Esophageal cancer can metastasize to virtually any organ in the body. Widespread distant metastases are almost always present at the time of death. The extensive lymphatic drainage pathways in the esophagus and the long-time interval during which tumors typically remain asymptomatic may contribute to the high incidence of lymph node metastases. For all but the earliest stage tumors, surgical resection alone is inadequate. In fact, as many as 30% of patients with early (T1) lesions may have lymph node metastases. For this reason, multimodality regimens have been designed to achieve better survival in this disease.
The rationale for using preoperative radiotherapy is to reduce marginally resectable tumors to a more resectable size, to reduce the risk of tumor spread during surgical manipulation, and to treat extension of tumor beyond the surgical specimen. Surgery then removes the central, more radioresistant tumor mass. It does not appear that preoperative radiotherapy has an adverse effect on resectability or surgical morbidity.
Preoperative radiation doses of 30 to 45 Gy have been reported to result in a complete pathologic response rate of 15% to 30%. It is important to note that precise reporting of the rates of tumor sterilization is not possible, because not all patients who are irradiated undergo surgery and not all those operated on are resectable. Some clinical trials have suggested that survival after preoperative radiotherapy is correlated with the extent of tumor destruction seen in the resected specimen. A multicenter randomized controlled trial conducted by the European Organization for Research and Treatment of Cancer involved the administration of 33 Gy in 10 fractions in the treatment arm, followed by esophagectomy within 8 days. There were no significant differences in resectability or operative mortality between the study arms. Locoregional failure was decreased significantly in the radiotherapy arm from 67% to 46%. This was not associated with a survival benefit.52 Current consensus sees no role for neoadjuvant XRT alone.
Neoadjuvant chemotherapy in patients with esophageal cancer who appear to have locoregional disease may diminish the incidence of unrecognized systemic metastases. The potential benefits of preoperative chemotherapy include downstaging the disease to facilitate surgical resection, improving local control, and eradicating micrometastatic disease. Surgical resection subsequently provides an opportunity to assess the tumor response to chemotherapy and to evaluate the patient for possible postoperative adjuvant therapy. In patients with localized, resectable tumors, chemotherapy-related toxicity occasionally can result in prolonged delay or even cancellation of planned surgical resection, risking further spread of disease. The resulting need for careful patient selection for participation in clinical trials of preoperative chemotherapy can bias treatment results. An American multi-institutional randomized trial of 440 patients compared surgery alone versus neoadjuvant chemotherapy followed by surgery. Preoperative chemotherapy consisted of three cycles of fluorouracil (5-fluorouracil or 5-FU) and cisplatin. Surgical resection followed 2 to 4 weeks later. Patients received two additional cycles of chemotherapy postoperatively. There was no significant difference in perioperative morbidity and mortality between the two groups. There was no significant difference in 1-year survival (60%), 2-year survival (35%), or local or distant recurrence rates. Survival did not differ between patients with squamous cell carcinoma and adenocarcinoma. Median survival time was 15 to 16 months in both treatment arms.53 A smaller randomized trial comprising 147 esophageal cancer patients from Hong Kong demonstrated a higher rate of curative resection, yet failed to show a survival benefit with neoadjuvant chemotherapy.54
A British randomized controlled trial of 802 patients also studied the use of preoperative 5-fluorouracil and cisplatin. The rate of microscopically complete resection was significantly higher for patients undergoing preoperative chemotherapy than for those undergoing surgery alone (60% vs. 54%). Postoperative complication rates were similar in both groups (41% vs. 42%). Patients undergoing preoperative chemotherapy achieved significantly improved median survival (16.8 vs. 13.3 months) and 2-year survival (43% vs. 34%).55 Results of this trial were updated in 2009, reporting 5-year survival of 23% for the neoadjuvant chemotherapy group versus 17% for the surgery alone group.56 The results of this trial, however, are potentially confounded by the fact that clinicians were allowed the option of giving preoperative radiotherapy to their patients irrespective of randomization.
An oft-quoted study is the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial which randomized 503 patients with gastroesophageal cancer to either perioperative chemotherapy or surgery alone.57 The chemotherapy was comprised of three cycles of epirubicin, cisplatin, and 5-fluorouracil followed by surgery and three additional cycles of the same regimen. It was originally designed to include gastric cancer only, but inclusion criteria were later extended to include cancers of the lower third of the esophagus. There was a survival benefit for perioperative chemotherapy (36% 5-year survival vs. 23%). It should be kept in mind, however, that only a quarter of these patients had tumors of the lower esophagus or gastroesophageal junction; the remainder were gastric cancers. Another more recent multicenter randomized study by Ychou et al.58 investigated a similar question of perioperative chemotherapy (cisplatin and 5-fluorouracil) versus resection alone for cancers of the esophagogastric junction. Of 224 patients, 11% involved the lower esophagus, 25% the stomach, and the remainder were true gastroesophageal junction tumors. There was again a survival benefit conferred by perioperative chemotherapy. Although some are conflicting, the majority of recent data, suggest a benefit of perioperative chemotherapy over surgery alone for the treatment of esophageal cancer.
