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Precise Clinical Staging Allows Treatment Modification of Patients With Esophageal Carcinoma

Precise Clinical Staging Allows Treatment Modification of Patients With Esophageal Carcinoma

ABSTRACT: Treatment of esophageal carcinoma requires the realization that this neoplasm is not a single entity with a uniformly poor prognosis. As with any other malignancy, disease stage has prognostic and therapeutic importance. Patients with stage T1-2,N0,M0 or lower tumors have acceptable surgical cure rates and should undergo immediate resection. Patients with more advanced tumors (T3 or N1) are still potentially curable but do poorly with surgery alone. These patients should be considered for multimodality therapy. Patients with hematogenous metastatic disease should be treated with palliative intent. Endoscopic ultrasound (EUS), an accurate, reproducible staging tool, allows for clinical staging of these patients and modification of treatment at the time of diagnosis. Our experience at The Cleveland Clinic Foundation using this algorithm of surgery alone in patients with EUS-defined early-stage carcinomas and multimodality therapy in patients with EUS-staged locally advanced disease is described. [ONCOLOGY 11(Suppl 9):58-62, 1997]

Introduction

The American Cancer Society estimates that in 1996, 12,300 patients were diagnosed with esophageal cancer and 11,200 died from this disease.[1] These data suggest an annual mortality in excess of 90%. Causes for this dismal prognosis are multiple and include tumor, treatment, and patient factors.

Unfortunately, the majority of patients with this neoplasm still present only after the development of dysphagia, a manifestation of advanced disease. Successful surgical resection is difficult due to the propensity of this tumor to spread rapidly through the esophageal wall into adventitial tissue and regional lymph nodes.

Locoregional disease remains the most common reason for treatment failure. Delivery of effective high-dose radiation therapy is complicated by the proximity of the esophagus to critical mediastinal structures, the lungs, and spinal cord. Chemotherapy alone, whether with single agents or multiple-drug combinations, is generally not curative and is ineffective in controlling this disease. The comorbidity often found in patients with this neoplasm is an additional complicating factor.

An extensive review of the literature performed by Earlam and Cunha-Melo[2] in 1980 estimated a 4% overall survival after surgical resection of esophageal carcinoma, and a surgical mortality of 29%. Radiation therapy alone achieved similar success, with an overall survival of 6%.[3] These unacceptable results have led many physicians to consider the treatment of esophageal carcinoma a palliative practice, with cure a serendipitous event.

From 1974 to 1991, there was a modest but statistically significant improvement in the survival of patients with esophageal carcinoma, although the 5-year survival is still only 7% to 11%.[1] Is there hope for patients with esophageal cancer, or will their prognosis continue to be dismal?

First, it must be realized that the surgical mortality reported in earlier series is excessive and no longer acceptable. Most major medical centers now consistently report surgical mortality figures of 5% to 10%. While still formidable, these are much more acceptable surgical risks, particularly when coupled with generally reported surgical cure rates of 10% to 20%. At the Cleveland Clinic Foundation in Ohio, the 5-year survival of all patients with surgically resected esophageal cancer is 18%, with a surgical mortality of 6%.

Second, it must be recognized that improvement in the treatment of this disease begins with the concept that esophageal carcinoma is not a single entity with a uniformly dismal prognosis. Unfortunately, current clinical staging is limited in its ability to preoperatively identify patients who will benefit from surgery. Both primary disease extent and regional nodal spread are prognosticators but are inaccessible to physical examination and are only poorly characterized endoscopically or radiographically.

Therefore, it has been difficult to clinically separate patients who may benefit from aggressive surgical therapy from those best treated palliatively. Accordingly, the results of series reporting the surgical management of all patients have been poor. If treatment results are analyzed by pathologic stage, however, a subgroup of patients with an acceptable prognosis after surgical resection can be retrospectively identified.

Significance of T, N, and M

The present staging system for esophageal carcinoma is a pathologic one, based on the depth of tumor invasion (T), the status of regional lymph nodes (N), and distant sites (M).[4] (Table 1) Although conceptually obvious and consistent with other gastrointestinal tumors, this simple staging system represents a significant advance in the treatment of esophageal carcinoma because it allows for the prognostic stratification of patients and appropriate treatment planning.

