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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.10.026 on June 14, 2004

Annals of Surgical Oncology 11:665-673 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Controversies in the Multimodality Management of Locally Advanced Esophageal Cancer: Evidence-Based Review of Surgery Alone and Combined-Modality Therapy

R. Iyer, MD, N. Wilkinson, MD, T. Demmy, MD and M. Javle, MD

From the Departments of Medical (RI, MJ) and Surgical (NW, TD) Oncology, Roswell Park Cancer Institute, Buffalo, New York.

Correspondence: Address correspondence and reprint requests to: Milind M. Javle, MD, Assistant Professor of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263; Fax: 716-845-8008; E-mail: milind.javle{at}roswellpark.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SURGERY
 RI: DEFINITIVE CHEMORADIATION IS...
 NEOADJUVANT THERAPY
 CONCLUSIONS AND RECOMMENDATIONS
 REFERENCES
 
Most patients with esophageal cancer present with locoregional disease, and the optimal initial management is controversial. The current National Comprehensive Cancer Network (NCCN) practice guidelines support diverse treatment options for locoregional disease, including surgical resection alone, definitive chemoradiation therapy, and preoperative combined-modality (neoadjuvant/trimodality) therapy. Many cancer centers worldwide favor a neoadjuvant approach, although the evidence supporting this practice is inconsistent. A concise review of the literature is presented. The topics discussed do not necessarily reflect each author’s opinions or clinical practices.

Key Words: Chemoradiation • Chemotherapy • Esophageal cancer • Neoadjuvant therapy • Surgery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SURGERY
 RI: DEFINITIVE CHEMORADIATION IS...
 NEOADJUVANT THERAPY
 CONCLUSIONS AND RECOMMENDATIONS
 REFERENCES
 
Esophageal cancer is uncommon, accounting for only 1% of all cancers in the United States. New cases of esophageal cancer in the United States in 2003 will total 13,900, and 13,000 deaths will result from this disease.1 Approximately 50% of these patients present with locoregional disease, for which the optimal therapy is unclear. Options include primary surgery, definitive chemoradiation, or neoadjuvant chemoradiation. While surgical therapy may be curative in the early stages, 5-year survival rarely exceeds 30% for regionally advanced cases—a number closely matched by definitive chemoradiation studies. In the ensuing paragraphs, the merits and disadvantages of each of these modalities are discussed by a surgical oncologist (NW) and a medical oncologist (RI). This review is based on a debate presented at Roswell Park Cancer Institute by the Departments of Surgery and Medical Oncology.


   SURGERY
TOP
 ABSTRACT
 INTRODUCTION
 SURGERY
RI: DEFINITIVE CHEMORADIATION IS...
 NEOADJUVANT THERAPY
 CONCLUSIONS AND RECOMMENDATIONS
 REFERENCES
 
NW: Surgery Remains the Standard of Care
Surgery is the oldest form of cancer therapy. Patients with solid tumors are cured more with surgery as a single modality than with any other therapy.2 Even with the effectiveness of modern multimodality therapy, patients with solid tumors usually still require surgery as part of management. Esophagectomy has traditionally represented the only "curative" option for esophageal cancer. Billroth performed the first esophagectomy in 1888, while Franz Torek performed the first total esophagectomy for cancer on March 14, 1913.3 Early surgical series had high postoperative morbidity and mortality, whereas contemporary data from high-volume cancer centers show an acceptable surgical mortality of 2% to 3%.