Both chemotherapy and radiotherapy have been reported to improve survival in patients with esophageal cancer when administered preoperatively. The notion of downstaging esophageal cancer before surgical resection is appealing. In an attempt to improve resectability and survival in esophageal cancer, chemotherapy has been combined with radiotherapy in the neoadjuvant setting. Most reports of so-called trimodality therapy for esophageal carcinoma describe concurrent neoadjuvant chemoradiation using combinations of cisplatin and 5-fluorouracil while administering 30 to 45 Gy of radiation. Some studies have used additional postoperative chemotherapy. The results appear comparable at most experienced centers.
In an Irish study of 113 patients who had esophageal adenocarcinoma, patients were randomly allocated to surgery alone versus trimodality therapy with neoadjuvant chemoradiation.59 Patients randomized to the trimodality arm received two cycles of 5-fluoruracil and cisplatin given concurrently with 40 Gy of radiation, followed by surgery. Neoadjuvant chemoradiation was associated with a pathologic complete response rate of 25%. Trimodality therapy was associated with significantly increased median survival (16 vs. 11 months) and 3-year survival (32% vs. 6%). It should be noted that, at the time of surgery, the incidence of lymph node involvement was significantly higher in the group undergoing surgery alone. Survival with surgery alone was lower than that reported in most other series.
A French randomized trial of 282 patients compared surgery alone with two cycles of cisplatin chemotherapy and concurrent radiotherapy (total 37 Gy) followed 2 to 4 weeks later by surgery.60 Neoadjuvant chemoradiation was associated with a pathologic complete response rate of 26% but with significantly increased operative mortality (12.3% vs. 3.6%). Despite a significantly increased rate of microscopically complete resection, longer local disease-free survival time, longer overall disease-free survival time, and fewer cancer-related deaths in the trimodality arm, overall survival time was 18.6 months in both treatment arms. A randomized trial from the University of Michigan looked at 100 patients receiving either preoperative chemoradiation (total 45 Gy) or surgery alone.61 All resections were performed using a transhiatal approach. With a median follow-up of 8 years, there was no difference in survival.
Meta-analyses of randomized trials of trimodality therapy versus surgery alone for esophageal carcinoma have revealed a trend toward increased treatment-related mortality and slightly increased overall survival. Among patients treated with trimodality therapy for esophageal carcinoma, the best predictor of survival appears to be the finding of a pathologic complete response at the time of surgical resection.62,63
Cancer and Leukemia Group B 9781 was a prospective, randomized intergroup trial of trimodality therapy versus surgery alone for the treatment of stages I to III esophageal cancer.64 Patients were randomized to treatment with either surgery alone or cisplatin (100 mg/m2) and 5-fluorouracil (1000 mg/m2 per day × 4 days) during weeks 1 and 5 concurrent with radiation therapy (50.4 Gy at 1.8 Gy/daily fraction over 5.6 weeks) followed by esophagectomy with lymph node dissection. A total of 56 patients were entered into the study between October 1997 and March 2000 when the trial was closed as a consequence of poor accrual. Thirty patients were randomized to trimodality therapy and 26 to surgery alone. An intent-to-treat analysis showed a median survival of 4.5 versus 1.8 years in favor of trimodality therapy (log rank p = 0.02). A log-rank test with stratifications by N stage, staging approach, and histology demonstrated a p value of 0.005. The 5-year survival was 39% (95% confidence interval: 21%–57%) versus 16% (95% confidence interval: 5%–33%) in favor of trimodality therapy.
Van der Gaast et al.65 presented results in 2010 of the largest randomized study to date looking at neoadjuvant chemoradiotherapy compared to surgery alone. The multicenter phase III CROSS trial investigated 363 esophageal cancer patients undergoing neoadjuvant chemoradiation (utilizing a different chemotherapy regimen and a total of 41.4 Gy) versus surgery alone. The R0 resection rate was 92% in the neoadjuvant arm versus 65% in the surgery alone arm. Median survival was 49 months compared to 26 months in favor of trimodality therapy. The benefit was most pronounced in patients with squamous cell histology. The final results have recently been published in manuscript form and confirm these findings.66
An Australian randomized phase II trial investigated whether the addition of concurrent radiation to a preoperative chemotherapy regimen is advantageous.70 Seventy-five patients with esophageal adenocarcinoma received either neoadjuvant chemotherapy or chemoradiotherapy. There was no statistically significant difference in survival. The major pathologic response rate (pCR + <10% viable cells) was significantly improved in the arm receiving radiation (8% vs. 31%; p = 0.01). However, the advantage in 5-year survival was not statistically significant, suggesting that the study may have been underpowered.
