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Clinical Investigations: SURGERY |

Preoperative Chemoradiotherapy for Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus*: A Phase II Study FREE TO VIEW

Ferdinando De Vita, MD, PhD; Natale Di Martino, MD; Michele Orditura, MD, PhD; Angelo Cosenza, MD; Gennaro Galizia, MD; Alberto Del Genio, MD; Giuseppe Catalano, MD, PhD
Author and Funding Information

*From the Divisions of Medical Oncology (Drs. De Vita, Orditura, and Catalano) and Surgical Oncology (Drs. Di Martino, Cosenza, Galizia, and Del Genio), “F. Magrassi” Department of Clinical and Experimental Medicine, Second University of Naples School of Medicine, Naples, Italy.

Correspondence to: Ferdinando De Vita, MD, PhD, Via Pansini, 5, 80131 Napoli, Italy; e-mail: orditura@sirio-oncology.it



Chest. 2002;122(4):1302-1308. doi:10.1378/chest.122.4.1302
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Published online

Objectives: This study evaluated the concurrent treatment of chemoradiation followed by esophagectomy in the management of locoregional esophageal carcinoma. The main end points were to determine the resectability of the tumor and the pathologic tumor response. An accessory aim was to evaluate the survival rate.

Patients and methods: Thirty-nine patients were treated as follows: 5-fluoruracil, 1,000 mg/m2, by 24-h IV infusion for 4 days, and cisplatin, 100 mg/m2, on day 1. Concurrent radiotherapy was delivered at a total dose of 40 Gy in daily fractions of 2 Gy five times per week. The performance of an esophagectomy was planned 4 weeks after induction treatment and restaging.

Results: All patients completed the preoperative treatment. A potentially radical resection was performed in 29 patients, and a complete or partial histologically proven response was observed in 9 patients (23%) and 20 patients (51%), respectively. The 3-year overall survival rate was 40%. The 3-year rates of overall survival and disease-free survival were 88% and 76%, respectively, in patients with complete response (p < 0.0012), and 16% and 17%, respectively, in patients with partial response (p < 0.0013). Age, histology, and response represented the best prognostic model related to survival.

Conclusions: The results of this combined approach appear to be better than those reported with surgery alone. Despite the small number of patients in the series and the inclusion of patients with different histotypes, we concluded that patients with the squamous histotype show a better outcome than those with adenocarcinoma.

Figures in this Article

While still relatively rare in Western countries, esophageal cancer is a very aggressive tumor, and only 40 to 60% of patients present with clinically localized disease. These patients usually are treated predominantly with surgery. However, resection is often not radical, and the overall 5-year survival rate remains poor, with only 10% of patients alive after surgery.1This poor prognosis reflects the fact that few esophageal tumors are diagnosed at an early stage and that, even in localized stages, early lymphatic and hematogenous dissemination occurs owing to the underlying anatomy.2Therefore, esophageal cancer may not be cured by local approaches, such as surgery or radiotherapy. Combination chemoradiotherapy provides a clear survival advantage when compared to radiation therapy alone.34 Chemoradiotherapy with subsequent esophagectomy has been reported to be effective as well, although the value of surgery is still not unequivocal. The goal of this approach was predominantly aimed at eliminating micrometastases and facilitating complete tumor resection, which is the requisite for long-term survival. Chemotherapy agents such as 5-fluorouracil, cisplatin, mitomycin, and bleomycin have been shown to be highly effective in previously untreated patients, particularly when associated with concurrent radiotherapy. Preoperative chemoradiotherapy has been demonstrated to result in a pathologic complete response (CR) rate of approximately 20 to 30%.56 However, a wide range of pathologic CR, survival, and mortality rates have been reported in the literature. Factors influencing these results include the modality of patient sampling, the design of the studies, and inadequate staging.78 The use of positron emission tomography using 18-fluorodeoxyglucose has been shown to improve the clinical staging of patients with locally advanced esophageal cancer.910 Moreover, improvements in staging procedures have been achieved with endoscopic ultrasonography (EUS), which is superior to both CT scanning and MRI in assessing esophageal involvement.1112 Although currently not useful in patient management, EUS does enhance the precision in clinical staging and should be used to select or stratify patients in clinical trials. Here we report the results of a phase II study employing concurrent preoperative chemoradiotherapy in patients with both adenocarcinoma and squamous cell carcinoma of the esophagus staged with EUS. The main goal of this trial was to investigate the influence of a primary treatment on tumor resectability, pathologic tumor response, and prognosis.

