Ann Thorac Surg 2004;78:1783-1789
© 2004 The Society of Thoracic Surgeons
Original article: general thoracic
Induction Therapy Does Not Increase Surgical Morbidity After Esophagectomy for Cancer
Frank C.-F. Lin, MDa,
Amy E. Durkin, MS, PA-Ca,
Mark K. Ferguson, MDa,*
a Department of Surgery, The University of Chicago, Chicago, Illinois, USA
Accepted for publication April 27, 2004.
* Address reprint requests to Dr Ferguson, Department of Surgery, 5841 S Maryland Ave MC5035, Chicago, IL 60637, USA
mferguso{at}surgery.bsd.uchicago.edu
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Abstract
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BACKGROUND: A complete pathological response after induction therapy for esophageal cancer offers survival benefits, but induction therapy may increase the risk of postoperative complications and mortality.
METHODS: We performed a retrospective review of consecutive patients who underwent esophagectomy for esophageal cancer to identify preoperative predictors of complications and assess the possible influence of induction therapy on surgical outcomes.
RESULTS: Between 1988 and 2003, 170 esophagectomies were performed on our service; 95 (55.9%) underwent surgery alone and 75 (44.1%) received preoperative chemotherapy, 35 of whom also had preoperative radiation therapy. Based on multivariable regression analyses, independent covariates for complication categories included performance status (pulmonary, cardiovascular, total complications, and death), age (cardiovascular and other complications), and FEV1% (pulmonary complications). Whether patients received induction therapy was unrelated to the incidence of postoperative complications.
CONCLUSIONS: We found no evidence that induction therapy adversely influences the incidence of postoperative morbidity or mortality after esophagectomy for cancer.
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Introduction
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Multimodality therapy as an adjuvant to surgery for esophageal cancer has been a focus of investigation since its potential benefits were first suggested by Steiger and colleagues [1]. Most early efforts at multimodality therapy focused on providing adjuvant therapy after resection. Despite a plethora of postoperative adjuvant treatment options there is no convincing evidence that such therapy provides a survival benefit [2–4]. As a result, a growing interest has developed in induction therapy for esophageal cancer patients who are candidates for resection. Recent meta-analyses of randomized controlled trials comparing the results of induction chemotherapy or chemotherapy and radiation therapy followed by surgery with surgery alone demonstrated improved 2- and 3-year survival, reduced local-regional recurrence, and a higher rate of R0 resection [5, 6]. Advantages have been attributed to tumor downstaging, local tumor response permitting a more complete surgical ablation, and treatment of unrecognized systemic disease before the development of surgically induced immunosuppression [7–13].
Although the reports of improved outcomes with induction therapy are encouraging, the evidence for this benefit is limited, and many investigators have shown no survival benefit with induction therapy [14–16]. Despite the lack of conclusive evidence regarding the benefit of induction therapy, such therapy is being used routinely for esophageal cancer outside of any investigation setting. The potential increase in intraoperative risks and postoperative complications continues to pose a threat to surgical patients after undergoing induction chemoradiotherapy. Pulmonary complications, impaired wound healing causing anastomotic leaks, and surgical difficulties related to inflammation may all increase postoperative morbidity and mortality [17–19].
Few reports have looked specifically into the surgical risks and postoperative complications associated with induction therapy. Thus we performed a retrospective review to study the influence of induction therapy on postoperative complications and mortality.
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Material and Methods
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We performed a retrospective review of consecutive patients who underwent esophagectomy for esophageal cancer on the Thoracic Surgery Service at The University of Chicago Medical Center from January 1988 to December 2002. Approval for this study was granted by our institutional review board. Patients were grouped according to treatment: surgery alone, preoperative cisplatin-based chemotherapy alone, or combined treatment with radiotherapy and chemotherapy. Preoperative, operative, and postoperative data were obtained from chart reviews for patients undergoing operation during 1988 and 1989, and from a prospective database that was initiated in 1990 for the remaining patients. Demographic and laboratory values were collected from the preoperative evaluation. The incisions used to perform the operation (grouped as transthoracic or transhiatal resections) and the organ and route used for reconstruction were noted. Postoperative complications were categorized as pulmonary, cardiovascular, infectious, surgical, other complications, any complication, and death. Pulmonary complications included pneumonia, the need for reintubation for isolated respiratory insufficiency postoperatively, the need for ventilator support for more than 24 hours postoperatively, lobar collapse, and pleural effusion. Cardiovascular complications included pulmonary embolism, arrhythmia, myocardial infarction, and the need for inotropic support to maintain blood pressure and perfusion (excluding the use of dopamine at doses less than 5 mg · kg–1 · min–1). Infectious complications included empyema (unrelated to anastomotic leak), wound infection, and intraabdominal abscess. Surgical complications included chylothorax, recurrent laryngeal nerve injury, anastomotic leak, and necrosis of the reconstructive organ. Death was defined as mortality during hospitalization for esophagectomy or within 30 days of esophagectomy. Intraoperative blood loss and transfusion, postoperative hospital stay, and the time period of ventilator use were also recorded.
