Klinikum rechts der Isar
Technische Universität München
Oesophageal carcinoma is one of the most aggressive malignant diseases, with most tumours being diagnosed at an advanced stage. Metastatic oesophageal cancer is not curable, and the overall five-year survival rate for all stages is poor, as it does not exceed 14%.(1) The life risk of this cancer increases with age, with a mean age at diagnosis of 67 years.(1,2) Worldwide, oesophageal cancer is the sixth leading cause of death from cancer.(3)
More than 90% of oesophageal cancers are either squamous cell carcinomas or adenocarcinomas.(2) Both histological subtypes should be studied and treated as two different entities, especially when it comes to surgery.(4) Approximately three-quarters of all adenocarcinomas are found in the distal oesophagus, whereas squamous cell carcinomas are more frequent between the middle and lower third of the oesophagus.(2,5)
The pathogenesis of oesophageal cancer remains unclear, although the risk factors associated with increased incidence of the condition are well known. Any factor that causes chronic irritation and inflammation of the oesophageal mucosa appears to increase the incidence of squamous cell carcinoma. Specifically, substantial alcohol intake in combination with smoking could account for more than 90% of all cases of squamous cell carcinomas in the developed world.(6) Other causes of oesophageal irritation include achalasia, oesophageal diverticuli(7,8) and frequent consumption of extremely hot beverages.(9,10) Squamous cell cancers are more frequent in patients with a low socioeconomic status.(6) On the other hand, in individuals with longstanding gastro-oesophageal reflux disease, a cause of Barrett’s oesophagus, there is an eightfold increase in the risk of oesophageal adenocarcinoma.(11)
Other risks are obesity and smoking.(6,12)
Symptoms and diagnostic workflow
Patients suffering from oesophageal cancer mainly present with dysphagia and weight loss. In cases of advanced disease pain, dyspnoea and cough are also commonly found.
The initial diagnostic approach should be an endoscopy, which typically allows for the visualisation and histological verification of the disease. In patients with a tumour restricted to the oesophagus, endoscopic ultrasonography is the most reliable locoregional staging method (see Figure 1).(13,14) This technique can be used to predict the depth of tumour invasion (T category) and, with less sensitivity, the extent of lymph node involvement (N category). In addition to endoscopic ultrasonography, computed tomography is routinely performed. Positron emission tomography (PET) with 18-fluorodeoxyglucose has a high specificity (84–100%) but limited sensitivity (38–77%) for the detection of nodal or metastatic disease (see Figure 2).(15–19) After staging, more than 50% of patients prove to have unresectable or metastatic disease.
Management of local disease
For patients with early cancer, limited resection, laparoscopic procedures and sentinel node detection are under evaluation.(20–24)
For adenocarcinoma of the oesophagogastric junction type II and III according to Siewert’s classification (the so-called cardia and subcardial carcinomas), total gastrectomy with transhiatal resection of the distal oesophagus and extended (D2) lymphadenectomy is the recommended procedure. (25–28) For oesophageal cancer, extended transthoracic resection with mediastinal lymphadenectomy offers the best chance for complete tumour excision and long-term survival.(29) Nevertheless, the long-term outcome for patients with locally advanced cancer treated with surgery alone remains unsatisfactory. Therefore, many research teams try to improve the outcome by combining chemotherapy or chemoradiation with surgical resection in a neoadjuvant or adjuvant setting.(4)
In the locally advanced stages T3 and T4, virtually all patients have locoregional lymphatic spread.(5,30) Therefore, neoadjuvant chemoradiotherapy or chemotherapy alone followed by resection has been intensively studied in different settings over the past decade. Although some studies failed to demonstrate a survival advantage for preoperative (neoadjuvant) fluorouracil 5-FU–cisplatin-based treatment, other protocols indicated a survival benefit for neoadjuvant chemoradiotherapy or chemotherapy alone in patients with locally advanced carcinomas.(31) There is currently no evidence that, after complete resection, postoperative (adjuvant) chemotherapy or radiotherapy lead to higher survival rates.(32,33) For patients who are not eligible for oesophageal resection, the combination of radiotherapy and concurrent chemotherapy with cisplatin and 5-FU has led to long-term survival in approximately 25% of patients.(34–36)
Management of advanced disease
Metastases are found in 50% of patients with oesophageal cancer at the time of first presentation. In addition, the majority of patients with local disease at initial presentation will later develop metastases. Chemotherapy is the treatment of choice in cases with systemic spread. Therefore, there is an urgent need for chemotherapeutic agents with promising antitumour activity on the one hand and acceptable toxicity on the other hand.
