Treatment Option Overview for Esophageal Cancer
The prevalence of Barrett metaplasia in adenocarcinoma of the esophagus suggests that Barrett esophagus is a premalignant condition. Strong consideration should be given to resection in patients with high-grade dysplasia in the setting of Barrett metaplasia. Endoscopic surveillance of patients with Barrett metaplasia may detect adenocarcinoma at an earlier stage more amenable to curative resection. The survival rate of patients with esophageal cancer is poor. Asymptomatic small tumors confined to the esophageal mucosa or submucosa are detected only by chance. Surgery is the treatment of choice for these small tumors. Once symptoms are present (e.g., dysphagia, in most cases), esophageal cancers have usually invaded the muscularis propria or beyond and may have metastasized to lymph nodes or other organs.
In the presence of complete esophageal obstruction without clinical evidence of systemic metastasis, surgical excision of the tumor with mobilization of the stomach to replace the esophagus has been the traditional means of relieving the dysphagia. In the United States, the median age of patients who present with esophageal cancer is 67 years. The results of a retrospective review of 505 consecutive patients who were operated on by a single surgical team over 17 years found no difference in the perioperative mortality, median survival, or palliative benefit of esophagectomy on dysphagia when the group of patients older than 70 years were compared to their younger peers.[Levels of evidence: 3iiA and 3iiB] All of the patients in this series were selected for surgery on the basis of potential operative risk. Age alone should not determine therapy for patients with potentially resectable disease.
The optimal surgical procedure is controversial. One approach advocates transhiatal esophagectomy with anastomosis of the stomach to the cervical esophagus. A second approach advocates abdominal mobilization of the stomach and transthoracic excision of the esophagus with anastomosis of the stomach to the upper thoracic esophagus or the cervical esophagus. One study concluded that transhiatal esophagectomy was associated with lower morbidity than transthoracic esophagectomy with extended en bloc lymphadenectomy; however, median overall disease-free and quality-adjusted survival did not differ significantly. Similarly, no differences in long-term quality of life (QOL) using validated QOL instruments have been reported. In patients with partial esophageal obstruction, dysphagia may, at times, be relieved by placement of an expandable metallic stent  or by radiation therapy if the patient has disseminated disease or is not a candidate for surgery. Alternative methods of relieving dysphagia have been reported, including laser therapy and electrocoagulation to destroy intraluminal tumor.[7-10]
Surgical treatment of resectable esophageal cancers results in 5-year survival rates of 5% to 30%, with higher survival rates in patients with early-stage cancers. This is associated with a less than 10% operative mortality rate. In an attempt to avoid this perioperative mortality and to relieve dysphagia, definitive radiation therapy in combination with chemotherapy has been studied. A Radiation Therapy Oncology Group randomized trial (RTOG-8501) of chemotherapy and radiation therapy versus radiation therapy alone resulted in an improvement in 5-year survival for the combined modality group (27% vs. 0%).[Level of evidence: 1iiA] An eight-year follow-up of this trial demonstrated an overall survival (OS) rate of 22% for patients receiving chemoradiation therapy. An Eastern Cooperative Oncology Group trial (EST-1282) of 135 patients showed that chemotherapy plus radiation provided a better 2-year survival rate than radiation therapy alone, which was similar to that shown in the Intergroup trial.[Level of evidence: 1iiA] In an attempt to improve upon the results of RTOG-8501, Intergroup-0123 (RTOG-9405) randomly assigned 236 patients with localized esophageal tumors to chemoradiation with high-dose radiation therapy (64.8 Gy) and four monthly cycles of fluorouracil (5-FU) and cisplatin versus conventional-dose radiation therapy (50.4 Gy) and the same chemotherapy schedule. Although originally designed to accrue 298 patients, this trial was closed in 1999 after a planned interim analysis showed that it was statistically unlikely that there would be any advantage to using high-dose radiation. At 2 years' median follow-up, no statistical differences were observed between the high-dose and conventional-dose radiation therapy arms in median survival (13 months vs. 18 months), 2-year survival (31% vs. 40%), or local/regional failures (56% vs. 52%).[Level of evidence: 1iiA]
Preoperative Chemoradiation Therapy
Chemoradiation followed by surgery is a standard treatment option for patients with stages IB, II, III, and IVA esophageal cancer, based on the results of several randomized trials.
The ongoing CROSS study randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m2 of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over 5 weeks.[Level of evidence: 1iiA] The majority of the patients enrolled in the study have adenocarcinoma (75%).
With a median follow-up of 45 months, preoperative chemoradiation was found to improve median OS from 24 months in the surgery-alone group to 49.4 months (hazard ratio [HR], 0.657; 95% confidence interval [CI], 0.495–0.871, P = .003). Additionally, preoperative chemoradiation improved the rate of R0 resections (R0 is defined as complete resection with no tumor within 1 mm of resection margins, 92% vs. 69%, P < .001). A complete pathologic response was achieved in 29% of patients who underwent resection after chemoradiation therapy. Postoperative complications and in-hospital mortality were equivalent in both groups. The most common hematologic side effects in the chemoradiation group were leukopenia (6%) and neutropenia (2%). The most common nonhematologic side effects were anorexia (5%) and fatigue (3%).
