Drug Combination Shrinks Breast Cancer Metastases In Brain
ScienceDaily (Dec. 17, 2007) — A combination of a "targeted" therapy and chemotherapy shrank metastatic brain tumors by at least 50 percent in one-fifth of patients with aggressive HER2-positive breast cancer, according to data presented by Dana-Farber Cancer Institute investigators at the San Antonio Breast Cancer Symposium.
Lapatinib (Tykerb) and capecitabine (Xeloda) were paired in an extension of a Phase 2 clinical trial in which lapatinib given alone shrank brain metastases significantly in six percent of 241 patients.
In the extension trial, capecitabine was added to lapatinib in 49 patients whose metastases -- cancerous colonies in the brain spread from their primary cancer -- had progressed while on treatment. With the combination therapy, brain metastases shrank by 20 percent or more in 18 patients (37 percent) and shrank by at least 50 percent in 10 patients (20 percent), reported Nancy Lin, MD, of Dana-Farber's Breast Oncology Center.
"Very few medications have shown activity in the treatment of brain metastases, particularly in HER-2-positive metastatic breast cancer patients," said Lin, who led the study with Eric Winer, MD, director of the Dana-Farber Breast Oncology Center. "Therefore, these data are quite encouraging, and further studies are warranted."
Lapatinib is an oral small-molecule drug from GlaxoSmithKline that is approved along with capecitabine for treating patients with advanced or metastatic breast cancer whose tumors are driven by the abnormal growth signal, HER-2, and who have already undergone therapy including trastuzumab (Herceptin), a taxane drug, and an anthracycline compound. Lapatinib, like trastuzumab, blocks the HER-2 signal.
Up to one-third of women with advanced, HER-2-positive breast cancer may develop metastases to the brain.
"Although radiation treatment is often effective, as women live longer with metastatic cancer, some develop worsening of brain metastases despite radiation," said Lin. "Because cancer in the brain can have a major impact on quality of life, it is important to have treatment options to address this problem."
The data was presented on Dec. 16, 2007.
LINK
Brain tumor radiation resistance defeated
DURHAM, N.C., Dec. 10 (UPI) -- U.S. scientists say they discovered how stem cells in a type of malignant brain resist radiation, and then used a drug to reduce that resistance.
Researchers from Duke University and the Cleveland Clinic said their work was based on research showing cancer stem cells can better resist the effects of radiation than other cancer cells. The earlier research identified a signaling pathway in normal cells called "Notch" that controls cell growth and differentiation.
The researchers then identified the Notch signaling pathway as the most likely reason for the radiation resistance of the cancer stem cells.
The lead author of the study, Jialiang Wang of Duke University, said the finding marked the first report that Notch signaling in tumor tissue is related to the failure of
"This makes the Notch pathway an attractive drug target," Wang said. "The right drug may be able to stop the real bad guys, the glioma stem cells."
The Duke and Cleveland Clinic researchers say they targeted a key enzyme of the Notch pathway by using drugs called gamma-secretase inhibitors. Senior author Dr. Bruce Sullenger of Duke said use of such drugs, in combination with radiation, "caused massive cell death in the and significantly reduced survival of glioma stem cells."
The research is detailed in the journal Stem Cells.
Efficacy of intracerebral delivery of cisplatin in combination with photon irradiation for treatment of brain tumors
| Journal | Journal of Neuro-Oncology |
| Publisher | Springer Netherlands |
| ISSN | 0167-594X (Print) 1573-7373 (Online) |
| Category | Laboratory Investigation - Human/Animal Tissue |
| DOI | 10.1007/s11060-009-0074-3 |
| Subject Collection | Medicine |
| SpringerLink Date | Friday, December 11, 2009 |
Julia Rousseau
1, 2, 3, Rolf F. Barth
4, Manuel Fernandez
1, 2, 3, Jean-François Adam
1, 2, 3, Jacques Balosso
1, 2, 3, 5, François Estève
1, 2, 3, 5 and Hélène Elleaume
1, 2, 3, 5 
| (1) | INSERM U836, Equipe 6, ESRF, Medical Beamline, BP 220, 38043 Grenoble Cedex 9, France |
| (2) | Université Joseph Fourier, Grenoble, France |
| (3) | European Synchrotron Radiation Facility, Grenoble, France |
| (4) | Department of Pathology, The Ohio State University, Columbus, OH 43210, USA |
| (5) | Centre Hospitalier Universitaire, Grenoble, France |
Received: 17 August 2009
Accepted: 13 November 2009
Published online: 11 December 2009
Abstract We have evaluated the efficacy of intracerebral (i.c.) convection-enhanced delivery (CED) of cisplatin in combination with photon irradiation for the treatment of F98 glioma-bearing rats. One thousand glioma cells were stereotactically implanted into the brains of Fischer rats and 13 days later cisplatin (6 μg/20 μl) was administered i.c. by CED at a flow rate of 0.5 μl/min. On the following day the animals were irradiated with a single 15 Gy dose of X-rays, administered by a linear accelerator (LINAC) or 78.8 keV synchrotron X-rays at the European Synchrotron Radiation Facility (ESRF). Untreated controls had a mean survival time (MST) ± standard error of 24 ± 1 days compared to >59 ± 13 days for rats that received cisplatin alone with 13% of the latter surviving >200 days. Rats that received cisplatin in combination with either 6 MV (LINAC) or 78.8 keV (synchrotron) X-rays had almost identical MSTs of >75 ± 18 and >74 ± 19 days, respectively with 17 and 18% long-term survivors. Microscopic examination of the brains of long-term surviving rats revealed an absence of viable tumor cells and cystic areas at the presumptive site of the tumor. Our data demonstrate that i.c. CED of cisplatin in combination with external X-irradiation significantly enhanced the survival of F98 glioma-bearing rats. This was
independent of the X-ray beam energy and probably was
not due to the production of Auger electrons as we previously had postulated. Our data provide strong support for the approach of concomitantly administering platinum-based chemotherapy in combination with radiotherapy for the treatment of brain tumors. Since a conventional LINAC can be used as the radiation source, this should significantly broaden the clinical applicability of this approach compared to synchrotron radiotherapy, which could only be carried out at a very small number of specialized facilities.
Keywords F98 rat glioma - Cisplatin - Convection-enhanced delivery - Chemotherapy - Radiotherapy
Presented in part at the 100th Annual Meeting of the American Association for Cancer Research, Denver, CO, April 18–22, 2009.