Racette, Ashley L. PA‐C, MPAS; Miller, Richard T. MD
Esophageal carcinoma is the sixth leading cause of cancer death in the world,1 and despite multiple studies evaluating different treatment modalities the mortality rate remains high.2 Treatment for esophageal cancer may involve chemotherapy, radiation therapy, and surgery. Recently, there has been an interest in trimodality therapy in an effort to improve survival in patients with moderate‐stage disease.
RISK FACTORS AND DIAGNOSIS
The main risk factors for esophageal cancer are tobacco use, Barrett's esophagus, alcohol abuse, and radiation therapy to the mediastinum. Histologically, 90% of esophageal cancers are either adenocarcinoma or squamous cell carcinoma.1 Studies performed on animals suggest that oxidative damage from chronic irritation of the esophagus can cause esophagitis, and increased cell turnover may trigger the carcinogenic process.1 Dysphagia is the most common symptom at the time of diagnosis. Physical examination is usually unremarkable, but a thorough and efficient workup is necessary. At the time of diagnosis, more than 50% of patients have either unresectable disease or radiographic evidence of metastases. Such a high incidence of lymph node involvement may be due to the extensive lymphatic drainage found in the lamina propria and muscularis mucosa deep to the basement membrane, which makes the esophagus unique among the gastrointestinal hollow viscus organs.3 Additionally, patients may develop cancer before they develop cancer‐specific symptoms, often producing a long lead time between the onset of cancer and tissue diagnosis.
Diagnosis The diagnostic workup for esophageal cancer includes a barium swallow; upper GI endoscopy with biopsy; staging imaging studies including CT of the chest, abdomen, and pelvis; and possible whole‐body PET (positron emission tomography). The barium swallow study may reveal stricture or partial obstruction of the esophagus that may show the classic radiographic apple core lesion. On upper endoscopy, esophageal cancer appears as a friable or ulcerated mass (Figure 1). Biopsies of the mass may be obtained to determine histology. PET and CT scans of the chest, abdomen, and pelvis can reveal possible metastasis. CT scans help to exclude metastases to the lungs and liver as well as to demonstrate possible invasion of the disease to adjacent structures. PET scans can assess possible metastasis to lymph nodes and/or bone. Both studies are noninvasive and are considered a useful and efficient part of the workup for esophageal cancer.
Staging The gold standard for regional staging of esophageal cancer is endoscopic esophageal ultrasound (EUS). This method is accurate in determining the depth of a tumor, or T stage. EUS can also assess tumor involvement in local lymph nodes. Staging for esophageal cancer is classified according to the American Joint Committee on Cancer tumor‐node‐metastasis (TNM) staging system, which considers histology of the primary tumor, local nodal metastases, and distant metastases.
Esophageal cancer can be treated with surgery, radiation therapy, or chemotherapy. In order for the cancer to be curable, treatment must focus on eliminating the primary lesion as well as eliminating or preventing metastases.4 Chemotherapy and radiation can be applied before surgery as neoadjuvant therapy, after surgery as adjuvant therapy, or as definitive therapy without surgery. Although esophageal cancer has been widely studied, a well‐designed, large‐scale, randomized controlled trial has not yet been performed. Factors that complicate the completion of such a study include patient recruitment, differences in surgical techniques, and variations in chemotherapy and radiation treatments. The 5‐year survival rate for patients with esophageal cancer is poor for all but those with the earliest‐stage tumors, but this rate has improved slightly over the past decade.
Optimal treatments for patients with midstage esophageal cancers remain controversial and are dictated by the stage of disease. For example, stage III disease often requires chemotherapy plus radiation therapy with or without subsequent surgery. In more advanced disease (stages II and III), surgery alone with complete resection of the lesion and other areas with gross disease has a median survival of 12 to 18 months and a 20% 5‐year survival rate.1,4,5 Because of the low cure rates with resection and the high incidence of recurrent disease, other treatment modalities have been used in an effort to increase survival rates. Recently, there has been discussion about the use of neoadjuvant chemoradiation followed by subsequent surgery for the treatment of locally advanced esophageal cancer. Some studies suggest that trimodality therapy may yield more successful results and better prognosis for patient survival.
