ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
John W.C. Entwistle, III
Melvyn Goldberg
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Entwistle, J. W.C.
Right arrow Articles by Goldberg, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Entwistle, J. W.C., III
Right arrow Articles by Goldberg, M.
Related Collections
Right arrow Esophagus - cancer

Ann Thorac Surg 2002;73:1009-1015
© 2002 The Society of Thoracic Surgeons

Review

Multimodality therapy for resectable cancer of the thoracic esophagus

John W.C. Entwistle, III, MD, PhDa, Melvyn Goldberg, MD*a

a Department of Surgical Oncology, Division of Thoracic Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

* Address reprint requests to Dr Goldberg, Division of Thoracic Oncology, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111 USA
e-mail: m_goldberg{at}fccc.edu


   Abstract
Top
 Abstract
Introduction
 Diagnosis and staging
 Single-modality therapy for...
 Adjuvant postoperative therapy...
 Neoadjuvant preoperative therapy...
 Future directions
 Conclusions
 References
 
The frequency of esophageal carcinoma continues to increase in North America primarily because of the increased incidence of Barrett’s epithelium in the distal esophagus and its malignant potential. Aggressive treatments involving multimodality therapies have been offered to improve overall poor survival rates. A review of this experience follows, to explain the rationale and to compare results of therapies. Although preoperative chemoradiation therapy is commonly used for locally advanced disease, few data support its superiority over surgical resection alone, followed by adjuvant therapy when appropriate. Hence this regimen should be limited to patients enrolled in controlled, randomized studies until the data support its widespread use.


   Introduction
Top
 Abstract
 Introduction
Diagnosis and staging
 Single-modality therapy for...
 Adjuvant postoperative therapy...
 Neoadjuvant preoperative therapy...
 Future directions
 Conclusions
 References
 
Locally advanced esophageal cancer represents a highly malignant form of cancer for which the optimal treatment remains undefined. In its earliest stages, esophageal cancer is readily curable with surgical treatment alone, with 5-year survival rates approaching 80%. By the time tumors manifest symptoms, they have usually increased in size and depth of penetration with higher frequencies of lymph node involvement and distant metastasis. At this stage, 5-year survival rates may be as high as 34% for early nodal disease, but are typically in the range of 10% to 15% for locally advanced lesions, with no long-term survivors with metastatic disease.

Tobacco and alcohol consumption are associated with an increased risk of the squamous cell variety. Adenocarcinoma is more prevalent in the setting of Barrett’s esophagus, in which the normal squamous lining of the esophagus has been replaced with intestinal-type columnar cells in response to chronic reflux of gastric and intestinal contents.


   Diagnosis and staging
Top
 Abstract
 Introduction
 Diagnosis and staging
Single-modality therapy for...
 Adjuvant postoperative therapy...
 Neoadjuvant preoperative therapy...
 Future directions
 Conclusions
 References
 
The initial diagnostic study is often an esophagram but esophagogastroscopy is essential for assessing tumor location and involvement of the proximal stomach, and for obtaining tissue for histologic diagnosis. If the tumor involves the middle or upper esophagus, bronchoscopy is essential to rule out airway involvement. A computed tomography (CT) scan of the chest and upper abdomen is the minimal requirement for assessing local and regional disease. It may demonstrate the degree of tumor bulk within the esophageal bed, mediastinal lymph node enlargement suggestive of regional spread, pulmonary metastases, and metastases to the liver and celiac axis lymph nodes.

For any given patient, inaccurate pretreatment staging may result in inadequate therapy based on the presumed presence or absence of regional disease. To this end, endoscopic ultrasound (EUS) has become a standard method of pretreatment staging in many centers because it can assess the depth of tumor penetration and the presence of enlarged lymph nodes. Needle biopsies of enlarged lymph nodes may provide tissue for histologic tumor staging.

Recently, alternative methods of staging include the use of combined thoracoscopy (VATS) and laparoscopy (LAP) [1, 2], radio-guided sentinel node mapping [3], and positron emission tomography (PET) [4–6]. However, these techniques are not considered to be the standard of care and most studies do not use them in the preoperative evaluation.

The prognosis of esophageal cancer is related to the stage of the disease at the time of presentation. The TNM system describes a tumor, based on the depth of penetration of the primary tumor (T), the presence or absence of lymph node involvement (N), and the presence or absence of metastases (M) (Table 1). The tumors are assigned to a stage that carries prognostic significance based on the TNM descriptors (Table 2)[7]. Tumors considered for surgical resection include any tumor stage IIB or less and non-T4 stage III tumors.