Patient Selection

Between February 1994 and June 1999, 73 patients with previously untreated, biopsy-proven adenocarcinoma or squamous cell carcinoma of the esophagus were admitted at our hospital. On evaluation, 3 patients had tumors of the cervical esophagus, 9 patients were affected by metastatic disease, 7 patients had early-stage disease (ie, T1-T2, N0), and 15 patients had poor performance status (PS), which made them eligible for best supportive care only. Therefore, the remaining 39 patients with locally advanced disease (ie, T3-T4 N0 or any TN+), Eastern Cooperative Oncology Group PS 0 to 2, adequate pulmonary function to tolerate an esophagectomy, and no preexisting renal, hepatic, or hematologic dysfunction were eligible for concurrent preoperative chemoradiation. The pretreatment evaluation included physical examination, serum chemistry tests, barium esophagogram, contrast CT scanning of the chest and abdomen, and esophageal EUS. Bronchoscopy was performed in patients with tumors at or above the carina. Based on the results of the EUS, patients were assigned to a preoperative clinical stage according to the 1992 TNM System of the American Joint Committee on Cancer. All patients gave written informed consent.

Treatment Plan and Criteria for Response and Toxicity

Chemotherapy consisted of 5-fluorouracil (1,000 mg/m2) by 24-h infusion for 4 days in a volume of 2,000 mL normal saline solution per day. On day 1, patients received a bolus a of cisplatin (100 mg/m2). Two cycles of chemotherapy were administered 3 weeks apart. During chemotherapy, CBC and platelet counts were performed at least two times per week. All patients were hospitalized throughout the duration of chemotherapy for appropriate hydration and antiemetic therapy, and in case of thrombocytopenia of < 20,000 cells/μL or leukopenic fever. Radiotherapy was delivered via a millielectron volt linear accelerator. Each patient received a total dose of 40 Gy in daily fractions of 2 Gy five times per week, starting on day 1 of chemotherapy. The treatment fields had longitudinal and lateral margins of at least 4 and 2 cm, respectively, away from the gross tumor volume, as defined by CT scan and esophagogram. After the completion of two courses of chemotherapy and a full dose of radiotherapy, patients were re-evaluated. The process of restaging included a routine complete blood workup, chest and abdomen CT scans with contrast, and an EUS evaluation with an endoscopy biopsy. Response criteria were defined as follows: CR, normal barium esophagogram and no visible tumor as determined by esophagoscopy with negative biopsy results and normal CT scan findings; partial response (PR), > 50% tumor regression evaluated by CT scan and > 50% reduction of intraesophageal tumor extension assessed by barium swallow and esophagoscopy; and no change, < 50% regression of tumor extension and no evidence of tumor progression. Progressive disease was considered as a > 25% increase of the measurements or the appearance of new lesions. Treatment-induced toxicity was classified according to World Health Organization (WHO) criteria. Esophagectomy was planned 4 to 6 weeks after the induction treatment. According to the usual surgical technique in the authors’ surgical unit, thoracic esophageal cancers are treated with laparotomy, thoracotomy, and cervicotomy followed by total esophagectomy, lymphadenectomy, and gastroesophageal anastomosis in the left neck. In abdominal esophageal cancers, after gastric mobilization by laparotomy, esophagectomy was performed by right thoracotomy and mediastinal esophagogastro anastomosis. A radical resection (R0, according to the criteria of the Union Internacional Contra la Cancrum) was defined as the removal of all macroscopic tumoral tissue, no evidence of distant metastases, the absence of microscopic residual tumor, free resection margins, and lymphadenectomy extended beyond the involved nodes at postoperative pathologic examination. A resection was judged as nonradical when microscopic (R1) or macroscopic (R2) residual tumor was found. Patients with evidence of residual disease after surgery received two additional cycles of chemotherapy. After treatment, the patients were followed-up every 3 months for the first 2 years and every 6 months thereafter. Follow-up was updated from the Tumor Registry of the Department. No patient was lost to follow-up, and the study was completed by December 31, 2000.

