From OncoLog, July 2010, Vol. 55, No. 7

Compass: Locoregional Cancer of the Esophagus
Timing Surgery and Other Therapies for Resectable Disease

By Sunni Hosemann

Introduction

More than 90% of esophageal cancers are either squamous cell carcinomas or adenocarcinomas. This discussion focuses on those two types of esophageal cancer, specifically the intermediate stages known as locoregional disease.

Locoregional disease is defined here as resectable disease that has invaded beyond the submucosa and may involve regional lymph nodes and other structures including the pleura, pericardium, or diaphragm. Locoregional disease is thus differentiated from early disease (a tumor that is in situ or involves only the lamina propria or mucosal layers of esophageal tissue) and from disease that is unresectable or has metastasized beyond the regional lymph nodes (having spread to distant lymph nodes, distant organs, or certain adjacent structures, such as the aorta, vertebral body, or trachea).

Several treatment approaches for locoregional disease are currently considered standard, but for individual patients, there are options that require considerable analysis and discussion.

About Esophageal Cancer

Esophageal cancer is not common, but it is considered one of the deadliest cancers. According to the latest estimates of the American Cancer Society, 16,470 people in the United States were diagnosed with esophageal cancer and 14,530 died of the disease in 2009. The 5-year overall survival rate is only 18%, according to the Surveillance, Epidemiology, and End Results Program of the U.S. National Cancer Institute.

One of the reasons for the low survival rate of patients with this cancer is that it is often advanced before it is found. Two factors contribute to the likelihood of late detection: First, esophageal cancer does not cause alarming early symptoms; the most common presenting symptom is dysphagia. Typically, the dysphagia is progressive and easily ignored, and consultation is not sought until the patient has difficulty swallowing soft foods or even liquids, by which time the lumen of the esophagus is often substantially obstructed by the tumor.

The second factor is the anatomy of the esophagus itself. Unlike the rest of the gastrointestinal tract, the esophagus lacks a serosal layer of tissue, making it more vulnerable to local invasion by cancer cells. The esophagus is also richly supplied by adjacent lymphatics, which provide a conduit for rapid spread of cancer cells to regional cervical, mediastinal, paraesophageal, gastric, and celiac lymph nodes. As a result, esophageal cancer is associated with early invasion of adjacent structures—including the pericardium, heart, trachea, vertebral body, and lung—and early metastasis, most commonly to the lung, liver, and bone. In fact, regional lymph node involvement is found in more than 75% of esophageal cancer patients at presentation, according to Steven Hsesheng Lin, M.D., Ph.D., an assistant professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center.

Over the past 2 decades, there has been a dramatic shift in incidence of histologic type and tumor location for esophageal cancers in the United States. Prior to the 1990s, squamous cell carcinoma was the predominant histology, and it is still the most common worldwide. But in the United States, adenocarcinomas have become the most common, and in fact, adenocarcinoma of the esophagus has the fastest growing incidence rate of all cancers.

The primary risk factors for squamous cell cancers of the esophagus are tobacco and alcohol use. These cancers are also associated with achalasia, lye strictures, and therapeutic radiation as well as Plummer-Vinson syndrome (a condition characterized by dysphagia and esophageal webs) and tylosis (a hereditary cutaneous disorder). Squamous cell carcinomas can occur in any location within the esophagus. Adenocarcinomas, on the other hand, tend to occur in the distal esophagus and at the gastroesophageal junction and are strongly associated with chronic gastrointestinal reflux and obesity. Barrett esophagus is also considered a strong risk factor for adenocarcinoma of the esophagus.

Treatment Overview

The cornerstone of curative treatment for esophageal cancer has traditionally been surgery (esophagectomy). Thus, a primary objective of the initial patient evaluation is to determine whether the disease is resectable. According to Stephen Swisher, M.D., a professor in and chairman of the Department of Thoracic and Cardiovascular Surgery, the major technical barrier to resectability in the thorax is tumor involvement of the aorta or tracheobronchial airways. Even if the tumor is resectable, circumferential margins are often very close owing to the proximity of critical surrounding structures. Because of this, preoperative chemoradiation has been used in conjunction with surgery to help achieve complete resections with uninvolved proximal, distal, and circumferential margins.

Esophagectomy is a major and complex operation in which the tumor-bearing esophagus is removed and the alimentary tract is reconstructed using the stomach or, in some cases, the intestine. One potentially serious complication is an anastomotic leak, which has led to the high morbidity and mortality rates historically associated with this surgery. Morbidity and mortality have been reduced in recent years by high-volume centers specialized in esophageal resection. Referral of esophageal cancer patients to a high-volume center is therefore recommended.

Surgery alone, however, has proven curative in only 20% of patients with locoregional esophageal cancers, suggesting that microlymphatic disease is probably present in most cases and that additional therapy is needed to achieve both regional and distant disease control. Radiation therapy and chemotherapy have been studied alone and as single adjuncts to surgery, given either preoperatively (neoadjuvantly) or postoperatively, but the most significant improvements in survival have been seen using both.

Although large trials to date have not proven chemotherapy plus radiation therapy given preoperatively to be superior to that given postoperatively, there is a strong rationale for preoperative use. “The whole idea behind adjuvant therapy is to manage occult distant disease,” said Linus Ho, M.D., Ph.D., an associate professor in the Department of Gastrointestinal Medical Oncology. “But valuable time passes if we wait until after surgery and surgical recovery, so we prefer neoadjuvant therapy because it addresses occult disease earlier.” Dr. Ho also noted that the adjuvant treatment is better tolerated before surgery. “In fact, among patients who have surgery first, 30%–50% will never receive postoperative therapy because it is more difficult to tolerate after surgery,” he said. “And that represents a lost opportunity.” According to Dr. Ho, there is an additional benefit to neoadjuvant therapy: improvement of symptoms. Many patients present with substantial esophageal obstruction as well as weight loss and nutritional deficits. Some require temporary gastrostomy or jejunostomy tubes to provide nutritional support via enteral feedings, but by the end of chemoradiation treatments, many such patients are able to eat normally.

