Treatment
Treatment options for the various disease stages are given in Table 2, along with 5-year survival rates.
Localized Disease
Only 40% to 60% of patients with esophageal cancer present with clinically localized disease. The National Comprehensive Cancer Network (NCCN) guidelines state that patients with clinically localized disease may be treated with resection or chemotherapy plus irradiation (Tables 3 and 4). The overall 5-year survival rates for either surgery alone or combined chemotherapy and irradiation appear equivalent.
Chemoradiation therapy as primary management of localized or locoregionally confined esophageal cancer has been shown to be superior to irradiation alone. A series of randomized trials have demonstrated that adjuvant postoperative chemoradiation therapy does not offer a survival advantage to patients with esophageal cancer, save perhaps for those affected at the GE junction, as demonstrated in part in INT-0116. Adequate patient selection, tumor staging, and treatment standardization will be required before the optimal therapeutic modalities in these patients will be determined.
Surgery
Preoperative medical evaluation. Preoperative medical evaluation helps determine the patient's risk of postoperative complications and mortality. In addition to the staging and nutritional status, it should include an evaluation of the pulmonary, cardiac, renal, and hepatic functions.
Extent of surgical resection. The extent of resection depends on the location of the primary tumor, histology of the tumor, and nature of the procedure (palliative vs curative). A retrospective study has reported that superficial mucosal lesions may be treated via endoscopic mucosal resection, but those patients with submucosal invasion require esophagectomy. Indeed, the line between diagnostic and therapeutic endoscopic procedures has become somewhat blurred in the setting of esophageal disease, in particular in the management of Barrett's disease. Thus, there are studies ongoing about the efficacy of endoscopic mucosal resection, potentially followed by radiation with or without chemotherapy in the setting of early stage, minimally invasive esophageal cancer, especially in patients who are poor candidates for more invasive esophagectomies. However, at this time, the role of such procedures in the treatment of most patients with esophageal cancer, in comparison with more established therapies such as esophagectomy, radiation, and chemotherapy is uncertain.
Treatment options and survival by stage in esophageal cancer
Chemotherapy regimens for esophageal carcinoma
Postoperative chemoradiation therapy for gastric/esophageal cancerFor tumors of the intrathoracic esophagus (squamous cell carcinomas) and tumors with extensive Barrett's esophagus (adenocarcinomas), it is necessary to perform a total esophagectomy with cervical anastomosis to achieve a complete resection. For distal lesions of the abdominal esophagus (adenocarcinomas) and cardia, it is often possible to perform an intrathoracic esophageal anastomosis above the azygos vein, although many surgeons would prefer to perform a total esophagectomy.
The resected esophagus may be replaced with tubularized stomach in patients with tumors of the intrathoracic esophagus or with a colon interposition in patients with tumors involving the proximal stomach, because such involvement makes this organ unsuitable for esophageal reconstruction. The esophageal replacement is usually brought up through the posterior mediastinum, although the retrosternal route is often used in palliative procedures.
Patient selection. The indications for esophagectomy in esophageal cancer vary from center to center within the United States.
Clearly, patients with distant metastases, evidence of nodal metastases in more than one nodal basin, or tumor extension outside the esophagus (airway, mediastinum, vocal cord paralysis) are candidates for palliative therapy. Patients with disease limited to the esophagus and no evidence of nodal metastases (stages I and IIA) may be treated with esophagectomy, although these patients can also be considered for definitive treatment with chemoradiation therapy.
Method of resection. Considerable controversy also exists among surgeons regarding the method of resection. To date, two randomized studies have compared transhiatal esophagectomy (without thoracotomy) with the Ivor-Lewis (transthoracic) esophagectomy (with thoracotomy). These studies failed to show differences between the two procedures with regard to operative morbidity and mortality. In a randomized trial of 220 patients treated with either an extended transthoracic esophagectomy or limited transhiatal esophageal resection, no significant overall survival benefit was found for either approach, although extended transthoracic esophagectomy showed a trend toward an improvement in 5-year survival. Over the past 5 years, successful attempts have been made to use minimally invasive approaches to esophageal cancer with thoracoscopy and laparoscopy. Although those studies have shown a decrease in morbidity and the minimally invasive approach appears to be oncologically sound from the point of view of resection margins, the number of nodes resected is still not comparable to that of the standard transthoracic approach.
The need for pyloric drainage (pyloroplasty) following esophagectomy is another area of debate. A meta-analysis of nine randomized trials that included 553 patients showed a trend favoring pyloric drainage in improving gastric emptying and nutritional status, whereas bile reflux was better in the nondrainage group. The gastric emptying time evaluated by scintigraphy was twice as long in the nondrainage group as in the pyloric drainage groups.
Lymphadenectomy. Considerable controversy exists regarding the need for radical lymphadenectomy in esophageal disease. Much of the controversy is due to the fact that different diseases are being compared.
