motexafin-gadolinium and Neoplasm-Metastasis

Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.

Topics: Brain Neoplasms; Carcinoma, Renal Cell; Dacarbazine; Humans; Kidney Neoplasms; Metalloporphyrins; Neoplasm Metastasis; Radiation Oncology; Radiation-Sensitizing Agents; Radiosurgery; Temozolomide

Thioredoxin reductase (Trx) has been implicated in activation of hypoxia-inducible factor-1alpha, which is overexpressed in > 85% of renal cell carcinomas (RCCs). We evaluated the safety and efficacy of motexafin gadolinium (MGd), a Trx inhibitor, as a single-agent therapy for metastatic RCC.. Patients with metastatic RCC were infused daily with MGd 5 mg/kg on days 1-5 and days 15-19 of each 28-day cycle. Patients were evaluated for response on days 21-28 of every third cycle. Those with tumor response or stable disease (SD) continued treatment for < or = 12 cycles. Twenty-five patients with confirmed metastatic RCC were enrolled. All were evaluable for toxicity, and 20 were evaluable for response.. While no clinical responses were observed, 8 patients had SD after 3 treatment cycles, as did 4 after 6 cycles. Median overall survival was 10.1 months, and median progression- free survival was 2.7 months. The most common treatment-related toxicities were grade 1/2 pain, nausea, skin discoloration, fatigue, blisters, and headache. The most common grade 3 toxicity was hypophosphatemia, observed in 5 patients. MGd was reasonably tolerated, and disease stabilization was observed in several patients with metastatic RCC.. These results show promise for the use of MGd in combination with other molecularly targeted therapies in previously treated patients with metastatic RCC. However, further investigation of MGd alone for metastatic RCC is not recommended.

Topics: Adult; Aged; Carcinoma, Renal Cell; Drug Administration Schedule; Female; Humans; Kidney Neoplasms; Male; Metalloporphyrins; Middle Aged; Neoplasm Metastasis

The purpose of this study was to determine clinical variables affecting motexafin gadolinium (MGd) pharmacokinetics. Motexafin gadolinium (4-5.3 mg/kg/d) was administered intravenously for 2 to 6.5 weeks. Plasma samples from 3 clinical trials were analyzed for MGd using liquid chromatography/mass spectroscopy. The pooled data were analyzed using population pharmacokinetic (POP-PK) methods. The POP-PK model included 243 patients (1575 samples). Clearance (CL) was 14% lower in women, but weight-normalized clearance was only 5% lower in women. Clearance decreased with increasing alkaline phosphatase, increasing age, and decreasing hemoglobin. Administration of phenytoin increased CL by approximately 30%. Central compartment volume (V1) was 21% lower in women and increased with increasing serum creatinine. For all covariates, except sex and phenytoin, the predicted change in CL or V1 (5th and 95th percentiles) varied < or =13% from the population mean CL or V1 estimate. It was concluded that a 3-compartment, open, POP-PK model predicts small but significant effects of age, sex, alkaline phosphatase, hemoglobin, serum creatinine, and phenytoin on MGd pharmacokinetics.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alkaline Phosphatase; Anticonvulsants; Antineoplastic Agents; Brain Neoplasms; Clinical Trials as Topic; Creatinine; Data Interpretation, Statistical; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Metabolic Clearance Rate; Metalloporphyrins; Middle Aged; Models, Biological; Neoplasm Metastasis; Phenytoin; Sex Factors; Software