Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases Journal Article
| Authors: | Mathew, P.; Thall, P. F.; Bucana, C. D.; Oh, W. K.; Morris, M. J.; Jones, D. M.; Johnson, M. M.; Wen, S.; Pagliaro, L. C.; Tannir, N. M.; Tu, S. M.; Meluch, A. A.; Smith, L.; Cohen, L.; Kim, S. J.; Troncoso, P.; Fidler, I. J.; Logothetis, C. J. |
| Article Title: | Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases |
| Abstract: | 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 wasm ore 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. © 2007 American Association for Cancer Research. |
| Keywords: | adult; cancer chemotherapy; controlled study; protein expression; protein phosphorylation; treatment outcome; treatment response; aged; aged, 80 and over; bone neoplasms; disease-free survival; middle aged; major clinical study; overall survival; prednisone; clinical trial; drug activity; fatigue; placebo; diarrhea; drug dose reduction; drug withdrawal; treatment duration; bone metastasis; drug megadose; anorexia; imatinib; drug inhibition; edema; controlled clinical trial; multiple cycle treatment; cohort studies; blood toxicity; gastrointestinal symptom; nausea; neuropathy; randomized controlled trial; stomatitis; vomiting; antineoplastic combined chemotherapy protocols; opiate; dexamethasone; steroid; bone pain; platelet derived growth factor receptor; pyrimidines; hematuria; docetaxel; dyspnea; hyperglycemia; pneumonia; prostate cancer; rash; prostatic neoplasms; drug fatality; gastrointestinal toxicity; acetylsalicylic acid; cyclooxygenase 2 inhibitor; heart infarction; nonsteroid antiinflammatory agent; cardiotoxicity; thrombosis; spinal cord compression; neoplasm metastasis; taxoids; colon perforation; piperazines; castration; taxane derivative; embolism; crossover procedure; brain ischemia; heart ventricle arrhythmia; leukocyte; heart muscle ischemia; bone marrow toxicity; placebos; receptors, platelet-derived growth factor; desquamation; diphenhydramine; bone turnover; receptor, platelet-derived growth factor beta; heart supraventricular arrhythmia; peritonitis; effusion; famotidine; conjunctiva disease; conjunctival tearing; diverticular perforation |
| Journal Title: | Clinical Cancer Research |
| Volume: | 13 |
| Issue: | 19 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2007-10-01 |
| Start Page: | 5816 |
| End Page: | 5824 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-07-1269 |
| PUBMED: | 17908974 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 29" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus" |