Japanese series include mostly patients with squamous cell carcinomas of the intrathoracic esophagus, with 80% of the tumors located in the proximal and middle sections of the esophagus. Americans report combined series, with at least 40% to 50% of patients with adenocarcinomas of the distal esophagus. Skinner and DeMeester favor en bloc esophagectomy with radical (mediastinal and abdominal) lymphadenectomy, based on 5-year survival rates of 40% to 50% in patients with stage II disease, as compared with rates of 14% to 22% in historic controls.
In a retrospective study, Akiyama found a 28% incidence of cervical node metastases in patients with squamous cell carcinomas located in the middle and distal portions of the esophagus, as opposed to 46% in those with tumors of the proximal third. Overall survival at 5 years was significantly better in patients who underwent extended lymphadenectomy (three fields) than in those who had conventional lymphadenectomy (two fields); this finding was true in patients with negative nodes (84% and 55%, respectively) and in those with positive nodes (43% and 28%, respectively). Extended lymphadenectomy was not associated with a survival advantage in patients with tumors in the distal third of the esophagus.
In a study of 1,000 patients with esophagogastric junction adenocarcinomas, the tumors were classified according to the location of the center of the tumor mass in adenocarcinomas of the distal esophagus, cardia, and subcardia. The tumors located in the cardia and subcardia regions spread primarily to the paragastric and left gastric vessel nodes and did not benefit from extended esophagectomy. Kato et al have studied the use of sentinel node mapping to improve the sensitivity of lymphadenectomy.
Preoperative chemotherapy
The frequency of metastatic disease as the cause of death in patients with esophageal cancer has resulted in exploration of the early application of systemic therapy for esophageal cancer. The first of the two large studies was RTOG (Radiation Therapy Oncology Group) trial 8911 (USA Intergroup 113). A total of 440 patients were treated with surgical resection alone or preceded by three cycles of cisplatin(Drug information on cisplatin) and fluorouracil(Drug information on fluorouracil) (5-FU). Objective responses were reported in only 19% of patients who received chemotherapy. No difference in resectability, operative mortality, median survival (14.9 months with chemotherapy vs 16.1 months with surgery alone), or 2-year survival (35% vs 37%) was reported.
However, the Medical Research Council evaluated 802 patients with resectable esophageal cancer in a similar study. Patients randomized to receive chemotherapy were administered two cycles of cisplatin (80 mg/m2) and 5-FU (1 g/m2/d as a continuous infusion for 4 days). Microscopically complete resection was performed more frequently in patients receiving chemotherapy, with no difference found in postoperative complications or mortality. Moreover, patients who receivied neoadjuvant chemotherapy had significantly longer median survival (16.8 months vs 13.3 months) and 2-year survival (43% vs 34%) than patients treated with surgery alone. With a median follow-up of 6 years, the updated results of this study continued to demonstrate a significant difference in overall survival at 5 years: 23% for patients who received preoperative chemotherapy vs 17% for patients treated with surgery alone—and this benefit was present in both histologies. The reasons for the differences in the outcomes are unclear but may be related to the chemotherapy regimen and schedule employed in the Intergroup study, patient population, or study design. As a result, the role of neoadjuvant chemotherapy remains in question but is promising, especially with the potentially more efficacious, newer-generation chemotherapy agents.
Polee et al have evaluated a biweekly combination of cisplatin and paclitaxel(Drug information on paclitaxel) in this setting in a phase II study, with promising results. Objective responses occurred in 59% of 49 patients. No patients had progressive disease. Although 71% of patients had severe neutropenia, it was often asymptomatic. Forty-seven patients underwent resection subsequently. Complete pathologic responses occurred in 14% of patients. The median survival of patients in this study was 20 months, but it was 32 months in patients who had disease responsive to chemotherapy. The 3-year survival rate was 32%.
Given the uncertainty about the efficacy of preoperative chemotherapy and chemoradiation therapy, some investigators have administered preoperative chemotherapy, followed by chemoradiation therapy, then surgery. The true utility of this approach will need to be defined by randomized studies, but clearly it is feasible, without a significant increase in toxicity or operative morbidity. Interestingly, these reports have also demonstrated that most patients had significant improvement or resolution of dysphagia with the induction chemotherapy alone.
Adjuvant/postoperative chemotherapy
Because the most common source of treatment failure in patients with esophageal cancer who have undergone surgical resection is distant metastatic disease, postoperative chemotherapy has also undergone limited investigation. The Japanese Cooperative Oncology Group has compared preoperative and postoperative chemotherapy in 330 patients with stage II or III esophageal squamous cell carcinomas. Patients received two courses of either preoperative or postoperative chemotherapy with cisplatin/5-FU. The patients who received preoperative chemotherapy demonstrated a significant improvement in progression-free survival (2.9 years vs 2 years). Thus, the investigators determined that preoperative therapy would be the new standard therapy.