View this table:
[in this window]
[in a new window]
  		Table 1. TNM Staging System for Esophageal Cancer

 

View this table:
[in this window]
[in a new window]
  		Table 2. Staging of Esophageal Cancer

 

   Single-modality therapy for esophageal cancer
Top
 Abstract
 Introduction
 Diagnosis and staging
 Single-modality therapy for...
Adjuvant postoperative therapy...
 Neoadjuvant preoperative therapy...
 Future directions
 Conclusions
 References
 
Surgical therapy has remained the mainstay for potentially curable disease. Resections include the Ivor-Lewis, transhiatal, and three-field esophagectomies. A given patient may be particularly suited for a specific operation. The ultimate choice is usually based on the surgeon’s training and personal biases. The complication rates are similar and no study has demonstrated a long-term survival benefit with any one of the operations.

For early stage disease (T1 N0 M0), surgical resection can provide long-term survival rates as high as 80%. Survival rates drop rapidly as the depth of tumor penetration increases or as lymph nodes become involved. For stage III disease (T3 N1 M0 or T4 N0 M0), 5-year survival rates are only 10% to 15% with surgery alone [8–14]. The potential for cure with surgical resection is limited as it has no therapeutic value in the treatment of systemic disease. As such, alternative treatment strategies with and without the inclusion of surgery in the therapeutic regimen have been investigated.

Radiation as a single-modality therapy has been used primarily for palliation and represents a form of local disease control. In early stage esophageal cancer, radiation therapy (50 to 60 Gy) alone can provide long-term survival and cure although the results are inferior to those of surgery alone. In several reviews of the use of radiation therapy as sole treatment, there was a 6% to 17% long-term survival [15, 16]. At present curative radiation therapy is most useful for the patient who is not a candidate for or refuses surgery.

Chemotherapy offers the treatment of distant foci of tumor. Most patients present with advanced disease and many treated with either surgery or radiation therapy die of distant disease. However, the results from the use of chemotherapy as a single line of therapy have been universally disappointing. Although many of the tumors respond to the chemotherapy with an initial decrease in size, this is usually limited and provides only temporary reprieve from the aggressive nature of this disease.


   Adjuvant postoperative therapy for esophageal cancer
Top
 Abstract
 Introduction
 Diagnosis and staging
 Single-modality therapy for...
 Adjuvant postoperative therapy...
Neoadjuvant preoperative therapy...
 Future directions
 Conclusions
 References
 
In several randomized controlled studies, the postoperative use of radiation therapy demonstrated either no increase [17, 18] or a decrease [19] in survival compared with resection alone. Adjuvant radiation therapy also produces postoperative complications including anastomotic strictures [17, 19]. Thus radiation therapy is seldom offered in the postoperative setting to patients who have undergone complete resection of tumor. Despite the lack of a survival advantage, however, postoperative radiation therapy may decrease the incidence of local tumor recurrence [18, 19]. Postoperative chemotherapy has also been compared with surgical management alone in randomized controlled trials, without demonstrable improvement in survival [20, 21]. There is an improvement in 5-year disease-free survival [22], however, despite the increase in complications due to the addition of chemotherapy [20]. These trials utilized cisplatin-based regimens and were limited to patients with squamous carcinoma of the esophagus.


   Neoadjuvant preoperative therapy for esophageal cancer
Top
 Abstract
 Introduction
 Diagnosis and staging
 Single-modality therapy for...
 Adjuvant postoperative therapy...
 Neoadjuvant preoperative therapy...
Future directions
 Conclusions
 References
 
Preoperative radiotherapy
Five prospective randomized studies have examined the use of preoperative radiation therapy and only one has demonstrated a survival benefit [23]. In this study, 186 patients with squamous cell carcinoma were randomly assigned to one of four treatment arms: surgery alone, preoperative chemotherapy followed by surgery, preoperative radiotherapy followed by surgery, or sequential chemotherapy and radiation therapy followed by surgery. Although the addition of radiation therapy did not improve survival compared with surgery alone, both preoperative radiotherapy and combined preoperative chemoradiotherapy produced significantly better survival than did preoperative chemotherapy. In addition, the survival rate of the pooled groups receiving radiotherapy was superior to that of the pooled groups not receiving radiotherapy, suggesting that the addition of preoperative radiotherapy was beneficial. The study characteristics and results for this and other neoadjuvant studies are summarized in Table 3.