There is no consensus regarding the best operation for esophageal adenocarcinoma. Transhiatal approaches are the most common in North America, while Ivor-Lewis (transthoracic) esophagectomy is favored world-wide.4,5 A recent randomized clinical trial sought to determine whether surgical technique had an impact on morbidity, mortality, and survival outcome.6 Extended transthoracic resection (extended resection) was compared with limited transhiatal resection (THE) in 220 resected esophageal cancer patients. No neoadjuvant therapy was permitted. The clinical groups were similar, with 96% having adenocarcinoma and 50% being node-positive. Minimum follow-up was 2.5 years, and median follow-up was 4.7 years. Surgical morbidity was 27% for THE and 57% for extended resection (P= .001). Surgical mortality was 2% for THE and 4% for extended resection (P = .45). The estimated 5-year survival was 29% for THE and 39% for extended resection, a difference that did not reach statistical significance (P = .38). Survival figures reported from the above study and for the "control" arm of surgery alone in a recent intergroup trial7 averaged 1.5 years, remarkably similar to findings in some "definitive" chemoradiation series (Table 1).


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  		TABLE 1. Definitive chemo-radiotherapy trials
 
"Minimally invasive esophagectomy" is a recent technique involving laparoscopic transhiatal resection and thoracoscopic mobilization.8 This procedure is associated with low postoperative mortality and is being investigated in a multicenter trial by the Eastern Cooperative Oncology Group (ECOG). Two- and three- field dissections have been advocated in Japan, involving lymphatic dissection of upper abdominal with mediastinal and cervical areas, respectively, along with esophageal resection (en bloc esophagectomy). These techniques have resulted in improved 5-year survival of 50% (across all stages), although the three-field technique is associated with significant morbidity.9,10 These results have also been replicated in North America.11 No therapy thus far has been proven to be superior to surgery for locoregional esophageal cancer. Select surgical data are discussed below.

We conducted a retrospective analysis of 400 consecutive patients with local or regional esophageal cancer (SEER stage) treated at Roswell Park Cancer Institute between September 23, 1971 and September 20, 2002.12 Initial therapy was combined modality in 231 and single modality in the rest (radiation, 85; surgery, 76; chemotherapy, 8). Postoperative (30-day) mortality was 3.9%. Median survival for all patients was 18.9 months and was better for local stage with surgery (75 months) than with neoadjuvant therapy (31 months) or definitive chemoradiation (19 months; P < 0.001). Durations of survival of patients with regional disease treated with surgery alone or with neoadjuvant or definitive chemoradiation were 16.8, 19.6, and 10.6 months, respectively (P= NS).

The association of prognostic factors with overall survival was evaluated with Cox proportional hazards regression analysis and two-sided Wald’s {chi}2 tests. On multivariate analysis, there was a statistically significant association between treatment modality (inclusion of surgery) and stage with overall survival. Histology (adenocarcinoma vs. squamous) did not have prognostic impact in our series. These results are reported in Table 2. The report of another, larger series (with over 1000 consecutive esophagectomies) in Europe described adenocarcinoma as a "favorable" predictor for long-term survival, as compared with squamous histology.13


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  		TABLE 2. RPCI experience: 400 consecutive patients with locoregional esophageal cancer
 
University of Southern California investigators reported on a highly selected series of 100 consecutive patients undergoing en bloc esophagectomy as sole therapy.14 In this series, no patient received neoadjuvant or adjuvant therapy. Instead, an aggressive en bloc esophagectomy with two-field lymphadenectomy (thoracic and celiac nodal regions) was performed. Stage I and IIA patients (node-negative) had >90% and 60% long-term estimated survival, respectively. Tumors that invaded the muscularis propria (T2) had a high likelihood of harboring nodal disease (30% to 40% local and 23% to 27% celiac). Current American Joint Commission on Cancer (AJCC) staging guidelines classify celiac node involvement as M1 disease. As such, the 5-year survival rate for M1 disease was 30% without adjuvant therapy. This series demonstrates promising results in a selected group with use of en bloc esophagectomy as the sole modality of therapy and compares favorably with findings in definitive chemoradiation studies (Table 1).

The debate within the surgical community regarding which surgical technique is ideal is likely to continue, because the "ideal" technique has not been developed. Yet, the above studies demonstrate that resection achieves meaningful results comparable to those of nonsurgical multimodality therapy, albeit at the acceptable cost of postoperative morbidity. Nonsurgical multimodality approaches have not improved on these results but might with the addition of effective neoadjuvant therapy to optimal surgical resection.

