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Ann Thorac Surg 2001;72:885-888
© 2001 The Society of Thoracic Surgeons

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Original article: general thoracic

Induction chemotherapy increases perioperative complications in patients undergoing resection for non–small cell lung cancer

^a Department of Cardiac and Thoracic Surgery, Vanderbilt University Hospital, Nashville, Tennessee, USA

Accepted for publication May 9, 2001.

Address reprint requests to Dr Roberts, Department of Cardiac and Thoracic Surgery, Vanderbilt University Hospital, 2986 Vanderbilt Clinic, Nashville, TN 37232
e-mail: bob.roberts{at}mcmail.vanderbilt.edu

	Abstract

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Background. Neoadjuvant chemotherapy before resection is the standard of care for stage IIIA non–small cell lung cancer in many institutions. Further, neoadjuvant therapy is being studied in earlier stage lung cancer and may be applied more broadly in the future. There is little information about the effect of preoperative chemotherapy on the perioperative complications and mortality after lung resection.

Methods. All patients undergoing anatomic resection after neoadjuvant chemotherapy by a single surgeon at a single institution were compared with patients undergoing similar resections without preoperative chemotherapy. Complications were analyzed as life-threatening (pneumonia, emergency surgery, transfer to the intensive care unit, or intubation), major (prolonging hospital stay but not necessarily dangerous), and minor. The incidence of life-threatening complications, major complications, reintubation, tracheostomy, and mortality were analyzed to determine whether neoadjuvant chemotherapy might have an effect on these complications. Mortality was defined as hospital mortality. Two-tailed Student’s t test was used to analyze differences in means and ² to determine differences in proportions. Differences less than 0.05 were considered significant.

Results. Thirty-four patients underwent resection after neoadjuvant chemotherapy, and 67 patients underwent resection without preoperative therapy. No differences between the two groups in age, pulmonary function, or comorbid diseases were found. The patients receiving chemotherapy did have a more advanced stage (2.52 versus 1.55, p < 0.0001). Striking increases were found in incidence of life-threatening complications (6.0% versus 26.5%, p = 0.0036), major complications (19.4% versus 47.1%, p = 0.0037), reintubation (3.0% versus 17.6%, p = 0.0093), and tracheostomy (0% versus 11.8%, p = 0.0042) in those patients who received preoperative chemotherapy. There was no hospital mortality. However, 2 (neoadjuvant) patients died within 90 days after discharge from the hospital of pneumonia and pulmonary embolus. This difference was also significant (0% versus 5.89%, p = 0.045).

Conclusions. Neoadjuvant carboplatin and Taxol increased the perioperative life-threatening complications in this cohort of patients compared with a similar cohort undergoing operations by the same surgeon in the same institution. The most common life-threatening complication in patients receiving induction chemotherapy was the failure to respond to antibiotics given for pneumonia. Strategies to prevent these complications will be important, especially if chemotherapy before resection becomes the standard for earlier stages of non–small cell lung cancer.

	Introduction

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Neoadjuvant chemotherapy followed by surgical resection is the current standard of care for patients with stage IIIA non–small cell lung cancer in many institutions. Recent studies have demonstrated significant improvements in 5-year survival for such patients treated in this fashion [1, 2]. Further, other studies have demonstrated neoadjuvant therapy and operation to be feasible in patients with earlier stage disease—a multiinstitutional study is under way to evaluate its efficacy in this setting [3].

Chemotherapy induces both a transient and a relatively permanent immune deficit in treated patients. The most common cause of postoperative morbidity and mortality after lung resection is infectious, whether caused by pneumonia or by aspiration. It is reasonable to expect that neoadjuvant chemotherapy could affect the chances of postoperative morbidity and mortality.

Surgical mortality has never been analyzed with respect to the stage of the disease in patients undergoing resection, perhaps because most patients who are candidates for resection are of high performance status and because the presence of cancer, except for advanced disease, does not affect perioperative mortality. Lung resection is among the riskiest of surgical procedures, significantly more dangerous than coronary artery bypass graft procedures. Table 1 lists reported perioperative mortality after lobectomy and pneumonectomy. The average mortality after a lobectomy, garnered from these series, is 2.7% and after a pneumonectomy, 7.0%. Other series list perioperative mortality after sleeve resections between 4% and 6%.

	Material and methods

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All patients undergoing resection for the treatment of non–small cell lung cancer at Vanderbilt University between September 1997 and May 1999 were eligible for comparison. Mediastinoscopy before resection was routine, and all patients who were found to have stage IIIA disease received neoadjuvant chemotherapy with, typically, three cycles of carboplatin and Taxol. Many earlier stage patients received two, or three, cycles of carboplatin and Taxol preoperatively as part of their participation in the Bimodality Lung Oncology Trial (BLOT). The period of time between the last chemotherapy treatment and resection was 4 weeks. No patients received preoperative radiotherapy. All patients were performance status 0.

