In 1995, 12,100 new cases of esophageal cancer were diagnosed in the United States, and the vast majority, 10,900 patients, will die of the disease. Esophageal cancer represents 2% of American cancer deaths and 9% of deaths due to gastrointestinal cancer. In Western countries, there is a clear association between the development of squamous cell carcinoma of the esophagus and the abuse of tobacco and alcohol(Drug information on alcohol). Although esophageal squamous cell cancer remains relatively uncommon in the United States, it is a leading worldwide cause of cancer, with a particularly high incidence observed in northern China, the Caspian Littoral, and the Transkei province of South Africa.
Adenocarcinoma of the esophagus, which in the past represented only a small proportion of cases of esophageal cancer, is rapidly overtaking squamous cell carcinoma as the predominant disease histology in the United States and currently represents half of newly diagnosed cases. Indeed, esophageal adenocarcinoma poses a potentially daunting health care problem, with cases increasing at an annual rate exceeding that of any other malignancy, including malignant melanoma. Although Barrett's esophagus is one established premalignant precursor of esophageal adenocarcinoma, the factors responsible for the rapid rise in the incidence of adenocarcinoma have yet to be determined. Recent epidemiologic studies have implicated obesity and tobacco abuse as potential risk factors for the development of adenocarcinoma of the esophagus. The epidemiologic factors responsible for the geographic variability in the incidence of esophageal squamous cell cancer, including potential dietary and environmental carcinogens, also remain indeterminate.
The prognosis for patients with esophageal cancer treated with the standard approaches of surgery or radiation therapy is poor. The poor prognosis for patients with locally advanced esophageal carcinoma is compounded by poor patient tolerance of therapy, given the comorbid cardiac, hepatic, and pulmonary diseases that accompany long-standing alcohol and tobacco abuse. The largest retrospective series of patients treated with either surgery alone or radiotherapy alone, reviewed by Earlam and Cunha-Melo, reported equally poor 5-year survival rates of 4% for surgery alone and 6% for radiotherapy alone.[6,7] In this early surgical review, the operative mortality for patients treated surgically was a sobering 29%. This significant operative mortality has fueled an ongoing debate regarding the relative efficacy of surgery and radiation therapy for treating local disease, although more recent surgical series from single institutions have reported an operative mortality of 5% to 15% for esophagectomy, with Muller et al citing an overall rate of 12.5% in a review of the surgical literature.
Optimal Surgical Approach
The optimal surgical approach in the local management of esophageal cancer has been vigorously debated. Of all esophageal surgical procedures, a laparotomy is performed first, to mobilize the stomach or colon to reconstitute the upper gastrointestinal tract. One standard approach, the Ivor Lewis esophagectomy, employs a separate right thoracotomy for resection of the esophageal tumor, dissection of regional lymph nodes, and intrathoracic gastroesophageal reanastomosis.
The use of thoracotomy in surgery for esophageal cancer has been advocated because it allows direct visualization of the mediastinal contents. Another approach, transhiatal esophagectomy, avoids thoracotomy and employs an abdominal approach to resect the esophageal tumor and to dissect mediastinal lymph nodes; it achieves gastroesophageal reanastomosis via a cervical incision. Proponents of transhiatal esophagectomy argue that this approach reduces operative morbidity and mortality. Surgical series, however, have indicated comparable operative morbidity and mortality whether or not a thoracotomy is performed, and critics of the transhiatal approach argue that an adequate mediastinal dissection cannot be performed without a thoracotomy, particularly for proximal or mid-thoracic esophageal lesions.
At the other end of the spectrum, even more radical surgical approaches have been advocated, involving either en bloc resection of the mediastinal contents or a three-field lymph node dissection involving resection of the cervical and abdominal lymph nodes in addition to the traditional mediastinal lymph node dissection. Although proponents of more radical surgical approaches contend that greater local control may lead to an improvement in survival, this is achieved at the potential cost of higher surgical morbidity and mortality. The optimal surgical management of a locally advanced esophageal lesion remains to be established. However, regardless of the approach taken, ultimately, the majority of patients treated with surgery are destined to die of recurrent disease.
