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Ann Thorac Surg 2002;74:227-231
© 2002 The Society of Thoracic Surgeons

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Original article: general thoracic

Postesophagectomy morbidity, mortality, and length of hospital stay after preoperative chemoradiation therapy

^a Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
^b Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

* Address reprint requests to Dr Heitmiller, 3333 N Calvert St, Johnston Professional Building, Ste 610, Union Memorial Hospital, Baltimore, MD 21218-2895 USA
e-mail: richardhe{at}helix.org

Presented at the Forty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 8–10, 2001.

	Abstract

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Background. Data suggest that preoperative chemoradiation improves survival in patients with stage II and III esophageal tumors. Whether preoperative therapy increases postesophagectomy morbidity and mortality has not been determined. This study evaluates our postoperative results after chemoradiation therapy.

Methods. From 1989 through 1998, 120 consecutive patients underwent chemoradiation therapy followed by esophagectomy at our institution. The medical records for these patients were reviewed to determine patient age, sex, race, cell type, operative technique, complications, deaths, and length of hospital stay (LOS).

Results. There were 106 (88%) men and 14 (12%) women with a mean age of 58 (32 to 77) years. White patients predominated (114 of 120, 95%); 98 (82%) had adenocarcinoma and 22 (18%) had squamous cell carcinoma. Operative technique was transhiatal in 91 (76%) patients, three-incision in 23 (19%), Ivor-Lewis in 4 (3%), and thoracoabdominal in 2 (2%). There was 1 death. Complications developed in 44 (37%) patients; 59% (13 of 22) of squamous cell carcinoma patients and 32% (31 of 98) of adenocarcinoma patients developed complications. Respiratory complications occurred in 32% (7 of 22) of squamous cell carcinoma patients and in 3% (3 of 98) of adenocarcinoma patients. Mean length of stay after surgery was 15 days (range 7 to 163).

Conclusions. Postesophagectomy results after chemoradiation therapy are comparable to those reported after esophagectomy alone. Squamous cell carcinoma patients are nearly twice as likely to develop postoperative complications and are more likely to have respiratory complications than adenocarcinoma patients.

	Introduction

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The incidence of esophageal carcinoma continues to rise in the United States and despite aggressive surgical treatment approaches, overall 5-year survival rates at major centers in the United States remain poor [1]. The majority of patients at the time of diagnosis have locally advanced disease with either extension of the primary tumor through the esophageal wall or to regional lymph nodes. For these patients, postesophagectomy survival is associated with extremely poor cure rates.

Combination therapy treatment protocols were developed to attempt to improve postsurgical survival in patients with locally advanced disease. Of these, protocols that use chemoradiation followed by surgery seem to hold the greatest promise of improved survival. These treatment plans aim to increase local tumor control and reduce the incidence of distant treatment failure after surgery. Early reports using preoperative chemoradiation followed by surgery have been encouraging with one prospective, single-center series demonstrating significantly improved survival using combination therapy compared with surgery alone [2–5]. Local disease control has been excellent in all of these series and modifications in treatment administration have reduced the toxicity of the preoperative treatment, thereby allowing the majority of patients to complete a full course of chemoradiation before surgery.

Little is known, however, about the effect of preoperative chemoradiation on immediate outcomes after esophagectomy. Earlier small series of patients undergoing various chemoradiation treatment protocols before esophagectomy have reported mortality rates of 2% to 18% and morbidity rates of 15% to 57% [6–9]. The frequency of specific postoperative complications in these series and their potential relationship to the preoperative therapy have not been well described. Similarly the effect of preoperative chemoradiation therapy on postoperative length of hospitalization has not been documented. The purpose of this study was to evaluate postesophagectomy morbidity, mortality, and length of hospitalization after preoperative chemoradiation therapy.

	Material and methods

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Patient population
A total of 120 consecutive patients treated in phase II chemoradiation trials conducted at the Johns Hopkins Medical Institutions from 1989 through 1998 were studied prospectively. The specific criteria and treatment details for each phase II trial have been previously reported [4, 10–11]. Criteria for eligibility in these trials included newly diagnosed and histologically confirmed squamous cell carcinoma or adenocarcinoma; no prior treatment; disease limited to the esophagus and regional lymph nodes that could be encompassed in a single radiation therapy field, patient a surgical candidate, Karnofsky performance status greater than or equal to 60%, white blood cell and platelet counts of more than 3,500 and 100,000, respectively; creatinine clearance of more than 50 mL/minutes; and pretreatment tumor stage 2 or 3. The treatment protocols were approved by the committee for human research at the Johns Hopkins Medical Institutions.