Radiotherapy
Although radiotherapy alone is inferior to chemoradiation therapy in the primary management of locoregionally confined esophageal cancer, it may offer palliation to patients with advanced local disease too frail for chemotherapy.
Preoperative radiotherapy. Preoperative radiotherapy has been shown to be of little value in converting unresectable cancers into resectable ones or in improving survival. However, it decreases the incidence of locoregional tumor recurrence.
Postoperative radiotherapy. Postoperative radiotherapy (usually to 50 or 60 Gy) can decrease locoregional failure following curative resection, but it has no effect on survival.
Brachytherapy. Intraluminal isotope radiotherapy (intracavitary brachytherapy) allows high doses of radiation to be delivered to a small volume of tissue. Retrospective studies suggest that a brachytherapy boost may result in improved rates of local tumor control and survival over external beam radiation therapy (EBRT) alone. This technique can be associated with a high rate of morbidity if not used carefully.
A multi-institution prospective phase I/II trial of 49 patients was conducted by the RTOG to determine the feasibility and toxicity of chemotherapy, EBRT, and esophageal brachytherapy in potentially curable patients with esophageal cancer. Nearly 70% of patients in RTOG study 9207 were able to complete EBRT, brachytherapy, and at least two cycles of 5-FU/cisplatin. The median survival was 11 months, and the 1-year survival was 49%. Because of the 12% incidence of fistula formation, the investigators (Gaspar et al: Cancer J 2001) urged caution in the routine application of brachytherapy as part of a definitive treatment plan.
Chemoradiation therapy
Preoperative chemoradiation therapy. Initial trials of preoperative chemoradiation therapy reported unacceptably high operative mortality (approximately 26%). Subsequent trials reported operative mortality of 4% to 11%, median survival as long as 29 months, and 5-year survival rates as high as 34%. In general, 25% to 30% of patients have no residual tumor in the resected specimen, and this group tends to have a higher survival rate than those who have a residual tumor discovered by the pathologist.
The superiority of preoperative chemoradiation therapy over surgery alone in esophageal adenocarcinoma has been investigated in several prospective trials. The first trial (Walsh et al: N Engl J Med 1996), in Ireland, included 113 patients with adenocarcinoma of the esophagus. These patients were randomized to receive either preoperative chemoradiation therapy (two courses of 5-FU and cisplatin given concurrently with 40 Gy of radiotherapy in 15 fractions) or surgery alone. Median survival was statistically superior in the combined-modality arm compared with the surgery-alone arm (16 months vs 11 months). Rates of 3-year survival again statistically favored the combined-modality arm (32% vs 6%). Although toxicity was not severe, the short survival in the surgery control arm has minimized the impact of these results in the United States.
More recently, Dutch investigators studied radiation therapy with weekly (for 5 weeks) carboplatin(Drug information on carboplatin) (area under the curve [AUC]=2), with paclitaxel (50 mg/m2). Most of the 363 patients enrolled in this study, all of whom had potentially resectable disease at the time of enrollment, had adenocarcinoma. The addition of neoadjuvant chemoradiation increased the likelihood of a complete resection (from 64.9% to 92.3% with neoadjuvant chemoradiation) and survival, both median (from 26 months vs 49 months with neoadjuvant therapy) and at 3 years (48% vs 59% with neoadjuvant therapy). There was no significant difference in operative morbidity or mortality reported.
A meta-analysis of randomized trials comparing neoadjuvant chemoradiation therapy followed by surgery with surgery alone found that neoadjuvant concurrent chemoradiation therapy improved 3-year survival (odds ratio, 0.66) compared with surgery alone, with a nonsignificant trend toward increased treatment mortality with neoadjuvant chemoradiation.
Most recently, van Hagen et al presented the results of a randomized study that compared chemotherapy (carboplatin/paclitaxel)/radiotherapy (41.4 Gy) followed by surgery with surgery alone (75% adenocarcinoma, 23% squamous cell carcinoma). The pathologic complete response rate was 29% in those who underwent preoperative therapy, and there was a survival benefit to preoperative chemotherapy/radiotherapy vs surgery alone (median survival, 49.4 months vs 24 months). There was no difference in postoperative complications or in-hospital mortality between the two arms.
Newer chemotherapy agents are active and may improve outcome over these older trials.
A phase II trial from Memorial Sloan-Kettering Cancer Center combined cisplatin and irinotecan(Drug information on irinotecan) with 50.4 Gy of radiation therapy followed by surgery. Twenty-five percent of patients had a pathologic complete response.