Continuous data were analyzed with unpaired Student's t test and categorical data were analyzed with 
2 test. We performed univariate analyses to compare the types and the rates of complications between groups with and without induction therapy and to identify potential preoperative risk factors for complications. Variables deemed to be potentially important (p < 0.2) were entered into multivariable, backward stepwise logistic regression analyses evaluating individual complications, complication categories, and death. To assess whether chemotherapy affected the incidence of complications, that factor was added to each logistic regression analysis model. Preoperative laboratory data that were unavailable for more than 25% of patients (at least 42) were excluded from multivariable analyses.
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Results
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A total of 170 patients underwent esophagectomy for cancer during the reference period. The demographic and other preoperative characteristics are presented in Table 1. The mean age in the group (137 men and 33 women) was 61.2 years (range 30 to 83 years). When administered, induction therapy was usually recommended by community-based medical or radiation oncologists and typically consisted of cisplatin-based doublet therapy with or without 45 to 60 Gy of radiation therapy. Of these patients, 95 (55.9%) received surgery alone and 75 (44.1%) received preoperative induction therapy, including 35 (20.6%) patients who underwent both preoperative chemotherapy and radiotherapy and 40 (23.5%) patients who received preoperative chemotherapy alone. Of the 40 patients undergoing induction therapy before 1995, 31 (78%) had chemotherapy only; of the 35 patients who had induction therapy from 1995 to 2002, 26 (74%) received combined chemotherapy and radiation therapy (p < 0.001).
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Table 1. Comparison of Preoperative Data for Patients Who Received Induction Therapy Followed by Surgery or Surgery Alone
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Patients who underwent induction therapy were substantially younger, had a lower incidence of tobacco use, had a higher incidence of important dysphagia, reported more weight loss, and had lower blood counts just before their operations. Otherwise the two groups were similar. Operative data and postoperative outcomes are shown in Tables 1 through 3. More patients in the induction therapy group underwent transthoracic esophagectomy, although the difference did not reach statistical significance. No other important differences were noted in the intraoperative or postoperative outcomes between these two groups. There were significantly more patients with adenocarcinoma than with squamous cell carcinoma in the surgery-only group, a finding that was related to that group's higher incidence of Barrett's adenocarcinoma, which often was detected at an early stage. The pathologic complete response rate to induction therapy was 16% (12/75). All of the complication rates were slightly higher in the surgery-only group, although none of the differences approached statistical significance.
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Table 2. Intra- and Postoperative Data for Patients Who Received Induction Therapy Followed by Surgery or Surgery Alone
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Table 3. Postoperative Complications of Patients Who Received Induction Therapy Followed by Surgery or Surgery Alone
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We analyzed outcomes for each of the individual complications listed that comprised the complication categories, comparing the surgery-only and induction therapy groups. No clinically important or statistically significant differences were noted in individual complication rates between the groups. To determine whether radiation therapy had an effect on outcomes, we divided the induction therapy group into patients who underwent preoperative chemotherapy alone and patients who received combined preoperative radiotherapy and chemotherapy. We repeated the comparisons outlined above among these two groups and the surgery-only group (data not shown). Other than the absence of prior myocardial infarction in the chemoradiotherapy group, no additional clinically important or statistically significant differences were noted among the groups.
