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Multimodality Therapy for Esophageal Cancer

Multimodality Therapy for Esophageal Cancer

ABSTRACT: Recent developments in the epidemiology, staging, and treatment of esophageal and gastroesophageal junction cancers have led to significant changes in the way these malignancies are managed. Although a relationship between gastroesophageal reflux disease and esophageal cancer has been demonstrated, antireflux surgery has been shown to have no preventive effect with regard to the development of esophageal adenocarcinoma. The newly modified staging system of the World Esophageal Cancer Consortium has helped define the optimal number of lymph nodes to dissect during an esophagectomy. Incorporating modern techniques, such as esophageal ultrasound, fine needle aspiration, and positron emission tomography, can improve the prognostic value of staging. Use of higher-volume centers and higher-volume surgeons for the performance of procedures in upper gastrointestinal cancers is associated with better outcomes. Neoadjuvant chemoradiation using a wide variety of chemotherapy regimens appears to have become the new standard of care for stage II and III esophageal cancer.

There have been practice-changing developments in the treatment of esophageal and gastroesophageal junction (GEJ) cancers over the past several years. New directions have been reported in the epidemiology, staging, and treatment of these cancers. This review will update the reader on the latest in all aspects of the management of these malignancies, including staging, surgery, and multimodality therapy. Particular attention will be paid to recently published and unpublished data.

Epidemiology

Tobacco smoking is a well-established risk factor for the development of squamous cell carcinomas and adenocarcinomas of the esophagus. A study by Duan and colleagues evaluated the intensity of passive smoking exposure by counting the number of smokers who smoked in a participant’s presence for at least one year and measuring the duration of each exposure. The tobacco exposure of 1,716 participants was compared to that in twice as many controls. The authors found no evidence that in persons who have never actively smoked, exposure to passive smoke during their childhood years or during their adult years influences their risk of esophageal adenocarcinoma.[1]

Human papillomavirus has now been implicated in esophageal cancer in reports from both Europe and China, where there is an increasing association, primarily with squamous cell carcinomas.[2] A recent study from the Swedish authors who first described the relationships between gastroesophageal reflux disease, obesity, and esophageal cancer made the observation that antireflux surgery had no preventive effect on the development of esophageal adenocarcinoma. In a population-based cohort study comparing 14,102 people who had had antireflux surgery (representing 120,514 person-years at risk) with the population at large, the overall risk of esophageal adenocarcinoma (n=39) was 12 times higher in those who had had the surgery; no decrease in risk was found with time after antireflux surgery (P=.86).[3]

Staging and Prognosis

Peritoneal Washings

The impact of positive peritoneal washings on gastric cancer outcomes was evaluated retrospectively in patients with gastric cancer who underwent laparoscopy with peritoneal washings. Of these patients, 198 had peritoneal or visceral metastases at the time of laparoscopy and were designated as having M1 disease. The remaining 93 patients had M0cyt+ disease, defined as cytology indicative of metastatic tumor but with no visible visceral or peritoneal metastases. Patients with M0cyt+ tumors had a significantly longer disease-specific survival (DSS) than did those with M1cyt+ disease (P<.0001). Patients with M0cyt+ disease who received subsequent chemotherapy resulting in a conversion to negative cytology at next laparoscopy had better DSS.[4]

Sentinel Node Mapping

Sentinel node mapping is a strategy whose value has been validated in the surgical management of patients with melanoma and breast cancer; it has been shown to reduce complications resulting from unnecessary lymph node dissections. A similar strategy, recently described for lung cancer,[5] has been proposed for gastric and esophageal cancers. A recent study enrolled 433 patients with early gastric cancer whose disease was limited to T1 or T2,N0,M0 tumors; all tumors were less than 4 cm in size, and patients had received no prior therapies. A dual-tracer method that employed radioactive colloid and blue dye was used to detect involved nodes. The rate of detection of involved sentinel lymph nodes was 387/397 (97.5%). The mean number of sentinel nodes per case was 5.6. Use of sentinel node status for the detection of metastases has been reported to have a 93% sensitivity.[6] Further development of the sentinel node concept is ongoing, and this approach may represent a feasible and clinically reasonable option for reducing the extent of resection in the treatment of very early stage esophageal and gastric cancers.

Revised Staging System

In several papers published since 2008, the World Esophageal Cancer Consortium (WECC) has presented a newly modified staging system for esophageal cancer (Table). The revised system includes significant changes in definitions for lymph node (LN) involvement as well as stage groupings for this disease. For the first time, the staging system has been based on a large cohort of patients who underwent surgical resection using modern staging techniques and for whom good clinical annotations were available. The essential changes to the system include the addition of tumor grade and of N (node)1 and N2 categories based on the number of LNs involved (fewer than 5, or 5 or more).[7]

TABLE Table 1
New WECC/AJCC Staging System for Esophageal Cancer

Using WECC data, the relationship between survival and extent of lymphadenectomy (LND) have been described, and the optimum LND defined. A total of 4,627 patients with esophageal cancer who were treated with esophagectomy alone were identified. The risk-adjusted 5-year survival was averaged for each number of lymph nodes resected, and the optimum number of nodes that should be resected to maximize 5-year survival was determined. In moderately and poorly differentiated pN0M0 cancers and in all node-positive (pN+) cancers, 5-year survival improved with increasing extent of LND. In pN0M0 cancers, no optimum LND was defined for pTis; optimum LND was 10 to 12 nodes for pT1, 15 to 22 nodes for pT2, and 31 to 42 nodes for pT3/T4 (depending on histopathologic cell type). In pN+M0 cancers with 1 to 6 positive nodes, the optimum LND was 10 nodes for pT1, 15 nodes for pT2, and 29 to 50 nodes for pT3/T4. Greater extent of LND was associated with increased survival for all patients with esophageal cancer except at the extremes of disease severity (TisN0M0 cancers, and 7 or more regional lymph nodes positive for cancer) and in well-differentiated pN0M0 cancer. Maximum 5-year survival is modulated by T classification: resecting 10 nodes for pT1, 20 nodes for pT2, and 30 or more nodes for pT3/T4 is recommended.[8]

The proposed WECC esophageal system is superior to the current American Joint Committee on Cancer (AJCC) gastric and esophageal staging systems for resected GEJ tumors regardless of neoadjuvant status. The WECC system incorporates GEJ tumors into the esophageal staging system and has the potential for harmonization with the gastric staging system. Unfortunately, there are still challenges involved in using this system as a pretreatment clinical tool in patients with esophageal cancer.[9-11]

Use of Modern Techniques for Staging

In addition, recent reports have emphasized the importance of using modern techniques such as esophageal ultrasound (EUS) and EUS fine needle aspirations (FNA) in pretreatment clinical staging. The use of restaging after neoadjuvant treatment has also advanced and has resulted in the identification of subgroups of patients who may or may not benefit from surgery and/or chemoradiation.[12] The postchemoradiation percentage decrease from baseline in the standardized uptake value (SUV) of positron emission tomography (PET) was shown to correlate with overall survival (OS) and pathologic response. Baseline and postchemoradiation PET/computed tomography (CT) studies were performed in 151 consecutive patients with gastroesophageal adenocarcinoma who had been treated with chemoradiation and surgery. A decrease in SUV of more than 52% was associated with a longer OS (P=.023) and a lower risk of death (P<.01). Pathologic response (50% or less residual cancer) was also associated with longer OS (P=.003). In the multivariate model, the percentage SUV decrease was the only prognostic indicator of OS (P=.01). The percentage SUV decrease was not associated with pathologic complete response.

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