Antiangiogenic therapy with mammalian target of rapamycin inhibitor RAD001 (Everolimus) increases radiosensitivity in solid cancer.

PURPOSE: Radiotherapy exerts direct antivascular effects in tumors and also induces a proangiogenic stress response in tumor cells via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. Therefore, the combination of radiotherapy and antiangiogenic therapy with mTOR inhibitor RAD001 (Everolimus) might exert additive/synergistic effects on tumor growth. EXPERIMENTAL DESIGN: Effects of radiation combined with mTOR inhibitor RAD001 were studied on proliferation of murine colon cancer CT-26, human pancreatic cancer L3.6pl, and human umbilical vascular endothelial cells in vitro. In vivo tumor growth of subcutaneous colon cancer CT 26 and orthotopic pancreatic cancer L3.6pl was assessed after fractionated radiotherapy (5 x 2 or 5 x 4 Gy) with or without the addition of the mTOR inhibitor RAD001. RAD001 (1.5 mg/kg/d) was administered until the end of experiments beginning before or after radiotherapy. RESULTS: A single dose of 2 Gy reduced in vitro proliferation of L3.6pl (-16%), CT-26 (-70%), and human umbilical vascular endothelial cells (HUVEC; -72%). The mTOR inhibitor RAD001 (10 ng/mL) suppressed proliferation of HUVEC (-83%), L3.6pl (-8%), and CT-26 (-82%). Combination of even low concentrations of 0.01 ng/mL RAD001 and 0.25 Gy radiation significantly reduced proliferation of HUVECs (-57%), whereas additive effects of RAD001 and radiation on tumor cells were seen only at the highest concentrations tested. In vivo, RAD001 introduced before radiotherapy (5 x 2 Gy) improved tumor growth control in mice (L3.6pl: 326 mm(3) versus 1144 mm(3); CT-26: 210 mm(3) versus 636 mm(3); P < 0.05 versus control). RAD001 turned out to possess a dose-modifying effect on radiotherapy. CONCLUSION: Endothelial cells seem to be most sensitive to combination of mTOR inhibition and radiotherapy. Additive tumor growth delay using the mTOR inhibitor RAD001 and radiotherapy in vivo therefore might rely on combined antiangiogenic and antivascular effects.

Irradiation treatment of laryngeal cancer in a patient with an implantable cardioverter-defibrillator (ICD).

BACKGROUND: Due to an aging population the incidence of both cardiac and tumor-related illnesses is increasing. A problem may arise if radiotherapy is necessary in close anatomic proximity to an implantable cardioverter-defibrillator (ICD). These highly precise devices may respond to ionizing radiation with a loss of function or uncontrolled stimulation, with both effects being potentially life threatening. Available guidelines recommend the dose maximum to a pacemaker to be cumulative below 2 Gy. For most patients undergoing radiation therapy of the neck or of the chest this limit is exceeded, thus making a removal of the device and an implantation of an external ICD necessary. CASE REPORT: A patient with severe cardiac problems underwent an implantation of an ICD. However, a recurrence of a laryngeal cancer was diagnosed. The irradiation dose after resection was 60 Gy to the tumor region and 50 Gy to the lymph nodes. Irradiation peakload to the ICD was calculated to be 2.5 Gy. This dose was verified with thermoluminescence measurements. The ICD was externally deactivated during the sessions of irradiation. Device checks demonstrated no malfunction. CONCLUSION: Even though the dose limits of the ICD of 2 Gy were exceeded, the device demonstrated a regular function during and after radiotherapy.