Given the advantages of neoadjuvant therapy, the current standard recommendations for patients with locoregional disease include chemoradiation alone or chemoradiation followed by surgery. Chemotherapy followed by surgery is also considered a standard for adenocarcinomas in the distal esophagus or gastroesophageal junction, but at MD Anderson, combined-modality neoadjuvant treatment is favored over neoadjuvant chemotherapy for these patients, too. “Based on large studies and our own experience, neoadjuvant chemoradiation is our preferred approach,” Dr. Lin explained. He pointed out that some of the large European trials showing significant results with neoadjuvant or perioperative chemotherapy (without radiation) included gastric cancers in the study population, which may account for the difference in results from other studies and the experience at MD Anderson.

Treatment Decisions

The primary treatment decision for patients presenting with locoregional esophageal cancer is whether to employ chemoradiation alone or to follow it with surgery. Overall, survival rates are superior when surgery is included. However, because esophagectomy is a major and complex surgery, the decision for individual patients can vary. In addition, chemoradiation alone is curative in 25% of patients—this was demonstrated in a large trial (Radiation Therapy Oncology Group [RTOG]-8501) that compared chemoradiation alone to radiation alone in patients with unresectable esophageal cancer and further corroborated by the observation of complete pathologic responses in 25% of patients after chemoradiation therapy. Clearly, there are some patients who do not require surgery. “The problem is that we don’t know ahead of time which patients those are,” said Dr. Lin, pointing out that the remaining 75% of patients who receive chemoradiation alone have varying degrees of residual disease (from 1%–80%). When there is a complete response to therapy, long-term overall survival is greater than 60%.

In general, one of the primary considerations in the esophagectomy decision is where the surgery will occur—specifically, whether the patient will be treated at a center that performs a (Continued on page 6) high volume of esophagectomies. Numerous studies have confirmed that mortality rates from various surgeries are related to the volumes of those surgeries performed at an institution. Esophagectomy is a surgery for which the difference in mortality rates between high- and low-volume centers is marked, with high mortality rates in centers where few procedures are performed. Surgeon experience and the availability of supportive perioperative care, including specialty services to detect and manage leaks should they occur, are critical factors. Access to a high-volume center is therefore an important risk consideration.

At MD Anderson, the medical decision between trimodality therapy or chemoradiation alone hinges primarily on the patient’s performance status—which indicates how well surgery will be tolerated—and on the relative risk of recurrence. Patients who are otherwise in poor health or who have comorbidities that would compromise recovery are often better suited to receive chemoradiation alone. But for patients who are healthy and good surgical candidates, the question of whether to have surgery is a personal one that requires substantial discussion between physician and patient.

Should a locoregional recurrence occur later, it may be more difficult to resect completely. “For some patients, this might mean that we missed an opportunity for a cure while disease was at an earlier stage,” said Dr. Swisher. On the other hand, the surgery requires a substantial recovery period and lifestyle changes—for example, eating smaller, more frequent meals—that may factor into the decision. “Patients usually make these adjustments and over time don’t find them to be major problems,” Dr. Swisher said, “but these lifestyle changes are something that we discuss.”

Dr. Swisher spends a considerable amount of time ensuring that patients are fully informed and comfortable with their decision. “Some patients don’t want to take any chances—they want to do everything possible up front to get rid of their cancer and minimize the possibility of the cancer returning,” he said. “Others would like to avoid the surgery if they possibly can, and we assure them that this approach is also reasonable.” The size and extent of tumor may also play a role in the decision if they influence the complexity and risk of the surgery.

A large clinical trial (RTOG-0246) recently completed sheds some additional light on the appropriateness of “selective surgery.” In this trial, patients received induction chemotherapy followed by definitive chemoradiation and were monitored thereafter at 3-month intervals with computed tomography and positron emission tomography if no disease was detected after chemoradiaton. Surgery was done only if residual or recurrent disease was detected. In the study, about 40% of patients were found to have residual disease following chemoradiation. Of the remaining 60%, about 10%–20% had a recurrence requiring surgery and another 20% had distant recurrence and therefore may not have benefitted from esophagectomy anyway. “For those patients who ultimately need delayed surgery, the risks may go up because of the delay, particularly for complications such as anastomotic leaks. Because of this and the high risk of residual disease, we still recommend planned surgery for patients who are physically fit, although selective surgery is always offered as an option,” Dr. Swisher said.

Another initiative that holds promise for making the treatment decision easier is aimed at identifying the 25% of patients in whom chemoradiation will result in a cure. According to Dr. Lin, post-treatment biopsies are not reliable predictors of pathologic response, and although better outcomes are seen in patients who have a complete response to chemoradiation as gauged by imaging, the possibility of residual disease cannot be ruled out by imaging. Dr. Lin believes that the key to identifying patients who can be cured by chemoradiation lies in understanding the molecular biology of tumor subtypes and identifying the phenotypic signature of those tumors likely to have a complete response to chemoradiation. Current studies are using genetic profiling techniques to analyze tissues from pretreatment endoscopic biopsy specimens, and molecular subtypes of esophageal cancer have been identified.

“We hope this leads to the identification of biomarkers that will enable us to predict those patients who will have complete responses to neoadjuvant therapy and can thus safely forego surgery,” Dr. Lin said.

References

National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology, Esophageal Cancer V1.2010 [PDF]

For more information on this topic or for questions about MD Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

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