A Phase II Clinical Trial of Neoadjuvant Ketoconazole and Docetaxel Chemotherapy Before Radical Prostatectomy in High Risk Patients

Womble, Paul R.; Vanveldhuizen, Peter J.; Nisbet, Alan A.; Reed, Greg; Thrasher, J. Brantley; Holzbeierlein, Jeffrey M.

doi:10.1016/j.juro.2011.04.087

Cited by 29 publications

(12 citation statements)

References 25 publications

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“…docetaxel. 22 Neoadjuvant ketoconazole and docetaxel chemotherapy has been reported to achieve 36% of PSA-free survival, 23 which showed no remarkable improvement compared with the previous literatures.…”

Section: Discussionmentioning

confidence: 93%

Safety and effectiveness of neoadjuvant luteinizing hormone-releasing hormone agonist plus low-dose estramustine phosphate in high-risk prostate cancer: a prospective single-arm study

Koie

Οhyama

Yamamoto

et al. 2012

Prostate Cancer Prostatic Dis

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BACKGROUND: Radical prostatectomy (RP) has limited cancer control potential for the patient with high-risk prostate cancer (Pca). We prospectively examined the efficacy and safety of neoadjuvant therapy with luteinizing hormone-releasing hormone (LHRH) agonist þ low-dose estramustine phosphate (EMP) (LHRH þ EMP) followed by RP. METHODS: High-risk Pca was defined by the D'Amico stratification system. A total of 142 patients with high-risk Pca were enrolled in this trial from September 2005 to March 2011. The LHRH þ EMP therapy included administration of LHRH agonist and 280 mg day --1 EMP for 6 months before RP. Pathological cancer-free (pT0) rate on the surgical specimen was the primary end point. Secondary end points were PSA-free survival and toxicity. RESULTS: The average patient age was 67.4 years (interquartile range (IQR) 72, 65) and the median initial PSA level was 14.80 ng ml --1 (IQR 26.22, 7.13). The median Gleason score was 9 (IQR 9, 7) and 97 patients (68.3%) had clinical stage T2c or T3. All patients completed 6 months of LHRH þ EMP neoadjuvant therapy with no delays in RP. Seven patients (4.9%) achieved pT0. Surgical margins were negative in 125 patients (87.0%). At a median follow-up period of 34.9 months, PSA-free survival was 84.3%. No serious adverse events were reported during the study and there were no toxicityrelated deaths. CONCLUSIONS: Six months of LHRH þ EMP neoadjuvant therapy followed by RP is safe and oncological outcomes are acceptable. Although this study was a single-arm trial with a relatively short follow-up, this treatment may have a potential to improve PSA-free survival in high-risk Pca patients. Further clinical trials are warranted.

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Section: Discussionmentioning

confidence: 93%

Safety and effectiveness of neoadjuvant luteinizing hormone-releasing hormone agonist plus low-dose estramustine phosphate in high-risk prostate cancer: a prospective single-arm study

Koie

Οhyama

Yamamoto

et al. 2012

Prostate Cancer Prostatic Dis

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“…Over the past decade, several studies have attempted to integrate immunotherapy into the existing standard treatments, such as ADT, radiotherapy, or chemotherapy, to improve overall survival in tumorbearing hosts (37)(38)(39)(40). The rationale for a reciprocal potentiating action of ADT and immunotherapy is promising, but the results have not been convincing so far (33,41,42).…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse

Liang

et al. 2016

Sci. Transl. Med.

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Surgical and medical androgen deprivation therapy (ADT) is a cornerstone for prostate cancer treatment, but relapse usually occurs. We herein show that orchiectomy synergizes with immunotherapy, whereas the more widely used treatment of medical ADT involving androgen receptor (AR) antagonists suppresses immunotherapy. Furthermore, we observed that the use of medical ADT could unexpectedly impair the adaptive immune responses through interference with initial T cell priming rather than in the reactivation or expansion phases. Mechanistically, we have revealed that inadvertent immunosuppression might be potentially mediated by a receptor shared with g-aminobutyric acid. Our data demonstrate that the timing and dosing of antiandrogens are critical to maximizing the antitumor effects of combination therapy. This study highlights an underappreciated mechanism of AR antagonist-mediated immunosuppression and provides a new strategy to enhance immune response and prevent the relapse of advanced prostate cancer.

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“…11 C-acetate-PET/CT may also help to identify patients likely to benefit from multimodality therapy. Currently, studies on neoadjuvant therapy before radical prostatectomy focus on clinical parameters (PSA, biopsy Gleason score, and clinical stage) and are investigational (30,31). While clinical parameters may identify patients with high risk of metastasis, they do not provide confirmation of metastasis as PET/CT may.…”

Section: Discussionmentioning

confidence: 99%

2038 11c-Acetate Pet/Ct Before Radical Prostatectomy: Nodal Staging and Treatment Failure Prediction

et al. 2012

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Despite early detection programs, many patients with prostate cancer present with intermediate-or high-risk disease. We prospectively investigated whether 11 C-acetate PET/CT predicts lymphnode (LN) metastasis and treatment failure in men planned for radical prostatectomy.Methods-107 men with intermediate-or-high-risk localized prostate cancer with negative conventional imaging underwent PET/CT with 11 C-acetate. Five underwent LN staging only and 102 LN staging and prostatectomy. PET/CT findings were correlated with pathologic nodal status. Treatment-failure-free survival (TFFS) was estimated by Kaplan-Meier method. The ability of PET/CT to predict outcomes was evaluated by multivariate Cox proportional hazards analysis.Results-PET/CT was positive for pelvic LN or distant metastasis in 36 of 107 patients (33.6%). LN metastasis was present histopathologically in 25 (23.4%). The sensitivity, specificity, positiveand negative-predictive values of PET/CT for detecting LN metastasis were 68.0%, 78.1%, 48.6% and 88.9% respectively. 64 patients failed: 25 with metastasis, 17 with persistent postprostatectomy prostate specific antigen (PSA) >0.20 ng/mL, and 22 with biochemical recurrence (PSA >0.20 ng/mL after nadir) during follow-up for a median of 44.0 months. TFFS was worse in PET-positive than in PET-negative patients (p<0.0001) and in those with false-positive versus true-negative scans (p<0.01), suggesting that PET may have demonstrated nodal disease not removed surgically or identified pathologically. PET positivity independently predicted failure in preoperative (hazard ratio=3.26, p<0.0001) and postoperative (HR=3.07, p=0.0001) multivariate models.Conclusion-In patients planned for or completing prostatectomy, 11 C-acetate-PET/CT detects LN metastasis not identified by conventional imaging and independently predicts TTFS.

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A Phase II Clinical Trial of Neoadjuvant Ketoconazole and Docetaxel Chemotherapy Before Radical Prostatectomy in High Risk Patients

Abstract: Neoadjuvant ketoconazole combined with docetaxel has appreciable but acceptable toxicity with 73% of the patients completing all 4 courses of therapy. Of those who underwent radical prostatectomy 36% remained continuously biochemically free of recurrence at a median followup of 18 months.

Cited by 29 publications

References 25 publications

Safety and effectiveness of neoadjuvant luteinizing hormone-releasing hormone agonist plus low-dose estramustine phosphate in high-risk prostate cancer: a prospective single-arm study

Safety and effectiveness of neoadjuvant luteinizing hormone-releasing hormone agonist plus low-dose estramustine phosphate in high-risk prostate cancer: a prospective single-arm study

Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse

2038 11c-Acetate Pet/Ct Before Radical Prostatectomy: Nodal Staging and Treatment Failure Prediction

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