Diethylstilbestrol and docetaxel: A phase II study of tubulin active agents in patients with metastatic, androgen-independent prostate cancer

R. Bruce Montgomery, Peter S. Nelson, Daniel Lin, Christopher Ryan, Mark Garzotto, Tomasz (Tom) Beer

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

BACKGROUND. The addition of diethylstilbestrol to docetaxel modified tubulin composition and improved the response of prostate cancer to chemotherapy in preclinical models. An attempt was made to recapitulate the observations in a clinical trial. METHODS. Twenty-nine patients with progressive, metastatic, chemotherapy-naive androgen-independent prostate cancer were treated with diethylstilbestrol 1 mg daily and 5 mg on the day before docetaxel and docetaxel 36 mg/m2 intravenously weekly for 3 weeks of a 4-week cycle. Prophylactic anticoagulation was used in all patients. Patients were assessed by prostate-specific antigen (PSA) monthly and computed tomography (CT) and bone scans every 3 cycles. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria and PSA decline by >50% maintained for 4 weeks were used to assess activity. RESULTS. The median age was 68 years (range, 56-84 years), Southwest Oncology Group performance status 0 (score range, 0-2), alkaline phosphatase 120 U/L (range, 49-523), hemoglobin (Hgb) 12.6 g/dL (range, 9.2-16.3), PSA 66 ng/dL (range, 4-1962). The median number of cycles administered was 6. Soft tissue metastases were present in 51% of patients and bone metastases in 93%. Twenty-nine patients are evaluable for response. Of these, 20 patients (69%, 95% confidence interval [CI], 49%-85%) had a PSA decline of >50% and the PSA declined by >90% in 12 patients (41%, 95% CI, 23.1%-58.9%). Of 15 patients with measurable disease, 6 (40%, 95% CI, 23.5%-61%) had a partial response. Median time to progression was 6 months (range, 3-19 months). Fifteen patients (51%) suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid-induced ulcer. Six patients developed thrombosis and of those tested 75% had Factor V mutations. Pretreatment PSA, performance status, Hgb, and alkaline phosphatase had no impact on the likelihood of response. CONCLUSIONS. The combination of diethylstilbestrol and docetaxel produces a significant level of activity, measured by PSA decline and measurable disease response rate, and except for venous thrombosis the toxicity appears similar to that seen with docetaxel plus prednisone. These results suggest that tubulin modulation with diethylstilbestrol may improve the therapeutic efficacy of docetaxel and the combination is worthy of further study.

Original languageEnglish (US)
Pages (from-to)996-1002
Number of pages7
JournalCancer
Volume110
Issue number5
DOIs
StatePublished - Sep 1 2007

Fingerprint

docetaxel
Diethylstilbestrol
Proxy
Tubulin
Androgens
Prostatic Neoplasms
Prostate-Specific Antigen
Confidence Intervals
Alkaline Phosphatase
Hemoglobins
Neoplasm Metastasis
Bone and Bones
Drug Therapy

Keywords

  • Chemotherapy
  • Diethylstilbestrol
  • Docetaxel
  • Estrogen
  • Hormone-refractory prostate cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Diethylstilbestrol and docetaxel : A phase II study of tubulin active agents in patients with metastatic, androgen-independent prostate cancer. / Montgomery, R. Bruce; Nelson, Peter S.; Lin, Daniel; Ryan, Christopher; Garzotto, Mark; Beer, Tomasz (Tom).

In: Cancer, Vol. 110, No. 5, 01.09.2007, p. 996-1002.

Research output: Contribution to journalArticle

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title = "Diethylstilbestrol and docetaxel: A phase II study of tubulin active agents in patients with metastatic, androgen-independent prostate cancer",
abstract = "BACKGROUND. The addition of diethylstilbestrol to docetaxel modified tubulin composition and improved the response of prostate cancer to chemotherapy in preclinical models. An attempt was made to recapitulate the observations in a clinical trial. METHODS. Twenty-nine patients with progressive, metastatic, chemotherapy-naive androgen-independent prostate cancer were treated with diethylstilbestrol 1 mg daily and 5 mg on the day before docetaxel and docetaxel 36 mg/m2 intravenously weekly for 3 weeks of a 4-week cycle. Prophylactic anticoagulation was used in all patients. Patients were assessed by prostate-specific antigen (PSA) monthly and computed tomography (CT) and bone scans every 3 cycles. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria and PSA decline by >50{\%} maintained for 4 weeks were used to assess activity. RESULTS. The median age was 68 years (range, 56-84 years), Southwest Oncology Group performance status 0 (score range, 0-2), alkaline phosphatase 120 U/L (range, 49-523), hemoglobin (Hgb) 12.6 g/dL (range, 9.2-16.3), PSA 66 ng/dL (range, 4-1962). The median number of cycles administered was 6. Soft tissue metastases were present in 51{\%} of patients and bone metastases in 93{\%}. Twenty-nine patients are evaluable for response. Of these, 20 patients (69{\%}, 95{\%} confidence interval [CI], 49{\%}-85{\%}) had a PSA decline of >50{\%} and the PSA declined by >90{\%} in 12 patients (41{\%}, 95{\%} CI, 23.1{\%}-58.9{\%}). Of 15 patients with measurable disease, 6 (40{\%}, 95{\%} CI, 23.5{\%}-61{\%}) had a partial response. Median time to progression was 6 months (range, 3-19 months). Fifteen patients (51{\%}) suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid-induced ulcer. Six patients developed thrombosis and of those tested 75{\%} had Factor V mutations. Pretreatment PSA, performance status, Hgb, and alkaline phosphatase had no impact on the likelihood of response. CONCLUSIONS. The combination of diethylstilbestrol and docetaxel produces a significant level of activity, measured by PSA decline and measurable disease response rate, and except for venous thrombosis the toxicity appears similar to that seen with docetaxel plus prednisone. These results suggest that tubulin modulation with diethylstilbestrol may improve the therapeutic efficacy of docetaxel and the combination is worthy of further study.",
keywords = "Chemotherapy, Diethylstilbestrol, Docetaxel, Estrogen, Hormone-refractory prostate cancer",
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T2 - A phase II study of tubulin active agents in patients with metastatic, androgen-independent prostate cancer

