Although relatively rare in the United States, esophageal cancer is the seventh leading cause of cancer-related death in American men, and adenocarcinoma of the esophagus represents the most rapidly increasing solid tumor malignancy. Survival achieved with surgery or chemoradiotherapy is only 25% to 35% at 5 years. With the use of combined chemoradiotherapy followed by surgery, 5-year survival rarely exceeds 30% to 35%. The limitations of combined modality mandate the evaluation of novel investigational approaches. Trials of newer chemotherapy regimens combining paclitaxel or irinotecan with cisplatin and radiation have suggested a potential to improve the therapeutic index of chemoradiotherapy. Weekly paclitaxel or irinotecan in combination with cisplatin and concurrent radiotherapy is now the subject of national trials being conducted by the Eastern Cooperative Oncology and Radiation Therapy Oncology Groups. Although research continues with conventional cytotoxic agents, it is increasingly clear that we may have reached the limit of the benefit that can be achieved with conventional chemotherapeutic agents. The identification of specific, biologic mechanisms of growth regulation, tumor angiogenesis, and metastasis has led to new drug development in an attempt to target and inhibit these specific pathways. Promising targets include growth factor receptors and their activating ligands, the tyrosine kinase pathways responsible for signal transduction across these receptors, and the downstream pathways within the cell.
The trial by Safran and colleagues represents a significant step forward in combined modality therapy trials in esophageal cancer. These authors have now added a monoclonal antibody to combined chemoradiotherapy, Trastuzumab, directed against a member of the epidermal growth factor receptor (EGFr) family, HER-2/neu. The choice was based on preclinical data indicating synergy of Trastuzumab with both paclitaxel and cisplatin, as well as the potential for EGFr blockade to potentiate the effect of radiotherapy. The authors screened tumors for HER-2/neu overexpression by immunohistochemistry, and then validated the overexpression by both cytogenetic and gene expression studies. Therapy with Trastuzumab was limited to patients whose tumors overexpressed HER-2/neu because previous studies in breast cancer of Trastuzumab alone or in combination with chemotherapy indicated that a benefit for the targeted therapy was limited to patients whose tumors overexpressed the target. The selection of HER-2/neu as a target was justified because up to 30% of patients' tumors overexpressed the target. The addition of a targeted agent was shown to be feasible and well tolerated. The small number of patients treated rendered assessment of the efficacy of the targeted agent unclear. The surrogate of efficacy in combined chemoradiotherapy trials in esophageal cancer has traditionally been the achievement of a pathologic complete response rate. However, because targeted agents may exert their effect by cytostatic properties rather than cytotoxic properties, a response rate endpoint may not be appropriate or may not indicate a benefit from addition of a targeted agent, which may have an impact on overall and disease-free survival rather than antitumor response.
The authors' strategy represents the priority of future research, studying the tumor for expression of a target, and combining a targeted agent with conventional chemotherapy and radiotherapy in a phase I design to ensure safety and tolerance. Unanswered questions include the optimal sequencing and optimal combination of targeted agents with other modalities, such as chemotherapy, radiotherapy, and surgery. Given the more recent trials of tyrosine kinase inhibitors combined with chemotherapy in lung cancer, which failed to show benefit for the addition of targeted therapy to chemotherapy, it is clear that the optimal strategy to include these agents in combination with conventional therapies remains to be defined. In targeted therapy trials, each targeted agent must be assessed on a tumor-by-tumor basis, as well in combination with specific chemotherapy agents, and either as a first-line or salvage treatment.
The future is exciting given the number of targeted agents in development. The inclusion of targeted agents in clinical practice will ultimately require validation in controlled clinical trials to establish benefit of these agents and to potentially rule out antagonism with conventional therapy.
David H. Ilson, M.D., Ph.D.