not be used to distinguish between the two. No significant financial relationships to disclose.

ANTI-INFLAMMATORY AND ANGIOSTATIC THERAPY IN HORMONE REFRACTORY PROSTATE CANCER (HRPC)

2008 ◽  
Vol 7 (3) ◽  
pp. 233
Author(s):  
M. Albrecht ◽  
M. Vogelhuber ◽  
A. Stenzl ◽  
S. Feyerabend ◽  
B. Walter ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Hormone Refractory Prostate Cancer ◽  
Anti Inflammatory ◽  
Hormone Refractory

Identification of candidate biomarkers of therapeutic response to docetaxel in hormone-refractory prostate cancer by proteomic profiling

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11010-11010
Author(s):  
L. Horvath ◽  
L. Zhao ◽  
B. Lee ◽  
D. Brown ◽  
M. Molloy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Plasma Levels ◽  
Therapeutic Targets ◽  
Predictive Biomarkers ◽  
Protein Profiling ◽  
Hormone Refractory Prostate Cancer ◽  
Psa Response ◽  
Pc3 Cells ◽  
Hormone Refractory

11010 Background: Docetaxel (DTX)-based chemotherapy improves symptoms and survival in men with advanced hormone-refractory prostate cancer (HRPC). However, approximately 50% of patients do not respond to DTX but are exposed to significant toxicity without direct benefit. This study aimed to identify novel therapeutic targets and predictive biomarkers of DTX-resistance in HRPC. Methods: Protein profiling using iTRAQ mass spectrometry compared the PC3-Rx and DTX-sensitive PC3 cells and DTX-resistant PC3-Rx developed by DTX dose-escalation. Functional validation experiments were performed using recombinant protein treatment and siRNA knockdown experiments. Plasma/serum samples were collected from 41 men with metastatic HRPC treated with DTX-based chemotherapy (36 with paired samples pre- and post- cycle 1 DTX). Serum/plasma levels of MIC-1 were measured by ELISA. The association between MIC-1 levels, PSA response and overall survival (OS) were assessed by non-parametric tests and Kaplan-Meier survival analysis. Results: The IC50 for DTX in PC3-Rx was 10-fold higher than that in parent PC-3 cells. Protein profiling identified that MIC-1 levels were elevated 2.4 fold and AGR2 decreased 2.4 fold in DTX resistant cells. Knockdown of AGR2 expression in PC3 cells resulted in increased DTX resistance (p=0.03). PC-3 cells treated with recombinant MIC-1 also became resistant to DTX (p=0.001). Conversely, treating PC3-Rx cells with MIC1-siRNA restored sensitivity to DTX (p=0.002). In HRPC patients, pre-treatment MIC-1 levels did not correlate with PSA response to treatment (p=0.6). In contrast, increased serum/plasma levels of MIC-1 after cycle one of chemotherapy were associated with DTX resistance (p=0.006) and shorter overall survival (p=0.002). Conclusions: These results suggest that both AGR2 and MIC-1 play a role in DTX resistance in HRPC. Furthermore, changes in serum/plasma MIC-1 levels are associated with DTX resistance in a correlative human cohort. While a larger study is needed to validate these findings, the data provide evidence that MIC-1 as a potential predictive biomarker and both MIC-1 and AGR2 are potential therapeutic targets in DTX resistance. No significant financial relationships to disclose.

Ixabepilone (Epothilone B Analogue BMS-247550) Is Active in Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer: A Southwest Oncology Group Trial S0111

2005 ◽  
Vol 23 (34) ◽  
pp. 8724-8729 ◽  
Author(s):  
Maha Hussain ◽  
Catherine M. Tangen ◽  
Primo N. Lara ◽  
Ulka N. Vaishampayan ◽  
Daniel P. Petrylak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Performance Status ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Hematologic Toxicity ◽  
Hormone Refractory Prostate Cancer ◽  
Grade 5 ◽  
Psa Response ◽  
Hormone Refractory ◽  
Grade 3

Purpose The epothilones are a new class of tubulin-polymerizing agents with activity in taxane-sensitive and resistant tumor models. We evaluated ixabepilone (BMS-247550) in patients with metastatic hormone-refractory prostate cancer (HRPC). Methods Eligible patients had chemotherapy-naive metastatic HRPC, a Zubrod performance status of 0 to 2, and adequate organ function. All patients received BMS-247550 at 40 mg/m2 over 3 hours every 3 weeks. The primary end point was proportion of patients achieving a prostate-specific antigen (PSA) response. Results Forty-eight patients with metastatic HRPC were registered. Forty-two patients were eligible, with a median age of 73 years and a median PSA level of 111 ng/mL; 78% had bone-only or bone and soft tissue metastases, and 88% had objective radiologic disease progression at registration. Grade 3 and 4 adverse events (AEs) occurred in 16 and three patients, respectively. All grade 4 toxicities were neutropenia or leukopenia. The most frequent grade 3 AEs were neuropathy (eight patients), hematologic toxicity (seven patients), flu-like symptoms, and infection (five patients each). There were no grade 3/4 thrombocytopenia or grade 5 AEs. There were 14 confirmed PSA responses (33%; 95% CI, 20% to 50%); 72% of PSA responders had declines greater than 80%, and two patients achieved an undetectable PSA. The estimated median progression-free survival is 6 months (95% CI, 4 to 8 months), and the median survival is 18 months (95% CI, 13 to 24 months). Conclusion Ixabepilone has demonstrated activity in patients with chemotherapy-naive metastatic HRPC. Major toxicities were neutropenia and neuropathy. Further testing to define its activity relative to standard therapy is warranted.