RI: Problems with Esophagectomy
Historically, the standard of care for the primary management of esophageal cancer has been surgical resection. However, even when performed with a curative intent, surgery is curative only for a select few. Of patients with locally advanced disease, <30% are alive 5 years after surgery.15,16 In a 25-year study of 657 esophagogastrectomies in patients with either squamous carcinomas or adenocarcinomas of the esophagus and cardia, 5-year survival was 36% for stage I, 21% for stage II, and 5% for stage III.17 The reasons for this poor outcome are severalfold.

(1) The esophagus lacks a serosal layer and can distend considerably to accommodate any intraluminal growth. Patients may have 75% intraluminal obstruction before experiencing dysphagia or weight loss. Thus, at diagnosis only 50% have locoregional disease (T0–T3, N0–N1), and of these, only 60% are eligible for a potentially curative surgery.

(2) Of those who undergo surgery, 50% to 60% (only 15% of all newly diagnosed cases) actually have an R0 or microscopically margin-negative surgery. In addition, 70% to 80% of all surgical specimens harbor lymph node metastases.1,2 Lymph node and surgical margin status has been correlated with 5-year survival.18 These data suggest that patients who benefit from surgery have early stage, node-negative disease for which microscopically negative margins can be achieved. Unfortunately, this is not the case for most patients.

(3) Current diagnostic and staging tools for this disease have significant limitations. Flamen et al.19 investigated some of these diagnostic modalities prospectively in a cohort of 74 patients. Endoscopic ultrasound (EUS) was superior for T stage (sensitivity, 81%; specificity, 67%) and N stage (sensitivity, 63%; specificity, 88%). Positron emission tomography (PET) was superior for distant metastasis (sensitivity, 74%; specificity, 90%) in comparison with computed tomography (CT). Several retrospective studies have shown the superiority of EUS and PET in accurate staging, yet these tools are not routinely available or employed. EUS is also highly operator-dependent and cannot be used in patients with obstructing tumors. Hence, some patients are "upstaged" intraoperatively.

(4) Yet another limitation is the generous longitudinal anatomic lymphatic drainage of the esophagus, which is difficult to address with a segmental surgical excision. While this can be circumvented by a total esophagectomy, the procedure is limited to a few centers and is associated with increased morbidity. Furthermore, there is high incidence of skip metastases in esophageal cancer. Thus, 30% of mid- and lower esophageal carcinomas have positive deep cervical nodes, and 10% of upper-third and 40% of mid-third esophageal cancers have positive abdominal nodes.20

Even with the improvements in postoperative and supportive care, esophagectomy is associated with relatively high morbidity and mortality, particularly in low-volume centers. Using the national Medicare claims database and the nationwide inpatient sample, Birkmeyer et al.21 reported the operative mortality among Medicare patients undergoing selected cardiovascular or cancer procedures. The difference in operative mortality for esophagectomy in low-volume versus high-volume centers was significant (18.9% vs. 8.1%). Morbidity was also found to be higher in low-volume centers, by Dimick et al.22 Low-volume hospitals had a profound increase in the risk of several complications, such as renal failure, pulmonary failure, septicemia, reintubation, and aspiration. Nonsurgical approaches, such as definitive chemoradiation, are therefore important in this disease, where access to a high-volume surgical center is limited.


   RI: DEFINITIVE CHEMORADIATION IS AN ACCEPTABLE ALTERNATIVE TO SURGERY
TOP
 ABSTRACT
 INTRODUCTION
 SURGERY
 RI: DEFINITIVE CHEMORADIATION IS...
NEOADJUVANT THERAPY
 CONCLUSIONS AND RECOMMENDATIONS
 REFERENCES
 
