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(Radiology. 1999;213:67-72.)
© RSNA, 1999

Radiation Oncology

Resectable Esophageal Carcinoma: Local Control with Neoadjuvant Chemotherapy and Radiation Therapy1

Mark A. Chidel, MD, Thomas W. Rice, MD, David J. Adelstein, MD, Patrick A. Kupelian, MD, John H. Suh, MD and Mark Becker, MD

1 From the Departments of Radiation Oncology (M.A.C., P.A.K., J.H.S., M.B.), Thoracic Surgery (T.W.R.), and Hematology and Oncology (D.J.A.), Cleveland Clinic Foundation, 9500 Euclid Ave, Desk T-28, Cleveland, OH 44195. From the 1997 RSNA scientific assembly. Received September 22, 1998; revision requested November 4; revision received December 22; accepted March 8, 1999. Address reprint requests to P.A.K.


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To evaluate the usefulness of neoadjuvant chemotherapy and radiation therapy before esophagectomy for invasive cancer of the esophagus or gastroesophageal junction (GEJ).

MATERIALS AND METHODS: The authors conducted a retrospective analysis of 154 patients who underwent esophagectomy for invasive cancer between September 1, 1991, and December 31, 1995. The end points evaluated were overall, disease-free, local-regional relapse–free, and systemic relapse–free survival.

RESULTS: Seventy of the 154 patients received neoadjuvant combined-modality therapy (CMT) consisting of concurrent cisplatin and fluorouracil administration and accelerated, hyperfractionated radiation therapy. The remaining 84 patients underwent immediate esophagectomy. With a median follow-up of 34.7 months, the 3-year overall, disease-free, and distant metastatic relapse–free survival rates were 38.0%, 41.9%, and 56.0%, respectively. Although neoadjuvant therapy did not appear to prevent distant metastases, there was a dramatic effect on local control. After CMT, the 5-year local control rate was 90% compared to 64% after surgery (P < .001). Tumors in the GEJ recurred more frequently (P = .01); however, multivariate analysis showed CMT was the only independent predictor of local control. Postoperative mortality was 15.7% after CMT versus 5.9% without CMT (P = .05).

CONCLUSION: Local control of esophageal cancer is excellent following neoadjuvant chemotherapy and radiation therapy. However, the effects of CMT on overall and disease-free survival are less clear due to significant differences between the treatment groups.

Index terms: Chemotherapy, 71.1299 • Esophagus, neoplasms, 71.32 • Esophagus, surgery, 71.451 • Esophagus, therapeutic radiology, 71.1299 • Therapeutic radiology, preoperative, 71.1299


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
An estimated 12,500 cases of esophageal cancer are diagnosed annually in the United States, and more than 90% of patients will ultimately die of their disease (1). Contributing to this bleak outlook is the advanced stage of the disease at the time of diagnosis, with approximately 60% of patients having unresectable or metastatic disease at the time of diagnosis (2,3). For many of these patients, palliative therapy, which results in symptomatic relief in 60%–80% of cases, is most appropriate. Historically, patients with more limited disease have been treated with esophagectomy, radiation therapy, or a combination of the two. Despite these efforts, the 5-year survival rates have remained below 20% and local recurrences have been noted in up to 50% of cases (2–13).

Over the past 2 decades, several refinements in therapy have been evaluated, most notably in the use of combined-modality therapy. Definitive chemotherapy and radiation therapy have yielded encouraging results. The Radiation Therapy Oncology Group reports a median survival of 14.1 months and an overall survival rate of 27% at 5 years (14,15). Despite encouraging survival rates, persistent disease or local-regional failure occurred in 45% of these patients (14,15). Investigators in other trials (16,17) also reported similar findings. To improve these results, the Radiation Therapy Oncology Group protocol 94–05, a phase III randomized trial designed to evaluate the effect of increasing the dose of radiation therapy given concurrently with chemotherapy, has been formed.