The results of univariate analyses identified multiple potential covariates that were used in the multivariable analyses (data not shown, but are available directly from the corresponding author). Pulmonary complication rates were higher for patients with prior myocardial infarction, poorer performance status, poorer pulmonary function (spirometry and diffusing capacity), transthoracic resection, higher white blood cell counts, or lower body mass index, and those operated on earlier in the study period. Patients with cardiovascular complications had worse performance status, more often had a smoking history, had lower spirometry values, had lower serum creatinine levels, and were older than patients without such complications. Patients with infectious complications had a higher incidence of prior myocardial infarction. No association of preoperative variables with surgical complications was noted. Patients with other complications had worse performance status and dysphagia grade, were 4 years older on average, and were operated on earlier in the study period. Total complications were related to earlier year of operation, worse performance status, worse dysphagia grade, a history of myocardial infarction, and alcohol use. Operative mortality was related to male sex, poorer performance status, a lower incidence of dysphagia, and higher white blood cell counts. The need for blood transfusion was related to most complications and death, and was statistically significant in pulmonary, cardiovascular, surgical, other complications, and death.
For the multivariable analyses we used percent forced expiratory volume in 1 second (FEV1%) to represent spirometric variables, which were all highly interrelated. We also chose dysphagia grade as a surrogate for weight loss and body mass index. Intraoperative blood loss and perioperative blood transfusion were not used in the analyses because we chose to evaluate only preoperative factors for identifying predictors of outcomes.
The results of the multivariable analyses are expressed by their odds ratios and 95% confidence intervals (Fig 1). Because of the important differences in age between the induction therapy and surgery-only groups, an interaction variable was created and the multivariable analyses were repeated for all complication categories; no evidence was noted for interaction between these variables. Evidence was found for an interaction between the year of operation variable and performance status, type of operation, and a history of prior myocardial infarction. Analyses were repeated for relevant complication categories after construction of dummy variables.
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Fig 1. Association between preoperative factors and complications after esophagectomy for cancer expressed as odds ratios (•) and 95% confidence intervals (error bars). Note that the x-axis is a logarithmic scale. Performance status refers to an Eastern Cooperative Oncology Group performance status of 2 to 4; FEV1% represents the risk per each 10-percentage-point decrease in FEV1 (forced expiratory volume in 1 second) expressed as a percent of predicted; serum creatinine represents the risk per each 1-mg/dL increase; age represents the risk for each 10-year increase; serum hemoglobin represents the risk per each 1-g/dL increase; serum albumin represents the risk per each 1-mg/dL increase; advanced dysphagia refers to the risk for dysphagia scores of 3 or 4; year of operation represents the time interval before 2002 in 5-year increments.
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Independent predictors of complications were as follows: pulmonary complications—poor performance status and FEV1%; cardiovascular complications—poor performance status, higher serum creatinine levels, and advanced age; infectious complications—prior myocardial infarction; surgical complications—none; other complications—advanced age; total complications—earlier year of operation, current alcohol use, and poor performance status; death—poor performance status, less dysphagia, and possibly male sex. In no instance did induction chemotherapy approach significance as an independent predictor of complications.
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Comment
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Esophagectomy has long been recognized as being associated with high surgical morbidity and mortality. Although some centers with extensive experience have reported mortality rates as low as a few percent, typical mortality rates, even for so-called high-volume hospitals, remain as high as 12% [20]. Morbidity rates associated with esophagectomy are also higher than after most other major general surgical procedures. Adding to these risks is the fact that preoperative induction therapy induces myelosuppression, mucositis with odynophagia, and appetite suppression. The resultant suppression of the immune system and nutritional depletion may have undesirable effects on wound healing and infectious complications. The edema, inflammation, and fibrosis that develop in the regions of resection as a result of induction therapy also theoretically increase the risks of bleeding, iatrogenic injury to adjacent tissues such as the trachea and thoracic duct, and anastomotic leak. Recent publications have reported an increase in operative mortality associated with induction therapy before esophagectomy [6, 8].
Among theoretical benefits to induction therapy are a reduction in tumor size that may render the operation easier or the resection more complete, and control of micrometastases before the development of surgically induced immunosuppression. Each of these potential benefits may contribute to improved survival, and recent randomized studies provide support for this contention [7, 21]. In addition to this potential survival benefit, some reports have suggested that induction therapy has no important detrimental effect on surgical morbidity or mortality after esophagectomy [14–16, 22, 23]. Given the potential advantage of induction therapy and the controversy regarding its possible adverse effects, we sought to determine whether induction therapy influenced operative outcomes in our patients undergoing esophagectomy for cancer.
