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J Thorac Cardiovasc Surg 2006;132:549-555
© 2006 The American Association for Thoracic Surgery

General Thoracic Surgery

Neoadjuvant chemoradiation may increase the risk of respiratory complications and sepsis after transthoracic esophagectomy

Department of Surgery, St James's Hospital and Trinity College, Dublin, Ireland.

Received for publication January 24, 2006; accepted for publication May 9, 2006.

^_* Address for reprints: John V. Reynolds, MD, Department of Clinical Surgery, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland (Email: reynoljv{at}tcd.ie).

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion Conclusions References

 
BACKGROUND: The role of neoadjuvant chemotherapy and radiation therapy before resection in esophageal cancer remains controversial. Operative risks may be increased, but this has not been systematically addressed in published trials or reports.

METHODS: This was a prospective, nonrandomized, restricted cohort design of patients (n = 200) from 1997 to 2003 with resectable cancer of the esophagus or esophagogastric junction. A total of 102 patients underwent multimodal therapy with 5-fluorouracil, cisplatin, and radiation therapy before surgery, and 98 patients opted for surgery alone. In-hospital mortality and morbidity were the primary end points, and cancer survival was a secondary end point.

RESULTS: In patient cohorts matched for operative risk factors, the odds ratio for postoperative sepsis (P = .007), respiratory failure (P = .009), and acute respiratory distress syndrome (P = .02) was increased in the multimodal group. There was no significant difference between groups comparing median and 1-, 2-, and 3-year survivals.

CONCLUSIONS: Multimodal therapy was associated with increased respiratory and septic complications compared with a surgery-only cohort undergoing the equivalent surgery. Respiratory failure was in most cases idiopathic. The data suggest that efforts should be made to limit radiation lung exposure in multimodal regimens, and to understand and modulate the local and systemic effects of preoperative chemoradiation.

	Introduction

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Dr Reynolds

Carcinoma of the esophagus and gastroesophageal junction represents aggressive disease with a poor prognosis even in patients undergoing curative resection.^1,2 Where squamous cell histology once predominated, the incidence of esophageal adenocarcinoma in the Western world has increased dramatically over the past 3 decades.^3,4 Surgical resection remains the standard of care for most esophageal surgeons, but even with en bloc resections and radical 2- or 3-field lymphadenectomy, 3-year survival rarely exceeds 40%.^5-7

The disappointing outcomes from surgery alone have resulted in considerable interest in multimodal approaches, either neoadjuvant chemotherapy alone or combined with radiation therapy.¹ However, the interpretation of randomized clinical trials to date is controversial. For chemotherapy alone, an appropriately powered randomized study (Intergroup Trial) of 440 North American patients showed no benefit from a preoperative and postoperative combination of 5-fluorouracil and cisplatin, with a 2-year survival of 35% in the combination group compared with 37% in the group treated with surgery alone.⁸ In contrast, a similar study from the United Kingdom of 802 patients reported an improved survival at 2 years (43% vs 34%) in the combined modality group.⁹ Analysis of trials of combination chemotherapy and radiation therapy before surgery,^10-16 and meta-analysis,^17,18 is also difficult for several reasons: Only 2 of 8 studies,^13,15 both negative, appear adequately powered with more than 200 patients; there is a mix of pathologic types, adenocarcinoma and squamous cell cancer, in all but 1 study;¹² the total dose of radiation therapy administered (and treatment fractions) is different across trials; and the interpretation of the 1 trial showing a benefit for multimodal therapy¹² (undertaken in patients with adenocarcinoma at this center between 1990 and 1995) is complicated by relatively small numbers, limited cross-sectional imaging in preoperative staging, and an outcome in the surgery alone arm below standard benchmarks. The most recent trial, an adequately powered Australasian study of 256 patients, 61% of whom had adenocarcinoma, failed to show a survival benefit from neoadjuvant chemoradiotherapy.¹⁶

Notwithstanding the controversy whether oncologic benefit accrues from multimodal regimens, informed decision-making requires better information on other end points, including quality of life outcomes, toxicity of neoadjuvant regimens, and operative complications. Intuitively, the administration of chemotherapy and radiation therapy before major surgery presents an added challenge, both through treatment-related immunosuppression and direct tissue toxicity from radiation. One large randomized trial¹³ was stopped because of increased postoperative mortality and morbidity in the multimodal group, and in other trials operative outcomes have not been rigorously reported. In this report, postoperative complications are reported in detail from a prospective cohort of patients undergoing multimodal therapy. A contemporaneous cohort undergoing surgery alone, but equivalent in clinical stage, risk factors, performance status, and magnitude of surgery, served as a comparison group. This article highlights the apparent added risks of multimodal therapy, in particular that of idiopathic respiratory failure.

