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Neoadjuvant dasatinib for muscle-invasive bladder cancer with tissue analysis of biologic activity.
- Source :
-
Urologic Oncology . Jan2016, Vol. 34 Issue 1, p4.e11-4.e17. 1p. - Publication Year :
- 2016
-
Abstract
- <bold>Objectives: </bold>Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC).<bold>Materials and Methods: </bold>A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test.<bold>Results: </bold>The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) had<pT2 disease. Analysis of pre- and posttreatment tumors demonstrated significantly decreased pSFK (P = 0.003) but no overall significant changes in Ki-67 or Cas3. In total, 4 cases demonstrated a nonsignificant decrease in Ki-67, of which 3 cases also demonstrated a decrease in pSFK and 2 cases had marginal increase in Cas3.<bold>Conclusions: </bold>Neo-D in miUCB patients was feasible and safe. Overall, significant inhibition of pSFK was observed without overall reduction of cellular proliferation or increase of apoptosis, although biologic anti-tumor activity may exist in a small subset of patients. These results highlight the potential utility of the neoadjuvant trial paradigm and suggest that clinical benefit of single-agent SFK inhibition in unselected patients with miUCB is unlikely. [ABSTRACT FROM AUTHOR]
- Subjects :
- *DASATINIB
*ADJUVANT treatment of cancer
*BLADDER cancer treatment
*TISSUE analysis
*BIOACTIVE compounds
*KINASE inhibitors
*ANTINEOPLASTIC agents
*CANCER invasiveness
*CLINICAL trials
*COMBINED modality therapy
*COMPARATIVE studies
*IMMUNOENZYME technique
*LONGITUDINAL method
*RESEARCH methodology
*MEDICAL cooperation
*MUSCLE tumors
*PROGNOSIS
*RESEARCH
*TUMOR classification
*PILOT projects
*EVALUATION research
BLADDER tumors
Subjects
Details
- Language :
- English
- ISSN :
- 10781439
- Volume :
- 34
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Urologic Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 111420787
- Full Text :
- https://doi.org/10.1016/j.urolonc.2015.08.005