Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma.
ABSTRACT To determine the overall survival for patients with locally advanced, HER2 overexpressing, esophageal adenocarcinoma receiving trastuzumab, paclitaxel, cisplatin, and radiation on a Phase I-II study.
Patients with adenocarcinoma of the esophagus without distant organ metastases and 2+/3+ HER2 overexpression by immunohistochemistry (IHC) were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation therapy (RT) 50.4 Gy. Patients received trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg.
Nineteen patients were entered: 7 (37%) had celiac adenopathy, and 7 (37%) had retroperitoneal, portal adenopathy, or scalene adenopathy. Fourteen of 19 patients (74%) had either 3+ HER2 expression by immunohistochemistry, or an increase in HER2 gene copy number by HER2 gene amplification or high polysomy by fluorescence in situ hybridization. The median survival of all patients was 24 months and the 2-year survival was 50%.
Assessment of the effect of trastuzumab in the treatment of patients with esophageal adenocarcinoma overexpressing HER2 is limited by the small number of patients in this study. Overall survival, however, was similar to prior studies without an increase in toxicity. Evaluation of HER2 status should be performed in future trials for patients with adenocarcinoma of the esophagus that investigate therapies targeting the HER family.
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ABSTRACT: New strategies to facilitate the improvement of physical and integrated biological optimization of high-precision treatment protocols are an important priority for modern radiation oncology. From a clinical perspective, as knowledge accumulates from molecular radiobiology, there is a complex and exciting opportunity to investigate novel approaches to rational patient treatment stratification based on actionable tumor targets, together with the appropriate design of next-generation early-phase radiotherapy trials utilizing targeted therapeutics, to formally evaluate relevant clinical and biomarker endpoints. A unique aspect in the development pathway of systemic agents with presumed radiosensitizing activity will also be the need for special attention on patient eligibility and the rigorous definition of radiation dose-volume relationships and potential dose-limiting toxicities. Based on recent experience from systematically investigating histone deacetylase inhibitors as radiosensitizing agents, from initial studies in preclinical tumor models through the conduct of a phase I clinical study to evaluate tumor activity of the targeted agent as well as patient safety and tumor response to the combined treatment modality, this communication will summarize principles relating to early clinical evaluation of combining radiotherapy and targeted therapeutics.Radiotherapy and Oncology 07/2013; 108(1). DOI:10.1016/j.radonc.2013.06.007 · 4.86 Impact Factor
Article: Combining targeted therapies[Show abstract] [Hide abstract]
ABSTRACT: Therapeutics in oncology are rapidly changing, with the advent of the so-called “targeted drugs.” A clear example is trastuzumab, an anti-HER2 monoclonal antibody, and its role in the treatment of breast cancer. Trastuzumab was followed by other monoclonal antibodies like cetuximab (anti-EGFR) and bevacizumab (anti-VEFG) and by tyrosine kinase inhibitors such as imatinib, gefitinib (anti-EGFR) and others. The complex biology of the cancer cell leads us to search combination strategies to act simultaneously in different points of signals transduction pathways to enhance the anticancer effect. Here we review various clinical trials and also experimental data exploring these new drugs in combination. Combination with chemotherapy is beyond the scope of this review. For this review, we have selected the following agents: cetuximab, trastuzumab, bevacizumab, panitumumab, imatinib, erlotinib, gefitinib, sorafenib, sunitinib, and lapatinib.Targeted Oncology 11/2007; 2(4):241-252. DOI:10.1007/s11523-007-0062-5 · 3.46 Impact Factor
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ABSTRACT: In the authors' preceding work they constructed physical models of the processes occurring in the cathode spot of a vacuum arc, combining these models with a more or less rigorous mathematical statement of the problem. The solutions to the problems were found numerically using computer simulation. Here, they develop approximate analytical models, distinguishing the principal physical phenomena responsible for a given process in the cathode spot. Such models are based on the idea that the processes in the cathode spot of a vacuum arc are nonsteady-state and cyclic in nature. The analytical results are compared with the predictions of numerical simulations and with available experimental dataDischarges and Electrical Insulation in Vacuum, 1996. Proceedings. ISDEIV., XVIIth International Symposium on; 08/1996