View this table:
[in this window]
[in a new window]
  		Table 3. Phase III Studies Comparing Neoadjuvant Chemoradiation With Surgery Alone

 
Arnott and colleagues [24] performed a metaanalysis of the available data regarding the potential benefits of preoperative radiotherapy for a total of 1,147 patients who had previously been randomized in five trials. This meta-analysis included updated data on each patient that provided longer term survival data than that available at the time of publication of the individual trials. With a median follow-up of 9 years, there was only a 3% survival advantage at 2 years and a 4% advantage at 5 years, although these differences only approached statistical significance (p = 0.062). Thus, if any survival benefit were to be achieved with preoperative radiotherapy, this study suggests that it would be modest at best. The majority of the patients involved in the study had squamous cell histology, and too few patients had adenocarcinoma to detect a survival advantage with this histology.

Preoperative chemotherapy
Roth and coworkers [25] published an early randomized trial comparing neoadjuvant cisplatin, vindesine, and bleomycin with surgical resection alone. Patients receiving preoperative chemotherapy were also treated similarly with 6 months of postoperative therapy. Thirty-nine patients were randomly assigned to treatment. Of those who received preoperative chemotherapy, 47% demonstrated a response and 1 patient had a complete pathologic response. Rates of surgical resection were similar and there was no significant difference in overall median survival (9 months). A survival advantage was seen in the subgroup of patients who responded to chemotherapy.

Schlag [26] reported the results of three cycles of preoperative fluorouracil and cisplatin in patients with squamous cell carcinoma. Although 77 patients were evaluated, only 46 patients agreed to randomization and 2 of these patients were unevaluable. Despite the low rate of randomization, survival results were reported for the group of 77 as a whole. Overall, 34 evaluable patients received preoperative chemotherapy, whereas 41 underwent surgical management alone. Of the patients treated with chemotherapy, only 29 of the 34 proceeded to resection. Of these, 70% were resectable compared with 79% of those treated with surgery alone. There was no improvement in overall survival among patients treated with chemotherapy, with a median survival of 10 months in both groups. Among patients who had a decrease in tumor size in response to chemotherapy, survival was prolonged (median 13 months) compared with patients who did not respond to chemotherapy (median 5 months).

In the Scandinavian study reported by Nygaard and colleagues [23], two of the four treatment groups compared the use of preoperative chemotherapy with operation alone for squamous cell carcinoma of the esophagus. Patients were treated with either two cycles of cisplatin and bleomycin followed by surgery (n = 50) or with surgical resection alone (n = 41). No benefit was seen in rate of curative resectability or survival, and there was no increase in postoperative complications associated with preoperative chemotherapy.

Law and associates [27] reported the results of a prospective randomized trial comparing the use of preoperative cisplatin and 5-fluorouracil in squamous cell carcinoma of the esophagus to surgical resection alone (n = 147). Of the 74 patients receiving preoperative chemotherapy, 58% had a significant response and 6.7% (4 patients) had a complete pathologic response. Although the rate of resection was similar between the groups, patients treated with chemotherapy had a significantly higher rate of curative resection (67% versus 35%), defined as no evidence of gross or microscopic tumor remaining after resection. In addition, fewer patients in the chemotherapy group had locally advanced tumors (T3 and T4) and N1 disease compared with those undergoing resection without pretreatment. Despite the responses to therapy, no difference was seen in overall survival, with a median survival of 16.8 months for patients treated with chemotherapy compared with 13 months for those without pretreatment. A subgroup analysis demonstrated improved survival (median 42.2 months) in patients demonstrating a response to chemotherapy.

Kelsen and coworkers [28] reported the results of the largest randomized study of preoperative chemotherapy published to date for both squamous cell carcinoma (n = 204) and adenocarcinoma (n = 236). In this multi-institutional study, surgery alone was compared with three cycles of preoperative cisplatin and fluorouracil followed by surgery and an additional two cycles of chemotherapy. Only 71% of patients received all three cycles of preoperative chemotherapy and 83% completed at least two cycles. By radiographic assessment, 19% of pretreated patients had either a partial or complete response. Of the 213 patients in the chemotherapy arm of the trial, only 171 proceeded to surgery. The overall rate of curative resection was similar between the two groups (chemotherapy/surgery 62% versus surgery 59%). In the group assigned to receive chemotherapy, only 52% received any postoperative chemotherapy and only 38% were able to complete the postoperative portion of the chemotherapy protocol. The median survival for pretreated patients (14.9 months) was not significantly different from that of patients treated with surgery alone (16.1 months). Cell type produced no difference in survival and the survival of patients with a negative microscopic margin was independent of receipt of chemotherapy.

The use of preoperative chemotherapy for resectable esophageal cancer has not improved survival for either squamous cell or adenocarcinoma tumors. Response rates to chemotherapy are approximately 20% and there are few complete pathologic responses. The lack of a survival benefit suggests that the use of preoperative chemotherapy alone is not justified with resectable tumors.

