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Ann Thorac Surg 2003;75:331-336
© 2003 The Society of Thoracic Surgeons

Original article: general thoracic

Value of radiotherapy after radical surgery for esophageal carcinoma: a report of 495 patients

Ze Fen Xiao, MDa*, Zong Yi Yang, MDa,* , Jun Liang, MDa, Yan Jun Miao, MDa, Mei Wang, MDa, Wei Bo Yin, MDa, Xian Zhi Gu, MDa, De Chao Zhang, MDb, Ru Gang Zhang, MDb, Liang Jun Wang, MDb

a Department of Radiation Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
b Department of Thoracic Surgical Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China

Accepted for publication September 9, 2002.

* Address reprint requests to Dr Xiao, Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Chao Yang District, PO Box 2258, Beijing 100021, China
e-mail: xiaozf{at}263.net


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and methods
 Results
 Coment
 Acknowledgments
 References
 
BACKGROUND: Despite three decades of debate, no conclusion has been reached concerning the effectiveness of postoperative radiotherapy for resected esophageal carcinoma. From 1986 through 1997, a prospective randomized study was carried out with 495 patients in an attempt to define the value of this therapeutic modality.

METHODS: A total of 495 patients with esophageal cancer who had undergone radical resection were randomized by the envelope method into a surgery-alone group (S) of 275 patients and a surgery plus radiotherapy group (S + R) of 220 patients. Radiation treatment was started 3 to 4 weeks after the operation. The portals encompassed the entire mediastinum and bilateral supraclavicular areas. A midplane dose of 50 to 60 Gy in 25 to 30 fractions was delivered over 5 to 6 weeks.

RESULTS: The overall 5-year survival rate was 31.7% for the S group and 41.3% (p = 0.4474) for the S + R group. The 5-year survival rates of patients who were lymph node positive were 14.7% and 29.2% (p = 0.0698), respectively. Five-year survival rates of stage III patients were 13.1% and 35.1% (p = 0.0027), respectively.

CONCLUSIONS: Postoperative prophylactic radiotherapy improved the 5-year survival rate in esophageal cancer patients with positive lymph node metastases and in patients with stage III disease compared with similar patients who did not receive radiation therapy. These results were almost significant for patients with positive lymph node metastases and highly significant for patients with stage III disease.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and methods
 Results
 Coment
 Acknowledgments
 References
 
Despite 30 years of debate, the effect of postoperative radiotherapy on patients with radically resected esophageal cancer has been unknown. This lack of consensus was related to a scarcity of reports and insufficient numbers of patients studied. Further, it was unknown which patients, if any, would benefit from such treatment, as was how to apply radiation treatment to achieve a beneficial response. To answer these questions, we developed a prospective randomized study of 495 patients within the Departments of Radiation Oncology and Thoracic Surgical Oncology from September 1986 through December 1997.


   Material and methods
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
Results
 Coment
 Acknowledgments
 References
 
From September 1986 through December 1997, 495 patients with esophageal carcinoma who had undergone radical resection were divided into two groups: a surgery-alone group (S) of 275 patients and a surgery plus radiotherapy group (S + R) of 220 patients. Randomization was carried out weekly at a joint conference of physicians in the Departments of Thoracic Surgical Oncology, Radiation Oncology, Imaging, Pathology, andMedical Oncology. All patients with esophageal cancer who had undergone radical resection were presented. Patients meeting the following four criteria were randomized through the envelope method: (1) a diagnosis of squamous cell carcinoma confirmed by pathology studies; (2) maximum age 68 years; (3) tumors at least 4.0 cm; and (4) lesions located in the thoracic segment. Clinical data of the patients are shown in Table 1. Aside from a higher frequency of lymph node metastases (p = 0.001) and male patients (p = 0.019), the remaining data in the S and S + R groups were comparable. Fifty-four patients were subsequently excluded from the S+R group because of low dosage (< 40 Gy) due to poor liver function (3 patients), postoperative diarrhea and poor health (9 patients), leukopenia (5 patients), severe radiation reaction (8 patients), and lack of participation due to social difficulties (29 patients).


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  		Table 1. Patient Demographics

 
Surgery
Patient selection, approach, and operative procedures were determined by the surgeons. A three-phase abdominothoracic McKeown resection through a right thoracotomy using the stomach for esophageal replacement was generally performed for lesions in the upper third of the thoracic segment. For lesions in the mid and lower third, esophagectomy was performed on the left side using the stomach to establish digestive continuation. In each case, lymph nodes were removed as completely as possible. Juxtatumoral, paraesophageal, superior gastric, left gastric, and paracardial lymph nodes were analyzed individually to determine a final stage classification according to the 1997 International Union Against Cancer system. A total of 8,656 lymph nodes (median 16, range 2 to 45) were dissected for pathologic stage examination using the hematoxylin–eosin method.