Combination chemotherapy, mainly cisplatin-based, results in partial responses in 25–50% of patients with metastatic disease (see Table 1).
The most common combination regimen is cisplatin combined with a continuous infusion of 5-FU over 4–5 days. Compared with single-agent cisplatin therapy, this regimen demonstrated a higher response rate of 35% in the combination, versus 19% in the cisplatin arm.(37) Although greater activity was demonstrated for cisplatin–5-FU in combination, this was achieved at the expense of substantially increased toxicity, mainly mucositis and myelosuppression. Nevertheless, this regimen is widely used and is regarded as the standard of care for patients with metastatic oesophageal tumours. The limited efficacy of cisplatin and 5-FU and the significant toxicity of this regimen prompted the evaluation of new agents in advanced disease.
To find combination therapies with a better tolerance profile and fewer side-effects, a phase II study was conducted to evaluate the efficacy and safety of vinorelbine and cisplatin in previously untreated patients with metastatic squamous cell carcinoma. This study showed that the combination of cisplatin and vinorelbine reaches response rates similar to that obtained with the cisplatin-5-FU regimen, while reducing the level of fatal treatment-related toxicity substantially.(38) In another study, vinorelbine was administered as a single agent in patients with chemo-naive and with pretreated squamous cell carcinoma of the oesophagus. This study demonstrated an overall response rate of 15% in chemo-naïve patients, which indicates that vinorelbine is an active agent with excellent tolerance profile and low toxicity.(39)
More recent trials evaluated newer chemotherapeutic agents, such as taxanes. A phase II study was performed to evaluate the use of paclitaxel in combination with cisplatin and 5-FU in patients with squamous cell carcinoma or adenocarcinoma of the oesophagus.(40) Response rates were between 46% and 48% for patients with adeno- and squamous cell carcinomas. However, severe toxicity led to dose attenuation in 46% of patients treated. This shows that the optimal dosage and schedule of paclitaxel in combination chemotherapy for oesophageal cancer patients has not yet been found.(40)
For patients who relapsed after a cisplatin-containing regimen, a phase II study was performed to assess the activity of weekly docetaxel in combination with the topoisomerase-II inhibitor irinotecan. In these extensively pretreated cancer patients, activity was moderate, with a disease stabilisation rate of only 33%.(41) Another phase II study evaluated a regimen of weekly irinotecan and cisplatin. This study showed an overall response rate of 57%, with comparable response rates seen in adeno- and squamous cell carcinomas. This therapy was well tolerated except for myelosuppression, which led to therapy delays and dose reductions in nearly two-thirds of the patients.(42) Ongoing clinical research focuses on the identification of new molecular tumour targets. Particularly promising in the treatment of gastrointestinal cancer are agents that target and inhibit the epidermal growth factor receptor (EGFR) pathway. In October 2004, the Munich centre for clinical studies at the Klinikum rechts der Isar (Germany) will start a randomised multicentre phase II trial to assess the effectiveness of the EGFr antibody cetuximab in combination with chemotherapy in advanced squamous cell cancer of the oesophagus.
As many problems in the management of oesophageal cancer are unresolved, patients should be treated within clinical trials. The combination cisplatin–5-FU has long been the treatment of choice in advanced disease. Recent studies indicate that newer agents, such as vinorelbine, irinotecan and the taxanes, may broaden the spectrum of active drugs. In the future, a further amelioration of the systemic treatment may come from targeted therapies, first of all EGFr antagonists such as cetuximab.
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American Society of Clinical Oncology
European Society of Medical Oncology
International Society for Diseases of the Esophagus