Several schedules of oxaliplatin(Drug information on oxaliplatin) (Eloxatin) and 5-FU concurrently with radiation have been investigated. None of the studies have been large enough or the results conclusive enough to result in the widespread adoption of oxaliplatin in place of carboplatin or cisplatin with radiation in esophageal cancer. The Southwest Oncology Group (SWOG) has investigated a schedule of oxaliplatin, 85 mg/m2 every other week, with a protracted infusion of 5-FU. This appeared tolerable, with efficacy similar to that of other platinum regimens. The FOLFOX4 (oxaliplatin, leucovorin, 5-FU) schedule concurrent with radiation has also been studied. Conroy et al presented a randomized phase III study at ASCO 2012 that compared FOLFOX/radiation therapy with cisplatin/5-FU/radiation therapy. The study included 267 patients, of which 86% had squamous histology and 52% had stage III disease. Three-year progression-free survival was 18.2% vs 17.4%, respectively, showing no benefit to FOLFOX in progression-free survival.
Leichman et al reported at ASTRO 2010 an update on pathologic response from the phase II trial SWOG S0536, in which patients with stage II/III esophageal cancer received oxaliplatin and protracted 5-FU with radiotherapy before surgery. Ninety patients were analyzed, and 29% had a pathologic complete response after central review. This is a high pathologic complete response rate, but further data on survival is awaited.
Primary chemoradiation therapy. Patients with locally advanced esophageal cancer (T1-4 N0-1 M0) may be cured with definitive chemoradiation therapy. Randomized trials have demonstrated a survival advantage for chemoradiation therapy over radiotherapy alone in the treatment of esophageal cancer. In an RTOG randomized trial involving 129 patients with esophageal cancer, 80% of whom had squamous cell cancers, irradiation (50 Gy) with concurrent cisplatin and 5-FU provided a significant survival advantage (27% vs 0% at 5 years) and improved local tumor control over radiation therapy alone (64 Gy). Median survival also was significantly better in the combined-therapy arm than in the irradiation arm (14.1 months vs 9.3 months). Survival outcomes were also somewhat better for squamous cell cancers. These data were confirmed in a similar study by the Eastern Cooperative Oncology Group (ECOG) using mitomycin(Drug information on mitomycin)-C rather than cisplatin with infusional 5-FU.
RTOG 94-05/Intergroup 0123 randomized patients to conventional-dose radiotherapy (50.4 Gy) or high-dose radiotherapy (64.8 Gy), both with 5-FU/cisplatin chemotherapy. The study was closed early because of increased morbidity of the high-dose arm. Kachnic et al reported a subsequent quality-of-life analysis that confirmed lower mean quality of life in the high-dose radiotherapy arm, providing further data that 50.4 Gy is the recommended dose of radiation therapy in the definitive setting.
The epidermal growth factor receptor (EGFR) antagonist cetuximab(Drug information on cetuximab) has been demonstrated to have radiation sensitization effects in squamous cell carcinomas of the head and neck. Naturally, agents of this class are being evaluated in esophageal cancers. De Vita et al employed cetuximab with radiation after induction therapy with FOLFOX/cetuximab. Overall, the preoperative therapy was fairly well tolerated, and a pathologic compete response was found in 27% of patients. Cisplatin, docetaxel(Drug information on docetaxel), and cetuximab were combined with radiation therapy by Ruhstaller et al prior to surgery, and this was found to be tolerable, with a complete or near complete pathologic regression in 68% of the patients. In addition, Li et al reported on a small series of patients who received cisplatin, paclitaxel, and radiation therapy with erlotinib, 150 mg daily. The 2-year overall survival was 70.1%, and relapse-free survival was 57.4%, with acceptable tolerability.
Bedenne et al presented results of a randomized trial of preoperative chemoradiation therapy vs chemoradiation therapy alone, in which there was no difference in median or 2-year overall survival rates. A randomized intergroup trial was designed to investigate the role of high-dose irradiation in conjunction with systemic therapy. This study compared doses of 50.4 Gy with doses of 64.8 Gy. Both treatment arms of the study administered concurrent 5-FU and cisplatin. This trial was stopped after an interim analysis revealed no statistically significant difference in survival between the two groups. The authors concluded that higher-dose radiation therapy did not offer any survival benefit over the 50.4-Gy dose.
Newer forms of radiation therapy, such as proton beam therapy, are being studied in combination with chemotherapy. Lin et al published a single-institution experience of treating 62 patients with proton beam radiotherapy/chemotherapy, of which 29 went on to surgery. With a median relative biologic equivalence dose of 50.4 Gy, toxicities were similar to those in previous photon beam radiotherapy/chemotherapy studies. The pathologic complete response rate was 28% in those who underwent surgery. Prospective comparison of proton beam radiotherapy/chemotherapy vs conventional photon beam radiotherapy is awaited.
• Patient selection—Patients with disease involving the mid to proximal esophagus are excellent candidates for definitive chemoradiation therapy because resection in this area can be associated with greater morbidity than resection of more distal tumors.