Causes of Treatment Failure
The failure of standard surgical or radiation-based therapy, even in patients with disease clinically limited to the locoregional area prior to treatment, is due to both locoregional failure and early systemic dissemination of disease. Autopsy series verify the frequent systemic nature of squamous cell carcinoma, even at or shortly after the initial presentation. Despite the brief duration of illness for these patients, the majority were found to have evidence of distant metastatic disease, often in association with locally recurrent or persistent disease, at autopsy. Adenocarcinoma of the distal esophagus or gastroesophageal junction appears to have a natural history of disease similar to that of squamous cell esophageal carcinoma, with equally poor survival after surgical therapy due to a combination of local and systemic disease recurrence. The clear need to address the early systemic spread of esophageal carcinoma with systemic treatment has led to the incorporation of chemotherapy into combined-modality therapy employing surgery and radiation therapy.
Clinical trials of systemic chemotherapy administered preoperatively for esophageal cancer, also termed neoadjuvant or primary chemotherapy, have been undertaken largely because of the poor results achieved with conventional surgery or radiation therapy and the frequent systemic pattern of disease recurrence. Such combined-modality trials employing chemotherapy have taken one of three different approaches: chemotherapy followed by a planned surgical procedure, chemotherapy given concurrently with radiation therapy followed by surgery, and chemotherapy and radiation therapy without subsequent surgical intervention.
The rationale, both preclinical and clinical, for neoadjuvant chemotherapy has been reviewed. For patients with esophageal cancer, the approach of preoperative chemotherapy offers several potential clinical benefits, including enhancing resectability by downstaging the primary tumor. Another potential advantage is the assessment of the response to preoperative chemotherapy directly in the primary tumor, making the end point of adjuvant therapy more precise by identifying patients who respond to chemotherapy and who might therefore benefit from further chemotherapy postoperatively. Administering chemotherapy early in the course of disease also has the advantage of treating subclinical but established micrometastatic disease, when chemotherapy is likely to have its greatest impact, given the limited effectiveness of systemic therapy for clinically apparent metastatic disease. A disadvantage of preoperative chemotherapy is the delay in achieving local control of disease.
The rationale for concomitant chemotherapy and radiation has also been reviewed. Concurrent chemoradiotherapy potentially allows for the achievement of enhanced local tumor control, as well as the simultaneous treatment of systemic micrometastases.
Although a neoadjuvant, combined-modality approach to esophageal cancer should be reserved for patients at high risk of death due to disease recurrence, most US patients present with high-risk transmural (T3) or lymph node-positive (N1) disease and are therefore candidates for neoadjuvant therapy. Use of the recently available technique of endoscopic ultrasonography may provide greater ability to stage locoregional disease in the esophagus, particularly the degree of local tumor extension by T-stage and the detection of regional node involvement. Evaluation by endoscopic ultrasonography is increasingly being used in clinical trials for staging and evaluating response, but assessing response by endoscopic ultrasonography should still be considered investigational.
Preoperative Chemotherapy Followed by Surgery
The use of preoperative chemotherapy for locally advanced esophageal carcinoma has been the subject of numerous clinical trials. Most studies have been single-arm, phase II trials evaluating preoperative chemotherapy in one to up to six cycles followed by a definitive surgical procedure. In early trials, patients with T3 or node-positive disease went on to undergo postoperative radiotherapy. However, in more recent trials, radiotherapy has not been added preoperatively or postoperatively, because randomized clinical trials have failed to show a survival benefit resulting from the addition of radiotherapy to surgery (discussed below). Also, in these more recent trials, chemotherapy has been performed both preoperatively and postoperatively. The results of selected phase II trials of preoperative chemotherapy for esophageal cancer are summarized in Table 1.
Phase II Trials--Virtually all preoperative chemotherapy trials for esophageal cancer have employed cisplatin(Drug information on cisplatin) (Platinol)-based combination chemotherapy. Although earlier trials treated squamous cell carcinoma, with the increased incidence of adenocarcinoma, both histologies have been treated on preoperative protocols. Early trials combined bleomycin(Drug information on bleomycin) (Blenoxane) with cisplatin and other agents, but the pulmonary toxicity associated with bleomycin and the marginal antitumor activity observed with the combination of bleomycin and cisplatin in preoperative therapy prompted trials of other cisplatin-based combinations. In these trials, major antitumor responses were seen in up to 50% to 60% of patients, with pathologic complete responses in up to 11% of patients. Most patients were operable after preoperative chemotherapy, with an operative mortality ranging from 0% to 24%. Median survival ranged from only 8 to 28 months.
Kelsen et al reported long-term follow-up of a single trial of 34 patients with squamous cell carcinoma treated preoperatively with the combination of cisplatin, vindesine(Drug information on vindesine), and bleomycin. In this study, survival was encouraging, with 18% of patients alive and free of disease at 5 years and no recurrences occurring after 3.5 years, representing a doubling of survival compared with historic surgical controls.