Preoperative chemoradiation therapy
Nygaard and associates [23] studied a group of patients with squamous cell carcinoma who received preoperative chemotherapy and radiation therapy (n = 47) compared with resection alone (n = 41) (Table 3). Three weeks after two cycles of cisplatin and bleomycin, the patients received 35 Gy of irradiation over a 4-week period. Three weeks later an Ivor-Lewis resection was performed. There was a trend toward a higher rate of resectability among patients undergoing pretreatment (55% versus 37%, p = 0.079). However, there was no difference in either postoperative complications or survival.

Le Prise and colleagues [29] studied the use of preoperative sequential chemotherapy and radiation therapy. In a randomized study, 41 patients received 20 Gy sandwiched between two cycles of cisplatin and fluorouracil, followed by resection 3 weeks later. Forty-five patients were randomly assigned to resection alone. Eleven of the pretreated patients had no histologic evidence of residual tumor in endoscopic biopsies taken after the induction therapy and only 4 patients (11% of those undergoing resection) had a complete pathologic response at resection. Postoperative morbidity and mortality rates were similar and there was no significant difference in long-term survival. Three-year survival was 19.2% for the induction group and 13.8% for the surgery alone group.

Urba and colleagues [30] studied the use of cisplatin, vinblastine, and fluorouracil with 45 Gy of concomitant radiation therapy followed by a transhiatal esophagectomy, based on data from a nonrandomized pilot study that demonstrated a 34% 5-year survival rate and a 60% 5-year survival rate among patients with a complete pathologic response. Fifty patients each were randomly assigned to either combined modality therapy or to resection alone. Ninety percent of patients in both arms underwent a curative resection. Although the complete pathologic response rate among pretreated patients was 28%, there was no demonstrable survival advantage with preoperative chemoradiation therapy. At 3 years, patients undergoing pretreatment had a 30% survival rate compared with 16% for patients undergoing surgery alone (p = 0.15). Multivariate analysis demonstrated an improvement in survival in patients with adenocarcinoma compared with squamous cell histology, regardless of the treatment protocol used.

Walsh and associates [31] assigned patients to receive multimodality therapy (n = 58) with two cycles of fluorouracil and cisplatin concurrent with radiation therapy (40 Gy) given over a 3-week period. Resection was performed 8 weeks after the initiation of treatment. This group was compared with patients undergoing resection alone (n = 55). In the induction group, there were fewer patients with either positive nodes or metastases at the time of resection (42% versus 82%) and 25% of these patients had a complete pathologic response at the time of resection. Overall, median survival among patients assigned to multimodality therapy was 16 months compared with 11 months for patients assigned to surgery alone (p = 0.01). Multimodality therapy produced a 3-year survival rate of 32% compared with 6% for control patients. The control group survival is well below that of historic controls and the 16% reported by Urba and coworkers [30]. This low survival rate may contribute to the statistical significance and may not be universally justified.

The European Organization for Research and Treatment of Cancer (EORTC) compared preoperative chemoradiation therapy and surgery alone and included 282 eligible and evaluable patients with squamous cell carcinoma [32]. Patients (n = 143) underwent two 1-week courses of radiation therapy (37 Gy), with cisplatin given 0 to 2 days before each course of radiation therapy. Surgery was performed 2 to 4 weeks after the conclusion of radiation. Resection alone was performed in 139 patients. The rate of curative resection was significantly higher in the combined modality treatment group (81%) compared with the surgical control group (69%). The postoperative mortality rate was 12% in the combined modality group and 3.6% in the surgical group. Pretreated patients had a complete pathologic response of 26% and an additional 20% had a major response to pretreatment. Overall, the patients in the multimodality arm had a lower tumor (T) and nodal (N) stage after treatment. The overall median survival was 18.6 months in both groups, although patients receiving induction therapy had a longer disease-free survival, and were less likely to die from their esophageal cancer. Patients who had a curative resection did significantly better than patients with residual disease.

Law and coworkers [33] have compared 40 patients assigned to preoperative cisplatin and fluorouracil, 40 Gy of radiation, and subsequent surgical resection, with 40 patients treated with resection alone. All patients had squamous cell carcinoma. Pretreated patients had a complete pathologic response rate of 23% but overall median survival was 25 months, not significantly different from the 28 months for patients treated with surgery alone.

