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.
"Nimotuzumab did not seem to increase the acute toxicity of radiotherapy. Safran et al have reported incidence rates of 23%, 15%, and 5% for skin rash, esophagitis and hypersensitivity of grades 3 or higher, respectively, in patients receiving HER2-targeted therapy for esophageal tumors.21 "
[Show abstract][Hide abstract] ABSTRACT: To determine the safety and therapeutic effects of nimotuzumab (h-R3) combined with radiotherapy in esophageal cancer.
This Phase II clinical trial involved 42 patients with stage II (inoperable or refused surgery) to stage IV (supraclavicular lymph node metastasis only) esophageal cancers treated between November 2008 and July 2010. All patients had squamous cell carcinomas, and all received three-dimensional conformal radiotherapy and 200 mg nimotuzumab per week during radiotherapy.
There were 9, 25, and 8 patients with stage II, III and IV disease, respectively. All except two patients received 50-70 Gy radiation; 37 patients (88.1%) received more than five nimotuzumab doses. Grade III toxicities (21.4% of all adverse events) included esophagitis and gastrointestinal, dermatological and hematological toxicities. Complete response, partial response, stable disease, and progressive disease were observed in 0, 22 (52.4%), 17 (40.5%) and 3 (7.1%) patients at 1 month after the treatment. The epidermal growth factor receptor (EGFR) overexpression rate was 95.2%. After a median follow-up of 37 months, the median survival time (MST) was 14 months. The 2 year and 3 year overall survival (OS) rates were 33.3% and 26.2%, respectively. The median progression-free survival (PFS) time was 10 months. The 2 year and 3 year PFS rates were 24.5% and 22.1%, respectively. The MST in the 13 patients with (+++) EGFR expression (group A) and 7 patients with (++) EGFR expression (group B) was 15 and 11 months, respectively. The 2 year and 3 year OS rates were 46.2% and 38.5% in group A and 28.6% and 28.6% in group B, respectively (P = 0.405).
Although concurrent chemoradiotherapy was the standard care for locally advanced esophageal cancer, radiotherapy was the choice for those who were refused or could not tolerate chemoradiotherapy. Our study shows that nimotuzumab combined with radiotherapy was well tolerated in patients with esophageal cancer. EGFR overexpression was more common than previously reported. OS was higher after combined therapy than after historical control radiotherapy alone. Further studies are required to confirm the therapeutic efficacy of nimotuzumab in esophageal cancer.
OncoTargets and Therapy 11/2013; 6:1589-96. DOI:10.2147/OTT.S50945 · 2.31 Impact Factor
"Gy once daily/30 days Local disease control Safety DLT determined Safe combination I 2007  Breast AC ERBB2 None 2.0. Gy once daily/25 days Preoperative Safety and efficacy Toxicity and response determined Safe and active combination II 2010  Esophageal AC ERBB2 Paclitaxel and cisplatin 1.8 Gy once daily/28 days Local disease control Safety Toxicity determined No additional toxicity I 2004  Esophageal AC ERBB2 Paclitaxel and cisplatin 1.8 Gy once daily/28 days Local disease control Efficacy Response determined No additional response I/II 2007  Esophageal AC or SCC EGFR Tegafur and oxaliplatin 1.8 Gy once daily/33 days Local disease control Safety, tolerability, and efficacy DLT, MTD, and response determined Safe combination with significant response I 2012  Esophageal AC or SCC EGFR Irinotecan and cisplatin 1.8 Gy once daily/28 days Local disease control Safety and efficacy Toxicity and response determined, trial terminated Significant toxicity II 2012  Esophageal AC EGFR and VEGF (two agents) 5-FU, paclitaxel, and carboplatin 1.8 Gy once daily/25 days Preoperative Safety and efficacy Toxicity and response determined No additional response II 2012  6 Targeted drugs and radiotherapy Abdomen Pancreatic AC EGFR Gemcitabine 1.8 Gy once daily/28 days Local disease control Safety Toxicity determined Acceptable toxicity I 2011  Pancreatic AC EGFR Gemcitabine 1.8 Gy once daily/28 days Local disease control Safety, tolerability, and efficacy DLT, MTD, and response determined Active and reasonably well tolerated combination I 2008  Pancreatic AC EGFR Gemcitabine 2.0. Gy once daily/15– 19 days Local disease control Safety and tolerability DLT and MTD determined Phase 2 radiation dose determined I 2012  Pancreatic AC EGFR Capecitabine 1.8 Gy once daily/28 days Preoperative Safety DLT in 6 of 10 patients, trial terminated Significant toxicity I 2006  Pancreatic AC EGFR Paclitaxel 1.8 Gy once daily/28 days Local disease control Safety and tolerability Toxicity determined Acceptable toxicity I 2009  "
[Show abstract][Hide abstract] 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 · 4.36 Impact Factor
"These data suggested that a proportion of ESCC patients could be candidates for Trastuzumab targeted therapy. Results from early clinical trials demonstrated a correlation between HER-2 expression and gene amplification with Trastuzumab therapeutic efficacy in patients with esophageal adenocarcinomas . However, over expression and amplification of HER-2 appeared to be fundamentally different within esophageal squamous cell carcinoma, with a tendency of lower positive rates and lower level amplification, compared to adenocarcinoma . "
[Show abstract][Hide abstract] ABSTRACT: Background
Trastuzumab is currently approved for the clinical treatment of breast and gastric cancer patients with HER-2 positive tumors, but not yet for the treatment of esophageal carcinoma patients, whose tumors typically show 5 ~ 35% HER-2 gene amplification and 0 ~ 56% HER-2 protein expression. This study aimed to investigate the therapeutic efficacy of Trastuzumab in patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models.
PDECX models were established by implanting patient esophageal squamous cell carcinoma (ESCC) tissues into immunodeficient (SCID/nude) mice. HER-2 gene copy number (GCN) and protein expression were determined in xenograft tissues and corresponding patient EC samples by FISH and IHC analysis. Trastuzumab anti-tumor efficacy was evaluated within these PDECX models (n = 8 animals/group). Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient’s ESCC tissues. Similarity between the PDECX models and their corresponding patient’s ESCC tissue was confirmed by histology, morphology, HER-2 GCN and mutation.
None of the PDECX models (or their corresponding patient’s ESCC tissues) harbored HER-2 gene amplification. IHC staining showed HER-2 positivity (IHC 2+) in 2 PDECX models and negativity in 3 PDECX models. Significant tumor regression was observed in the Trastuzumab-treated EC044 HER-2 positive model (IHC 2+). A second HER-2 positive (IHC 2+) model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363. In summary, we established 5 PDECX mouse models and demonstrated tumor regression in response to Trastuzumab treatment in a HER-2 IHC 2+ model, but resistance in a HER-2 IHC 2+/PIK3CA mutated model.
This study demonstrates Trastuzumab-induced tumor regressions in HER-2 positive tumors, and highlights PIK3CA mutation as a potential resistance mechanism to Trastuzumab treatment in pre-clinical patient-derived EC xenograft models.
Journal of Translational Medicine 08/2012; 10(1):180. DOI:10.1186/1479-5876-10-180 · 3.93 Impact Factor
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