Multicenter Randomized Phase II Study of Two Schedules of Docetaxel, Estramustine, and Prednisone Versus Mitoxantrone Plus Prednisone in Patients With Metastatic Hormone-Refractory Prostate Cancer

2005 ◽  
Vol 23 (15) ◽  
pp. 3343-3351 ◽  
Author(s):  
Stéphane Oudard ◽  
Eugeniu Banu ◽  
Philippe Beuzeboc ◽  
Eric Voog ◽  
Louis Marie Dourthe ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Specific Antigen ◽  
Hormone Refractory Prostate Cancer ◽  
Randomized Phase Ii ◽  
Psa Response ◽  
Psa Progression ◽  
Hormone Refractory ◽  
To Receive

Purpose Mitoxantrone-corticosteroid is currently the standard palliative treatment in hormone-refractory prostate cancer (HRPC) patients. Recent clinical trials documented the high activity of the docetaxel-estramustine combination. We conducted a randomized phase II study to evaluate prostate-specific antigen (PSA) response (primary end point) and safety of two docetaxel-estramustine-prednisone (DEP) regimens and mitoxantrone-prednisone (MP). Patients and Methods One hundred thirty metastatic HRPC patients were randomly assigned to receive docetaxel (70 mg/m2 on day 2 or 35 mg/m2 on days 2 and 9 of each 21-day cycle) and estramustine (280 mg PO tid on days 1 through 5 and 8 through 12) or mitoxantrone 12 mg/m2 every 3 weeks; all patients received prednisone (10 mg daily). Results One hundred twenty-seven patients were assessable for PSA response and safety. A ≥ 50% PSA decline was found in a greater percentage of patients in the docetaxel arms (67% and 63%) compared with MP (18%; P = .0001). Median time to PSA progression was five times longer with DEP than with MP (8.8 and 9.3 v 1.7 months, respectively; P = .000001). Overall survival was better in the docetaxel arms (18.6 and 18.4 months) compared with the MP arm (13.4 months), but not significantly so (P = .3). Crossover rates differed significantly among treatment arms (16%, 10%, and 48% in arms A, B, and C, respectively; P = .00001). Treatment-related toxicities were mild and mainly hematologic. Conclusion The results of this randomized phase II study showed significantly higher PSA decline ≤ 50% and longer times to progression in HRPC patients receiving DEP-based chemotherapy than MP, and that DEP could be proposed in this setting.

Prospective Randomized Study Comparing Docetaxel, Estramustine, and Prednisone With Docetaxel and Prednisone in Metastatic Hormone-Refractory Prostate Cancer

2008 ◽  
Vol 26 (32) ◽  
pp. 5261-5268 ◽  
Author(s):  
Jean-Pascal Machiels ◽  
Filomena Mazzeo ◽  
Marylene Clausse ◽  
Bertrand Filleul ◽  
Luc Marcelis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Response Rate ◽  
Randomized Study ◽  
Specific Antigen ◽  
Hormone Refractory Prostate Cancer ◽  
Serious Adverse Events ◽  
Psa Response ◽  
Psa Progression ◽  
Hormone Refractory ◽  
Grade 3

PurposeTo assess the efficacy and toxicity of the addition of estramustine to docetaxel (D) for the treatment of metastatic hormone-refractory prostate cancer.Patients and MethodsOne hundred fifty patients were randomly assigned to D alone (35 mg/m2on days 2 and 9, every 3 weeks) or D in combination with estramustine (D/E; 280 mg orally three times a day on days 1 to 5 and 8 to 12, every 3 weeks). All patients received prednisone (10 mg/d). The primary end point was prostate-specific antigen (PSA) response rate, which was defined as a decrease in PSA ≥ 50% from baseline. The study was powered to test the hypothesis that D/E would improve the PSA response rate by 25%.ResultsThe PSA response rate was not statistically different between the two groups. PSA of less than 4 ng/mL occurred in 29 (41%) of 71 patients receiving D/E and in 17 (25%) of 69 patients receiving D (P = .05). No significant differences were found for median time to PSA progression (D/E, 6.9 months; D, 7.3 months) or median overall survival time (D/E, 19.3 months; D, 21 months). More patients had at least one grade 3 or 4 toxicity with D/E (45%) compared with D (21%; P = .005), mainly as a result of grade 3 or 4 GI toxicity (P = .05). Serious adverse events were more frequent with D/E (n = 20) than with D (n = 9; P = .04).ConclusionThe addition of estramustine to weekly D does not provide any clinically relevant advantage. Both regimens are well tolerated, although the toxicity profile favors D without estramustine.