Given the data available, it is difficult to conclude that there is a role for preoperative chemoradiation therapy in the management of esophageal cancer regardless of the chemotherapeutic agents given, the radiation doses, and the sequencing of the therapies. A recent metaanalysis of 26 phase II and III preoperative chemoradiation therapy trials has demonstrated that increasing the dose of preoperative radiation therapy produces a higher rate of complete pathologic response. In addition, higher doses of either fluorouracil or cisplatin are also associated with a higher response rate [34]. Most studies have shown that there is improved long-term survival for patients having a complete pathologic response.

Despite the lack of convincing data to support its use, the combined use of chemotherapy and radiation therapy followed by surgical resection has become the standard of care in most centers for anything but the earliest tumors of the esophagus. As such, accrual of patients to randomized studies comparing preoperative treatment with surgery alone has become difficult owing to the impression of both physicians and patients that preoperative therapy is superior. In fact, the CALGB 9781 trial was designed to compare the results of concomitant chemoradiation therapy with subsequent surgical resection versus resection alone. This study was closed prematurely in April 2000 because of poor recruitment of patients. At the time of closure, only 56 of the expected 500 patients had undergone random assignment.

Although responders to neoadjuvant chemotherapy and radiation therapy have demonstrated impressive long-term survival rates, most studies have failed to demonstrate a survival benefit for the overall group of patients assigned to preoperative chemoradiation therapy. That may merely reflect the identification of a subgroup with a less aggressive tumor and a better overall survival rate, regardless of the treatment strategy employed. Therefore, it seems that the routine use of preoperative chemoradiation therapy is not justified given the available data. As such, its use should be limited to patients in a clinical trial, until the cost and use of medical resources can be justified.

Multimodality therapy without surgery
Although surgical resection is widely regarded as the cornerstone in the management of esophageal cancer, patients with resectable tumors are still occasionally treated with nonoperative protocols. Some of these patients are not candidates for or refuse surgical intervention. In other cases, it reflects the biases of the treating physician or the lack of an available surgeon skilled in the techniques of esophagectomy.

The RTOG 85-01 trial randomly assigned patients with localized cancer to receive either 64 Gy of radiation alone or 50 Gy of radiation with concomitant cisplatin and fluorouracil [35]. Despite a high incidence of life-threatening toxic events associated with the combined therapy arm, the trial was halted prematurely because of improved long-term survival associated with combined therapy. The patients assigned to combined therapy demonstrated 26% 5-year survival compared with 0% for the group receiving radiation therapy alone. After trial closure, additional patients were recruited into the combined therapy arm of the protocol, and those patients had a 14% 5-year survival.

The intergroup study INT 0123 represented a variation of the RTOG 85-01 protocol in which patients were randomly assigned to receive either standard (50.4 Gy) or high-dose (64.8 Gy) radiation therapy in addition to the chemotherapy. The study consisted of 236 patients, and preliminary results demonstrate no survival difference between the two treatment arms [36]. Long-term data are not yet available.

Ongoing trials
There are several active trials to assess the potential benefits of combined modality therapy in the treatment of resectable carcinoma of the esophagus. Details of these studies can be found on CancerNet, the National Cancer Institute Web site (available at: http://cancernet.nci.nih.gov). This database includes detailed information concerning the eligibility criteria, treatment outline, and status of various protocols. In addition, the database lists criteria for trials that have recently closed, for which results are pending.


   Future directions
Top
 Abstract
 Introduction
 Diagnosis and staging
 Single-modality therapy for...
 Adjuvant postoperative therapy...
 Neoadjuvant preoperative therapy...
 Future directions
Conclusions
 References
 
Superior survival rates have been demonstrated for patients who have had a complete pathologic response after neoadjuvant chemoradiation therapy. It is clear that these patients still benefit from resection, however, as one cannot determine complete pathologic response on endoscopic biopsies alone. The critical part of this treatment scheme would be the accurate determination of those patients who had exhibited a complete pathologic response. In addition, it would be useful to identify another subgroup of patients whose tumor had spread beyond the scope of a surgical resection.

Esophagoscopy is inaccurate in determining complete pathologic response, as 41% of the patients with a negative esophagoscopy have residual tumor in the surgical specimen [37]. In addition, long-term survival can be obtained by as many as 25% of the patients with residual tumor in the esophagus at the time of resection, suggesting that resection was indicated for these patients [37, 38]. Unfortunately, the combined use of CT, endoscopy, and EUS does not improve upon the ability to accurately predict which patients will have a complete pathologic response, as it may overestimate response twofold [39]. Although not currently part of the NCCN guidelines, PET scanning may identify the presence or absence of residual disease after preoperative treatment [40]. Given the experience with PET scanning for malignancies of the lung, however, such scanning may not be sensitive enough to determine if a patient has undergone complete tumor regression, as a small volume of residual tumor may escape detection.