To date, there is no completely reliable preoperative method for identifying a pathologic complete response after neoadjuvant chemoradiation. There is conflicting evidence regarding whether a restaging PET scan is a reliable predictor of a complete pathologic response prior to resection.67,68 However, we now know that the survival of patients with microscopic residual disease approaches that of patients with a complete pathologic response, whereas gross residual disease is a poor prognostic factor.69
At this point, there is adequate prospective evidence that the addition of radiation to a neoadjuvant chemotherapy regimen improves survival, as well as the rate of a complete pathologic response.66
Radiotherapy is commonly considered postoperatively to “sterilize” residual microscopic disease and to control gross residual locoregional tumor. As an advantage, reserving radiotherapy for postoperative use avoids the necessity of subjecting all patients with completely resectable disease to the damaging effects of radiation. As a disadvantage, the use of postoperative radiation in patients who have undergone gastric pull-up or colonic interposition exposes large volumes of normal tissue to harm and is a potential cause of late morbidity. A French randomized trial of 221 patients with squamous cell carcinoma arising in the distal two-thirds of the esophagus compared surgical resection alone versus surgery followed by postoperative radiotherapy doses of 45 to 55 Gy in daily fractions of 1.8 Gy. Among patients with negative lymph nodes, local recurrence rates were lower in the group that received postoperative radiotherapy. There was no significant difference in survival between the two groups.71 A randomized trial from Hong Kong studied 130 patients undergoing either palliative or curative resection for esophageal cancer. Patients randomized to the postoperative radiotherapy arm of the study received doses of 49 to 52.5 Gy in daily fractions of 3.5 Gy. The very high daily radiation dose used in this study was associated with a significantly decreased median survival compared with surgery alone (8.7 vs. 15.2 months). In patients undergoing curative resection, postoperative radiotherapy was not associated with any improvement in local control. Although postoperative radiotherapy was associated with improved local control in patients undergoing palliative resection with gross residual disease, there was no survival benefit.72 A prospective Chinese study of 495 patients who had undergone surgical resection of esophageal cancer randomized patients to a postoperative radiotherapy group or a control group. A midplane dose of 50 to 60 Gy was administered in daily fractions of 2 Gy. A trend toward improved 5-year survival in patients who received postoperative radiotherapy (41.3% vs. 31.7%) was not statistically significant. This trend was somewhat stronger in patients with positive lymph nodes (29.2% vs. 14.7%, p = 0.07). Postoperative radiotherapy was associated with a statistically significant improvement in 5-year survival only among patients with stage III disease (35.1% vs. 13.1%).73 This is corroborated by a more recent retrospective analysis of the Surveillance, Epidemiology and End Results (SEER) database suggesting a survival benefit for stage III patients with either squamous cell carcinoma or adenocarcinoma who receive postoperative radiation as opposed to resection alone. There was no benefit associated with postoperative radiation among stage II patients.74
Adjuvant chemotherapy also has been studied. A multi-institutional Japanese randomized controlled trial of 242 patients who had undergone complete surgical resection for esophageal squamous cell carcinoma studied the effects of adjuvant chemotherapy with two cycles of cisplatin and 5-fluorouracil. Adjuvant chemotherapy was associated with significantly improved 5-year disease-free survival in patients with lymph node involvement (52% vs. 38%). Despite improved disease-free survival, there was no significant improvement in overall survival. Among node-negative patients receiving adjuvant chemotherapy, a trend toward improved 5-year disease-free survival (76% vs. 70%) was not statistically significant.75 To date, there are no published North American data suggesting that postoperative chemotherapy in the absence of documented metastatic disease is associated with prolonged survival.
In light of the relatively high morbidity and mortality rates associated with esophageal resection, definitive chemoradiation has been advocated as a reasonable approach for the treatment of esophageal cancer. Two similar phase III studies compared the efficacy of neoadjuvant chemoradiotherapy and definitive chemoradiotherapy, with concordant results. A French study only randomized chemoradiotherapy nonresponders (of 444 eligible patients, only 259 were randomized). Of the remaining patients who responded clinically to chemoradiation, there was no difference in survival when surgery was added to the treatment regimen. However, the surgical arm had more early deaths yet better local control and palliation of dysphagia.76 A German study also failed to reveal a survival difference between treatment arms, yet resected patients had better progression-free survival. Clinical response to induction chemotherapy was a good prognostic factor in each group.77 For elderly patients, however, definitive chemoradiation is associated with significant morbidity and poor survival.78 It may be reasonable to consider resection alone for elderly patients who are of acceptable surgical risk.
It is clear from patterns-of-care study surveys that a multimodality approach is increasing in popularity across the country.79 Novel restaging techniques, as well as further study of the risks and benefits of neoadjuvant chemoradiotherapy, are needed.
Although patients with early localized disease benefit from complete surgical resection, there is increasing evidence that multimodality therapy (neoadjuvant chemoradiation followed by surgical resection) has increased survival benefits when compared to surgery alone for more advanced stages.59