The operative complication rates for esophagectomy in this study were comparable to some previously reported rates for mortality [20] and morbidity [18, 24, 25]. Pulmonary complications, which occurred at a rate similar to that reported by others [7, 22, 25], were of particular interest to us because of their frequency and their close association with operative mortality. Our cardiovascular complication rate was little higher than that reported in other series [7, 23, 25], whereas the surgical, infectious, and other complication rates were similar to those reported by others [22, 26].
The etiology of morbidity and mortality after esophagectomy is usually multifactorial. Our search for preoperative conditions that were associated with these complications identified two variables that tended to recur in our analyses: poor performance status and advanced age. Poor performance status has previously been associated with increased morbidity and mortality after esophagectomy [27, 28]. The adverse influence of advancing age on complications after esophagectomy is well recognized and is always a topic of debate because of the limited options that are otherwise available for these patients [22, 27, 29]. Patients in our study who received induction therapy were 8 years younger on average than patients in the surgery-only group, a fact that was likely a result of patient selection in this retrospective study. This difference may have helped to reduce the surgical complication rates in our induction patients, although our statistical analyses suggested that advancing age, and not induction therapy, was associated with an increase in complication rates. Reduced pulmonary function was associated with a substantial increase in pulmonary complications in this series. This relationship has previously been reported, and does not appear to be independently influenced by the type of approach used for the operation when categorized as transhiatal or transthoracic [19, 28, 30].
We identified significantly reduced blood hemoglobin levels and white blood cell counts in the induction therapy group in our study. Perioperative blood transfusion, which is possibly required more often in patients who have undergone induction therapy, has been shown to increase the risk of postoperative infections [31, 32]. We found no such association in our study using univariate analysis. Because we wished to focus our analyses on identifiable preoperative predictors of surgical complications, variables for estimated operative blood loss and the amount of perioperative transfusion were not included in multivariable analyses. In addition, the nutritional status was somewhat poorer in our neoadjuvant therapy patients. Although small, this difference might have put the induction therapy patients at higher risk for operative complications, but none was evident based on univariate or multivariable analyses. These findings are in keeping with those of other authors [14–16, 21, 22].
The results suggest that cisplatin-based induction chemotherapy does not materially influence the outcome of esophagectomy in appropriately selected patients. Because the numbers of patients in the subgroup that received combination induction chemotherapy and radiation therapy was small, our study was not powered sufficiently to draw definitive conclusions regarding any additional risks that induction radiation therapy might pose. The fact that demographics and results in the chemotherapy-only and combined therapy subgroups in our study were similar suggests that any effect of radiation therapy was probably minimal.
This retrospective study suffered the usual shortcomings of such methodology. Our patients did not represent a uniform population, and patient selection for induction therapy, the type and timing of induction therapy, and surgical techniques varied according to individual physician preferences. Most patients who received induction therapy were treated by community-based medical and radiation oncologists usually on an ad-hoc basis rather than on specific protocols. Barrett's adenocarcinoma was sometimes diagnosed as a result of surveillance endoscopy, providing for a subgroup of patients having younger age and earlier stage cancers. These factors accounted for some of the differences we observed in age, type of operation, histologic type, and pathologic stage between the induction and surgery-only groups. A prospective trial that focuses on the incidence of and factors related to postoperative complications, or further analyses of existing data from completed prospective randomized trials, will be needed to further address the question of whether induction therapy increases surgical morbidity and mortality.
The 5-year survival after esophagectomy approaches 60% for patients with pathologic complete response after induction therapy [11, 33]. Because there appears to be no important increase in surgical mortality and morbidity for patients undergoing esophagectomy after induction therapy, additional trials of this approach are encouraged. However, the current pathologic complete response rates are low, averaging 20% to as high as 30%. New drugs or other biologic response modifiers and treatment protocols that reduce toxicities and achieve higher pathologic complete response rates are necessary to generate greater enthusiasm for this approach.
In time, combined systemic therapy and radiation therapy may produce clinical outcomes currently achieved only by multimodality therapy including surgery. In such a setting esophagectomy may be relegated to salvage resection for patients who respond incompletely to nonsurgical therapy. Until then, resection remains a mainstay of potentially curative therapy for esophageal cancer. However, for patients with poor performance status, substantially reduced pulmonary function, and advanced age, the recommendation regarding esophagectomy should be considered carefully.
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Abstract
Introduction