Esophagectomy after neoadjuvant chemotherapy and radiation therapy is another treatment approach under investigation. Multiple randomized and nonrandomized studies (18–21), several of which demonstrated very encouraging results, have been reported on. Since September 1991, the Cleveland Clinic Foundation, Ohio, has evaluated the use of concurrent chemotherapy with accelerated, hyperfractionated radiation therapy followed by transthoracic esophagectomy. To evaluate the effectiveness of our treatment regimen in patients undergoing esophagectomy for invasive cancer of the esophagus or gastroesophageal junction, in this retrospective review we compared the patients who underwent combined-modality therapy with those who underwent immediate esophagectomy during the same period.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The records of 154 consecutive patients were reviewed retrospectively. Each patient underwent esophagectomy for primary invasive cancer of the esophagus or gastroesophageal junction at the Cleveland Clinic Foundation between September 1991 and December 1995. The charts of patients who underwent esophagectomy for reasons other than primary invasive cancer of the esophagus or gastroesophageal junction were not reviewed. Eighty-four patients immediately underwent esophagectomy, and 70 patients underwent neoadjuvant chemotherapy and radiation therapy followed by esophagectomy.

Patients selected for combined-modality therapy typically had endoesophageal ultrasonographic (US) findings of tumor invasion beyond the esophageal wall (clinical stage T3) or involvement of periesophageal lymph nodes (clinical stage N1)(22), although some patients with earlier stage disease were also included. Patients with visceral metastases were specifically excluded from this protocol. This protocol was approved by the institutional review board of the Cleveland Clinic Foundation, and all patients enrolled in this protocol signed an appropriate informed consent form.

A total of 72 patients were treated in this protocol, and 65 underwent resection. Of the seven patients treated in this protocol who did not undergo esophagectomy and are not included in this analysis, four had clinical deterioration (including one death due to a toxic reaction during neoadjuvant therapy), two were found to have unresectable or metastatic disease at the time of exploration, and one refused surgery. Five additional patients who were not in the protocol received the same chemotherapy but received once daily radiation therapy due to travel or insurance constraints. One of these patients received a total of 60 Gy preoperatively. All diagnostic biopsy specimens were reviewed for confirmation of invasive carcinoma.

The treatment regimen consisted of concurrent chemotherapy and accelerated hyperfractionated radiation therapy (Fig 1). Cisplatin (20 mg/m2/d; Platinol AQ; Bristol Laboratories, Princeton, NJ) and fluorouracil (1,000 mg/m2/d; Adrucil; Pharmacia, Kalamazoo, Mich) were delivered as a 96-hour continuous intravenous infusion on days 1–5 and 22–26. Further details regarding chemotherapy have been published previously (23).



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  		Figure 1. Diagram demonstrates the neoadjuvant chemotherapy and radiation therapy regimen. BID = twice daily, CDDP = cisplatin, fx = fraction, IV = intravenous, XRT = radiation therapy, 5-FU = fluorouracil.

 
On days 1–5 and 8–10, patients received megavoltage radiation therapy by using multiple fields, for a total dose of 24 Gy, with 1.5 Gy per fraction administered twice daily. After an 11-day break, radiation therapy was restarted, and on days 22–26, 29, and 30, a total of 21 Gy was delivered, with 1.5 Gy per fraction administered twice daily. Combined-modality therapy was completed on day 30, after two cycles of chemotherapy and a total of 45 Gy of external-beam radiation therapy.

Hyperfractionated, accelerated radiation therapy was used in this protocol in an effort to exploit the radiobiologic advantages of fractionation without hindering disease control. Although treatment breaks in radiation therapy are generally considered unacceptable, this trial did include a 10-day break to maximize the effect of radiosensitization associated with concurrent chemotherapy and radiation therapy. Similar fractionation schedules are used in the treatment of other malignancies and appear to be effective; for example, Wang et al (24) employ a regimen of 1.6 Gy administered twice a day to a total dose of 64 Gy, with a planned 10–14-day break after 38.4 Gy.

The radiation treatment volume for this study was dependent on the location of the primary tumor. For lesions of the cervical esophagus, the supraclavicular and cervical lymph nodes were included within the field and an inferior margin of at least 5 cm below all known disease was given. For lesions of the distal esophagus, the celiac nodes were included and a superior margin of 5 cm above all known disease was given. For lesions in the middle part of the esophagus, the entire mediastinum, supraclavicular fossa, and celiac nodes were treated. The lateral margin on the mediastinum was a minimum of 1 cm. Opposed anteroposterior and posteroanterior fields were used at the beginning of treatment. The spinal cord dose was limited to a total of 45 Gy for the entire course of radiation therapy by using opposed-oblique or three-field techniques.

