Showing Latest Articles
Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase I trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors
Cancer Chemotherapy and Pharmacology, 02/04/2010
Exclusive author commentary
Morgan RJ et al. – This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid. The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m2/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.
Methods- Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m2/d IV, administered as a 72 h continuous infusion on days 1–3, followed by carboplatin AUC = 3, IV on day 3
- Cycles repeated every 4 weeks
- Seventeen patients received 39 cycles of treatment: median 2, (range 1–5)
- Tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma
- Median Karnofsky performance status was 70% (range 60–90%) and age: 52 (range 24–75)
- Eleven patients were female and six male
- Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF)
- At 1.0 mg/m2/d, the median CSF/plasma ratio was 19.4% (range 15.1–59.1%)
- Total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02–3.83)
- Two had minor responses
- One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs
Robert J. Morgan (02/12/2010) comments:
We found that the combination of the three agents was very tolerable in this patient population. The observed responses suggest that the levels crossing into the central nervous system are adequate to achieve cytotoxicity.