Historically, radiation therapy alone has been used as a definitive therapy for inoperable patients with poor long-term results. Chemoradiation as a treatment modality was therefore compared with radiation therapy for inoperable patients. RTOG-8501 was a landmark study from the Radiation Therapy Oncology Group (RTOG) that evaluated concurrent chemoradiotherapy, consisting of four cycles of 5-fluorouracil (5-FU) (1000 mg/m2 by continuous infusion for the first 4 days of weeks 1, 5, 8, and 11) plus cisplatin (75 mg/m2 day 1, every 4 weeks) and radiation therapy (50 Gy in 25 fractions over 5 weeks), in comparison with radiation therapy alone (64 Gy in 32 fractions over 6.5 weeks), among patients with locoregional thoracic esophageal cancer (T1–3, N0–1, M0).23

Ninety percent of the trial participants had squamous cell carcinoma. The trial was closed prematurely after enrollment of 121 patients. An interim analysis showed a significant survival advantage in the chemoradiotherapy arm. Combined modality was associated with a significantly better median survival (14 vs. 9.3 months), 5-year survival (27% vs. 0%), and 10-year survival (20% vs. 0%).24 As a result of this trial, combined chemoradiotherapy has become the standard of care for inoperable patients. Recent phase II studies have incorporated newer agents such as irinotecan, capecitabine, paclitaxel, and oxaliplatin into chemoradiation programs with success.25–28

Two randomized studies have investigated the role of surgery after chemoradiation. These studies have been reported in abstract form: the French study- FCCD 910229 and a German study reported by Stahl et al.30 The primary endpoint of FCCD 9102 was overall survival, with a hypothesis that both treatments were equivalent if there was <15% difference in 2-year overall survival between the two arms. All 259 patients with operable squamous or adenocarcinomas of esophagus, stage T3–4 N0–1 M0, received two cycles of 5-FU and cisplatin with radiotherapy, either protracted (46 Gy in 4.5 weeks) or split-course (2 x 15 Gy days 1–5 and 22–26). If there was at least a partial response and no contraindication for chemoradiation or surgery, patients were randomized between arm A (surgery) and arm B (continuation of chemoradiation: 3 cycles of 5-FU-cisplatin with radiotherapy protracted [20Gy] or split-course [15Gy]).

The authors reported a two-year survival rate of 34% in the preoperative chemoradiation plus surgery arm versus 40% in definitive chemoradiation arm (P= .56). The postoperative mortality within 3 months of surgery or starting induction treatment was 9% (arm A) versus 1% (arm B) (P = .002). Hospital stay was shorter and performance status (PS) after treatment also tended to favor the definitive chemoradiation arm. However, patients in the surgery-alone arm had better local control, requiring an esophageal stent (13% vs. 27%; P = .005) or dilations (22% vs. 32%; P = .07) less often. According to the authors, early mortality is lower, hospital stay is shorter, and performance status better after definitive chemoradiation. However, palliative procedures for dysphagia are more frequent when surgery is eliminated altogether. This trial is limited by its short follow-up, unconventional radiation schema, and accrual in several centers, some of which had a low surgical volume, thus potentially contributing to a higher operative morbidity and mortality.

A trial in Germany included 177 patients with locally advanced squamous cell carcinoma of the esophagus (T3–4, N0–1, M0) with the primary endpoint of overall survival.24 The study compared arm A (3 cycles of 5-FU/leucovorin/etoposide/cisplatin, followed by chemoradiation [cisplatin/etoposide + 40Gy], followed by surgery [transthoracic esophagectomy with two-field lymphadenectomy] with arm B (same chemotherapy, followed by definitive chemoradiation [cisplatin/etoposide + >60Gy]). Treatment-related mortality was 10% in arm A versus 3.5% in arm B.

There was a trend toward improved local tumor control in the surgical arm (P = .08), with the site of first recurrence observed locally in 64% vs. 81%. Median survival time and 3-year survival rate were 16 months and 28% (arm A) vs. 15 months and 20% (arm B) (log rank P = .22). Despite improved local control, surgery after chemoradiation did not improve 3-year survival for patients with locally advanced squamous cell carcinoma of the esophagus, in comparison with chemoradiation alone. Although limited by short follow-up, these two randomized trials involving cases of locally advanced operable esophageal cancer suggest equivalence between chemoradiation with surgery and chemoradiation without surgery.