Most of the trials demonstrating the efficacy of chemoradiation therapy have had a high proportion of patients with squamous cell cancers. Chemoradiation therapy has thus become standard treatment of locoregionally confined squamous cell cancer of the esophagus. It is essential that chemotherapy be given concurrently with irradiation when this approach is chosen as primary treatment for esophageal cancer. A typical regimen is 50 to 60 Gy over 5 to 6 weeks, with cisplatin (75 mg/m2) and 5-FU (1 g/m2/24 hours for 4 days) on weeks 1, 5, 8, and 11.
The literature also supports offering primary surgery, preoperative chemoradiation therapy, or primary chemoradiation therapy with surgical salvage if necessary to patients with adenocarcinoma. Entering these patients on protocols will allow us to further define standard treatment.
Sequential preoperative chemotherapy and radiation therapy. Only modest benefits have been found with preoperative chemoradiation therapy to date, with systemic failure continuing to be an important problem. Thus, sequential therapy with chemotherapy followed by chemoradiation therapy has been explored.
Ajani et al reported on a series of 43 patients who received 12 weeks of cisplatin and irinotecan followed by weekly paclitaxel with infusional 5-FU and concurrent radiation therapy (4,500 cGy) and then esophagectomy. Therapy was well tolerated, with no deaths from chemotherapy or chemoradiation therapy, and an operative mortality rate of 5%. Cisplatin and irinotecan induced responses in 37% of patients, and 91% of patients underwent complete resection. Pathologic complete responses occurred in 26% of patients, and some tumor shrinkage was noted in 63% of patients. With a median follow-up of more than 30 months, the median progression-free survival was 10.2 months, the median survival was 22.1 months, and the 2-year survival was 42%. The patients who had a pathologic response to therapy had significantly better outcomes than the rest of the study population. However, systemic recurrences remained a prominent cause of failure, with five patients experiencing recurrence first in the brain and an additional five patients, in the liver.
Esophagectomy following induction chemotherapy and chemoradiation therapy. Controversy exists regarding the need for esophagectomy following chemoradiation therapy. Although previously described studies randomized patients to receive surgery with or without preoperative chemoradiation therapy, Stahl et al randomized patients to receive chemoradiation therapy with or without surgery. Also, all 172 patients in the study underwent initial induction chemotherapy (bolus 5-FU, leucovorin, etoposide(Drug information on etoposide), and cisplatin for three cycles). Those randomized to receive preoperative chemoradiation therapy received cisplatin/etoposide with 40 Gy of radiation, followed by surgery 3 to 4 weeks later. Those randomized to receive definitive chemoradiation therapy received cisplatin/etoposide with 65 Gy of radiation.
After a 6-year median follow-up, the local progression-free survival favored the group that underwent surgery (64% vs 41%). However, the treatment-related mortality was higher in those patients who underwent surgery (13% vs 4%), and so overall survival was statistically equivalent (at 3 years, 31% vs 24%). Since induction chemotherapy was used in all patients, these results should not be extrapolated to indicate the value of esophagectomy following chemoradiotherapy alone.
Stahl et al reported on a randomized trial comparing preoperative chemotherapy with chemoradiotherapy in 126 patients with T3-4 NX adenocarcinoma of the lower esophagus/gastric cardia. Pathologic complete response was higher (15.6% vs 2%) and 3-year survival was trending toward improvement (47% vs 28%) in those patients who received preoperative chemoradiotherapy.
The incidence of residual disease in patients who have a complete clinical response to chemoradiation therapy is 40% to 50%, and those patients who have a pathologic complete response to chemoradiation therapy have the best survival rates with surgery.
Treatment in elderly patients. Since esophageal cancer is being diagnosed in more patients at older ages, research is ongoing as how best to treat elderly patients. Retrospective studies from Nallapareddy et al have found chemoradiaton therapy is tolerable in elderly patients, whereas Rice et al have found a trimodality approach of chemoradiation therapy followed by surgery is also tolerable in the elderly. Close monitoring for toxicities such as dehydration, nutritional concerns, anemia, and postoperative arrhythmia was recommended in these two studies.
Advanced Disease
The goal of esophageal cancer treatment is generally palliative for patients with bulky or extensive retroperitoneal lymph nodes or distant metastatic disease. Therapeutic approaches should temper treatment-related morbidity with the overall dismal outlook. Most data relating to the treatment of unresectable and metastatic esophageal cancer are often derived from clinical trials in which patients with esophageal and gastric and gastroesophageal carcinomas are enrolled. Similarly, patients in such studies may have either squamous cell carcinomas or adenocarcinomas. However, although subset analysis of data suggests a similar survival outcome in both histologic subsets, it is possible that there is a difference in response rates, by histology.
Local treatment
In patients with a good performance status, the combination of 5-FU/mitomycin, or 5-FU/cisplatin, and radiotherapy (50 Gy) results in a median survival of 7 months to 9 months. This regimen usually renders patients free of dysphagia until death.