Statistical Analysis

Statistical software (BMDP Statistical Software Inc; Los Angeles, CA) was used for statistical analysis of the data. All tests were two-tailed. A p value of < 0.05 was considered to be statistically significant. The following 11 prognostic factors were considered: gender, age, tumor, nodes, PS, histology, grading, hemoglobin, leukocytes, weight loss, and pathologic response. For all data, mean ± SD, range, median, and lower and upper 95% confidence intervals (CIs) for the mean are provided. The correlation between individual prognostic factors and the type of response was performed by using one-way analysis of variance (ANOVA). Multiple linear regression by groups, which was performed using variables with a significant value on ANOVA, was used to characterize the influence of every covariate on a positive response to radiochemotherapy. Overall survival (OS) was measured from the date of registration to the date of death or last follow-up visit. The length of disease-free survival (DFS) was calculated from the time of surgery through the last follow-up or documented recurrence. Univariate analysis related to OS and DFS was performed on each variable, and significance was determined by log-rank test (Mantel-Cox).

Survival curves were plotted using the product-limit method (Kaplan-Meier) and were analyzed using the generalized Savage test or Mantel-Cox test (BMDP1 L; BMDP Statistical Software, Inc.).

The independent significance of every prognostic variable related to OS and DFS was determined by multivariate analysis, using the Cox proportional hazards model. Coefficient, SE, and hazard rate were considered. Level of significance was obtained by the score test (BMDP2 L; BMDP Statistical Software, Inc.). Finally, a stepwise multivariate analysis was performed, and a predictive model of the best linear combination of variables predicting OS and DFS was developed. The maximum partial likelihood ratio test was used with remove and enter limits of 0.15 and 0.10, respectively (BMDP2 L).

Chemoradiotherapy

All 39 patients completed the preoperative treatment, and a total of 78 courses of chemotherapy combined with radiotherapy were administered. The acute toxicities were mild during the induction regimen. Seven patients developed grade 3 granulocytopenia, one patient developed grade 4 granulocytopenia, and two patients developed grade 3 thrombocytopenia. Seven patients developed grade 3 esophagitis. Thirty-five of the 39 patients received their planned doses of chemoradiotherapy. In 4 of 39 patients, the planned dose of chemoradiotherapy was reduced. One patient had WHO grade 4 neutropenia, and three patients had simultaneous WHO grade 3 esophagitis and hematologic toxicity. No patient died as a result of the induction treatment. Thirteen patients (33.3%) were considered to have had a CR by endoscopic and imaging techniques on reevaluation, 19 patients (48.7%) were considered to have had a PR, and 7 patients (18%) were considered to have had stabilization of disease (no change). An ANOVA test showed that PS, tumor, nodes, histology, leukocytosis, and weight loss significantly correlated with response. Multiple linear regression showed that response to preoperative chemoradiation was significantly predicted by low WBC count and squamous histotype (p = 0.02 and p = 0.04, respectively). Patients without weight loss and metastatic nodes were more likely to show a good response to therapy (Table 1 ).

Surgery

All patients underwent surgery. Radical resection with no evidence of carcinoma cells at the resection margins (R0 resection, according to Union Internacional Contra la Cancrum criteria) was obtained in 29 patients (74%). For the group as a whole, 9 of 39 patients (23%) had no residual tumor in the resected esophagus and regional lymph nodes, corresponding to a pathologic CR. Twenty patients (51%) had residual tumor in the resected surgical specimen. Therefore, the pathologic evaluation confirmed the absence of tumor only in 9 of 13 patients with negative histology from the preresection biopsy specimens or negative imaging results by EUS. Of the remaining 10 patients, 7 underwent palliative surgery due to misdiagnosed (just under the Glisson sheath) liver metastases (3 patients) and celiac node involvement (4 patients), and 3 patients underwent nonradical resections. The operative mortality rate was 5% (2 of 39 patients). One patient who had been treated with palliative surgery died in the immediate perioperative period of myocardial infarction, while a patient who had undergone nonradical resection experienced an anastomotic leak. None of the patients who had undergone radical resection died postoperatively. After undergoing esophagectomy, one patient developed vocal cord paralysis, presumably from the operative procedure. Three patients developed perioperative pulmonary complications. One patient developed late small bowel obstruction, which was managed with conservative therapy. A dilatation was required in three patients due to the occurrence of anastomotic strictures.