Other phase III trials have compared preoperative concurrent chemoradiation therapy to surgery alone for patients with esophageal cancer.[15-19][Level of evidence: 1iiA] A multicenter prospective randomized trial in which preoperative combined chemotherapy (i.e., cisplatin) and radiation therapy (37 Gy in 3.7 Gy fractions) followed by surgery was compared to surgery alone in patients with squamous cell carcinoma showed no improvement in OS and a significantly higher postoperative mortality (12% vs. 4%) in the combined modality arm. In patients with adenocarcinoma of the esophagus, a single-institution phase III trial demonstrated a modest survival benefit (16 months vs. 11 months) for patients treated with induction chemoradiation therapy consisting of 5-FU, cisplatin, and 40 Gy (2.67 Gy fractions) plus surgery over resection alone. A subsequent single-institution trial randomly assigned patients (75% with adenocarcinoma) to 5-FU, cisplatin, vinblastine, and radiation therapy (1.5 Gy twice daily to a total of 45 Gy) plus resection versus esophagectomy alone. At a median follow-up of more than 8 years, there was no significant difference between the surgery alone and combined modality therapy with respect to median survival (17.6 months vs. 16.9 months), OS (16% vs. 30% at 3 years), or disease-free survival (16% vs. 28% at 3 years). An Intergroup trial (CALGB-9781) planned to randomly assign 475 patients with resectable squamous cell or adenocarcinoma of the thoracic esophagus to treatment with preoperative chemoradiation therapy (5-FU, cisplatin, and 50.4 Gy) followed by esophagectomy and nodal dissection or surgery alone.[Level of evidence: 1iiA] The trial was closed as a result of poor patient accrual; however, the results of the 56 enrolled patients, with a median follow-up of 6 years, were reported. The median survival was 4.48 years (95% CI, 2.4 years to not estimable) for trimodality therapy versus 1.79 years (95% CI, 1.41–2.59 years) for surgery alone (P = .002), with 5-year OS of 39% (95% CI, 21%–57%) versus 16% (95% CI, 5%–33%) for trimodality therapy versus surgery alone.
A phase III German trial also compared induction chemotherapy (three courses of bolus 5-FU, leucovorin, etoposide, and cisplatin) followed by chemoradiation therapy (cisplatin, etoposide, and 40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiation therapy (at least 65 Gy) without surgery (arm B) for patients with T3 or T4 squamous cell carcinoma of the esophagus.[Level of evidence: 1iiA] OS was the primary outcome. The analysis of 172 eligible, randomly assigned patients showed that OS at 2 years was not statistically significantly different between the two treatment groups (arm A: 39.9%; 95% CI, 29.4%–50.4%; arm B: 35.4%; 95% CI, 25.2%–45.6%; log-rank test for equivalence with 0.15, P < .007). Local progression-free survival (PFS) was higher in the surgery group (2-year PFS, 64.3%; 95% CI, 52.1%–76.5%) than in the chemoradiation therapy group (2-year PFS, 40.7%; 95% CI, 28.9%–52.5%; HR for arm B vs. arm A, 2.1; 95% CI, 1.3–3.5; P < .003). Treatment-related mortality was higher in the surgery group compared with the chemoradiation therapy group (12.8% vs. 3.5%, respectively; P < .03).
Preoperative Chemotherapy Alone
The effects of preoperative chemotherapy are being evaluated in randomized trials, as was done in the NCT00525785 trial.[21,22][Level of evidence: 1iiA]. An Intergroup trial randomly assigned 440 patients with local and operable esophageal cancer of any cell type to three cycles of preoperative 5-fluorouracil (5-FU) and cisplatin followed by surgery and two additional cycles of chemotherapy versus surgery alone. After a median follow-up of 55 months, there were no significant differences between the chemotherapy/surgery and surgery-alone groups in median survival (14.9 months and 16.1 months, respectively) or 2-year survival (35% and 37%, respectively). The addition of chemotherapy did not increase the morbidity associated with surgery. The Medical Research Council Oesophageal Cancer Working Party randomly assigned 802 patients with resectable esophageal cancer also of any cell type to two cycles of preoperative 5-FU and cisplatin followed by surgery versus surgery alone. At a median follow-up of 37 months, median survival was significantly improved in the preoperative chemotherapy arm (16.8 months vs. 13.3 months with surgery alone; difference 3.5 months; 95% CI, 1–6.5 months), as was 2-year OS (43% and 34% respectively; difference 9%; 95% CI, 3–14 months). The interpretation of the results from both of these trials is challenging because T or N staging was not reported and prerandomization and radiation could be offered at the discretion of the treating oncologist.
The Japanese Clinical Oncology Group randomly assigned 330 patients with clinical stage II or III, excluding T4, squamous cell carcinomas to receive either two cycles of preoperative cisplatin and 5-FU (fluorouracil) followed by surgery versus surgery followed by postoperative chemotherapy of the same regimen.[Level of evidence: 1iiC] A planned interim analysis was conducted after patient accrual, and although the primary endpoint of PFS was not met, there was a significant benefit in OS among patients treated with preoperative chemotherapy (P = .01). As a result of these findings, the Data and Safety Monitoring Committee recommended early publication.
With a median follow-up of 61 months, the 5-year OS was 55% among patients treated with preoperative chemotherapy compared with 43% among patients treated with postoperative chemotherapy (P = .04). However, there was no significant difference between groups with respect to PFS (5-year PFS, 39% vs. 44%; P = .22). Additionally, there were no significant differences between the two groups with respect to postoperative complications or treatment-related toxicities. Based on these results, preoperative chemotherapy without radiation therapy should still be considered under clinical evaluation.
Two randomized trials have shown no significant OS benefit for postoperative radiation therapy over surgery alone.[24,25][Level of evidence: 1iiA] All newly diagnosed patients should be considered candidates for therapies and clinical trials comparing various treatment modalities.
Information about ongoing clinical trials is available from the NCI Web site.
Special attention to nutritional support is indicated in any patient undergoing treatment of esophageal cancer. (Refer to the PDQ summary on Nutrition in Cancer Care for more information.)
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