Photodynamic therapy
Porfimer (Photofrin) and an argon-pumped dye laser can provide effective palliation of dysphagia in patients with esophageal cancer. A prospective, randomized multicenter trial comparing photodynamic therapy (PDT) with neodymium/yttrium-aluminum-garnet (Nd:YAG) laser therapy in 236 patients with advanced esophageal cancer found that improvement of dysphagia was equivalent with the two treatments.
A review of 119 patients treated with endoluminal palliation reported a significant improvement in dysphagia scores and an increased ability to relieve stenosis caused by tumor when PDT was used in conjunction with laser therapy and irradiation.
Other approaches
Other approaches include EBRT with or without an intracavitary brachytherapy boost, simple dilatation, placement of stents, and laser recannulization of the esophageal lumen.
Palliative resection
Palliative resection for esophageal cancer is rarely warranted, although it does provide relief from dysphagia in some patients.
Chemotherapy
Phase I and II studies have demonstrated moderate response rates to chemotherapy in esophageal cancer.
Although chemotherapy alone may produce an occasional long-term remission, there is no standard regimen for patients with metastatic cancer. Patients with advanced disease should be encouraged to participate in well-designed trials exploring novel agents and chemotherapy combinations.
In Britain, the ECF regimen, a combination of epirubicin(Drug information on epirubicin) (50 mg/m2) and cisplatin (60 mg/m2), both repeated every 21 days, with continuous infusion of 5-FU (200 mg/m2/d), is considered to be a standard regimen for advanced esophagogastric cancers. However, in the remainder of the world, there is no regimen that is considered to be the standard treatment of metastatic esophageal cancer. Difficulties in determining optimal therapy for this disease include the possible differences between esophageal squamous cell cancers and adenocarcinomas. Moreover, most of the available data regarding the treatment of metastatic esophageal cancer are derived from studies in which most patients had gastric cancer or from small phase II studies.
Although the regimen has been fairly well tolerated, infusional 5-FU has rendered the combination unpopular in other countries. Several phase III studies have been performed and consistently demonstrated objective responses in about 40% of patients, with a median survival of 9 months and a 1-year survival of 36% to 40%. The main severe toxicities of this regimen are neutropenia, in about one-third of patients (32% to 36%), lethargy (18%), and nausea and vomiting (11% to 17%). The REAL-2 study evaluated 1,002 patients (60% esophageal or GE junction cancer) with advanced esophagogastric cancers. They were randomly assigned to receive epirubicin (50 mg/m2 every 21 days) with either cisplatin (60 mg/m2) or oxaliplatin (130 mg/m2) every 21 days, and either infusional 5-FU (200 mg/m2/d) or capecitabine(Drug information on capecitabine) (Xeloda; 625 mg/m2 twice daily). In this study, the outcomes were similar in the resultant treatment groups, with median survivals of about 10 months and 1-year survivals between 39% and 45%. Indeed, the single best-performing arm was EOX (epirubicin, oxaliplatin, Xeloda [capecitabine]), with a median survival of 11.2 months and a 1-year survival of 46.8%, although these results were not significantly superior to the other arms.
With the advent of many new chemotherapeutic agents (the taxoids, paclitaxel and docetaxel [Taxotere], irinotecan, and gemcitabine(Drug information on gemcitabine) [Gemzar]) with varying mechanisms of activity, further studies have been conducted, and each of these drugs has demonstrated activity, with responses achieved in approximately 15% to 30% of patients.
However, the primary route of investigation for these new agents has been in combination with cisplatin and/or 5-FU. The results available to date suggest promising activity, with response rates often around 50% in phase II studies. Irinotecan (65 mg/m2) and cisplatin (30 mg/m2) administered weekly for 4 weeks every 6 weeks have also been active, with responses in 20 of 35 patients (57%) and an impressive median survival of 14.6 months. A Korean phase II study did not confirm these results but did suggest the combination was active, with a response rate of 31% of 32 patients, and a median survival of 9.6 months.
Combination chemotherapy in advanced diseasePaclitaxel (180 mg/m2 over 3 hours) and cisplatin (60 mg/m2 over 3 hours) administered every 14 days have been extensively evaluated in Europe. They were reported to produce objective responses in 43% of 51 patients, including two complete responses, and 43% of patients were alive 1 year after initiation of therapy (Table 5).
Because of the toxic and logistic difficulties of using cisplatin, carboplatin has become a popular chemotherapeutic drug. Several studies of carboplatin with paclitaxel in esophageal cancer have been undertaken. El-Rayes et al administered carboplatin (at an AUC of 5) with paclitaxel (200 mg/m2 over 3 hours) every 3 weeks in 33 chemotherapy-naive patients. Objective responses were reported in 45% of patients, with a median survival of 9 months and 1-year and 2-year survival rates of 43% and 17%, respectively.