OS and DFS

The mean follow-up time for 39 patients was 24.6 ± 14.2 months (range, 0.1 to 82.2 months; 95% CI for the mean, 4.4). Of the 39 patients, 26 died—22 because of the cancer itself, 2 following treatment, and 2 because of other causes unrelated to the tumor. The median survival time was 23.6 months. The 12-month, 24-month, and 36-month OS rates were 96%, 58%, and 40%, respectively.

OS and DFS analyses were performed only on the 29 radically resected patients. The mean follow-up time was 28.1 ± 14.5 months (range, 3.5 to 82.2 months; 95% CI, 5.3). At the end of the study, 16 patients had died and 13 were alive. The mean survival time was 45.4 months (75th quartile, 20.1 months; median, 27.4 months). The OS rates for 1 to 5 years were 96.5%, 64.1%, 39.3%, 39.3%, and 39.3%, respectively. All but one of nine patients with pathologic CRs were alive (88.9% at the 7-year follow-up). Of the 20 patients with residual tumor in the resected surgical specimen, 5 are still alive and 15 have died, with a mean survival time of 25.1 months (75th quartile, 16.4 months; 50th quartile, 23.2 months; and 25th quartile, 29.2 months). The 12-month, 24-month, and 36-month OS rates were 95%, 46%, and 16%, respectively. When comparing the patients who obtained a pathologic CR with those who had a PR, the log-rank test of equality of survival generated a p value of 0.0012 in favor of the patients with pathologic CRs. Patients with residual tumor in the resected surgical specimen had a more than 12-fold increased risk of death compared to patients with pathologic CR (Fig 1 ).

When suspected, local recurrence or distant metastases were investigated by standard diagnostic tools and always were confirmed by routine histopathologic examination of the biopsy specimen. Of the 29 radically resected patients, 2 patients with pathologic CRs and 16 patients with residual tumor experienced tumor recurrence (distant recurrence, 13 patients; local recurrence, 2 patients; and both types of recurrence, 3 patients). The mean length of DFS for all patients who underwent radical resection was 37.6 months (75th quartile, 16.2 months; median, 23.1 months), and DFS rates at 1 to 5 years were 89.2%, 52.3%, 36.7%, 27.5%, and 27.5%, respectively. The mean length of DFS in patients with a pathologic CR was 68.9 months (DFS rates at 1 to 5 years, 100%, 100%, 76.1%, 76.1%, and 76.1%, respectively). The mean length of DFS in the 20 patients with residual tumor in resected specimens was 21.2 months (75th quartile, 12.9 months; 50th quartile, 18.5 months; and 25th quartile, 24.8 months). In these patients, the DFS rates at 1 to 3 years were 84.2%, 28.5%, and 17.1%, respectively. The log-rank test of equality of the survival curves generated a p value of 0.0013 in favor of the patients with pathologic CR. Patients with histologically proven PRs had a more than sevenfold increased risk of tumor recurrence when compared to patients with pathologic CRs (Fig 2 ).

Using multivariate analysis, pathologic response was the only covariate that was independently associated with OS. Stepwise regression indicated age, histology, and response as the best prognostic model related to survival (Table 2 ). Covariates independently associated with DFS were age, sex, PS, nodal status, grading, and response. The best model to predict DFS, as analyzed by stepwise regression, included age, weight loss, and response (Table 3 ).