The 1992–1994 patterns of care study also suggested that at 4 years there is no difference in survival between patients treated with neoadjuvant chemoradiation plus surgery and those treated with definitive chemoradiation only.31 Several small phase II studies have reported 3-year survival with chemoradiation alone among patients with operable esophageal cancer to be around 28%, and long-term follow-up from the RTOG 85–01 study suggests a 20% long-term survival for patients with locally advanced esophageal cancer.21 These data suggest that definitive chemoradiation may be an acceptable alternative to surgery and may provide long-term survival equivalent to that in contemporary surgical series.

NW: Definitive Chemoradiation May Be Inadequate; Surgery Treats Persistent Disease Postchemoradiation
Longest-follow-up data regarding definitive chemoradiation for the management of esophageal cancer are from the RTOG 8501 study, as noted above.

Participation in this study was offered to patients with squamous cell carcinoma, and all patients were staged clinically. It should be noted that endoscopic ultrasound18 or FDG PET scans were unavailable at the time; thus, accurate staging for these patients could not be performed. A total of 130 patients received definitive chemoradiation between 1985 and 1991. Many had either persistent disease (46%) or regional disease (58%) following the completion of therapy. Twenty-four of these patients had long-term survival (18%). RTOG 8501 did not have a surgery-alone arm and thus cannot be compared with other studies that included surgery. However, other definitive chemoradiation trials confirm the limited success of this approach (Table 1).

One of the major difficulties with definitive chemoradiation is the high incidence of persistent disease posttherapy. It may be argued that surgery can be reserved for patients with persistent disease only. Unfortunately, there is no investigation that can accurately predict complete response other than a complete surgical pathological examination of the resected esophagus. Our study revealed that endoscopic examination of the esophagus has a poor negative predictive value in this setting.32 Two European studies have investigated the role of surgery after chemoradiation, as noted above.24,25 The authors’ conclusion that surgery postchemoradiation offers no additional survival benefit is questionable, as the surgical mortality in these studies is unacceptably high at 10%. In these studies, local control was superior in the surgical arm.

Some patients and oncologists choose to treat esophageal cancer with definitive chemoradiation, with the hope of treating future local recurrences successfully with salvage esophagectomy. Such an approach may be flawed, however, as salvage esophagectomy for recurrent tumors after chemoradiotherapy may be associated with unacceptably high mortality.33 Definitive chemoradiation therapy is accompanied by significant toxicity. Data from the landmark RTOG 8501 study reveal that 8% of the cohort randomly assigned to combined modality therapy experienced acute life-threatening (i.e., grade 4) toxic effects on the RTOG acute morbidity scale, and an additional 2% died as a direct consequence of treatment. Twenty-nine percent of patients randomized to the chemoradiation arm experienced grade 3 or 4 toxicity, primarily with esophagitis, myelosuppression, and pneumonitis. Yet, with increasing experience, this therapy is becoming safer. Definitive chemoradiation remains an acceptable alternative for inoperable patients. In operable patients, however, trimodality therapy, which includes surgery and neoadjuvant chemoradiation therapy, is worth consideration. Relevant data from important neoadjuvant studies are summarized below.


   NEOADJUVANT THERAPY
TOP
 ABSTRACT
 INTRODUCTION
 SURGERY
 RI: DEFINITIVE CHEMORADIATION IS...
 NEOADJUVANT THERAPY
CONCLUSIONS AND RECOMMENDATIONS
 REFERENCES
 
RI: Neoadjuvant Therapy Remains Investigational
Three randomized trials compared neoadjuvant chemotherapy followed by surgery with surgery alone but failed to show a significant survival advantage.34–36 These trials are summarized in Table 3. All of these studies were small and did not have the power to detect any important differences in the two treatment modalities. Two large randomized trials have been conducted to address this question: the Intergroup 0113 study and the MRC study. In the Intergroup 0113 study, 467 patients with potentially resectable esophageal cancer were randomly assigned to surgery alone or three cycles of preoperative chemotherapy consisting of cisplatin and 5-FU, followed by surgery.37 There were no differences between the groups in rate of complete resection (65% vs. 66%), treatment-related mortality (6.4% vs. 4.0%), median survival (14.9 vs. 16.1 months), or survival.


