motexafin-gadolinium and Breast-Neoplasms

Topics: Anticonvulsants; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Dacarbazine; Dementia, Vascular; Humans; Lung Neoplasms; Melanoma; Metalloporphyrins; Prednisolone; Radiation-Sensitizing Agents; Radiotherapy, Adjuvant; Temozolomide

To report the neurocognitive findings in a phase III randomized trial evaluating survival and neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd).. Patients were randomly assigned to receive WBRT 30 Gy in 10 fractions with or without MGd 5 mg/kg/d. Monthly neurocognitive testing for memory, executive function, and fine motor skill was performed.. Four hundred one patients were enrolled (251 with non-small-cell lung cancer, 75 with breast cancer, and 75 with other cancers); 90.5% patients had impairment of one or more neurocognitive tests at baseline. Neurocognitive test scores of memory, fine motor speed, executive function, and global neurocognitive impairment at baseline were correlated with brain tumor volume and predictive of survival. There was no statistically significant difference between treatment arms in time to neurocognitive progression. Patients with lung cancer (but not other types of cancer) who were treated with MGd tended to have improved memory and executive function (P =.062) and improved neurologic function as assessed by a blinded events review committee (P =.048).. Neurocognitive tests are a relatively sensitive measure of brain functioning; a combination of tumor prognostic variables and brain function assessments seems to predict survival better than tumor variables alone. Although the addition of MGd to WBRT did not produce a significant overall improvement between treatment arms, MGd may improve memory and executive function and prolong time to neurocognitive and neurologic progression in patients with brain metastases from lung cancer.

Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Breast Neoplasms; Cognition Disorders; Cranial Irradiation; Disease Progression; Female; Humans; Lung Neoplasms; Male; Memory Disorders; Metalloporphyrins; Middle Aged; Motor Skills; Psychometrics; Survival Analysis; Treatment Outcome

Clinical use of radio- or photo-sensitizing agents in anti-cancer treatments may be limited by patient specific variability in the pharmacokinetics (PK) of the sensitizing compound. Previously, our group reported motexafin gadolinium (MGd) concentrations in mouse tissues measured noninvasively by the optical pharmacokinetic system (OPS) in vivo, nondestructively by OPS in situ, and destructively by HPLC ex vivo. This study utilized those reported data to develop compartmental PK models of MGd disposition in plasma, tumor, and skin. The model predicted both the rapid initial distribution and slow elimination phases of MGd in plasma, the fast transport of MGd out of the skin (with no MGd detectable after 120 min), and MGd retention at long times in the tumor (with detectable MGd at 24 h). The same compartmental structure was used to model MGd concentrations vs. time as measured by OPS in situ and HPLC ex vivo. In vivo tumor MGd concentrations measured using OPS were estimated by a linear combination of the model predicted PK profiles in plasma and tumor tissue, which suggests that tissue-specific PK knowledge may be needed in order to interpret volume-averaged optical measurements in vivo. The PK modeling techniques presented here are extensible to other optically active compounds and, potentially, to the development of patient-specific treatment schedules.

Topics: Animals; Breast Neoplasms; Computer Simulation; Elasticity Imaging Techniques; Female; Humans; Image Interpretation, Computer-Assisted; Metabolic Clearance Rate; Metalloporphyrins; Mice; Mice, SCID; Models, Biological; Photosensitizing Agents; Skin; Tissue Distribution

Efficient design of anti-cancer treatments involving radiation- and photo-sensitizing therapeutics requires knowledge of tissue-specific drug concentrations. This study investigates the use of the optical pharmacokinetic system (OPS) to measure concentrations of the anti-cancer agent motexafin gadolinium (MGd) in mouse tissues noninvasively and nondestructively using elastic-scattering spectroscopy. The magnitude of MGd absorbance was quantitated by integration of the MGd peak absorbance area, and MGd concentrations were estimated by comparison with standard curves that were validated by high performance liquid chromatography (HPLC). In tissue-simulating phantoms in vitro, MGd peak absorbance area correlated with MGd concentration. Female C.B-17 SCID mice, bearing subcutaneous MDA-MB-231 human breast cancer xenografts, were dosed with 23 mg/kg MGd i.v. At specific times between 5 min and 24h after dosing, noninvasive OPS measurements were made on skin overlaying the subcutaneous tumor and skin on the opposite flank in vivo, and following exsanguination, nondestructive measurements were made on tumor, skin, and internal tissues in situ. OPS measurements on tissues in vivo detected MGd present in both tissue and blood perfusing the tissue. Both the OPS and the HPLC detected selective localization of MGd in malignant tissues compared with surrounding non-malignant tissues, and neither technique detected MGd in brain tissue. Comparison of MGd concentrations measured by HPLC and OPS is complicated by mismatch between measured tissue volumes, heterogeneous spatial distribution of MGd in tissues, and blood-localized MGd at early time points. Tumor-specific MGd concentrations measured by HPLC correlated with those measured by OPS in vivo and in situ. Best fit lines to the concentration estimates (forced through zero) had slopes of 0.900 and 1.185, respectively; however, the variability was significant (r(2)=0.477 and 0.269). The clinical utility of the OPS to quantitate MGd concentrations remains to be validated.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Humans; Metalloporphyrins; Mice; Photosensitizing Agents; Skin Neoplasms; Spectrum Analysis; Time Factors; Tissue Distribution; Transplantation, Heterologous