Esophageal cancer patients have poor survival rates with treatment by surgery alone, because of the early occurrence of metastases. A review of the international literature on surgery outcome found a survival rate of 10% at 2 years.1More recent reports confirmed the discouraging results obtained with surgical treatment, showing a 3-year survival rate of 10 to 15%.2 At a median follow-up of 24.6 months, our 3-year survival rate for all patients who underwent radical resection was 39.3%. Although not randomized, these results appear to be superior to those reported with surgery alone. While past studies on preoperative treatment suffered from insufficient clinical staging, our data were obtained from carefully staged patients using CT scans, bronchoscopy, and, above all, esophageal EUS. On the other hand, the sample size was small, and the study population was highly selected.

The published trials of esophageal cancer with preoperative cisplatin regimens and concurrent radiotherapy yielded a resection rate of 80%, a pathologic CR rate of 20 to 30% with a median survival time of 16 to 24 months, and a therapy-related mortality rate of 10 to 12%.6 Based on these results, many investigators believe now that preoperative treatment with chemoradiation is superior in increasing local control, DFS, and OS than surgery alone. However, these conclusions were obtained only from nonrandomized studies. The results of only a few phase III trials1317 of preoperative radiochemotherapy vs surgery have been reported, showing conflicting results. However, it is interesting to note that the only studies showing a statistically significant advantage for OS or DFS were those reporting a preoperative concomitant chemoradiation treatment, as opposed to a sequential modality of treatment.15,17

A major question is whether surgery after chemoradiation may help to improve the outcome of these patients when compared to chemoradiation alone. Studies in which patients with locoregional esophageal cancer were treated with chemoradiation alone reported high local failure rates. Leichman et al18reported a 64% rate of local recurrences, while Coia et al19 observed that 48% of local recurrences were associated with local disease as a component of failure.

Cooper et al,4 in an intergroup study, compared radiation therapy (64 Gy) with chemotherapy plus radiotherapy with a total dose of 50.4 Gy. In this trial, distant metastases remained the most important problem, but a high local failure rate was reported.4 On the other hand, Forastiere et al20obtained in patients with residual tumor a 5-year survival rate of 32%, and Bates et al21 reported a 3-year survival rate of 25% among patients with residual disease at the time of the esophagectomy. Our trial confirms the low number of locoregional relapses in all resected patients and shows a small but significant percentage of long-term survivors among patients with persistent tumor in the resected esophagus. All these data strongly suggest the value of surgery after chemoradiation to improve outcome. Furthermore, since local recurrences negatively affect the quality of life, as well as the length of survival, the role of surgery after chemoradiation remains an important question.

It is interesting to note that patients treated with chemoradiotherapy who had no tumor on reevaluation could, theoretically, avoid surgery. However, in our experience, 30% of patients with negative test results of biopsy specimens were found to have only a partial remission at the time of surgery. These data argue against the elimination of surgery as part of the chemoradiation protocol based on the results of esophagoscopy biopsies, as in some patients the tumor may persist more deeply in the esophageal wall. Furthermore, even EUS restaging after induction chemoradiotherapy cannot accurately identify those patients who have achieved a pathologic CR at surgery, confirming that EUS has a limited value in assessing the response to induction treatment.22

However, the definitive evaluation of whether surgery should be an essential component of the management of patients with esophageal cancer treated with chemoradiotherapy awaits the results of prospective randomized trials. In the current study, we used a conventional chemoradiation treatment with radiotherapy delivered at 2 Gy per fraction up to a total dose of 40 Gy plus standard 5-fluoruracil and cisplatin; with this regimen, we observed a pathologic CR of 23%, a rate that is similar to the one reported for fluorouracil/cisplatin and concurrent radiotherapy in localized esophageal cancer, in which pathologic CR rates of 20 to 30% have been achieved. In our study, the survival of patients with pathologic CR was significantly better than the survival of patients with surgical specimens that were positive for disease using the log-rank test (p = 0.0012). Furthermore, on multivariate analysis, the pathologic response was the only covariate that was independently associated with OS. It is interesting to note that all of our patients with a pathologic CR were experiencing epidermoid cancer. Indeed, histology turned out to be one of the prognostic variables that significantly correlated with the response to chemoradiotherapy. However, histology was not shown to be an independent prognostic factor that was related to survival on multivariate analysis. This apparent discrepancy was likely due to the relatively low number of patients recruited for this study.