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  		TABLE 3. Summary of randomized trials comparing preoperative chemotherapy to surgery alone
 
In a Cochrane review of seven randomized trials that included 1653 patients who were randomly assigned to either surgery alone or chemotherapy followed by surgery, the odds ratio for mortality between chemotherapy followed by surgery and surgery alone at 2 years was 0.8 (95% confidence interval, 0.65–0.99), and the results at 3, 4, and 5 years favored chemotherapy but were not significantly different.38 Thus there is no role for neoadjuvant chemotherapy in the management of esophageal cancer outside of a clinical trial.

Neoadjuvant chemoradiation has been compared with surgery alone in numerous nonrandomized and five randomized studies. The nonrandomized trials of chemoradiation are summarized in a review by Geh et al.39 Six randomized studies done so far are summarized in Table 4. Although these studies focused on overall survival as their endpoint, several studies reported the prognostic value of pathological complete response, which is seen in approximately 25%.17,19,20 The EORTC study randomized 282 patients with locally advanced squamous esophageal cancers to surgery alone or surgery preceded by chemoradiotherapy.40 Preoperative therapy consisted of cisplatin (80 mg/m2 on days 1 and 22) prior to each split course of radiation (18.5 Gy in 5 fractions of 3.7 Gy each, 5 fractions per week, administered during weeks 1 and 4). Surgery was performed 2 to 4 weeks after completion of this therapy.


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  		TABLE 4. Summary of randomized trials comparing preoperative chemoradiation to surgery alone
 
After a median follow-up of 55 months, preoperative treatment yielded a higher frequency of curative resection, a significantly longer disease-free survival, time to local failure, and a lower rate of cancer-related death. However, the median survival was identical (18.6 months in both groups). Combined modality therapy was also associated with significantly higher postoperative mortality (12.3% vs. 4%). Limitations of this study included early termination due to an unexpectedly high number of deaths in the combined arm, inadequate radiation dose-fractionation schedule, and the use of single-agent cisplatin rather than the more standard multiagent chemotherapy.

In a large Australasian study reported at the American Society of Clinical Oncology meeting in 2002, 256 patients with resectable esophageal cancers of both histologies were randomized to surgery alone or cisplatin (80 mg/m2 on day 1) and 5-FU (800 mg/m2 days 2–5) combined with radiation therapy (35 Gy in 15 fractions) and followed by surgery.41 The overall treatment-related mortality was 4.6%. Pathological complete response rate in the patients receiving neoadjuvant therapy was 15.1%. Median overall survival for combined therapy was 21.7 months, compared with 18.5 months (P = .38) in the surgery arm. Walsh et al.42 have reported the only randomized prospective study that claims superior results with neoadjuvant chemoradiation. In this study, 113 patients with esophageal adenocarcinoma were assigned randomly to surgery alone or surgery preceded by chemoradiotherapy. Preoperative treatment consisted of two courses of 5-FU (15 mg/kg by bolus, days 1 to 5) and cisplatin (75 mg/m2, on day 7 of each cycle), both administered during weeks 1 and 6, and concurrent radiotherapy (40 Gy in 15 fractions over 3 weeks).

A complete pathologic response was noted in 25% of patients treated with preoperative chemoradiotherapy. Combined-modality therapy was associated with significantly longer median survival (16 vs. 11 months) and 3-year survival (32% vs. 6%). This study has been criticized because the surgery-alone arm did very poorly compared with other contemporary series.11,13 Additional problems in this study included a large number of withdrawals in the study arm, variability in surgical procedures, unplanned early analysis, and nonuniformity of preoperative staging.