	Patients and Methods

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Eligibility Criteria
The inclusion criteria for multimodal therapy of esophageal adenocarcinoma or squamous cell cancer approved by the institutional review board at this center is as follows:¹² age less than 77 years; satisfactory performance status and medical fitness for surgery, including subjective evaluation by the surgeon, American Society of Anesthesiologists score (1 or 2), Karnofsky index (>90%), and respiratory physiology (forced expiratory volume in 1 second at minimum of 1.5 L); leukocyte count greater than 3500/mm³, platelet count greater than 100,000/mm³, serum creatinine less than 124 µmol/L; and no previous chemotherapy or radiation therapy. Patients receiving this treatment regimen were compared with patients treated with surgery alone who also fulfilled these same criteria. Patients with any one of the following were excluded from this analysis: age more than 77 years; high-grade dysplasia or carcinoma in situ; emergency esophagectomy after esophageal rupture; surgery determined preoperatively to be palliative based on tumor extent or patient performance; evidence of bronchial invasion based on computed tomography (CT) imaging and bronchoscopy; tumor classified as T₄, N_any by the multidisciplinary esophageal panel; and resections not involving a thoracotomy, including transhiatal resections and total gastrectomy.

All patients underwent clinical examination, esophagoscopy, and computerized tomography of the neck, thorax, and abdomen. Endoscopic ultrasound was not routinely used because its access is limited at this center. 18F-deoxyglucose positron emission tomography scans are now routine, but became available only in mid-2003. With CT criteria, the mediastinal and left gastric nodes were classified as N1 (invaded) if the maximal transverse diameter of these nodes was larger than 1 cm. Resectable disease was defined as T_1-3, N_0-1. All tumors at the esophagogastric junction were assigned as Type I, II, or III, per Siewert and Stein:¹⁷ Type I is adenocarcinoma of the distal esophagus, usually arising in specialized intestinal metaplasia; Type II is a true adenocarcinoma of the cardia arising immediately at the esophagogastric junction; and Type III is a subcardial gastric carcinoma infiltrating the esophagogastric junction and distal esophagus from below. Patients with Type II and III junctional tumors underwent a staging laparoscopy as part of their workup.

All patients since 1997 with localized disease (T_2-3, N_0-1; predicted R0 resection) of the esophagus or junction (Type I and II) were offered the option of either surgery alone or the multimodal regimen; patients with Type III esophagogastric junction tumors had surgery alone. Patients if medically fit with locally advanced unresectable disease were treated with radical radiation therapy and chemotherapy and no consideration of surgery.

Neoadjuvant Therapy
The majority of patients (n = 49) in the neoadjuvant treatment arm were given a standard protocol of chemoradiotherapy consisting of 40 Gy/15 fractions on days 1 to 5, 8 to 12, and 15 to 19, and concurrent chemotherapy of 5-fluorouracil (15 mg/kg) on days 1 to 5 and cisplatin (75 mg/m²) on day 7.¹² Chemotherapy was repeated on week 6. Since 2002 an increasing number of patients (n = 41) have been given 44 Gy in 22 fractions. Three patients in this analysis were referred from another institution where they had received 50 Gy in 25 fractions. In the remaining patients, 8 received 40 Gy in 20 fractions, and 1 received 45 Gy in 25 fractions. Patients were restaged by CT and esophagoscopy at week 8 and scheduled for surgery at week 9. Surgery took place if the neutrophil count was greater than 2 x 10⁶/mL^-1, the performance status had not significantly deteriorated, and there was no evidence of local or systemic progression of disease on imaging.

Surgical Procedure
All patients underwent a thoracotomy as a component of their surgical management, either combined with an abdominal and neck exploration (3-stage) for mid and upper-esophageal cancers, or cancer arising in long-segment Barrett's esophagus, or with an abdominal exploration (2-stage) for most lower third and junctional tumors, or combined with a total gastrectomy for junctional tumors with significant gastric extension (Type III). A 2-field lymphadenectomy (abdominal and thoracic) was performed in all cases. All patients were extubated immediately after surgery and managed in a high-dependency unit. All patients with a gastric remnant underwent a pyloroplasty, and patients were fed enterally from 12 hours postoperatively through a needle catheter jejunostomy. A Gastrografin contrast study was routinely performed on postoperative day (POD) 7 or 8 before initiating oral fluids.

Postoperative Complications
All complications from surgery to discharge from hospital were prospectively documented. Respiratory failure was defined as the requirement for mechanical ventilation beyond 24 hours after surgery. Acute respiratory distress syndrome (ARDS) and multiple organ failure were defined as per Bone and colleagues,¹⁸ sepsis required evidence of systemic inflammatory response syndrome with microbiologic evidence of infection, and the diagnosis of pneumonia required positive sputum cultures or clear clinical and radiographic evidence of consolidation.

