Clinical
The classical LFS malignancies - sarcoma, cancers of the breast, brain, and adrenal glands - comprise about 80% of all cancers that occur in this syndrome. The risk of developing any invasive cancer (excluding skin cancer) is about 50% by age 30 (1% in the general population) and is 90% by age 70. Early-onset breast cancer accounts for 25% of all the cancers in this syndrome. This is followed by soft-tissue sarcomas (20%), bone sarcoma (15%), and brain tumors - especially glioblastomas - (13%). Other tumours seen in this syndrome include leukemia, lymphoma, and adrenocortical carcinoma. About 90% of females with LFS develop breast cancer by age 60 years; the majority of these occur before age 45 years. Females with this syndrome have almost a 100% lifetime risk of developing cancer. This compares with 73% for affected males. The difference may be due to much smaller breast tissue in males and increased estrogen levels in females. The risks of sarcoma, female breast cancer, and haematopoietic malignancies in mutation carriers are more than 100 times greater than those seen in the general population. Other tumours reported in this syndrome, but not yet proved to be linked with it, include melanoma, Wilms and other kidney tumors, hepatocellular carcinoma, gonadal germ cell, pancreatic, gastric, choroid plexus, colorectal, and prostate cancers. Around 80% of children with adrenocortical carcinoma and 2–10% of childhood brain tumors have p53 mutations.
Tivozanib, sold under the brand name Fotivda, is a medication used for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC). It is an oral VEGF receptor tyrosine kinase inhibitor.The most common side effects include fatigue, hypertension, diarrhea, decreased appetite, nausea, dysphonia, hypothyroidism, cough, and stomatitis.Tivozanib was approved for medical use in the European Union in August 2017, and in the United States in March 2021. Medical uses
Tivozanib is used for the treatment of adults with relapsed or refractory advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Contraindications
Tivozanib must not be combined with St. Johns Wort, an inducer of the liver enzyme CYP3A4 (see interactions below). It should not be taken during pregnancy as it is teratogenic, embryotoxic and fetotoxic in rats. Adverse effects
The most common side effects in studies were hypertension (high blood pressure, in 48% of patients), dysphonia (hoarse voice, 27%), fatigue and diarrhoea (both 26%). A hypertensive crisis occurred in 1% of patients. Interactions
Administration of a single dose of tivozanib with rifampicin, a strong inducer of the enzyme CYP3A4, cuts the biological half-life and total exposure (AUC) of tivozanib in half, but has no relevant influence on highest concentrations in the blood. Combination with ketoconazole, a strong CYP3A4 inhibitor, has no relevant effects. The clinical significance of these findings is not known. Pharmacology
Mechanism of action
A quinoline urea derivative, tivozanib suppresses angiogenesis by being selectively inhibitory against vascular endothelial growth factor (VEGF). It is designed to inhibit all three VEGF receptors.