Antiandrogen Withdrawal Alone or in Combination With Ketoconazole in Androgen-Independent Prostate Cancer Patients: A Phase III Trial (CALGB 9583)

2004 ◽  
Vol 22 (6) ◽  
pp. 1025-1033 ◽  
Author(s):  
Eric J. Small ◽  
Susan Halabi ◽  
Nancy A. Dawson ◽  
Walter M. Stadler ◽  
Brian I. Rini ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progressive Disease ◽  
Specific Antigen ◽  
Phase Iii ◽  
Adrenal Androgen ◽  
Phase Iii Trial ◽  
Androgen Ablation ◽  
Psa Response ◽  
Androgen Levels ◽  
Androgen Independent

Purpose Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of ≥ 50%) in 15% to 30% of androgen-independent prostate cancer (AiPCa) patients. Thereafter, adrenal androgen ablation with agents such as ketoconazole (K) is commonly utilized. The therapeutic effect of AAWD alone was compared with simultaneous AAWD and K therapy. Patients and Methods AiPCa patients were randomized to undergo AAWD alone (n = 132), or together with K (400 mg orally [po] tid) and hydrocortisone (30 mg po each morning, 10 mg po each evening; n = 128). Patients who developed progressive disease after AAWD alone were eligible for deferred treatment with K. Results Eleven percent of patients undergoing AAWD alone had a PSA response, compared to 27% of patients who underwent AAWD and simultaneous K (P = .0002). Objective responses were observed in 2% of patients treated with AAWD alone compared to 20% in patients treated with AAWD/K (P = .02). There was no difference in survival. PSA and objective responses were observed in 32% and 7%, respectively, of patients receiving deferred K, and were more common in patients with prior AAWD response. Treatment with K was well tolerated, and resulted in a decline in adrenal androgen levels, which rose at the time of disease progression. Conclusion K has modest activity in AiPCa patients, while AAWD alone has minimal activity. Adrenal androgen levels fall with treatment with K and then climb at the time of progression, suggesting that progressive disease while on K may be due to tachyphylaxis to the adrenolytic properties of K.

scholarly journals Phase III Trial of Androgen Ablation With or Without Three Cycles of Systemic Chemotherapy for Advanced Prostate Cancer

2008 ◽  
Vol 26 (36) ◽  
pp. 5936-5942 ◽  
Author(s):  
Randall E. Millikan ◽  
Sijin Wen ◽  
Lance C. Pagliaro ◽  
Melissa A. Brown ◽  
Brenda Moomey ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Standard Therapy ◽  
Metastatic Prostate Cancer ◽  
Specific Antigen ◽  
Hormone Treatment ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Androgen Ablation ◽  
Castrate Resistant

Purpose We conducted a phase III trial in patients with previously untreated metastatic prostate cancer to test the hypothesis that three 8-week cycles of ketoconazole and doxorubicin alternating with vinblastine and estramustine, given in addition to standard androgen deprivation, would delay the appearance of castrate-resistant disease. Patients and Methods Eligible patients had metastatic prostate cancer threatening enough to justify sustained androgen ablation and were fit enough for chemotherapy. The primary end point was time to castrate-resistant progression as shown by increasing prostate-specific antigen, new radiographic lesions, worsening cancer-related symptoms, or receipt of any other systemic therapy. Results Three hundred six patients were registered; 286 are reported. Median time to progression was 24 months (95% CI, 18 to 39 months) in the standard therapy arm, and 35 months (95% CI, 26 to 44 months) in the chemohormonal group (P = .39). At median follow-up of 6.4 years, overall survival was 5.4 years (95% CI, 4.7 to 7.8 years) in the standard therapy arm versus 6.1 years (95% CI, 5.1 to 10.1 years; P = .41). Prostate-specific antigen kinetics at the time of androgen ablation and the nadir after hormone treatment were strongly correlated with survival. Chemotherapy significantly increased the burden of therapy, with 51% of patients experiencing an adverse event of grade 3 or worse, especially thromboembolic events. Conclusion There is no role for ketoconazole and doxorubicin alternating with vinblastine and estramustine before emergence of a castrate-resistant phenotype.