Urba et al. reported on the University of Michigan experience wherein 100 patients with locoregional esophageal cancer (74% of whom had adenocarcinoma) were randomly assigned to transhiatal esophagectomy with or without preoperative chemoradiotherapy.43 Neoadjuvant treatment consisted of cisplatin (20 mg/m2 per day, by continuous infusion on days 1 to 5 and 17 to 21), 5-FU (300 mg/m2 per day, by continuous infusion on days 1 to 4 and 17 to 20), and vinblastine (1 mg/m2 per day, by IV bolus, on days 1 to 4 and 17 to 20) with concurrent radiotherapy (45 Gy in 1.5-Gy fractions, given twice daily for 3 weeks) administered with a three-dimensional (3-D) conformal treatment planning technique. Surgery was performed 3 weeks after completion of chemoradiation. A complete pathologic response was observed in 28% of patients and was found to correlate with survival. At an average follow-up of 8.2 years, median survival was similar with both treatments (16.9 versus 17.6 months for multimodality therapy and surgery, respectively). An improvement noted in 3-year survival (30% vs. 16 %) did not reach statistical significance.

In conclusion, the only positive study supporting neoadjuvant chemoradiation is the Walsh study, which has been faulted because of the poor outcome in the surgery arm. None of the other randomized prospective studies noted thus far have shown a statistically significant improvement in overall survival, and thus the role of neoadjuvant chemoradiation remains uncertain.

NW: Neoadjuvant Approaches Hold Promise
Neoadjuvant therapy has several theoretical advantages: (1) tumor downstaging, with increased feasibility of R0 resection; (2) early treatment of micrometastases; and (3) assessment of therapeutic response.

The neoadjuvant chemotherapy trials are limited by short follow-up, and most have failed to demonstrate a survival advantage with neoadjuvant chemotherapy. The Medical Research Council (MRC) of the United Kingdom conducted the largest randomized neoadjuvant chemotherapy study thus far. This study randomized 802 patients with esophageal cancer to either cisplatin (80 mg/m2 over 4 hours) with 5-FU (1000 mg/m2 daily for 4 days, 3 weeks apart, for a total of two cycles) followed by surgery (n = 400) or surgery alone (n = 402).44 Resection was microscopically complete in 233 (60%) of patients in the combined arm, compared with 215 (54%) in the surgery arm, a difference that was statistically significant. After a median follow-up of about 3 years, 2-year overall survival was better in the combined arm (43% vs. 34%) (hazard ratio, 0.79; 95% CI, 0.67–0.93; P = .004). The study is limited, however, by its short follow-up. The MRC trial was the only one that looked at dysphagia control and performance status and found improvement in dysphagia and local recurrence rates in the combined modality arm.

Neoadjuvant chemoradiation trials have been discussed above and, of all the prospective randomized studies, only one has been reported to be positive (Table 4). Yet, because of the heterogeneity of treatments used (surgical technique, chemotherapy, and radiation dosages), interpretation of these randomized trials is difficult. The study at the University of Michigan by Urba et al.43 was reported as a negative trial. It must be noted, however, that this trial was powered to detect a very optimistic increase in survival by 1 year—a figure that may not be matched by cisplatin-based chemoradiation. The CALGB attempted to address this question with a prospective, randomized phase III trial (CALGB study 9781) comparing trimodality therapy to surgery alone, but it had to be terminated early because of poor accrual. Yet single-institution experience suggests an advantage to the neoadjuvant chemoradiation approach.

A phase II trial evaluated continuous intravenous infusion of cisplatin and 5-FU and a total dose of 44 Gy of radiation.45 Transhiatal esophagogastrectomy was planned for approximately 4 weeks after the completion of chemoradiotherapy. Paclitaxel and cisplatin were administered as postoperative adjuvant therapy. Ninety-two patients were treated in two successive trials with this regimen. Eighty-seven percent of these patients had a margin-negative resection, and the pathologic complete remission rate was 33%. The 5-year overall and disease-specific survival rates were 40% and 49%, respectively, while the median survival for all patients was 35 months.46 These survival figures demonstrate that optimal combined-modality therapy can improve outcome significantly as compared with historical controls.