Polee et al explored a weekly schedule of these drugs in a phase I study. With therapy administered for 3 consecutive weeks, followed by a 1-week break, a dose of carboplatin (at AUC 4) with paclitaxel (100 mg/m2) was recommended for further investigation. Responses were noted in half of the 40 patients, with a median survival of 11 months and a 1-year survival of 46%. Both of these combinations were well tolerated, with the primary toxicity of myelosuppression.
The combination of docetaxel, cisplatin, and infusional 5-FU (DCF) has been approved by the US Food and Drug Administration for the treatment of metastatic gastric and GE junction adenocarcinomas. The activity of this regimen in esophageal cancers is unclear. Tebbutt et al performed a randomized phase II study in 106 patients with advanced esophagogastric cancers. Two different modifications of the DCF regimen were evaluated, either docetaxel (30 mg/m2, 2 weeks on, 1 week off) with capecitabine (1,600 mg/m2 daily, divided into two separate doses), or a similar docetaxel with cisplatin at a lower dose (60 mg/m2) and a continuous infusion of 5-FU. This study demonstrated that the modified DCF appeared to have a better response rate (47% vs 26%) but similar overall survival (11.2 months and 10.1 months, respectively) and progression-free survival (5.9 months vs 41 months).
Another response to the toxicity of the DCF regimen has been the elimination of the 5-FU, and exploration of cisplatin and docetaxel alone or substitution of oxaliplatin for cisplatin. Kim et al evaluated this combination, with a dose of 70 mg/m2 of each agent, administered every 21 days in 39 Korean patients with squamous cell carcinomas of the esophagus. They reported a 33% response rate, which included three complete responses (7.7%), and a median survival time of 8.3 months. The regimen was reported as well tolerated, with about one-third of patients experiencing grade 3 or 4 neutropenia.
The antimetabolite gemcitabine has also been evaluated in combination with cisplatin in esophageal cancer. A SWOG study, reported by Urba et al, combined 1,000 mg/m2 of gemcitabine on days 1, 8, and 15 with 100 mg/m2 of cisplatin on day 15 in 64 patients. Approximately one-quarter of these patients had received prior chemotherapy. Therapy was well tolerated, with severe neutropenia occurring in 31% of patients. The median survival of patients treated on this study was 7.3 months, and the 1-year survival rate was 20%. However, the heterogeneity of the patient population makes the efficacy of the therapy somewhat difficult to assess.
Oxaliplatin may also have a role in the treatment of esophageal cancer, both as a radiosensitizer and an agent in advanced disease. Mauer and colleagues reported the results of treatment with oxaliplatin, 5-FU, and leucovorin according to the FOLFOX4 schedule (oxaliplatin, 85 mg/m2 on day 1; leucovorin, 500 mg/m2 over 2 hours on days 1 and 2; and 5-FU, 400 mg/m2 bolus, then 600 mg/m2 over 22 hours on days 1 and 2, repeated every 14 days). Of 35 patients who were treated, objective responses were noted in 40%. The median survival rate was 7.1 months, the 1-year survival rate was 31%, and the 2-year survival rate was 11%. The median progression-free survival was 4.6 months. Although differences in patient populations were noted, these results are similar to those of other reported combinations.
The combination of oxaliplatin (130 mg/m2 on day 1) with capecitabine (1,000 mg/m2 twice daily on days 1 to 14) repeated every 21 days has also been studied in esophageal cancer. Thirty-eight percent of the 51 treated patients had objective responses, with a median survival of 8 months and a 1-year survival rate of 26%. This study was conducted in the Netherlands, and the tolerability and efficacy of this regimen in American patients remain to be determined.
The primary toxicity of these regimens is severe neutropenia, occurring in about 40% to 70% of patients. Severe diarrhea, nausea, and vomiting occur in approximately 10% to 15% of patients in many studies. Fatigue and asthenia also were significant side effects with both therapies.
With improving toxicity profiles and modest improvements in therapeutic outcomes, second-line therapy for advanced esophageal cancer is also increasingly being explored. Muro et al treated 28 Japanese patients with squamous cell carcinoma of the esophagus with docetaxel (70 mg/m2) every 3 weeks; these patients had previously received cisplatin and 5-FU. As expected, severe neutropenia was the dominant toxicity (88%, including nine episodes of febrile neutropenia), with severe anorexia, fatigue, and anemia also reported. Objective responses were noted in 16% of these patients.
In addition, Lordick et al determined that irinotecan (55 mg/m2) and docetaxel (25 mg/m2) given on days 1, 8, and 15, with cycles repeated every 28 days, were tolerable, with severe asthenia in 21% of 24 patients and severe diarrhea in 13%. However, only three partial responses (13%) and eight patients with stable disease were noted, with a resultant median survival of 26 weeks. Although these studies suggest the feasibility of second-line cytotoxic chemotherapy in esophageal cancer, the significant toxicity and limited objective response rate warrant its use only with caution and preferably on a clinical study. In another study of second-line chemotherapy, Shim et al treated 38 patients who had previously been treated with cisplatin/5-FU, with cisplatin 75 mg/m2 and docetaxel 70 mg/m2 IV every 3 weeks. In this setting, a response rate of 35% was reported, with a median survival of 7.4 months.