The acute toxicities of this combined treatment appeared to be less severe than those reported in other studies of chemoradiation alone or chemoradiation followed by surgery. No patient died as a result of the induction therapy. The treatment mortality rate in our series was 5% (2 of 39 patients). In similar studies,19,2122 the treatment-related mortality rates were not different.

It is clear that concurrent chemotherapy and radiotherapy can produce a pathologic CR in one third of patients. Given the significant correlation between pathologic response and long-term survival, it is important to identify more effective induction regimens to increase cure rates.

Furthermore, the need for more effective systemic therapies comes from the fact that distant metastases are the major problem after preoperative chemoradiation. For instance, in our trial, 16 patients (55%) experienced a distant recurrence. A number of new systemic agents are entering clinical trials in patients with esophageal cancer and could be more active in the control of micrometastatic disease. Paclitaxel has been identified as an active agent,23while irinotecan and gemcitabine are about to undergo extensive testing. Several of these drugs are also potent radiation sensitizers, and thus it might be possible for them to improve local control when combined with radiotherapy.2426 In conclusion, we think that preoperative chemoradiotherapy should be reserved for patients treated in clinical trials and that surgery remains the standard therapy for locoregionally confined esophageal cancer.

Abbreviations: ANOVA = analysis of variance; CR = complete response; DFS = disease-free survival; EUS = endoscopic ultrasonography; OS = overall survival; PR = partial response; PS = performance status; WHO = World Health Organization

Table Graphic Jump Location
Table 1. Individual Prognostic Significance Related to Response*
* 

Hb = hemoglobin.

 

Indicates significant difference.

Table Graphic Jump Location
Table 2. Multivariate Analysis Related to OS* (Cox Proportional Hazard Model and Stepwise Regression)*
* 

NE = no entry into the model. See Table 1 for abbreviation not used in the text.

 

Cox proportional hazards model.

 

Stepwise regression.

§ 

Indicates significant value.

Table Graphic Jump Location
Table 3. Multivariate Analysis Related to DFS*
* 

See Table 1 for abbreviation not used in the text.

 

Cox proportional hazards model.

 

Stepwise regression.

§ 

Indicates significant value.

The authors thank Dr. Ciro Romano, MD, PhD (“F. Magrassi” Department of Clinical and Experimental Medicine, Second University of Naples School of Medicine, Napoli, Italy) for his help in writing the article.

Muller, JM, Erasmi, H, Stelzner, M, et al (1990) Surgical therapy of esophageal carcinoma.Br J Surg77,845-857. [PubMed] [CrossRef]
 
Roder, JD, Busch, R, Stein, HJ, et al Ratio of invaded to removed lymph node are predictor of survival in squamous cell carcinoma of the esophagus.Br J Surg1994;81,410-413. [PubMed]
 
Smith, TJ, Ryan, LM, Douglas, HO, Jr, et al Combined chemoradiotherapy vs radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of Eastern Cooperative Oncology Group.Int J Radiat Oncol Biol Phys1998;42,269-276. [PubMed]
 
Cooper, JS, Guo, MD, Herskovic, A, et al Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85–01): Radiation Therapy Oncology Group.JAMA1999;281,1623-1627. [PubMed]
 
Philip, PA, Ajani, JA Has combined modality therapy improved outcome of patients with carcinoma of the esophagus?Oncology1994;8,37-42. [PubMed]
 
Ajani, JA Current status of new drugs and multidisciplinary approaches in patients with carcinoma of the esophagus.Chest1998;113(suppl),112S-119S
 
Minsky, BD Nonsurgical treatment approaches for esophageal cancer.Educational book of the American Society of Clinical Oncology.,164-174 Perry MC. Denver, CO:
 
Urba, SG Multimodality therapy of esophageal carcinoma.Educational book of the American Society of Clinical Oncology.1997,175-178 Perry MC. Denver, CO:
 
Lerut, T Histopathologic validation of lymph node staging with FDG-PET scan in cancer of the esophagus and gastroesophageal junction: a prospective study based on primary surgery with extensive lymphadenectomy.Ann Surg2000;232,743-752. [PubMed]
 
Brucher, BL Neoadjuvant therapy of esophageal squamous cell carcinoma: response evaluation by positron emission tomography.Ann Surg2001;233,300-309. [PubMed]
 
Tio, TL, Cohen, P, Coene, PP, et al Endosonography and computed tomography of esophageal carcinoma: preoperative classification compared to the new (1987) TNM system.Gastroenterology1989;96,1478-1486. [PubMed]
 
Rosch, T Endosonographic staging of esophageal cancer: a review of literature results.Gastrointest Endosc Clin N Am1995;5,537-547. [PubMed]
 
Nygaard, K, Hagen, S, Hansen, HS, et al Preoperative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of preoperative radiotherapy and chemotherapy; the second Scandinavian trial in esophageal cancer.World J Surg1992;16,1104-1110. [PubMed]
 
Le Prise, E, Etienne, PL, Meunier, B, et al A randomized study of chemotherapy, radiation therapy and surgery vs surgery for localized squamous cell carcinoma of the esophagus.Cancer1994;73,1779-1784. [PubMed]
 
Walsh, TN, Noonan, N, Hollywood, D, et al A comparison of multimedial theraphy and surgery for esophageal adenocarcinoma.N Engl J Med1996;335,462-467. [PubMed]
 
Bosset, JF, Gignoux, M, Triboulet, JP, et al Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus.N Engl J Med1997;337,161-167. [PubMed]
 
Urba, S, Orringer, M, Turris, A, et al A randomized trial comparing surgery/S) to preoperative concomitant chemoradiation plus surgery in patient with respectable esophageal cancer [abstract]. Proc Am Soc Clin Oncol Annu Meet. 1997;;16 ,.:277
 
Leichman, L, Herskovic, A, Leichman, CG, et al Nonoperative therapy for squamous-cell cancer of the esophagus.J Clin Oncol1987;5,365-370. [PubMed]
 
Coia, LR, Engstrom, PF, Paul, AR, et al Long-term results of infusional 5-fluorouracil, mitomycin-C, and radiation as primary management of esophageal carcinoma.Int J Radiat Oncol Biol Phys1991;20,29-36. [PubMed]
 
Forastiere, AA, Orringer, MB, Perez-Tamaio, C, et al Preoperative chemoradiation followed by transiatal esophagectomy for carcinoma of the esophagus: final report.J Clin Oncol1993;11,1118-1123. [PubMed]
 
Bates, BA, Detterbeck, FC, Bernard, SA, et al Concurrent radiation therapy and chemotherapy followed by esophagectomy for localized esophageal carcinoma.J Clin Oncol1996;14,156-163. [PubMed]
 
Zuccaro, GJR, Rice, TW, Golblum, J Endoscopic ultrasound cannot determine suitability for esophagectomy after aggressive chemoradiotherapy for esophageal cancer.Am J Gastroenterol1999;94,906-912. [PubMed]
 
Ajani, JA, Ilson, DH, Daugherty, K, et al Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus.J Natl Cancer Inst1994;86,1086-1091. [PubMed]
 
Lynch, TJ, Choi, N, Wright, C, et al A phase I/II trial of preoperative taxol (T), 5-fluorouracil and concurrent boost radiation (XRF) in esophageal cancer [abstract]. Proc Am Soc Clin Oncol Annu Meet. 1997;;16 ,.:261
 
Weiner, LM, Colarusso, P, Goldberg, M, et al Combined-modality therapy for esophageal cancer: phase I trial of escalating doses of paclitaxel in combination with cisplatin, 5-fluorouracil and high-dose radiation before esophagectomy.Semin Oncol1997;24(suppl),19-95
 
Meluch, AA, Hainsworth, JD, Gray, JR, et al Preoperative combined modality therapy with paclitaxel, carboplatin, prolonged infusion 5-fluorouracil and radiation therapy in localized esophageal cancer: preliminary results of a Minnie Pearl Cancer Research Network phase II trial.Cancer J Sci Am1999;5,84-91. [PubMed]
 

Tables

Table Graphic Jump Location
Table 1. Individual Prognostic Significance Related to Response*
* 

Hb = hemoglobin.