Many patients who undergo "complete pathologic response" still die of recurrent disease. The proper identification of complete pathologic response depends on both the pathologist and the technology available. Microscopic residual disease may be very difficult to identify with standard staining techniques and light microscopy alone. Newer techniques of molecular biology may improve the ability to accurately identify residual disease. In one study, half of the node-negative patients were found to stain positive with the monoclonal antiepithelial-cell antibody Ber-EP4. These patients had significantly decreased disease-free and overall survival compared with patients who had Ber-EP4-negative nodes [41], suggesting that they may not have truly been node negative. The use of molecular techniques may therefore alter the diagnosis of complete pathologic response by identifying patients with minimal residual disease. These patients may have a poorer prognosis and thus may benefit from additional therapy after resection.

Future trends in the treatment of esophageal cancer will likely focus on attempts to identify patients who are likely to demonstrate a major response to chemoradiation therapy, as those who respond to preoperative treatment fare better than those who do not. Molecular markers from pretreatment biopsies of the tumor and involved nodes may provide the same prognostic information before the initiation of any therapy. The proliferative index has been shown to correlate with overall survival [42, 43] but, interestingly, has not been shown to correlate to either the endoscopic or pathologic response of the tumor [42]. Other possible molecular markers to assess a patient’s potential response to therapy are the thymidylate synthase and excision repair cross complementing (ERCC1) gene products. These represent biochemical determinants of fluorouracil and cisplatin activity, respectively. Low levels of these products have been associated with improved survival presumably owing to improved responsiveness of the tumor to the chemotherapeutic agents [44]. An analysis of several molecular markers found within the pretreatment biopsy specimen has identified a positive correlation between overexpression of HER-2/neu and survival and a negative correlation between overexpression of P-glycoprotein and survival [45]. In squamous carcinoma of the esophagus, the expression of the p53 and p21 gene products may convey prognostic significance [46]. Such data may better define the subgroups of patients referred for aggressive multimodality therapy in the future. Finally, through the use of reverse transcriptase-polymerase chain reaction technology (RT-PCR), the messenger RNA encoding carcinoembryonic antigen may be identified in some nodes, suggesting the presence of micrometastatic disease [47]. The definition of complete pathologic response is likely to change in the future to only include patients who are node negative by both histologic and molecular techniques.


   Conclusions
Top
 Abstract
 Introduction
 Diagnosis and staging
 Single-modality therapy for...
 Adjuvant postoperative therapy...
 Neoadjuvant preoperative therapy...
 Future directions
 Conclusions
References
 
Surgical therapy remains the cornerstone in managing resectable esophageal cancer. There is no demonstrated benefit to postoperative chemotherapy or radiation therapy for completely resected patients. While there is no definite benefit to combined preoperative chemotherapy and radiation therapy, one study has suggested that there may be a benefit when administered concomitantly to patients with adenocarcinoma of the thoracic esophagus. However, more data are needed to fully elucidate the best course of treatment. Until such studies are performed, it cannot be concluded that preoperative chemoradiation therapy offers a survival advantage to patients with resectable tumors of the thoracic esophagus. Ongoing and future studies may further clarify this issue.

Improved pretreatment staging strategies may help better select patients who can benefit from combined modality therapy. Molecular markers may help assess the anticipated responsiveness of a given tumor to multimodality therapy. Finally, the ability to accurately define complete pathologic response after resection may be improved with the use of molecular techniques such as RT-PCR. This information may be useful both for assigning prognosis and for determining which patients are likely to benefit from additional therapy.


   References
Top
 Abstract
 Introduction
 Diagnosis and staging
 Single-modality therapy for...
 Adjuvant postoperative therapy...
 Neoadjuvant preoperative therapy...
 Future directions
 Conclusions
 References
 