scholarly journals An evaluation of high-doses ketoconazole with hydrocortisone substitution in hormone-refractory prostate cancer

2005 ◽  
Vol 52 (4) ◽  
pp. 51-54
Author(s):  
Djordje Argirovic
Keyword(s):  
Prostate Cancer ◽  
Median Duration ◽  
Progressive Disease ◽  
Salvage Chemotherapy ◽  
High Dose ◽  
Hormone Refractory Prostate Cancer ◽  
Time To Progression ◽  
Psa Response ◽  
Hormone Refractory ◽  
High Doses

We investigated the efficacy of ketoconazole, an inhibitor of testicular and adrenal biosynthesis, for treating patients with progression of hormonerefractory prostate cancer. The study comprised 35 patients with progressive disease despite salvage treatment with estramustine with or without vinblastine. Treatment consisted high-doses ketoconazole (400 mg three times daily) and hydrocortisone substitution. Patients were monitored clinically and with serial PSA measurements every 3 months. The principal endpoint of the study was PSA response to applied therapy. Of the 35 patients, 18 (51.4%) showed a decrease in PSA 50% with a median duration of 30 weeks (range 6-60 weeks). A PSA reduction 50% was seen in 15 of 31 patients (48.4%) with established metastasis. Twelve patients (34.2%), all of whom had metastasis, exhibited a PSA decrease 80% with median duration of 9 months (range 3-48 months). The median time to progression was 6.3 months (range 0-27 months) and the median survival time was 12.5 months (range 3-48 months). Twelve (34.3%) reported toxicity related to ketoconazole, whereas no patients required discontinuation of therapy. It is apparent from this study that a reasonable percentage of patients failing salvage chemotherapy (estramustine with or without vinblastine) respond favorably to high-dose ketoconazole and that toxicity is mild. In the absence of studies demonstrating better survival with chemotherapy, we believe that a trail of ketoconazole should be considered when progression of PSA occurs, following initial hormonal androgen deprivation.

Phase II screening study to assess the combination of a LHRH analogue, dexamethasone and a somatostatin analogue versus a LHRH analogue with dexamethasone in hormone refractory prostate cancer patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4565-4565 ◽  
Author(s):  
F. Silva ◽  
F. M. Calais Da Silva ◽  
F. Gonçalves ◽  
T. Oliver
Keyword(s):  
Prostate Cancer ◽  
Median Time ◽  
Median Duration ◽  
Prostatic Carcinoma ◽  
Response Rate ◽  
Hormone Refractory Prostate Cancer ◽  
Treatment Regimens ◽  
Psa Response ◽  
Psa Progression ◽  
Hormone Refractory

4565 Background: Hormonal changes and the possible resulting imbalance between androgen and estrogen levels in elderly men may play an important role in prostatic pathogenesis. Androgen suppression can induce regression of prostatic carcinoma. Ample laboratory and clinical research have contributed to evidence that a direct link exists between prostatic cell growth, prostatic carcinoma cell growth and hormones, mainly testicular androgens. As far as prostatic cancer is concerned, we know that SMS blocks GH, PRL, tissular growth factors (TGF) and that it has a direct antiproliferative growth cellular growth effect. The simultaneous administration of depot forms of SMS and LHRH analogues induced the greatest decrease in tumor growth. Methods: A randomized Phase II trial was carried out in M0 (PSA ≥ 20 ng/ml) and M1 patients with hormone refractory prostate cancer to simultaneously screen decapeptyl and dexamethasone, both with and without somatulin (120 mg every 4 weeks), with respect to PSA response rate, time to PSA progression, duration of survival and toxicity. Results: 72 patients with a median time PSA of 77 ng/ml were randomized by 3 institutions, 35 to decapeptyl, dexamethasone and somatulin (DDS) and 37 to decapeptyl and dexamethasone (DD). 21 of 33 (64%) patients on DDS and 21 of 32 on DD (66%) had a PSA response (a decrease of at least 50 % as compared to baseline). The median duration of PSA response was 6.6 months on DDS and 3.4 months on DD. Overall, the median time to PSA progression was 5.8 months on DDS and 1.8 months on DD. The median duration of survival has not yet been reached. Both treatment regimens were well tolerated. The most frequent toxicities on DDS and DD were hot flushes (27%, 10%), gastrointestinal (18%, 20%), and skin complaints (12%, 10%). Conclusions: Both treatment regimens are active and safe in the treatment of hormone refractory prostate cancer. Although the PSA response rate is about 65%, the median duration of response and median time to progression were longer in the somatulin arm; so, the data suggest a possible advantage of DDS with respect to both the duration of the PSA response and the time to PSA progression. Further follow-up is required to assess survival. No significant financial relationships to disclose.

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