Oral tyrosine kinase inhibitors of the EGFR have also been investigated in esophageal cancer. Gefitinib(Drug information on gefitinib) (Iressa), at a daily dose of 500 mg, as second-line therapy in patients with esophageal adenocarcinomas was evaluated by Ferry et al. It produced partial responses in 11% of 27 patients, and an additional seven patients had stable disease. In patients with esophageal cancer that had previously been treated with platinum-based chemotherapy, Janmaat et al treated 37 patients with the same regimen. They reported a confirmed response in only one patient and stable disease in another 10, although 18% of patients were free of disease progression at 6 months, suggesting that some patients indeed experience disease control and benefit from this therapy. However, Radovich et al reported only one response in 23 patients treated with erlotinib (Tarceva; 150 mg daily). The toxicities were as expected, including rash, diarrhea, vomiting, and elevation in transaminase levels. As with lung and colon cancers, the optimal population for treatment with these targeted agents remains to be defined.
The other class of agents that target the EGFR pathway, monoclonal antibodies such as cetuximab, has provided mixed results in patients with esophageal cancer. For example, a German study of cisplatin/5-FU with or without cetuximab (Erbitux) as initial therapy in patients with metastatic esophageal squamous cell cancers with EGFR expression by immunohistochemistry suggested an improvement in patient outcomes. Sixty-two patients were randomized in a non-blinded fashion on the study, and crossover to cetuximab with cisplatin/5-FU was allowed in the patients who received initial cisplatin/5-FU alone. The response rates were similar in the two arms (33% with cetuximab, vs 30%), but patients who received the additional cetuximab had a superior disease-control rate (75% vs 57%), median time to disease progression (5.9 months vs 3.6 months), and median overall survival (9.5 months vs 5.5 months). Moreover, of the five patients who crossed over to second-line cetuximab, two had partial responses (one with single-agent therapy), and one had stable disease. However, given the sample size, and the unblinded nature of the study with crossover, caution must be exercised when interpreting these results.
More recently, the CALGB performed a randomized phase II study combining cetuximab with several other typical chemotherapy regimens, including ECF, cisplatin/irinotecan, and FOLFOX, in patients with metastastic esophageal and GE junction cancers. Each arm included about 80 patients; the response rates were 58%, 38%, and 51%, respectively, and median survivals were 8 to 10 months. Each arm surpassed the prespecified endpoint, suggesting enough promise to further explore in phase III studies. Again, however, the number of patients treated was too low to consider any of the regimens to be a standard at this time. Panitumumab is undergoing study in the United Kingdom in a phase III study (REAL-3) in the first-line setting with EOX, presented at ASCO 2012. However, another EGFR antagonist, matuzumab, in combination with chemotherapy, was not suggested to improve outcomes in a randomized phase II study, suggesting again that all EGFR antagonists are not equal and need to be considered independently.
The SWOG studied cetuximab as a single agent as second-line therapy for metastatic esophageal adenocarcinoma. Of the 55 eligible and evaluable patients, only one (2%) had a partial response, and six (11%) had stable disease. The median progression-free survival was 1.8 months, the median survival was 4 months, and the 6-month survival rate was 36%. The authors concluded that although the drug was well tolerated as single-agent therapy, it did not meet its primary endpoint and so could not be recommended as second-line therapy in esophageal cancer. The discordant results represented in these studies, between histologies and drugs, may reflect the differing biologies of esophageal adenocarcinomas and squamous cell carcinomas. Alternatively, they may reflect alterations in cancers after undergoing chemotherapy.
The role of the vascular endothelial growth factor (VEGF) pathway in esophageal cancer also remains unclear. A phase II study of a modified DCF with bevacizumab(Drug information on bevacizumab) demonstrated a response rate of 67% and median survival of 16.8 months in 44 patients with GE cancer, which is superior to DCF alone, suggesting a potential utility of bevacizumab in this disease. In addition, a study of sorafenib(Drug information on sorafenib), 400 mg twice daily, demonstrated one complete response and one prolonged stable disease in 20 patients. Taken together, these data suggest that inhibiting the VEGF pathway may improve outcomes in metastatic disease, and further investigation is ongoing.
In addition to the EGFR and VEGF antagonists, it is anticipated that other targeted therapies, such as MEK and met inhibitors, will be evaluated in this disease. Such avenues of exploration, in addition to early diagnosis of and therapy for early-stage disease, are the most likely path toward significant improvements in therapy for esophageal cancer.