T-Status

In node-negative (N0) patients without evidence of distant metastases (M0), the depth of tumor invasion is the critical factor affecting survival. Patients with high-grade dysplasia (Tis; intraepithelial carcinoma) and T1 intramucosal carcinomas (carcinomas limited to the lamina propria and muscularis mucosa) have similar 5-year survival rates after surgery (80% to 85%).[5] However, in node-negative (N0) patients, when the tumor breaches the muscularis mucosa, survival falls dramatically.

Our data suggest that there is no difference between T1 submucosal and T2 carcinomas (tumors that invade but do not breach the muscularis propria), with a 5-year survival of 40% to 50% for each.[6] When the tumor invades beyond the muscularis propria (T3), survival falls even further (< 25% at 5 years).

N1 Disease

Stratification by T-status is unnecessary if regional lymph node metastases (N1) have occurred. In our experience, the survival rates for patients with T1,N1,M0, T2,N1,M0, and T3,N1,M0 carcinomas are similar and are much worse than those for patients with T3,N0,M0 carcinomas.[6] Although survival of patients with N1 disease is independent of T-status, an important relationship between T and N1 exists.

The esophagus is unique among gastrointestinal hollow viscus organs in that its lymphatics are found in the lamina propria and muscularis mucosa. In the stomach and small and large intestines, lymphatics are not encountered by invading tumors until they reach the submucosa. This superficial presence of lymphatics results in a small but significant incidence (5%) of regional lymph node metastases (N1) in T1 intramucosal carcinomas.[5]

As the tumor invades deeper into the esophageal wall, the rate of regional lymph node metastases (N1) increases, with positive regional lymph nodes found in approximately 25% of T1 submucosal tumors, 40% to 50% of T2 tumors, and 80% of T3 or T4 tumors. Since no lymphatics penetrate the basement membrane, regional lymph node metastases are not seen in high-grade dysplasia (Tis) carcinomas.

There is a small population of patients with N1 disease who will have long-term survival after surgery alone. Metastatic burden is a prime predictor of survival for these patients. In our experience, as the absolute number and percentage of positive nodes in a resection specimen increase, there is a corresponding decrease in survival. Patients with three or fewer positive nodes or those in whom less than 10% of resected nodes are positive will have a two- to threefold better chance of 5-year survival than the group as a whole.

M1 Disease

The definition of M1 disease includes the involvement of distant nodal station (eg, supraclavicular and celiac) as well as blood-borne metastases. Distant hematogenous metastatic disease precludes long-term survival. Although considered M1 disease by definition, our experience suggests that celiac axis lymph node metastases (M1) in esophagogastric junction carcinomas may not reduce survival any more than do regional lymph node metastases (N1). Our practice is to treat this subset of M1 carcinomas in the same way that we treat those with regional lymph node metastases.

Impact of Endoscopic Ultrasound on Surgical Management

Accurate clinical staging is necessary for appropriate treatment decisions and prognostication. The development and refinement of endoscopic ultrasound (EUS) and its application to the clinical staging of esophageal carcinoma is a major advance. Clinical staging can now be accomplished with an accuracy of 80% or more for both primary tumor extent (T) and regional nodal involvement (N)—an accuracy not possible with any other staging modality.[7,8]

Once distant metastatic disease is excluded by CT scanning, EUS is performed so as to detect both regional lymph node metastases (N1) and invasion beyond the esophageal wall (T3 or T4). Although several technical limitations do exist, these generally do not detract from the overall staging effort. First, EUS does not adequately identify the boundaries between the epithelium, lamina propria, and muscularis mucosa and microinvasion of the submucosa may be difficult to detect.

However, differentiation of the depth of tumor invasion of these superficial carcinomas does not have an impact on therapy. If these patients are medically fit, they represent the group with the best survival following resection. Current EUS equipment is not useful in the surveillance of patients with Barrett's esophagus.[9] Even in superficial carcinomas, the role of EUS is limited to excluding the regional lymph node metastases.

A second limitation of EUS is its inability to scan the entire malignant stricture in approximately 20% of symptomatic patients. The inability to pass the EUS probe through a malignant stricture, however, provides an accurate and sensitive staging sign. More than 90% of patients will have stage III or IV carcinomas. This is a prognostic accuracy greater than that obtained if only an incomplete examination above the stricture is performed, and patients with this finding are clinically diagnosed with locally advanced carcinomas.[10]

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