Randomized, Multicenter, Phase II Trial of Two Multicomponent Regimens in Androgen-Independent Prostate Cancer

2003 ◽  
Vol 21 (5) ◽  
pp. 878-883 ◽  
Author(s):  
Randall Millikan ◽  
Peter F. Thall ◽  
Sang-Joon Lee ◽  
Donnah Jones ◽  
M.W. Cannon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Median Survival ◽  
Phase Ii ◽  
First Generation ◽  
Specific Antigen ◽  
Community Setting ◽  
Phase Iii ◽  
Group Setting ◽  
Clinically Significant ◽  
Androgen Independent

Purpose: Several multicomponent regimens have been reported to be useful in advanced androgen-independent prostate cancer. We used a randomized phase II design to evaluate and compare two such regimens. Patients were accrued primarily in the community setting. Patients and Methods: Patients with progressive, androgen-independent prostate cancer were randomly assigned to one of two treatments: either ketoconazole/doxorubicin alternating with vinblastine/estramustine (KA/VE) or paclitaxel, estramustine, and oral etoposide (TEE). Patients were prospectively stratified on the basis of disease volume. The primary end points were response and overall survival time. Results: A total of 75 patients were registered; 71 are included in the analysis. By the criterion of an 80% prostate-specific antigen reduction maintained for at least 8 weeks, 11 (30%) of 37 patients in the TEE arm responded, whereas 11 (32%) of 34 assigned to KA/VE responded. Median survival was 16.9 months (95% confidence interval [CI], 10.5 to 21.2 months) in the TEE arm and 23.4 months (95% CI, 12.9 to 30.6 months) for patients treated with KA/VE. Many patients (24%) failed to complete at least 6 weeks of therapy, including five (8%) treatment-related early deaths. Conclusion: Each of these regimens produced clinically significant responses, and the observed median survival (18.9 months for all 71 patients) compares favorably with previously published results, especially in the community setting. Nonetheless, it is apparent that these first-generation regimens must be applied judiciously, and thus we view efforts at better patient selection and the development of more tolerable therapies as higher priorities than carrying either of these regimens to phase III evaluation in the cooperative group setting.

Use of adrenal androgen levels to predict response to ketoconazole in patients with androgen independent prostate cancer: Results from CALGB 9583

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 4558-4558
Author(s):  
C. J. Ryan ◽  
S. Halabi ◽  
E. Kaplan ◽  
N. Vogelzang ◽  
P. Kantoff ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adrenal Androgen ◽  
Androgen Levels ◽  
Androgen Independent

scholarly journals Pretreatment neutrophil-to-lymphocyte ratio and Mean Platelet Volume in castration-resistant prostate cancer patients treated with first-line docetaxel

2019 ◽  
Author(s):  
Barbaros Başeskioğlu ◽  
Berna Bozkurt Duman ◽  
Bülent Yıldız ◽  
Timuçin Çil ◽  
Murat Dinçer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mean Platelet Volume ◽  
Specific Antigen ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Platelet Volume ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Castration Resistant ◽  
Psa Response

Abstract Background:Patients who have evidence of disease progression (eg, increase in serum prostate-specific antigen [PSA], new metastases, progression of existing metastases) while being managed with androgen deprivation therapy (ADT) are considered to have castration-resistant disease. Docetaxel (75 mg/m2) given every three weeks in combination with daily prednisone (5 mg twice a day) significantly prolonged overall survival compared with mitoxantrone plus prednisone in the TAX 327 phase III trial [3]. Based upon those results, docetaxel plus prednisone has become the standard initial regimen when chemotherapy is indicated for CRPC Methods: Inflammation-based markers, such as the Neutrophile/Lymphocyte Ratio (NLR), are widely available and inexpensive measurements that are easy to integrate into pretreatment evaluation. Mean platelet volume (MPV) is a marker of activated platelets is associated some types of cancer including ovarian, gastric cancer. We retrospectively evaluated the predictive impact of neutrophil-lymphocyte ratio (NLR) and MPV as a marker for in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel.Results: A significant correlation was not observed between NLR and PSA response. A significant correlation was not also observed between MPV and PSA response.There no correlation was found between MPV and NLR with total PSA level and response (p:0.355, p:0.673 respectively)Conclusion: . In our study; We didn’t show any correlation between MWP level, NLR ratio and response to Docetaxel therapy A significant correlation was not also observed between NLR , MPV and PSA response.

Effect of Docetaxel in Patients With Hormone-Dependent Prostate-Specific Antigen Progression After Local Therapy for Prostate Cancer

2005 ◽  
Vol 23 (15) ◽  
pp. 3352-3357 ◽  
Author(s):  
Susan Goodin ◽  
Patrick Medina ◽  
Terry Capanna ◽  
Weichung J. Shih ◽  
Sybil Abraham ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Early Stage ◽  
Specific Antigen ◽  
Local Therapy ◽  
Phase Iii ◽  
Early Disease ◽  
Androgen Ablation ◽  
Days Of Therapy ◽  
Psa Progression

