Cancer of the Esophagus
Summary of Key Points
Classification
• Esophageal cancer is subdivided into the following four groups: epithelial tumors, metastatic tumors, lymphomas, and sarcomas.
• Cancers of epithelial origin, predominantly squamous cell and adenocarcinomas, are the most common, and other histologic types are rare.
• The appropriate categorization of gastroesophageal junction tumors has been controversial, and patients have been included in clinical trials directed both at esophageal and gastric cancers.
Incidence
• Within the United States, the incidence of esophageal cancer in persons younger than 80 years is 3.2 per 100,000 persons.
• Historically and internationally, squamous cell tumors are the most common histologic type; however, a dramatic increase in the incidence of adenocarcinoma has been documented in the United States, United Kingdom, and Western Europe.
Pathogenesis
• The data support the hypothesis that epithelial tumors arise as a result of chronic irritation from a wide variety of sources, including gastric contents in chronic reflux and known carcinogens.
• A strong association of Barrett esophagus and adenocarcinoma is seen, but a benefit to screening endoscopy for those at risk for or with known Barrett esophagus is unknown as the overall risk of cancer-related mortality is low. Studies with longer-term follow-up are needed to clarify this issue. Other identified risk factors are gastroesophageal reflux disease (GERD), obesity, and smoking.
• Squamous cell carcinoma is associated with smoking as well as alcohol use, and the declining incidence has paralleled the decline in smoking.
• Point mutations, increased copy number, and promotor region hypermethylation all appear important in the progression to malignancy.
Diagnosis and Staging
• Symptoms and demographics will strongly suggest the diagnosis.
• Endoscopy is the best screening examination but esophagram may also be used.
• Diagnosis is made by endoscopy with cytology and biopsy of tumor.
• Transesophageal ultrasound should be used to assess T and N stage to guide optimal definitive therapy.
• Computed tomography (CT) of chest and abdomen is useful in screening for metastatic disease.
• Positron emission tomographic (PET) scan is useful to detect additional cases of metastatic disease before costly and toxic definitive therapy. It may be superior to endoscopic ultrasound (EUS) in detecting intraabdominal lymph nodes, but not periesophageal nodes adjacent to the primary tumor.
• Additional studies include laparoscopy, thoracoscopy, bone scan, and CT of the brain when indicated by clinical circumstances.
• The new AJCC/UICC 7 staging system contains important changes: adenocarcinoma and squamous cell carcinoma are separate; grade of histology is incorporated; the gastroesophageal junction is defined; nodal staging is based on number of involved nodes, similar to gastric cancer; Tis includes high graded dysplasia; and T4 is subcategorized by features suggestive of resectability.
• Staging is based on pathological findings at the time of resection, but therapy is often guided by staging estimated by clinical testing.
Treatment
• Treatment of premalignant dysplasia is guided by grade of histology. Low-grade dysplasia should be closely followed by endoscopy. High-grade dysplasia is treated with endoscopic therapy or esophagectomy, although close follow-up may be appropriate for selected patients.
• Selection of appropriate treatment for carcinoma depends on tumor stage and patient performance status.
• Surgery is an accepted single-modality therapy for patients with early localized disease (T1-2N0M0) or for patients who may not tolerate combined-modality therapy. The selection of surgical approach depends upon location and experience, but no approach has been demonstrated to lead to superior cure rates.
• Combined chemoradiation leads to prolonged median survival and long-term survival compared with radiation alone used as a definitive nonoperative approach, at the price of increased toxicity. This represents a potentially curative alternative to surgery for squamous cell cancers and is appropriate for most unresectable T4N and M0 lesions of either histology. Because most patients treated on prospective chemoradiation trials had squamous cell carcinomas, the benefits of nonoperative management for adenocarcinoma are not known.
• Randomized trials have not confirmed a survival benefit with surgery added to potentially curative chemoradiation in squamous cell carcinoma, but there was a significant local control benefit. This question has not been well studied for adenocarcinoma, for which definitive chemoradiation is of uncertain curative potential.
• Accumulating evidence convincingly demonstrates that combination therapy with preoperative chemoradiation followed by surgery survival compared with surgery alone for both locally advanced (clinically staged T2-T4 or node positive) adenocarcinoma and squamous cell carcinoma. There is less certainty about the value of preoperative chemotherapy alone.
• Postoperative adjuvant chemotherapy or chemoradiation is less well studied in locally advanced esophageal cancer, but trials in gastric cancer including gastroesophageal junction adenocarcinoma have demonstrated a benefit.
• Combined-modality chemotherapy regimens frequently include 5-fluorouracil (5-FU) or paclitaxel and platinum agents; other commonly used regimens include docetaxel and irinotecan.