Thoracoscopic staging was performed in all patients. Resection was performed through muscle-sparing thoracotomy or posterolateral thoracotomy, depending on the size of the lesion. Complete mediastinal lymphadenectomy was performed for all lesions and included subcarinal nodes and paratracheal nodes for lesions on both sides as well as aortopulmonary nodes for left-sided lesions. Patients received preoperative epidurals for pain management, which typically remained in place for 4 days or until chest tubes could be removed. Patients were then switched over to intravenous patient-controlled anesthesia or to oral narcotics. Other postoperative management included routine early ambulation, gastrointestinal tract management, and aggressive pulmonary toilet, including bronchoscopy, as necessary.

Data collected included age, sex, stage of disease, pulmonary function testing, type of resection, postoperative complications, reintubation, tracheostomy, and death. Pulmonary function tests were not repeated after chemotherapy. Diffusing capacity was measured only in those patients with poor pulmonary function. Complications were further defined as follows: life-threatening complications required either intubation, cardioversion, emergency surgery, or transfer to an intensive care unit; major complications were those that prolonged hospital stay but were not life-threatening (such as atelectasis, supraventricular tachyarrhythmia, or bronchitis); and minor complications required therapy but did not prolong hospital stay.

Mortality is defined as hospital mortality, or postoperative death during the hospital admission. Thirty-day mortality is misleading, always underestimates actual hospital mortality, and will not be used. Outpatient mortality was also analyzed and included deaths up to 90 days after operation.

Data are reported as mean ± standard deviation or as proportions. Data were analyzed using Student’s t test for comparison of means, and ² analysis for comparison of proportions. Significance was accepted as p values less than 0.05.

	Results

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One hundred one sequential patients underwent resection for treatment of non–small cell lung cancer at Vanderbilt Medical Center during this period. Approximately one third (n = 34) of the patients received preoperative carboplatin and Taxol and two thirds (n = 67) underwent immediate resection without chemotherapy (Table 2). When patients receiving preoperative chemotherapy were compared with those who did not, there was no difference in age (63.6 versus 61.9 years of age, p = 0.5), fraction of women (29% versus 37%, p = 0.43), or forced expiratory volume in 1 s (1.67 versus 1.75 L). There was a significant difference in preoperative stage (2.52 versus 1.55, p < 0.001), though no difference in preoperative performance status, as all patients were performance status 0.

Striking differences in the incidences of complications were seen (Table 3). Forty-seven percent of those patients receiving preoperative chemotherapy suffered some major complication, compared with 19.4% of those who did not (p = 0.0037). Similar differences were found in the incidence of life-threatening complications, reintubation, and tracheostomy, with similar statistical significance, as detailed in Table 3.

Because the mortality after lobectomy is significantly less than that for sleeve resection or for pneumonectomy, we performed a case-control analysis, whereby all patients with resections greater than lobectomy were compared. Table 4 details the demographics of these larger resections. In this group there was no longer any difference in stage, and continued to be no difference in age or pulmonary function. However, the difference in complications persisted (Table 5), and for life-threatening complications, increased. Because the number of patients was small, statistical significance was not reached for the incidence of reintubation and for tracheostomy, but a strong tendency toward significance was found.

	Comment

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Perioperative mortality is only a portion of the risk of concern. Treatment-related mortality includes both deaths strictly related to chemotherapy complications before operation as well as surgical mortality. The Southwest Oncology Group evaluated the results of the neoadjuvant treatment (cisplatin and etoposide) of stage IIIA and stage IIIB non–small cell lung cancer with both chemotherapy and radiation. Although the surgical mortality was only 5.5%, the overall treatment-related mortality was greater than 10% [14].

Many studies have been performed to attempt to predict perioperative risk after lung resection. Exercise testing, whether by stair-climbing, room oximetry [15], or more invasive means [16], has been found to be predictive of postoperative risk. Wang and colleagues [17] have extensively studied postoperative risk after lung resection and have demonstrated that diffusing capacity is an accurate predictor of complications. In perhaps the most telling study to predict postoperative risk, Kohman and associates [6] evaluated 37 preoperative and 12 postoperative classes of risk factors in 476 patients undergoing pulmonary resection. All of the preoperative and postoperative risk factors together accounted for only 40% of the perioperative morbidity. They concluded that "the remainder of the risk of death must be attributed either to factors not considered or to purely random factors."

Our data indicate that neoadjuvant chemotherapy increases the perioperative life-threatening complications after lung resection for non–small cell lung cancer. With enough patients, it is reasonable to expect that perioperative mortality would also increase. Most of these complications were infectious, and it was striking that some patients developed infectious problems (Pseudomonas pneumonias, fungal bronchitis) that did not respond to appropriate antibiotics. To that end, we routinely culture sputum at the time of resection in hopes of identifying organisms before pneumonia develops, and have a low threshold for either postponing operations in those patients with bronchitis or treating positive sputum cultures.

	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. Roberts David Johnson Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roberts, J. R. Articles by Johnson, D. Search for Related Content PubMed PubMed Citation Articles by Roberts, J. R. Articles by Johnson, D. Related Collections Lung - cancer