Preoperative radiation In patients with locally advanced esophageal cancer, preoperative radiation can be used to debulk the tumor and sterilize nodal areas. Several studies have demonstrated that this treatment regimen does not improve survival in patients but may help to lower the rate of local recurrence in patients with positive margins.6
Neoadjuvant chemotherapy Similar to preoperative radiation, neoadjuvant chemotherapy is used to downsize the tumor for surgical resection, enhance local control, and prevent micrometastatic disease. Research suggests that preoperative chemotherapy may provide some survival benefit in persons who have a complete pathological response to treatment.4 However, the data remain conflicting because of variations in dosing and number of treatments administered. Adjuvant chemotherapy is used in patients with nodal involvement. A randomized controlled trial performed in Japan demonstrated an improved 5‐year survival rate but did not show statistical significance in overall survival rates. There was no improvement in overall 5‐year survival rates in subjects who underwent adjuvant chemotherapy with no nodal involvement.4 Definitive chemoradiotherapy in locally advanced esophageal cancer has curative potential, but the rates of local recurrence and metastatic disease can be high with this treatment, with a local recurrence rate of approximately 50%.7
Surgery Surgical resection is the treatment of choice for early‐stage esophageal cancer (stages 0 and I) and is chosen based on the extent and location of the lesion.8 Stages I and II cancers are usually treated with surgery alone or followed by subsequent chemoradiation and/or radiation. The rate of recurrence with surgery is around 50%, and most patients present with more advanced‐stage disease at the time of recurrence. Multimodality treatment regimens have been used in an attempt to debulk tumors, sterilize lymph nodes, increase survival rates, and prevent recurrence of disease. Cure rates and long‐term survival remain unsatisfactory when compared to those for other GI malignancies, such as gastric and colon cancers.2
All esophagectomy techniques have a significantly high mortality and morbidity rate, but with proper patient selection and appropriate surgical technique, this operation can be safe. The Ivor Lewis technique is the most frequently performed procedure for resection of the thoracic esophagus.3 This procedure consists of an abdominal incision to explore and mobilize the stomach, followed by a right thoracotomy to dissect the esophagus. The stomach is then pulled up into the thorax and divided, and anastomosis between the distal end of the esophagus and the fundus of the stomach is completed.3 This procedure allows for excellent visualization of the anatomy.
The transhiatal esophagectomy (THE) is performed for cervicothoracic lesions. This surgical technique is used in cases where the portion of the esophagus that extends from the distal trachea to the subcarinal region is normal.9 This area cannot be visualized from either the neck or the abdomen and must be digitally dissected. Within this area, the mediastinal esophageal space is closely surrounded by trachea anteriorly, the aorta and azygos vein laterally, and the vertebral body posteriorly. A bloodless plane consisting of smaller vessels that come off the larger surrounding arterial supply is present.9 When dissected, these smaller vessels spasm and clot. This technique differs from other esophagectomies in that the esophageal dissection is performed blindly; therefore, adhesions or fibrosis from exposure to radiation around the esophagus present a major risk during surgery using this technique.
The McKeown esophagectomy is not commonly used. This operation consists of a right thoracotomy, laparotomy, and left neck incision. An approach that allows for excellent visualization of the anatomy, it also allows for a two‐ or three‐field lymph node dissection that provides thorough staging of the cancer.
There has been much discussion of the use of trimodality therapy to improve survival benefit in patients with locally advanced esophageal cancer. This approach appears to be gaining acceptance in Europe and North America.2 A number of phase I and phase II trials have had conflicting conclusions regarding the efficacy of trimodality therapy in esophageal cancer. Evidence remains inconclusive as a result of limitations in the study designs, such as small sample sizes, variable chemotherapy and radiation therapy regimens, and differences in surgical techniques. The meta‐analysis of these individual trials suggests a survival advantage in pathological complete responders to treatment versus patients with residual tumor and/or nodal disease, but conclusions are tempered by the fact that that the meta‐analysis is of multiple small studies.2,10,11 Recent literature suggests that patients with intermediate‐stage esophageal cancer who are complete responders to neoadjuvant therapy have a survival advantage compared to surgery or chemotherapy and radiation alone.
A Mayo Clinic study reported promising results in a trial conducted between 1998 and 2003. During the study, 162 patients were treated with neoadjuvant chemoradiation followed by surgical resection. The majority of the participants underwent an Ivor Lewis esophagectomy. Pathological response to treatment could only be established after surgery, and patients were classified to one of the following categories: complete pathological response (CP) with absence of any viable tumor; near complete pathological response (NCP) with microscopic viable tumor cells in a necrotic specimen with no evidence of tumor in the lymph nodes; or partial pathological response (PP) with macroscopic viable tumor cells at the primary tumor site and/or positive lymph nodes.12 Pathological response was complete in 42 patients (26%), near complete in 27 patients (17%), and partial in 88 patients (54%). The 5‐year survival rate for overall responders was 34%, 55% in the CP group, and 27% in both the NCP and PP groups. Patients who were complete responders had an improved long‐term survival rate compared to patients who were classified as NCP or PP. Participants who were downstaged from N1 to N0 lymph node stage also benefitted from longer survival rates.12
Another phase III trial presented at the 2006 Gastrointestinal Cancers Symposium verified a statistically significant improvement in long‐term survival in patients treated with neoadjuvant chemoradiation followed by subsequent surgery for the treatment of esophageal cancer.7 The results favored trimodality therapy as an appropriate standard of care for the treatment of moderate‐stage esophageal cancer. The overall 5‐year survival rate was 39% in the trimodality therapy group versus 16% in the surgery‐alone group. In addition, patients who were downstaged experienced improved long‐term survival.
To date, meta‐analysis performed on neoadjuvant chemoradiation for resectable esophageal cancer suggests a significant survival benefit with preoperative chemoradiation.10,11,13 However, a well‐designed, large‐scale, randomized controlled trial is required to further demonstrate the efficacy of neoadjuvant chemoradiation therapy and survival benefit for resectable esophageal cancer. Phase I and phase II trials have demonstrated fairly good results with these regimens, and the benefits of local control with better survival rates seem favorable. For now, perhaps selecting patients with good performance status and administering standard preoperative chemotherapy and radiation followed by surgical intervention may help to solidify the utility of trimodality therapy. Given the complexity of trimodality treatment and the timing of therapy, this type of care may be best delivered by a multidisciplinary thoracic oncology team.
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