Multimodality Therapy for Esophageal Cancer

Overview: Principles of Multimodality Therapy

Achieving real improvement in the treatment outcomes for esophageal cancer has been a slow process. Arguably, the major hurdles impeding our ability to diagnose and treat the disease were, for the most part, overcome in the last century. Establishing reliable and safe anesthetic techniques for thoracic surgery and minimizing mortality from an esophageal resection while maximizing local/regional control (to the extent that radical surgery is capable) had significant impact in placing surgery at the forefront of esophageal cancer therapy. Yet, the breakthrough discovery that would allow us to cure a significant percentage of people with this diagnosis eludes us. Radical surgery reached a ceiling of effectiveness, and the field is now in the process of backing away from larger resections in favor of minimizing trauma and operative morbidity. Nominal improvements in survival outcomes have been made by avoiding mortality rather than salvaging sicker patients, by focusing on more appropriate patient selection by avoiding those that are at high risk for perioperative mortality or distant failure. Whereas this gives the impression that we are improving, it leaves behind the patients who are not salvageable with existing local/regional therapies. Even though resection has been considered the backbone of esophageal cancer treatment, we have learned that radical resections with or without other forms of local/regional therapy are not adequate to cure advanced disease in most cases. Distant recurrence continues to be the main cause of death in patients with esophageal cancer.

As long as we lack truly effective methods of screening, most patients with esophageal cancer will present with locally advanced disease. Strategies that address both local/regional as well as distant disease have the most potential to realize real gains in survival outcomes for patients who have esophageal cancer. The early evolution of a multimodality treatment paradigm started decades ago, first with the recognition that a cure could be obtained in some patients without the use of surgery. But the relatively poor local/regional control attained with (nonoperative) medical therapy led to the concept that multimodality therapy that involved surgery could be feasible and could more effectively address both compartments of disease, local and lymphatic. The combination of local and systemic therapies has become the focus of many clinical trials investigating the role and timing of each method.

Preoperative (neoadjuvant) combination therapy is based on principles of patient tolerance and compliance with therapy compared to postoperative therapy (adjuvant). What became apparent in early trials of multimodality therapy was that patients were more frequently able to receive all of their therapy if it was administered before surgery. Also of interest is that when patients receive therapy while tumor is in vivo, therapy response can be directly observed via imaging and later pathologically assessed after resection. These clinical findings amount to surrogate endpoints of efficacy. In contrast, advocates of adjuvant therapy administer therapy only to patients with indications based on final pathologic analysis, thus sparing some patients the unnecessary toxic effects of treatment.

Radiation Therapy

Before the surgical era, radiation was considered the primary treatment modality for esophageal cancer. Early experience with radium bougies demonstrated esophageal tumor regression but rarely complete cure. With the evolution of surgical care, external beam radiation became a component of a multidisciplinary approach to esophageal cancer therapy with the goal of sterilizing areas within or around the operative field.

Chemotherapy

There are several reasons that chemotherapy would seem to be an attractive treatment modality for esophageal cancer. The most frequent mode of death from esophageal cancer is attributed to metastatic disease. Naturally, the concept of delivering systemic chemotherapy to treat hematogenous disease would seem advantageous. Chemotherapy is also capable of downstaging larger, marginally resectable tumors, which could allow for an improvement in complete (R0) resection rates and decrease the incidence of local/regional recurrence. Shrinking tumors also allows patients to become nutritionally replete and independent from supplements as dysphagia resolves. Finally, chemotherapy acts synergistically with radiation as a local/regional therapy, further strengthening arguments for its use.

Current chemotherapeutic regimens are typically delivered as a doublet or triplet combination based on platinum compounds given in concert with 5-fluorouracil (5-FU) or a taxane. This approach has had encouraging results in early phase II trials, in some cases producing clinical responses in up to 50% of patients with the occasional complete pathologic response.