Approximately 3 weeks after completion, all patients were reevaluated and then underwent esophagectomy. If residual viable tumor was documented in the esophagectomy specimen, then a third course of chemotherapy and radiation therapy was offered and scheduled to begin within 6–8 weeks after surgery. The chemotherapy was unchanged, and an additional 24 Gy was delivered as 1.5-Gy fractions twice a day to the area of residual disease plus a 1.5-cm margin. The anastomosis was included if the margin of resection was involved with tumor. The total dose to this site was therefore 69 Gy. Twenty-five patients underwent this course of treatment.

The end points for analysis were over-all survival, disease-free survival, local-regional relapse–free survival, and distant metastatic relapse–free survival. Local-regional failure was defined as recurrence of tumor in the reconstructed neoesophagus or in the mediastinal, supraclavicular, or celiac lymph nodes. Failure in any other area was deemed a distant metastasis. Disease-free survival was determined by the date of first treatment failure, either local or distant. Death due to postoperative complications was defined as any death that occurred within 30 days of the surgical procedure.

Differences between the treatment groups as related to pretreatment characteristics and postoperative mortality were determined by using the {chi}2 test. The influence of pretreatment patient characteristics was evaluated by using both univariate and multivariate analyses. Actuarial curves were calculated by using the Kaplan-Meier method, and testing for significant differences between the curves was based on the log-rank statistic. Cox regression multivariate time-to-failure analysis was used to evaluate the independent predictive value of different pretreatment and treatment-related variables, including age, sex, weight loss, tumor location, tumor grade, US stage (based on the American Joint Committee on Cancer, or AJCC, 1992 system [22]), histologic findings, presence of Barrett metaplasia, and treatment group. The perioperative mortality rates for the two treatments were compared with the {chi}2 test. A one-sided P value of .05 or less was considered to indicate a statistically significant difference.


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The Table summarizes the patient and tumor characteristics for all 154 patients. Median follow-up for those at risk was 34.7 months (range, 0.6–66.9 months). Seventy patients received neoadjuvant chemotherapy and radiation therapy followed by esophagectomy; 84 patients immediately underwent esophagectomy.


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  		Pretreatment Patient and Clinical Characteristics
 
There were some notable differences between the two groups. Patients selected for immediate esophagectomy were older (P < .001) but had a better Karnofsky performance status (P = .009). This group also had more tumors arising from the gastroesophageal junction (P < .001), which resulted in an increased ratio of adenocarcinoma to squamous cell carcinoma (P = .012). Most important, the patients treated surgically were also more likely to have earlier stage disease, as reflected at pretreatment US (P = .002). The differences noted between the treatment groups can be only partially explained by the selection criteria of the neoadjuvant protocol (23). Patients in whom distal tumors or early-stage disease was diagnosed were preferentially treated with immediate esophagectomy.

Esophagectomy via a thoracoabdominal approach with mediastinal lymph node dissection was performed in 131 patients. Gastric reconstruction was the mainstay, with either cervical or intrathoracic anastomosis. Nine patients underwent esophageal reconstruction by using part of the jejunum. Four patients underwent pharyngolaryngoesophagectomy for tumors of the cervical or high thoracic esophagus. Distal esophagectomy and proximal gastrectomy with an intraabdominal anastomosis were performed in five patients with tumors limited to the gastroesophageal junction. Transhiatal esophagectomy was performed in eight patients who were thought to have only preinvasive disease. Six patients underwent resection that could not be evaluated from the records available.

Postoperative radiation was given to 20 patients who did not receive neoadjuvant therapy; eight were also given concurrent chemotherapy. Fourteen of these patients had poorly differentiated tumors, and 19 had direct invasion of the adventitia. Sixteen had regional nodal spread, and six had celiac metastases. Treatment was delivered by using 6–18-MV photons via anteroposterior and posteroanterior fields and, when appropriate, oblique fields that excluded the spinal cord were used to a median dose of 54 Gy (range, 28.8–61.2 Gy). This treatment did not appear to improve outcome by any measure; however, this may be due to the characteristics of this population rather than a lack of treatment efficacy.

