ABSTRACT
Individuals with Li-Fraumeni syndrome (LFS) have a significantly increased lifetime cancer risk affecting multiple organ sites. Therefore, novel comprehensive screening approaches are necessary to improve cancer detection and survival in this population. The objective of this study was to determine the diagnostic performance of whole body MRI (WB-MRI) and dedicated brain MRI screening as part of a comprehensive screening clinic called Li-Fraumeni Education and Early Detection (LEAD) at MD Anderson Cancer Center. Adult (≥21 year old) and pediatric (<21 year old) patients were referred to the LEAD clinic by healthcare providers or self-referred and screened at 6 month intervals. During the study period, 63 LFS individuals were seen in the LEAD clinic including 49 adults (11 male, 38 female) and 14 children (7 male, 7 female). Fifty-three of 63 potentially eligible individuals underwent baseline WB-MRI (41 adults and 12 children) with primary tumors detected in six patients, tumor recurrence in one patient and cancer metastases in one patient. Thirty-five of 63 patients (24 adults and 11 children) underwent baseline brain MRI with primary brain tumors detected in three individuals, also noted on subsequent WB-MRI scans. Three additional tumors were diagnosed that in retrospect review were missed on the initial scan (false negatives) and one tumor noted, but not followed up clinically, was prospectively found to be malignant. The high incidence of asymptomatic tumors identified in this initial screening (13%), supports the inclusion of WB-MRI and brain MRI in the clinical management of individuals with LFS.
Subject(s)
Early Detection of Cancer/methods , Genetic Predisposition to Disease , Li-Fraumeni Syndrome/diagnostic imaging , Neoplasm Recurrence, Local/diagnostic imaging , Tumor Suppressor Protein p53/genetics , Adolescent , Adult , Asymptomatic Diseases/epidemiology , Brain/diagnostic imaging , Brain/pathology , Child , Child, Preschool , Female , Germ-Line Mutation , Heterozygote , Humans , Incidence , Infant , Infant, Newborn , Li-Fraumeni Syndrome/epidemiology , Li-Fraumeni Syndrome/genetics , Magnetic Resonance Imaging/methods , Male , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/genetics , Whole Body Imaging/methods , Young AdultABSTRACT
PURPOSE: Anti-angiogenic agents combined with histone deacetylase inhibitors act synergistically in vitro and in vivo. We conducted a phase I study of the combination of the anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers. METHODS: Bevacizumab was administered at escalating dosages of 2.5-11 mg/kg on days 1 and 15, and oral valproic acid at dosages of 5.3-10 mg/kg on days 1-28 every 28 days to determine the maximum tolerated dose. Pharmacodynamic parameters were assessed in peripheral blood mononuclear cells (histone H3 acetylation) and serum (valproic acid levels). RESULTS: Fifty-seven patients were enrolled. Dose-limiting toxicities were grade 3 altered mental status (n = 2), related to valproic acid. Bevacizumab 11 mg/kg given on days 1 and 15 and valproic acid 5.3 mg/kg daily were the recommended phase II dosages. Stable disease (SD) ≥6 months was reported in 4/57 (7 %) of patients, including two patients with colorectal cancer who had progressed previously on bevacizumab. Of the 39 patients evaluated for histone acetylation, 2 of 3 (67 %) patients with SD ≥6 months showed histone acetylation, while 8 of 36 (22 %) without SD ≥6 months demonstrated histone acetylation (p = 0.16). Patients with any grade of hypertension, compared to others, had a prolonged median survival (11.1 vs. 5.8 months; p = 0.012). CONCLUSIONS: The combination of bevacizumab 11 mg/kg and valproic acid 5.3 mg/kg is safe in patients with advanced malignancies, with activity in colorectal, gastroesophageal junction, and prostate cancer. Patients with hypertension had improved overall survival.
