Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases
Autor: | D. Jones, A. A. Meluch, Lorenzo Cohen, Michael J. Morris, Marcella M. Johnson, Lon Smith, Shi Ming Tu, Lance C. Pagliaro, Peter F. Thall, Nizar M. Tannir, Sun Jin Kim, Christopher J. Logothetis, Corazon D. Bucana, Patricia Troncoso, William Oh, Sijin Wen, Isaiah J. Fidler, Paul Mathew |
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Rok vydání: | 2007 |
Předmět: |
Oncology
Adult Male Cancer Research medicine.medical_specialty medicine.medical_treatment Bone Neoplasms Docetaxel Disease-Free Survival Piperazines Bone remodeling Cohort Studies Placebos Receptor Platelet-Derived Growth Factor beta Prostate cancer Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Receptors Platelet-Derived Growth Factor Castration Neoplasm Metastasis neoplasms Aged Aged 80 and over Chemotherapy Taxane business.industry Bone metastasis Prostatic Neoplasms Imatinib Middle Aged medicine.disease Imatinib mesylate Endocrinology Pyrimidines Benzamides Imatinib Mesylate Taxoids business medicine.drug |
Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 13(19) |
ISSN: | 1078-0432 |
Popis: | Purpose: To further assess preclinical and early clinical evidence that imatinib mesylate, a platelet-derived growth factor receptor (PDGFR) inhibitor, modulates taxane activity in prostate cancer and bone metastases, a randomized study was conducted. Experimental Design: Men with progressive castration-resistant prostate cancer with bone metastases (n = 144) were planned for equal randomization to i.v. 30 mg/m2 docetaxel on days 1, 8, 15, and 22 every 42 days with 600 mg imatinib daily or placebo, for an improvement in median progression-free survival from 4.5 to 7.5 months (two-sided α = 0.05 and β = 0.20). Secondary end points included differential toxicity and bone turnover markers, tumor phosphorylated PDGFR (p-PDGFR) expression, and modulation of p-PDGFR in peripheral blood leukocytes. Results: Accrual was halted early because of adverse gastrointestinal events. Among 116 evaluable men (57 docetaxel + imatinib; 59 docetaxel + placebo), respective median times to progression were 4.2 months (95% confidence interval, 3.1-7.5) and 4.2 months (95% confidence interval, 3.0-6.8; P = 0.58, log-rank test). Excess grade 3 toxicities (n = 23) in the docetaxel + imatinib group were principally fatigue and gastrointestinal. Tumor p-PDGFR expression was observed in 12 of 14 (86%) evaluable bone specimens. In peripheral blood leukocytes, p-PDGFR reduction was more likely in docetaxel + imatinib–treated patients compared with docetaxel + placebo (P < 0.0001), as were reductions in urine N-telopeptides (P = 0.004) but not serum bone-specific alkaline phosphatase (P = 0.099). Conclusions: These clinical and translational results question the value of PDGFR inhibition with taxane chemotherapy in prostate cancer bone metastases and are at variance with the preclinical studies. This discordance requires explanation. |
Databáze: | OpenAIRE |
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