Preoperative chemoradiation therapy
Preoperative treatment varied slightly according to the current phase II protocol under implementation but in general consisted of a 30-day period of chemotherapy and radiation followed by esophagectomy (Fig 1). Chemotherapeutic regimens included an induction dose of cisplatin (20 to 26 mg/m² per day) administered by continuous intravenous infusion during the first 5 days and during the last 5 days of therapy. 5-Fluorouracil (225 to 300 mg/m² per day) was also administered by continuous intravenous infusion throughout the duration of the chemotherapy period. Radiation was administered in daily fractions of 2 Gy using a three- or four-field technique for a total dose of 40 to 46 Gy.

View larger version (51K): [in this window] [in a new window]   Fig 1. Sample chemoradiation protocol: cisplatin 20 mg/m2 per day continuous intravenously for days 1 to 5 and days 26 to 30; 5-fluorouracil 225 mg/m2 per day continuous intravenously for days 1 to 30; radiation 200 cGy per day for a total dose of 4,000 to 4,600 cGy.

Operative technique
The principles of surgery were to completely remove the tumor and the regional lymph nodes (one-field lymphatic dissection) and to reconstruct the esophagus with mobilized stomach whenever possible. The specific surgical approach was left to the discretion of the surgeon. Transhiatal, three-incision, Ivor-Lewis, and left thoracoabdominal esophagectomy techniques were employed using standard techniques. A hand-sewn, two layered anastomosis was performed. The preferred surgical technique was transhiatal esophagectomy or three-incision esophagectomy with a cervical esophagogastric anastomosis.

Postoperative care was standardized using a patient care pathway approach that was identical to that used for patients who did not receive preoperative treatment. The most salient features of our postesophagectomy care include airway protection against aspiration by keeping patients intubated for the first postoperative night, video esophagograms before resuming oral feeding, and a graduated postesophagectomy diet. An adjuvant jejunostomy tube was placed if it was not placed earlier at prechemoradiation staging laparoscopy. Low-rate jejunostomy tube feeding was used before oral feeding. The jejunostomy tube was removed before discharge if the patient was eating without obstruction or aspiration. The projected discharge date for patients using this pathway approach has slowly be reduced over the period of this study. Currently the projected posteroperative length of stay is 7 to 8 days.

Data collection and analysis
The medical records for these patients were reviewed to determine patient age, sex, race, cancer cell type, operative technique, need for packed red blood cell transfusion, complications, deaths, postoperative length of hospital stay (LOS), and whether the jejunostomy tube was needed after discharge. Postoperative deaths were defined as any death within 30 days of surgery or during the initial hospitalization regardless of length of stay. Outcomes were evaluated by individual cell type and for the entire study population. Mean LOS results were determined for the entire group of patients and for those patients whose LOS did not exceed 14 days.

	Results

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Patient characteristics
From 1989 to 1998, 120 consecutive patients underwent chemoradiation followed by esophagectomy at the Johns Hopkins Medical Institutions. Preoperative demographic data are summarized in Table 1. The majority of patients were white males with adenocarcinoma. Mean age of the patient population was 58 years. Most patients underwent transhiatal esophagectomy (91 of 120, 76%) or three-incision esophagectomy (23 of 120, 19%). A minority of patients underwent Ivor-Lewis (4 of 120, 3%) or thoracoabdominal (2 of 120, 2%) esophagectomy.

Forty-four (36.7%) patients developed a complication during the postoperative period. Morbidity data are summarized in Table 2. Arrhythmias (8 of 98, 8.2%) were more common in patients with adenocarcinoma than in patients with squamous cell carcinoma (1 of 22, 4.5%). Pleural effusion, pneumonia, and respiratory insufficiency were 10-fold more common in patients with squamous cell carcinoma (7 of 22, 31.8%) than patients with adenocarcinoma (3 of 98, 3.1%). A cervical anastomotic leak occurred in only 1 (0.8%) patient. Although abdominal wound infections were more common in patients with adenocarcinoma (8 of 98, 8.2%) than in patients with squamous cell carcinoma (0%), overall wound complications were similar (adenocarcinoma 11 of 98, 11.2%; squamous cell carcinoma 2 of 22, 9.1%). Overall complications occurred nearly twice as frequently in patients with squamous cell carcinoma (13 of 22, 59.1%) as in patients with adenocarcinoma (31 of 98, 31.6%).

	Comment

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Some authors have postulated that preoperative chemoradiation could potentially increase the morbidity and mortality of subsequent esophagectomy because of chemoradiation-induced leukopenia, anorexia, and weight loss. Published data at the time of this report have been inconclusive however, with some authors reporting increased morbidity and mortality with various preoperative modalities and others reporting no difference [2–9, 12–14]. In addition, the number of patients in these studies have been small. Our experience was that patients who received preoperative chemoradiation did just as well after esophagectomy as those who received no preoperative therapy. Only 3 patients failed to complete chemoradiation or esophagectomy or both. One patient committed suicide before surgery, 1 patient declined surgery after repeat endoscopy demonstrated complete response to chemotherapy, and 1 patient was found to have evidence of metastatic disease, signifying progression of disease on chemotherapy. Previously published data from our institution in patients undergoing esophagectomy without preoperative chemoradiation showed an overall mortality rate of 2.7% [15]. Our postesophagectomy care plan is the same for both sets of patients.

