ABSTRACT
PURPOSE: The combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of preclinical evidence of synergy between these drugs. According to our phase I study, the combination of capecitabine and everolimus is safe and feasible, with potential activity in pancreatic cancer patients. METHODS: Patients with advanced adenocarcinoma of the pancreas were enrolled. Eligible patients had a WHO performance status 0-2 and adequate hepatic and renal functions. The treatment regimen consisted of capecitabine 1000 mg/m(2) BID day 1-14 and everolimus 10 mg daily (5 mg BID) in a continuous 21-day schedule. Tumor assessment was performed with CT-scan every three cycles. Primary endpoint was response rate (RR) according to RECIST 1.0. Secondary endpoints were progression-free survival, overall survival and 1-year survival rate. RESULTS: In total, 31 patients were enrolled. Median (range) treatment duration with everolimus was 76 days (1-431). Principal grade 3/4 toxicities were hyperglycemia (45 %), hand-foot syndrome (16 %), diarrhea (6 %) and mucositis (3 %). Prominent grade 1/2 toxicities were anemia (81 %), rash (65 %), mucositis (58 %) and fatigue (55 %). RR was 6 %. Ten patients (32 %) had stable disease resulting in a disease control rate of 38 %. Median overall survival was 8.9 months (95 % CI 4.6-13.1). Progression-free survival was 3.6 months (95 % CI 1.9-5.3). CONCLUSIONS: The oral regimen with the combination of capecitabine and everolimus is a moderately active treatment for patients with advanced pancreatic cancer, with an acceptable toxicity profile at the applied dose level.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Capecitabine , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Everolimus , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/analogs & derivatives , Humans , Male , Middle Aged , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/mortality , Protein Kinase Inhibitors/adverse effects , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/analogs & derivatives , Survival RateABSTRACT
BACKGROUND: Esophagogastric adenocarcinoma (EGC) is a molecular heterogeneous disease, and therefore, strategies with targeted therapy may be effective. AIM: This review will discuss phase III studies in advanced EGC concerning biologic agents targeting molecular pathways, such as EGFR, HER2, VEGFR, mTOR and c-MET. RESULTS: HER2 inhibition with trastuzumab in combination with first line chemotherapy results in a significant survival benefit for HER2 positive carcinoma patients. Chemotherapy in combination with bevacizumab does not prolong survival in an unselected EGC patient cohort. Preliminary results of trials with EGFR, VEGFR and mTOR inhibitors are, thus far, disappointing in unselected patient cohorts. Promising studies in biomarker selected cohorts with HER2, EGFR and c-MET inhibitors are ongoing. CONCLUSION: Targeted therapy in EGC is emerging. Improved insight in the biologic background of EGC is needed to improve patient selection, combine agents and discover new targets and agents. This may improve outcome for metastasized EGC patients.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Esophageal Neoplasms/drug therapy , Molecular Targeted Therapy , Stomach Neoplasms/drug therapy , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Clinical Trials as Topic , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Humans , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathologyABSTRACT
The aim of this investigation was to examine whether the treatment of bitches with doramectin is able to prevent pre-natal and galactogenic infections with Toxocara canis in their pups. Five experimentally infected beagle bitches were treated subcutaneously with 1 mg doramectin per kg body weight on each of days 40 and 55 of their pregnancy. Another infected bitch served as an untreated control. The efficacy of the medication was examined by counting the intestinal stages and somatic larvae in bitches and pups. The treatment did not completely prevent perinatal infections with T. canis. Intestinal stages and/or somatic larvae occurred in 16 of 20 pups. Seven pups developed patent infections. Compared to the control pups, the average worm burden (intestinal stages) of pups from treated bitches was less than 1%. No impairment of condition or physical development was noticed in the pups during the investigations. From the second week of life, the pups of the non-medicated bitch showed signs of a severe toxocarosis. No side effects were seen in the bitches after treatment with doramectin.