AU - Montgomery, R. Bruce

AU - Nelson, Peter S.

AU - Lin, Daniel

AU - Ryan, Christopher

AU - Garzotto, Mark

AU - Beer, Tomasz (Tom)

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N2 - BACKGROUND. The addition of diethylstilbestrol to docetaxel modified tubulin composition and improved the response of prostate cancer to chemotherapy in preclinical models. An attempt was made to recapitulate the observations in a clinical trial. METHODS. Twenty-nine patients with progressive, metastatic, chemotherapy-naive androgen-independent prostate cancer were treated with diethylstilbestrol 1 mg daily and 5 mg on the day before docetaxel and docetaxel 36 mg/m2 intravenously weekly for 3 weeks of a 4-week cycle. Prophylactic anticoagulation was used in all patients. Patients were assessed by prostate-specific antigen (PSA) monthly and computed tomography (CT) and bone scans every 3 cycles. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria and PSA decline by >50% maintained for 4 weeks were used to assess activity. RESULTS. The median age was 68 years (range, 56-84 years), Southwest Oncology Group performance status 0 (score range, 0-2), alkaline phosphatase 120 U/L (range, 49-523), hemoglobin (Hgb) 12.6 g/dL (range, 9.2-16.3), PSA 66 ng/dL (range, 4-1962). The median number of cycles administered was 6. Soft tissue metastases were present in 51% of patients and bone metastases in 93%. Twenty-nine patients are evaluable for response. Of these, 20 patients (69%, 95% confidence interval [CI], 49%-85%) had a PSA decline of >50% and the PSA declined by >90% in 12 patients (41%, 95% CI, 23.1%-58.9%). Of 15 patients with measurable disease, 6 (40%, 95% CI, 23.5%-61%) had a partial response. Median time to progression was 6 months (range, 3-19 months). Fifteen patients (51%) suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid-induced ulcer. Six patients developed thrombosis and of those tested 75% had Factor V mutations. Pretreatment PSA, performance status, Hgb, and alkaline phosphatase had no impact on the likelihood of response. CONCLUSIONS. The combination of diethylstilbestrol and docetaxel produces a significant level of activity, measured by PSA decline and measurable disease response rate, and except for venous thrombosis the toxicity appears similar to that seen with docetaxel plus prednisone. These results suggest that tubulin modulation with diethylstilbestrol may improve the therapeutic efficacy of docetaxel and the combination is worthy of further study.

AB - BACKGROUND. The addition of diethylstilbestrol to docetaxel modified tubulin composition and improved the response of prostate cancer to chemotherapy in preclinical models. An attempt was made to recapitulate the observations in a clinical trial. METHODS. Twenty-nine patients with progressive, metastatic, chemotherapy-naive androgen-independent prostate cancer were treated with diethylstilbestrol 1 mg daily and 5 mg on the day before docetaxel and docetaxel 36 mg/m2 intravenously weekly for 3 weeks of a 4-week cycle. Prophylactic anticoagulation was used in all patients. Patients were assessed by prostate-specific antigen (PSA) monthly and computed tomography (CT) and bone scans every 3 cycles. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria and PSA decline by >50% maintained for 4 weeks were used to assess activity. RESULTS. The median age was 68 years (range, 56-84 years), Southwest Oncology Group performance status 0 (score range, 0-2), alkaline phosphatase 120 U/L (range, 49-523), hemoglobin (Hgb) 12.6 g/dL (range, 9.2-16.3), PSA 66 ng/dL (range, 4-1962). The median number of cycles administered was 6. Soft tissue metastases were present in 51% of patients and bone metastases in 93%. Twenty-nine patients are evaluable for response. Of these, 20 patients (69%, 95% confidence interval [CI], 49%-85%) had a PSA decline of >50% and the PSA declined by >90% in 12 patients (41%, 95% CI, 23.1%-58.9%). Of 15 patients with measurable disease, 6 (40%, 95% CI, 23.5%-61%) had a partial response. Median time to progression was 6 months (range, 3-19 months). Fifteen patients (51%) suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid-induced ulcer. Six patients developed thrombosis and of those tested 75% had Factor V mutations. Pretreatment PSA, performance status, Hgb, and alkaline phosphatase had no impact on the likelihood of response. CONCLUSIONS. The combination of diethylstilbestrol and docetaxel produces a significant level of activity, measured by PSA decline and measurable disease response rate, and except for venous thrombosis the toxicity appears similar to that seen with docetaxel plus prednisone. These results suggest that tubulin modulation with diethylstilbestrol may improve the therapeutic efficacy of docetaxel and the combination is worthy of further study.

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KW - Diethylstilbestrol

KW - Docetaxel

KW - Estrogen

KW - Hormone-refractory prostate cancer

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