Among patients undergoing combined-modality therapy, histopathologic complete or partial response was documented in 20 (28%) or 21 (30%) patients, respectively. Twenty-five (36%) patients had no response to therapy, and four (6%) patients developed progressive disease during the preoperative treatment. Attainment of a complete response or partial response was associated with an overall survival rate of 55% at 3 years compared to only 20% for those without a response (P = .006). It also was found that patients who responded to neoadjuvant therapy had improved disease-free survival (P = .005) and distant metastatic relapse–free survival (P = .05) when compared with those who did not respond to treatment.

The median survival time for the entire group was 16.4 months (range, 0.7–73.6 months); the 3-year overall survival rate was 38.0% (Fig 2). The 3-year overall survival rate was 40.7% for patients who underwent combined-modality therapy and 35.6% for patients who underwent immediate esophagectomy. Univariate analysis revealed that a well to moderately differentiated (low-grade) tumor (P = .012) was predictive of improved overall survival. US stage 0–IIa (P = .076) was associated with improved survival as well; however, this did not reach statistical significance. The addition of postoperative radiation therapy in the surgical group had no apparent effect on outcome.



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  		Figure 2. Graph shows the overall survival rate for all patients.

 
Twenty-two patients died without evidence of disease due to unrelated causes 0–55 months after treatment for esophageal cancer. The causes of death for the 14 patients treated surgically were indeterminate (n = 9), cardiac (n = 2), pneumonia (n = 1), lung cancer (n = 1), and ruptured abdominal aortic aneurysm (n = 1). In the eight patients treated with combined-modality therapy, the causes of death were cardiac (n = 4), pneumonia (n = 2), lung cancer (n = 1), and uterine sarcoma (n = 1).

Death within 30 days of the surgical procedure was marked. Of the 70 patients who received combined-modality therapy, 11 (16%) died within the immediate postoperative period. Causes of death included pulmonary emboli (n = 2), anastomotic leak or fistula (n = 3), and adult respiratory distress syndrome with or without sepsis (n = 6). Seven additional patients underwent treatment with preoperative intent but were unable to undergo esophagectomy. Of these patients, one (14%) experienced a toxic reaction that resulted in death.

In the surgical group, there was significantly less postoperative mortality (P = .05). Five (6%) of the 84 patients in the surgical group died of myocardial infarction, ruptured abdominal aortic aneurysm, hemorrhagic gastritis, tracheoesophageal fistula, or adult respiratory distress syndrome.

Eight additional patients, four from each treatment group, died 1–12 months after treatment due to treatment-related morbidity. Cause of death in these patients was bacterial meningitis from an infected cervical spine epidural catheter (n = 1), chronic aspiration pneumonia due to vocal cord paralysis (n = 1), chylothorax (n = 1), or respiratory failure (n = 5).

A total of 62 patients had failed primary treatment for esophageal cancer. The median time to treatment failure was 21.4 months (range, 0.7–73.6 months). The 3-year disease-free survival rate was 41.9% (Fig 3). Well or moderately differentiated (low-grade) tumors (P = .033) and US stage (P = .026) were associated at univariate analysis with improved disease-free survival. Multivariate analysis revealed that stage 0–IIa tumors (P = .04) and tumors arising from the upper two-thirds of the esophagus (P = .016) were independently predictive of improved disease-free survival.



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  		Figure 3. Graph shows the disease-free survival rate for all patients.

 
Due to significant differences between the two treatment groups, particularly with regard to US stage and Karnofsky performance status, comparisons of overall survival and disease-free survival were not feasible. Patterns of recurrence, however, were very illustrative. Distant metastases occurred in 44% of patients regardless of treatment at 3-years follow-up (Fig 4). The rate was nearly identical among those treated surgically and those treated with neoadjuvant combined-modality therapy, with a total of 55 patients developing metastases. In the surgical group, 12 patients developed distant metastases alone, and 16 had both distant and local failure. Of the 27 patients with metastases in the group receiving combined-modality therapy, only one developed local failure. The Karnofsky performance status (P = .029), weight loss (P = .029), tumor grade (P = .027), US stage (P = .020), and tumor location (P = .015) were associated with distant metastatic relapse–free survival. Multivariate analysis revealed that both stage (P = .025) and location (P = .003) were independently predictive of the development of metastatic disease.



