Pre- and peri-operative strategies are becoming standard for the management of Localized gastro-esophageal cancer. For localized gastric/gastro-esophageal junction (GEJ) cancer there are conflicting data that a peri-operative approach with cisplatin-based chemotherapy improves survival, with the benefits seen in esophageal cancer likely less than a 5—10% incremental improvement. Further trends toward improvement in local control and survival, when combined chemotherapy and radiation therapy are given pre-operatively, are suggested by recent phase III trials. In fit patients, a significant survival benefit with pre-operative chemoradiation is seen in those patients who achieve a pathologic complete response. In esophageal/GEJ cancer, definitive chemoradiation is now considered in medically inoperable patients. In squamous cell carcinoma of the esophagus, surgery after primary chemoradiation is not clearly associated with an improved overall survival, however, local control may be better. In localized gastric/GEJ cancer, the integration of bevacizumab with pre-operative chemotherapy is being explored in large randomized studies, and with chemoradiotherapy in pilot trials. The addition of anti-epidermal growth factor receptor and anti-human epidermal growth factor receptor-2 antibody treatment to pre-operative chemoradiation continues to be explored. Early results show the integration of targeted therapy is feasible. Metabolic imaging can predict early response to pre-operative chemotherapy and biomarkers may further predict response to pre-operative chemo-targeted therapy. A multimodality approach to localized gastro-esophageal cancer has resulted in better outcomes. For T3 or node-positive disease, surgery alone is no longer considered appropriate and neo-adjuvant therapy is recommended. The future of neo-adjuvant strategies in this disease will involve the individualization of therapy with the integration of molecular signatures, targeted therapy, metabolic imaging and predictive biomarkers.
Globally both gastric and esophageal cancers are significant health problems and account for approximately 1.4 million new cases per year with 1.1 million cancer-related deaths [Parkin et al. 2005]. This annual mortality is higher than that for both breast and colorectal cancers combined. In the United States, in 2008, an estimated 16,470 patients will be diagnosed with esophageal cancer resulting in 14,280 deaths, making this disease the seventh leading cause of cancer death in men, and 21,500 cases of gastric cancer will be diagnosed resulting in 10,880 deaths [Jemal et al. 2008].
The last three decades have seen a dramatic epi-demiologic shift in the location of both gastric and esophageal cancers as well as the histologic subtype of esophageal cancers. Tumors of the lower esophagus and proximal stomach are classified as gastro-esophageal junction (GEJ) cancers and this cancer has been increasing in incidence by 5—10% per year since the mid 1970s and is the most rapidly increasing cancer in many Western countries [Kamangar et al. 2006]. Distal esophageal and GEJ adenocarcinoma is now the predominant esophageal cancer subtype, and the majority of gastric cancers are now located in the proximal stomach [Pera et al. 1993].
The 5-year survival of patients with gastro-esophageal cancers (distal esophagus, GEJ, and proximal stomach making up the majority of cases) has not changed significantly over the last 25—30 years. Approximately 50—60% of patients present with distant metastatic disease and median overall survival (OS) with systemic chemotherapy has remained at less than one year [Van Cutsem et al. 2008]. However, progress has been made in the treatment of localized disease. Combinations of pre-operative (neo-adjuvant) chemotherapy, peri-operative chemotherapy or pre-operative (neo-adjuvant) chemoradiotherapy with surgery have resulted in R0 resection rates between 40 and 80% and 5-year survival rates from 20 to 40%.
A variety of combination chemotherapeutic agents have been used in the treatment of gastro-esophageal cancers over the last 30 years. These include fluoropyrimidines, anthracyclines, platinums, taxanes and campothecins. Combining different classes of drug exploits the different modes of action in the cancer cell and may allow lower doses of each individual drug to be given in the combination regimen thus reducing side effects. Work over the last decade has identified distinct molecular pathways leading to tumorigenesis, angiogenesis and metastasis. Drug development has led to direct treatment at specific molecular targets. This review will focus on the integration of targeted therapy into the neo-adjuvant treatment of gastro-esophageal cancers.
Filed Under: Research