  1. Krasna M.J., Reed C.E., Hollis D.R., et al. The feasibility of thoracoscopy/laparoscopy in the staging of esophageal cancer: results of a prospective multicenter phase II trial (CALGB 9380). Proc ASCO 2000;19:239a.
  2. Luketich L.D., Schauer P.R., Landreneau R., et al. Minimally invasive surgical staging is superior to endoscopic ultrasound in detecting lymph node metastases in esophageal cancer. J Thorac Cardiovasc Surg 1997;114:817-823.[Abstract/Free Full Text]
  3. Kitagawa Y., Ando N., Kubota T., et al. Radio-guided sentinel node mapping for gastrointestinal cancers. Proc ASCO 2000;19:318a.
  4. Block M.I., Patterson G.A., Sundaresan R.S., et al. Improvement in staging of esophageal cancer with the addition of positron emission tomography. Ann Thorac Surg 1997;64:770-777.[Abstract/Free Full Text]
  5. Luketich L.D., Schauer P.R., Meltzer C.C., et al. Role of positron emission tomography in staging esophageal cancer. Ann Thorac Surg 1997;64:765-769.[Abstract/Free Full Text]
  6. Luketich J.D., Friedman D.M., Weigel T.L., et al. Evaluation of distant metastases in esophageal cancer: 100 consecutive positron emission tomography scans. Ann Thorac Surg 1999;68:1133-1136.[Abstract/Free Full Text]
  7. In: Beahrs O.H., Henson D.E., Hutter R.V.P., Kennedy B.J., eds. American Joint Committee on Cancer. Manual for staging cancer, 4th ed. Philadelphia: JB Lippincott, 1992.
  8. Ellis F.H., Heatley G.J., Krasna M.J., et al. Esophagogastrectomy for carcinoma of the esophagus and cardia: a comparison of findings after standard resection in three consecutive eight-year intervals with improved staging criteria. J Thorac Cardiovasc Surg 1997;113:836-846.[Abstract/Free Full Text]
  9. Altorki N.K., Girardi L., Skinner D.B. En bloc esophagectomy improves survival for stage III esophageal cancer. J Thorac Cardiovasc Surg 1997;114:948-955.[Abstract/Free Full Text]
  10. Sabanathan S., Shah R., Mearns A.J., et al. Results of surgical treatment of esophageal cancer. J R Coll Surg Edinb 1996;41:295-301.[Medline]
  11. Killinger W.A., Rice T.W., Adelstein D.J., et al. Stage II esophageal carcinoma. The significance of T and N. J Thorac Cardiovasc Surg 1996;111:935-940.[Abstract/Free Full Text]
  12. Millikan K.W., Silverstein J., Hart V., et al. A 15-year review of esophagectomy for carcinoma of the esophagus and cardia. Arch Surg 1995;130:617-624.[Abstract/Free Full Text]
  13. Lieberman M.D., Shriver C.D., Bleckner S., Burt M. Carcinoma of the esophagus. Prognostic significance of histologic type. J Thorac Cardiovasc Surg 1995;109:130-138.[Abstract/Free Full Text]
  14. Lerut T.E., de Leyn P., Coosemans W., et al. Advanced esophageal carcinoma. World J Surg 1994;18:379-387.[Medline]
  15. Earlam R., Cunha-Melo J.R. Oesophageal squamous cell carcinoma. II: A critical review of radiotherapy. Br J Surg 1980;67:457-461.[Medline]
  16. Pearson J.G. The present status and future potential of radiotherapy in the management of esophageal cancer. Cancer 1977;39(Suppl 2):882-890.[Medline]
  17. Zieren H.U., Müller J.M., Jacobi C.A., et al. Adjuvant postoperative radiation therapy after curative resection of squamous carcinoma of the thoracic esophagus: a prospective randomized study. World J Surg 1995;19:444-449.[Medline]
  18. Tènière P., Hay J.-M., Fingerhut A., Fagniez P.L. Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus as shown by a multicenter controlled trial. Surg Gynecol Obstet 1991;173:123-130.[Medline]
  19. Fok M., Sham J.S.T., Choy D., et al. Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study. Surgery 1993;113:138-147.[Medline]
  20. Pouliquen X., Levard H., Hay J.M., et al. 5-Fluorouracil, and cisplatin therapy after palliative surgical resection of squamous cell carcinoma of the esophagus. A multicenter randomized trial. Ann Surg 1996;223:127-133.[Medline]
  21. Ando N., Iizuk T., Kakegawa T., et al. A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group study. J Thorac Cardiovasc Surg 1997;114:205-209.[Abstract/Free Full Text]
  22. Ando N., Iizuka T., Ide H., et al. A randomized trial of surgery alone versus surgery plus postoperative chemotherapy with cisplatin and 5-fluorouracil for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group study (JCOG 9204). Proc ASCO 1999;18:269a.
  23. Nygaard K., Hagen S., Hansen H.S., et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma. A randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 1992;16:1104-1110.[Medline]
  24. Arnott S.J., Duncan W., Gignoux M., et al. Preoperative radiotherapy in esophageal carcinoma: a meta-analysis using individual patient data (Oesophageal Cancer Collaborative Group). Int J Radiation Oncology Biol Phys 1998;41:579-583.[Medline]