Statistical Analysis
Statistical analysis was performed using STATA statistical package, version 8.2 for Windows (StataCorp, College Station, Tex). Quantitative data are expressed as median and 95% confidence intervals. Qualitative data are described as percentages. Postoperative complications were compared using the Mann Whitney U test. Univariate and multivariate logistic regression models were used to identify the odds ratio of postoperative morbidity and mortality. Operative mortality was defined as any death within the hospital after surgery. Actuarial survival was calculated from the date of first treatment by the Kaplan-Meier method, and comparisons between the groups were made by the log-rank test.

	Results

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Patient Demographics
In this period, resection with curative intent (anticipated R0) was undertaken in 200 patients. The patients in each group are shown in Table 1, with 102 in the multimodal group and 98 in the surgery only group. The median age at diagnosis was 59 years in the multimodal group and 63 years in the surgery only group (P = .08). The multimodal group had significantly (P < .05) better forced expiratory volume in 1 second, but there was no difference between groups in performance status, American Society of Anesthesiologists grades, nutritional status, or comorbid disease. Adenocarcinoma was the predominant pathology, 75% in the multimodal group and 59% in the surgery group (P = .03).

Surgery was undertaken in 98 patients in the surgery only group and in 88 patients in the multimodal group. Sixteen patients (18%) achieved a complete pathologic response to neoadjuvant therapy, and 25% of patients in the multimodal group had Stage 3 disease compared with 46% in the surgery only group (P < .01 pathologic staging comparing multimodal and surgery only group).

In-Hospital Complications
In-hospital morbidity and mortality are shown in Table 2. Six patients died (7%) in the multimodal group, compared with 4 patients (4%) in the surgery only group (P = .3). There was a significant increase in sepsis (P = .007), respiratory failure (P = .03), and ARDS (P = .008) in the multimodal group. The odds ratio (95% confidence interval; P value) was 7.02 (1.7-29; P = .007) for sepsis, 6.9 (1.6-19; P = .009) for respiratory failure, and 13.3 (1.4-122; P = 0.02) for ARDS in the multimodal group compared with surgery alone. There was no difference in other complications, in particular pneumonia, arrhythmia, pulmonary embolus, and anastomotic leak. Comparing the multimodal with surgery only groups, there was no significant difference in the median estimated blood loss (400 vs 550 mL, respectively), median blood transfusions (0 vs 0, respectively), median days ventilated (0 vs 0, respectively), and length of stay in the high-dependency unit or intensive care unit (3 vs 3, respectively).

For adenocarcinoma alone, the median survival was 27 months in both groups (Figure 1). The 1, 2, and 3-year survivals in the multimodal group were 74%, 57%, and 34%, respectively, compared with 74%, 55%, and 43%, respectively, in the surgery alone group. For R0 resections alone, the 1, 2, and 3-year survivals in the multimodal group were 80%, 63%, and 42%, respectively, compared with 73%, 61%, and 42%, respectively, in the surgery only group (P = .5).

View larger version (28K): [in this window] [in a new window]   Figure 1. Survival estimates: adenocarcinoma only.

	Discussion

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This report represents the experience of a unit with a high-volume surgeon and support team, with approximately 40 esophageal resections per year, in a tertiary cancer center with a long tradition of managing patients with esophageal and thoracic malignancy. The groups compared are not randomized but are contemporaneous and equal in fulfilling strict criteria for surgery, including absence of T4 or M1 disease on CT imaging, and adequate performance status. The type and magnitude of surgery, with a thoracotomy in all patients, are similar in both groups, as was the metabolic and immuno-inflammatory response reflected by albumin, glucose, and C-reactive levels in the postoperative period (data not shown). The in-hospital mortality rate was 7% in the multimodal group compared with 4% in patients treated with surgery alone. Although this increase in mortality was not significant, a highly significant increase in ARDS, respiratory failure, and sepsis was observed, and the respiratory complications were directly related to death in all patients in the multimodal group. Inexplicably, no precipitating factor was identified in 4 cases; in particular, there was no evidence of pneumonia, anastomotic leak, or gastric ischemia. Moreover, 3 of 16 patients (19%) who had a complete pathologic response to preoperative therapy died of respiratory failure; this response was idiopathic in 2 cases and related to mediastinal sepsis in 1 case, perhaps suggesting a link between the tumor response and an exaggerated normal tissue response.