Postoperative radiotherapy
Radiotherapy was begun 3 to 4 weeks after the operation. The initial portal was cephalad and encompassed the bilateral supraclavicular areas with the tip of the cricoid cartilage serving as the upper border and 1.0 cm below the lower margin of the clavicles serving as the lower border. This field was extended caudad to include the entire mediastinum, the site of anastomosis, and the left epiploic and paracardiac lymphatics (T3-T12 or L1). An initial midplane dose of DT 40 Gy in 20 fractions was delivered over 4 weeks. Next, two horizontal portals (5.0 cm wide) were used to administer 20 Gy. DT 50 Gy was delivered to the supraclavicular areas. The spinal cord dose was established at DT 40 Gy in 20 fractions over 4 weeks. The total dose for the midplane was DT 60 Gy in 30 fractions over 6 weeks. The dose for the transpositioned stomach was 50 Gy in 25 fractions over 5 weeks.

Statistical methodology
Statistical analysis was performed using SPSS 10.0 software (SPSS Inc, Chicago, IL). Stage I plus stage IIa and stage IIb plus stage III patients were grouped together because of an insufficient number of patients in each batch (stage I plus stage IIa [3 + 192] and IIb plus stage III [28 + 272], respectively). Survival rates of stage IIa and stage III patients were calculated respectively using the Kaplan–Meier method and their differences examined by the log-rank test.

Follow-up of patients
Patients were instructed to return for follow-up that included clinical examination, barium swallow, chest radiography, abdominal ultrasonography, and thoracic computer tomography (CT) at 3- to 6-month intervals. If ultrasonography results of the abdomen were suspicious, abdominal CT was performed. Local failure was determined by positive pathologic diagnosis or roentgenographic evidence of mediastinal lesions revealed by CT scan. Signs or symptoms of vocal cord paralysis or tracheal compression combined with mediastinal lesions shown on CT were also considered local failures. Patients unable to return for follow-up were instructed to report to their local hospitals or clinics for examination and completion and return of study data forms. Although some of these reports were unclear, especially when the patients died, all patients were followed through the end of 1999.


   Results
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
Coment
 Acknowledgments
 References
 
Survival rates
Overall 1-, 3-, 5-, and 10-year survival rates were 79.3%, 47.1%, 39.4%, and 29.8% respectively. Five-year survival rates of stage I and IIa patients and stage IIb and III patients were 52.3% and 28%, respectively (Fig 1). This difference was significant (p = 0.0000).



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  		Fig 1. Influence of stage on survival in patients with esophageal carcinoma.

 
The 1-, 3-, and 5-year survival rates of the S and S + R groups (excluding the 54 patients excluded from the S + R group) were 79.1%, 43.5%, and 37.1% for the S group and 79.3%, 50.9%, and 41.3% for the S + R group (Fig 2). These results were not significantly different (p = 0.4474).



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  		Fig 2. Influence of treatment on survival in patients with esophageal carcinoma. (S = surgery; S + R = surgery plus radiotherapy.)

 
The 1-, 3-, and 5-year survival rates of the S and S + R groups with negative lymph nodes were 86.7%, 54.9%, and 51.0% in the S group and 88.3%, 64.8%, and 52.8% in the S + R group, respectively (Fig 3). These results were not significantly different (p = 0.9511). The corresponding survival rates of the S and S + R groups with positive lymph nodes were 69.7%, 24.7%, and 14.7% in the S group and 72.3%, 38.2%, and 29.2% in the S + R group (Fig 4). These differences nearly reached statistical significance (p = 0.0698).



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  		Fig 3. Influence of treatment on survival in patients with negative lymph nodes. (S = surgery; S + R = surgery plus radiotherapy.)

 


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  		Fig 4. Influence of treatment on survival in patients with positive lymph nodes. (S = surgery; S + R = surgery plus radiotherapy.)

 
In patients with stage IIa lesions, the 1-, 3-, and 5-year survival rates were 88.2%, 56.0%, and 51.3% in the S group and 88.6%, 64.0%, and 50.3% in the S + R group. This difference was not significant (p = 0.6344). In patients with stage III lesions, the 1-, 3-, and 5-year survival rates were 67.5%, 23.3%, and 13.1% in the S group and 75.5%, 43.2%, and 35.1% in the S + R group (Fig 5). These results were highly significant (p = 0.0027).



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  		Fig 5. Influence of treatment on survival in stage III patients. (S = surgery; S + R = surgery plus radiotherapy.)

 
The 1-, 3-, and 5-year survival rates of the 54 patients excluded from the S + R group were 77.7%, 44.4%, and 29.2%. These patients did not finish the original protocol. Their survival rates are slightly less than either the S group or the S + R group.

Multivariate analysis shows that the status of lymph node metastases and method of treatment were closely related to the final outcome (p = 0.013, 0.040).

Site of failure
The unspecified death of 61 patients left 434 patients for a study of site and cause of failure. Treatment failure occurred in 8.8% (38/434) of patients because of metastases to the supraclavicular and middle and lower neck regions (Table 2). A total of 13.2% (32/243) of these patients were from the S group and only 3.1% (6/191) were from the S + R group (p = 0.000). These findings clearly show that postoperative radiotherapy reduced the incidence of recurrence in the supraclavicular and neck regions. It is also apparent that postoperative radiotherapy reduced the incidence of recurrence in the chest and at the anastomosis (p < 0.05), but not in the abdomen or through the blood (p > 0.05).


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  		Table 2. Cause of Failure as Related to Treatment

 
Complications
The frequency of anastomotic stenosis in all patients in this study was 2.8% (14/494): 1.8% (5/275) in the S group and 4.0% (9/220) in the S + R group. This difference was not statistically significant. Early untoward reactions related to radiation treatment were observed at the rates of 33.2% (73/220) for nausea and anorexia and 7.3% (16/220) for leukopenia. Late complications included radiation lung injury (fibrosis) at a rate of 2.3% (5/220) and noncancerous pericardial effusion or pleural effusion at a rate of 3.2% (7/220). Multiple thoracentesis and cytologic examination for cancer cells consistently produced negative results in these 7 patients. Because they survived at length despite the effusion, the fluid was assumed to be innocent. Gastrointestinal (GI) bleeding occurred in 2 patients (2/220) in the S+R group. Although study results on these 2 patients were negative, subsequent communications indicated that their eventual deaths were the result of GI tract bleeding.


   Coment
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Coment
Acknowledgments
 References
 
Preoperative irradiation therapy is an accepted modality in the treatment of esophageal cancer. The therapy is thought to improve resection rates, increase survival rates, and decrease lymph node metastases [1–3]. In contrast, our series of patients who underwent surgery plus postoperative radiotherapy had an overall 5-year survival rate (39.4%) that was higher than the 5-year survival rates in two other studies (23% and 29.6%) [4, 5]. Our results are similar to those of three other studies (38.3%, 34.7%, and 35.8%) [6–8], but the results achieved in the different stages differ appreciably. Our 5-year survival rate for stages I and IIa (51.3%) was higher than the 28% survival rate for stages IIb and III. Hence, the stage distribution is an important prognostic factor. The presence of lymph node metastases also changes the prognosis. The 5-year survival rate of the S + R group (29.2%) was considerably higher than the 14.7% survival rate of the S group (p = 0.0698). The lack of statistical significance is probably related to the limited number of patients. The benefit of postoperative radiotherapy is clear in stage III (T4 N0 to 1 or T3 N1) patients. The 5-year survival rate of the S + R group was 35.1%, which was much higher than the 13.1% survival rate of the S group (p = 0.0027). Based on these results, we believe that patients found to have stage III disease during operation should be treated with postoperative radiotherapy.

We do not recommend radiation therapy for patients with stage IIa and negative lymph nodes because their 1- and 5-year survival rates show no benefit from this treatment and the 3-year survival rate increases only minimally (7% to 10%). We believe there is no reason to treat patients after radical resection of thoracic esophageal carcinoma with radiotherapy unless they have stage III lesions or positive lymph nodes.

In 1987, Huang and associates [5] reported that 77.4% of resected patients died either from recurrence or metastasis within 2 years of operation, and 40% of those surviving for more than 5 years eventually succumbed to esophageal cancer. Detailed analyses disclosed that the chief causes of death were lymphatic or hematogenous spread. In our study, the frequency of intrathoracic lymphatic failure of the S + R group was 16.2%, which was significantly lower than the 25% rate in the S group (p = 0.0015). Additionally, the frequency of anastomotic recurrence and the supraclavicular, lower, and middle neck lymphatic metastases were 0.5% and 3.1% compared with 5.8% and 13.2%, respectively (p < 0.05). These results demonstrate the effectiveness of postoperative prophylactic radiotherapy in lowering the local recurrence within the range of radiation portals. We were unable to reduce the occurrence of intraabdominal metastasis, possibly because we failed to include the relapse site in the field of irradiation. Why the hematogenous metastasis in the S + R group (23.6%) was slightly higher, but without statistical significance, than the S group (18.1%) is unknown. However, we suspect the reason is related to the higher incidence of lymph node metastasis (58.6%) in the S + R group than that (48%) in the S group (p = 0.015) (Table 1). No other evidence of reduced immunoactivity by the radiotherapy is apparent [9, 10].

Postoperative radiotherapy at our dose level does not increase the frequency of anastomotic stenosis (4.0% versus 1.8%), an insignificant difference. One third of the S + R patients experienced nausea and anorexia during the course of radiation. About 7% of them developed transient leukopenia, which normalized with conservative management and which did not interfere with the planned treatment. As most of our patients were operated upon with a left posterolateral approach, the radiation portal included part of the transpositioned stomach and, in some cases, the entire stomach. In cases involving part of the transpositioned stomach, the dose to the stomach was allowed to reach 60 Gy by fractions of 10 Gy per week and, with the entire stomach, the dose was limited to 50 Gy over 5 weeks. No serious reactions, either immediate or remote, were observed in the transpositioned stomach. In 1993, Fok and associates [11] reported the incidence of fatal hemorrhage from gastric ulcer secondary to radiotherapy. We believe this death rate might have been due to the delivery of too large a fractional dose (350 cGy per fraction). In our series, about 3% of the patients developed postradiational lung fibrosis, which was silent and did not produce symptoms in most patients. The fibrosis was discovered most frequently by CT and, at times, accompanied pericardial effusion or pleural effusion. Two (0.9%) of our patients eventually died from fatal GI tract hemorrhage without any evidence of cancer relapse. Consequently, we believe that the protocol we have outlined is safe and effective.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Coment
 Acknowledgments
References
 
We thank Joe McLaughlin, MD, for his kind revision, especially of the English syntax.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and methods
 Results
 Coment
 Acknowledgments
 References
 
* Dr Yang passed away on August 4, 2000. Back


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Coment
 Acknowledgments
 References
 

  1. Zhang Z.X., Feng Q.F., Gu X.Z., et al. Evaluation of preoperative radiotherapy for esophageal carcinoma—report on 1012 patients. Chin J Radiat Oncol 1992;1:169-171.
  2. Huang G.J., Gu X.Z., Zhang R.G., et al. Experience with combined preoperative irradiation and surgery for carcinoma of the esophagus. Chinese Med J 1981;94:73-76.
  3. Mei W., Gu X.Z., Huang G.J., et al. Prospective randomized trial on preoperative radiotherapy for esophageal carcinoma. Chin J Radiat Oncol 2001;10:168-172.
  4. Orringer M.B., Marshall B., Iannettoni M.D. Transhiatal esophagectomy: clinical experience and refinements. Ann Surg 1999;230:392-403.[Medline]
  5. Huang G.J., Wang L.J., Zhang D.W. Surgery of esophageal cancer. Long-term follow-up studies. Zhonghua Wai Ke Za Zhi 1987;25:449-451.[Medline]
  6. Akiyama H., Tsurumaru M., Udagawa H., Kajiyama Y. Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg 1994;220:364-373.[Medline]
  7. Shao L.F., Li Z.C., Wang M.F. Results of surgical treatment in 6123 cases of carcinoma of the esophagus and gastric cardia. Zhonghua Wai Ke Za Zhi 1987;25:452-455.[Medline]
  8. Wang Y., Wang L., Zhang D. Characteristics of lymph node metastasis of squamous cell carcinoma of thoracic esophagus and its clinical significance. Zhonghua Zhong Liu Za Zhi 2000;22:241-243.[Medline]
  9. Teniere 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. French University Association for Surgical Research. Surg Gynecol Obstet 1991;173:123-130.[Medline]
  10. Maeta M., Koga S., Kanayama H., Murakami A., Ikeda Y., Inoue Y. Does preoperative radiation for thoracic esophageal cancer promote intramural lymphatic invasion?. Jpn J Surg 1986;16:84-89.[Medline]
  11. Fok M., Sham J.S., Choy D., Cheng S.W., Wong J. Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study. Surgery 1993;113:138-147.[Medline]



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