  25. Roth J.A., Pass H.I., Flanagan M.M., et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 1988;96:242-248.[Abstract]
  26. Schlag P.M. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. Arch Surg 1992;127:1446-1450.[Abstract/Free Full Text]
  27. Law S., Fok M., Chow S., et al. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg 1997;114:210-217.[Abstract/Free Full Text]
  28. Kelsen D.P., Ginsberg R., Pajak T.F., et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339:1979-1984.[Abstract/Free Full Text]
  29. Le Prise E., Etienne P.L., Meunier B., et al. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 1994;73:1779-1784.[Medline]
  30. Urba S.G., Orringer M.B., Turrisi A., et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19:305-313.[Abstract/Free Full Text]
  31. Walsh T.N., Noonan N., Hollywood D., et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335:462-467.[Abstract/Free Full Text]
  32. Bosset J.-F., Gignoux M., Triboulet J.-P., et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell carcinoma of the esophagus. N Engl J Med 1997;337:161-167.[Abstract/Free Full Text]
  33. Law S., Kwong D.L.W., Tung H.M., et al. Preoperative chemoradiation for squamous cell esophageal cancer: a prospective randomized trial. Can J Gastroenterol 1998;12(Suppl B):56B.
  34. Geh J.I., Bond S.J., Bentzen S.M., Glynne-Jones R. Preoperative chemoradiotherapy in esophageal cancer: evidence of dose response. Proc ASCO 2000;19:247a.
  35. Al-Sarraf M., Martz K., Herskovic A., et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 1997;15:277-284.[Abstract/Free Full Text]
  36. Minsky B.D., Berkey B., Kelsen D.K., et al. Preliminary results of intergroup INT 0123 randomized trial of combined modality therapy (CMT) for esophageal cancer: standard vs. high dose radiation therapy. Proc ASCO 2000;19:239a.
  37. Bates B.A., Detterbeck F.C., Bernard S.A., et al. Concurrent radiation therapy and chemotherapy followed by esophagectomy for localized esophageal carcinoma. J Clin Oncol 1996;14:156-163.[Abstract]
  38. Forastiere A.A., Heitmiller R., Kleinberg L., et al. Long follow-up of patients with esophageal cancer treated with preoperative cisplatin/5-FU and concurrent radiation. Proc ASCO 1999;18:270a.
  39. Alexander E.P., Lipan T., Harmon J., Wadleigh R. Aggressive multimodality therapy for stage III esophageal cancer: a phase I/II study. Ann Thorac Surg 2000;69:363-368.[Abstract/Free Full Text]
  40. Couper G.W., McAteer D., Wallis F., et al. Detection of response to chemotherapy using positron emission tomography in patients with oesophageal and gastric cancer. Br J Surg 1998;85:1403-1406.[Medline]
  41. Izbicki J.R., Hosch S.B., Pichlmeier U., et al. Prognostic value of immunohistochemically identifiable tumor cells in lymph nodes of patients with completely resected esophageal cancer. N Engl J Med 1997;337:1188-1194.[Abstract/Free Full Text]
  42. Zhang X.D., Coventry B.J., Jamieson G.G., Gill P.G. The utility of the proliferative index in pretreatment biopsy specimens of esophageal squamous cell carcinoma. Dis Esophagus 1998;11:215-220.[Medline]
  43. Imdahl A., Jenker J., Ihling C., et al. Is MIB-1 proliferation index a predictor for response to neoadjuvant therapy in patients with esophageal cancer?. Am J Surg 2000;179:514-520.[Medline]
  44. Moore-Joshi M.H., Danenberg K.D., Lord R.V., et al. Low thymidylate synthase and ERCC1 gene expressions are associated with increased survival after neoadjuvant 5-FU/cisplatin/radiotherapy for esophageal adenocarcinoma. Proc ASCO 2000;19:244a.
  45. Harpole D.H., Moore M.H., Aloia T.A., et al. Molecular markers of treatment resistance or sensitivity in esophageal cancer patients. Proc ASCO 1999;18:387a.
  46. Nakashima S., Natsugoe S., Matsumoto M., et al. Expression of p53 and p21 is useful for the prediction of preoperative chemotherapeutic effects in esophageal carcinoma. Anticancer Res 2000;20:1933-1937.[Medline]
  47. Luketich J.D., Kassis E.S., Shriver S.P., et al. Detection of micrometastases in histologically negative lymph nodes in esophageal cancer. Ann Thorac Surg 1998;66:1715-1718.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
John W.C. Entwistle, III
Melvyn Goldberg
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Entwistle, J. W.C.
Right arrow Articles by Goldberg, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Entwistle, J. W.C., III
Right arrow Articles by Goldberg, M.
Related Collections
Right arrow Esophagus - cancer

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS