Treatment Of Gastroesophageal Cancer Research Articles

Targeting Angiogenesis in Gastroesophageal Cancer: Industry‐Sponsored Trials are not the Answer

Angiogenesis is a dynamic process essential for tumor growth. Maeda et al. first reported its association with poor prognosis in gastric cancer in 1996 and, since then, there have been numerous similar studies examining various factors that mediate angiogenesis such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor [1]. It is therefore surprising that a decade and a half later there is still no clear consensus on the role of antiangiogenic agents in the treatment of gastroesophageal cancer and, more importantly, recognition of the patient subset who are most likely to benefit from these expensive agents. In this issue of the Journal, Liu et al. [2] report that VEGF expression is an independent prognostic factor for tumor recurrence and decreased survival in patients with node-negative gastric cancer. Unlike prior studies, the authors excluded all node-positive patients in the hopes of stratifying node-negative patients into lowand high-risk groups for tumor recurrence. This is an important step in identifying patients most likely to benefit from adjuvant therapy, but the manner in which patients were deemed node-negative is particularly relevant. What was the median number of nodes resected, and how were the nodes examined? It seems unusual that 11 patients with pT4 tumors were node-negative. If we presume all nodes were examined using a single section and conventional [hematoxylin-eosin (H&E)] staining, then this means that only about 1% of the lymph node tissue was examined, and some node-positive patients almost certainly were missed. In a retrospective study last year, we found that almost one-third of esophageal cancer patients who were node-negative by conventional histology proved to have occult tumor deposits in their lymph nodes after serial sectioning and immunohistochemical evaluation [3]. In other words, until standardized and more stringent histopathology is performed on lymph nodes, it is difficult for the reader to be confident that all patients were truly nodenegative. Also, in Liu et al.’s study, it is possible that 24 of 55 (44%) patients who were VEGF-positive and had a worse survival were those who might have been nodepositive with more stringent histopathologic testing. Nevertheless, their study raises an interesting question. Should patients with early gastric cancer and positive VEGF staining be given an antiangiogenic agent to reduce their risk of tumor recurrence? Bevacizumab (Avastin), a recombinant humanized monoclonal antibody directed against VEGF-A, was approved for patients with metastatic colorectal cancer in 2004, in combination with 5-fluorouracil chemotherapy, after a Phase III (randomized controlled multicenter) study showed an increase in survival of 4.7 months with the inclusion of this agent in the treatment regimen [4]. This study paved the way for a myriad of other clinical trials evaluating more than 40 antiangiogenesis agents in various solid tumors. In gastric cancer, a Phase III trial called AVAGAST (Avastin in Gastric Cancer) has just been published in the Journal of Clinical Oncology on the back of three Phase II (nonrandomized) trials evaluating the addition of bevacizumab to chemotherapy in patients with unresectable or metastatic gastroesophageal cancer [5]. Although the smaller Phase II trials reported response rates of 65 to 68% with encouraging progression-free survival [6], the Phase III trial found only a 2 month survival benefit between groups, which was not significant [5]. Subsequently, bevacizumab has not been S. K. Thompson (&) Department of Surgery, Royal Adelaide Hospital, University of Adelaide, Level 5, Eleanor Harrald Building, Adelaide, South Australia 5000, Australia e-mail: sarah.thompson@adelaide.edu.au

Her-2 in gastroesophageal cancer: pathobiology, diagnostic and therapeutic implications

BACKGROUND: The human epidermal growth factor receptor-2 (Her-2) is a membrane-bound tyrosine kinase that is overexpressed in about 15% of gastroesophageal adenocarcinomas. Since recently the first anti-Her-2 targeted therapy (trastuzumab) in combination with standard chemotherapy was approved for the treatment of metastatic and locally advanced gastroesophageal adenocarcinoma. METHODS: Review of the literature. RESULTS: This review gives an overview on the pathobiology of Her-2 and its therapeutical implications in gastroesophageal cancer. Special emphasis is placed on the clinical relevant issues of Her-2 testing and biopsy sampling. CONCLUSIONS: Anti-Her-2 targeted therapies offer novel therapeutic opportunities in advanced stage gastroesophageal adenocarcinomas. With the possible extension of the approval of Her-2 targeted therapies also to the perioperative setting and the possible introduction of alternative Her-2 targeting substances to trastuzumab, Her-2 will stay a highly relevant topic in the treatment of gastroesophageal cancer.

Challenges in the Treatment of Gastroesophageal Cancer: Reply

Challenges in the Treatment of Gastroesophageal Cancer: Reply

HER-2/neuTesting and Therapy in Gastroesophageal Adenocarcinoma

Despite ongoing advances in the treatment of gastroesophageal cancer, prognosis remains poor. The best promise to improve this poor survival is provided by new targeted agents. Of these, human epidermal growth factor receptor 2 (HER2) is currently in the spotlight. In this review, we provide an overview of recent developments in HER2 testing and results of clinical trials targeting HER2 in gastroesophageal adenocarcinoma. Based on the encouraging ToGA trial findings it is now expected that routine HER2 testing will be included in the diagnostic work-up of patients with advanced gastric cancer. With regard to this testing, overexpression of the HER2 protein seems to possess the best predictive properties. However, HER2 immunohistochemistry (IHC) is subject to assay and interobserver variability, so standardization and internal and external proficiency testing is an absolute prerequisite, especially as the IHC scoring system in gastric cancer is different from that of breast cancer. Further study is needed to investigate the clinical meaning of the significant heterogeneity observed in both gene amplification and protein overexpression in gastroesophageal cancer. Highly effective therapies for gastroesophageal cancer can only be accomplished by a multi-targeted approach, considering crosstalk between pathways and continuing to optimize chemotherapy.

Advances in the Pharmacological Treatment of Gastro-Oesophageal Cancer

Advances in the Pharmacological Treatment of Gastro-Oesophageal Cancer

Advances in the Pharmacological Treatment of Gastro-Oesophageal Cancer

Despite a sharp decline in the incidence of gastric cancer during the second half of the 20th century, this malignancy remains the second leading cause of cancer mortality in the world. The incidence and mortality rate of gastric cancer increase with age; at present, the median ages at diagnosis are 67 years for men and 72 years for women in the US. This article reviews and discusses current medical treatment options for both the general population and elderly gastric cancer patients. Management of localized gastric cancer has changed significantly over recent years. Adjuvant chemoradiation is not generally recommended outside the US. After decades of trials of adjuvant chemotherapy with inconclusive results, a significant survival benefit for perioperative combination chemotherapy - as compared with surgery alone - in patients with resectable or locally advanced gastro-oesophageal cancer was recently demonstrated in the UK MAGIC trial. A further large, randomized trial from Japan demonstrated a significant survival benefit for adjuvant chemotherapy with S-1 after D2 resection for gastric cancer. However, both trials are applicable only to the population in which the trials were conducted. Specific data on elderly patients are missing. For patients with metastatic disease, oral fluoropyrimidines, such as capecitabine, have been developed. In Asian patients, treatment with the oral fluoropyrimidine S-1 is safe and effective. Docetaxel, oxaliplatin and irinotecan have demonstrated activity against gastric cancer in appropriately designed, randomized, phase III trials and have increased the available treatment options significantly. In addition, according to preliminary data, trastuzumab in combination with chemotherapy has significantly improved activity when compared to chemotherapy alone in patients with human epidermal receptor (HER)-2-positive gastric and gastro-oesophageal cancers. Thus, therapeutic decisions in patients with advanced gastric cancer may be adapted to the molecular subtype and co-morbidities of the individual patient. Data from retrospective analyses suggest that oxaliplatin seems to be better tolerated than cisplatin in elderly patients.