 

Indicates significant difference.

Table Graphic Jump Location
Table 2. Multivariate Analysis Related to OS* (Cox Proportional Hazard Model and Stepwise Regression)*
* 

NE = no entry into the model. See Table 1 for abbreviation not used in the text.

 

Cox proportional hazards model.

 

Stepwise regression.

§ 

Indicates significant value.

Table Graphic Jump Location
Table 3. Multivariate Analysis Related to DFS*
* 

See Table 1 for abbreviation not used in the text.

 

Cox proportional hazards model.

 

Stepwise regression.

§ 

Indicates significant value.

References

Muller, JM, Erasmi, H, Stelzner, M, et al (1990) Surgical therapy of esophageal carcinoma.Br J Surg77,845-857. [PubMed] [CrossRef]
 
Roder, JD, Busch, R, Stein, HJ, et al Ratio of invaded to removed lymph node are predictor of survival in squamous cell carcinoma of the esophagus.Br J Surg1994;81,410-413. [PubMed]
 
Smith, TJ, Ryan, LM, Douglas, HO, Jr, et al Combined chemoradiotherapy vs radiotherapy alone for early stage squamous cell carcinoma of the esophagus: a study of Eastern Cooperative Oncology Group.Int J Radiat Oncol Biol Phys1998;42,269-276. [PubMed]
 
Cooper, JS, Guo, MD, Herskovic, A, et al Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85–01): Radiation Therapy Oncology Group.JAMA1999;281,1623-1627. [PubMed]
 
Philip, PA, Ajani, JA Has combined modality therapy improved outcome of patients with carcinoma of the esophagus?Oncology1994;8,37-42. [PubMed]
 
Ajani, JA Current status of new drugs and multidisciplinary approaches in patients with carcinoma of the esophagus.Chest1998;113(suppl),112S-119S
 
Minsky, BD Nonsurgical treatment approaches for esophageal cancer.Educational book of the American Society of Clinical Oncology.,164-174 Perry MC. Denver, CO:
 
Urba, SG Multimodality therapy of esophageal carcinoma.Educational book of the American Society of Clinical Oncology.1997,175-178 Perry MC. Denver, CO:
 
Lerut, T Histopathologic validation of lymph node staging with FDG-PET scan in cancer of the esophagus and gastroesophageal junction: a prospective study based on primary surgery with extensive lymphadenectomy.Ann Surg2000;232,743-752. [PubMed]
 
Brucher, BL Neoadjuvant therapy of esophageal squamous cell carcinoma: response evaluation by positron emission tomography.Ann Surg2001;233,300-309. [PubMed]
 
Tio, TL, Cohen, P, Coene, PP, et al Endosonography and computed tomography of esophageal carcinoma: preoperative classification compared to the new (1987) TNM system.Gastroenterology1989;96,1478-1486. [PubMed]
 
Rosch, T Endosonographic staging of esophageal cancer: a review of literature results.Gastrointest Endosc Clin N Am1995;5,537-547. [PubMed]
 
Nygaard, K, Hagen, S, Hansen, HS, et al Preoperative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of preoperative radiotherapy and chemotherapy; the second Scandinavian trial in esophageal cancer.World J Surg1992;16,1104-1110. [PubMed]
 
Le Prise, E, Etienne, PL, Meunier, B, et al A randomized study of chemotherapy, radiation therapy and surgery vs surgery for localized squamous cell carcinoma of the esophagus.Cancer1994;73,1779-1784. [PubMed]
 
Walsh, TN, Noonan, N, Hollywood, D, et al A comparison of multimedial theraphy and surgery for esophageal adenocarcinoma.N Engl J Med1996;335,462-467. [PubMed]
 
Bosset, JF, Gignoux, M, Triboulet, JP, et al Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus.N Engl J Med1997;337,161-167. [PubMed]
 
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