Hofsetter et al.47 reviewed the MD Anderson experience with 1079 consecutive esophagectomies over a 30-year period. They reported an increasing use of neoadjuvant chemoradiation in the last 4 years of the study (59% vs. 2%). This was accompanied with an increased R0 resection rate and median survival. The authors concluded that preoperative chemoradiation was associated with a longer median survival and likelihood of a complete resection. A recent meta-analysis of randomized controlled trials compared neoadjuvant chemoradiation and surgery with surgery alone for the treatment of esophageal cancer. The study showed an improved 3-year survival, reduced locoregional recurrence, and improved rate of R0 resection with the neoadjuvant chemoradiation approach.48 Optimal, targeted neoadjuvant approaches need to be investigated in this disease and may improve outcomes.


   CONCLUSIONS AND RECOMMENDATIONS
TOP
 ABSTRACT
 INTRODUCTION
 SURGERY
 RI: DEFINITIVE CHEMORADIATION IS...
 NEOADJUVANT THERAPY
 CONCLUSIONS AND RECOMMENDATIONS
REFERENCES
 
The National Comprehensive Cancer Network (NCCN) panel, in its current guidelines,49 recommends surgery for early cervical esophageal cancers. For all other operable patients, neoadjuvant or definitive chemoradiation are now considered as reasonable alternatives to surgery alone. In this era of targeted therapy, it is important to incorporate newer agents and biologics such as epidermal growth factor receptor (EGFR) blockers, vascular endothelial growth factor (VEGF) agents, and antisense oligonucleotides in our therapeutic armamentarium to improve the dismal outlook for these patients. Future research efforts should be directed in the following areas.

  1. Preventive and surveillance strategies represent the most promising areas in esophageal cancer; efforts should focus on early detection and aggressive management of premalignant lesions.
  2. Better locoregional staging with the use of EUS, CT-PET, and newer imaging modalities may help select appropriate candidates for surgery.
  3. Surgery remains the standard of care for operable early stage esophageal cancer. However, surgical approaches need to be optimized. Referrals to regionalized centers of excellence need to be maximized.
  4. Chemoradiation is superior to radiation alone, can be delivered with acceptable toxicity, and is a valid therapy for locally advanced cancers. Newer chemotherapeutic agents and targeted therapies need to be incorporated into multimodality strategies.
  5. Preoperative chemoradiation with cisplatin and 5-FU has not been demonstrated to be more beneficial than surgery alone. However, it may improve resectability (R0 resection) and locoregional control. This old paradigm, however, may no longer apply with targeted approaches and newer surgical techniques.


   FOOTNOTES
 
Medical and surgical oncologists have diverse opinions regarding the optimal application of surgery, neoadjuvant or definitive chemoradiation for locally advanced esophageal cancer management. A review of current literature is presented.

Received for publication October 29, 2003. Accepted for publication March 17, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SURGERY
 RI: DEFINITIVE CHEMORADIATION IS...
 NEOADJUVANT THERAPY
 CONCLUSIONS AND RECOMMENDATIONS
 REFERENCES
 

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  2. Pollock RE, Morton DL. Principles of Surgical Oncology: Cancer Medicine. 5th ed. Hamilton, Ontario, Canada: B.C. Decker Inc, 2000.
  3. Naef AP. The mid-century revolution in thoracic and cardiovascular surgery: Part 1. Interact Cardiovasc Thorac Surg 2003; 2: 219–26.[Free Full Text]
  4. Orringer MB, Marshall B, Iannettoni MD. Transhiatal esophagectomy: clinical experience and refinements. Ann Surg 1999; 230: 392–400.[CrossRef][Medline]
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