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  		Figure 4. Graph shows the distant metastatic relapse-free survival rate for each treatment modality. CMT = combined-modality therapy.

 
Local-regional control after combined-modality therapy was remarkable, with only a single failure within the supraclavicular or celiac nodes, mediastinum, or neoesophagus. This patient developed symptoms of gastric outlet obstruction and ultimately was found to have malignant celiac adenopathy. He subsequently developed progressive metastases and was alive with disease 8 months after recurrence. In the surgical group, 23 patients experienced locally recurrent disease. Seven of these patients had an isolated local failure, and 16 were found to have distant metastases as well. Tumors arising in the gastroesophageal junction were more likely to recur locally (P = .01), but this did not prove to be independently predictive of local-regional relapse–free survival. The only factor independently predictive of local-regional control was the use of combined-modality therapy (Fig 5). The 5-year local-regional relapse–free survival rate after combined-modality therapy was 90%; it was only 64% after immediate esophagectomy. This was highly significant at both univariate (P < .001) and multivariate (P = .006) analysis.



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  		Figure 5. Graph shows the local-regional relapse-free survival rate for each treatment modality. CMT = combined-modality therapy.

 

   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Current trends in the management of esophageal cancer have resulted in the adoption of more intensive therapeutic regimens. Results of previously reported trials from both the United States and Europe (18–21,23,24), as well as the investigational policy of the Cleveland Clinic Foundation, exemplify this trend. Prior to 1980, patients with operable esophageal cancer underwent esophagectomy. Unfortunately, only 168 (56%) of 299 cases were operable, and only one-half of these were amenable to curative resection, which resulted in a 2-year overall survival rate for all patients of only 17% (5). In the late 1980s, a trial (25) of preoperative chemotherapy was undertaken; however, no remarkable tumor regression was noted.

This article details the results of the next step taken by the Cleveland Clinic Foundation in the management of esophageal cancer. The 3-year overall survival rate of 40.7% for patients undergoing neoadjuvant combined-modality therapy is a marked improvement over the survival rate in previous years, and it compares favorably with that in recently reported randomized trials (14,15,18–21).

In this study, distant metastases occurred at a rate of 44% at 3 years, a rate that is also comparable to that reported in the literature (7,10,14,15,17,18,20). Among the 154 patients treated, a total of 55 developed distant metastases, and only five remained alive at the time of this analysis. It is concerning that the use of combined-modality therapy did not seem to influence this outcome; however, it is possible that patient selection contributed to this finding. It is clear that stage is a strong predictor of long-term prognosis, and in this series, patients treated with neoadjuvant therapy typically had more advanced disease diagnosed. Despite this fact, the two treatments resulted in nearly identical rates of distant metastases.

The clinical importance of local-regional failure remains a matter of debate, and some claim it does not convey a poor prognosis (5,26). In contrast, all seven of our patients who experienced isolated local-regional failure died. The use of combined-modality therapy for our patients has resulted in a remarkable rate of local control, with a 5-year local-regional relapse–free survival rate of 90%. This represents a marked improvement over immediate esophagectomy and compares favorably with recently published results of randomized trials that show rates of local control ranging from 55% to 80% (4,7,10,11,14,15,17,18,20,21).

Despite our encouraging overall survival and local-regional control rates after neoadjuvant therapy, the reported postoperative mortality rate remains a concern, especially in light of conflicting reports in the literature. Walsh et al (19) and Bosset et al (20) both noted a higher postoperative mortality rate after combined modality therapy, whereas LePrise et al (18), Arnott et al (13), and Nygaard et al (8) did not. In the present review, five deaths were noted in the surgical group, compared to 11 in the combined-modality therapy group, with the majority of these deaths being respiratory in nature. Of the 11 patients in the combined-modality therapy group who died, three had a complete histopathologic response to therapy and one had disease confined to the esophagus at pretreatment US.

A simple explanation for this morbidity could be the use of neoadjuvant therapy. Several authors report similar findings to the current series, with mortality rates from 7% to 15% (27–31); however, equally aggressive regimens are reported without such mortality. Forastiere et al (32) report no perioperative mortality among 47 patients who underwent resection. There are important differences in the treatment regimen when compared with that in the current series, however, as the chemotherapeutic doses were lower, the radiation therapy was administered once daily, and the surgery was a transhiatal esophagectomy. It is likely that the cause of the mortality rate in the current study is multifactorial, and it is not clear what role each of the treatment modalities has in this regard.