The 10 largest series reported to date for surgical resection as sole therapy for esophageal carcinoma comprise a cohort of nearly 3,000 patients from respected centers in the United States, Europe, and Asia [16–25]. Mortality in these series ranged from 2.2% to 9.0% and morbidity ranged from 22% to 74%. Length of stay after surgery was infrequently reported but ranged from 13 to 25 days. The data reported here from the current series compares favorably with these large series. Our operative mortality was low at 0.8% and overall complication rate was comparable at 36.7%. Overall postoperative length of stay after surgery in our series was 15 days.

Additionally, the nature and incidence of morbidity in our series of patients was similar to that previously reported for isolated esophagectomy. Specifically, rates of cardiac, pulmonary, wound, and anastomotic complications in our series were 9.2%, 8.3%, 10.8%, and 0.8%, respectively. Review of data from a meta-analysis performed by Hulscher and colleagues [26] of the last 10 years of published articles on isolated esophagectomy for esophageal cancer shows rates of cardiac, pulmonary, wound, and anastomotic complications of 11.7%, 15.5%, 10.7%, and 5.8%, respectively.

There have been eight smaller series over the last 10 years reporting outcomes for esophagectomy after preoperative radiation, chemotherapy, or both modalities [2, 5–8, 12–14]. Mortality from these series ranged from 2.1% to17.9% and complication rates ranged from 14.9% to 56.1%. Length of stay from these reports ranged from 12 to 27 days. Table 4 summarizes the data from all of these series and compares our results with these overall reported results.

The subset of patients with squamous cell carcinoma had a much higher incidence of pleural effusion, pneumonia, and respiratory insufficiency with an overall incidence of complications twice that of patients with adenocarcinoma. The cause of this is unknown but it can be postulated that many of these patients had extensive alcohol and tobacco use, and the operative approach requiring thoracotomy for tumors that are in the midportion of the esophagus can also impair postoperative pulmonary recovery. The number of patients (n = 22) with squamous cell carcinoma in the series is unfortunately too small to allow for meaningful statistical analysis of this subset.

In conclusion mortality, morbidity, and length of stay for patients in this series undergoing preoperative chemoradiation followed by esophagectomy were comparable with results reported after esophagectomy alone. Squamous cell carcinoma patients were nearly twice as likely to develop postoperative complications and were more likely to have respiratory complications than adenocarcinoma patients. The potential beneficial role of preoperative chemoradiation in long-term survival after esophagectomy has yet to be confirmed but should be investigated by multicenter, prospective, randomized trials.

	Discussion

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DR CAROLYN E. REED (Charleston, SC): Obviously one of the questions is why this difference between squamous cell and adenocarcinoma. Is it perhaps because these patients were heavy smokers, heavy drinkers, those factors that usually are present with squamous cell that are not uniformly present with adenocarcinoma? Did you look at that and can you tell us whether this group of patients was different and how they were different from the adenocarcinoma group? You really would not suspect that they would have different types of complications since they all got the same operation.

DR DOTY: Thank you for your question. We did not look at those data given the small number of patients we had with squamous cell carcinoma. Your suggestions may well be correct but we did not look at that.

DR JOHN R. ROBERTS (Nashville, TN): I enjoyed your presentation very much and I would like to congratulate you on your results. I had three specific questions. One, your reported mortality: was that 30-day mortality or hospital mortality? And then two other questions that perhaps relate to the squamous cell cancer question that Dr Reed was raising: did you look at either preoperative pulmonary function testing or at the fraction of patients who required a thoracotomy, since the squamous cancers are more likely to require thoracotomy than the adenocarcinomas?

DR DOTY: Thank you for your question. Mortality for this series of patients was operative mortality, meaning any patient death within 30 days of operation or without leaving the hospital.

DR ROBERTS: Do you have hospital mortality?

DR DOTY: There was a single death—one patient died 183 days after surgery in the intensive care unit. We did not for the purpose of this paper evaluate the impact of pulmonary function tests or operative approach of thoracotomy for patients with squamous cell carcinoma.

DR TODD L. DEMMY (Columbia, MO): What is your protocol for oral hygiene? This may be an important but underappreciated point in esophageal surgery. We have an oral surgeon see all our patients. Perhaps your squamous cell patients have worse oral hygiene and therefore aspirate saliva contaminated by periodontal disease.

DR DOTY: We currently do not have an established protocol for oral hygiene. We simply rely on our videoesophagography results.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): John R. Doty Jorge D. Salazar Richard F. Heitmiller Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Doty, J. R. Articles by Heitmiller, R. F. Search for Related Content PubMed PubMed Citation Articles by Doty, J. R. Articles by Heitmiller, R. F. Related Collections Esophagus - cancer