Purpose To evaluate docetaxel in the treatment of patients with early-stage prostate cancer with prostate-specific antigen (PSA) progression after local therapy without androgen ablation therapy. Patients and Methods Twenty-five patients with adenocarcinoma of the prostate with PSA progression despite local therapy were treated with 70 mg/m2 docetaxel every 21 days. Treatment was planned for eight cycles. Patients were followed up for effects on PSA, testosterone, and toxicity. Results Twenty-three of 25 patients completed at least one full cycle of therapy. Ten (43%) of 23 patients demonstrated a decrease in PSA by ≥ 50% for at least 4 weeks. The nadir decrease in PSA occurred beyond 150 days of therapy in most patients. Therapy was well tolerated. Grade 4 neutropenia with fever occurred in only six cycles (4.5%). Two patients required 25% dose reductions, both occurring with cycle 6, secondary to increased transaminases in one patient, and grade 3 lacrimation in the other patient. Two patients were removed after the first cycle of therapy due to toxicity (deep venous thrombosis, chest palpitations). Mean testosterone levels were not reduced in 17 patients assessed before and during therapy (P = .12). Conclusion This study demonstrated the activity of docetaxel alone, without androgen ablation, in patients with PSA progression after completion of local therapy. Treatment with docetaxel in this population with early disease progression was well tolerated, biochemically active, and was not androgen ablative. Accrual to national phase III studies in early disease is now critical and should be strongly encouraged to determine the ability of early chemotherapy to improve survival.

Double-Blinded Randomized Study of High-Dose Calcitriol Plus Docetaxel Compared With Placebo Plus Docetaxel in Androgen-Independent Prostate Cancer: A Report From the ASCENT Investigators

2007 ◽  
Vol 25 (6) ◽  
pp. 669-674 ◽  
Author(s):  
Tomasz M. Beer ◽  
Christopher W. Ryan ◽  
Peter M. Venner ◽  
Daniel P. Petrylak ◽  
Gurkamal S. Chatta ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Performance Status ◽  
Specific Antigen ◽  
Hazard Ratio ◽  
High Dose ◽  
Weekly Docetaxel ◽  
End Point ◽  
Psa Response ◽  
Grade 3 ◽  
Androgen Independent

Purpose To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel. Patients and Methods Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m2 intravenously for 3 weeks of a 4-week cycle combined with either 45 μg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later. Results Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%). Conclusion This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.

Response to low-dose ketoconazole and subsequent dose escalation to high-dose ketoconazole in patients with androgen-independent prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4646-4646
Author(s):  
M. Nakabayashi ◽  
W. Xie ◽  
M. M. Regan ◽  
D. M. Jackman ◽  
P. W. Kantoff ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Hormonal Therapy ◽  
Dose Escalation ◽  
Low Dose ◽  
Specific Antigen ◽  
High Dose ◽  
Time To Progression ◽  
Subsequent Dose ◽  
Psa Response ◽  
Androgen Independent

4646 Background: High dose ketoconazole (HDK) in combination with steroids has been recognized as an effective secondary hormonal therapy in androgen independent prostate cancer (AIPC). However, HDK causes more severe adverse events than low dose ketoconazole (LDK). Relatively little is known about the efficacy of LDK in AIPC. We evaluated the efficacy of LDK and of subsequent dose escalation from LDK to HDK as secondary hormonal therapy in patients with AIPC. Methods: We retrospectively identified patients with AIPC in a single institution treated with LDK (200 mg PO TID) as secondary hormonal therapy with or without concomitant steroids. Additionally, patients were identified who received dose escalation to HDK (400 mg PO TID) after experiencing a rising prostate-specific antigen (PSA). Results: 138 patients were eligible for the study. Median age was 64 years (range: 41–84); median PSA at initiation of ketoconazole was 37.4 ng/ml (range: 0.8–2279). Patients received LDK as either second (25.4%), third (50.0%) or fourth (21.7%) line hormonal therapy. Thirty-nine of 138 patients (28.3%, 95% CI 20.9%–36.6%) treated with LDK treatment experienced PSA declines ≥50%. Median duration of LDK was 6.4 months in responders and 2.9 months in non-responders. Dose escalation to HDK subsequently was performed in 55 (40%) patients, seven of whom (12.7%) demonstrated a subsequent PSA decline ≥50% (5 LDK responders and 2 LDK non-responders, respectively). Overall time to progression with LDK with or without dose escalation was 3.5 months (range 0.1+–61 months). The most common reversible adverse effect on LDK was grade 1 or 2 fatigue (12.3%). 41.8% of dose escalation group experienced either aggravation or development of toxicities. The most common toxicities on HDK were nausea (16.4%) and fatigue (14.5%). Conclusions: LDK is associated with a PSA response rate comparable to HDK as secondary hormonal therapy in patients with AIPC, and appears to be less toxic. Few patients responded to the dose escalation from LDK to HDK but durable additional responses occurred in some. No significant financial relationships to disclose.

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