This added operative risk of multimodal therapy has received little direct attention in the literature. In the Veterans Affairs study, Bailey and colleagues²² reported that neoadjuvant therapy was independently associated with perioperative mortality. In a recent meta-analysis of randomized controlled trials, Fiorica and colleagues²⁶ reported increased postoperative mortality, from 22 of 355 patients (6%) treated with surgery alone to 39 of 328 patients (12%) treated with multimodal therapy (odds ratio 2.1, confidence interval 1.18-3.7, P = .001). In a study of patients with only adenocarcinoma, Walsh and associates¹² found an increase in perioperative mortality (10.7% vs 3.7%) in the multimodal group, and Nygard and colleagues¹⁰ observed a 1.8-fold (24% vs 13%) increase in the multimodal group. The short-term postoperative risk of multimodal therapy was highlighted in the multicenter, randomized, controlled trial performed by Bosset and coworkers¹³ in France. In an adequately powered study of 297 patients with esophageal squamous cell cancer, this group reported that 17 of 138 patients with multimodal therapy died after surgery, compared with 5 of 137 patients in the surgery only group, and this difference was the result of respiratory failure and mediastinal infection. This study was criticized for larger fractions of radiation, with a fractional dose of 3.7 Gy compared with 1.8 to 2.67 Gy per fraction in other trials.

The best surgical outcomes in multimodal regimens was achieved in a small randomized trial performed by Urba and colleagues,¹⁴ who used a hyperfractionated regimen, with 1.67 Gy per fraction; only 1 of 47 patients died after transhiatal esophagectomy. In this study, the fractional dose administered was 2 to 2.67 Gy, and no significant pattern of difference was evident between these 2 regimens. Normal tissue radiation response is a dynamic process involving inflammatory responses, tissue repair processes, altered cell–cell communication, changes in cytokines, and radiation fibrosis.²⁷ The genetic characteristics of the host, moreover, can impact on the radiation response. It is impossible to spare the lung from preoperative treatment planning, but whether idiopathic ARDS or respiratory failure relates to priming or sensitizing of immunoinflammatory cells in the lung to the further effect of 1-lung anesthesia and the trauma of surgery, or acts through alternate mechanisms, requires further study. The role of the immunosuppressive effect of chemotherapy is unclear. Heidecke and colleagues²⁸ reported a defective proliferation of T cells in patients after chemoradiotherapy, when compared with patients undergoing esophagectomy alone. The standard requirement before surgery is for adequate neutrophil count recovery, but whether neutrophils, lymphocytes, and other cells actually function normally in the blood, lungs, and other tissues is unknown, and this is the subject of our current laboratory research.

This study was not randomized, and potential biases may exist. Nonetheless, this should not apply to the primary end point, that is, postoperative complications. The operative insult was similar in both groups, and all patients underwent a thoracotomy and 1-lung anesthesia as components of their surgery. The patients in the multimodal group were younger, had significantly superior preoperative pulmonary function test results, and had a lower pathologic stage compared with the surgery only group, suggesting strongly that the negative impact of the only variable, chemoradiation, is a true effect.

The study was an observational study with a restricted cohort design, and this adapts principles of the randomized, controlled trial design as follows:²⁹ The baseline criteria were identified for patient eligibility; inclusion and exclusion criteria were the same as in randomized trials; and statistical methods, including intention-to-treat analysis, were similar to that of randomized trials. The authors recognize that cancer outcomes in a nonrandomized comparison should be extrapolated with caution; nevertheless, in cohorts with an identical preoperative clinical stage no difference in overall outcomes was observed, or any difference where outcomes for adenocarcinoma alone were analyzed. At a minimum, these cancer outcome data support the conclusion of a recent trial¹⁶ that a randomized trial would require the enrollment of many hundreds of patients to be adequately powered.

	Conclusions

Top Abstract Introduction Patients and Methods Results Discussion Conclusions References

 
In patients matched for performance status, tumor stage, and magnitude of operative insult, this study highlights postoperative respiratory complications associated with neoadjuvant chemoradiation, as well as an increased incidence of sepsis. Patients attending this unit are informed of this risk, and we continue to offer the multimodal regimen to patients with good respiratory reserve. Efforts should be made to both minimize lung exposure to radiation and understand the immunologic consequences of chemoradiation both at the systemic level and the tissue level. Large randomized trials are required to establish Grade A evidence for multimodal approaches, and we urge rigorous prospective analysis and reporting of operative complications in trials that encompass a multimodal arm. Perhaps studies of inflammation biology modulators, including free-radical scavengers, pentoxifylline, and angiotensin-converting enzyme inhibitors, may have rationale in the design of future clinical trials that encompass mediastinal irradiation.³⁰

	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 Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reynolds, J. V. Articles by Byrne, P. Search for Related Content PubMed PubMed Citation Articles by Reynolds, J. V. Articles by Byrne, P. Related Collections Esophagus - cancer