• Endoscopic palliative therapy includes laser or electrical fulguration, mucosal resection, photodynamic therapy (PDT), or stenting. Excepting very superficial lesions, these therapies are not alternatives to surgery as they do not address deeper disease or lymphatic spread.
• Radiation therapy, with or without chemotherapy, may be used to palliate local symptoms.
• Chemotherapy may be used for metastatic disease, but response rates and duration of response are modest for most patients. Clinical trials are recommended.
1. Which surgical approach leads to optimal survival outcome for adenocarcinoma of the esophagus?
2. Which approach to neoadjuvant therapy leads to improved survival outcome?
3. Which assessment of response to neoadjuvant therapy is prognostic for pathological response and survival outcome?
4. The American Joint Committee on Cancer (AJCC) 7 staging system differs from the previous AJCC 6 system as follows:
A Adenocarcinoma and squamous cell carcinoma are distinct.
B There are nodal classifications based on the number of involved nodes rather than the echelon of involved nodes.
C T4 is divided into a T4a and T4b based on whether the invasion of a neighboring structure is likely to be completely resectable.
D Barrett esophagus is now considered similar to carcinoma in situ.
E The system includes clinical staging increasing applicability to patients treated neoadjuvantly.
5. What is the appropriate nonoperative therapy for a stage T3N1M0 squamous cell carcinoma of the esophagus in a medically fit patient?
1. Answer: F. There has not been any identified difference in outcome related to the choice of surgical technique. Survival is, however, related to successfully achieving a gross total resection with negative margins. Therefore, for an individual patient, an approach should be selected that is likely to achieve that goal. The choice should also be based on the expertise of the surgical team.
2. Answer: D. Preoperative chemotherapy and preoperative chemoradiation. Preoperative chemotherapy and preoperative chemoradiation have both been demonstrated in randomized trials to improve survival outcome. Although these approaches have not been compared in well-powered randomized trials, preoperative chemoradiation has been more convincingly demonstrated to be beneficial albeit at the price of additional radiation-related toxicities. Although a well-powered British trial of preoperative cisplatin and 5-fluorouracil chemotherapy demonstrated a survival benefit, a U.S. trial using a similar regimen did not create uncertainty about the benefits of this approach. A well-powered randomized trial, the CROSS trial, has demonstrated a meaningful benefit in long-term survival to neoadjuvant concurrent paclitaxel, carboplatin, and radiotherapy with additional supporting evidence from several smaller randomized trials using platinum-based chemotherapy regimens. The role of radiotherapy as well as chemotherapy in improving outcome may be important as both locoregional and distant failure is common after surgery alone for locally advanced disease. A randomized trial comparing radiochemotherapy with chemotherapy given neoadjuvantly was closed without sufficient patient accrual but did suggest a benefit. This observed benefit matches the modestly improved survival suggested by uncontrolled comparison of prospective trials with or without concurrent radiotherapy. Neoadjuvant or adjuvant radiation without chemotherapy has not been demonstrated to affect survival outcome and is not generally used.
3. Answer: D. Assessing response to neoadjuvant therapy is challenging, especially when radiotherapy is used, as it may cause edema, inflammation, and disruption of tissues that can confound the comparison with the pretreatment extent of tumor. Measurement of tumor size, CT scanning, and EUS have not been demonstrated to have sufficient sensitivity and specificity to be recommended as valuable in guiding decisions about proceeding with surgery based on local response. PET scanning assessment of response, measured by decrease in metabolic activity of the tumor (SUV), has been demonstrated to predict pathological response and to be prognostic for better survival outcome. There are no data to demonstrate that altering therapy based on PET response will improve outcome, but studies are underway.
4. Answer: F. High-grade dysplasia is now considered similar to carcinoma in situ, but Barrett esophagus is not consider to be an early neoplasm. Although unaddressed high-grade dysplasia will frequently progress to an invasive neoplasm, Barrett esophagus may progress to adenocarcinoma for under 0.4% per patient-year whereas high-grade dysplasia appears to progress with an incidence of 3% to 5% per year.
The AJCC 7 system continues to rely purely on pathological staging, and its value in clinically staged patients is presumed but not validated.
5. Answer: B. Concurrent chemotherapy and radiotherapy. Concurrent chemotherapy and radiation has been demonstrated to be of curative value in randomized trials in patients with squamous cell carcinoma, although there are limited data to justify this approach for adenocarcinoma patients with resectable disease. Randomized trials, including squamous cell carcinoma patients, have not confirmed improved survival when surgery is performed subsequent to chemoradiation, although there may be a local control benefit. Radiation alone rarely results in cure and is not appropriate. Sequential chemotherapy and radiotherapy, although it may result in less toxicity than concurrent therapy, has not been demonstrated to be as beneficial. As patients with this stage of disease can be cured, supportive or palliative care alone is not recommended for a fit patient.
