Dr. Hwang has thoroughly and thoughtfully reviewed chemotherapy options for gastroesophageal cancer—but the catalogued trials tell a story of ponderously slow though incremental progress without identifying one optimal treatment regimen or modality.

Evolving Regimens

Most patients with gastroesophageal cancer eventually develop metastatic disease. As nicely outlined by Dr. Hwang, despite a large number of published phase II/III trials and occasional claims to the contrary, no chemotherapy has yet won the title of "standard of care" for either metastatic esophageal or gastric cancer. In metastatic gastroesophageal (GE) junction and gastric tumors, cisplatin(Drug information on cisplatin)/fluorouracil (5-FU) combinations have long served as the backbone of treatment.

Recent phase III trials using newer agents such as docetaxel, irinotecan(Drug information on irinotecan) (Camptosar), and oxaliplatin(Drug information on oxaliplatin) (Eloxatin) have reported encouraging results. In particular, the EOX (epirubicin [Ellence], oxaliplatin, capecitabine(Drug information on capecitabine) [Xeloda]) arm of the REAL-2 trial (in which substitutes oxaliplatin for cisplatin, and capecitabine for continuous-infusion 5-FU, in the ECF regimen) demonstrated a median survival of 11.2 months, with modest toxicity.[1] The DCF regimen (docetaxel, cisplatin, 5-FU) also has demonstrated efficacy, producing a time to progression of 5.6 months and a median survival of 9.2 months. However, this outcome came at the cost of what we consider to be an unacceptable rate of grade 3/4 toxicity (81%) and febrile neutropenia/neutropenia with infection (30%).[2] Different iterations of DCF may have an impact on both toxicity and efficacy in metastatic GE cancer.

Differing Histologies

In his discussion of esophageal cancer, Dr. Hwang makes a clear distinction between squamous cell carcinomas and adenocarcinomas of the esophagus, suggesting that these should be treated differently. He appropriately notes that the incidence of distal esophageal and GE junction adenocarcinomas is on the rise in the Western world, and that the inciting factors for squamous cancers and adenocarcinomas differ. However, we disagree with his assertion that these histologies behave differently enough to necessitate a different treatment paradigm.

On the one hand, there is ample evidence to suggest that distal esophageal adenocarcinomas and adenocarcinomas of the GE junction are very similar to proximal gastric cancers in their etiology and biology and, therefore, can be approached similarly. In a recent pooled analysis from four randomized clinical trials that enrolled patients with esophageal, GE junction, and gastric adenocarcinomas, investigators found no difference in clinical efficacy or toxicity of chemotherapy.[3] Thus, there is good justification for treating these diseases similarly.

On the other hand, although it is logical, given the anatomic proximity, similar epidemiology, and histopathology, to approach squamous cell esophageal cancers in the same way as head and neck cancers, there is little evidence to either support or refute this strategy. In fact, in the metastatic setting, squamous cell cancers and adenocarcinomas behave similarly, with a short-lived but high rate of chemotherapy responsiveness.[4] Thus, it is reasonable to palliate a patient with metastatic squamous cell carcinoma of the esophagus with either a head and neck cancer or gastric cancer regimen.

Trimodality Therapy

In localized disease, however, we believe it is a mistake to recommend against trimodality therapy (chemoradiotherapy and surgery). In esophageal cancer, where our treatments are not targeted to tumor biology and are only modestly effective, anatomic considerations seem to play a crucial role. In the case of cervical esophageal cancers, where proximity of the esophagus to vital structures often precludes acceptable functional preservation with resection, definitive chemoradiotherapy as used in head and neck cancer is the best option.