Survival and Neurologic Outcomes in a Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation Therapy in Brain Metastases

Mehta, Minesh P.; Rodrigus, P.; Terhaard, C.; Rao, Aroor R.; Suh, John H.; Roa, Wilson; Souhami, Luís; Bezjak, Andrea; Leibenhaut, Mark H.; Komaki, Ritsuko; Schultz, Christopher G.; Timmerman, Robert; Curran, Walter J.; Smith, Jennifer A.; Phan, See; Miller, Richard A.; Renschler, Markus F.

doi:10.1200/jco.2003.12.122

Cited by 420 publications

(251 citation statements)

References 27 publications

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“…The mixture was hydrolyzed with 0.5 M NaOH (6.8 ml) at 80-90 °C for 8 h under air. To the cooled mixture, was added 30 ml of CH 2 13 were added. The reaction mixture was then stirred while heating at reflux for an additional 24 h under air.…”

Section: Methodsmentioning

confidence: 99%

“…1) has completed two Phase III clinical trials as an agent for treating brain metastases in conjunction with whole brain radiation therapy, with strong positive trends being seen in both trials for patients with non-small cell lung cancer. [1][2][3] Recent preclinical and early stage clinical trials have provided support for the notion that this gadolinium texaphyrin derivative may also have utility as a stand-alone anticancer agent. 4 One proposed mechanism of action involves the concept of redox cycling, [5][6][7] wherein a reduced texaphyrin species, formed by reaction with endogenous electron rich species such as ascorbate or glutathione, serves to form reactive oxygen species including superoxide and peroxide that are known to act as apoptosis triggering agents.…”

Section: Introductionmentioning

confidence: 99%

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New polyethyleneglycol-functionalized texaphyrins: synthesis and in vitro biological studies

et al. 2006

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The synthesis of four new analogues of motexafin gadolinium (MGd), a gadolinium(III) texaphyrin complex in clinical trials for its anticancer properties, is described. These new derivatives contain either 1,2-diaminobenzene or 2,3-diaminonaphthalene subunits as the source of the imine nitrogens and bear multiple 2-[2-(2-methoxyethoxy)ethoxy]ethoxy (PEG) groups, on either meso aryl or beta-pyrrolic substituents, to increase their water solubility. All four analogues were found to be more active in vitro than the parent system MGd as judged from cell proliferation assays using the PC3 and A549 cell lines.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New polyethyleneglycol-functionalized texaphyrins: synthesis and in vitro biological studies

et al. 2006

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“…To date a number of potential radiosensitising agents such as metallotexaphyrins, synthetic allosteric modifiers of haemoglobin or other chemotherapeutic drugs have been used without a demonstrable improvement in survival of patients with BM (Komarnicky et al, 1991;Phillips et al, 1995;Mehta et al, 2003). Therefore, the investigation of newer promising agents needs to continue.…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine twice weekly as a radiosensitiser for the treatment of brain metastases in patients with carcinoma: a phase I study

et al. 2005

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Conventional treatment for brain metastases (BM) is whole-brain radiotherapy (WBRT). Efficacy is poor. It might be increased by a potent radiosensitiser such as gemcitabine which is believed to cross the disrupted blood -brain barrier. Primary objective of this study was to determine the maximum tolerated dose (MTD) of twice weekly gemcitabine given concurrently with WBRT. Patients with BM from carcinoma were included. The dose of WBRT was 30 Gys (10 daily fractions). Gemcitabine was given 2 -4 h prior to WBRT on days 1 and 8 for the first cohort of patients and then on days 1, 4, 8 and 11. Starting dose was 25 mg m À2 , escalated by 12.5 mg m À2 increments. At least three patients were included per level. Dose limiting toxicity (DLT) was defined as grade 4 haematological or grade X3 nonhaematological toxicity. A total of 25 patients were included; 74% had a PS 1 (ECOG). In all, 23 had non-small-cell lung cancer, six colorectal, four breast, two renal cell and one oesophageal carcinoma. A total of 92% had concurrent extracranial disease. Six had single BM, 13 had two or three BM and six multiple. Up to 50 mg m À2 (level 4) no DLT was observed. At 62.5 mg m À2 , one out of six patients developed DLT (thrombocytopenia-bleeding). The next dose level (75 mg m À2 ) was abandoned after grade 4 bone marrow toxicity (fatal neutropenic sepsis) was seen in one out of two patients. So that the dose of 50 mg m À2 will be taken forward for further study. British Journal of Cancer (2005) (Patchel, 2003). Except for very few cases where surgery may be indicated, the mainstream accepted therapeutic modality is whole brain radiotherapy (WBRT). Gamma-knife radiosurgery and conformal radiotherapy are recent developments that may confer a prognosis improvement to selected patients mostly in cases of single BM and controlled extracranial disease. The prognosis of the vast majority of patients who develop BM is poor. The median survival for treated patients with WBRT is approximately 4 months and the 1-year survival only 12% (Lagerwaard et al, 1999). Chemotherapy is not usually given and if the patient is actually receiving chemotherapy, it is often discontinued. This attitude has been fostered by the theoretical difficulty of drugs to pass the blood -brain barrier and achieve therapeutic significance in brain micrometastases. This however is probably not the case with macroscopic metastases. Brain metastases in patients with many chemosensitive tumours (e.g. testicular cancer, lymphoma, choriocarcinoma) are well known to respond to chemotherapy. A recent study by Postmus et al (2000) in patients with small-cell carcinoma and BM showed a 22% response rate to chemotherapy alone. However, the combination of chemotherapy and radiotherapy produced a 57% response rate and the control in the brain disease in these patients was longer than in patients who received only chemotherapy. A phase III study of early vs late WBRT with concurrent cisplatin and vinorelbine in patients with non-smallcell lung cancer (NSCLC) and BM was reported by Robi...

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“…[18] Six randomised controlled trials have evaluated the role of PCI in LA-NSCLC, with five studies demonstrating a statistically significant reduction in the incidence of BM with PCI, but no survival advantage. [10,[19][20][21][22][23] The most recent of these studies was underpowered for a survival endpoint.…”

Section: Discussionmentioning

confidence: 99%

Patient preferences regarding prophylactic cranial irradiation: A discrete choice experiment

Lehman

Gorayski

Watson

et al. 2016

Radiotherapy and Oncology

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Survival and Neurologic Outcomes in a Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation Therapy in Brain Metastases

Cited by 420 publications

References 27 publications

New polyethyleneglycol-functionalized texaphyrins: synthesis and in vitro biological studies

New polyethyleneglycol-functionalized texaphyrins: synthesis and in vitro biological studies

Gemcitabine twice weekly as a radiosensitiser for the treatment of brain metastases in patients with carcinoma: a phase I study

Patient preferences regarding prophylactic cranial irradiation: A discrete choice experiment

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