Since the completion of the first trial of neoadjuvant therapy, changes have been made in the protocol to minimize treatment morbidity. Paclitaxel (Taxol; Mead-Johnson, Princeton, NJ) has been substituted for fluorouracil, and in an effort to diminish the risk of anastomotic leak or fistula, the radiation therapy volume has been modified in an attempt to spare at least one end of the future anastomosis. In addition, to help prevent postoperative adult respiratory distress syndrome, the volume of normal lung irradiated was limited by using opposed oblique fields as the mainstay of the off-cord boost rather than opposed lateral fields. This most recent trial has been recently closed and is being evaluated.

The use of neoadjuvant chemotherapy and radiation therapy in preparation for esophagectomy is slowly gaining popularity in both the United States and Europe. Overall survival and local control rates are encouraging and appear to be improved with more aggressive therapy.

In the current study, patients treated surgically were more likely to have earlier stage disease at presentation, which reflects the approach to esophageal cancer taken by the Cleveland Clinic Foundation. Despite the fact that patients treated surgically had less advanced disease, the use of combined-modality therapy was able to provide outstanding local-regional control, which was significantly better than that after immediate esophagectomy. Unfortunately, the use of combined-modality therapy did not influence the rate of distant metastasis. Perhaps this may be explained by the more advanced extent of disease in the patients who underwent neoadjuvant treatment. This is a question, however, that ultimately needs to be addressed in a phase III randomized trial comparing neoadjuvant combined-modality therapy versus immediate esophagectomy, where stratification is based on pretreatment US findings.


   Footnotes
 
Author contributions: Guarantors of integrity of entire study, M.A.C., D.J.A., P.A.K.; study concepts, M.A.C., D.J.A., M.B., P.A.K.; study design, M.A.C.; definition of intellectual content, M.A.C., D.J.A., P.A.K.; clinical studies, M.A.C., D.J.A., T.W.R., M.B.; literature research, M.A.C.; data acquisition, M.A.C., D.J.A., T.W.R., M.B.; data analysis, M.A.C., P.A.K., T.W.R.; statistical analysis, M.A.C., P.A.K., T.W.R.; manuscript preparation and review, M.A.C., P.A.K., D.J.A., T.W.R., J.H.S.; manuscript editing, M.A.C., P.A.K., D.J.A., J.H.S.


   References
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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S. R. DeMeester
Adenocarcinoma of the Esophagus and Cardia: A Review of the Disease and Its Treatment
Ann. Surg. Oncol., January 1, 2006; 13(1): 12 - 30.
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R. M. Abou-Jawde, T. Mekhail, D. J. Adelstein, L. A. Rybicki, P. J. Mazzone, M. A. Caroll, and T. W. Rice
Impact of Induction Concurrent Chemoradiotherapy on Pulmonary Function and Postoperative Acute Respiratory Complications in Esophageal Cancer
Chest, July 1, 2005; 128(1): 250 - 255.
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M. Goldberg, J. Farma, C. Lampert, P. Colarusso, L. Coia, H. Frucht, E. Goosenberg, M. Beard, and L. M. Weiner
Survival following intensive preoperative combined modality therapy with paclitaxel, cisplatin, 5-fluorouracil, and radiation in resectable esophageal carcinoma: A phase I report
J. Thorac. Cardiovasc. Surg., October 1, 2003; 126(4): 1168 - 1173.
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P. Thirion, Y. Piedbois, and D. J. Adelstein
Preoperative Chemoradiotherapy Using Taxanes for Locally Advanced Esophageal Carcinoma
J. Clin. Oncol., March 15, 2001; 19(6): 1880 - 1882.
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M. RIEDEL, H. J. STEIN, L. MOUNYAM, F. ZIMMERMANN, U. FINK, and J. R. SIEWERT
Influence of Simultaneous Neoadjuvant Radiotherapy and Chemotherapy on Bronchoscopic Findings and Lung Function in Patients with Locally Advanced Proximal Esophageal Cancer
Am. J. Respir. Crit. Care Med., November 1, 2000; 162(5): 1741 - 1746.
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