The combination of cisplatin and 5-fluorouracil (5-FU), given by continuous infusion for 4 to 5 days, has also been extensively studied in preoperative chemotherapy trials. Major responses have been observed in 40% to 60% of patients, with pathologic complete responses in up to 11% of patients; the majority of patients had resectable disease after preoperative treatment, with an acceptable operative mortality. Subsequent trials for both esophageal squamous cell cancer and adenocarcinoma combining cisplatin with etoposide(Drug information on etoposide)
(VePesid) and 5-FU, leucovorin and 5-FU, or doxorubicin(Drug information on doxorubicin) and etoposide have noted similar response proportions, rates of resectability, operative mortality, and survival comparable to those of 5-FU and cisplatin alone.[19-21] Toxicity in these trials, mainly mucositis, myelosuppression, and nephrotoxicity, has been substantial but tolerable.
Overall, preoperative treatment with cisplatin-based combination chemotherapy achieves a major response in 50% of patients, with occasional pathologic complete responses. The use of preoperative chemotherapy appears to be safe, with no demonstrable adverse effect on surgical outcome. However, the overall survival of patients treated with preoperative chemotherapy has been disappointing, with a median survival ranging from 10 to 28 months in larger series, although a trend toward improved survival has been suggested in these trials.
The duration of chemotherapy delivered in preoperative chemotherapy trials has also undergone evolution. Although earlier trials administered only one to two cycles of chemotherapy preoperatively without subsequent postoperative therapy, more recent trials have given up to three or more cycles of preoperative therapy and two or three cycles of postoperative chemotherapy. The treatment outcome of earlier and more recent trials may not be directly comparable, particularly with regard to the impact of additional cycles of systemic therapy on systemic recurrence.
Phase III Trials--The role of preoperative chemotherapy in the treatment of locoregional esophageal carcinoma can be clearly defined only in the context of random-assignment trials with a surgery-only control arm. Four small, randomized trials comparing surgery alone with preoperative chemotherapy followed by surgery have been published, and a fifth trial compared preoperative chemotherapy with preoperative radiotherapy (Table 1). Roth et al randomized patients to receive preoperative chemotherapy with cisplatin, bleomycin, and vindesine vs surgery alone. Reporting in abstract form only, Schlag randomly assigned patients to undergo surgery alone or to re- ceive three cycles of preoperative chemotherapy with 5-FU and cisplatin. Nygaard et al randomized patients to receive surgery alone, preoperative chemotherapy with cisplatin and bleomycin, preoperative radiotherapy, or preoperative treatment with sequential chemotherapy and radiotherapy. LePrise et al compared surgery alone with sequential preoperative chemotherapy as well as cisplatin and 5-FU and radiotherapy to a dose of 6,000 cGy, given in two split courses. None of these small, randomized trials demonstrated a survival advantage for preoperative chemotherapy.
In the study by Roth et al, the subgroup of patients who responded to chemotherapy showed a trend toward improved survival, compared with surgical controls, that nearly reached statistical significance. A prognostic factor analysis identified percentage of weight loss prior to diagnosis and objective response to chemotherapy as predictive of long-term survival. No survival benefit was conveyed by preoperative chemotherapy in the study by Nygaard et al and the patients with the poorest survival at 3 years (3%) received preoperative chemotherapy.
Kelsen et al randomly assigned 96 patients to receive treatment with either preoperative high-dose radiotherapy, 5,500 cGy delivered over 5.5 to 6.0 weeks by a multifield technique, or preoperative chemotherapy with cisplatin, vindesine, and bleomycin. In this trial, a survival comparison between the two treatment groups could not be made because the trial design permitted a postoperative crossover to the other treatment modality, and most patients received both chemotherapy and radiation therapy. The actuarial survival rate observed for all patients was 20% at 5 years, which was superior to that of historic controls, with the subgroup of responders to either chemotherapy or radiotherapy showing a trend toward improved survival.
At present, for patients treated surgically, surgery alone remains the standard of care, and the use of preoperative chemotherapy outside an investigational setting cannot be recommended. A conclusive evaluation of preoperative chemotherapy using the best currently available combination chemotherapy regimen awaits the completion of ongoing, random-assignment clinical trials. A national intergroup trial (Intergroup Trial 113) randomizing patients to receive three preoperative and two postoperative chemotherapy cycles with cisplatin and 5-FU vs surgery alone has now been completed, and data analysis of this trial is under way.